[Federal Register Volume 73, Number 196 (Wednesday, October 8, 2008)]
[Proposed Rules]
[Pages 59382-59446]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E8-23127]
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Part III
Environmental Protection Agency
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40 CFR Parts 158 and 161
Data Requirements for Antimicrobial Pesticides; Proposed Rule
Federal Register / Vol. 73, No. 196 / Wednesday, October 8, 2008 /
Proposed Rules
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Parts 158 and 161
RIN 2070-AD30
Data Requirements for Antimicrobial Pesticides
AGENCY: Environmental Protection Agency (EPA).
ACTION: Proposed rule.
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SUMMARY: EPA proposes to revise and update the existing data
requirements for antimicrobial pesticides. The proposed revisions are
needed to reflect current scientific knowledge and current Agency
regulatory practices, and to improve protection of the general
population as well as sensitive subpopulations. The proposed
requirements are intended to further enhance the Agency's ability to
make regulatory decisions about the human health and environmental fate
and effects of antimicrobial pesticide products.
DATES: Comments must be received on or before January 6, 2009.
ADDRESSES: Submit your comments, identified by docket identification
(ID) number EPA-HQ-OPP-2008-0110, by one of the following methods:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the on-line instructions for submitting comments.
Mail: Office of Pesticide Programs (OPP) Regulatory Public
Docket (7502P), Environmental Protection Agency, 1200 Pennsylvania
Ave., NW., Washington, DC 20460-0001.
Delivery: OPP Regulatory Public Docket (7502P),
Environmental Protection Agency, Rm. S-4400, One Potomac Yard (South
Bldg.), 2777 S. Crystal Dr., Arlington, VA 22202. Deliveries are only
accepted during the Docket's normal hours of operation (8:30 a.m. to 4
p.m., Monday through Friday, excluding legal holidays). Special
arrangements should be made for deliveries of boxed information. The
Docket Facility telephone number is (703) 305-5805.
Instructions: Direct your comments to docket ID number EPA-HQ-OPP-
2008-0110. EPA's policy is that all comments received will be included
in the docket without change and may be made available on-line at
http://www.regulations.gov, including any personal information
provided, unless the comment includes information claimed to be
Confidential Business Information (CBI) or other information whose
disclosure is restricted by statute. Do not submit information that you
consider to be CBI or otherwise protected through regulations.gov or e-
mail. The regulations.gov website is an ``anonymous access'' system,
which means EPA will not know your identity or contact information
unless you provide it in the body of your comment. If you send an e-
mail comment directly to EPA without going through regulations.gov,
your e-mail address will be automatically captured and included as part
of the comment that is placed in the docket and made available on the
Internet. If you submit an electronic comment, EPA recommends that you
include your name and other contact information in the body of your
comment and with any disk or CD-ROM you submit. If EPA cannot read your
comment due to technical difficulties and cannot contact you for
clarification, EPA may not be able to consider your comment. Electronic
files should avoid the use of special characters, any form of
encryption, and be free of any defects or viruses.
Docket: All documents in the docket are listed in the docket index
available in regulations.gov. To access the electronic docket, go to
http://www.regulations.gov, select ``Advanced Search,'' then ``Docket
Search.'' Insert the docket ID number where indicated and select the
``Submit'' button. Follow the instructions on the regulations.gov
website to view the docket index or access available documents.
Although listed in the index, some information is not publicly
available, e.g., CBI or other information whose disclosure is
restricted by statute. Certain other material, such as copyrighted
material, is not placed on the Internet and will be publicly available
only in hard copy form. Publicly available docket materials are
available either in the electronic docket at http://www.regulations.gov, or, if only available in hard copy, at the OPP
Regulatory Public Docket in Rm. S-4400, One Potomac Yard (South Bldg.),
2777 S. Crystal Dr., Arlington, VA 22202. The hours of operation of
this Docket Facility are from 8:30 a.m. to 4 p.m., Monday through
Friday, excluding legal holidays. The Docket Facility telephone number
is (703) 305-5805.
FOR FURTHER INFORMATION CONTACT: Kathryn Boyle, Field and External
Affairs Division, Office of Pesticide Programs, Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460-
0001; mail code 7506P; telephone number: 703-305-6304; fax number: 703-
305-5884; e-mail address: [email protected].
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
You may be affected by this action if you are a producer of
pesticide products (NAICS 32532), antifoulants (NAICS 32551),
antimicrobial pesticides (NAICS 32561) or wood preservatives (NAICS
32519), importers of such products, or any person or company who seeks
to register an antimicrobial, antifoulant coating, ballast water
treatment, or wood preservative pesticide or to obtain a tolerance for
such a pesticide. This listing is not intended to be exhaustive, but
rather provides a guide for readers regarding entities likely to be
affected by this action. Other types of entities not listed above could
also be affected. The North American Industrial Classification System
(NAICS) codes have been provided to assist you and others in
determining whether this action might apply to certain entities. If you
have any questions regarding the applicability of this action to a
particular entity, please contact Norm Cook, Chief of the Risk
Assessment and Science Support Branch in the Antimicrobials Division of
the Office of Pesticide Programs at 703-308-8253 or via email,
[email protected].
B. What Should I Consider as I Prepare My Comments for EPA?
1. Docket. EPA has established a docket for this action under
docket identification (ID) number EPA-HQ-OPP-2008-0110. Publicly
available docket materials are available either in the electronic
docket at http://www.regulations.gov, or, if only available in hard
copy, at the Office of Pesticide Programs (OPP) Regulatory Public
Docket in Rm. S-4400, One Potomac Yard (South Bldg.), 2777 S. Crystal
Dr., Arlington, VA 22202. The hours of operation of this Docket
Facility are from 8:30 a.m. to 4 p.m., Monday through Friday, excluding
legal holidays. The Docket Facility telephone number is (703) 305-5805.
2. Tips for preparing your comments. When submitting comments,
remember to:
i. Identify the document by docket ID number and other identifying
information (subject heading, Federal Register date and page number).
ii. Follow directions. The Agency may ask you to respond to
specific questions or organize comments by referencing a Code of
Federal Regulations (CFR) part or section number.
iii. Explain why you agree or disagree; suggest alternatives and
substitute language for your requested changes.
[[Page 59383]]
iv. Describe any assumptions and provide any technical information
and/or data that you used.
v. If you estimate potential costs or burdens, explain how you
arrived at your estimate in sufficient detail to allow for it to be
reproduced.
vi. Provide specific examples to illustrate your concerns and
suggest alternatives.
vii. Explain your views as clearly as possible, avoiding the use of
profanity or personal threats.
viii. Make sure to submit your comments by the comment period
deadline identified.
II. Background
A. What Action is the Agency Taking?
The Environmental Protection Agency (EPA or the Agency) is
proposing to establish a separate listing of the data requirements for
antimicrobial pesticides in Title 40 of the Code of Federal Regulations
(CFR) in subpart W of part 158. This proposal sets out use patterns
that are designed to make it easier to determine which requirements
apply to antimicrobial products. In addition to retaining most current
data requirements for antimicrobials, this proposal incorporates nine
new data requirements and revises other existing data requirements.
This rule, once final, is intended to further enhance the Agency's
ability to make regulatory decisions about the human health, and
environmental fate and effects of antimicrobial pesticide products.
The Agency has previously issued updated data requirements for
conventional pesticides, and biochemical and microbial pesticides in
part 158. This proposal is part of a larger effort to update and
improve all of the data requirements for pesticide regulatory purposes.
Data requirements for antimicrobial pesticides, currently contained in
part 161, are proposed to be revised and included in part 158 upon
promulgation.
Generally, antimicrobials are considered to be those chemicals that
disinfect and sanitize. However, within this proposal EPA is using the
term antimicrobials to collectively refer to antimicrobial pesticides,
antifoulant coatings and paints, and wood preservatives.
As discussed in Unit XVIII.A., EPA has prepared a white paper
entitled ``Use of Structure-Activity Relationship (SAR) Information and
Quantitative SAR (QSAR) Modeling For Fulfilling Data Requirements for
Antimicrobial Pesticide Chemicals and Informing EPA's Risk Management
Process,'' a copy of which is contained in the docket for this proposed
rule (Ref. 43). The white paper discusses the current level of
information and usage of structure-activity-relationship (SAR)
assessments and Quantitative SAR (QSAR) modeling to fulfill data
requirements in the Pesticide Program. The Agency specifically seeks
comment on this support document.
Since many antimicrobial pesticides are typically rinsed down the
drain, EPA has considered the potential impacts of pesticides that are
discharged into wastewater treatment plants (WWTPs). This proposed rule
addresses the issue of down-the-drain antimicrobials by proposing four
new data requirements for use in a screening-level assessment on the
fate of antimicrobials that reach a WWTP. To assess the impacts of this
screening assessment and utility of the new data requirements for
decision-making, EPA prepared four case studies (Ref. 42). The case
studies, copies of which are contained in the docket for this proposed
rule, are discussed in more detail in Unit XII.D. The Agency
specifically seeks comment on the proposed approach for evaluating the
potential impact of antimicrobial pesticide chemicals on WWTPs and
nontarget organisms in receiving water bodies, and on the case studies,
including the assumptions used in those studies, that were used to
develop the proposed approach. EPA will consider comments specific to
the case studies along with comments on the proposed approach, as the
Agency evaluates the use of the proposed approach for down-the-drain
antimicrobials in the final rule for antimicrobial data requirements.
On October 26, 2007, EPA promulgated final rules establishing data
requirements for conventional pesticides (72 FR 60934), and biochemical
pesticides and microbial pesticides (72 FR 60988). These final rules
were effective on December 24, 2007, and are therefore the current part
158. As part of those actions, on October 24, 2007, (72 FR 60251) EPA
preserved the original part 158 data requirements to provide continued
regulatory coverage for antimicrobial pesticides until the Agency could
promulgate a final regulation. To accomplish this, EPA transferred
intact the original 1984 data requirements of part 158 into a new part
161, entitled ``Data Requirements for Antimicrobial Pesticides.'' Part
161, which applies only to antimicrobial pesticides, contains the
current data requirements for antimicrobial pesticide chemicals.
As explained in the preamble to the conventional pesticide final
rule, EPA intended to preserve the existing data requirements for
antimicrobial pesticides until a new rule tailored specifically to
antimicrobial pesticides could be promulgated. Part 161 is intended to
be transitional. Once subpart W of part 158 is promulgated, there will
be no need for part 161. Accordingly, EPA proposes to revoke part 161
upon the effective date of a final rule arising from today's proposal.
B. Reasons for Today's Action
Since the promulgation of part 158 in 1984, the Agency has
recognized that the tables and test notes promulgated in 1984 failed to
adequately address the unique applications, use patterns, and other
factors germane to antimicrobial pesticides. Part 158 specifies the
types of data and information generally required for making sound
regulatory judgments under the Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA). The types of actions for which these data are
needed include experimental use, registration, amended registration,
reregistration, or registration review (collectively referred to in
this proposal as ``registration''). The information required under
FIFRA for registration of food-use pesticides is also information the
Agency needs in order to grant tolerances or exemptions from the
requirement of tolerances under section 408 of the Federal Food, Drug,
and Cosmetic Act (FFDCA).
Required data are intended to provide information about the
potential adverse effects of uses of pesticides, and to define what is
generally expected from applicants for registration in support of their
products. However, it must be emphasized that each applicant has the
continuing obligation under FIFRA to demonstrate that an individual
product meets the standard for registration under section 3 of FIFRA or
section 408 of FFDCA. Accordingly, as indicated in current Sec. 158.75
and Sec. 161.75, additional data may be needed to reflect the
characteristics and use of specific pesticide products under review.
Since the data requirements now set out in part 161 (formerly part
158) were first published in 1984, every disciplinary area and
requirement has been reconsidered and many have been revised in
practice. These changes have been needed because the state of the
science underlying the data requirements has advanced, and because the
Agency has learned in specific registration actions that additional or
different data are necessary to make sound regulatory decisions. These
case-by-case decisions have been made in accordance with Sec. 158.75,
which allows the Agency to impose additional data requirements
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beyond those specified in part 158 and now part 161.
Use patterns specific to antimicrobial pesticides are not specified
in part 161, as they were not set out separately when originally
promulgated in 1984. As a result, applicants have needed to interpret
the data requirements often via extensive consultation with and
interpretation from the Agency to determine the antimicrobial data
requirements for a particular product. Today, EPA is proposing that the
antimicrobial pesticide requirements be codified in a separate subpart
W to part 158 with use patterns (see Unit IV.I. of this preamble) and
groups of use patterns specific to antimicrobials.
Today's proposed rule is part of a series of rules to update all of
the data requirements for pesticide products. On October 26, 2007, EPA
published in the Federal Register two final rules to promulgate the
data requirements for conventional (72 FR 60934), and biochemical and
microbial (72 FR 60988) pesticide chemicals. These rules and their
proposals (conventional (March 11, 2005) (70 FR 12276) and biochemical
and microbial (March 8, 2006) (71 FR12072)) state the rationales for
requiring and/or revising particular data requirements. With few
exceptions, these rationales are also applicable to antimicrobial
pesticide chemicals, and as such have not been repeated in today's
proposed rule. Today's proposal discusses in detail only those
revisions that are singularly applicable to antimicrobial pesticides,
including antifoulants and wood preservatives.
C. Benefits of this Proposal
Greater detail on the benefits of this proposal is provided in the
document entitled ``Economic Analysis of the Proposed Change in Data
Requirements for Antimicrobial Pesticides'' which is available in the
docket for this rulemaking (Ref. 44). The following briefly highlights
the anticipated benefits:
1. More refined assessments mean less uncertainty and clearer
understanding of actual risks. EPA's current applicator/user exposure
data base is not comprehensive, especially regarding exposures to
antimicrobials in industrial and residential settings. The new data
that would be collected once this proposal becomes final would allow
the Agency to conduct improved pre- and post-application exposure
assessments for applicators/users, and the general public. This will
benefit not only workers (including applicators) and consumers by
helping EPA to make better informed regulatory decisions that are
neither too stringent nor too lenient, but also benefit the regulated
industry by reducing the uncertainty in Agency risk assessments. Thus,
today's proposal will reduce, but not eliminate, uncertainty related to
the risks posed by antimicrobial pesticides.
2. Clarity and transparency to regulated community means savings.
The enhanced clarity and transparency of the information presented in
part 158, subpart W should enhance the ability of industry to
efficiently manage their antimicrobial registration submissions.
Applicants may save time and money by understanding when studies are
needed. Having all required studies available to EPA at the time of
application should halt potential delays in the registration process,
thereby enabling registration of antimicrobial pesticides sooner.
Products would enter the market faster.
3. EPA information assists other communities in assessing pesticide
risks. Scientific, environmental, and health communities find
antimicrobial pesticide toxicity information useful to respond to a
variety of needs. For example, medical professionals are concerned
about the health of patients exposed to antimicrobials; poison control
centers use and distribute information on toxicity and treatment
associated with poisoning; and scientists use toxicity information to
characterize the effects of antimicrobial pesticides and to assess
risks of pesticide exposure. Similarly, those responsible for
protection of nontarget wildlife need reliable information about
antimicrobial pesticides and assurance that pesticides do not pose an
unreasonable threat. The proposed changes will help the scientific,
environmental, and health communities by increasing the breadth,
quality, and reliability of Agency regulatory decisions by improving
their scientific underpinnings.
4. Better informed users mean informed risk-reduction choices.
Better regulatory decisions resulting from the proposed changes should
also mean that the label will provide better information on the use of
the antimicrobial pesticide. A pesticide label is the user's direction
for using pesticides safely and effectively. It contains important
information about where to use (or not use) the product, health and
safety information to be read and understood before using a pesticide
product, and how to dispose of that product. This benefits users by
enhancing their ability to obtain antimicrobial pesticide products
appropriate to their needs, and to use and dispose of products in a
manner that is safe and environmentally sound. Applicators/users may
benefit from label information based on the data submitted to the
extent it helps inform their decisions about whether or how to use
particular pesticides to avoid potential exposure.
D. What is the Agency's Authority for Taking this Action?
This action is issued under the authority of sections 3, 4, 5, 10,
12, and 25 of FIFRA as amended and section 408 of FFDCA. The data
required for a registration, reregistration, experimental use permit,
or tolerance are listed in 40 CFR part 158.
III. Statutory and Historical Framework
A. FIFRA
Under FIFRA section 3, every pesticide product must be registered
with EPA or specifically exempted under FIFRA section 25(b) before
being sold or distributed in the United States. Under FIFRA, an
applicant for a new registration or an existing registrant
(collectively referred to as applicant in this proposal) must
demonstrate to the Agency's satisfaction that, among other things, the
pesticide product, when used in accordance with widespread and commonly
recognized practice, will not cause ``unreasonable adverse effects'' to
humans or the environment. This safety determination requires the
Agency to weigh the risks of the use of the pesticide against any
benefits. EPA must determine that the standard for registration
contained in FIFRA is met before granting a registration.
1. Registration. Section 3 of FIFRA contains the requirements for
registration. Specifically, FIFRA section 3(c)(2) provides EPA broad
authority, before and after registration, to require scientific testing
and submission of the resulting data to the Agency by applicants for
registration of pesticide products. An applicant must furnish EPA with
substantial amounts of data on the pesticide, its composition,
toxicity, potential human exposure, environmental properties, and
ecological effects, as well as information on its product performance
(efficacy) in certain cases. Although the data requirements are imposed
primarily as a part of initial registration, EPA is authorized under
FIFRA section 3(c)(2)(B) to require a registrant to develop and submit
additional data to maintain a registration.
2. Reregistration. FIFRA section 4 requires that EPA reregister
each pesticide product first registered before November 1984. This date
was chosen because pesticides registered after 1984 were subject to the
part 158 requirements of the 1984 regulation.
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EPA has completed the reregistration/tolerance reassessment process for
food-use pesticides and expects to complete all reregistration
activities by the statutory deadline of August 2008.
3. Registration review. FIFRA section 3(g) mandates that the
registrations of all pesticides are to be periodically reviewed.
Changes in science, public policy, and pesticide use practices occur
over time. Through the new registration review program implemented via
a regulation promulgated on August 9, 2006 (71 FR 45719) (40 CFR part
155, subpart C), the Agency is periodically reevaluating all registered
pesticides to assure that they continue to meet the statutory standard
of no unreasonable adverse effects. Starting in 2006, registration
review began to replace EPA's reregistration program as the mechanism
for systematic review of existing pesticides. The registration review
process begins by reviewing the available information in the possession
of the Agency and then determining the specific data needed for
assessing a particular pesticide. Thus, the data needed, and the scope
and depth of the Agency's review will be tailored to the specific
circumstances of a particular pesticide. This means that reviews will
be commensurate with the complexity of the issues associated with each
pesticide.
4. Experimental Use Permits (EUPs). Subject to some exceptions,
FIFRA section 5 requires persons seeking permission for experimental
use of a pesticide under controlled condition to obtain an experimental
use permit. A EUP allows limited use of a pesticide for specified
experimental and data collection purposes intended to support future
registration of the pesticide. Because a EUP is for limited use under
controlled conditions, the data needed to support issuance of the
permit are correspondingly less than those required for full
registration. The regulations governing the issuance of EUPs are found
in 40 CFR part 172. In its final rule ``Data Requirements for
Conventional Pesticides'' EPA promulgated subpart C of part 158 to
contain the data requirements for EUPs, which will be applied on a
case-by-case basis to any EUP applications for an antimicrobial
pesticide.
5. Registration requirements for antimicrobials. FIFRA section 3(h)
requires that EPA evaluate its registration process to identify
improvements and reforms that will reduce historical review times for
antimicrobial applications. This includes defining the classes of
antimicrobial use patterns and the types of application review,
conforming reviews to risks and benefits, ensuring efficacy, and
meeting review time goals. EPA believes that this rule assists in
meeting the section 3(h) mandate. By defining the 12 use patterns for
antimicrobials in relation to the data required for a registration
under FIFRA, EPA is providing clearer and more transparent information
to applicants. This should result in submissions to EPA that contain
the required data and therefore can be reviewed and evaluated more
expeditiously.
B. FFDCA
FFDCA requires EPA to determine that the level of pesticide
chemical residues in food and feed will be safe for human consumption.
The safety standard set under FFDCA section 408(b) and (c) defines safe
as ``a reasonable certainty that no harm'' will result from exposures
to pesticide chemical residues. The combination of aggregate and
cumulative exposure assessments required by FFDCA section 408 increases
the nature and scope of EPA's risk assessment, and potentially
increases the types and amounts of data needed to determine that the
FFDCA safety standard is met.
Under FFDCA section 408, EPA is authorized to establish tolerances
for pesticide residues in food and feed, or to exempt a pesticide from
the requirement of a tolerance, if warranted. In this preamble,
references to tolerances include exemptions from tolerance since the
standards and procedures for both are the same. The safety standard
applies to tolerances in a number of regulatory situations, including:
Tolerances that support registration under FIFRA;
Tolerances for imported products which are established to
allow importation of pesticide-treated commodities, but for which no
U.S. registration is sought;
Time-limited tolerances which are established for FIFRA
section 18 emergency exemptions; and
Temporary tolerances established for experimental use
permits under FIFRA section 5.
C. Linking FIFRA and FFDCA Safety Standards
Under FIFRA section 2(bb), a pesticide that is inconsistent with,
or does not meet, the FFDCA section 408 safety standard poses an
unreasonable adverse effect that precludes new or continued
registration. Given this linkage between registration and tolerances,
it makes sense for EPA to define data requirements for both purposes:
The data required to support a determination of ``reasonable certainty
of no harm'' under FFDCA are an integral part of the data needed for an
``unreasonable adverse effects'' determination under FIFRA.
Consequently, when promulgated, these proposed data requirements would
encompass the basic data requirements for both registration and
tolerance-setting determinations. EPA has authority to require
additional data on a case-by-case basis.
D. Scope of Proposed Subpart W
FIFRA contains a number of provisions specific to ``antimicrobial
pesticides'' as defined in FIFRA section 2(mm). The statutory
definition contains a complex construction of functionality, types of
organisms, and intended use to describe what is encompassed by the term
``antimicrobial pesticide.'' EPA believes that the definition was
primarily intended to be used in conjunction with the provisions of
section 3(h), which contains requirements for process improvements,
timeframes for review purposes, and other regulatory matters, but,
significantly, does not include provisions pertaining to data
requirements. The definition in section 2(mm) as it relates to section
3(h) was discussed fully in a proposed rule issued in the Federal
Register of September 17, 1999 (64 FR 50672).
The statutory definition, however, does not mesh with the Agency's
needs in developing this proposed rule concerning data requirements.
Data requirements depend upon the use pattern, taking into account the
pesticide's hazard and exposure profiles. How well the pesticide kills
or repels particular pests are relevant factors in the determination of
product performance data requirements.
Neither FIFRA section 3(c)(2) nor section 3(h) requires the Agency
to develop data requirements for an ``antimicrobial pesticide'' as
defined specifically in section 2(mm). Therefore, the scope of this
proposal has been expanded beyond ``antimicrobial pesticide'' as
defined by FIFRA section 2(mm) to include related pesticides that are
excluded from the 2(mm) definition. The broader applicability of this
40 CFR part 158, subpart W is intended to ensure that all pesticides
currently considered as antimicrobial products for purposes of FIFRA
section 33 fees and review periods are covered.
Accordingly, this proposal applies to:
Antimicrobial pesticides, as defined in FIFRA section
2(mm).
Pesticide products for antimicrobial uses in/on food or
feed.
Antifoulant paints and coatings.
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Wood preservatives.
Pesticide products intended to be manufactured into any of
the above.
IV. Introduction to Subpart W
A. Data Requirements for Registration
First promulgated in 1984, EPA's pesticide data requirements
outline the kinds of data and related information typically needed to
register a pesticide. In this proposal, the data requirements are
organized by scientific discipline (e.g., toxicology), just as the
existing data requirements in part 158 for conventional, and
biochemical and microbial pesticides and those in part 161 for
antimicrobials. A significant change in this proposal from the existing
data requirements in part 161 is the introduction of 12 use patterns
specific to antimicrobials. Since there is much variety in pesticide
chemistry, exposure, and hazard, the requirements are designed to be
flexible. Test notes to the data requirements tables explain the
conditions under which data are typically needed. Essentially, the data
requirements identify the questions that the applicant will need to
answer regarding a pesticide product before the Agency can register it.
Data requirements address both components of a risk assessment, i.e.,
the hazards that the pesticide presents, and the estimated level of
exposure to humans or nontarget species. Having the appropriate
information enables the Agency to understand when those hazards pose
risks. The answer to one question may inform the kind of information
needed to answer other questions. For example, a pesticide that is
persistent and toxicologically potent may require more extensive
exposure data to help establish a safe level of exposure. In addition,
because a number of antimicrobials are used for public health purposes
(for example, disinfectants, sterilants, or sanitizers), there are
product performance data requirements to assure that the antimicrobial
product works as intended.
B. Structure of Part 158
At this time data requirements for conventional, biochemical, and
microbial pesticides are established in 40 CFR part 158. Data
requirements for antimicrobial pesticides are established in 40 CFR
part 161.
Part 158 contains general provisions concerning all pesticide data
(subpart A), instructions on how to use the data tables that follow
(subpart B), and a series of disciplinary data tables that are focused
on conventional pesticides (subparts C - O). Individual subparts are
devoted to biochemical (subpart U) and microbial (subpart V)
pesticides. The revised data requirements for antimicrobial pesticides
would be incorporated into part 158 as subpart W.
C. Subpart W of Part 158
Subpart W is proposed to be a freestanding series of tables and
regulatory text establishing specific data requirements for each
scientific discipline for antimicrobial pesticides. EPA recognizes that
antimicrobial uses are generally different from the uses more typically
associated with conventional pesticides (e.g., agricultural outdoor
uses) and therefore can have different combinations of exposure
considerations. The use patterns and expected exposures typically
determine the data requirements for any pesticide. Antimicrobial
pesticides are no different in this regard from conventional,
biochemical, and microbial pesticides.
The order of proposed subpart W mirrors that of the larger part
158: from product chemistry, to efficacy, to hazard/toxicity
requirements (both human health and ecological toxicity), to exposure
data requirements (application and post-application human exposures,
and exposure to residues in food), and environmental fate requirements,
which overlap human exposure through drinking water. Units V-XIV of
this preamble describe the revisions to the current requirements. The
proposed data requirement tables are comprehensive. Generally, the data
requirements for each discipline are discussed separately, but the
applicator and post-application exposure disciplines are discussed
together in a single unit.
D. Clarifying How to Use the Data Tables
Part 158 subpart B contains a step-wise process to assist the
applicant in determining the data needed to support its particular
product. At this time subpart B is specific to the needs of
conventional, and biochemical and microbial pesticides. The process
needed for antimicrobials is no different. EPA is proposing certain
clarifying changes to subpart B to specify the needs of antimicrobial
pesticides. Specifically, EPA proposes to include antimicrobial use
patterns in Sec. 158.100 and a reference to the antimicrobial use site
index that will be available on the EPA website.
While EPA is attempting to assist the applicant in subpart B, it is
important to emphasize that it is the applicant's obligation under
FIFRA to demonstrate that an individual product meets the standard
under FIFRA and that of FFDCA. Accordingly, applicants are encouraged
to consult with the Agency on the appropriate data requirements, as
proposed here, as related to their specific product prior to and during
the registration process.
EPA is continuing its current system of identifying the
applicability of data requirements in the data tables. In essence, the
data requirements illustrate the questions the registrant will need to
answer about the safety of the pesticide product before the Agency can
register it. Because of the variety of chemicals and use patterns, and
because EPA must retain flexibility to tailor data requirements as
appropriate, only qualitative descriptors are in the tables. Test notes
provide more specific information on the applicability of specific data
requirements.
The table descriptors NR (not required), R (required), and CR
(conditionally required) should be viewed as a general presentation,
indicating the likelihood that the data requirement applies. The use of
R does not necessarily indicate that a study is always required, but
that it is more likely to be required than not. For example, if the
applicant wanted to apply his pesticide to apples, then crop field
trials would be required almost always on apples. However, if the
physical/chemical properties of the chemical did not lend themselves to
the test, such as performing an inhalation test with a chemical that is
a solid and has an extremely low vapor pressure, then a waiver might be
granted. Generally test notes for R studies discuss any particular
circumstances when the testing might not be required.
The use of CR means a study is less likely to be required. Triggers
in the test notes indicate the circumstances under which the Agency has
learned through experience that the information is needed. Although
only an approximation, if percentages were to be assigned to indicate
the need for a particular study, then R could be viewed as representing
the submission of a study 50% to 100% of the time and CR would be up to
50%.
Thus, NR, R, and CR are used for convenience to make the table
format feasible, but serve only as a general indication of the
applicability of a data requirement. In all cases, the test notes
referred to in the table must be consulted to determine the actual need
for the data. Applicants are also encouraged to visit the Agency's
website, entitled ``Data Requirements for Pesticide Registration'' (see
http://www.epa.gov/pesticides/regulating/data_requirements.htm). Since
it is not
[[Page 59387]]
possible to sufficiently delineate all circumstances in test notes,
consultation with EPA is encouraged.
The table format includes a column heading entitled ``Guideline,''
which refers to the OPPTS (Office of Pollution Prevention and Toxic
Substances) Harmonized Test Guidelines. Guideline numbers are provided
as information/guidance to applicants. These Guidelines set forth
recommended instructions and test methods for performing a study to
generate the required data. Since these are guidance documents, the
applicant is not required to use these Guidelines, but may instead seek
to fulfill the data requirement by other appropriate means such as
alternative test methods, submission of an article from open
literature, or use of modeling. The applicant may submit a protocol of
his own devising for the Agency to review. However, the OPPTS
Harmonized Guidelines have been developed through a rigorous scientific
process, including extensive peer review by the FIFRA Scientific
Advisory Panel. Additionally, many of the Guidelines have been
harmonized internationally. As such, they represent the recommended
approach to developing high-quality data that should satisfy EPA's data
needs for risk assessment.
E. The Nature of Changes to Requirements
Proposed subpart W does not differ greatly from the data
requirements for conventional pesticides promulgated in October 2007.
Where this proposal differs is in the explicit adaptation of those data
requirements to antimicrobials. As previously discussed, antimicrobial
uses were covered in the original (1984) part 158. However part 158
(now transitioned for antimicrobials as part 161) was developed
primarily for agricultural pesticides. Since the use patterns which now
appear in tables in part 161 are not specific to antimicrobials, often
it has been difficult to discern directly from such tables the data
requirements for certain antimicrobials. Without extensive consultation
with and interpretation from the Agency, frequently it has been
difficult for applicants to effectively use the tables to determine
which data requirements apply to antimicrobials.
Today's proposal reflects the Agency's current needs for risk
assessment of antimicrobials. Describing the antimicrobial data
requirements in terms of use patterns specific to antimicrobial uses
provides a clarity that should reduce the need for extensive
consultations.
There are nine new data requirements for antimicrobials set out in
this proposal. Two (developmental neurotoxicity and immunotoxicity) are
the same new data requirements as promulgated in the final rule for
conventional chemicals (72 FR 60934) (see Unit VIII). While
photodegradation in soil studies have been routinely required for
conventional chemicals, this study would be a new data requirement for
wood preservatives (see Unit XII). Similarly, two new exposure data
requirements (soil residue dissipation and non-dietary ingestion
exposure) are today proposed for antimicrobials (see Unit IX.D).
Four new data requirements (activated sludge sorption isotherm
study; ready biodegradability study; porous pot study; and modified
activated sludge, respiration inhibition test) are proposed today for
antimicrobials that are not included in the final rule for conventional
pesticides. This is due to the nature of antimicrobial pesticides,
which includes many down-the-drain uses, i.e. those discharged to
public treatment systems, and is discussed in Units XII.B. and C.
Most screening-level environmental fate assessments would be
performed using the hydrolysis, photodegradation in water, activated
sludge sorption isotherm, ready biodegradability, and modified
activated sludge, respiration inhibition tests. For wood preservatives,
the results of the photodegradation in soil study may also be
considered in the screening-level assessment. If the porous pot study
is triggered based on the results of the ready biodegradability study,
then those results would also be considered.
EPA notes that its proposed approach for performing a screening-
level fate assessment could potentially result in the submission of
higher-tiered studies. There are seven higher-tiered environmental fate
studies, that could be triggered based on a weight-of-evidence
evaluation of the results of the screening-level studies. For example,
if the screening-level assessment were to indicate that a down-the-
drain chemical would partition to sludge, soil, or sediment, then
higher-tiered environmental fate studies such as the aerobic and
anaerobic soil metabolism studies may be required. If the chemical
would partition to water then higher-tiered ecotoxicity studies such as
the fish early life stage may be required. Thus, the higher-tiered
studies that could be triggered include both the environmental fate and
ecotoxicity scientific disciplines.
While not a new data requirement, subchronic dermal testing of end-
use products has not been routinely required and therefore would be
considered a new testing requirement. The circumstances for requiring
the testing is the same as for conventional chemicals. (See Unit VIII).
Each data requirement proposed in Units, VIII, IX, X, XII, XIII,
and XIV is described as ``new,'' ``current practices,'' or
``existing.'' ``New'' means that the data requirement has never been
required or has rarely been required on a case-by-case basis, and has
not been routinely considered during the Agency's evaluation of the
data needed for the purpose of risk assessment.
``Current practices'' encompasses the data that is typically
required to register an antimicrobial pesticide product. This would
include existing data requirements that are codified in part 161 as
well as those that are not codified in part 161 and are now being
proposed for codification in part 158, subpart W. It would also include
any study that has been routinely required on a case-by-case basis, or
any study that is routinely considered during the Agency's evaluation
of the data needed for the purpose of risk assessment but is
infrequently required because the triggers for that study are
infrequently met.
``Existing'' requirements are a subset of ``current practices.''
This particular subset means that the data requirement is codified in
part 161 and being transferred to part 158, subpart W either ``as is''
or with specified changes to the test notes, to the Rs, CRs, and NRs,
or to the use patterns for which required. If there are proposed
revisions to an existing data requirement, then clarifications on these
proposed revisions are included in the preamble. Such revisions include
proposing changes such as a change from conditionally-required to
required, a change in the number of test species, or expanding the
number of use patterns for which the test is required.
As previously discussed, there are frequently consultations to
discern data requirements for certain of the antimicrobial use
patterns. These consultations have led to general understandings as to
the data required for a particular use pattern. For certain use
patterns, all of the studies are considered to be the Agency's current
practices. As an example, for the wood preservative use patterns, there
is not a good fit to any of the part 161 use patterns in the tables and
therefore the data needed to register a wood preservative is difficult
to interpret from those tables. Given these circumstances,
[[Page 59388]]
EPA developed a series of requirements developed specifically for wood
preservatives. These requirements are not codified in CFR, but the
applicants understand that these are the data needed for wood
preservatives and they routinely provide these studies to EPA.
F. Tiered Data Requirements
The Agency has organized the proposed requirements for
antimicrobial pesticide products to support a tiered testing approach.
Under such an approach the Agency prescribes a specific subset of
``lower tier'' studies that are conducted first. The results of this
first- or lower-tiered testing are then used in conjunction with
exposure data or other information to determine the need for more
complex ``higher tier'' studies. The risk assessment must provide
sufficient information to make the risk management decisions needed to
register the product or establish a tolerance. This is a significant
factor in the tiering process.
Data requirements have been tiered when EPA believes it can
adequately conduct a risk assessment using a tiered approach. The
conditions for ``triggering'' these higher tiered studies are specified
in the test notes to the tables in proposed subpart W. A tiered data
submission process is intended to allow the Agency to assess a
pesticide's risk without requiring the applicant to conduct and submit
studies that may not be needed for the regulatory decision. For certain
chemicals, data from lower tiered requirements may be sufficient in and
of themselves or in combination with other data to address the Agency's
risk concerns without submission of higher tiered data requirements. In
other cases, data from lower tiered requirements may indicate that
higher tiered data need to be provided. The Agency expects applicants
to consult with the Agency, as needed, to determine when submission of
higher tiered data may be required.
The Agency has tiered the data requirements based on an
understanding of the potential exposure for a specific use pattern. As
an example, for toxicology studies used to support human health risk
assessments, the high human exposure grouping specifies 19 toxicology
studies as required at the lower tier. The low human exposure grouping
specifies 13 toxicology studies as required. The Agency considered the
frequency, duration, and/or magnitude of the exposure to determine the
lower tier of toxicology testing requirements for both the high and low
human exposure groupings.
For ecotoxicity data requirements, the Agency requires a first tier
of required data for all antimicrobials regardless of the use pattern.
The need for higher tiered data depends not only on the frequency,
duration, or magnitude of the exposure, but also on the results of the
first tier of the data.
Such a flexible approach allows EPA to require enough data, but not
more than enough, to make the required safety finding. Such an approach
is the same as that used for other pesticides; however, for
antimicrobials the progression from lower to higher tier requirements
may differ from that of conventional pesticides because the uses and
expected exposures are different.
G. Impact of this Proposal on Future and Existing Registrations
This proposal concerns prospective data requirements for future
registrations of antimicrobial pesticides. That is, these proposed data
requirements, once final, would apply to all new applications for
registration of antimicrobial pesticides submitted after the effective
date of the rule. The new data requirements would also apply to
applications of antimicrobial pesticides that are undergoing Agency
review when the new regulation goes into effect. EPA believes that
there may be a need for some type of a limited transition ``window''
for certain antimicrobial registration applications. EPA anticipates
applicants of applications that were submitted, but not yet approved
when the new regulations go into effect, may need to discuss with EPA
the specifics of their application and whether additional time may be
needed to complete generation of certain studies that may then be
required to fulfill new data requirements. The Agency specifically
requests comment on implementing the effective date of the final rule
for antimicrobials with regards to future registrations of
antimicrobials.
The Agency does not intend to apply these requirements
automatically or routinely to all existing pesticide registrations.
While EPA intends a flexible approach to imposing the new requirements
upon existing products, the Agency may find it necessary to call-in
data on certain existing registrations, for example, as warranted by
emerging risks of concern for particular pesticides or as a result of
possible future programmatic changes and priorities on existing
pesticides, or during registration review.
However, EPA notes that issuance of this proposed rule provides
notice to applicants of potential new data requirements and of
potential expansion of existing data requirements to additional
antimicrobial use patterns. Applicants and potential applicants for new
registrations as well as registrants of existing products may wish to
evaluate their products in light of the proposed requirements. As
always, the Agency encourages applicants to consult with EPA, if they
have any questions regarding data requirements.
H. Weight-of-Evidence Approach
The weight-of-evidence (WOE) approach is referenced in several
subpart W test notes. Such an approach requires a critical analysis of
the entire body of available data for consistency and biological
plausibility. Some considerations in this approach are listed below:
Sufficiency of data. Studies that completely characterize
both the effects and exposure of the agent have more credibility and
support than studies that contain data gaps.
Quality of the data. Potentially relevant studies are
judged for quality and studies of higher quality are given more weight
than those of lower quality.
Evidence of causality. The degree of correlation between
the presence of an agent and some adverse effect is an important
consideration.
Corroborative information. Supplementary information
relevant to the conclusions reached in the assessment is incorporated,
e.g., studies demonstrating agreement between model predictions and
observed effects.
WOE considers the kinds of evidence available, how that evidence
fits together in drawing conclusions, and significant issues/strengths/
limitations of the data and conclusions. WOE is not simply tallying the
number of positive or negative studies.
I. Use Patterns in Subpart W
The general use pattern groups described in subpart B of part 158
are not used as the bases for describing antimicrobial data
requirements. Those general use patterns were developed for and are
appropriate to conventional pesticide chemicals.
Some years ago, 12 use categories were developed specifically for
antimicrobials. At that time the Agency's data requirements for all
pesticide chemicals were specified by use patterns developed for and
appropriate to conventional pesticide chemicals. To fit antimicrobial
uses into this agricultural scheme, the antimicrobial use categories
referred back to the then-existing use patterns. With the Agency's
intention to establish specific data requirements for
[[Page 59389]]
antimicrobials in subpart W, this referral is no longer needed.
Therefore, the Agency is proposing that the use categories employed
in recent years to generalize the range of uses for individual
antimicrobial pesticide chemicals, now constitute the use patterns for
specifying the antimicrobials data requirements in the tables in
proposed subpart W. Additionally, EPA is proposing to codify in Sec.
158.2201 the specific use patterns for antimicrobials.
FIFRA section 3(h)(3)(A)(ii)(I) requires that EPA ``define the
various classes of antimicrobial use patterns.'' For antimicrobial
pesticides, the Agency proposes to structure its requirements by using
a system of 12 use patterns based on similarity of use, purpose,
pesticidal function, the nature of the exposure, and, in some cases,
application methods. Today's proposal meshes with the statutory mandate
to identify classes of antimicrobial use patterns by defining for each
use pattern the data requirements that apply. EPA requests comment not
only on the 12 antimicrobial use patterns described in this Unit, but
also on the usefulness of these use patterns. EPA also requests comment
on whether or not any different/additional use patterns should be
codified by splitting or recombining the existing use patterns to make
separate and distinct use patterns.
Antimicrobial use patterns also reflect environmental concerns for
indoor versus outdoor use, as well as food versus nonfood-use, and high
versus low human exposure. The 12 general use patterns for
antimicrobial pesticides are described below. Examples within each use
pattern are provided:
1. Agricultural premises and equipment. This use pattern includes
many indirect food uses with mostly indoor use sites.
Farm and farm animal premises such as animal houses and
pens (including milk houses), parlors, stalls, and barns.
Transportation vehicles used to transport animals.
Equipment such as forks, shovels, scrapers; halters,
ropes, other restraining equipment; racks, mangers, feeders, waterers,
troughs, and fountains.
Food-handling equipment such as milking equipment.
2. Food-handling/storage establishments, premises, and equipment.
This use pattern also includes many indirect food uses due to the
treatment of food contact surfaces and the resultant human exposures.
All use sites are indoor.
Food or feed processing plants.
Eating establishments such as restaurants and cafeterias.
Food storage or distribution facilities.
Commercial transportation vehicles, shipping, and storage
containers.
Food or feed stores and markets.
Vending machines.
3. Commercial, institutional and industrial premises and equipment.
This use pattern includes nonfood contact areas of commercial sites.
Typically, antimicrobial pesticides would be applied to ceilings,
doors, doorknobs, fixtures, floors, light switches, stairs, walls,
windows, and woodwork as part of routine cleaning practices. Included
within this use pattern are residential school and daycare
institutions.
This use pattern includes both indoor and outdoor uses. Some of the
uses have the potential for significant exposure due to the repetitive
nature of certain exposures and therefore may be considered as high
human exposure.
4. Residential and public access premises. This use pattern
includes mostly nonfood areas, although it includes food-handling areas
in homes. Some of the uses have the potential for significant exposure
due to the repetitive nature of certain exposures and therefore may be
considered as high human exposure. Most uses are indoor.
Premises, contents, and equipment of homes, apartments,
mobile homes and shelters, including home-based daycare.
Public areas, public buildings, and public rooms.
Commercial kennels, or living quarters of pets, zoo
animals, race horses, or laboratory animals.
5. Medical premises and equipment. Medical waste is defined as any
solid waste that is generated in the diagnosis, treatment, or
immunization of human beings or animals, in research pertaining
thereto, or in the production of biologicals including, but not limited
to, culture and stocks, pathological wastes, human blood and blood
products, and sharps. This use pattern is considered to be indoor
nonfood. Some of the uses have the potential for repeated exposure and
therefore may be considered as high human exposure.
Hospital or medical environments such as clinics, dental
offices, nursing homes, sick rooms, morgues, and veterinary clinics.
Non-critical medical equipment such as bedpans, basins,
and furniture.
6. Human drinking water systems. Human drinking water systems
include any methods used to provide potable water from raw water
supplies. This use pattern is considered to be high human exposure due
to the potential for human exposures via drinking water, as well as
dermal exposures to the treated water.
Public water systems.
Individual water systems.
Emergency water systems.
Water purifier units.
Private water systems of individual homes, farms,
institutions, camps, resorts, and industrial plants.
Emergency water systems for the public, campers,
travelers, military, and fishermen.
7. Materials preservatives. Materials preservatives are
antimicrobial chemicals added during industrial processes to prevent
the growth of microorganisms. Examples of such uses include paints,
coatings, adhesives, textiles, and paper. This use pattern includes
food and nonfood, and mostly indoor uses.
8. Industrial processes and water systems. Certain antimicrobial
chemicals, known as microbiocides, are used to control the growth of
bacteria, fungi, and algae in circulating water systems. There are two
types of systems: ``once-through'' and ``recirculating.''
For ``once-through'' systems, the water is not re-used and is
therefore released into the aquatic environment or a wastewater
treatment plant after a single cycle through the system. Once-through
uses have the potential for significant environmental exposure when the
treated water is released to the environment. Large volumes of water
(as much as millions of gallons per minute) may be released directly to
a river, estuary, or marine environment within minutes or hours of
adding the antimicrobial to the system. In addition to the potential
for environmental exposure after release, there is the potential for
high human exposure via drinking water if the intake pipe for a
drinking water treatment plant is downstream. Also, the water could be
used in crop and/or livestock production thus providing for additional
human exposure.
However, for many uses of water in industrial plants the treated
water is re-used repeatedly within the system, ``recirculating'' in the
system multiple times until released into the aquatic environment or a
wastewater treatment plant. EPA has assumed that the releases are
scheduled as the antimicrobial has been ``used-up.'' Given the lower
frequency of release, resulting in lower volumes released to the
environment, recirculating uses are likely to have less environmental
exposure than that of once-through systems.
As will be explained later in Unit XI, for the purposes of
determining data requirements for environmental fate and
[[Page 59390]]
ecological effects, the industrial processes and water systems use
pattern will be subdivided. Because of the distinct differences between
the once-through and recirculating water systems, the once-through
water system will be grouped with those use patterns with potential for
higher environmental exposures and the recirculating water system with
those use patterns with the potential for lower environmental
exposures.
9. Antifoulant paints and coatings. Antifoulants are coatings and
paints applied to boat hulls and bottoms, crab and lobster pots, and
underwater structures or equipment to control the growth of freshwater
or marine fouling organisms. Antifoulant coatings have the potential
for high environmental exposure most particularly for marine (both
freshwater and saltwater) environments.
Also included within this use pattern is ballast water, that is,
the water that is pumped in and out of ballast tanks as a ship's weight
changes due to loading and unloading of cargo. Ballast water provides
needed stability for safe operation of marine vessels. In recent years
there have been significant concerns about transport of marine species
from one marine environment to another in ballast water. When
discharged into a new environment, the new species may become invasive
and disrupt the native ecology. Ballast water treatments (such as
adding an antimicrobial to the ballast water before discharge) are
intended to prevent this. The Agency has reviewed few applications for
ballast water treatments, presumably because treatment of ballast water
to prevent the transfer of microorganisms from one marine environment
to another is relatively new. Since ballast water treatments also have
the potential for high exposure to the aquatic (both freshwater and
seawater) environment, EPA has grouped the ballast water treatment
pesticide chemicals with the antifoulant coating pesticide chemicals.
10. Wood preservatives. Wood preservative products are those which
claim to control wood degradation problems due to fungal rot or decay,
sapstain, molds, or wood-destroying insects. This use pattern has the
potential for high exposure for both humans and the environment with
mostly outdoor use sites. Certain uses can be food-uses. The types of
wood and the products that can be manufactured with this treated wood
are:
Freshly cut logs or lumber.
Seasoned building materials.
Utility poles, fence posts and rails.
Structural members.
Structures and dwellings.
Transportation vehicles (truck beds and support
structures).
Crop containers.
Lawn furniture and decks.
Playground equipment.
Garden/landscape timbers.
Log homes.
11. Swimming pools. Products in this use pattern are used to
prevent/control the growth of bacteria or algae in the water systems of
swimming pools, Jacuzzis, and hot tubs. This use pattern is considered
to be high human exposure. Under routine use little or no environmental
exposure is expected, as the water in swimming pools, Jacuzzis, or hot
tubs is considered to be separated from the natural environment.
However, when draining is needed, depending on the volume of water and
the location of the pool or hot tub, it is most likely that discharge
would be down-the-drain to a wastewater treatment plant, to a storm
drain that discharges to a stream, or directly to soil.
12. Aquatic areas. Products in this use pattern are designed to
control or kill slime-forming bacteria, fungi, or algae in lakes,
ponds, streams, drainage ditches, and other bodies of water. In
addition to the potential for environmental exposure, there is the
potential for high human exposure via drinking water if the intake pipe
for a drinking water treatment plant is in a lake or downstream, or
through recreational activities such as swimming. Also, the water could
be used in crop and/or livestock production thus providing for
additional human exposure.
J. Use Site Index
As part of this action, the Agency is proposing to place on its
website an Antimicrobial Use Site Index similar to the existing
Pesticide Use Site Index at http://www.epa.gov/pesticides/regulating/usesite/index.htm. Information similar to that which would be included
on the Antimicrobial Use Site Index is included in the docket for this
action (Ref. 41). The existing Pesticide Use Site Index will be re-
titled, the Pesticide Use Site Index for Conventional, Biochemical, and
Microbial Pesticides to distinguish it from the Antimicrobial Use Site
Index.
K. Request for Comments
The Agency invites the public to provide its views and suggestions
for changes on all of the various proposals in this document.
Specifically included within the Agency's request for comments are the
following proposals:
SAR white paper.
Four case studies.
12 general use patterns, suggestions for different/
additional use patterns, and their utility.
Proposed new down-the-drain requirements.
Additionally, in other parts of this proposed rule, EPA is
specifically requesting comments on certain issues.
As appropriate during the development of this proposal, EPA has
occasionally shared information with the regulated community on the
data requirements that were under consideration. Commenters are
encouraged to comment on such sharing of information as part of the
administrative process of developing this proposed rule.
The Agency welcomes comments on the following topics of particular
interest to the Agency:
All aspects of the administrative process used to develop
this proposed rule including outreach activities.
The need for, value of, and any alternatives to, the data
requirements described in this document.
The scientific basis of this proposed rule.
The clarity of the proposed data requirements for
antimicrobial pesticides and the relationship between the proposed data
requirements and EPA's statutory determinations.
The economic analysis of the proposed rule, as well as on
its underlying assumptions, economic data, and high- and low-cost
options and alternatives.
Commenters are encouraged to present any data or information that
should be considered by EPA during the development of the final rule.
Describe any assumptions and provide any technical information and data
used in preparing your comments. Explain estimates in sufficient detail
to allow for them to be reproduced for validation. EPA's underlying
principle in developing the proposed revisions has been to strike an
appropriate balance between the need for adequate data to make the
statutorily mandated determinations and informed risk management
decisions, while minimizing data collection burdens on applicants.
V. Product Chemistry
The Agency proposes to apply the product chemistry data
requirements for conventional pesticide chemicals, in subpart D, to
antimicrobial products. These requirements were promulgated in the
final rule on October 26, 2007, (72 FR 60934). Product chemistry
requirements identify the basic identity, and chemical and physical
characteristics of a pesticide chemical.
[[Page 59391]]
These data, to a limited extent, are used to determine if a pesticide
contains contaminants which are of toxicological or environmental
concern and are necessary to determine proper label precautions.
Product chemistry requirements are generally not dependent on a
pesticide's intended use pattern, and therefore it is appropriate to
apply the same requirements to antimicrobial pesticides as required for
conventional pesticides. If circumstances particular to antimicrobial
pesticides should arise, then the Agency has the authority to require
the appropriate product chemistry data on a case-by-case basis.
VI. Product Performance Data Requirements
EPA is not proposing to revise product performance data
requirements (Sec. 158.2220) at this time. At this time there are
nearly identical product performance data requirements for
antimicrobial chemicals in both Sec. 158.400 and part 161. EPA
proposes to transfer the contents of the existing product performance
data requirements for antimicrobial pesticides into subpart W,
specifically Sec. 158.2220. The table is transferred essentially
unchanged. EPA is also proposing to delete the duplicative data
requirements for antimicrobials from the table in Sec. 158.400. After
the publication of the final rule, all product performance data
requirements for antimicrobials will be contained in Sec. 158.2220.
In the Federal Register of September 17, 1999, (64 FR 50726), EPA
published a proposed rule entitled, ``Registration Requirements for
Antimicrobial Pesticide Products and Other Pesticide Regulatory
Changes.'' In that proposed rule, EPA proposed various definitions for
public health pesticides. Today, the Agency is re-proposing definitions
for the following terms: disinfectant, fungicide, microbiological water
purifier, sanitizer, sterilant, tuberculocide, and virucide. These
proposed definitions are identical to those in the 1999 proposal. The
Agency is also re-proposing the 1999 criteria that EPA would use to
consider whether a product makes a public health claim. The comments
that were received on the 1999 proposed rule were considered for
today's proposed rule.
The current regulations in part 161 require that each applicant
must ensure through testing that its products are efficacious when used
in accordance with label directions and commonly accepted practices.
The requirement to submit product performance data is directly linked
to making a public health claim. Today's proposal makes explicit what
antimicrobial claims would be considered public health claims for
purposes of product performance data submission.
At the time of application, EPA requires the submission of product
performance data for products making a public health claim. An
application will not be approved in the absence of acceptable data
substantiating a public health claim. EPA requires the development of
product performance data for all other (non-public-health) products,
but does not review or approve such data as part of a new or amended
registration. If, after the product has been registered, EPA has reason
to review such data (for example, there are indications that the
product does not perform as claimed), then EPA will require the
registrant to submit such data within a reasonable time. A request for
submission of product performance data after product registration is
not required to be done under the Data Call-In provisions of FIFRA
section 3(c)(2)(B), but is instead authorized by regulation.
Accordingly, if an antimicrobial product makes a claim to control
microorganisms that pose a threat to human health, the applicant is
then required to submit product performance data to support its
registration. The types of product performance data required by the
Agency to support registration of an antimicrobial are determined by
the types of claims made on the product's label (e.g., sanitizer,
disinfectant) and the intended use site for the product (e.g., hard
surface, fabric).
VII. Human Health Risk Assessment
The data needed to conduct a human health risk assessment include
both toxicology and exposure data. Toxicology studies are used to
assess hazards of pesticides to humans and domestic animals, and
include a variety of acute, subchronic, and chronic toxicity studies;
developmental/reproductive tests; and tests to assess mutagenicity and
pesticide metabolism. To assess human health risk, there must be
sufficient information to select the appropriate doses and end-points,
i.e., the Agency must know the level of exposure at which an adverse
effect is observed. This requires a toxicological database that is not
only complete in the endpoints it covers, but is also of acceptable
quality. The duration of the toxicity study approximates the estimated
duration of the human exposure, while considering species differences
in maturational milestones and overall life span. The toxicology data
requirements are discussed in Unit VIII of this preamble.
For EPA to assess the potential risks that antimicrobial products
pose to humans, it is necessary not only to assess the hazard of the
antimicrobial active ingredient based on toxicology information, but
also to estimate human exposures to the antimicrobial based on the
product use patterns. For antimicrobials, three types of exposure data
are required: applicator, post-application, and residue chemistry
(which includes exposure via food and water).
Applicator and post-application exposure data are used to evaluate
exposures to persons in occupational and non-occupational settings,
including residential, commercial, institutional, and recreational
sites. Exposure data include: dermal and inhalation exposure data for
applicators, post-application residue data, post-application monitoring
data, use information, and human activity information. Applicator and
post-application data requirements are discussed in Unit IX of this
preamble.
Residue chemistry information is used to establish tolerances for
residues of pesticide chemicals (and any metabolites of concern) in/on
food crops, processed foods, and animal products consumed by humans
when the animal consumes a feed item derived from these crops. The
Agency estimates the dietary exposure of the general population and
various population subgroups to pesticide residues in food by using the
residue data as inputs to the dietary modeling. The dietary exposure is
then used in conjunction with toxicity data to determine risk. Residue
chemistry data requirements are discussed in Unit X.
VIII. Toxicology Data Requirements
A. Toxicology Data Requirements for Antimicrobials
EPA proposes to adapt the basic toxicology data types as listed in
subpart F of current part 158 to support applications for antimicrobial
products. However, EPA also proposes to modify the applicability of
those requirements to reflect the differing risks of and levels of
exposure to antimicrobials.
As with conventional pesticides, the types of toxicology studies
required for antimicrobials can include acute, subchronic, and chronic
toxicity studies, as well as carcinogenicity, prenatal developmental
toxicity, reproductive toxicity, mutagenicity, neurotoxicity,
immunotoxicity, and other studies.
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1. Acute toxicity studies provide information that serves as a
basis for classification and precautionary labeling and the need for
child resistant packaging.
2. Subchronic toxicity studies provide information that can be used
to assess human health hazards that may result from repeated exposures
to a pesticide over a limited period of time. These data also provide
information for selecting proper dose levels for chronic/
carcinogenicity studies.
3. Chronic toxicity studies are used to assess potential hazards
resulting from prolonged and repeated exposures to a pesticide over a
significant portion of the life span.
4. Prenatal developmental toxicity studies are designed to assess
the potential of a pesticide to induce effects in offspring as the
result of exposure of the mother during pregnancy.
5. Multigeneration reproduction studies are designed to provide
information concerning the general effects of a pesticide on overall
reproductive capability.
6. Mutagenicity studies assess the ability of the pesticide to
interact directly or indirectly with cellular DNA, RNA, proteins, or
chromosomes and the potential for adverse effects on cellular genetic
material.
7. Neurotoxicity studies evaluate the potential of the pesticide to
adversely affect the structure and functions of the nervous system.
8. Immunotoxicity studies evaluate the potential of the pesticide
to adversely impact the immune system.
9. Metabolism studies evaluate the absorption, distribution,
biotransformation, and excretion of the pesticide.
B. The History of Toxicology Requirements for Antimicrobials
By 1984, the Agency had reconsidered its toxicology data
requirements for all pesticides, including antimicrobials. For
instance, it had become clear that exposure to antimicrobial pesticides
might well be long-term and frequent since many antimicrobials were
used indoors in close proximity to humans. Occupational users often
were exposed to concentrated antimicrobial products while mixing and
diluting the product for use, and might be exposed to an antimicrobial
pesticide for large portions of their working lifetimes. In response to
the reregistration program initiated under the 1988 amendments to
FIFRA, EPA concluded that additional data were needed to properly
evaluate the potential hazards associated with antimicrobial
pesticides. Consequently, the Agency began to require more toxicity
data for antimicrobials. In 1987, based on its evolving understanding
of antimicrobial uses, the Agency issued an Antimicrobial Toxicology
Data Call-In (DCI) Notice (52 FR 595, January 7, 1987) (Ref. 24), which
specified a tiered approach for submission of toxicology and human
exposure data.
The 1987 Antimicrobial Toxicology DCI divided antimicrobial
pesticides into three exposure categories: low, medium, and high. The
toxicology data required was tiered according the amount of exposure.
The first tier toxicology data requirements (low exposure) were the
standard acute studies, a 90-day dermal or inhalation study, a prenatal
developmental toxicity study in one species, and a battery of
mutagenicity studies. The second tier (medium exposure) included the
first-tier toxicology studies and a subchronic feeding study, a
prenatal developmental study in a second species, and a dermal
absorption study. The third tier (high exposure) included the first-
and second-tier studies and the chronic feeding, carcinogenicity,
reproduction, and metabolism studies. All food-use antimicrobials were
considered high exposure.
Applicants could fulfill the toxicology data requirements by
submitting the appropriate toxicity studies or by submitting a
combination of toxicity studies and exposure data. The Agency used the
exposure data and submitted toxicology data to determine whether and
which additional toxicology studies were needed to assess the hazard of
the antimicrobial.
In proposing part 158, subpart W, the Agency is specifying the
toxicology data requirements it believes are appropriate for specific
antimicrobial use categories, drawing upon EPA's experience since 1987.
EPA is now proposing two groupings: Low- and high-exposure. In
practice, the submission, review, and evaluation of toxicity data
merged the low- and medium-exposure categories. Therefore, the low- and
medium-exposure categories from the 1987 DCI were combined to create
what is today the low exposure category.
Today's proposed approach conceptually follows the tiering approach
used in 1987. Generally, data requirements proceed in a tiered manner
from simpler to more complex studies considering the frequency,
duration, and magnitude of exposure as well as the dermal absorption of
the pesticide. Knowledge gained from results of assessments performed
using these lower tiered studies is used to indicate if any higher
tiered studies are required. The Agency does not prescribe a required
sequence of toxicological testing. There are many factors that could
affect the testing progression. Rather, decisions regarding the
sequence in which the tests are conducted are left up to the applicant.
Thus, the applicant has flexibility to determine the sequence of
testing, as best suited for their particular chemical. Early
consultation with the Agency is recommended to attain a common
understanding of the sequencing that should be used.
C. Groupings for Antimicrobial Toxicology Data Requirements
1. Overview. This proposal divides the antimicrobial uses into two
groups, high human exposure and low human exposure uses. Because high
human exposure uses may pose higher risks, more toxicology studies are
required than for uses with less exposure. For the purpose of
determining toxicology data requirements, high human exposure is
defined as that resulting in human exposures over a considerable
portion of the human lifespan. Exposure to food and water, which occurs
throughout the human life span, is therefore a high human exposure. For
other exposures such as occupational and residential, the Agency has
considered the frequency, duration, or magnitude of the exposure to
determine in its best professional judgment if the exposure is high.
One or a combination of these parameters led the Agency to make the
determination that the exposure is high. As an example, swimmers may
swim daily or weekly, from several minutes to several hours with almost
their entire body in the water. There are workers who manually pour
concentrates into vessels for mixing (with water or other chemicals) in
order to prepare dilute solutions for use. Such exposures can occur
daily, weekly, monthly, or episodically as dictated by the
circumstances of the job. Particularly in the absence of personal
protective equipment, these workers have the potential for high dermal
and inhalation exposures. Accordingly, for the purposes of defining
data requirements, EPA proposes to categorize food and feed uses and
certain nonfood-uses as high human exposure.
As discussed, the Agency considers high human exposure uses to be
those that could result in pesticide residues occurring in food or
feed, or in drinking water. These would include, but are not limited
to:
Human or animal drinking water.
Fruit and vegetable rinses.
Egg washes.
Outdoor aquatic uses in lakes, rivers, or streams which
have the potential to contaminate potable water.
[[Page 59393]]
Indirect food uses with residues equal to or greater than
200 parts per billion (ppb).
Any use that requires a tolerance or tolerance exemption
(except for indirect food uses requiring a tolerance or tolerance
exemption in which residues are less than 200 ppb).
EPA also considers high human exposure uses to be those uses that
could result in high exposure to applicators, and any other
antimicrobial uses which could result in high exposure to humans. These
would include but are not limited to:
Wood preservatives.
Metal cutting (metalworking) fluids.
Swimming pools.
This list is not exhaustive. There may be other uses that the
Agency would consider high human exposure uses based on their potential
for human exposure. Low human exposure uses are defined as those that
are not high human exposure uses.
The Agency is proposing an approach that might allow an applicant
for registration of a pesticide with low human exposure uses to
generate fewer studies in total than would be required for high human
exposure uses. Under this proposal, applicants with low human exposure
antimicrobials may perform tests in a tiered fashion. As previously
explained, for toxicology studies the high human exposure grouping
specifies 19 toxicology studies as required, and for the low human
exposure grouping, 13 toxicology studies as required. After the 13
required studies for low human exposure are reviewed by the Agency,
additional testing may be required for low-exposure uses based on the
result(s) of the lower-tiered studies. These 13 studies could indicate
a low risk potential or could trigger the need for additional data.
The table in proposed Sec. 158.2230 presents the toxicology data
requirements. The proposed toxicology data requirements for the two
groupings (high human exposure and low human exposure) are separated
into two columns showing test by test whether it is typically required
(shown as R) or conditionally required (shown as CR).
The Agency recognizes that toxicology testing can represent a large
burden on applicants and can involve significant animal testing.
Consequently, the Agency works with applicants, the scientific
community, and other stakeholders to ensure that data requirements
produce the information needed to enable the Agency to make the safety
findings required under FIFRA and FFDCA. The tiering process proposed
within the toxicology data requirements requires fewer studies for
lower exposures. The Agency also works to design study protocols that
minimize the development burden and limit uses of test animals.
Toxicity testing requirements may be satisfied in a combined study,
such as combining the prenatal developmental and reproductive toxicity
testing requirements in a single study. However, if this option is
chosen, the protocol must be approved by the Agency prior to the
initiation of the study. Details for developing protocols are available
from the Agency.
2. Data requirements for high human exposure uses. For high human
exposure uses, EPA is proposing to require the following studies: Acute
oral, dermal, and inhalation toxicity; primary eye and dermal
irritation; dermal sensitization; subchronic studies in two species;
mutagenicity studies; acute and subchronic neurotoxicity testing;
prenatal developmental toxicity studies in two species; a two-
generation reproduction study; a chronic feeding study in one species;
carcinogenicity studies in two species; a mammalian metabolism study;
and an immunotoxicity study. Based on a weight-of-evidence evaluation,
a developmental neurotoxicity study may be required. If the Agency
determines, based on use information that dermal exposure is the major
route of exposure, then EPA may require dermal absorption testing or
toxicological studies conducted by the dermal route.
i. Wood preservatives. For wood preservatives, the Agency may
require toxicity data on both the active ingredient which is
incorporated into the wood and on transformation/degradation products
which occur in wood post-treatment. Such transformation/degradation
products would include dislodgeable residues (i.e., residues that occur
from hand contact with treated wood) or leachate residues (i.e.,
residues that occur in soil or water in contact with treated wood).
ii. Metal working fluids (MWFs). While both ``open'' and ``closed''
MWF systems are high human exposure uses, under the appropriate
circumstances, the Agency distinguishes between ``open'' and ``closed''
systems. Fewer toxicity data may be required for a ``closed'' system.
If the use of the MWF is limited to ``closed'' systems only, the
applicant clearly identifies the use as such, and the Agency agrees,
then fewer toxicity studies would be required for that ``closed''
system. Based upon review and evaluation of the submitted toxicity
studies and exposure data, EPA may determine that fewer additional
toxicity studies than would generally be submitted are required. Upon
request the Agency will provide written guidance concerning exposure,
toxicity, and other data requirements for ``open'' and ``closed'' MWF
systems.
3. Data requirements for low human exposure uses. As previously
discussed, the Agency proposes to apply a tiered system to toxicology
testing requirements for low human exposure antimicrobials. The
required data are: Acute oral, dermal, and inhalation toxicity; primary
eye and dermal irritation; dermal sensitization; a subchronic toxicity
study in the rodent; prenatal developmental toxicity studies in two
species; a two-generation reproduction study; mutagenicity studies; and
immunotoxicity testing.
Based on the review of these studies, additional studies may be
required if there is evidence of significant toxicity in the submitted
studies. Evidence that could trigger concerns may include data
indicating neurotoxicity, immunotoxicity, developmental, reproductive,
or other systemic toxicity such as the presence of neoplastic growth or
significant target organ toxicity. In such cases, appropriate studies
to address the Agency's hazard or risk concern would be required. The
table in proposed Sec. 158.2230 contains test notes that explain how
these toxicology requirements are proposed to be applied to low human
exposure antimicrobials.
4. Data requirements for indirect food uses. For the purpose of
determining toxicology data requirements, an antimicrobial use is
considered an indirect food use when the antimicrobial pesticide is
applied to a surface or incorporated into a material that may contact
food, but is not applied directly to food. Residues of the pesticide or
its degradates can be transferred to the food when it comes into
contact with these treated surfaces and articles. Examples of
antimicrobial uses which may result in residues in food, through normal
use, are sanitizers and disinfectants, which may be used in food-
handling areas, but not directly applied to the food.
With the passage of the Food Quality Protection Act of 1996 (FQPA),
as later modified by the Antimicrobial Regulation Technical Corrections
Act of 1998 (ARTCA), EPA currently has the responsibility for
establishing tolerances or tolerance exemptions for all pesticide uses
that result in residues in or on food, except for:
Residues that result from the use of antimicrobial
substances on food or in water that comes into contact with food, if
such substances are used where food
[[Page 59394]]
is prepared, packed, or held for commercial purposes. (For raw food
commodities, this exclusion does not apply if the antimicrobial is
applied in a facility where only such foods are treated and the
treatment of the foods does not constitute food processing.)
Antimicrobial substances used as food contact substances
in or on food, such as those used in the manufacture of food contact
packaging. This exclusion does not apply to objects impregnated with a
food contact substance (other than food packaging material) if the
inclusion of the substance is intended to have an antimicrobial effect
on the food contact surface of the object.
FDA has the responsibility for regulating these antimicrobial
substances as food additives under section 409 of the FFDCA. However,
under the provisions of FIFRA section 2(bb) prior to registration of a
pesticide that may result in residues of that pesticide in or on food
(including sanitizers, disinfectants, and slimicides), EPA must make a
safety finding that the pesticide residue meets the standard set forth
in section 408 of FFDCA. This applies even if FDA will establish a food
additive regulation for the use of the antimicrobial substance under
section 409 of the FFDCA.
Since publication in 2002 of its final guidance for toxicology
recommendations for food contact substances, FDA has used an approach
with several tiers: residues less than 0.5 ppb, between 0.5 and 50 ppb,
between 50 ppb and 1,000 ppb, and greater than 1,000 ppb. EPA
recognizes the historic usefulness of the FDA's tiered approach and
proposes to adopt it conceptually, but with a modification appropriate
to antimicrobials (biocides). FDA's guidance (Ref. 8) specifically
recommends that a factor of 5 be used to account for the toxicity of
biocides. Further modifications to this approach are needed for EPA to
perform an assessment of risk that conforms to the FFDCA section 408
safety finding which now requires consideration of the ``... special
susceptibility of infants and children to the pesticide chemical
residues....''. Thus, additional studies are needed even for the lower
exposures for which FDA historically would not have required data.
Accordingly, EPA proposes to classify indirect food uses of
antimicrobials which result in residues in or on food of less than 200
ppb as low human exposure uses for purposes of subpart W. Given FDA's
historical experience with biocides, EPA believes that the 200 ppb
(1,000 ppb divided by 5) benchmark is a reasonable delineation between
high and low human exposures. Antimicrobials used in a manner which
results in residues in food from an indirect use that are equal to or
greater than 200 ppb would be considered high exposure uses. The Agency
specifically requests comment on the use of 200 ppb residues in food as
the differentiation between the high and low human exposure for the
purposes of subpart W.
For indirect food uses, the applicant should begin the process by
collecting all available information. Since many indirect food uses
were previously evaluated by FDA, there may be a petition that was
submitted to FDA. For some chemicals, toxicity testing may have been
conducted and reviewed in the open literature. After identifying the
available reliable information, the applicant should compare this
information to the data requirements in the appropriate column in the
table in Sec. 158.2230. If the applicant believes that an existing
study satisfies the data requirement, then this should be discussed
with EPA.
The applicant is also encouraged to review the approach discussed
in Unit XVIII.A. of this preamble on the use of Structure-Activity-
Relationship (SAR) assessments to ascertain if such techniques could
provide useful information in preparing a submission to EPA.
D. Acute Toxicity Studies for End-Use Products
EPA proposes to add a test note to clarify that the currently
required six acute toxicity studies are to be conducted on the product
as formulated for sale and distribution. These six acute studies may
also be needed for the product as diluted for use. Many antimicrobial
products are diluted at the point of use, but can still lead to
significant exposure. The applicant has the option of also conducting
certain studies using the highest diluted concentration (i.e., the
least diluted product) permitted by the labeling. This test note
codifies EPA's current practices. Consultation with the Agency is
highly suggested to assure that the appropriate product and any
appropriate dilutions are tested.
E. Neurotoxicity
EPA promulgated toxicity requirements for conventional pesticide
chemicals, in which the data requirements for neurotoxicity were
revised. The former test battery of three studies was revised to
include only two studies. The rationale for those revisions was
discussed in Unit XI of that proposed rule (March 11, 2005) (70 FR
12276), and in the final rule preamble (October 26, 2007) (72 FR
60934). That rationale is also applicable to antimicrobial pesticide
chemicals.
EPA proposes to adopt the current conventional pesticide data
requirements for neurotoxicity testing to antimicrobials. Adopting the
battery of two neurotoxicity studies would codify the Agency's current
practices.
The current adult neurotoxicity test battery for antimicrobials in
part 161 consists of three studies: Acute delayed neurotoxicity (hen),
90-day neurotoxicity (hen), and 90-day neurotoxicity (mammal). The
mammal subchronic neurotoxicity study is required if the acute oral,
dermal, or inhalation toxicity studies show neurotoxicity or
neuropathy. The existing required data are inadequate for evaluating
neurotoxic effects of some chemicals.
The proposed battery of two studies in the rat is more sensitive
than the neurotoxicity tests currently required in part 161. The
objective of the proposed acute and subchronic neurotoxicity battery is
to evaluate the incidence and severity of the functional and behavioral
effects, the level of motor activity, and the histopathology of the
nervous system following exposure to a pesticide chemical.
Under this proposal, an adult neurotoxicity test battery of two
studies would replace the current battery of three studies. The two
studies are an acute and a subchronic 90-day neurotoxicity study in
rats. The acute study would detect possible neurotoxic effects
resulting from a single exposure. The subchronic study would detect
possible effects resulting from repeated exposures. These studies were
presented to the FIFRA SAP in 1994, which endorsed them, and the Agency
has generally required them on a case-by-case basis since 1992 for all
pesticides, including antimicrobial pesticides.
The required parameters for a subchronic neurotoxicity study may be
incorporated into the standard 90-day subchronic feeding study in rats.
The acute and subchronic neurotoxicity studies in adult rats, in
addition to providing data on the potential for adverse neurotoxic
effects, may also provide a basis for comparing the potential for age-
related differences in impacts on the nervous system if a developmental
neurotoxicity study is triggered for the same chemical.
For high human exposure uses, EPA proposes to require both the
acute neurotoxicity and subchronic neurotoxicity studies in the rat.
For low human exposure uses, both
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neurotoxicity studies are proposed to be conditionally required (CR)
and would be triggered if there is evidence of neurotoxic effects in
the 90-day oral study in rodents or if other data show evidence of
neurotoxicity.
F. 90-Day Oral Studies
EPA proposes to adopt the current conventional pesticide data
requirements for subchronic (90-day) studies to antimicrobials. Oral
90-day toxicity studies in two species are currently required in part
161 for high human exposure uses and conditionally required in part 161
for low human exposure uses. The Agency is proposing to continue this
existing requirement for high human exposure uses in part 158, subpart
W. The Agency is proposing to require an oral 90-day study in one
species (rodent) for low human exposure uses and to conditionally
require testing in a second species (non-rodent). For low human
exposure uses, this change from two conditionally required studies to
one required and one conditionally required study would codify current
practices.
Often, range-finding studies of at least 90 days are needed to
select the appropriate dose levels for the mouse carcinogenicity study.
Thus, 90-day studies are often performed routinely by most
investigators prior to the initiation of the carcinogenicity study.
Often the range-finding studies have been submitted to the Agency for
review. Because of their utility in determining the dose levels in the
mouse carcinogenicity study, in the test notes, the Agency encourages
the use of range-finding studies in the mouse.
Additionally, all 90-day subchronic studies in the rodent can be
designed to simultaneously fulfill the requirements of the 90-day
neurotoxicity study by adding separate groups of animals for testing.
Although the subchronic guidelines include the measurement of certain
neurological endpoints, they do not meet the requirement for a 90-day
neurotoxicity study.
G. 21/28-day Dermal and 90-day Dermal Testing with End-Use Product
Currently in part 161 there is a conditional requirement for 21-day
and/or 90-day dermal toxicity studies for all use patterns. The Agency
is proposing to continue to conditionally require 21/28-day and/or 90-
day dermal toxicity studies for all antimicrobials. As determined by
the Agency, based on the use pattern, frequency of exposure, and
magnitude of exposure, the 21/28 day study may provide the appropriate
information for risk assessment purposes.
Just as with conventional pesticides, the Agency is proposing to
require subchronic dermal testing of the end-use product if the product
or any component of the product may increase dermal absorption of the
active ingredient(s) or could potentiate toxic or pharmacologic
effects. Testing of an end-use (formulated) product in either of these
studies has not been routinely required and therefore would be a new
testing requirement for antimicrobials. A test note has been added to
both of these existing data requirements to describe the triggers for
end-use product testing.
Currently, end-use products are required to be tested for acute
dermal toxicity and dermal irritation. Without additional subchronic
testing of the end-use product, risk from dermal exposure to an end-use
product may be underestimated for those products that contain an inert
ingredient that increases the dermal absorption of the active
ingredient. An example of such an inert ingredient would be dimethyl
sulfoxide.
H. 90-day Dermal and 90-day Inhalation Testing for HVAC&R Uses
Heating, ventilation, air conditioning, and refrigeration systems
(collectively referred to as HVAC&R) refer to systems which
refrigerate, exclusively air condition, or exclusively heat, as well as
those in which one system provides both heating and cooling. HVAC&R
systems are present in industrial, institutional, commercial, and
residential establishments, and include, but are not limited to: air
ducts, duct fittings, duct liners, fans, supply ducts, return ducts,
exhaust ducts, intakes, outlets, louvers, diffusers, dampers, plenums,
outdoor air intakes, air handling units, and any other ductwork and
similar components. The Agency is concerned with potential exposures
and risks from application of antimicrobial pesticide products used to
treat the surfaces of HVAC&'s system components. An example of such
treatment would be use of an antimicrobial as part of air duct
cleaning.
HVAC&R is a unique use site which must be specifically identified
on the label of the antimicrobial product. The application of an
antimicrobial product to an HVAC&R system represents a use pattern
substantially different from other hard surface disinfection or
sanitizer treatments. Application to HVAC&R systems may require that
larger volumes of the antimicrobial be applied to both internal and
external system components than would typically be used as a
disinfection/sanitizer application to a hard surface such as a desktop.
Thus, there is a greater potential for the applicator to be exposed to
large amounts of pesticide. In addition, many of the components of
HVAC&R systems are typically inaccessible and could create unique
exposure scenarios for applicators. Post-application exposure to
building occupants is also a concern. When the treated system resumes
operation, the potential exists for the pesticide to be readily spread
throughout the building.
For these reasons, the Agency is proposing to modify the
requirement for 90-day subchronic studies to address HVAC&R uses.
Specifically, the Agency is proposing to replace the 90-day oral
toxicity test with two 90-day toxicity tests, one by the dermal route,
and one by the inhalation route. These are the primary routes of
exposure from HVAC&R uses, and such route-specific studies are intended
to provide the Agency with the information needed to characterize the
hazard for the risk assessment for HVAC&R uses of antimicrobial
pesticides.
I. Chronic Studies
Currently in part 161 a chronic toxicity study in two species is
required for all food-uses and conditionally required for all other use
patterns. Today the Agency is proposing to continue this existing
requirement by requiring a chronic study in the rodent for high human
exposures and conditionally requiring the study for low human
exposures.
In its final rule for conventional pesticide chemicals, the Agency
eliminated the requirement for an oral chronic study in a second, non-
rodent species, usually the dog. Similarly, EPA is proposing to
eliminate the 1-year dog study as a data requirement for antimicrobial
pesticides. EPA's reasoning is fully explained in the final rule (Unit
X) for conventional pesticides (Refs. 36, 37, and 38). For
antimicrobials EPA would adopt the same criteria (as set out in the
applicable test note to the table in proposed Sec. 158.2230) for the
rare circumstances when a 1-year dog study might be required.
J. Carcinogenicity Studies
Currently in part 161 two carcinogenicity studies are required for
all food-uses and conditionally required for all other use patterns.
Today the Agency is proposing to continue this existing requirement by
requiring carcinogenicity studies in two species for high human
exposures and conditionally requiring the studies for low human
exposures.
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K. Prenatal Developmental Toxicity
The Agency proposes to require two oral prenatal developmental
toxicity studies (one in rodents and one in a non-rodent species) to
support the registration of every antimicrobial pesticide product. This
not only codifies the Agency's current practices, but also harmonizes
the requirements for antimicrobials with those of conventional
pesticides.
The Agency encourages applicants for registration to consider the
use of combined study protocols in satisfying this requirement. A
prenatal developmental toxicity study segment could be added to a two-
generation reproduction study in rodents. By combining protocols, a
single study could satisfy the requirement for both prenatal
developmental and reproductive toxicity in the rodent. While it is
recognized that the cost of the reproduction study would increase
somewhat due to the additional work scope, the total cost of the
combined study would be substantially less than that incurred by
conducting the two studies separately. Moreover, a combined
reproduction/developmental protocol should not require the use of
additional animals and would increase the efficient utilization of the
animals being studied. The second required prenatal developmental
toxicity study in the non-rodent would then be performed separately.
The Agency may require an additional prenatal developmental study
by another route of exposure (usually dermal) if there is evidence of
developmental toxicity in any of the available studies and the other
route of exposure is, in the Agency's judgment, a significant route of
exposure (Refs. 3, 18, and 35). Submission of such a study is an
infrequent occurrence: only one dermal prenatal developmental toxicity
study has been submitted for an antimicrobial.
L. Reproduction
The Agency proposes to require a reproductive toxicity study to
support the registration of every antimicrobial pesticide product. This
codifies the Agency's current practices.
For many years, for nonfood-uses, the Agency did not require a
reproductive toxicity study for low human exposure antimicrobials.
However, in 1997, it was suggested that, without a reproductive
toxicity study, the Agency could be missing reproductive risks of
concern. For example, the Pest Management Regulatory Agency (PMRA) of
Canada, presented the results of a retrospective analysis during the
public comment portion of the FIFRA SAP in June 1997 (Ref. 13).
Although the SAP did not comment on this analysis, the Agency
determined that a reproductive toxicity study would ensure that it did
not miss potential reproductive risks of concern.
In making the safety finding under FFDCA, the Agency is required to
consider the special susceptibility/sensitivity of infants and children
to pesticide chemical residues. EPA cannot adequately characterize the
susceptibility of infants and children without a reproduction and
fertility effects study that assesses the occurrence of biologically
adverse effects on the male and female reproductive system, as well as
on the developing organisms from exposure prior to conception (either
parent), during prenatal development, or post-natally in the offspring
up to the time of sexual maturation. Thus, to make the safety finding
requires reproduction testing, since reproductive toxicity testing
endpoints are not adequately assessed in the other required toxicity
studies. Therefore, these other studies do not provide adequate
``triggers'' which would indicate the potential for reproductive
toxicity.
Today's proposal harmonizes the requirements for antimicrobials
with those of conventional pesticides. EPA has been requiring a
reproductive toxicity study for all antimicrobials for the last several
years.
As noted in Unit VIII.K. of this preamble, the prenatal
developmental and reproductive toxicity testing requirements may be
combined in a single study. If the applicant does not choose this
option, then separate developmental and reproductive toxicity studies
must be conducted.
M. Developmental Neurotoxicity (DNT)
In practice, EPA evaluates each pesticide using all available
toxicological information that might indicate a need for a
developmental neurotoxicity study. The DNT study has been required on a
case-by-case basis for certain conventional chemicals for food-use and
nonfood-use registrations since 1991.
Just as with conventional pesticide chemicals, the Agency is now
proposing that DNT testing be conditionally required for all
antimicrobial pesticides. This would be a new requirement for
antimicrobial pesticides. The study is triggered based upon a weight-
of-evidence evaluation of the toxicological database. The criteria
involved in this weight-of-evidence evaluation are the same as those
for conventional pesticide chemicals and are presented below:
1. The antimicrobial pesticide causes treatment-related
neurological effects in adult animal studies, such as:
Clinical signs of neurotoxicity.
Neuropathology.
Functional or behavioral effects.
2. The antimicrobial pesticide causes treatment-related
neurological effects in developing animals, following pre- or post-
natal exposure such as:
Nervous system malformations or neuropathy.
Brain weight changes in offspring.
Functional or behavioral changes in the offspring.
3. The antimicrobial pesticide elicits a causative association
between exposures and adverse neurological effects in human
epidemiological studies.
4. The antimicrobial pesticide evokes a mechanism that is
associated with adverse effects on the development of the nervous
system, such as:
SAR relationship to known neurotoxicants.
Altered neuroreceptor or neurotransmitter responses.
EPA proposes the addition of the developmental neurotoxicity study
to the toxicology testing requirements as a conditional requirement.
The two required developmental toxicity studies do not include an in-
depth assessment of the development of the nervous system and therefore
do not provide the same information as the DNT. In implementing this
conditional requirement, applicants are encouraged to apply what is
known about the chemical and its toxicity to develop a rational,
science-based approach to this testing.
N. Mutagenicity
Mutagenicity testing is required in part 161; however, just as with
conventional pesticide chemicals, the Agency is proposing to change the
specific types of tests to be performed to satisfy the mutagenicity
testing requirement (Refs. 4 and 26). A battery of mutagenicity tests
is currently required in part 161 to assess the potential of the test
chemical to adversely affect the genetic material in the cell and
subsequently serve as part of the Agency's weight-of-evidence approach
for classifying potential human carcinogens. Mutagenicity data are also
used to evaluate potential heritable effects in humans. Mutagenicity
testing would no longer be subdivided into the categories of gene
mutation, structural chromosomal aberrations, and other genotoxic
effects, with selection from a wide range of mutagenicity tests
satisfying these categories.
[[Page 59397]]
For conventional pesticides, the Agency requires in Sec. 158.500
an initial battery for mutagenicity testing that consists of a
bacterial reverse mutation assay with Salmonella typhimurium and
Escherichia coli, an assay with mammalian cells in culture, and an in
vivo cytogenetics assay. The Agency has selected the bacterial assay
because it is a primary test for detecting intrinsic mutagenicity of
many classes of biologically active chemicals. The genetics of each
test strain of Salmonella and select strains of E. coli have been well-
validated, and the assay is easy to perform, is used routinely
throughout the world, and has an extensive data base of tested
chemicals. The mammalian cells in culture assay will detect a wider
spectrum of possible genetic endpoints not assayed in the bacterial
test. The in vivo cytogenetics assay provides an important examination
of the potential effect a test compound may have on an intact mammalian
system. Data from this study provide information on in vivo metabolism,
repair capabilities, pharmacokinetic factors (e.g., biological half-
life, absorption, distribution, excretion) and target organ/tissue
effects.
EPA is proposing to modify the requirement for a bacterial reverse
mutation assay conducted with Salmonella typhimurium and Escherichia
coli. For antimicrobials, it is not always practical to test
antimicrobials for mutagenicity in bacterial test systems such as the
bacterial reverse mutation assay. Most antimicrobial pesticides are
toxic to bacteria, and therefore can only be tested at very low doses
in bacterial assays. This means that, for antimicrobials, negative
results in studies done in bacterial test systems do not necessarily
demonstrate non-mutagenicity. Given this limitation of bacterial
reverse mutation assays such as the Ames test, EPA must carefully
review Ames studies conducted using antimicrobials. Cytotoxicity and
the test levels used in the study are critical factors to consider when
determining if the results of an Ames test is acceptable or not, that
is, whether the test fulfills the data requirement. However, the Agency
has previously accepted Ames tests for antimicrobials after review and
evaluation indicates the validity of the results. If the results of the
Ames tests are not valid, then the applicant would need to discuss
other mutagenicity testing with the Agency, such as a forward mutation
assay conducted using mouse lymphoma L5178Y cells. The test notes to
the proposed mutagenicity requirements have been modified accordingly.
Since there are many different mutagenicity tests available besides
those in the initial battery, other types of testing may have been
performed in the course of product research and development. In
addition to the initial battery, data from such mutagenicity tests must
be submitted to the Agency, along with a reference list of all studies
and papers known to the applicant concerning the mutagenicity of the
test chemical. Having this information at the beginning of a
mutagenicity assessment will greatly facilitate EPA's effort to provide
a more accurate assessment of the mutagenicity of the antimicrobial
pesticide in question.
O. Immunotoxicity
Just as with conventional pesticide chemicals, the Agency proposes
to require immunotoxicity testing for all antimicrobial pesticides.
This would be a new data requirement. Immunotoxicity testing is
necessary to evaluate the potential of a chemical to produce adverse
effects on the immune system. Immune system suppression has been
associated with increased incidences of infections and neoplasia
(abnormal and uncontrolled cell growth). In 1993, the National Research
Council reviewed the technical literature and found that some
pesticides are immunosuppressive (Ref. 19).
Because the immune system is highly complex, studies not
specifically conducted to assess immunotoxic function are inadequate to
characterize a pesticide's potential immunotoxicity, even if some
tissues subject to immunotoxic insult are examined. While data from
hematology, lymphoid organ weights, and histopathology of routine
chronic or subchronic toxicity studies may offer useful information on
potential immunotoxic effects, these endpoints alone are insufficient
to predict effects on immunotoxic function (Refs. 15 and 16).
Therefore, the Agency is proposing to require functional immunotoxicity
testing along with the data from immunotoxicity endpoints in other
studies to predict the potential risk of pesticides on the immune
system more accurately.
P. Metabolism and Pharmacokinetics
Currently in part 161 a metabolism study is required for all food-
uses and conditionally required for all other use patterns. Today the
Agency is proposing to continue this existing requirement by requiring
a metabolism and pharmacokinetics study for high human exposures and
conditionally requiring the study for low human exposures.
Q. Companion Animal Safety
Currently in part 161 a domestic animal safety study is
conditionally required. According to the test note in Sec. 161.340
this study would be required on a case-by-case basis. Today the Agency
is proposing to continue this existing requirement by conditionally
requiring the study for all antimicrobial use patterns. The test note
specifies that the study would be triggered if the product's use would
result in exposure to domestic animals.
R. Dermal Penetration
Currently in part 161 a dermal penetration study is conditionally
required for all antimicrobial use patterns. Today the Agency is
proposing to continue this existing requirement by conditionally
requiring a dermal penetration study for all antimicrobial use
patterns.
IX. Handler and Post-Application Exposure Data Requirements
A. General
Exposure data are used in the evaluation of the exposures to
persons in occupational and non-occupational settings (Sec. 158.2260
and Sec. 158.2270). For antimicrobials this includes residential,
commercial and industrial, institutional, agricultural premises, and
recreational sites. Data include dermal, inhalation, and non-dietary
oral exposures.
Most past exposure research with antimicrobial products has studied
either handler exposure (i.e., exposure of people who mix, load, or
apply antimicrobial pesticides in the course of the application process
or through other work-related tasks) or post-application exposure of
people to residues of antimicrobial pesticides after application, in
treated areas or on treated surfaces.
Handler exposure research may measure exposure to undiluted
antimicrobial products as the products are mixed for application, or it
may measure exposure to antimicrobial products diluted for use.
Antimicrobial pesticide applicators may be industrial or other workers,
professional applicators, or consumers using the product in or around
their homes.
EPA considers handler exposure data essential for fulfilling its
mandate to protect human health from pesticide risk, including
aggregate and cumulative risk, and is therefore proposing to require
handler exposure studies for all antimicrobial products, when the
toxicity and exposure criteria are
[[Page 59398]]
triggered. Codifying this requirement would assist applicants for
registration of antimicrobial pesticides to determine which studies are
required and then to design and conduct acceptable studies measuring
handler exposure.
Post-application exposure research measures exposures of people to
residues of antimicrobial pesticides after their use or application,
and thus does not involve the direct exposure that occurs during use.
Of particular concern to EPA is the potential exposure of infants and
children to post-application residues of products used in and around
homes, daycare centers, or schools.
The data requirements proposed here are based on the Agency's
current practice of requiring exposure data when certain toxicity and
exposure criteria are met. These criteria are described in proposed
Sec. 158.2260 and Sec. 158.2270. Today's proposal seeks to harmonize
the exposure requirements for antimicrobials with those of conventional
pesticides. The applicator (handler) exposure data requirements are the
same as those codified for conventional pesticides. The post-
application data requirements are the same as conventionals, with the
exception of one study (Dislodgeable Foliar Residue and Turf
Transferable Residues) that is not needed for antimicrobials.
The proposed requirement of such data for antimicrobial products
when the toxicity and exposure criteria are triggered would allow the
Agency to conduct more thorough exposure assessments for residential as
well as occupational sites, and to cover all use and exposure scenarios
for such sites. EPA presented the need for additional handler exposure
data to the SAP in January 2007 (Ref. 39) and to the Human Studies
Review Board (HSRB) in April 2007 (Ref. 40). Both groups agreed that
additional data are warranted.
Research undertaken to address the proposed handler and post-
application data requirements may involve intentional exposure of human
subjects as those terms are defined in EPA's rules at 40 CFR 26.1102,
and if they do, protocols and supporting documentation as specified in
that rule must be submitted for review by EPA and the HSRB before any
subjects are enrolled in the research. If research involving
intentional exposure of human subjects is initiated without EPA's prior
review, the resulting data will not be accepted in support of
registration. Parties who are unsure whether proposed research involves
intentional exposure are encouraged to consult with EPA before
proceeding with the research.
B. Use of Surrogate Data
To support registration of an antimicrobial pesticide product,
according to the proposed tables in Sec. 158.2260 and Sec. 158.2270,
applicants would generate needed exposure data with a typical end-use
product. However, the Agency recognizes the need to minimize the
economic burden of generating data to meet human exposure data
requirements while obtaining sufficient data and information for
exposure and risk assessments. Whenever appropriate, surrogate data may
be used for the assessment of antimicrobial pesticides. The Agency is
currently working with several industry Task Forces that are generating
exposure monitoring data that may be able to be used as surrogate data
sources. The Antimicrobial Exposure Assessment Task Force (AEATF-II) is
developing handler exposure data for antimicrobial applications (such
as mopping, wiping, aerosol sprays, painting, etc.). Task Force members
can consider using this surrogate data, if determined by the Agency to
be suitable, to assess antimicrobial handler risk instead of generating
their own data. If surrogate data are inadequate for the Agency to
adequately predict likely exposures and the resultant risks, then
applicants would need to submit chemical-specific and/or product-
specific data.
C. Handler Exposure
The Agency proposes to require data addressing handler exposure for
antimicrobials when the toxicity and exposure criteria are triggered.
As discussed in Unit IX.A., this not only codifies the Agency's current
practices, but also harmonizes the requirements for antimicrobials with
those of conventional pesticides. EPA now proposes to codify these
requirements in proposed Sec. 158.2260 and set out explicitly in Sec.
158.2260(b) the triggers describing the circumstances under which such
data must be submitted.
For handler exposure, the proposed data requirements are as
follows:
1. Dermal exposure studies. EPA proposes to require data for both
outdoor and indoor dermal exposures to estimate the dermal exposure to
persons directly handling pesticides. The number of exposure studies
that may be required depends on the variety of use sites, their
similarities, and whether the uses are indoor or outdoor. In the
absence of surrogate data, generally, the selection of the appropriate
testing site(s) is based on the exposure sites with the highest
potential for exposure. Generally, this is determined based on the
label uses and use rates. Consultation with the Agency is recommended
for determining the appropriate use site(s) for testing. Studies of
dermal exposure are often designed to concurrently measure inhalation
exposure.
2. Inhalation exposure studies. Just as with the dermal exposure
studies, EPA proposes to require data for both outdoor and indoor
inhalation exposure studies. In the absence of surrogate data,
generally, the selection of the appropriate testing site(s) is based on
the exposure sites with the highest potential for exposure. For
inhalation exposure studies, the use sites with the potential for the
highest exposure are almost always indoors. Based on its experience,
the Agency believes potential exposure is highest indoors because the
pesticide is confined in a closed area and therefore is less likely to
be rapidly diffused or dispersed. This means that if the application
rates are the same for an indoor scenario and an outdoor scenario, then
the Agency may require only the indoor inhalation study, as that would
have the highest potential exposure. Consultation with the Agency is
recommended for determining the appropriate use site(s) for testing.
Studies of inhalation exposure are often designed to concurrently
measure dermal exposure.
3. Biological monitoring. Biological monitoring is the only type of
applicator exposure study proposed as a conditional requirement. Data
from biological monitoring studies provide the Agency with estimates of
the internal dose or amount of a pesticide in the body. EPA proposes to
allow the submission of biological monitoring data in addition to, or
in lieu of, dermal or inhalation exposure data, provided the human
pharmacokinetics of the pesticide residue is sufficiently understood to
permit the back calculation to determine the total internal dose, and
providing further that there are adequate analytical methods available.
Biological monitoring offers the advantage of assessing the internal
dose, as opposed to the exposure or amount of chemical coming in
contact with the surface of the skin or available for inhalation in the
lungs as measured using passive dosimetry techniques. Because
biological monitoring is necessarily specific to the material tested,
generally it cannot be conducted using a surrogate chemical.
4. Data reporting and calculations. EPA proposes to require
applicants to submit data reporting and calculation information
whenever applicator exposure data are submitted. These data are needed
by Agency scientists for an
[[Page 59399]]
appropriate level of review and evaluation, and offer a submission
format that the Agency has found useful. This information is important
because it allows EPA to assess the quality and validity of the
exposure study and thus the accuracy of the estimates and resultant
exposure calculations derived from that study. The types of information
that would be included under this data requirement include:
The chemical formulas used in the calculations.
The data used in the calculations, including the raw data
manipulation/correction used in order to calculate limits of detection/
limits of quantification.
The statistical analyses required.
The quality control data for lab/field recovery and
storage stability.
The actual calculations.
Included within the data reporting and calculations requirement
would be information on the ethical conduct of the research. EPA
regulations at 40 CFR 26.1303 require that the ethical conduct of all
research involving human subjects be fully documented at the time of
submission of the data resulting from the research. This requirement
will apply to all exposure studies involving human subjects submitted
to EPA under the pesticide laws, without regard to whether the research
involves intentional exposure. Data from exposure studies not
accompanied by the required documentation of ethical conduct will not
be accepted for review.
5. Product use information. EPA is proposing to require product use
information for both occupational and residential use patterns. Product
use information assists EPA to more accurately assess pesticide
exposure to applicators by describing how the pesticide is actually
used and applied. EPA requires this information because differences in
use can translate to significant differences in exposure, and thus in
risk. For applicator exposure, use information may include, but is not
limited to, who applies the antimicrobial pesticide, the use sites,
site locations, use directions, application rates and frequencies,
application equipment and methods, protective equipment used,
protective clothing worn, and other information that will determine
exposure to antimicrobial pesticide handlers.
The Agency acknowledges that the guideline for applicator product
use information has not yet been finalized. However, the guideline for
applicator product use information should be substantially similar to
the one for post-application. The guideline for post-application
product use information was presented to the FIFRA Science Advisory
Panel (SAP) in March 1998. (The draft guideline is available at http://www.epa.gov/scipoly/sap/meetings/1998/march/contents.htm.) The Agency
will finalize both guidelines before publishing a final rule
establishing antimicrobial data requirements.
D. Post-Application Exposure
The current data requirements for post-application exposure in
Sec. 161.390 are focused on reentry to treated areas by agricultural
workers. Since the promulgation of these requirements in 1984, the
Agency has become increasingly concerned about post-application risks
to persons in occupational settings other than conventional food, feed,
and fiber crop agriculture. The Agency is now proposing to require
post-application exposure data for other settings where people may be
exposed, regardless of whether they are on-the-job or bystanders. Under
current practice, post-application exposure data are generally required
for occupational and residential settings on a case-by-case basis when
specific toxicity and exposure criteria have been met. Moreover, FFDCA
mandates that EPA perform additional scientific analyses which before
1996 had not been a routine part of the Agency's risk assessment
process, including the assessment of aggregate exposures from multiple
pathways including dietary and non-dietary routes of exposure.
The Agency proposes to require data addressing post-application
exposure for antimicrobials when the toxicity and exposure criteria are
triggered. Two new exposure data requirements (soil residue dissipation
and non-dietary ingestion exposure) are today proposed for
antimicrobials. As discussed in Unit IX.A., this not only codifies the
Agency's current practices, but also harmonizes the requirements for
antimicrobials with those of conventional pesticides. EPA now proposes
to codify these requirements in proposed Sec. 158.2270 and set out
explicitly in Sec. 158.2270(b) the triggers describing the
circumstances under which such data must be submitted.
For post-application exposure, the proposed data requirements are
as follows:
1. Soil residue dissipation. These data are needed to characterize
exposures to residues of antimicrobials, and most particularly wood
preservatives, that occur through contact with outdoor soils. This
information is critical for assessing risks to children who play around
and are in contact with treated wood structures such as decks, play
sets, and gazebos, and the surrounding soils. This would be a new data
requirement for antimicrobials. Protocols must be approved by the
Agency prior to the initiation of the study. Details for developing
protocols are available from the Agency.
2. Indoor surface residue dissipation. The Agency proposes to
require the indoor surface residue dissipation study (sometimes known
as a surface wipe sampling study). This study supplies information on
residue dissipation from treated areas and articles such as carpets,
hardwood floors, and counter tops, after antimicrobial pesticides have
been used. It is also used to determine residue dissipation from decks
and other structures manufactured from treated wood.
These data would quantify residue loads and characterize the
dissipation rate (i.e., how fast pesticide residues disperse over time
following application) of antimicrobial pesticides on indoor surfaces.
The Agency could then assess the magnitude and duration of human
exposure to antimicrobials present as surface residues. Without such
data, the Agency has no precise means of calculating human exposures to
such substances from contacting surfaces over time. This requirement
would not apply to uses that are not surface treatments, e.g., aquatic
areas, swimming pools, antifoulant coatings and paints.
The draft guideline for indoor surface residue dissipation is
available at http://www.epa.gov/scipoly/sap/meetings/1998/march/contents.htm. This draft guideline was externally peer-reviewed before
presentation to the SAP in 1998. An examination of the FIFRA SAP
website since 1998 to the present will show many presentations to the
SAP on assessing occupational and residential exposures. Science has
evolved in this area.
EPA notes that it has reviewed and accepted many studies, on a
case-by-case basis, that were not conducted in accordance with current
guidelines, but which serve its needs and provide suitable information
for risk assessment purposes. The guidelines themselves do not impose
mandatory requirements. Instead, they present recognized standards for
conducting acceptable tests, guidance on evaluating and reporting data,
definition of terms, and suggested study protocols. The draft
guideline, therefore, serves as a starting point for pre-protocol
submission meetings where the Agency's scientists can provide guidance
to registrants or task forces on aspects of study design.
[[Page 59400]]
The Agency's scientists are always willing to work with individual
registrants to develop study designs to fulfill data requirements. The
Agency will finalize this guideline before publishing a final rule
establishing antimicrobial data requirements.
For wood preservatives, EPA has worked with the Consumer Product
Safety Commission (CPSC) to develop methodologies for conducting
surface wipe sampling studies on wood. Protocols for wood preservative
treated surface wipe sampling studies must be approved by the Agency
prior to the initiation of the study. Details for developing protocols
are available from the Agency.
3. Dermal exposure. EPA proposes to require dermal exposure data
for both outdoor and indoor dermal exposures to estimate the dermal
exposure to persons exposed after the pesticide application has been
completed. The discussion in Unit IX.C. of this preamble for handler
dermal studies is also applicable to post-application exposures.
4. Inhalation exposure. EPA proposes to require inhalation exposure
data for both outdoor and indoor inhalation exposures to estimate the
inhalation exposure to persons exposed after the pesticide application
has been completed. The discussion in Unit IX.C. of this preamble for
handler inhalation studies is also applicable to post-application
exposures.
5. Biological monitoring. A conditional requirement for biological
monitoring data was discussed in Unit IX.C. That discussion is also
applicable to the proposed conditional requirement for biological
monitoring for post-application exposure which codifies the Agency's
current practices.
6. Product use information. EPA proposes to require product use
information for all antimicrobials. Such information has been routinely
submitted to EPA by applicants and is now being codified as a separate
and distinct requirement. For post-application exposure, required
product use information includes information on reapplication rates and
frequencies, post-application entry restrictions, re-entry intervals,
rinsing and other residue removal practices, and other use data
relevant to exposure after application. The draft guideline for post-
application product use information is available at http://www.epa.gov/scipoly/sap/meetings/1998/march/contents.htm. The Agency will finalize
this guideline before promulgating a final rule establishing
antimicrobial data requirements.
7. Description of human activity. For post-application exposure the
Agency is proposing to require a description of human activities.
Information on those persons who may enter treated areas after the
application is complete has been routinely submitted to EPA by
applicants and is now being codified as a separate and distinct
requirement
These data will allow for a more accurate evaluation of the
exposure potential associated with use of an antimicrobial pesticide.
The description of human activity data would define the activity
patterns that affect exposures (e.g., defining the exposed populations
in commercial/institutional and residential settings, the application
sites, site-specific information on exposure time per activity, type of
protective clothing worn, and any other relevant use activity data).
The description of human activity information would be used with the
use information (both application and post-application), to help the
Agency determine whether the exposure potential for humans is likely to
be significant, and if additional data will be needed.
8. Data reporting and calculations. EPA proposes to require
applicants to submit data reporting and calculation information
whenever post-application exposure data are submitted. Such information
has been routinely submitted to EPA by applicants as part of any
submission of exposure data and is now being codified as a separate and
distinct requirement. The discussion in Unit IX.C. of this preamble for
handler data reporting and calculations is also applicable to post-
application exposures. Note in particular the discussion of the
requirement at 40 CFR 26.1303 for full documentation of the ethical
conduct of all submitted research involving human subjects, whether or
not they were intentionally exposed.
9. Non-dietary ingestion exposure. The Agency proposes to require a
non-dietary ingestion exposure study for residential types of exposures
only. This study is not required for occupational exposures since the
primary concern for adult workers is exposure via the dermal and
inhalation routes. This would be a new data requirement that evaluates
the potential oral exposures to humans, particularly children, from
antimicrobial pesticide residues from sources other than food.
Note that EPA regulations at 40 CFR 26.1203 prohibits, without
exception, conduct of any research intended for submission to EPA under
the pesticide laws which involves intentional exposure of children
under 18. Thus, any study of potential exposure of children, oral or by
any other pathway, to antimicrobial pesticide residues must only be an
observational study, involving no intentional exposure of children.
Incidental oral exposure via hand-to-mouth, object-to-mouth and
direct mouthing/ingestion is an important exposure pathway for infants
and toddlers. The results from these studies will be used to assess the
risks associated with the incidental ingestion of antimicrobial
pesticides by children following antimicrobial pesticide applications
in residential or public settings, or exposure to treated surfaces
(e.g., carpets, toys, wood structures). This study would be required
for uses in and around the home, daycare centers and schools.
The Agency is primarily concerned with non-dietary exposures
immediately following application of the antimicrobial pesticide;
therefore, dissipation studies alone would not provide the information
needed to assess risks from non-dietary ingestion. Information such as
frequency/duration of hand-to-mouth activities and surface area mouthed
are often needed as input values for the calculations that are
performed to assess non-dietary ingestion exposure. When appropriate,
EPA's Exposure Factors Handbooks (see http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=20563) can be used as the source of this
frequency/duration information. However, the data in these Handbooks
cannot replace chemical-specific information from studies of treated
articles/surfaces that quantifies the amount of pesticide residue on
such surfaces.
Non-dietary ingestion may also occur through hand-to-mouth or
object-to-mouth transfer of antimicrobial pesticide residues during
activities performed by children (e.g., crawling) that put them in
close proximity with treated surfaces. Non-dietary ingestion exposure
would be expected in residential or public (e.g., schools, daycare)
settings following exposures to:
Soils in contact with, or adjacent to, preservative-
treated wood structures such as play structures.
Outdoor surfaces such as decks.
Indoor surfaces such as antimicrobial pesticide-treated
paint chips, or antimicrobial-sprayed floors or walls.
Antimicrobial-treated textiles, polymers, or other items
(e.g., clothing, bedding, carpets, or toys).
Non-dietary ingestion studies would, for example, monitor the
amounts of pesticide residues in the rinsate from hand washing, and
thus allow the Agency to develop science-based models or formulas to
estimate
[[Page 59401]]
inadvertent exposure. The draft guideline for non-dietary ingestion is
available at http://www.epa.gov/scipoly/sap/meetings/1998/march/contents.htm. This draft guideline was externally peer-reviewed before
presentation to the SAP in 1998. An examination of the FIFRA SAP
website since 1998 to the present will show many presentations to the
SAP on assessing occupational and residential exposures. Science has
evolved in this area.
EPA notes that it has reviewed and accepted many studies, on a
case-by-case basis, that were not conducted in accordance with current
guidelines, but which serve its needs and provide suitable information
for risk assessment purposes. The guidelines themselves do not impose
mandatory requirements. Instead, they present recognized standards for
conducting acceptable tests, guidance on evaluating and reporting data,
definition of terms, and suggested study protocols. The draft
guideline, therefore, serves as a starting point for pre-protocol
submission meetings where the Agency's scientists can provide guidance
to registrants or task forces on aspects of study design. The Agency's
scientists are always willing to work with individual registrants to
develop study designs to fulfill data requirements. The Agency will
finalize this guideline before publishing a final rule establishing
antimicrobial data requirements.
X. Residue Chemistry Data Requirements
A. General
EPA proposes to adapt the basic residue chemistry data requirements
(Sec. 158.2290) as listed in subpart O of current part 158 to support
applications for antimicrobial products. However, EPA also proposes to
modify the applicability of those requirements to reflect the differing
risks and levels of exposure of antimicrobials. Residue chemistry data
are used by the Agency to estimate dietary exposure to pesticide
residues from food. If there are no direct or indirect food uses for
the antimicrobial, then no residue chemistry data are required.
The proposed changes will allow EPA to better estimate human
dietary exposure to antimicrobial residues in or on food or feed, to
more accurately assess tolerances and tolerance exemptions, and to
provide additional tools for the enforcement of pesticide residue
tolerances to ensure that food entering the commercial market meets the
``reasonable certainty of no harm'' standard under FFDCA.
The residue chemistry database is designed to determine the
composition of the pesticide residue and how much of that residue is
present in food or animal feed. Residue chemistry studies include those
which define:
The nature of the residue, i.e., metabolism studies.
The magnitude of the residue, i.e., those studies which
measure how much of the residue of concern is present in food, feed,
and water.
Food-use pesticides require both types of studies. Both plant and
livestock metabolism studies are needed to determine the breakdown of
the pesticide chemical in a living system, that is, whether the
chemical stays intact or is converted into metabolites. Occasionally,
the metabolites are toxic and are included in the analyses as a residue
of concern. Magnitude of the residue (MOR) studies are performed to
determine the level of residues of concern in food. Data collection
residue analytical methods are reviewed by EPA as part of the
validation of the metabolism and MOR studies which are used to
establish tolerances.
In addition to dietary risk assessments, residue chemistry data are
used to establish pesticide tolerances, the maximum level of pesticide
residue that may remain on food. Because these are legal limits
enforced by FDA, enforcement methods for detecting the presence and
amount of the residue are needed, and are used by FDA, USDA, and the
States for food inspection purposes.
There are distinct differences between the residue chemistry
requirements of conventional pesticides that are applied to crops in a
field setting and those of antimicrobials that are more likely to be
applied in a confined setting such as a food processing plant. Those
differences are reflected in the data requirements. For example, no
migration studies are required for terrestrial food and feed uses in
part 158, subpart O, and no rotational crop studies are required for
any antimicrobial uses. Certain test notes in part 158, subpart O and
in subpart W are also different. As expected, the differences result
from the different use patterns.
Units X.B. and C. of this preamble discuss the two main categories
of food-uses for the purpose of antimicrobial residue chemistry data
requirements, direct and indirect. Units X.D. through Q. of this
preamble explain changes to specific residue chemistry data
requirements appropriate to antimicrobials. For the purpose of
determining antimicrobial residue chemistry data requirements, most
antimicrobial pesticides will be classified as either direct or
indirect food uses, which are generally delineated in Units X.B. and C.
of this preamble. For the purposes of defining the residue chemistry
data requirements for antimicrobials, the table in proposed Sec.
158.2290 further delineates direct and indirect uses into four
categories: direct and indirect food uses, agricultural premises, and
aquatic uses. Applicants should consult with the Agency on the
appropriate category(ies) for their product.
B. Direct Food Uses
If the antimicrobial is applied directly to food or water, it is a
direct food use. Such uses would include, but are not limited to:
Livestock.
Livestock feed.
Drinking water for humans, livestock and/or poultry.
Egg washes.
Fruit and vegetable rinses.
Aquatic areas that have the potential to contaminate
potable water.
Post-harvest applications that occur in the field, at a
treatment facility (such as a packing shed), during transport, and
while in storage, until the processing of the raw agricultural
commodity begins.
No currently registered antimicrobial products are applied to
agricultural field crops. Should an application for such an
antimicrobial product be submitted to EPA, then the Agency would likely
require the same data as specified in part 158, subpart O for other
field-use pesticides applied to crops, as the test notes more
accurately reflect the conditionalities of a terrestrial use pattern.
C. Indirect Food Uses
For the purpose of determining residue chemistry data requirements,
an antimicrobial use is considered an indirect food use when the
antimicrobial pesticide is applied to a surface or incorporated into a
material that will subsequently contact food, that is, the pesticide is
not applied directly to the food. Residues of the pesticide or its
degradates can be transferred to the food when it comes into contact
with these treated surfaces and articles.
Antimicrobial products labeled for treatment of hard non-porous
surfaces which may come into contact with food (e.g., food area
premises and equipment) are classified as indirect food contact uses.
Sanitizers and disinfectants which remain on the surface of food-
handling or processing equipment are indirect food uses. Sanitizers
incorporated into articles (e.g., plastic products such as coffee cups
or cutting boards) intended
[[Page 59402]]
for food contact are also indirect food uses.
Hard surfaces are considered to be food surfaces when food is
prepared for consumption, either commercially or residentially on such
surfaces. Examples of hard surfaces are eating utensils, dinnerware,
pots and pans, cutting boards, food preparation surfaces, countertops,
refrigerator shelves, refrigerator bins, ice trays, dining table tops,
and cabinet shelves. Wood treated with an antimicrobial pesticide
product could be used to construct or maintain a bee hive, a cattle
trough or feeding station. These and other indirect contacts with food
or feed are assessed to evaluate the need for a tolerance or tolerance
exemption.
For the purpose of conducting a risk assessment for a sanitizer (an
antimicrobial not rinsed from food-contact surfaces), the Agency uses
the directions on the antimicrobial product label in combination with
modeled data to determine the amount of the sanitizer remaining. Under
this approach, EPA will initially assume that all of the sanitizer
residues remain on the surface and thus have the potential to enter the
food. This is a worst-case or screening-level assumption. EPA will then
use this modeled estimate in combination with toxicity data to
determine if there is a risk of concern and/or whether to establish a
tolerance or tolerance exemption. If there are risk concerns and if
scientifically appropriate, EPA may refine the estimate of residues
remaining on the surface using more realistic model assumptions. If no
risks of concern are identified using these refined assumptions, then
most likely EPA would not require higher-tiered, measured surface
residue data. Of course, as an alternative to the Agency's use of these
screening-level or refined, modeled estimates, the applicant may
provide data that measures the actual amount of sanitizer remaining on
the treated surface or transferring to food.
For disinfectants (antimicrobials with potable water rinses) EPA
proposes to generally follow the risk assessment approach outlined for
sanitizer solutions. EPA would disregard the potable water rinsing and
assume that worst-case residues (estimated using the sanitizer model)
are available for entering food items. Alternatively, the applicant can
provide data measuring the actual amount of disinfectant remaining on
the surface or transferring to food after rinsing the treated surface.
If the antimicrobial is to be incorporated into products with food
contact uses and bears a claim of surface sanitizing activity, the
Agency will generally, in the absence of data, evaluate the need for a
tolerance or tolerance exemption by assuming complete transference of
the chemical into food over the lifetime of the treated product.
Alternatively, the applicant may submit migration studies to
demonstrate the rate or amount of transference of the antimicrobial
into food items.
D. Chemical Identity
Currently in part 161, information on chemical identity is required
for all use patterns. Today the Agency is proposing to continue this
existing requirement by requiring information on chemical identity for
all antimicrobial use patterns.
E. Directions for Use
Currently in part 161, directions for use are required for all use
patterns. Today the Agency is proposing to continue this existing
requirement by requiring this information for all antimicrobial use
patterns.
F. Proposed Tolerance
Currently in part 161, a proposed tolerance is required for all
food-use patterns. Today the Agency is proposing to continue this
existing requirement by requiring a proposed tolerance for all
antimicrobial food-use patterns.
G. Reasonable Grounds in Support of Petition
Currently in part 161, reasonable grounds in support of petition is
required for all food-use patterns. Today the Agency is proposing to
continue this existing requirement by requiring this information for
all antimicrobial food-use patterns.
H. Submittal of Analytical Reference Standards
Currently in part 161, submittal of analytical reference standards
is required for all food-use patterns. Today the Agency is proposing to
continue this existing requirement by requiring submittal of these
standards for all antimicrobial food-use patterns.
I. Nature of the Residue in Plants
The Agency proposes to continue to require a nature of the residue
study in plants for aquatic uses and direct food contact uses. The
Agency proposes to continue to conditionally require this study to
support agricultural premise uses.
J. Nature of the Residue in Livestock
The Agency proposes to continue to require a nature of the residue
in livestock study to support agricultural premise uses. The Agency is
also proposing to continue to conditionally require a nature of the
residue in livestock study to support direct food contact uses and
aquatic areas. As with the data requirements for conventional pesticide
chemicals EPA is proposing to change the chemical substance with which
the test is performed. This would codify existing practices.
For antimicrobials used to treat animal drinking water, or to treat
wood in contact with animals or animal feed, or in aquatic areas, the
Agency proposes to change the test substance for the nature of the
residue in livestock study from ``pure active ingredient, radiolabeled
(PAIRA) and plant metabolites'' to ``PAIRA or radiolabeled plant
metabolite.'' The test substance ``metabolites'' will be changed to
``metabolite'' to clarify that dosing with more than one compound in
any one study is not acceptable. This is needed because in studies
involving simultaneous dosing with both the active ingredient and plant
metabolites, it is impossible to determine the amount of metabolite due
to active metabolism from that introduced through intentional dosing.
Simultaneous dosing with the active ingredient and any metabolites may
not produce useful results, because the active ingredient and
metabolites may have different metabolic pathways that cannot be
differentiated. In most cases dosing with only the parent compound is
necessary. However, in cases where plant and animal metabolites are
found to differ, separate studies in which livestock are dosed
separately with each unique plant metabolite may also be required.
The Agency proposes to specify in the test note that the livestock
metabolism study would be required when an antimicrobial is applied
directly to livestock, to livestock premises, to livestock drinking
water, to livestock feed, or to crops used for livestock feed. This
would also include antimicrobial uses to treat wood in contact with
animals or animal feed, or in aquatic areas given the potential use for
crop and livestock production. Such applications may result in both
oral and dermal exposure of animals to the pesticide and, depending on
the results, may necessitate magnitude of the residue studies to
quantify the residues in meat, milk, poultry, and eggs.
K. Residue Analytical Methods
EPA proposes to require development and submission of analytical
methods whenever a numerical tolerance is established. Residue
analytical methods have two primary purposes:
To collect residue data for establishing tolerance levels
and
[[Page 59403]]
conducting dietary exposure assessments.
To enforce the tolerances established by EPA in 40 CFR
part 180.
Residue analytical methods are currently required in part 161, and
EPA proposes to continue this requirement. These methods are required
only if a numerical tolerance is established and since numerical
tolerances are rarely established for antimicrobials, submission of
this data should be a rare occurrence.
In part 158, subpart W, EPA is proposing to create separate entries
in the proposed table in Sec. 158.2290 for these two types of residue
analytical methods to clearly indicate the need for both types of
methods, or a method that can be used for both data collection and
enforcement purposes. EPA believes that the separation of the combined
requirement into separate and distinct requirements will provide
clarity to applicants.
The enforcement method has the following characteristics:
Analyzes for the residues of regulatory concern, i.e.,
those named in the established tolerance.
Is reasonably rapid (typically one day or less).
Uses readily available equipment and reagents.
Must be clearly and completely described in a stepwise
manner such that laboratory personnel competent using similar
procedures can successfully perform the procedure on the first trial.
Is subject to an independent laboratory validation.
Has a mechanism to confirm the results.
The data collection method has the following characteristics:
Analyzes for all residues of toxicological concern.
No limitation on duration of procedure.
May use specially-developed and very expensive equipment.
Validation is subject only to internal laboratory
controls.
If the applicant can develop one method and the Agency finds that
this one method satisfies the criteria for both the enforcement and the
data collection method, then only one method needs to be submitted.
Otherwise, two methods must be submitted. For the proposed table in
Sec. 158.2290 the ``Rs'' and ``CRs'' specified in the residue
analytical method data requirements reflect the Agency's best
professional estimate of the likelihood of a numerical tolerance being
established for an antimicrobial pesticide chemical and thus resulting
in the requirement to submit the data.
As with the data requirements for conventional pesticide chemicals,
the Agency proposes to change the chemical substance for residue
analytical methods from ``TGAI and metabolites'' to ``residue of
concern.'' This would codify existing test practices.
As with conventional pesticide chemicals (subpart O of part 158),
the Agency is proposing to require an independent laboratory validation
(ILV) of residue analytical methods to ensure the accuracy and
reproducibility of data used for tolerance enforcement purposes.
Codifying this current (since 1988) practice (Ref. 28) would promote
development of clearly written, complete descriptions of analytical
methods that can be used by Federal and State enforcement agencies.
L. Multiresidue Method Testing
The current requirement in 40 CFR part 161 for residue analytical
methods actually encompasses several submissions to the Agency. The
first is the chemical-specific method(s) discussed in Unit X.K. of this
preamble and the second is the multiresidue testing. In promulgating
its part 158 conventional pesticide data requirements, the Agency
separated this combined requirement into separate and distinct
requirements. EPA is proposing to do the same for antimicrobial
pesticides.
Today, the Agency is proposing to codify the requirement for
testing the residue of concern of the antimicrobial pesticide using the
FDA's and the USDA's multiresidue methods (MRM) as a separate data
requirement. As above, the Rs and CRs in the proposed table in Sec.
158.2290 reflect the Agency's best professional estimate of the
likelihood of a numerical tolerance being established. This testing is
required only if a numerical tolerance is established and since
numerical tolerances are rarely established for antimicrobials,
submission of this data should be a rare occurrence.
MRMs are important components of pesticide monitoring and
enforcement programs. In food monitoring programs, such as those of FDA
and USDA, it is not practical or feasible to test for each individual
pesticide in a separate test. The MRMs are used to detect the presence
of many pesticides, and then if needed, re-testing is done with the
chemical-specific tolerance enforcement method. Since the residue
analytical method requirement is intended to refer to a method that is
specific for one pesticide (sometimes called a ``single residue
method'') and the multiresidue methods currently in use are designed to
measure as many pesticides as possible, it is clearer to list these as
two separate data requirements.
M. Storage Stability
As with conventional pesticides, the Agency proposes to add a
storage stability study as an explicit requirement to validate the
results of the various magnitude of the residue studies. Such data have
been required previously as a part of the magnitude of the residue
study, but will now, as with conventional pesticides, be codified as a
separate requirement. As discussed in a test note to the proposed table
in Sec. 158.2290 storage stability data are required for any food or
feed use requiring magnitude of the residue studies unless analytical
samples are stored frozen for 30 days or less, and the active
ingredient is not know to be volatile or labile. This test note would
clarify when storage stability data are needed and also harmonizes the
requirements for antimicrobials with those of conventional pesticides.
Magnitude of the residue studies address how levels of pesticide
residues in samples of human foods and livestock feeds are determined.
These samples are often stored for extended periods of time prior to
analysis. Since tolerances are based on residues at the time of harvest
(or sample collection) and the residues may be lost by processes such
as degradation and volatilization during storage prior to analysis,
storage stability data predicting the pattern of degradation, if any,
of residues during this period are critical to understanding the
results of the field trial studies.
N. Magnitude of Residue (MOR) Studies
As with conventional pesticides, the Agency proposes to change the
test substance from EP (end-use product) to TEP (typical end-use
product) for the following types of MOR studies: Crop field trials,
processed food or feed, potable water, fish, irrigated crops, and food
handling studies.
Residue data are needed for only one TEP of each formulation type
used on a given commodity or site. When newer or other types of
formulations are proposed for use, either additional residue data can
be submitted to show that the use of these new or different
formulations result in residues comparable to those arising from the
original formulation for which residue chemistry data already exist, or
side-by-side bridging studies can be conducted for the different types
of formulations. If the new formulation results in residues higher than
those from use of the original formulation, then the same number of
trials would generally be
[[Page 59404]]
required for the new formulation as was required for the original
formulation. This would codify a longstanding practice at EPA for
various MOR studies. The Rs and CRs reflect the likelihood of the need
for MOR studies in the Agency's best professional judgment. Test notes
to the table in the proposed Sec. 158.2290 describe the specific
circumstances in which MOR studies may be required for an
antimicrobial.
O. Magnitude of Residue in Meat, Milk, Poultry, and Eggs
Similar to the livestock metabolism study, the Agency proposes to
change the test substance for the meat/milk/poultry/egg (M/M/P/E) MOR
studies. Due to the difficulties in interpreting results of studies in
which a mixture is fed, the Agency is currently discouraging the
feeding of mixtures and is instead requesting the feeding of isolated
compounds in livestock studies. Hence, to codify current practice, the
test substance will be changed to read a single plant metabolite
instead of metabolites in the plural. Provided that plant and animal
metabolites are the same, the parent compound must be the test
substance in livestock feeding studies. If any plant metabolite exists
that is not also an animal metabolite, a separate feeding study may be
required involving dosing with that unique plant metabolite. The Agency
will inform the applicant when this additional testing is required. It
is expected that this study will be rarely requested.
The Agency proposes to continue the conditional requirement for M/
M/P/E MOR studies for agricultural premises, indirect food uses, direct
food uses and aquatic uses. There are three types of M/M/P/E MOR
studies: livestock feeding studies, direct livestock treatments, and
agricultural premise treatments. The Agency proposes to clarify that
livestock feeding studies generally are not required when (1) residues
are not found in/on feed items or (2) livestock metabolism studies
indicate minimal transfer of the pesticide residue to tissues, milk or
eggs. For those pesticides which leave non-detectable or low residues
in feed items and for which the livestock metabolism study shows little
transfer of radioactivity to tissues, the Agency may be able to
conclude that data on the level of residues in livestock and their
byproducts are not necessary. Livestock premise treatment studies are
required for those antimicrobials used to clean or otherwise treat
livestock premises such as feedlots. These are expected to be the most
common studies applicable to antimicrobials.
P. Anticipated Residues
The term ``anticipated residue'' (AR) refers to exposure data that
would permit significant refinement of dietary exposure estimates.
Refinement means that the Agency would estimate very realistic dietary
exposure estimates after first using the screening-level estimates that
allow EPA to perform a very quick, but conservative dietary risk
assessment.
As previously discussed, no currently registered antimicrobial
products are applied to agricultural field crops. Generally, for
antimicrobial direct food-uses, when performing the initial, screening-
level dietary risk assessment, EPA uses the antimicrobial tolerances as
the input values for dietary modeling. If there are risk concerns and
if scientifically appropriate, EPA may refine (that is to be more
realistic) the input values by using data showing the pesticide
residues in food closer to the point of consumption. Market basket
surveys are an example of one source of residue data that could be used
to generate more realistic dietary exposure estimates for direct food-
uses. Anticipated residue data would be required when estimates of risk
using residues at the tolerance level result in a risk of concern, and
a more realistic estimate is needed.
However, antimicrobials also include indirect food uses such as
sanitizers and disinfectants which remain on the surface of food-
handling or processing equipment. For these indirect food-uses,
generally when performing the initial, screening-level dietary risk
assessment, EPA uses several high-end (over-estimated) assumptions as
the input values for dietary modeling. In such an assessment, the same
assumptions are used for every dietary assessment. Such an assessment
can be performed quickly, and if there are no risk concerns, then the
dietary assessment is considered to be complete. However, if there are
risk concerns and as scientifically appropriate, EPA would begin a
process of using the available information and data to refine, that is
to be more realistic, in estimating input values.
Since the screening-level risk assessment did not consider the
particular use pattern of the antimicrobial chemical, as a first
refinement, EPA would modify the assumptions to account for the
particular use pattern of the chemical. Refinements to the assumptions
can also be made if measured data such as a migration study were
available.
AR data would be required when estimates of risk have been refined
using information and any measured data initially available to EPA, and
these refined risks result in a risk of concern. Taking samples from
treated hard surfaces is an example of one source of residue data that
could be used to generate more realistic dietary exposure estimates for
an indirect food-use.
If there is no food-use, then AR data would not be submitted to
EPA. AR data would be a conditional requirement that is triggered only
when estimates of risk conducted using residues at the tolerance level
may result in a risk of concern. This means that AR data would be
required only for a food-use, and only if a numerical tolerance is
established, and then only if the risk assessment conducted at
tolerance level results in a risk of concern. This would be an
infrequent occurrence for antimicrobials. Establishing this data
requirement for antimicrobials not only codifies the Agency's current
practices, but also harmonizes the requirements for antimicrobials with
those of conventional pesticides.
Q. Food Migration Studies
This study is unique to antimicrobials and this proposal codifies
current practices. EPA is proposing to conditionally require a
migration study for indirect food uses when modeled estimates of the
amount of antimicrobial residues transferred to the food or feed may
result in a risk of concern. This study would not be required for any
other uses.
A migration study is performed to determine the amount of a
chemical substance that can enter a food commodity through contact with
a treated surface. There are two basic types of migration studies. The
first type includes sanitizing and disinfecting solutions that are
applied to equipment in a food-processing facility. The second type
includes matrices such as wood, plastic, paper, cloth, or rubber which
may be impregnated with antimicrobial pesticides. The migration of the
antimicrobial into the food occurs when the food commodity comes into
contact with the treated surface or the impregnated matrix.
As previously discussed, the Agency believes that it is possible to
model a worst-case estimate of the amount of the antimicrobial chemical
that migrates into the food commodity. If the worst-case estimates do
not result in a risk of concern, then the applicant would not need to
submit a migration study. As an alternative to these worst-case
estimates, the applicant may provide data for the
[[Page 59405]]
amount of sanitizer/disinfectant remaining on the surface.
There is no Agency guideline for conducting a migration study. EPA
routinely accepts studies performed according to FDA's food migration
protocol/guidance. Applicants are encouraged to use existing FDA
methodologies. Information that could be of value to applicants
developing protocols is on the FDA website (Refs. 7, 9, 10, and 11).
Protocols must be approved by the Agency prior to the initiation of the
study. However, if a migration study has been reviewed and accepted by
FDA, then this fact should be included in the submission to EPA, along
with the migration study.
XI. Environmental Risk Assessment
A. General
Environmental fate studies evaluate the mobility, distribution and
dissipation of a pesticide in various compartments of the environment,
such as water, soil, air, and sediment. These studies are designed to
identify which dissipation processes are likely to occur when the
pesticide is released into the environment and characterize the
significant degradates likely to result from these processes. Data from
these studies are used as inputs in exposure models, and, in
conjunction with ecological effects studies, are used to assess whether
a pesticide has the potential to cause adverse effects to wildlife,
fish, plants, and humans. Environmental fate studies are discussed in
Unit XII. of this preamble.
Ecological effects data are used by the Agency to determine the
toxicological hazards of pesticides to various nontarget organisms,
such as birds, mammals, fish, bees, terrestrial and aquatic
invertebrates, and plants. These tests include short-term acute,
subacute, reproduction, simulated field, and full field studies
arranged in a tiered system that progresses from the basic laboratory
tests to the applied field tests. Ecological effects testing for
nontarget organisms are discussed in Unit XIII, and nontarget plants in
Unit XIV of this preamble.
These data provide a foundation for an environmental risk
assessment. The results of the environmental fate assessment are
evaluated in conjunction with the results of the ecological effects
data to determine the potential of the pesticide to cause harmful
effects to nontarget organisms and plants.
The Agency has divided the antimicrobial pesticides into two groups
for determining environmental fate and ecotoxicity data requirements:
the low environmental exposure grouping and high environmental exposure
grouping as discussed in Unit XI.B.
B. Determination of the Two Groupings: Low and High Environmental
Exposure
1. Factors considered in determining the groupings. As previously
discussed, EPA is proposing to establish its 12 antimicrobial use
patterns in Sec. 158.2201. EPA examined these use patterns and
identified those that occur outdoors, discharge effluent directly to
the outdoors, or result in materials treated with antimicrobials (i.e.,
wood preservatives and antifoulants) being placed in the environment.
Given this direct link to the environment, and correspondingly higher
exposure potential, there is a greater potential for concern. In fact,
EPA has been requiring more data for such use patterns than for other
antimicrobial use patterns.
2. The high environmental exposure grouping. The Agency believes
that the potential for environmental exposure is high for three of the
use patterns and part of a fourth use pattern. For the purposes of
requiring data, the following use patterns represent the high
environmental exposure grouping for environmental fate (Sec. 158.2280)
and ecotoxicity (Sec. 158.2240 and Sec. 158.2250) data requirements:
Once-through industrial processes and water systems (part
of the industrial processes and water systems use pattern).
Antifoulant paints and coatings.
Wood preservatives.
Aquatic areas.
The data that have been typically required for the use patterns now
included in the high environmental exposure grouping are used to
calculate estimated environmental concentrations (EECs) of the
pesticide in different environmental media. These EECs are needed to
conduct quantitative environmental and ecological risk assessments.
These data would also have applicability to drinking water exposure
assessments that are used in human health risk assessments.
3. The low environmental exposure grouping. The low environmental
exposure grouping is defined as those use patterns that are not
included in the high environmental exposure grouping. For the purposes
of requiring data, the following use patterns represent the low
environmental exposure grouping for environmental fate (Sec. 158.2280)
and ecotoxicity (Sec. 158.2240 and Sec. 158.2250) data requirements:
Agricultural premises and equipment.
Food-handling and storage establishments, premises and
equipment.
Commercial, institutional and industrial premises and
equipment.
Residential and public access premises.
Medical premises and equipment.
Human drinking water systems.
Materials preservatives.
Swimming pools.
Recirculating industrial processes and water systems (part
of the industrial processes and water systems use pattern).
C. Data Requirements for Wood Preservatives
As discussed previously in this proposal, wood preservatives are
considered to be an antimicrobial use pattern with high expectation of
environmental exposure. Wood that has been treated with a wood
preservative product is placed directly into the outdoor environment,
thus leading to the potential for significant release of the wood
preservative into the environment. The data required to register a wood
preservative product depend on the use site of the treated wood, which
can be land-only, aquatic-only or both. For instance, a wood
preservative product which would be used in or near water will usually
have more data requirements concerning the effects of the pesticide on
aquatic organisms than a product that is not used in or near water.
Therefore, if a product specifies that wood that has been treated
with that product cannot be used in areas with the potential for that
wood coming into contact with water, then EPA believes that the
potential for exposure is decreased. Accordingly, it is current EPA
practice to require fewer environmental fate and ecological effects
studies for such products. In practice it is difficult to assure that
wood treated with a wood preservative that is for land-use only will
not come in contact with water. Treated wood intended for a use with
little potential aquatic exposure could be inadvertently diverted to
other uses, such as marine docks or pilings, which would have
considerable aquatic exposure. The Agency does not know if or how often
this kind of diversion occurs. However, the Agency notes that in the
United States, wood preservatives are categorized using the American
Wood Preservers' Association Use Category system. These categories
describe the exposure conditions which treated wood products can be
subjected to when in service. The categories, although general, provide
some measure of control over how treated wood products are used.
[[Page 59406]]
A concern that has been raised to EPA is the difference in how
different countries regulate wood preservative products. This could
present a challenge for joint reviews of wood preservatives since
different data requirements and differing programmatic objectives could
result in different regulatory decisions.
Today's proposed data requirements are based on EPA's current
practice of determining the data required for a wood preservative
product dependent on the usage (land-only versus land and aquatic). The
Agency requests comments on the regulation of wood preservative
products, and based on the comments received could continue with the
split usage or determine to no longer have such a split usage.
XII. Environmental Fate Data Requirements
A. Environmental Fate Data Requirements for Antimicrobials
The Agency proposes to adapt the basic environmental fate data
types (Sec. 158.2280) as listed in subpart N of current part 158 to
support applications for antimicrobial products. EPA also proposes to
modify the applicability of those requirements to antimicrobials to
reflect differing risks and levels of exposure. Moreover, new types of
data are needed to evaluate the risks associated with use patterns more
typically associated with antimicrobials, such as discharge through
sewer systems and wastewater treatment plants to the environment. As
discussed in this Unit, such studies could include: Activated sludge
sorption isotherm, ready biodegradability, and modified activated
sludge, respiration inhibition test.
Fate studies characterize how a pesticide chemical dissipates once
it is released into the environment, and identify the significant
transformation products likely to result from these processes. Fate
studies include both laboratory and field studies. Such studies can
provide input parameters needed in simulation modeling. Under a tiered
testing scheme, a specified set of laboratory studies determined by the
use patterns is performed first, and then a preliminary, qualitative
environmental fate and transport assessment is developed from the
results of those lower-tiered studies and the modeling. This assessment
could determine that no additional studies are needed. Or, this
assessment could trigger higher-tiered laboratory-based studies, and/or
to design or trigger appropriate field studies. Fate studies can also
be used as triggers for determining which ecological effects data will
be needed to support registration.
Once the higher-tiered studies have been reviewed and evaluated,
then the Agency would use all these data to develop quantitative
environmental fate and drinking water exposure assessments, and to
calculate estimated environmental concentrations of the pesticide in
different media (such as water, sediment, or soils) under various
pesticide application and site scenarios. The Agency uses these
estimates of exposure in conjunction with toxicity data to assess
whether a pesticide has the potential to cause adverse effects on human
health via exposure through drinking water and the environment via
exposures through both water and soil.
B. History of Environmental Fate Data Requirements for Antimicrobials
In 1984, at the time of promulgation of the original part 158 data
requirements, there were no environmental fate data requirements for
the indoor use pattern. At that time, EPA assumed that many of the
indoor uses went down-the-drain to a wastewater treatment plant (WWTP),
at which point dilution and degradation, or removal by WWTP processes
would mitigate environmental concerns. Thus, currently, in part 161,
there are no environmental fate data requirements for the indoor use
pattern.
In 1997, the Agency presented a draft of the antimicrobial data
requirements to the FIFRA Science Advisory Panel (SAP) (Ref. 29). As
part of its presentation EPA explained its intent to divide
antimicrobial uses into two groupings based on the potential for
environmental exposure (high environmental exposure and low
environmental exposure). In 1997, the Agency defined the low
environmental exposure grouping as the following eight use scenarios:
Agricultural premises and equipment; food-handling/storage
establishments premises and equipment; commercial, institutional and
industrial premises and equipment; residential and public access
premises; medical premises and equipment; human drinking water systems;
materials preservatives; and swimming pools. For these eight use
scenarios for environmental fate data the Agency intended to require a
very reduced data set (hydrolysis data).
In its report, the SAP expressed its concerns about ``the lack of
chemical fate data,'' indicated that hydrolysis would be an important
pathway of concern for only a subset of antimicrobial chemicals, and
stated that both biodegradation data, and microbial data should also be
required. According to the SAP, this was ``to ensure the safety of
environmental discharge but also for protection of publicly owned
treatment works (POTWs) and other treatment systems which often rely on
microbial treatment processes.'' In response to the SAP's concerns, the
Agency reexamined the need for environmental fate data other than
hydrolysis. As a result of this 1997 reexamination, the Agency
determined to conditionally require data on photodegradation in water
for low environmental exposures. At that time, the Agency determined
not to require biodegradation or microbial data.
More recently, as part of its development of this proposed rule,
EPA re-evaluated the 1997 SAP recommendations concerning the data
requirements for environmental fate, and nontarget plant and organisms.
The reason for this re-evaluation was, in part, due to certain comments
that were received in response to the 2005 proposed rule for
conventional pesticide chemicals (70 FR 12276, March 11, 2005).
Additionally, the Agency was also becoming increasingly aware of
detections of antimicrobial chemicals in various environmental
compartments.
The Agency received comments from four California water treatment
authorities and from environmental agencies from two cities in
California. The comments centered on their strong recommendations that
FIFRA data requirements should be equivalent to the data required to
develop water quality criteria (WQC) under the Clean Water Act (CWA)
and should consider water quality issues related to urban pesticide
use. California water-treatment authorities questioned the adequacy of
the Agency's assessment of risks with regard to water quality
considerations including: Use of aquatic toxicity data, surface water
quality studies, and urban uses of pesticides, particularly when these
uses result in pesticide residues in receiving waters from storm sewers
or sewage treatment plants.
EPA believes that even though these comments were received in
response to the conventional pesticide chemicals proposed rule, the
submitted information on receiving waters for wastewater treatment
plants is particularly applicable to antimicrobials, many of which are
used indoors. This means that the antimicrobial goes down-the-drain and
eventually reaches a wastewater treatment plant. Therefore, in its
response to comments document for the final rule for conventional
pesticide chemicals, EPA agreed that pesticide discharge into municipal
sewage systems is an important issue
[[Page 59407]]
particularly for those antimicrobial pesticides which are typically
rinsed down the drain. EPA stated it would consider the issue of down-
the-drain chemicals in the proposed rule for antimicrobials.
As a first step toward re-evaluating its processes and procedures
for conducting a risk assessment for an antimicrobial chemical that
goes down-the-drain, the Pesticide Program discussed these issues with
EPA's Office of Water (OW). The Agency is becoming increasingly aware
of detections of antimicrobial pesticide chemicals in various
environmental compartments, including surface water. An example of a
chemical with such detections is triclosan (Refs. 12, 17, 22, and 23).
The detection of such chemicals in surface water indicates that the
antimicrobial (or its degradate) is moving from the area of
application, down-the-drain to a WWTP, and then into the environment
via the treated effluent. Certain chemicals can pose a risk even at low
levels. Based on the Agency's concerns about the potential effects of
antimicrobials on the biological treatment processes used in WWTPs,
concerns about potential bioconcentration of antimicrobials after
release, and possible effects on nontarget species, the Agency now
believes that new environmental fate data requirements are needed for
down-the-drain antimicrobial uses.
Therefore, EPA is proposing to require data to address
environmental fate (degradation), biodegradation data, and microbial
data, for the low environmental exposure grouping (as defined in Unit
XI.B. and once-through industrial processes and water systems. These
data reflect the Agency's concern about the potential movement of
antimicrobials and their degradates from the indoor environment to the
outdoor environment. Additionally, these lower-tiered data will allow
EPA to conduct screening-level environmental fate assessments which can
then indicate the need for higher-tiered fate and ecotoxicity studies
and higher-tiered environmental assessments.
EPA specifically requests comments on the Agency's rationale for
requiring data to perform a screening assessment on down-the-drain
antimicrobial uses, the potential for performing higher-tiered studies
based on the results of the screening assessment, and the cost and
burden of performing the studies.
EPA also notes that three use patterns, wood preservatives,
antifoulants, and aquatic uses are not considered down-the-drain use
patterns. As previously discussed, these uses either occur outdoors and
thus discharge directly to the environment, or result in materials
treated with antimicrobials being placed in the environment. Since
these use patterns are unlikely to go down-the-drain, a screening-level
environmental fate assessment is not needed.
C. Today's Proposal for Low Environmental Exposure Antimicrobials
The Agency believes that environmental exposures from the use
patterns discussed in Unit XI.B.3. of this preamble are likely to be
small, because (1) the sites where these uses occur are not rapidly or
directly connected to aquatic environments, (2) some of the
applications occur on a very infrequent basis and other applications
involve very small amounts of the antimicrobial, and (3) in many cases
wastewaters containing these antimicrobials are processed in WWTPs. The
indirect movement of antimicrobials from the use sites into the outdoor
environment occurs mostly through water. In many cases, leachates,
rinsates, and flushes are released down-the-drain, and eventually reach
a WWTP. WWTPs degrade chemicals in their influent, although the degree
of degradation varies widely depending on the chemical, the treatment
process and other factors (e.g., ambient temperature). After treatment,
the effluent (the treated water and any chemicals remaining in that
water) is released into the aquatic environment, or to the terrestrial
environment via land application of sewage sludge.
Given the expectation of low exposures to the environment, EPA
proposes to use a tiered system of data requirements to determine the
type of environmental fate assessment needed for the low environmental
exposure grouping. A screening-level assessment would be used to
determine the potential of the antimicrobial chemical to directly harm
the microbial treatment processes present in wastewater treatment
systems, the environmental compartment(s) that the antimicrobial is
likely to partition to, and the amount of antimicrobial that could be
present in the effluent that the treatment plant releases to the
environment. The presence of antimicrobials in an effluent release
means that an ecological assessment could be required to evaluate risks
to endangered species. It is also possible that estimation of
concentrations to use in a drinking water assessment could be required.
The lower-tiered environmental fate studies being proposed for the
screening-level assessment for the low environmental exposure grouping
are discussed in detail in Units XII.E. - K. of this preamble. The
higher-tiered studies that would be triggered are based on a weight-of-
evidence evaluation of the results of the lower-tiered studies are
discussed in Units XII.L. - Q. EPA's proposal to conditionally require
these data for the low environmental exposure grouping would for these
studies expand the number of use patterns for which the test is
conditionally required.
It may be possible to model some of the needed parameters. The
applicant is encouraged to review the approach discussed in Unit
XVIII.A. of this preamble on the use of Structure-Activity-Relationship
(SAR) assessments to ascertain if such techniques could provide useful
information in preparing their submission to EPA.
EPA is proposing to conduct the screening-level of its fate
assessment for these low environmental exposure antimicrobials with
non-direct, delayed environmental connections in a three-pronged
approach. The three prongs are designed to (1) estimate the number of
days per year of exceedance of the antimicrobial surface water
concentration of concern to aquatic organisms in a surface water body
downstream of a treatment plant, (2) determine any negative effect of
the antimicrobials in the influent on the activated sludge biomass in
biological wastewater treatment systems, and (3) determine the
potential for the antimicrobial to accumulate in sediment or in
organisms downstream from the WWTP release, or for there to be negative
impacts on nontarget organisms in the receiving water body.
For the first prong, modeling would be used to estimate a
screening-level exposure concentration of the antimicrobial in a
surface water body that receives effluent from a WWTP. EPA anticipates
using the Down-the-Drain model with the Probabilistic Dilution Model
(PDM) option in the Exposure and Fate Assessment Screening Tool (E-
FAST) (Version 2.0) available from the Agency's website (see http://www.epa.gov/oppt/exposure/pubs/efast.htm). This model option uses
readily available data as inputs to estimate conservative (i.e., high-
end) exposure concentrations. E-FAST has been independently peer-
reviewed by EPA's Science Advisory Board. Comments from that peer
review have been incorporated into Version 2.0 of E-FAST.
The PDM option of E-FAST can predict downstream chemical
concentrations from an industrial discharge and from disposal of
consumer products into household wastewater. The module uses a simple
[[Page 59408]]
mass balance approach that uses probability distributions as inputs.
The concentration of the chemical in the receiving surface water body
is also calculated as a probability distribution of the ratio of WWTP
effluent flow and stream flow immediately downstream of the WWTP. The
Down-the-Drain Model can be run with or without the PDM option.
The Down-the-Drain Model requires as an input value the production
volume of the chemical. If this information cannot be supplied by the
applicant, then the Agency would need to estimate the volume. The
production volume would be used as if the entire volume of the chemical
were expected to go down the drain. However, the Agency would be able
to modify the production volume to account for the percentage of the
chemical that is expected to actually go down the drain. As an example,
almost all of a toilet bowl cleaner can be reasonably expected to go
down the drain, but a hard surface cleaner could also vaporize into the
air, dry on the surface, or be disposed of on paper towels into the
trash. Therefore it may be reasonable to adjust the production volume
used as an input to the Down-the-Drain model. The model estimates human
exposure from ingestion of drinking water and fish, and concentrations
of chemicals in surface waters downstream of WWTPs. The PDM option
estimates the number of days of exceedance of a concentration of
concern for aquatic organisms. Concentrations of concern are based on
measurements of acute and/or chronic effects to aquatic organisms.
For the second prong of the assessment, EPA intends to require five
environmental fate studies to determine the potential of the
antimicrobial to harm the microbial treatment processes in wastewater
treatment systems, and to determine the potential amount of
antimicrobial present in the effluent that the treatment plant releases
to the environment. Higher-tiered studies would be triggered based on a
weight-of-evidence evaluation of the results of the following lower
tiered studies: Hydrolysis; photodegradation in water; modified
activated sludge, respiration inhibition test; activated sludge
sorption isotherm; and ready biodegradability. These tests are
discussed in Units XII.E., F., H., I., and K. of this preamble.
The data from the hydrolysis study would allow EPA to
determine if the antimicrobial hydrolyzes in water during transport to
the WWTP, and also after release to the environment. These data are
routinely used to understand the persistence of a chemical in the
environment, and when the hydrolysis breakdown products should also be
considered in the environmental fate assessment.
The data from the photodegradation in water study would
allow EPA to determine if the antimicrobial degrades in shallow water
due to exposure to sunlight. These data are used to understand the
persistence of a chemical in surface water.
The modified activated sludge, respiration inhibition test
would allow EPA to identify antimicrobials which could harm the
microorganisms found in biological wastewater treatment systems and
would also indicate suitable antimicrobial concentrations for use in
the ready biodegradability test.
The activated sludge sorption isotherm study would allow
EPA to assess the distribution of the antimicrobial between the sludge
and aqueous phases.
The ready biodegradability study would allow the Agency to
determine whether the chemical tested achieves ``pass levels'' for
ready biodegradability. These screening tests are so stringent that it
is assumed that the chemicals that meet the pass levels will rapidly
and completely biodegrade in aquatic environments under aerobic
conditions.
Modeling could also be used to predict the removal of a chemical in
a sewage treatment plant. STPWINTM is part of the EPI SUITE
modeling available via the Agency's website (see http://www.epa.gov/oppt/exposure/pubs/episuite.htm). STPWINTM can predict
values not only for the total removal but also three contributing
processes: Biodegradation, sorption to sludge, and stripping to air.
The third prong of the fate assessment would use the available
product chemistry data (for example octanol/water partition
coefficient, vapor pressure, or solubility in water) or predicted/
modeled data to determine the potential for the antimicrobial to
bioconcentrate. This is consistent with the approach used in the
Agency's PBT profiler, an assessment tool that estimates environmental
persistence (P), bioconcentration potential (B), and aquatic toxicity
(T) of a chemical based on its molecular structure. (see http://www.epa.gov/oppt/pbtprofiler.)
The Agency would then use the results of all three prongs to
conduct a screening-level environmental fate assessment. It is also
possible that information from open literature could be useful to the
Agency for its assessment. By combining the modeled exposure estimates
with information on the persistence of the antimicrobial, its
distribution in the environment, and its ability to harm the
microorganisms found in a biological WWTP, the Agency could determine
if there are risk concerns. Based on the concerns, EPA would be able to
determine if a more in-depth risk assessment would be required for
certain environmental media. Higher-tiered data could be required to
support such a risk assessment. The specific data would depend on the
environmental medium in which the antimicrobial and its transformation
products reside, and on the concentrations in the environment.
If the antimicrobial is completely degraded to non-toxic
degradates, then it is likely that no higher-tiered environmental fate
data would be required.
If the antimicrobial is not completely degraded by the
WWTP and is in the effluent released to surface water, then depending
on the concentrations that then occur in the environment, an assessment
similar to that of an antimicrobial with high environmental exposure
could be needed.
If the antimicrobial partitions to water, then the
possible higher-tiered environmental fate studies would include:
Leaching and adsorption/desorption, and aerobic and anaerobic aquatic
metabolism.
If the antimicrobial is likely to partition to sludge,
soil, or sediment, then possible higher-tiered environmental fate
studies would include aerobic and anaerobic soil metabolism studies,
and sediment studies. EPA has considered that antimicrobials may be
present in biosolids (sewage sludge) that are land applied. While soil
and sediment data would be required for an antimicrobial risk
assessment, these data may also be useful to EPA's Biosolids Program
conducted under 40 CFR part 503.
The Agency specifically seeks comment on this proposed approach for
performing a screening-level environment fate assessment and the
potential for triggering higher-tiered studies.
D. Case Studies
To assess whether the proposed approach provides the data needed to
assess exposure and risk of antimicrobial pesticides released to the
environment via down-the-drain use patterns, the Agency has conducted
four case studies. All of the models used for the case studies are
peer-reviewed, and publicly available. These case studies, entitled
``Four Case Studies of Antimicrobial Pesticides in the Down-the-Drain
Screening Model, Using the Proposed Approach for a Screening-Level
Environmental fate Assessment'' (Ref. 42) reflect a particular
integration
[[Page 59409]]
of the modeling results specific to the needs of antimicrobials.
Four antimicrobial pesticides that have completed scientific review
in the reregistration process were selected to represent a range of
influent volumes to WWTPs, and general environmental fate and transport
properties. Antimicrobials undergoing reregistration were chosen
because they have fairly complete supporting data bases, and are well
understood; that is, they allow a comparison of the proposed approach
with real-world information.
In selecting these four chemicals, the Agency attempted to select
at least one chemical that should trigger higher tier data requirements
and one that should trigger no higher tier data requirements. The
environmental fate and transport characteristics considered during the
case studies were environmental persistence, biodegradability,
hydrolytic stability, and sorption potential. Although not intended to
represent all possible combinations of chemical characteristics, use
scenarios, and usage volumes, the four antimicrobials selected for the
case studies were intended to include a sufficiently broad range of
possible outcomes to credibly assess the proposed approach.
Chemical A was intended to represent a chemical with a
high loading (mass) within the WWTP's influent, high toxicity to fish
and aquatic invertebrates, high hydrolytic stability, relatively high
potential to biodegrade during wastewater treatment, and low to
moderate potential to adsorb to activated sludge. This chemical was
picked as a ``worst-case'' example.
Chemical B was intended to represent a chemical with a
relatively low to moderate loading (mass) within the WWTP's influent,
high toxicity to fish and aquatic invertebrates, high hydrolytic
stability, and no available data on biodegradability during wastewater
treatment or the potential to adsorb to activated sludge.
Chemical C represents a ``best-case'' example. It is an
organic acid that has a high loading (mass) within the WWTP's influent,
potential to bioaccumulate, high water solubility, no environmental
fate data, and no ecotoxicity data. This chemical was selected as a
case study because it degrades quickly and would be expected to have
little potential for ecotoxicity.
Chemical D represents a mixture of two organic chemicals
with relatively low loading (mass) within the WWTP's influent volume,
high resistance to biodegradation during wastewater treatment, low
potential to sorb to activated sludge, and fairly low toxicity to fish
and aquatic invertebrates.
The specific identities of the antimicrobials have been ``blinded''
to focus those who may wish to comment on the proposed approach, and
not what the result ``should'' be for a particular chemical.
Many, but not all, of the values selected for input data for the
case studies were based on measured or estimated values for existing
antimicrobial pesticides. In some instances, values for input data
needed to run models to assess exposure and risk from down-the-drain
releases were not available. In those instances, hypothetical values
were used. Hypothetical values were also sometimes selected to enable
the cases to have sufficiently different key environmental fate and
transport properties to be able to more rigorously test the proposed
tiered approach for assessing exposure and risk to chemicals that are
released down-the-drain.
Table 1.--Case Studies
------------------------------------------------------------------------
Study Results
------------------------------------------------------------------------
Chemical A: A Chemical that Does Not The proposed approach
Hydrolyze and Only Partially Biodegrades indicated Chemical A has
considerable potential to
pose ecological concerns.
Aerobic and anaerobic soil
metabolism studies are
needed to refine
environmental fate and
dissipation, and higher-
tier ecotoxicity studies
are needed to determine
risk to nontarget species.
------------------------------------------------------------------------
Chemical B: A Chemical Which Is Stable to The proposed approach
Hydrolysis, But There Is No Data on the indicated that the lower
Potential to Biodegrade During Wastewater tiered environmental fate
Treatment or Adsorb to Activated Sludge studies are needed to
determine Chemical B's
dissipation rate in
wastewater treatment
plants. Several higher
tiered ecotoxicity studies
are needed to determine
risk to nontarget species.
------------------------------------------------------------------------
Chemical C: An Organic Acid that is Highly There are no data to show
Soluble in Water that Chemical C would harm
microorganisms found in
biological wastewater
treatment systems.
------------------------------------------------------------------------
Chemical D: A Mixture of Chemicals Chemical D does not appear
to pose ecological risks at
the assumed production
levels. However, the
potential for
biodegradation and any
potential impacts on waste
water treatment plant
organisms could not be
ascertained with the
available information.
Therefore, the proposed new
lower tiered environmental
fate studies are required.
------------------------------------------------------------------------
From these case studies the Agency concludes that the proposed
approach produces the results desired by the Agency. The proposed
approach effectively distinguishes between chemicals that will require
more in-depth review and therefore higher-tiered studies versus
chemicals that require only the lower tiered environmental fate and
ecotoxicity studies to determine that no or few additional higher
tiered studies are needed.
The Agency specifically seeks comment on the case studies (Ref. 42)
performed, including the assumptions used as model inputs. EPA will
consider comments specific to the case studies along with comments on
the proposed approach, as the Agency evaluates the use of the proposed
approach for down-the-drain antimicrobials in the final rule for
antimicrobial data requirements.
E. Hydrolysis Study
EPA proposes to require a hydrolysis study for all antimicrobial
pesticides. In 40 CFR part 161, hydrolysis studies are currently
required for all use patterns except indoor. (The indoor part 161 use
pattern is being considered by EPA to be similar to the low
environmental exposure grouping.) Accordingly, EPA proposes to continue
to require hydrolysis studies for all of the high environmental
exposure use patterns (once-through industrial processes and water
systems, antifoulant paints and coatings, wood preservatives, and
[[Page 59410]]
aquatic areas) and to codify the requirement for all other
antimicrobial use patterns. In practice, hydrolysis studies have been
required for all antimicrobial chemicals for over 10 years.
As previously discussed, EPA intends to require the hydrolysis
study as part of the lower tier of environmental fate data requirements
for down-the-drain chemicals. Chemicals that hydrolyze rapidly to less
toxic chemicals may need few higher tiered studies. This study will
allow EPA to determine how fast the antimicrobial breaks down in the
presence of water and what degradates are formed.
F. Photodegradation in Water
In 40 CFR part 161, the photodegradation in water study is required
for aquatic use patterns. The Agency proposes to continue its existing
requirement for a photodegradation in water study for the antimicrobial
aquatic areas use pattern. The Agency also proposes to require the
study for all other antimicrobial uses. This would expand the number of
use patterns for which this study is required.
This study will allow EPA to determine the degradation of the
pesticide in shallow water bodies as a result of exposure to sunlight.
Chemicals that degrade quickly in the environment may need few higher
tier studies. As with the data requirements for conventional pesticide
chemicals, EPA intends to clarify in a test note certain conditions
when photodegradation testing would not be required. Data on
photodegradation in water would not be required when the electronic
absorption spectra, measured at pHs 5, 7, and 9 of the chemical and its
hydrolytic products, if any, do not show absorption or tailing between
290 and 800 nanometers. If no absorption or tailing occurs in this
range, it is unlikely that photodegradation occurs (Refs. 25 and 27).
G. Photodegradation in Soil
The Agency is proposing to require the photodegradation in soil
study for wood preservatives only. Leaching of wood preservatives (both
the parent or transformation products) from preservative-treated wood
could contaminate the surrounding soils. This would be a new data
requirement which would provide data on the dissipation, nature and
persistence of wood preservative degradation products formed by soil
surface catalyzed photolysis. Using these data the Agency can assess
the extent and duration of human (e.g., children playing below decks)
and/or nontarget organism exposures to soils adjacent to preservative-
treated wood structures. Such soils may contain the parent compound
and/or transformation products, which could include those formed via
photodegradation processes.
H. Activated Sludge Sorption Isotherm
The activated sludge sorption isotherm study would be a new data
requirement. EPA is proposing to require this study only for the low
environmental exposure grouping and the once-through industrial
processes and water systems. This study is not required for wood
preservatives, antifoulants, or aquatic areas.
For antimicrobial chemicals that go down-the-drain and reach a
WWTP, as part of its screening-level environmental fate assessment, EPA
will analyze the potential impact of the antimicrobial chemical on the
microorganisms in the typical biological treatment processes of a WWTP.
The activated sludge sorption isotherm study would allow EPA to assess
the distribution of the antimicrobial between the sludge and aqueous
phases. This information is important in determining the method used in
the ready biodegradability test and the higher-tiered studies that may
be required. Antimicrobials that are predominantly in the water column
and do not sorb to sludge may not need testing that focuses on sediment
and soils, such as the aerobic and anaerobic soil metabolism studies.
Antimicrobials that predominantly sorb to the sludge, soil, and
sediment may not need testing that focuses on water, such as the
aerobic and anaerobic aquatic metabolism studies.
I. Ready Biodegradability
The ready biodegradability study would be a new data requirement.
EPA is proposing to require this study only for the low environmental
exposure grouping and the once-through industrial processes and water
systems. This study is not required for wood preservatives,
antifoulants, or aquatic areas.
For antimicrobial chemicals that go down-the-drain and reach a
WWTP, as part of its screening-level environmental fate assessment, EPA
will analyze the potential impact of the antimicrobial chemical on the
microorganisms in the biological treatment processes of a WWTP.
Biodegradation is an important environmental pathway in which the
antimicrobial is broken down into ``smaller'' chemicals by bacteria.
This study supplies information on the rate of breakdown and the
completeness of the degradation to carbon dioxide and water. A ready
biodegradability study would allow the Agency to determine whether the
chemical achieves ``pass levels'' for ready biodegradability (e.g., 70%
removal of dissolved organic carbon). These screening tests are so
stringent that it is assumed that antimicrobials that ``pass'' will
rapidly and completely biodegrade in aquatic environments under aerobic
conditions. Chemicals that degrade quickly and completely may need few
higher tiered studies.
J. Porous Pot Test
The Agency is proposing to conditionally require the porous pot
study for antimicrobials based on the results of the ready
biodegradability test. This would be a new data requirement. EPA is
proposing to require this study only for the low environmental exposure
grouping and the once-through industrial processes and water systems.
This study is not required for wood preservatives, antifoulants, or
aquatic areas.
The porous pot study simulates the processes in the aeration basin
of the activated sludge sewage treatment process. It is therefore a
more realistic test than the biodegradability test. A chemical that did
not ``pass'' the biodegradability test could degrade (partially or
completely) under different conditions. The porous pot study would
provide a measure of the extent of biodegradation or removal likely to
occur during sewage treatment. An antimicrobial that degrades quickly
and completely in a typical wastewater treatment plant may need few
higher tiered studies.
K. Modified Activated Sludge, Respiration Inhibition Test
The modified activated sludge, respiration inhibition test would be
a new data requirement. EPA is proposing to require this study only for
the low environmental exposure grouping and the once-through industrial
processes and water systems. This study is not required for wood
preservatives, antifoulants, or aquatic areas.
For antimicrobial chemicals that go down-the-drain and reach a
WWTP, as part of its screening-level environmental fate assessment, EPA
will analyze the potential impact of the antimicrobial chemical on the
microorganisms in the biological treatment processes of a WWTP. The
modified activated sludge, respiration inhibition test would allow EPA
to identify antimicrobials which could harm the microorganisms found in
WWTPs and thus impair the ability of these bacteria to carry out their
intended function. Additionally, this study would also indicate
suitable
[[Page 59411]]
concentrations for use in the ready biodegradability test.
L. Leaching and Adsorption/Desorption
In 40 CFR part 161, leaching and adsorption/desorption studies are
required for all use patterns except the indoor. Accordingly, EPA
proposes to continue to require the leaching and adsorption/desorption
studies for all of the high environmental exposure use patterns: Once-
through industrial processes and water systems, antifoulant paints and
coatings, wood preservatives, and aquatic areas.
EPA is also proposing to conditionally require these data for the
low environmental exposure grouping. This would expand the number of
use patterns for which the test is conditionally required. For the low
environmental exposure grouping, the leaching and adsorption/desorption
study is considered to be a higher-tiered study that would be triggered
based on a weight-of-evidence evaluation of the results of the
hydrolysis, photodegradation in water, activated sludge sorption
isotherm, ready biodegradability, and modified activated sludge,
respiration inhibition tests.
The leaching and adsorption/desorption study would provide
information on the mobility of the antimicrobial pesticide in soils.
The antimicrobial pesticide may or may not be transported to surface
water and/or ground water bodies used for drinking water. The presence
of an antimicrobial pesticide in drinking water sources could
contribute to exposure via drinking water.
M. Aerobic Soil Metabolism
The Agency proposes to adapt its current requirement in 40 CFR part
161 for an aerobic soil metabolism study to the specific needs of
antimicrobial chemicals. Currently, 40 CFR part 161 requires this study
for terrestrial and outdoor types of uses.
The aerobic soil metabolism study would be conditionally required
for the low environmental exposure grouping, and once-through
industrial processes and water systems. This would expand the number of
use patterns for which the test is conditionally required. The aerobic
soil metabolism study is considered to be a higher-tiered study that
would be triggered based on a weight-of-evidence evaluation of the
results of the hydrolysis, photodegradation in water, activated sludge
sorption isotherm, ready biodegradability, and modified activated
sludge, respiration inhibition tests.
For aquatic areas, data would be required only for use sites that
are intermittently dry. This would codify current practices for aquatic
areas.
For wood preservatives, the Agency proposes to require an aerobic
soil metabolism study. This would codify current practices for wood
preservatives.
The aerobic soil metabolism study would allow EPA to better
understand the antimicrobial pesticide's degradation under aerobic
(oxygen-rich) conditions in the laboratory. The results of the study
would help to determine how fast the antimicrobial degrades in the
presence of microorganisms in different natural soils, and what
metabolites are formed. Chemicals that degrade quickly in soil are
likely to have lower exposure estimates.
N. Anaerobic Soil Metabolism
Due to a printing error, the data requirement for an anaerobic soil
metabolism study was inadvertently omitted from the data tables (now in
40 CFR part 161) in 1991, and subsequent publications of the CFR. EPA
asserts that this requirement is still in existence: This data
requirement was never intentionally removed from the CFR by notice and
comment rulemaking, and is not considered a new requirement. Therefore,
EPA proposes to adapt its current requirement for an anaerobic soil
metabolism study to the specific needs of antimicrobial chemicals by
conditionally requiring the study for the low environmental exposure
grouping, and wood preservatives.
EPA is expanding the number of use patterns for which the test is
conditionally required. For the low environmental exposure grouping,
the anaerobic soil metabolism study is considered to be a higher-tiered
study that would be triggered based on a weight-of-evidence evaluation
of the results of the hydrolysis, photodegradation in water, activated
sludge sorption isotherm, ready biodegradability, and modified
activated sludge, respiration inhibition tests.
For wood preservatives, the anaerobic soil metabolism study would
be required if treated wood is used in aquatic environments or in soils
which may become flooded or waterlogged. This would codify current
practices for wood preservatives.
The anaerobic soil metabolism study would facilitate a better
understanding of the antimicrobial pesticide's degradation under
anaerobic (oxygen-poor) conditions in the laboratory. The results of
the study would help to determine how fast the antimicrobial degrades
in the presence of microorganisms in different natural soils, and what
metabolites are formed. Chemicals that degrade quickly in soil are
likely to have lower exposure estimates.
O. Aerobic and Anaerobic Aquatic Metabolism
In 40 CFR part 161 both the aerobic and anaerobic aquatic
metabolism studies are required for aquatic uses. For antimicrobial
chemicals, the Agency considers this to include the following uses:
Once-through industrial processes and water systems, antifoulant paints
and coatings, and aquatic areas. Therefore, the Agency proposes to
continue its current requirement for aerobic and anaerobic aquatic
metabolism studies for these uses. For wood preservatives these studies
have been required on a case-by-case basis; therefore, this proposal
would codify current practices.
EPA is also proposing to conditionally require these two studies
for the low environmental exposure grouping. This would expand the
number of use patterns for which the test is conditionally required..
Anaerobic aquatic metabolism studies describe and measure the
formation of pesticide residues in the water column or sediment under
low-oxygen conditions. Aerobic aquatic metabolism studies determine the
effects that exposure to aerobic, or oxygen-rich conditions in the
water column or sediment can have on a pesticide when it is dispersed
through the aquatic environment. Since the degradation or dissipation
pathways of pesticides in aquatic environments are almost always
different from those of terrestrial systems, soil metabolism studies
may not clearly define the paths of degradation found in aquatic
environments. For the low environmental exposure grouping, the aerobic
and anaerobic aquatic metabolism studies are considered to be higher-
tiered studies that would be triggered based on a weight-of-evidence
evaluation of the results of the hydrolysis, photodegradation in water,
activated sludge sorption isotherm, ready biodegradability, and
modified activated sludge, respiration inhibition tests. Chemicals that
degrade quickly in water or sediment are likely to have lower exposure
estimates.
P. Aquatic Sediment Studies
Aquatic sediment studies are required for aquatic use patterns in
40 CFR part 161. Accordingly, the Agency proposes to continue its
current requirement for aquatic sediment studies for the antimicrobial
aquatic areas use pattern. EPA is also proposing to conditionally
[[Page 59412]]
require an aquatic sediment study for all other antimicrobial use
patterns based on the antimicrobial's potential for aquatic exposure.
For the low environmental exposure grouping, the aquatic sediment
study is considered to be a higher-tiered study that would be triggered
based on a weight-of-evidence evaluation of the results of the
hydrolysis, photodegradation in water, activated sludge sorption
isotherm, ready biodegradability, and modified activated sludge,
respiration inhibition tests. This would expand the number of use
patterns for which the test is conditionally required.
For the once-through industrial processes and water systems,
antifoulant paints and coatings, and wood preservatives, data would be
required based on the potential for aquatic exposure and if the weight-
of-evidence indicates that the active ingredient or principal
transformation products are likely to have the potential for
persistence, mobility, nontarget aquatic toxicity or bioaccumulation.
This would codify current practices.
The aquatic field dissipation study is used to determine the
nontarget fate of a terrestrially applied pesticide that has a high
potential to enter aquatic environments and to substantiate laboratory
findings. The laboratory studies address one environmental fate process
at a time. The aquatic field dissipation study examines pesticide loss
or movement in water and sediment. Under field conditions degradation/
dissipation processes can proceed differently from how they occurred
under laboratory conditions. Data from this study can reduce the
potential overestimation to both exposure and risk that can result from
having only laboratory generated data. Protocols must be approved by
the Agency prior to the initiation of the study. Details for developing
protocols are available from the Agency.
Q. Monitoring of Representative U.S. Waters
The Agency is proposing to conditionally require monitoring of
representative U.S. waters for all antimicrobial use patterns. This
would include freshwater, saltwater, surfacewater, and groundwater.
This would codify current practices.
The Agency would use a weight-of-evidence approach taking into
account factors such as available monitoring data; the vulnerability of
the freshwater, estuarine, or marine water resources; and the
persistence and fate of the pesticide active ingredient (or degradate).
Protocols must be approved by the Agency prior to the initiation of the
study. Details for developing protocols are available from the Agency.
Based on past experience, the Agency believes that these monitoring
data would be required only for a very small number of antimicrobial
pesticide registrations. Monitoring for tributyltin antifoulants of the
near coastal waters of the United States including the Great Lakes was
required under the Organotin Anti-fouling Paint Control Act of 1988. In
1989, pesticide registrants were required to provide these monitoring
data under FIFRA section 3(c)(2)(B). These tributyltin antifoulants
data are the only monitoring of representative U. S. waters that has
been required for an antimicrobial to date.
R. Special Leaching Study
The Agency is proposing to require special leaching studies for
antifoulant paints and coatings, and wood preservatives. Part 161 is
not explicit in the data that are currently required because those use
patterns are not delineated sufficiently for antimicrobial pesticide
chemicals. This proposal would codify the Agency's current practices.
These studies are needed because leaching from treated materials is the
primary source of environmental exposure to antifoulants and wood
preservatives. These studies would provide basic information about the
availability of the pesticide to the environment, and would be used to
perform exposure and risk assessments.
There is no OPPTS Harmonized guideline for these studies. The
applicant may perform the study with a protocol of their choice, or may
use the American Wood Preservers' Association's (AWPA) Standard Method
of Determining the Leachability of Wood Preservatives (AWPA E11-97),
AWPA's Standard Method for Determining the Leachability of Wood
Preservatives in Soil Contact (AWPA E20-04), and the American Society
for Testing and Materials (ASTM) Standard Test Method for Organotin
Release Rates of Antifouling Coating Systems in Sea Water (ASTM D5108-
90), or their equivalents. As stated in the test notes to the table in
proposed Sec. 158.2280, prior approval by the Agency of studies
conducted according to AWPA E11-97 or ASTM D5108-90 is not required.
However, all studies that would be conducted according to other
protocols must be approved by the Agency prior to the initiation of the
study. Details for developing protocols are available from the Agency.
XIII. Nontarget Organisms Data Requirements
A. Nontarget Organisms Data Requirements for Antimicrobials
EPA proposes to adapt the basic nontarget organism data types
(Sec. 158.2240) as listed in subpart G of current part 158 to support
applications for antimicrobial products. EPA proposes to modify the
applicability of those requirements to antimicrobials to reflect
differing risks and levels of exposure. Part 161 is not explicit in the
data that are currently required because those use patterns are not
delineated sufficiently for antimicrobial pesticide chemicals. The
proposed table, in Sec. 158.2240, will provide greater transparency
and clarity.
Ecological effects testing includes short-term, acute, subacute,
chronic, and reproduction studies, which progress from laboratory tests
to applied field tests. These data allow the Agency to determine if the
standard for registration is met and whether precautionary label
statements concerning toxicity or potential adverse effects to
nontarget organisms are necessary.
The Agency is proposing to use a tiered system of ecological
effects testing to assess the potential risks of pesticide uses to
nontarget animals (aquatic and terrestrial vertebrates and
invertebrates) for antimicrobial pesticide chemicals. For the first
tier of testing EPA proposes to require for all antimicrobial
pesticides three types of acute ecological effects studies.
Avian acute oral LD50.
Acute freshwater fish LC50.
Acute freshwater invertebrates EC50.
These acute studies measure toxicity in representative species of
the nontarget species most likely to be adversely affected and allow
EPA to develop precautionary labeling. Such labeling includes
statements such as ``This product is extremely toxic to birds'' or
``This product is toxic to fish.'' These statements provide needed
information in case of unintended or co-incident exposure to
antimicrobials, such as a transportation accident. And, in fact, these
studies are currently required for an application for registration.
These first tier data would be required for all antimicrobial use
patterns and performed with the technical grade active ingredient
(TGAI). Higher-tiered data would be required when the appropriate
trigger in Sec. 158.2240 is met. For instance, results from these
first tier studies may indicate the need for acute toxicity testing in
an additional species, or higher-tiered studies to assess hazard
[[Page 59413]]
to other species or in other parts of the environment. Other factors,
such as, toxicity, persistence, and/or potential for bioaccumulation,
may indicate the need for higher-tiered ecological effects and
environmental fate data. All typical end-use product (TEP) testing is
considered to be higher tier. An applicant must carefully consider
whether studies listed in the higher tier data requirements are
required for registration of his product and should consult with the
Agency, as needed.
The Agency has divided the antimicrobial pesticides into two groups
for determining ecological effect data requirements, based on their
expected environmental exposure. The two groupings are the same
groupings used for environmental fate data requirements: Low and high
environmental exposure groupings. (see Unit XI.B of this preamble.)
B. The Low Environmental Exposure Grouping
The use patterns within this grouping are the same as those
described in Unit XI.B. of this preamble for environmental fate data
requirements. As previously discussed in this Unit, EPA proposes to
require a first tier of three ecological effects studies for all
antimicrobials. These three acute ecotoxicity studies in combination
with the screening-level environmental fate assessment proposed to be
required for assessing the impacts of antimicrobial pesticides on
WWTPs, are the initial studies for environmental modeling for risk
assessment purposes. For the low environmental exposure grouping,
higher-tiered ecotoxicity studies are conditioned on a weight-of-
evidence evaluation of the results of the tier one ecotoxicity studies
and/or the results of the screening-level environmental fate
assessment. Thus, the studies described in Unit XIII.F., G., I., J.,
K., L., and M. could be triggered.
C. The High Environmental Exposure Grouping
As with the environmental fate data requirements, the high exposure
environmental group consists of the once-through industrial processes
and water systems, antifoulant paints and coatings, aquatic areas, and
wood preservatives. These uses either occur outdoors, discharge
effluent directly to the outdoors, or result in materials treated with
antimicrobials (e.g., wood preservatives and antifoulants) being placed
in the environment, thereby leading to potentially significant
environmental exposure. For the high environmental exposure grouping,
EPA proposes to require three first tier ecological effects studies and
depending on the use pattern, other ecotoxicity studies such as avian
studies and TEP testing. The Agency may require additional ecotoxicity
studies based on the results of these studies or on other information.
D. Acute Avian Oral Toxicity
In 40 CFR part 161 acute avian studies are conditionally required
for ``indoor'' uses of antimicrobials, and are required for aquatic
uses of antimicrobials. (The indoor part 161 use pattern is being
considered by EPA to be similar to the low environmental exposure
grouping.) The Agency is proposing to require submission of acute avian
LD50 toxicity studies for all antimicrobial use patterns.
These studies are needed as part of the tier one ecotoxicity testing,
and as previously explained are used to develop precautionary labeling.
Testing in one avian species is required for the low environmental
exposure grouping. The shift from CR to R for the low environmental
exposure grouping would expand the number of use patterns for which
this study is required.
For antimicrobial chemicals, the Agency considers the aquatic use
pattern in part 161 to include the following antimicrobial use
patterns: Once-through industrial processes and water systems,
antifoulant paints and coatings, and aquatic areas. Therefore, the
Agency proposes to continue its current requirement for acute avian
oral acute toxicity studies for these uses. For wood preservatives
these studies have been required on a case-by-case basis; therefore,
this proposal would codify current practices.
As with the data requirements for conventional pesticide chemicals,
the Agency is proposing to change the testing requirement from one
species to two species for all antimicrobial use patterns except the
low environmental exposure grouping. The change to two species is
consistent with the Agency's current practices.
The species proposed in this proposal differ from those in the
requirements for conventional pesticides. Many conventional chemicals
are applied outdoors and are considered to be terrestrial uses. For
antimicrobials the Agency is proposing that the testing be conducted
with a waterfowl species and an upland game bird species. The selection
of waterfowl and upland game species is consistent with the current
submissions by registrants of antimicrobial products and reflects the
data needed for the many indoor and aquatic uses of antimicrobials.
E. Acute Aquatic Toxicity Studies
The Agency is proposing to require acute aquatic toxicity studies
(LC50 fish and EC50 invertebrate) for all
antimicrobial uses. These studies are needed as part of the tier one
ecotoxicity testing, and as previously explained are used to develop
precautionary labeling.
1. Tier 1 testing. In part 161, acute aquatic toxicity studies are
conditionally required for ``indoor'' uses of antimicrobials, and are
required for aquatic uses of antimicrobials.
For antimicrobial chemicals, the Agency considers the aquatic use
pattern in part 161 to include the following uses: Once-through
industrial processes and water systems, antifoulant paints and
coatings, and aquatic areas. Therefore, the Agency proposes to continue
its current requirement for two acute aquatic fish toxicity studies
(one warm water and one cold water species) and one invertebrate
toxicity study for these use patterns. For wood preservatives these
three studies have been required on a case-by-case basis; therefore,
this proposal would codify current practices.
For the low environmental exposure grouping, the Agency is
proposing to require the acute freshwater fish toxicity study in one
species, either a warm water or a cold water species. Testing on a
second species is required if the active ingredient or principal
transformation products are stable in the environment or if the
LC50 in the first species tested is greater than 1 part per
million (ppm) or 1 milligram/liter (mg/L). This would codify existing
practices. Additionally, the shift from CR to R for the low
environmental exposure grouping (which contains many of the ``indoor''
uses) would also codify current practices.
2. TEP testing. Typical End-Use Product (TEP) testing is proposed
for both the acute freshwater fish and invertebrate toxicity studies.
This is an existing requirement according to the test notes to the
table in Sec. 161.490.
F. Avian Dietary Toxicity
Currently in part 161 an avian dietary LC50 study is
conditionally required for the greenhouse and indoor use patterns and
required for all other use patterns. Today the Agency is proposing to
continue this existing requirement by requiring the avian dietary study
for aquatic areas and conditionally requiring the study for all other
antimicrobial use patterns.
G. Avian Reproduction
The Agency has adapted the current data requirements in part 161
for avian
[[Page 59414]]
reproduction testing to determine the avian reproduction data
requirements for antimicrobial chemicals. An avian reproduction study
is conditionally required for aquatic uses in part 161.
The Agency is proposing to require the avian reproduction study for
the antimicrobial aquatic areas use pattern. The proposed change from
conditionally required to required is consistent with the Agency's
current practices.
For all other antimicrobial use patterns, the Agency is proposing
to conditionally require the avian reproduction study. For wood
preservatives this study has always been considered when EPA made its
case-by-case determinations on the data needed for risk assessment;
therefore, this proposal would codify the current practices used for
wood preservatives. Since part 161 conditionally requires this testing
for ``aquatic uses,'' the Agency's proposal continues the existing data
requirement for the once-through industrial processes and water
systems. Since the testing is also proposed to be conditionally
required for the low environmental exposure grouping, this would expand
the number of use patterns for which these studies are conditionally
required.
H. Acute Estuarine and Marine Study
Acute estuarine and marine toxicity studies are performed on three
species: An estuarine/marine mollusk, an estuarine/marine invertebrate,
and an estuarine/marine fish. These studies measure toxicity in
representative estuarine and marine species of the nontarget species
most likely to be adversely affected.
1. TGAI testing. The Agency is proposing to require these three
acute estuarine and marine studies for antifoulant paints and coatings,
and conditionally require these studies for wood preservatives. This
would codify the Agency's current practices.
Testing for all other antimicrobial use patterns would also be
conditionally required. The Agency is proposing in part 158, subpart W
to use the same conditionalities (as described in the test notes) for
requiring these studies as in part 161, i.e. the testing is required if
residues from the parent compound and/or transformation products are
likely to enter the estuarine/marine environment.
Part 161 conditionally requires this testing for ``aquatic uses.''
Therefore, the Agency's proposal continues the existing data
requirement for the once-through industrial processes and water
systems, and aquatic areas. Since the testing is also proposed to be
conditionally required for the low environmental exposure grouping,
this would expand the number of use patterns for which these studies
are conditionally required.
2. TEP testing. For the acute estuarine and marine studies, TEP
testing is proposed to be conditionally required for the low
environmental exposure grouping, once-through industrial processes and
water systems, and aquatic areas. This is an existing requirement
according to the table in Sec. 161.490.
I. Fish Early Life Stage and Aquatic Invertebrate Life-Cycle Study
The Agency proposes in Sec. 158.2240 to require both a fish early
life stage and an aquatic invertebrate life-cycle study for once-
through industrial processes and water systems, antifoulant paints and
coatings, and aquatic areas. For these use patterns this would codify
current practices.
The Agency also proposes to conditionally require both studies for
the low environmental exposure grouping. This would expand the number
of use patterns for which the test is conditionally required.
The Agency proposes to conditionally require both studies for wood
preservatives. The studies would be required if pesticide residues from
treated wood would be likely to enter freshwater or estuarine/marine
environments, as determined by the Agency.
Currently, in part 161 only one of these studies is conditionally
required. Part 161 requires the submission of either the fish early
life stage or the aquatic invertebrate life-cycle study, based on the
more sensitive of the two species, as determined by the acute
ecotoxicity studies. However, since both fish and invertebrates may be
exposed when an antimicrobial pesticide enters natural waters, the
Agency now believes both studies are needed. Neither study would
adequately substitute for the other. While data from acute invertebrate
and acute fish studies would be available, EPA does not believe that
these acute studies would predict chronic sensitivity.
For the low environmental exposure grouping the requirements are
triggered if antimicrobial pesticide residues from the parent compound
and/or transformation products are likely to enter freshwater or
estuarine/marine environments, as determined by the Agency. For wood
preservatives the requirements are triggered if antimicrobial pesticide
residues from the parent compound, transformation products, and/or
leachates from preservative-treated wood are likely to enter freshwater
or estuarine/marine environments, as determined by the Agency.
J. Fish Life Cycle
Currently, this existing data requirement is conditionally required
for all antimicrobials except ``indoor'' uses in part 161. The Agency
is now proposing to expand this conditional requirement to all
antimicrobial use patterns.
The fish life cycle study is a two generation reproductive study in
fish that can characterize a number of sensitive life stages. Just as
with conventional pesticide chemicals, it is triggered on the results
of the fish early-life stage or invertebrate life cycle test, or other
information indicating the reproductive physiology of fish may be
affected. For the low environmental exposure grouping, the screening-
level fate assessment would also inform the determination to require
this study. If the antimicrobial is not degraded by the processes in
the WWTP and is in the effluent released to surface water, then this
study may be required.
K. Aquatic Organisms, Bioavailability, Biomagnification Toxicity Tests
This data requirement is composed of three studies: The oyster
bioconcentration factor, the fish bioconcentration factor, and the
aquatic food chain transfer. All three studies are not needed for every
antimicrobial. The most commonly submitted study is the fish
bioconcentration factor.
Currently, these studies are conditionally required for all
antimicrobials except ``indoor'' uses in part 161. The Agency is now
proposing to expand this conditional requirement to all antimicrobial
use patterns. For the low environmental exposure grouping, the
screening-level fate assessment would also inform the determination to
require this study. If the antimicrobial is not degraded by the
processes in the WWTP and is in the effluent released to surface water,
then this study may be required.
For antimicrobials that have the potential to reach freshwater or
saltwater, these studies are needed to identify those antimicrobials
that could concentrate in various aquatic taxa. EPA is proposing to
clarify in the test notes the three specific circumstances under which
the study is not required. These three circumstances are the same as in
the final rule for conventional pesticide chemicals.
[[Page 59415]]
L. Simulated or Actual Field Testing for Aquatic Organisms
For all antimicrobial use patterns, the Agency is proposing to
conditionally require simulated or field studies for aquatic organisms.
These studies would be triggered when under actual use conditions
significant impairment of nontarget aquatic organisms is likely to
occur in the natural environment. This proposal would codify current
practices.
The Agency currently determines whether simulated or field studies
are required for antimicrobials on a case-by-case basis, considering
information such as:
The pesticide's intended use.
The pesticide's use rates.
The pesticide's toxicity.
The pesticide's physical and chemical properties.
The parent compound's environmental fate characteristics
and transformation products (such as metabolites and degradation
products).
Nontarget organisms likely to be exposed.
Likelihood of exposure.
As with conventional pesticides, the Agency is proposing to require
independent laboratory validation of the environmental chemistry
methods used to generate the data associated with this study.
M. Sediment Testing
The Agency is proposing to require acute invertebrate sediment
testing, both freshwater and marine, for antifoulant paints and
coatings and to conditionally require these studies for once-through
industrial processes and water systems, wood preservatives, and aquatic
areas. This would codify current practices. Additionally, EPA proposes
to expand the conditional requirement to all other antimicrobial use
patterns. This study would be triggered based on the antimicrobials
presence in the water column (for example when released from a WWTP),
the potential to sorb to sediment, and the persistence of the
antimicrobial.
The Agency is proposing to conditionally require chronic
invertebrate sediment testing, both freshwater and marine, for all
antimicrobial use patterns. This study is triggered by the same
criteria as the acute sediment study, but would be of longer duration
as determined by the persistence of the antimicrobial. This conditional
requirement would codify current practices for the high environmental
exposure grouping, and would then expand the requirement to the low
environmental exposure grouping.
Testing of aquatic organisms exposed to treated sediments allows
EPA to assess the effects of sediment-bound pesticide residues in
aquatic environments. The effects of sediment-bound pesticides (or
their degradates) on aquatic environments cannot be accurately assessed
from bioassays on compounds suspended in the water column alone. For
example, lipophilic or hydrophobic chemicals can dissipate from the
water column, but may remain in the aquatic environment adsorbed to
sediment. As discussed in the proposed rule for conventional pesticides
(70 FR 12275) sediment-bound pesticides may differ significantly from
pesticides in solution, showing different physical, chemical, and
biological properties, chemical partitioning, bioavailability,
concentrations in interstitial or pore water, exposure from sediment
ingestion and possible manifestations of food chain effects. By serving
as a potential pesticide sink, exposure to these compounds may lead to
significant environmental risk to a wide variety of fish and aquatic
invertebrates which live and feed at the bottom of a lake or stream.
Sediment toxicity testing is needed to assess the bioavailability of a
sediment-bound compound and to characterize the possible impact to
sediment-dwelling benthic organisms.
Once the Agency determines or extrapolates that the use pattern has
the likelihood for chemical exposure to an aquatic system, then the
available information on the adsorption of the chemical is reviewed. If
the Agency determines that the antimicrobial meets one or more of the
criteria for adsorption, then the available information on persistence
of the chemical is reviewed. If one or more of the criteria for
persistence are met, then a sediment study is required. Persistence
(half-life of the pesticide in sediment) drives the decision regarding
whether the acute or chronic study is conducted.
Before designing the protocol, consultation with the Agency is
needed if the applicant is uncertain as to which length of study is
appropriate. For certain antimicrobials that are highly persistent,
only the chronic study may be required. Protocols must be approved by
the Agency prior to the initiation of the study. Details for developing
protocols are available from the Agency.
N. Honeybee Protection
The current data requirements for testing pesticide toxicity to
honeybees at Sec. 161.590 require the honeybee acute contact
LD50 study when honeybees are likely to be exposed. The
Agency proposes to conditionally require the acute study for wood
preservatives and the low environmental exposure grouping. Since the
study would be required only for uses involving treatment of beehives,
empty or occupied, and since there are few such uses for
antimicrobials, this study would be infrequently required. This study
may not be required if the use pattern (as described on the label)
prohibits fumigating or spraying beehives.
Since beehives can be constructed of materials that have been
treated with antimicrobials, the Agency proposes to conditionally
require a study to determine the toxicity of treated wood and other
materials to bees. This study must be conducted in a manner similar to
that of the Honey Bee Toxicity of Residues on Foliage. This would
codify current practices. Protocols must be approved by the Agency
prior to the initiation of the study. Details for developing protocols
are available from the Agency.
XIV. Plant Protection Data Requirements
A. Plant Protection Data Requirements
EPA proposes to adapt the basic nontarget plant protection data
types as listed in 40 CFR part 158, subpart G to support applications
for antimicrobial products. EPA proposes to modify the applicability of
those requirements to antimicrobials to reflect differing risks and
levels of exposure. Part 161 is not explicit in the data that are
currently required because those use patterns are not delineated for
antimicrobial pesticide chemicals. The proposed table in Sec. 158.2250
will provide greater transparency and clarity.
Plants represent the most basic component of any functioning
ecosystem by providing oxygen and a food source for aquatic and
terrestrial animals. Therefore, it is important to determine the
toxicity of the antimicrobial to plants. The data obtained from these
studies will be used to conduct nontarget plant risk assessments. For
aquatic environments such an assessment could include an effluent from
a wastewater treatment plant being released into the environment. For
terrestrial environments such an assessment could include wood
preservatives in contact with soil, land-application of biosolids, or
antimicrobials that partition to soil and sediment.
B. Requirement for Tier II Testing for Antimicrobials
The Agency's guidelines for conducting nontarget plant protection
[[Page 59416]]
studies specify two types of tests: Single-dose studies (referred to in
the guidelines as Tier I tests) and multiple-dose studies (Tier II).
Usually, the applicant would conduct the single-dose studies first, and
then, based on the results of the single-dose studies, proceed to the
multiple-dose studies, which evaluate the effects of multiple dosage
levels on plant growth and are used to determine acute toxicity levels
in comparison with environmental concentrations. Such studies are used
to estimate the risk to nontarget plants and endangered plant species.
Many antimicrobial pesticides are used to control plant pests such
as algae in industrial processes (paper making, cooling towers,
wastewater, sewage water treatment), and residential uses (swimming
pools, ornamental ponds, moss growing on roofs). Some antifoulants,
ballast water treatments, and wood preservatives are also intended to
control plant pests. Therefore, antimicrobial pesticides used for plant
pest control are expected to be phytotoxic to nontarget plants once
released into terrestrial or aquatic environments.
Accordingly, for all antimicrobial use patterns, the Agency is
proposing only to require multiple-dose studies, which is consistent
with the testing of certain phytotoxic conventional chemicals such as
herbicides which also start at Tier II. In part 161, for most plant
studies, the Tier II study is conditionally required and the Tier I
study is required. For antimicrobials, EPA believes that the nontarget
plant studies have been interpreted in the context of, and consistent
with other phytotoxic chemicals, and this proposal would codify the
shift from the use of the Tier I study to a Tier II study.
If the applicant is in possession of single-dose studies that the
applicant believes provide sufficient information, then the applicant
is encouraged to consult early in the application process with EPA. The
Agency can evaluate the information and inform the applicant as to the
sufficiency, or the need for multiple-dose studies. If the applicant
does not have any studies, then multiple-dose studies must be
conducted.
C. The Low Environmental Exposure Grouping
The use patterns within this grouping are the same as those
described in the Unit XI.B. of this preamble for environmental fate
data requirements.
D. The High Environmental Exposure Grouping
The use patterns within this grouping are the same as those
described in the Unit XI.B. of this preamble for environmental fate
data requirements.
E. Seedling Emergence (Tier II - Dose-Response)
This terrestrial plant toxicity test is designed to evaluate
toxicity to germinating seedlings and their ability to survive after
chemical uptake from the surrounding soil. The Agency is proposing to
require this study for the high environmental exposure grouping. This
proposal would codify the shift from the use of the Tier I study to a
Tier II study and thereby would codify current practices.
The Agency is also proposing to conditionally require the Tier II
study for low environmental exposure grouping based on the results of
the algal study. This would expand the number of use patterns for which
this study is conditionally required.
F. Vegetative Vigor (Tier II - Dose-Response)
This terrestrial plant toxicity test is designed to evaluate
toxicity to young plants. The antimicrobial is applied to the foliage
to evaluate uptake of the antimicrobial from the exposed green tissue.
The Agency is proposing to require this study for wood preservatives
and aquatic areas. For wood preservatives, this would codify current
practices. For aquatic areas, this would codify the shift from the use
of the Tier I study to a Tier II study and thereby would codify current
practices.
The Agency is also proposing to conditionally require this study
for the low environmental exposure grouping, and industrial processes
and water systems (once-through). This would expand the number of use
patterns for which this study is conditionally required.
G. Aquatic Plant Growth (Lemna gibba) (Tier II - Dose-Response)
The Agency is proposing to require the Aquatic Plant Growth (Lemna
gibba) (Tier II - Dose-Response) study for the high environmental
exposure grouping. This would codify the shift from the use of the Tier
I study to a Tier II study and thereby would codify current practices.
The Agency is also proposing to conditionally require the Tier II
study for low environmental exposures based on the results of the algal
study. This would expand the number of use patterns for which this
study is conditionally required.
Lemna gibba or duckweed is an important wildfowl food source and is
used in wastewater reclamation. Therefore, it is important to
understand the impact of an antimicrobial on this food source.
H. Aquatic Plant Growth (Tier II - Dose-Response)
The Agency is proposing to require one or more of the Aquatic Plant
Growth (Tier II - Dose-Response) studies for all antimicrobial use
patterns. As with the aquatic plant study discussed in the previous
section, part 161 requires the Tier I study and conditionally requires
the Tier II study. For the high environmental exposure grouping, this
would codify the shift from the use of the Tier I study to a Tier II
study and thereby would codify current practices. Testing is required
for four species representing green algae, freshwater cyanobacteria, a
freshwater diatom and a marine diatom. These four species are used to
represent hundreds of different species.
Testing is required in only one species (green algae) for the low
environmental exposure grouping. This would expand the number of use
patterns for which this study is required.
Green algae produce oxygen, serve as a food source for aquatic
animals, and provide the basic energy needs of any aquatic ecosystem.
The results of the green algae study will allow the Agency to determine
if the other three aquatic plant growth studies are required for the
low environmental exposure grouping.
I. Terrestrial and Aquatic Field Studies
The Agency is proposing to conditionally require Terrestrial and
Aquatic Field Studies for all antimicrobial use patterns. Field studies
provide more realistic information on a pesticide's impacts than
laboratory studies which focus only on one parameter, because field
studies consider all potential impacts on plant growth. The need for
these higher tier studies would be based on the results of the lower
tier plant protection studies, adverse incident reports, intended use
pattern, and environmental fate characteristics that indicate potential
exposure.
These two studies are conditionally required in part 161 for three
use patterns. Due to the use patterns currently used in part 161, there
is not sufficient delineation for comparison to the antimicrobial use
patterns proposed today. While EPA routinely considers the need for
these studies in determining the data needed for its risk assessments,
it has required these
[[Page 59417]]
studies based on case-by-case circumstances on a very infrequent basis
for antimicrobials.
Since the testing is proposed to be conditionally required for all
antimicrobial pesticide use patterns, this would expand the number of
use patterns for which these studies are conditionally required.
Additionally, this would harmonize the requirements for antimicrobials
with those of conventional pesticides.
XV. Peer Review
A. National Research Council Recommendations
The National Academy of Sciences issued a report in 1993 entitled,
``Pesticides in the Diets of Infants and Children'' (Ref. 19). The
study, conducted by the National Research Council (NRC), was initiated
to address the question of whether the current regulatory system
adequately protected infants and children from pesticide residues in
food. The Council reviewed EPA's then-current practices and data
requirements related to dietary risk assessment as well as testing
modifications planned by the Agency. The panel of experts concluded
that, at that time, EPA approaches to data requirements and risk
assessments emphasized the evaluation of the effects of pesticides in
mature animals and, in general, there was a lack of data on pesticide
toxicity in developing organisms.
The Council's recommendations with respect to regulatory needs for
data development included the following:
Discussed the need to investigate the effects of pesticide
exposure on immunotoxic responses in infants and children.
Supported the need for acute and subchronic neurotoxicity
testing and encouraged the Agency to have these studies as part of the
required data for all food-use pesticides.
Encouraged further work in the area of developmental
neurotoxicity.
Many of the NRC recommendations were incorporated into the data
requirements that were promulgated for conventional pesticides (72 FR
60933), and for biochemical and microbial pesticides (72 FR 60988). By
deliberately building on the foundation of these promulgated rules, and
harmonizing to the extent practicable considering the differences in
use patterns, many of the NRC recommendations, such as immunotoxicity
testing, are incorporated into this proposed rule for antimicrobial
pesticides.
B. FIFRA Scientific Advisory Panel (SAP)
1. 1994 meeting. In 1994, EPA held a 2-day meeting of the SAP to
review the Agency's proposed amendments to the data requirements for
pesticide registrations contained in 40 CFR part 158, which covered
antimicrobials. The SAP was asked to comment on each data requirement
and identify, in their scientific opinion, which requirements were
necessary to fully and thoroughly evaluate the potential hazard of a
chemical compound and which were not intrinsically useful in providing
practical scientific information. The revisions presented to the Panel,
i.e., the changes to the data requirements presented in this document,
were generally endorsed. A very complete discussion of the 1994 SAP
meeting was presented in the proposed rule for conventional pesticides
(70 FR 12276).
2. June 1997 meeting: A set of scientific issues being considered
by the Agency to determine antimicrobial issues. On June 3, 1997, the
Agency presented an early version of the part 158, subpart W proposal
in an open meeting to the SAP. The Agency asked for specific comments
in five areas covered by proposed 158W data requirements: Toxicology;
residue chemistry, ecological effects and environmental fate, human
exposure, and efficacy. The SAP's full comments are found in the docket
for this action (Ref. 29) and are summarized here.
i. Toxicology. The Agency asked if its division of antimicrobial
pesticide uses into high human exposure and low human exposure groups,
with extensive data requirements for high exposure uses and tiered data
requirements for low exposure uses, was an acceptable approach. The SAP
agreed that the Agency's tiered approach was reasonable, and made
several suggestions to improve the proposal. Two of these suggestions
were ``unambiguous trigger points indicating next Tier level of
toxicity testing,'' and ``to continue dialogue with Canadian
counterparts to harmonize, clearly define trigger points, and improve
the guidelines.''
The Agency has worked to provide clear, unambiguous triggers in the
test notes to the toxicology data requirements tables. EPA is also
committed to dialogue with its Canadian counterpart. PMRA has routinely
received updates on the status of the draft antimicrobial data
requirements, and has been actively engaged throughout the development
of this proposal.
ii. Residue chemistry. The Agency asked the SAP if the scientific
approach to obtaining dietary residue information in general, but
specifically for indirect food contact sanitizers, was reasonable. The
SAP agreed that the scientific approach was reasonable, and remarked
extensively on the residue chemistry data requirements for indirect
food uses such as sanitizers. They noted that such products had
generally been of low toxicity or low persistence, and their belief
that a tolerance or tolerance exemption for such uses was unnecessary,
based on FDA's practice with such products. The SAP also suggested the
use of default surface residue values for estimating sanitizer residues
to obviate the need for measured data.
Although the SAP believes that a tolerance or tolerance exemption
is unnecessary, under FFDCA, EPA is required to establish either a
numerical tolerance, or an exemption from the requirement of a
tolerance for indirect food uses. To obviate the need for measured
data, EPA uses modeling and ``worst-case'' estimates, as appropriate.
As discussed in Unit X. of this preamble, if such estimates when paired
with the toxicity data do not indicate a concern, then it is unlikely
that measured surface residue data would be required.
iii. Human exposure. The Agency asked the SAP if the approaches
presented were reasonable and if the Agency had adequately accounted
for all antimicrobial use and exposure scenarios. Additionally, the
Agency asked if multiple exposure scenarios for one pesticide product
would be better accounted for by data for all applicable exposure
scenarios or a subset of applicable scenarios.
The SAP agreed that the Agency's 12 use categories for
antimicrobials were a reasonable approach to organizing exposure data
requirements, and were, in fact, similar to the approaches used by PMRA
and the California EPA. EPA is proposing that these use categories be
codified in Sec. 158.2201 as the antimicrobial use patterns.
The SAP also advised that initially, all applicable
exposure scenarios should be considered for a single antimicrobial
product. The Agency accepted this recommendation which is now part of
its standard exposure assessment practices.
The SAP expressed concern that post-application exposure
might be too narrowly defined, and noted some possible exposure
scenarios involving persons not in the 1997 presentation. In response,
the Agency has broadened the scope of post-application exposure to
[[Page 59418]]
include persons who may come in contact with materials after treatment.
This includes contact with impregnated materials and children's
exposure to treated wood. In response, the Agency is proposing to
require the indoor surface residue dissipation study and the non-
dietary ingestion exposure study for residential uses to address this
concern.
iv. Ecological effects and environmental fate. For the 1997
presentation to the SAP, EPA divided the antimicrobial use sites into
two groupings: high expected environmental exposure and low expected
environmental exposure. The Agency asked if a tiered data set to
support an ecological risk assessment for uses with high expected
environmental exposure was appropriate. The SAP agreed that a tiered
data set to support an ecological risk assessment would be appropriate.
EPA also asked if ecological risk assessments were necessary for
the low expected environmental exposure grouping. In its presentation
EPA stated its intention to require a very reduced data set suitable
for developing precautionary labeling for manufacturing and certain
end-use products. At that time EPA considered that ``indoor'' uses had
minimal environmental exposures or releases of pesticide residues to
the environment. The SAP commented that the reduced data set could be
justified only if data available from other programs within EPA and
elsewhere were adequate to assess ecological risk. As a result of the
SAP's concerns, the Pesticide Program discussed these issues with EPA's
Office of Solid Waste and Office of Water.
As a result of these discussions in the late 1990s, the Pesticide
Program continued to believe that
``Indoor'' residential uses of antimicrobials with the
rinses going down-the-drain had minimal environmental exposures or
releases of pesticide residues to the environment,
Industrial effluents that could possibly contain
antimicrobials would be adequately regulated via the permitting process
under the National Pollutant Discharge Elimination System Program of
the Clean Water Act and wastes possibly containing antimicrobials would
be adequately regulated under the Resource Conservation and Recovery
Act.
Therefore, in 1997, the Agency determined not to require
biodegradation or microbial data.
More recently, as part of its development of this proposed rule,
EPA re-evaluated its belief that ``indoor'' residential uses had
minimal environmental exposures. EPA is now proposing to require the
environmental fate and ecological effects data for conducting an
ecological risk assessment for down-the-drain antimicrobials. The
rationale for this decision is discussed in Unit XII.B. of this
preamble.
The SAP expressed its concerns about ``the lack of chemical fate
data,'' and also stated that biodegradation data (both aerobic and
anaerobic) should be required.
In response to the SAP, EPA reexamined the need for
environmental fate data other than hydrolysis, and as a result of this
1997 reexamination, the Agency determined to conditionally require data
on photodegradation in water for these low expected environmental
exposures. EPA is now proposing to require the photodegradation in
water study for all antimicrobial chemicals, including the low
environmental exposure grouping.
Initially, in 1997, the Agency determined to not require
biodegradation data. EPA has reconsidered this 1997 decision and today
is proposing to require an activated sludge sorption isotherm, a ready
biodegradability test, and a modified activated sludge, respiration
inhibition study for the low environmental exposure grouping.
The SAP also questioned why microbial data to protect publicly
owned treatment works (POTWs) and other treatment systems which often
rely on microbial treatment processes were not required. The Agency
investigated this possibility, but could not in the early 1990s
determine a satisfactory set of data that would then be useful in
protecting the highly variable conditions of specific POTWs. EPA is
proposing as part of its environmental fate data requirements, to
require the data that would allow EPA to assess the impacts of
antimicrobials on wastewater treatment plants.
The SAP questioned the use of precautionary labeling to protect
fish and wildlife from improper use of antimicrobials, especially
considering that some use categories would pose exposure via sewage
systems. As a result, EPA prepared sample labeling to reduce this
source of exposure: ``This product is toxic to fish and aquatic
invertebrates. Do not discharge effluent containing this product into
lakes, streams, ponds, estuaries, oceans, or public water unless this
product is specifically identified and addressed in a NPDES permit. Do
not discharge effluent containing this product to sewer systems without
previously notifying the sewage treatment plant authority.'' This type
of labeling is still in use today.
The SAP cautioned that although wildlife exposure to antimicrobials
via water was the most likely source of exposure, terrestrial exposure
is also possible. The Agency concurred, and is proposing to require for
the aquatic areas use pattern and to conditionally require for all
other use patterns, the avian dietary and avian reproductive studies
for performing such an assessment.
Finally, the SAP expressed concern that antimicrobial metabolites
may be more toxic than their parent compounds, and therefore may also
need to be tested. The Agency agrees, and has revised many of the test
notes in this proposal to clarify the need for data on metabolites when
the available information demonstrate that the metabolites are more
toxic or otherwise pose environmental risks.
3. 1998 and 1999 meetings. Data requirements, as related to the
application of the newly mandated FFDCA safety factor (required under
the FQPA amendments) were presented to the SAP in 1998 and 1999. Copies
of documents prepared for the 1998 and 1999 SAP meetings and the final
reports from each of the meetings are in the docket for this action
(Refs. 30, 31, 32, and 33) and can be found on EPA's web site at http://www.epa.gov/scipoly/sap. A summary of the issues specific to the
proposed antimicrobial data requirements follows:
i. Toxicology. In December 1998, EPA presented the SAP an issues
paper on the use of the FQPA safety factor to address the special
sensitivity of infants and children to pesticides. The discussion on
the developmental neurotoxicity study was specifically discussed in the
context of the appropriateness of using an additional safety factor. At
that time, the SAP did not reach a consensus recommendation on whether
this study should be routinely or conditionally required. The issue of
what is a complete and reliable data set was brought before the SAP
again in May 1999. The majority of the Panel supported the Agency's
approach to applying data requirements but advised the Agency to
revisit the first tier of required toxicity studies every few years to
update data requirements as needed. The Panel also agreed with the
Agency on the need to require the neurotoxicity battery of studies,
including developmental neurotoxicity testing, for high exposure
pesticides such as food-use pesticides. The SAP's recommendations are
reflected in today's proposed antimicrobial data requirements for
developmental neurotoxicity and immunotoxicity. This also harmonizes
the data requirements
[[Page 59419]]
for conventional pesticides and for antimicrobials.
ii. Post-application exposure. Working in collaboration with Health
Canada and the Organization for Economic Cooperation and Development
(OECD), EPA drafted guidelines for post-application exposures studies.
They were internally peer-reviewed and shared with the California
Department of Pesticide Regulation, representatives from academia, and
the American Crop Protection Association. The Agency presented its
post-application exposure guidelines and standard operating procedures
to the SAP in 1998 and again in 1999. In 1999, the SAP commended the
Agency for making significant strides toward developing scenario-based
residential and non-occupational exposure assessments that are
sufficiently conservative as to not underestimate exposures. The data
requirements proposed for post-application exposure to antimicrobials
are drawn from this body of work.
4. 2000 meeting. In its response to an April 2000 presentation on
certain scientific issues concerning probabilistic ecological risk
assessment, the SAP was asked for recommendations on sediment toxicity
testing. The SAP stated that the extent to which a compound partitions
from the aqueous phase to the sediment is a key consideration in
determining the need for testing benthic organisms. There was a
consensus among SAP members that compounds with high Kocs
(organic carbon-water partition coefficient) or Kows
(octanol-water partition coefficient) required sediment testing for
benthic fish or invertebrates. A copy of the final report is in the
docket for this action (Ref. 34) and can be found on EPA's web site at
http://www.epa.gov/scipoly/sap. Based on this meeting, the guidelines
for sediment testing were developed. For antimicrobials, acute and
chronic sediment testing are proposed to be required or conditionally
required.
XVI. International Activities
EPA actively works through international and regional organizations
and directly with other countries to develop common or compatible
international approaches to pesticide registration, including data
requirements. Joint reviews and work sharing are two of the approaches
used by EPA to increase the harmonization of pesticide regulatory
programs. EPA believes that making pesticide regulatory programs more
consistent internationally will:
Maintain high standards for the protection of human health
and the environment.
Increase the efficiency of the registration process by
lessening the resource burden on governments and the regulatory
community.
Provide more equal access to pest management tools.
Strengthen the regulatory process.
Facilitate the registration of alternative pest control
tools.
Minimize trade problems.
Harmonization activities are increasing and evolving as agencies
and applicants build upon their experiences.
A. Joint Data Reviews and Evaluations
EPA is working closely with other countries toward greater
uniformity in testing, reviewing and evaluating all pesticides. The
benefits of international regulatory cooperation on antimicrobials are
potentially great: Improved science through greater information
exchange, and reduced regulatory and resource burdens on national
governments and regulated parties through harmonized pesticide
regulatory review. Over the last several years, substantial progress
has been made toward international cooperation on pesticide regulatory
review. Member countries of the Organization for Economic Cooperation
and Development (OECD), including the United States, have agreed upon
harmonized guidance for the formats of industry data submissions
(dossiers) and country data review reports (monographs). Countries now
frequently exchange pesticide reviews or consult with one another on
key technical aspects of a review.
Under the North American Free Trade Act (NAFTA), EPA has worked
cooperatively with Canada and/or Mexico, dividing up detailed
evaluation work on a number of pesticides. The Agency has also entered
into similar information exchange and comparative review arrangements
with other countries. There have been multiple bilateral joint reviews
and/or work sharing with member countries of the European Union.
Trilateral joint reviews and workshares have been performed with Canada
and Australia. A global joint review is being conducted among six
countries (the United States, Australia, New Zealand, Canada, Ireland,
and the United Kingdom.) The peer reviewers will be four other EU
countries. The primary objective of all of these arrangements has been
to use resources in the most efficient way possible.
Concerning antimicrobials, since 2000, Health Canada's Pest
Management Regulatory Agency (PMRA), the USEPA and California's EPA
have been cooperating on a joint review for the re-evaluation/
reregistration of the following three heavy-duty wood preservatives:
Pentachlorophenol, creosote, and chromated copper arsenate. The review
of submitted data, writing of the risk assessments, and peer review
activities are being shared. Exposure data used in the preliminary risk
assessment were collected from both U.S. and Canadian wood-treatment
facilities. Both PMRA and EPA are contributing to the public comment
process. The cooperative activities continue as both EPA and PMRA work
toward issuance of their decision documents in September 2008.
B. Harmonization of Data Requirements
As the international regulatory community works toward greater
harmonization on pesticide review, attention has also focused on the
data requirements, how the requirements compare from one country to
another, and what can or should be done to establish common
requirements. To the extent that data requirements for pesticide
registration are similar, sharing reviews and comparing evaluations is
easier and more meaningful. Requirements that differ considerably from
one country to another can mean that applicants who are looking to
register a pesticide in more than one country may have to conduct many
different studies to satisfy all the various national requirements.
Therefore, from the perspective of the applicant, establishing similar
requirements also can reduce the resources that must be spent to
conduct testing.
OECD Member countries have had discussions about harmonizing
pesticide data requirements within the OECD community. The pesticide
industry took on the complex task of looking at data requirement
differences among Member countries to identify areas that might benefit
from harmonization. Preliminary findings presented to the OECD Working
Group on Pesticides Meeting in June 2001, reported, consistent with the
positions of scientific reviewers in OECD Member countries, that
toxicology data requirements are quite similar across countries. This
does not mean that there is no room for additional harmonization work
on toxicology data requirements, but rather that there are other
testing areas where there is much less consistency on data requirements
across countries.
Ecotoxicological and environmental fate studies present a
particular
[[Page 59420]]
challenge for harmonization. Data requirements in these areas can
differ considerably from one country to another depending upon how
countries' tiered approaches to data requirements are applied. National
data requirements must be tied to national use patterns and
environmental and ecological conditions. A reliable environmental
hazard assessment, for example, must be based on studies that
accurately reflect the climate, soil types and agricultural practices
of the country doing the assessment. Because ecological and
environmental studies must be representative of national conditions to
adequately support national risk assessments, harmonization of data
requirements for these types of studies can be difficult. Harmonization
can require extensive dialogue between scientists to determine which
data requirements can act as common requirements. Such dialogue can
also include discussions of test ``conditionalities,'' that are
reflected in the test notes to the tables for the proposed data
requirements.
Since 1995, the United States and Canada under the NAFTA Technical
Working Group on Pesticides, Harmonization of the Evaluation of
Antimicrobial Pesticides Project have worked together to harmonize data
requirements for antimicrobials. These harmonization activities
represent two efforts. EPA coordinates with Canada's PMRA on
harmonization activities for all disciplines except efficacy. For
harmonization activities for efficacy requirements EPA coordinates with
Health Canada's Therapeutic Product Directorate (TPD).
EPA and PMRA approach antimicrobial data requirements differently.
EPA uses a tiered testing strategy, while PMRA bases its data
requirements on a defined use pattern approach. EPA and PMRA's data
requirements have been carefully compared. TPD and EPA recently
completed a crosswalk of EPA and TPD efficacy data requirements, which
is being used for planning purposes to explore future harmonization
activities. The data requirements proposed in this document for
antimicrobials represent U.S. national requirements but they reflect
extensive consultation with Canada. The data requirements are
harmonized to a high degree. The two countries plan to continue to work
together to keep data requirements for all disciplines as similar as
possible.
OECD has not conducted any activity specifically aimed at
harmonizing data requirements for biocides. In 1997-1998, the OECD
Pesticide Program conducted a survey to collect information on the
existing requirements across countries. The survey served two purposes:
(1) To improve OECD's understanding of how Member countries regulate
biocides, and (2) to provide information that could be used to prepare
the way for future efforts to increase international co-operation in
biocide regulation. The survey shows great variability. At this time
OECD has no plans to work toward harmonizing these data requirements,
but instead has worked at harmonizing tools and methodologies in order
to reduce duplication and harmonize review procedures for possible work
sharing.
C. Protocol/Guideline Harmonization
Harmonization can also involve protocol/guideline development or
revisions so that the studies produced can meet common data
requirements.
Issues can arise because the study protocols or guidelines used to
generate the studies to meet the requirements can be different. In
other words, a particular data requirement might be the same from one
country to the next, but the study submitted to meet the requirement
can run into acceptance problems if done according to a protocol that
is acceptable in one country, but not in another. There is significant
commonality in protocol design for toxicology studies among various
countries, but less for ecotoxicology and environmental fate studies.
Information on how to satisfy data requirements is specified in Sec.
158.70. This section provides for both the recommended use of EPA
Guidelines and for the acceptability of OECD protocols with certain
caveats. Section 158.80 allows for the use of data developed in foreign
countries, again with certain caveats to ensure that the data will meet
EPA's needs under FIFRA and FFDCA.
D. Ballast Water Treaty
Both domestically and internationally, an emerging significant use
of antimicrobials is the treatment of ballast water. Ballast water
provides needed stability for safe operation of marine vessels. It is
the water that is pumped in and out of the ship's ballast tanks to
ensure safe operation, such as compensating for the ship's weight
changes due to loading and unloading of cargo. In recent years there
have been significant concerns about transport of marine species from
one marine environment to another, via ballast water. Ballast water
treatments are intended to kill the marine species prior to discharge.
When discharged into a new environment, a new species may become
invasive and disrupt the native ecology.
The International Convention for The Control and Management of
Ships' Ballast Water and Sediments, 2004 (also referred to as the
Ballast Water Convention) was adopted by consensus at a diplomatic
conference in London on February 13, 2004. The U. S. delegation was led
by the Coast Guard with participation by EPA and other Federal
agencies. The treaty opened for signature on June 1, 2004, and will
enter into force 12 months after ratification by 30 countries
representing 35% of the world's merchant shipping tonnage. Once in
force, the treaty will require that ships manage their ballast water to
meet discharge standards according to a schedule in the treaty. In
order to meet those discharge standards, ships will need to install
equipment to treat their ballast water, including disinfection. To
date, ten countries representing 3.42% of the world shipping tonnage
have become Parties to the treaty.
Although the United States has not signed the treaty, ballast water
discharges in U.S. waters are already regulated by the Coast Guard
under the Nonindigenous Aquatic Nuisance Prevention and Control Act, as
amended (16 U.S.C. 4701 et seq.) The existing Coast Guard ballast water
management regulations can be found at 33 CFR part 151, subparts C and
D. At present, the Coast Guard is engaged in further rulemaking that
would set a performance standard for the quality of ballast water
discharged in U.S. waters and which will further foster development of
ballast water treatment technologies.
The Agency has reviewed few applications for ballast water
treatments, presumably because such treatments and technologies are
relatively new. Therefore, for the purpose of determining data
requirements EPA determined to group ballast water treatments with
antifoulant paints and coatings since both have the potential for
exposure to marine organisms. OECD has not developed data requirements
for ballast water.
XVII. Research Involving Human Subjects
Research with human subjects which is conducted or supported by the
U. S. government is subject to regulations for the protection of human
subjects referred to as the Common Rule. EPA was one of many federal
departments and agencies who jointly promulgated the Common Rule in
1991. EPA's codification of the Common Rule appears at 40 CFR part 26,
subpart A.
[[Page 59421]]
On February 6, 2006, EPA published in the Federal Register (71 FR
6138) a final rule amending 40 CFR part 26 by adding nine new subparts.
These amendments extend regulatory protection to human subjects of
research involving intentional exposure and intended for submission to
EPA under the pesticide laws, when the research is conducted not by the
Federal government but by private parties with no support from Federal
Common Rule departments or agencies. As subsequently amended effective
August 22, 2006 (71 FR 36171), this rule (1) forbids both EPA and third
parties who intend to submit the research to EPA to conduct new
research involving intentional exposure of pregnant or nursing women or
of children; (2) extends the substantive provisions of the Common Rule
to third-party human research involving intentional exposure of non-
pregnant adults that is intended for submission to EPA under the
pesticide laws; (3) requires submission to EPA of protocols and related
information about covered human research before it is initiated; (4)
establishes an independent Human Studies Review Board to review both
proposals for new research and reports of covered human research on
which EPA proposes to rely under the pesticide laws; and (5) forbids
EPA to rely, in its actions under the pesticide laws, on research
involving intentional exposure of pregnant or nursing women or of
children, or which otherwise fails to meet criteria for acceptance,
except in narrowly defined circumstances.
The provisions of this amended rule directly affecting third-party
research intended for submission to EPA are 40 CFR part 26, subparts K,
L, and M. Subpart K extends the substantive provisions of the Common
Rule to third-party research involving intentional exposure of non-
pregnant adult subjects that is intended for submission to EPA under
the pesticide laws. Subpart K also requires submission to EPA of
proposals for any covered research for review by EPA staff and the
Human Studies Review Board before it is initiated, and specifies the
range of information required to support any such proposal. Subpart L
prohibits conduct of any new third-party research intended for
submission to EPA involving intentional exposure of pregnant or nursing
women or of children. Subpart M specifies the range of information
required to be submitted with every report of completed research with
human subjects to document its ethical conduct.
Studies required under proposed 40 CFR part 158, subpart W which
involve intentional exposure of human subjects are also subject to
subparts K, L, and M of 40 CFR part 26. The following data requirements
in proposed Sec. 158.2260 and Sec. 158.2270 call for studies likely
to involve intentional exposure of human subjects:
Biological monitoring studies.
Mixer/loader or applicator exposure studies.
Post-application exposure studies.
If any studies undertaken to address these requirements involve
intentional exposure of a human subject (as defined at 40 CFR
Sec. 26.1102(i)), then the study must not be initiated before
submission of protocols and supporting documentation for review by EPA
and the Human Studies Review Board. The requirements for protocol
submissions are specified at 40 CFR 26.1125. It may be possible to
design some studies responsive to the proposed data requirements for
antimicrobials so that they do not meet the regulatory definition of
research involving intentional exposure of a human subject. If there is
any question, however, about whether a proposed study intended for
submission to EPA falls within or outside this regulatory definition,
consultation with EPA is recommended before initiating the study. If
EPA did not review the protocol for a study involving intentional
exposure of a human subject, the study if subsequently submitted to the
Agency would not be acceptable under 40 CFR 26.1705.
XVIII. Alternative Testing Paradigms
As with conventional pesticide chemicals, the Agency is committed
to moving towards a more efficient and refined testing/risk assessment
paradigm for antimicrobial pesticide chemicals.
A. Structure Activity Relationship (SAR)
EPA must rely upon information of appropriate quality and
reliability for each decision made by the Agency. In the Office of
Pesticide Programs (OPP), the evaluation process for a pesticide
chemical traditionally begins with the applicant's submission of a set
of studies conducted with the specific pesticide chemical of interest.
The use of the results of such testing (measured data) is a logical,
scientifically-rigorous process that identifies the physical, chemical,
and environmental fate properties of the pesticide, as well as the dose
and endpoints at which an adverse effect can occur in various animal
species.
Today, there is significant interest in determining alternative
testing paradigms that could offer more flexibility in the design of an
integrated approach in which the selection of the required studies as
well as the design of the study protocols is influenced by the
existing, reliable information about the chemical. EPA is committed to
moving towards alternative testing paradigms that are more efficient,
reduce the use of animal testing, take full advantage of advances in
science, and provide a sufficient, credible amount of data for use in a
risk assessment that will support a risk management decision.
EPA is charged with developing a pesticide regulatory program that
is protective of human health and the environment. Other factors that
also deserve consideration in the implementation of such a program are
efficiency and effectiveness. It would be a poor use of societal
resources to routinely require the submission and governmental review
of a multi-million dollar database for every active ingredient if there
were alternative methods of determining which chemicals could be
evaluated in a scientifically rigorous manner using means other than
measured data. From the Agency's perspective an alternative testing
paradigm may also allow for a stream-lined review process for chemicals
of potential lower toxicity, thus freeing resources for more in-depth,
complex reviews of higher toxicity chemicals.
An integrated approach would focus on using all relevant, credible
information on the chemical of interest. Applicants are cautioned that
such an approach will require a different type of thought process which
will incorporate significantly more planning and ``data mining'' types
of activities than making arrangements to conduct the required studies.
However, it could also offer a flexibility that is not always present
under the currently-used, guideline-driven (study-by-study) approach.
Both SAR and QSAR techniques play a critical role in an integrated
approach. In the SAR process, a chemical's molecular structure is
compared to that of other chemicals for which data are available. These
structural similarities are then used to make predictive judgments
about a chemical's physical, chemical, and biological properties. Thus,
the chemical's physical, chemical, and biological properties are a
function of (or directly related to) the chemical's molecular
structure. Quantitative SAR is referred to as QSAR. To develop a QSAR,
a selected set of measured data on a single physical, chemical, or
biological property are used to derive a model (an equation) to predict
the value of that property.
[[Page 59422]]
EPA's Office of Pollution Prevention and Toxics administers two
programs, the Interagency Testing Committee (ITC) and the New Chemicals
Program (NCP) under the Toxic Substances Control Act, that have been
using various forms of SAR and QSAR since the late 1970s. The ITC is an
independent advisory committee that screens chemicals or classes of
chemicals and prioritizes them for testing. The NCP uses an expert
judgment SAR process to assess human health and has developed QSAR
models to evaluate physical, chemical and environmental fate properties
and ecological effects.
Additionally, other agencies (both U.S. and non-U.S.) are
investigating how to use these alternative techniques. OECD has devoted
a significant amount of time and effort to coordinating model
development and model validation for such an integrated approach. EPA
has participated on these workgroups.
During the last 6 years, OPP has made increasing use of SAR as part
of its regulatory decision-making process. Documents to establish
tolerance exemptions, documents to support tolerance reassessment, and
Reregistration Eligibility Decision Documents have incorporated the use
of SAR, when appropriate. OPP recognizes the usefulness of
incorporating predictive techniques into its hazard and risk
assessments, and that for certain chemicals SAR assessments and QSAR
modeling could potentially form a scientifically-sound basis for hazard
and risk assessments used for regulatory decisions. Over time, OPP has
progressed from using SAR techniques to support a dataset of guideline
type studies to, for certain assessments, relying on SAR techniques as
an acceptable source of information on the chemical. OPP is now
considering when and how to codify in subpart A of current part 158
that information derived from SAR assessments and/or QSAR modeling
could be acceptable for fulfilling a data requirement. The submitter of
such information would be expected to supply a rationale describing the
utility of the information and provide documentation on the scientific
validity of the information. The determination that the predicted data
fulfills the data requirement would be at the sole discretion of the
Agency. The Agency seeks comment on the use of predictive techniques to
fulfill the part 158 subpart W data requirements, and specifically on
when and if the use of SAR and QSAR should be codified in part 158,
subpart A. Codification in part 158, subpart A means that SAR and QSAR
techniques would be applicable to conventional, biochemical and
microbial, and antimicrobial pesticide chemicals. The Agency
specifically seeks comment on this issue. Comments will be used in the
further development of SAR and QSAR approaches for fulfilling data
requirements, but will not be addressed in the final rule for
antimicrobial data requirements.
Those applicants considering use of SAR and QSAR as part of a
submission package to OPP should realize SAR and Quantitative SAR
(QSAR) modeling results can sometimes be used instead of measured data,
but modeled data cannot be preferentially substituted for well-
conducted studies (measured data). If measured data are available for a
particular endpoint, then the measured data should carry the greatest
weight for hazard and risk assessment purposes. Applicants are
cautioned that if the Agency determines that the SAR and/or QSAR do not
fulfill the data requirement, then the registration may be delayed
while a study (measured data) is generated according to part 158
requirements.
At this time, the Agency intends to continue its initial
explorations and begin the process to shift from the current guideline-
driven (study-by-study) approach to a more integrated approach in which
the use of predicted data, generated using validated models, is
considered along with information from open literature and studies
specifically generated under part 158 data requirements. All relevant
information would be considered as part of a weight-of-evidence
evaluation.
The shift to an integrated approach would occur over some time. OPP
has deliberately chosen to begin this shift with antimicrobial
pesticide chemicals instead of conventional pesticide chemicals for two
reasons: First, most conventional pesticide chemicals are deliberately
created for their biological activity and many require complex risk
assessments. Few conventional pesticides have non-pesticidal uses.
Second, antimicrobials also have biological activity, but are more
likely to have non-pesticidal uses and, in fact, may have been assessed
by other regulatory agencies. The ready availability of published
literature and publicly-available assessments offer a unique
opportunity for the applicant to use the available information as a
starting point for fulfilling data requirements, and offering the
possible option, when appropriate, of SAR and QSAR for those data
requirements that are not yet fulfilled by measured data.
It should be realized that just as measured data have
uncertainties, predicted data also have uncertainties. Use of different
models (developed using different sets of data) would necessarily have
trade-offs. Therefore, QSAR models must be used with caution. Expert
judgment is required to determine the appropriate model to use and if
the results of the model strike the correct balance of accuracy and
precision, with the potential for few false negatives or false
positives.
At this time, EPA believes that for certain endpoints, especially
physical/chemical and fate properties, that SAR and QSAR might be
effectively utilized to fulfill these data requirements for many
antimicrobial pesticide chemicals. When considering biological
properties, EPA believes that SAR and QSAR can be most effectively
utilized in the evaluation of chemicals that exhibit lower toxicity for
human health and/or ecotoxicity parameters. This is appropriate because
the risk assessment for lower toxicity chemicals can be streamlined,
i.e., through use of a screening-level assessment procedure rather than
multiple tiers of assessments with progressively more data
requirements.
As appropriate, OPP will consider the use of SAR and/or QSAR
predictive techniques as part of the hazard assessment, and eventually
the dose and endpoint selection process for antimicrobial chemicals.
Under a QSAR-based approach an applicant could provide the Agency with
an analysis that could frame the actual data required to register the
antimicrobial pesticide chemical. For some antimicrobials, applicants
may have the option of characterizing certain of the active ingredient
properties via predictive techniques. It is the responsibility of the
applicant to provide sufficient information to conduct a risk
assessment that can be used to support a risk management decision. If
the applicant believes that a SAR assessment and/or QSAR model would
provide scientifically credible information that would be useful to
EPA, then it is the responsibility of the applicant to provide to the
Agency a rationale on the appropriateness of SAR or QSAR for that
particular endpoint and sufficient documentation on how the assessment
and/or model is scientifically valid. Without such information OPP
cannot judge the validity of the model and therefore the acceptability
of the results of the model for OPP's decision-making purposes.
At this time, the use of SAR is not yet a standardized approach in
OPP, and is being handled on a case-by-case basis. Therefore, OPP has
not yet developed a standardized format for submission of such
information. Further information on OPP's current thinking on how SAR
[[Page 59423]]
and QSAR modeling can be used as part of an integrated approach to
hazard and risk assessment to support a regulatory decision-making
process and guidance on submission formats is contained in the support
document, ``Use of Structure-Activity Relationship (SAR) Information
and Quantitative SAR (QSAR) Modeling For Fulfilling Data Requirements
for Antimicrobial Pesticide Chemicals and Informing EPA's Risk
Management Process'' which is contained in the docket for this proposed
rule (Ref. 43). The Agency specifically seeks comment on this support
document.
B. International Life Sciences Institute and Health and Environmental
Sciences Institute Approaches
In both the proposed (70 FR 12276) and final (72 FR 60934) rules
for conventional pesticide chemicals, EPA discussed the relevance and
importance of the ILSI/HESI project. There have been discussions on
alternative testing paradigms with the International Life Sciences
Institute (ILSI) Health and Environmental Sciences Institute (HESI)
under the Agricultural Chemical Safety Assessment (ACSA) Technical
Committee, since 2001 (Ref. 14). The focus of this effort has been
toxicity testing for agricultural chemicals, but the results would also
be applicable to antimicrobial pesticides.
This project, with the participation of EPA scientists, represents
an evolution of the current paradigm of animal (in vivo) toxicity
testing toward a more integrated tiered testing approach for pesticide
chemicals. Under this integrated approach, both the selection of
studies that would be required, as well as the design of the tests
themselves, could be influenced by other substantive and reliable
information about the pesticide.
The goals being pursued by EPA for this next generation of toxicity
testing are to:
Incorporate advances in science and technology in an
expeditious manner.
Identify cost effective and scientifically sound
alternatives to current animal tests.
Define a transparent, step wise plan that leads to an
evolution, not revolution, in testing and assessment.
Define a clear and credible process, with external peer-
review and stakeholder participation.
All available information would be considered: Not only toxicity
and dose-response data from other guideline or non-guideline studies,
but also structure-activity relationships, data on the mechanism or
mode of action of the chemical, pharmacokinetic data, studies that
examine age-related sensitivity or susceptibility to chemical exposure,
and information on potential or actual exposure to humans. These data
could be used to inform a more targeted testing approach in the design
of studies, or to support a position that the requirement for specific
toxicology tests should be waived (i.e., the studies are not needed)or
fulfilled via a means other than data generation, such as SAR.
ACSA represents the first comprehensive effort to scientifically
re-design the toxicology animal-testing framework for pesticide
chemicals. A series of reports authored by HESI/ILSI were published in
a special edition of the Journal of Critical Reviews in Toxicology in
January 2006 (Refs. 1, 2, 3, and 6). These four articles summarized the
initial findings and recommendations.
The ACSA proposal is consistent with EPA's direction and goals to
develop a more efficient and reliable testing paradigm. The ACSA
approach departs significantly from the current standardized list of
hazard studies used by many national and international authorities to
assess pesticides. Some studies could be eliminated while endpoint
coverage might be increased in redesigned studies based on responses
observed in a core set of toxicity tests. Thus, it will be essential to
conduct retrospective and prospective data analyses to determine
whether this new testing paradigm will meet EPA's risk assessment
needs.
The first retrospective analysis has been completed for the 1-year
chronic dog study. Based on this retrospective analysis, which was
reviewed by the FIFRA SAP, the 1-year chronic dog study is no longer
required for conventional pesticide chemicals and is not proposed as a
data requirement for antimicrobial chemicals. Another retrospective
analysis on the 2-generation reproductive toxicity study is underway.
To this end, the Office of Pesticide Programs is currently working with
EPA's National Center for Computational Toxicology to populate a
Toxicological Reference Database (ToxRef) with data from the rat 2-
generation reproductive study, prenatal developmental toxicity and
systemic toxicity studies on hundreds of pesticides that represent
different classes, modes of action, and toxicity profiles. EPA will use
this relational database to determine the value of endpoints currently
evaluated in risk assessment (i.e., the F1 versus
F2 responses).
From these analyses the Agency will gain other information critical
for gaining scientific consensus. Such information would be the
triggers, that is, the points at which a concern is indicated and thus
a higher level of testing is needed. The retrospective analyses will
aid the Agency in confirming the proposed ACSA triggers or in
determining new ones. Once the analysis is complete, EPA will be able
to complete draft guidance on testing. EPA plans to request SAP review
and public comment of the analyses and draft guidance in 2008.
Additionally, there are plans to conduct several case studies using
the ACSA tiered testing proposal. It is essential to test how the ACSA
scheme works in practice. From such case studies, EPA will be able to
assess the feasibility of a testing laboratory's ability to perform
such a complex study, and will have the opportunity to evaluate the
ability of the approach and its parameters to characterize known
toxicants and address risk assessment needs.
In considering regulatory changes to reflect the results of EPA's
consideration of ACSA, the Agency will develop scientific position
papers on the new approach and recommendations for internal and
external review. Internal review includes review by the FIFRA SAP and
opportunities for public comment. External peer review and
acceptability by other national and international regulatory
authorities are considered before implementation of any new testing
paradigm and data requirements. Harmonization of data requirements with
our NAFTA and OECD partners is also an important factor. International
regulations currently require studies that were omitted in ACSA. If EPA
had requirements that were significantly different from those of the
international community, then there could be significant problems for
applicants in trying to satisfy multiple and different requirements
world-wide.
Thus, as these analyses and the needed peer reviews are completed,
EPA will have the opportunity to determine if the new testing paradigm
will meet its risk assessment needs. EPA will then be able to determine
what revisions to current data requirements and testing guidelines may
be appropriate.
C. Computational Toxicology
EPA's Office of Research and Development (ORD) established the
National Center for Computational Toxicology (NCCT) in 2005. The NCCT
is developing computational tools for interpreting data from
computational chemistry, high-throughput screening
[[Page 59424]]
(HTS) and genomic technologies as follows:
Computational chemistry is the integration of modern
computing and information technology with information on molecular
biology and chemistry to predict bioactivity profiles.
HTS is a system to rapidly and efficiently test large
batches of chemicals for bioactivity utilizing robotics and automation
applied to molecular biology and assay methods.
Genomics is the study of all the genes of a cell or
tissue, and their function.
EPA's ToxCastTM Program began in 2006. The underlying
hypothesis for ToxCastTM is that an organism's toxicological
response is driven by interactions between chemicals and biomolecular
targets. ToxCastTM also includes model development to
predict the potential toxicity of environmental chemicals based on
bioactivity profiles. These models will identify predictive signatures,
derived from the bioassay data. This means that EPA under
ToxCastTM will develop methods of prioritizing chemicals for
further screening and testing to assist the Agency's programs in the
management and regulation of environmental contaminants (Ref. 5).
There are three phases to the development of ToxCastTM:
1. The proof-of-concept phase of ToxCastTM will examine
more than 300 chemicals, with rich toxicological databases, in over 400
different HTS bioassays. Predictive signatures will be created by
correlating the HTS bioassay data to the known toxicity of the 300
chemicals.
2. A signature evaluation and expansion phase will focus on testing
and extending the ToxCastTM predictive signatures, through
the generation of HTS data on over 1,000 additional chemicals.
3. The application phase of ToxCastTM will be expanded
to include a variety of high-priority chemicals that are either
regulated and/or considered for regulation by EPA and potentially
thousands of environmental chemicals requiring prioritization.
ToxCastTM is envisioned as delivering an affordable,
science-based system for categorizing chemicals.
In 2007 the NCCT awarded nine contracts for the generation of HTS
and genomics data as part of the ToxCastTM chemical
prioritization research program, in order to develop the ability to
predict, or forecast toxicity based on bioactivity profiling. State-of-
the-art HTS and genomic approaches developed by the pharmaceutical
industry provide information on the impact of chemicals on biological
pathways critical for the function of systems such as the heart, lungs,
brain, or reproductive organs quickly and in a cost-efficient manner.
Thus, results from these bioassays will provide a comprehensive and
detailed overview of the potential impact of environmental chemicals
upon key cellular activities.
As the ToxCastTM database grows so will confidence in
the models developed from that data, as well as the resultant
predictions of toxicity and potential mechanisms of action derived from
the models. This could result in changing and/or reducing the use and
numbers of animals in toxicity testing. This could also result in fewer
in vivo tests being conducted as scientists and regulators learn how to
interpret and use ToxCastTM predictions to then determine
the chemicals that must be tested using traditional toxicity testing.
Results from the first phase of ToxCastTM are anticipated by
the summer of 2008. However, significant effort will be needed as
ToxCastTM transitions from proof-of-concept to a useful
prioritization tool.
D. National Academy of Sciences (NAS) Report Concerning Toxicity
Testing and Assessment of Environmental Agents
EPA asked NAS to undertake a comprehensive review of established
and emerging toxicity-testing methods and strategies. In response to
this request NAS convened the Committee on Toxicity Testing and
Assessment of Environmental Agents. EPA asked the Committee to conduct
their assessment in two parts. Part I is a review document, discussing
current and near-term methods and strategies for collecting information
for human health risk assessment. Part II is a long-range vision and
strategic plan for changes to human health risk assessment paradigms.
In June 2006, NAS released Toxicity Testing for Assessment of
Environmental Agents: Interim Report (Ref. 20). This report fulfills
EPA's Part I request. In conducting its research NAS considered
numerous documents and resources such as (1) current toxicity testing
protocols and various testing strategies using these protocols, (2)
impediments to the use of human data, (3) strategies that rank or
screen chemical substances, and (4) human health risk assessment
guidance documents. The Part I report identified four objectives that
EPA should strive to meet as it works to evolve its current paradigm of
toxicity testing:
Depth, providing the most accurate, relevant information
possible for hazard identification and dose-response assessment.
Breadth, providing data on the broadest possible universe
of chemicals, endpoints, and life stages.
Animal welfare, causing the least animal suffering
possible and using the fewest possible animals.
Conservation, minimizing the expenditure of money and time
on testing and regulatory review.
The report acknowledged that it was difficult to simultaneously
meet all four objectives.
In 2007 NAS released its Part II report entitled ``Toxicity Testing
in the 21st Century: A Vision and a Strategy'' (Ref. 21). According to
NAS, toxicity testing is approaching a ``scientific pivot point.''
Today, there are advances in the biological sciences that are already
impacting how toxicity testing is conducted. NAS concluded that a
paradigm shift would be needed to transform the current testing system
but that ``the result will be a more efficient, informative and less
costly system for assessing the hazards posed by industrial chemicals
and pesticides.''
E. Next Steps
EPA will undertake rule-makings on a timely basis as the science
progresses and changes to the data requirements are appropriate.
XIX. Animal Welfare Concerns
The Agency understands many people's concern about the use of
animals for research and data development purposes. In both the
proposed rule (70 FR 12276) and in the final rule (72 FR 60934) for
conventional pesticide chemicals, EPA discussed its commitment to the
development and use of alternative approaches to animal testing.
Taking into consideration principles of sound science and the
requirements of FIFRA to protect humans and the environment, the Agency
is committed to avoiding unnecessary or duplicative animal testing. As
a result, the Agency has invested significant resources to investigate
more integrated testing approaches that include, in silico, in vitro,
and focused in vivo testing. The Agency's long-term goal is to create a
testing paradigm so that chemicals are tested in animals only for those
endpoints most relevant to each chemical's exposure or intended use.
The Agency acknowledges that substantial work remains to achieve this
long-term goal, but the Agency is also working on the important short-
term goal to make the existing animal testing paradigm more efficient,
reliable, and
[[Page 59425]]
responsive to its risk assessment and management needs.
As a result of the Agency's activities to move towards a more
efficient animal paradigm, EPA is proposing to eliminate the existing
requirement for the 1-year chronic dog study for antimicrobial
pesticide chemicals.
XX. Potential Rule-Makings of the Future for Endangered Species
EPA is charged with protecting endangered and threatened species
from potential harm from pesticide use. Under the Endangered Species
Act, EPA must ensure that the registered uses of pesticides will not
jeopardize the continued existence of endangered or threatened species,
or adversely modify habitat designated as critical by the U.S. Fish and
Wildlife Service or National Marine Fisheries Service. Accordingly, in
its proposed and final rules for both conventional pesticide chemicals,
and biochemical and microbial pesticide chemicals, the Agency discussed
the possibility of future data and information needs to develop and/or
refine risk assessments for endangered and threatened species. As a
result of those proposed rules, EPA received comments. For the present,
EPA will consider those comments in the context of its ongoing risk
assessments, including those for antimicrobials. If EPA finds that it
needs to amend subpart W of part 158 to normalize endangered species
data requirements, it will consider those comments and any comments
submitted in response to this proposed rule in the development of a
future proposed rule.
For agricultural pesticides, there is generally greater specificity
relative to where a pesticide may be used. If adequate geographic
delineation of the use site is possible, then overlap with the
locations of an endangered or threatened species may also be possible.
However, antimicrobial pesticides are different from agricultural
pesticides. The Agency expects that most antimicrobial uses with
potential for environmental exposure (e.g., wood preservatives,
antifoulant paints, industrial wastewater discharges, ballast water
discharges) could impact geographic areas of the United States that are
less well defined. For example, vessels treated with antifoulant paints
can occur in freshwater, estuarine, or marine areas within the U.S.
(such as lakes and rivers) and in coastal waters. Wood preservatives
could be used in locations that may result in an impact to terrestrial
and/or aquatic organisms depending on the use of the wood, which could
occur throughout the United States. Antimicrobial use sites will be
much more difficult to delineate, and overlay with endangered or
threatened species locations.
The Agency seeks comment on:
1. The types of data that could be useful for conducting the
assessment required.
2. Projections of how long it would take to generate the needed
data.
3. Whether antimicrobial use sites can be adequately correlated
with endangered species locations, and suggested methods for doing so.
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42. USEPA (December 31, 2007). Four Case Studies of Antimicrobial
Pesticides in the Down-the-Drain Screening Model, Using the Proposed
Approach for a Screening-Level Environmental Fate Assessment. USEPA,
Antimicrobials Division, Office of Pesticide Programs.
43. USEPA (December 17, 2007). Use of Structure-Activity
Relationship (SAR) Information and Quantitative SAR (QSAR) Modeling For
Fulfilling Data Requirements for Antimicrobial Pesticide Chemicals and
Informing EPA's Risk Management Process.
44. USEPA (2008). Economic Analysis of the Proposed Data
Requirements for Antimicrobial Pesticides, EAB/BEAD/OPP.
45. USEPA (August 26, 2008). Supporting Statement for an
Information Collection Request (ICR), Data Requirements for
Antimicrobial Pesticides (Proposed Rule), EPA ICR No. 2318.01, OMB
Control No. 2070-(new).
XXII. FIFRA Review Requirements
Under FIFRA section 25(a), EPA has submitted a draft of the
proposed rule to the Secretary of the Department of Agriculture and the
appropriate Congressional Committees. There were no comments in
response to these submissions.
Under FIFRA section 21(b) EPA submitted a draft of the proposed
rule to the Secretary of Health and Human Services (HHS). Their
comments on this proposed rule included requests for (1) clarification
on the application of these new testing requirements to current
registrants, (2) information about prions, (3) the possible effects of
antimicrobial residues present in food on intestinal flora, and (4) the
potential for antimicrobial resistance.
EPA agrees with HHS that both current antimicrobial pesticide
registrants and applicants seeking an antimicrobial registration should
understand the applicability of the proposed data requirements, once
[[Page 59427]]
promulgated. Once effective, EPA would use the promulgated data
requirements as the standard for reviewing new applications. These same
promulgated data requirements, once effective, would also be used
during Registration Review, when the Agency's scientists prepare the
publicly available documentation on the data needed during Registration
Review to complete the needed risk assessments.
EPA also agrees that the criteria for determining the efficacy of
proposed anti-prion agents have not yet been established.
Concerning HHS's Center for Veterinary Medicine's (CVM) comment on
intestinal flora, EPA believes that the studies proposed in this rule
for use in a pesticide risk assessment are protective of human health.
EPA has no specific information on effects on antimicrobial residues
that would not be captured by the required health effects studies.
HHS's CVM is correct that this proposed rule does not address
potential antimicrobial resistance as a result of the use of a
pesticide product. While the Pesticide Program is aware of this issue,
we have neither determined the extent of the problem nor how data
requirements could be developed to address the issue. The Pesticide
Program will continue to monitor efforts such as those of the CODEX ad
hoc Intergovernmental Task Force on Antimicrobial Resistance and the
Interagency Task Force on Antimicrobial Resistance, on which EPA is a
participant (see http://www.cdc.gov/drugresistance/actionplan/). The
research being conducted by the collaborating federal agencies, which
is primarily focused on antibiotics, may eventually form the basis for
the Pesticide Programs' approach to potential resistance as a result of
the use of pesticide products. We have the authority to require studies
on a case-by-case basis and to revise our data requirements in the
future, if appropriate.
EPA requested that the SAP waive its review of this proposal based
on the SAP's 1997 review. The SAP waived its review of this proposal on
February 19, 2008.
XXIII. Statutory and Executive Order Reviews
A. Executive Order 12866
Pursuant to Executive Order 12866, entitled Regulatory Planning and
Review (58 FR 51735, October 4, 1993), the Office of Management and
Budget (OMB) has determined that this proposed rule is a ``significant
regulatory action'' because this action might raise novel legal or
policy issues arising out of legal mandates, the President's
priorities, or the principles set forth in the Executive Order.
Accordingly, as a result of this OMB determination, EPA submitted this
proposed rulemaking to OMB for review under Executive Order 12866. Any
changes made in response to OMB comments have been documented in the
public docket for this rulemaking as required by section 6(a)(3)(E) of
the Executive Order.
EPA has prepared an economic analysis of the potential costs
associated with this proposed action, entitled ``Economic Analysis of
the Proposed Change in Data Requirements for Antimicrobial
Pesticides.'' It is noted that this analysis applies only to new
antimicrobial pesticides submitted for registration, and to new uses of
currently registered antimicrobial pesticides. For conducting its
economic analysis, EPA considered a registration action as referring to
an application for registration of a new product that contains an
active ingredient that is not included in any currently registered
product, an application for a new product that includes the addition of
a use pattern that is not currently registered for one or more active
ingredients contained in the product, and an amendment of a
registration of a product that includes the addition of a use pattern
that is not currently registered for one or more active ingredients
contained in the product.
A copy of the economic analysis (Ref. 44) can be found in the
public docket for this action, and is briefly summarized here.
In the proposed rule, EPA is:
Proposing newly codified data requirements, which are not
currently established in part 161, but are routinely considered in
current practice.
Proposing changes to some of the existing data
requirements such as a change from conditionally-required to required,
a change in the number of test species, or expanding the number of use
patterns for which the test is required.
Proposing new data requirements, which have never been
required or have rarely been required on a case-by-case basis, and have
not been routinely considered during the Agency's evaluation of the
data needed for the purpose of risk assessment.
Proposing to eliminate the requirement for the chronic
nonrodent study currently established in part 161.
To calculate the potential costs associated with this proposal, EPA
first identified the studies that would generate the data to fulfill
the proposed data requirements, and then gathered information on the
price that laboratories might charge to conduct that study. To the
extent possible, several cost estimates were compiled for each study.
The low and high cost estimates provided by the various laboratories
were averaged to account for price variations related to differences in
the assumptions about the study performed (e.g., protocol, species
used), and differences in the price charged by different laboratories.
EPA assumed that each data requirement would always be fulfilled
and therefore data would always need to be generated for each
requirement. This assumption could lead to an overestimate of the
burden of the proposal, because sometimes the data are already
available because the firm generated it for their own use. In such
cases, the firm would simply need to submit those data to EPA, which
involves less burden and cost than generating it. Some firms may have
surrogate data that could be used, while others may qualify for a
waiver. Some firms may share the cost of generating the data. All of
these would involve lower costs than generating the data anew.
EPA then used historical data on antimicrobial pesticide
registration actions that occurred from 2000 to 2005 to identify the
entities that sought pesticide registration actions in the past. The
data required for each registration action depends on several factors,
including the type of registration action (e.g., registration of a new
active ingredient food-use, registration of a new active ingredient
nonfood-use, registration and amendments to registrations involving a
major new use); scientific discipline (e.g., toxicology, residue
chemistry, human exposure), and use pattern. The percentage of time a
particular test would be required was estimated from this information.
For the new data requirements, the percentage of time was estimated by
EPA scientists, based on their past experience in the program and their
understanding of the need for and the use of the new data requirements.
The Agency prepared an industry profile using the same historical
data on pesticide registration actions to identify the companies
involved in those actions, and based it on public information gathered
about those companies. EPA also used this industry profile to analyze
the potential impacts of the proposed rule on small businesses, the
results of which are summarized in Unit XXIII.B below.
Overall the potential impact of this proposal on businesses is
small, and
[[Page 59428]]
therefore the Agency believes that a negative effect on the
availability of antimicrobial pesticide products to users is unlikely.
On balance, the Agency believes that the costs of the proposed rule are
justified by the benefits from enhanced protection of human health and
the environment.
Table 2.--Total Antimicrobial Industry Cost per Year
------------------------------------------------------------------------
Total Industry Cost per Year
($1000)
------------------------------------------------------------------------
Baseline (BL) 11,080
------------------------------------------------------------------------
Current Practices (CP) 11,726
------------------------------------------------------------------------
Proposed Rule (PR) 14,961
------------------------------------------------------------------------
Incremental Costs (PR - BL) 3,882
------------------------------------------------------------------------
Newly Imposed Costs (PR-CP) 3,236
------------------------------------------------------------------------
Thus, the difference between the baseline (the existing data
requirements that were codified in 1984) and the Agency's current
practices in requiring data is $646,000 annually. The difference
between the proposed data requirements and current practices is $3.2
million annually. The difference between the proposed data requirements
and the existing data requirements is $3.9 million annually. The
average cost per registration action of a new antimicrobial active
ingredient is approximately $1 million to $4.5 million. It is noted
that this analysis applies only to new antimicrobial pesticides
submitted for registration, and to new uses of currently registered
antimicrobial pesticides.
For existing chemicals, the proposed part 158 subpart W data
requirements would be relevant to the registration review program which
began to replace the reregistration program in 2006 as a means of
systematically reviewing existing registrations against the standards
of FIFRA. Data needs identified under registration review for existing
chemicals must be imposed under the Agency's Data Call-In (DCI)
program.
EPA has not evaluated the potential burden of the proposed data
requirements on registrants of existing chemicals in this proposal.
However, EPA anticipates that there will be additional costs associated
with the proposed studies under Registration Review. For each chemical,
EPA will evaluate the specific need for additional data, including
studies proposed today. Stakeholders and the public have opportunities
for input, consultation and involvement concerning individual pesticide
cases throughout the registration review process. Although EPA has
identified the schedule for which chemicals will be reviewed over the
next few years, the evaluation of data needs has not been done. Thus,
the costs are unknown. EPA will articulate the specific burden and
costs associated with each DCI pursuant to the appropriate Information
Collection Request (ICR) approvals under the Paperwork Reduction Act
(PRA).
B. Regulatory Flexibility Act
Pursuant to section 605(b) of the Regulatory Flexibility Act (RFA),
5 USC 601 et seq., the Agency hereby certifies that this action will
not have a significant adverse economic impact on a substantial number
of small entities. The factual basis for the Agency's determination is
presented in the small entity impact analysis prepared as part of the
economic analysis for this proposed rule (Ref. 44), which is summarized
in Unit XXIII.A., and a copy of which is available in the docket for
this rulemaking. The following is a brief summary of the factual basis
for this certification.
Under the RFA, small entities include small businesses, small
organizations, and small governmental jurisdictions. For purposes of
assessing the impacts of today's proposed rule on small entities, small
entity is defined in accordance with the RFA as: (1) a small business
as defined by the Small Business Administration's (SBA) regulations at
13 CFR 121.201, which is based on either the maximum number of
employees or on the sales for small businesses in each industry sector,
as defined by a 6-digit NAICS code; (2) a small governmental
jurisdiction that is a government of a city, county, town, school
district or special district with a population of less than 50,000; and
(3) a small organization that is any not-for-profit enterprise which is
independently owned and operated and is not dominant in its field. EPA
has determined that this rulemaking does not impact any small
governmental jurisdictions or any small not-for-profit enterprise
because these entities are rarely pesticide applicants or registrants.
Some of the small entities directly regulated by this rulemaking
are in the pesticide and other agricultural chemical manufacturing
industry sector (NAICS code 325320). Firms in this sector are
considered small under the RFA definition if they employ 500 or fewer
people. The economic analysis for this proposed rule specifies the
NAICS code used for each of the firms analyzed.
As detailed in the Economic Analysis, EPA estimates that 750 unique
parent companies constitute the total universe of pesticide
antimicrobial registrants. Of these, based on the SBA definition of a
small business and the available sales data for these firms, EPA
estimates that 500, or approximately 67%, qualify as a small business.
The available antimicrobial pesticide registration data for 2000-2005
indicates that only a small portion of the 500 registrants are likely
to be impacted by the proposed regulation. Specifically, 64 firms with
antimicrobial registrations would have incurred additional costs under
the proposed rule. Of the 64 firms, EPA estimates that a total of 25
small pesticide registrants would have incurred additional costs under
the proposed rule.
The impacts to small antimicrobial registrants are measured as the
per firm incremental cost, which is the difference between the existing
data requirements in part 161 (the baseline) and those proposed in this
rule. The impact of the regulation is expressed as the proportion of
the average annual per firm incremental costs to the average annual
firm sales.
The Agency's analysis of impacts on small businesses indicates
that:
About 25 (5%) of the 500 small firms subject to the
proposal are likely to experience some impact (greater than 0%).
[[Page 59429]]
About 22 (4.4%) of the 500 small firms are likely to
experience an economic impact of 1% or more of gross sales.
About 14 (2.8%) of the 500 small firms are likely to
experience an economic impact of 3% or more of gross sales.
Based on the Agency's small business impact analysis, the Agency
does not anticipate that the additional costs to industry resulting
from this proposed rule will cause a significant adverse economic
impact on a substantial number of small entities because the additional
costs are a small share of gross revenues for most firms and less than
5% of small firms are likely to experience some impact.
EPA is particularly interested in receiving comment from small
businesses as to the benefits, costs and impacts of this rule. Any
comments should be submitted to the Agency in the manner specified
under ADDRESSES.
C. Paperwork Reduction Act
The information collection requirements contained in this proposed
rule have been submitted for approval to the Office of Management and
Budget (OMB) under the Paperwork Reduction Act (PRA), 44 U.S.C. 3501 et
seq. EPA has prepared a new Information Collection Request (ICR)
document identified by EPA ICR No. 2318.01, a copy of which has also
been placed in the docket for this proposed rule. (Ref. 45).
Under the PRA, ``burden'' is defined at 5 CFR 1320.3(b). In
addition, an agency may not conduct or sponsor, and a person is not
required to respond to an information collection request unless it
displays a currently valid OMB control number, or is otherwise required
to submit the specific information by a statute. The OMB control
numbers for certain EPA regulations in 40 CFR, after appearing in the
preamble of the final rule, are listed in 40 CFR part 9 and, if
applicable, included with the related collection instrument (e.g., form
or survey).
The information collection activities related to the submission of
data to EPA in order to register, amend or retain a new or existing
pesticide product or obtain a tolerance for that product are already
approved by OMB under the PRA. As such, this ICR only addresses the
proposed changes to the data requirements that impact the information
collection activities related to antimicrobial pesticides. The
procedures for submitting data to EPA under FIFRA and the FFDCA are not
changed in this proposal, and are already approved by OMB as follows:
1. The data submission activities associated with the establishment
of a tolerance are currently approved under OMB Control No. 2070-0024
(EPA ICR No. 0597);
2. The data submission activities associated with the application
for a new or amended registration of a pesticide are currently approved
under OMB Control No. 2070-0060 (EPA ICR No. 0277);
3. The data submission activities associated with the generation of
data for reregistration are currently approved under OMB Control No.
2070-0107 (EPA ICR No. 1504); and
4. The data submission activities associated with the generation of
data for special review or registration review are currently approved
under OMB Control No. 2070-0057 (EPA ICR No. 0922).
These program activities are an integral part of the Agency
pesticide program and the corresponding ICRs are regularly renewed
every three years as required by the PRA. The total estimated average
annual public reporting burden currently approved by OMB for these
various activities range from 8 hours to approximately 3,000 hours per
respondent, depending on the activity and other factors surrounding the
particular pesticide product.
In the new ICR for this proposed rule, which is based on the
Economic Analysis (Ref. 44), EPA estimates that the typical current
annual paperwork burden for registrants per antimicrobial pesticide
registration is 194 burden hours and $12,631. This represents the
baseline antimicrobial pesticide registration burden and costs. When
considering the potential increase in this estimated annual burden and
cost resulting from the new data requirements in this proposed rule,
the Agency estimated the incremental burden and cost to be 35% of the
baseline burden and costs, i.e., 68 burden hours and $4,421. Assuming
an annual number of 15 antimicrobial pesticide registrations, the total
annual registrant paperwork burden and costs for antimicrobial
pesticide registrations are estimated to be approximately 3,929 hours
and $255,773.25, of which 1,019 hours and $66,150 represent burden
related to new data requirements, and $158.25 represents estimated
delivery costs.
Any comments on the Agency's need for this information, the
accuracy of the provided burden estimates, and any suggested methods
for minimizing respondent burden, should be directed to the docket for
this proposed rule, under Docket ID number EPA-HQ-OPP-2008-0110. See
ADDRESSES section at the beginning of this document for where to submit
comments to EPA.
You may also submit a copy of your comments on the ICR directly to
OMB. Comments to OMB should be sent to the Office of Information and
Regulatory Affairs, Office of Management and Budget (OMB), 725 17th
Street, NW, Washington, DC 20503, Attention: Desk Office for EPA. Since
OMB is required to make a decision concerning the ICR between 30 and 60
days after October 8, 2008, a comment to OMB is best assured of having
its full effect if OMB receives it by November 7, 2008.
In the final rule, the Agency will address any comments received
regarding the information collection requirements contained in this
proposal. In addition, after the ICR for the final rule is approved,
EPA will incorporate the increased burden into the existing ICRs as
appropriate.
D. Unfunded Mandates Reform Act
Under Title II of the Unfunded Mandates Reform Act of 1995 (UMRA)
(Public Law 104- 4), EPA has determined that this action does not
contain a Federal mandate that may result in expenditures of $100
million or more for State, local, and tribal governments, in the
aggregate, or the private sector in any one year. As described in this
document, the incremental costs for the proposed part 158 subpart W
data requirement changes for antimicrobial pesticides is estimated at
nearly $3.9 million per year for the private sector, which is below the
$100 million threshold. Since State, local, and tribal governments are
rarely pesticide applicants, the proposed rule is not expected to
significantly or uniquely affect small governments. Accordingly, this
action is not subject to the requirements of sections 202 and 205 of
UMRA.
E. Executive Order 13132
Pursuant to Executive Order 13132, entitled Federalism (64 FR
43255, August 10, 1999), EPA has determined that this proposed rule
does not have ``federalism implications,'' because it will not have
substantial direct effects on the states, on the relationship between
the national government and the states, or on the distribution of power
and responsibilities among the various levels of government, as
specified in the Order. As indicated above, instances where a state is
a registrant are extremely rare. Therefore, this proposed rule may
seldom affect a state government. Thus, Executive Order 13132 does not
apply to this proposed rule. In the spirit of the Order,
[[Page 59430]]
and consistent with EPA policy to promote communications between the
Agency and State and local governments, EPA specifically solicits
comment on this proposed rule from State and local officials.
F. Executive Order 13175
As required by Executive Order 13175, entitled Consultation and
Coordination with Indian Tribal Governments (65 FR 67249, November 6,
2000), EPA has determined that this proposed rule does not have tribal
implications because it will not have substantial direct effects on
tribal governments, on the relationship between the Federal government
and the Indian tribes, or on the distribution of power and
responsibilities between the Federal government and Indian tribes, as
specified in the Order. As indicated above, at present, no tribal
governments hold, or have applied for, a pesticide registration. Thus,
Executive Order 13175 does not apply to this proposed rule. In the
spirit of the Order, and consistent with EPA policy to promote
communications between the Agency and State and local governments, EPA
specifically solicits comment on this proposed rule from tribal
officials.
G. Executive Order 13045
This section is not subject to Executive Order 13045, entitled
Protection of Children from Environmental Health Risks and Safety Risks
(62 FR 19885, April 23, 1997) because it does not propose an
environmental standard that is intended to have a negatively
disproportionate effect on children. To the contrary, this action will
provide added protection for children from pesticide risk. The proposed
data requirements are intended to address risks that, if not addressed,
could have a disproportionate negative impact on children. EPA will use
the data and information obtained by this proposed rule to carry out
its mandate under FFDCA to give special attention to the risks of
pesticides to sensitive subpopulations, especially infants and
children.
H. Executive Order 12898
This proposed rule does not have an adverse impact on the
environmental and health conditions in low-income and minority
communities because this proposed rule only impacts entities that
intend to register or currently hold a registration for an
antimicrobial pesticide. Therefore, under Executive Order 12898,
entitled Federal Actions to Address Environmental Justice in Minority
Populations and Low-Income Populations (59 FR 7629, February 16, 1994),
the Agency does not need to consider environmental justice-related
issues.
I. National Technology Transfer and Advancement Act
Section 12(d) of the National Technology Transfer and Advancement
Act of 1995 (NTTAA), 15 U.S.C. 272 note) directs EPA to use voluntary
consensus standards in its regulatory activities unless to do so would
be inconsistent with applicable law or impractical. Voluntary consensus
standards are technical standards (e.g., materials specifications, test
methods, sampling procedures, etc.) that are developed or adopted by
voluntary consensus standards bodies. NTTAA directs EPA to provide
Congress, through OMB, explanations when the Agency decides not to use
available and applicable voluntary consensus standards. This regulation
proposes the types of data to be required to support antimicrobial
pesticide registration but does not propose to require specific methods
or standards to generate those data.
This proposed regulation does not impose any technical standards
that would require Agency consideration of voluntary consensus
standards. The Agency invites comment on its conclusion regarding the
applicability of voluntary consensus standards to this rulemaking.
J. Executive Order 12630
EPA has complied with Executive Order 12630, entitled Governmental
Actions and Interference with Constitutionally Protected Property
Rights (53 FR 8859, March 15, 1988), by examining the takings
implications of this rule in accordance with the ``Attorney General's
Supplemental Guidelines for the Evaluation of Risk and Avoidance of
Unanticipated Takings'' issued under the Executive Order.
K. Executive Order 12988
In issuing this rule, EPA has taken the necessary steps to
eliminate drafting errors and ambiguity, minimize potential litigation,
and provide a clear legal standard for affected conduct, as required by
section 3 of Executive Order 12988, entitled Civil Justice Reform (61
FR 4729, February 7, 1996).
L. Executive Order 13211
This rule is not subject to Executive Order 13211, entitled
``Actions concerning Regulations that Significantly Affect Energy
Supply, Distribution, or Use'' (66 FR 28355, May 22, 2001) because it
is not likely to have any adverse effect on the supply, distribution,
or use of energy.
Lists of Subjects in 40 CFR Part 158
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and record
keeping requirements.
Lists of Subjects in 40 CFR Part 161
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and record
keeping requirements.
Dated: September 24, 2008.
Stephen L. Johnson,
Administrator.
Therefore, it is proposed that 40 CFR part 158 and part 161 be
amended as follows:
1. The authority citation for part 158 continues to read as
follows:
Authority: 7 U.S.C. 136-136y and 21 U.S.C. 346a.
2. Section 158.1(c)(4) is revised to read as follows:
Sec. 158.1 Purpose and scope.
* * * * *
(c) * * *
(4) Antimicrobial pesticides. Subparts A, B, C, D, and W apply to
antimicrobial pesticides.
3. Section 158.100 is amended by revising the heading of paragraph
(a); by revising paragraph (b); by redesignating paragraph (c) as
paragraph (e); and by adding new paragraphs (c) and (d) to read as
follows:
Sec. 158.100 Pesticide use patterns.
(a). General use patterns for conventional, biochemical, and
microbial pesticides. * * *
(b) Pesticide use site index for conventional, biochemical, and
microbial pesticides. The Pesticide Use Site Index for Conventional,
Biochemical, and Microbial Pesticides is a comprehensive list of
specific pesticide use sites. The index is alphabetized separately by
site for all agricultural and all nonagricultural uses. The Pesticide
Use Site Index associates each pesticide use site with one or more of
the 12 general use patterns. It may be used in conjunction with the
data tables to determine the applicability of data requirements to
specific uses. The Pesticide Use Site Index for Conventional,
Biochemical, and Microbial Pesticides, which will be updated
periodically, is available from
[[Page 59431]]
the Agency or may be obtained from the Agency's website at http://www.epa.gov/pesticides.
(c) Antimicrobial pesticide use patterns. The general use patterns
for antimicrobial pesticides are described in Sec. 158.2201.
(d) Pesticide use site index for antimicrobial pesticides. The
Pesticide Use Site Index for Antimicrobial Pesticides is a
comprehensive list of specific antimicrobial use sites. The index is
alphabetized by antimicrobial use sites, and associates each
antimicrobial use site with one or more of the antimicrobial use
patterns. It may be used in conjunction with the data tables to
determine the applicability of data requirements to specific uses. The
Pesticide Use Site Index for Antimicrobial Pesticides, which will be
updated periodically, is available from the Agency or may be obtained
from the Agency's website at http://www.epa.gov/pesticides/regulating/usesite/.
(e) * * *
Sec. 158.400 [Amended]
4. The table in Sec. 158.400(d) is amended by removing the
category ``Efficacy of antimicrobial agents'' and all of the entries
under that category.
5. Part 158 is amended by adding subpart W to read as follows:
Subpart W--Antimicrobial Pesticide Data Requirements
Sec
Sec. 158.2200 Applicability.
Sec. 158.2201 Antimicrobial use patterns.
Sec. 158.2203 Definitions.
Sec. 158.2210 Product chemistry.
Sec. 158.2220 Product performance.
Sec. 158.2230 Toxicology data.
Sec. 158.2240 Nontarget organisms.
Sec. 158.2250 Nontarget plant protection.
Sec. 158.2260 Applicator exposure.
Sec. 158.2270 Post-application exposure.
Sec. 158.2280 Environmental fate.
Sec. 158.2290 Residue chemistry.
Subpart W--Antimicrobial Pesticide Data Requirements
Sec. 158.2200 Applicability.
Subpart W establishes data requirements for any pesticide product
that is:
(a) A pesticide that is intended for use as an ``antimicrobial
pesticide'' within the meaning of FIFRA section 2(mm)(1)(A), regardless
of whether it also meets the criterion of FIFRA section 2(mm)(1)(B).
That criterion excludes from the definition any antimicrobial product
that is intended for a food-use requiring a tolerance or exemption
under FFDCA section 408 or a food additive regulation under FFDCA
section 409. EPA will apply this subpart to all products intended for
an antimicrobial use, purpose or function; the exclusion in FIFRA
section 2(mm)(1)(B) does not exclude products from the data
requirements of this subpart.
(b) A product that bears both antimicrobial and non-antimicrobial
uses or claims is subject to the data requirements for pesticides in
subparts C - O, and U or V of this part with respect to its non-
antimicrobial uses and claims, and to the requirements of this subpart
W with respect to its antimicrobial uses and claims.
(c) A wood preservative, including a product that is intended to
prevent wood degradation problems due to fungal rot or decay, sapstain,
or molds.
(d) An antifoulant, including a product that is intended to kill or
repel organisms that can attach to underwater surfaces, such as boat
bottoms.
Sec. 158.2201 Antimicrobial use patterns.
(a) Antimicrobial use patterns. The 12 general use patterns used in
the data tables in this subpart are:
(1) Agricultural premises and equipment.
(2) Food-handling/storage establishments, premises and equipment.
(3) Commercial, institutional and industrial premises and
equipment.
(4) Residential and public access premises.
(5) Medical premises and equipment.
(6) Human drinking water systems.
(7) Materials preservatives.
(8) Industrial processes and water systems.
(9) Antifoulant paints and coatings.
(10) Wood preservatives.
(11) Swimming pools.
(12) Aquatic areas.
(b) Use site index. The Antimicrobial Use Site Index is a
comprehensive list of specific antimicrobial use sites. The Index
associates antimicrobial use sites with one or more of the 12
antimicrobial use patterns. It is to be used in conjunction with the
data tables in this subpart to determine the applicability of data
requirements to specific uses. The Antimicrobial Pesticide Use Site
Index, which will be updated periodically, is available from the Agency
or may be obtained from the Agency's website at http://www.epa.gov/pesticides/regulating/usesite/.
(c) An applicant unsure of the correct use pattern(s) for his
product should consult the Agency.
Sec. 158.2203 Definitions.
(a) Definitions. The following terms are defined for the purposes
of this subpart:
(1) Disinfectant means a substance that destroys or eliminates a
specific species of infectious or other public health microorganism,
but not necessarily bacterial spores, in the inanimate environment.
(2) Fungicide means a substance that destroys fungi (including
yeasts) and fungal spores pathogenic to man or other animals in the
inanimate environment.
(3) Microbiological water purifier means any unit, water treatment
product or system that removes, kills or inactivates all types of
disease-causing microorganisms from the water, including bacteria,
viruses and protozoan cysts, so as to render the treated water safe for
drinking.
(4) Sanitizer means a substance that reduces the bacterial
population in the inanimate environment by significant numbers, but
does not destroy or eliminate all bacteria or other microorganisms.
(5) Sterilant means a substance that destroys or eliminates all
forms of microbial life in the inanimate environment, including all
forms of vegetative bacteria, bacterial spores, fungi, fungal spores,
and viruses. For purposes of this subpart, ``sporicide'' and
``sterilant'' are synonymous.
(6) Tuberculocide means a substance that destroys or irreversibly
inactivates tubercle bacilli in the inanimate environment.
(7) Virucide means a substance that destroys or inactivates viruses
in the inanimate environment.
(b) Public health claim. An antimicrobial pesticide is considered
to make a public health claim if the pesticide product bears a claim to
control pest microorganisms that pose a threat to human health, and
whose presence cannot readily be observed by the user, including but
not limited to, microorganisms infectious to man in any area of the
inanimate environment. A product makes a public health claim if one or
more of the following apply:
(1) A claim is made for control of specific microorganisms or
classes of microorganisms that are directly or indirectly infectious or
pathogenic to man (or both man and animals). Examples of specific
microorganisms include, but are not limited to, Mycobacterium
tuberculosis, Pseudomonas aeruginosa, Eschericha coli (E. coli), human
immunodeficiency virus (HIV), Streptococcus, and Staphylococcus aureus.
Claims for control of microorganisms infectious or pathogenic only to
animals (such as canine distemper virus or hog cholera virus) are not
considered public health claims.
[[Page 59432]]
(2) A claim is made for the pesticide product as a sterilant,
disinfectant, virucide, sanitizer, or tuberculocide regardless of the
site of use of the product, and regardless of whether specific
microorganisms are identified.
(3) A claim is made for the pesticide product as a fungicide
against fungi infectious or pathogenic to man, or the product does not
clearly state that it is intended for use only against non-public
health fungi.
(4) A claim is made for the pesticide product as a microbiological
water purifier or microbial purification system.
(5) A non-specific claim is made that the pesticide product will
beneficially impact or affect public health at the site of use or in
the environment in which applied (such as a `sanitary' claim), and:
(i) The pesticide product contains one or more ingredients that,
under the criteria in 40 CFR 153.125(a), is an active ingredient with
respect to a public health microorganism and there is no other
functional purpose for the ingredient in the product; or
(ii) The pesticide product is similar in composition to a
registered pesticide product that makes explicit antimicrobial public
health claims.
Sec. 158.2210 Product chemistry.
The product chemistry data requirements of subpart D of this part
apply to antimicrobial products covered by this subpart.
Sec. 158.2220 Product performance.
(a) General. (1) Product performance requirement for all
antimicrobial pesticides. Each applicant must ensure through testing
that his product is efficacious when used in accordance with label
directions and commonly accepted pest control practices. The Agency may
require, on a case-by-case basis, submission of product performance
data for any pesticide product registered or proposed for registration.
(2) Product performance data for each product that bears a public
health claim. Each product that bears a public health claim, as
described in Sec. 158.2203(b), must be supported by product
performance data, as listed in the table in this paragraph. Product
performance data must be submitted with the application for
registration or amended registration.
(3) Determination of data requirements. Subpart B of this part and
Sec. 158.2201 describe how to use the table in paragraph (c) of this
section to determine the product performance data requirements for
antimicrobial pesticide products.
(b) Key. R = Required; EP = End-use product;
(c) Table. The following table shows the data requirements for
product performance.
Table -- Antimicrobial Product Performance Data Requirements
----------------------------------------------------------------------------------------------------------------
Guideline Number Data Requirement All Use Patterns Test Substance
----------------------------------------------------------------------------------------------------------------
91-2 Products for use on R EP
hard surfaces
----------------------------------------------------------------------------------------------------------------
91-3 Products requiring R EP
confirmatory data
----------------------------------------------------------------------------------------------------------------
91-4 Products for use on R EP
fabrics and textiles
----------------------------------------------------------------------------------------------------------------
91-5 Air sanitizers R EP
----------------------------------------------------------------------------------------------------------------
91-7 Products for control of R EP
microbial pests
associated with human
and animal wastes
----------------------------------------------------------------------------------------------------------------
91-8 Products for treating R EP
water systems
----------------------------------------------------------------------------------------------------------------
Sec. 158.2230 Toxicology data.
(a) General. Subpart B of this part and Sec. 158.2201 describe how
to use the table in paragraph (d) of this section to determine the
toxicology data requirements for an antimicrobial pesticide product.
Notes that apply to an individual test including specific conditions,
qualifications, or exceptions are listed in paragraph (e) of this
section.
(b) Uses. The applicant for registration must first determine
whether the use is a high human exposure use or a low human exposure
use. If an applicant is not sure if a specific use is a high human
exposure or a low human exposure use, the applicant should consult the
Agency.
(1) High human exposure uses. For the purpose of determining data
requirements, high human exposure includes those uses which are likely
to result in human exposure over a considerable portion of the human
lifespan, and which are significant in terms of frequency, duration, or
magnitude of exposure, i.e., uses for which there is an expectation of
high, prolonged, or repeated exposure. High human exposure uses of
antimicrobials include but are not limited to:
(i) Any use which requires a tolerance or tolerance exemption
(except for indirect food uses requiring a tolerance or tolerance
exemption in which residues are less than 200 ppb).
(ii) Indirect food uses with residues equal to or greater than 200
ppb.
(iii) Use in human or animal drinking water.
(iv) Fruit and vegetable rinses.
(v) Egg washes.
(vi) Swimming pools.
(vii) Outdoor aquatic uses in lakes, rivers or streams which have
the potential to contaminate potable water.
(viii) Wood preservatives.
(ix) Metalworking fluids.
(2) Low human exposure nonfood and low human exposure indirect food
uses. Generally, low exposure uses are those not listed in paragraph
(b)(1) of this section as high exposure uses.
(3) Tiering of data requirements. Applicants for registration of
antimicrobials may perform tests in a tiered fashion. After the
initially required tests are conducted, additional testing may be
required if results of the initial tests trigger the need for
additional data. Conditions that trigger the need for additional data
are given in the test notes in paragraph (e) of this section.
[[Page 59433]]
(c) Key. R = Required; CR = Conditionally required; NR = Not
required; MP = Manufacturing-use product; EP = End-use product; TGAI =
Technical grade of the active ingredient; TEP = Typical end-use
product; PAI = Pure active ingredient; PAIRA = Pure active ingredient,
radiolabeled; Choice = choice of several test substances depending on
studies required.
(d) Table. The following table shows the data requirements for
toxicology. The test notes appear in paragraph (e) of this section.
Table -- Antimicrobial Toxicology Data Requirements
--------------------------------------------------------------------------------------------------------------------------------------------------------
Use Pattern Test Substance to Support
---------------------------------------------------------
Guideline Number Data Requirement High Low Human Test Note No.
Human20Exposure Exposure MP EP
Uses Uses
--------------------------------------------------------------------------------------------------------------------------------------------------------
Acute Testing..........................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.1100 Acute oral toxicity - rat R R MP and TGAI EP and TGAI 1, 2
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.1200 Acute dermal toxicity R R MP and TGAI EP and TGAI 1, 2, 3
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.1300 Acute inhalation toxicity - R R MP and TGAI EP and TGAI 4
rat
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.2400 Primary eye irritation - R R MP and TGAI EP and TGAI 1, 2, 3
rabbit
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.2500 Primary dermal irritation R R MP and TGAI EP and TGAI 1, 2, 3
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.2600 Dermal sensitization R R MP and TGAI EP and TGAI 1, 2, 3, 5
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.6200 Acute neurotoxicity - rat R CR TGAI TGAI 6
--------------------------------------------------------------------------------------------------------------------------------------------------------
Subchronic Testing.....................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.3100 90-Day oral toxicity - rodent R R TGAI TGAI 7, 8, 9, 15
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.3150 90-Day oral toxicity - R CR TGAI TGAI 7, 10, 11, 15
nonrodent
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.3250 21/28-Day dermal toxicity CR CR TGAI EP and TGAI 12, 13
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.2500 90-Day dermal toxicity CR CR TGAI EP and TGAI 7, 13, 14, 15
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.3465 90-Day inhalation - toxicity - CR CR TGAI TGAI 7, 15, 16, 17
rat
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.6200 90-Day neurotoxicity - rat R CR TGAI TGAI 6, 8
--------------------------------------------------------------------------------------------------------------------------------------------------------
Chronic Testing........................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.4100 Chronic oral toxicity - R CR TGAI TGAI 18, 19, 20
rodent
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.4200 Carcinogenicity - two rodent R CR TGAI TGAI 19, 21, 22
species - rat and mouse
preferred
--------------------------------------------------------------------------------------------------------------------------------------------------------
Developmental Toxicity and Reproduction................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.3700 Prenatal developmental R R TGAI TGAI 23, 24, 25, 26
toxicity - rat and rabbit
preferred
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.3800 Reproduction and fertility R R TGAI TGAI 26, 27, 28, 29
effects
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.6300 Developmental neurotoxicity CR CR TGAI TGAI 28, 29, 30
--------------------------------------------------------------------------------------------------------------------------------------------------------
Mutagenicity...........................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.5100 Reverse mutation assay R R TGAI TGAI 31, 32
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.5300 In vitro mammalian gene R R TGAI TGAI 31, 33
870.5375................................... mutation
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 59434]]
870.5380 In vivo cytogenetics R R TGAI TGAI 31, 34
870.5385...................................
870.5395...................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Special Testing........................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.7485 Metabolism and R CR PAI or PAIRA PAI or PAIRA 35
pharmacokinetics
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.7200 Companion animal safety CR CR NR Choice 36
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.7600 Dermal penetration CR CR Choice Choice 37
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.7800 Immunotoxicity R R TGAI TGAI --
--------------------------------------------------------------------------------------------------------------------------------------------------------
(e) Test notes. The following test notes apply to the data
requirements in the table to paragraph (d) of this section:
1. Not required if test material is a gas or highly volatile
liquid.
2. For the six acute toxicity studies conducted with the end-use
product, the test must be conducted using the product as formulated
for sale and distribution. However, if the end-use product is
labeled that the product is to be diluted for use, the applicant may
also conduct certain studies using the highest diluted concentration
(i.e. the least diluted product) permitted by the labeling. The end-
use dilution testing is in addition to the as- formulated-for-sale
testing and used only for labeling purposes. Consultation with the
Agency is highly suggested to assure that the appropriate product
and any appropriate dilutions are tested.
3. Not required if test material is corrosive to skin or has pH
less than 2 or greater than 11.5.
4. Data are required when the product consists of, or under
conditions of use will result in, a respirable material (e.g., gas,
vapor, aerosol or particulates).
5. Data are required if repeated dermal exposure is likely to
occur under conditions of use.
6. For low exposure uses, data are required if the neurotoxicity
screen in the 90-day oral rodent study or other data indicate
neurotoxicity.
7. The 90-day dermal toxicity study or 90-day inhalation
toxicity study may be substituted for the 90-day oral toxicity study
if the Agency determines that dermal or inhalation exposure is a
major route of exposure.
8. All 90-day subchronic studies in the rodent can be designed
to simultaneously fulfill the requirements of the 90-day
neurotoxicity study by adding separate groups of animals for
testing.
9. The 90-day study is required in the rodent for hazard
characterization (possibly endpoint selection) and dose-setting for
the chronic/carcinogenicity study. It is not required in the mouse,
but the Agency would encourage the applicant to conduct a 90-day
range finding study for the purposes of dose selection for the mouse
carcinogenicity study to achieve adequate dosing and an acceptable
study. The applicant is also encouraged to consult with the Agency
on the results of the 90-day mouse study prior to conducting the
carcinogenicity study.
10. A 1-year non-rodent study (i.e., 1-year dog study) may be
required if the Agency finds that a pesticide chemical is highly
bioaccumulating and is eliminated slowly. Thus it does not achieve
steady state or sufficient tissue concentrations to elicit an effect
during a 90-day study. EPA may require the appropriate tier II
metabolism and pharmacokinetic studies to evaluate more precisely
bioavailability, half life, and steady state to determine if a
longer duration dog toxicity study is needed.
11. For low human exposure uses, data are required if any of the
following criteria are met:
i. The use of the pesticide is likely to result in repeated
human exposure over a limited portion of the human lifespan, as
determined by the Agency.
ii. The use is an indirect food use (less than 200 ppb).
12. Data are required if the intended use of the antimicrobial
pesticide product is expected to result in human exposure to the
product, and the three following conditions are met:
i. Human exposure is via skin contact.
ii. Expected human exposure is not purposeful, and is over a
limited portion of the human lifespan; however, as determined by
EPA, the exposure is significant in terms of the frequency of
exposure, magnitude of exposure, or the duration of exposure.
iii. Data from a subchronic 90-day dermal toxicity study are not
available and the 90-day dermal toxicity study has not been
triggered.
13. EP testing is required if the product or any component of
the product may increase dermal absorption of the active
ingredient(s) or increase toxic or pharmacologic effects, as
determined by testing the TGAI or based on available information
about the toxic effects of the product or its components.
14. Data are required if the use pattern is such that the dermal
route would be the major route of exposure or if the active
ingredient of the product is known or expected to be metabolized
differently by the dermal route of exposure than by the oral route,
and a metabolite of the active ingredient is the toxic moiety.
15. A 90-day oral toxicity test is not required for heating,
ventilation, air conditioning, and refrigeration systems
(collectively referred to as HVAC), and two 90-day toxicity tests,
one by the dermal route and one by the inhalation route are
required.
16. Data are required if there is the likelihood of significant
repeated inhalation exposure to the pesticide as a gas, vapor, or
aerosol.
17. Based on estimates of the magnitude and duration of human
exposure, studies of shorter duration, e.g., 21- or 28-days, may be
sufficient to satisfy this requirement. Applicants for registration
may consult with the Agency to determine whether studies of shorter
duration would meet this requirement.
18. Based on the positive results of the acute and/or 90-day
neurotoxicity studies, or on other data indicating neurotoxicity, a
chronic/neurotoxicity study (i.e. a chronic study with additional
neurotoxicity evaluations) may be required to provide information
about potential neurotoxic effects from long-term exposures.
19. Studies which are designed to simultaneously fulfill the
requirements of both the chronic oral and carcinogenicity studies
(i.e., a combined study) may be conducted.
20. For low exposure, data are required if either of the
following criteria are met:
i. The use of the pesticide is likely to result in repeated
human exposure over a limited portion of the human lifespan, as
determined by the Agency, or
ii. The use requires that a tolerance or a tolerance exemption
be established.
[[Page 59435]]
21. For low exposure, data are required if any of the following
criteria, as determined by the Agency, are met:
i. The use of the pesticide is likely to result in significant
human exposure over a considerable portion of the human life span
which is significant in terms of frequency time, duration, and/or
magnitude of exposure.
ii. The use requires that a tolerance or a tolerance exemption
be established.
iii. The active ingredient, metabolite, degradate, or impurity
A. is structurally related to a recognized carcinogen,
B. causes mutagenic effects as demonstrated by in vitro or in
vivo testing, or
C. produces a morphologic effect in any organ (e.g.,
hyperplasia, metaplasia) in subchronic studies that may lead to a
neoplastic change.
22. If the requirement for a carcinogenicity study in any
species is modified or waived for any reason, then a subchronic 90-
day oral study in the same species may be required.
23. Testing in two species is required for all uses.
24. The oral route, by oral intubation, is preferred, unless the
chemical or physical properties of the test substance, or the
pattern of exposure, suggest a more appropriate route of exposure.
25. Additional testing by other routes of exposure may be
required if the pesticide is determined to be a prenatal
developmental toxicant after oral dosing.
26. The developmental toxicity study in rodents may be combined
with the two-generation reproduction study in rodents by using a
second mating of the parental animals in either generation.
Protocols must be approved by the Agency prior to the initiation of
the study. Details for developing protocols are available from the
Agency.
27. A two-generation reproduction study is required.
28. An information-based approach to testing is preferred, which
utilizes the best available knowledge on the chemical (hazard,
pharmacokinetic, or mechanistic data) to determine whether a
standard guideline study, an enhanced guideline study, or an
alternative study should be conducted to assess potential hazard to
the developing animal, or in some cases to support a waiver for such
testing. Applicants must submit any alternative proposed testing
protocols and supporting scientific rationale to the Agency.
Protocols must be approved by the Agency prior to the initiation of
the study. Details for developing protocols are available from the
Agency.
29. The use of a combined two-generation reproduction/
developmental neurotoxicity study that utilizes the two-generation
reproduction study in rodents as a basic protocol for the addition
of other endpoints or functional assessments in the immature animal
is encouraged.
30. A DNT study is required using a weight-of-evidence approach
when:
i. The pesticide causes treatment-related neurological effects
in adult animal studies (i.e, clinical signs of neurotoxicity,
neuropathology, functional or behavioral effects).
ii. The pesticide causes treatment-related neurological effects
in developing animals, following pre- or post-natal exposure (i.e.,
nervous system malformations or neuropathy, brain weight changes in
offspring, functional or behavioral changes in the offspring).
iii. The pesticide elicits a causative association between
exposures and adverse neurological effects in human epidemiological
studies.
iv. The pesticide evokes a mechanism that is associated with
adverse effects on the development of the nervous system (i.e.,
structure-activity-relationship (SAR) to known neurotoxicants,
altered neuroreceptor or neurotransmitter responses).
31. To enhance the weight-of-evidence determination for the
pesticide's mutagenicity, the Agency requires submission of other
mutagenicity test results, besides those specifically listed in this
table, that may have been performed for other endpoints that may be
predictive of mutagenicity. A reference list of all studies and
papers known to the applicant concerning the mutagenicity of the
test chemical must be submitted with the required studies.
32. Testing in Salmonella and E. coli may be acceptable, if the
testing can be conducted at high enough levels, as determined by the
Agency. If the testing cannot be conducted at high enough levels,
then the applicant must consult with the Agency to determine other
needed mutagenicity testing.
33. For the in vitro mammalian gene mutation study, there is a
choice of assays using either mouse lymphoma L5178Y cell thymidine
kinase (tk) gene locus, maximizing assay conditions for small colony
expression and detection; Chinese hamster ovary (CHO) or Chinese
hamster lung fibroblast (v79) cells, hypoxanthine-guanine
phosphoribosyl transferase (hgprt) gene locus, accompanied by an
appropriate in vitro test for clastogenicity; or CHO cells strains
AS52, xanthine-guanine phosphoribosyl transferase (xprt) gene locus.
34. There is a choice of assays, but initial consideration
should be given to the rodent bone marrow assay. The micronucleus
rodent bone marrow assay is preferred; the rodent bone marrow assays
using metaphase analysis (aberrations) are acceptable.
35. For low exposure, these data are required when chronic or
carcinogenicity studies are also required. These data may be
required if significant adverse effects are seen in available
toxicology studies and these effects can be further elucidated by
metabolism studies.
36. These data may be required if the product's use will result
in exposure to domestic animals through, but not limited to, direct
application.
37. A risk assessment assuming that dermal absorption is equal
to oral absorption must be performed to determine if the dermal
penetration study is required, and to identify the doses and
duration of exposure for which dermal absorption is to be
quantified.
Sec. 158.2240 Nontarget organisms.
(a) General. Subpart B of this part and Sec. 158.2201 describe how
to use the table in paragraph (e) of this section to determine the
terrestrial and aquatic nontarget organisms and nontarget plant
protection data requirements for a particular antimicrobial pesticide
product. Notes that apply to an individual test including specific
conditions, qualifications, or exceptions are listed in paragraph (f)
of this section.
(1) Terrestrial and aquatic nontarget organism data are required to
support the registration of most end-use and manufacturing-use
antimicrobial products.
(2) Data are generally not required to support end-use products of
a gas, highly volatile liquid, highly reactive solid, or a highly
corrosive material.
(3) If the Agency determines that the transformation products of
the parentcompound are more toxic, persistent, bioaccumulative, or have
been shown to cause adverse effects in mammalian or aquatic
reproductive studies, then data on those transformation products are
required to support registration.
(4) For wood preservatives, the Agency may require data on both the
parent compound, which is incorporated into wood, and on
transformation/degradation products which occur in wood post-treatment
or occur as dislodgeable residues (such as hand contact with treated
wood) or leachate residues (such as from soil or water contact with
treated wood).
(b) Low environmental exposures. For the purpose of determining
data requirements, the low environmental exposure grouping of use
patterns includes the following use patterns or partial use patterns:
(1) Agricultural premises and equipment.
(2) Food-handling/storage establishments, premises, and equipment.
(3) Commercial, institutional and industrial premises and
equipment.
(4) Residential and public access premises.
(5) Medical premises and equipment.
(6) Human drinking water systems.
(7) Materials preservatives.
(8) Swimming pools.
(9) Recirculating industrial processes and water systems in which
the treated water is re-used repeatedly within the system.
(c) High environmental exposures. For the purposes of determining
data requirements, the high environmental exposure grouping of use
patterns includes the following use patterns or partial use patterns:
(1) Once-through industrial processes and water systems in which
the water is not re-used, and is released after a single cycle through
the system.
[[Page 59436]]
(2) Antifoulant paints and coatings.
(3) Wood preservatives.
(4) Aquatic areas.
(d) Key. MP = Manufacturing use product; EP = End use product; R =
Required; CR = Conditionally required; NR = Not required; TGAI =
Technical grade of the active ingredient; TEP = Typical end-use
product; PAIRA = Pure active ingredient radiolabeled; a.i. = active
ingredient.
(e) Table. The following table shows the data requirements for
nontarget organisms. The test notes appear in paragraph (f) of this
section.
Table -- Antimicrobial Nontarget Organism Data Requirements
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Use Pattern Test Substance to
------------------------------------------------------------------------- Support
High Environmental Exposure ------------------------
---------------------------------------------------------- Test Note
Guideline Number Data Requirement Low Industrial No.
Environmental Processes and Antifoulant Wood Aquatic MP EP
Exposure Water Systems Coatings and Preservatives Areas
(Once-Through) Paints
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Tier One Testing................................................................................................................................................................................
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
850.2100 Acute avian oral toxicity R R R R R TGAI TGAI 1
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
850.1010 Acute freshwater invertebrates R R R R R TGAI TGAI 2
toxicity
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
850.1075 Acute freshwater fish toxicity R R R R R TGAI TGAI 3
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Higher Tier Testing.............................................................................................................................................................................
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Avian Testing
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
850.2200 Avian dietary toxicity CR CR CR CR R TGAI TGAI 4, 5
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
850.2300 Avian reproduction CR CR CR CR R TGAI TGAI 1, 6
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Aquatic Organisms Testing
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
850.1010 Acute freshwater invertebrates CR R NR NR R --- TEP 2, 7
toxicity
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
850.1075 Acute freshwater fish toxicity CR R NR NR R --- TEP 7
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
850.1025 Acute estuarine and marine CR CR R CR CR TGAI TGAI 8, 9
850.1035...................................... organisms toxicity
850.1045......................................
850.1055......................................
850.1075......................................
-------------------------------------------------------------------------------------------------------------------------------------------------
Acute estuarine and marine CR CR NR NR CR --- TEP 7, 8
organisms toxicity
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
850.1400 Fish early-life stage CR R R CR R TGAI TGAI 10
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
850.1300 Aquatic invertebrate life- cycle CR R R CR R TGAI TGAI 10
850.1350......................................
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
850.1500 Fish life-cycle CR CR CR CR CR TGAI TGAI 11, 12
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 59437]]
850.1710 Aquatic organisms, CR CR CR CR CR TGAI.PAI, TGAI.PAI, 13
850.1730...................................... bioavailability, degradate degradate
850.1850...................................... biomagnification, toxicity tests
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
850.1950 Simulated or actual field testing CR CR CR CR CR TEP TEP 14, 15, 16
for aquatic organisms
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Sediment Testing
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
850.1735 Whole sediment; acute freshwater CR CR R CR CR TGAI TGAI 15, 17
invertebrates
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
850.1740 Whole sediment; acute marine CR CR R CR CR TGAI TGAI 15, 17, 19
invertebrates
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
None Whole sediment; chronic CR CR CR CR CR TGAI TGAI 15, 18, 19
invertebrates fresh-water and
marine
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Insect Pollinator Testing
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
850.3020 Honeybee acute contact CR NR NR CR NR TGAI TGAI 20
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
850.3030 Toxicity of residues to honeybees CR NR NR CR NR TGAI TEP or 21
treated
wood
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
(f) Test notes. The following test notes apply to the data
requirements in the table to paragraph (e) of this section:
1. For low environmental exposures, data are required for one
avian species. For industrial processes and water systems (once-
through), antifoulant paints and coatings, wood preservatives, and
aquatic areas, data are required for one waterfowl species and one
upland game bird species.
2. Data are required on one freshwater aquatic invertebrate
species.
3. For low environmental exposures, data are required on one
species of fish, either one cold water species or a warm water
species. Testing on a second species is required if the active
ingredient or principal transformation products are stable in the
environment and the LC50 in the first species is greater
than 1 ppm or 1mg/L. For all other use patterns, data are required
on two species of fish, one cold water species and one warm water
species.
4. For low environmental exposures, industrial processes and
water systems (once-through), antifoulant paints and coatings, and
wood preservatives, data are required for one waterfowl species, if
the avian acute oral LD50 (TGAI testing) is less than or
equal to 100 mg a.i./kg and a.i. residues or its principal
transformation products are likely to occur in avian feed items.
Data on one upland game bird species are required if the avian
dietary LC50 in the first species tested is less than or
equal to 500 ppm a.i. in the diet.
5. For aquatic areas, data are required on one waterfowl species
and one upland game bird species.
6. For low environmental exposures, industrial processes and
water systems (once-through), antifoulant paints and coatings, and
wood preservatives, data are required if one or more of the
following criteria are met:
i. Birds may be subjected to repeated or continued exposure to
the pesticide or any of its transformation products, especially
preceding or during the breeding season.
ii. The pesticide or any of its major metabolites or degradation
products are stable in the environment to the extent that a
potentially toxic amount may persist in avian feed.
iii. The pesticide or any of its major metabolites or
degradation products are stored or accumulated in plant or animal
tissues, as indicated by the octanol/water partition coefficient
(Kow is greater than or equal to 1,000), accumulation
studies, metabolic release and retention studies, or as indicated by
structural similarity to known bioaccumulative chemicals.
iv. Any other information, such as that derived from mammalian
reproduction studies that indicate that reproduction in terrestrial
vertebrates may be adversely affected by the anticipated use of the
pesticide product.
[[Page 59438]]
7. TEP testing is required for any product which meets one or
more of the following conditions:
i. The estimated environmental concentration (EEC) in the
aquatic environment is equal to or greater than one-half the
LC50/EC50 of the TGAI when the end-use product
is used as directed.
ii. An ingredient in the end-use product other than the active
ingredient is expected to enhance the toxicity of the active
ingredient or to cause toxicity to aquatic organisms.
8. Data are required on one estuarine/marine mollusk, one
estuarine/marine invertebrate, and one estuarine/marine fish
species.
9. For low environmental exposures, industrial processes and
water systems (once-through), wood preservatives, and aquatic areas,
data are required if the pesticide residues from the parent compound
and/or transformation products are likely to enter the estuarine/
marine environment.
10. For low environmental exposures, data are required if
pesticide residues from the parent compound or transformation
products are likely to enter freshwater or estuarine/marine
environments, as determined by the Agency. For wood preservatives,
data are required if pesticide residues from the parent compound,
transformation products, and/or leachates from preservative-treated
wood are likely to enter freshwater or estuarine/marine
environments, as determined by the Agency. Testing should be
conducted with the most sensitive organism (either freshwater or
estuarine/marine vertebrates, or freshwater or estuarine/marine
invertebrates), as determined from the results of the acute toxicity
tests (acute EC50 freshwater invertebrates; acute
LC50/EC50 estuarine and marine organisms;
acute freshwater fish LC50.)
11. Data are required on estuarine /marine species if the
product is intended for direct application to the estuarine or
marine environment, or the product is expected to enter this
environment in significant concentrations (as determined by the
Agency) because of its expected use or mobility patterns.
12. Data are required on freshwater species if the end-use
product is intended to be applied directly to water, or is expected
to be transported to water from the intended use site, and when one
or more of the following conditions apply:
i. If the Estimated Environmental Concentration (EEC) in water
is equal to or greater than 0.1 of the no-observed-effect
concentration or no-observed-effect level (NOEC/NOEL) in the fish
early-life stage or invertebrate life-cycle tests.
ii. If studies of other organisms indicate that the reproductive
physiology of fish may be affected.
13. Not required when:
i. The octanol/water partition coefficients of the pesticide and
its major degradates are less than 1,000; or
ii.There are no potential exposures to fish and other nontarget
aquatic organisms; or
iii. The hydrolytic half-life is less than 5 days at pH 5, 7,
and 9.
14. Environmental chemistry methods used to generate data
associated with this study must include results of a successful
confirmatory method trial by an independent laboratory. Test
standards and procedures for independent laboratory validation are
available as addenda to the guideline for this test requirement.
15. Protocols must be approved by the Agency prior to the
initiation of the study. Details for developing protocols are
available from the Agency.
16. Data are required if the intended use pattern, and the
physical/chemical properties and environmental fate characteristics
of the antimicrobial indicate significant potential exposure and
based on the results of the acute and chronic aquatic organism
testing significant impairment of nontarget aquatic organisms could
result.
17. Data are required if the half-life of the pesticide in the
sediment is equal to or less than 10 days in either the aerobic soil
or aquatic metabolism studies, and if one or more of the following
conditions are met:
i. The soil partition coefficient (Kd) is equal to or
greater than 50.
ii. The log Kow is equal to or greater than 3.
iii. The Koc is equal to or greater than 1,000.
18. Data are required if the EEC in sediment is > 0.1 of the
acute LC50/EC50 values and if one or more of
the following conditions are met:
i. The soil partition coefficient (Kd) is equal to or
greater than 50 L/kg.
ii. The log Kow is equal to or greater than 3.
iii. The Koc is equal to or greater than 1,000.
19. Sediment testing with estuarine/marine test species is
required if the product is intended for direct application to the
estuarine or marine environment or the product is expected to enter
this environment in significant concentrations (as determined by the
Agency) either by runoff or erosion, because of its expected use or
mobility pattern.
20. Data are required only for beehive applications when the
beehive (empty or occupied) is treated.
21. If beehives are constructed of treated wood a study similar
to ``Honey Bee Toxicity of Residues on Foliage'' is required using
treated wood instead of the foliage. Protocols must be approved by
the Agency prior to the initiation of the study. Details for
developing protocols are available from the Agency.
Sec. 158.2250 Nontarget plant protection.
(a) General. Subpart B of this part and Sec. 158.2201 describe how
to use the table in paragraph (e) of this section to determine the
nontarget plant protection data requirements for a particular
antimicrobial pesticide product. Notes that apply to an individual test
including specific conditions, qualifications, or exceptions are listed
in paragraph (f) of this section.
(b) Low environmental exposures. For the purpose of determining
data requirements, the low environmental exposure grouping of use
patterns includes the following use patterns or partial use patterns:
(1) Agricultural premises and equipment.
(2) Food-handling/storage establishments, premises, and equipment.
(3) Commercial, institutional and industrial premises and
equipment.
(4) Residential and public access premises.
(5) Medical premises and equipment.
(6) Human drinking water systems.
(7) Materials preservatives.
(8) Swimming pools.
(9) Recirculating industrial processes and water systems in which
the treated water is re-used repeatedly within the system.
(c) High environmental exposures. For the purposes of determining
data requirements, the high environmental exposure grouping of use
patterns includes the following use patterns or partial use patterns:
(1) Once-through industrial processes and water systems in which
the water is not re-used, and is released after a single cycle through
the system.
(2) Antifoulant paints and coatings.
(3) Wood preservatives.
(4) Aquatic areas.
(d) Key. MP = Manufacturing use product; EP = End use product; R =
Required; CR = Conditionally required; NR = Not required; TGAI =
Technical grade of the active ingredient; TEP = Typical end-use
product.
(e) Table. The following table shows the data requirements for
nontarget plant protection. The test notes appear in paragraph (f) of
this section.
[[Page 59439]]
Table -- Nontarget Plant Protection Data Requirements
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Use Pattern Test Substance to Support
----------------------------------------------------------------------------------------------------
High Environmental Exposure
----------------------------------------------------
Industrial Test Note
Guideline Number Data Requirement Low Environmental Processes No.
Exposure and Water Antifoulant Wood Aquatic MP EP
Systems Coatings Preservatives Areas
(Once- and Paints
Through)
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
850.4225 Seedling emergence, Tier II - CR R R R R TEP TEP 1, 2
dose response
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
850.4250 Vegetative vigor, Tier II - CR CR NR R R TEP TEP 1, 3
dose response
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
850.4400 Aquatic plant growth (aquatic CR R R R R TGAI, TEP TGAI, TEP 2, 4
vascular plant) Tier II - dose
response
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
850.5400 Aquatic plant growth (algal) R R R R R TGAI, TEP TGAI, TEP 4, 5, 6
Tier II (dose response)
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
850.4300 Terrestrial field CR CR CR CR CR TEP TEP 7, 8, 9
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
850.4450 Aquatic field CR CR CR CR CR TEP TEP 7, 8, 9
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
(f) Test notes. The following test notes apply to the data
requirements in the table to paragraph (e) of this section:
1. Data on only one plant species (rice, Oryza sativa) are
required.
2. For low environmental exposures, data are required if the
aquatic (algal) plant growth Tier II study demonstrates detrimental
effects at less than 1.0 ppm or mg/L.
3. For low environmental exposures, and industrial processes and
water systems (once-through), data are required if one or more of
the following criteria are met:
i. The octanol/water partition coefficient (Kow) for
the active ingredient or principal transformation products >= 1,000
for the active ingredient or principal transformation products;
ii. The hydrolysis half-life of the active ingredient or
principal transformation products in water is > 4 days.
iii. The results of the ready biodegradability study [Sec.
158.2280] indicate that the active ingredient or principal
degradation products are not biodegradable in 28 days, i.e. the
biodegradation curve has not reached a plateau for at least three
determinations within the 28 days.
4. For TEP testing, data are required for the applicant's end-
use product if an ingredient in the end-use product, other than the
active ingredient, is expected to enhance the toxicity of the active
ingredient.
5. One Tier II (dose response) study, conducted with Selenastrum
capricornutum, is required for the low environmental exposure
category grouping. If the results of this study exhibits detrimental
effects (is less than 1.0 ppm or mg/L), then additional Tier II
(dose response) studies are required on three species (Anabaena
flos-aquae, Navicula pelliculosa, and Skeletonema costatum.
6. For industrial processes and water systems (once-through),
antifoulant coatings and paints, wood preservatives, and aquatic
areas, Tier II (dose response) studies are required on four species
(Anabaena flos-aquae, Navicula pelliculosa, Skeletonema costatum,
and Selenastrum capricornutum.
7. Environmental chemistry methods used to generate data must
include the results of a successful confirmatory method trial by an
independent laboratory.
8. Tests are required on a case-by-case basis based on the
results of lower tier plant protection studies, adverse incident
reports, intended use pattern(s), and environmental fate
characteristics that indicate potential exposure.
9. Protocols must be approved by the Agency prior to the
initiation of the study. Details for developing protocols are
available from the Agency.
Sec. 158.2260 Applicator exposure.
(a) General. Subpart B of this part and Sec. 158.2201 describe how
to use the table in paragraph (d) of this section to determine the
applicator exposure data requirements for antimicrobial pesticide
products. Notes that apply to an individual test including specific
conditions, qualifications, or exceptions are listed in paragraph (e)
of this section.
(1) If EPA determines that industrial standards, such as the
workplace standards set by the Occupational Safety and Health
Administration, provide adequate protection for a particular pesticide
or a particular use pattern, applicator exposure data may not be
required for that pesticide or the use pattern. Applicants should
consult with the Agency on appropriate testing before the initiation of
studies.
(2) The Agency may accept surrogate exposure data estimations from
other sources to satisfy applicator exposure data requirements if the
data meet the
[[Page 59440]]
basic quality assurance, quality control, good laboratory practice, and
other scientific requirements set by EPA. In order to be acceptable,
the Agency must find that the surrogate exposure data estimations have
adequate information to address applicator exposure data requirements
and contain enough adequate replicates of acceptable quality to reflect
the specific use prescribed on the label and the applicator activity of
concern, including formulation type, application methods and rates,
type of activity, and other pertinent information. The Agency will
consider using such surrogate data for evaluating human exposure on a
case-by-case basis.
(3) Occupational uses include not only handlers, mixers, loaders,
and applicators, but also commercial applications to residential sites.
Residential uses are limited to non-occupational, i.e., non-
professional, antimicrobial applications. Both occupational and
residential applicator data may be required for the same product.
(b) Criteria for testing. Applicator exposure data described in
paragraph (d) of this section are required based on toxicity and
exposure criteria. Data are required if a product meets, as determined
by the Agency, at least one of the toxicity criteria in paragraph
(b)(1) of this section, and at least one of the exposure criteria in
paragraph (b)(2) of this section.
(1) Toxicity criteria. i. Evidence of potentially significant
adverse effects have been observed in any applicable toxicity studies.
ii. Scientifically sound epidemiological or poisoning incident data
indicate that adverse health effects may have resulted from handling of
the pesticide.
(2) Exposure criteria. i. Dermal exposure may occur during use.
ii. Respiratory exposure may occur during use.
(c) Key. R = Required; CR = Conditionally required; TEP = Typical
end-use product.
(d) Table. The following table shows the data requirements for
applicator exposure. The test notes appear in paragraph (e) of this
section.
Table -- Antimicrobial Applicator Exposure Data Requirements
--------------------------------------------------------------------------------------------------------------------------------------------------------
Guideline Number Data Requirements Occupational Residential Test Substance Test Note No
--------------------------------------------------------------------------------------------------------------------------------------------------------
875.1100 Dermal outdoor R R TEP 1, 2, 3
exposure
--------------------------------------------------------------------------------------------------------------------------------------------------------
875.1200 Dermal indoor exposure R R TEP 1, 2, 3, 4
--------------------------------------------------------------------------------------------------------------------------------------------------------
875.1300 Inhalation outdoor R R TEP 1, 2, 3
exposure
--------------------------------------------------------------------------------------------------------------------------------------------------------
875.1400 Inhalation indoor R R TEP 1, 2, 3, 4
exposure
--------------------------------------------------------------------------------------------------------------------------------------------------------
875.1500 Biological monitoring CR CR TEP 1, 2, 3
--------------------------------------------------------------------------------------------------------------------------------------------------------
875.1600 Data reporting and R R TEP 5
calculations
--------------------------------------------------------------------------------------------------------------------------------------------------------
875.1700 Product use R R TEP --
information
--------------------------------------------------------------------------------------------------------------------------------------------------------
(e) Test notes. The following test notes apply to the data
requirements in the table to paragraph (d) of this section:
1. Protocols must be approved by the Agency prior to the
initiation of the study. Details for developing protocols are
available from the Agency.
2. Biological monitoring data may be submitted in addition to,
or in lieu of, dermal and inhalation passive dosimetry exposure
data, provided the human pharmacokinetics of the pesticide or
metabolite/analog compounds (i.e., whichever method is selected as
an indicator of body burden or internal dose) allow for the back
calculation to the total internal dose.
3. For products with both indoor and outdoor uses, and similar
conditions of use, data are generally required for the indoor
applications only. However, data for outdoor uses are required if
the Agency expects outdoor uses to result in greater exposure than
indoor uses (e.g., higher use rates and application frequency, or
longer exposure duration, or application methods/equipment create
potential for increased dermal or inhalation exposure in outdoor
versus indoor use sites). In certain cases, when a pesticide is used
both indoors and outdoors under dissimilar conditions of use, the
Agency may require submission of applicator exposure data for both
use patterns.
4. For metal working fluids (MWFs), the Agency can provide
written guidance concerning exposure, toxicity, and other data
requirements for ``open'' and ``closed'' MWF systems.
5. Data reporting and calculations are required when handler
exposure data are required.
Sec. 158.2270 Post-application exposure.
(a) General. Subpart B of this part and Sec. 158.2201 describe how
to use the table in paragraph (d) of this section to determine the
post-application exposure data requirements for antimicrobial pesticide
products. The data generated during these studies are used to determine
the quantity of pesticide to which people may be exposed after
application. Notes that apply to an individual test, including specific
conditions, qualifications, or exceptions to the designated test, are
listed in paragraph (e) of this section.
(1) For all end-use products, post-application exposure data are
required when certain toxicity criteria are met and the human
activities associated with the pesticide's use pattern can lead to
potential adverse exposures.
(2) If EPA determines that industrial standards, such as the
workplace standards set by the Occupational Safety and Health
Administration, provide adequate protection for a particular pesticide
or a particular use pattern, post-application exposure data may not be
required for that pesticide or the use pattern. Applicants should
consult with the Agency on appropriate testing before the initiation of
studies.
(3) The Agency may accept surrogate exposure data estimations from
other sources to satisfy applicator exposure data requirements if the
data meet the basic quality assurance, quality control, good laboratory
practice, and other scientific requirements set by EPA. In order to be
acceptable, the Agency must find that the surrogate exposure data
estimations have adequate information to address applicator exposure
data requirements and contain enough adequate replicates of acceptable
quality to reflect the specific use prescribed on the label and the
applicator activity of concern, including formulation type, application
methods and rates, type of activity, and other pertinent information.
The Agency will consider using such surrogate data for evaluating human
exposure on a case-by-case basis.
[[Page 59441]]
(b) Criteria for Testing. Post-application exposure data described
in paragraph (d) of this section are required based on toxicity and
exposure criteria. Data are required if a product meets, as determined
by the Agency, at least one of the toxicity criteria in paragraph
(b)(1) of this section, and at least one of the exposure criteria in
paragraph (b)(2) of this section.
(1) Toxicity criteria. (i) Evidence of potentially significant
adverse effects have been observed in any applicable toxicity studies.
(ii) Scientifically sound epidemiological or poisoning incident
data indicate that adverse health effects may have resulted from
handling of the pesticide.
(2) Exposure criteria. (i) Outdoor uses. (A) Occupational human
post-application exposure to residues of antimicrobial pesticides could
occur as the result of, but is not limited to, worker re-entry into
treatment sites, clean-up and equipment maintenance tasks, handling
wood preservative-treated wood, or other work-related activity.
(B) Residential human post-application exposure to residues of
antimicrobial pesticides could occur following the application of
antimicrobials pesticides to outdoor areas and spaces at residential
sites, such as, but not limited to homes, daycare centers, and other
public buildings.
(ii) Indoor uses. (A) Occupational human post-application exposure
to pesticide residues could occur following the application of the
antimicrobial pesticide to indoor spaces or surfaces.
(B) Residential human post-application exposure to pesticide
residues could occur following the application of the antimicrobial
pesticide to indoor spaces or surfaces at residential sites, such as,
but not limited to homes, daycare centers, hospitals, schools, and
other public buildings.
(c) Key. R = Required; CR = Conditionally required; NR = Not
required; TEP = Typical end-use product.
(d) Table. The following table shows the data requirements for
post-application exposure. The test notes appear in paragraph (e) of
this section.
Table -- Antimicrobial Post-Application Exposure Data Requirements
--------------------------------------------------------------------------------------------------------------------------------------------------------
Use Sites
Guideline Number Data Requirement ---------------------------------------- Test Substance Test Note
Occupational Residential No.
--------------------------------------------------------------------------------------------------------------------------------------------------------
875.2200 Soil residue dissipation CR CR TEP 1, 2, 3
--------------------------------------------------------------------------------------------------------------------------------------------------------
875.2300 Indoor surface residue R R TEP 1, 3, 4, 5,
dissipation 6
--------------------------------------------------------------------------------------------------------------------------------------------------------
875.2400 Dermal exposure R R TEP 1, 3, 7, 8
--------------------------------------------------------------------------------------------------------------------------------------------------------
875.2500 Inhalation exposure R R TEP 1, 8, 9
--------------------------------------------------------------------------------------------------------------------------------------------------------
875.2600 Biological monitoring CR CR TEP 1, 8, 10
--------------------------------------------------------------------------------------------------------------------------------------------------------
875.2700 Product use information R R TEP ---
--------------------------------------------------------------------------------------------------------------------------------------------------------
875.2800 Description of human activity R R TEP ---
--------------------------------------------------------------------------------------------------------------------------------------------------------
875.2900 Data reporting and calculations R R TEP 11
--------------------------------------------------------------------------------------------------------------------------------------------------------
875.3000 Non-dietary ingestion exposure NR R TEP 1, 12
--------------------------------------------------------------------------------------------------------------------------------------------------------
(e) Test notes. The following test notes apply to the data
requirements in the table to paragraph (d) of this section:
1. Protocols must be approved by the Agency prior to the
initiation of the study. Details for developing protocols are
available from the Agency.
2. For residential wood preservative uses, data are required if
there is likely to be soil in contact with or adjacent to treated
wood, including but not limited to decks, play sets, and gazebos.
3. The applicant must submit residue dissipation data in
conjunction with dermal exposure data, to establish chemical
transfer coefficients used to estimate transfer of residues to human
skin.
4. For wood preservatives, data are required for treated wood
surfaces where post-application contact with treated wood is
anticipated.
5. For occupational uses, data are required if the pesticide is
applied to or around surfaces, and if the human activity data
indicate that workers are likely to have post-application dermal
contact with treated indoor surfaces while participating in typical
activities.
6. Data are required for residential sites. This includes but is
not limited to the following use patterns: commercial,
institutional, and industrial premises and equipment (including
residential school and daycare institutions); residential and public
access premises; material preservatives (including those used in
residential products including but not limited to paints and plastic
toys) and wood preservatives (when contact with treated wood is
likely to occur).
7. Data are required for occupational and residential use sites
if the human activity data indicate the potential for post-
application dermal exposures while participating in typical
activities.
8. Biological monitoring data may be submitted in addition to,
or in lieu of, dermal and inhalation passive dosimetry exposure data
provided the human pharmacokinetics of the pesticide or metabolite/
analog compounds (i.e., whichever method is selected as an indicator
of body burden or internal dose) allow for a back-calculation to the
total internal dose.
9. Data are required for occupational sites if the vapor
pressure is greater than 1E-3 mmHg at 25[deg] C and there is the
potential for bystander exposure. Data are also required if aerosols
are generated where bystanders may be exposed.
10. Biological monitoring data are required when passive
dosimetry techniques are not applicable for a particular exposure
scenario (such as a swimmer/spa exposure) and exposure estimates
from modeling techniques used in conjunction with the toxicity data
indicate a risk of concern.
11. Data reporting and calculations are required when any post-
application exposure monitoring data are required.
12. Data are required for residential sites if post-application
exposures, particularly those of children, are likely. The selection
of a sampling method will depend on the non-dietary pathway(s) of
interest. Data must be generated to consider all potential pathways
of non-dietary ingestion exposure that are applicable (e.g., soil
ingestion, hand-to-mouth transfer, and object-to-mouth transfer of
surface residues).
[[Page 59442]]
Sec. 158.2280 Environmental fate.
(a) General. Subpart B of this part and Sec. 158.2201 describe how
to use the table in paragraph (e) of this section to determine the
environmental fate data requirements for antimicrobial pesticide
products. Notes that apply to an individual test including specific
conditions, qualifications, or exceptions are listed in paragraph (f)
of this section.
(1) Environmental fate data are required to support the
registrations of all end-use and manufacturing-use antimicrobial
products.
(2) If the Agency believes that the transformation products of the
parent compound are more toxic, persistent, or bioaccumulative than the
parent compound, or have been shown to cause adverse effects in
mammalian or aquatic reproductive studies, then data on those
transformation products are also required to support registration.
(3) For wood preservatives, the Agency may require data on both the
parent compound that is incorporated into the wood, and on
transformation/degradation products that occur in wood post-treatment
or occur as dislodgeable residues (such as hand contact with treated
wood) or leachate residues (such as from soil or water contact with
treated wood).
(b) Low environmental exposures. For the purpose of determining
data requirements, the low environmental exposure grouping of use
patterns includes the following use patterns or partial use patterns:
(1) Agricultural premises and equipment.
(2) Food-handling/storage establishments, premises, and equipment.
(3) Commercial, institutional and industrial premises and
equipment.
(4) Residential and public access premises.
(5) Medical premises and equipment.
(6) Human drinking water systems.
(7) Materials preservatives.
(8) Swimming pools.
(9) Recirculating industrial processes and water systems in which
the treated water is re-used repeatedly within the system.
(c) High environmental exposures. For the purposes of determining
data requirements, the high environmental exposure grouping of use
patterns includes the following use patterns or partial use patterns:
(1) Once-through industrial processes and water systems in which
the water is not re-used, and is released after a single cycle through
the system.
(2) Antifoulant paints and coatings.
(3) Wood preservatives.
(4) Aquatic areas.
(d) Key. MP = Manufacturing use product; EP = End use product; R =
Required; CR = Conditionally required; NR = Not required; TGAI =
Technical grade of the active ingredient; TEP = Typical end-use
product; PAIRA = Pure active ingredient radiolabeled.
(e) Table. The following table shows the data requirements for
environmental fate. The test notes appear in paragraph (f) of this
section.
Table--Antimicrobial Environmental Fate Data Requirements
--------------------------------------------------------------------------------------------------------------------------------------------------------
Use Pattern Test Substance to Support
-----------------------------------------------------------------------------------------------
High Environmental Exposure
----------------------------------------------------
Data Industrial Test Note
Guideline Number Requirement Low Pro-cesses No.
Environmental and Water Antifoulant Wood Aquatic MP EP
Exposure Systems Coatings Preservatives Areas
(Once- and Paints
Through)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Degradation Studies - Laboratory........................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
835.2120 Hydrolysis R R R R R TGAI or TGAI or 1
PAIRA PAIRA
--------------------------------------------------------------------------------------------------------------------------------------------------------
835.2240 Photodegradatio R R R R R TGAI or TGAI or 2
n in water PAIRA PAIRA
--------------------------------------------------------------------------------------------------------------------------------------------------------
835.2410 Photodegradatio NR NR NR R NR TGAI or TGAI or --
n in soil PAIRA PAIRA
--------------------------------------------------------------------------------------------------------------------------------------------------------
Biodegradation Studies - Laboratory....................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
835.1110 Activated R R NR NR NR TGAI TGAI --
Sludge
Sorption
Isotherm
--------------------------------------------------------------------------------------------------------------------------------------------------------
835.3110 Ready R R NR NR NR TGAI TGAI 3
Biodegradabili
ty
--------------------------------------------------------------------------------------------------------------------------------------------------------
850.6800 Modified R R NR NR NR TGAI TGAI --
Activated
Sludge,
Respiration
Inhibition
Test
--------------------------------------------------------------------------------------------------------------------------------------------------------
835.3220 Porous Pot CR CR NR NR NR TGAI TGAI 4
Study
--------------------------------------------------------------------------------------------------------------------------------------------------------
Mobility Studies........................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
835.1230 Leaching and CR R R R R TGAI or TGAI or 5, 7
835.1240.................... adsorption/ PAIRA PAIRA
desorption
--------------------------------------------------------------------------------------------------------------------------------------------------------
Metabolism Studies - Laboratory.........................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 59443]]
835.4100 Aerobic soil CR CR NR R CR TGAI or TGAI or 5, 6, 8, 9
metabolism PAIRA PAIRA
--------------------------------------------------------------------------------------------------------------------------------------------------------
835.4200 Anaerobic soil CR NR NR CR NR TGAI or TGAI or 5, 8, 10
metabolism PAIRA PAIRA
--------------------------------------------------------------------------------------------------------------------------------------------------------
835.4300 Aerobic aquatic CR R R CR R TGAI or TGAI or 5, 8, 10
metabolism PAIRA PAIRA
--------------------------------------------------------------------------------------------------------------------------------------------------------
835.4400 Anaerobic CR R R CR R TGAI or TGAI or 5, 8, 10
aquatic PAIRA PAIRA
metabolism
--------------------------------------------------------------------------------------------------------------------------------------------------------
Dissipation Studies -- Field............................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
835.6200 Aquatic CR CR CR CR R TEP TEP 5, 11, 12,
(sediment) 13
--------------------------------------------------------------------------------------------------------------------------------------------------------
Ground and Surface Water Monitoring.....................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
None Monitoring of CR CR CR CR CR residue of residue of 11, 12, 14
representative concern concern
U.S. waters
--------------------------------------------------------------------------------------------------------------------------------------------------------
Special Studies.........................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
None Special NR NR R R NR TGAI TEP 15, 16
leaching
--------------------------------------------------------------------------------------------------------------------------------------------------------
(f) Test notes. The following test notes apply to the data
requirements in the table in paragraph (e) of this section:
1. For testing antifoulant paints and coatings, testing is to be
performed with both sterile buffered distilled water and sterile
synthetic seawater at pH 5, 7, and 9.
2. Not required when the electronic absorption spectra, measured
at pHs 5, 7 and 9, of the chemical and its hydrolytic products, if
any, show no absorption or tailing between 290 and 800 nm.
3. The selection of the particular biodegradation study depends
on the physical and chemical properties of the test substance, and
the results of the activated sludge sorption isotherm and the
modified activated sludge studies.
4. Required if the pass criteria for the ready biodegradation
study are not met. This means 70% or greater removal of dissolved
organic carbon and 60% or greater of theoretical oxygen demand or
theoretical carbon dioxide. These pass values must be reached in a
10-day window within the 28-day period of the test.
5. For low environmental exposure uses, data are required based
on a weight-of-evidence evaluation of the results of the hydrolysis,
photodegradation in water, activated sludge sorption isotherm, ready
biodegradability, and modified activated sludge, respiration
inhibition tests.
6. For industrial processes and water systems (once-through),
data are required based on a weight-of-evidence evaluation of the
results of the hydrolysis, photodegradation in water, activated
sludge sorption isotherm, ready biodegradability, and modified
activated sludge, respiration inhibition tests.
7. Adsorption and desorption using a batch equilibrium method is
preferred. In some cases, as when the antimicrobial pesticide
degrades rapidly, soil column leaching with unaged or aged columns
may be more appropriate to fully characterize the potential mobility
of the parent compound and major transformation products.
8. The environmental media (soil, water, hydrosoil, and biota)
to be utilized in these studies must be collected from areas
representative of potential use sites.
9. For industrial processes and water systems (once-through),
and aquatic areas, data are required for use sites that are
intermittently dry.
10. For wood preservatives, data are required if treated wood is
used in aquatic environments or in soils which may become flooded or
waterlogged.
11. Environmental chemistry methods used to generate data
associated with this study must include results of a successful
confirmatory method trial by an independent laboratory.
12. Protocols must be approved by the Agency prior to the
initiation of the study. Details for developing protocols are
available from the Agency.
13. For industrial processes and water systems (once-through),
antifoulant paints and coatings, and wood preservatives, data are
required based on the potential for aquatic exposure and if the
weight-of-evidence indicates that the active ingredient or principal
transformation products are likely to have the potential for
persistence, mobility, nontarget aquatic toxicity, or
bioaccumulation.
14. Data are required if the weight-of-evidence indicates that
the active ingredient or principal transformation products are
likely to occur in nontarget freshwater, estuarine, or marine waters
such that human or environmental exposures are likely to occur. The
Agency takes into account other factors such as the toxicity of the
chemical(s), available monitoring data and the vulnerability of the
freshwater, estuarine, or marine water resources in the
antimicrobial use area.
15. For wood preservatives, an aquatic leaching study is
required. A soil leaching study is required if human or
environmental exposures are likely to occur from leachates that
contain the active ingredient or principal transformation products
from wood treated with a preservative product. For these studies,
the Agency accepts the following methods or their equivalents:
American Wood Preservers' Association (AWPA) Method E11-97 (aquatic
leaching), and AWPA Method E20-04 (soil leaching). Prior approval of
studies conducted according to E11-97 is not required. All other
protocols
[[Page 59444]]
must be approved by the Agency prior to the initiation of the study.
Details for developing protocols are available from the Agency.
16. For antifoulant paints and coatings, a leaching study is
required. The Agency accepts the following method or its equivalent:
American Society for Testing and Materials (ASTM) Method D5108-90.
Prior approval of studies conducted according to D5108-90 is not
required. All other protocols must be approved by the Agency prior
to the initiation of the study. Details for developing protocols are
available from the Agency.
Sec. 158.2290 Residue chemistry.
(a) General. Subpart B of this part and Sec. 158.2201 describe how
to use the table in paragraph (f) of this section to determine the
residue chemistry data requirements for antimicrobial pesticide
products.
(b) Residue chemistry data are required for products described in
this paragraph.
(1) Each end-use product bearing label directions for food-uses
that require a tolerance or tolerance exemption, including, but not
limited to the following:
(i) Direct food uses such as antimicrobial products used to treat
animal or poultry drinking water, for egg washing, or fruit and
vegetable rinses.
(ii) Indirect food uses such as antimicrobial products applied to a
surface or incorporated into a material that may contact food or feed.
Residues may be expected to transfer to such food or feed. Data are
required regardless of whether the antimicrobial is applied or
impregnated for the purpose of imparting antimicrobial protection to
external surfaces of the substance or article, or for the purpose of
protecting the substance or article itself.
(iii) Aquatic uses that have the potential to result in residues in
potable water, or in water used for livestock and poultry drinking
water, irrigation of crops, or water containing fish that may be used
for human food.
(iv) Wood preservative or antifoulant products intended for
treating wood that may be used for food purposes (e.g., lobster pots,
fish cages, or fish farms).
(2) Each manufacturing-use product bearing directions for
formulation into an end-use product bearing food-uses described in
paragraph (b)(1) of this section.
(c) Except as described in paragraph (b) of this section, residue
chemistry data are not required to support a tolerance exemption if
dietary exposure estimates are not needed due to low toxicity of the
active ingredient or theoretical (modeled) estimates of exposure are
adequate to assess dietary risk.
(d) Key. R = Required; CR = Conditionally required; NR = Not
required; TGAI = Technical grade of the active ingredient; TEP =
Typical end-use product; PAI = Pure active ingredient; PAIRA = Pure
active ingredient radiolabeled; the residue of concern is determined by
the Agency.
(e) Table. The following table shows the data requirements for
residue chemistry. The test notes appear in paragraph (f) of this
section.
Table -- Antimicrobial Residue Chemistry Data Requirements
--------------------------------------------------------------------------------------------------------------------------------------------------------
Use Pattern
--------------------------------------------------
Direct Test Note
Guideline Number Data Requirement Agricultural Indirect Food Aquatic Test substance No.
Premises Food Uses Contact Uses
Uses
--------------------------------------------------------------------------------------------------------------------------------------------------------
Supporting Information..................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
860.1100 Chemical identity R R R R TGAI --
--------------------------------------------------------------------------------------------------------------------------------------------------------
860.1200 Directions for use R R R R -- --
--------------------------------------------------------------------------------------------------------------------------------------------------------
860.1550 Proposed tolerance R R R R -- 1
--------------------------------------------------------------------------------------------------------------------------------------------------------
860.1560 Reasonable grounds in R R R R -- 1
support of petition
--------------------------------------------------------------------------------------------------------------------------------------------------------
860.1650 Submittal of analytical R R R R PAI and residue of 2
reference standards concern
--------------------------------------------------------------------------------------------------------------------------------------------------------
Nature of the residue...................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
860.1300 Nature of the residue in CR NR R R PAIRA 3, 4, 5
plants
--------------------------------------------------------------------------------------------------------------------------------------------------------
860.1300 Nature of the residue in R NR CR CR PAIRA or radiolabeled 6, 7, 8
livestock plant metabolite
--------------------------------------------------------------------------------------------------------------------------------------------------------
Analytical methods......................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
860.1340 Residue analytical CR CR R CR Residue of concern 9
methods for enforcement
of tolerances
--------------------------------------------------------------------------------------------------------------------------------------------------------
860.1340 Residue analytical CR CR R CR Residue of concern 10
methods for data
collection
--------------------------------------------------------------------------------------------------------------------------------------------------------
860.1360 Multiresidue method CR CR R CR Residue of concern 11
testing
--------------------------------------------------------------------------------------------------------------------------------------------------------
Magnitude of the residue................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
860.1380 Storage stability R R R R TEP or residue of 12
concern
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 59445]]
860.1500 Crop field trials CR CR R R TEP 13, 14
--------------------------------------------------------------------------------------------------------------------------------------------------------
860.1520 Processed food or feed NR CR CR CR TEP 15
--------------------------------------------------------------------------------------------------------------------------------------------------------
860.1480 Meat/milk/poultry/eggs CR CR CR CR TGAI or plant metabolite 16, 17
--------------------------------------------------------------------------------------------------------------------------------------------------------
860.1400 Potable water R NR NR R TEP 18
--------------------------------------------------------------------------------------------------------------------------------------------------------
860.1400 Fish NR NR NR R TEP 19
--------------------------------------------------------------------------------------------------------------------------------------------------------
860.1400 Irrigated crops NR NR NR CR TEP 20
--------------------------------------------------------------------------------------------------------------------------------------------------------
860.1460 Food-handling NR CR R NR TEP 21
--------------------------------------------------------------------------------------------------------------------------------------------------------
860.1540 Anticipated residues CR CR CR CR Residue of concern 22
--------------------------------------------------------------------------------------------------------------------------------------------------------
None Migration studies NR CR NR NR TGAI 23
--------------------------------------------------------------------------------------------------------------------------------------------------------
(f) Test notes. The following test notes apply to the data
requirements in the table to paragraph (e) of this section:
1. A petition proposing a numerical tolerance or a tolerance
exemption is required for any food or feed use subject to section
408 of the FFDCA if the use is not covered by an existing tolerance
or tolerance exemption.
2. An analytical reference standard is required for any food or
feed use requiring a tolerance. Material safety data sheets must
accompany analytical standards as specified by OSHA in 29 CFR
1910.1200.
3. For agricultural premises, data are required for postharvest
storage of plant commodities.
4. Data are required for direct food contact uses, excluding egg
washes, to determine the transformation products in representative
foods.
5. Data are required to support applications to water if any
residues could occur in irrigated crops, or to crops treated
directly in the field.
6. Data are required when an antimicrobial pesticide is applied
directly to livestock, to livestock premises, to livestock drinking
water, to livestock feed, or to crops used for livestock feed.
7. Data are required for aquatic uses if there is the potential
that the treated water could be used eventually for drinking
purposes by livestock.
8. If results from the plant metabolism study show differing
metabolites in plants from those found in animals, then additional
livestock metabolism study(ies) involving dosing with the plant
metabolite(s) may be required.
9. A residue analytical method suitable for enforcement purposes
is required whenever a numeric tolerance is proposed. Enforcement
methods must be supported by results of an independent laboratory
validation.
10. A residue analytical method suitable for collecting data to
establish tolerances must quantitate all residues of concern, as
determined by the Agency.
11. Data are required to determine whether the FDA/USDA
multiresidue methodology would detect and identify the antimicrobial
active ingredient and its metabolites.
12. Data are required for any food or feed use requiring
magnitude of the residue studies unless analytical samples are
stored frozen for 30 days or less, and the active ingredient is not
known to be volatile or labile.
13. Residue data are required if antimicrobial chemicals are to
be applied to mushroom houses, empty or occupied beehives, wood used
to construct beehives, or any use which could result in residues in
food or feed.
14. If the antimicrobial chemical is applied to growing crops in
the field, then the requirements of 40 CFR part 158, subpart O
(terrestrial food or feed use pattern) apply.
15. Data on the nature and level of residues in processed food
or feed are required if residues could potentially concentrate on
processing, thus requiring the establishment of a separate tolerance
higher than that of the raw agricultural commodity.
16. Data are required when the pesticide use is a direct
application to livestock.
17. Data are required if livestock premises are treated or if
pesticide residues are present in or on livestock feed items or
intentionally added to drinking water. These studies, however, may
not be required in cases where the livestock metabolism studies
indicate negligible transfer of pesticide residues of concern to
tissues, milk, and eggs at the maximum expected exposure level for
the animals.
18. Data are required for antimicrobial pesticides applied
directly to water, if there is the potential that the treated water
could be used for drinking purposes by man or animals.
19. For aquatic uses, data for fish are required for
antimicrobial pesticides applied directly to water inhabited, or
which will be inhabited, by fish that may be caught or harvested for
human consumption.
20. Data are required for antimicrobial pesticides applied
directly to water that could be used for irrigation or to irrigation
facilities such as ditches.
21. Data are required whenever a pesticide is to be used in a
food-handling or feed handling establishment unless theoretical
calculations, radiolabeled laboratory data, the nature of the
residue study, or other data show that residues will not occur in
food or feed. Use in a food-handling establishment also includes
fresh fruits and vegetables that undergo a rinse with either a
sanitizing solution, or with a disinfectant followed by a potable
water rinse.
22. Data are required when estimates of risk using residues at
the tolerance level may result in a risk of concern. These data may
include washing, cooking, processing or degradation studies as well
as market basket surveys for a more precise residue determination.
[[Page 59446]]
23. Migration of residue data are required for antimicrobial
pesticides applied to hard food surfaces or incorporated into
substrates (wood, plastic, paper, cloth, rubber or similar products)
intended for contact with food or feed when theoretical (modeled)
estimates of the amount of antimicrobial residue transferred to the
food or feed may result in a risk of concern. Protocols must be
approved by the Agency prior to the initiation of the study. Details
for developing protocols are available from the Agency.
PART 161--[AMENDED]
6. The authority citation for part 161 continues to read as
follows:
Authority: 7 U.S.C. 136 - 136y.
Part 161 [Removed]
7. Part 161 is removed:
[FR Doc. E8-23127 Filed 10-7-08; 8:45 am]
BILLING CODE 6560-50-S