[Federal Register Volume 75, Number 243 (Monday, December 20, 2010)]
[Proposed Rules]
[Pages 79320-79323]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-31887]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 500
[Docket No. FDA-2010-N-0612]
Animal Drugs, Feeds, and Related Products; Regulation of
Carcinogenic Compounds in Food-Producing Animals
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
its regulations regarding compounds of carcinogenic concern used in
food-producing animals. Specifically, the Agency is clarifying the
definition of ``So'' and revising the definition of
``Sm'' so that it conforms to the clarified definition of
So. Other clarifying and conforming changes are also being
made.
DATES: Submit either electronic or written comments on the proposed
rule by March 7, 2011. Submit comments on information collection issues
under the Paperwork Reduction Act of 1995 by January 19, 2011 (see the
``Paperwork Reduction Act of 1995'' section of this document).
ADDRESSES: You may submit comments, identified by Docket No. FDA-2010-
N-0612, by any of the following methods, except that comments on
information collection issues under the Paperwork Reduction Act of 1995
must be submitted to the Office of Regulatory Affairs, Office of
Management and Budget (OMB) (see the ``Paperwork Reduction Act of
1995'' section of this document).
Electronic Submissions
Submit electronic comments in the following way:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.
Written Submissions
Submit written submissions in the following ways:
Fax: 301-827-6870.
Mail/Hand delivery/Courier (for paper, disk, or CD-ROM
submissions): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
Instructions: All submissions received must include the Agency name
and Docket No. and Regulatory Information Number (RIN) (if a RIN number
has been assigned) for this rulemaking. All comments received may be
posted without change to http://www.regulations.gov, including any
personal information provided. For additional information on submitting
comments, see the ``Comments'' heading of the SUPPLEMENTARY INFORMATION
section of this document.
Docket: For access to the docket to read background documents or
comments received, go to http://www.regulations.gov and insert the
docket number, found in brackets in the heading of this document, into
the ``Search'' box and follow the prompts and/or go to the Division of
Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Kevin Greenlees, Center for Veterinary
Medicine (HFV-100), Food and Drug Administration, 7500 Standish Pl.,
Rockville, MD 20855, 301-827-6975. e-mail: [email protected].
SUPPLEMENTARY INFORMATION:
I. Background
The Federal Food, Drug, and Cosmetic Act (the FD&C Act) contains
three anticancer, or Delaney, clauses: Sections 409(c)(3)(A),
512(d)(1)(I), and 721(b)(5)(B)(i) (21 U.S.C. 348(c)(3)(A),
360b(d)(1)(I), and 379e(b)(5)(B)(i)), pertaining to food additives, new
animal drugs, and color additives, respectively.
[[Page 79321]]
These clauses prohibit approval of substances that have been shown to
induce cancer in man or animals. However, each clause contains an
exception, termed the ``Diethylstilbestrol (DES) Proviso,'' that
permits administration of such substances to food-producing animals
where: (1) The food additive, color additive, or new animal drug will
not adversely affect the animal; and (2) no residue of the food
additive, color additive, or new animal drug will be found in any
edible portion of that animal by a method of examination prescribed or
approved by the Secretary of Health and Human Services by regulation.
The regulations under part 500 (21 CFR part 500), subpart E entitled
``Regulation of Carcinogenic Compounds Used in Food-Producing
Animals,'' implement the DES Proviso. To elaborate on how to determine
that there is no residue, and thus demonstrate that the second prong of
the DES Proviso has been satisfied, the regulations define several
terms, including So and Sm.
So is currently defined as the concentration of the
compound of carcinogenic concern in the total diet of test animals that
corresponds to a maximum lifetime risk of cancer to the test animals of
1 in 1 million, and is calculated from tumor data of the cancer
bioassays using a statistical extrapolation procedure. The definition
of So also provides that FDA will assume that the
So corresponds to the concentration of residue of
carcinogenic concern in the total human diet that represents no
significant increase in the risk of cancer to people. The
concentration, derived from the So, of residues of
carcinogenic concern in a specific edible tissue is termed the
Sm. Sponsors are required to submit to FDA a regulatory
analytical method that is an aggregate of all experimental procedures
for measuring and confirming the presence of the marker residue of the
sponsored compound in the target tissue of the target animal. FDA can
be assured that there is no residue of carcinogenic concern when no
residue of the compound is detectable (that is, the marker residue is
below the limit of detection) using the approved regulatory analytical
method.\1\ A marker residue is selected whose concentration is in a
known relationship to the concentration of the residue of carcinogenic
concern in the last tissue to deplete to its Sm. This tissue
is known as the target tissue and the concentration of the marker
residues is known as the Rm. The limit of detection of the
approved regulatory analytical method must be capable of measuring the
selected marker residue at the Rm in the selected target
tissue. When residues of carcinogenic concern are below the
Rm in the target tissue as measured by the approved
regulatory analytical method, the residues of carcinogenic concern in
target tissue and all other edible tissues are below their respective
Sm and therefore consumption of tissues containing these
residues would not exceed the So. The detection of the
marker residue in the target tissue below the Rm by the
approved regulatory analytical method can be taken as confirmation that
the residue of carcinogenic concern does not exceed Sm in
each of the edible tissues and, therefore, that the residue of
carcinogenic concern in the diet of people does not exceed
So. However, any detectable concentration of the marker
residue by the approved regulatory analytical method, even if below the
Rm, fails to satisfy the statutory requirements of the DES
Proviso. The detection of any concentration would mean that the second
prong of the DES Proviso has not been satisfied because it has not been
shown that no residue of the substance is present in any edible portion
of the animal at issue.
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\1\ The submission of such a method is approved as a collection
of information under Office of Management and Budget (OMB) Control
No. 0910-0032.
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As described previously, the approach for evaluating compounds of
carcinogenic concern currently set forth in Sec. 500.84 utilizes a
statistical extrapolation procedure that calculates a concentration of
residue of carcinogenic concern that corresponds to a maximum lifetime
risk to the test animal of 1 in 1 million. In addition, to provide
flexibility, Sec. 500.90 permits the use of alternative procedures to
satisfy the DES Proviso, when the person requesting the use of
alternative procedures clearly sets forth the reasons why the
alternative procedures will provide a basis for concluding that
approval of the compound satisfies the requirements of the Delaney
Clause provisions of the FD&C Act, including the DES Proviso.
In recent years, FDA has, at times, been asked to consider allowing
the use of alternative procedures to satisfy the DES Proviso. Some of
these proposed alternative procedures did not rely on a statistical
extrapolation of the data to a 1 in 1 million risk of cancer to test
animals, but nevertheless the So, Sm,
Rm, and regulatory analytical method resulting from these
alternative approaches would be expected to ensure that consumption of
food derived from animals treated with the carcinogenic new animal drug
would result in no significant increase in the risk of cancer to
people. In the course of considering these proposed alternative
procedures, FDA has also considered whether the term So, as
currently defined, adequately addresses concentrations of residues of
carcinogenic concern in the total human diet that are found to
represent no significant increase in the risk of cancer to people, but
which are not derived from a statistical extrapolation of data to a 1
in 1 million risk of cancer to test animals.
The current definition in Sec. 500.82 primarily defines
So as the concentration of the compound of carcinogenic
concern that corresponds to the 1 in 1 million lifetime risk of cancer
to the test animals and secondarily as corresponding to the
concentration of residue of carcinogenic concern in the total human
diet that represents no significant increase in a risk of cancer to
people. Therefore, as presently constructed, the definition of
So is not primarily defined as the concentration of residues
of carcinogenic concern in the total human diet derived from procedures
not involving the extrapolation of data to a 1 in 1 million risk of
cancer to the test animals. Thus, were FDA to allow the use of
alternative procedures that do not rely on a statistical extrapolation
of the data to a 1 in 1 million risk of cancer to test animals to
satisfy the DES Proviso, it would have to develop a new set of
terminology to describe the Center for Veterinary Medicine's (CVM's)
approach for evaluating these compounds of carcinogenic concern. The
proposed changes to the definitions of So and Sm
are intended to enable CVM to consider allowing the use of alternative
procedures to satisfy the DES Proviso without requiring the development
of a second, alternative, set of terminology.
FDA believes that a careful reading of the December 31, 1987, final
rule (52 FR 49572 at 49586), suggests that an emphasis on no
significant increase in the risk of cancer to the human consumer,
rather than on the specific 1 in 1 million risk of cancer to the test
animals approach, reflects the original intent of the regulation. (See,
e.g., 52 FR 49572 at 49575 and 49582.) FDA has concluded that the
proposed redefinition of So is consistent with this original
intent of the regulation.
For clarification purposes, FDA is also proposing a redefinition of
Sm in Sec. 500.82 to conform this definition with the
redefinition of So as described previously. Specifically,
Sm would mean the concentration of a residue of carcinogenic
concern in a specific edible tissue corresponding to no
[[Page 79322]]
significant increase in the risk of cancer to the human consumer.
However, the definition of Sm would also retain the existing
reference to a maximum lifetime risk of cancer in the test animals of 1
in 1 million.
Finally, FDA is proposing to amend Sec. 500.84(c) to clarify that
for each compound that is regulated as a carcinogen, FDA will analyze
the data submitted using either a statistical extrapolation procedure
as provided in Sec. 500.84(c)(1) or an alternate approach as provided
in Sec. 500.90.
FDA's goal in these changes is to clarify that the terms
So and Sm apply even when the alternative
procedures provided for in Sec. 500.90 are used to satisfy the DES
Proviso, not to alter the usual process for approving compounds of
carcinogenic concern. As such, in the absence of a waiver of the
requirements of Sec. 500.84(c)(1), FDA maintains that sponsors must
meet the conditions for approval set for in Sec. 500.84, including the
default approach of a 1 in 1 million lifetime risk to the test animal.
II. Legal Authority
This rule, if finalized, would amend part 500, subpart E in a
manner consistent with the Agency's current understanding and
application of these provisions. FDA was given authority in 21 U.S.C.
348, 360b, and 379e to establish methods of examination to determine
that no residue of a food additive, new animal drug, or color additive
of carcinogenic concern would be found in any edible portion of animals
after slaughter or in any food yielded by or derived from living
animals. Furthermore, FDA has the authority to take the actions
proposed in this rule under various statutory provisions. These
provisions include 21 U.S.C. 321, 331, 348, 360b, 371, and 379e.
III. Environmental Impact
The Agency has determined under 21 CFR 25.30(h) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
IV. Analysis of Economic Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and
the Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4). Executive
Order 12866 directs Agencies to assess all costs and benefits of
available regulatory alternatives and, when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The Agency believes that
this proposed rule is not a significant regulatory action as defined by
the Executive order.
The Regulatory Flexibility Act requires Agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because the proposed rule would not impose any
direct or indirect costs on industry or government through the changes
to the definitions of So and Sm and to Sec.
500.84(c), but rather would clarify these definitions to enable FDA to
consider using alternative procedures to satisfy the DES Proviso
without requiring the development of a second, alternative, set of
terminology, the Agency proposes to certify that the final rule will
not have a significant economic impact on a substantial number of small
entities.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that Agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and Tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $135 million, using the most current (2009) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
proposed rule to result in any 1-year expenditure that would meet or
exceed this amount.
V. Federalism
FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the proposed rule, if finalized, would not contain policies that would
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.
Accordingly, the Agency tentatively concludes that the proposed rule
does not contain policies that have federalism implications as defined
in the Executive order and, consequently, a federalism summary impact
statement is not required.
VI. Paperwork Reduction Act of 1995
This proposed rule refers to previously approved collections of
information found in FDA regulations. These collections of information
are subject to review by OMB under the Paperwork Reduction Act of 1995
(44 U.S.C. 3501-3520). The collections of information in Sec. 500.84
have been approved under OMB Control No. 0910-0032.
VII. Request for Comments
FDA requests comments to the proposed revisions to the definitions
of Sm and So currently found in Sec. 500.82(b)
and to the proposed conforming changes to Sec. 500.84(c).
Specifically, the Agency requests that comments focus on the proposal
to emphasize ``no significant increase in the risk of cancer to the
human consumer,'' rather than the more specific ``1 in 1 million risk
of cancer to the test animals'' approach currently found in the
definitions of Sm and So.
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) either electronic or written comments regarding this
document. It is only necessary to send one set of comments. It is no
longer necessary to send two copies of mailed comments. Identify
comments with the docket number found in brackets in the heading of
this document. Received comments may be seen in the Division of Dockets
Management between 9 a.m. and 4 p.m., Monday through Friday.
VIII. Proposed Effective Date
The Agency is proposing that any final rule that may issue based
upon this proposed rule become effective upon publication in the
Federal Register.
List of Subjects in 21 CFR Part 500
Animal drugs, Animal feeds, Cancer, Labeling, Packaging and
containers, Polychlorinated biphenyls (PCB's).
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR part 500 be amended as follows:
PART 500--GENERAL
1. The authority citation for 21 CFR part 500 is revised to read as
follows:
Authority: 21 U.S.C. 321, 331, 342, 343, 348, 351, 352, 353,
360b, 371, 379e.
2. Revise the definitions of ``Sm'' and
``So'' in paragraph (b) of Sec. 500.82 to read as follows:
Sec. 500.82 Definitions.
* * * * *
(b) * * *
Sm means the concentration of a residue of carcinogenic concern in
a specific edible tissue corresponding to no significant increase in
the risk of
[[Page 79323]]
cancer to the human consumer. For the purpose of Sec. 500.84(c)(1),
FDA will assume that this Sm will correspond to the
concentration of residue in a specific edible tissue that corresponds
to a maximum lifetime risk of cancer in the test animals of 1 in 1
million.
So means the concentration of a residue of carcinogenic concern in
the total human diet that represents no significant increase in the
risk of cancer to the human consumer. For the purpose of Sec.
500.84(c)(1), FDA will assume that this So will correspond
to the concentration of test compound in the total diet of test animals
that corresponds to a maximum lifetime risk of cancer in the test
animals of 1 in 1 million.
* * * * *
3. Revise the introductory text of paragraph (c) of Sec. 500.84 to
read as follows:
Sec. 500.84 Conditions for approval of the sponsored compound.
* * * * *
(c) For each sponsored compound that FDA decides should be
regulated as a carcinogen, FDA will either analyze the data from the
bioassays using a statistical extrapolation procedure as outlined in
paragraph (c)(1) of this section or evaluate an alternate procedure
proposed by the sponsor as provided in Sec. 500.90. In either case,
paragraphs (c)(2) and (c)(3) of this section apply.
* * * * *
Dated: December 15, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2010-31887 Filed 12-17-10; 8:45 am]
BILLING CODE 4160-01-P