[Federal Register Volume 75, Number 248 (Tuesday, December 28, 2010)]
[Proposed Rules]
[Pages 81536-81543]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-32344]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 170, 184, 186, and 570
[Docket No. FDA-1997-N-0020; Formerly Docket No. 1997N-0103]
Substances Generally Recognized as Safe; Reopening of the Comment
Period
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule; reopening of the comment period.
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SUMMARY: The Food and Drug Administration (FDA) is reopening the
comment period for the proposed rule published in the Federal Register
of April 17, 1997 (the 1997 proposed rule). The 1997 proposed rule
would replace the voluntary petition process to affirm the generally
recognized as safe (GRAS) status of a substance intended for use in
food for humans or animals with a voluntary notification procedure. FDA
is reopening the comment period to update comments. The proposed rule
would also clarify the criteria for exempting the use of a substance as
GRAS.
DATES: The comment period for the proposed rule published April 17,
1997 (62 FR 18938), is reopened. Submit either electronic or written
comments on the proposed rule by March 28, 2011. Submit comments on
information collection issues under the Paperwork Reduction Act of 1995
by February 28, 2011, (see the ``Paperwork Reduction Act of 1995''
section of this document).
ADDRESSES: You may submit comments, including comments regarding the
proposed collection of information, identified by Docket No. FDA-1997-
N-0020, by any of the following methods:
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. FDA-1997-N-0020, 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: With regard to substances that would
be used in human food: Paulette M. Gaynor, Center for Food Safety and
Applied Nutrition (HFS-255), Food and Drug Administration, 5100 Paint
Branch Pkwy., College Park, MD 20740, 301-436-1192.
With regard to substances that would be used in food for animals:
Geoffrey K. Wong, Center for Veterinary Medicine (HFV-224), Food and
Drug Administration, 7519 Standish Pl., Rockville, MD 20855, 240-453-
6879.
With regard to the information collection: Denver Presley Jr.,
Office of Information Management, Food and Drug Administration, 1350
Piccard Dr., PI50-400B, Rockville, MD 20850, 301-796-3793.
SUPPLEMENTARY INFORMATION:
I. Background
In the 1997 proposed rule, FDA proposed to replace the voluntary
GRAS affirmation petition process in Sec. Sec. 170.35(c) and 570.35(c)
(21 CFR 170.35(c) and 570.35(c)) with a voluntary notification
procedure whereby any person may notify us of a determination that a
particular use of a substance in human food (proposed Sec. 170.36) or
in food for animals (proposed Sec. 570.36) is GRAS.\1\ We also
proposed to clarify the criteria in Sec. Sec. 170.30 (21 CFR 170.30)
and 570.30 (21 CFR 570.30) whereby the use of a substance is not
subject to the premarket approval requirements of the FD&C Act because
it is GRAS. To simplify the discussion in this document, in general,
[[Page 81537]]
we refer to provisions of the 1997 proposed rule and issues for further
comment from the perspective of the regulations that would be
established in part 170 (21 CFR part 170). Unless we say otherwise,
however, the issues discussed also apply to the corresponding
provisions for part 570.
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\1\ As an error, the authority citation we listed for the
proposed amendments to part 570 (21 CFR part 570) did not include an
existing authority citation, i.e., section 408 of the Federal Food,
Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 346a). Nothing in
the 1997 proposed rule would alter the citation to section 408.
Therefore, the authority citation for part 570 will continue to
include section 408.
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Under the proposed notification procedure, a GRAS notice would
include: (1) A ``GRAS exemption claim'' in which a notifier would take
responsibility for a GRAS determination; (2) information about the
identity of the notified substance, including information about the
method of manufacture (excluding any trade secrets); (3) information
about any self-limiting levels of use; and (4) a comprehensive
discussion of the basis for the GRAS determination. We would evaluate
whether the notice provides a sufficient basis for a GRAS determination
and would respond to the notifier in writing. We would immediately make
available to the public the notice's ``GRAS exemption claim'' and our
response to the notice, and disclose other releasable information in a
notice in accordance with our regulations, in part 20 (21 CFR part 20),
implementing the Freedom of Information Act.
We invited interested persons who determine that a use of a
substance is GRAS to notify us of those determinations, under the
framework of the 1997 proposed rule, during the interim between the
proposed and final rules (62 FR 18938 at 18954). We said that we would
determine whether our experience in administering such notices
suggested that modifications to the proposed notification procedure
were necessary (62 FR 18938 at 18954). During the period from February
1, 1999, through December 31, 2009 (the interim period), our Center for
Food Safety and Applied Nutrition (CFSAN) received approximately 26
GRAS notices per year about substances intended for use in human food.
The Center for Veterinary Medicine (CVM) established a pilot
notification program only recently. (See the Federal Register of June
4, 2010; 75 FR 31800.)
The memorandum in reference 1 of this document describes CFSAN's
experience (through December 31, 2009). In the remainder of this
document, we refer to this memorandum as the ``experience document.''
Because CVM's pilot program began relatively recently, the experience
document does not describe any experience under CVM's pilot
notification program.
Also, from 2008 to 2010, the Government Accountability Office (GAO)
conducted a study related to food ingredients determined to be GRAS
and, in 2010, issued a report (Ref. 2, the GAO report) that included a
number of recommendations for FDA's food ingredient program. FDA
responded to the GAO's recommendations, and that response is also
included in the GAO report.
II. Request for Comments
Because of the length of time that has elapsed since publication of
the 1997 proposed rule, we are interested in updating comments before
issuing a final rule. In addition, based on CFSAN's experience with
GRAS notices during the interim period, comments we received on the
proposed rule, and GAO's recommendations, we have identified a number
of issues within the scope of the proposed rule that may require
further clarification. Specifically, these issues relate to the
proposed revisions to Sec. 170.30 (Issue 1), the proposed
establishment of a notification procedure (Issues 2 through 16), and
the effect of the proposed notification procedure on existing GRAS
petitions (Issue 17).\2\ Accordingly, we are requesting comments on the
entire 1997 proposed rule as well as on the specific issues identified
in this document.
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\2\ With regard to GAO's recommendations, we are requesting
comment on the recommendations that FDA obtain more information
about the use of engineered nanomaterials (Issue 10(c)), that FDA
strive to minimize the potential for conflict of interest (Issue
15), and that FDA issue guidance on how to document GRAS
determinations (Issue 16). GAO also recommended that FDA develop a
strategy to finalize the proposal to establish a notification
program for GRAS ingredients, and this notice reopening the comment
period is the first step of such a strategy. FDA is not seeking
comment on the remaining GAO recommendations, that FDA request that
any company conducting a GRAS determination provide the Agency with
basic information about that determination, and that FDA develop a
strategy to reconsider the safety of certain GRAS substances. We
consider those recommendations, and any comments on them, to be
beyond the scope of this comment request because they raise issues
about matters other than how a notification program should be run.
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Comments previously submitted to the Division of Dockets Management
(previously the Dockets Management Branch), including comments
submitted to the Division of Dockets Management after the comment
period closed on July 16, 1997, but before December 28, 2010, do not
need to be resubmitted in response to this notice because all such
comments will be considered in any final rule based on the 1997
proposed rule and this document.\3\
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\3\ After we issued the 1997 proposed rule, a Presidential
Memorandum dated June 1, 1998 (the Plain Language Memorandum) (Ref.
3) prescribed a government-wide initiative (the Plain Language
Initiative, or ``PLI'') to write regulations using ``Plain
Language.'' As outlined in that memorandum, documents written in
plain language use ``you'' and other pronouns. Any final rule based
on the 1997 proposed rule and this document would use such pronouns.
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A. Issue 1. Description of Common Knowledge Element and Related
Definition of ``Scientific Procedures''
In the 1997 proposed rule, we proposed to revise Sec. 170.30 to
broaden the description of the common knowledge element to clarify the
types of technical evidence of safety that would form the basis of a
GRAS determination, and to clarify the role of publication in
satisfying the common knowledge element. Specifically, we proposed
revising Sec. 170.30(b) from ``* * * ordinarily be based upon
published studies which may be corroborated by unpublished studies and
other data and information.'' to ``based upon generally available and
accepted scientific data, information, methods, or principles, which
ordinarily are published and may be corroborated by unpublished
scientific data, information, or methods.'' We also proposed a
companion change to the definition of scientific procedures (Sec.
170.3(h)) from ``Scientific procedures include those human, animal,
analytical, and other scientific studies, whether published or
unpublished, appropriate to establish the safety of a substance.'' to
``Scientific procedures include scientific data (such as human, animal,
analytical, or other scientific studies), information, methods, and
principles, whether published or unpublished, appropriate to establish
the safety of a substance.''
Most of the comments addressing these proposed amendments supported
the amendments. In general, these comments expressed the opinion that
the proposed amendments would more accurately reflect the state of
contemporary science than the provisions they would replace. One
comment objected to the proposed amendment to Sec. 170.30(b). This
comment asserted that the proposed amendment would de-emphasize or
eliminate the existing criterion for peer-reviewed studies. One comment
objected to the proposed amendment to Sec. 170.3(h) because, under the
proposed amendment, an ``unpublished principle'' could inappropriately
be considered a sufficient scientific procedure for demonstrating the
safety of a food substance.
In light of these comments, we reviewed our proposed inclusion of
scientific ``principles'' in the proposed amendments to Sec. Sec.
170.3(h) and 170.30(b). ``Principle'' can be defined as
[[Page 81538]]
a fundamental cause or basis of something; a primary element, force, or
law determining a particular result; or a fundamental truth or
proposition on which others depend (Shorter Oxford English Dictionary,
5th Edition, 2002). Thus, a principle is a different genre than data,
information, and methods and is, by its very nature, generally
available and accepted. An ``unpublished principle'' is a non-sequitur.
Therefore, the adjectives ``published'' and ``unpublished'' should not
modify scientific ``principles.''
We also reviewed our use of the term ``study'' in the proposed
companion change to the definition of scientific procedures. A
procedure can be defined as a particular mode or course of action
(Shorter Oxford English Dictionary, 5th Edition, 2002); a ``study'' can
be defined as the devotion of time and attention to acquiring
information or knowledge or as applying the mind to acquiring
knowledge, especially devoting time and effort to this end (Id.). The
terms ``procedure'' and ``study'' each carry the connotation of an
action. However, ``data and information'' would be the outcome of a
study or procedure and do not carry the connotation of an action. To be
a ``procedure,'' data, information, methods or principles would need to
be acquired or applied.
We are seeking comment on the use of those terms. For example, we
are considering whether to revise the second sentence of Sec.
170.30(b) to require that general recognition of safety through
scientific procedures be based upon the application of generally
available and accepted scientific data, information, or methods, which
ordinarily are published, as well as the application of scientific
principles, and may be corroborated by the application of unpublished
scientific data, information, or methods. We also are considering
whether to revise the definition of scientific procedures to include
the application of scientific data (including, as appropriate, data
from human, animal, analytical, and other scientific studies),
information, and methods, whether published or unpublished, as well as
the application of scientific principles, appropriate to establish the
safety of a substance.
B. Issue 2. Terms
In the 1997 proposed rule, we used the terms ``determine'' and
``determination'' to describe the action of a person who informs us
that the use of a food substance is GRAS under the proposed
notification procedure. However, as discussed in the experience
document, during the interim period CFSAN responded to approximately 5
percent of submitted GRAS notices with a letter informing the notifier
that the notice did not provide a basis for a ``GRAS determination''
(Ref. 1). Clearly, in these cases it was CFSAN's view that the notifier
had not ``determined'' GRAS status. To clarify that the submission of a
GRAS notice reflects the view of the notifier and may not necessarily
provide an adequate basis for a GRAS determination, we have tentatively
concluded that the terms ``conclude'' and ``conclusion'' in lieu of
``determine'' and ``determination'' would be more appropriate, and
therefore in this document we use the terms ``conclude'' and
``conclusion.'' We seek comment on these terms.
C. Issue 3. Definitions
In the 1997 proposed rule, we did not propose definitions of terms
that would be associated with the GRAS notification procedure. However,
it would be consistent with the Plain Language Initiative for a final
rule to include definitions of terms used in the rule. While the
meanings of some terms (such as ``notified substance'') were implicit
in the discussion of the proposed notification procedure, to ensure the
opportunity to comment on these definitions, we include them here. In
addition, some terms not used in the 1997 proposed rule may be useful
in light of comments already received. We seek comment on the
definitions described in the following paragraphs.
(Issue 3a). ``Amendment'' and ``supplement.'' Several comments
asked FDA to allow a notifier to address questions FDA had about a GRAS
notice by submitting an amendment to the notice. As discussed in the
experience document (Ref. 1), during the interim period several
notifiers submitted one or more amendments to their GRAS notices. We
would define ``amendment'' to mean any data or other information that
you submit regarding a filed GRAS notice before we respond to the
notice.
As discussed in the experience document (Ref. 1), during the
interim period several notifiers submitted information to a GRAS notice
after CFSAN responded to the notice. We would define ``supplement'' to
mean any data or other information that you submit regarding a filed
GRAS notice after we respond to the notice.
(Issue 3b) ``Notified substance,'' ``notifier,'' and ``qualified
expert.'' We would define ``notified substance'' to mean the substance
that is the subject of your GRAS notice. We would define ``notifier''
to mean the person who is responsible for the GRAS notice, even if
another person (such as an attorney, agent, or qualified expert)
prepares or submits the notice or provides an opinion about the basis
for a conclusion of GRAS status. Consistent with section 201(s) of the
FD&C Act (21 U.S.C. 321(s)), we would define ``qualified expert'' to
mean an individual who is qualified by scientific training and
experience to evaluate the safety of substances added to food.
D. Issue 4. Incorporation by Reference
One comment requested that a notifier be permitted to reference a
previously submitted GRAS notice to support a view that an additional
use of the applicable substance is GRAS. In the comment's view, this
process, known as ``incorporation by reference,'' would be
administratively efficient. As discussed in the experience document
(Ref. 1), during the interim period CFSAN encouraged notifiers to use a
process such as that recommended in the comment.
We are therefore seeking comment on whether to include a provision
in the final rule to expressly permit the notifier to incorporate by
reference either data and information that were previously submitted by
the notifier, or public data and information submitted by another
party, when such data and information remain in our files, such as data
and information contained in a previous GRAS notice, a food additive
petition, or a food master file.
While the data and information in a previously submitted GRAS
notice are generally publicly available, other data and information
that have been submitted to us may be confidential. We do not
anticipate that a notifier would have access to another party's
confidential data or information.
We note that, regardless of whether a notifier incorporates by
reference data or information, we may consider taking into account
other relevant data or information that we have from other sources. As
discussed in the experience document (Ref. 1), during the interim
period CFSAN did review information that was available in its files but
not available to the applicable notifier.
E. Issue 5. Request That FDA Cease To Evaluate a GRAS Notice
Several comments requested that the notification procedure provide
for a notifier to withdraw a notice in light of our questions about the
notice. These comments considered such a provision would provide the
notifier with an opportunity to resubmit a notice addressing our
questions.
Under Sec. 20.29, no person may withdraw records submitted to FDA.
While a notifier cannot withdraw a GRAS notice submitted to FDA, when
[[Page 81539]]
we issued the proposed rule, we considered a request that FDA cease to
evaluate a GRAS notice to be an implicit prerogative not needing
explicit authorization in the rule. For GRAS notices that FDA has
ceased to evaluate at the request of the notifier, the GRAS notices
remain in our files and, thus, are available for public disclosure,
subject to procedures established in part 20.
As discussed in the experience document (Ref. 1), at the request of
the notifier, CFSAN ceased to evaluate approximately 16 percent of GRAS
notices that came to closure by December 31, 2009. Persons who rely
only on the provisions of proposed Sec. 170.36, without referring to
our letters responding to GRAS notices, may not be aware of the
implicit prerogative to request that FDA cease to evaluate a GRAS
notice.
Therefore, we are seeking comment on whether the rule should
explicitly state that you may request in writing that we cease to
evaluate your GRAS notice at any time during our evaluation of your
GRAS notice.
F. Issue 6. Notifier's Responsibility for a GRAS Conclusion
(Issue 6a) Under proposed Sec. 170.36(c)(1), the GRAS notice would
be dated and signed by the notifier or by the notifier's attorney or
agent or (if the notifier is a corporation) by an authorized official.
As discussed in the experience document (Ref. 1), during the interim
period CFSAN received some GRAS notices in which the combination of an
illegible signature and the lack of a typed or printed name to
accompany the signature made it impossible to identify the person who
was signing the document. Therefore, we are seeking comment on how to
best ensure that the identity and authority of the person who is
signing the GRAS notice is made clear. For example, we are considering
requiring that the GRAS notice state the name and the position or title
of the person who signs it.
(Issue 6b) Under the GRAS affirmation petition process, a
petitioner is required to submit a petition for GRAS affirmation under
21 CFR part 10 (Sec. 170.35(c)(1)(v)). As part of this petition, a
petitioner is required to submit a statement that, ``to the best of his
knowledge, it [the GRAS affirmation petition] is a representative and
balanced submission that includes unfavorable information, as well as
favorable information, known to him and pertinent to the evaluation of
the safety of the substance.'' (Sec. 170.35(c)(1)(v)). We implicitly
proposed this provision under proposed Sec. 170.36(c)(4), which
proposed to require, among other things, that a GRAS notice include a
comprehensive discussion of any reports of investigations or other
information that may appear to be inconsistent with the conclusion of
GRAS status. We are seeking comment on whether the GRAS notification
procedure should be as explicit on this point as the GRAS affirmation
petition process it would replace.
We also are seeking comment on whether to require a notifier to
certify to this statement, which would be consistent with the
certification in item E. Certification in Sec. 10.30(b). Such
certification also would be consistent with the procedures established
for another notification program in CFSAN, the premarket notification
program for food contact substances. (See Sec. 171.101(e) and FDA Form
No. 3480 (Ref. 4).)
G. Issue 7. Appropriately Descriptive Term for the Notified Substance
In the 1997 proposed rule, we proposed to require that the GRAS
notice include the common or usual name of the notified substance
(proposed Sec. 170.36(c)(1)(ii)). We also advised that notifiers with
questions concerning the common or usual name for a substance consult
with CFSAN's Office of Food Labeling (now the Office of Nutrition,
Labeling and Dietary Supplements) (for a substance that would be used
in human food) or with CVM's Division of Animal Feeds (for a substance
that would be used in animal food).\4\ As discussed in the experience
document (Ref. 1), in 2004, CFSAN began to routinely advise notifiers
that its use of a particular term to identify the notified substance in
a letter responding to a GRAS notice should not be considered an
endorsement or recommendation of that term as an appropriate common or
usual name for the purpose of complying with the labeling provisions of
the FD&C Act.
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\4\ For example, a notifier may have a question about the common
or usual name where it is not established by regulation.
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A GRAS notice addresses sections 201(s) and 409 of the FD&C Act and
does not address the labeling provisions of the FD&C Act or FDA's
corresponding regulations. We are seeking comment on whether to revise
proposed Sec. 170.36(c)(1)(ii) to make this more clear. For example,
instead of requiring that the GRAS notice include the common or usual
name of the notified substance, we are considering requiring that the
GRAS notice include the name of the notified substance, using an
appropriately descriptive term. We note that this may be the same as
the term which you may believe would be the common or usual name of the
substance under 21 CFR parts 102 (human food) and 502 (animal food).
H. Issue 8. Public Disclosure
Under proposed Sec. 170.36(f)(1), the elements listed in proposed
Sec. 170.36(c)(1)) would be immediately available for public
disclosure on the date the notice is received. As a practical
consequence of this proposed provision, the fact that we had received a
GRAS notice (i.e., the existence of the GRAS notice) would be
immediately available to the public. As discussed in the experience
document (Ref. 1), we have made this information readily accessible to
the public. CFSAN currently is making a ``GRAS Notice Inventory''
available on its Internet site. CFSAN presents notice-specific
information (such as the name and address of the notifier, the name of
the notified substance, and the intended conditions of use) extracted
from the information submitted under proposed Sec. 170.36(c)(1). CFSAN
expects that the ways by which we make this information readily
accessible to the public will evolve over time.
Because, under proposed Sec. 170.36(f)(1), the information
submitted under proposed Sec. 170.36(c)(1) would be immediately
available for public disclosure, it is implicit in this provision that
a person submitting information under proposed Sec. 170.36(c)(1)
should not include in this portion any non-public information such as
trade secret information, confidential commercial or financial
information, and personal privacy information. Based on our experience,
notifiers did not identify any information in the information submitted
under proposed Sec. 170.36(c)(1) as being confidential. We are seeking
comment on whether the final rule should explicitly require that the
information submitted under proposed Sec. 170.36(c)(1) exclude non-
public information.
I. Issue 9. Including Confidential Information in a GRAS Notice
We proposed that the method of manufacture in a GRAS notice exclude
any trade secrets (proposed Sec. 170.36(c)(2)). However, we stated
that a notifier who considers that certain information in a submission
should not be available for public disclosure should identify as
confidential the relevant portions of the submission for our
consideration (62 FR 18938 at 18952). We further stated we would review
the identified information, determine
[[Page 81540]]
whether that information is exempt from public disclosure under part 20
and release or protect the information in accordance with our
determination. We advised that, in most cases, we would be likely to
determine all information in a GRAS notice is available for public
disclosure, because a conclusion of GRAS status must be based on
generally available data and information.
We received several comments about whether confidential information
should be included in a GRAS notice. In essence, these comments
suggested that we both provide for the submission of trade secrets or
other confidential information in a GRAS notice and protect the trade
secrets or other confidential information from public disclosure, just
as we would in the case of submissions such as food additive petitions.
As discussed in the experience document (Ref. 1), during the
interim period CFSAN did accept some GRAS notices that included
information identified by the notifier as confidential. When a GRAS
notice included such information, in no case did CFSAN disclose the
identified information. In some cases, including confidential
information in a GRAS notice did not present a problem because it was
corroborative information. However, in other cases CFSAN questioned
whether there could be a basis for a conclusion of GRAS status if
qualified experts generally did not have access to the confidential
information.
In light of both the comments and CFSAN's experience, we are
seeking comments relevant to including confidential information in a
GRAS notice. We note that, while the decision to submit a GRAS notice
would be voluntary, the provisions governing the GRAS notification
procedure, including the information to be submitted, would be
mandatory.
(Issue 9a) We are seeking comment on whether proposed Sec.
170.36(c)(2) should stipulate that the method of manufacture exclude
any trade secrets, as it was proposed.
(Issue 9b) We are seeking comment on whether to require that a
notifier who identifies one or more trade secret(s), as defined in
Sec. 20.61(a), in the GRAS notice explain why it is trade secret
information and how qualified experts could conclude that the intended
use of the notified substance is GRAS without access to the trade
secret(s).
(Issue 9c) We are seeking comment on whether to require that a
notifier who identifies confidential commercial or financial
information, as defined in Sec. 20.61(b), in the GRAS notice explain
why it is confidential commercial or financial information and how
qualified experts could conclude that the intended use of the notified
substance is GRAS without access to such information.
J. Issue 10. Describing the Identity of a Notified Substance
Under proposed Sec. 170.36(c)(2), a GRAS notice would include
``Detailed information about the identity of the notified substance,
including, as applicable, its chemical name, Chemical Abstracts Service
Registry Number, Enzyme Commission number, empirical formula,
structural formula, quantitative composition, method of manufacture
(excluding any trade secrets and including, for substances of natural
biological origin, source information such as genus and species),
characteristic properties, any content of potential human toxicants,
and specifications for food-grade material.''
(Issue 10a) Based on our experience, we have found that when the
source of a notified substance is a biological material (e.g., a plant,
animal, or microorganism), taxonomic information about genus and
species may be insufficient to identify a biological source. The
experience document (Ref. 1) provides examples of GRAS notices
including information such as genus, species, variety, strain, part of
a plant source (such as fruit, seeds or seed husks, expressed oil,
flowers, roots, leaves, pulp, wood, or bark), and part of an animal
source (such as fluid, muscle mass, egg, shells, or extracted oil). We
note that some GRAS substances are derived from animal organs (e.g.,
the enzyme preparation ``catalase'' is manufactured from cow's liver
(21 CFR 184.1034)) or tissue (e.g., the enzyme preparation ``animal
lipase'' is manufactured from edible forestomach tissue or from animal
pancreatic tissue (21 CFR 184.1415)). We request comment on what
scientific information would be sufficient to identify the biological
source.
(Issue 10b) Based on our experience, we have found that information
about substances known to be toxicants is relevant regardless of the
state of the science regarding the specific toxicity of the substance
to humans. For example, during the interim period CFSAN evaluated a
GRAS notice about a substance derived from a biological source that is
known to contain mutagenic substances (Ref. 1). Therefore, we are
seeking comment on whether to require that information about the
identity of the notified substance specify any known toxicants that
could be in the source.
(Issue 10c) Substances that have a small particle size often have
chemical, physical, or biological properties that are different from
those of their larger counterparts (Ref. 5) and, thus, particle size
and associated chemical and physical properties may be relevant to the
identity of the notified substance. GAO's recent recommendations also
encouraged us to obtain more information about the use of engineered
nanomaterials (Ref. 2). Therefore, we are seeking comment on whether
the final rule should address, as part of identity, particle size and
other chemical and physical properties that may be used to characterize
engineered materials.
K. Issue 11. Dietary Exposure
We proposed to require that a notice regarding a conclusion of GRAS
status through scientific procedures include a comprehensive discussion
of, and citations to, generally available and accepted scientific data,
information, methods, or principles that the notifier relies on to
establish safety, including a consideration of the ``probable
consumption of the substance and the probable consumption of any
substance formed in or on food because of its use and the cumulative
effect of the substance in the diet, taking into account any chemically
or pharmacologically related substances in such diet'' (proposed Sec.
170.36(c)(4)(i)(A)). This proposed provision restated the statutory
language of section 409(c)(5) of the FD&C Act regarding dietary
exposure.
We proposed to require that a notice regarding a conclusion of GRAS
status through experience based on common use in food include a
comprehensive discussion of, and citations to, generally available data
and information that the notifier relies on to establish safety,
including evidence of a substantial history of consumption of the
substance by a significant number of consumers \5\ (proposed Sec.
170.36(c)(4)(ii)(A)). This proposed provision was silent on the
probable consumption of the substance by present-day consumers.
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\5\ In this document, references to ``consumers'' for the
purposes of part 170 are references to ``animals'' for the purposes
of part 570.
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We are seeking comment on issues related to the proposed provisions
for information about dietary exposure to a notified substance.
(Issue 11a) We are seeking comment on whether proposed Sec.
170.36(c)(4)(i)(A) should continue to restate the statutory language of
section 409(c)(5) of the FD&C Act or whether this provision should be
stated more clearly, for example, by requiring information about
[[Page 81541]]
dietary exposure (i.e., the amount of the notified substance that
consumers are likely to eat or drink as part of a total diet).
(Issue 11b) Over 50 years have passed since passage of the 1958
Food Additives Amendment establishing the requirements for food
additives and the corresponding provisions for GRAS substances in food.
In evaluating whether use of a substance is GRAS through experience
based on common use in food, we rely on information documenting that
the ``common use in food'' of a substance satisfies the definition in
Sec. 170.3(f) such that adverse health effects, if they occurred,
could be noted. In other words, a substance is not eligible for GRAS
status merely because it was used in food before January 1, 1958, if
such use were not sufficiently widespread (62 FR 18938 at 18949).
Therefore, we are seeking comment on whether a GRAS notice should be
required to include information about dietary exposure to contemporary
consumers regardless of whether the determination of GRAS status is
through scientific procedures or through experience based on common use
in food.
(Issue 11c) Some substances are administered to certain animal
species through their drinking water. Section 201(f) of the FD&C Act
defines food as ``articles used for food or drink for man or other
animals.'' In the proposed rule, we utilized the terms, ``foods'' and
``diet,'' when addressing the intended use and safety evaluation of
notified substances. We are seeking comment on whether it is necessary
to clarify that the GRAS notification procedure is applicable to
substances used in both food and drinking water of animals and, if so,
whether it would be necessary to clarify this in the provisions of
proposed Sec. 570.36.
(Issue 11d) Under proposed Sec. 570.36(c)(1)(iii), notifiers would
submit information about the applicable conditions of use of the
notified substance, including a description of the population expected
to consume the substance. For substances added to animal food, the
applicable population is the specific animal species intended to
consume the substance. Animal species differ in their physical
characteristics, digestive physiology, and metabolic pathways.
Therefore, a substance that is safe for use in one animal species may
not be safe for use in other species, and FDA would need to know the
intended species in order to properly evaluate the notifier's safety
assessment of the intended use of the substance. We are seeking comment
on whether it is necessary to clarify proposed Sec. 570.36(c)(1)(iii)
to explicitly require submission of information about the animal
species expected to consume the substance.
(Issue 11e) Proposed Sec. 570.36(c)(2) would require that
notifiers submit detailed information about the notified substance,
including any content of potential human or animal toxicants.
Additionally, proposed Sec. Sec. 570.36(c)(4)(i)(A) and (c)(4)(ii)(A)
would require that notifiers submit a comprehensive discussion of, and
citations to, the information that the notifier relies on to establish
safety. Where a substance is intended for use in the food of an animal
used to produce human food, these sections of the proposed rule would
require that the notifier include citations to information about both
target animal (i.e., the specific animal species that are fed the
notified substance) and human safety. The information provided would
need to be sufficient to show that the use of the substance is
generally recognized among qualified experts to be safe for animals
consuming food containing the substance as well as for humans consuming
food derived from such animals (i.e., under its intended conditions of
use). A GRAS notice for a substance intended for use in the food of an
animal used to produce human food submitted without such information
would likely receive a response from FDA stating that FDA has
identified questions regarding whether the intended use of the
substance is GRAS. (See the proposed rule (62 FR 18938 at 18950).)
Therefore, we are seeking comment on whether it is necessary to clarify
applicable sections of the proposed rule to explicitly require, for
substances intended for use in the food of an animal used to produce
human food, the submission of information about both target animal and
human safety.
L. Issue 12. Filing Decision
Some comments to the 1997 proposed rule recommended that we conduct
a preliminary review of a submission, before we file it as a GRAS
notice, to determine whether it appears, on its face, to meet the
format requirements. Some comments suggested that we ``decline to
file'' a notice that appears to be inadequate, e.g., because it lacks
critical data or information. These comments considered that a
preliminary review that resulted in a ``filing decision'' would be
analogous to the current procedure whereby we review a GRAS affirmation
petition to determine whether it appears, on its face, to meet the
format requirements for the GRAS affirmation petition process.
As discussed in the experience document (Ref. 1), CFSAN routinely
conducted such a preliminary review of each submitted GRAS notice.
Based on our experience, it was the complete evaluation process that
identified those data or information that are critical to establish
GRAS status. Therefore, a decision on our part to file a submission as
a GRAS notice has not reflected our judgment as to whether the notice
addressed all issues or discussed all critical data or information.
We are seeking comment on whether we should make explicit the
process by which FDA makes such a filing decision, including the
factors we should use to determine whether to file a submission as a
GRAS notice. Some potential factors could be the following:
Whether your submission includes all required sections;
Whether you provided all required copies;
Where information provided is identified as being
confidential, whether you explain the basis for your conclusion of GRAS
status;
Whether we still retain as a record any data or
information that you ask us to incorporate by reference; and
Whether the subject of your submission is: (1) Already
authorized for use under our regulations or (2) a mixture of substances
that are already authorized for use under our regulations. For example,
if we receive a submission about a mixture of substances, each of which
is affirmed as GRAS under 21 CFR part 184 for use as an antimicrobial
in human food, and the intended use of the mixture is as an
antimicrobial, we may treat the submission as general correspondence
and inform the notifier that we do not devote resources to evaluating
the use of such mixtures under the GRAS notification procedure.
M. Issue 13. Substances Intended for Use in Products Subject to
Regulation by the U.S. Department of Agriculture
Subsequent to the 1997 proposal, we issued a final rule amending
the GRAS affirmation petition process to provide for simultaneous
review of a GRAS notice by FDA and the U.S. Department of Agriculture's
(USDA's) Food Safety and Inspection Service (FSIS) when the intended
use of the notified substance includes use in products subject to
regulation by FSIS (65 FR 51758, August 25, 2000). Under Sec.
170.35(c)(3)(i), we forward a copy of a GRAS affirmation petition to
FSIS for simultaneous review under the Poultry Products Inspection Act
(PPIA) (21 U.S.C 451 et seq.) or the Federal Meat Inspection Act (FMIA)
(21 U.S.C. 601 et seq.). Under
[[Page 81542]]
Sec. 170.35(c)(3)(ii), we ask USDA to advise whether the proposed uses
comply with the FMIA or PPIA or, if not, whether use of the substance
would be permitted in products under USDA jurisdiction under specified
conditions or restrictions. The provisions of this review process
reflect interagency coordination to ease the burden on regulated
industries and consumers.
In addition, as discussed in the experience document (Ref. 1),
during the interim period CFSAN developed a Memorandum of Understanding
(MOU) with USDA's FSIS (65 FR 33330, May 23, 2000), which provides for
the same coordinated review process for GRAS notices when the intended
use of the notified substance includes use in products subject to
regulation by FSIS. Under the terms of the MOU, CFSAN forwards a copy
of an applicable GRAS notice to FSIS. CFSAN then simultaneously
evaluates the basis for GRAS status while FSIS evaluates whether the
intended use of the notified substance in meat or poultry products
complies with the FMIA or PPIA or, if not, whether use of the substance
would be permitted in products under FSIS jurisdiction under specified
conditions or restrictions. In addition, during the interim period
responsibility to administer the Egg Products Inspection Act (EPIA) (21
U.S.C. 1031 et seq.) was transferred from the Agricultural Marketing
Service of USDA to FSIS (69 FR 1647; January 12, 2004). In light of
this transfer of responsibility, FSIS provided its review of the use of
a notified substance in egg products when a GRAS notice that CFSAN sent
to USDA for its review under the PPIA or the FMIA also described a use
in egg products (Ref. 1).
As discussed in the experience document (Ref. 1), more than 25
percent of GRAS notices filed during the interim period included the
use of the notified substance in products subject to regulation by FSIS
under the FMIA or the PPIA, and FDA obtained FSIS review for these
substances.
We are seeking comment on whether to make our coordinated review
process with FSIS explicit in the final rule. We also are seeking
comment on whether such a procedure should provide that a notifier who
submits a GRAS notice for the use of a notified substance in products
subject to regulation by FSIS provide an additional paper copy or an
electronic copy of the GRAS notice that we could send to FSIS. This
would improve the efficiency of a simultaneous review process. We note
that FSIS, under statutes it administers, does not review the use of
substances intended for use in food for animals and therefore there
would be no need for a counterpart provision in proposed Sec. 570.36
for substances intended for use in food for animals.
O. Issue 14. Timeframe for FDA's Evaluation of a GRAS Notice
Section 170.35 does not specify a timeframe for FDA to complete the
rulemaking associated with a GRAS affirmation petition. However, we
proposed to respond to a GRAS notice within 90 days to reflect both a
commitment to operational efficiency and a belief that our evaluation
of whether a notice provides a sufficient basis for a conclusion of
GRAS status could likely be accomplished in such a period. We also
considered whether the timeframe for our response should be longer than
90 days, and specifically requested comment on whether the proposed 90-
day timeframe for an Agency response should be lengthened, e.g., to 120
days or 150 days. In addition, we noted that comments on the proposal
may justify a longer timeframe for notifications concerning substances
used in animal food.
Several comments favored a 90-day timeframe because a 90-day
timeframe would provide an incentive for manufacturers to submit GRAS
notices. Other comments questioned whether the proposed 90-day
timeframe would allow sufficient time for us to adequately evaluate a
GRAS notice and urged us to establish a realistic timeframe that we
would hold ourselves accountable to.
As shown in the experience document (Ref. 1), during the interim
period CFSAN responded to approximately 12 percent of GRAS notices
within 90 days, and required more than 180 days to respond to more than
31 percent of GRAS notices. As discussed in the experience document
(Ref. 1), the scientific challenges associated with the safety
assessment conducted by the notifier were a factor in the time CFSAN
needed to respond to a GRAS notice. We request comment on whether we
should retain a set timeframe for us to respond to a GRAS notice, and,
if so, whether it should be 90 days or another timeframe.
O. Issue 15. Conflict of Interest
In the GAO report (Ref. 2), GAO noted that we have not issued any
conflict of interest guidance that companies can use to help ensure
that the members of their expert panels are independent. Further, GAO
recommended that FDA develop a strategy to minimize the potential for
conflicts of interest, including taking steps such as issuing guidance
for companies on conflict of interest and requiring information in GRAS
notices regarding expert panelists' independence. As discussed in the
GAO report (Ref. 2), we consider that the use of an expert panel is one
way to demonstrate consensus (i.e., the common knowledge element of
safety) and we do not consider the view of an expert panel alone to be
determinative for establishing safety. We seek comment on whether
companies would find it useful to have guidance on potential conflicts
of interest of GRAS expert panelists. If such guidance would be useful,
we seek comment on what companies currently do to mitigate such a
conflict. We also seek comment on whether to require that GRAS notices
include information regarding expert panelists' independence.
P. Issue 16. Additional Guidance on Documenting GRAS Conclusions
The GAO report recommended that FDA issue guidance on how to
document GRAS conclusions (Ref. 2). In our response to GAO, we noted
the guidance in the preamble to the GRAS proposal and the guidance on
our Web site that answers common questions about the food ingredients
classified as GRAS in the form of frequently asked questions (Ref. 6).
We seek comment whether there is a need to clarify that this guidance
also applies to a GRAS conclusion that is not submitted to FDA under
the proposed notification procedure and whether there is a need for FDA
to develop further guidance on documenting such a GRAS conclusion.
Q. Issue 17. Pending GRAS Affirmation Petitions
In the 1997 proposed rule, we proposed to presumptively convert any
filed, GRAS affirmation petition that is pending on the effective date
of the rule (hereinafter referred to as a ``pending petition'') to a
GRAS notice. The conversion would take place on the effective date of
the final rule. Any person (hereinafter referred to as an ``affected
petitioner'') who had submitted a GRAS affirmation petition could amend
the converted petition by submitting the dated and signed document that
would be required under proposed Sec. 170.36(c)(1). In essence, we
would waive the requirement for an affected petitioner who submitted
such a document to agree to provide us with access to applicable data
and information upon request if the affected petitioner informed us
that the complete record that supports the conclusion of GRAS status
had been submitted in the applicable GRAS petition. The proposed
procedures for our review and administration of a converted petition
would be similar to those for a newly
[[Page 81543]]
submitted GRAS notice. However, by 90 days after the effective date of
the final rule,\6\ we would inform any affected petitioner who had not
submitted a certification that the converted petition was inadequate as
a notice.
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\6\ Proposed Sec. 170.36(g)(3)(iii) stated that we would inform
a petitioner who did not submit a conversion amendment that the
notice was inadequate within 90 days of publication of the final
rule, rather than within 90 days of the effective date of the final
rule. This was an error.
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A few comments stated that the 1997 proposed rule did not discuss
the fate of a pending petition if the petitioner elected not to submit
a conversion amendment. These comments did not understand the
implications of the proposed provisions which, in essence, would
consider that the affected petitioner had not provided a basis for a
conclusion of GRAS status.
Many comments objected to the proposed provisions regarding pending
petitions. In general, these comments expressed the opinion that our
proposal was fundamentally unfair to an affected petitioner because an
affected petitioner had invested considerable time and resources in the
petition process. Some comments suggested that we ``grandfather'' a
pending petition (i.e., complete the rulemaking that began under the
petition process), as a matter of course, in those circumstances where
we had completed our scientific review and had no outstanding
scientific questions. Other comments suggested that such a
``grandfather'' provision be an option available to an affected
petitioner rather than a matter of course. One comment recommended that
the final rule provide a petitioner with a period of 180, rather than
90, days to submit the dated and signed document providing information
in proposed Sec. 170.36(c)(1). This comment argued that many of these
petitions had been pending for years, that the subjects of the
petitions had been marketed during those years, and that there would
therefore be no urgency in closing the applicable files.
In light of the view of the comments that our proposed disposition
of pending petitions was unfair, in this document we are seeking
comments regarding pending petitions. Specifically, we seek comment on
how to reduce the impact on affected petitioners while retaining the
principle that we will not devote resources to pending petitions. We
seek comment on whether an outcome of ``withdrawal without prejudice''
instead of ``insufficient basis'' would be more appropriate when an
affected petitioner simply chooses not to have the pending petition
considered under the GRAS notification procedure. We are seeking
comment on whether an affected petitioner could request that we
incorporate by reference a withdrawn GRAS affirmation petition into a
GRAS notice, and if so, if any requirements of the GRAS notification
procedure should be waived.
We also note that, as discussed in the experience document (Ref.
1), during the interim period we processed a pending petition as a food
additive petition and issued a food additive regulation for the
petitioned substance (21 CFR 172.780; 70 FR 8032, February 17, 2005).
We note that CVM has no pending GRAS petitions and thus, this
discussion is not applicable to GRAS affirmation petitions for food for
animals.
III. Costs and Benefits
FDA requests comments on how the issues discussed in this document
could affect the costs and benefits estimated in the 1997 proposed
rule, e.g., whether these issues would result in costs or benefits that
would be either greater than, or less than, those estimated in the 1997
proposed rule (62 FR 18938 at 18958).
IV. Paperwork Reduction Act of 1995
The 1997 proposed rule contains information collection provisions
that are subject to review by the Office of Management and Budget under
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). Interested
persons are requested to send comments regarding information collection
to FDA (see DATES and ADDRESSES).
V. Comments
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.
VI. References
We have placed the following references on display in the Division
of Dockets Management (see ADDRESSES). You may see them between 9 a.m.
and 4 p.m., Monday through Friday. (FDA has verified the Web site
addresses, but FDA is not responsible for any subsequent changes to Web
sites after this document publishes in the Federal Register.)
1. Experience With GRAS Notices Under the 1997 Proposed Rule,
Memorandum Dated November 4, 2010, from Linda S. Kahl of FDA to Docket
No. FDA-1997-N-0020.
2. United States Government Accountability Office, Report to
Congressional Requestors on Food Safety: FDA Should Strengthen Its
Oversight of Food Ingredients Determined To Be Generally Recognized as
Safe (GRAS), Report No. GAO-10-246, February 2010, Accessible at http://www.gao.gov/new.items/d10246.pdf, Accessed and printed on May 3, 2010.
3. Memorandum for the Heads of Executive Departments and Agencies,
Dated June 1, 1998, Signed by President William J. Clinton, Accessible
at http://www.plainlanguage.gov/whatisPL/govmandates/memo.cfm, Accessed
and printed on July 14, 2008.
4. FDA Form No. 3480, Notification for New Use of a Food Contact
Substance, Accessible at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/ucm076880.pdf, Accessed and printed on
October 13, 2010.
5. FDA, 2007, Nanotechnology Task Force Report 2007, Accessible at
http://www.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/NanotechnologyTaskForceReport2007/default.htm, Accessed and printed on
October 13, 2010.
6. Guidance for Industry: Frequently Asked Questions About GRAS,
Accessible at http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/FoodIngredientsandPackaging/ucm061846.htm, Accessed and printed on
October 13, 2010.
Dated: December 17, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2010-32344 Filed 12-27-10; 8:45 am]
BILLING CODE 4160-01-P