inventory of GRAS notices could suffice to document that certain
notices raised no significant issues.
    (Response 118) We agree that a publicly available inventory of GRAS
notices can document which notices result in a ``no questions letter,
e.g., by prominently listing the category of our response. The
Inventory of GRAS Notices developed during the Interim Pilot program
prominently classifies each response letter as ``no questions,''
``insufficient basis,'' and ``cease to evaluate'' (Ref. 46). However,
we disagree that merely displaying the category of our response,
without providing the full text of a letter that places that category
of response in context, is appropriate, regardless of whether the
response to the GRAS notice is ``no questions,'' ``insufficient
basis,'' or ``cease to evaluate.'' For example, even when we answer
``FDA has no questions,'' our response letter highlights key safety
considerations, such as the importance of ensuring that the method of
manufacture removes potential contaminants.
    (Comment 119) One comment asks us to provide ``public notice'' of
all GRAS notices and the information provided therein. Another comment
asks us to make the ``GRAS exemption claim'' readily accessible to the
public by publishing information that would be in the publicly
accessible file in the Federal Register in addition to placing the
``GRAS exemption claim'' in a readily accessible file. This comment
states that doing so would provide the public with access to as much
information as possible about what substances would be used in food on
the basis of the GRAS provision if FDA is

going to ``forgo its role'' in the evaluation of the safety of GRAS
substances. This comment also asks us to publish the receipt of the
notice and all of our subsequent responses to the notice in the Federal
Register.
    Another comment asks us to publish semi-annually, either in a
Federal Register notice or by regulation, a list of GRAS notices that
receive a ``no questions letter'' in addition to posting the Inventory
of GRAS notices on our Web site. This comment explains that questions
are sometimes raised--especially from outside the United States--about
the regulatory status of a substance used in food on the basis of the
GRAS provision unless that use of the substance is either incorporated
into the CFR or otherwise officially published. This comment asserts
that periodic publications in the Federal Register would assist in
addressing this concern.
    (Response 119) By specifying that we will make a list of filed GRAS
notices readily accessible (currently, through the inventory on the
Internet), the rule requires us to actively disclose those GRAS
notices. There is a gap between the date on which we receive a GRAS
notice and the date on which we add it to the inventory, e.g., CFSAN
currently updates its inventory on an approximately monthly basis.
However, in practice during the Interim Pilot program there was ample
public notice of the receipt of the GRAS notice before CFSAN responded
to it (see the discussion of the timeframe for CFSAN's response in
section III.M of CFSAN's 2010 experience document (Ref. 18)). In
addition, the rule provides that we may send a subsequent letter about
the GRAS notice if circumstances warrant; such circumstances could
include data and information, received from a member of the public,
after we responded to the GRAS notice.
    We decline the requests to provide public notice through an
announcement in the Federal Register. Publishing an announcement in the
Federal Register requires an expenditure of our resources (including
time and cost of publication) that would be inconsistent with our goal
of using our resources efficiently and effectively. Even if we
conserved resources by publishing such a notice only on a semi-annual
basis, we disagree that ``officially publishing'' a list of GRAS
notices that receive a ``no questions letter'' in the Federal Register
would address concerns, in the domestic or international community,
about the regulatory status of the use of a substance when that use is
not listed in our regulations. It is the Code of Federal Regulations,
not the Federal Register, that is the official repository of our
regulations listing authorized uses of food substances.
    We disagree that we are forgoing our role in the evaluation of the
safety of substances used in food on the basis of the GRAS provision.
See Response 25.
    (Comment 120) One comment asks us to place the entire GRAS notice,
rather than only the proposed ``GRAS exemption claim,'' in a readily
accessible paper file, e.g., at the Division of Dockets Management. In
the comment's view, a simple provision that a notifier submit one
additional paper copy would mitigate our concerns about the
administrative inefficiency of maintaining duplicate files at both the
center and Agency levels. Another comment asks us to make the entire
notice readily accessible in electronic form.
    (Response 120) We currently make a hyperlink to an electronic copy
of each GRAS notice accessible from within the entry for that GRAS
notice in the inventory, after appropriate redaction (e.g., of privacy
information, copyrighted material, and any data and information that
are exempt from public disclosure) (Ref. 18, footnote 3). As a
practical matter, placing paper files on public display requires space,
which is finite, and our Division of Dockets Management scans paper
submissions into electronic format.

C. Public Disclosure of a GRAS Notice Is in Accordance With Our Public
Information Regulations in Part 20

    (Comment 121) One comment agrees that information submitted under
the proposed ``GRAS exemption claim'' should exclude from public
disclosure the non-public confidential information with the exception
of safety data.
    (Response 121) This comment appears to have misinterpreted the
proposed provisions regarding submission of non-public information and
how the public disclosure provisions of this rule apply to non-public
information. The proposed ``GRAS exemption claim'' is the precursor of
Part 1 of a GRAS notice (which we are establishing in Sec.  170.225).
The rule specifies that you must not include any information that is
trade secret or confidential commercial information in Part 1 of your
GRAS notice, except in the statement of your view as to whether any of
the data and information in Parts 2 through 7 of your GRAS notice are
exempt from disclosure under the FOIA. Part 1 of a GRAS notice includes
signed statements and a certification, not ``safety data.'' The
``safety data'' would be included in Parts 2 through 7 of the GRAS
notice. Consistent with the view of this comment, the rule provides
that those data and information are available for public disclosure
upon receipt (see Sec.  170.275(a)(2)). See also Response 50.
    (Comment 122) Some comments ask us to alert the notifier, and grant
the notifier an option to withdraw the notice, in order to protect
information designated as confidential from disclosure.
    (Response 122) We decline this request. A person who submits a
record to us may not withdraw that record from our files (Sec.  20.29).
Rather, the procedures that govern the release of information that a
notifier identifies as confidential in a GRAS notice are established in
Sec. Sec.  20.61 and 20.27. Under Sec.  20.61(d), a person who submits
records to us may designate part or all of the information in such
records as exempt from disclosure under exemption 4 of FOIA. However,
under Sec.  20.27 marking records submitted to us as confidential, or
with any other similar term, raises no obligation by FDA to regard such
records as confidential, to return them to the person who has submitted
them, to withhold them from disclosure to the public, or to advise the
person submitting them when a request for their public disclosure is
received or when they are in fact disclosed.

XXII. Submission of a Supplement

    The rule provides that you may submit a supplement to a GRAS notice
after we respond to your notice based on our evaluation of your notice
or cease to evaluate your notice (Sec.  170.280). However, if our
response to your GRAS notice raises questions about your conclusion
that the notified substance is GRAS under the conditions of its
intended use, the appropriate mechanism for you to address those
questions would be to submit a new GRAS notice or other regulatory
submission (such as a food additive petition) rather than to submit a
supplement. See section III.C.2 of CFSAN's 2010 experience document for
examples of supplements that CFSAN received during the Interim Pilot
program (Ref. 18).

XXIII. Comments on the Administrative Process for Pending GRAS
Affirmation Petitions

    We proposed that any pending petitions would be presumptively
converted to a GRAS notice on the date the final rule becomes effective
(proposed Sec.  170.36(g)(1)). An affected petitioner would have an
opportunity to amend the converted petition to meet the requirements of
the GRAS notification procedure by submitting a

``GRAS exemption claim'' (proposed Sec.  170.36(g)(2)). A GRAS
affirmation petition that is converted to a notice and that the
affected petitioner amends would be reviewed and administered according
to the provisions of the GRAS notification procedure; the date of
receipt of the amendment would be the date of receipt of the notice
(proposed Sec.  170.36(g)(3)(i)). After 90 days from the date of
publication of the final rule, we would inform any affected petitioner
who had not amended an applicable petition that the converted petition
is inadequate as a GRAS notice.
    In the 2010 notice, we requested comments on three issues related
to the pending petitions as shown in table 23. Although the 2010 notice
classified all of these issues as ``Issue 17,'' for presentation
purposes in this document we classify the three issues as 17a, 17b, and
17c.

 Table 23--Issues in the 2010 Notice Regarding Pending GRAS Affirmation
                                Petitions
------------------------------------------------------------------------
              Description of
 Issue No.   our request for                   Reference
                 comment
------------------------------------------------------------------------
17a.......  How to reduce the  75 FR 81536 at 81542-81543.
             impact on
             affected
             petitioners
             while retaining
             the principle
             that we will not
             devote resources
             to pending
             petitions.
17b.......  Whether an         75 FR 81536 at 81542-81543.
             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.
17c.......  Whether an         75 FR 81536 at 81542-81543.
             affected
             petitioner could
             request that we
             incorporate into
             a GRAS notice a
             withdrawn GRAS
             affirmation
             petition into a
             GRAS notice, and
             if so, if any
             requirements of
             the GRAS
             notification
             procedure should
             be waived.
------------------------------------------------------------------------

    In the following paragraphs, we discuss comments regarding the
disposition of pending petitions in light of the deletion of the GRAS
affirmation petition process. After considering these comments, we are
establishing provisions for the pending petitions as shown in table 24,
with editorial, clarifying, and conforming changes as shown in table
29. (See Sec.  170.285.) Table 24 identifies changes we made relative
to the proposed rule or the description in the 2010 notice other than
the editorial, clarifying, and conforming changes shown in table 29 and
the additional editorial changes associated with the redesignation of
proposed Sec.  170.36(g) as Sec.  170.285.

               Table 24--Final Requirements for Disposition of Pending GRAS Affirmation Petitions
----------------------------------------------------------------------------------------------------------------
                                                                                Revisions (other
                                                                                than editorial,
                                         Proposed        Issue No. in                          clarifying, and
     Final designation in the       designation in the     the 2010         Description      conforming changes)
    regulatory text  (Sec.   )       regulatory text        notice                              relative to the
                                        (Sec.   )                                              proposed rule or
                                                                                the  2010 notice
----------------------------------------------------------------------------------------------------------------
170.285(a).......................  170.36(g)(1).......     17a and 17b  On the effective     We administratively
                                                                         date of the rule,    close the docket
                                                                         we will close the    for the GRAS
                                                                         docket for any       affirmation
                                                                         GRAS affirmation     petition
                                                                         petition that is     rulemaking rather
                                                                         still pending as     than convert the
                                                                         of that date.        pending petition
                                                                                to a GRAS notice.
170.285(b).......................  170.36(g)(2).......             17c  Any person who       The affected
                                                                         submitted a GRAS     petitioner submits
                                                                         affirmation          a GRAS notice
                                                                         petition that is     rather than an
                                                                         pending as of the    amendment to a
                                                                         date of the final    ``converted
                                                                         rule may submit a    petition''.
                                                                         GRAS notice and
                                                                         request that we
                                                                         incorporate the
                                                                         GRAS affirmation
                                                                         petition.
N/A..............................  170.36(g)(3)(i)....             N/A  N/A................  No longer specifies
                                                                                the procedures for
                                                                                FDA's evaluation
                                                                                of a former
                                                                                pending petition.
N/A..............................  170.36(g)(3)(ii)...     17a and 17b  N/A................  No longer treats a
                                                                                pending petition
                                                                                that is not
                                                                                evaluated as a
                                                                                GRAS notice as
                                                                                having an
                                                                                insufficient basis
                                                                                to support GRAS
                                                                                status.
----------------------------------------------------------------------------------------------------------------

    (Comment 123) Some comments to the proposed rule support our
proposal to convert pending GRAS affirmation petitions to GRAS notices
on the effective date of the rule. However, as discussed in the 2010
notice, many comments to the proposed rule object to our proposal for
administering the pending petitions as being fundamentally unfair,
because an affected petitioner had invested considerable time and
resources in the petition process and should not be penalized by our
adoption of a new GRAS notification procedure. Some of these comments
state that, in most cases, FDA also had dedicated significant resources
to the review of these petitions and, in some cases, had even arranged
for an additional third party to review the substance that was the
subject of the petition. These comments suggest options such as
``grandfathering'' pending petitions, i.e., completing the rulemaking
process for them, particularly if we had completed our scientific
review with no outstanding questions. Some comments ask us to provide
an affected petitioner 180 days, rather than 90 days, to amend the
converted petition to satisfy the requirements of the GRAS notification
procedure. One of these comments argues that there need not be any
urgency in closing the applicable files because many of these petitions
had been pending for years, and the subjects of the petitions had been
marketed during those years.
    Some comments to the proposed rule assert that more resources would
be needed to review a petition that is converted to a GRAS notice than
would be needed to complete the review of each pending petition and
issue a

regulation. One comment suggests that it would be simpler and more
efficient administratively to allow an affected petitioner an option to
update a GRAS affirmation petition to include additional conditions of
use or new specifications than to require separate GRAS notices for
such changes.
    Other comments ask us to clarify the procedures we would use to
convert a GRAS affirmation petition to a GRAS notice as well as
procedures for amending a petition that was converted to a GRAS notice
through an additional submission. Some comments assert that we should
not require an affected petitioner to submit such an amendment because
all of the pertinent information would already be included in the
petition and argue that technical adherence to the format of a GRAS
notice should not take precedence over administrative efficiency and
common sense. Other comments express concern that it was not clear that
the proposed additional submission (proposed Sec.  170.36(g)(2)) was in
fact a skeleton notice that primarily would cross-reference the
original GRAS affirmation petition.
    Some comments to the 2010 notice suggest that a pending petition
could be ``withdrawn without prejudice'' or ``suspended'' so that it
would no longer require FDA resources to review it. Other comments to
the 2010 notice express the view that a simple letter of conversion
should be adequate, but that if an affected petitioner chose not do so
then the outcome of the converted petition would more appropriately be
described as ``withdrawn without prejudice'' rather than
``insufficient'' as a GRAS notice. Other comments to the 2010 notice
continue to express the view that we should ``grandfather'' a pending
petition. One of these comments asserts that failure to grandfather
those affirmation petitions where FDA had completed its review and no
outstanding scientific issues exist would be unfair because the GRAS
notification procedure results in a lower level of authoritativeness
than the GRAS affirmation petition process, and the affected
petitioners had invested considerable time and resources in the
petition process. This comment also notes that after we published the
proposed rule we continued to review GRAS affirmation petitions and
completed the process for six GRAS affirmation petitions before
discontinuing further activity in 1999. Comments that address Issue 17c
recommend that an affected petitioner be allowed to incorporate
information from a ``withdrawn'' GRAS affirmation petition into a GRAS
notice.
    We received no comments asking us to waive any of the requirements
of the notification procedure.
    (Response 123) We have revised the proposed provisions regarding
the disposition of pending petitions in light of the concern of the
comments that the proposed process was unfair to affected petitioners.
The final rule provides that on the effective date of the rule, we will
close the docket for any GRAS affirmation petition that is still
pending as of that date (Sec.  170.285(a)). Any person who submitted a
GRAS affirmation petition that is pending as of the date of the final
rule may submit a GRAS notice and request that we incorporate the GRAS
affirmation petition (Sec.  170.285(b)). We are closing the docket for
the petition by operation of law because the process that would be
necessary to bring a petition to closure (i.e., Sec.  170.35(c)) no
longer exists. We decided to close the docket for the petition, rather
than classify the petition as withdrawn without prejudice, for two
reasons. First, closing the docket is an administrative option that is
open to us, whereas in our petition processes withdrawing a petition is
an option that falls to the petitioner (see, e.g., Sec.  171.1(j) for
withdrawal of a food additive petition without prejudice). Second,
``withdrawal without prejudice'' generally means ``without prejudice to
a future filing,'' and ``future filing'' refers to the same type of
filing; however, we have eliminated the GRAS affirmation petition
process and, thus, an affected petitioner could not submit another GRAS
affirmation petition.
    Closing the docket is neutral with respect to a conclusion by an
affected petitioner that the petitioned substance is GRAS under the
conditions of its intended use, because closing the docket does not
result in a publicly available ``insufficient basis letter.'' To
clarify that closing the petition is without prejudice to eligibility
for classification of the use of the substance as GRAS, the final rule
specifically provides that an affected petitioner may incorporate the
former GRAS affirmation petition into a GRAS notice. Given the passage
of time since the pending petitions were submitted, it is likely that
some of the data and information in the petition would need to be
updated. In addition, the affected petitioner would need to follow all
format requirements for a GRAS notice, including the narrative required
in Part 6 of a GRAS notice.
    We acknowledge that our response to a GRAS notice does not have the
same level of ``authoritativeness'' as a listing in our regulations.
However, some of the comments that objected to the proposal to convert
a pending petition to a GRAS notice assert that the substances that are
the subject of the pending petitions have been marketed for years;
clearly, these affected petitioners are able to market the substance
without a listing in our regulations.
    We agree that it is appropriate to extend the timeframe for an
affected petitioner to take action with respect to a pending petition.
Under final Sec.  170.285(b), there is no limit on the timeframe for an
affected petitioner to submit a GRAS notice that incorporates a GRAS
affirmation petition.
    We decline the request to ``grandfather'' any pending petitions. We
simply do not have sufficient resources to devote to the rulemaking
process that is required for GRAS affirmation, regardless of whether we
already have completed our scientific review. For example, even if we
have completed our scientific review, the Administrative Procedures Act
(5 U.S.C. 553) requires that we consider relevant data, views, or
arguments submitted to us by interested persons and that we publish a
concise general statement of the basis and purpose of the regulation.
In addition, Executive Order 12866 requires that we assess the costs
and benefits of available regulatory alternatives when we conduct
rulemaking, and the Regulatory Flexibility Act (5 U.S.C. 601-612)
requires that we consider alternatives that would minimize the economic
impact of our regulations on small entities. Thus, to complete the
rulemaking associated with the GRAS affirmation petition process, we
require significant resources beyond those associated with scientific
review. Even if we did ``grandfather'' a pending petition, it is highly
unlikely that we would be able to devote resources to this voluntary
process in light of competing programs that are required by statute.
For example, the resources that could be directed to the GRAS
affirmation petition process must be considered together with the
resources that are required to administer the food and color additive
petition processes and the premarket notification process for food
contact substances, which are required programs under sections 409 and
721 of the FD&C Act.
    For the reasons discussed in the previous paragraph, we disagree
that we would have needed more resources to review a petition that is
converted to a GRAS notice than to complete the review of each pending
petition and issue a regulation. We also disagree that it would be
simpler and more efficient administratively to allow an affected

petitioner an option to update a GRAS affirmation petition. As
discussed in CFSAN's 2016 experience document (Ref. 19), during the 10-
year period extending from 1990 through 1999, CFSAN completed the
rulemaking process for 24 GRAS affirmation petitions, with an average
elapsed time of approximately 7.9 years (median elapsed time
approximately 6.9 years). In contrast, under the final rule we will
respond to a GRAS notice in 180 days, with an option to extend the
timeframe by an additional 90 days (see Response 98).
    As of August 17, 2016 there are 45 pending GRAS affirmation
petitions. We intend to contact each affected petitioner to inform the
petitioner that: (1) We are closing the affected docket as of October
17, 2016; and (2) the petitioner may submit a GRAS notice that
incorporates the former GRAS affirmation petition.
    (Comment 124) One comment asks us to issue a regulation, to be
included in part 184, that lists the pending petitions. The comment
also asks us to include a statement that the lack of an affirmation
regulation does not indicate that FDA disagrees with the affected
petitioner's GRAS determination.
    (Response 124) We decline this request. Our regulations in part 184
represent our own conclusions regarding the GRAS status of a listed
substance under the conditions of its intended use. It is inappropriate
for our regulations to become a catalog of circumstances where we have
not reached our own conclusion regarding GRAS status.
    However, under final Sec.  170.275(b), we will make a list of filed
GRAS notices readily accessible to the public. The inventory of GRAS
notices that currently makes this list available includes a link to
information about each listed GRAS notice. When the GRAS notice was
originally submitted as a GRAS affirmation petition, we have included
the petition number. We intend to continue this practice under the
final rule.
    We also have placed a list of the pending petitions that we are
closing in the docket for this rule (Ref. 48).

XXIV. Other Comments

A. GRAS Panels and Conflict of Interest

    In the 2010 notice, we explained that the GAO report 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 (75 FR 81536 at 81542). The GAO report recommended that we
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. In the 2010 notice, we
requested comments on three issues related to GAO's recommendation
regarding conflict of interest as shown in table 25. Although the 2010
notice classified all of these issues as ``Issue 15,'' for presentation
purposes in this document we classify the three issues as 15a, 15b, and
15c.

  Table 25--Issues in the 2010 Notice Regarding Guidance on Conflict of
                                Interest
------------------------------------------------------------------------
              Description of
 Issue No.   our request for                   Reference
                 comment
------------------------------------------------------------------------
15a.......  Whether companies  75 FR 81536 at 81542.
             would find it
             useful to have
             guidance on
             potential
             conflicts of
             interest of GRAS
             expert panelists.
15b.......  If guidance on     75 FR 81536 at 81542.
             potential
             conflicts of
             interest of GRAS
             expert panelists
             would be useful,
             what companies
             currently do to
             mitigate such a
             conflict.
15c.......  Whether to         75 FR 81536 at 81542.
             require that
             GRAS notices
             include
             information
             regarding expert
             panelists'
             independence.
------------------------------------------------------------------------

    (Comment 125) Most of the comments that addressed Issues 15a and
15b ask us to provide guidance regarding potential conflicts of
interest of GRAS panel members. One of these comments provided an
example of a draft guidance for our consideration. Other comments
provide criteria that they ask us to consider in the guidance. One
comment asks us to provide an opportunity for industry, academia, and
the public to comment on our proposed course of action for the topic of
conflict of interest.
    One comment asserts that there is no need for guidance regarding
potential conflicts of interest of GRAS panel members because industry
is aware of the importance of disclosing and addressing potential
conflicts of interest and often has Standard Operating Procedures
delineating rules for disclosure.
    (Response 125) We have decided to issue guidance regarding conflict
of interest. We will do so as Level 1 guidance within the framework of
our good guidance practices regulation (see Sec.  10.115(c) and (g)).
Under that framework, we prepare a draft of Level 1 guidance and then:
(1) Publish a notice in the Federal Register announcing that the draft
guidance document is available; (2) post the draft guidance document on
the Internet and make it available in hard copy; and (3) invite public
comment on the draft guidance document. After providing an opportunity
for public comment on a Level 1 guidance document, FDA will: (1) Review
any comments received and prepare the final version of the guidance
document that incorporates suggested changes, when appropriate; (2)
publish a notice in the Federal Register announcing that the guidance
document is available; (3) post the guidance document on the Internet
and make it available in hard copy; and (4) implement the guidance
document. We will consider the recommendations and draft guidance
submitted in the comments to this rule in developing our draft guidance
for public comment.
    We acknowledge that some members of industry are aware of the
importance of disclosing and addressing potential conflicts of
interest. However, we disagree that this awareness means that we should
not issue a guidance regarding conflict of interest. A guidance from us
on conflict of interest could promote consistency in addressing
conflict of interest by different companies.
    (Comment 126) One comment notes that an external GRAS panel is not
required for a conclusion of GRAS status when the conclusion is
supported by peer-reviewed literature or a ``long history of safe
use.'' (By ``long history of safe use,'' we assume that the comment is
referring to the provision that GRAS criteria may be satisfied through
experience based on common use in food prior to January 1, 1958. See
Sec.  170.30(a) and (c)).
    (Response 126) We agree that an external GRAS panel is not required
for a conclusion of GRAS status. As we previously noted, convening a
GRAS panel has historically been a way to provide evidence that
generally available data and information are

generally accepted by the expert scientific community, but convening a
GRAS panel is not the only way to provide such evidence (62 FR 18938 at
18943).
    (Comment 127) Some comments address Issue 15c and recommend that a
notifier include information on independence of the panel members in a
submitted GRAS notice.
    (Response 127) The rule neither requires that a notifier convene a
GRAS panel nor establishes any other requirements applicable to a GRAS
panel. Therefore, we are addressing issues regarding a GRAS panel in
guidance rather than in the regulation. See also Comment 14 and
Response 14.

B. Guidance on Documenting Conclusions of GRAS Status

    In the 2010 notice, we explained that the GAO report recommended
that we issue guidance on how to document a conclusion of GRAS status
(75 FR 81536 at 81542). We noted that there is guidance in the preamble
to the proposed rule and in our guidance for industry entitled
``Frequently Asked Questions About GRAS'' (Ref. 49). We requested
comments on two issues related to guidance on documenting a conclusion
of GRAS status as shown in table 26. Although the 2010 notice
classified both of these issues as ``Issue 16,'' for presentation
purposes in this document we classify the two issues as 16a and 16b.

  Table 26--Issues in the 2010 Notice Regarding Guidance on Documenting
                            GRAS Conclusions
------------------------------------------------------------------------
              Description of
 Issue No.   our request for                   Reference
                 comment
------------------------------------------------------------------------
16a.......  Whether there is   75 FR 81536 at 81542.
             a need to
             clarify that our
             guidance
             applying to GRAS
             submissions also
             applies to a
             GRAS conclusion
             that is not
             submitted to us
             in the form of a
             GRAS notice.
16b.......  Whether there is   75 FR 81536 at 81542.
             a need for us to
             develop further
             guidance on
             documenting a
             GRAS conclusion
             when the GRAS
             conclusion is
             not submitted to
             us as a GRAS
             notice.
------------------------------------------------------------------------

    (Comment 128) Most of the comments that addressed Issue 16a
recommend that we clarify that the same standards apply to a conclusion
of GRAS status regardless of whether the conclusion is submitted to us
as a GRAS notice or is not submitted to us.
    (Response 128) To reach a conclusion of GRAS status, the proponent
of GRAS status must: (1) Establish that the substance is safe under the
conditions of its intended use within the meaning of section 409(c)(5)
of the FD&C Act and our implementing regulation in Sec.  170.3(i); and
(2) establish that the safety of the substance under the conditions of
its intended use is generally recognized within the meaning of section
201(s) of the FD&C Act and our regulations in Sec.  170.30 governing
the eligibility for classification as GRAS. See the discussion in
section I.C of the proposed rule of the elements of the GRAS standard,
where we described the evaluation of safety as the ``technical
element'' of the GRAS standard and the evaluation of general
recognition as the ``common knowledge element'' of the GRAS standard.
In considering whether GRAS criteria are satisfied because the
available data and information demonstrate that the use of a substance
is safe and the safety is generally recognized, we do not distinguish
between a conclusion of GRAS status submitted to us as a GRAS notice
and an independent conclusion of GRAS status that remains with the
proponent. As discussed in Response 41, in this rulemaking we made
conforming changes to current regulations regarding the use of GRAS
substances in food, and our affirmation of GRAS status on our own
initiative, to emphasize that point (see the changes to Sec. Sec.
170.3(i) and (k), 170.30(c), 170.30(e), and 170.35(a) and (b) in table
29). As already noted in section I.E of this document, we advise any
company that intends to market a food substance on the basis of an
independent conclusion of GRAS status to carefully consider whether
this use fully satisfies the criteria for eligibility for
classification as GRAS and to carefully review the discussions in this
document relevant to those criteria, such as the discussion in Response
9 regarding the role of corroborative data and information, the
discussions in Response 10 and Response 11 regarding the limitations of
a published report of a GRAS panel, and the discussion in Response 69
regarding the ramifications of providing trade secret information (or
other non-public information) to a GRAS panel.
    Our 2004 guidance entitled ``Frequently Asked Questions About
GRAS'' generally applies to a conclusion of GRAS status regardless of
whether that conclusion of GRAS status is submitted to us as a GRAS
notice. Exceptions include current questions specific to the
notification procedure as it operated during the Interim Pilot program,
such as ``Where do I send my GRAS notice? '' We are modifying that
guidance to update it in light of the publication of this rule.
    We believe that the provisions of the GRAS notification procedure
in part 170, subpart E will be a useful resource to any person who
intends to use a substance in food based on a conclusion of GRAS
status, regardless of whether the conclusion of GRAS status is
submitted to us in a GRAS notice or is an independent GRAS conclusion
that is not submitted to us. For example, the requirements in Part 3 of
a GRAS notice make clear that a conclusion of GRAS status requires
consideration of dietary exposure. Likewise, the requirements in Part 6
of a GRAS notice demonstrate the importance of a complete and balanced
evaluation of all applicable data and information, including data and
information that are, or may appear to be, inconsistent with a
conclusion of GRAS status. Therefore, we recommend that any person who
intends to use a substance in food based on a conclusion of GRAS
status, but does not intend to submit a GRAS notice to us, use the
provisions of part 170, subpart E as guidance. We also recommend that
such persons organize the data and information that support an
independent conclusion of GRAS status according to the organization
presented by Parts 1 through 7 of a GRAS notice. Doing so would
facilitate our evaluation of that independent conclusion of GRAS status
if circumstances warrant, e.g., if we have cause to question the
independent conclusion of GRAS status. Because we make information
about GRAS notices readily accessible to the public, we also recommend
that you make the basis for your independent GRAS conclusion publicly
available (e.g., by making publicly available a document analogous to
the narrative of a GRAS notice, a report of a GRAS panel (if you
convene a GRAS panel), or both a narrative and a report of a GRAS
panel).
    General recognition of safety based upon scientific procedures
requires the same quantity and quality of scientific evidence as is
required to obtain

approval of a food additive regulation for the ingredient (Sec.
170.30(b)). We address scientific issues associated with demonstrating
the safety of a food substance in a series of guidance documents on our
Internet (Ref. 6, Ref. 25, and Ref. 32 through Ref. 35). Currently,
some of these scientific guidance documents are expressly directed to
evaluation of the safety of food additives. For example, in Response 66
we noted that our guidance entitled ``Recommendations for Submission of
Chemical and Technological Data for Direct Food Additive Petitions''
(Ref. 31) currently is structured to address the specific requirements
of a food additive petition, even though many of the recommendations in
that guidance could nonetheless be useful to any person who evaluates
whether a substance is GRAS under the conditions of its intended use.
As resources allow, we intend to re-visit these scientific guidance
documents to determine whether and how to modify them to clarify that
our guidance on evaluating the safety of a food substance generally
applies regardless of whether the substance would be used in food as a
food additive or as a GRAS substance. Regardless of any implication, in
the title or text of these guidance documents, that the subject of the
document applies to a food additive, we recommend that you consider
that the scientific recommendations in these guidance documents may
also apply to substances that would be used in food on the basis of a
GRAS conclusion.
    Some scientific guidance documents already do make clear that they
apply regardless of the regulatory status of a substance (e.g., as a
food additive, color additive, food contact substance, or GRAS
substance) (Ref. 6). In addition, as discussed in Response 37, we
recently issued a notice announcing a public meeting, and requesting
comments, on our intent to update our guidance entitled ``Guidance for
Industry and Other Stakeholders: Toxicological Principles for the
Safety Assessment of Food Ingredients'' (79 FR 64603), and reiterated
that general recognition of safety based upon scientific procedures
requires the same quantity and quality of evidence as is required to
approve a food additive.
    (Comment 129) Some comments support issuing additional guidance on
documenting a conclusion of GRAS status, particularly for a GRAS
conclusion that is not submitted to us. One comment asserts that there
is no need for us to develop additional guidance on documenting a
conclusion of GRAS status that is not submitted to us. One comment
agrees with the recommendation in the GAO report that we take steps to
ensure that companies maintain proper documentation to support a
conclusion of GRAS status.
    (Response 129) We agree that companies should maintain proper
documentation to support a conclusion of GRAS status. As we discussed
in the proposed rule (62 FR 18938 at 18947), any person who concludes
that a substance is GRAS under the conditions of its intended use
should have assembled and evaluated the evidence that forms the basis
of that conclusion, regardless of whether the person subsequently
notifies us. Preserving the applicable data and information represents
prudent practice for those who assert that the statutory premarket
review requirements do not apply to the use of a substance in food.
    To emphasize the importance of maintaining the data and information
that support an independent conclusion of GRAS status, we are issuing a
guidance directed to any person who evaluates whether the available
data and information regarding the safety of a substance under the
conditions of its intended use satisfy GRAS criteria. The purpose of
the guidance is to: (1) Remind such persons of their responsibilities
under the FD&C Act regarding a conclusion of GRAS status, regardless of
whether the conclusion of GRAS status is submitted to us as a GRAS
notice; and (2) refer such persons to key resources, such as those
discussed in Response 128, for evaluating the safety of the substance
under the conditions of its intended use and for evaluating whether the
available data and information regarding safety satisfy the criteria
for eligibility for classification as GRAS in Sec.  170.30. We believe
that such guidance is appropriate in light of the recommendations of
the GAO report.

C. Compliance With Other FDA Regulations

    We proposed that a GRAS notice would not constitute compliance with
the requirements for a health claim petition in Sec.  101.14(b)(3)(ii)
or for a new infant formula submission in Sec.  106.120(b)(6)(ii). We
specified that any person who submits a health claim petition, or who
submits a new infant formula submission, must comply in full with the
requirements of the applicable program (proposed Sec.  170.36(a)(2)).
    (Comment 130) Several comments object to the perceived implication
that a GRAS notice could never be used to support a health claim
petition or a new infant formula submission. In general, the comments
maintain we should consider, on a case-by-case basis, whether a
particular GRAS notice is sufficient to comply with the requirements of
the applicable program rather than categorically disallow a GRAS notice
as a means for satisfying the requirements of the applicable program.
    (Response 130) We are not including this proposed provision in the
final rule because it is not necessary to do so. Any person who submits
a health claim petition, or who submits a new infant formula
submission, must comply in full with the requirements of the applicable
program whether this rule says so or not. An FDA office that evaluates
a health claim petition or a new infant formula submission will take
into account our response to a GRAS notice when evaluating the health
claim petition or new infant formula submission. In practice during the
Interim Pilot program, an FDA office evaluated a health claim petition
or a new infant formula submission for several substances that were the
subject of a previously submitted GRAS notice. In each case, FDA's
evaluation of the health claim petition or new infant formula
submission had an outcome that was consistent with our response to that
GRAS notice (see section IV.A of CFSAN's 2010 experience document (Ref.
18)).

D. Impact on Other Federal Agencies

    In our discussion in the proposed rule of the proposed procedures
for making information about GRAS notices readily accessible to the
public, we stated our belief that there would be considerable interest,
from a broad segment of the public, including other Federal agencies,
in notices received under the proposed notification procedure (62 FR
18938 at 18952). We also stated our expectation that such groups will
likely want to know whether we are aware that a substance is being used
in food on the basis of the GRAS provision and whether we have advised
a notifier that we have identified a problem with the notice.
    (Comment 131) The Bureau of Alcohol, Tobacco and Firearms (BATF)
(in the U.S. Department of the Treasury (now TTB) submitted a comment
stating that it has no major problem with our proposal to replace the
GRAS affirmation petition process with a notification procedure, but
that there are two ways in which the proposed rule would impact TTB.
First, TTB's wine regulations in 27 CFR 24.250 (Application for use of
new treating material or process) require that a proprietor who wishes
to use a new

wine treating material submit to TTB an application that includes
documentary evidence of FDA's approval of the material under the
conditions of its intended use. If we issue a final rule to establish a
GRAS notification procedure, TTB would need to amend this requirement
to state that TTB needs either evidence of FDA approval or evidence
that FDA has been notified of a conclusion of GRAS status and has no
questions about that conclusion.
    Second, certain alcoholic beverage products require formula
approval by TTB due to the ingredients (such as colors, flavors, herbs,
and spices) in the products. Currently, TTB requires that these
ingredients be approved by FDA before TTB approves the formula. If we
issue a final rule to establish a GRAS notification procedure, TTB
would still check the ingredients in these formulas before approving
the formula, but could accept evidence that FDA has been notified of a
conclusion of GRAS status and has no questions about that conclusion.
    TTB asks us to include the conditions of use in our response to a
GRAS notice so that TTB would know the parameters that FDA evaluated in
considering the GRAS notice (i.e., the foods and beverages and the
amounts in those foods and beverages). TTB also asks us to publish and
update a list of GRAS notices on a frequent basis, and to include the
conditions of use that FDA evaluated in this list.
    (Response 131) The provisions of this rule are consistent with
TTB's requests. The rule specifies that we will make a list of filed
GRAS notices, including the information described in Sec.
170.225(c)(2) through (c)(5), readily accessible to the public (see
Sec.  170.275(b)(1)). The information the rule specifies will be
readily accessible includes the intended conditions of use of the
notified substance, including the foods in which the substance will be
used, the levels of use in such foods, and the purpose(s) for which the
substance will be used (see Sec.  170.225(c)(4)). The response letters
that we issued during the Interim Pilot program described the
conditions of use of the notified substance, and we intend to continue
describing the conditions of use of the notified substance in letters
issued under the final rule.
    (Comment 132) Some comments assert that our affirmation of GRAS
status established a clear standard that was needed by other Federal
agencies to carry out their own regulatory responsibilities. The
comments cite BATF (now TTB), FSIS (in USDA), and EPA as examples of
such Federal agencies. In general, these comments maintain that the
applicable Federal agency must be able to accept our response to a GRAS
notice in lieu of a regulation affirming GRAS status. One comment notes
that the proposed rule did not explicitly address the impact of the
proposed rule on other Federal agencies and urges us to consult with
the cited Federal agencies prior to issuing the final rule.
    (Response 132) None of the Federal agencies cited by these comments
have advised us that the absence of a regulation affirming GRAS status
for the use of a food substance would preclude the applicable Agency
from carrying out its statutory responsibilities. As discussed in the
following paragraphs, we have interacted with each of these agencies as
requested.
    TTB. As discussed in section IV.B of CFSAN's 2010 experience
document (Ref. 18), during the Interim Pilot program CFSAN received and
filed several GRAS notices for substances intended for use in alcoholic
beverage products. These notices demonstrate that manufacturers of
alcoholic beverage products are aware of the GRAS notification
procedure and are using GRAS notices as a means to satisfy TTB's
regulations. As also discussed in section IV.B of CFSAN's 2010
experience document (Ref. 18), on September 29, 2005, representatives
of TTB met with representatives of CFSAN in the offices of CFSAN's
Office of Food Additive Safety. At that meeting, representatives of
CFSAN described the GRAS notification procedure that was operating
under the framework of the proposed rule. CFSAN provided a copy of
TTB's comments to these representatives, and none of TTB's
representatives expressed any concern about the operation of the
program.
    FSIS. As discussed in section III.L of CFSAN's 2010 experience
document (Ref. 18), during the period 1998 through 2009 more than 25
percent of GRAS notices filed by CFSAN described use of the notified
substance in meat, meat food products, or poultry products. During
CFSAN's review of these GRAS notices, CFSAN consulted with FSIS
regarding the use of the applicable substance. FSIS provided feedback
to CFSAN about the use of the notified substance in products regulated
by FSIS and requested that CFSAN provide this feedback to the notifier.
In 2000, FDA and FSIS formalized this process of inter-agency
consultation in a MOU (65 FR 33330, May 23, 2000). Subsequently, FDA
and FSIS have amended the MOU to include simultaneous evaluation of
substances subject to regulation by USDA under the Egg Products
Inspection Act (21 U.S.C. 1033(a)(2)) (Ref. 36). The final rule
includes the procedures CFSAN will use when coordinating its evaluation
of a GRAS notice with FSIS (see Sec.  170.270).
    EPA. CFSAN has discussed the concerns raised by these comments with
representatives from EPA (Ref. 50). The representatives from EPA
deferred to CFSAN regarding the appropriate process for voluntary
interaction between us and the regulated industry with respect to GRAS
substances.

E. Impact on International Trade

    In the proposed rule, we requested comment on whether the proposed
substitution of a GRAS notification procedure for the GRAS affirmation
petition process would have any impact on international trade (62 FR
18938 at 18955).
    (Comment 133) Comments that responded to this request for comment
express the view that whether the proposed substitution of a GRAS
notification procedure for the GRAS affirmation petition process would
have a positive, neutral, or negative impact on international trade
would depend on the nature of our response to a GRAS notice,
particularly when we do not question the notifier's basis for a
conclusion of GRAS status. The comments explain that the proposed rule
could have a positive or neutral impact on international trade if our
response is clear and definitive, provides regulatory significance, and
is as affirmative as possible, but could have a negative impact on
international trade if our response is neutral or vague. One comment
expresses the opinion that any impact on international trade would be
minimal because JECFA frequently assesses uses of a food ingredient,
and foreign regulatory agencies frequently reach a decision to allow
uses of a food ingredient, before we complete our rulemaking under the
GRAS affirmation petition process.
    (Response 133) The ``no questions letters'' we issued during the
Interim Pilot program make clear that the notifier (rather than FDA) is
responsible for the conclusion of GRAS status, and place our statement
that we have no questions about the notifier's conclusion of GRAS
status in the contexts of both time and the available data and
information (see table 1). These features of the ``no questions
letters'' make the letters clear and definitive and provide regulatory
significance (i.e., regulatory status), and we intend to retain these
features in letters we issue under the final rule. Moreover, the fact
that many GRAS notices were submitted by foreign firms demonstrates
that foreign firms see value in submitting GRAS notices to us (Ref.
51).

    Under the final rule, we will respond to a GRAS notice within 180
days after we file a submission as a GRAS notice, with an option to
extend the timeframe by an additional 90 days as needed (see Sec.
170.265(b)(1)). As discussed in Response 123, during the ten year
period extending from 1990 through 1999, we completed the rulemaking
process for 24 GRAS affirmation petitions, with an average elapsed time
of approximately 7.9 years (median elapsed time approximately 6.9
years). Thus, we believe that the GRAS notification procedure will come
to closure more quickly than the GRAS affirmation petition process.

F. Audits

    In the proposed rule, we stated that it would be prudent for us
monitor compliance with the essence of the statutory requirements for
GRAS status (i.e., that there is common knowledge among qualified
experts that there is reasonable certainty that the substance is not
harmful under the conditions of its intended use) and announced that we
intended to conduct random audits of data and information maintained by
the notifier (62 FR 18938 at 18947). In addition, because the proposed
substitution of a GRAS notification procedure for the GRAS affirmation
petition process would allow us to direct our resources to priority
questions about GRAS status, we might conduct an audit on a broad issue
or class of products if the issue or use of a class of products raises
important public health issues.
    (Comment 134) One comment asks us to renew our commitment to random
auditing to ensure that companies maintain proper recordkeeping
practices.
    (Response 134) As discussed in section IV.C of CFSAN's 2010
experience document (Ref. 18), during the Interim Pilot program, CFSAN
did not conduct any random audits of data and information maintained by
the notifier. However, CFSAN did not hesitate to ask a notifier to
provide certain data or information as an amendment to a GRAS notice.
(See also the discussion in section III.C.1 of CFSAN's 2010 experience
document regarding amendments to GRAS notices.) In essence, CFSAN used
its resources to seek access to data and information on a priority,
rather than a random, basis. At this time, we intend to continue
directing our resources on a priority basis under the final rule.
    (Comment 135) One comment asks us to provide a notifier with the
option of converting a GRAS notice to a GRAS affirmation petition if we
audit the data supporting a GRAS notice.
    (Response 135) As discussed in Response 24 and Response 123, we
have eliminated the former GRAS affirmation petition process.
Therefore, the administrative process requested by these comments is no
longer operative.
    (Comment 136) One comment asks us to incorporate two procedures to
avoid any uncertainty regarding the results of the audit. First, the
comment asks us to provide the notifier with a letter confirming that
the audit is completed and we have no basis to question the conclusion
of GRAS status if that is the outcome of our audit. Second, the comment
asks us to apply any appeal mechanism specified by the rule to
circumstances in which we question a conclusion of GRAS status based on
an audit.
    (Response 136) We decline these requests. If we have no questions
about the notifier's conclusion of GRAS status, we would respond with a
``no questions letter'' based on our evaluation of the entire GRAS
notice, not based solely on the results of an audit of the data and
information maintained by the notifier to support the notifier's GRAS
notice. As discussed in Response 108, the rule does not include an
appeals process that would be specific to the GRAS notification
procedure.
    (Comment 137) One comment suggests that our audit examine the same
``quantum of evidence'' as we would review to affirm GRAS status, and
asserts that a strong statement of confidence, if not outright
affirmation, would be appropriate after successful completion of this
type of an indepth review.
    (Response 137) The purpose of the audit would be to verify that a
notifier maintains the data and information specified in the notice,
not to conduct a full scientific evaluation of those data and
information (62 FR 18938 at 18947). Therefore, we decline the request
to examine the same ``quantum of evidence'' as we would review to
affirm GRAS status. Because the purpose of an audit would be to verify
compliance with the statutory requirements for GRAS criteria, we
disagree our response to a GRAS notice following a favorable audit
should result in a ``strong statement of confidence'' rather than a
``no questions letter.'' However, we intend that our response letter
would mention any audit that we conduct before responding to a GRAS
notice.

G. Lack of an Environmental Assessment

    (Comment 138) One comment suggests that a GRAS notice is ideal in
circumstances where our evaluation of an environmental assessment,
which is required for a food additive petition, precludes timely action
by us on a petition.
    (Response 138) We advise potential notifiers that the lack of a
requirement to submit an environmental component (e.g., an
environmental assessment) with a GRAS notice does not eliminate a
notifier's responsibility to comply with applicable Federal, State,
tribal, and local law or requirements regarding protection of the
environment.

H. Substances Affirmed as GRAS With Specific Limitations

    (Comment 139) One comment asks us to ``modernize the standard'' in
Sec.  184.1(b)(2) to allow expedited review under the notification
program of new uses of substances affirmed as GRAS under Sec.
184.1(b)(2). (Section 184.1(b)(2) specifies that if an ingredient is
affirmed as GRAS with specific limitation(s), it shall be used in food
only within such limitation(s), including the category of food(s), the
functional use(s) of the ingredient, and the level(s) of use, and any
use of such an ingredient not in full compliance with each such
established limitation shall require a food additive regulation.)
    (Response 139) We decline the request to amend Sec.  184.1(b)
beyond the editorial, clarifying, and conforming changes listed in
table 29. The comment provides no basis for us to do so. As discussed
during the rulemaking to establish Sec.  184.1(b)(2) (41 CFR 53600 at
53601, December 7, 1976), that regulation does not require that a
subsequent use be covered by a food additive regulation even though it
may be GRAS. As an alternative to a food additive regulation, the
regulation affirming a substance as GRAS with specific limitations on
the conditions of use may be amended to cover additional uses that have
become GRAS. Importantly, both mechanisms (i.e., food additive
regulation and GRAS affirmation regulation) require rulemaking, and the
appropriate mechanism for a manufacturer to lawfully use a substance
outside the limitations established in a regulation affirming specific
uses of the substance as GRAS with specific limitations is to submit a
petition to us. A manufacturer may submit a food additive petition
asking us to conduct rulemaking that results in a food additive
regulation; alternatively, now that the GRAS affirmation petition
process is no longer operative, the manufacturer may submit a citizen
petition in accordance with Sec.  10.30 asking us to conduct rulemaking
that amends the regulation affirming a

substance as GRAS with specific limitations on the conditions of use.
(See also Ref. 4.58 to CFSAN's 2010 experience document).
    See section III.N.2 of CFSAN's 2010 experience document (Ref. 18)
for a discussion of a GRAS affirmation petition to amend a specific
regulation that affirmed a substance as GRAS with specific limitations
on the conditions of use; we converted that GRAS affirmation petition
to a food additive petition and authorized the additional conditions of
use in a food additive regulation. We advise persons who wish to
petition us to provide for additional uses of substances that have been
affirmed as GRAS with specific limitations that under Sec.  10.30(e) we
may advise that we are denying the request to initiate rulemaking to
amend the GRAS affirmation regulation, but note that we could
accommodate the request to conduct rulemaking through the food additive
petition process.

XXV. Comments on Substances Intended for Use in Animal Food

A. Issues in the 2010 Notice Specific to Animal Food

    In the 2010 notice, we discussed several issues associated with the
requirements for a GRAS notice for an intended use in animal food to
consider dietary exposure (see table 27). Although we discussed these
issues in a section entitled ``Dietary exposure,'' these issues broadly
applied to several provisions of the rule (see, e.g., Sec. Sec.
570.30, 570.225(c)(4), 570.235, 570.245, and 570.250). In the following
sections, we discuss how comments on these issues, and associated
conforming changes, lead to specific revisions to the regulatory text.
See table 28 for the principal changes specific to the proposed animal
food rule other than the editorial, clarifying, and conforming changes
shown in table 29 and the additional editorial changes associated with
the redesignation of the proposed notification procedure (proposed
Sec.  570.36) as part 570, subpart E. Table 28 does not include those
changes that we made to the proposed requirements when we made an
analogous change to the human food regulations in part 170.

       Table 27--Issues in the 2010 Notice Specific to Animal Food
------------------------------------------------------------------------
              Description of
 Issue No.   our request for                   Reference
                 comment
------------------------------------------------------------------------
11c.......  Whether it is      75 FR 81536 at 81541.
             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 the proposed
             notification
             procedure.
11d.......  Whether it is      75 FR 81536 at 81541.
             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.
11e.......  Whether it is      75 FR 81536 at 81541.
             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.
------------------------------------------------------------------------

 Table 28--Summary of Principal Changes Specific to the Proposed Animal
                                Food Rule
------------------------------------------------------------------------
  Regulatory section in the final
               rule                                Change
------------------------------------------------------------------------
Sec.   570.30(a), (b), and (c)....  Specify that general recognition of
                                     safety is based on data and
                                     information that addresses safety
                                     for both the target animal and for
                                     humans consuming human food derived
                                     from food-producing animals.
Sec.   570.225(c)(4)..............  Requires you to describe the
                                     intended conditions of use of a
                                     notified substance in animal food
                                     by specifying the levels of use in
                                     foods or drinking water.
Sec.   570.235....................  In part 3 of your GRAS notice, you
                                     must provide data and information
                                     about exposure to the target animal
                                     and to humans consuming human food
                                     derived from food-producing
                                     animals.
Sec.   570.250(a) and (b).........  You must explain how the generally
                                     available data and information in
                                     your notice provide a basis for
                                     your view that the notified
                                     substance is generally recognized
                                     as safe, among qualified experts,
                                     under the conditions of its
                                     intended use for both the target
                                     animal and for humans consuming
                                     human food derived from food-
                                     producing animals.
------------------------------------------------------------------------

B. Criteria for Eligibility for Classification as GRAS for a Substance
Intended for Use in Animal Food (Sec.  570.30)

    (Comment 140) Comments that address Issue 11e agree that data and
information in a GRAS notice must be sufficient to address safety for
both the target animal and for humans consuming human food derived from
food-producing animals (see Comment 150 and Comment 151).
    (Response 140) We have modified several provisions of the GRAS
notification procedure to specify how the notifier must provide data
and information to address the safety of the notified substance under
the conditions of its intended use for both the target animal and for
humans consuming human food derived from food-producing animals (see
Sec. Sec.  570.225(c)(4), 570.235, 570.245, and 570.250). To clarify
that the submission requirements reflect the GRAS criteria for the use
of a substance in animal food, we also have modified Sec.  570.30(a),
(b), and (c) to specify that general recognition of safety is based on
data and information that addresses safety for both the target animal
and for humans consuming human food derived from food-producing
animals. See the regulatory text of Sec.  570.30. See also Response 141
regarding the definition of common use in food in Sec.  570.3(f).
    (Comment 141) One comment notes that the proposed human food
regulations, but not the proposed animal food regulations, include
specific criteria for eligibility for classification as GRAS through
experience based on common use in food prior to 1958 when that use
occurred exclusively or primarily outside the United States (see Sec.
170.30(c)(2)). This comment asks us to maintain parallel criteria for
eligibility for classification as GRAS through experience based on
common use in food in the human food regulations and the animal food
regulations by amending Sec.  570.30(c) of the animal food regulations
to include a provision analogous to Sec.  170.30(c)(2).
    (Response 141) We are amending Sec.  570.30(c) to include a
provision analogous to Sec.  170.30(c)(2). See the regulatory text of
Sec.  570.30(c)(1) and (2). For consistency with the clarifying

amendment to the general criteria in Sec.  570.30(a), we also are
revising Sec.  570.30(c) to clarify that general recognition of safety
through experience based on common use in food shall address safety for
both the target animal and for humans consuming human food derived from
food-producing animals. For consistency with the clarifying amendment
to the general criteria in Sec.  570.30(a), we also are revising the
definition of common use in food to mean a substantial history of
consumption of a substance by a significant number of animals of the
species to which the substance is intended to be fed (and, for food-
producing animals fed with such substance, also means a substantial
history of consumption by humans consuming human foods derived from
those food-producing animals), prior to January 1, 1958 (see Sec.
570.3(f) and table 29).

C. Part 1 of a GRAS Notice for a Substance Intended for Use in Animal
Food: Name of the Notified Substance (Sec.  570.225(c)(3))

    As shown in table 6, in the 2010 notice we asked for comment on
whether to require that the GRAS notice include the name of the
notified substance, using an appropriately descriptive term, instead of
the ``common or usual name'' of the notified substance (Issue 7). The
final rule requires that Part 1 of a GRAS notice for an intended use of
a notified substance in animal food include the name of the notified
substance, using an appropriately descriptive term (Sec.
570.225(c)(3)). The appropriately descriptive term may be the same as
the common or usual name of the substance. You may consult with CVM's
staff in operating divisions that address the labeling requirements of
the FD&C Act, currently CVM's Division of Animal Feeds, regarding any
common or usual name for a substance used in animal food. In addition,
for substances used in animal food, the Association of American Feed
Control Officials (AAFCO) annually publishes its Official Publication,
a handbook which contains, among other things, Official Feed Terms,
which define many of the terms commonly used in the animal food
manufacturing industry. It also contains Official and Tentative
Definitions of Feed Ingredients, a set of definitions for ingredients
commonly used in animal food. Under CVM's Compliance Policy Guide CPG
665.100 (Common or Usual Names for Animal Feed Ingredients), the
definitions, as they appear in the AAFCO Official Publication, are
generally regarded as constituting the common or usual name for animal
food ingredients, including pet food (Ref. 52).

D. Part 1 of a GRAS Notice for a Substance Intended for Use in Animal
Food: Intended Conditions of Use (Sec.  570.225(c)(4))

    (Comment 142) One comment asks us to require that a notifier
specify whether the intended use of the notified substance is in food
or in drinking water. Another comment asks CVM to accept the
anticipated consumption levels by animals that are based upon general
formulation principles that consider the availability of contemporary
feedstuffs.
    (Response 142) The final requirements for Part 1 of a GRAS notice
require you to describe the intended conditions of use of a notified
substance in animal food by stating whether the substance will be added
to food (including drinking water) for animals in which the substance
will be used, and by identifying the foods to which it will be added
and the levels of use in such foods (see Sec.  570.225(c)(4)). In
describing the levels of use of the notified substance, you may base
the levels of use upon general formulation principles that consider the
availability of contemporary feedstuffs. See also Response 148
regarding the calculation of target animal exposure.
    (Comment 143) Some comments ask us to specifically require
submission of information about the animal species expected to consume
the substance. One comment states that specifying the target animal is
as important as specifying whether the substance would be consumed by
humans in human food derived from the animal. Another comment suggests
that requiring submission of information about the animal that would
consume the substance would avoid the unnecessary delays associated
with CVM's questions that result in an amendment to the notice with
information about the animal species expected to consume the substance.
    (Response 143) The final requirements for Part 1 of a GRAS notice
require you to describe the intended conditions of use of a notified
substance in animal food, including the animal species for which the
foods are intended. In addition, the final requirements for Part 1 of a
GRAS notice specify that in describing the intended conditions of use
of a notified substance in animal food, you must, when appropriate,
describe any ``subpopulation'' expected to consume the notified
substance; the life stage of an animal is an example of what we mean by
``subpopulation.'' The physical, physiologic, and absorption/
distribution/metabolism/elimination characteristics of a given animal
species may vary based on life stages within the same animal species. A
substance that is safe for use in an animal species at one stage of
life may not be safe for use in the same animal species at a different
stage of life. See also Response 51.

E. Part 2 of a GRAS Notice for a Substance Intended for Use in Animal
Food: Data and Information Bearing on the Physical or Other Technical
Effect of the Notified Substance (Sec.  570.230(d))

    (Comment 144) Several comments discuss CVM's practice, during the
Interim Pilot program, of asking a notifier to provide data or
information demonstrating the effectiveness, or utility, of the
substance. Some comments ask us to limit the notification procedure to
the information necessary to conduct an appropriate safety assessment,
without submission of additional data and information to demonstrate
the technical effect of the substance within animal food in cases where
the technical effect has no impact on safety. Some comments agree that
the intended conditions of use of the notified substance in animal food
must be described and supported in the notice, but assert that the need
for utility data generated from target animal feeding studies is
inappropriate and unnecessary because the pivotal issue is whether the
ingredient is safe to feed to animals.
    (Response 144) We have added a requirement for Part 2 of a GRAS
notice to include relevant data and information bearing on the physical
or other technical effect the notified substance is intended to
produce, including the quantity of the notified substance required to
produce such effect, when necessary to demonstrate safety (see Sec.
570.230(d)). We agree that data and information bearing on the physical
or other technical effect the notified substance is intended to produce
are only necessary when they bear on safety. This relationship to
safety is consistent with the requirements of the FD&C Act for a
petition to establish the safety of a food additive (see section
409(b)(2)(C) of the FD&C Act).
    The physical or other technical effects of substances added to
animal food fall into two main categories: (1) Substances fed for a
nutritive effect in the animal (e.g., providing one or more nutrients
or other nutritive effect); and (2) substances that have technical
effects in the food (e.g., anti-caking agents, binders, emulsifiers,
enzymes, mixing

aids, preservatives, processing aids, stabilizers, and substances added
for aroma, flavor, or other technical effects) rather than nutritive
effects in the animal. As discussed in the following paragraphs, a
substance added for either a nutritive effect or for a technical effect
in animal food can have an impact on safety for the target animal.
    Nutritive effect in the animal. Data and information bearing on the
nutritive effect of a substance may be necessary to demonstrate safety
because animals (e.g., food-producing animals, companion animals)
typically are fed the same diet formula for long periods of their life.
These diets are formulated to supply all of the animal's daily nutrient
needs for a specific life stage (e.g., growth, reproduction, adult
maintenance). The diet must provide appropriate amounts of all
nutrients the animal requires in a form that the animal can use and
consume daily; otherwise, a nutrient deficiency or toxicity can result,
causing adverse effects to animal health, including poor growth,
excessive weight loss, organ system failures, and death. Under these
constraints of how animals are fed, a substance intended to provide one
or more nutrients becomes unsafe if the nutrients are, in fact, not
provided in a form usable by the animals consuming the diet.
    The typical approach to support the nutritive effect of a substance
intended for use in animal food is to combine generally available and
accepted data and information about the general function of the
substance with animal feeding studies demonstrating that the substance
acts as intended. When an appropriate animal feeding study (i.e., an
animal feeding study that is relevant, properly designed, and well-
controlled) is already generally available (e.g., in the peer-reviewed
scientific literature), it can be possible to support the nutritive
effect of a substance without conducting a new study. If an appropriate
animal feeding study is not already generally available, an animal
feeding study specifically conducted to support the nutritive effect
would ordinarily be published and, as discussed in Response 19, there
would be a time gap between the publication of the study and the use of
the published study to support a conclusion of GRAS status. (As
discussed in Response 9, unpublished studies can be used to
corroboratively support the intended nutritive effect of the substance
under the conditions of its intended use.) In addition, for any animal
feeding study a factor to be considered is whether data and information
obtained from a feeding study conducted in one animal species (or in
one stage of life of an animal species) can be used to support safety
in another animal species (or in a different stage of life in the same
animal species). See Response 145 for a discussion of when data and
information that are obtained from an animal study and bear on the
nutritive effect of a substance could be extrapolated from one animal
species to another animal species, or to a different stage of life of
the same animal species. In the following paragraphs, we provide
examples of when data and information bearing on the nutritive effect
of a substance intended for use in animal food could be established
through the use of generally available and accepted data and
information, or likely would need to be established through an animal
feeding study that specifically supports the nutritive effect of the
substance under the conditions of its intended use.
    For some types of substances, generally available and accepted data
and information about the function of a substance may be adequate to
support the nutritive effect of the substance without also relying on
an animal feeding study. For example, generally available and accepted
data and information about the function of fat and carbohydrates as
sources of dietary energy often can be used for substances providing
fat intended as a source of dietary energy (rather than as a source of
essential fatty acids) and for substances providing carbohydrates
intended as a source of dietary energy. Likewise, generally available
and accepted data and information about the nutritive content of human
food can provide support for the nutritive effect of unsalable human
food products (such as bruised produce) being collected for animal food
use for their nutritional content rather than entering landfills or
being incinerated.
    For other types of substances, an animal feeding study (whether
previously published or newly conducted) is the norm to support the
nutritive effect of the substance. For example, for an ingredient that
is intended to supply an essential mineral (such as phosphorus or
zinc), generally available data and information can provide support
that the mineral is an essential nutrient for the animal, but the
bioavailability of the mineral in the ingredient that would be added to
animal food generally needs to be determined in an animal feeding study
conducted with that specific ingredient, because data regarding the
amount of the mineral that is added to the feed in the ingredient (or
that can be detected analytically in the feed or in the ingredient)
would not provide evidence that the mineral is in a form that is
available to the animal. However, for an ingredient that is intended to
provide an essential amino acid, the need for an animal feeding study
can depend on the form and composition of the ingredient. For example,
it can be possible to rely on published literature to establish that a
crystalline amino acid will be bioavailable to an animal (and, thus,
functional). However, if a complex matrix, such as a biomass composed
of microbial cells or a processed oilseed meal, is intended to be a
source of amino acids, an animal feeding study generally would be
needed to provide evidence that the bioavailability of the amino acids
has not been adversely impacted by the other substances present in the
complex matrix.
    Technical effect in the food (rather than nutritive effect in the
animal). As with a substance intended to provide a nutritive effect in
the animal, data and information bearing on a substance's technical
effect in the food (e.g., substances such as anti-caking agents,
binders, emulsifiers, enzymes, mixing aids, preservatives, processing
aids, stabilizers, and substances added for aroma, flavor or other
technical effects) may be necessary to demonstrate safety because of
the physical form and properties of animal diets. Although generally
available and accepted data and information can provide evidence of a
technical effect in the food, it is common for studies to be conducted
with the animal food to demonstrate the intended technical effect.
Depending on the intended technical effect, an animal feeding study
(whether previously published or newly conducted) may be also needed to
demonstrate the intended technical effect of the substance. In the
following paragraphs, we provide examples of when animal feeding
studies may be needed to support the intended technical effect of the
substance. We also provide examples of when an intended technical
effect in animal food could be established through the use of generally
available and accepted data and information about the technical effect
and the studies conducted with the intended animal food matrix. As with
a substance intended to provide a nutritive effect in the animal, when
an appropriate study, which may be an animal feeding study, is already
generally available (e.g., in the peer-reviewed scientific literature),
it can be possible to support the technical effect of a substance in
the food without conducting a new study. If an appropriate study is not
already generally available, a study conducted

to support the technical effect in the food would ordinarily be
published and, as discussed in Response 19, there would be a time gap
between the publication of the study and the use of the published study
to support a conclusion of GRAS status.
    Enzymes are often added to animal food to alter the bioavailability
of nutrients already in the food. For example, it is well known that
the enzyme phytase increases the bioavailability to animals of the
phosphorus present in grain (Ref. 53), and substances that provide
phytase activity are often added to diets for poultry and swine.
Poultry and swine diets are typically formulated with the minimal
amount of phosphorus. If the phytase enzyme does not carry out the
effect of improving phosphorus availability to the animal as intended,
the consequence will be a diet that is deficient in phosphorus and
therefore results in adverse impacts on animal health in the form of
decreased growth, increased orthopedic disease (e.g., rickets), and
suffering animals (Ref. 54). As another example, protease enzymes can
be added to an animal food to affect the digestibility of proteins in
the food (Ref. 55). Both animal feeding studies and stability studies
(to assess the stability of the enzyme in the food and, thus, its
ability to perform its intended technical effect) are the norm when
enzymes are added to animal food. However, when the function of an
enzyme in animal food is well known, it is also common to use generally
available and accepted data and information about the function of the
enzyme in combination with animal feeding studies and stability studies
to support the function of the enzyme (see section IV in CVM's
experience document (Ref. 20)).
    Substances such as binders, lubricants, and pelleting agents are
added to animal food that will be fed as pellets. In some cases, such
substances are added to ensure that the pellet retains its desired form
and that the individual ingredients remain agglomerated, making it more
difficult for an animal to select only those ingredients it prefers. In
aquaculture foods, such substances are added to prevent the pellet from
dissolving or prevent the nutrients from leaching out of the pellet.
Depending on the circumstances, either technical effect studies
conducted with the animal food, or generally available and accepted
data and information about the function of the substance, can be used
to support the intended technical effect, such as that of a binder,
lubricant, or pelleting agent, etc., when added to animal food.
    Flavors are added to animal food for certain species, generally for
specific life stages of that species. For example, flavors can be added
to animal food intended for consumption by piglets being transitioned
from a milk-based diet to a commercial growth diet to increase
consumption of the commercial growth diet. Flavors also are added to
commercial animal food intended for aquaculture to attract newly
hatched fish (fish fry) to the commercial food when the commercial food
does not resemble the food that fish fry would consume in nature. If
the fish fry are not attracted to the commercial food, the fish fry can
starve to death. Animal feeding studies are the norm to support the
function of the substance as a flavor when added to animal food.
    Substances such as emulsifiers and stabilizers are added to animal
food to ensure that an animal consumes all of the ingredients in the
correct proportions in order to meet its nutritional needs.
Inconsistent nutrient content and delivery of a diet to the animal can
cause either nutrient deficiency diseases, or toxicities. For example,
liquid cattle foods are often available to the animal at all times and
cattle simply lick the feeding device to obtain the food. If the
minerals present in the liquid fall out of suspension and settle to the
bottom, the first animals to access the feeder will consume lower
nutrient levels than expected, while those animals that access the
feeder later and consume the bottommost material may be at risk of
toxicity due to higher nutrient levels. For dry ingredients, the
ingredients in the formulated diet must be uniformly dispersed and
mixed, remain mixed during handling, and be physically stable as a
formulated animal diet is moved through augers and conveyors, and
transported in bulk in trucks, which can result in the loss of
nutrients through sifting or ``unmixing.'' These effects are assessed
on the diet itself through appropriate studies.
    (Comment 145) One comment asks us to accept reasonable arguments as
to the worst-case exposures (inclusion levels) if the substance or
class of substances has well-established use patterns rather than
require utility data to support the intended nutritional effect. This
comment also asks us to be flexible when utility data are warranted to
support an entirely new use in animal feeds when utility data from one
representative species would be sufficient to address utility in the
target animal.
    (Response 145) When animal feeding studies are necessary to provide
data and information bearing on the nutritive effects of a substance
intended for use in animal food, the potential to extrapolate from the
conclusions of a feeding study conducted in one animal species to
another animal species depends on the similarities of their digestive
systems, physiology, and diets. For example, when a bioavailability
study for selenium present in selenium yeast is conducted in cattle
(which have a fermentative digestive tract), it can be possible to
extrapolate the conclusions of that bioavailability study to other
animal species that have fermentative digestive tracts. However, when a
bioavailability study for copper is conducted in a ruminant animal
species, it may not be appropriate to extrapolate the conclusions of
that bioavailability study to sheep, even though sheep are ruminants,
because sheep physiology is such that sheep are much more sensitive to
copper toxicity than other ruminant species. In addition, when a
bioavailability study for a nutrient is conducted in animals other than
fish, it may not be possible to extrapolate the conclusions of that
bioavailability study to aquaculture-fed fish, because aquaculture
diets that are consumed in the water present special challenges,
particularly for slow-feeding or bottom-feeding aquaculture species,
where the diet pellet must retain its form and nutrient content until
the pellet is consumed. For example, it is possible for nutrients that
are soluble in water to dissolve out of the pellet before consumption,
preventing the aquaculture animal from accessing all the required
nutrients.
    See Response 144 for a discussion of circumstances where generally
available and accepted data and information can be used to provide
evidence bearing on the nutritive effects of a substance intended for
use in animal food (e.g., for substances providing fat intended as a
source of dietary energy, for substances providing carbohydrates
intended as a source of dietary energy, for unsalable human food
products, and when a crystalline amino acid is added to animal food).
See also Response 150 for additional discussion of limitations on the
use of generally available and accepted data and information, such as a
weight of evidence approach, for the extrapolation of available data
and information from an animal species other than the target animal.
    Regardless of whether the intended use of the notified substance is
to provide nutritive value or technical effect, any person who
concludes that the available data and information regarding the safety
of a notified substance under the conditions of its intended use
satisfy GRAS criteria must

have a basis for the conclusion of GRAS status, irrespective of whether
that person notifies us of that conclusion in a GRAS notice. If you
submit your conclusion of GRAS status to FDA, you must explain how the
data and information in your GRAS notice provide the basis for your
conclusion, e.g., in Part 2 of the GRAS notice (where you would
describe the applicable data and information), in the narrative in Part
6 of your GRAS notice, or in both Parts 2 and 6 of your GRAS notice. We
would then evaluate whether the data, information, and narrative in
your GRAS notice support your conclusion. When data and information
bearing on the physical or other technical effect of the notified
substance are necessary to support safety, we could conclude that a
GRAS notice that does not discuss such data and information is
incomplete, and either contact a notifier to request an amendment
discussing such data and information, or issue an insufficient basis
letter.
    (Comment 146) One comment asserts that a requirement for proof of
utility, with subsequent publication of utility data, is unnecessary,
and that a requirement for utility data to be documented by means of a
peer-reviewed publication would burden the industry with additional
cost, not only to conduct the studies but also to prepare the
manuscript and have it accepted for publication. This comment also
asserts that finding a journal willing to publish such germane studies
may be challenging because the manuscript may be viewed as serving the
manufacturer's interest rather than providing any new scientific
information. As alternatives to publication of a target animal feeding
study, this comment suggests means such as documenting the chemical
nature of the substance in relation to same (or similar) substance with
ample public information, and placing unpublished studies conducted by
the notifier in the context of published literature about the use of
the substance or related substances. This comment also asserts that CVM
and industry resources could be better utilized to demonstrate the
safety of the intended use of the substance with a focus on
establishing the worst-case exposure and relating it to available
safety information to establish a margin of safety.
    (Response 146) See Response 15, in which we respond to comments
asserting it can be difficult to publish data and information that do
not raise an issue of concern. Consistent with CFSAN's experience
during the Interim Pilot program, we believe that some journals
directed to food safety would be willing to publish data and
information bearing on the physical or other technical effect the
notified substance is intended to produce when those data and
information are necessary to demonstrate safety (see section III.A.1 of
CFSAN's 2010 experience document (Ref. 18)).
    See also Response 144 for a discussion of circumstances where
generally available and accepted data and information can be used to
provide evidence bearing on the nutritive effects of a substance
intended for use in animal food. There may be situations where
sufficient generally available and accepted data and information on
exposure to the substance or class of substances can satisfy GRAS
criteria without publication of specific data and information bearing
on the physical or other technical effect the notified substance is
intended to produce. For example, as discussed in section IV of CVM's
experience document during the Interim Pilot program CVM responded with
a ``no questions letter'' when the use of published information for
technical effects such as nutrient, enzyme, and component of a defoamer
was used, in whole or in part, to support such technical effects (Ref.
20). As discussed in Response 12, GRAS status may be corroborated by
unpublished scientific data, information, or methods, and there may be
some unpublished scientific data, information, or methods regarding the
safety of a use of a food substance. As discussed in Response 8, the
criteria for GRAS status through scientific procedures provide for the
application of ``generally available and accepted'' scientific data,
information, or methods, which ``ordinarily'' are published and, thus,
provide flexibility for supporting a conclusion of GRAS status through
the application of scientific data, information, or methods that are
generally available through a mechanism other than publication in a
peer-reviewed scientific journal.
    See the discussion in Response 150 regarding the evaluation of
safety studies, including the applicability of worst-case exposure on a
case-by-case basis.

F. Part 3 of a GRAS Notice for a Substance Intended for Use in Animal
Food: Target Animal and Human Exposures (Sec.  570.235)

1. Substances Intended for Use in Food or Drinking Water for Animals
    (Comment 147) Comments that address Issue 11c support clarifying
that the GRAS notification procedure is applicable to substances used
in both food and drinking water of animals.
    (Response 147) The final requirements for Part 3 of a GRAS notice
specify that ``animal food'' includes ``drinking water.'' See also
Response 142.
2. Data and Information About the Dietary Exposure for the Target
Animal
    (Comment 148) One comment states that exposure information can
usually be obtained from published data sources and that if a worst-
case exposure cannot be established without new data, then data for one
representative animal species are sufficient, especially if the
selected species represents a worst-case scenario. As an example, the
comment suggests that data from one representative poultry species
would be sufficient to address the conditions of use of a notified
substance intended for poultry. As noted in Comment 142, another
comment asks CVM to accept the anticipated consumption levels by
animals that are based upon general formulation principles that
consider the availability of contemporary feedstuffs.
    (Response 148) See the regulatory text of Sec.  570.235(a) for the
requirements for what you must provide in Part 3 of a GRAS notice
regarding exposure to the target animal. The regulatory text addressing
the types of exposure to the target animal parallels the regulatory
text for dietary exposure to a notified substance in the human food
regulations (see Sec.  170.235). As noted in Response 142, you may base
the levels of use upon general formulation principles that consider the
availability of contemporary feedstuffs. We agree that exposure
information may be available from published data sources. If exposure
cannot be established without new data, then data for one
representative animal species may be sufficient if the selected species
represents a worst-case scenario.
    (Comment 149) One comment asks that any restatement of the
regulatory text regarding dietary exposure consider how to use the word
``consumer,'' because ``consumers'' are humans for the purpose of part
170 but are ``animals'' for the purpose of part 570.
    (Response 149) To reduce the potential for confusion, the final
requirements for part 3 of a GRAS notice for a substance intended for
use in animal food do not use the term ``consumer.''

G. Data and Information in a GRAS Notice About Safety for the Target
Animal (Sec.  570.250)

    (Comment 150) Comments that address Issue 11e agree that data and
information in a GRAS notice must be

sufficient to address safety for the target animal. However, most of
these comments express concern about the standard for demonstrating
safety to the target animal, specifically whether safety must be
established through feeding studies specific to the target animal or
could be extrapolated from data and information regarding species other
than the target animal. Although one comment asserts that a notifier
must submit evidence that the substance is safe for all the species in
question if a substance is expected to be consumed by different animal
species, other comments emphasize that safety could be established
through either feeding studies in the target animal or through
extrapolation of data obtained from species other than the target
animal. Some comments suggest that the rule require a clear and concise
written explanation of how studies in non-target species relate to the
target animal rather than require safety data in the target animal
species.
    One comment disagrees that the GRAS notification procedure should
establish any absolute requirement for data addressing safety for the
target species. This comment asserts that CVM should not require
species-specific data for all substances and species covered by the
intended use of the notified substance because recognized scientific
procedures, such as a weight of evidence approach, allow for the
extrapolation of data and that these types of scientific procedures can
be applied to notified substances. This comment also asserts that a CVM
requirement for safety data in the target animal, rather than a written
explanation of how studies in non-target species relate to the target
animal, cannot be scientifically justified and will put the animal feed
industry at a disadvantage for obtaining recognition of new GRAS
substances, and that the additional cost and time will stifle
innovation and reduce growth in the U.S. feed industry and animal
agriculture.
    (Response 150) Whether species-specific data and information (such
as feeding studies) are necessary to satisfy GRAS criteria depends on
the intended use of the notified substance. We recognize that there may
be situations where scientific procedures, such as a weight of evidence
approach, allow for the extrapolation of available data and information
from an animal species other than the target animal. For example, CVM
had no questions regarding an enzyme preparation intended for use in
food for turkeys, broiler chickens, and laying hens, when the feeding
studies used to support target animal safety were conducted only on
broiler chickens (Ref. 20). In such cases, you would explain the
relevance of the available data to the target species in the narrative
required in Part 6 of a GRAS notice rather than describe species-
specific data and information.
    However, extrapolating data from one animal species to another is
not always appropriate because a substance that is safe for use in one
animal species may not be safe for use in another species or in the
same species at a different stage of life. For example, a substance
that is safe for use in a species that is a ruminant animal (e.g.,
cattle) may not be safe for use in a species considered a monogastric
animal (e.g., swine) because of the difference in their digestive
systems and different nutrient requirements. For example, in ruminant
animals, non-protein nitrogen compounds (e.g., urea and biuret) release
ammonia, which is then metabolized by rumen microorganisms into
microbial proteins. These microbial proteins are a useful source of
protein to ruminant animals. However, in monogastric animals, the
liberated ammonia from non-protein nitrogen compounds is absorbed
directly by the animal, resulting in adverse toxicological events, and
possibly death. Even within the same species of animal, or for
different species in the same class of animals (e.g., chicken, duck,
turkey), extrapolating safety data may not be appropriate. For example,
a substance that is safe for laying hens may not be safe for use in
broilers because of the different nutrient requirements, such as the
higher calcium level in a laying hen diet (which is intended to meet
the nutrient demand for egg production). If that high level of calcium
is consumed by broiler chickens, the potential calcification of soft
tissue such as that of kidneys could become detrimental to the broiler
chickens. Likewise, a substance that is safe for chickens may not be
safe for ducks or turkeys because the nutrient requirements for
different species of poultry vary widely. Feeding a diet intended for
one species of poultry to another species could cause nutrient
imbalances, deficiencies, or excesses, which could have adverse
consequences ranging from loss of production to damages to tissues and
organs and even to death. When extrapolating data and information from
another animal species is not appropriate, in Part 6 of your GRAS
notice you would discuss data and information developed specifically
for the target animal, or for the stage of life in the same animal
species, rather than explain how you extrapolated available data and
information from an animal species other than the target animal, or how
you extrapolated available data and information from the same animal
species to a different life stage of that animal species.
    Any person who concludes that the available data and information
regarding the safety of a notified substance under the conditions of
its intended use satisfy GRAS criteria must have a basis for the
conclusion of GRAS status, regardless of whether that person notifies
us of that conclusion in a GRAS notice. A resource that may help
determine when it could be appropriate to extrapolate species-specific
data and information from one animal species to another animal species
is our guidance entitled ``Guidance for Industry: Recommendations for
Preparation and Submission of Animal Food Additive Petitions'' (# 221)
(June 2015) (Ref. 56). Section G.2 of that guidance (on target animal
safety) recommends that target animal safety studies be conducted using
the life stage and animal species for which the food additive will be
marketed. In cases where the food additive is intended for multiple
animal species or life stages, the food additive should be tested in
the most sensitive life stage and/or species. The guidance recommends
using current scientific literature to identify the most sensitive life
stage and/or species. As with guidance documents prepared by CFSAN,
CVM's scientific recommendations in a guidance directed to food
additives can be applied to the evaluation of whether a substance is
GRAS under the conditions of its intended use (see Response 66).
    Another resource is a book entitled ``Safety of Dietary Supplements
for Horses, Dogs, and Cats'' by the National Research Council (Ref.
57), which identifies five factors to consider when selecting
appropriate surrogates for horses, dogs and cats. In addition, it
advises considering nutritional, metabolic, pharmacokinetic, and
natural dietary patterns when selecting appropriate animal model
species. Although the material is directed to only three target
animals, some aspects of its approach can be generalized.
    If you submit your conclusion of GRAS status to FDA, you must
explain how the data and information in your GRAS notice provide the
basis for your conclusion; we would then evaluate whether the data,
information, and narrative in your GRAS notice support your conclusion.

H. Data and Information in a GRAS Notice About the Safety for Humans
Consuming Human Food Derived From a Food-Producing Animal (Sec. Sec.
570.235 and 570.250)

    (Comment 151) Some comments support clarifying the rule to
explicitly require the submission of information about safety for both
the target animal and for humans consuming human food derived from
food-producing animals. One comment states that the safety and
wholesomeness of food given to animals that eventually end up in human
food must be held to the same standard as for a substance intended for
use in human food. Another comment asks us to specify that the
submission of data and information about both target animal and human
safety is required when such data and information are developed for
food-producing animals.
    One comment states that it is the responsibility of the notifier to
determine the extent of the safety assessment of a substance intended
for use in the food of a food-producing animal. This comment asserts
that there is no need to set explicit standards for addressing both
target animal and human food safety in applicable sections of the rule,
because whether new data, such as tissue residue data, would be
warranted would be determined through application of general scientific
principles from the fields of animal nutrition and metabolism.
    Another comment asserts that neither human feeding studies nor
tissue residue accumulation data should be required when available
scientific information can be used to draw conclusions using a weight
of the evidence approach, as CFSAN does for human food substances. This
comment asserts that CVM must clarify what data need to be provided
regarding safety for humans consuming human food derived from food-
producing animals before industry could agree to the requirement.
    (Response 151) We are clarifying the requirement to address safety
for humans consuming human food derived from food-producing animals in
Parts 3 and 6 of a GRAS notice.
    In the requirements for Part 3 of a GRAS notice for a substance
intended for use in animal food, we have modified the title of the
regulatory text to specify that Part 3 addresses exposures to both the
target animal and to humans consuming human food derived from food-
producing animals (see Sec.  570.235). When the intended use of the
notified substance is in food for food-producing animals, you must
provide: (1) The potential quantities of any residues that humans may
be exposed to in edible animal tissues; and (2) the data and
information you rely on to establish the potential quantities of such
residues (see Sec.  570.235(b)). These requirements parallel the
requirements for target animal exposure, but are directed to the
quantity of potential residues of the notified substance, and of any
other substance that is expected to be formed in or on the animal food
because of the use of the notified substance, and those residues from
any other substances present with the notified substance, whether
naturally, due to its manufacture (e.g., contaminants or by-products),
or produced as a metabolite in edible animal tissues when the notified
substance is consumed by a food-producing animal. It is well
established that substances consumed by food-producing animals, and
substances such as metabolites produced by a food-producing animal, can
accumulate in edible animal tissues and have an adverse impact on
public health. For example, aflatoxin M1 is a metabolite of aflatoxin
B1 that is produced during normal biological processes of animals
ingesting the toxin (e.g., from food contaminated with aflatoxin B1)
and has been shown to cause liver cancer in certain animals (Ref. 58).
As another example, there can be human food safety concerns about the
level of selenium in animal tissues when food-producing animals consume
large amounts of a substance that contains selenium in their diets.
    We agree that the specific data and information that are necessary
to determine the safety for humans consuming human food derived from a
food-producing animal would be determined through the application of
general scientific principles from the fields of animal nutrition and
metabolism and that it is the notifier's responsibility to determine
what those specific data and information are. Therefore, we have
modified the requirements for the narrative in Part 6 of a GRAS notice
to clarify that the narrative must address the safety for both the
target animal and for humans consuming human food derived from food-
producing animals (see Sec.  570.250(a)(1) and (b)).

I. Filing Decision, Opportunity for a Notifier To Submit an Amendment,
and Asking Us To Cease To Evaluate a GRAS Notice for a Substance
Intended for Use in Animal Food (Sec. Sec.  570.260 and 570.265)

    (Comment 152) Some comments express concern about differences in
how CFSAN and CVM administered GRAS notices during the Interim Pilot
program. Some comments describe CFSAN's practice of using conference
calls to obtain a clarification or additional information, with a
reasonable period of time for the notifier to provide the clarification
or additional information. These comments assert that CVM's practice is
different from CFSAN's practice because CVM does not contact a notifier
to discuss CVM's questions after a submission has been accepted for
filing. One comment asserts that CVM has informally indicated that once
a GRAS notice is accepted for filing, there will be no further
communication with the notifier and the GRAS notice will be judged
solely on what was accepted for filing. This comment further asserts
that such a process is unreasonable because the error or omission may
be trivial and/or easily remedied. This comment also asserts that
allowing informal contacts (including telephone, email, and fax) to
address minor issues would be consistent with how FDA has handled a
wide range of submissions that require review. Another comment asserts
that CVM's practice of not contacting the notifier is a major concern
for the industry and that CVM's reviewers may have questions that could
be easily answered by the notifier, if contacted.
    Some comments ask CVM to engage in the same informal practice as
CFSAN, with respect to contacting the notifier and allowing remedial
action, if such action may be completed in a reasonable period of time.
Some comments ask the Centers to establish a uniform system of contact
and communication after a submission (and/or agreeing to evaluate an
amendment to a GRAS notice) to prevent delays or other inefficiencies
over issues that could easily be clarified and resolved. Some comments
note that uniformity between CFSAN and CVM in the submission and
handling of requests to cease to evaluate a GRAS notice is of great
importance in maintaining transparency and efficiency in the GRAS
notification procedure.
    (Response 152) The regulatory text governing what CVM will do with
a GRAS notice (Sec.  570.265) is the same as the regulatory text
governing what CFSAN will do with a GRAS notice (Sec.  170.265). In
addition, the regulatory text that provides for a notifier who submits
a GRAS notice to CVM to submit a timely amendment to a filed GRAS
notice, and to ask us to cease to evaluate a GRAS notice (Sec.
570.260), is the same as the regulatory text that provides for a
notifier who submits a GRAS notice to CFSAN to submit a timely
amendment to a filed GRAS

notice, and to ask us to cease to evaluate a GRAS notice (Sec.
170.260).
    We disagree that CVM did not contact notifiers during the Interim
Pilot program. As shown in table 1 in CVM's experience document (Ref.
20), CVM contacted the notifier regarding 9 of 18 GRAS notices during
its evaluation process. CVM issued ``no questions letters'' to seven of
these nine notices after the notifiers provided clarifying amendments.
    Moving forward under the final rule, CVM intends to consider the
same factors that CFSAN considers regarding whether to file a
submission as a GRAS notice (see Response 85), the purpose of
contacting a notifier (including whether to provide an opportunity for
a notifier to ask us to cease to evaluate a GRAS notice) (see Response
80), and the transparency of the reasons for a ``cease to evaluate
letter'' (see Response 81). Because our factors regarding the purpose
of contacting a notifier, and the provisions that provide an
opportunity for a notifier to submit an amendment, consider whether an
amendment is (or could be) timely, the final rule does, as requested by
the comments, consider whether an amendment could be prepared and
submitted in a reasonable period of time. Importantly, as discussed in
Response 101, the role of an amendment is to clarify questions that we
have about your conclusion of GRAS status, rather than to substantively
amend the notice. Whether we will evaluate an amendment to a GRAS
notice before responding to the notice is a matter that we will
consider on a case-by-case basis.

J. Opportunity for a Notifier To Submit a Supplement to a GRAS Notice
for a Substance Intended for Use in Animal Food (Sec.  570.280)

    (Comment 153) One comment asks CVM to adopt CFSAN's approach of
allowing a notifier to submit information to a GRAS notice after FDA
responds to the notice.
    (Response 153) The rule provides that, if circumstances warrant, a
notifier who submits a GRAS notice to CVM may submit a supplement to a
filed GRAS notice after we respond to your notice by letter or cease to
evaluate your notice (Sec.  570.280). As discussed in section VI of
CVM's experience document (Ref. 20), as of December 31, 2015, CVM had
not received any supplements to a GRAS notice.

K. GRAS Affirmation Petitions for Substances Used in Animal Food

    CVM has no pending GRAS affirmation petitions and, thus, the final
animal food regulations do not include provisions for the disposition
of pending GRAS affirmation petitions for substances used in animal
food.

XXVI. Editorial, Clarifying, and Conforming Amendments

    The revised regulatory text includes several changes that we have
made to make the requirements more clear and improve readability. The
revised regulatory text also includes several conforming changes that
we have made when a change to one provision affects other provisions.
We summarize the principal editorial and conforming changes in table
29.

    Table 29--Principal Editorial, Clarifying, and Conforming Changes
------------------------------------------------------------------------
     Designation in the
 regulatory text  (Sec.   )         Revision             Explanation
------------------------------------------------------------------------
Sec.   20.100(c)(46)........  Add new paragraph     Conforming change in
                               (c)(46) to clarify    light of the new
                               applicability of      GRAS notification
                               Sec.   20.100 (the    procedures
                               handling of FDA       established in Sec.
                               records upon a         Sec.   170.36 and
                               request for public    570.36.
                               disclosure) to GRAS
                               notices in Sec.
                               Sec.   170.36(h)
                               and 570.36(h).
Sec.   25.20(k).............   Replace       Conforming
                               ``Affirmation of a    change in light of
                               food substance as     the deletion of the
                               GRAS for humans or    GRAS affirmation
                               animals, on FDA's     petition process.
                               initiative or in      Correct the
                               response to a         list of applicable
                               petition, under       categorical
                               parts 182, 184,       exclusions that
                               186, or 582 of this   apply to include
                               chapter'' with        the categorical
                               ``Establishment or    exclusions listed
                               amendment of a        in Sec.   25.32(i)
                               regulation for a      and (j).
                               food substance as
                               GRAS under the
                               conditions of its
                               intended use for
                               humans or animals
                               under parts 182,
                               184, 186, 582, or
                               584 of this
                               chapter''.
                               Replace
                               ``unless
                               categorically
                               excluded in Sec.
                               25.32(f), (k), or
                               (r)'' with ``unless
                               categorically
                               excluded in Sec.
                               25.32(f), (i), (j),
                               (k), or (r)''.
Sec.   25.32(f).............  Replace                Clarify
                               ``Affirmation of a    that GRAS
                               food substance as     affirmation applies
                               GRAS for humans or    to the intended
                               animals on FDA's      conditions of use
                               initiative or in      of a substance, not
                               response to a         the substance
                               petition, under       itself.
                               parts 182, 184,       Conforming
                               186, or 582 of this   change in light of
                               chapter'' with        the deletion of the
                               ``Establishment or    GRAS affirmation
                               amendment of a        petition process.
                               regulation for a
                               food substance as
                               GRAS under the
                               conditions of its
                               intended use for
                               humans or animals
                               under parts 182,
                               184, 186, 582, or
                               584 of this
                               chapter''.
Sec.   25.32 (i), (j), (k),   Replace ``or GRAS      Clarify
 and (r).                      affirmation           that GRAS
                               petition'' with       affirmation applies
                               ``establishment or    to the intended
                               amendment of a        conditions of use
                               regulation for a      of a substance, not
                               food substance as     the substance
                               GRAS under the        itself.
                               conditions of its     Conforming
                               intended use for      change in light of
                               humans or animals     the deletion of the
                               under parts 182,      GRAS affirmation
                               184, 186, 582, or     petition process.
                               584 of this
                               chapter''.
Sec.   170.3(h), Sec.          Specify       Clarify
 570.3(h).                     ``data from human,    that the four
                               animal, analytical,   listed types of
                               or other scientific   studies (human,
                               studies'' rather      animal, analytical,
                               than ``data from      and other) do not
                               human, animal,        necessarily apply
                               analytical, and       in all
                               other scientific      circumstances.
                               studies''.
                               Replace       Include
                               ``appropriate to      statutory language
                               establish the         from section 201(s)
                               safety of a           of the FD&C Act to
                               substance'' with      clarify that GRAS
                               ``appropriate to      status applies to
                               establish the         the intended
                               safety of a           conditions of use
                               substance under the   of a substance, not
                               conditions of its     the substance
                               intended use''.       itself.

170.3(i)....................  In the definition of  Conforming change to
                               ``safe'' or           consistently use
                               ``safety,'' replace   the exact statutory