use in food. These comments assert that many conclusions of GRAS status
are based on both statutory criteria.
    (Response 52) We disagree that this modification is needed. The
final rule does not prevent you from basing your conclusion of GRAS
status on both statutory criteria. Importantly, if you assert that your
conclusion of GRAS status is based on both statutory criteria, you must
fully support each conclusion and address all requirements of the rule
regarding each conclusion; partial support for each of the two
statutory criteria for a conclusion of GRAS status is not adequate. You
could not, for example, assert that a substance is GRAS under the
conditions of its intended use through scientific procedures, but
``fill in data gaps'' by also asserting that the substance was commonly
used in food before 1958. Likewise, you could not assert that a
substance is GRAS under the conditions of its intended use through
experience based on common use in food if you cannot provide evidence
of a substantial history of consumption of the notified substance for
food use by a significant number of consumers prior to January 1, 1958.
    These comments highlight the importance of fully supporting a
conclusion of GRAS status through each of the statutory criteria.
Because the general criteria in Sec.  170.30(a), as well as the
specific criteria in Sec.  170.30(b) or (c), must be satisfied to
support a conclusion of GRAS status, the final rule specifies that a
conclusion of GRAS status through scientific procedures is in
accordance with both Sec.  170.30(a) and (b) and that a conclusion of
GRAS status through experience based on common use in food is in
accordance with both Sec.  170.30(a) and (c).

E. Agreement To Make Data and Information Available Upon Request

    (Comment 53) Some comments recommend that there be a means for us
to request non-public information if we deem it necessary for our
evaluation of the intended conditions of use of the notified substance,
provided that the information can be considered as confidential and
protected from disclosure.
    (Response 53) These comments appear to misinterpret the reach of
the proposed requirement to agree to provide us access to data and
information that a notifier relies on to support a conclusion of GRAS
status. Some of the data and information that we may ask to see during
our evaluation of a GRAS notice may be ``public'' data and information
in that it would be data and information that we would provide in
response to a request under the FOIA (see Response 48), even though it
may not have been disseminated to the public (e.g., in the scientific
literature or on the Internet (e.g., when a science-based organization
uses the Internet to disseminate scientific or technical information or
recommendations)). If we receive data and information that are non-
public, such data and information would be protected from public
disclosure in accordance with part 20.
    (Comment 54) One comment states that the phrase ``at reasonable
times'' refers not only to hours of a day, but also to a reasonable
amount of time following the submission of a GRAS notice. This comment
recommends that ``several years (for example, five years)'' after
submission of a GRAS notice would be a reasonable time for notifiers to
retain such data and information in their active files.
    (Response 54) By ``at reasonable times,'' we meant the time of day
that we would have access to data and information you retained but did
not include in your GRAS notice. To clarify that the requirement
relates to the time of day rather than to the timeframe for retaining
the data and information, the final rule specifies that you agree to a
procedure in which we can access data and information ``during
customary business hours'' rather than ``at reasonable times.''
    As previously discussed (62 FR 18938 at 18951), we may, at some
point after our response to a GRAS notice, receive additional
information about a notified substance that raises questions about the
safety of that substance. To address this possibility, the rule
specifies that we will send you a subsequent letter about your GRAS
notice if circumstances warrant (see Sec.  170.265(c)). Although the
rule does not specify any timeframe to retain the data and information
that support your conclusion of GRAS status, preservation of the data
and information that are the basis for the conclusion of GRAS status
represents prudent practice for those who claim an exclusion from a
statutory requirement regardless of whether the person subsequently
notifies us (62 FR 18938 at 18947).
    (Comment 55) One comment asks us to clarify that electronic records
are acceptable for documenting the data and information that support a
conclusion of GRAS status.

    (Response 55) Electronic records are acceptable for documenting the
data and information that support a conclusion of GRAS status. If we
ask you to send us such data and information for a notified substance
that would be used in human food, we recommend that you do so by
following the instructions in CFSAN's guidance entitled ``Guidance for
Industry: Providing Regulatory Submissions in Electronic or Paper
Format to the Office of Food Additive Safety'' (Ref. 37), which
includes instructions for making an electronic submission through our
Electronic Submission Gateway, as well as on media that we can access
on our network computers. CFSAN's procedures for making an electronic
submission through our Electronic Submission Gateway use a form that
CFSAN developed for a GRAS notice when a substance would be used in
human food (i.e., Form FDA 3667) (Ref. 38). Form FDA 3667 prompts a
notifier to include certain elements of a GRAS notice in a standard
format. The form, and elements that would be prepared as attachments to
the form, may be submitted in electronic format via the Electronic
Submissions Gateway, as electronic files on physical media, or in paper
format. At this time, we cannot accept media such as thumb drives,
which can present a security risk.
    (Comment 56) One comment asks us to develop criteria for the
required documentation underlying industry conclusions of GRAS status.
    (Response 56) We are not establishing criteria in the rule for the
documentation a notifier would have regarding a conclusion of GRAS
status. Regardless of whether a person who concludes that a use of a
food substance is GRAS notifies us, the applicable documentation would
address the safety of the substance as described in the definition of
``safe'' or ``safety'' (see Sec.  170.3(i)); as applicable, the
definition of ``common use in food'' (see Sec.  170.3(f) and/or the
definition of ``scientific procedures'' (Sec.  170.3(h)); and the
criteria for general recognition of safety (see Sec.  170.30)).

F. Statements and Any Applicable Explanation Regarding Data and
Information That a Notifier Views as Exempt From Disclosure Under FOIA

    In Issue 9 in the 2010 notice (75 FR 81536 at 81539-81540), we
discussed three issues regarding confidential data and information that
are included in a GRAS notice. See table 8. Most of the comments that
address Issue 9 address Issue 9a, particularly with respect to how we
would protect trade secret or confidential commercial information from
public disclosure. See sections XIII.B and XXI.C for a discussion of
those comments, and our response to those comments. In the following
paragraphs, we discuss comments on Issues 9b and 9c, and respond to
those comments.

   Table 8--Issues in the 2010 Notice Regarding Confidential Data and
                      Information in a GRAS Notice
------------------------------------------------------------------------
              Description of
 Issue No.   our request for                   Reference
                 comment
------------------------------------------------------------------------
9a........  Whether the final  75 FR 81536 at 81539-81540.
             rule should
             stipulate that
             the method of
             manufacture
             exclude any
             trade secrets,
             as we proposed.
9b........  Whether to         75 FR 81536 at 81539-81540.
             require that a
             notifier who
             identifies one
             or more trade
             secret(s), as
             defined in Sec.
              20.61(a), in
             the GRAS notice
             explain why it
             is trade secret
             information and
             how qualified
             experts could
             conclude that
             the intended use
             of the notified
             substance is
             safe without
             access to the
             trade secret(s).
9c........  Whether to         75 FR 81536 at 81539-81540.
             require that a
             notifier who
             identifies
             confidential
             commercial or
             financial
             information, as
             defined in Sec.
              20.61(b), in
             the GRAS notice
             explain why it
             is confidential
             commercial or
             financial
             information and
             how qualified
             experts could
             conclude that
             the intended use
             of the notified
             substance is
             safe without
             access to such
             information.
------------------------------------------------------------------------

    (Comment 57) One comment supports the recommendation we made in the
proposed rule for a notifier who considers that certain information in
a submission should not be available for public disclosure to identify
as confidential the relevant portions of the submission for our
consideration (62 FR 18938 at 18952). Those comments that address
Issues 9b and 9c agree with the outcome of our discussion, in the 2010
notice, that we should require that a notifier who identifies a trade
secret or confidential commercial information explain why it is a trade
secret or confidential commercial information and how qualified experts
can conclude that the use of a substance is safe without access to the
trade secret or confidential commercial information.
    (Response 57) The final rule requires a notifier to state his view
as to whether any of the data and information in Parts 2 through 7 of a
GRAS notice are exempt from disclosure under the FOIA (e.g., as trade
secret or as commercial or financial information that is privileged or
confidential) (Sec.  170.225(c)(8)). Requiring this statement in Part 1
of a GRAS notice will give us notice as to whether we will need to
evaluate specific data and information under the FOIA and take steps to
protect applicable data and information from public disclosure. See
also Sec.  170.250(d), which requires that Part 6 of a GRAS notice (a
narrative) identify specific data and information that a notifier views
as exempt from disclosure under the FOIA. Whereas Part 1 of a GRAS
notice only requires that the signed statements in a GRAS notice state
the notifier's view as to whether any of the data and information in
Parts 2 through 7 of a GRAS notice are exempt from disclosure under the
FOIA, in Part 6 of a GRAS notice the notifier would specifically
identify the applicable data and information.
    During the Interim Pilot program, we sometimes received a
curriculum vitae (e.g., of a GRAS panel member) containing personal
privacy information that we needed to redact before we could make the
GRAS notice available to the public. The rule does not require that a
notifier submit such information, and redaction of unnecessary privacy
information takes resources that we would otherwise use to evaluate the
GRAS notice. We ask that notifiers exclude personal privacy information
from a GRAS notice whenever possible. If a notifier does include such
information, in Part 1 of a GRAS notice the notifier should state his
view that the GRAS notice contains personal privacy information. In
Part 6 of a GRAS notice, the notifier should identify the personal
privacy information.

G. Certification Statement

    (Comment 58) Several comments support a requirement for a GRAS
notice to include a certification statement similar to the
certification statement that had been required in a GRAS affirmation
petition. One

comment agrees that the notifier should submit a statement that the
notice is a representative and balanced submission, but does not agree
that the notifier needs to certify the statement.
    (Response 58) The final rule requires a certification statement as
described in the 2010 notice, with one modification (see Sec.
170.225(c)(9)). We added that the statement certify that the GRAS
notices is ``complete'' in addition to ``representative'' and
``balanced,'' to emphasize your responsibility to identify, discuss,
and place in context, data and information that are, or may appear to
be, inconsistent with a conclusion of GRAS status, regardless of
whether those data and information are generally available (see the
requirements of the narrative in Part 6 of a GRAS notice (Sec.
170.250, in particular Sec.  170.250(c))). The certification is
appropriate and necessary to underscore your legal responsibility for
the conclusion of GRAS status. As discussed in the 2010 notice, the
specific text of the certification statement that you must include in a
GRAS notice is consistent with the specific text of the certification
statement in the GRAS affirmation petition process that the
notification procedure is replacing. The use of certification
statements has become routine in other submissions to FDA for food
programs (see, e.g., the certification statement in Part V of Form FDA
3480 (for a food contact notification submission) (Ref. 39); and the
certification statement in Section 13 of Form FDA 3537 (for
registration of a food facility) (Ref. 40)).
    By ``complete,'' we also mean that your GRAS notice identifies, and
places in context, unpublished data and information that you believe
corroborate GRAS status. For example, if you conduct six toxicology
studies, but only publish three of the studies, it may be that you
consider the remaining three studies to be corroborative of safety. As
an example, it may be that you were dissatisfied with the study design
of one study, repeated that study with an improved study design, and
published the study with the improved study design. If you consider
that the findings of the unpublished studies corroborate safety, even
if they do not establish it, a ``complete, representative, and
balanced'' submission would briefly describe the unpublished studies.
In addition, we expect that you would describe, and place in context,
unpublished data and information if you consider that the findings of
the unpublished data and information warrant sharing with any ``GRAS
panel'' that you convene. See also the discussion in Response 69 and
Response 78.
    (Comment 59) One comment asks us to specify that the statement
include the date the statement was certified.
    (Response 59) The rule requires that Part 1 of a GRAS notice be
dated and signed by a responsible official of your organization, or by
your attorney or agent (see Sec.  170.225(a)). The certification
statement is included in Part 1 of the GRAS notice; it is not necessary
to date each statement included in Part 1.

H. Person Signing Part 1 of the GRAS Notice

    (Comment 60) Several comments support a provision to require a GRAS
notice to clearly identify the person signing the GRAS notice, such as
by printing or stating the name and the title of the person signing the
GRAS notice.
    (Response 60) The final rule requires you to state both the name
and position or title of the person who signs the GRAS notice (see
Sec.  170.225(c)(10)).

I. Authorization for FDA To Send Trade Secret Information to FSIS

    In the 2010 notice, we described some of the terms of a MOU,
between FDA and USDA's FSIS, that provides for a coordinated evaluation
process with FSIS when the intended conditions of use of a notified
substance include use in a product or products subject to regulation by
USDA under statutes that it administers (75 FR 81536 at 81541-81542);
in 2015 we amended that MOU to include more details about the
procedures FDA and FSIS will follow to do so (Ref. 36). We also asked
for comment on whether to make our coordinated evaluation process with
FSIS explicit in the final rule (see Issue 13, 75 FR 81536 at 81541-
81542).
    In accordance with our public information regulations in Sec.
20.85 (Disclosure to other Federal government departments and
agencies), we can share confidential commercial information with
another Federal agency pursuant to a written agreement that the record
will not be further disclosed. The amended MOU between FDA and USDA's
FSIS now provides for FDA to share with FSIS confidential commercial
information in a submission such as a GRAS notice (Ref. 36). We
generally cannot share trade secret information with other Federal
agencies under section 301(j) of the FD&C Act (21 U.S.C. 331(j)), and
therefore we would need your authorization to share this information
with FSIS. For efficiency in administering the coordinated evaluation
of a GRAS notice with FSIS, we have added a requirement for a notifier
who submits a GRAS notice that we would send to FSIS to include in part
1 of the GRAS notice a statement as to whether the notifier: (1)
Authorizes us to send any trade secrets to FSIS; or (2) asks us to
exclude any trade secrets from the copy of the GRAS notice that we will
send to FSIS (see Sec.  170.225(c)(11)). Under the provisions that make
the coordinated evaluation of a GRAS notice with FSIS explicit, we will
exclude any trade secrets unless you have authorized us to send trade
secret information to FSIS (see Sec.  170.270). These provisions will
enable us, with your authorization, to share a GRAS notice that
includes trade secret information with FSIS without first redacting the
GRAS notice to remove the trade secret information and, thus, will
reduce the time it takes for us to provide FSIS with a copy of the GRAS
notice. These provisions also will clarify your expectations regarding
whether we should share trade secret information with FSIS and, thus,
require us to redact the trade secret information from the copy we send
to FSIS when consistent with your express wishes.
    Note that our rule establishing the requirements of the GRAS
notification procedure does not specify the data and information that
FSIS will need to evaluate whether the intended use of the notified
substance complies with applicable statutes and regulations, or, if
not, whether the use of the substance would be permitted in products
under FSIS jurisdiction under specified conditions or restrictions. We
recommend that you contact the appropriate staff at FSIS regarding the
data and information that FSIS will need you to provide. FSIS provides
contact information for its programs on its Web site (Ref. 41).

XIII. Comments on Part 2 of a GRAS Notice: Identity, Method of
Manufacture, Specifications, and Physical or Technical Effect

    We proposed to require that a GRAS notice include detailed
information about the identity of the notified substance, including, as
applicable, its chemical name, Chemical Abstracts Service (CAS)
Registry Number, Enzyme Commission number, empirical formula,
structural formula, quantitative composition, method of manufacture
(excluding any trade secrets and including, for a substance of natural
biological origin, source information such as genus and species),
characteristic properties, any content of potential human toxicants,
and specifications for food-grade material (proposed Sec.
170.36(c)(2)). In the 2010 notice, we requested comment on

several issues relevant to the proposed requirements for detailed
information about the identity of the notified substance (see table 9).

 Table 9--Issues in the 2010 Notice Regarding the Proposed Requirements
  for Detailed Information About the Identity of the Notified Substance
------------------------------------------------------------------------
              Description of
 Issue No.   our request for                   Reference
                 comment
------------------------------------------------------------------------
9a........  Whether the final  75 FR 81536 at 81539-81540.
             rule should
             continue to
             stipulate that
             the method of
             manufacture
             exclude any
             trade secrets,
             as proposed.
10a.......  What scientific    75 FR 81536 at 81540.
             information
             would be
             sufficient to
             identify the
             biological
             source.
10b.......  Whether to         75 FR 81536 at 81540.
             require that
             information
             about the
             identity of the
             notified
             substance
             specify any
             known toxicants
             that could be in
             the source.
10c.......  Whether the final  75 FR 81536 at 81540.
             rule should
             address, as part
             of identity,
             particle size
             and other
             chemical and
             physical
             properties that
             may be used to
             characterize
             engineered
             materials.
------------------------------------------------------------------------

    Some comments support the proposed requirements, with the potential
modifications described in the 2010 notice, without change. For
example, most of the comments that address the issue of scientific
information sufficient to identify a biological source support
requiring both taxonomic information and the part of any animal or
plant used as a source. As another example, several comments that
address the issue of scientific information sufficient to identify a
biological source support requiring that this information specify
toxicants that could be in the source.
    Most of the comments regarding our proposal to require that a GRAS
notice include detailed information about the identity of the notified
substance address the issues discussed in 2010 notice. In the following
sections, we discuss these and other comments. After considering these
comments, we are establishing requirements for Part 2 of a GRAS notice
to include information about the identity, method of manufacture,
specifications, and physical or technical effect of the notified
substance as shown in table 10, with editorial, clarifying, and
conforming changes as shown in table 29. (See Sec.  170.230). Table 10
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(c)(2) as Sec.  170.230.

    Table 10--Final Requirements for Detailed Information in Part 2 of a GRAS Notice About the Identity of a
                                               Notified Substance
----------------------------------------------------------------------------------------------------------------
                                                                                Revisions (other
                                                                                than editorial,
                                         Proposed        Issue No.  in  Description. Part 2    clarifying, and
    Final designation in  the       designation in the     the 2010        of your  GRAS     conforming changes)
    regulatory text  (Sec.   )       regulatory text        notice            notice:           relative to the
                                        (Sec.   )                                             proposed rule  or
                                                                                the 2010 notice
----------------------------------------------------------------------------------------------------------------
170.230(a)(1)....................  170.36(c)(2).......             N/A  Must include         N/A.
                                                                         scientific data
                                                                         and information
                                                                         that identifies
                                                                         the notified
                                                                         substance.
170.230(a)(1)....................  170.36(c)(2).......             10a  Must include data     Must
                                                                         and information      provide taxonomic
                                                                         sufficient to        information at the
                                                                         identify a           sub-species level
                                                                         biological source    (e.g., variety,
                                                                         of a notified        strain) in
                                                                         substance.           addition to genus
                                                                                and species.
                                                                                Must
                                                                                specify the part
                                                                                of any plant or
                                                                                animal used as the
                                                                                source.
170.230(a)(2)....................  170.36(c)(2).......             10b  Must include data    N/A.
                                                                         and information
                                                                         sufficient to
                                                                         identify any known
                                                                         toxicants that
                                                                         could be in the
                                                                         source.
170.230(b).......................  170.36(c)(2).......              9a  Must include the      No longer
                                                                         method of            requires that the
                                                                         manufacture of the   method of
                                                                         notified substance   manufacture
                                                                         in sufficient        exclude any trade
                                                                         detail to evaluate   secrets.
                                                                         the safety of the    Requires
                                                                         notified substance   ``sufficient
                                                                         as manufactured.     detail to evaluate
                                                                                the safety of the
                                                                                notified substance
                                                                                as manufactured''
                                                                                rather than
                                                                                ``detailed
                                                                                information.''
170.230(c).......................  170.36(c)(2).......             N/A  Must include         N/A.
                                                                         specifications for
                                                                         food-grade
                                                                         material.
170.230(d).......................  N/A................             N/A  When necessary to    New requirement
                                                                         demonstrate          based on comments
                                                                         safety, must         that addressed
                                                                         include relevant     experience during
                                                                         data and             CVM's Interim
                                                                         information          Pilot program (see
                                                                         bearing on the       section XXV.E).
                                                                         physical or other
                                                                         technical effect
                                                                         the notified
                                                                         substance is
                                                                         intended to
                                                                         produce, including
                                                                         the quantity of
                                                                         the notified
                                                                         substance required
                                                                         to produce such
                                                                         effect.
----------------------------------------------------------------------------------------------------------------

A. Scientific Information About the Identity of a Notified Substance

1. Scientific Information Sufficient To Identify a Biological Source
    (Comment 61) One comment asserts that the scientific information,
beyond the standard taxonomic information, that is sufficient to
identify a biological source for a notified substance should be
determined on a case-by-case basis consistent with established practice
and publicly available guidance. Another comment asserts that
identifying the source organism by the genus and species (without
additional information such as strain or variety) is sufficient when
the notified substance is an enzyme preparation produced by a
microorganism. However, this comment also asserts that if safety
concerns for a specific genus and species have been addressed (i.e., by
genetic modification to remove a characteristic of concern) for a
specific strain within that species then information about the strain
would be appropriate. This comment emphasizes that the description of
the source of a biological material should be based on the safety of
that source and consider all relevant information related to safety.
    (Response 61) The information, beyond the standard taxonomic
information, that we discussed in the 2010 notice is consistent with
established practice (see section III.J.1 of CFSAN's 2010 experience
document (Ref. 18)) and the final rule specifies that when the source
of a notified substance is a biological material, your GRAS notice must
include both taxonomic information (e.g., genus, species), including as
applicable data and information at the sub-species level (e.g.,
variety, strain) and the part of any plant or animal used as the source
(see Sec.  170.230(a)(2)). We agree that the specific scientific
information, beyond the standard taxonomic information, that is
sufficient to identify a biological source is determined on a case-by-
case basis, and section III.J.1 of CFSAN's 2010 experience document
demonstrates that the specific scientific information included in a
GRAS notice to describe a biological source varied on a case-by-case
basis. For example, when the notified substance was derived from a
microorganism, the notifier specified a particular strain or subspecies
or stated the strain was a nontoxigenic and nonpathogenic strain; when
the notified substance was derived from a plant, the notifier
identified the specific part(s) of the plant used as the starting
material, such as fruit, seeds or seed husks, expressed oil, flowers,
roots, leaves, pulp, wood, or bark. However, we disagree that we should
use guidance, rather than the regulatory text of this rule, to describe
the types of data and information that are necessary to sufficiently
identify the biological source because the types of information we are
specifying are necessary--rather than merely recommended--information.
For example, data and information at the sub-species level (e.g.,
variety, strain) is necessary for source microorganisms because so many
microorganisms (e.g., Escherichia coli and Saccharomyces cerevisiae)
have multiple strains, and although some strains are both non-toxigenic
and non-pathogenic, others are not. For example, there are several
pathogenic strains of Saccharomyces cerevisiae, even though
nonpathogenic strains are commonly used in food and in the production
of enzyme preparations. As another example, both Aspergillus oryzae and
Aspergillus niger naturally produce mycotoxins, but strains that do not
produce mycotoxins have been developed and are used for production of
enzyme preparations. In addition, for phage production some host
strains have been pathogens (e.g., Listeria monocytogenes) and produce
toxins. Likewise, data and information about the part of a plant used
as a source is necessary because some plants that have edible parts
also secrete toxins in non-edible parts. For example, the leaf stalks
(petioles) of rhubarb (Rheum rhaponticum) are edible, but the leaves
contain notable quantities of oxalic acid. As another example, the
leaves and stems of tomato (Solanum lycopersicum) contain solanine.
    We agree that the description of a biological source should be
based on the safety of that source and consider all relevant
information related to safety. The regulatory text requires taxonomic
information beyond genus and species, such as variety or strain, ``when
applicable'' for a source microorganism such as those used to produce
enzyme preparations. Examples of when information such as variety or
strain would be applicable are those microbial sources, such as some
fungi, for which there are multiple strains or subspecies that have
different properties with respect to the ability to produce toxins,
antibiotics, or other substances that are not suitable for use in food.
    (Comment 62) One comment asks us to specify that information
identifying a substance derived from a biological source must include
the breed of animal or plant.
    (Response 62) During the Interim Pilot program we did not evaluate
any GRAS notices in which the breed of an animal or plant source was a
taxonomic descriptor necessary to sufficiently identify that animal or
plant source. Therefore, although breed may be an appropriate taxonomic
descriptor in some circumstances, the circumstances are rare enough
that we have not seen it as necessary information in more than 15
years. Therefore, we are not specifying it as an example of applicable
taxonomic information in the rule. In a specific circumstance where
breed is necessary to adequately identify a particular animal or plant
source, and you do not specify the breed, we intend to ask you to amend
your GRAS notice to identify the breed.
    (Comment 63) One comment asks us to address substances produced
from microorganisms, particularly bioengineered microorganisms. This
comment explains that the development of a production microorganism
through bioengineering is, for the most part, highly confidential and
cannot be disclosed publicly. In addition, the production microorganism
often is modified on an ongoing basis, e.g., to improve yield. This
comment asks us to specify the point at which subsequent modification
of a production microorganism would trigger submission of a new GRAS
notice and notes that in some cases subsequent modification of a
production organism could be incorporated into the original GRAS notice
by ``amendment'' or by reference. This comment also asserts that
submission of a new GRAS notice should not be needed in the case of
safe strain lineage as described in the scientific literature (Ref.
42).
    Another comment asks us to specify that information identifying a
substance derived from a biological source must specify whether the
plant or animal is genetically engineered or cloned.
    (Response 63) We recommend that notifiers consult our guidance
entitled ``Assessing the Effects of Significant Manufacturing Process
Changes, Including Emerging Technologies, on the Safety and Regulatory
Status of Food Ingredients and Food Contact Substances, Including Food
Ingredients that Are Color Additives'' (Ref. 6). That guidance lists a
change in the source microorganism (including a change in strain) used
for a food substance derived from fermentation of a microorganism as an
example of a significant manufacturing process change. Whenever there
has been a significant manufacturing process change for a food
substance that is the subject of a previous conclusion of GRAS status,
the guidance recommends that the manufacturer consider whether the GRAS
status of the use of the food substance would be affected; consult

with us regarding the conclusions about the impact of the significant
manufacturing change on the safety and regulatory status of the use of
the food substance; and make an appropriate regulatory submission to us
as circumstances warrant. In the specific circumstance of a production
microorganism that is modified on an ongoing basis, a modification that
results in a new strain would no longer fall within the description of
the source, which must include information at the sub-species level
(see Sec.  170.230(a)(2)(i)). If a notifier concludes that a
modification that results in a new strain has no impact on the
conclusion of GRAS status, one approach could be to submit a supplement
to the GRAS notice. Doing so would be consistent with CFSAN's 2010
experience during the Interim Pilot program. See section IV.J of
CFSAN's 2010 experience document (Ref. 18), in which CFSAN discusses a
GRAS notice in which a notifier consulted with CFSAN about mechanisms
to inform CFSAN about its conclusion that additional uses of the
notified substance are also GRAS. The notifier supplemented its
original GRAS notice with a letter informing CFSAN of the additional
conclusion of GRAS status and CFSAN issued a second ``no questions
letter'' to the notifier as additional correspondence.
    We decline the request to require that information identifying a
substance derived from a biological source specify whether the plant or
animal is ``genetically engineered'' or ``cloned.'' We consider that
the more general requirement to identify a biological source at the
sub-species level is adequate to identify the source. In practice
during the Interim Pilot program, notifiers routinely informed us about
the use of such techniques in describing production microorganisms,
particularly for GRAS notices about the intended conditions of use of
enzyme preparations. (See, e.g., the list of enzyme preparations in
section IV.N of CFSAN's 2010 experience document (Ref. 18).) The source
microorganisms for several of the listed enzyme preparations were
developed using bioengineering techniques.
    When confidential data and information about the development of a
production microorganism through bioengineering are necessary to
provide evidence that a notified substance produced from that
production organism is safe under the conditions of its intended use,
the use of the notified substance would not satisfy GRAS criteria. See
the discussion in Response 69, where we explain that it may be possible
to explain that confidential information (whether included in a GRAS
notice, or provided privately to a GRAS panel) is corroborative of
safety, rather than necessary to demonstrate safety, if, for example,
the method of manufacture included in a GRAS notice meets the
requirements of the rule to provide sufficient detail to evaluate the
safety of the notified substance as manufactured. Alternatively, the
notifier could describe the development of the production microorganism
in sufficient detail to address any safety issues associated with use
of that production microorganism. For enzyme preparations that would be
used in human food, we recommend that notifiers consult our guidance
entitled ``Guidance for Industry: Enzyme Preparations: Recommendations
for Submission of Chemical and Technological Data for Food Additive
Petitions and GRAS Notices'' (Ref. 33), and ``Food-Processing Enzymes
From Recombinant Microorganisms--A Review'' (Ref. 43), for details
about our recommendations for safety information regarding enzyme
preparations derived from bioengineered microorganisms.
2. Potential Toxicants in the Source of the Notified Substance
    (Comment 64) One comment agrees that a review of known toxicants
that could be produced by the biological source of a notified substance
should be part of the safety review, but recommends that the depth of
the review be addressed on a case-by-case basis and be tailored to the
substance and the source of the substance. This comment asserts that it
would be difficult and impractical to define a method for this review
or to define the specific toxicants that are required to be reviewed
for each particular substance.
    (Response 64) We agree that the safety review should be tailored to
the substance and its source because of the diversity of toxicants that
could be in the biological source. It is your responsibility to
determine how to conduct the safety review; the rule does not prescribe
any method for this review or any specific toxicants that must be
reviewed for a particular substance or source. In some cases (e.g.,
when it is well established in the scientific community that a source
is non-toxigenic), citations to publicly available information about a
biological source may be sufficient to address the safety of the
notified substance with respect to potential toxicants in the source.
In other cases (e.g., when a source is known to be toxigenic), the
information about the toxigenic source would lead you to a discussion,
in the narrative required in Part 6 of a GRAS notice, of how the method
of manufacture and specifications for the notified substance lead you
to conclude that the notified substance as manufactured is safe and
that the criteria for general recognition are satisfied.
    (Comment 65) One comment refers to a statement we made, in the 2010
notice, that we have found that information about substances known to
be toxicants is relevant regardless of the state of the science
regarding the specific toxicity of the substance to humans (75 FR 81536
at 81540). This comment asserts that specifying that the identity of
the notified substance include any known toxicants that could be in the
source does not fully address whether the toxicants cause a safety
concern. Another comment states that the ``GRAS process'' should
contain a safety/risk assessment for known toxicants, not just identify
the toxicants.
    (Response 65) We agree that a GRAS notice must address the safety
concerns associated with toxicants known to be in a biological source,
not just identify the toxicants. See the requirements for a GRAS notice
to include the method of manufacture of the notified substance (Sec.
170.230(b)), specifications for food-grade material (Sec.  170.230(c)),
and a narrative explaining why the data and information in a GRAS
notice provide a basis for the notifier's view that the notified
substance is safe under the conditions of its intended use (Sec.
170.250).
    (Comment 66) One comment recommends using our guidance entitled
``Recommendations for Submission of Chemical and Technological Data for
Direct Food Additive Petitions'' (Ref. 31) as a more ``holistic''
approach to addressing potential safety concerns regarding known
toxicants in a biological source, because the guidance describes how to
use the manufacturing process to control, reduce, or concentrate
toxicant levels and explains the importance of establishing limits for
any known natural toxicants in or on food additives derived from a
natural source. The comment asserts that this guidance should apply to
GRAS substances as well as food additives because general recognition
of safety through scientific procedures requires the same quantity and
quality of evidence as is required to establish a food additive
regulation for the use of the substance, and therefore the information
about the identity of the substance should be consistent with the
requirements for food additives. This comment notes that section III.A
of ``Recommendations for Submission of Chemical and Technological Data
for

Direct Food Additive Petitions'' clearly outlines the information
needed for ``allowing the unequivocal identification and
characterization of the food additive'' and that the principles in
specific sections in section III.A of the guidance apply to GRAS
substances even though they are written to specifically address food
additives.
    (Response 66) We agree that many of the recommendations in our
guidance entitled ``Recommendations for Submission of Chemical and
Technological Data for Direct Food Additive Petitions'' (Ref. 31) could
be useful to a person who assesses whether a substance is GRAS under
the conditions of its intended use. As the comment points out, the
guidance currently is structured to address the specific requirements
in Sec.  171.1 (particularly Sec.  171.1(c)) for food additive
petitions. Consistent with available resources, we will consider
revising that guidance to clarify how its recommendations apply to an
evaluation of whether a substance is GRAS under the conditions of its
intended use.

3. Particle Size

    In the 2010 notice, we noted that substances that have a small
particle size often have chemical, physical, or biological properties
that are different from those of their larger counterparts (75 FR 81536
at 81540). We requested comment on whether the final rule should
address, as part of identity, particle size and other chemical and
physical properties that may be used to characterize engineered
materials (see table 9).
    (Comment 67) Some comments recommend that a GRAS notice discuss
particle size only if it is relevant to the safety or effectiveness of
the notified substance. One comment recommends that the rule not
address particle size, at least until this area is better understood.
Another comment asks us to clarify what we mean by the term ``small
particle size'' if we include that term in the rule.
    One comment asks us to require information about particle size and
other physical/chemical properties that may be used to characterize
engineered materials. This comment asserts that nanoparticles are not
simply smaller versions of materials; instead nanoparticles are
specifically engineered to create new properties and behaviors that
give products certain attributes and highly reactive nanoparticles can
exhibit a toxic reaction with their environments, including the cells
of living organisms. This comment also notes that the U.S.
Environmental Protection Agency (EPA) has already made case-by-case
rulings on the safety of certain nanoparticles.
    Several comments assert that any requirement for a GRAS notice to
address particle size and other chemical or physical properties should
apply only to engineered nanomaterials, and that it is not typically
necessary to address such properties for non-engineered materials. One
comment asserts that engineered nanomaterials could never be eligible
for classification as GRAS because they either are new materials with
unfamiliar properties or represent a significant new use of a material.
    (Response 67) The final rule requires that a GRAS notice include
scientific information that identifies the notified substance, and
includes ``characteristic properties'' in a list of examples of
appropriate information that a notifier would include. We agree that
data and information about particle size, and any chemical and physical
properties attributable to small particle size, are appropriate for
engineered nanomaterials; a GRAS notice about an engineered
nanomaterial likely would not provide an adequate basis for a
conclusion of GRAS status without such information. We also agree that
data and information about particle size may not be relevant for non-
engineered materials and, thus, we are including the broad example of
``characteristic properties'' in the final rule without adding the
narrow example of ``particle size'' (see Sec.  170.230(a)(1)).
    We note that we have several guidances applicable to significant
manufacturing changes in food, including nanotechnology (Ref. 6; Ref.
8; and Ref. 44). Our guidance entitled ``Guidance for Industry:
Assessing the Effects of Significant Manufacturing Process Changes,
Including Emerging Technologies, on the Safety and Regulatory Status of
Food Ingredients and Food Contact Substances, Including Food
Ingredients that are Color Additives'' (Ref. 6) states: ``At present,
for nanotechnology applications in food substances, there are questions
related to the technical evidence of safety as well as the general
recognition of that safety, that are likely to be sufficient to warrant
formal premarket review and approval by FDA, rather than to satisfy
criteria for GRAS status.'' However, that guidance reflects the
generally available data and information at present, and we disagree
that data and information supporting the safety of engineered
nanomaterials could never satisfy GRAS criteria. Whether the generally
available data and information supporting the safety of the intended
conditions of use of any substance--including an engineered
nanomaterial--satisfy GRAS criteria is a case-by-case conclusion that
depends on whether the generally available data and information support
a conclusion that the substance is generally recognized, among
qualified experts, to be safe under the conditions of its intended use.
Section 201(s) of the FD&C Act does not limit the eligibility of a
substance for classification as GRAS based on factors such as its
characteristic properties.
4. Other Comments About the Identity of the Notified Substance
    (Comment 68) One comment asserts that the criteria used to conclude
that a particular substance is GRAS, including details regarding
biological source, known toxicants, particle size, etc., should be
based on what qualified experts determine to be necessary.
    (Response 68) We disagree that the role of qualified experts in a
conclusion of GRAS status means that the requirements for a GRAS notice
should be silent on the types of data and information that generally
apply to any conclusion of GRAS status--in this case, data and
information regarding the identity of the substance. In the narrative
required by part 6 of a GRAS notice, a notifier must explain why the
data and information in the notice provide a basis for the notifier's
view that the notified substance is safe under the conditions of its
intended use (Sec.  170.250(a)(1)); identify what specific data and
information that the notifier discusses to support his view that the
notified substance is safe under the conditions of its intended use are
generally available, and what specific data and information that the
notifier discusses are not generally available (Sec.  170.250(a)(2));
and explain how the generally available data and information that a
notifier relies on to establish safety provide a basis for the
notifier's conclusion that the notified substance is generally
recognized, among qualified experts, to be safe under the conditions of
its intended use (Sec.  170.250(b)). The narrative is the appropriate
mechanism for a notifier to explain how the view of qualified experts
supports his view that the notified substance is GRAS under the
conditions of its intended use.

B. Method of Manufacture

    (Comment 69) Several comments address Issue 9a, i.e., whether the
final rule should continue to stipulate that the method of manufacture
exclude any trade secrets, as proposed. Some of these comments support
stipulating that the method of manufacture exclude any trade secrets.
The stated reasons varied.

For example, some comments state that in the past experience of
notifiers, it is generally possible to include sufficient information
on the manufacturing process without disclosing trade secrets. One
comment states that transparency, by both FDA and industry, and the use
of publicly available information is critical to the continued success
of the GRAS notification procedure. One comment states that the common
knowledge element of the GRAS standard inherently limits the submission
of confidential information and/or trade secrets by the notifier to
substantiate a conclusion of GRAS status.
    Other comments point to the proposed requirement that a GRAS notice
include ``detailed information about the . . . method of manufacture
(excluding any trade secrets . . .)'' and question whether a method of
manufacture that excludes trade secrets can be sufficiently detailed to
meet the requirements of a GRAS notice. One comment recommends that we
clarify the rule by requiring that the notice include appropriate
information on the method of manufacture, sufficient to conduct an
adequate safety review, so that confidential information would not be
submitted when a very general and non-confidential description
suffices.
    Several comments acknowledge that there may be situations where
trade secret information is necessary to complete the description of
the method of manufacture and recommend that the final rule provide
flexibility for a notifier to provide trade secret information when
appropriate (e.g., to help us evaluate the GRAS notice), and for FDA to
protect trade secrets or other confidential information in a GRAS
notice from public disclosure, just as we would in the case of
submissions such as food additive petitions. To promote clarity and
transparency, some of these comments recommend revising the rule to
require that a notifier who includes trade secret information explain
why the information is trade secret and why the trade secret
information has a corroborative role in the safety assessment. Some
comments emphasize that a notifier who submits trade secret information
must mark the information as non-public. Other comments assert that
information identified as trade secret or confidential information
should only be allowed if the information is not critical to a
conclusion of GRAS status.
    One comment suggests that a notifier could provide trade secret
information to a GRAS panel for review on a confidential basis because
deliberations of the panel would not necessarily be subject to public
disclosure. One comment notes that supporting information can be
valuable to a GRAS panel and allowing submission of confidential
information in a GRAS notice could inform FDA of the full range of
information taken into consideration by a GRAS panel.
    Some comments cite our regulations for new drugs, premarket
notification for medical devices, and premarket approval of medical
devices as evidence that our regulations implementing FOIA specifically
regard methods of manufacture as confidential and urge us to adopt a
similar approach for GRAS notices.
    See also Comment 57.
    (Response 69) See table 11, and the regulatory text in Sec. Sec.
170.230(b), 170.225(c)(8), 170.250(d), and 170.250(e), for a series of
changes we made to the rule to address these comments about the method
of manufacture included in a GRAS notice, including comments about
trade secret information associated with the method of manufacture.
Although the changes in Parts 1 and 6 of a GRAS notice broadly apply to
any non-public information, in this response we focus on how these
provisions apply to trade secret information that you may include in
the description of the method of manufacture. Collectively, these
changes: (1) Emphasize that the description of the method of
manufacture must be in sufficient detail to evaluate the safety of the
notified substance as manufactured, without stipulating that the method
of manufacture exclude any trade secrets (Sec.  170.230(b)); (2)
require the notifier to include a signed statement with his view as to
whether the method of manufacture includes trade secret information
(Sec.  170.225(c)(8)); (3) require the notifier to identify any trade
secret information in the method of manufacture (Sec.  170.250(d)); and
(4) require the notifier to explain how there could be a basis for a
conclusion of GRAS status if qualified experts do not have access to
trade secret information that the notifier considered in concluding
that the substance is safe under the conditions of its intended use
(Sec.  170.250(e)). See also Response 57, Response 78, and section
XVII.

  Table 11--Requirements That Apply When a Notifier Includes Trade Secret or Other Non-Public Information in a
                                                   GRAS Notice
----------------------------------------------------------------------------------------------------------------
                                     Proposed designation
     Final designation in the         in the regulatory            Description                  Revision
    regulatory text  (Sec.   )         text  (Sec.   )
----------------------------------------------------------------------------------------------------------------
170.230(b)........................  170.36(c)(2).........  In Part 2 of your GRAS       We replaced
                                                            notice, you must include    ``detailed'' with
                                                            a description of the        ``sufficient detail to
                                                            method of manufacture in    evaluate the safety of
                                                            sufficient detail to        the notified substance
                                                            evaluate the safety of      as manufactured''.
                                                            the notified substance as   We no longer
                                                            manufactured.               stipulate that the
                                                                                description of the
                                                                                method of manufacture
                                                                                must exclude trade
                                                                                secret information.
170.225(c)(8).....................  N/A..................  In Part 1 of your GRAS      Requires a notifier who
                                                            notice, you must state      includes information
                                                            your view as to whether     that the notifier views
                                                            any of the data and         as non-public
                                                            information in Parts 2      information to make FDA
                                                            through 7 of your GRAS      aware of that view. See
                                                            notice are exempt from      Response 57.
                                                            disclosure under the FOIA
                                                            (e.g., as trade secret or
                                                            as commercial or
                                                            financial information
                                                            that is privileged or
                                                            confidential).
170.250(d)........................  N/A..................  In Part 6 of your GRAS      Requires a notifier who
                                                            notice (the narrative),     includes information
                                                            if you view any of the      that the notifier views
                                                            data and information in     as non-public
                                                            your notice as exempt       information to identify
                                                            from disclosure under the   the non-public
                                                            FOIA, you must identify     information. See section
                                                            the specific data and       XVII.
                                                            information.

170.250(e)........................                         In Part 6 of your GRAS      Requires a notifier to
                                                            notice (the narrative),     place non-public
                                                            you must explain how        information in the
                                                            there could be a basis      context of a conclusion
                                                            for a conclusion of GRAS    of GRAS status. See
                                                            status if qualified         section XVII.
                                                            experts generally do not
                                                            have access to non-
                                                            public, safety-related
                                                            data and information.
170.275(c)........................  170.36(f)(1).........  We will disclose all        Uses active voice to
                                                            remaining data and          emphasize that we will
                                                            information that are not    apply the protections
                                                            exempt from public          from public disclosure
                                                            disclosure in accordance    under the FOIA to non-
                                                            with part 20.               public information
                                                                                included in a GRAS
                                                                                notice.
----------------------------------------------------------------------------------------------------------------

    This rule establishes requirements for the information that a
notifier submits to FDA in a GRAS notice. GRAS criteria require that
any conclusion of GRAS status be based on common knowledge (see Sec.
170.30(a)) and, thus, there could be no basis for a conclusion of GRAS
status if trade secret information (or other non-public information) is
necessary for qualified experts to reach a conclusion that the notified
substance is safe under the conditions of its intended use. In the
particular case of a conclusion of GRAS status through scientific
procedures, GRAS criteria require that the conclusion of GRAS status be
based on data, information, and methods that are generally available
(see Sec.  170.30(b)). Non-public information may be used to
corroborate safety but cannot be used to establish safety; as discussed
in Response 9, qualified experts must be able to conclude that the
substance is not harmful under the conditions of its intended use
without access to ``corroborative'' information (see Sec.  170.30(a)).
    We believe that it will be rare for a GRAS notice to include trade
secret information. Likewise, we expect it will be rare that trade
secret information would warrant sharing with members of a GRAS panel,
because a notifier must write a non-confidential description of the
method of manufacture to include in the GRAS notice and could share
this non-confidential description, rather than trade secret
information, with the GRAS panel. If the GRAS panel had questions about
that description of the method of manufacture, we expect that the
notifier would revise the description to address those questions rather
than provide the GRAS panel with trade secret information to address
those questions. If, however, a notifier does provide the GRAS panel
with trade secret information, we agree that the notifier should inform
us of the full range of information taken into consideration by the
GRAS panel, consistent with the signed statement that the GRAS notice
is a complete, representative, and balanced submission (see Response 58
and Sec.  170.225(c)(9)). The notifier could do so either by including
in his GRAS notice a non-confidential description of the trade secret
information that was shared, or by providing the trade secret
information shared with a GRAS panel. Importantly, the notifier would
be required to explain how there could be a basis for a conclusion of
GRAS status if qualified experts generally do not have access to non-
public, safety related data and information (see Response 78 and Sec.
170.250(e)). If the public description of the method of manufacture
that a notifier includes in a GRAS notice cannot provide sufficient
detail to evaluate the safety of the notified substance as
manufactured, there could be no basis to support a conclusion of GRAS
status. However, if that public description meets the requirements of
the rule to provide sufficient detail to evaluate the safety of the
notified substance as manufactured (see Sec.  170.230(b)), it may be
possible to explain that trade secret information that a GRAS panel
evaluated is corroborative of safety rather than necessary to
demonstrate safety.
    Under Sec.  20.61, trade secrets and commercial or financial
information which is privileged or confidential are exempt from public
disclosure. Under Sec. Sec.  20.100(c)(7) and 171.1(h)(2)(i),
manufacturing methods or processes, including quality control
procedures, are exempt from public disclosure unless they have been
previously disclosed to the public (as defined in Sec.  20.81) or they
relate to a product or ingredient that has been abandoned. If a
notifier believes that all information about the method of manufacture
should be non-public, it is unlikely that the notifier has a basis to
conclude that the notified substance is GRAS under the conditions of
its intended use. The use of the substance would be a food additive use
and, if the notifier submits a food additive petition for that use, our
regulations governing a food additive petition would protect the
information from public disclosure, as do our regulations for new
drugs, premarket notification for medical devices, and premarket
approval of medical devices.
    (Comment 70) Several comments express concern about the possibility
that we would determine that information a notifier identifies as a
trade secret or as confidential commercial information is available for
public disclosure. One comment asserts that if we choose to allow the
submission of confidential information in a GRAS notice, we should not
be the party who determines whether information should be publicly
disclosed. Another comment asks us to provide an opportunity for a
notifier to make a ``cease to evaluate'' request before we disclose
confidential information.
    One comment asks us to allow the submission of limited confidential
information to supplement (or corroborate) the publicly available
information in a GRAS notice, such as by providing sufficient
information in a GRAS notice to support a conclusion of GRAS status but
also including additional, corroborating information in a food master
file. The comment explains that the public GRAS notice would be
complete and sufficient to form a conclusion of GRAS status, but we
would have access to additional, confidential information that would
ensure that we are informed of new manufacturing or technological
developments. This comment points out that we have for many years
employed food, drug, and medical device master files for the submission
of confidential information.

    (Response 70) We disagree that we should not be the party who
determines whether information should be publicly disclosed. Under our
public information regulations in part 20, we have the responsibility
to determine whether information should be publicly disclosed,
regardless of whether a person who submits the information has marked
it as non-public. 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 (see Sec.  20.27). We also
disagree that providing an opportunity for a notifier to ask us to
cease to evaluate a GRAS notice would impact the public disclosure of
data and information that do not satisfy the criteria in part 20 for
exemption from disclosure; under Sec.  20.29 a GRAS notice is available
for public disclosure in accordance with part 20.
    Data and information submitted to us are available for public
disclosure based on the nature of the data and information, not the
name of the file where we store the data and information. Thus, asking
us to store data and information that you view as confidential in a
specific type of file, such as a ``food master file,'' would not
automatically protect the information from public disclosure.
Furthermore, in Part 6 of your GRAS notice you would be required to
explain how there could be a basis for a conclusion of GRAS status if
qualified experts generally do not have access to the confidential data
and information in the separate file. We also would expect that you
provide a statement in Part 1 of your GRAS notice with your view that
the additional data and information in the separate file are exempt
from disclosure under the FOIA (see Sec.  170.225(c)(8)). Because part
20 already provides protection of non-public information from
disclosure, and because your GRAS notice would need to both acknowledge
the data and information in the separate file and explain how there
could be a basis for a conclusion of GRAS status if qualified experts
generally do not have access to these data and information, we consider
it administratively inefficient to maintain the data and information
submitted in support of a conclusion of GRAS status in two separate
files, and we may decide to decline to file a GRAS notice that is
accompanied by a separate file containing data and information that you
view as non-public.
    (Comment 71) Some comments assert that many manufacturers will
choose not to notify us of a conclusion of GRAS status because they
expect that we will determine that all information submitted in a GRAS
notice is available for public disclosure in most circumstances.
    (Response 71) Our experience during the Interim Pilot program does
not support the assertions in these comments. As noted in Response 24
and Response 26, CFSAN has filed more than 600 GRAS notices between
1998 and 2015, for an average of approximately 34 GRAS notices per
year.
    (Comment 72) One comment states that commercial and financial
information are not relevant to the determination of safety of a
notified substance.
    (Response 72) Confidential commercial information may on occasion
be used to corroborate safety. One example is an article that has been
accepted for publication, but has not yet been published. This article
would likely be considered confidential until it is published, but it
could be used to corroborate other published information.

C. Specifications for the Notified Substance

    We received no comments that disagreed with our proposed
requirement for a GRAS notice to include specifications for food-grade
material and we are finalizing it as proposed for a substance used in
human food. See table 29 for an editorial change we made to the
regulatory text for specifications for a substance used in animal food.

D. Data and Information Bearing on the Physical or Other Technical
Effect of the Notified Substance

    As discussed in section XXV.E, several comments discuss their
experience with CVM's practice, during the Interim Pilot program, of
asking a notifier to provide data or information demonstrating the
effectiveness, or utility, of the notified substance. After considering
these comments, 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.  170.230(d)
and Response 144). 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). An example of when such data and
information would be relevant to safety is when the intended use of the
notified substance is as an antimicrobial agent. For example, an
antimicrobial agent may change the microbiological profile of food such
that it suppresses one group of pathogenic microorganisms while
allowing others to proliferate, thereby creating a potential health
problem (Ref. 32).

XIV. Comments on Part 3 of a GRAS Notice: Dietary Exposure

    We proposed that a notice regarding a conclusion of GRAS status
through scientific procedures include a comprehensive discussion of,
and citations to, generally available and accepted scientific data,
information, methods, or principles that the notifier relies on to
establish safety, including a consideration of the probable consumption
of the substance and the probable consumption of any substance formed
in or on food because of its use and the cumulative effect of the
substance in the diet, taking into account any chemically or
pharmacologically related substances in such diet (proposed Sec.
170.36(c)(4)(i)(A)). In the 2010 notice, we requested comment on
several issues relevant to the proposed requirements for a
comprehensive discussion that considers the probable consumption of the
substance and the probable consumption of any substance formed in or on
food because of its use and the cumulative effect of the substance in
the diet, and noted that the simple term ``dietary exposure'' could be
used in place of the statutory language (i.e., derived from section
409(c)(5) of the FD&C Act) we used in the proposed rule (see table 12).
See table 27 for issues in the 2010 notice regarding dietary exposure
when a notified substance would be added to animal food.

  Table 12--Issues in the 2010 Notice Regarding Dietary Exposure When a
             Notified Substance Would Be Added to Human Food
------------------------------------------------------------------------
                  Description of our request for
   Issue No.                 comment                     Reference
------------------------------------------------------------------------
11a............  Whether the final rule should    75 FR 81536 at 81540-
                  continue to restate the          81541.
                  statutory language of section
                  409(c)(5) of the FD&C Act or
                  whether this provision should
                  be stated more clearly, for
                  example, by requiring
                  information about dietary
                  exposure (i.e., the amount of
                  the notified substance that
                  consumers are likely to eat or
                  drink as part of a total diet).
11b............  Whether a GRAS notice should be  75 FR 81536 at 81540-
                  required to include              81541.
                  information about dietary
                  exposure to contemporary
                  consumers regardless of
                  whether the determination of
                  GRAS status is through
                  scientific procedures or
                  through experience based on
                  common use in food.
------------------------------------------------------------------------

    In the following sections, we discuss comments on the proposed
requirements applicable to dietary exposure and the issues discussed in
the 2010 notice. After considering these comments, we are establishing
requirements for Part 3 of a GRAS notice as shown in table 13, with
editorial, clarifying, and conforming changes as shown in table 29.
(See Sec.  170.235). Table 13 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 some
of the regulatory text of proposed Sec.  170.36(c)(4)(i)(A) as Sec.
170.235.

     Table 13--Final Requirements for Data and Information About Dietary Exposure in Part 3 of a GRAS Notice
----------------------------------------------------------------------------------------------------------------
                                                                                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
----------------------------------------------------------------------------------------------------------------
170.235..........................  170.36(c)(4)(i)(A).             11a  In Part 3 of your     Uses the
                                                                   11b   GRAS Notice, you     term ``dietary
                                                                         must provide data    exposure'' and
                                                                         and information      describes it as
                                                                         about dietary        meaning ``the
                                                                         exposure (i.e.,      amount of relevant
                                                                         the amount of        substances that
                                                                         relevant             consumers are
                                                                         substances that      likely to eat or
                                                                         consumers are        drink as part of a
                                                                         likely to eat or     total diet.''
                                                                         drink as part of a   Requires
                                                                         total diet),         data and
                                                                         regardless of        information about
                                                                         whether your         dietary exposure
                                                                         conclusion of GRAS   regardless of
                                                                         status is through    whether your
                                                                         scientific           conclusion of GRAS
                                                                         procedures or        status is through
                                                                         through experience   scientific
                                                                         based on common      procedures or
                                                                         use in food.         through experience
                                                                                based on common
                                                                                use in food.
170.235(a).......................  170.36(c)(4)(i)(A).             11a  In Part 3 of your    Uses the term
                                                                         GRAS Notice, you     ``dietary
                                                                         must provide data    exposure.''
                                                                         and information
                                                                         about dietary
                                                                         exposure to the
                                                                         notified substance
                                                                         that includes
                                                                         exposure from its
                                                                         intended use and
                                                                         all sources in the
                                                                         diet.
170.235(b).......................  170.36(c)(4)(i)(A).             11a  When applicable, in   Uses the
                                                                         Part 3 of your       term ``dietary
                                                                         GRAS Notice you      exposure.''
                                                                         must provide data    Gives
                                                                         and information      examples of
                                                                         about dietary        substances that
                                                                         exposure to any      could be formed in
                                                                         other substance      or on food because
                                                                         that is expected     of the use of the
                                                                         to be formed in or   notified
                                                                         on food because of   substance.
                                                                         the use of the
                                                                         notified substance
                                                                         (e.g., hydrolytic
                                                                         products or
                                                                         reaction products).
170.235(c).......................  170.36(c)(4)(i)(A),             11a  When applicable, in  Requires an
                                    170.36(c)(2).                        Part 3 of your       estimate of
                                                                         GRAS Notice you      dietary exposure
                                                                         must provide data    to substances such
                                                                         and information      as contaminants
                                                                         about dietary        and by-products as
                                                                         exposure to any      a means to
                                                                         other substance      establish
                                                                         that is present      specifications for
                                                                         with the notified    applicable
                                                                         substance either     contaminants and
                                                                         naturally or due     by-products.
                                                                         to its manufacture
                                                                         (e.g.,
                                                                         contaminants or by-
                                                                         products).
170.235(d).......................  170.36(c)(4)(i)(A).             11a  In Part 3 of your    Specifies a
                                                                         GRAS notice, you     necessary aspect
                                                                         must describe the    of the proposed
                                                                         source of any food   ``comprehensive
                                                                         consumption data     discussion'' of
                                                                         that you use to      scientific data,
                                                                         estimate dietary     information, and
                                                                         exposure.            methods.
170.235(e).......................  170.36(c)(4)(i)(A).             11a  In Part 3 of your    Specifies a
                                                                         GRAS notice, you     necessary aspect
                                                                         must explain any     of the proposed
                                                                         assumptions you      ``comprehensive
                                                                         made to estimate     discussion'' of
                                                                         dietary exposure.    scientific data,
                                                                                information, and
                                                                                methods.

170.250(a)(1)....................  170.36(c)(4)(i)(A).             N/A  In Part 6 of your    N/A.
                                                                         GRAS notice, you
                                                                         must explain why
                                                                         the data and
                                                                         information in
                                                                         your notice
                                                                         provide a basis
                                                                         for your view that
                                                                         the notified
                                                                         substance is safe
                                                                         under the
                                                                         conditions of its
                                                                         intended use,
                                                                         considering all
                                                                         dietary sources
                                                                         and taking into
                                                                         account any
                                                                         chemically or
                                                                         pharmacologically
                                                                         related substances
                                                                         in such diet.
----------------------------------------------------------------------------------------------------------------

    See section XXV.F for a discussion of comments on the issues listed
in table 27 regarding dietary exposure when a notified substance would
be added to animal food and for changes we made to the regulatory text
regarding dietary exposure when a notified substance would be added to
animal food.
    (Comment 73) Some comments support retaining the statutory language
derived from section 409(c)(5) of the FD&C Act when stating the
requirement for a comprehensive discussion in a GRAS notice that
considers dietary exposure. One of these comments states that the
proposed statutory language regarding dietary exposure is consistent
with the criteria for general recognition of safety through scientific
procedures, which requires the same quantity and quality of scientific
evidence necessary for a food additive petition. Other comments support
revising the proposed requirement as a means of clarifying that the
comprehensive discussion in a GRAS notice must consider dietary
exposure.
    (Response 73) We agree that: (1) The requirements of the rule
regarding what a notifier must include in a GRAS notice regarding
dietary exposure must be clear; and (2) the statutory language of
section 409(c)(5)(A) of the FD&C Act is consistent with the criteria
for general recognition of safety through scientific procedures, which
requires the same quantity and quality of scientific evidence necessary
for a food additive petition. To meet both of these goals, the final
rule requires information about dietary exposure (i.e., the amount of
relevant substances that consumers are likely to eat or drink as part
of a total diet), as we suggested in the 2010 notice, but also retains
the detailed statutory direction as proposed (see Sec.  170.235(a)
through (c), Sec.  170.250(a)(1), and table 13). In addition to
requiring an estimate of dietary exposure to the notified substance
(Sec.  170.235(a)), the rule requires, when applicable, that a notifier
provide data and information about dietary exposure to any other
substance that is expected to be formed in or on food because of the
use of the notified substance (e.g., hydrolytic products or reaction
products) (Sec.  170.235(b)). Example of such substances are benzoates
(which react with ascorbic acid (such as in beverages) to form benzene)
and sulfur dioxide (which reacts irreversibly with thiamine, such that
we have prescribed limitations on the use of sulfur dioxide in some
food products (see Sec.  182.3862)). The rule also requires, when
applicable, that a notifier provide data and information about dietary
exposure to any other substance that is present with the notified
substance either naturally or due to its manufacture (e.g.,
contaminants or by-products). An estimate of dietary exposure to
substances such as contaminants and by-products is necessary to
establish specifications for applicable contaminants and by-products
(see Sec.  170.230(c), which requires that a GRAS notice include
specifications for food-grade material). See also Response 75.
    (Comment 74) One comment asks us to allow for a reasonable
methodology that does not overestimate dietary exposure in the extreme.
    (Response 74) The rule neither prescribes the methodology you would
use to estimate dietary exposure nor requires that you overestimate
dietary exposure. Consistent with the proposed requirement for the
consideration of dietary exposure to be a ``comprehensive discussion,''
the rule requires you to describe the source of any food consumption
data that you use to estimate dietary exposure and any assumptions you
made to estimate dietary exposure; such information is necessary for
the estimates of dietary exposure to be scientifically sound and
provides an opportunity for you to explain why the methodology you used
is reasonable (see Sec.  170.235(d) and (e) and table 13). Our guidance
entitled ``Estimating Dietary Intake of Substances in Food'' provides
general recommendations for calculating and submitting estimates of
dietary intake to support the documentation of the safety of substances
introduced into food either intentionally to accomplish a technical
effect, adventitiously as a component of an added substance, or
inadvertently through contamination resulting from processing (Ref.
25).
    (Comment 75) One comment emphasizes that the requirement for
consideration of dietary exposure must discuss the potential cumulative
effect of the notified substance.
    (Response 75) We agree. We are specifying that the narrative
included in Part 6 of a GRAS notice must address the safety of the
notified substance, considering all dietary sources and taking into
account any chemically or pharmacologically related substances in such
diet (see Sec.  170.250(a)(1)).
    (Comment 76) Some comments support requiring that a GRAS notice
include information about dietary exposure to contemporary consumers
when the conclusion of GRAS status is through experience based on
common use in food prior to 1958, e.g., because dietary exposure to
contemporary consumers serves as a baseline for future studies/
assessment. Other comments do not support such a requirement and assert
that it is not critical to update the exposure data if consumption of
the GRAS substance was already widespread before 1958, or that
information about dietary exposure to contemporary consumers would only
be necessary if the exposure has significantly changed since 1958.
    One comment questions the value of requiring information about
contemporary dietary intake of an ingredient that is GRAS through
experience based on common use in foods. This comment asserts that the

FD&C Act deems an ingredient to be GRAS if it was commonly used in
foods prior to January 1, 1958, and that FDA has long recognized that a
conclusion of GRAS status through experience based on common use in
food may be made without the quantity or quality of scientific
procedures required for establishment of a food additive regulation.
This comment asserts that there is no requirement for a GRAS ingredient
to be consumed at the same use level as in 1958 and that imposition of
such a new requirement may be impracticable, e.g., because there may
not be any databases that would allow for the calculation of dietary
exposures prior to 1958. This comment also asserts that in many
instances there may be insufficient information to establish an
acceptable daily intake (ADI) for the ingredient because studies that
can be used to calculate ADIs may not be available for many of these
ingredients, and that without information about the ADI it would be
difficult to imagine the relevance of the estimated daily intake, which
would be calculated through dietary exposure.
    Another comment asserts that Sec. Sec.  170.30(c) and 170.3(f)
clearly provide that for a substance to be GRAS through experience
based on common use in food there must be a substantial history of
consumption of the substance in food by a significant number of people
prior to 1958 and that the requirements for information about
consumption data in a GRAS notice should be consistent with those
regulatory provisions. This comment also asserts that requiring
information about dietary exposure to contemporary consumers would
represent an additional regulatory burden that would not impact the
original conclusion of GRAS status through experience based on common
use in food if there are no safety concerns when the notified substance
is used in accordance with the intended conditions of use.
    (Response 76) We are requiring that a notifier provide data and
information about dietary exposure, regardless of whether the
conclusion of GRAS status is through scientific procedures or through
experience based on common use in food (see Sec.  170.235). The FD&C
Act and our regulations do not provide that a substance is necessarily
GRAS under the conditions of its intended use merely because it was
commonly used in food prior to 1958. Rather, the FD&C Act provides that
such a substance must be generally recognized, among experts qualified
by scientific training and experience to evaluate its safety, through
experience based on common use in food, to be safe under the conditions
of its intended use. Under both the FD&C Act and the definition of
``safe'' in our regulations, relevant factors must be considered,
including the ``probable consumption of the substance and of any
substance formed in or on food because of its use'' (see section
409(c)(5)(A) of the FD&C Act and Sec.  170.3(i)(1)). We recognize that
a conclusion of GRAS status through experience based on common use in
food does not require the same quantity or quality of scientific
information required for establishment of a food additive regulation;
however, this means that a conclusion of GRAS status through experience
based on common use in food is not necessarily supported by the same
testing data as would be required to support establishment of a food
additive regulation. See, for example, the 1976 final rule establishing
GRAS criteria, which provides, ``for those substances that were widely
used before 1958, under the terms of the statute FDA must consider
available data and may not prohibit use of a substance merely because
tests that would be required for new food additives have not been
performed.'' (41 FR 53600, December 7, 1976). Like a conclusion of GRAS
status based on scientific procedures, a conclusion of GRAS status
through experience based on common use in food requires that the
substance be ``safe,'' as defined in 21 CFR 170.3(i), under the
conditions of its intended use.
    The rule requires that a notifier provide evidence of substantial
history of consumption of the substance for food use by a significant
number of consumers prior to January 1, 1958, but does not require an
estimate of dietary exposure prior to 1958 (see Sec.  170.245). The
rule requires that the narrative in Part 6 of a GRAS notice explain why
the data and information in the notice provide a basis for the
notifier's view that the notified substance is safe under the
conditions of its intended use, considering all dietary sources and
taking into account any chemically or pharmacologically related
substances in such diet (Sec.  170.250(a)); to do so, the notifier must
consider the estimated dietary exposure (which this comment refers to
as ``estimated daily intake''). However, the rule does not specify that
a notifier must determine an ``acceptable daily intake'' as part of the
narrative.

XV. Comments on Part 4 of a GRAS Notice: Self-Limiting Levels of Use

    We proposed that a GRAS notice must include information on any
self-limiting levels of use (proposed Sec.  170.36(c)(3)). We did not
receive comments disagreeing with this proposed requirement. Therefore,
we are establishing a requirement for you to include in Part 4 of your
GRAS notice data and information on self-limiting levels of use in
circumstances where the amount of the notified substance that can be
added to food is limited because food containing levels of the notified
substance above a particular level would become unpalatable or
technologically impractical (see Sec.  170.240). We included an
explanation of the circumstances in which the level of use is self-
limiting for clarity.

XVI. Comments on Part 5 of a GRAS Notice: Common Use in Food Before
1958

    We proposed that a GRAS notice include a comprehensive discussion
of, and citations to, generally available data and information that the
notifier relies on to establish safety, including evidence of a
substantial history of consumption of the substance by a significant
number of consumers, for a conclusion of GRAS status through experience
based on common use in food (proposed Sec.  170.36(c)(4)(ii)(A)).
During the Interim Pilot program, we received fewer than a dozen GRAS
notices where the statutory basis was through experience based on
common use in food (Ref. 45).
    We did not receive comments disagreeing with this proposed
requirement and we are establishing a requirement for you to include in
Part 5 of your GRAS notice evidence of a substantial history of
consumption of the notified substance for food use by a significant
number of consumers prior to January 1, 1958 if the statutory basis for
your conclusion of GRAS status is through experience based on common
use in food (see Sec.  170.245). See table 29 for conforming changes
for a substance used in animal food.

XVII. Comments on Parts 6 and 7 of a GRAS Notice: Narrative and List of
Supporting Data and Information

    We proposed that a GRAS notice must include a detailed summary of
the basis for the notifier's determination that a particular use of the
notified substance is exempt from the premarket approval requirements
of the FD&C Act because such use is GRAS (proposed Sec.  170.36(c)(4)).
Regardless of whether the conclusion of GRAS status was based on
scientific procedures or through experience based on common use in
food, we proposed to require: (1) A comprehensive discussion of, and
citations to, generally available and accepted scientific data and
information that the notifier relies on to establish

safety (proposed Sec.  170.36(c)(4)(i)(A) and 170.36(c)(4)(ii)(A)); (2)
a comprehensive discussion of any reports of investigations or other
information that may appear to be inconsistent with the GRAS
determination (proposed Sec.  170.36(c)(4)(i)(B) and (c)(4)(ii)(B));
and (3) the basis for concluding, in light of the data and information
in the GRAS notice, that there is consensus among experts qualified by
scientific training and experience to evaluate the safety of substances
added to food that there is reasonable certainty that the substance is
not harmful under the intended conditions of use (proposed Sec.
170.36(c)(4)(i)(C) and (c)(4)(ii)(C)). When the conclusion of GRAS
status is based on scientific procedures, we also proposed that the
discussion of generally available and accepted information that the
notifier relies on to establish safety include methods and principles,
and include a consideration of the probable consumption of the
substance and the probable consumption of any substance formed in or on
food because of its use and the cumulative effect of the substance in
the diet, taking into account any chemically or pharmacologically
related substances in such diet (proposed Sec.  170.36(c)(4)(i)(A)).
    In the 2010 notice, we requested comment on issues relevant to the
applicability of confidential data and information to a conclusion that
a substance is GRAS under the conditions of its intended use (see table
14).

   Table 14--Issues in the 2010 Notice Regarding the Applicability of
    Confidential Data and Information to a Conclusion of GRAS Status
------------------------------------------------------------------------
              Description of
 Issue No.   our request for                   Reference
                 comment
------------------------------------------------------------------------
9b........  Whether to         75 FR 81536 at 81539-81540.
             require that a
             notifier who
             identifies one
             or more trade
             secret(s), as
             defined in Sec.
              20.61(a), in
             the GRAS notice
             explain why it
             is trade secret
             information and
             how qualified
             experts could
             conclude that
             the intended use
             of the notified
             substance is
             safe without
             access to the
             trade secret(s).
9c........  Whether to         75 FR 81536 at 81539-81540.
             require that a
             notifier who
             identifies
             confidential
             commercial or
             financial
             information, as
             defined in Sec.
              20.61(b), in
             the GRAS notice
             explain why it
             is confidential
             commercial or
             financial
             information and
             how qualified
             experts could
             conclude that
             the intended use
             of the notified
             substance is
             safe without
             access to such
             information.
------------------------------------------------------------------------

    In the following paragraphs, we discuss comments on the proposed
requirements applicable to a detailed summary of the basis for the
notifier's conclusion of GRAS status and the issues discussed in the
2010 notice. After considering these comments, we are establishing
requirements for Part 6 of a GRAS notice to include a narrative as
shown in table 15, and for Part 7 of a GRAS notice to include a list of
supporting data and information as shown in table 16, with editorial,
clarifying, and conforming changes as shown in table 29. (See
Sec. Sec.  170.250 and 170.255.)
    Table 15 and table 16 identify 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(c)(4) as Sec. Sec.  170.250 and 170.255.

                     Table 15--Final Requirements for a Narrative in Part 6 of a GRAS Notice
----------------------------------------------------------------------------------------------------------------
                                                                                Revisions (other
                                                                                than editorial,
                                         Proposed        Issue No. in   Description. Part 6    clarifying, and
     Final designation in the       designation in the     the 2010        of your  GRAS     conforming changes)
    regulatory text  (Sec.   )       regulatory text        notice            notice:           relative to the
                                        (Sec.   )                                              proposed rule or
                                                                                the  2010 notice
----------------------------------------------------------------------------------------------------------------
170.250..........................  170.36(c)(4).......             N/A  You must include a   N/A.
                                                                         narrative that
                                                                         provides the basis
                                                                         for your
                                                                         conclusion of GRAS
                                                                         status.
170.250(a)(1)....................  170.36(c)(4).......             N/A  You must explain     N/A.
                                                                         why the data and
                                                                         information in
                                                                         your notice
                                                                         provide a basis
                                                                         for your view that
                                                                         the notified
                                                                         substance is safe
                                                                         under the
                                                                         conditions of its
                                                                         intended use,
                                                                         considering all
                                                                         dietary sources
                                                                         and taking into
                                                                         account any
                                                                         chemically or
                                                                         pharmacologically
                                                                         related substances
                                                                         in such diet.
170.250(a)(2)....................  170.36(c)(4).......  9a, 9b, and 9c  You must identify    Requires that your
                                                                         what specific data   narrative clarify
                                                                         and information      the status of all
                                                                         are generally        data and
                                                                         available, and       information that
                                                                         what specific data   you rely on to
                                                                         and information      establish safety.
                                                                         are not generally
                                                                         available, by
                                                                         providing
                                                                         citations to the
                                                                         list of data and
                                                                         information that
                                                                         you include in
                                                                         Part 7 of your
                                                                         GRAS notice.

170.250(b).......................  170.36(c)(4).......             N/A  You must explain     Uses the term
                                                                         how the generally    ``generally
                                                                         available data and   recognized''
                                                                         information that     rather than the
                                                                         you rely on to       term
                                                                         establish safety     ``consensus.''
                                                                         provide a basis
                                                                         for your
                                                                         conclusion that
                                                                         the notified
                                                                         substance is
                                                                         generally
                                                                         recognized, among
                                                                         qualified experts,
                                                                         to be safe under
                                                                         the conditions of
                                                                         its intended use.
170.250(c).......................  170.36(c)(4).......              6b  You must either:     When applicable,
                                                                         (1) Identify,        requires an
                                                                         discuss, and place   affirmative
                                                                         in context, data     statement that you
                                                                         and information      have reviewed the
                                                                         that are, or may     available data and
                                                                         appear to be,        information and
                                                                         inconsistent with    are not aware of
                                                                         your conclusion of   any data and
                                                                         GRAS status,         information that
                                                                         regardless of        are, or may appear
                                                                         whether those data   to be,
                                                                         and information      inconsistent with
                                                                         are generally        your conclusion of
                                                                         available; or        GRAS status.
                                                                        (2) State that you
                                                                         have reviewed the
                                                                         available data and
                                                                         information and
                                                                         are not aware of
                                                                         any data and
                                                                         information that
                                                                         are, or may appear
                                                                         to be,
                                                                         inconsistent with
                                                                         your conclusion of
                                                                         GRAS status..
170.250(d).......................  N/A................       9b and 9c  In Part 6 of your    N/A.
                                                                         GRAS notice (the
                                                                         narrative), if you
                                                                         view any of the
                                                                         data and
                                                                         information in
                                                                         your notice as
                                                                         exempt from
                                                                         disclosure under
                                                                         the FOIA, you must
                                                                         identify the
                                                                         specific data and
                                                                         information.
170.250(e).......................  N/A................       9b and 9c  In Part 6 of your    Your explanation
                                                                         GRAS notice (the     must address all
                                                                         narrative), you      non-public safety-
                                                                         must explain how     related data and
                                                                         there could be a     information, not
                                                                         basis for a          just confidential
                                                                         conclusion of GRAS   data and
                                                                         status if            information
                                                                         qualified experts    included in your
                                                                         generally do not     GRAS notice.
                                                                         have access non-
                                                                         public, safety-
                                                                         related data and
                                                                         information.
----------------------------------------------------------------------------------------------------------------

      Table 16--Final Requirements for a List of Supporting Data and Information in Part 7 of a GRAS Notice
----------------------------------------------------------------------------------------------------------------
                                                                                Revisions (other
                                                                                than editorial,
                                         Proposed        Issue No. in   Description. Part 7    clarifying, and
     Final designation in the       designation in the     the 2010        of your  GRAS     conforming changes)
    regulatory text  (Sec.   )       regulatory text        notice            notice:           relative to the
                                        (Sec.   )                                              proposed rule or
                                                                                the  2010 notice
----------------------------------------------------------------------------------------------------------------
170.255(a).......................               9a, 9b, and 9c  You must include a   Clarifies that the
                                    170.36(c)(4)(i)(A).                  list of all of the   list includes all
                                                                 data and             data and
                                    170.36(c)(4)(ii)(A                   information that     information, not
                                    ).                                   you discuss in       just generally
                                                                         part 6 of your       available data and
                                                                         GRAS notice to       information.
                                                                         provide a basis
                                                                         for your view that
                                                                         the notified
                                                                         substance is safe
                                                                         under the
                                                                         conditions of its
                                                                         intended use.
170.255(b).......................               9a, 9b, and 9c  The data and         Requires that you
                                    170.36(c)(4)(i)(A).                  information that     characterize each
                                                                 you list must        item in your list
                                    170.36(c)(4)(ii)(A                   specify which data   as to whether it
                                    ).                                   and information      is generally
                                                                         are generally        available.
                                                                         available, and
                                                                         which data and
                                                                         information are
                                                                         not generally
                                                                         available.
----------------------------------------------------------------------------------------------------------------

    In the requirements for Parts 6 and 7 of the final rule, we made
changes to require that the narrative in Part 6 of your GRAS notice,
and the accompanying list of supporting data and information in Part 7
of your GRAS notice, clarify the status of all data and information
that you rely on to establish safety as to whether it is generally
available (see Sec. Sec.  170.250(a)(2) and 170.255, table 15, and
table 16). We made these changes relative to the proposed requirements
for a detailed summary and comprehensive discussion for consistency
with: (1) The criteria for eligibility for classification as GRAS
through scientific procedures (which provide that a conclusion of GRAS
status may be corroborated by the application of unpublished scientific
data, information, or methods (see Sec.  170.30(b), Response 8, and
Response 12)); and (2) the provisions of the rule that allow you to
include data and information that are not generally available (see
Sec.  170.230(b) (which no longer stipulates that the method of
manufacture must exclude trade secret), Sec.  170.225(c)(8), Response
57 and Response 69).
    In the requirements for Part 6 of a GRAS notice, we also made a
change to require that your narrative either: (1) Identify, discuss,
and place in context, data and information that are, or may appear to
be, inconsistent with your

conclusion of GRAS status, regardless of whether those data and
information are generally available; or (2) state that you have
reviewed the available data and information and are not aware of any
data and information that are, or may appear to be, inconsistent with
your conclusion of GRAS status. See Sec.  170.250(c) and table 15. We
made this change relative to the proposed requirement for a
comprehensive discussion of any reports of investigations or other
information that may appear to be inconsistent with a conclusion of
GRAS status to emphasize your responsibility to seek out such reports
and information, as we do during our evaluation of a GRAS notice. See
also Sec.  170.225(c)(9) and Response 58, in which we discuss the
requirements for a statement certifying that the GRAS notice is
``complete'' in addition to ``representative'' and ``balanced,'' to
emphasize your responsibility to identify, discuss, and place in
context, data and information that are, or may appear to be,
inconsistent with a conclusion of GRAS status. Under Sec. Sec.
170.225(c)(9) and 170.250(c), we expect you to describe unpublished
reports of investigations or other information that may appear to be
inconsistent with a conclusion of GRAS status, not just published
reports. If we identify relevant information that was not discussed in
the GRAS notice, we may question the credibility of the certification
statements in the GRAS notice and respond with an ``insufficient basis
letter.'' As noted in Response 58, the use of certification statements
has become routine in other submissions to FDA for food programs, and
the certification statements in Form FDA 3480 (for a food contact
notification submission) (Ref. 39) and in Form FDA 3537 (for
registration of a food facility) (Ref. 40) remind the submitter of
criminal penalties under 18 U.S.C. 1001 for a materially false,
fictitious, or fraudulent statement to the U.S. Government. Now that