[Federal Register Volume 83, Number 195 (Tuesday, October 9, 2018)]
[Rules and Regulations]
[Pages 50490-50503]
[FR Doc No: 2018-21807]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 172 and 177

[Docket No. FDA-2015-F-4317]

Food Additive Regulations; Synthetic Flavoring Agents and
Adjuvants

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule; notification of partial denial of petition.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
partially granting a petition submitted by the Breast Cancer Fund (now
known as the Breast Cancer Prevention Partners), Center for
Environmental Health, Center for Food Safety, Center for Science in the
Public Interest, Consumers Union, Environmental Defense Fund,
Environmental Working Group, Improving Kids' Environment, Natural
Resources Defense Council, WE ACT for Environmental Justice, and Mr.
James Huff, by amending the food additive regulations to no longer
authorize the use of benzophenone, ethyl acrylate, eugenyl methyl
ether, myrcene, pulegone, and pyridine as synthetic flavoring
substances for use in food. We are taking this action because, despite
FDA's scientific analysis and determination that these substances do
not pose a risk to public health under the conditions of their intended
use, the petitioners provided data demonstrating that these additives
induce cancer in laboratory animals, and, as a result of this finding
in animals, FDA cannot as a matter of law maintain the listing of these
synthetic flavoring substances in the food additive regulations.
Because of evidence that benzophenone causes cancer in animals, FDA
also is amending the food additive regulations to no longer provide for
the use of benzophenone as a plasticizer in rubber articles intended
for repeated use in contact with food. FDA is denying as moot the
portions of the petition proposing that the food additive regulations
be amended to no longer authorize the use of styrene as a synthetic
flavoring substance because this use has been permanently and
completely abandoned. In addition, FDA is declining to act on the
petitioners' request to issue a regulation to prohibit the use of these
synthetic flavoring substances in food because that issue is not the
proper subject of a food additive petition.

DATES: This rule is effective October 9, 2018. See section IX for
further information on the filing of objections. Submit either
electronic or written objections and requests for a hearing on the
final rule by November 8, 2018.

ADDRESSES: You may submit objections and requests for a hearing as
follows. Please note that late, untimely filed objections will not be
considered. Electronic objections must be submitted on or before
November 8, 2018. Objections received by mail/hand delivery/courier
(for written/paper submissions) will be considered timely if they are
postmarked or the delivery service acceptance receipt is on or before
that date.

Electronic Submissions

    Submit electronic objections in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Objections submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your objection will be
made public, you are solely responsible for ensuring that your
objection does not include any confidential information that you or a
third party may not wish to be posted, such as medical information,
your or anyone else's Social Security number, or confidential business
information, such as a manufacturing process. Please note that if you
include your name, contact information, or other information that
identifies you in the body of your objection, that information will be
posted on https://www.regulations.gov.
     If you want to submit an objection with confidential
information that you do not wish to be made available to the public,
submit the objection as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper objections submitted to the Dockets
Management Staff, FDA will post your objection, as

well as any attachments, except for information submitted, marked and
identified, as confidential, if submitted as detailed in
``Instructions.''
    Instructions: All submissions received must include the Docket No.
FDA-2015-F-4317 for ``Food Additives Permitted for Direct Addition to
Food for Human Consumption; Synthetic Flavoring Agents and Adjuvants.''
Received objections, those filed in a timely manner (see ADDRESSES),
will be placed in the docket and, except for those submitted as
``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m.
and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit an objection with
confidential information that you do not wish to be made publicly
available, submit your objections only as a written/paper submission.
You should submit two copies total. One copy will include the
information you claim to be confidential with a heading or cover note
that states ``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' We
will review this copy, including the claimed confidential information,
in our consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Judith Kidwell, Center for Food Safety
and Applied Nutrition (HFS-265), Food and Drug Administration, 5001
Campus Dr., College Park, MD 20740-3835,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

Table of Contents:

I. Introduction
II. Background
    A. Statutory and Regulatory Background
    B. Abandonment of Use of Styrene Authorized Under 21 CFR 172.515
    C. History of the Regulation of the Synthetic Flavoring
Substances and Adjuvants
    D. Summary and Context of Determination
III. Evaluation of Carcinogenicity
    A. Benzophenone
    B. Ethyl Acrylate
    C. Methyl Eugenol
    D. Myrcene
    E. Pulegone
    F. Pyridine
IV. Comments on the Notice of Petition
    A. Legal and Policy Issues
    B. Scientific Issues
V. Conclusion
VI. Public Disclosure
VII. Analysis of Environmental Impacts
VIII. Paperwork Reduction Act
IX. Objections
X. References

I. Introduction

    In the Federal Register of January 4, 2016 (81 FR 42), we announced
that the Center for Science in the Public Interest, Natural Resources
Defense Council, Center for Food Safety, Consumers Union, Improving
Kids' Environment, Center for Environmental Health, Environmental
Working Group, Environmental Defense Fund, and James Huff (the
petitioners), c/o Mr. Tom Neltner, 1875 Connecticut Ave. NW,
Washington, DC 2009, had jointly filed a food additive petition (FAP
5A4810). Subsequently, the Breast Cancer Fund (now known as Breast
Cancer Prevention Partners) and WE ACT for Environmental Justice joined
as co-petitioners.
    The petition proposed that we take two separate regulatory actions:
(1) Amend the food additive regulations in Sec.  172.515 Synthetic
flavoring substances and adjuvants (21 CFR 172.515) to no longer
authorize the use of seven listed synthetic flavoring food additives
and (2) to establish zero tolerances in Sec.  172.515 for these
additives. However, the food additive regulation is not the appropriate
section for a ``zero tolerance,'' and this request is not the proper
subject of a food additive petition. A food additive petition must
either propose the issuance of a regulation prescribing the conditions
under which a food additive may be safely used (see section 409(b)(1)
of the Federal Food, Drug, & Cosmetic Act (FD&C Act) (21 U.S.C.
348(b)(1)), or propose the amendment or repeal of an existing food
additive regulation (see section 409(i) of the FD&C Act. Only the
petitioners' request to amend Sec.  [thinsp]172.515 to remove the seven
synthetic flavorings and adjuvants from FDA's regulations permitting
their use as additives in food falls within the statutory scope of a
food additive petition. Therefore, the petitioners' request that we
establish zero tolerances for these seven flavoring additives falls
outside the scope of a food additive petition. As a result, we are not
addressing that request further in this rule. (An interested person may
use the citizen petition process to request the issuance of a
regulation, including a request to establish a ``zero tolerance,''
which we interpret as a request to issue a regulation prohibiting a
substance from human food under part 189 (see 21 CFR 189.1(c)
(referring to 21 CFR part 10, which sets forth FDA's citizen petition
process)). (In addition, we understand the petitioners are no longer
pursuing this request based on a public filing with a U.S. court of
appeals (stating ``[t]he Petition also requested that FDA `establish a
zero tolerance [standard]. . . for the use of these seven flavors.' . .
. Petitioners are no longer pursuing this aspect of the Petition'').
(See In Re Breast Cancer Prevention Partners, No. 18-71260 (9th Cir.)).
Thus, in this rule we focus solely on the request to amend the food
additive regulations.
    The seven food additives that are the subject of this petition are:
    1. Benzophenone (also known as diphenylketone) (CAS No. 119-61-9);
    2. Ethyl acrylate (CAS No. 140-88-5);
    3. Eugenyl methyl ether (also known as 4-allylveratrole or methyl
eugenol) (CAS No. 93-15-2);
    4. Myrcene (also known as 7-methyl-3-methylene-1,6-octadiene) (CAS
No. 123-35-3);
    5. Pulegone (also known as p-menth-4(8)-en-3-one) (CAS No. 89-82-
7);
    6. Pyridine (CAS No. 110-86-1); and
    7. Styrene (CAS No. 100-42-5).
    We stated in the notice of petition that, although the petition
only proposes to amend Sec.  172.515 to no longer provide for the use
of these seven synthetic flavoring substances, FDA's action in response
to the petition could affect other regulations that provide for the use
of the additives. Specifically, in the notice we identified the use of
benzophenone, which is approved as an indirect food additive, i.e., a
plasticizer (diphenylketone in Sec.  177.2600 (21 CFR
177.2600(c)(4)(iv))), as potentially being impacted by our regulatory
decision. The notice of petition gave interested parties until March 4,
2016, to submit

comments on the filed food additive petition. In response to a written
request submitted to the docket, we extended the comment period to May
3, 2016 (81 FR 8867, February 23, 2016).
    This final rule partially granting the request to revise the
regulations to no longer provide for the use of these synthetic
flavorings in food, and the partial denial given the petitioners'
request falls outside the scope of the food additive petition process,
completely responds to the petition.

II. Background

A. Statutory and Regulatory Background of Food Additive Regulation

    The FD&C Act authorizes us to regulate ``food additives'' (see
section 409(a) of the FD&C Act). The FD&C Act defines ``food
additive,'' in relevant part, as any substance the intended use of
which results or may reasonably be expected to result, directly or
indirectly, in its becoming a component of food (see section 201(s) of
the FD&C Act (21 U.S.C. 321(s))). Food additives can include both
substances added directly to food and ``food contact substance[s]''
(i.e., substances intended for use in materials that come into contact
with food, for instance in food packaging or manufacturing, but which
are not intended to have any technical effect in the food (see Sec.
170.3(e)(3) (21 CFR 170.3(e)(3))). Food additives are deemed unsafe and
prohibited except to the extent that we approve their use (see, e.g.,
section 301(a) and (k) (21 U.S.C. 331(a) and (k)) and 409(a) of the
FD&C Act).
    The FD&C Act provides a process through which persons who wish to
use a food additive may submit a petition proposing the issuance of a
regulation prescribing the conditions under which the additive may be
safely used (see section 409(b)(1) of the FD&C Act). Such a petition is
referred to as a ``food additive petition.'' A food additive petition
must either propose the issuance of a regulation prescribing the
conditions under which a food additive may be safely used (see section
409(b)(1) of the FD&C Act), or propose the amendment or repeal of an
existing food additive regulation (see section 409(i) of the FD&C Act).
When we conclude that a proposed use of a food additive is safe, we
issue a regulation called a ``food additive regulation'' authorizing a
specific use of the substance.
    A food additive cannot be approved for use unless the data
presented to FDA establish that the food additive is safe for that use
(section 409(c)(3)(A) of the FD&C Act). To determine whether a food
additive is safe, the FD&C Act requires FDA to consider, among other
relevant factors: (1) Probable consumption of the additive; (2)
cumulative effect of such additive ``in the diet of man or animals'';
and (3) safety factors recognized by experts ``as appropriate for the
use of animal experimentation data'' (section 409(c)(5) of the FD&C
Act). FDA's determination that a food additive use is safe means that
there is a ``reasonable certainty in the minds of competent scientists
that the substance is not harmful under the intended conditions of
use'' (Sec.  170.3(i)). However, FDA cannot approve a food additive if
it is found ``to induce cancer when ingested by man or animal, or if it
is found, after tests which are appropriate for the evaluation of the
safety of food additives, to induce cancer in man or animal'' (section
409(c)(3)(A) of the FD&C Act). This provision, which is often referred
to as the ``Delaney Clause,'' was added to the FD&C Act by the Food
Additives Amendment of 1958 (Pub. L. 85-929). The Delaney Clause limits
FDA's discretion to determine the safety of food additives, in that it
prevents FDA from finding a food additive to be safe if it has been
found to induce cancer when ingested by humans or animals, regardless
of the probability, or risk, of cancer associated with exposure to the
additive or of the extent to which the experimental conditions of the
animal study or the carcinogenic mode of action provide insight into
the health effects of human consumption and use of the additive in
question. In Public Citizen v. Young, the DC Circuit Court of Appeals
held that Congress intended for the Delaney Clause to be
``extraordinarily rigid,'' to protect the public from cancer-causing
substances without exception, rejecting FDA's argument that a
particular color additive, which was subject to a similarly worded
Delaney Clause for color additives, should be approved because it did
not pose more than a de minimis cancer risk (831 F.2d 1108, 1122 (DC
Cir. 1987); see also Les v. Reilly, 968 F.2d 985, 986 (9th Cir. 1992)
(holding that the Environmental Protection Agency's refusal to revoke
regulations permitting the use of certain pesticides (which were
regulated as food additives at the time of the court decision), on the
grounds that they pose a de minimis cancer risk, is contrary to the
provisions of the Delaney Clause).
    The FD&C Act provides that FDA must by regulation prescribe the
procedure by which a food additive regulation may be amended or
repealed (see section 409(i) of the FD&C Act). Our regulation specific
to the administrative actions for food additives provides that the
Commissioner of Food and Drugs (the Commissioner), on his or her own
initiative or on the petition of any interested person, may propose the
issuance of a regulation amending or repealing a regulation pertaining
to a food additive (see Sec.  [thinsp]171.130(a) (21 CFR 171.130(a))).
Our regulation, at Sec.  [thinsp]171.130(b), further provides that any
such petition must include an assertion of facts, supported by data,
showing that new information exists with respect to the food additive
or that new uses have been developed or old uses abandoned, that new
data are available as to toxicity of the chemical, or that experience
with the existing regulation or exemption may justify its amendment or
repeal.
    The specific food additive regulation at issue in the petition,
Sec.  [thinsp]172.515, lists synthetic flavoring substances and
adjuvants that may be safely used in food in accordance with the
conditions in the regulation. At issue in the petition are seven
synthetic flavorings and adjuvants listed in this regulation:
Benzophenone (also known as diphenylketone), ethyl acrylate, eugenyl
methyl ether (also known as 4-allylveratrole or methyl eugenol),
myrcene (also known as 7-methyl-3-methylene-1,6-octadiene), pulegone
(also known as p-menth-4(8)-en-3-one, pyridine, and styrene. The
petitioners assert that new data establish that these synthetic
flavoring additives are carcinogenic and therefore not safe for use in
food pursuant to the Delaney Clause.

B. Abandonment of Use of Styrene Authorized Under 21 CFR 172.515

    Related to FAP 5A4810, in a document published in the Federal
Register on June 15, 2016 (81 FR 38984), we announced that we filed a
food additive petition (FAP 6A4817) proposing that we amend Sec.
172.515 to no longer provide for the use of styrene as a synthetic
flavoring substance and adjuvant in food because the use has been
abandoned. Elsewhere in this issue of the Federal Register, we have
published a final rule in response to FAP 6A4817 granting that petition
and amending Sec.  172.515 to no longer authorize the use of styrene as
a synthetic flavoring substance and adjuvant in food because its use
under Sec.  172.515 has been permanently and completely abandoned.
Because the final rule issued in response to FAP 6A4817 removes styrene
from Sec.  172.515--thereby taking one of the actions requested in this
petition--the petitioners' request is moot, and it is neither necessary
nor an efficient use of our resources to address the petitioners'

assertions regarding the safety of the food additive use of styrene
that is no longer authorized. Therefore, we are denying as moot the
request in FAP 5A4810 to remove styrene from Sec.  172.515.

C. History of the Regulation of the Synthetic Flavoring Substances and
Adjuvants

    In the Federal Register of May 27, 1964 (29 FR 6957), FDA published
a proposed rule to establish a regulation for synthetic flavoring
substances and adjuvants used in food. The purpose of the proposed
regulation was to identify those synthetic substances that may be
safely used as flavoring substances or flavor adjuvants in food. The
proposed regulation listed many synthetic flavoring substances and
adjuvants in use at the time, including benzophenone, ethyl acrylate,
eugenyl methyl ether, myrcene, pulegone, and pyridine. The proposed
rule stated that, in reaching a conclusion about the safety of the
substances listed in the proposed order, FDA relied upon experience
based on the common use of these substances in food prior to 1958; the
fact that many of the synthetic flavoring substances have a natural
counterpart in food or in natural substances used to flavor foods; that
metabolic and toxicity data representing studies made on selected
flavoring substances were reviewed and safety established; and that
relatively low and essentially self-limiting quantities are involved
when these substances are used in food, consistent with good
manufacturing practice. (29 FR 6957). In the Federal Register of
October 27, 1964 (29 FR 14625), FDA issued a final rule based on this
proposal with a few changes based on comments that were received and
established this regulation in 21 CFR 121.1164. This regulation also
limited the amount of the synthetic flavoring substance that could be
added to food to the smallest amount necessary to achieve the desired
flavoring effect. In the Federal Register of March 15, 1977 (42 FR
14302 at 14492), 21 CFR 121.1164 was redesignated Sec.  172.515.

D. Summary and Context of Determination

    We have evaluated the data and information submitted by the
petitioners, as well as other relevant carcinogenicity data and
information, and have determined the remaining six synthetic flavoring
substances (i.e., other than styrene) that are the subject of FAP
5A4810 are unlikely to pose a potential or significant carcinogenic
risk for humans at the levels that these synthetic flavoring substances
are used in foods, and that the use of these food additives is safe for
human consumption. In other words, FDA has a reasonable certainty that
the substances do no harm under the intended conditions of use (the
standard for approving food additives). However, because data submitted
by the petitioners demonstrate that these synthetic flavoring
substances have been shown to induce cancer in animal studies, FDA
cannot consider these synthetic flavoring substances to be safe as a
matter of law because of the Delaney Clause, and must revoke the
listings providing for the use of these synthetic flavoring substances
and adjuvants, as described further in section III.
    In making this determination, we reiterate the point, first made in
our 1964 proposed rulemaking, that all of the synthetic flavoring
substances that are the subject of the petition have a natural
counterpart in food or in natural substances used to flavor foods. For
example, benzophenone is present in grapes, ethyl acrylate is present
in pineapple, eugenyl methyl ether (methyl eugenol) is present in
basil, myrcene is present in citrus fruit, pulegone is present in
peppermint, and pyridine is present in coffee. FDA's revocation of the
listings providing for the use of these synthetic flavoring substances
and adjuvants does not affect the legal status of foods containing
natural counterparts or non-synthetic flavoring substances extracted
from food, and there is nothing in the data FDA has reviewed in
responding to the pending food additive petition that causes FDA
concern about the safety of foods that contain natural counterparts or
extracts from such foods.

III. Evaluation of Carcinogenicity

    The petitioners assert that each of the synthetic flavoring
substances (i.e., benzophenone, ethyl acrylate, methyl eugenol,
myrcene, pulegone, and pyridine) has been shown to induce cancer in
animals by studies sponsored by the Department of Health and Human
Services' National Toxicology Program (NTP). The petitioners also cite
conclusions of the International Agency for Research on Cancer (IARC)
and the California Environmental Protection Agency's Office of
Environmental Health Hazard Assessment (OEHHA), and assert that
information that became available after these food additives were
listed in Sec.  172.515 demonstrates that ``they are not safe for use
in food pursuant to the Delaney Clause''; however, we note that the
conclusions from IARC and OEHHA are based primarily on results from the
NTP studies. Thus, our review of whether the synthetic flavoring
substances that are the subject of the petition induce cancer in humans
or animals focused on results of the NTP studies, as well as other
available relevant information discussed in this rule.
    As part of our scientific review, we also evaluated the
genotoxicity of the synthetic flavoring substances. Based on their
biological activities, chemical carcinogens can be classified as
genotoxic (directly DNA reactive) and non-genotoxic (not directly DNA
reactive but operating through a secondary mechanism) (Ref. 1). In
cancer risk assessments, the traditional assumption for chemicals that
are genotoxic is that there is no threshold exposure level below which
there is no risk of cancer and that there is a risk of cancer at any
level of exposure. In contrast, non-genotoxic carcinogens are assumed
to have a threshold of exposure level below which tumor development is
not anticipated and the risk of cancer is negligible (Ref. 2).
    Additionally, as part of our review, we calculated Margins of
Exposure (MOE) for each of the six synthetic flavoring substances. The
MOE is the ratio between a point of departure (e.g., no-observed-
adverse-effect-dose or benchmark dose) and estimates of human dietary
exposure. As a risk characterization tool, the MOE can be used to
provide information on the level of public health concern. The MOE is
invaluable in risk management for chemicals present in food, when a
health-based guidance level is impossible to derive, such as with
genotoxic and carcinogenic contaminants and veterinary drug residues
(Refs. 2 and 3). If the MOE is very large (such as greater than
10,000), it can be an indication of a low level of human health risk
(Ref. 3).
    We also estimated dietary exposure for the six synthetic flavoring
substances using information from the 2015 Poundage and Technical
Effects Survey that the Flavor and Extract Manufacturers Association
(FEMA) collected from its member companies that formulate flavoring
substances (Ref. 4). (The acronym FEMA, as used throughout this rule,
refers to the Flavor and Extract Manufacturers Association. It should
not be confused with the Federal Emergency Management Agency that
commonly is referred to by this same acronym.) Every 5 years FEMA
surveys its members to estimate the total volume of flavoring
substances added to food, or ``poundage data.'' (The 2015 poundage data
were the most recent available.) FEMA's members include flavor
manufacturers, flavor users, flavor

ingredient suppliers, and others with an interest in the U.S. flavor
industry. According to FEMA, their flavor manufacturing members produce
more than 95 percent of flavors consumed in the United States.
    To estimate dietary exposure to the synthetic flavoring substances,
we used a ``per-capita times ten'' approach that conservatively assumes
10 percent of the population consumes 100 percent of the available
flavoring substance. Because the FEMA poundage data include the total
poundage for both synthetic and naturally-sourced flavoring substances,
our estimates of dietary exposure assumed that all of the flavoring
substances added annually to food are synthetic; thus, for most of
these substances, actual exposure to these synthetic flavoring
substances is less than our conservative exposure estimates (Refs. 5
and 6).
    As explained in more detail later in this section, although there
were findings of carcinogenicity in animal studies, none of the data in
our evaluations of the six synthetic flavoring substances supports a
finding that they are human carcinogens when consumed at the levels of
intended use. Additionally, with the exception of the data concerning
methyl eugenol, the data from the animal studies demonstrated that the
modes of action (MOA) of carcinogenicity are not acting through
mechanisms of genotoxic alterations and are not relevant to humans.
    For methyl eugenol, the data showed evidence for a potential
concern for carcinogenic risk to humans based on the findings that: (1)
A metabolite of methyl eugenol was found to be genotoxic and able to
covalently bind with DNA to form DNA adducts (a DNA adduct is a segment
of DNA bound to a cancer causing chemical); (2) methyl eugenol-DNA
adducts have been detected in human lung and liver tissues; and (3)
there is a potential metabolic pathway by which methyl eugenol could
metabolize to a reactive metabolite, under specific reaction conditions
that then may proceed to tumor formation and carcinogenesis. However,
there are no available clinical or epidemiological data reporting tumor
formation and carcinogenicity from methyl eugenol exposure in humans.
    Additionally, we concluded that the risk of carcinogenicity in
humans from consumption of methyl eugenol added to food as a synthetic
flavoring substance is further reduced by the following mitigating
factors: (1) The metabolic pathway, in which methyl eugenol converts to
a genotoxic metabolite subsequently leading to tumor formation, does
not serve as the primary metabolic/detoxification pathway for methyl
eugenol in humans and the amount of the genotoxic metabolite generated
is dose-dependent, occurring at higher doses and (2) compared to the
low levels of added synthetic methyl eugenol as a flavoring substance,
the levels of methyl eugenol tested in the NTP animal studies were very
high test doses that likely overwhelmed physiological conditions of
normalcy and overloaded systemic repair systems.
    In assessing the potential human carcinogenicity of methyl eugenol
associated specifically with the use of synthetic methyl eugenol as a
flavoring substance, we also considered data indicating that exposure
to methyl eugenol from foods that naturally contain methyl eugenol
(e.g., basil and other spices/herbs) is significantly higher
(approximately 488 times higher) than exposure expected from the
addition of synthetic methyl eugenol as a flavoring substance, and that
these foods have been ingested by humans for millennia without apparent
harm (Ref. 7). Based on our review of published literature up to May
2018, there is no clinical or epidemiological evidence suggesting an
association between the typical dietary consumption of food items that
naturally contain methyl eugenol and carcinogenic effects.
    In sum, although the data do not indicate that these synthetic
flavoring substances pose a public health risk as a human carcinogen,
because these six synthetic flavoring substances have been found to
induce cancer in animal studies, the Delaney Clause requires that FDA
consider these synthetic flavoring substances to be unsafe as a matter
of law, and FDA must revoke the listings providing for the use of these
synthetic flavoring substances.
    Below is a summary of FDA's analysis of each of the six synthetic
flavoring substances and adjuvants.

A. Benzophenone

1. Exposure
    Under Sec.  172.515, benzophenone is permitted for use as a
synthetic flavoring substance and adjuvant in foods in accordance with
current good manufacturing practices (CGMP). FEMA estimated an annual
production volume of 5 kilograms (kg) for benzophenone used as a
flavoring substance and adjuvant in food based on information from the
2015 FEMA Poundage and Technical Effects Survey (Ref. 4). FEMA also
estimated that 133 kg of benzophenone are available for consumption
annually in the United States from its natural presence in foods (Ref.
8). Thus, benzophenone is present from natural sources in the food
supply (e.g., grapes) at a level 27 times greater than that from its
use as a flavoring substance and adjuvant. Using the FEMA poundage data
(assuming all reported poundage is for the synthetically-prepared
flavoring substance) and a ``per-capita times ten'' approach, we
estimated dietary exposure from benzophenone added to food as a
synthetic flavoring and adjuvant to be 0.43 micrograms per person per
day ([micro]g/p/d), or 7.2 x 10\-3\ [micro]g/kilogram body weight/d
([micro]g/kg bw/d) for a 60 kg person (Refs. 6 and 9).
    Benzophenone also is permitted for use as a plasticizer in rubber
articles intended for repeated use under Sec.  177.2600. The upper-
bound limit to the dietary exposure for benzophenone from this use is
estimated to be 45 [micro]g/p/d. This estimate assumes that 100 percent
of an individual's diet is processed using rubber articles containing
benzophenone as a plasticizer. While the exposure estimate for the use
of benzophenone as a plasticizer in repeat use rubber articles is an
overestimate of the actual exposure from this use, the estimated
exposure is greater than that from the use of benzophenone as a
flavoring substance by a factor of approximately 500. Thus, the
combined exposure to benzophenone from its uses as a flavoring
substance and as a plasticizer in food contact applications was
estimated to be no more than 45 [micro]g/p/d, or 0.75 [micro]g/kg bw/d
(Refs. 5 and 9).
2. Toxicology Studies
    FDA reviewed data from 2 NTP-sponsored 105-week carcinogenic
bioassays on benzophenone in F344/N rats and B6C3F1 mice. In these
studies, the rats and mice were administered feed containing
benzophenone at 0, 312, 625, or 1,250 parts per million per day (ppm/d)
or milligrams per kilogram of feed/day (mg/kg/d). This dosing is
equivalent to average daily doses of approximately 15, 30, and 60 mg
benzophenone/kg bw to male rats and 15, 30, and 65 mg/kg bw to female
rats; equivalent to average daily doses of approximately 40, 80, and
160 mg/kg bw to male mice and 35, 70, and 150 mg/kg bw to female mice
(Ref. 9).
    The NTP reported several carcinogenicity findings from these
studies. They noted that there was some evidence of carcinogenicity due
to increased incidence of renal (kidney) tubular tumors in treated male
rats and increased incidence of mononuclear cell leukemia (MNCL) in all
treated female rats. The mean incidence of MNCL in

the 625 ppm female dose group was significantly greater than that in
the control female rats. The NTP also reported some evidence of
carcinogenic activity in male mice based on increased incidence of
hepatocellular (liver) neoplasms and some evidence of carcinogenicity
in female mice based on increased incidence of histiocytic (originating
from blood cells) sarcomas. Results showed that benzophenone produced
tumors at the two highest doses in the studies. Occurrence of the key
tumor types (i.e., those tumor types the NTP considered to constitute
``some evidence'' of carcinogenicity) in animals at the lowest dose was
not significantly different from that of the control groups. The NTP
classified the occurrence of the key tumor types as constituting some
evidence of carcinogenic activity rather than being clear evidence of
carcinogenic activity (NTP's highest level of evidence of
carcinogenicity). Benzophenone also was tested in several genotoxicity
assays and found to be non-genotoxic.
    Based on results from the NTP studies, FDA concluded that, under
the conditions of the 2-year NTP bioassays, benzophenone induced renal
tubular tumors in male rats and hepatocellular tumors in male mice
(Ref. 9).
3. Risk Characterization
    Based on the results of the NTP 2-year carcinogenicity studies we
concluded that benzophenone induced cancer in animals under the test
conditions of the studies. However, benzophenone is not genotoxic and
unlikely to produce cancer through a direct DNA-reactive mechanism.
Chronic progressive nephropathy (CPN, a spontaneous age-related disease
that occurs commonly in rats) may be involved in benzophenone inducing
renal tumors in rats; however, CPN as a MOA, a biologically plausible
sequence of key events leading to an observed endpoint supported by
robust experimental observations and mechanistic data (Ref. 10), for
renal tumors in humans has not been established. Regarding the
incidence of MNCL in female F344/N rats, we determined that it was not
dose-dependent and that the incidence of this tumor in the control rats
was outside the historical range. Therefore, we concluded that the
occurrence of renal tumors in this study is not related to treatment
with benzophenone. Additionally, MNCL is species- and strain-specific
to the F344/N rat, and of little or no relevance to humans (Ref. 9).
    Regarding the results from the mouse study, several authors have
observed that hepatocellular neoplasms seen in 2-year bioassays in
B6C3F1 mice typically are secondary responses to chronic hepatic
toxicity and regenerative cellular proliferation or hypertrophy as a
function of dose (Ref. 9). Evidence of hepatotoxicity in short duration
studies also has been shown to be a good predictor of hepatic neoplasia
in chronic studies and the higher susceptibility of the male mouse
(Ref. 9). Although there is no definitive MOA for the development of
benzophenone-associated liver tumors in the NTP study, the B6C3F1 male
mouse has been shown to have a high incidence of spontaneously-
occurring hepatocellular tumors, which is elevated after chemical
exposure. Introduction of high doses of benzophenone may produce
hepatotoxicity that exacerbates this propensity toward tumor
development and results in their increased occurrence by a non-
genotoxic mechanism. Although rarely reported in NTP studies,
histiocytic sarcomas observed in the B6C3F1 mice have been reported to
occur at a mean incidence of 5.5 percent in female B6C3F1 mice used as
controls in 2-year carcinogenicity studies conducted at Bayer AG,
Institute of Toxicology. This result was based on historical data
accumulated over a 10-year period (1986-1996) and is in line with the 6
percent occurrence observed in the high dose (1,250 ppm) group in the
benzophenone NTP study. Other authors also reported similar findings in
B6C3F1 mice, with incidences of 3.5 percent and 5.5 percent in control
males and females, respectively. Histiocytic sarcomas are rarely
reported in humans, accounting for less than 1 percent of all the
neoplasms reported in the lymph nodes or soft tissues. The histiocytic
sarcomas identified in the female mice in the NTP study were not dose
related (i.e., 5/50 at 625 ppm and 3/50 at 1,250 ppm) and were found
only at dose levels that induced overt toxicity (Ref. 9).
    The lowest test dose (312 ppm) in the NTP 2-year studies was a dose
at which no statistically significant treatment-related increase in
tumor incidence was reported in rats or mice. This finding suggests
that there may be a threshold level below which benzophenone does not
induce tumors in rodents. Additionally, there is a large margin of
exposure (MOE; 2.1 x 10\6\ for rats, 4.7 x 10\6\ for male mice, and 5.6
x 10\6\ for female mice) between the lowest test dose and the estimated
dietary exposure of 0.43 [micro]g benzophenone/p/day (equivalent to 7.2
x 10 -\3\ [micro]g/kg bw/day) from its use as a flavoring
substance. When benzophenone is used as a plasticizer in repeat use
rubber articles exposed to food, the MOE for male and female rats is
calculated to be 2 x 10\4\ and for male and female mice, 5.3 x 10\4\
and 4.7 x 10\4\, respectively. Although these MOE values are lower than
those for benzophenone's use as a synthetic flavoring substance, they
are still sufficient to ensure an acceptable margin of safety (Ref. 9).
It should also be noted that these results are based on estimated
worst-case dietary exposure of 45 [micro]g/person/d (0.75 [micro]g/kg
bw/d) from its use as a plasticizer (Ref. 5) and actual MOEs for this
use probably would be higher. Considering these findings in a weight-
of-evidence analysis, we concluded that benzophenone is unlikely to
induce tumors in humans at current use levels as a synthetic flavoring
substance and adjuvant in food (Ref. 9).

B. Ethyl Acrylate

1. Exposure
    Under Sec.  172.515, ethyl acrylate is permitted for use as a
synthetic flavoring substance and adjuvant in foods in accordance with
CGMP. FEMA estimated an annual production volume of 18 kg for ethyl
acrylate used as a flavoring substance and adjuvant in food based on
information from the 2015 FEMA Poundage and Technical Effects Survey
(Ref. 4). FEMA also estimated that 9.2 kg of ethyl acrylate are
available for consumption annually in the United States from its
natural presence in foods (e.g., pineapple) (Ref. 8). Thus, ethyl
acrylate is present in foods from natural sources at 50 percent of the
level from its use as a flavoring substance. Using the FEMA poundage
data (assuming all reported poundage is for the synthetically-prepared
flavoring substance) and a ``per-capita times ten'' approach, we
estimated dietary exposure from ethyl acrylate's use as a synthetic
flavoring substance and adjuvant in food to be 1.5 [micro]g/person/d,
or 0.025 [micro]g/kg bw/d for a 60 kg person (Refs. 6 and 11).
2. Toxicology Studies
    FDA reviewed data from 2 NTP-sponsored 103-week carcinogenic
bioassays on ethyl acrylate in F344/N rats and B6C3F1 mice. In these
studies, rats and mice were administered ethyl acrylate at 0, 100, or
200 mg/kg bw by gavage 5 days per week. The NTP reported
carcinogenicity findings were confined to the forestomach of rats and
mice. They also reported that the occurrence of these forestomach
tumors had a statistically positive trend compared to the control
animals. Ethyl acrylate also was tested in several genotoxicity
studies. Based on the available data from these studies, we

concluded that ethyl acrylate is not genotoxic (Ref. 11).
    We also concluded that under the test conditions of NTP's 2-year
hazard assessment studies ethyl acrylate is a rodent carcinogen.
Evidence, however, supports the findings that these tumors were
produced by a non-genotoxic mechanism (Ref. 11).
3. Risk Characterization
    The tumors observed in the NTP study were initiated by
administering bolus doses of ethyl acrylate by gavage onto the
forestomach of the treated rats and mice, which resulted in irritation,
inflammation, and hyperplasia of the forestomach mucosa. Repeated
dosing over a 2-year period exacerbated this irritation and resulted in
the development of papillomas and carcinomas, which were confined to
the forestomach. No other treatment-related tumors were observed in the
animals. Forestomach tumors were observed at both doses tested (100 mg/
kg bw and 200 mg/kg bw) in both male and female mice and rats. Humans
do not have a forestomach and a human counterpart for the forestomach
does not exist. The function of the rodent forestomach is to store and
concentrate feed; therefore, high concentrations of ethyl acrylate were
present in the forestomach over the duration of the 2-year study. This
concentration effect precluded our determining a no-significant-effect-
level for the occurrence of the forestomach tumors. Therefore, we
cannot make an MOE comparison between a no-effect-dose level for
significant incidences of tumors and the estimated dietary exposure of
ethyl acrylate as a synthetic flavoring substance and adjuvant in food
(1.5 [mu]g ethyl acrylate/p/d, or 0.025 [micro]g/kg bw/d) (Ref. 11).
    The 2-year NTP studies were conducted at doses higher than the
expected exposures for flavoring substances. In general, flavoring
substances have significantly lower dietary exposures than the doses
used in 2-year carcinogenicity studies. For example, the lowest dose of
ethyl acrylate tested in the NTP studies was 100 mg/kg bw, or
approximately 1.8 x 10 \6\ times greater than the estimated dietary
exposure from its use as a synthetic flavoring substance and adjuvant
in food (Ref. 11).
    Importantly, the NTP Board of Scientific Counselors Report on
Carcinogens (RoC) Subcommittee concluded, based on the totality of the
evidence, that ethyl acrylate should not be considered a human
carcinogen (Ref. 12). We concur with the RoC and concluded that ethyl
acrylate is a non-genotoxic rodent carcinogen with a carcinogenic
effect limited to the rodent forestomach (a rodent-specific organ) due
to chronic irritation. This MOA is not relevant to humans and, at the
current intake level, there is no concern of carcinogenicity from the
intake of ethyl acrylate intentionally added to food as a flavoring
substance and adjuvant (Ref. 11).

C. Eugenyl Methyl Ether (Methyl Eugenol)

1. Exposure
    Under Sec.  172.515, methyl eugenol is permitted for use as a
synthetic flavoring substance and adjuvant in foods in accordance with
CGMP. FEMA estimated an annual production volume of 86 kg for methyl
eugenol used as a flavoring substance and adjuvant in food based on
information from the 2015 FEMA Poundage and Technical Effects Survey
(Ref. 4). FEMA also estimated that 447,450 kg of methyl eugenol are
available for consumption annually in the United States from its
natural presence in foods (e.g., basil) (Ref. 8). The 69th Joint Food
and Agriculture Organization/World Health Organization (WHO) Expert
Committee on Food Additives (JECFA) estimated an upper bound annual
volume for methyl eugenol of 41,992 kg from its natural presence in
herbs and spices. The most significant difference between the two
estimates is that FEMA presumed a maximum content of methyl eugenol in
basil of 4.1 percent, whereas JECFA presumed a maximum content of 0.118
percent (Refs. 5 and 8). Natural sources of basil have varying levels
of methyl eugenol. It is unlikely, however, that most basil used in the
United States would consistently have levels as high as 4.1 percent
and, as such, JECFA's estimate of the amount of methyl eugenol from
natural sources is suitably conservative and representative of probable
consumption. Using the JECFA estimate, methyl eugenol is estimated to
be present in the food supply from natural sources at a level 488 times
greater than that from its use as a synthetic flavoring substance or
adjuvant in food. Using the FEMA poundage data (assuming all reported
poundage is for the synthetically prepared flavor) and a ``per-capita
times ten'' approach, we estimated dietary exposure from methyl
eugenol's use as a synthetic flavoring substance and adjuvant in food
to be 7.4 [micro]g/person/d, or 0.12 [micro]g/kg bw/d for a 60 kg
person (Refs. 6 and 13).
2. Toxicology Studies
    FDA reviewed data from 2 NTP-sponsored 2-year carcinogenicity
bioassays on methyl eugenol in F344/N rats and B6C3F1 mice. In these
studies, methyl eugenol was administered to the animals at 0, 37, 75,
or 150 mg/kg bw by gavage, 5 days per week, for 105 weeks. These test
doses are 220,000 to 890,000 times higher than the estimated human
dietary exposure from its use as a flavoring substance.
    The NTP reported significantly increased incidence of liver tumors
(combined adenomas or carcinomas), compared to the concurrent control
groups, occurring in a dose-dependent manner across the treatment
groups in both genders of rats and mice. Although the mortality in some
treated groups was higher than 50 percent, tumors were the main cause
of death in these groups. Further, most deaths occurred late in the
studies. Another type of tumor, glandular stomach neuroendocrine
neoplasms, were found in both genders of rats, but in only two male
mice. The NTP, JECFA, and FDA do not consider these glandular stomach
neuroendocrine neoplasms relevant to tumor formation in humans due to
considerations of the mechanism of development of these neoplasms.
Based on the overall data, we concluded that methyl eugenol, under the
test conditions of the NTP 2-year carcinogenicity bioassays, induced
cancer in rodents (Ref. 13).
    Regarding the genotoxicity potential of methyl eugenol, results
from several genotoxicity assays were negative; however, in testing
systems that provided adequate metabolic activation, specifically 1'-
hydroxylation and sulfonation, or those systems directly testing the
1'-hydroxyl metabolite of methyl eugenol, positive genotoxic effects
were observed.
    There is evidence showing that methyl eugenol treatment leads to
the formation of covalent DNA adducts in vitro and in vivo. In cancer
risk assessment, the formation of DNA adducts is a biomarker of
exposure and suggestive of potential cancer risk. However, the
observation of adducts itself should not be used to predict cancer. The
relevance of DNA adducts for cancer assessment should be investigated
in the context of other information, such as the quantity and
persistency of the adducts. The level of methyl eugenol-specific
adducts was shown to be dose-dependent in experimental animals.
Therefore, since human dietary consumption of methyl eugenol from use
as a synthetic flavoring substance in food is much lower than the dose
received by the animals in the NTP studies, much lower levels of DNA
adducts would be formed in humans compared to that in the test

animals. Additionally, there is evidence that the formation of these
adducts requires specific metabolic activation of methyl eugenol (i.e.,
hydroxylation followed by sulfonation, leading to the formation of 1'-
sulfooexymethyleugenol, the ultimate metabolite that binds to DNA).
Based on the physiology-based pharmacokinetic model of methyl eugenol,
this pathway is not a major metabolic pathway in humans. Even after
hydroxylation occurs, the hydroxylated intermediates can be eliminated
by glucuronization and oxidation, so that only a trace amount of
ingested methyl eugenol is metabolized to 1'-sulfooexymethyleugenol. In
regard to the persistence of the adducts, there is evidence showing
that in rats given methyl eugenol, the levels of methyl eugenol-
specific adducts reduced after the treatment was stopped, suggesting
that these adducts are repairable with considerable low persistency
(Ref. 13).
    There are only few studies measuring methyl eugenol-specific DNA
adducts in humans. The adducts have been detected in 150 of 151 human
liver biopsy samples and 10 of 10 tested human lung biopsy samples,
indicating that the bioactive metabolites form in these subjects with
typical dietary exposure, and are capable of binding with human DNA.
However, these human data have limitations. We note that all but one
the human tissue donors in these studies were patients with cancer or
chronic liver diseases, who may have DNA-repair deficiencies,
compromised detoxification pathways, or weakened control mechanisms
that prevent the promotion of carcinogenesis from DNA adducts, whereas
such control mechanisms would be expected to be operable in healthy
humans. Therefore, it is difficult to extrapolate DNA-adduct results
found in these unhealthy subpopulations to the general healthy
population (Ref. 13).
3. Risk Characterization
    In our evaluation of the carcinogenic potential of methyl eugenol
in humans using a weight-of-evidence approach, we concluded that a
genotoxic MOA is likely involved in the carcinogenicity observed in the
NTP animal studies. This MOA involves formation of a bioactivated
metabolite that forms DNA-adducts that leads to subsequent cancer
initiation and development. Current scientific data on methyl eugenol
suggest that bioactivation to the DNA-reactive metabolite, DNA adduct
formation, and subsequent tumor formations are dose-dependent. Although
methyl eugenol-specific DNA adducts have been identified in
hospitalized subpopulations, there are no clinical or epidemiological
data that provide concrete evidence that methyl eugenol is a human
carcinogen. In the general healthy population, DNA-repair mechanisms
and damage-response pathways may effectively prevent cancer development
from an initiation event such as a DNA adduct. Therefore, the extremely
low level of DNA adducts formed in humans from dietary exposure to
methyl eugenol as an added food flavoring substance likely is below a
threshold level necessary for subsequent cancer development. However,
the current science is inadequate to quantitate the carcinogenic
potential risk (if any) of methyl eugenol in humans (Ref. 13).
    Carcinogenicity data on methyl eugenol also demonstrated that non-
genotoxic MOAs for the observed tumors in animals, especially in mice,
may be operating in conjunction with the genotoxic MOA. However, data
for the non-genotoxic MOA are insufficient (Ref. 13).
    The MOE for synthetic methyl eugenol as a flavoring substance and
adjuvant in food is very large. Two dose-response assessments have been
conducted to derive a point of departure for the liver carcinogenicity
of methyl eugenol; both derived a lower bound benchmark dose
(BMDL10) based on data from the NTP bioassays. Using the
more conservative BMDL10 (7.7 mg/kg/d), and the estimated
dietary exposure of methyl eugenol as a flavoring substance (0.12
[micro]g/kg bw), the MOE is approximately 6.4 x 10 \4\. This MOE is
based on an estimated dietary exposure that assumed 100 percent of the
reported poundage data are exclusively synthetic methyl eugenol. Thus,
the actual MOE for synthetically prepared methyl eugenol added to foods
likely is larger. Although the carcinogenic potential cannot be
definitively ruled out, this large MOE translates into a very small
risk for carcinogenicity in humans and a low public health concern
(Ref. 13).
    As for methyl eugenol from natural sources, other components in
such sources may modulate bioactivation and/or detoxification, so the
toxicity data related to the use as a synthetic flavoring substance may
not be relevant to its presence from natural sources. For example, a
flavonoid derived from basil extracts, nevadensin, was found to be a
sulfotransferase inhibitor, and it significantly reduced methyl
eugenol-induced DNA adduct formation in F344/N rats (Ref. 13).
    In conclusion, although there is evidence of genotoxicity for a
bioactive metabolite of methyl eugenol, we concluded based on currently
available scientific evidence that, despite the potential carcinogenic
concern and lack of definitive quantitative cancer risk measurement,
such risk in humans is mitigated by factors such as low exposure from
its use as a flavoring substance, pharmacokinetics/metabolism, DNA-
repair mechanisms, and the lack of clinical and epidemiological
evidence of the carcinogenic effect in humans from oral exposure to
methyl eugenol. Therefore, it is unlikely that consumption of methyl
eugenol presents a risk to public health from use as a flavoring
substance.

D. Myrcene

1. Exposure
    Under Sec.  172.515, myrcene is permitted for use as a synthetic
flavoring substance and adjuvant in foods in accordance with CGMP. FEMA
estimated an annual production volume of 860 kg for myrcene used as a
flavoring substance and adjuvant in food based on information from the
2015 FEMA Poundage and Technical Effects Survey (Ref. 4). FEMA also
estimated that 14,177,215 kg of myrcene are available for consumption
annually in the United States from its natural presence in foods (e.g.,
citrus juices) (Ref. 8). Thus, myrcene is present naturally in foods at
a level 16,500 times greater than that from use as a flavoring
substance and adjuvant. We estimated dietary exposure to myrcene as a
synthetic flavoring substance using the FEMA poundage data (assuming
all reported poundage is for the synthetically prepared flavoring
substance) and a ``per-capita times ten'' approach to be 74 [micro]g/
person/d, or 1.23 [micro]g/kg bw/d for a 60 kg person (Refs. 6 and 14).
2. Toxicology Studies
    FDA reviewed data from 2 NTP-sponsored carcinogenicity bioassays on
myrcene ([beta]-myrcene) in F344/N rats and B6C3F1 mice. In the rat
study, male and female rats were administered 0, 0.25, 0.50 or 1.0 g
myrcene/kg bw by gavage, 5 days per week for up to 105 weeks. Results
from the study showed increased incidence of renal tubule tumors in
both sexes. All high dose (1 g/kg bw) male rats died prior to the end
of the study due to renal toxicity. Incidence of nephrosis were
significantly increased in all dosed male and female rats when compared
to controls. Incidence of CPN were significantly increased in all
myrcene-treated female rats but not male rats. There also was
significantly increased incidence of nephrosis in all myrcene-

treated male and female rats compared to controls. However, incidence
of mineralization of renal papilla also was significantly increased in
all dosed male rats but not in female rats. Based on increased
incidence of renal tubule neoplasms, NTP concluded that there was clear
evidence of carcinogenic activity of myrcene in male F344/N rats and
equivocal evidence of carcinogenic activity of myrcene in female rats
(Ref. 14).
    In the NTP mouse study, male and female mice were administered 0,
0.25, 0.50 or 1.0 g myrcene/kg bw by gavage, 5 days per week for up to
104 (females) and 105 weeks (males). Based on increased incidence of
liver neoplasms, NTP concluded that there was clear evidence of
carcinogenic activity of myrcene in male mice and equivocal evidence of
carcinogenic activity of myrcene in female mice (Ref. 14).
    Myrcene also was tested in several in vivo and in vitro
genotoxicity assays sponsored by the NTP. The NTP concluded that
myrcene was not genotoxic based on the negative Ames assays (Salmonella
typhimurium (S. typhimurium) and Escherichia coli (E. coli)) and in
vivo micronucleus assays in male and female B6C3F1 mice (Ref. 14).
    Based on our evaluation of the data in the NTP 2-year myrcene
studies, we concluded that, under the test conditions of the studies,
myrcene induced renal tubular tumors in F344/N rats and hepatocellular
tumors in B6C3F1 mice. We also concluded that myrcene is non-genotoxic
(Ref. 14).
3. Risk Characterization
    Our review of relevant scientific data and information suggests
that myrcene may be operating through multiple MOAs to induce kidney
and liver tumors in rodents. While, a definitive MOA for the induction
of tumors by myrcene in rodents has not been established, because
myrcene is not genotoxic, the induction of rodent tumors likely is
occurring through an indirect non-DNA mediated MOA. One potential MOA
in male and female rats is an unusual nephrosis. Another potential MOA,
[alpha]2u-globulin (a low molecular-weight protein synthesized in the
male rat liver) hyaline nephropathy, and renal tubular hyperplasia may
collectively contribute to the development of renal tubule neoplasia in
male rats following myrcene treatment (the [alpha]-2u-globulin
nephropathy occurs only in male rats and is not operative in humans)
(Ref. 14).
    The B6C3F1 mouse strain used in the NTP-sponsored study with
myrcene is known to have a high spontaneous background incidence of
liver neoplasms and is a sensitive strain for the induction of liver
tumors. The observed hepatocellular tumors in myrcene-dosed mice
exceeded concurrent and historical controls. The MOA for the induction
of hepatocellular tumors in myrcene dosed mice is not well understood.
We are not aware of any robust mechanistic studies conducted to
determine the MOA(s) responsible for the induction of hepatocellular
neoplasia reported in myrcene-treated mice (Ref. 14).
    In the NTP 2-year rat study, increased incidence of renal tubular
tumors was observed in all doses of myrcene treated male rats. Because
a no significant effect dose level was not observed in this study, we
derived a BMDL10 of 64,000 [micro]g/kg bw/d based on the
most sensitive endpoint, the combined renal tubular adenomas and
carcinomas in male rats. Based on this BMDL10 and the
estimated dietary exposure to myrcene, we calculated an MOE of 5.2 x 10
\4\ (Ref. 14).
    Using a weight-of-evidence analysis, we concluded that myrcene is
unlikely to induce tumors in humans at its current exposure level when
used as a synthetic flavoring substance and adjuvant in food based on
the following: (1) Myrcene is non-genotoxic; (2) the MOA for kidney
tubule tumors likely involves multiple MOAs that may include renal
toxicity (nephrosis), [alpha]2u-globulin nephropathy (a mechanism not
operative in humans), and hyperplasia in male rats. In female rats,
nephrosis and hyperplasia are likely MOAs; (3) B6C3F1 mice are prone to
spontaneous hepatocellular adenomas, carcinomas, and hepatoblastomas
with high background tumor incidence, and (4) a MOE of 5.2 x10 \4\
indicates a low risk concern from a public health point of view (Ref.
14).

E. Pulegone

1. Exposure
    Under Sec.  172.515, pulegone is permitted for use as a synthetic
flavoring substance and adjuvant in foods in accordance with CGMP. FEMA
estimated an annual production volume of 6 kg for pulegone used as a
flavoring substance and adjuvant in food based on information from the
2015 FEMA Poundage and Technical Effects Survey (Ref. 4). FEMA
estimated that 866 kg of pulegone are available for consumption
annually in the U.S. from its natural presence in foods (e.g., mint)
(Ref. 8). Thus, pulegone is present from natural sources in the food
supply at a level 144 times greater than that from use as a flavoring
substance and adjuvant. Using FEMA poundage data (assuming all reported
poundage is for the synthetically prepared flavor) and a ``per-capita
times ten'' approach, we estimated dietary exposure from pulegone's use
as a synthetic flavoring substance and adjuvant in food to be 0.5
[micro]g/person/d, equivalent to 0.008 [micro]g/kg bw/d for a 60 kg
person (Refs. 6 and 15).
2. Toxicology studies
    FDA reviewed data from 2 NTP-sponsored 2-year carcinogenicity
bioassays on pulegone in F344/N rats and B6C3F1 mice. In the rat study,
pulegone was administered by gavage at 0, 18.75, 37.5, or 75 mg
pulegone/kg bw to male rats and 0, 37.5, 75, or 150 mg pulegone/kg bw
to female rats 5 days a week for up to 104 weeks. The NTP reported
that, in female rats, the primary tumors observed were urinary bladder
papillomas and carcinomas. In male rats, no urinary bladder neoplasms
were reported. Only transitional epithelial hyperplasia was observed in
the pulegone-treated male rats at the lowest dose tested; no epithelial
hyperplasia was observed in male rats at the mid or high doses.
Pulegone administration also was associated with the occurrence of non-
neoplastic lesions in the liver and nose of male and female rats, and
in the forestomach of male rats. The NTP concluded that under the
conditions of the experiment, there was no evidence of carcinogenic
activity of pulegone in male F344/N rats and clear evidence of
carcinogenic activity of pulegone in female F344/N rats based on
increased incidence of urinary bladder neoplasms.
    In the mouse study, pulegone was administered by gavage at 0, 37.5,
75 or 150 mg/kg bw 5 days a week for 105 weeks. The NTP reported that
the primary tumors observed in the study were liver neoplasms in male
and female mice. The NTP concluded that under the conditions of the
experiment, there was clear evidence of carcinogenic activity of
pulegone in male and female B6C3F1 mice.
    Pulegone also was tested in several in vitro and in vivo
genotoxicity assays. Overall, results were mostly negative. However,
NTP concluded that pulegone is genotoxic based on a single positive
result in the Ames Assay in S. typhimurium strain TA 98 and E. coli
strain WP2 uvrA/PKM101 in the presence of metabolic activation.
    Based on the findings of statistically significant increased
incidence of urinary bladder papilloma and carcinoma in female F344/N
rats and liver neoplasms in B6C3F1 male and female mice in the 2-year
NTP

bioassays, we concluded that under the conditions of the 2 NTP studies,
pulegone is a rodent carcinogen. Based on the totality of evidence from
available genotoxicity studies, we also concluded that pulegone is
likely non-genotoxic (Ref. 15).
3. Risk Characterization
    According to NTP, the dose-related increase in the incidence of
urinary bladder neoplasms in female rats was most likely related to the
genotoxic activity of pulegone. However, we concluded that pulegone
likely is non-genotoxic based on negative results in the majority of
genotoxicity studies, along with a lack of available evidence reporting
that DNA adducts related to pulegone treatments are formed. This
suggests that the urinary bladder neoplasms observed in female F344/N
rats treated with pulegone were caused by a non-genotoxic MOA.
    Urinary bladder carcinogenesis likely is occurring in the rat
through cytotoxicity as a result of chronic exposure to high
concentrations of pulegone and its metabolites, followed by
regenerative urothelial cell (a cell type that lines much of the
urinary tract) proliferation, that further led to urothelial tumors
(Ref. 15). Da Rocha et al. (2012) (Ref. 16) concluded that the
carcinogenic MOA for urinary bladder tumors was not relevant to humans,
based on the assertion that humans would never be exposed to pulegone
long enough to develop hyperplasia because pulegone is highly volatile,
noxious, and a nasal irritant, and that genotoxicity of pulegone has
not been demonstrated.
    The metabolic fate of pulegone has been studied extensively in
rodents and is well understood. Pulegone is metabolized by multiple
pathways in the rodent. One important intoxication (bioactivation)
pathway involves the formation of menthofuran, the proximate toxic
metabolite of pulegone, which is further oxidized in the liver to yield
[gamma]-ketoenal, 8-pulegone aldehyde. [gamma]-ketoenal, 8-pulegone
aldehyde is the ultimate toxic metabolite of pulegone in rodents. In
general, at dose levels at or below 80 mg/kg bw, cellular
concentrations of pulegone and its metabolites are effectively
detoxified by conjugation with glutathione and glucuronic acid in
rodents (Ref. 15).
    In a human metabolism study in which pulegone was administered
orally at doses of 0.5 to 1 mg/kg bw, 10-hydroxypulegone, not
menthofuran, was the major metabolite. In this study, 10-
hydroxypulegone was conjugated with glucuronic acid or sulfuric acid
and detoxified. Based on the limited, available human metabolism data,
the toxic metabolite of pulegone, menthofuran, is not formed at
toxicologically significant levels in humans at the dietary exposure
levels expected from the use of pulegone as a flavoring substance (Ref.
15).
    Protein adduct formation and glutathione depletion have been
postulated as potential MOAs of pulegone via menthofuran formation,
which could cause cytotoxicity and chronic cell proliferation, and
ultimately lead to liver neoplasms. In vivo and in vitro studies showed
an association between hepatocellular damage caused by menthofuran and
its metabolic activation to [gamma]-ketoenal, 8-pulegone aldehyde and
covalent binding to target organ proteins. Further, p-cresol, another
pulegone metabolite produced in rodents given high doses of pulegone,
depletes glutathione levels. This may lead to chronic regenerative cell
proliferation, which may be related to the liver carcinogenicity
observed in experimental B6C3F1 mice (Ref. 15)
    Considering genotoxicity data, metabolism, MOA, and the sensitivity
of the B6C3F1 strain to develop hepatocellular tumors, the mouse liver
tumors likely are not relevant to humans at the current use level of
pulegone as a synthetic flavoring substance and adjuvant in food (Ref.
15).
    An MOE was calculated using the no-significant effect level at
which no treatment-related tumors were reported in the 2-year NTP mouse
study of pulegone in male rats (i.e., no significant effect level
(18.75 mg/kg bw, equivalent to 13.39 m g/kg bw/day)). This dose was
selected because in female rats, combined incidence of urinary bladder
papilloma or carcinoma (a rare tumor) was significantly increased at
the high dose (150 mg/kg bw), exceeding historical control ranges for
2-year corn oil gavage studies and concurrent controls. In male mice,
the incidence of hepatocellular adenomas in the 37.5 mg/kg bw dose
group exceeded that in the concurrent and historical control ranges for
2-year corn oil gavage studies. In addition, in female mice, the
incidence of hepatocellular adenomas in the 37.5 mg/kg bw dose group
exceeded that in the concurrent and historical control ranges for 2-
year corn oil gavage studies. Although not statistically significant,
these occurrences may be biologically relevant, given that they
exceeded those of the historical and concurrent controls, and there
were statistically significant increases in some proliferative non-
neoplastic lesions in the liver of male mice at this dose. The MOE
based on the estimated dietary exposure of 0.5 [micro]g/p/d (equivalent
to 0.008 [micro]g/kg bw/d) for pulegone as a flavoring substance in
humans is 1.7 x 10 \6\, which indicates a very low potential
carcinogenic risk for humans (Ref. 15).
    Using a weight-of-evidence analysis considering that: (1) Pulegone
is non-genotoxic; (2) pulegone has a potential cytotoxicity MOA; (3)
available data suggest a dose-dependent, metabolic activation of
pulegone in humans and rodents, an indication of a threshold effect;
(4) there is a no-significant effect level below which no tumors were
formed in the 2 NTP year studies; (5) dietary exposure from use as a
synthetic flavoring substance added to food is low with a MOE of 1.7 x
10 \6\, we concluded that pulegone at its current use level as a
synthetic flavoring substance and adjuvant in food, is unlikely to
induce urinary bladder cancer and liver neoplasms in humans and does
not pose a public health concern (Ref. 15).

F. Pyridine

1. Exposure
    Under Sec.  172.515, pyridine is permitted for use as a synthetic
flavoring substance and adjuvant in foods in accordance with CGMP. FEMA
estimated an annual production volume of 27 kg for pyridine used as a
flavoring substance and adjuvant in food based on information from the
2015 FEMA Poundage and Technical Effects Survey (Ref. 4). FEMA also
estimated that 73,861 kg of pyridine are available for consumption
annually in the U.S. from its natural presence in foods (e.g., coffee)
(Ref. 8). Thus, pyridine is present from natural sources in the food
supply at a level 2,736 times greater than that from use as a flavoring
substance. Using the FEMA poundage data (assuming all reported poundage
is for the synthetically prepared flavoring substance) and a ``per-
capita times ten'' approach, we estimated dietary exposure from
pyridine's use as a synthetic flavoring substance and adjuvant in food
to be 2.3 [micro]g/person/day, or 0.038 [micro]g/kg bw/d for a 60 kg
person (Refs. 6 and 17).
2. Toxicology studies
    FDA reviewed data from 3 NTP-sponsored 2-year carcinogenicity
bioassays on pyridine in F344/N rats, Wistar rats, and B6C3F1 mice. In
the F344/N rat study, pyridine was administered in drinking water at 0,
100, 200, or 400 ppm (mg pyridine/kg drinking water) for 104 (males)
and 105 (females) weeks. These dose levels were equivalent to doses of
7, 14, or 33 mg pyridine/kg bw/d, respectively. The

NTP reported a statistically significant increased incidence of renal
tubule adenomas and renal tubule hyperplasia only in the high dose
F344/N male rats. In addition, NTP reported significantly elevated
incidences of MNCL in F344/N female rats at the 200 ppm and 400 ppm
dose levels. MNCL is a commonly occurring spontaneous neoplasm in
untreated, older F344/N rats. One study found that MNCL occurs in
untreated, aged F344/N rats at a high and variable rate; that MNCL as a
lesion is uncommon in most other rat strains; and the background
incidence of MNCL in F344/N rats has increased significantly over the
years (Ref. 17).
    Recognizing the species specificity and high background levels of
MNCL in F344/N rats, the NTP conducted a 2-year carcinogenicity study
in male Wistar rats (a rat strain that does not have a high background
of MNCL neoplasms). In this study, pyridine was administered in
drinking water at 0, 100, 200, or 400 ppm for 104 weeks to male Wistar
rats. These dose levels were equivalent to doses of 8, 17, or 36 mg
pyridine/kg bw/d. The study showed no increased incidences of MNCL in
any of the treatment groups. The NTP reported a statistically
significant increased incidence of interstitial cell adenomas in the
400 ppm dose group. Observed increased incidence of interstitial cell
adenomas of the testes in Wistar rats exposed to 400 ppm pyridine were
marginally above the historical control range. A statistically
significant increased incidence of kidney hyperplasia was observed at
the 100 ppm dose group, along with increased incidence of kidney
adenomas that were not statistically significant. There also was
increased incidence of nephropathy in all pyridine-treated Wistar rats
as well as in the controls (Ref. 17).
    The NTP concluded that under the conditions of the 2-year F344/N
rat oral drinking water study there was some evidence of carcinogenic
activity of pyridine in male F344/N rats based on increased incidence
of renal tubule neoplasms and equivocal evidence of carcinogenic
activity of pyridine in female F344/N rats based on increased incidence
of MNCL. The NTP considered the increased incidence of interstitial
cell adenomas of the testes in the Wistar rat study to be equivocal
evidence for carcinogenicity.
    In the mouse study, pyridine was administered in drinking water to
male B6C3F1 mice at concentrations of 0, 250, 500 or 1,000 ppm (doses
equivalent to 35, 65, or 110 mg pyridine/kg bw/d, respectively) for 104
weeks. Groups of female B6C3F1 mice were administered pyridine at doses
of 0, 125, 250 or 500 ppm (doses equivalent to 15, 35, or 70 mg
pyridine/kg bw/d, respectively) in drinking water for 105 weeks. The
NTP reported statistically significant increased incidence of
hepatocellular carcinomas at all dose levels in the male and female
mice and concluded that there was clear evidence of carcinogenic
activity of pyridine in male and female B6C3F1 mice.
    Pyridine also was tested in several in vitro and in vivo
genotoxicity assays. The NTP concluded that pyridine was non-genotoxic.
Based on evidence from available studies, we also concluded that
pyridine is non-genotoxic (Ref. 17).
    Under the test conditions of the 2-year NTP studies, we concluded
that pyridine is a rodent carcinogen based on the observed pyridine-
induced renal tumors in male F344/N rats and pyridine-induced liver
tumors in B6C3F1 mice (Ref. 17).
3. Risk Characterization
    Our review of relevant scientific data and information suggests
that pyridine may be operating through multiple MOAs in its capability
to induce kidney and liver tumors in rodents. A definitive MOA for the
induction of tumors in rodents has not been established. However,
because pyridine is not genotoxic, the induction of rodent tumors
likely is occurring through an indirect non-DNA mediated MOA.
    While NTP discounted the kidney neoplasms observed in the F344/N
rats as being associated with an [alpha]2[micro]-globulin MOA, we
concluded that pyridine may be a weak inducer of [alpha]2[micro]-
globulin in F344/N male rats, based on the observation of statistically
significant increased incidence in granular casts and hyaline
degeneration in the 1000 ppm pyridine-treated rats along with higher
staining intensity for [alpha]2[micro]-globulin in the kidney tissues
from F344/N male rats exposed to 1000 ppm pyridine (Ref. 17).
    Using a weight-of-evidence analysis, we concluded that pyridine is
unlikely to induce tumors in humans at its current exposure level as a
synthetic flavoring substance and adjuvant in foods based on the
following: (1) Pyridine is non-genotoxic; (2) renal tubule neoplasms
likely involve multiple MOAs that may include [alpha]2[micro]-globulin
nephropathy and CPN, which are not relevant to humans. These postulated
mechanisms, specifically [alpha]2[micro]-globulin nephropathy, are
species- and sex-specific; (3) B6C3F1 mice are prone to spontaneous
hepatocellular adenomas, carcinomas, and hepatoblastomas with high
background incidence; and (4) active metabolites of pyridine differ
across species and appear to be dose-dependent.
    Further, there is a large MOE (3.7 x 10\5\) between the estimated
dietary exposure of pyridine as a synthetic flavoring substance
intentionally added to food (0.038 [micro]g/kg bw/d) compared to the
highest dose of pyridine at which no treatment-related, statistically
significant tumors were observed in the NTP studies (14,000 [micro]g/kg
bw/d (rats)) (Ref. 17). This large MOE further supports our conclusion
that pyridine, when used as a flavoring substance, is unlikely to
induce cancer in humans.

IV. Comments on the Notice of Petition

    FDA received a number of comments in response to the notice of the
petition. Most comments expressed general support for revocation of the
regulations for the seven synthetic flavoring substances, without
providing any additional information. Several comments expressed
concern about the safety of these synthetic flavoring substances and
asked that FDA ban them from foods; however, these comments did not
provide any information to support their claim that the use of these
additives is unsafe.
    We summarize and respond to relevant portions of comments in this
final rule. To make it easier to identify comments and FDA's responses
to the comments, the word ``Comment'' will appear in parentheses before
the description of the comment, and the word, ``Response'' will appear
in parentheses before FDA's response. We have also numbered each
comment to make it easier to identify a particular comment. The number
assigned to each comment is for organizational purposes only and does
not signify the comment's value, importance, or the order in which it
was submitted.

A. Legal and Policy Issues

    (Comment 1) One comment stated that these synthetic flavoring
substances should not be revoked based on the Delaney Clause because
``. . . the Delaney Clause does not mandate that FDA flatly prohibit
the use of the substance under any circumstances.'' The comment goes on
to say that ``[t]he determination that a substance triggers the Delaney
Clause is not the same as a determination that the substance is
necessarily unsafe in food and that ``. . . an outright ban of any of
the flavorings identified by the petitioner would require FDA to
explain--in a rulemaking procedure--why the substance not only triggers
the Delaney Clause but also why there are no circumstances under which
the substance could otherwise be

considered safe for food use under specified conditions of use.''
Several comments stated that FDA should interpret the Delaney Clause in
a manner similar to the approach used by FDA in its Constituents Policy
(i.e., FDA may determine that a food or color additive is ``safe'' if
it contains a carcinogenic constituent but is not itself carcinogenic,
see 47 FR 14464, April 2, 1982) for carcinogenic contaminants present
in certain food additives.
    (Response 1) We disagree. The language of the Delaney Clause is
straightforward. For most food additives, FDA has discretion to review
a number of factors to determine whether a food additive is safe
(section 409(c)(5) of the FD&C Act). However, for food additives that
are shown ``to induce cancer in man or animal,'' the Delaney Clause
limits FDA's discretion and requires that FDA conclude that the food
additive is not safe. Furthermore, as described above, courts have
rejected the interpretations of the Delaney Clause suggested in the
comments and have concluded that the Delaney Clause completely bans
additives found to induce cancer in humans or animals. Thus, as a
matter of law, FDA cannot find these synthetic flavoring substances to
be safe.
    (Comment 2) One comment said that the Delaney Clause applies only
to food additives that induce cancer in test animals through a direct,
genotoxic mechanism of carcinogenicity. The comment further stated that
there are numerous examples of food ingredients that produce increased
incidence of tumors in high dose rodent studies through a threshold
secondary mechanism.
    (Response 2) We disagree. The Delaney Clause does not differentiate
between non-genotoxic and genotoxic carcinogens. Nor does it permit FDA
to find a food additive safe for human consumption if the food additive
has induced cancer in animal. The Delaney Clause is a strict legal
standard that precludes FDA from using its expertise to evaluate a
substance under its intended condition of use and its risk to public
health.
    (Comment 3) One comment stated that the petitioners call for a
radical departure from long-established regulatory framework of FDA
conducting its own comprehensive review of the scientific data that
bear on the safety assessment. Further, the comment stated that the
petitioners' approach is contrary to the statute and cannot be
implemented without amendment of the law. The comment stated that if,
contrary to the statute and long precedent, FDA believes it should
delegate its authority to external organizations, it must consider such
policy changes through notice-and-comment rulemaking. The comment also
stated that while an FAP is the correct vehicle to appeal/amend a food
additive regulation, it is not appropriate for FDA to consider, much
less implement, ``radical new interpretations'' of the statute through
a food additive petition.
    (Response 3) FDA disagrees with this comment. FDA's regulations
permit petitioning the agency to revoke a food additive regulation. In
response to such a petition, FDA conducts its own review of scientific
data that bear on the petition. FDA then takes action based on its own
evaluation of the data in accordance with the FD&C Act and its
implementing regulations. The Delaney Clause is in the FD&C Act and
this rulemaking is in accordance with the language of the law and case
law interpreting it.

B. Scientific Issues

    (Comment 4) One comment included a lengthy discussion of relevant
carcinogenicity and genotoxicity studies for each of the additives that
are the subject of the petition and argued that none of the synthetic
flavoring substances are direct carcinogens. Instead, the comment
contended that tumors observed in the NTP studies were the result of
secondary mechanisms and not direct, genotoxic effects.
    (Response 4) Our review included an evaluation of all relevant
carcinogenicity studies for each of the additives. The toxicology
memoranda for each of the six synthetic flavoring substances and
section III include a full discussion of the relevant studies and
address each scientific point outlined in the comment.
    (Comment 5) Several comments believed that FDA should not base its
safety decision solely on classifications by NTP or IARC and that any
decision should be based on an independent FDA assessment. Another
comment stated that FDA must consider new studies since the NTP and
IARC reviews were completed.
    (Response 5) FDA agrees with the comments and has conducted its own
evaluation of available relevant data to reach its conclusions on each
synthetic flavoring substance, and did not solely rely on NTP and IARC
classifications as the basis for our decision.
    (Comment 6) One comment noted that IARC is not subject to U.S. law
and relying on its conclusions is inappropriate and legally vulnerable
for FDA. Another comment noted that IARC warns that its monographs are
not the basis for governmental action, pointing out that the preamble
to IARC monographs is clear that they are a starting place for
government agencies, not a basis for regulation.
    (Response 6) We agree that relying solely on IARC conclusions would
not be appropriate in making a decision on the petition, and, as such,
FDA has conducted its own comprehensive carcinogenicity evaluation of
the flavoring substances using all available relevant information.
    (Comment 7) One comment stated that the international health and
safety community has moved away from rote reliance on IARC and NTP. The
comment further said that the NTP and IARC classifications do not make
those substances carcinogens under the Occupational Safety and Health
Administration (OSHA) Hazard Communication Standard and that these
reviews are not viewed as weight-of-evidence conclusions by
international authorities; therefore, it would be incongruent for FDA
to view them in this manner. The comment cited an action in 2012, where
OSHA reversed three decades of automatically requiring employers to
classify a substance as a carcinogen based on an NTP or IARC
classification.
    (Response 7) FDA acknowledges that the NTP studies are designed for
hazard identification and not for assessing the human carcinogenicity
risk of chemicals under specific conditions of use; however, FDA must
evaluate the results from the NTP studies and other available
information within the context of the FD&C Act, including the Delaney
Clause.
    (Comment 8) Some comments expressed concern that compliance and
enforcement of a zero tolerance policy is not possible and that a zero
tolerance policy is not feasible for naturally occurring substances.
    (Response 8) FDA has not addressed the request for FDA to establish
zero tolerances for the food additives that are the subject of this
petition because such a request is not the proper subject of a food
additive petition, and because the petitioners have indicated that they
are abandoning that claim.
    (Comment 9) Several comments expressed concern over the use of
these substances in food packaging applications.
    (Response 9) Benzophenone is the only synthetic flavoring substance
that is the subject of this petition that also is approved as a food
additive for use in food packaging (Sec.  177.2600(c)(4)(iv)
diphenylketone). As explained earlier, we are repealing the regulation
for the

use of this substance as a plasticizer in food packaging based on
results of the NTP studies.
    (Comment 10) One comment said that the use of ethyl acrylate should
not be revoked, because the studies used to assess carcinogenicity were
not appropriate and noted that NTP has removed it from its list of
human carcinogens.
    (Response 10) FDA acknowledges that NTP has removed ethyl acrylate
from its list of human carcinogens; however, the flavoring substance
induced cancer in animals under the conditions of the 2-year NTP
carcinogenicity studies. As such, we are required under the Delaney
Clause to deem the additive to be unsafe as a matter of law. (See
Section III.B, Ethyl Acrylate.)
    (Comment 11) One comment submitted on behalf of several industry
interests supported removal of styrene from Sec.  172.515 based solely
on abandonment and subsequently submitted a petition (FAP 6A4817 (81 FR
38984)) providing data to support their claim.
    (Response 11) FDA is responding to this comment as part of our
response to FAP 6A4817, which is published elsewhere in this edition of
the Federal Register.
    (Comment 12) One comment stated that the petitioner should follow
the National Environmental Policy Act and submit an environmental
assessment but did not provide any supporting data.
    (Response 12) FDA disagrees. As discussed in section VII, we have
determined that the action we are taking on the petition does not have
a significant effect on the human environment and neither an
environmental assessment nor an environmental impact statement is
required.

V. Conclusion

    Upon review of the available information, we have determined that
the information provided in the petition and other publicly available
relevant data demonstrate that synthetic benzophenone, ethyl acrylate,
methyl eugenol, myrcene, pulegone, and pyridine have been shown to
cause cancer in animals. Despite FDA's scientific analysis and
determination that these substances do not pose a risk to public health
under the conditions of their intended use, under the Delaney Clause
this finding of carcinogenicity renders the additives ``unsafe'' as a
matter of law and FDA is compelled to amend the authorizations for
these substances as food additives to no longer provide for the use of
these synthetic flavoring substances. Additionally, because of evidence
that benzophenone causes cancer in animals, FDA also is amending the
food additive regulations to no longer provide for the use of
benzophenone as a plasticizer in rubber articles intended for repeated
use in contact with food. Therefore, we are amending parts 172 and 177
as set forth in this document. Upon the publication, these food
additive uses are no longer authorized.
    FDA realizes that the food industry needs sufficient time to
identify suitable replacement ingredients for these synthetic flavoring
substances and reformulate products and for these products to work
their way through distribution. Therefore, FDA intends to not enforce
applicable requirements of the final rule with regard to food products
manufactured (domestically and internationally) prior to October 9,
2020 that contain one or more of these six synthetic flavoring
substances, to provide an opportunity for companies to reformulate
products prior to enforcing the requirements of this final rule.

VI. Public Disclosure

    In accordance with Sec.  171.1(h) (21 CFR 171.1(h)), the petition
and the documents that we considered and relied upon in reaching our
decision to approve the petition will be made available for public
disclosure (see FOR FURTHER INFORMATION CONTACT). As provided in Sec.
171.1(h), we will delete from the documents any materials that are not
available for public disclosure.

VII. Analysis of Environmental Impacts

    As stated in the January 4, 2016, Federal Register notice of
petition for FAP 5A4810 (81 FR 42), the petitioners claimed a
categorical exclusion from preparing an environmental assessment or
environmental impact statement under 21 CFR 25.32(m). We have
determined that the categorical exclusion under Sec.  25.32(m) for
actions to prohibit or otherwise restrict or reduce the use of a
substance in food, food packaging, or cosmetics is warranted. We have
determined under Sec.  25.32(m) that this action is of a type that does
not individually or cumulatively have a significant effect on the human
environment. Therefore, neither an environmental assessment nor an
environmental impact statement is required.

VIII. Paperwork Reduction Act of 1995

    This final rule contains no collection of information. Therefore,
clearance by the Office of Management and Budget under the Paperwork
Reduction Act of 1995 is not required.

IX. Objections

    If you will be adversely affected by one or more provisions of this
regulation, you may file with the Dockets Management Staff (see
ADDRESSES) either electronic or written objections. You must separately
number each objection, and within each numbered objection you must
specify with particularity the provision(s) to which you object, and
the grounds for your objection. Within each numbered objection, you
must specifically state whether you are requesting a hearing on the
particular provision that you specify in that numbered objection. If
you do not request a hearing for any particular objection, you waive
the right to a hearing on that objection. If you request a hearing,
your objection must include a detailed description and analysis of the
specific factual information you intend to present in support of the
objection in the event that a hearing is held. If you do not include
such a description and analysis for any particular objection, you waive
the right to a hearing on the objection.
    Any objections received in response to the regulation may be seen
in the Dockets Management Staff between 9 a.m. and 4 p.m., Monday
through Friday, and will be posted to the docket at https://www.regulations.gov.

X. References

    The following references marked with an asterisk (*) are on display
at the Dockets Management Staff (see ADDRESSES), under Docket No. FDA-
2015-F-4317, and are available for viewing by interested persons
between 9 a.m. and 4 p.m., Monday through Friday, they also are
available electronically at https://www.regulations.gov. References
without asterisks are not on display; they are available as published
articles and books.

1. Bevan, R.J. (2017). ``Threshold and Non-Threshold Chemical
Carcinogens: A survey of the Present Regulatory Landscape.''
Regulatory Toxicology and Pharmacology, 88, 291-302.
2. JECFA (2006). ``The Formulation of Advice on Compounds That are
Both Genotoxic and Carcinogenic.'' WHO Food Additives Series No. 55,
Annex 4.
3. Barlow, S. et al. (2006). ``Risk Assessment of Substances That
are Both Genotoxic and Carcinogenic: Report of an International
Conference organized by EFSA and WHO with Support of ILSI Europe.''
Food and Chemical Toxicology, 44, 1636-1650.
4. Flavor and Extract Manufacturers Association Transmittal Letter
to Szabina Stice (FDA, CFSAN), April 27, 2018.*
5. FDA Memorandum from D. Folmer, CFSAN Chemistry Review Group,

Division of Petition Review, to J. Kidwell, Regulatory Group I,
Division of Petition Review, June 24, 2016.*
6. FDA Memorandum from D. Folmer, CFSAN Chemistry Review Group,
Division of Petition Review, to J. Kidwell, Regulatory Group I,
Division of Petition Review, June 20, 2018.*
7. Food and Agriculture Organization of the United Nations and the
World Health Organization. Principles and Methods for the Risk
Assessment of Chemicals in Food. 2009. Available at http://www.inchem.org/documents/ehc/ehc/ehc240_index.htm. (Last accessed
September 12, 2017.)
8. Flavor and Extract Manufacturers Association Letter to Judith
Kidwell (FDA, CFSAN), April 11, 2016.*
9. FDA Memorandum from S. Thurmond, CFSAN Toxicology Team, Division
of Petition Review, to J. Kidwell, Regulatory Group I, Division of
Petition Review, June 21, 2018. *
10. Boobis, A.R. et al. (2006). ``IPCS Framework for Analyzing the
Relevance of a Cancer Mode of Action for Humans.'' Critical Reviews
in Toxicology, 36:10, 781-792.
11. FDA Memorandum from S. Thurmond, CFSAN Toxicology Team, Division
of Petition Review, to J. Kidwell, Regulatory Group I, Division of
Petition Review, June 21, 2018.*
12. National Toxicology Program. Report on Carcinogens Background
Document for Ethyl Acrylate. December 2-3, 1998.
13. FDA Memorandum from J. Zang, CFSAN Toxicology Team, Division of
Petition Review, to J. Kidwell, Regulatory Group I, Division of
Petition Review, June 21, 2018.*
14. FDA Memorandum from A. Khan, CFSAN Toxicology Team, Division of
Petition Review, to J. Kidwell, Regulatory Group I, Division of
Petition Review, June 21, 2018.*
15. FDA Memorandum from N. Anyangwe, CFSAN Toxicology Team, Division
of Petition Review, to J. Kidwell, Regulatory Group I, Division of
Petition Review, June 21, 2018.*
16. Da Rocha, M.S., Dodmane, P.R., Arnold, L.L., et al. (2012).
``Mode of Action of Pulegone on the Urinary Bladder of F344 Rats.''
Toxicological Sciences, kfs035.
17. FDA Memorandum from T. Tyler, CFSAN Toxicology Team, Division of
Petition Review, to J. Kidwell, Regulatory Group I, Division of
Petition Review, June 27, 2018.*

List of Subjects

21 CFR Part 172

    Food additives, Reporting and recordkeeping requirements.

21 CFR Part 177

    Food additives, Food packaging.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts
172 and 177 are amended as follows:

PART 172--FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR
HUMAN CONSUMPTION

0
1. The authority citation for part 172 continues to read as follows:

    Authority:  21 U.S.C. 321, 341, 342, 348, 371, 379e.

Sec.  172.515   [Amended]

0
2. Amend Sec.  172.515(b) by removing the entries for ``benzophenone;
diphenylketone,'' ``ethyl acrylate,'' ``eugenyl methyl ether; 4-
allylveratrole; methyl eugenol,'' ``myrcene; 7-methyl-3-methylene-1,6-
octadiene,'' ``pulegone; p-menth-4(8)-en-3-one,'' and ``pyridine.''

PART 177--INDIRECT FOOD ADDITIVES: POLYMERS

0
3. The authority citation for part 177 continues to read as follows:

    Authority:  21 U.S.C. 321, 342, 348, 379e.

Sec.  177.2600   [Amended]

0
4. In Sec.  177.2600(c)(4)(iv), remove the entry for ``diphenyl
ketone.''

    Dated: October 2, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-21807 Filed 10-5-18; 8:45 am]
 BILLING CODE 4164-01-P