[Federal Register Volume 90, Number 10 (Thursday, January 16, 2025)]
[Rules and Regulations]
[Pages 4628-4634]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2025-00830]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 74
[Docket No. FDA-2023-N-0437]
Color Additive Petition From Center for Science in the Public
Interest, et al.; Request To Revoke Color Additive Listing for Use of
FD&C Red No. 3 in Food and Ingested Drugs
AGENCY: Food and Drug Administration, HHS.
ACTION: Final amendment; order.
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SUMMARY: The Food and Drug Administration (FDA or we) is granting a
color additive petition submitted by Center for Science in the Public
Interest, et al., by repealing the color additive regulations that
permit the use of FD&C Red No. 3 in foods (including dietary
supplements) and in ingested drugs. The petitioners provided data
demonstrating that this additive induces cancer in male rats.
Therefore, FDA is revoking the authorized uses in food and ingested
drugs of FD&C Red No. 3 in the color additive regulations.
DATES: This order is effective January 15, 2027, except for amendatory
instruction 4, which is effective January 18, 2028. If any provisions
are delayed or stayed by the filing of proper objections, FDA will
publish such notification in the Federal Register. Submit either
electronic or written objections and requests for a hearing on the
order by February 18, 2025. See
[[Page 4629]]
section X for further information on the filing of objections.
ADDRESSES: You may submit objections and requests for a hearing as
follows. Please note that late, untimely filed objections will not be
considered. The https://www.regulations.gov electronic filing system
will accept comments until 11:59 p.m. Eastern Time at the end of
February 18, 2025. Objections received by mail/hand delivery/courier
(for written/paper submissions) will be considered timely if they are
received 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-2023-N-0437 for ``Color Additive Petition from Center for Science
in the Public Interest, et al.; Request to Revoke Color Additive
Listing for Use of FD&C Red No. 3 in Food and Ingested Drugs.''
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, 240-402-7500.
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 objections. 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 objections 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.govinfo.gov/content/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, 240-402-7500.
FOR FURTHER INFORMATION CONTACT: Shayla West-Barnette, Office of Pre-
market Additive Safety, Human Foods Program, Food and Drug
Administration, 5001 Campus Dr., College Park, MD 20740, 240-402-1262;
or Alexandra Beliveau, Office of Policy, Regulations, and Information,
Human Foods Program, Food and Drug Administration, 5001 Campus Dr.,
College Park, MD 20740, 240-402-2378.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Introduction
II. Background
A. Statutory and Regulatory Background of Color Additive
Regulation
B. Chemical Identity and Nomenclature of FD&C Red No. 3
C. History of FDA's Regulatory Actions for FD&C Red No. 3
III. Summary and Context of Determination
IV. Evaluation of Petition
V. Comments on the Notice of Petition
VI. Conclusion
VII. Public Disclosure
VIII. Analysis of Environmental Impacts
IX. Paperwork Reduction Act of 1995
X. Objections
XI. References
I. Introduction
In the Federal Register of February 17, 2023 (88 FR 10245), we
announced that we filed a color additive petition (CAP 3C0323) jointly
submitted by the Center for Science in the Public Interest, Breast
Cancer Prevention Partners, Center for Environmental Health, Center for
Food Safety, Chef Ann Foundation, Children's Advocacy Institute,
Consumer Federation of America, Consumer Reports, Defend Our Health,
Environmental Defense Fund, Environmental Working Group, Feingold
Association of the United States, Food & Water Watch, Healthy Babies
Bright Futures, Life Time Foundation, Momsrising, Prevention Institute,
Public Citizen, Public Health Institute, Public Interest Research
Group, Real Food for Kids, Lisa Y. Lefferts, Linda S. Birnbaum, and
Philip J. Landrigan, c/o Mr. Jensen Jose, 1250 I Street NW, Ste 500,
Washington, DC 20005 (the petitioners).
The petition proposed that we repeal the color additive regulations
for FD&C Red No. 3 in Sec. 74.303 (21 CFR 74.303), which permits the
use of FD&C Red No. 3 in foods (including dietary supplements), and
Sec. 74.1303 (21 CFR 74.1303), which permits the use of FD&C Red No. 3
in ingested drugs. The notice of petition gave interested parties until
April 18, 2023, to submit comments on the filed color additive
petition. In response to a written request submitted to the docket, we
extended the comment period to May 18, 2023 (88 FR 19026, March 30,
2023). This order granting the request to revise the regulations to no
longer provide for these uses of FD&C Red No. 3 responds to the
petition.
II. Background
A. Statutory and Regulatory Background of Color Additive Regulation
The Federal Food, Drug, and Cosmetic Act (FD&C Act) authorizes us
to regulate ``color additives'' (see section 721(b) of
[[Page 4630]]
the FD&C Act (21 U.S.C. 379e(b))). The FD&C Act defines ``color
additive'' as ``a material which . . . is a dye, pigment, or other
substance made by a process of synthesis or similar artifice, or
extracted, isolated, or otherwise derived, with or without intermediate
or final change of identity, from a vegetable, animal, mineral, or
other source, and . . . [that] when added or applied to a food, drug,
or cosmetic, or to the human body or any part thereof, is capable
(alone or through reaction with [an]other substance) of imparting color
thereto . . . The term ``color'' includes black, white, and
intermediate grays . . .'' (see section 201(t) of the FD&C Act (21
U.S.C. 321(t))). Color additives used in or on a food, drug, cosmetic,
or certain medical devices are deemed unsafe and prohibited except to
the extent that we approve their use (see section 721(a) of the FD&C
Act). Certain color additives must be certified by FDA (see section
721(c) of the FD&C Act).
The FD&C Act provides a process through which any person who wishes
to use a color additive in or on food, drugs, certain devices, or
cosmetics, may submit a petition proposing the issuance of a color
additive regulation listing such use with supporting information. A
color additive petition may also be submitted to propose the amendment
or repeal of any existing color additive regulation (see section
721(b)(5)(C) and (d) of the FD&C Act). In response to a color additive
petition, FDA may issue a regulation listing a color additive for use
in or on food, drugs, devices, or cosmetics only if it determines that
the additive is suitable and safe for such use (see section
721(b)(2)(A) of the FD&C Act). FDA's determination that a color
additive is safe means that there is convincing evidence that
establishes with reasonable certainty that no harm will result from the
intended condition of use of the color additive (21 CFR 70.3(i)), which
we refer to as ``a reasonable certainty of no harm.'' This safety
standard is referred to as the ``general safety clause'' for color
additives. To determine whether a color additive is safe under the
general safety clause, the FD&C Act requires FDA to consider, among
other relevant factors: (1) probable consumption of, or other relevant
exposure from, the additive and of any substance formed in or on food,
drugs or device, or cosmetics because of the use of the additive; (2)
cumulative effect, if any, of such additive ``in the diet of man or
animals,'' taking into account the same or any chemically or
pharmacologically related substance or substances in such diet; and (3)
safety factors recognized by experts ``as appropriate for the use of
animal experimentation data'' (see section 721(b)(5)(A) of the FD&C
Act).
In addition, section 721(b)(5)(B) of the FD&C Act, often referred
to as the Delaney Clause, deems color additives unsafe under certain
circumstances. The Delaney Clause consists of two parts. The first part
(section 721(b)(5)(B)(i) of the FD&C Act) pertains specifically to
ingested color additives. The second part (section 721(b)(5)(B)(ii) of
the FD&C Act) applies to noningested color additives. For purposes of
our review of this petition, we reviewed these uses of FD&C Red No. 3
under the first part because these uses result in ingestion. Section
721(b)(5)(B)(i) of the FD&C Act states that a color additive shall be
deemed unsafe for any use which will or may result in ingestion of all
or part of such additive, if the additive is found by the Secretary to
induce cancer when ingested by man or animal, or if it is found by the
Secretary, after tests which are appropriate for the evaluation of the
safety of additives for use in food, to induce cancer in man or animal.
Courts have concluded that the Delaney Clause completely bans additives
found to induce cancer in humans or animals. In Public Citizen v.
Young, 831 F.2d 1108, 1122 (D.C. Cir. 1987), the court 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
should be approved because it did not pose more than a de minimis
cancer risk; 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 and
subject to a similarly worded Delaney Clause for food additives, on the
grounds that they pose a de minimis cancer risk, is contrary to the
provisions of the Delaney Clause).
There is a similar Delaney Clause provision for food additives
under section 409(c)(3) of the FD&C Act (21 U.S.C. 348(c)(3)), which
states that no food additive shall be deemed safe if it is found to
induce cancer when ingested by man or animal. In revoking certain
authorizations for food additives under the Delaney Clause, FDA stated
that the Delaney Clause limits FDA's discretion to determine the safety
of food additives. FDA stated that the Delaney Clause 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'' (83 FR 50490 at 50492, October 9, 2018).
Section 721(d) of the FD&C Act provides for the issuance,
amendment, or repeal of regulations authorizing the use of a color
additive, and, among other things, it specifies that the safety
provisions of section 721(b)(5) apply to such actions. For FDA to grant
a petition that seeks repeal of a color additive regulation based upon
new data concerning the safety of the color additive, such data must be
adequate for FDA to conclude that there is no longer a reasonable
certainty of no harm for the intended use of the color additive or that
it must be deemed unsafe under the Delaney Clause.
B. Chemical Identity and Nomenclature of FD&C Red No. 3
Our regulation, at Sec. 74.303, describes FD&C Red No. 3 as
principally the monohydrate of 9 (o-carboxyphenyl)-6-hydroxy-2,4,5,7-
tetraiodo-3H-xanthen-3-one, disodium salt, with smaller amounts of
lower iodinated fluoresceins. The color is also called erythrosine or
other names, including Colour Index (C.I.) Acid Red 51; C.I. No. 45430;
and C.I. Food Red 14. FD&C Red No. 3 is required to be certified by FDA
that it complies with Sec. Sec. 74.303 and 74.1303. The designation
``FD&C Red No. 3'' is permitted only for those batches of the color
additive that have been certified by FDA.
C. History of FDA's Regulatory Actions for FD&C Red No. 3
FD&C Red No. 3, as erythrosine, was first listed in 1907 under the
provisions of the Food and Drugs Act of 1906 (Food Inspection Decision
76), and later provisionally listed in 1960 as Red No. 3 for food,
drug, and cosmetic use (25 FR 9759, October 12, 1960) (see also Ref.
1). In 1969, FD&C Red No. 3 was permanently listed for use in food and
ingested drugs (34 FR 7446, May 8, 1969), now codified in Sec. Sec.
74.303 and 74.1303. In 1990, FDA did not extend the provisional listing
of FD&C Red No. 3 for use in cosmetics and externally applied drugs (55
FR 3516, February 1, 1990) based on thyroid neoplasia in rat
carcinogenicity studies, which terminated this listing. The decision
did not revoke the existing permanent listing for food and ingested
drugs from 1969.
[[Page 4631]]
III. Summary and Context of Determination
We have evaluated the data and information submitted in the
petition as well as other relevant data. FDA finds that FD&C Red No. 3
can induce cancer in male rats, through a rat specific hormonal
mechanism. Therefore, we are revoking the listings providing for these
uses of this color additive under section 721(b)(5)(B) of the FD&C Act
as a matter of law, as described further below.
IV. Evaluation of Petition
The petitioners state that FD&C Red No. 3 has been shown to induce
cancer in male laboratory rats. The petitioners discuss multiple
regulatory conclusions that FD&C Red No. 3 is carcinogenic in male
rats, which are based on some in vivo studies. Specifically, data
reported in the publication entitled ``Lifetime Toxicity/
Carcinogenicity Study of FD&C Red No. 3 (erythrosine) in Rats'' by
Borzelleca et al., a compilation of two separate chronic toxicity and
carcinogenicity studies, was published in 1987. These conclusions
include a 1990 conclusion from FDA (55 FR 3520, February 1, 1990); a
1983 National Toxicology Program (NTP) subcommittee conclusion; a 1989
European Commission's Scientific Committee for Food report (Ref. 2);
and Joint Food and Agricultural Organization/World Health Organization
(FAO/WHO) Expert Committee on Food Additives (JECFA) conclusions (Refs.
3 and 4).
FDA evaluated the data cited by the petitioner, as well as other
available data. Based on our review of this data and information, we
conclude that the Delaney Clause applies because FD&C Red No. 3 has
been found to ``induce cancer when ingested by . . . animal.''
Specifically, some in vivo studies have shown FD&C Red No. 3 can induce
thyroid tumors in male rats. Thyroid tumors in male rats appear to
result from perturbation in the hypothalamic-pituitary-thyroid hormonal
axis (Refs. 5 and 6). These perturbations are initiated by an increase
in circulating thyroid stimulating hormone (TSH), causing follicular
hyperplasia, which has the potential to develop into thyroid tumors
(Refs. 5 and 6). Thus, increased TSH levels appears to be a key event
for thyroid tumor development from FD&C Red No. 3 exposure in male rats
(Refs. 5 and 6).
Based on the available data and information, FD&C Red No. 3-induced
thyroid tumors in male rats are of limited relevance to humans. FDA's
Center for Food Safety and Applied Nutrition (CFSAN)'s Cancer
Assessment Committee (CAC) concluded that while studies show FD&C Red
No. 3 induces thyroid tumors in male rats, the risk of developing such
tumors in humans at low exposure levels from the current uses is
unlikely (Ref. 5). FD&C Red No. 3 is likely not genotoxic (in other
words, it is not directly DNA reactive) (Refs. 5 and 6). FD&C Red No. 3
appears to induce thyroid tumors in male rats through a key event--an
increase in circulating TSH--and rodents show much higher sensitivity
to such perturbations compared to humans (Refs. 5 and 6). There is no
conclusive available clinical evidence that demonstrates increased TSH
levels either promote or actively cause thyroid carcinogenesis in
humans (Refs. 5 and 6). Further, studies in humans to date have failed
to show convincing evidence that FD&C Red No. 3 exposure results in
consistent perturbations in any thyroid hormone levels, including TSH
(Refs. 5 and 6). FDA estimated the highest exposure for FD&C Red No. 3
from the approved uses as a color additive in conventional food,
dietary supplements, and ingested drugs to be 0.25 milligrams per
kilogram of bodyweight per day (mg/kg bw/day) (Ref. 7). When compared
against the No Observed Adverse Effect Level for thyroid hormone
effects associated with thyroid tumors in male rats of 35.8 mg/kg bw/
day, a 210-fold margin of exposure was derived (Ref. 5). Based on the
available data and information, FDA and other regulatory agencies
including JECFA, the European Food Safety Authority (EFSA), and the
Food Standards Australia New Zealand (FSANZ) have concluded that FD&C
Red No. 3-induced thyroid tumors in rats are of limited relevance to
humans (Refs. 5 and 6). In addition, the carcinogenicity of FD&C Red
No. 3 was not observed when tested in other animals including female
rats and either sex of mice, gerbils, or dogs (Refs. 5 and 6).
Despite its limited relevance to humans, the cumulative data and
information show that high exposure to FD&C Red No. 3 induces thyroid
tumors in male rats (Refs. 5 and 6).
V. Comments on the Notice of Petition
FDA received a number of comments in response to the notice of
filing of the petition. Most comments expressed general support for
revocation of the regulations for FD&C Red No. 3, without providing any
additional information.
We summarize and respond to relevant portions of comments in this
order. To make it easier to identify comments and FDA's responses to
the comments, the word ``Comment'' will appear in parenthesis 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 help distinguish between different comments. 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.
(Comment 1) Several comments argued that the Delaney Clause does
not apply because the scientific community's understanding of the
carcinogenicity potential of FD&C Red No. 3 has evolved since inclusion
of the Delaney Clause in the FD&C Act and since FDA's conclusion (55 FR
3520) that FD&C Red No. 3 induces cancer in male rats. Some comments
argue that FDA has discretion to exercise scientific judgment in
determining whether FD&C Red No. 3 induces cancer for purposes of the
Delaney Clause.
(Response 1) We agree that a large body of literature has been
published since FDA's conclusion that FD&C Red No. 3 induces cancer in
male rats. We have reviewed the currently available data and
information pertaining to the safety of FD&C Red No. 3 as a color
additive and concluded that the FD&C Red No. 3-induced thyroid tumors
in male rats are of limited relevance to humans (Refs. 5 and 6).
However, the current literature continues to support the finding that
high exposure to FD&C Red No. 3 induces cancer in male rats (Ref. 6).
Because of this finding, we disagree that FDA has discretion to
determine that FD&C Red No. 3 does not induce cancer under the Delaney
Clause. The language of the Delaney Clause is straightforward. Under
the general safety clause for color additives, FDA has discretion to
review a number of factors to determine whether a color additive is
safe (section 721(b)(5)(A) of the FD&C Act). However, for ingested
color 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 color additive is not safe as a matter of law.
(Comment 2) Several comments argued that the Delaney Clause does
not apply because FD&C Red No. 3 is non-genotoxic and induces tumors
through a secondary mechanism. The comments assert that FDA's action to
terminate the provisional listing FD&C Red No. 3 in 1990 was because
there was inadequate evidence at the time to demonstrate that FD&C Red
No. 3 was non-genotoxic, and now that there is evidence demonstrating
that FD&C Red No. 3 is non-genotoxic, FDA has discretion to
[[Page 4632]]
determine that FD&C Red No. 3 does not cause cancer.
(Response 2) We agree that FD&C Red No. 3 is non-genotoxic based on
the available data and information. FD&C Red No. 3 induces tumors in
male rats through a key event (increased TSH production) (Ref. 6). We
refer to the increase in TSH levels as a ``key event'' and not as a
secondary mechanism because the exact mechanism of FD&C Red No. 3-
induced carcinogenesis in male rats has not been determined.
Nonetheless, we disagree with the comments' assertion that the Delaney
Clause does not apply. As we concluded in our 2018 action revoking the
authorizations of certain food additives under a similarly worded
Delaney Clause, the Delaney Clause does not differentiate between non-
genotoxic and genotoxic carcinogens (83 FR 50490 at 50501). Nor does
the Delaney Clause permit FDA to find an ingested color additive safe
for human consumption if the color additive has been found to induce
cancer in animals. Consistent with our conclusion in revoking certain
food additive approvals based on the Delaney Clause (83 FR 50490), FDA
concludes that the Delaney Clause limits FDA's discretion to determine
the safety of color additives that are intended to be ingested (such as
the use of FD&C Red No. 3 in food and ingested drugs) in that it
prevents FDA from finding such a color 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.
(Comment 3) One comment argued that the evidence demonstrating that
FD&C Red No. 3 induces thyroid tumors in male rats is insufficient to
invoke the Delaney Clause.
(Response 3) We disagree. Again, we acknowledge the large body of
published literature that does not show FD&C Red No. 3 inducing cancer
in female rats, or multiple other animal species, including humans
(Refs. 5 and 6). However, under the Delaney Clause, these negative
findings do not outweigh or negate the positive findings of the two
chronic feeding studies. Because FD&C Red No. 3 has been found to
induce tumors in male rats, FDA must revoke the regulations providing
for these uses of the color additive as a matter of law.
(Comment 4) One comment argued that the Delaney Clause does not
apply because the dose range used for the two chronic feeding studies
in rats render the positive findings unreliable. Specifically, the
comment asserts that in its 1990 order, the study FDA relied on was
unreliable because the dose of FD&C Red No. 3 exceeded the maximum
tolerated dose. The comment asserts that this violates the testing
guidelines of the National Cancer Institute.
(Response 4) We disagree. The two chronic feeding studies in rats
were appropriately designed and considered to be positive bioassays
(Ref. 5). These two studies reported within a single manuscript were
considered appropriate and not to have exceeded the maximum tolerated
dose (MTD) per current guidance (Redbook 2000, Chapters II.C.5.A. and
IV.C.7. or IV.C.8) (Ref. 5). Redbook 2000 uses the NTP's definition of
MTD, which states that the MTD is ``that dose which, when given for the
duration of the chronic study as the highest dose, will not shorten the
treated animals' longevity from any toxic effects other than the
induction of neoplasms.'' The data that was deemed to demonstrate FD&C
Red No. 3 is carcinogenic in male rats used a maximum dose of 4 percent
(Borzelleca et al., 1987), which did not impact the longevity of the
treated animals' life spans, resulted in no systemic toxic effects
other than the induction of neoplasms, and did not cause unacceptable
side effects. Thus, the dose scheme used by Borzelleca et al. (1987)
fits the FDA Redbook 2000 definition of MTD. Furthermore, while rats
may not be an ideal model to assess the carcinogenicity potential of
FD&C Red No. 3 in humans, these chronic feeding studies do reasonably
demonstrate that FD&C Red No. 3 induces thyroid tumors in male rats.
These studies are sufficient to invoke the Delaney Clause because the
Delaney Clause is not limited to inducing cancer in humans.
(Comment 5) One comment requested that FDA convene a Color Additive
Advisory Committee if FDA delists FD&C Red No. 3 on the basis of the
Delaney Clause.
(Response 5) We decline to convene the meeting requested by the
comment. Section 721(b)(5)(c)(i) of the FD&C Act states that any person
who will be adversely affected by a proposal if placed into effect may
request, within the specified time period, that the petition or order
be referred to an advisory committee for a report and recommendations
with respect to any matter arising under subparagraph (B) (here, the
Delaney clause, (B)(i)) that is involved in the proposal) and that
requires the exercise of scientific judgment. Upon such request, the
Secretary must appoint an advisory committee. FDA's determination that
FD&C Red No. 3 has been shown to cause cancer in laboratory animals is
based on a comprehensive review of all relevant carcinogenicity studies
(Ref. 6). After reviewing these studies, FDA did not find there to be a
genuine debate regarding the science--specifically, that FD&C Red No. 3
induced cancer in male rats. Thus, FDA's conclusion that FD&C Red No. 3
has been shown to cause cancer in laboratory animals is not a matter
that requires referral to an advisory committee because it did not
require the exercise of scientific judgment.
(Comment 6) A couple of comments stated that the highest dietary
exposure to FD&C Red No. 3 is below the Acceptable Daily Intake (ADI)
and therefore, dietary exposure from its use as a food color additive
does not present a safety concern. Another comment stated that because
of the relatively low dietary exposure to FD&C Red No. 3, revoking the
regulations authorizing its use would not significantly reduce risk to
the public.
(Response 6) Based on our evaluation of the dietary exposure to
FD&C Red No. 3 and the available scientific evidence, we conclude that
FD&C Red No. 3 meets the safety standard of a reasonable certainty of
no harm required for a color additive (see Refs. 6 and 7). We derived a
210-fold margin of exposure between the highest dietary exposure to
FD&C Red No. 3 (0.25 mg/kg bw/d) and the No Observed Adverse Effect
Level chosen by the CAC (35.8 mg/kg bw/d) (Ref. 6). We agree that the
highest dietary exposure to FD&C Red No. 3 is below the ADI established
by JECFA in 2018 (6 mg/kg bw/d). We also agree with JECFA's conclusion
that the possibility of developing thyroid tumors in humans at low
dietary exposure levels from the current uses of FD&C Red No. 3 is
unlikely (Ref. 6). However, as a matter of law (see section
721(b)(5)(B) of the FD&C Act), we must revoke the regulations
authorizing the uses of FD&C Red No. 3 because it has been shown to
induce cancer in male rats.
(Comment 7) Several comments stated that the findings that FD&C Red
No. 3 induces cancer in male rats are not applicable to humans and,
therefore, do not indicate that the color additive would induce tumors
in humans. These comments asserted that the conclusions of other
regulatory agencies and authoritative risk assessment bodies support
that the use of FD&C Red No. 3 is unlikely to cause tumors in humans.
(Response 7) We agree that there are physiological differences
between rats
[[Page 4633]]
and humans that require contextualization when extrapolating the
relevance of animal studies to humans. There is no conclusive evidence
that increased TSH production--a key event for tumor induction in male
rats--causes thyroid carcinogenesis in humans (see Ref. 6).
Furthermore, studies in humans have not demonstrated that dietary
exposure to FD&C Red No. 3 causes consistent perturbations of TSH or
other hormones. In fact, studies in humans demonstrate a lack of
effects on the thyroid. Based on the scientific evidence, we agree that
the thyroid tumors observed in male rats are of limited relevance to
humans, and we note that JECFA, EFSA, and the FSANZ have also reached
this same conclusion (Ref. 6). However, as stated earlier, we must
revoke the regulations authorizing the uses of FD&C Red No. 3 because
it has been shown to induce cancer in male rats (see section
721(b)(5)(B) of the FD&C Act). The Delaney Clause prevents us from
finding its use to be safe, regardless of the extent to which the
experimental conditions of the animal study provide insight into the
health effects of human consumption and use of the color additive in
question.
(Comment 8) One comment asserts that FDA is required to consider
reasonable alternatives to revoking the color additive listings for
FD&C Red No. 3. The comment also asserts that the ``proposed rule does
not indicate whether FDA investigated this issue of reasonably viable
alternatives to FD&C Red. 3.''
(Response 8) Under section 721(b) of the FD&C Act, a color additive
may not be marketed unless FDA determines that the additive is suitable
and safe for such use. Under section 721(b)(5)(B) of the FD&C Act, also
referred to as the Delaney Clause, a color additive shall be deemed
unsafe, and shall not be listed, if certain conditions are met. As FDA
has determined that the Delaney Clause applies to the authorized uses
of FD&C Red No. 3, FDA does not have discretion to consider
alternatives to revoking the color additive listing, and that is true
regardless of whether there are ``reasonably viable alternatives'' for
this color additive.
(Comment 9) One comment asserts that FDA did not disclose the
relevant studies in the filing notice.
(Response 9) We disagree. As required under section 721(d)(1), FDA
is required to publish ``notice of the proposal made by the petition .
. . in general terms.'' Furthermore, we note that the petition, which
was included in the public docket, included citations to the relevant
studies.
VI. 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 FD&C Red No. 3 has been shown to cause
cancer in laboratory animals. Under the Delaney Clause this finding of
carcinogenicity renders the color additive ``unsafe'' as a matter of
law. FDA is revoking the authorizations for this substance as a color
additive to no longer provide for the use of FD&C Red No. 3 in food and
ingested drugs. Therefore, we are amending 21 CFR part 74 as set forth
in this document. We consider this action to also partially respond to
CSPI's 2008 citizen petition (Docket No. FDA-2008-P-0349).
Because the effective date for the removal of Sec. 74.303 will
occur before the effective date for the removal of Sec. 74.1303, we
are also amending Sec. 74.1303 to add the identity and specifications
from Sec. 74.303(a)(1) and (b), which are currently referenced in
Sec. 74.1303(a). This amendment will become effective on the effective
date for the removal of Sec. 74.303.
Upon the removal of these color additive listings, FDA will no
longer provide certificates for FD&C Red No. 3. In accordance with 21
CFR 80.32(h), all certificates for existing batches and portions of
batches of FD&C Red No. 3 will cease to be effective for use in food on
the effective date for the removal of Sec. 74.303 and for use in
ingested drugs on the effective date for the removal of Sec. 74.1303,
and any lots of FD&C Red No. 3 will be regarded as uncertified after
the relevant date(s). Use of FD&C Red No. 3 after its certificate
ceases to be effective will result in such food or ingested drugs being
adulterated. When FD&C Red No. 3 has been used in food or ingested
drugs while its certificate is still effective, such food or ingested
drugs will not be regarded as adulterated by reason of the use of such
color additive.
VII. Public Disclosure
In accordance with Sec. 71.15 (21 CFR 71.15), 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. 71.15, we
will delete from the documents any materials that are not available for
public disclosure.
VIII. Analysis of Environmental Impacts
We have determined under 21 CFR 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.
IX. Paperwork Reduction Act of 1995
This order contains no collection of information. Therefore,
clearance by the Office of Management and Budget under the Paperwork
Reduction Act of 1995 is not required.
X. Objections
This order is effective as shown in the DATES section, except as to
any provisions that may be stayed by the filing of proper objections
under sections 701(e)(2) and 721(d) of the FD&C Act (21 U.S.C.
371(e)(2) and 379e(d)). 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. We will publish notice of the objections that we
have received or lack thereof in the Federal Register.
XI. References
The following references marked with an asterisk (*) are on display
at the Dockets Management Staff (see ADDRESSES) 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 public
[[Page 4634]]
display at https://www.regulations.gov because they have copyright
restriction. Some may be available at the website address, if listed.
References without asterisks are available for viewing only at the
Dockets Management Staff. Although FDA verified the website addresses
in this document, please note that websites are subject to change over
time.
* 1. Memorandum from S. West-Barnette, Division of Food Ingredients,
Regulatory Review Branch, to M. Honigfort, Division of Food
Ingredients, Regulatory Review Branch, June 6, 2024.
2. SCF. Reports of the Scientific Committee for Food (21st series),
1989. Available at: http://ec.europa.eu/food/fs/sc/scf/reports/scf_reports_21.pdf (accessed January 16, 2024).
3. JECFA, Evaluation of Certain Food Additives and Contaminants:
Thirty-seventh Report, 1991. Available at: https://www.who.int/publications/i/item/9241208066 (accessed January 16, 2024).
4. JECFA, Safety Evaluation of Certain Food Additives: Eighty-sixth
Report, 2020. Available at: https://www.who.int/publications/i/item/9789240004580 (accessed January 16, 2024).
* 5. CFSAN CAC Full Committee Review, Memorandum of Meeting, October
15, 2019.
* 6. Memorandum from J. Gingrich, Division of Food Ingredients,
Toxicology Review Branch, to S. West-Barnette, Division of Food
Ingredients, Regulatory Review Branch, June 18, 2024.
* 7. Memorandum from D. Doell, Chemistry Review Group, Division of
Petition Review (DPR), Office of Food Additive Safety (OFAS), CFSAN,
FDA, to J. Kidwell, Regulatory Review Group I, DPR, OFAS, CFSAN,
FDA, September 18, 2015.
List of Subjects in 21 CFR Part 74
Color additives, Cosmetics, Drugs.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
74 is amended as follows:
PART 74--LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION
0
1. The authority citation for part 74 continues to read as follows:
Authority: 21 U.S.C. 321, 341, 342, 343, 348, 351, 352, 355,
361, 362, 371, 379e.
Sec. 74.303 [Removed]
0
2. Remove Sec. 74.303.
0
3. Revise Sec. 74.1303 to read as follows:
Sec. 74.1303 FD&C Red No. 3.
(a) Identity. (1) The color additive FD&C Red No. 3 is principally
the monohydrate of 9 (o-carboxyphenyl)-6-hydroxy-2,4,5,7-tetraiodo-3H-
xanthen-3-one, disodium salt, with smaller amounts of lower iodinated
fluoresceins.
(2) Color additive mixtures for ingested drug used made with FD&C
Red No. 3 may contain only those diluents that are suitable and that
are listed in part 73 of this chapter as safe for use in color additive
mixtures for coloring ingested drugs.
(b) Specifications. FD&C Red No. 3 shall conform to the following
specifications and shall be free from impurities other than those named
to the extent that such other impurities may be avoided by good
manufacturing practice:
(1) Volatile matter (at 135 [deg]C) and chlorides and sulfates
(calculated as the sodium salts), total not more than 13 percent.
(2) Water-insoluble matter, not more than 0.2 percent.
(3) Unhalogenated intermediates, total not more than 0.1 percent.
(4) Sodium iodide, not more than 0.4 percent.
(5) Triiodoresorcinol, not more than 0.2 percent.
(6) 2(2',4'-Dihydroxy-3', 5'-diiodobenzoyl) benzoic acid, not more
than 0.2 percent.
(7) Monoiodofluoresceins not more than 1.0 percent.
(8) Other lower iodinated fluoresceins, not more than 9.0 percent.
(9) Lead (as Pb), not more than 10 parts per million.
(10) Arsenic (as As), not more than 3 parts per million.
(11) Total color, not less than 87.0 percent.
(c) Uses and restrictions. FD&C Red No. 3 may be safely used for
coloring ingested drugs in amounts consistent with good manufacturing
practice.
(d) Labeling. The label of the color additive and any mixtures
prepared therefrom intended solely or in part for coloring purposes
shall conform to the requirements of Sec. 70.25 of this chapter.
(e) Certification. All batches of FD&C Red No. 3 shall be certified
in accordance with regulations in part 80 of this chapter.
Sec. 74.1303 [Removed]
0
4. Effective January 18, 2028 remove Sec. 74.1303.
Dated: January 10, 2025.
P. Ritu Nalubola,
Associate Commissioner for Policy.
[FR Doc. 2025-00830 Filed 1-15-25; 8:45 am]
BILLING CODE 4164-01-P