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[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
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