Rule2026-15920
Micro-Tracers, Inc.; Response to Objections and Requests for a Public Hearing
Primary source
Metadata and text below are from the Federal Register, a public-domain U.S. government work. Always verify the official published version before relying on it for any legal matter.
Published
August 5, 2026
Effective
January 15, 2027
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA or we) received objections and requests for a public hearing submitted by Buchanan Ingersoll & Rooney PC, on behalf of Micro-Tracers, Inc. (Micro-Tracers or objector), on the order granting a color additive petition (3C0323) requesting that we repeal specified regulations to no longer provide for the safe use of FD&C Red No. 3 in food (including dietary supplements) and ingested drugs. After reviewing the objections, we have concluded that the objections do not raise issues of material fact that justify a hearing. We are also providing notice that the administrative stay of the effective date for the repeal and delisting of the color additive regulations is now lifted.
Full Text
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[Federal Register Volume 91, Number 149 (Wednesday, August 5, 2026)]
[Rules and Regulations]
[Pages 50475-50482]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2026-15920]
[[Page 50475]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 74
[Docket No. FDA-2023-N-0437]
Micro-Tracers, Inc.; Response to Objections and Requests for a
Public Hearing
AGENCY: Food and Drug Administration, HHS.
ACTION: Notification; response to objections and denial of public
hearing requests; removal of administrative stay.
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SUMMARY: The Food and Drug Administration (FDA or we) received
objections and requests for a public hearing submitted by Buchanan
Ingersoll & Rooney PC, on behalf of Micro-Tracers, Inc. (Micro-Tracers
or objector), on the order granting a color additive petition (3C0323)
requesting that we repeal specified regulations to no longer provide
for the safe use of FD&C Red No. 3 in food (including dietary
supplements) and ingested drugs. After reviewing the objections, we
have concluded that the objections do not raise issues of material fact
that justify a hearing. We are also providing notice that the
administrative stay of the effective date for the repeal and delisting
of the color additive regulations is now lifted.
DATES: This order that published in the Federal Register of January 16,
2025 (90 FR 4628) with effective dates of January 15, 2027, and January
18, 2028, was administratively stayed by the filing of objections under
section 701(e)(2) of the Federal Food, Drug, and Cosmetic Act (FD&C
Act) (21 U.S.C. 371(e)(2)) as of February 18, 2025. FDA lifts the
administrative stay as of August 5, 2026. The effective dates of
January 15, 2027, and January 18, 2028, for amendatory instruction 4,
for the order published on January 16, 2025 (90 FR 4628), are
confirmed.
ADDRESSES: For access to the docket to read background documents or
comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> and insert the
docket number found in brackets in the heading of this final rule 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: 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 and International Engagement,
Human Foods Program, Food and Drug Administration, 5001 Campus Dr.,
College Park, MD 20740, 240-402-2378.
SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of February 17, 2023 (88 FR 10245), we
announced that we filed a color additive petition (CAP 3C0323)
(petition) jointly submitted by the Center for Science in the Public
Interest, Breast Cancer Prevention Partners, Center for Environmental
Health, et al. (petitioners), which proposed that we repeal the color
additive regulations for FD&C Red No. 3 at Sec. Sec. 74.303 (21 CFR
74.303) and 74.1303 (21 CFR 74.1303) to no longer provide for the safe
use of FD&C Red No. 3 in food (including dietary supplements) and
ingested drugs, respectively. The petition cited section 721(b)(5)(B)
of the FD&C Act (21 U.S.C. 379e(b)(5)(B)), often referred to as the
Delaney Clause, which deems color additives unsafe under certain
circumstances. The relevant provision, 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 of Health and Human
Services (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.
In the Federal Register of January 16, 2025 (90 FR 4628), we issued
an order titled ``Color Additive Petition from Center for Science in
the Public Interest, et al.; Request to Revoke Color Additive Listing
for Use for FD&C Red No. 3 in Food and Ingested Drugs'' (January 2025
order) amending the color additive regulations at Sec. Sec. 74.303 and
74.1303 to no longer provide for the safe use of FD&C Red No. 3 in food
(effective January 15, 2027) and ingested drugs (effective January 18,
2028), respectively. We determined that information provided in the
petition and other publicly available relevant data demonstrated that
FD&C Red No. 3 has been shown to cause cancer in male rats, and thus
its use as a color additive was deemed unsafe under the Delaney Clause
as a matter of law (90 FR 4628 at 4631). We gave interested persons
until February 18, 2025, to file objections and requests for a hearing
on the order.
II. Objections and Requests for a Hearing
Sections 701(e)(2) and 721(d) of the FD&C Act collectively provide
that, within 30 days after publication of an order relating to a color
additive regulation, any person adversely affected by such an order may
file objections, specifying with particularity the provisions of the
order deemed objectionable, stating the grounds therefor, and
requesting a public hearing upon such objections. We may deny a hearing
request if the objections to the order do not raise genuine and
substantial issues of fact that can be resolved at a hearing (Sec.
12.24(b)(1) (21 CFR 12.24(b)(1))). (See also Community Nutrition
Institute v. Young, 773 F.2d 1356, 1364 (D.C. Cir. 1985)).
Under our regulations at 21 CFR 71.30, objections and requests for
a hearing relating to color additive regulations are governed, in part,
by 21 CFR part 12. Under 21 CFR 12.22(a), each objection must: (1) be
submitted on or before the 30th day after the date of publication of
our decision; (2) be separately numbered; (3) specify with
particularity the provision of the regulation or proposed order
objected to; (4) specifically state each objection on which a hearing
is requested (failure to request a hearing on an objection constitutes
a waiver of the right to a hearing on that objection); and (5) include
a detailed description and analysis of the factual information to be
presented in support of the objection if a hearing is requested
(failure to include a description and analysis for an objection
constitutes a waiver of the right to a hearing on that objection).
Following the publication of the final order in which we granted
the petition to amend the color additive regulations to no longer
provide for the safe use of FD&C Red No. 3 in food and ingested drugs,
we received one submission from Buchanan, Ingersoll & Rooney PC, on
behalf of Micro-Tracers (see submission from Edward John Allera, Of
Counsel, Barbara A. Binzak Blumenfeld, Ph.D., Shareholder, Natalie C.
Oehlers, Associate, and Natalie Crow, Associate, Buchanan, Ingersoll &
Rooney PC (Counsel for Micro-Tracers) submitted to the Dockets
Management Staff, Food and Drug Administration, dated February 18,
2025) (submission). The submission states that it raises three specific
objections to the order and requests hearings on each of them.
We note that the submission includes a copy of comments from Micro-
Tracers on the notice of filing of the petition (submission attachment
2). However, because these comments, dated
[[Page 50476]]
November 13, 2023, were submitted after the comment period closed on
May 18, 2023 (88 FR 19026, March 30, 2023), they were not included in
the docket.
III. Standards for Granting a Hearing
The criteria for granting a hearing are set out in Sec. 12.24(b).
Under that regulation, a hearing will be granted if the material
submitted by an objector shows that: (1) there is a genuine and
substantial factual issue for resolution at a hearing (a hearing will
not be granted on issues of policy or law); (2) the factual issue can
be resolved by available and specifically identified reliable evidence
(a hearing will not be granted on the basis of mere allegations or
denials or general descriptions of positions and contentions); (3) the
data and information submitted, if established at a hearing, would be
adequate to justify resolution of the factual issue in the way sought
by the objector (a hearing will be denied if the data and information
submitted are insufficient to justify the factual determination urged,
even if accurate); (4) resolution of the factual issue in the way
sought by the objector is adequate to justify the action requested (a
hearing will not be granted on factual issues that are not
determinative with respect to the action requested, e.g., if the action
would be the same even if the factual issues were resolved in the way
sought); (5) the action requested is not inconsistent with any
provision in the FD&C Act or any FDA regulation particularizing
statutory standards (the proper procedure in those circumstances is for
the person requesting the hearing to petition for an amendment or
waiver of the regulation involved); and (6) the requirements in other
applicable regulations, e.g., 21 CFR 10.20, 12.21, 12.22, 314.200,
514.200, and 601.7(a), and in the document issuing the final regulation
or the notice of opportunity for a hearing are met.
In general, in an administrative proceeding under section 701(e) of
the FD&C Act (21 U.S.C. 371(e)), FDA is authorized to issue a decision
without holding a part 12 hearing when a party's objections do not
raise a genuine and material issue of fact that, if proved in that
party's favor, would suffice to warrant the relief requested (see
Community Nutrition Inst. v. Young, 773 F.2d 1356, 1364 (D.C. Cir.
1985), cert. denied, 475 U.S. 1123 (1986); see also Vermont Dep't of
Pub. Serv. v. FERC, 817 F.2d 127, 140 (D.C. Cir. 1987)). A party
seeking a hearing must meet a ``threshold burden of tendering evidence
suggesting the need for a hearing'' (Costle v. Pacific Legal
Foundation, 445 U.S. 198, 214-215 (1980), citing Weinberger v. Hynson,
Westcott & Dunning, Inc., 412 U.S. 609, 620-621 (1973)). An allegation
that a hearing is necessary to ``sharpen the issues'' or to ``fully
develop the facts'' does not meet this test (Georgia Pacific Corp. v.
EPA, 671 F.2d 1235, 1241 (9th Cir. 1982)). If a hearing request fails
to identify sufficient factual evidence that would be the subject of a
hearing, there is no reason to hold one. In judicial proceedings, a
court is authorized to issue summary judgment without an evidentiary
hearing whenever it finds that there are no genuine issues of material
fact in dispute, and a party is entitled to judgment as a matter of law
(see Rule 56, Federal Rules of Civil Procedure). The same principle
applies to administrative proceedings (see Sec. 12.24). In reviewing
whether an objecting party made an ``adequate proffer of evidence'' to
show that an ``actual dispute exist[s],'' courts consider whether the
dispute lies in ``a highly technical area [within] the agency's
expertise'' (see Cerro Wire & Cable Co. v. FERC, 677 F.2d 124, 129
(D.C. Cir. 1982)).
A hearing request must not only contain evidence, but that evidence
also must raise a material issue of fact ``concerning which a
meaningful hearing might be held'' (Pineapple Growers Ass'n of Haw. v.
FDA, 673 F.2d 1083, 1085 (9th Cir. 1982)). Where the issues raised in
the objection are, even if true, legally insufficient to alter the
decision, an agency need not grant a hearing (see Dyestuffs and
Chemicals, Inc. v. Flemming, 271 F.2d 281, 286 (8th Cir. 1959), cert.
denied, 362 U.S. 911 (1960)). A hearing is justified only if the
objections are made in good faith and if they raise ```material' issues
of fact'' (Pineapple Growers Ass'n, 673 F.2d at 1085 (quoting Pactra
Indus., Inc. v. CPSC, 555 F.2d 677, 684 (9th Cir. 1977)). The issues
raised in objections ``must be material to the question involved; that
is, the legality of the order attached'' (Pineapple Growers Ass'n, 673
F.2d at 1085 (quoting Dyestuffs and Chemicals, 271 F.2d at 286)). A
hearing need not be held to resolve questions of law and policy (see
Kourouma v. FERC, 723 F.3d 274, 278 (D.C. Cir. 2013) (citing Citizens
for Allegan County., Inc. v. FPC, 414 F.2d 1125, 1128 (D.C. Cir. 1969);
Sun Oil Co. v. FPC, 256 F.2d 233, 240 (5th Cir. 1958)).
IV. Analysis of Objections and Response to Hearing Requests
The submission contains three numbered objections and requests a
hearing on each objection. We address each objection below, as well as
the evidence and information filed in support of each, including our
evaluation of whether each objection and the information submitted in
support of it satisfies the standards for granting a hearing in Sec.
12.24(b).
A. Objection 1
In Objection 1, the objector states that it objects to the
``scientific basis'' for the revocation of these color additive
listings and argues that ``FDA erred in its statistical interpretation
of the data that formed the basis for FDA's decision to revoke these
two regulations'' (submission at page 20). In support of these
assertions, the objector provides an opinion titled ``Bayesian
Statistical Reanalysis of Red Dye 3 Thyroid Neoplasms'' by Lyle D.
Burgoon, Ph.D. (submission attachment 4). For purposes of our
discussion of the objector's arguments, we group them under two general
categories: (1) FDA's use of the sum of carcinomas and adenomas and (2)
FDA's analysis of the data.
First, the objector asserts that FDA should not have used the sum
of carcinomas and adenomas when determining that FD&C Red No. 3 caused
cancer in male rats. The objector argues that the Delaney Clause does
not permit FDA to consider adenomas when determining whether a color
additive ``induces cancer.'' The objector asserts ``the Delaney Clause
specifically prohibits the use of color additives . . . that will
`induce cancer' when ingested by humans or animals . . . . Carcinomas
are malignant (cancerous tumors), but adenomas are benign (non-
cancerous) tumors. Therefore, it was arguably inappropriate to include
the sum of carcinomas and adenomas when assessing the historical data''
(submission at page 21 and submission attachment 4 at page 1). The
objector also asserts that ``it is well established that thyroid
adenomas rarely become carcinomas, especially thyroid follicular
adenomas (5 percent of adenomas are reported to be cancers according to
StatPearls). Thus, it is wholly inappropriate to sum adenomas and
carcinomas, under the assumption that adenomas will become carcinomas''
(submission attachment 4 at page 2).
Second, the objector disagrees with FDA's analysis of the data. The
objector asserts that (1) FDA did not consider all of the data together
in its statistical analysis, (2) the data was unreliable, and (3) based
on his statistical analysis of the data, the ``4-percent group did not
actually see an increase in carcinomas once you consider all of the
data together, and once you consider the historical background rate of
thyroid
[[Page 50477]]
carcinomas in the vehicle animals'' (id. at pages 1 through 2).
With respect to FDA's consideration of data in its statistical
analysis, the objector asserts: ``FDA takes an antiquated approach (by
today's standards) to analyze the cancer data . . . . [R]elying
strictly on a p-value for decision making is highly inappropriate . . .
. Ronald Fisher, the father of the p-value, has stated in numerous
texts that all that a significant p-value means is that additional
testing is warranted . . . . A more robust and modern way to analyze
this data is to take a more Bayesian approach . . . The advantage of
this approach is that we can get a better sense of the background/
historical cancer rate in the vehicle control animals'' (id. at page
7). The objector asserts that FDA ``did not consider all of the data
together--it still only considers the data separately. Thus, . . . FDA
is not considering the fact of regression towards the mean nor is [FDA]
considering the impacts of small sample sizes in causing false positive
results'' (id. at page 1). The objector also asserts that ``A
reasonable scientist considers the total weight of the evidence, not
any one, singular study on its own'' (id.).
With respect to the reliability of the data, the objector asserts
that the sample sizes of the studies were ``too small to be reliable
predictors of the population response'' (submission at page 22). The
objector asserts that the ``studies included potentially confounding
variables, including differences in mean body weight, food consumption,
and thyroid follicular cell hyperplasia'' (id.). The objector further
asserts that ``Sprague-Dawley rats have a relatively high background
rate of follicular cell adenomas and carcinomas, according to
historical control data from LabCorp published in the journal
Toxicologic Pathology'' (submission attachment 4 at page 2).
With respect to conclusions made based on the objector's
statistical analysis of the data, the objector asserts that ``the 4-
percent group is not meaningfully different from the vehicle
controls,'' as evidenced by the difference distribution calculation,
and FDA should have considered the petitioners' data unreliable due to
sample bias and rejected the petition (id. at pages 11 through 12). The
objector reiterates the basis for this decision as being three-fold:
``(1) relying upon unreliable data, (2) relying upon data that showed
there was too much uncertainty to draw a conclusion (thus, the data
were unreliable), and (3) when looking at all of the data together, it
is clear that there is no evidence that the 4-percent group caused
cancers at a higher rate than the vehicle controls (i.e., FD&C Red No.
3 does not cause cancer at a rate that is biologically meaningfully
different from the background rate)'' (id. at page 12). Additionally,
the objector asserts that FDA erred when combining instances of
adenomas and carcinomas, as ``over 95 percent of adenomas do not become
carcinomas'' (id.) The objector also states that Congress, when passing
the amendment that included the Delaney Clause, was ``clear and
unambiguous'' in its understanding that the definition of ``cancer''
does not include ``benign tumors'' or ``adenomas'' (id.). Therefore,
the objector concludes that FDA ``erred and violated the clear
direction given by Congress'' in our reading of the Delaney Clause
(id.).
Finally, the objector also argues that ``FDA should have convened a
Color Additive Advisory Committee, as one comment on the Petition had
requested, because there is genuine debate about the science underlying
the Final Order'' (submission at page 22).
FDA's Response: We disagree with the objector's assertions that
that the scientific basis for our decision was erroneous or that we
erred in our statistical interpretation of the data. The objector
asserts that there is an ``ongoing controversy regarding whether [FD&C
Red No. 3] is a known animal carcinogen'' (submission attachment 4 at
page 2). However, FDA's conclusion that FD&C Red No. 3 induces cancer
in male rats, and therefore, is subject to the Delaney Clause, has long
been agreed upon by scientific experts.
First, we address the objector's arguments regarding our including
the sum of carcinomas and adenomas. The objector asserts that the
Delaney Clause does not permit FDA to consider adenomas (id. at pages 1
and 7); however, this is an issue of law, and no hearing is warranted
to adjudicate it (Sec. 12.24(b)(1)). Furthermore, the objector asserts
that ``it is well-established that thyroid adenomas rarely become
carcinomas''; however, the objector fails to support these assertions
with supporting studies and only mentions StatPearls without any
further citation (id. at page 2). These general and unsupported
assertions fail to raise a ``factual issue [that] can be resolved by
available and specifically identified reliable evidence'' (21 CFR
12.24(b)(2)).
We also conclude that the objector's arguments about including the
sum of carcinomas and adenomas do not provide a basis for amending or
revoking our January 2025 order. We discussed the rationale for
including the sum of carcinomas and adenomas in male rats administered
FD&C Red No. 3 in our denial of CAP 9C0096 (which requested the
permanent listing of FD&C Red No. 3 as a color additive for use in
cosmetics, including lipsticks and other ingested cosmetics, and
externally applied drugs) (55 FR 3520, February 1, 1990). In our
denial, which was based on the Delaney Clause, we stated that the
petition's ``failure to find a significant tumorigenic effect was
apparently because its statistical analysis treated adenomas and
carcinomas as separate tumor classes'' (id. at 3525). Specifically, we
stated that the petitioners ``apparently distinguished between
oncogenicity and carcinogenicity and between the ability of FD&C Red
No. 3 to induce adenomas and carcinomas'' (id.). We further explained
that the petitioners used this separation of tumors into adenomas and
carcinomas as the basis for later testing for statistically significant
differences of tumor incidence between treated and control groups. By
contrast, we explained that although FDA also separately analyzes the
incidences of adenomas and carcinomas, we extend our analysis further
by using the combined incidences of adenomas and carcinomas and then
statistically comparing the combined incidence of tumors in treated
animals with the control groups (id.). We concluded that our ``approach
to tumor analysis is appropriate because it is entirely sound to
interpret thyroid follicular cell adenomas as an earlier stage in a
series of progressive proliferative changes leading to the expression
of follicular cell carcinomas'' (id.). We also noted that the National
Toxicology Program (NTP) Subcommittee, in conducting its review, also
considered the combining of carcinomas and adenomas to be an
appropriate procedure (id.). As we describe below, this continues to be
NTP's approach.
We disagree with the objector's assertion that ``it is wholly
inappropriate to sum adenomas and carcinomas, under the assumption that
adenomas will become carcinomas'' (submission attachment 4 at page 2).
The Center for Food Safety and Applied Nutrition (now the Human Foods
Program (HFP))'s Cancer Assessment Committee (CAC) described the likely
mode of action which resulted in the thyroid cancer in male rats that
was observed in the Borzelleca et al. study and the weight of evidence
for that mode of action (Ref. 1) (2018 CAC Memorandum). The 2018 CAC
Memorandum states ``the committee agreed that there were hormonal key
events leading to thyroid follicular neoplasia in male rats based on
[[Page 50478]]
proliferative changes including dose- and time-dependent thyroid
follicular hyperplasia in the lifetime bioassay and hypertrophy in
shorter mechanistic studies. The committee also discussed the reported
impact of FD&C Red No. 3 on levels of serum thyroid-stimulating hormone
(TSH) and other thyroid hormones (T4/T3/rT3), and the well-
characterized causal connection between high levels of TSH in the rat
and the resulting induction of thyroid follicular cell neoplasia'' (id.
at page 8). The 2018 CAC Memorandum further states that ``the rats
exhibited a spectrum of lesions characterized as pre-neoplastic
(thyroid follicular hyperplasia), benign neoplastic (follicular cell
adenoma) and malignant neoplastic (follicular cell carcinoma, more
specifically adenocarcinoma)'' (id.). The CAC determined that increased
incidences of thyroid follicular hyperplasia and follicular cell
neoplasia (measured as combined adenomas and carcinomas) represented a
treatment-related increase in incidences of thyroid neoplasia in male
rats (id.).
As part of their discussion of the relevance of the rat mechanism
of action to thyroid carcinogenesis in other mammals, the CAC requested
input from an expert in endocrine disease in laboratory and domestic
animals. The 2018 CAC memorandum noted that the expert explained that
``veterinary pathologists agree that rat thyroid carcinogenesis in
response to TSH involves a well-characterized proliferative process of
the thyroid follicular tissue, starting with hypertrophy (initially
diffuse) followed by multifocal hyperplasia which then progresses to
adenomas and ultimately with sufficient time and dose (exposure) to
carcinomas'' (id. at page 9). The expert ``pointed out that veterinary
pathologists consider TSH an indirect carcinogen and a promoter of
neoplasia in the male rat and that as little as a two-fold chronic
increase in TSH is sufficient to initiate this proliferative process in
this species/sex'' (id.). The expert also stated that ``even if
carcinomas are not observed in a particular study, elevated TSH will
likely lead to thyroid neoplasia (adenomas and carcinomas) over time in
male rats'' (id. at page 10).
The NTP's website titled ``Cancer Evaluation Criteria'' discusses
considerations for evaluating evidence of carcinogenic activity (Ref.
2). The NTP states that considerations of carcinogenicity data should
consider that ``some benign neoplasms have the capacity to regress but
others (of the same morphologic type) progress. At present, it is
impossible to identify the difference. Therefore, where progression is
known to be a possibility, the most prudent course is to assume that
benign neoplasms of those types have the potential to become
malignant'' (id.). The NTP also states that the consideration of
carcinogenicity data should include ``combining benign and malignant
tumor incidences known or thought to represent stages of progression in
the same organ or tissue'' (id.). A guide published in 2024 by a
Working Group of biopharmaceutical experts from international societies
of toxicologic pathology (Society of Toxicologic Pathology, British
Society of Toxicologic Pathology, European Society of Toxicologic
Pathology, FDA, the International Harmonization of Nomenclature and
Diagnostic Criteria initiative, and members of the Standard for
Exchange of Nonclinical Data initiative) was published to assist
pharmacology/toxicology reviewers and biostatisticians in statistical
analysis of nonclinical tumor data (Ref. 3). The guide outlines the
approach to determining appropriate combinations of tumors for analysis
and lists the following recommendations: ``A. Combine benign tumors of
the same cell type by site for analysis. B. Combine malignant tumors of
the same cell type by site for analysis. C. Combine benign and
malignant tumors of the same cell type by site for analysis'' (id.).
Additionally, FDA conducted further analyses, which note that the
probability of adenomas progressing into carcinomas ``depends on
several factors, such as aging, changes in chromosomal stability and
altered metabolism'' (Ref. 4). We also found that the scientific
literature reports that 20 percent of nonfunctioning follicular cell
adenomas (with oncogene mutations) can progress into a carcinoma (id.).
This indicates that there is a possibility of adenomas becoming
malignant (i.e., carcinoma), and the probability of this progression
may vary depending on the organ-type, underlying mechanisms, and other
factors, as stated elsewhere in this document. In the absence of
information on such specific factors, it is not possible to estimate
the exact percentage of the chance of progression of adenomas to
carcinomas in a particular organ-type or study (id.).
The approach of combining adenomas and carcinomas has also been
used by the NTP to evaluate the potential for carcinogenicity of
substances. The NTP considers a dose-related increase in either
malignant or benign neoplasms, or the combination of malignant and
benign tumors for an organ, appropriate to determine if there is
evidence of carcinogenic activity of the test substance in the
conditions of the reviewed study (id.). Thus, FDA considers using the
combined incidences of adenomas and carcinomas as a well-established
and conservative approach to cancer risk assessment.
Second, we address the objector's arguments regarding our analysis
of the data. The objector argues that the rat carcinogenicity bioassays
were insufficiently designed, stating that ``sample sizes in the
studies cited are too small to be reliable predictors of the population
response'' and ``rat feeding studies include potentially confounding
variables, including differences in mean body weight, food consumption,
and thyroid follicular cell hyperplasia'' (submission at page 22). In
our denial of CAP 9C0096, we discussed our determination that the rat
feeding study design was appropriate (55 FR 3520). We stated ``[t]he
experimental design for the [International Research Development
Corporation (IRDC)] studies of FD&C Red No. 3 benefited from knowledge
of the protocol deficiencies in previously conducted carcinogenesis
bioassays and other chronic toxicity testing. Improvements in study
design included: (1) The use of large numbers of animals of both sexes
. . . (3) two control groups (thereby effectively doubling the number
of controls) . . . . All of these protocol changes significantly
increased the power of these tests to detect dose-related effects. For
this reason, FDA believes that the results of the IRDC chronic feeding
studies constitute a reliable basis for assessing the safety of FD&C
Red No. 3'' (id. at 3524).
Furthermore, the CAC stated that the FD&C Red No. 3 rat
carcinogenicity study was appropriately designed and that the CAC
determined in 1982-1989 that thyroid neoplasia (tumors) was induced in
male rats (Ref. 1). The rat study ``is still appropriate per current
guidelines (Redbook 2000, Chapters II.C.5.a. and IV.C.7. or IV.C.8.)
and CAC continues to consider it a positive rodent bioassay for mode of
action . . . or risk assessment evaluations'' (id.). The CAC previously
reviewed the data and information on FD&C Red No. 3 in 1984, 1985, and
1989, and the available data and information were also reviewed by a
panel convened by the NTP in 1983 and by an FDA peer review panel in
1987 (Ref. 1). These reviews all reached the conclusion that the
dietary administration of FD&C Red No. 3 at high doses (4 percent) was
associated with an increase in the incidence of thyroid follicular cell
neoplasia in male rats (id.). Furthermore, as discussed in the
toxicology memorandum supporting
[[Page 50479]]
the January 2025 order, a 1989 European Commission's Scientific
Committee for Food report and Joint FAO/WHO Expert Committee on Food
Additives also concluded that FD&C Red No. 3 causes cancer in male rats
(Ref. 5).
We disagree with the objector's assertion that ``FDA did not
consider all of the data together, instead only considering the data
separately'' (submission at page 22). Regarding the total weight of
evidence for the statistical analysis and statistical power of the
carcinogenicity study, FDA reaffirms that ``the study design and
protocol for the study were in compliance with FDA's Redbook and OECD
Test Guideline 451 for carcinogenicity studies . . . to ensure that
sufficient statistical power was achieved'' (Ref. 4). We further note
that reliance on the derived p-value to support statistical
significance is generally supportive of causation per OECD Test
Guidance 116 (id.). In addition to the statistical analysis, FDA
pathologists independently examined microslides derived from thyroid
tissues of male rats from this study and confirmed a treatment-related
increase in thyroid follicular cell neoplasia in the male rats (id.).
Thus, FDA's assessment demonstrates a consideration of ``the totality
of the available information on the study and utilized an approach
based on statistical analysis as well as pathological examination to
conclude FD&C Red No. 3 caused thyroid tumors in male rats under the
conditions of the study'' (id.).
We disagree with the objector's assertion that ``male rats fed FD&C
Red No. 3 at 4 percent of their feed did not see an increase in
carcinomas when considering all data together and the historical
background rate of thyroid carcinomas in vehicle animals'' (submission
at page 22). In our denial of CAP 9C0096, we stated our review found
14/68 or 20.6 percent follicular cell adenomas in the 4-percent group
compared with 1/68 or 1.5 percent in the controls (55 FR 3520 at 3524).
In addition, our review found carcinomas in 5/68 or 7.4 percent of the
4-percent group compared with 1/68 or 1.5 percent of the controls
(id.). FDA's analysis of the incidence of combined adenomas and
carcinomas demonstrated a statistically significant increase (p <
0.0007 in such tumors: 18/68 (26.5 percent) in the 4-percent group
compared with 2/68 (2.9 percent) in controls (id. at 3524 through
3525). Based on our evaluation of the data from the IRDC studies, we
concluded that FD&C Red No. 3 causes cancer in male rats (id. at 3525).
We note that data provided on the ``high background rate of follicular
cell adenomas'' from LabCorp, published in the journal Toxicologic
Pathology, report lifetime background instances of thyroid follicular
cell adenomas to be 2.8 percent in males and 0.7 percent in females,
and thyroid follicular cell carcinomas to be 0.9 percent in males and
0.7 percent in females. Therefore, these historical data generated from
over 3,600 rats support our evaluation that a 26.5 percent combined
incidence of thyroid follicular cell adenomas and carcinomas, as
observed in the 4-percent group, is substantially higher than the
background instance rate of 2.8 percent and is thus likely a
toxicologically relevant observation.
Furthermore, in the 2018 CAC Memorandum, we addressed the previous
findings of the CAC and a panel of the NTP. The CAC reviewed the
submitted data and information on FD&C Red No. 3 in 1984, 1985, and
1989, and the available data and information were also reviewed by a
panel convened by the NTP in 1983 and by an FDA peer review panel in
1987. These reviews all reached similar conclusions. The dietary
administration of FD&C Red No. 3 at high doses (4 percent) was
associated with an increase in the incidence of thyroid follicular cell
neoplasia in male rats (Ref. 1). Our conclusion on the results of the
rat feeding study has not changed, as discussed in the January 2025
order and supporting toxicology memorandum (90 FR 4628 and Ref. 2).
We disagree with the objector's assertion that a Bayesian
statistical approach should have been taken when analyzing the data
versus a non-Bayesian approach (Ref. 4). We note that Bayesian
statistics have the advantage of incorporating the prior distribution
or prior knowledge to strengthen the analyses, but the choice of the
prior information can influence the results and be seen as introducing
bias. In contrast, ``non-Bayesian statistics (i.e., frequentist) are
driven by the collected data only and are not affected by the
subjectivity from prior distribution or knowledge. Further, non-
Bayesian statistics have well-established protocols and interpretation
frameworks, as a result of which, such frequentist statistics are
applied for scientific research if the sample size (i.e., number of
animals per group in a study) is adequate'' (id.). Thus, frequentist
statistics are applied for analyzing data from studies with an adequate
sample size. In the carcinogenicity study of FD&C Red No. 3, the sample
size was adequate for FDA to appropriately use such statistical method
of data analysis in our conclusion that FD&C Red No. 3 induced thyroid
tumors in male rats under the conditions of the study (id.).
Third, regarding FDA's denial of a request to refer this matter to
a color additive advisory committee, neither section 701(e) of the FD&C
Act nor our regulations provide for the opportunity to submit
objections or request a hearing on such a denial. Section
721(b)(5)(C)(i) of the FD&C Act provides for the referral to an
advisory committee for a matter arising under the Delaney Clause that
requires the exercise of scientific judgement (see also 21 CFR 14.140).
We received one comment in response to the notice of filing of the
color additive petition requesting that we refer this matter to a color
additive advisory committee. In the January 2025 order, we explained
that we declined to convene a color additive advisory meeting because
there is not a genuine scientific debate on whether FD&C Red No. 3
induces cancer in male rats, and therefore, the proposal did not
require the exercise of scientific judgment (90 FR 4628 at 4632).
Because FDA's denial of this request is not the proper subject of
objections or a request for a hearing under section 701(e) or section
721(b)(5)(C)(i) of the FD&C Act, the objector's arguments do not
provide a basis for us to grant a hearing or to modify or revoke our
January 2025 order.
B. Objection 2
In Objection 2, the objector argues that FDA failed to consider:
(1) the safety of the specific use of FD&C Red No. 3 in color-coded
tracers (submission at page 22); and (2) ``additional legal uses of
FD&C Red No. 3 under the general safety provisions of the [FD&C] Act,
outside the scope of the Delaney Clause'' (id. at page 20). The
objector also references the provision in the Delaney Clause that
exempts the use of a color additive as an ingredient in feed for
animals which are raised for food production if the Secretary finds
that such additive will not adversely affect the animals for which the
feed is intended, and that no residue of the additive will be found (by
methods of examination prescribed or approved by the Secretary by
regulations) in any edible portions of such animals after slaughter or
in any food yielded by or derived from the living animal (section
721(b)(5)(B) of the FD&C Act). However, the objector does not assert
that this provision, often referred to as the Diethylstilbestrol (DES)
Proviso, applies to the intended use of FD&C Red No. 3 in color-coded
tracers.
First, the objector asserts that ``these color-coded tracers can be
safely used in
[[Page 50480]]
food-producing animals'' (id. at page 22). The objector asserts that
``considering the use levels of FD&C Red No. 3 on color-coded tracers .
. . the amount of color expected in edible animal tissue, and the human
intake of the color, the amounts are vanishingly small'' (id. at page
23). The objector provides estimates on the residues that remain in
animal feed and animal tissue (submission attachment 3 at page 2).
Therefore, the objector asserts, these amounts can be considered safe
under the general safety provisions of the FD&C Act based on the expert
statements (submission at page 23).
Second, the objector argues that the Delaney Clause does not apply
to FD&C Red No. 3 because ``[w]hen [it] is intended to be used on a
color-coded tracer as an analytical tool . . ., it is not a food
additive or a color additive; instead, it is subject to the general
safety provisions of the [FD&C] Act including [21 U.S.C. 336, 342, 351,
and 360b]'' (id. at page 15). Specifically, the objector cites 21 CFR
70.3(g), which provides that a material otherwise meeting the statutory
definition of a color additive under section 201(t) of the FD&C Act (21
U.S.C. 321(t)) can be exempt from section 721 of the FD&C Act if it is
used in a way that any color imparted is clearly unimportant insofar as
the appearance, value, marketability, or consumer acceptability is
concerned (id. at pages 16 through 17). The objector argues that colors
used as tracers are not used to change food color and do not make the
food more appealing for purchase or animal consumption, and that there
is no impact on the value or marketability of the medicated article or
feed (id. at page 17). Therefore, the objector argues that this use of
FD&C Red No 3 is not a color additive use and is not subject to the
Delaney Clause (id.).
The objector further argues that the intended use of FD&C Red No. 3
in a color-coded tracer is not a food additive use because it is not
intended to become a component of food or to affect the characteristics
of the food (id. at pages 17 through 18). The objection argues that
color used on a tracer ``is acceptable under [sections 309 and 406 of
the FD&C Act] as an unavoidable component'' (id. at page 18). The
objector argues that these are ``fact-specific issues'' that require a
hearing (id. at page 19).
FDA's Response: With regard to the objector's first argument
regarding the safety of the use of FD&C Red No. 3 in tracers, we
reiterate that our revocation of the authorization of FD&C Red No. 3
was based on a finding under the Delaney Clause that FD&C Red No. 3 can
induce cancer in male rats (90 FR 4628 at 4631). It was not based on a
finding that the intended uses are no longer safe under the general
safety clause for color additives (see section 721(b)(2)(A) of the FD&C
Act; see also 21 CFR 70.3(i): ``safe means that there is convincing
evidence that establishes with reasonable certainty that no harm will
result from the intended use of the color additive''). FDA does not
have discretion to list a color additive determined to be safe under
the general safety clause if it is found to induce cancer under the
Delaney Clause. The Delaney Clause clearly states that such color
additive ``shall be deemed unsafe, and shall not be listed'' (see
section 721(b)(5)(B) of the FD&C Act). Therefore, the objector's
argument does not demonstrate how the outcome of this proceeding would
be different if its assertions regarding the safety of this intended
use were shown to be correct. Courts have recognized the issues raised
in objections ``must be material to the question involved; that is, the
legality of the order attached'' (Pineapple Growers Ass'n of Haw., 673
F.2d at 1085). Therefore, we are denying the objector's request for a
hearing because the factual issues are not determinative with respect
to the action requested (21 CFR 12.24(b)(4)), and we conclude that the
objector has not provided a basis to modify or revoke the January 2025
order.
With regard to the objector's arguments that the intended use of
FD&C Red No. 3 in a tracer is not subject to regulation as a color
additive, these arguments are not relevant to the revocation of the
listing of FD&C Red No. 3 because the revocation does not change the
regulatory status of non-color additive uses. Therefore, these
arguments are not within the proper scope of an objection and request
for a hearing under section 701(e) of the FD&C Act and do not provide a
basis for us to grant a hearing or to modify or revoke the January 2025
order.
Nonetheless, because the objector's assertions misconstrue the
definition of a color additive, we briefly address these assertions
here to avoid future confusion on this point. Based on its intended use
in tracers (Microtracers F), FD&C Red No. 3 is regulated as a color
additive because the synthetic dye is added to iron particles used in
medicated premixes for purposes of imparting color during a quality
assurance testing phase (see 21 U.S.C. 321(t)(1); 21 CFR 70.3(f)
through (g)). Specifically, the colored iron particles are isolated
from medicated feed samples using a mason jar with a magnetic lid that
attracts the colored iron particles (Ref. 6). The colored particles are
then sprayed with a water/alcohol mixture. After spraying, the color of
the microtracer is clearly visible, which confirms the presence of a
specific medicated premix in a finished feed (Refs. 7 and 8).
Microtracer F-Red uses FD&C Red No. 3 in medicated premixes containing
the new animal drug Skycis (narasin) manufactured by Elanco (submission
attachment 3 at page 6). Microtracer FS-Red/Natural Yellow uses FD&C
Red No. 3 in combination with Natural Yellow for medicated premixes
containing Rumensin (monensin), which is also manufactured by Elanco
(id.). Micro-Tracers works with animal drug manufacturers such as
Elanco to formulate microtracers that identify their products as
proprietary (Ref. 9). This use allows consumers to confirm, based on
the color visible during the testing phase, that a medicated feed
contains Elanco's proprietary drug instead of generic or no drug at
all. Therefore, the use of the color is important with respect to the
value, marketability, and consumer acceptability of the medicated feed
and is not exempt from the definition of ``color additive'' (21 CFR
70.3(g)). Furthermore, we note that even if the intended use of FD&C
Red No. 3 were not regulated as a color additive, it would be regulated
as a food additive, which is also subject to the Delaney Clause under
section 409(c)(3) of the FD&C Act. Because FD&C Red No. 3 is
intentionally added to the tracer, it would not be considered an
``unavoidable component.''
C. Objection 3
In Objection 3, the objector argues that FDA should have either
exempted the use of FD&C Red No. 3 in tracers from the revocation of
Sec. 74.303 and 74.1303 or should have allowed its use in tracers
through the establishment of a safe tolerance level and proposes
specific regulatory language (submission at page 21 and submission
attachment 7). The objector asserts that FDA ``has not considered the
impact of the revocation of these regulations on the use of color-coded
tracers intended for use as analytical tools at safe levels of use in
medicated articles and medicated feed, nor has it exempted or proposed
a safe tolerance level for its continued use for this specific
purpose'' (submission at page 21).
FDA's Response: The objector's arguments fail to raise a genuine
and substantial issue of fact, and therefore, they do not warrant a
hearing (21 CFR 12.24(b)(1)). Nor do the objector's arguments provide a
basis for FDA to
[[Page 50481]]
modify or revoke the January 2025 order. The only exemption provided
for under the Delaney Clause is the DES Proviso. As noted in the
discussion of Objection 2, although the objector references the DES
Proviso (submission at page 10), the objector has not taken the steps
under FDA's regulations to obtain this exemption. The DES Proviso
requires a method of examination, as prescribed or approved by
regulation, to show that no residue of a color additive will be found
in food derived from animals that consume feed containing that color
additive (section 721(b)(5)(B) of the FD&C Act). This method of
examination is known as a ``regulatory method.'' FDA has codified the
steps a sponsor of a compound must follow to establish a regulatory
method in 21 CFR part 500, subpart E. Notably, the sponsor is
responsible for submitting a proposed method and providing data to show
that the method satisfies FDA's operational definition of ``no
residue'' (see 21 CFR 500.88). There is no approved regulatory method
for FD&C Red No. 3, and the objector does not assert that the necessary
data exist to establish a method that complies with the requirements of
section 721(b)(5)(B) of the FD&C Act and 21 CFR part 500, subpart E.
Without this information, there is no genuine and substantial issue of
fact for resolution at a hearing regarding the potential applicability
of the DES Proviso to FD&C Red No. 3 as used in color-coded tracers in
medicated animal feed (see 21 CFR 12.24(b)(1)).
The DES Proviso cannot exempt the use of FD&C Red No. 3 on tracers
used in animal feed unless a proponent demonstrates to FDA that such
use will not adversely affect the animals for which such feed is
intended, and that no residue of the additive will be found in any
edible portion of such animals after slaughter or in any food yielded
by or derived from the living animal under an approved regulatory
method (see section 721(b)(5)(B) of the FD&C Act). A proponent must
provide the required data to FDA to establish a regulatory method (21
CFR 500.88). Because there is no approved regulatory method, the DES
Proviso does not exempt the use of FD&C Red No. 3 in color-coded
tracers in animal feed from the Delaney Clause.
Although the objector states that FDA could set a tolerance for the
use of FD&C Red No. 3 in color-coded tracers in animal feed, the term
``tolerance'' is legally incompatible with the requirements of the DES
Proviso. ``Tolerance'' refers to the maximum concentration of a marker
residue, or other residue indicated for monitoring, that can legally
remain in a specific edible tissue of a treated animal (21 CFR 556.3).
Under the DES Proviso, there must be ``no residue'' of a carcinogenic
color additive found in edible tissue or food yielded from the treated
animal. In other words, the approved regulatory method cannot find any
level of the carcinogenic color additive.
Furthermore, establishing a tolerance limitation for a color
additive requires that the proposed use of the color additive be deemed
safe (section 721(b)(7) of the FD&C Act). However, as discussed
elsewhere in this document, a color additive must be deemed unsafe 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 (section 721(b)(5)(B) of the
FD&C Act). Because FD&C Red No. 3 has been found to induce tumors in
male rats, it is deemed unsafe as a color additive under the Delaney
Clause. As such, the Secretary cannot establish a tolerance limitation
for FD&C Red No. 3.
V. Summary and Conclusions
After evaluating the objections, we conclude that the submission
does not provide a basis to support modifying or revoking the denial of
CAP 3C0323. Therefore, we are overruling the objections and denying the
requests for a public hearing.
Under sections 701(e)(2) and 721(d) of the FD&C Act, the filing of
objections operates to stay automatically the effectiveness of our
repeal of Sec. Sec. 74.303 and 74.1303 until we take final action on
the objections. We have completed our evaluation of the objections and
conclude that a continuation of the administrative stay of the
effective dates for the repeal of Sec. Sec. 74.303 and 74.1303 is not
warranted.
In the absence of any other objections and requests for a hearing,
we conclude that this document constitutes final action on the
objections received in response to the January 2025 order as prescribed
in section 701(e)(2) of the FD&C Act. Under Sec. 12.28, we are
providing notice of our denial and confirming the effective dates of
the January 2025 order. Therefore, we are ending the administrative
stay of the January 2025 order, and under the January 2025 order we are
repealing the listing for FD&C Red No. 3 in Sec. 74.303 as a color
additive in food and Sec. 74.1303 as a color additive in ingested
drugs effective January 15, 2027, and January 18, 2028, respectively.
FDA is repealing these authorizations in a manner consistent with its
international obligations. This decision is consistent with the United
States' long-standing Appropriate Level of Protection regarding
carcinogenic additives in food, which seeks to eliminate exposure to
additives that have been found to induce cancer in man or animals.
VI. 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>. References without asterisks are not on public
display at <a href="https://www.regulations.gov">https://www.regulations.gov</a>, 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. Center for Food Safety and Applied Nutrition CAC Full Committee
Review, Memorandum of Meeting, October 15, 2019.
* 2. National Institutes of Health, National Toxicology Program.
``Cancer Evaluation Criteria.'' <a href="http://NIH.gov">NIH.gov</a>. Accessed February 2, 2026.
Available at <a href="https://ntp.niehs.nih.gov/whatwestudy/testpgm/cartox/criteria">https://ntp.niehs.nih.gov/whatwestudy/testpgm/cartox/criteria</a>.
3. Keenan, C., M. Al-Haddawi, J.G. Bienvenu, et al. ``Guide for
Combining Primary Tumors for Statistical Analysis in Rodent
Carcinogenicity Studies.'' Toxicologic Pathology, 52(1):13-20, 2024.
Accessed February 2, 2026. Available at <a href="https://doi.org/10.1177/01926233241230553">https://doi.org/10.1177/01926233241230553</a>.
* 4. Memorandum from T. Cheng, Division of Food Contact Substances,
Toxicology Review Branch, to J. Gingrich, Division of Food
Ingredients, Toxicology Review Branch, May 1, 2026.
* 5. 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.
6. Micro-Tracers, Inc. ``Quality Assurance with Microtracer F.''
July 2013. Accessed February 2, 2026. Available at <a href="https://microtracers.com/wp-content/uploads/2020/04/A-1-Quality-Assurance-with-Microtracer-F-6-12-13-ZE-1.pdf">https://microtracers.com/wp-content/uploads/2020/04/A-1-Quality-Assurance-with-Microtracer-F-6-12-13-ZE-1.pdf</a>.
7. Micro-Tracers, Inc. ``Micro-Tracers Mason Jar Procedure.'' July
2022. Accessed February 2, 2026. Available at <a href="https://www.youtube.com/watch?v=pJ2anNgrdyk">https://www.youtube.com/watch?v=pJ2anNgrdyk</a>.
8. Huvepharma. ``Microtracer Colour Card.'' 2019. Accessed February
2, 2026. Available at <a href="https://microtracers.com/wp-content/uploads/2019/10/huvepharma_color_card_3c-1.pdf">https://microtracers.com/wp-content/uploads/2019/10/huvepharma_color_card_3c-1.pdf</a>.
[[Page 50482]]
9. Micro-Tracers, Inc. ``Our Story.'' 2025. Accessed September 30,
2025. Available at <a href="https://microtracers.com">https://microtracers.com</a>.
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2026-15920 Filed 8-4-26; 8:45 am]
BILLING CODE 4164-01-P
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</html>Indexed from Federal Register on August 5, 2026.
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