[Federal Register Volume 90, Number 133 (Tuesday, July 15, 2025)]
[Rules and Regulations]
[Pages 31586-31590]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2025-13175]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 73
[Docket No. FDA-2021-C-0522]
Listing of Color Additives Exempt From Certification; Gardenia
(Genipin) Blue
AGENCY: Food and Drug Administration, HHS.
ACTION: Final amendment; order.
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[[Page 31587]]
SUMMARY: The Food and Drug Administration (FDA or we) is amending the
color additive regulations to provide for the safe use of gardenia
(genipin) blue in various foods, at levels consistent with good
manufacturing practice (GMP). We are taking this action in response to
a color additive petition (CAP) submitted by Exponent, Inc., on behalf
of the Gardenia Blue Interest Group (GBIG).
DATES: This order is effective August 29, 2025. See section XI for
further information on the filing of objections. Submit either
electronic or written objections and requests for a hearing on the
order by August 14, 2025.
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 August
14, 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-2021-C-0522 for ``Listing of Color Additives Exempt from
Certification; Gardenia (genipin) blue.'' 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 comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.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: Stephen DiFranco, Office of Pre-market
Additive Safety, Human Foods Program, Food and Drug Administration,
5001 Campus Dr., College Park, MD 20740, 240-402-2710; or Deirdre
Jurand, 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:
I. Introduction
In a document published in the Federal Register on June 30, 2021
(86 FR 34664), we announced that we filed a color additive petition
(CAP 1C0319) submitted by GBIG, c/o Exponent, Inc., 1150 Connecticut
Ave. NW, Suite 1100, Washington, DC 20036. The petition proposed to
amend the color additive regulations in part 73 (21 CFR part 73),
``Listing of Color Additives Exempt from Certification,'' to provide
for the safe use of gardenia (genipin) blue at levels consistent with
GMP in (1) sport drinks, (2) flavored or enhanced non-carbonated water,
(3) fruit drinks and ades, (4) ready-to-drink teas, (5) hard candy, and
(6) soft candy.
II. Background
Gardenia (genipin) blue is a dark purple or dark blue liquid or
powder prepared by the polymerization of genipin obtained from the
fruit of Gardenia jasminoides Ellis with soy protein hydrolysate.
Gardenia (genipin) blue is mainly composed of a genipin-peptide polymer
(the principal coloring component), carriers (for powder form), and
water (for liquid form).
The color additive is manufactured by sourcing, drying, and
crushing the mature fruit of Gardenia jasminoides Ellis. The fruit is
used to produce the raw material for manufacture of gardenia (genipin)
blue because it contains iridoid glycosides, of which 3-8 percent is
geniposide. The soluble components are extracted using a mixture of
ethanol and water, and the solids are removed by filtration. The
extract is further refined to obtain genipin, which is reacted with soy
protein hydrolysate, followed by polymerization to produce the liquid
form of the principal coloring component (genipin-peptide polymer).
Optionally, the finished liquid may be mixed with a food-grade carrier
(dextrin or maltodextrin) and the mixture heat-sterilized, spray-dried
to powder, and sieved to produce the color additive as a powder (Ref.
1).
The raw material for gardenia (genipin) blue contains carboxymethyl
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functional groups, which may hydrolyze into methanol under the aqueous
conditions of the manufacturing process. Any methanol formed is likely
to be removed along with ethanol during the concentration steps in the
manufacturing process, as well as in the final drying step for the
powder form.
The petitioner proposed specifications for gardenia (genipin) blue
of not more than 5 milligrams per kilogram (mg/kg) (5 parts per million
(ppm)) of unreacted genipin, not more than 80 mg/kg (80 ppm) of
geniposide, not more than 6 mg/kg (6 ppm) of methanol, not more than 2
mg/kg (2 ppm) of arsenic, not more than 1 mg/kg (1 ppm) of cadmium, not
more than 2 mg/kg (2 ppm) of lead, and not more than 1 mg/kg (1 ppm) of
mercury.
III. Safety Evaluation
Under section 721(b)(4) of the Federal Food, Drug, and Cosmetic Act
(FD&C Act) (21 U.S.C. 379e(b)(4)), a color additive may not be listed
for a particular use unless the data and other information available to
FDA establish that the color additive is safe for that use. Our color
additive regulations, at 21 CFR 70.3(i), define ``safe'' to mean that
there is convincing evidence establishing with reasonable certainty
that no harm will result from the intended use of the color additive.
To establish with reasonable certainty that a color additive
intended for use in foods is not harmful under its intended conditions
of use, we consider the projected human dietary exposure to the color
additive, the additive's toxicological data, and other relevant
information (such as published literature) available to us. We compare
the estimated dietary exposure to the color additive from all dietary
sources to an acceptable daily intake (ADI) that is established by
toxicological data. The dietary exposure is determined by projections
based on the amount of the color additive intended for use in
particular foods and on data regarding the amount consumed from all
sources of the color additive. We commonly use the dietary exposure for
the 90th percentile consumer of a color additive as a measure of high
chronic dietary exposure.
IV. Safety of the Petitioned Use of the Color Additive
A. Dietary Exposure Estimate
The petitioner provided information on the proposed food categories
and the corresponding maximum use levels of gardenia (genipin) blue as
a color additive that represent levels consistent with GMP for each
proposed food category (Refs. 2 and 3). The petitioner used food
consumption data from the 2013-2016 National Health and Examination
Survey (NHANES) to estimate the dietary exposure to gardenia (genipin)
blue from the proposed uses. The petitioner estimated the eaters-only
dietary exposure to gardenia (genipin) blue to be the following:
32 mg/person (p)/day (d) (0.57 mg/kg body weight (bw)/d)
at the mean and 72 mg/p/d (1.27 mg/kg bw/d) at the 90th percentile for
the U.S. population aged 2 years and older; and
32 mg/p/d (1.90 mg/kg bw/d) at the mean and 73 mg/p/d
(4.60 mg/kg bw/d) at the 90th percentile for children aged 2-5 years.
The petitioner indicated that gardenia (genipin) blue could contain
up to 40 percent of the genipin-peptide polymer (the principal coloring
component). Assuming a maximum content of 40 percent of the genipin-
peptide polymer in the color additive, the petitioner estimated an
eaters-only dietary exposure to the principal coloring component from
the proposed uses to be 13 mg/p/d at the mean and 29 mg/p/d at the 90th
percentile for the U.S. population aged 2 years and older and for
children 2-5 years (Ref. 2). We concur with this approach to estimating
the dietary exposure to both the color additive and the genipin-peptide
polymer content expected in the diet from the petitioned uses (Ref. 2).
B. Toxicological Considerations
To support the safety of the petitioned use of gardenia (genipin)
blue, the petitioner provided unpublished safety data, data derived
from publicly available databases, and peer-reviewed studies. These
data included a mutagenicity and genotoxicity battery composed of (1) a
bacterial reverse mutation (Ames) test, (2) an in vitro mammalian
chromosomal aberration test, (3) an in vitro micronucleus test, (4) an
in vivo micronucleus assay (comet assay), (5) an in vivo reverse comet
assay, (6) an in vivo Pig-a gene mutation assay, and (7) a combined
chronic oral toxicity and carcinogenicity study. Data were provided
addressing the color additive's absorption, distribution, metabolism,
and excretion (ADME) profile, including studies using [\14\C]
radiolabled gardenia (genipin) blue in male and female rats and mice.
Further, the petitioner discussed the safety of genipin and geniposide
and potential residual impurities from the manufacturing of gardenia
(genipin) blue. The petitioner provided published literature on the
safety of genipin and genipinoside that addressed the safety of
exposure to these impurities. Unreacted genipin was not detected in the
final product.
The petitioner found no evidence suggesting that gardenia (genipin)
blue has been associated with any allergic or hypersensitivity
reactions. The allergenicity potential of gardenia (genipin) blue was
assessed via a search of the publicly available databases. The
petitioner found no available information that would suggest gardenia
(genipin) blue itself has allergenic potential. We concur with this
finding and find no additional data suggesting either genipin or
gardenia (genipin) blue is associated with allergic or hypersensitivity
reactions (Ref. 3).
The petitioner also addressed a potential allergenicity arising
from the use of soy protein hydrolysate in the manufacture of the color
additive and stated that allergens related to soy protein are not
expected to be detected in the final color additive since unreacted
protein hydrolysate is removed during manufacturing (Refs. 1, 3). In
support of this claim, the petitioner provided results of an enzyme-
linked immunoassay test that showed non-detectable levels of soy
protein residue in the final article of commerce (Ref. 3). The
petitioner included data from a 12-month chronic oral toxicity study
that used multiple doses of gardenia (genipin) blue. This study also
included an in utero exposure phase assessed at interim timepoints to
determine if reproductive toxicity hazards existed from the petitioned
use levels of gardenia (genipin) blue. We note that this study adheres
to the Redbook 2000 guidelines for carcinogenicity or chronic toxicity
studies, and that the study reported no adverse effects up to a nominal
concentration of 5 percent gardenia (genipin) blue in feed for rats
under the conditions of this study. Additionally, we identified no
deficiencies that would invalidate the study results for its intended
purpose, and no results from this study suggest that gardenia (genipin)
blue is a reproductive or developmental toxicant (Ref. 3). From this
chronic study, the petitioner determined a no-adverse-effect-level
(NOAEL) of 2854.5 and 3465.4 mg/kg bw/d in the parental generation
(males and females, respectively), and 3113.5 and 4049.6 mg/kg bw/d in
their offspring (males and females, respectively).
FDA searched the publicly available literature to identify any new
studies since the submission of the petition that might have examined
toxicological effects of gardenia (genipin) blue, or genipin or related
compounds. We
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found four new relevant publications, two of which reported data that
were part of the original submission: (1) the previously reviewed 12-
month in utero exposure study in rats; (2) the previously reviewed
absorption, distribution, metabolism and excretion studies of
[\14\C]Gardenia Blue in rats and mice; (3) an extended one-generation
reproductive toxicity study in rats; and (4) a combined 12-month
chronic oral toxicity and 24-month carcinogenicity study in rats, which
uses the same dosage scheme as the 12-month chronic oral tocicity study
with an in utero exposure phase that was provided with the petition.
The petitioner provided the full study report for the combined 12-month
chronic oral toxicity and 24-month carcinogenicity study in rats. We
determined that the chronic 24-month carcinogencity study was the most
appropriate study for deriving an ADI (Ref. 3). This study establishes
a NOAEL of 2175.3 mg/kg bw/day from the highest dose tested. After
applying a 100-fold safety factor, we determined the ADI of gardenia
(genipin) blue to be 21.75 mg/kg bw/d (Ref. 3).
Based on our review of the safety data provided by the petitioner,
including published and unpublished toxicology studies, and our review
of the publicly available literature, which do not present evidence of
safety concerns for gardenia (genipin) blue or residual impurities at
the expected dietary exposures, and given that the estimated 90th
percentile exposure for the color additive (1.27 mg/kg bw/d) does not
exceed the ADI, we conclude that gardenia (genipin) blue is safe for
the petitioned uses.
C. Allergen Labeling
Gardenia (genipin) blue is produced using soy protein hydrolysate.
Section 403(w)(1) of the FD&C Act (21 U.S.C. 343(w)(1)) requires that
the label of a food that is or contains an ingredient that contains a
major food allergen declare the allergen's presence. The FD&C Act
defines a ``major food allergen'' as one of nine foods or food groups
(i.e., milk, eggs, fish, Crustacean shellfish, tree nuts, peanuts,
wheat, soybeans, and sesame) or a food ingredient that contains protein
derived from one of those foods (21 U.S.C. 321(qq)). Because soy
protein hydrolysate is used in the manufacturing of gardenia (genipin)
blue, this color additive requires allergen labeling under the FD&C
Act, unless an exemption from the food allergen labeling requirements
is obtained through submission and approval of a petition containing
scientific evidence that demonstrates that the ingredient ``does not
cause an allergic response that poses a risk to human health'' (section
403(w)(6) of the FD&C Act (21 U.S.C. 343(w)(6))). On September 29,
2022, GBIG submitted a petition to FDA seeking a food allergen labeling
exemption from the requirements of section 403(w)(1) of the FD&C Act
(21 U.S.C. 343(w)(1)) for gardenia (genipin) blue. The petition is
currently under review.
VI. Conclusion
Based on the data and other information in the petition and other
available relevant information, we conclude that the petitioned use of
gardenia (genipin) blue as a color additive at levels consistent with
GMP in (1) sport drinks; (2) flavored or enhanced non-carbonated water;
(3) fruit drinks and ades; (4) ready-to-drink teas; (5) hard candy; and
(6) soft candy is safe.
We further conclude that this color additive will achieve its
intended technical effect and is suitable for the petitioned use (Ref.
1). Therefore, we are amending the color additive regulations in part
73 to provide for the safe use of this color additive. In addition,
based on the factors in our regulations, at 21 CFR 71.20(b), we
conclude that batch certification of gardenia (genipin) blue is not
necessary to protect the public health (Ref. 1).
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 Impact
As stated in the June 30, 2021 Federal Register document for CAP
1C0319 (86 FR 34664), the petitioner claimed that this action is
categorically excluded under Sec. 25.32(k) (21 CFR 25.32(k)) because
the substance is intended to remain in food through ingestion by
consumers and is not intended to replace macronutrients in food. We
further stated that if FDA determines a categorical exclusion applies,
neither an environmental assessment nor an environmental impact
statement is required. We did not receive any new information or
comments regarding this claim of categorical exclusion. We considered
the petitioner's claim of categorical exclusion and determined that
this action is categorically excluded under Sec. 25.32(k) (Ref. 4).
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. Section 301(ll) of the FD&C Act
Our review of this petition was limited to section 721 of the FD&C
Act (21 U.S.C. 379e). This order is not a statement regarding
compliance with other sections of the FD&C Act. For example, section
301(ll) of the FD&C Act (21 U.S.C. 331(ll)) prohibits the introduction
or delivery for introduction into interstate commerce of any food that
contains a drug approved under section 505 of the FD&C Act (21 U.S.C.
355), a biological product licensed under section 351 of the Public
Health Service Act (42 U.S.C. 262), or a drug or biological product for
which substantial clinical investigations have been instituted and
their existence has been made public, unless one of the exemptions in
section 301(ll)(1) to (4) of the FD&C Act applies. In our review of
this petition, we did not consider whether section 301(ll) of the FD&C
Act or any of its exemptions apply to food containing this color
additive. Accordingly, this order should not be construed to be a
statement that a food containing this color additive, if introduced or
delivered for introduction into interstate commerce, would not violate
section 301(ll) of the FD&C Act. Furthermore, this language is included
in all color additive orders that pertain to food and therefore should
not be construed to be a statement of the likelihood that section
301(ll) of the FD&C Act applies.
XI. 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.
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
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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.
XII. References
The following references 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 are also
available electronically at https://www.regulations.gov. FDA has
verified the website addresses, as of the date this document publishes
in the Federal Register, but websites are subject to change over time.
1. Memorandum from N. Belai, Color Technology Branch, Division of
Color Certification and Technology, Office of Cosmetics and Colors,
Office of the Chief Scientist, FDA to S. DiFranco, Division of Food
Ingredients (DFI), Office of Pre-market Additive Safety (OPMAS),
HFP, FDA, July 1, 2025.
2. Memorandum from H. Lee, Chemistry Evaluation Branch, DFI, OPMAS,
HFP, FDA to S. DiFranco, DFI, OPMAS, HFP, FDA, July 1, 2025.
3. Memorandum from J. Gingrich, Toxicology Review Branch, DFI,
OPMAS, HFP, FDA to S. DiFranco, DFI, OPMAS, HFP, FDA, July 1, 2025.
4. Memorandum from M. Pfeil, Lead Biologist, Environmental Review
Team, OPMAS, HFP, FDA to S. DiFranco, DFI, OPMAS, HFP, FDA, July 1,
2025.
List of Subjects in 21 CFR Part 73
Color additives, Cosmetics, Drugs, Foods, Medical devices.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
the authority delegated to the Commissioner of Food and Drugs, 21 CFR
part 73 is amended as follows:
PART 73--LISTING OF COLOR ADDITIVES EXEMPT FROM CERTIFICATION
0
1. The authority citation for part 73 continues to read as follows:
Authority: 21 U.S.C. 321, 341, 342, 343, 348, 351, 352, 355,
361, 362, 371, 379e.
0
2. Add Sec. 73.168 to subpart A to read as follows:
Sec. 73.168 Gardenia (genipin) blue.
(a) Identity. (1) The color additive gardenia (genipin) blue is
prepared by reacting genipin extracted from the fruit of Gardenia
jasminoides Ellis with soy protein hydrolysate. The color additive
contains a genipin-peptide polymer as the principal coloring component.
(2) Color additive mixtures for food use made with gardenia
(genipin) blue may contain only those diluents that are suitable and
are listed in this subpart as safe for use in color additive mixtures
for coloring foods.
(b) Specifications. Gardenia (genipin) blue must conform to the
following specifications and must be free from impurities, other than
those named, to the extent that such other impurities may be avoided by
good manufacturing practice:
(1) Genipin, not more than 5 milligram per kilogram (mg/kg) (5 part
per million (ppm)).
(2) Geniposide, not more than 80 mg/kg (80 ppm).
(3) Methanol, not more than 6 mg/kg (6 ppm).
(4) Lead, not more than 2 mg/kg (2 ppm).
(5) Arsenic, not more than 2 mg/kg (2 ppm).
(6) Mercury, not more than 1 mg/kg (1 ppm).
(7) Cadmium, not more than 1 mg/kg (1 ppm).
(c) Uses and restrictions. Gardenia (genipin) blue may be safely
used in amounts consistent with good manufacturing practice for
coloring sport drinks, flavored or enhanced noncarbonated water, fruit
drinks and ades, ready-to-drink teas, hard candy, and soft candy,
except that it may not be used for coloring foods for which standards
of identity have been issued under section 401 of the Federal Food,
Drug, and Cosmetic Act, unless the use of added color is authorized by
such standards.
(d) Labeling requirements. The label of the color additive and any
mixtures prepared therefrom intended solely or in part for coloring
purposes must conform to the requirements of Sec. 70.25 of this
chapter. The label of the powdered form of the additive must also
declare any additional ingredients used in its manufacture.
(e) Exemption from certification. Certification of this color
additive is not necessary for the protection of the public health, and
therefore batches of the color additive are exempt from the
certification requirements of section 721(c) of the Federal Food, Drug,
and Cosmetic Act.
Dated: July 9, 2025.
Martin A. Makary,
Commissioner of Food and Drugs.
[FR Doc. 2025-13175 Filed 7-14-25; 8:45 am]
BILLING CODE 4164-01-P