[Federal Register Volume 60, Number 71 (Thursday, April 13, 1995)]
[Rules and Regulations]
[Pages 18736-18739]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-9178]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 73
[Docket No. 87C-0316]
Listing of Color Additives Exempt From Certification; Astaxanthin
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending the color
additive regulations to provide for the safe use of astaxanthin as a
color additive in the feed of salmonid fish to enhance the color of
their flesh. This action is in response to a petition filed by
Hoffmann-La Roche, Inc.
DATES: Effective May 16, 1995, except as to any provisions that may be
stayed by the filing of proper objections; written objections and
request for a hearing by May 15, 1995.
ADDRESSES: Submit written objections to the Dockets Management Branch
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr.,
Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: James C. Wallwork, Center for Food
Safety and Applied Nutrition (HFS-217), Food and Drug Administration,
200 C St. SW., Washington, DC 20204, 202-418-3078.
SUPPLEMENTARY INFORMATION:
I. Background
In a notice published in the Federal Register of December 2, 1987
(52 FR 45867), FDA announced that a color additive petition (CAP
7C0211) had been filed by Hoffmann-La Roche, Inc., 340 Kingsland St.,
Nutley, NJ 07110-1199. The petition requested that the color additive
regulations in part 73 (21 CFR part 73) be amended to provide for the
safe use of astaxanthin as a color additive in the feed of salmonid
fish. The petition was filed under section 706(d) (now section 721(d))
of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 376(d)
(now 379e(d)).
II. Safety of the Petitioned Use
Astaxanthin is 3, 3'-dihydroxy-, -carotene-4, 4'-
dione. Pure crystalline astaxanthin must be stored in the absence of
light, heat, and oxygen to minimize chemical changes and decomposition
that would result in loss of color. Thus, it is necessary to produce a
stabilized form of astaxanthin for it to be marketed for addition to
salmonid feed for the purpose of coloring the fish flesh.
The petitioner manufactures crystalline astaxanthin in a stabilized
beadlet form and has presented evidence in the petition to establish
the length of the shelf-life of this beadlet. Under Sec. 70.25(a)(4)
(21 CFR 70.25(a)(4)), expiration dates for the product in sealed and
open containers must be stated on the label of a color additive. FDA
finds that, given the concerns about shelf life, the expiration dates
are a material fact that must be disclosed on the label of the product
under sections 201(n) and 403(a)(1) of the act (21 U.S.C. 321(n) and
343(a)(1).
Astaxanthin occurs in the flesh of wild salmon at levels ranging
from about 4 to 34 parts per million and is responsible for its pink or
red coloration (Ref. 1). Wild salmon consume astaxanthin as a component
of their natural diet and deposit a portion of the astaxanthin
unchanged in their flesh
[[Page 18737]]
(Ref. 2). The amount of astaxanthin that FDA is permitting for use in
finished feed (80 milligrams per kilogram (mg/kg), 72 grams (g) per
ton) (Sec. 73.35(c)(2)) will result in depositions of the color
additive in the flesh that will produce a coloration comparable to that
in the flesh of wild salmon. This conclusion is supported by the
similar values reported for astaxanthin levels in the flesh of
aquacultured salmon used in the pigmenting experiments in the petition
and in the flesh of wild salmon (Ref. 2). FDA has estimated that this
level of astaxanthin in fish flesh, whether caught in the wild or
aquacultured, will result in a mean consumer exposure of 15 micrograms/
person/day (/p/d) and a 90th percentile exposure of 29
/p/d.
FDA has evaluated the data in the petition and other relevant
information on astaxanthin and concludes that the petitioned use of the
color additive is safe. This conclusion is based on the following
facts: (1) The very small amount of astaxanthin deposited in salmonid
flesh that will result from the petitioned use; (2) synthetic
astaxanthin differs only in its optical isomeric distribution from
astaxanthin present in the flesh of wild salmon; and (3) human exposure
to astaxanthin from consumption of aquacultured salmon fed synthetic
astaxanthin is comparable to the exposure to astaxanthin from wild
salmon. In addition, the petitioner has submitted results from short-
term and long-term toxicity studies using synthetic astaxanthin. The
results of these studies support the conclusion that there is a
reasonable certainty of no harm from the petitioned use of astaxanthin
(Ref. 3).
FDA is adopting an identity and specifications for the color
additive in Sec. 73.35(a) and (b) to characterize the additive that has
been evaluated and to ensure its safe manufacture and use.
III. Comments on the Petition
Beginning in late 1992, FDA received a total of 21 letters that
were submitted as comments on the petition. One comment from a State
agency and one comment from a trade association endorsed the petitioned
use of astaxanthin. A manufacturer of Phaffia yeast, a source of
astaxanthin used in some foreign countries, submitted a series of five
comments containing considerable information on Phaffia yeast and
requested that the agency also grant approval for this source, and all
other safe and suitable sources, of astaxanthin. The comment also
requested that FDA grant authority for other parties to make
independent determinations that other sources of astaxanthin may be
considered safe and suitable sources of the color additive for use in
aquaculture.
The remaining 14 comments from a trade association, a foreign
national organization, 4 commercial companies, and 8 academic and
research institutes, generally supported the view that the regulation
for astaxanthin should be written to include all safe and suitable
sources of the color additive. One of the comments requested that the
regulation listing astaxanthin for use in salmonid feed be written to
include the comment's strain of Phaffia yeast as a source of
astaxanthin.
As justification for these requests, the comments asserted that
there should be no safety concerns with the use of astaxanthin for
coloring the flesh of fish because astaxanthin occurs in nature,
coloring the flesh of wild salmonids, and also because it occurs in a
variety of sources in nature that are consumed without harm as food by
wild fish and other wild animals. The comments also suggested that it
would be advantageous to the aquaculture# industry to be able to use as
many sources of astaxanthin as possible, and that it would be an
efficient use of the industry and FDA's resources if petitions for
these products did not have to be submitted and reviewed individually
by the agency. In the event that FDA was unable or unwilling to expand
the final regulation as requested, one comment requested that the
agency modify the specifications for astaxanthin requested by the
petitioner to authorize the use of other sources of astaxanthin,
including the source of astaxanthin used by the comment. The comment
specifically requested that the proposed specifications for astaxanthin
be modified to include a higher percentage of the cis isomer and a 10-
fold increase in carotenoids other than astaxanthin.
FDA has reviewed these comments and finds that two of the comments
fully support the petition, and that none of the comments has raised
concerns about the safety of astaxanthin or about its technical
effectiveness for the petitioned use. Thus, the agency concludes that
all the comments fully support FDA's conclusions regarding the safety
of astaxanthin for the petitioned use.
FDA has considered whether it should expand the scope of the
listing regulation to include Phaffia yeast and other materials
containing astaxanthin. The regulation set forth below does not specify
the source of astaxanthin or the manufacturing process because the
agency has made its safety determination based on the chemical
similarity of synthetic astaxanthin to astaxanthin from natural
sources. Therefore, any source could be used to produce the color
additive as long as the astaxanthin meets the identity, specifications,
and stability requirements defined in Sec. 73.35, and it is
manufactured in accordance with good manufacturing practice. However,
the specifications are listed to convey the fact that FDA has evaluated
only a particular form of the color additive.
Several of the comments have requested that they be allowed to use
a product derived from an organism such as Phaffia rhodozyma as a color
additive without isolating the astaxanthin. Thus, they wish to market a
biomass product that contains only a small amount of astaxanthin with
the rest of the material being residues from the organism. The agency
is concerned that deleterious materials may be included in fish feed
from these sources because they are not found in the habitat of
salmonids. Thus, interested parties should submit information
supporting the safety of these products, and that they perform their
intended effect, in the form of a new color additive petition to
demonstrate that provision for these materials should be made in
Sec. 73.35.
FDA also concludes that it cannot expand the scope of this petition
because an expanded review would require additional time to evaluate
the safety and suitability of other materials containing astaxanthin.
Such a review would cause an avoidable delay in the issuance of a final
rule for the petitioned use of the color additive. FDA believes that
such a delay would be unfair to the petitioner. The petitioner has
stated that it would be unwilling to acquiesce in such a delay. Any
such delay could cause significant economic loss to the petitioner and
could be responsible for a significant delay in the use of astaxanthin
by the United States aquaculture industry. Thus, FDA concludes that it
is appropriate to require that those parties who wish to use
astaxanthin products that do not comply with the listing regulation
submit their own color additive petitions for such use.
Regarding the requested modifications in the specifications for
astaxanthin, the agency cannot include the 10-fold increase in
carotenoids other than astaxanthin in the regulation because a color
additive with such a broad specification could be substantially
different from the astaxanthin that the agency evaluated for safety.
Regarding the comment on allowing a higher percentage of cis
isomers, astaxanthin can exist as different geometric isomers, known as
cis- or trans-isomers. In the cis configuration, the largest functional
groups on either
[[Page 18738]]
end of a double bond are on the same side of the molecule. In the trans
configuration, they are on the opposite sides of the molecule. In the
case of astaxanthin, there are nine double bonds that can have cis or
trans configurations to give a bent or nearly linear molecular
geometry. These isomers can be easily interconverted to give an
equilibrium mixture.
The requested specification for the cis-astaxanthin level is
unnecessary because no safety concerns have been demonstrated with
regard to the proportions of the cis and trans isomers of astaxanthin.
Furthermore, the isomeric forms are readily interconverted (Ref. 1),
occur in wild salmon, and color the flesh of salmonids. There is no
evidence to suggest that the ratio of isomeric forms would affect the
safety of astaxanthin. The proportion of cis/trans isomers of
astaxanthin in the petitioned color additive lies within the range of
the ratios found in astaxanthin extracted from the flesh of wild salmon
(Ref. 4). Therefore, the regulation presented below does not contain a
specification for the amount of cis-astaxanthin.
IV. References
The following references have been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
1. Schiedt, K., F. J. Leuenberger, and M. Vecchi, ``Natural
Occurrence of Enantiomeric and meso-Astaxanthin,'' Helvitica Chimica
Acta, 64:449-457, 1981.
2. Meyers, S. P., and H-M Chen, ``Astaxanthin and its Role in
Fish Culture,'' From The Proceedings of Warmwater Fish Culture
Workshop. Special Publication No. 3, pp. 153-165, 1992.
3. Welsh, J. J., Memorandum entitled ``Final Toxicology Memo on
CAP 7C0211 (Astaxanthin in Fish Feed)'' from the Additives
Evaluation Branch (HFS-227) to the Direct Additives Branch (HFS-
217), Center for Food Safety and Applied Nutrition, FDA, May 26,
1993.
4. Turujman, S. A., ``Rapid Direct Resolution of the
Stereoisomers of All-trans Astaxanthin on a Pirkle Covalent L-
Leucine Column,'' Journal of Chromatography, 631:197 (abstract),
1993; Poster presented at the 106th Annual AOAC International
Meeting, Cincinnati, OH, August 31 to September 3, 1992.
V. Conclusions
FDA has evaluated the data in the petition and other relevant
material and concludes that astaxanthin that meets the specifications
in Sec. 73.35(b) is safe and suitable for use in salmonid feed to
pigment their flesh, and that part 73 should be amended as set out
below. In addition, based upon the factors listed in Sec. 71.20(b) (21
CFR 71.20(b)), the agency concludes that certification of astaxanthin
is not necessary for the protection of the public health. To ensure its
safe use, FDA has limited the amount of astaxanthin that can be
incorporated into the finished fish feed to 80 mg/kg (72 g/ton).
To prevent economic fraud in salmonid fish containing added
astaxanthin, the regulation requires declaration of the presence of the
color additive in accordance with Secs. 101.22(k)(2), 101.100(a)(2),
and 501.4 (21 CFR 101.22(k)(2), 101.100(a)(2), and 501.4) for labeling
of bulk foods. Section 501.4 is referenced in Sec. 73.35(d)(2) to
ensure that the presence of astaxanthin in the fish feed will be
declared on the ingredient label. Sections 101.22(k)(2) and
101.100(a)(2) are referenced in Sec. 73.35(d)(3) to ensure that, at the
retail level, the presence of astaxanthin in the fish will be declared,
and that the labeling of the bulk fish container, including a list of
ingredients on the container or a counter card with similar
information, will be displayed, respectively. Several examples are
given in Sec. 101.22(k)(2) for an acceptable statement of declaration
of the presence of astaxanthin, e.g., ``Artificial Color,''
``Artificial Color Added,'' or ``Color Added.''
VI. Inspection of Documents
In accordance with Sec. 71.15(a) (21 CFR 71.15(a)), the petition
and the documents that FDA considered and relied upon in reaching its
decision to approve the petition are available for inspection at the
Center for Food Safety and Applied Nutrition (address above) by
appointment with the information contact person listed above. As
provided in Sec. 71.15(b), the agency will delete from the documents
any materials that are not available for public disclosure before
making the documents available for inspection.
VII. Environmental Impact
The agency has carefully considered the potential environmental
effects of this action. FDA has concluded that the action will not have
a significant impact on the human environment, and that an
environmental impact statement is not required. The agency's finding of
no significant impact and the evidence supporting that finding,
contained in an environmental assessment, may be seen in the Dockets
Management Branch (address above) between 9 a.m. and 4 p.m. Monday
through Friday.
VIII. Objections
Any person who will be adversely affected by this regulation may at
any time on or before May 15, 1995, file with Dockets Management Branch
(address above) written objections thereto. Each objection shall be
separately numbered, and each numbered objection shall specify with
particularity the provisions of the regulation to which objection is
made and the grounds for the objection. Each numbered objection on
which a hearing is requested shall specifically so state. Failure to
request a hearing for any particular objection shall constitute a
waiver of the right to a hearing on that objection. Each numbered
objection for which a hearing is requested shall include a detailed
description and analysis of the specific factual information intended
to be presented in support of the objection in the event that a hearing
is held. Failure to include such a description and analysis for any
particular objection shall constitute a waiver of the right to a
hearing on the objection. Three copies of all documents shall be
submitted and shall be identified with the docket number found in
brackets in the heading of this document. Any objections received in
response to the regulation may be seen in the Dockets Management Branch
between 9 a.m. and 4 p.m., Monday through Friday. FDA will publish
notice of the objections that the agency has received or lack thereof
in the Federal Register.
List of Subjects in 21 CFR Part 73
Color additives, Cosmetics, Drugs, Medical devices.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR 21
part 73 is amended as follows:
PART 73--LISTING OF COLOR ADDITIVES EXEMPT FROM CERTIFICATION
1. The authority citation for 21 CFR part 73 continues to read as
follows:
Authority: Secs. 201, 401, 402, 403, 409, 501, 502, 505, 601,
602, 701, 721 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
321, 341, 342, 343, 348, 351, 352, 355, 361, 362, 371, 379e).
2. New Sec. 73.35 is added to subpart A to read as follows:
Sec. 73.35 Astaxanthin.
(a) Identity. (1) The color additive astaxanthin is 3, 3'-
dihydroxy-, -carotene-4, 4'-dione.
(2) Astaxanthin may be added to the fish feed only as a component
of a
[[Page 18739]]
stabilized color additive mixture. Color additive mixtures for fish
feed use made with astaxanthin 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. Astaxanthin shall conform to the following
specifications and shall be free from impurities other than those named
to the extent that such impurities may be avoided by good manufacturing
practice:
Physical state, solid.
0.05 percent solution in chloroform, complete and clear.
Absorption maximum wavelength 484-493 nanometers (in chloroform).
Residue on ignition, not more than 0.1 percent.
Total carotenoids other than astaxanthin, not more than 4 percent.
Lead, not more than 5 parts per million.
Arsenic, not more than 2 parts per million.
Mercury, not more than 1 part per million.
Heavy metals, not more than 10 parts per million.
Assay, minimum 96 percent.
(c) Uses and restrictions. Astaxanthin may be safely used in the
feed of salmonid fish in accordance with the following prescribed
conditions:
(1) The color additive is used to enhance the pink to orange-red
color of the flesh of salmonid fish.
(2) The quantity of color additive in feed is such that the color
additive shall not exceed 80 milligrams per kilogram (72 grams per ton)
of finished feed.
(d) Labeling requirements. (1) The labeling of the color additive
and any premixes prepared therefrom shall bear expiration dates for the
sealed and open container (established through generally accepted
stability testing methods), other information required by Sec. 70.25 of
this chapter, and adequate directions to prepare a final product
complying with the limitations prescribed in paragraph (c) of this
section.
(2) The presence of the color additive in finished fish feed
prepared according to paragraph (c) of this section shall be declared
in accordance with Sec. 501.4 of this chapter.
(3) The presence of the color additive in salmonid fish that have
been fed feeds containing astaxanthin shall be declared in accordance
with Secs. 101.22(k)(2) and 101.100(a)(2) of this chapter.
(e) Exemption from certification. Certification of this color
additive is not necessary for the protection of the public health, and
therefore batches thereof are exempt from the certification
requirements of section 721(c) of the act.
Dated: April 10, 1995.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 95-9178 Filed 4-12-95; 8:45 am]
BILLING CODE 4160-01-F
