[Federal Register Volume 61, Number 193 (Thursday, October 3, 1996)]
[Rules and Regulations]
[Pages 51584-51587]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-25261]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 73
[Docket No. 91C-0189]
Listing of Color Additives for Coloring Contact Lenses; 1,4-
Bis[(2-hydroxyethyl)amino]-9,10-anthracenedione bis(2-propenoic)ester
copolymers
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 the colored
reaction products formed by copolymerizing 1,4-bis[(2-
hydroxyethyl)amino]-9,10-anthracenedione bis(2-propenoic)ester either
with glyceryl methacrylate/methyl methacrylate/ethylene glycol
dimethacrylate monomers or with N, N-dimethyl acrylamide/methyl
methacrylate/ethylene glycol dimethacrylate monomers to form contact
lenses. This action is in response to a petition filed by Sola/Barnes-
Hind.
DATES: Effective November 5, 1996, except as to any provisions that may
be stayed by the filing of proper objections; written objections and
requests for a hearing by November 4, 1996.
ADDRESSES: Submit written objections to the Dockets Management Branch
(HFA-305), Food and Drug Administration,
[[Page 51585]]
12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Helen R. Thorsheim, Center for Food
Safety and Applied Nutrition (HFS-216), Food and Drug Administration,
200 C St. SW., Washington, DC 20204, 202-418-3092.
SUPPLEMENTARY INFORMATION:
I. Introduction
In a notice published in the Federal Register of June 14, 1991 (56
FR 27518), FDA announced that a color additive petition (CAP 0C0226)
had been filed by Sola/Barnes-Hind (now Pilkington Barnes Hind), 810
Kifer Rd., Sunnyvale, CA 94086-5200. The petition proposed that the
color additive regulations be amended in 21 CFR part 73 to provide for
the safe use of 1,4-bis[(2-methacryloxyethylamino)-9,10-anthraquinone
to color contact lenses prepared with glyceryl methacrylate/methyl
methacrylate/ethylene glycol dimethacrylate copolymer and N, N-dimethyl
acrylamide/methyl methacrylate/ethylene glycol dimethacrylate
copolymer. The petition was filed under section 706(d)(1) of the
Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 376(d)(1)),
presently section 721(d)(1) of the act (21 U.S.C. 379e(d)(1)). The
agency has subsequently determined that 1,4-bis[(2-
methacryloxyethylamino)-9,10-anthraquinone is more appropriately
identified as 1,4-bis[(2-hydroxyethyl)amino]-9,10-anthracenedione
bis(2-propenoic)ester and that the color additives are the colored
reaction products formed by copolymerizing 1,4-bis[(2-
hydroxyethyl)amino]-9,10-anthracenedione bis(2-propenoic)ester either
with glyceryl methacrylate, methyl methacrylate, and ethylene glycol
dimethacrylate monomers, or with N, N-dimethyl acrylamide, methyl
methacrylate, and ethylene glycol dimethacrylate monomers.
II. Applicability of the Act
With the passage of the Medical Device Amendments of 1976 (Pub. L.
94-295), Congress mandated the listing of color additives for use in
medical devices when the color additive comes in direct contact with
the body for a significant period of time (21 U.S.C. 379e(a)). The use
of the reaction products of 1,4-bis[(2-hydroxyethyl)amino]-9,10-
anthracenedione bis(2-propenoic)ester either with glyceryl
methacrylate, methyl methacrylate, and ethylene glycol dimethacrylate
monomers, or with N, N-dimethyl acrylamide, methyl methacrylate, and
ethylene glycol dimethacrylate monomers as color additives in
manufacturing contact lenses is subject to this listing requirement.
The color additives are formed into contact lenses in such a way that
at least some of the color additives will come in contact with the eye
when the lenses are worn. In addition, the lenses are intended to be
placed on the eye for several hours a day, each day, for 1 year or
more. Thus, the color additives will be in direct contact with the body
for a significant period of time. Consequently, the use of the color
additives currently before the agency is subject to the statutory
listing requirement.
III. Identity
The color additives are produced by copolymerizing 1,4-bis[(2-
hydroxyethyl)amino]-9,10-anthracenedione bis(2-propenoic)ester (CAS
Reg. No. 109561-07-1) either with glyceryl methacrylate, methyl
methacrylate, and ethylene glycol dimethacrylate monomers, or with N,
N-dimethyl acrylamide, methyl methacrylate, ethylene glycol
dimethacrylate monomers. The resulting copolymeric product is formed
into a contact lens.
IV. Safety Evaluation
The agency believes that because 1,4-bis[(2-hydroxyethyl)amino]-
9,10-anthracenedione bis(2-propenoic)ester has a significantly lower
molecular weight than the subject copolymer, it would be the compound
most likely to migrate out of the lens into the ocular fluid and would
also be more readily absorbed into the body than the subject copolymer
and would thus be expected to show a greater toxic effect. Therefore,
the safety evaluation of the subject color additives focused on
exposure to unreacted 1,4-bis[(2-hydroxyethyl)amino]-9,10-
anthracenedione bis(2-propenoic)ester.
FDA concludes, from the data submitted in the petition and from
other relevant information, that the average daily exposure to 1,4-
bis[(2-hydroxyethyl)amino]-9,10-anthracenedione bis(2-propenoic)ester
from these petitioned uses in contact lenses would be no greater than
0.61 nanograms per person per day (ng/p/d). The agency-calculated upper
limit was based on two factors. First, the maximum use level
anticipated by the petitioner is 140 parts per million (ppm) of the
lens material or 11 micrograms (g) of 1,4-bis[(2-
hydroxyethyl)amino]-9,10-anthracenedione bis(2-propenoic)ester per
contact lens (Ref. 1). Second, the agency made two assumptions: (1) The
user will replace these lenses once each year with a new pair of
identical lenses; and (2) one percent of the 1,4-bis[(2-
hydroxyethyl)amino]-9,10-anthracenedione bis(2-propenoic)ester will
migrate from the lenses into the eyes over the 1-year period (Ref. 2).
Because these assumptions are conservative estimates, exposure to 1,4-
bis[(2-hydroxyethyl)amino]-9,10-anthracenedione bis(2-propenoic)ester
from these uses is likely to be less than 0.61 ng/p/d (Ref. 2).
To establish the safety of the subject additive, the petitioner
conducted toxicity studies with 1,4-bis[(2-hydroxyethyl)amino]-9,10-
anthracenedione bis(2-propenoic)ester, colored lenses, and colored lens
extracts. Studies submitted included 27 in vitro cytotoxicity studies:
4 by the inhibition of cell growth method (with lens extracts and 1,4-
bis[(2-hydroxyethyl)amino]-9,10-anthracenedione bis(2-propenoic)ester),
4 by the agar overlay method (with lens), and 19 by the direct-contact
method using mouse fibroblast cells (with lens, lens extracts and neat
1,4-bis[(2-hydroxyethyl)amino]-9,10-anthracenedione bis(2-
propenoic)ester). Both the lenses and lens extracts were found to be
noncytotoxic to mouse fibroblast cells. In addition, two guinea pig
maximization studies (Magnusson and Kligman) with lens extracts, two
72-hour ocular irritation studies with lens extracts in rabbits, one
intracutaneous skin reaction test with lens extracts in rabbits, two
acute systemic toxicity tests with lens extracts in mice, and four
ocular irritation studies with lenses in rabbits were submitted. The
most relevant tests for a color that is bound covalently to a contact
lens are those that compare colored to noncolored lenses in the rabbit
ocular irritation tests. These studies demonstrated no evidence of
ocular irritation or an allergic response in the test animals. The
maximum nontoxic concentration for 1,4-bis[(2-hydroxyethyl)amino]-9,10-
anthracenedione bis(2-propenoic)ester was determined to be 140
g/milliliter (mL) by the ocular irritation tests.
To relate the 140 g/mL nontoxic level, established in the
ocular irritation tests, to the 0.61 ng/p/d exposure from wearing the
colored lenses, the agency calculated the maximum concentration level
of 1,4-bis[(2-hydroxyethyl)amino]-9,10-anthracenedione bis(2-
propenoic)ester in each eye that would result from the use of the
contact lens. The agency estimated that the daily exposure to 1,4-
bis[(2-hydroxyethyl)amino]-9,10-anthracenedione bis(2-propenoic)ester
in each eye would be 0.30 ng and that
[[Page 51586]]
this would be diluted by the average daily tear film of 1.2 mL produced
in each eye. This concentration is equal to a maximum daily
concentration in the tear flow of the eye of 0.25 ng/mL, and represents
a more than a 55,000 fold safety factor for this proposed use of 1,4-
bis[(2-hydroxyethyl)amino]-9,10-anthracenedione bis(2-propenoic)ester,
when compared to the non-toxic level established in the ocular
irritation test.
Based upon the available toxicity data, the small amount of 1,4-
bis[(2-hydroxyethyl)amino]-9,10-anthracenedione bis(2-propenoic)ester
used to form the color additive in the contact lenses, and the agency's
exposure calculation for 1,4-bis[(2-hydroxyethyl)amino]-9,10-
anthracenedione bis(2-propenoic)ester, FDA finds that the reaction
products formed by copolymerizing 1,4-bis[(2-hydroxyethyl)amino]-9,10-
anthracenedione bis(2-propenoic)ester either with glyceryl
methacrylate, methyl methacrylate, and ethylene glycol dimethacrylate
monomers, or with N, N-dimethyl acrylamide, methyl methacrylate, and
ethylene glycol dimethacrylate monomers are safe for use as color
additives in contact lenses. FDA further concludes that the safety
margin is sufficiently large that no limitation is required beyond the
usual limitation that reactants may be used in amounts not to exceed
the minimum reasonably required to accomplish the intended technical
effect. Batch certification is not required to ensure safety.
V. Conclusions
Based on data contained in the petition and other relevant
material, FDA concludes that there is a reasonable certainty that no
harm will result from the petitioned use of the reaction products
formed by copolymerizing 1,4-bis[(2-hydroxyethyl)amino]-9,10-
anthracenedione bis(2-propenoic)ester either with glyceryl
methacrylate, methyl methacrylate, and ethylene glycol dimethacrylate
monomers, or with N, N-dimethyl acrylamide, methyl methacrylate,
ethylene glycol dimethacrylate monomers to form colored contact lenses,
and that the color additives are safe and suitable for their intended
use.
VI. Inspection of Documents
In accordance with Sec. 71.15 (21 CFR 71.15), 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 under the ``For Further Information
Contact'' section of this document. As provided in Sec. 71.15, 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 November 4, 1996, file with the 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.
IX. 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. Memorandum from the Chemistry Review Branch to the Indirect
Additives Branch, ``CAP 0C0226 (MATS# 494, M2.3, 2.4, and 2.5): Sola
Barnes Hind submissions dated 8-19-92, 10-5-92, and 1-25-93. BMAQ as
a colorant in contact lenses,'' dated June 28, 1993.
2. Memorandum of meeting dated August 19, 1994.
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 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. Section 73.3100 is added to subpart D to read as follows:
Sec. 73.3100 1,4-Bis[(2-hydroxyethyl)amino]-9,10-anthracenedione
bis(2-propenoic)ester copolymers.
(a) Identity. The color additives are 1,4-bis[(2-
hydroxyethyl)amino]-9,10-anthracenedione bis(2-propenoic)ester (CAS
Reg. No. 109561-07-1) copolymerized either with glyceryl methacrylate,
methyl methacrylate, and ethylene glycol dimethacrylate monomers, or
with N, N-dimethyl acrylamide, methyl methacrylate, and ethylene glycol
dimethacrylate monomers to form the contact lens material.
(b) Uses and restrictions. (1) The substances listed in paragraph
(a) of this section may be used in amounts not to exceed the minimum
reasonably required to accomplish the intended coloring effect.
(2) Authorization and compliance with these uses shall not be
construed as waiving any of the requirements of sections 510(k), 515,
and 520(g) of the Federal Food, Drug, and Cosmetic Act (the act) with
respect to the contact lens made from the color additives.
(c) Labeling. The label of the color additives shall conform to the
requirements of Sec. 70.25 of this chapter.
(d) Exemption from certification. Certification of these color
additives is not necessary for the protection of the public health and
therefore the color
[[Page 51587]]
additives are exempt from the certification requirements of section
721(c) of the act.
Dated: September 26, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-25261 Filed 10-2-96; 8:45 am]
BILLING CODE 4160-01-F
