[Federal Register Volume 60, Number 38 (Monday, February 27, 1995)]
[Rules and Regulations]
[Pages 10495-10497]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-4767]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 73
[Docket No. 93C-0380]
Listing of Color Additives for Coloring Contact Lenses; 1,4-
Bis[4-(2-Methacryloxyethyl) Phenylamino]Anthraquinone 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 product formed by copolymerizing 1,4-bis[4-(2-
methacryloxyethyl) phenylamino]anthraquinone with 3-
[tris(trimethylsiloxy)silyl]propyl vinyl carbamate (CAS Reg. No.
134072-99-4) and N-vinyl pyrrolidone to form contact lenses. This
action is in response to a petition filed by Bausch & Lomb, Inc.
DATES: Effective on March 30, 1995, except as to any provisions that
may be stayed by the filing of proper objections; written objections
and requests for a hearing by March 29, 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: 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 November 3, 1993
(58 FR 58699), FDA announced that a color additive petition (CAP
3C0242) had been filed by Bausch & Lomb, Inc., 1400 North Goodman St.,
Rochester, NY 14692-0450. The petition proposed that the color additive
regulations be amended in Sec. 73.3106 1,4-Bis[4-(2-methacryloxyethyl)
phenylamino]anthraquinone copolymers (21 CFR 73.3106) to provide for
the safe use of 1,4-bis[4-(2-methacryloxyethyl)
phenylamino]anthraquinone copolymerized with N-vinyl pyrrolidone and
3[tris(trimethylsiloxy)silyl] propyl vinyl carbamate to form contact
lenses. The filing notice erroneously indicated that the petition was
filed under section 409(b)(5) of the Federal Food, Drug, and Cosmetic
Act (the act) (21 U.S.C. 348(b)(5)). The correct section of the act is
721(d)(1) (21 U.S.C. 379e(d)(1)).
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 in the device comes in direct
contact with the body for a significant period of time (21 U.S.C.
379e(a)). The use of the reaction product of 1,4-bis[4-(2-
methacryloxyethyl) phenylamino]anthraquinone copolymerized with 3-
[tris(trimethylsiloxy)silyl]propyl vinyl carbamate and N-vinyl
pyrrolidone as a color additive in manufacturing contact lenses is
subject to this listing requirement. The color additive is formed into
contact lenses in such a way that at least some of the color additive
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 additive
will be in direct contact with the body for a significant period of
time. Consequently, the use of the color additive currently before the
agency is subject to the statutory listing requirement.
III. Identity
The color additive, when used to color contact lenses, is produced
by copolymerizing the dye 1,4-bis[4-(2-methacryloxyethyl)
phenylamino]anthraquinone (CAS Reg. No. 121888-69-5) with 3-
[tris(trimethylsiloxy)silyl]propyl vinyl carbamate (CAS Reg. No.
134072-99-4) and N-vinyl pyrrolidone monomers. The dye 1,4-bis[4-(2-
methacryloxyethyl) phenylamino]anthraquinone covalently bonds through
two methacrylate groups to the polymer matrix during polymerization.
The resulting copolymeric product is formed into a contact lens.
IV. Safety Evaluation
The agency believes that because 1,4-bis[4-(2-methacryloxyethyl)
phenylamino]anthraquinone has a significantly lower molecular weight
than the N-vinyl pyrrolidone/3-[tris(trimethylsiloxy)silyl]propyl vinyl
carbamate/1,4-bis[4-(2-methacryloxyethyl) phenylamino]anthraquinone
copolymer, it would be more readily absorbed into the body than the
copolymeric color additive and would thus be expected to show a greater
toxic effect. Therefore, the safety evaluation of the subject color
additive focused primarily on 1,4-bis[4-(2-methacryloxyethyl)
phenylamino]anthraquinone.
FDA concludes, from the data submitted in the petition and from
other relevant information, that the maximum daily exposure to 1,4-
bis[4-(2-methacryloxyethyl) phenylamino]anthraquinone from this
petitioned use in contact lenses would be no greater than 0.08
micrograms per person per day (g/p/d). The agency-calculated
upper limit was based on two factors. First, the maximum use level
anticipated by the petitioner is 300 parts per million (ppm) of the
lens material or 15 g of 1,4-bis[4-(2-methacryloxyethyl)
[[Page 10496]] phenylamino]anthraquinone per lens (Ref. 1). Second, the
agency made two worst-case assumptions: (1) The user will replace
lenses tinted with 1,4-bis[4-(2-methacryloxyethyl)
phenylamino]anthraquinone at the maximum use level once each year with
a new pair of identical lenses; and (2) one hundred percent of 1,4-
bis[4-(2-methacryloxyethyl) phenylamino]anthraquinone will migrate from
the lenses into the eyes over the 1-year period. Because these
assumptions are worst-case estimates, exposure to 1,4-bis[4-(2-
methacryloxyethyl) phenylamino]anthraquinone from its use in coloring
N-vinyl pyrrolidone/3-[tris(trimethylsiloxy)silyl]propyl vinyl
carbamate contact lenses is likely to be far less than 0.08 g/
p/d (Ref. 1).
To establish the safety of 1,4-bis[4-(2-methacryloxyethyl)
phenylamino]anthraquinone for coloring N-vinyl pyrrolidone/3-
[tris(trimethylsiloxy)silyl]propyl vinyl carbamate contact lenses, the
petitioner conducted toxicity studies with 1,4-bis[4-(2-
methacryloxyethyl) phenylamino]anthraquinone, colored lenses, and
colored lens extracts. The studies included five in vitro cytotoxicity
studies, three by the agar overlay method (with 1,4-bis[4-(2-
methacryloxyethyl) phenylamino]anthraquinone and lens) and two by the
direct-contact method (with 1,4-bis[4-(2-methacryloxyethyl)
phenylamino]anthraquinone and lens extract). The maximum noncytotoxic
concentration for 1,4-bis[4-(2-methacryloxyethyl) phenylamino]
anthraquinone was determined to be 1,810 g/milliliter (mL) by
the direct-contact method using mouse fibroblast cells. Both the lenses
and lens extracts were found to be noncytotoxic to mouse fibroblast
cells. A 21-day ocular irritation study with contact lenses in rabbits
and a guinea pig maximization (Kligman) study with lens extracts were
also conducted. These studies demonstrated no evidence of ocular
irritation or an allergic response in the test animals.
To relate the 1,810 g/mL no-effect level, established in
the direct-contact cytotoxicity study for the dye, to the 0.08
g/p/d exposure from wearing the colored lenses, the agency
calculated the maximum concentration level of 1,4-bis[4-(2-
methacryloxyethyl) phenylamino]anthraquinone in each eye that would
result from the use of the contact lens. The agency estimated that the
daily exposure to 1,4-bis[4-(2-methacryloxyethyl) phenylamino]
anthraquinone in each eye would be 0.04 g and that 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 0.04 g dye/mL. This concentration
represents a more than a 45,000 fold safety factor for this proposed
use of 1,4-bis[4-(2-methacryloxyethyl) phenylamino]anthraquinone.
Based upon the available toxicity data, the small amount of 1,4-
bis[4-(2-methacryloxyethyl) phenylamino]anthraquinone used to form the
color additive in the contact lenses, and the agency's exposure
calculation for 1,4-bis[4-(2-methacryloxyethyl)
phenylamino]anthraquinone, FDA finds that the reaction product formed
by copolymerizing 1,4-bis[4-(2-methacryloxyethyl)
phenylamino]anthraquinone with N-vinyl pyrrolidone and 3-
[tris(trimethylsiloxy)silyl]propyl vinyl carbamate is safe for use as a
color additive in contact lenses. FDA further concludes that the safety
margin is sufficiently large that no limitation is required beyond the
usual limitation that the 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 product formed
by copolymerizing 1,4-bis[4-(2-methacryloxyethyl)
phenylamino]anthraquinone with N-vinyl pyrrolidone and 3-
[tris(trimethylsiloxy)silyl]propyl vinyl carbamate to form colored
contact lenses, and that the color additive is safe and suitable for
its 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 listed above. 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 March 29, 1995, 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. Reference
The following reference has 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 3C0242 (MATS# 741)-Bausch & Lomb. Reactive
Blue 246 for coloring contact lenses, copolymerized with N-vinyl
pyrrolidinone and 3-[tris(trimethylsiloxy)silyl]propyl vinyl
[[Page 10497]] carbamate. Submission dated 9-10-93,'' dated February
22, 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 73.3106 is amended by revising paragraph (a) to read as
follows:
Sec. 73.3106 1,4-Bis[4-(2-methacryloxyethyl) phenylamino]anthraquinone
copolymers.
(a) Identity. The color additive is 1,4-bis[4-(2-methacryloxyethyl)
phenylamino]anthraquinone (CAS Reg. No. 121888-69-5), copolymerized
with hydroxyethyl methacrylate monomer, or a blend of hydroxyethyl
methacrylate and N-vinyl pyrrolidone monomers, or a blend of 3-
[tris(trimethylsiloxy)silyl]propyl vinyl carbamate (CAS Reg. No.
134072-99-4) and N-vinyl pyrrolidone monomers to form the contact lens
material.
* * * * *
Dated: February 17, 1995.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 95-4767 Filed 2-24-95; 8:45 am]
BILLING CODE 4160-01-F