[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 (<greek-m>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 <greek-m>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 <greek-m>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 <greek-m>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 <greek-m>g/mL no-effect level, established in 
the direct-contact cytotoxicity study for the dye, to the 0.08 
<greek-m>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 <greek-m>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 <greek-m>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