[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]


=======================================================================
-----------------------------------------------------------------------

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.

-----------------------------------------------------------------------

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