[Federal Register Volume 78, Number 62 (Monday, April 1, 2013)]
[Rules and Regulations]
[Pages 19413-19415]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2013-07294]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 73

[Docket Nos. FDA-2011-C-0344 and FDA-2011-C-0463]


Listing of Color Additives Exempt From Certification; Reactive 
Blue 246 and Reactive Blue 247 Copolymers

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA or we) is amending the 
color additive regulations to provide for the safe use of additional 
copolymers of 1,4-bis[4-(2-methacryloxyethyl)phenylamino]anthraquinone 
(C.I. Reactive Blue 246) and copolymers of 1,4-bis[(2-
hydroxyethyl)amino]-9,10-anthracenedione bis(2-methyl-2-propenoic)ester 
(C.I. Reactive Blue 247) as color additives in contact lenses. This 
action is in response to two color additive petitions (CAPs) filed by 
CooperVision, Inc.

DATES: This rule is effective May 2, 2013. See section VII for related 
information on the filing of objections. Submit either electronic or 
written objections and requests for a hearing by May 1, 2013.

ADDRESSES: You may submit either electronic or written objections and 
requests for a hearing, identified by Docket No. FDA-2011-C-0344 (C.I. 
Reactive Blue 246) or FDA-2011-C-0463 (C.I. Reactive Blue 247), by any 
of the following methods:

Electronic Submissions

    Submit electronic objections in the following ways:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.

Written Submissions

    Submit written objections in the following ways:
     Mail/Hand delivery/Courier (for paper or CD-ROM 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Agency name 
and the appropriate docket number (FDA-2011-C-0344 for C.I. Reactive 
Blue 246 or FDA-2011-C-0463 for C.I. Reactive Blue 247) for this 
rulemaking. All objections received will be posted without change to 
http://www.regulations.gov, including any personal information 
provided. For detailed instructions on submitting objections, see the 
``Objections'' heading of the SUPPLEMENTARY INFORMATION section.
    Docket: For access to the dockets to read background documents or 
objections received, go to http://www.regulations.gov and insert the 
docket numbers, found in brackets in the heading of this document, into 
the ``Search'' box and follow the prompts and/or go to the Division of 
Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Regarding CAP 1C0291 (C.I. Reactive 
Blue 246): Judith Kidwell, Center for Food Safety and Applied Nutrition 
(HFS-265), Food and Drug Administration, 5100 Paint Branch Pkwy., 
College Park, MD 20740-3835, 240-402-1071.
    Regarding CAP 1C0292 (C.I. Reactive Blue 247): Teresa Croce, Center 
for Food Safety and Applied Nutrition (HFS-265), Food and Drug 
Administration, 5100 Paint Branch Pkwy., College Park, MD 20740-3835, 
240-402-1281.

SUPPLEMENTARY INFORMATION:

I. Introduction

    In a notice published in the Federal Register of June 28, 2011 (76 
FR 37690), we announced that CooperVision, Inc., 6150 Stoneridge Mall 
Rd., suite 370, Pleasanton, CA 94588 (petitioner) had filed two color 
additive petitions (CAP 1C0291 and CAP 1C0292). The petitions proposed 
to amend the color additive regulations in 21 CFR part 73, subpart D, 
Medical Devices, to provide for the safe use of additional copolymers 
of 1,4-bis[(2-hydroxyethyl)amino]-9,10-anthracenedione bis(2-methyl-2-
propenoic)ester (C.I. Reactive Blue 247) and additional copolymers of 
1,4-bis[4-(2-methacryloxyethyl)phenylamino]anthraquinone (C.I. Reactive 
Blue 246) as color additives in contact lenses. The color additives are 
produced by copolymerizing the reactive dyes with various vinyl and/or 
acrylic monomers such that the dyes are bound covalently and cross-
linked in the resulting polymer matrix.\1\
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    \1\ According to the International Union of Pure and Applied 
Chemistry (IUPAC), a vinyl polymer is prepared from a monomer 
containing the vinyl group -CH=CH2. Acrylic polymers are 
one subclass of vinyl polymers; however, not all acrylic polymers 
(e.g., methacrylic polymers) are vinyl polymers using the IUPAC 
definition (Ref. 1). The term ``vinyl and/or acrylic monomers'' 
includes monomers that form vinyl polymers, monomers that form 
acrylic polymers (e.g., acrylate, methacylate, acrylamide, etc.), or 
any combination thereof.

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[[Page 19414]]

    Current regulations for C.I. Reactive Blue 246 and C.I. Reactive 
Blue 247 copolymers (21 CFR 73.3106 and 73.3100, respectively) list the 
reaction products of these reactive dyes with specific vinyl and/or 
acrylic monomers for use in coloring contact lenses.\2\ The petitions 
sought to expand the list of permitted monomers to include any suitable 
vinyl and/or acrylic monomer capable of forming a contact lens. The 
petitions were filed under section 721 of the Federal Food, Drug, and 
Cosmetic Act (the FD&C Act) (21 U.S.C. 379e). In Sec.  73.3100, 
Reactive Blue 247 is identified as 1,4-bis[(2-hydroxyethyl)amino]-9,10-
anthracenedione bis(2-propenoic)ester. As part of this final rule, we 
are correcting the nomenclature for Reactive Blue 247 by inserting ``2-
methyl'' before ``2-propenoic.''
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    \2\ 21 CFR 73.3106 originally allowed for the safe use of 1,4-
bis[4-(2-methacryloxyethyl) phenylamino]anthraquinone (C.I. Reactive 
Blue 246) copolymerized with hydroxyethyl methacrylate monomer or a 
blend of hydroxyethyl methacrylate and N-vinyl pyrrolidone monomers 
(58 FR 17506, April 5, 1993). The regulation was later amended to 
also allow for the safe use of C.I. Reactive Blue 246 copolymerized 
with a blend of 3-[tris(trimethylsiloxy)silyl]propyl vinyl carbamate 
and N-vinyl pyrrolidone monomers (60 FR 10495, February 27, 1995).
    21 CFR 73.3100 allows for the safe use of 1,4-bis[ (2-
hydroxyethyl)amino]-9,10-anthracenedione bis(2-propenoic)ester (C.I. 
Reactive Blue 247) 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 (61 FR 51584, October 3, 1996).
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II. Safety Evaluation

    Under section 721(b)(4) of the FD&C Act, a color additive may not 
be listed for a particular use unless the data available to FDA 
establishes that the color additive is safe for that use. Our color 
additive regulations at 21 CFR 70.3(i) define safe to mean that there 
is ``convincing evidence that establishes with reasonable certainty 
that no harm will result from the intended use of the color additive.''
    As part of our safety evaluation of the color additives, we 
considered exposure to unreacted C.I. Reactive Blue 246 and 247 and any 
impurities (e.g., reaction byproducts) from the petitioned use of the 
color additives. We also considered results from skin sensitization, 
ocular irritation, and cytotoxicity studies with either representative 
lens materials or extracts from the lens materials (i.e., the color 
additives that are the subjects of the petitions).\3\
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    \3\ Both the petitioner's representative formulations and 
currently regulated formulations consist of either C.I. Reactive 
Blue 246 or C.I. Reactive Blue 247 copolymerized with various vinyl 
and/or acrylic monomers.
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A. C.I. Reactive Blue 246

    We calculated an exposure estimate for C.I. Reactive Blue 246 from 
its proposed use in three representative contact lens formulations 
using vinyl and/or acrylic monomers based on results from a 
leachability study that was conducted by the petitioner. This study 
demonstrated that there was no detectable migration of C.I. Reactive 
Blue 246 at the limit of detection (LOD) of an appropriate analytical 
method for any of the lens formulations evaluated. We estimated the 
potential exposure to any one impurity using the maximum amount of 
total impurities determined in C.I. Reactive Blue 246.
    The average daily exposure to C.I. Reactive Blue 246 from its 
proposed use would be no greater than 13 nanograms (ng)/person/day (p/
d) and the maximum exposure to any one impurity will not exceed 0.6 ng/
p/d. These estimates represent worst-case exposure, and the actual 
exposure to C.I. Reactive Blue 246 and its impurities from the use of 
the color additive in contact lenses is expected to be significantly 
lower. Based on data submitted in the petitions, as well as other 
relevant information, we note that it is highly unlikely that either 
C.I. Reactive Blue 246 or its components would migrate from the contact 
lens into the aqueous environment of the eye because the reactive dye 
is covalently bound and cross-linked during polymerization such that 
any migration from the resulting copolymer matrix as a result of the 
proposed uses will be negligible. Therefore, we conclude that the 
exposure to the color additive, including any impurities that may be 
present in it, from the petitioned use would be negligible (Ref. 2).
    The petitioner submitted data from 24 toxicology studies on either 
representative lens materials or extracts from representative lens 
materials with and without C.I. Reactive Blue 246 to establish the 
safety of the copolymerized color additives of C.I. Reactive Blue 246. 
Studies included guinea pig maximization studies, in vivo ocular 
irritation studies in rabbits, and cytotoxicity studies. Based on our 
review of these studies, we conclude that there is no evidence of 
toxicity (Ref. 3).

B. C.I. Reactive Blue 247

    We calculated an exposure estimate for C.I. Reactive Blue 247 from 
its proposed use in three representative contact lens formulations 
using vinyl and/or acrylic monomers based on results from a 
leachability study that was conducted by the petitioner. This study 
demonstrated that there was no detectable migration of C.I. Reactive 
Blue 247 at the LOD of an appropriate analytical method for any of the 
lens formulations evaluated. We estimated the potential exposure to any 
one impurity using the maximum amount of total impurities determined in 
C.I. Reactive Blue 247.
    The average daily exposure to C.I. Reactive Blue 247 from its 
proposed use would be no greater than 10 ng/p/d and the maximum 
exposure to any one impurity will not exceed 0.5 ng/p/d. These 
estimates represent worst-case exposure, and the actual exposure to 
C.I. Reactive Blue 247 and its impurities from the use of the color 
additive in contact lenses is expected to be significantly lower. Based 
on data submitted in the petitions, as well as other relevant 
information, we note that it is highly unlikely that either C.I. 
Reactive Blue 247 or its components would migrate from the contact lens 
into the aqueous environment of the eye because the reactive dye is 
covalently bound and cross-linked during polymerization such that any 
migration from the resulting copolymer matrix as a result of the 
proposed uses will be negligible. Therefore, we conclude that the 
exposure to the color additive, including any impurities that may be 
present in it, from the petitioned use would be negligible (Ref. 4).
    The petitioner submitted data from 24 toxicology studies on either 
representative lens materials or extracts from representative lens 
materials with and without C.I. Reactive Blue 247 to establish the 
safety of the copolymerized color additives of C. I. Reactive Blue 247. 
Studies included guinea pig maximization studies, in vivo ocular 
irritation studies in rabbits, and cytotoxicity studies. Based on our 
review of these studies, we conclude that there is no evidence of 
toxicity (Ref. 5).

III. Conclusion

    Based on the data contained in the two petitions and other 
available relevant material, we conclude that the petitioned use of the 
reaction products formed by copolymerizing either C.I. Reactive Blue 
246 or C.I. Reactive Blue 247 with vinyl and/or acrylic-monomers to 
form colored contact lenses is safe and that the color additives will 
achieve their intended technical effect. We further conclude that there 
is no need for imposing a limitation on the amount of color additive to 
be used, beyond the limitation that reactants may be used in amounts 
not to exceed the minimum reasonably required to accomplish the 
intended technical effect. Therefore, we

[[Page 19415]]

are amending the regulations in part 73 (21 CFR part 73) as set forth 
in this document. In addition, based upon the factors listed in Sec.  
71.20(b) (21 CFR 71.20(b)), we have determined that batch certification 
of these color additives is not necessary for the protection of the 
public health.

IV. Public Availability of Documents

    In accordance with Sec.  71.15 (21 CFR 71.15), the petition and the 
documents that we considered and relied upon in reaching our decision 
to approve the petition will be made available for public disclosure 
(see FOR FURTHER INFORMATION CONTACT). As provided in Sec.  71.15, we 
will delete from the documents any materials that are not available for 
public disclosure.

V. Environmental Impact

    We previously considered the environmental effect of this rule, as 
stated in the June 28, 2011, Federal Register notice of petitions for 
CAP 1C0291 and CAP 1C0292 (76 FR 37690). We stated that we had 
determined, under 21 CFR 25.32(l), that this action ``is of a type that 
does not individually or cumulatively have a significant effect on the 
human environment'' such that neither an environmental assessment nor 
an environmental impact statement is required. We have not received any 
new information or comments that would affect our previous 
determination.

VI. Paperwork Reduction Act of 1995

    This final rule contains no collection of information. Therefore, 
clearance by the Office of Management and Budget under the Paperwork 
Reduction Act of 1995 is not required.

VII. Objections

    This rule is effective as shown in the DATES section; except as to 
any provisions that may be stayed by the filing of proper objections. 
Any person who will be adversely affected by this regulation may file 
with the Division of Dockets Management (see ADDRESSES) either 
electronic or written objections regarding this document. 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. It is only necessary to send one set of 
documents. Identify documents with the appropriate docket number found 
in brackets in the heading of this document. Any objections received in 
response to the regulation may be seen in the Division of Dockets 
Management between 9 a.m. and 4 p.m., Monday through Friday. FDA will 
publish notice of the objections that we have received or lack thereof 
in the Federal Register.

VIII. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday, 
and are available electronically at http://www.regulations.gov.

    1. Bar[oacute]n, M., K.-H. Hellwich, M. Hess, K. Horie, et al, 
``Glossary of Class Names of Polymers Based on Chemical Structure 
and Molecular Architecture (IUPAC Recommendations 2009)'', Pure and 
Applied Chemistry, 81(6), pp. 1131-1186, 2009.
    2. Memorandum from H. Lee, Division of Petition Review, 
Chemistry Review Team, to J. Kidwell, Division of Petition Review, 
Regulatory Group I, FDA, July 26, 2011.
    3. Memorandum from S. Park, Division of Petition Review, 
Toxicology Review Team, to M.Harry, Division of Petition Review, 
Regulatory Group I, FDA, November 30, 2011.
    4. Memorandum from H. Lee, Division of Petition Review, 
Chemistry Review Team, to T.Croce, Division of Petition Review, 
Regulatory Group II, FDA, August 16, 2011.
    5. Memorandum from T.Walker, Division of Petition Review, 
Toxicology Review Team, to T.Croce, Division of Petition Review, 
FDA, January 13, 2012.

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, and 
redelegated to the Director, Center for Food Safety and Applied 
Nutrition, 21 CFR part 73 is amended as follows:

PART 73--LISTING OF COLOR ADDITIVES EXEMPT FROM CERTIFICATION

0
1. The authority citation for part 73 continues to read as follows:

    Authority: 21 U.S.C. 321, 341, 342, 343, 348, 351, 352, 355, 
361, 362, 371, 379e.


0
2. Amend Sec.  73.3100 by revising the section heading and paragraph 
(a) to read as follows:


Sec.  73.3100  1,4-Bis[(2-hydroxyethyl)amino]-9,10-anthracenedione 
bis(2-methyl-2-propenoic)ester copolymers.

    (a) Identity. The color additives are the copolymers formed as the 
reaction product of 1,4-bis[(2-hydroxyethyl)amino]-9,10-anthracenedione 
bis(2-methyl-2-propenoic)ester (C.I. Reactive Blue 247) (CAS Reg. No. 
109561-07-1) with one or more vinyl and/or acrylic monomers to form the 
contact lens material.
* * * * *


0
3. Amend Sec.  73.3106 by revising paragraph (a) to read as follows:


Sec.  73.3106  1,4-Bis[4-(2-methacryloxyethyl) 
phenylamino]anthraquinone copolymers.

    (a) Identity. The color additives are the copolymers formed as the 
reaction product of 1,4-bis[4- (2-
methacryloxyethyl)phenylamino]anthraquinone (C.I. Reactive Blue 246) 
(CAS Reg. No. 121888-69-5) with one or more vinyl and/or acrylic 
monomers to form the contact lens material.
* * * * *

    Dated: March 25, 2013.
Susan M. Bernard,
Director, Office of Regulations, Policy and Social Sciences, Center for 
Food Safety and Applied Nutrition.
[FR Doc. 2013-07294 Filed 3-29-13; 8:45 am]
BILLING CODE 4160-01-P