
[Federal Register Volume 81, Number 211 (Tuesday, November 1, 2016)]
[Rules and Regulations]
[Pages 75689-75692]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-26310]


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

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 73 and 74

[Docket No. FDA-2016-F-0821]


Listing of Color Additives Exempt From Certification; Titanium 
Dioxide and Listing of Color Additives Subject to Certification; 
[Phthalocyaninato (2-)] Copper

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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

SUMMARY: The Food and Drug Administration (FDA or we) is amending the 
color additive regulations to provide for the safe use of titanium 
dioxide and [phthalocyaninato (2-)] copper to color orientation marks 
for intraocular lenses. This action is in response to a petition filed 
by Milton W. Chu, M.D.

DATES: This rule is effective December 2, 2016. See section IX for 
further information on the filing of objections. Submit either 
electronic or written objections and requests for a hearing by December 
1, 2016.

ADDRESSES: You may submit objections and requests for a hearing as 
follows:

Electronic Submissions

    Submit electronic objections in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments. Objections submitted 
electronically, including attachments, to http://www.regulations.gov 
will be posted to the docket unchanged. Because your objection will be 
made public, you are solely responsible for ensuring that your 
objection does not include any confidential information that you or a 
third party may not wish to be posted, such as medical information, 
your or anyone else's Social Security number, or confidential business 
information, such as a manufacturing process. Please note that if you 
include your name, contact information, or other information that 
identifies you in the body of your objection, that information will be 
posted on http://www.regulations.gov.
     If you want to submit an objection with confidential 
information that you do not wish to be made available to the public, 
submit the objection as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper objections submitted to the Division of 
Dockets Management, FDA will post your objection, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2016-F-0821 for ``Listing of Color Additives Exempt From 
Certification; Titanium Dioxide and Listing of Color Additives Subject 
to Certification; [Phthalocyaninato (2-)] Copper.'' Received objections 
will be placed in the docket and, except for those submitted as 
``Confidential Submissions,'' publicly viewable at http://www.regulations.gov or at the Division of Dockets Management between 9 
a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit an objection with 
confidential information that you do not wish to be made publicly 
available, submit your objections only as a written/paper

[[Page 75690]]

submission. You should submit two copies total. One copy will include 
the information you claim to be confidential with a heading or cover 
note that states ``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' 
The Agency will review this copy, including the claimed confidential 
information, in its consideration of comments. The second copy, which 
will have the claimed confidential information redacted/blacked out, 
will be available for public viewing and posted on http://www.regulations.gov. Submit both copies to the Division of Dockets 
Management. If you do not wish your name and contact information to be 
made publicly available, you can provide this information on the cover 
sheet and not in the body of your comments and you must identify this 
information as ``confidential.'' Any information marked as 
``confidential'' will not be disclosed except in accordance with 21 CFR 
10.20 and other applicable disclosure law. For more information about 
FDA's posting of comments to public dockets, see 80 FR 56469, September 
18, 2015, or access the information at: http://www.fda.gov/regulatoryinformation/dockets/default.htm.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to http://www.regulations.gov and insert the docket number, 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: Laura A. Dye, Center for Food Safety 
and Applied Nutrition (HFS-265), Food and Drug Administration, 5001 
Campus Dr., College Park, MD 20740-3835, 240-402-1275.

SUPPLEMENTARY INFORMATION: 

I. Introduction

    In a document published in the Federal Register of March 22, 2016 
(81 FR 15173), we announced that we had filed a color additive petition 
(CAP 6C0305), submitted by Milton W. Chu, M.D. (petitioner), 5800 Santa 
Rosa Rd., Suite 111, Camarillo, CA 93012. The petition proposed to 
amend the color additive regulations in Sec.  73.3126 (21 CFR 73.3126) 
and Sec.  74.3045 (21 CFR 74.3045) to provide for the safe use of 
titanium dioxide and [phthalocyaninato (2-)] copper to color 
orientation marks for intraocular lenses (IOLs). IOLs are devices made 
of materials such as glass or plastic and are intended to be implanted 
to replace the natural lens of an eye (21 CFR 886.3600). The 
orientation marks are intended to aid the surgeon in visualization and 
placement of IOLs during lens implantation surgery. Because IOLs are 
permanently implanted, titanium dioxide and [phthalocyaninato (2-)] 
copper, in the colored orientation marks, will come into direct contact 
with a patient's eye for a significant amount of time. These color 
additives are, therefore, subject to section 721 of the Federal Food, 
Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 379e).

II. Background

    Titanium dioxide is already approved as a color additive for foods 
(Sec.  73.575), drugs (Sec.  73.1575), cosmetics (Sec.  73.2575), and 
medical devices (Sec.  73.3126). Regarding its use in medical devices, 
titanium dioxide (CAS Reg. No. 13463-67-7, Color Index No. 77891) is 
currently approved under Sec.  73.3126(b)(1) for use as a color 
additive in contact lenses in amounts not to exceed the minimum 
reasonably required to accomplish the intended coloring effect and must 
meet the identity and specification requirements in Sec.  73.575(a)(1) 
and (b). Titanium dioxide is exempt from certification under section 
721(c) of the FD&C Act because we previously determined that 
certification was not necessary for the protection of public health (51 
FR 24815, July 9, 1986).
    [Phthalocyaninato (2-)] copper (CAS Reg. No. 147-14-8, Color Index 
No. 74160) is currently approved as a color additive under Sec.  
74.3045(c)(1) for use in coloring certain non-absorbable sutures for 
general and ophthalmic surgery, and for use in coloring specific 
monofilaments used as supporting side struts (haptics) that hold the 
IOLs in place in the eye, at a level up to 0.5 percent by weight of the 
suture or haptic material. In addition, it is currently approved as a 
color additive under Sec.  74.3045(c)(2) for use in coloring contact 
lenses in amounts not to exceed the minimum amount reasonably required 
to accomplish the intended coloring effect. We previously determined 
that batch certification was necessary to ensure the safety of 
[phthalocyaninato (2-)] copper (34 FR 6777, April 23, 1969).

III. Safety Evaluation

A. Determination of Safety

    Under section 721(b)(4) of the FD&C Act, a color additive may not 
be listed for a particular use unless the data and information 
available to FDA establish 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. To establish with reasonable certainty that these 
color additives intended to color IOL orientation marks are not harmful 
under their intended conditions of use, we considered exposure to the 
additives and their impurities, each additive's toxicological data, and 
other relevant information (such as published literature) available to 
us.

B. Safety of Petitioned Use of the Color Additives

    Regarding the petitioned use, titanium dioxide and 
[phthalocyaninato (2-)] copper are intended to color orientation marks 
for IOL materials (polymers) to create white and translucent or opaque 
blue marks that are typically 100-250 microns ([mu]m) in diameter and 
80-150 [mu]m in depth. Titanium dioxide will be used in amounts not to 
exceed the minimum reasonably required to accomplish the intended 
coloring effect of the orientation marks. [Phthalocyaninato (2-)] 
copper will be used at levels not to exceed 0.5 percent by weight of 
the orientation marks.
    To assess safety, we compared an individual's estimated exposure to 
these two color additives for the petitioned use to color IOL 
orientation marks to the approved uses of these color additives, 
including in IOL haptics and opaque contact lenses, because these uses 
are similar. As part of our previous approval for titanium dioxide used 
to color contact lenses, we estimated exposure to titanium dioxide from 
this use to be 270 nanograms per person per day (ng/p/d) over the lens 
lifetime (51 FR 24815), which does not significantly contribute to the 
cumulative exposure when compared to the exposure to titanium dioxide 
from the approved uses of mica-based pearlescent pigments (of which 
titanium dioxide is a component) in food and pharmaceuticals (Ref. 1). 
Similarly, we previously estimated exposure to [phthalocyaninato (2-)] 
copper from the use of surgical sutures, contact lenses, and specific 
monofilaments used as supporting haptics for IOLs to be 310 ng/p/d, 280 
ng/p/d, and 0.3 ng/p/d, respectively (64 FR 23185, April 30, 1999; 51 
FR 39370, October 28, 1986; and 52 FR 15944, May 1, 1987). With respect 
to the petitioned use, we estimated that the worst-case lifetime 
exposure to titanium dioxide and [phthalocyaninato (2-)] copper used to 
color orientation marks would be no greater than 0.06 ng/p/d and 0.004 
ng/

[[Page 75691]]

p/d, respectively, over a 70-year lifetime (Ref. 2). This exposure 
estimate is conservative as it assumes 100 percent migration of the 
color additives from the IOLs into the ocular fluid of the eye over a 
lifespan of 70 years following lens implantation. However, we expect 
that the color additives in the orientation marks will most likely be 
either chemically bound or otherwise integrated into the lens material, 
which would limit migration of the color additives into the ocular 
fluid of the eye. This means that the actual exposures to titanium 
dioxide and [phthalocyaninato (2-)] copper to color IOL orientation 
marks are expected to be far less than the worst-case exposure 
estimates for these color additives and insignificant in comparison to 
the cumulative exposures from the other approved uses of these color 
additives that we have already established to be safe (Ref. 2).
    In assessing biocompatibility and toxicity of IOLs, we consider the 
International Standard for intraocular lens testing for 
biocompatibility (ISO 11979-5) as an appropriate standard. In general, 
ISO 11979-5 recommends investigations on the following biological 
endpoints: Cytotoxicity, genotoxicity, local effects after 
implantation, and sensitization potential, in the context of 
physicochemical properties.
    The petitioner conducted a cytotoxicity study in which cultured 
cells were exposed to a mixture of titanium dioxide and 
[phthalocyaninato (2-)] copper in direct contact for at least 24 hours. 
Both color additives were found to be noncytotoxic in this study. 
Cytotoxicity studies of [phthalocyaninato (2-)] copper in previous 
petitions also indicated no cytotoxicity (Ref. 3). Additionally, the 
toxicology data for [phthalocyaninato (2-)] copper from previous 
petitions, as well as relevant data found in the Organization for 
Economic Cooperation and Development's Screening Information Dataset 
(OECD's SIDS) database, all indicated negative results for 
genotoxicity, carcinogenicity, implantation safety, and sensitization 
potential (Ref. 3). Similarly, data on titanium dioxide in OECD's SIDS 
database reported negative results for genotoxicity and sensitization 
potential. We conclude that the available toxicology data are 
sufficient to support the safety of the proposed expanded uses of 
titanium dioxide and [phthalocyaninato (2-)] copper.

IV. Conclusion

    Based on the data and information in the petition and other 
relevant material, we conclude that the petitioned use of titanium 
dioxide and [phthalocyaninato (2-)] copper to color orientation marks 
for IOLs is safe. We further conclude that these additives will achieve 
their intended technical effect and are suitable for the petitioned 
use. Consequently, we are amending the color additive regulations in 
parts 73 and 74 as set forth in this document. In addition, based upon 
the factors listed in 21 CFR 71.20(b), we conclude that certification 
of titanium dioxide remains unnecessary for the protection of the 
public health. We also conclude that batch certification of 
[phthalocyaninato (2-)] copper continues to be necessary to protect the 
public health.

V. Public Disclosure and Confidentiality of Data and Information in a 
Color Additive Rule

    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.

VI. Analysis of Environmental Impact

    We previously considered the environmental effects of this rule, as 
stated in the March 22, 2016, notice of petition for CAP 6C0305 (81 FR 
15173). 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.

VII. 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.

VIII. 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. 
If you will be adversely affected by one or more provisions of this 
regulation, you may file with the Division of Dockets Management (see 
ADDRESSES) either electronic or written objections. You must separately 
number each objection, and within each numbered objection you must 
specify with particularity the provision(s) of the regulation to which 
you object and the grounds for your objection. Within each numbered 
objection, you must specifically state whether you are requesting a 
hearing on the particular provision that you specify in that numbered 
objection. If you do not request a hearing for any particular 
objection, you waive the right to a hearing on that objection. If you 
request a hearing, your objection must include a detailed description 
and analysis of the specific factual information you intend to present 
in support of the objection in the event that a hearing is held. If you 
do not include such a description and analysis for any particular 
objection, you waive the right to a hearing on the objection.
    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, and will be posted to the docket at http://www.regulations.gov. We will publish notice of the objections that we 
have received or lack thereof in the Federal Register.

IX. References

    The following references are on display in the Division of Dockets 
Management (see ADDRESSES) and are available for viewing by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also 
available electronically at http://www.regulations.gov.


1. Memorandum from H. Lee, Division of Petition Review, Chemistry 
Review Team, to P. DeLeo, Division of Petition Review, Regulatory 
Group I, FDA, March 1, 2005.
2. Memorandum from H. Lee, Division of Petition Review, Chemistry 
Review Team, to L. Dye, Division of Petition Review, Regulatory 
Group I, FDA, April 20, 2016.
3. Memorandum from Y. Zang, Division of Petition Review, Toxicology 
Review Team, to L. Dye, Division of Petition Review, Regulatory 
Group I, FDA, June 30, 2016.

List of Subjects

21 CFR Part 73

    Color additives, Cosmetics, Drugs, Medical devices.

21 CFR Part 74

    Color additives, Cosmetics, Drugs.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs and re-
delegated to the Director, Center for Food Safety and

[[Page 75692]]

Applied Nutrition, 21 CFR parts 73 and 74 are 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. In Sec.  73.3126, revise paragraph (b)(1) to read as follows:


Sec.  73.3126  Titanium dioxide.

* * * * *
    (b) * * * (1) The substance listed in paragraph (a) of this section 
may be used as a color additive in contact lenses and intraocular lens 
orientation marks in amounts not to exceed the minimum reasonably 
required to accomplish the intended coloring effect.
* * * * *

PART 74--LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION

0
3. The authority citation for part 74 continues to read as follows:

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


0
4. In Sec.  74.3045, revise paragraphs (c)(1) introductory text and 
(c)(1)(i) to read as follows:


Sec.  74.3045   [Phthalocyaninato (2-)] copper.

* * * * *
    (c) * * * (1) The color additive [phthalocyaninato(2-)] copper may 
be safely used to color polypropylene sutures, polybutester (the 
generic designation for the suture fabricated from 1,4-
benzenedicarboxylic acid, polymer with 1,4-butanediol and alpha-hydro-
omega-hydroxypoly(oxy-1,4-butanediyl), CAS Reg. No. 37282-12-5) 
nonabsorbable sutures for use in general and ophthalmic surgery, 
polybutylene terephthalate nonabsorbable monofilament sutures for 
general and ophthalmic surgery, nonabsorbable sutures made from 
poly(vinylidene fluoride) and poly(vinylidene fluoride-co-
hexafluoropropylene) for general and ophthalmic surgery, 
polymethylmethacrylate monofilament used as supporting haptics for 
intraocular lenses, and polymers used in orientation marks for 
intraocular lenses, subject to the following restrictions:
    (i) The quantity of the color additive does not exceed 0.5 percent 
by weight of the suture, haptic material, or orientation mark.
* * * * *

    Dated: October 25, 2016.
Susan Bernard,
Director, Office of Regulations, Policy and Social Science, Center for 
Food Safety and Applied Nutrition.
[FR Doc. 2016-26310 Filed 10-31-16; 8:45 am]
 BILLING CODE 4164-01-P


