[Federal Register Volume 64, Number 117 (Friday, June 18, 1999)]
[Rules and Regulations]
[Pages 32803-32805]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-15512]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 74

[Docket No. 98C-0158]


Listing of Color Additives For Coloring Meniscal Tacks; D&C 
Violet No. 2

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 D&C Violet No. 2 to 
color absorbable meniscal tacks made from poly(L-lactic acid). This 
action responds to a petition filed by Linvatec Corp.

DATES: This regulation is effective July 20, 1999; except as to any 
provisions that may be stayed by the filing of proper objections; 
written objections and requests for a hearing by July 19, 1999.

ADDRESSES: Submit written objections to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Ellen M. Waldron, Center for Food 
Safety and Applied Nutrition (HFS-215), Food and Drug Administration, 
200 C St. SW., Washington, DC 20204, 202-418-3089.

SUPPLEMENTARY INFORMATION:

I. Introduction

    In a notice published in the Federal Register of March 13, 1998 (63 
FR 12473), FDA announced that a color additive petition (CAP 8C0255) 
had been filed by Linvatec Corp., P.O. Box 2917, Largo, FL 33779-2917. 
The petition proposed to amend the color additive regulations in 
Sec. 74.3602 D&C Violet No. 2 (21 CFR 74.3602) to provide for the safe 
use of D&C Violet No. 2 to color absorbable meniscal tacks made from 
poly(L-lactic acid). The petition was filed under section 721(d)(1) of 
the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 
379e(d)(1)).

[[Page 32804]]

II. Regulatory History

    The regulatory history of D&C Violet No. 2 was summarized in a 
final rule published in the Federal Register of May 7, 1990 (55 FR 
18865). Since the publication of the May 7, 1990, final rule, other 
uses of D&C Violet No. 2 have been approved by the agency. For example, 
in a final rule published in the Federal Register on April 23, 1998 (63 
FR 20096), FDA amended Sec. 74.3602 to list D&C Violet No. 2 as a color 
additive in glycolide/dioxanone/trimethylene carbonate tripolymer 
absorbable sutures for use in general surgery.

III. 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 into direct 
contact with the body for a significant period of time (section 721(a) 
of the act). D&C Violet No. 2 is added to absorbable meniscal tacks 
made from poly(L-lactic acid) in such a way that at least some of the 
color additive will come into contact with the body when the tacks are 
in place. In addition, the meniscal tacks are intended to be absorbed 
by the body, and during the absorption, the color additive will be 
deposited in body tissue. Thus, the color additive will be in direct 
contact with the body for a significant period of time. Consequently, 
the petitioned use of the color additive is subject to the statutory 
listing requirement.

IV. The Color Additive

    D&C Violet No. 2 is principally 1-hydroxy-4-[(4-
methylphenyl)amino]-9,10-anthracenedione (CAS Reg. No. 81-48-1). It is 
manufactured by either condensation of quinizarin with p-toluidine or 
by condensation of 1-hydroxy-halogenoanthroquinone with p-toluidine. 
Because no chemical reaction consumes all the starting materials and 
yields only the desired product, both the resulting reaction mixture 
and commercial product will contain residual amounts of the starting 
materials, including p-toluidine. This fact is significant because 
Weisburger et al., have demonstrated that p-toluidine is a carcinogen 
in the mouse (Ref. 1).
    Residual amounts of reactants, such as p-toluidine, and 
manufacturing aids are commonly found as impurities in chemical 
products, including color additives.

V. Determination of Safety

    Under the general safety standard of the act (section 721(b)(4)) 
for color additives, a color additive cannot be approved for a 
particular use unless a fair evaluation of the data available to FDA 
establishes that the color additive is safe for that use. FDA's color 
additive regulations (21 CFR 70.3(i)) define ``safe'' as ``reasonable 
certainty that no harm will result from the intended use of the color 
additive.''
    The color additives anticancer, or Delaney, clause of the color 
additive amendments (section 721(b)(5)(B)) provides that no noningested 
color additive shall be deemed safe and shall be listed if, after tests 
that are appropriate for evaluating the safety of the additive for such 
use, it is found to induce cancer in man or animal. Importantly, 
however, the Delaney clause applies to the additive itself and not to 
impurities in the additive. That is, where an additive itself has not 
been shown to cause cancer, but contains a carcinogenic impurity, the 
additive is properly evaluated under the general safety standard using 
risk assessment procedures to determine whether there is reasonable 
certainty that no harm will result from the intended use of the 
additive (Scott v. FDA, 728 F.2d 322 (6th Cir. 1984)).

VI. Safety of The Petitioned Use of The Additive

    FDA estimates that the petitioned use of the additive, D&C Violet 
No. 2, will result in exposure to no greater than 105 microgram 
(g) per person over a 70-year lifetime or an estimated daily 
intake (EDI) of 4 nanograms per person per day (ng/p/d) (Ref. 2).
    FDA does not ordinarily consider chronic toxicological studies to 
be necessary to determine the safety of an additive whose use will 
result in such low exposure levels (Ref. 3), and the agency has not 
required such testing here. However, the agency has reviewed the 
available toxicological data on the additive and concludes that the 
estimated small daily exposure resulting from the proposed use of this 
additive is safe.
    FDA has evaluated the safety of this additive under the general 
safety standard, considering all available data and using risk 
assessment procedures to estimate the upper-bound limit of lifetime 
human risk presented by p-toluidine, the carcinogenic chemical that may 
be present as an impurity in the additive. The risk evaluation of p-
toluidine has two aspects: (1) Assessment of exposure to the impurity 
from the proposed use of the additive, and (2) extrapolation of the 
risk observed in the animal bioassay to the conditions of exposure to 
humans.

A. p-Toluidine

    FDA has estimated the lifetime exposure to p-toluidine from the 
petitioned use of D&C Violet No. 2 in absorbable meniscal tacks made 
from poly(L-lactic acid) to be no more than 0.008 ng/p/d (Ref. 4). The 
agency used data from a long-term rodent bioassay on p-toluidine 
conducted by Weisburger et al. (Ref. 1), to estimate the upper-bound 
limit of lifetime human risk from exposure to this chemical resulting 
from the proposed use of the additive. The authors reported that the 
rodent bioassay showed that the test material caused an increased 
incidence of hepatomas (liver tumors).
    Based on the agency's estimate that exposure to p-toluidine will 
not exceed 0.008 ng/p/d, FDA estimates that the upper-bound limit of 
lifetime human risk from the petitioned use of the subject additive is 
5.3 x 10-13 or 5.3 in 10 trillion (Ref. 4). Because of the 
numerous conservative assumptions used in calculating the exposure 
estimate, the actual lifetime-averaged individual exposure to p-
toluidine is likely to be substantially less than the estimated 
exposure, and therefore, the probable lifetime human risk would be less 
than the upper-bound limit of lifetime human risk. Thus, the agency 
concludes that there is reasonable certainty that no harm from exposure 
to p-toluidine would result from the proposed use of the additive.

B. Specifications

    The agency also has considered whether specifications are necessary 
to control the amount of p-toluidine present as an impurity in D&C 
Violet No. 2. The additive is currently produced as a certified color 
additive for use in externally applied drugs and cosmetics, in sutures, 
and in contact lenses in accordance with 21 CFR part 80. Based upon the 
low level of exposure to p-toluidine that results under the current 
specifications for D&C Violet No. 2 in Sec. 74.1602 (21 CFR 74.1602), 
the agency concludes that the specifications listed in Sec. 74.1602 are 
adequate to ensure the safe use of this color additive and to control 
the amount of p-toluidine that may exist as an impurity in the color 
additive when used in absorbable meniscal tacks made from poly(L-lactic 
acid).

VII. Conclusions on Safety

    FDA has evaluated the data and information in the petition and 
other relevant material. Based on this information the agency concludes 
that: (1) The proposed use of D&C Violet No. 2, at a level not to 
exceed 0.15 percent

[[Page 32805]]

by weight of the tack material, for coloring absorbable meniscal tacks 
made from poly(L-lactic acid) is safe; and (2) the color additive will 
achieve its intended coloring effect, and thus, is suitable for this 
use. Further, the agency concludes that the color additive regulations 
in Sec. 74.3602 should be amended as set forth below.

VIII. 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.

IX. Environmental Impact

    The agency has previously considered the potential environmental 
effects of this rule as announced in the notice of filing for the 
petition (63 FR 12473, March 13, 1998). No new information or comments 
have been received that would affect the agency's previous 
determination that there is no significant impact on the human 
environment and that an environmental impact statement is not required.

X. Paperwork Reduction Act of 1995

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

XI. Objections

    Any person who will be adversely affected by this regulation may at 
any time on or before July 19, 1999, 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.

XII. 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. Weisburger, E. K. et al., ``Testing of Twenty-one 
Environmental Aromatic Amines or Derivatives for Long-Term 
Toxicology or Carcinogenicity,'' Journal of Environmental Pathology 
and Toxicology, 2:325-356, 1978.
    2. Memorandum from the Division of Product Manufacture and Use, 
Chemistry Review Team (FDA), to the Division of Product Policy 
(FDA), concerning ``CAP 8C0255 (MATS M2.0 & 2.1): Linvatec, Inc. 
(Submission of 28 January, 1998). Petition for the Safe Use of of 
[sic] D&C Violet #2 to Tint Poly(L-lactic acid) Meniscal Taks.'' 
dated April 13, 1998.
    3. Kokoski, C. J., ``Regulatory Food Additive Toxicology'' in 
Chemical Safety Regulation and Compliance, edited by F. Homburger 
and J. K. Marquis, published by S. Karger, New York, NY, pp. 24-33, 
1985.
    4. Memorandum from Division of Petition Control (FDA), to 
Executive Secretary, Quantitative Risk Assessment Committee (FDA), 
concerning ``Estimate of the Upper Bound Lifetime Risk From p-
toluidine in D&C Violet No. 2 Used as a Color Additive for Meniscal 
Tacks Made from Poly(L-lactic acid): CAP 8C0255,'' dated September 
28, 1998.

List of Subjects in 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, 21 CFR part 
74 is amended as follows:

PART 74--LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION

    1. The authority citation for 21 CFR part 74 continues to read as 
follows:

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

    2. Section 74.3602 is amended by redesignating paragraph (b)(4) as 
paragraph (b)(5) and by adding new paragraph (b)(4) to read as follows:


Sec. 74.3602  D&C Violet No. 2.

* * * * *
    (b) * * *
    (4) The color additive, D&C Violet No. 2, may be safely used for 
coloring absorbable meniscal tacks made from poly (L-lactic acid) at a 
level not to exceed 0.15 percent by weight of the tack material.
* * * * *

    Dated: June 3, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy Coordination.
[FR Doc. 99-15512 Filed 6-17-99; 8:45 am]
BILLING CODE 4160-01-F