[Federal Register Volume 65, Number 146 (Friday, July 28, 2000)]
[Rules and Regulations]
[Pages 46342-46344]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-19047]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 74

[Docket No. 99C-1455]


Listing of Color Additives for Coloring Sutures; 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 as 
a color additive in absorbable sutures prepared from homopolymers of 
glycolide for general surgery. The agency is also revising the 
nomenclature ``polyglactin 910 (glycolic-lactic acid polyester)'' to 
the generic nomenclature ``copolymers of 90 percent glycolide and 10 
percent L-lactide.'' This action responds to a petition filed by 
Genzyme Surgical Products Corp.

DATES: This rule is effective August 29, 2000; except as to any 
provisions that may be stayed by the filing of proper objections. 
Submit written objections and requests for a hearing by August 28, 
2000.

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 June 3, 1999 (64 
FR 29871), FDA announced that a color additive petition (CAP 9C0266) 
had been filed by Genzyme Surgical Products Corp., 600 Airport Rd., 
Fall River, MA 02720. 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 as a color additive in 
absorbable sutures prepared from homopolymers of glycolide for general 
surgery. The petition also proposed that the nomenclature ``polyglactin 
910 (glycolic-lactic acid polyester)'' be revised to the generic 
nomenclature ``copolymers of 90 percent glycolide and 10 percent L-
lactide.'' 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)).

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 of June 18, 1999 (64 
FR 32803), FDA amended Sec. 74.3602 to list D&C Violet No. 2 as a color 
additive in absorbable meniscal tacks made from poly(L-lactic acid).

III. Applicability of the Act

    With the passage of the Medical Device Amendments of 1976 (Public 
Law 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 sutures 
prepared from homopolymers of glycolide in such a way that at least 
some of the color additive will come into contact with the body when 
the sutures are in place. In addition, the sutures 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) of the act) 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

[[Page 46343]]

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 over a 70-year lifetime of 156 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 average individual lifetime exposure to p-
toluidine from the petitioned use of D&C Violet No. 2 in absorbable 
sutures prepared from homopolymers of glycolide to be no more than 0.3 
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 0.3 ng/p/d, FDA estimates that the upper-bound limit of 
lifetime human risk from the petitioned use of the subject additive is 
2 x 10-11 or 2 in 100 billion (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 has also 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, 
in meniscal tacks, 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 sutures prepared 
from homopolymers of glycolide.

VII. Conclusions

    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 0.2 percent by weight of the suture material, for coloring 
absorbable sutures prepared from homopolymers of glycolide for general 
surgery is safe; and (2) the color additive will achieve its intended 
coloring effect, and thus, is suitable for this use. Further, FDA has 
carefully considered the proposal to revise the nomenclature 
``polyglactin 910 (glycolic-lactic acid polyester),'' which is 
currently listed in Sec. 74.3602(b)(2)(i). The agency concludes that 
the nomenclature, which is a trade name, should be revised to the 
generic nomenclature ``copolymers of 90 percent glycolide and 10 
percent L-lactide.'' Finally, 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 environmental effects of 
this rule as announced in the notice of filing for CAP 9C0266 (64 FR 
29871, June 3, 1999). 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 file with the Dockets Management Branch (address above) 
written objections by August 28, 2000. 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 are to be 
submitted and are to be identified with the docket number found in 
brackets in the heading of this

[[Page 46344]]

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.

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 Petition Control 
(FDA), concerning ``CAP 9C0266 (MATS M2.0 & 2.1): Genzyme Surgical 
Products Corp. (Submission of March 18, 1999, facsimile dated April 
9, 1999, and amendment of April 29, 1999). Request for the Listing 
of D&C Violet No. 2 in Glycolide Homopolymer Absorbable Sutures for 
General Surgery,'' dated June 18, 1999.
    3. Kokoski, C. J., ``Regulatory Food Additive Toxicology,'' 
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 ``Estimation of the Upper-Bound Lifetime Risk From p-
Toluidine in D&C Violet No. 2 When Used as a Color Additive for 
Sutures Used in General Surgery: CAP 9C0266,'' dated July 21, 1999.

List of Subjects in 21 CFR Part 74

    Color additives, Cosmetics, Drugs, Foods, 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 
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 revising paragraph (b)(2)(i) and 
by adding paragraph (b)(2)(vi) to read as follows:


Sec. 74.3602  D&C Violet No. 2.

* * * * *
    (b) * * *
    (2) * * *
    (i) At a level not to exceed 0.2 percent by weight of the suture 
material for coloring copolymers of 90 percent glycolide and 10 percent 
L-lactide synthetic absorbable sutures for use in general and 
ophthalmic surgery; and
* * * * *
    (vi) At a level not to exceed 0.2 percent by weight of the suture 
material for coloring absorbable sutures prepared from homopolymers of 
glycolide for use in general surgery.
* * * * *

    Dated: July 20, 2000.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 00-19047 Filed 7-27-00; 8:45 am]
BILLING CODE 4160-01-F