[Federal Register Volume 63, Number 78 (Thursday, April 23, 1998)]
[Rules and Regulations]
[Pages 20096-20098]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-10779]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 74

[Docket No. 95C-0399]


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 glycolide/dioxanone/trimethylene carbonate 
tripolymer absorbable sutures for general surgery. This action responds 
to a petition filed by United States Surgical Corp.

DATES:  This regulation is effective May 27, 1998; except as to any 
provisions that may be stayed by the filing of proper objections; 
written objections and requests for a hearing by May 26, 1998.
ADDRESSES: Submit written objections to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857.

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

SUPPLEMENTARY INFORMATION:

I. Introduction

     In a notice published in the Federal Register of October 23, 1995 
(60 FR 54379), FDA announced that a color additive petition (CAP 
5C0248) had been filed by United States Surgical Corp., 150 Glover 
Ave., Norwalk, CT 06856. 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 
glycolide/dioxanone/trimethylene carbonate tripolymer absorbable 
sutures for general surgery. 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 on March 14, 1994 (59 
FR 11718), FDA amended Sec. 74.3602 to list D&C Violet No. 2 for use to 
color poly(<greek-e>-caprolactone) 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 glycolide/dioxanone/
trimethylene carbonate tripolymer absorbable sutures 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 clause of the act (section 721(b)(4) of 
the act) for color additives, a color additive cannot be listed 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 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 proposed 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 3.8 milligrams per 
person over a 70-year lifetime or an estimated daily intake (EDI) of 
0.15 microgram per person per day (/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 intake 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,

[[Page 20097]]

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 glycolide/dioxanone/trimethylene 
carbonate tripolymer absorbable sutures to be no more than is 0.3 
nanogram (ng)/p/d (Ref. 2). 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 proposed use of the subject additive is 2 
x 10<SUP>-11</SUP> 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, 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 glycolide/dioxanone/trimethylene 
carbonate tripolymer absorbable sutures for general surgery.

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 0.2 percent by weight of the suture material, for coloring 
glycolide/dioxanone/trimethylene carbonate tripolymer absorbable 
sutures is safe; and (2) the color additive will achieve its intended 
coloring effect, and thus, is suitable for this use. The agency 
therefore, is amending the color additive regulations in Sec. 74.3602 
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 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.

X. Objections

    Any person who will be adversely affected by this regulation may at 
any time on or before May 26, 1998, 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.

XI. 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 Chemistry Review Team, FDA, to the 
Indirect Additives Team, FDA, concerning ``CAP 5C0248: United States 
Surgical Corporation. Use of D&C Violet No. 2 as a colorant in 
synthetic absorbable surgical suture. Correction of Exposure 
Estimate.,'' dated March 6, 1997.
     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. Report of the Quantitative Risk Assessment Committee, FDA, 
concerning ``Upper Bound Lifetime Risk for p-Toluidine in D&C Violet 
No. 2 Used as a Color Additive for glycolide/dioxanone/trimethylene 
carbonate tripolymer absorbable sutures designated as USSC 
Monofilament polysorb sutures (UMPS),'' dated September 4, 1997.

 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 adding paragraph (b)(2)(v) to 
read as follows:


Sec. 74.3602   D&C Violet No. 2.

* * * * *

[[Page 20098]]

     (b) * * *
     (2) * * *
     (v) At a level not to exceed 0.2 percent by weight of the suture 
material for coloring glycolide/dioxanone/trimethylene carbonate 
tripolymer absorbable sutures for use in general surgery.
* * * * *

    Dated: April 16, 1998.
 William K. Hubbard,
 Associate Commissioner for Policy Coordination.
[FR Doc. 98-10779 Filed 4-22-98; 8:45 am]
BILLING CODE 4160-01-F