98-10779. Listing of Color Additives for Coloring Sutures; D&C Violet No. 2  

  • [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(-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,
    
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    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 10-11 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, 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
    
    
    

Document Information

Effective Date:
5/27/1998
Published:
04/23/1998
Department:
Food and Drug Administration
Entry Type:
Rule
Action:
Final rule.
Document Number:
98-10779
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.
Pages:
20096-20098 (3 pages)
Docket Numbers:
Docket No. 95C-0399
PDF File:
98-10779.pdf
CFR: (2)
21 CFR 74.1602
21 CFR 74.3602