[Federal Register Volume 64, Number 171 (Friday, September 3, 1999)]
[Rules and Regulations]
[Pages 48288-48290]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-22994]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 74

[Docket No. 92C-0348]


Listing of Color Additives for Coloring Bone Cement; FD&C Blue 
No. 2-Aluminum Lake on Alumina

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 FD&C Blue No. 2-
Aluminum Lake on alumina to color bone cement. This action responds to 
a petition filed by Biomet, Inc. The agency also is transferring the 
listing for FD&C Blue No. 2 in sutures to reflect the suture in which 
this color additive is used are devices not drugs.

DATES: This regulation is effective October 5, 1999; except as to any 
provisions that may be stayed by the filing of proper objections; 
written objections and requests for a hearing by October 4, 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), 200 C St. SW., Washington, DC 
20204, 202-418-3089.

SUPPLEMENTARY INFORMATION:

I. Introduction

    In a notice published in the Federal Register of November 19, 1992 
(57 FR 54598), FDA announced that a color additive petition (CAP 
2C0239) had been filed by Biomet, Inc., P.O. Box 587, Warsaw, IN 46581-
0587. The petition proposed to amend the color additive regulations to 
provide for the safe use of FD&C Blue No. 2-Aluminum Lake to color bone 
cement. The petition was filed under section 706(d)(1) of the Federal 
Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 376(d)(1)), presently 
designated as 721(d)(1) of the act (21 U.S.C. 379e(d)(1)).
    The agency is changing the name of the color additive used in the 
filing notice to FD&C Blue No. 2-Aluminum Lake on alumina to make it 
conform to the nomenclature proposed for the permanent listing of color 
additive lakes (61 FR 8372, March 4, 1996). To reflect that sutures in 
which this color additive is used are devices, not drugs, the agency 
also is transferring the listing for the use of FD&C Blue No. 2 in 
sutures from Sec. 74.1102 FD&C Blue No. 2 (21 CFR 74.1102) under 
subpart B--Drugs to new Sec. 74.3102 FD&C Blue No. 2 (21 CFR 74.3102) 
under subpart D--Medical Devices and is making nonsubstantive 
amendments to Sec. 74.1102. This transfer will provide for all medical 
device uses of FD&C Blue No. 2 and its lake to be listed uniformly and 
more correctly under subpart D--Medical Devices. Section 
74.1102(c)(1)(iv) is being removed because it is no longer applicable.
    The Medical Device Amendments (Public Law 94-295) (the amendments) 
were enacted into law on May 28, 1976, to provide a comprehensive 
system of regulation for devices. These amendments (21 U.S.C. 321, et 
seq.) expanded the definition of device, under section 201(h) of the 
act (21 U.S.C. 321(h)), to include many products that were previously 
regarded as drugs. These products are known as ``transitional'' devices 
and are subject to regulation under section 520(l) of the act (21 U.S. 
C. 360j(l)). In the Federal Register of December 16, 1977 (42 FR 
63472), FDA published a notice listing those products that had 
previously been considered to be drugs that FDA now considered to be 
devices under the amendments. FDA listed nonabsorbable surgical 
sutures, and absorbable surgical sutures as transitional devices in the 
December 1977 notice (42 FR 63472 at 63474). Various types of surgical 
sutures are classified as devices in 21 CFR 878.4493, 878.4830, 
878.5000, 878.5010, 878.5020, and 878.5030. Because all surgical 
sutures are regulated as devices, FDA is redesignating its listing of 
FD&C Blue No. 2 in sutures from Sec. 74.1102 under subpart B--Drugs to 
new Sec. 74.3102 under subpart D--Medical Devices.

II. Regulatory History and Current Listings

    In a final rule published in the Federal Register on February 13, 
1971 (36 FR 2967), FDA added 21 CFR 8.4022 (presently Sec. 74.1102) to 
list FD&C Blue No. 2 for use to color nylon sutures for general 
surgery. In this final rule, FDA also added specifications for FD&C 
Blue No. 2 for use to color sutures.
    In the Federal Register of February 4, 1983 (48 FR 5252), FDA 
issued a final rule adding Sec. 74.102 and amending Sec. 74.1102 to 
permanently list the color additive FD&C Blue No. 2 for use in food and 
ingested drugs, respectively. In the February 4, 1983, final rule, FDA 
also added new specifications for FD&C Blue No. 2 for use in food and 
ingested drugs that identified the color additive more precisely than 
those specifications that had previously been included in the 
provisional listing for FD&C Blue No. 2 in 21 CFR part 82. Further, to 
provide adequate assurance of safety, the agency specified in the 
February 4, 1983, final rule (48 FR 5252 at 5259-5260), through a 
general description, the manufacturing process for FD&C Blue No. 2.

 III. Applicability of the Act

    With the passage of the Medical Device Amendments of 1976 (Public

[[Page 48289]]

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). The color additive FD&C Blue No. 2-Aluminum Lake on 
alumina is added to bone cement in such a way that at least some of the 
color additive will come into contact with the body for a significant 
period of time when the bone cement is in place. In addition, the bone 
cement may be used in permanent joint replacements. Thus, for both of 
these uses, the color additive FD&C Blue No. 2-Aluminum Lake on alumina 
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

    The color additive that is the subject of this rule, FD&C Blue No. 
2-Aluminum Lake on alumina (CAS Reg. No. 16521-38-3), is the aluminum 
salt of the color additive FD&C Blue No. 2, extended on a substratum of 
alumina. The aluminum salt is formed when FD&C Blue No. 2 is mixed with 
aluminum sulfite, sodium carbonate, and water. The color additive FD&C 
Blue No. 2 is identified in Sec. 74.102(a)(1).

V. Safety Evaluation

    FDA estimates that the petitioned use of the additive, FD&C Blue 
No. 2-Aluminum Lake on alumina, at a level not to exceed 0.1 percent by 
weight of the bone cement, would result in exposure no greater than 90 
micrograms per person over a 70-year lifetime or an ``estimated daily 
intake'' of 3 nanograms per person per day. Actual exposure to the 
subject color additive from the proposed use is expected to be 
significantly lower, because lakes are deliberately formulated to be 
insoluble and the petitioner submitted data to demonstrate that FD&C 
Blue No. 2-Aluminum Lake on alumina does not leach from cured bone 
cement in detectable quantities under simulated conditions of use.
    To establish the safety of FD&C Blue No. 2-Aluminum Lake on 
alumina, the petitioner has submitted data from muscle implantation 
tests on the bone cement in rabbits, intraperitoneal toxicity studies 
of the cement in dogs, intracutaneous testing of cement extracts in 
rabbits, and cytotoxicity tests. No adverse effects attributable to 
FD&C Blue No. 2-Aluminum Lake on alumina were reported in these 
studies. Feeding studies available in agency files with the straight 
color, FD&C Blue No. 2, also demonstrated no adverse effects. The 
dietary route of exposure utilized in these studies with FD&C Blue No. 
2 is not comparable to the route of exposure from the proposed use of 
FD&C Blue No. 2-Aluminum Lake on alumina in bone cement, but the 
absence of adverse effects associated with exposure to FD&C Blue No. 2 
helps to mitigate concern for systemic toxicity from the use of FD&C 
Blue No. 2-Aluminum Lake on alumina in bone cement. Based on review of 
all available toxicological data on FD&C Blue No. 2 and FD&C Blue No. 
2-Aluminum Lake on alumina, the agency concludes that the limited 
exposure resulting from the proposed use of FD&C Blue No. 2-Aluminum 
Lake on alumina in bone cement is safe.

VI. 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 FD&C Blue No. 2-Aluminum Lake on alumina, 
at a level not to exceed 0.1 percent by weight of the bone cement, to 
color bone cement 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 part 74 (21 
CFR part 74) should be amended as set forth below.
    To reflect that sutures in which this color additive is used are 
devices, not drugs, the agency is redesignating the current listing for 
the use of the color additive FD&C Blue No. 2 in sutures from 
Sec. 74.1102, subpart B--Drugs to new Sec. 74.3102, subpart D--Medical 
Devices and is making nonsubstantive amendments to Sec. 74.1102.

VII. 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 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.

VIII. 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.

IX. 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.

X. Objections

    Any person who will be adversely affected by this regulation may at 
any time on or before October 4, 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. FDA will publish 
notice of the objections that the agency has received or lack thereof 
in the Federal Register.

List of Subjects in 21 CFR Part 74

    Color additives, Cosmetics, Drugs, 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:


[[Page 48290]]


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

Sec. 74.1102  [Amended]

    2. Section 74.1102 FD&C Blue No. 2 is amended by removing 
paragraphs (b)(1) and (c)(1); and by redesignating paragraphs (b)(2) 
and (c)(2) as paragraphs (b) and (c) respectively.
    3. Section 74.3102 is added to subpart D to read as follows:

Sec. 74.3102  FD&C Blue No. 2.

    (a) Identity. The color additive FD&C Blue No. 2 shall conform in 
identity to the requirements of Sec. 74.102(a)(1).
    (b) Specifications. (1) The color additive FD&C Blue No. 2 for use 
in coloring surgical sutures shall conform to the following 
specifications and shall be free from impurities other than those named 
to the extent that such impurities may be avoided by current good 
manufacturing practice:

    Sum of volatile matter at 135  deg.C (275  deg.F) and chlorides 
and sulfates (calculated as sodium salts), not more than 15 percent.
    Water insoluble matter, not more than 0.4 percent.
    Isatin-5-sulfonic acid, not more than 0.4 percent.
    Isomeric colors, not more than 18 percent.
    Lower sulfonated subsidiary colors, not more than 5 percent.
    Lead (as Pb), not more than 10 parts per million.
    Arsenic (as As), not more than 3 parts per million.
    Total color, not less than 85 percent.

    (2) The color additive FD&C Blue No. 2-Aluminum Lake on alumina for 
use in bone cement shall be prepared in accordance with the 
requirements of Sec. 82.51 of this chapter.
    (c) Uses and restrictions. (1) The color additive FD&C Blue No. 2 
may be safely used for coloring nylon (the copolymer of adipic acid and 
hexamethylene diamine) surgical sutures for use in general surgery 
subject to the following restrictions:
    (i) The quantity of color additive does not exceed 1 percent by 
weight of the suture;
    (ii) The dyed suture shall conform in all respects to the 
requirements of the United States Pharmacopeia XX (1980); and
    (iii) When the sutures are used for the purposes specified in their 
labeling, the color additive does not migrate to the surrounding 
tissues.
    (2) The color additive FD&C Blue No. 2-Aluminum Lake on alumina may 
be safely used for coloring bone cement at a level not to exceed 0.1 
percent by weight of the bone cement.
    (3) Authorization and compliance with these uses shall not be 
construed as waiving any of the requirements of sections 510(k), 515, 
and 520(g) of the Federal Food, Drug, and Cosmetic Act with respect to 
the medical device in which the color additive FD&C Blue No. 2 and the 
color additive FD&C Blue No. 2-Aluminum Lake on alumina are used.
    (d) Labeling. The labels of the color additive FD&C Blue No. 2 and 
the color additive FD&C Blue No. 2-Aluminum Lake on alumina shall 
conform to the requirements of Sec. 70.25 of this chapter.
    (e) Certification. All batches of FD&C Blue No. 2 and its lake 
shall be certified in accordance with regulations in part 80 of this 
chapter.

    Dated: August 25, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 99-22994 Filed 9-2-99; 8:45 am]
BILLING CODE 4160-01-F