[Federal Register Volume 59, Number 49 (Monday, March 14, 1994)]
[Unknown Section]
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From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-5788]
[[Page Unknown]]
[Federal Register: March 14, 1994]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 74
[Docket No. 90C-0221]
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 to
color poly(-caprolactone) absorbable sutures for general
surgery. This action responds to a petition filed by Concept, Inc.
DATES: Effective April 14, 1994, except as to any provisions that may
be stayed by the filing of proper objections; written objections by
April 13, 1994.
ADDRESSES: Submit written objections to the Dockets Management Branch
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr.,
Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Mitchell Cheeseman, Center for Food
Safety and Applied Nutrition (HFS-216), Food and Drug Administration,
200 C St. SW., Washington, DC 20204, 202-254-9511.
SUPPLEMENTARY INFORMATION:
I. Introduction
In a notice published in the Federal Register of August 6, 1990 (55
FR 31897), FDA announced that a color additive petition (CAP 0C0224)
had been filed by Concept, Inc., 11311 Concept Blvd., Largo, FL 34643.
The petition proposed that the color additive regulations in
Sec. 74.3602 D&C Violet No. 2 (21 CFR 74.3602) be amended to provide
for the safe use of D&C Violet No. 2 as a color additive in
poly(-caprolactone) absorbable sutures for general surgery.
Since the publication of the filing notice, Concept, Inc., has changed
its name to Linvatec Corp. The petition was filed under section 706
(currently section 721) of the Federal Food, Drug, and Cosmetic Act
(the act) (21 U.S.C. 376) (currently 21 U.S.C. 379e).
II. Regulatory History
The regulatory history of D&C Violet No. 2 is summarized in a final
rule published in the Federal Register of May 7, 1990 (55 FR 18865). In
the May 1990, final rule FDA permanently listed D&C Violet No. 2 for
use in coloring polymethylmethacrylate intraocular lens haptics
(Sec. 74.3602) in response to a color additive petition (CAP 9C0216).
In that final rule, FDA also transferred the listings for the use of
the color additive in sutures from Sec. 74.1602 (21 CFR 74.1602) under
Subpart B--Drugs to Sec. 74.3602 under Subpart D--Medical Devices.
Since the publication of the May 7, 1990, final rule, Sec. 74.3602 has
been amended to provide for the safe use of D&C Violet No. 2 as a color
additive in poliglecaprone 25 (-caprolactone/glycolide
copolymer) absorbable sutures.
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 (21 U.S.C.
379e(a)). D&C Violet No. 2 is added to the poly(-caprolactone)
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 use of the
color additive currently before the agency 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 mice (Ref.
1).
Residual amounts of reactants, such as p-toluidine and other
manufacturing aids, are commonly found among the impurities of many
color additives. The presence of such impurities is not unique to color
additives. Numerous minor impurities are present in all chemical
products, even in highly purified reagent-grade chemicals.
V. Determination of Safety
Under section 721(b)(4) of the act (21 U.S.C. 379e(b)(4)), the so-
called ``general safety clause'' for color additives, a color additive
cannot be listed for a particular use unless a fair evaluation of the
data and information available to FDA establish that the color additive
is safe for that use. FDA's color additive regulations (21 CFR 70.3(i))
define ``safe'' as ``a reasonable certainty in the minds of competent
scientists that the substance is not harmful under the intended
conditions of use.''
The anticancer or Delaney clause of the Color Additive Amendments
(section 721(b)(5)(B) of the act) provides that a noningested color
additive shall be deemed unsafe and shall not 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
constituents of 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 clause using
risk assessment procedures to determine whether there is a 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 upper limit of lifetime exposure to D&C
Violet No. 2 from its use in coloring poly(-caprolactone)
absorbable sutures is 3.7 milligrams (mg) per person (0.15 micrograms
(g) per person per day). The agency calculated this upper
limit of lifetime exposure based on several factors. First, the color
additive will be used at a level of 0.1 percent by weight of the
poly(-caprolactone) absorbable sutures. Second, the agency
made four assumptions: (1) Five meters is the maximum total length of
suture likely to be used in a single surgical operation, and 10 meters
of suture would be used in multiple operations over a person's
lifetime; (2) a lifespan of 70 years follows initial suture
implantation; (3) a size 2 suture is used for general surgery; and (4)
100 percent of the color additive migrates from the suture into the
body. Because these are conservative assumptions, the lifetime exposure
to D&C Violet No. 2 from its use in coloring poly(-
caprolactone) absorbable sutures is likely to be far less than 3.7 mg
per person (0.15 g per person per day).
FDA does not ordinarily consider chronic toxicological testing to
be necessary to determine the safety of an additive whose use will
result in such low exposure levels (Ref. 2), and the agency has not
required such testing in this case. Although the agency does not
normally require such testing, chronic studies supporting current
listings for the use of D&C Violet No. 2 are available in the agency's
files, and FDA's safety evaluation of the proposed use of the color
additive in absorbable sutures included a consideration of these
studies. Two-year carcinogenicity studies of dyed sutures implanted in
rats and a lifetime skin-painting study in mice showed no indication of
carcinogenicity. Additionally, teratology studies of sutures implanted
in rats and rabbits exhibited no evidence of teratogenic effects.
In its evaluation of the safety of the proposed use of the subject
additive, FDA has also considered other safety data submitted
previously to support current listings for the use of D&C Violet No. 2.
These toxicity studies of D&C Violet No. 2 included acute oral toxicity
studies in rats and dogs, acute toxicity studies of dyed sutures and
suture components in rats and mice, an evaluation of the tissue
response to dyed sutures implanted intramuscularly in rats, a
biological evaluation of dyed sutures implanted in rabbit's eyes, a
study of the tissue reaction to the color additive injected into rabbit
muscle, in vitro cytotoxicity studies, a pyrogenicity study of sutures,
7-month toxicity studies of implanted sutures in rats and dogs, a 119-
day evaluation of dyed sutures implanted intramuscularly in rats, and
six mutagenicity studies, including one Salmonella/reverse mutation
test (Ames test) using extracts of dyed sutures, one study of
chromosomal aberrations using dyed suture in Chinese hamster ovary
cells, one study of in vitro transformation using dyed suture in Balb/
c-3T3 cells, two mouse lymphoma forward mutation assays using dyed
suture, and one mouse lymphoma toxicity assay of dyed suture.
In addition, FDA evaluated the toxicity studies that the petitioner
provided to support the proposed use of D&C Violet No. 2 in
poly(-caprolactone) absorbable sutures for general surgery.
These studies included a hemolysis test by direct contact, a direct
contact cytotoxicity test on mouse fibroblast cells using extracts of
dyed sutures, a systemic toxicity test in mice using extracts of dyed
sutures, a guinea pig sensitization maximization test using extracts of
dyed sutures, a test of intracutaneous toxicity in rabbits using
extracts of dyed sutures, implantation tests (7, 32, and 89 days, and 6
and 9 months) in rabbits, a Salmonella/mammalian mutagenicity test
using extracts of dyed sutures, 52- and 32-week implantation tests in
rats, and 60- and 62-day evaluations of absorbable suture following
abdominal wound closure in rabbits.
There were no significant adverse effects from D&C Violet No. 2 in
any of the studies evaluated by the agency. Therefore, the agency has
concluded that these studies in conjunction with previously submitted
studies establish the safety of the proposed use of D&C Violet No. 2 as
a color additive in poly(-caprolactone) absorbable sutures.
FDA has evaluated the safety of this additive under the general
safety clause, considering all available data. The agency has also used
risk assessment procedures to estimate the upper-bound limit of risk
presented by p-toluidine, a carcinogenic chemical that may be present
as an impurity in the additive. The risk evaluation of p-toluidine has
two aspects: (1) Assessment of the exposure to the impurity from the
proposed use of the additive and (2) extrapolation of the risk observed
in the animal bioassays to the conditions of probable exposure to
humans.
A. p-Toluidine
Using risk assessment procedures, FDA estimates that the maximum
total lifetime exposure to p-toluidine that will result from the use of
poly(-caprolactone) absorbable sutures colored with D&C Violet
No. 2 that complies with the applicable specifications is 0.3 nanograms
(ng) per person per day. The agency used data reported by the National
Cancer Institute, which demonstrated that p-toluidine was carcinogenic
for male and female Charles River CD-1 (HaM/ICR derived) mice, causing
an increased incidence of hepatomas (liver tumors) (Ref. 1), to
estimate the upper-bound limit of lifetime human risk from exposure to
this chemical stemming from the proposed use of D&C Violet No. 2 as a
color additive in poly(-caprolactone) absorbable sutures (Ref.
3).
Based on a potential exposure of 0.3 ng per person per day, the
upper-bound limit of individual lifetime risk from the potential
exposure to p-toluidine from the proposed use of D&C Violet No. 2 as a
color additive in poly(-caprolactone) absorbable sutures is
2x10-11, or 2 in 100 billion (Ref. 3). Because of the numerous
conservatisms in the exposure estimate, actual lifetime-averaged
individual exposure to p-toluidine is expected to be substantially less
than the worst-case estimated daily exposure. Therefore, the actual
risk would be less than 2x10-11. Thus, the agency concludes that
there is a reasonable certainty of no harm from exposure to p-toluidine
that might result from the proposed use of D&C Violet No. 2 for
coloring poly(-caprolactone) absorbable sutures.
B. Specifications
D&C Violet No. 2 is currently produced as a certifiable 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, 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 poly(-caprolactone) absorbable sutures.
VII. Conclusions
Based upon the available toxicity data and the other relevant
considerations discussed above, FDA concludes that there is a
reasonable certainty that no harm will result from the petitioned use
of D&C Violet No. 2 for coloring poly(-caprolactone)
absorbable sutures when it is used at a level not to exceed 0.1 percent
by weight of the suture material. The agency also concludes on the
basis of available data that the color additive will perform its
intended coloring effect in poly(-caprolactone) absorbable
sutures and, thus, is suitable for this use. The agency, therefore, is
amending Sec. 74.3602 of the color additive regulations to provide for
use of the color additive at a maximum level of 0.1 percent by weight
in poly(-caprolactone) absorbable sutures.
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. 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. Kokoski, C. J., ``Regulatory Food Additive Toxicology'' in
``Chemical Safety Regulation and Compliance,'' F. Homburger and J.
K. Marquis, editors, S. Karger, New York, pp. 24-33, 1985.
3. Report of the Quantitative Risk Assessment Committee, ``Upper
Bound Lifetime Risk for p-Toluidine in D&C Violet No. 2 Used as a
Color Additive for Poly(epsilon-Caprolactone) Absorbable Sutures CAP
0C0224 (Concept, Inc.),'' July 30, 1991.
XI. Objections
Any person who will be adversely affected by this regulation may at
any time on or before April 13, 1994 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.
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: Secs. 201, 401, 402, 403, 409, 501, 502, 505, 601,
602, 701, 721 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
321, 341, 342, 343, 348, 351, 352, 355, 361, 362, 371, 379e).
2. Section 74.3602 is amended by adding new paragraph (b)(2)(iv) to
read as follows:
Sec. 74.3602 D&C Violet No. 2.
* * * * *
(b) * * *
(2) * * *
(iv) At a level not to exceed 0.1 percent by weight of the suture
material for coloring poly(-caprolactone) absorbable sutures
for use in general surgery.
* * * * *
Dated: March 4, 1994.
Michael R. Taylor,
Deputy Commissioner for Policy.
[FR Doc. 94-5788 Filed 3-11-94; 8:45 am]
BILLING CODE 4160-01-F