[Federal Register Volume 59, Number 153 (Wednesday, August 10, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-19483]
[[Page Unknown]]
[Federal Register: August 10, 1994]
=======================================================================
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 74
[Docket No. 92C-0294]
Listing of Color Additives Subject to Certification; D&C Green
No. 5
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is amending the color
additive regulations to provide for the safe use of D&C Green No. 5 for
coloring drugs and cosmetics intended for use in the area of the eye.
This action is in response to a petition filed by the Cosmetic,
Toiletry, and Fragrance Association (CTFA).
DATES: Effective September 12, 1994, except as to any provisions that
may be stayed by the filing of proper objections; written objections
and requests for a hearing by September 9, 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: Robert L. Martin, Center for Food
Safety and Applied Nutrition (HFS-217), Food and Drug Administration,
200 C St. SW., Washington, DC 20204, 202-254-9519.
SUPPLEMENTARY INFORMATION:
I. Introduction
In a notice published in the Federal Register of August 11, 1992
(57 FR 35833), FDA announced that a color additive petition (CAP
6C0204) had been filed by CTFA, 1101 17th St. NW., suite 300,
Washington, DC 20036. The petition proposed that the color additive
regulations for D&C Green No. 5 be amended to provide for the safe use
of D&C Green No. 5 for coloring drugs and cosmetics intended for use in
the area of the eye. 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 Green No. 5 is summarized in a final
rule that was published in the Federal Register of June 4, 1982 (47 FR
24278). In that final rule, FDA permanently listed D&C Green No. 5 for
use in drugs and cosmetics excluding use in the area of the eye. These
actions were taken in response to a color additive petition (CAP
8C0084).
III. Definitions
Section 70.3(s) (21 CFR 70.3(s)) defines the term ``area of the
eye'' as ``the area enclosed within the circumference of the supra-
orbital ridge and the infra-orbital ridge, including the eyebrow, the
skin below the eyebrow, the eyelids and the eyelashes, and conjunctival
sac of the eye, the eyeball, and the soft areolar tissue that lies
within the perimeter of the infra-orbital ridge.'' 21 CFR 70.5(a)
states that ``No listing or certification of a color additive shall be
considered to authorize the use of any such color additive in any
article intended for use in the area of the eye unless such listing or
certification of such color additive specifically provides for such
use.'' The petitioner has requested that the uses for D&C Green No. 5
be expanded to include drug and cosmetic uses in the area of the eye.
IV. The Color Additive
D&C Green No. 5 is principally the disodium salt of 2,2'-[(9,10-
dihydro-9,10-dioxo-1,4-anthracenediyl)diimino]bis-[5-
methylbenzenesulfonic acid] (CAS Reg. No. 4403-90-1). The manufacture
of D&C Green No. 5 is accomplished by the sulfonation of D&C Green No.
6 with fuming sulfuric acid. Because D&C Green No. 6 is the starting
material in this manufacturing process, the possibility exists that the
chemicals used in the synthesis of D&C Green No. 6 may be present in
minor amounts in D&C Green No. 5. D&C Green No. 6 is formed by
chemically reacting one molecule of quinizarin with two molecules of p-
toluidine. The significance of these components is that Weisburger et
al. have demonstrated that p-toluidine is a carcinogen in mice (Ref.
1). Residual amounts of reactants, such as p-toluidine and related
manufacturing aids, are commonly found among the constituents of many
color additives. The presence of such constituents, however, is not
unique to color additives. Numerous contaminants are unavoidably
present in all chemical products, even in highly purified reagent grade
chemicals.
Although D&C Green No. 5 has itself not been shown to cause cancer,
it does contain minor amounts of a carcinogenic impurity, p-toluidine.
The carcinogenicity of p-toluidine was discussed in the final rule,
published in the of Federal Register June 4, 1982 (47 FR 24278),
permanently listing D&C Green No. 5 for use in drugs and cosmetics,
excluding use in the area of the eye.
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 available to FDA establishes that the color additive is safe for
that use. FDA's color additive regulations (Sec. 70.3(i)) define safe
as ``convincing evidence that establishes with a reasonable certainty
that no harm will result from the intended use of the color additive.''
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 from the data submitted and other relevant
information that the exposure to D&C Green No. 5 from its use in drugs
and cosmetics intended for use in the area of the eye, is 0.56
milligrams per person per day (mg/p/d), based upon a maximum frequency
of application and maximum quantity applied.
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 here. Although the agency does not normally
require such testing, chronic studies supporting current listings for
the use of D&C Green No. 5 are available in the agency's files, and
FDA's safety evaluation for the proposed use of the color additive in
drugs and cosmetics intended for use in the area of the eye included a
consideration of these studies. Two-year carcinogenicity studies of D&C
Green No. 5 showed no indication of carcinogenicity.
FDA has evaluated the safety of this additive under the general
safety clause, considering all available data. The agency has used risk
assessment procedures to estimate the upper-bound limit of risk
presented by p-toluidine, the carcinogenic chemical that may be present
as an impurity in the additive. The risk evaluation of this chemical
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.
FDA estimates that the maximum total lifetime exposure to p-
toluidine that will result from the use of D&C Green No. 5 in drugs and
cosmetics intended for use in the area of the eye that complies with
the applicable specifications is 8.4 nanograms (ng)/p/d. This exposure
estimate was based on the use of this color additive in eyebrow pencil,
eyeliner, eye shadow, eye lotion, eye makeup remover, mascara, eye
cream, eye shadow base, and eye stick.
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 Green No. 5 as a color additive
in drugs and cosmetics intended for use in the area of the eye (Ref.
3).
Based on a potential exposure of 8.4 ng/p/d, FDA estimates that the
upper-bound limits of individual lifetime risk from the potential
exposure to p-toluidine from the proposed use of D&C Green No. 5 as a
color additive in eye area drugs and cosmetics is 2 x 10-9 or 2 in
1 billion (Ref. 4). Moreover, FDA points out that in an earlier
determination of the risk from exposure to p-toluidine from all other
uses of D&C Green No. 5, the agency calculated the upper-bound limits
of individual lifetime risk to be in the 1 in 30 million to 1 in 300
million range (47 FR 24278). Thus, the use of D&C Green No. 5 in eye
area drugs and cosmetics does not increase this risk in any way. The
agency also points out that because of the numerous conservative
assumptions used in calculating the exposure estimate, actual lifetime-
averaged individual exposure to p-toluidine is expected to be
substantially less than the worst-case exposure. Therefore, the actual
upper-bound limits of risk would be less than that cited above. 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 Green No. 5 for coloring drugs and cosmetics intended for use in
the area of the eye.
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 Green No. 5.
These toxicity studies of D&C Green No. 5, involving dogs, rats, and
mice, included acute oral toxicity studies, subchronic studies, and
chronic toxicity studies in which animals were exposed to the color
additive through diet and skin applications, and reproductive toxicity
studies. These studies did not produce any evidence that D&C Green No.
5 would be unsafe for the petitioned uses.
In addition, FDA evaluated the ocular toxicity studies that the
petitioner provided to support the proposed use of D&C Green No. 5 in
drugs and cosmetics intended for use in the area of the eye. Almost all
of the animals were free of signs of ocular irritation. The effects
noted in most animals that exhibited irritation were slight
conjunctival redness or discharge. These irritations were seen
sporadically in both control and test animals. Based on its review of
these studies, FDA finds that there were no significant adverse
clinical findings in the ocular irritation studies.
VII. Conclusions
A. Safety
Based upon the available toxicity data and other relevant
considerations discussed above, FDA concludes that there is a
reasonable certainty that no harm will result from the use of D&C Green
No. 5 as a color additive in drugs and cosmetics intended for use in
the area of the eye. The agency also concludes on the basis of
available data that the color additive will perform its intended
technical effect and thus is suitable for the petitioned uses. The
agency, therefore, is amending Secs. 74.1205(c)(2) and 74.2205(b) of
the color additive regulations to provide for the use of D&C Green No.
5 in drugs and cosmetics intended for use in the area of the eye.
B. Specifications
D&C Green No. 5 is currently produced as a certifiable color
additive for use in drugs and cosmetics excluding use in the area of
the eye in amounts consistent with current good manufacturing practices
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
Green No. 5 in Secs. 74.1205 and 74.2205 (21 CFR 74.1205 and 74.2205),
the agency concludes that the specifications listed in Sec. 74.1205 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 drugs and cosmetics intended for use in the area
of the eye.
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 September 9, 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.
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 Toxicity
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,'' edited by F.
Homburger and J. K. Marquis, S. Karger, NY, pp. 24-33, 1985.
3. Memorandum of Conference of the Cancer Assessment Committee,
``Para-Toluidine,'' February 24, 1981.
4. Report of the Quantitative Risk Assessment Committee,
``Estimation of the Upper-Bound Lifetime Risk from Para-Toluidine in
D&C Green No. 5 for Uses Requested in CAP 6C0204, Cosmetic,
Toiletry, and Fragrance Association,'' September 28, 1993.
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 74.1205 is amended by revising paragraph (c)(2) to read
as follows:
Sec. 74.1205 D&C Green No. 5.
* * * * *
(c) * * *
(2) D&C Green No. 5 may be safely used for coloring drugs
generally, including drugs intended for use in the area of the eye, in
amounts consistent with current good manufacturing practice.
* * * * *
3. Section 74.2205 is amended by revising paragraph (b) to read as
follows:
Sec. 74.2205 D&C Green No. 5.
* * * * *
(b) Uses and restrictions. D&C Green No. 5 may be safely used for
coloring cosmetics generally, including cosmetics intended for use in
the area of the eye, in amounts consistent with current good
manufacturing practice.
* * * * *
Dated: August 4, 1994.
Michael R. Taylor,
Deputy Commissioner for Policy.
[FR Doc. 94-19483 Filed 8-9-94; 8:45 am]
BILLING CODE 4160-01-F