[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]


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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.

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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 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