[Federal Register Volume 59, Number 228 (Tuesday, November 29, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-29253]


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[Federal Register: November 29, 1994]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 74 and 201

[Docket No. 92C-0293]

 

Listing of Color Additives Subject to Certification; FD&C Yellow 
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 and the drug labeling regulations to provide for 
the safe use of FD&C Yellow No. 5 and FD&C Yellow No. 5 Aluminum Lake 
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 November 30, 1994, except as to any provisions that 
may be stayed by the filing of proper objections; written objections 
and requests for a hearing by December 29, 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, 202-418-3074.

SUPPLEMENTARY INFORMATION:

I. Introduction

    In a notice published in the Federal Register of August 10, 1992 
(57 FR 35594), FDA announced that a color additive petition (CAP 
6C0205) had been filed by the CTFA, 1101 17th St. NW., suite 300, 
Washington, DC 20036. The petition proposed that the color additive 
regulations for FD&C Yellow No. 5 be amended to provide for the safe 
use of FD&C Yellow No. 5 and its lakes 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). CTFA 
later amended the petition to limit the lakes requested for area of the 
eye use to the FD&C Yellow No. 5 Aluminum Lake prepared in accordance 
with Sec. 82.51 (21 CFR 82.51).

II. Regulatory History

    The regulatory history of FD&C Yellow No. 5 is summarized in a 
final rule published in the Federal Register of September 4, 1985 (50 
FR 35774). In the September 1985, final rule, FDA permanently listed 
FD&C Yellow No. 5 for use in externally applied drugs and in cosmetics 
generally. FDA also removed FD&C Yellow No. 5 from the provisional list 
and removed a stay on the use of FD&C Yellow No. 5 in external 
cosmetics. These actions were taken in response to a color additive 
petition (CAP 5C0023). The use of FD&C Yellow No. 5 in food and 
ingested drugs was approved in the Federal Register of February 22, 
1966 (31 FR 3008), and revised on May 8, 1969 (34 FR 7447).

III. Definitions

    The term ``area of the eye'' is defined in Sec. 70.3(s) (21 CFR 
70.3(s)) 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.''
    The term ``lake'' is defined in Sec. 70.3 (l) as a ``straight color 
extended on a substratum by adsorption, coprecipitation, or chemical 
combination that does not include any combination of ingredients made 
by simple mixing process.''

IV. Applicability of the Act

    Section 70.5 (a) of FDA's regulations (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 FD&C Yellow No. 5 and FD&C 
Yellow No. 5 Aluminum Lake be expanded to include uses in the area of 
the eye.
    Part 82 (21 CFR part 82) lists the provisionally listed color 
additives that are subject to certification and the specifications for 
those color additives. It includes a description of, and specifications 
for, the lakes that are permitted for use in foods, drugs, and 
cosmetics. Sections 82.51 and 82.1051 list the acceptable substrata 
that can be combined with the straight colors listed therein to form 
lakes. The petitioner has requested that this order be limited to the 
Aluminum Lake of FD&C Yellow No. 5, prepared in accordance with 
Sec. 82.51. Section 82.51(a)(1) limits the substrata that can be used 
for FD&C lakes to alumina.
    Because of known allergic-type reactions, Sec. 74.1705(c) (21 CFR 
74.1705(c)) requires that the label of over-the-counter and 
prescription drug products that contain FD&C Yellow No. 5 and that are 
intended for human use and to be administered orally, nasally, 
rectally, or vaginally declare the presence of the color additive and 
bear a warning statement (Sec. 74.1705(c)(2) and (c)(3), and see 
Sec. 201.20(a) and (b) (21 CFR 201.20(a) and (b))). Because of the 
potential for drugs intended for use in the area of the eye to come 
into contact with mucous membranes, the agency is expanding this 
labeling requirement to include drugs containing FD&C Yellow No. 5 
intended for use in the area of the eye.

V. The Color Additive

    FD&C Yellow No. 5 is principally the trisodium salt of 4,5-dihydro-
5-oxo-1-(4-sulfophenyl)-4-[4-sulfophenyl-azo]-1H-pyrazole-3-carboxylic 
acid (CAS Reg. No. 1934-21-0). To manufacture the additive, 4-amino-
benzenesulfonic acid is diazotized using hydrochloric acid and sodium 
nitrite. The diazo compound is coupled with 4,5-dihydro-5-oxo-1-(4-
sulfophenyl)-1H-pyrazole-3-carboxylic acid or with the methyl ester, 
the ethyl ester, or a salt of this carboxylic acid. The resulting 
additive is purified and isolated as the sodium salt. As stated in the 
Federal Register of September 4, 1985, there are six carcinogenic 
impurities that may be found in commercial, certified batches of FD&C 
Yellow No. 5. The carcinogenic constituents are 4-aminoazobenzene, 4-
aminobiphenyl, aniline, azobenzene, benzidine, and 1,3-
diphenyltriazene. These impurities result from impurities in the 
starting materials used to manufacture FD&C Yellow No. 5 and from 
reactions involving these impurities during the manufacturing process. 
Residual amounts of impurities 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.

VI. 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 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 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 for any use of a color 
additive that will not result in ingestion of any part of such 
additive, the color additive shall be deemed to be 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)).

VII. Safety of the Petitioned Use of the Additive

    FDA estimates that the upper limit of lifetime exposure to FD&C 
Yellow 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 in the area of the eye.
    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. 1), 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 FD&C Yellow 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 
FD&C Yellow No. 5 showed no indication of carcinogenicity.
    In its evaluation of the safety of the proposed use of the subject 
color additive, FDA has also considered other safety data submitted 
previously to support current listings for the use of FD&C Yellow No. 
5. These toxicity studies of FD&C Yellow No. 5, involving dogs, 
hamsters, rabbits, rats, and mice, included acute oral toxicity 
studies; subchronic studies using dermal application and subcutaneous 
and intraperitoneal injection; chronic toxicity studies in which 
animals were exposed to the color additive through diet, skin 
application and subcutaneous injection; and reproductive toxicity 
studies. These studies did not produce any evidence that FD&C Yellow 
No. 5 would be unsafe for the petitioned uses. The data from dermal 
toxicity studies demonstrate that FD&C Yellow No. 5 is nonirritating 
when applied daily to either intact or abraded skin.
    In addition, FDA evaluated the ocular toxicity studies that the 
petitioner provided to support the proposed use of FD&C Yellow No. 5 in 
drugs and cosmetics intended for use in the area of the eye.
     Almost all of the animals in these studies were free of 
significant signs of ocular irritation. The effects noted in most 
animals that exhibited any irritation were slight conjunctival redness 
or discharge. These irritations were seen sporadically in both control 
and test animals throughout the studies. Based on this evidence, FDA 
finds that there were no significant adverse clinical findings in the 
ocular irritation studies.
    The agency has also used risk assessment procedures to estimate the 
upper-bound limit of risk presented by 4-aminoazobenzene, 4-
aminobiphenyl, aniline, azobenzene, benzidine, and 1,3-
diphenyltriazene, carcinogenic chemicals that may be present as 
impurities in the additive. The risk evaluation of these chemicals 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.

VIII. Exposure to the Impurities

    FDA estimates that the maximum lifetime exposure to 4-
aminoazobenzene, 4-aminobiphenyl, azobenzene, benzidine, and 1,3-
diphenyltriazene that will result from the use of FD&C Yellow No. 5 
that complies with the applicable specifications in drugs and cosmetics 
intended for use in the area of the eye to be 0.04 nanograms/person/day 
(ng/p/d), 0.003 ng/p/d, 4.56 ng/p/d, 0.02 ng/p/d, 0.0006 ng/p/d, and 
0.02 ng/p/d, respectively 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.

A. 4-Aminoazobenzene

    The agency evaluated reports showing that 4-aminoazobenzene is 
carcinogenic in the diet of rats (Refs. 2 and 3), and that it is 
carcinogenic when applied dermally to rats (Ref. 4) to estimate the 
upper-bound limit of lifetime human risk from exposure to this chemical 
stemming from the proposed use of FD&C Yellow No. 5 as a color additive 
in drugs and cosmetics intended for use in the area of the eye. The 
agency (Ref. 5) used data reported by Kirby et al. that demonstrated 
that 4-aminoazobenzene was carcinogenic by dietary administration to 
Wistar rats, causing liver cell neoplasms and papillomas of the 
stomach. (Refs. 2 and 3).
    Based on a potential exposure of 0.04 ng/p/d, FDA estimates that 
the upper-bound lifetime risk of cancer from the potential exposure to 
4-aminoazobenzene from the proposed use of FD&C Yellow No. 5 as a color 
additive in drugs and cosmetics intended for use in the area of the eye 
is 8 x 10-10 or 8 in 10 billion (Refs. 5 and 6). Because of the 
numerous conservative assumptions used in calculating the exposure 
estimate, actual lifetime-averaged individual exposure to 4-
aminoazobenzene is expected to be substantially less than the worst-
case exposure, therefore, the calculated upper-bound limits of risk 
would be less. In an earlier determination of the risk due to exposure 
of 4-aminoazobenzene from all other uses of FD&C Yellow No. 5, the 
agency calculated the individual lifetime risk of cancer to be less 
than 1 in 100 million. The use of FD&C Yellow No. 5 in drugs and 
cosmetics intended for use in the area of the eye will not add 
appreciably to this risk.Thus, the agency concludes that there is a 
reasonable certainty of no harm from exposure to 4-aminoazobenzene that 
might result from the proposed use of FD&C Yellow No. 5 for coloring in 
drugs and cosmetics intended for use in the area of the eye.

B. 4-Aminobiphenyl

    While a number of studies in different species have been performed 
on 4-aminobiphenyl, the agency has chosen dog studies reported both by 
Block et al. (Ref. 7) and by Rippe et al. (Ref. 8) for quantitative 
risk assessment because the data on these studies yield a higher risk 
estimate than data from other studies (Ref. 9). Animals treated with 4-
aminobiphenyl showed an increased incidence of bladder papillomas. 
Using these data, the agency estimates that the upper-bound lifetime 
risk of cancer from the potential exposure of the area of the eye to 4-
aminobiphenyl in products containing FD&C Yellow No. 5 is less than 2 x 
10-9  or 2 in 1 billion (Refs. 6 and 9). Because of the numerous 
conservative assumptions used in calculating the exposure estimate, 
actual lifetime-averaged individual exposure to 4-aminobiphenyl is 
expected to be substantially less than the worst-case exposure, and 
therefore, the calculated upper-bound limits of risk would be less. In 
an earlier determination of the risk due to exposure of 4-aminobiphenyl 
from all other uses of FD&C Yellow No. 5, the agency calculated the 
individual lifetime risk of cancer to be less than 1 in 10 million. The 
use of FD&C Yellow No. 5 in drugs and cosmetics intended for use in the 
area of the eye will not add appreciably to this risk. Thus, the agency 
concludes that there is a reasonable certainty of no harm from exposure 
to 4-aminobiphenyl that might result from the proposed use of FD&C 
Yellow No. 5 for coloring in drugs and cosmetics intended for use in 
the area of the eye.

C. Aniline

    The agency used data reported by the National Cancer Institute 
(NCI) (Ref. 11) and the Chemical Industry Institute of Toxicology (Ref. 
12) that demonstrated that aniline was carcinogenic to the spleen of 
Fischer 344 rats. Using these data, FDA estimates that the upper-bound 
lifetime risk of cancer from the potential exposure of the area of the 
eye to aniline in products containing FD&C Yellow No. 5 is less than 5 
x 10-13 or 5 in 10 trillion (Refs. 6 and 13). Because of the 
numerous conservative assumptions used in calculating the exposure 
estimate, actual lifetime-averaged individual exposure to aniline is 
expected to be substantially less than the worst-case exposure, and 
therefore, the calculated upper-bound limits of risk would be less. In 
an earlier determination of the risk due to exposure of aniline from 
all other uses of FD&C Yellow No. 5, the agency calculated the 
individual lifetime risk of cancer to be less than 5 in 100 billion. 
The use of FD&C Yellow No. 5 in drugs and cosmetics intended for use in 
the area of the eye will not add appreciably to this risk. Thus, the 
agency concludes that there is a reasonable certainty of no harm from 
exposure to aniline that might result from the proposed use of FD&C 
Yellow No. 5 for coloring in drugs and cosmetics intended for use in 
the area of the eye.

D. Azobenzene

    FDA used data in an NCI-sponsored bioassay which showed that 
azobenzene induced a dose-related increase in the incidence of sarcomas 
of the abdominal cavity, particularly the spleen, in both sexes of 
Fischer 344 rats (Ref. 14). From this study, the agency estimates that 
the upper-bound lifetime risk of cancer from the potential exposure of 
the area of the eye to azobenzene in products containing FD&C Yellow 
No. 5 is less than 2 x 10-12 or 2 in 1 trillion (Refs. 6 and 15). 
Because of the numerous conservative assumptions used in calculating 
the exposure estimate, actual lifetime-averaged individual exposure to 
azobenzene is expected to be substantially less than the worst-case 
exposure, and therefore, the calculated upper-bound limits of risk 
would be less. In an earlier determination of the risk due to exposure 
of azobenzene from all other uses of FD&C Yellow No. 5, the agency 
calculated the individual lifetime risk of cancer to be less than 2 in 
10 billion. The use of FD&C Yellow No. 5 in drugs and cosmetics 
intended for use in the area of the eye will not add appreciably to 
this risk. Thus, the agency concludes that there is a reasonable 
certainty of no harm from exposure to azobenzene that might result from 
the proposed use of FD&C Yellow No. 5 for coloring in drugs and 
cosmetics intended for use in the area of the eye.

E. Benzidine

    FDA used a human epidemiology study by Zavon (Ref. 16) and a study 
performed by Rinde and Troll in the Rhesus monkey (Ref. 17) as the 
basis for a quantitative risk assessment on benzidine.
    Zavon attempted to obtain good data on exposure to benzidine by 
analyzing the urine of workers in a plant that manufactures this 
substance. The workers were monitored until a number of them were 
diagnosed as having bladder neoplasms. Urine levels of benzidine in 
workers were measured before each work shift, after each work shift, 
and on every Monday morning. Average levels were: Before work, 0.01 mg/
liter (L); after work, 0.04 mg/L; and on Monday morning before work, 
somewhat below 0.005 mg/L.
    No controlled study with the administration of benzidine and the 
concomitant measurement of benzidine in the urine in humans has been 
performed. Thus, the conversion from urine concentration to total 
exposure cannot be made from human data alone. However, the Rinde and 
Troll study related ingestion of benzidine to amounts of benzidine and 
monoacetylbenzidine in the urine of Rhesus monkeys. The agency believes 
it is reasonable to use this study to relate urine concentration to 
exposure for humans (Ref. 18). This procedure yields a higher risk 
estimate than if the risk was estimated solely from an animal feeding 
study and thus is less likely to underestimate risk.
    In the Rinde and Troll study, benzidine was administered orally to 
Rhesus monkeys, and the 72-hour urine collection was analyzed for 
benzidine and monoacetylbenzidine. In two trials the amount of 
benzidine and monoacetylbenzidine excreted in the urine was 1.4 percent 
and 1.5 percent of the initial input. The agency used these data, and 
applied a safety factor of two to compensate for uncertainties, to 
estimate that the amount of benzidine and monoacetylbenzidine excreted 
in the urine of humans is approximately 3 percent of that consumed. The 
agency then calculated that the average human worker in the Zavon study 
was exposed to approximately 0.8 mg benzidine per work day.
    Based on these two studies the agency estimates that the upper-
bound lifetime risk of cancer from the potential exposure of the area 
of the eye to benzidine in products containing FD&C Yellow No. 5 is 
less than 4 x 10-9 or 4 in 1 billion (Refs. 6 and 18). Because of 
the numerous conservative assumptions used in calculating the exposure 
estimate, actual lifetime-averaged individual exposure to benzidine is 
expected to be substantially less than the worst-case exposure, and 
therefore, the calculated upper-bound limits of risk would be less. In 
an earlier determination of the risk due to exposure of benzidine from 
all other uses of FD&C Yellow No. 5, the agency calculated the 
individual lifetime risk of cancer to be less than 3 in 10 million. The 
use of FD&C Yellow No. 5 in drugs and cosmetics intended for use in the 
area of the eye will not add appreciably to this risk. Thus, the agency 
concludes that there is a reasonable certainty of no harm from exposure 
to benzidine that might result from the proposed use of FD&C Yellow No. 
5 for coloring in drugs and cosmetics intended for use in the area of 
the eye.

F. 1,3-Diphenyltriazene

    In doing risk assessments for this substance, the agency has used 
reports showing that 1,3-diphenyltriazene is carcinogenic in the diet, 
and that it is carcinogenic when applied dermally. A study performed by 
Otsuka (Ref. 19) showed that 1,3-diphenyltriazene produced forestomach 
tumors in mice upon dietary exposure. The agency estimates that 
exposure of the area of the eye to 1,3-diphenyltriazene from products 
containing FD&C Yellow No. 5 presents a lifetime risk of less than 2 x 
10-11 or 2 in 100 billion (Refs. 6 and 20). A lifetime skin 
painting study using 1,3-diphenyltriazene on mouse skin was performed 
by Kirby (Ref. 21). Based on this study, the agency estimates that the 
upper-bound lifetime risk of cancer from the potential dermal exposure 
to 1,3-diphenyltriazene from products for the area of the eye 
containing FD&C Yellow No. 5 is less than 2 x 10-12 or 2 in 1 
trillion (Refs. 6 and 20). Because of the numerous conservative 
assumptions used in calculating the exposure estimate, actual lifetime-
averaged individual exposure to 1,3-diphenyltriazene is expected to be 
substantially less than the worst-case exposure, and therefore, the 
calculated upper-bound limits of risk would be less. In earlier 
determinations of the risk due to exposure of 1,3-diphenyltriazene from 
all other uses of FD&C Yellow No. 5, the agency calculated the 
individual lifetime risk of cancer to be less than 2 in 1 billion. The 
use of FD&C Yellow No. 5 in drugs and cosmetics intended for use in the 
area of the eye will not add appreciably to this risk. Thus, the agency 
concludes that there is a reasonable certainty of no harm from exposure 
to 1,3-diphenyltriazene that might result from the proposed use of FD&C 
Yellow No. 5 for coloring in drugs and cosmetics intended for use in 
the area of the eye.

IX. 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 petitioned use 
of FD&C Yellow No. 5 and FD&C Yellow No. 5 Aluminum Lake as color 
additives 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. 74.1705 and 74.2705 of 
the color additive regulations to provide for the use of FD&C Yellow 
No. 5 and FD&C Yellow No. 5 Aluminum Lake in drugs and cosmetics 
intended for use in the area of the eye. In addition, FDA is amending 
Sec. 201.20 of the drug labeling regulations to reflect the fact that 
these color additives may be used in drugs intended for use in the area 
of the eye.

B. Specifications

    FD&C Yellow No. 5 is currently produced as a certifiable color 
additive for use in food, and in drugs and cosmetics generally in 
accordance with part 80 (21 CFR part 80). Based upon the low levels of 
exposure to 4-aminoazobenzene, 4-aminobiphenyl, aniline, azobenzene, 
benzidine, and 1,3-diphenyltriazene that results under the current 
specifications in Secs. 74.705 (21 CFR 74.705), 74.1705, and 74.2705 
(21 CFR 74.2705), the agency concludes that the specifications listed 
in Sec. 74.705 are adequate to ensure the safe use of this color 
additive and to control the amounts of 4-aminoazobenzene, 4-
aminobiphenyl, aniline, azobenzene, benzidine, and 1,3-diphenyltriazene 
that may exist as impurities in the color additive when used in drugs 
and cosmetics intended for use in the area of the eye.

X. 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.
    This document provides for the permanent listing of the aluminum 
lake of FD&C Yellow No. 5 for use in the area of the eye. Other uses of 
the lakes of FD&C Yellow No. 5 are provisionally listed under 
Secs. 81.1 (21 CFR 81.1), 82.51, 82.705 (21 CFR 82.705), and 82.1051. 
The agency notes that Secs. 74.1705 (b)(2) and 74.2705 (b)(2) refer to 
Sec. 82.51 for the manufacturing process and specifications for the 
lakes of FD&C Yellow No. 5. While the agency recognizes that this 
referral is to a section that is designated as provisional, FDA 
considers this referral to be appropriate because that section defines 
current good manufacturing practice and provides appropriate 
specifications to ensure the quality and purity of lakes made with the 
color additive. The agency has under consideration an action to 
permanently list all lakes that have been provisionally listed under 
parts 81 and 82 (21 CFR parts 81 and 82). When that action is 
completed, FDA intends to amend this referral as appropriate.

XI. 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.

XII. Objections

    Any person who will be adversely affected by this regulation may at 
any time on or before December 29, 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.

XIII. 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. 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.
    2. Kirby, A. H. M., ``Studies in Carcinogenesis with Azo 
Compounds,'' Cancer Research, 7:333-341, 1947.
    3. Kirby, A. H. M., and P. R. Peacock, ``The Induction of Liver 
Tumors by 4-Aminoazobenzene and its N,N-Dimethyl Derivative in Rats 
on a Restricted Diet,'' Journal of Pathology and Bacteriology, 59:1-
18, 1947.
    4. Fare, G., ``Rat Skin Carcinogenesis by Topical Applications 
of Some Azo Dyes,'' Cancer Research, 26:2406, 1966.
    5. Quantitative Risk Assessment Committee, memorandum, ``Report 
of the Committee on 4-Aminoazobenzene (Dietary and Skin Exposure),'' 
CAP 5C0023, December 20, 1983.
    6. Quantitative Risk Assessment Committee, memorandum, 
``Estimation of the Upper Bound Lifetime Risk from the Carcinogenic 
Impurities in FD&C Yellow No. 5,'' CAP 6C0205, September 28, 1993.
    7. Block, N. L. et. al., ``The Initiation, Progress, and 
Diagnosis of Dog Bladder Cancer Induced by 4-Aminobiphenyl,'' 
Investigative Urology, 16:50-54, 1978.
    8. Rippe, D. F. et al., ``Urinary Bladder Carcinogenesis in the 
Dog: Preliminary Studies on Cellular Immunity,'' Transplantation 
Proceedings, 7:495-501, 1975.
    9. Quantitative Risk Assessment Committee, memorandum, ``Report 
of the Committee on 4-Aminobiphenyl,'' CAP 5C0023, December 20, 
1983.
    10. Druckrey, H., ``Quantitative Aspects in Chemical 
Carcinogenesis,'' U.I.C.C. Monograph Series, 7:60-78, 1967.
    11. National Cancer Institute, ``Bioassay of Aniline 
Hydrochloride for Possible Carcinogenicity,'' NCI Technical Report 
No. 130, NCI-CG-TR-130, U.S. Department of Health, Education, and 
Welfare, Public Health Service, National Institutes of Health, 1978.
    12. Chemical Industry Institute of Toxicology, Research Triangle 
Park, NC. ``104 Week Chronic Toxicity Study in Rats: Aniline 
Hydrochloride,'' final report, January 4, 1982.
    13. Quantitative Risk Assessment Committee, memorandum, 
``Committee Report on Aniline,'' CAP 5C0023, December 20, 1983.
    14. National Cancer Institute, ``Bioassay of Azobenzene for 
Possible Carcinogenicity,'' NCI Technical Report No. 154, NCI-CG-TR-
154, U.S. Department of Health, Education, and Welfare, Public 
Health Service, National Institutes of Health, 1979.
    15. Quantitative Risk Assessment Committee, memorandum, 
``Committee Report on Azobenzene,'' CAP 5C0023, December 20, 1983.
    16. Zavon, M. R. et al., ``Benzidine Exposure as a Cause of 
Bladder Tumors,'' Archives of Environmental Health, 27:1-7, 1973.
    17. Rinde, E., and W. Troll, ``Metabolic Reduction of Benzidine 
Azo Dyes to Benzidine in the Rhesus Monkey,'' Journal of the 
National Cancer Institute, 55:181-182, 1975.
    18. Quantitative Risk Assessment Committee, memorandum, 
``Committee Report on Benzidine,'' CAP 5C0023, December 20, 1983.
    19. Otsuka, L., ``Uber die Experimentelle Papillomerzeugung im 
Vormagen der Mausen durch Diozoaminobenzol,'' Gann, 29:209-214, 
1935.
    20. Quantitative Risk Assessment Committee, memorandum, 
``Committee Report on 1,3-Diphenyltriazene (Dietary and Dermal 
Exposure),'' CAP 5C0023, December 20, 1983.
    21. Kirby, A. H., ``Further Experiments in Mice with p-
Diazoaminobenzene,'' British Journal of Cancer, 2:290-294, 1948.

List of Subjects

21 CFR Part 74

    Color additives, Cosmetics, Drugs.

21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts 
74 and 201 are 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 74.1705 is amended by redesignating paragraph (a)(2) as 
paragraph (a)(3), by adding new paragraph (a)(2), by revising paragraph 
(b), and the first sentence of paragraphs (c)(2) and (c)(3), 
respectively to read as follows:


Sec. 74.1705  FD&C Yellow No. 5.

    (a) * * *
    (2) FD&C Yellow No. 5 Aluminum Lake shall be prepared in accordance 
with the requirements of Sec. 82.51 of this chapter.
* * * * *
    (b) Uses and restrictions. (1) FD&C Yellow 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.
    (2) FD&C Yellow No. 5 Aluminum Lake may be safely used for coloring 
drugs intended for use in the area of the eye, when prepared in 
accordance with Sec. 82.51 of this chapter.

    (c) * * *
    (2) The label of OTC and prescription drug products intended for 
human use administered orally, nasally, rectally, or vaginally, or for 
use in the area of the eye, containing FD&C Yellow No. 5 shall 
specifically declare the presence of FD&C Yellow No. 5 by listing the 
color additive using the names FD&C Yellow No. 5 and tartrazine. * * *
    (3) For prescription drugs for human use containing FD&C Yellow No. 
5 that are administered orally, nasally, vaginally, or rectally, or for 
use in the area of the eye, the labeling required by Sec. 201.100(d) of 
this chapter shall, in addition to the label statement required under 
paragraph (c)(2) of this section, bear the warning statement ``This 
product contains FD&C Yellow No. 5 (tartrazine) which may cause 
allergic-type reactions (including bronchial asthma) in certain 
susceptible persons. * * *
* * * * *

    3. Section 74.2705 is amended by redesignating the introductory 
text of paragraph (b) as paragraph (b)(1) and revising it, by adding 
new paragraph (b)(2), and by revising paragraph (c) to read as follows:


Sec. 74.2705  FD&C Yellow No. 5.

* * * * *
    (b) Specifications. (1) FD&C Yellow No. 5 shall conform to the 
following specifications and shall be free from impurities other than 
those named to the extent that such other impurities may be avoided by 
good manufacturing practice:
* * * * *
    (2) FD&C Yellow No. 5 Aluminum Lake shall be prepared in accordance 
with the requirements of Sec. 82.51 of this chapter.
    (c) Uses and restrictions. (1) FD&C Yellow 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.
    (2) FD&C Yellow No. 5 Aluminum Lake may be safely used for coloring 
cosmetics intended for use in the area of the eye, subject to the 
restrictions on use of color additives in Sec. 70.5(b) and (c) of this 
chapter, in amounts consistent with current good manufacturing 
practice.
* * * * *

PART 201--LABELING

    4. The authority citation for 21 CFR part 201 continues to read as 
follows:

    Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 508, 
510, 512, 530-542, 701, 704, 721 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 358, 
360, 360b, 360gg-360ss, 371, 374, 379e); secs. 215, 301, 351, 361 of 
the Public Health Service Act (42 U.S.C. 216, 241, 262, 264).

    5. Section 201.20 is amended by revising the first sentence of 
paragraphs (a) and (b), respectively to read as follows:


Sec. 201.20  Declaration of presence of FD&C Yellow No. 5 and/or FD&C 
Yellow No. 6 in certain drugs for human use.

    (a) The label for over-the-counter and prescription drug products 
intended for human use administered orally, nasally, rectally, or 
vaginally, or for use in the area of the eye, containing FD&C Yellow 
No. 5 as a color additive using the names FD&C Yellow No. 5 and 
tartrazine. * * *
    (b) For prescription drugs for human use containing FD&C Yellow No. 
5 that are administered orally, nasally, vaginally, or rectally, or for 
use in the area of the eye, the labeling required by Sec. 201.100(d) 
shall bear the warning statement ``This product contains FD&C Yellow 
No. 5 (tartrazine) which may cause allergic-type reactions (including 
bronchial asthma) in certain susceptible persons. * * *
* * * * *

    Dated: November 18, 1994.
William K. Hubbard,
Interim Deputy Commissioner for Policy.
[FR Doc. 94-29253 Filed 11-28-94; 8:45 am]
BILLING CODE 4160-01-F