[Federal Register Volume 59, Number 228 (Tuesday, November 29, 1994)]
[Unknown Section]
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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
