[Federal Register Volume 63, Number 212 (Tuesday, November 3, 1998)]
[Rules and Regulations]
[Pages 59213-59215]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-29333]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 178
[Docket No. 96F-0214]
Indirect Food Additives: Adjuvants, Production Aids, and
Sanitizers
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending the food
additive regulations to provide for the safe use of 2,9-dichloro-5,12-
dihydroquinone[2,3-b]acridine-7,14-dione (C.I. Pigment Red 202) as a
colorant for polymers used in contact with food. This action is in
response to a petition filed by Ciba-Geigy Corp.
DATES: The regulation is effective November 3, 1998; submit written
objections and requests for a hearing December 3, 1998.
ADDRESSES: Submit written objections to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Vir D. Anand, Center for Food Safety
and Applied Nutrition (HFS-215), Food and Drug Administration, 200 C
St. SW., Washington, DC 20204, 202-418-3081.
SUPPLEMENTARY INFORMATION: In a notice published in the Federal
Register of July 5, 1996 (61 FR 35229), FDA announced that a food
additive petition (FAP 6B4512) had been filed by Ciba-Geigy Corp., 335
Water St., Newport, DE
[[Page 59214]]
19804 (currently, c/o Keller and Heckman, 1001 G St. NW., suite 500
West, Washington, DC 20001). The petition proposed to amend the food
additive regulations in Sec. 178.3297 Colorants for polymers (21 CFR
178.3297) to provide for the safe use of 2,9-dichloro-5,12-
dihydroquinone[2,3-b]acridine-7,14-dione (C.I. Pigment Red 202) as a
colorant in polymers used in contact with food.
In its evaluation of the safety of this additive, FDA has reviewed
the safety of the additive itself and the chemical impurities that may
be present in the additive resulting from its manufacturing process.
Although the additive itself has not been shown to cause cancer, it has
been found to contain minute amounts of para-chloroaniline, a
carcinogenic impurity resulting from the manufacture of the additive.
Residual amounts of reactants and manufacturing aids, such as para-
chloroaniline, are commonly found as contaminants in chemical products,
including food additives.
I. Determination of Safety
Under the so-called ``general safety clause'' of the Federal Food,
Drug, and Cosmetic Act (the act) (21 U.S.C. 348(c)(3)(A)), a food
additive cannot be approved for a particular use unless a fair
evaluation of the data available to FDA establishes that the additive
is safe for that use. FDA's food additive regulations (21 CFR 170.3(i))
define safe as ``a reasonable certainty in the minds of competent
scientists that the substance is not harmful under the intended
conditions of use.''
The food additive anticancer, or Delaney, clause of the act further
provides that no food additive shall be deemed safe if it is found to
induce cancer when ingested by man or animal. Importantly, however, the
Delaney clause applies to the additive itself and not 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 standard 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)).
II. Safety of Petitioned Use of the Additive
FDA estimates that the petitioned use of the additive, 2,9-
dichloro-5,12-dihydroquinone[2,3-b]acridine-7,14-dione, will result in
exposure to no greater than 2.5 parts per billion of the additive in
the daily diet (3 kilogram (kg)), or an estimated daily intake of 7.5
microgram per person per day (Ref. 1).
FDA does not ordinarily consider chronic toxicological studies 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. However, the agency has reviewed the
available toxicological data on the additive and concludes that the
estimated small dietary exposure resulting from the proposed use of
this additive is safe.
FDA has evaluated the safety of this additive under the general
safety clause, considering all available data and using risk assessment
procedures to estimate the upper-bound limit of lifetime human risk
presented by para-chloroaniline, the carcinogenic chemical that may be
present as an impurity in the additive. The risk evaluation of para-
chloroaniline has two aspects: (1) Assessment of exposure to the
impurity from the proposed use of the additive; and (2) extrapolation
of the risk observed in the animal bioassay to the conditions of
probable exposure to humans.
A. Para-Chloroaniline
FDA has estimated the exposure to para-chloroaniline from the
petitioned use of the additive as a colorant in polymers to be 20 parts
per trillion in the daily diet (3 kg), or 60 nanograms per person per
day (ng/p/d) (Ref. 1). The agency used data from a carcinogenicity
study of para-chloroaniline conducted by the National Toxicology
Program (NTP) (Ref. 3), to estimate the upper-bound limit of lifetime
human risk from exposure to this chemical resulting from the proposed
use of the additive. The results of the NTP carcinogenicity studies on
this chemical demonstrated that administration of the test material to
Fisher 344 rats by gavage caused increased incidence of splenic
sarcomas in male rats.
Based on the agency's estimated exposure to para-chloroaniline of
60 ng/p/d, FDA estimates that the upper-bound limit of lifetime human
risk from the proposed use of the subject additive is 1 x
10-8, or 1 in 100 million (Ref. 4). Because of the numerous
conservative assumptions used in calculating the exposure estimate, the
actual lifetime-averaged individual exposure to para-chloroaniline is
likely to be substantially less than the estimated exposure, and
therefore, the probable lifetime human risk would be less than the
upper-bound limit of lifetime human risk. Thus, the agency concludes
that there is reasonable certainty that no harm from exposure to para-
chloroaniline would result from the proposed use of the additive.
B. Need for Specifications
The agency has also considered whether specifications are
necessary to control the amount of para-chloroaniline present as an
impurity in the additive. The agency finds that specifications are not
necessary for the following reasons: (1) Because of the low level at
which para-chloroaniline may be expected to remain as an impurity
following production of the additive, the agency would not expect the
impurity to become a component of food at other than extremely low
levels; and (2) the upper-bound limit of lifetime human risk from
exposure to the impurity is very low, less than 1 in 100 million.
III. Conclusion
FDA has evaluated the data in the petition and other relevant
material. Based on this information, the agency concludes that the
proposed use of the additive as a colorant in polymers in contact with
food is safe, and that the additive will achieve its intended technical
effect. Therefore, the agency concludes that the regulations in
Sec. 178.3297 should be amended as set forth below.
In accordance with Sec. 171.1(h) (21 CFR 171.1(h)), 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. 171.1(h), the agency will delete from the documents
any materials that are not available for public disclosure before
making the documents available for inspection.
IV. 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.
V. Paperwork Reduction Act of 1995
This final rule contains no collection of information. Therefore,
clearance by the Office of Management and Budget
[[Page 59215]]
under the Paperwork Reduction Act of 1995 is not required.
VI. Objections
Any person who will be adversely affected by this regulation may at
anytime on or before December 3, 1998, file with the Dockets Management
Branch (address above) written objection 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
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 objection 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.
VII. 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. Memorandum dated August 29, 1996, from the Chemistry Review
Branch (HFS-247), to the file concerning FAP 6B4512, dietary
concentrations of the additive and the impurity (para-
chloroaniline).
2. Kokoski, C. J., ``Regulatory Food Additive Toxicology,'' in
Chemical Safety Regulation and Compliance, edited by F. Homburger
and J. K. Marquis, published by S. Karger, New York, NY, pp. 24-33,
1985.
3. Chhabra, R. S., Toxicology and Carcinogenesis Studies of
para-Chloroaniline Hydrochloride in F344/N Rats and B6C3F1 Mice
(Gavage Studies), National Toxicology Program, Technical Report
Series No. 351, July 1989.
4. Report of the Quantitative Risk Assessment Committee, FDA,
concerning ``Assessment of Carcinogenic upper-bound lifetime risk
resulting from contamination by para-chloroaniline residues in C.I.
Pigment Red 202 (Ciba-Geigy Corp.), FAP 6B4512, dates April 9, 1998.
List of Subjects in 21 CFR Part 178
Food additives, Food packaging.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
178 is amended as follows:
PART 178--INDIRECT FOOD ADDITIVES: ADJUVANTS, PRODUCTION AIDS, AND
SANITIZERS
1. The authority citation for 21 CFR part 178 continues to read as
follows:
Authority: 21 U.S.C. 321, 342, 348, 379e.
2. Section 178.3297 is amended in the table in paragraph (e) by
alphabetically adding an entry under the headings ``Substances'' and
``Limitations'' to read as follows:
Sec. 178.3297 Colorants for polymers.
* * * * *
(e) * * *
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Substances Limitations
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* * * * * *
*
2,9-Dichloro-5,12-dihydroquinone[2,3-b]acridine-7,14- For use at levels not to exceed 1.0 percent by weight
dione (C.I. Pigment Red 202, CAS Reg. No. 3089-17-6). of polymers.
* * * * * *
*
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Dated: October 26, 1998.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 98-29333 Filed 11-2-98; 8:45 am]
BILLING CODE 4160-01-F
