[Federal Register Volume 61, Number 238 (Tuesday, December 10, 1996)]
[Rules and Regulations]
[Pages 64989-64991]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-31361]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 178
[Docket No. 94F-0251]
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 1,4-bis[(2,4,6-
trimethylphenyl)amino]-9,10-anthracenedione as a colorant in
polyethylene phthalate polymers intended for use in food-contact
articles. This action is in response to a petition filed by
Registration and Consulting Co. AG.
DATES: Effective December 10, 1996; written objections and requests for
a hearing January 9, 1997.
ADDRESSES: Submit written objections to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,
Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Vir D. Anand, Center for Food Safety
and Applied Nutrition (HFS-216), 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 August 2, 1994 (59 FR 39366), FDA announced that a food
additive petition (FAP 4B4423) had been filed by Registration and
Consulting Co. AG, c/o Bruce A. Schwemmer, Bruce EnviroExcel Group,
Inc., 94 Buttermilk Bridge Rd., Washington, NJ 07882 (formerly, c/o
Reynaldo A. Gustilo, 125A 18th St., suite 142, Newport Plaza, Jersey
City, NJ 07310). 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 1,4-bis[(2,4,6-trimethylphenyl)amino]-
9,10-anthracenedione (C.I. Solvent Blue 104) as a colorant in
polyethylene phthalate
[[Page 64990]]
polymers complying with 21 CFR 177.1630, intended for use in food-
contact articles.
Upon review of information provided by the petitioner, FDA
concluded that the use of C.I. Solvent Blue 104 as a synonym for the
colorant may cause confusion because it is identified by a different
CAS Reg. No. (71872-84-9) than the CAS Reg. No. for the colorant itself
(116-75-6). Therefore, this final rule identifies the colorant only by
its CAS Reg. name (1,4-bis[(2,4,6-trimethylphenyl)amino]-9,10-
anthracenedione) and the corresponding CAS Reg. No. (116-75-6).
In FDA's evaluation of the safety of this food additive, the agency
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 2,4,6-
trimethylaniline, which is a carcinogenic impurity resulting from the
manufacture of the additive. Residual amounts of reactants and
manufacturing aids, such as 2,4,6-trimethylaniline, 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 (21
U.S.C. 348(c)(3)(A)) 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 to the impurities in 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).
II. Safety of Petitioned Use of the Additive
FDA estimates that the petitioned use of the additive, 1,4-
bis[(2,4,6-trimethylphenyl)amino]-9,10-anthracenedione, will result in
exposure to no greater than 0.2 part per billion of the additive in the
daily diet (3 kilograms (kg)) or an estimated daily intake (EDI) of 0.6
microgram per person per day (/person/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 to 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 2,4,6-trimethylaniline, the carcinogenic chemical that may
be present as an impurity in the additive. The risk evaluation of
2,4,6-trimethylaniline has two aspects: (1) Assessment of the worst-
case 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. 2,4,6-Trimethylaniline
FDA has estimated the hypothetical worst-case exposure to 2,4,6-
trimethylaniline from the petitioned use of the additive as a colorant
in polyethylene phthalate polymers to be 1.3 parts per trillion in the
daily diet (3 kg), or 3.9 nanograms (ng)/person/day (Ref. 1). The
agency used data from a long-term rodent bioassay on 2,4,6-
trimethylaniline conducted by Weisburger et al. (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 authors
reported that the test material caused significantly increased
incidence of liver tumors in male and female mice and female rats and
lung tumors in male rats.
Based on the estimated worst-case exposure to 2,4,6-
trimethylaniline of 3.9 ng/person/day, FDA's Center for Food Safety and
Applied Nutrition estimates that a worst-case upper-bound limit of
lifetime human risk from the use of the subject additive is 4.2 x
10-9, or 4.2 in a billion (Refs. 4, 5, and 6). Because of the
numerous conservative assumptions used in calculating the exposure
estimate, the actual lifetime-averaged individual exposure to 2,4,6-
trimethylaniline is likely to be substantially less than the worst-case
exposure, and therefore, the upper-bound lifetime human risk would be
less. Thus, the agency concludes that there is reasonable certainty
that no harm from exposure to 2,4,6-trimethylaniline 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 2,4,6-trimethylaniline 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 2,4,6-
trimethylaniline 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, even under worst-case assumptions, is very low, less than 1.1
in a billion.
III. Conclusion
FDA has evaluated the data in the petition and other relevant
material and concludes that the proposed use of the additive as a
colorant for polyethylene phthalate polymers in contact with food is
safe. Based on this information, the agency has also concluded that the
additive will have the 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 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
[[Page 64991]]
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. Objections
Any person who will be adversely affected by this regulation may at
any time on or before January 9, 1997, 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.
VI. 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 from the Chemistry Review Branch (HFS-247) to the
Indirect Additives Branch (HFS-216) concerning FAP 4B4423: Dietary
Concentrations of the Additive and the Impurity (2,4,6-
trimethylaniline), August 15, 1994.
2. Kokoski, C. J., ``Regulatory Food Additive Toxicology,'' in
Chemical Safety Regulation and Compliance, edited by F. Homburger,
J. K. Marquis, and S. Karger, New York, NY, pp. 24-33, 1985.
3. Weisburger, E. K., A. B. Russfield, F. Homburger, J. H.
Weisburger, E. Boger, C. G. Van Dongen, and K. C. Chu, ``Testing of
Twenty-One Environmental Aromatic Amines or Derivatives for Long-
Term Toxicity or Carcinogenicity,'' Journal of Environmental
Pathology and Toxicology, vol. 2, pp. 325-356, 1978.
4. Memorandum from Executive Secretary, Cancer Assessment
Committee (HFS-227) to Chairman, Cancer Assessment Committee, and
Chairman, Quantitative Risk Assessment Committee: Worst-case Risk
Assessment for 2,4,6-trimethylaniline, December 18, 1995.
5. Memorandum from Executive Secretary, Cancer Assessment
Committee (HFS-227) to Chairman, Cancer Assessment Committee, and
Chairman, Quantitative Risk Assessment Committee: Correction to
December 18, 1995, memorandum: Worst-case Risk Assessment for 2,4,6-
trimethylaniline, August 15, 1996.
6. Memorandum from Executive Secretary, Cancer Assessment
Committee (HFS-227) to Chairman, Cancer Assessment Committee, and
Chairman, Quantitative Risk Assessment Committee: Risk Assessment
for 2,4,6-trimethylaniline, August 16, 1996.
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: Secs. 201, 402, 409, 721 of the Federal Food, Drug,
and Cosmetic Act (21 U.S.C. 321, 342, 348, 379e).
2. Section 178.3297 is amended in the table in paragraph (e) by
alphabetically adding a new 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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1,4-Bis[(2,4,6-trimethylphenyl)amino]-9,10- For use at levels not to
anthracenedione (CAS Reg. No. 116-75-6). exceed 0.0004 percent by
weight of polyethylene
phthalate polymers
complying with Sec.
177.1630 of this chapter.
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Dated: November 27, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-31361 Filed 12-9-96; 8:45 am]
BILLING CODE 4160-01-F
