[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.

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    (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