[Federal Register Volume 62, Number 41 (Monday, March 3, 1997)]
[Rules and Regulations]
[Pages 9365-9367]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-5077]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 178

[Docket No. 93F-0028]


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 3,6-bis(4-
chlorophenyl)-2,5-dihydro-pyrrolo[3,4-c]pyrrole-1,4-dione (C.I. Pigment 
Red 254) as a colorant in polymers intended for use in contact with 
food. This action is in response to a petition filed by Ciba-Geigy 
Corp.

DATES: Effective March 3, 1997; written objections and requests for a 
hearing by April 2, 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: Richard H. White, Center for Food 
Safety and Applied Nutrition (HFS-216), Food and Drug Administration, 
200 C St. SW., Washington, DC 20204, 202-418-3094.

SUPPLEMENTARY INFORMATION: In a notice published in the Federal 
Register of March 17, 1993 (58 FR 14402), FDA announced that a food 
additive petition (FAP 3B4349) had been filed by Ciba-Geigy Corp., 315 
Water St., Newport, DE 19804-2434 (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 
3,6-bis(4-chlorophenyl)-2,5-dihydro-pyrrolo[3,4-c]pyrrole-1,4-dione 
(C.I. Pigment Red 254) as a colorant in polymers intended for use in 
contact with food.
    In its evaluation of the safety of this food additive, FDA reviewed 
the safety of the additive 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 may 
contain minute amounts of polychlorinated biphenyls (PCB's), which are 
carcinogenic impurities resulting from the manufacture of the additive. 
Residual amounts of reactants, manufacturing aids, and their 
constituent impurities, and byproducts, such as PCB's, 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 food 
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 additives anticancer, or Delaney, clause of the act (21 
U.S.C. 348(c)(3)(A)) provides that no food additive shall be deemed to 
be 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 food additive (Scott v. FDA, 728 F.2d 322 (6th Cir. 1984)).

II. Safety of the Petitioned Use of the Additive

    FDA estimates that the petitioned use of the food additive, 3,6-
bis(4-chlorophenyl)-2,5-dihydro-pyrrolo[3,4-c]pyrrole-1,4-dione (C.I. 
Pigment Red 254), will result in exposure to no greater than 0.2 parts 
per billion (ppb) of the food additive in the daily diet (3 kilograms 
(kg)) or an estimated daily intake (EDI) of 0.6 micrograms (g) 
per person per day (g/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 (acute toxicity and mutagenicity studies) 
on the additive and concludes that the small dietary exposure resulting 
from the proposed use of the 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 PCB's, carcinogenic chemicals that may be present as 
impurities in the additive. This risk evaluation of PCB's has two 
aspects: (1) Assessment of the worst-case exposure to these impurities 
from the proposed use of the additive; and (2) extrapolation of the 
risk observed in the animal bioassays to the conditions of worst-case 
exposure to humans.

A. PCB's

    FDA has estimated the hypothetical worst-case exposure to PCB's 
from the petitioned use of the food additive as a colorant in polymers 
to be less than 1x10-4 parts per trillion of the daily diet (3 
kg), or 0.3 picograms (pg)/person/day (Ref. 3). The agency used data 
from a carcinogenesis bioassay on PCB's, conducted by Norback and 
Weltman (Ref. 4), to estimate the upper-bound limit of lifetime human 
risk from exposure to these chemicals resulting from the proposed use 
of the food additive (Ref. 5). The results of the bioassay on a PCB 
mixture (Aroclor 1260) demonstrated that the material was carcinogenic 
for male and female rats under the conditions of the study. The test 
material caused significantly increased incidence of hepatocellular 
tumors in both female and male rats.
    Based on the estimated worst-case exposure to PCB's of 0.3 pg/
person/day, FDA estimates that the upper-bound limit of lifetime human 
risk from the use of the subject additive is less than 7.5x10-13, 
or 8 in 10 trillion (Refs. 6 and

[[Page 9366]]

7). Because of the numerous conservative assumptions used in 
calculating the exposure estimate, the actual lifetime-averaged 
individual exposure to PCB's is likely to be substantially less than 
the potential worst-case exposure, and therefore, the upper-bound limit 
of lifetime human risk would be less. Thus, the agency concludes that 
there is a reasonable certainty that no harm from exposure to PCB's 
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 PCB's present as impurities in the additive. 
The agency finds that specifications are not necessary for the 
following reasons: (1) Because of the low levels at which PCB's may be 
expected to remain as impurities following production of the additive, 
the agency would not expect these impurities to become components of 
food at other than extremely low levels; and (2) the upper-bound limit 
of lifetime human risk from exposure to these impurities, even under 
worst-case assumptions, is very low, less than 8 in 10 trillion.

III. Conclusion on Safety

    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, that the food additive will achieve its intended 
technical effect, and 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 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 April 2, 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 dated September 15, 1993, from the Chemistry 
Review Branch (HFS-247) to the Indirect Additives Branch (HFS-216), 
concerning ``FAP 3B4349 (MATS #678, M2.1)--Ciba-Geigy Corp. (CG)--
Irgazin DPP Red BO (Cromophtal DPP Red BP) as a colorant in all 
polymers. Submission dated 10-29-92.''
    2. Kokoski, C. J., ``Regulatory Food Additive Toxicology,'' in 
Chemical Safety Regulation and Compliance, edited by F. Homburger 
and J. K. Marquis, S. Karger, New York, NY, pp. 24-33, 1985.
    3. Memorandum dated February 21, 1995, from the Chemistry Review 
Branch (HFS-247) to the Indirect Additives Branch (HFS-216), 
concerning ``FAP 3B4349 (MATS #678, M2.7)--Ciba-Geigy Corp. (CG)--
Irgazin DPP Red BO (Cromophtal DPP Red BP) as a colorant in all 
polymers. Submission dated 8-31-94.''
    4. Norback, D. H., and R. H. Weltman, ``Polychlorinated Biphenyl 
Induction of Hepatocellular Carcinoma in the Sprague-Dawley Rat,'' 
Environmental Health Perspectives, 60:97-105, 1985.
    5. Gaylor, D. W., and R. L. Kodell, ``Linear Interpolation 
Algorithm for Low Dose Risk Assessment of Toxic Substances,'' 
Journal of Environmental Pathology and Toxicology, 4:305-312, 1980.
    6. Memorandum, Report of the Quantitative Risk Assessment 
Committee, August 18, 1995.
    7. Memorandum dated October 11, 1996, from the Quantitative Risk 
Assessment Committee (HFS-16) to the Indirect Additives Branch (HFS-
216) concerning ``Clarification of QRAC Memorandum of August 18, 
1995, re FAPs 9B4158 and 3B4349.''

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) * * *

[[Page 9367]]



                                                                        
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             Substances                          Limitations            
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  *                    *                    *                    *      
                   *                    *                    *          
3,6-Bis(4-chlorophenyl)-2,5-dihydro- For use only at levels not to      
 pyrrolo[3,4-c]pyrrole-1,4-dione      exceed 1 percent by weight of     
 (C.I. Pigment Red 254, CAS Reg.      polymers. The finished articles   
 No. 84632-65-5)                      are to contact food only under    
                                      conditions of use B through H,    
                                      described in Table 2 of Sec.      
                                      176.170(c) of this chapter.       
  *                    *                    *                    *      
                   *                    *                    *          
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    Dated: February 5, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-5077 Filed 2-28-97; 8:45 am]
BILLING CODE 4160-01-F