[Federal Register Volume 61, Number 17 (Thursday, January 25, 1996)]
[Rules and Regulations]
[Pages 2113-2116]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-1144]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES
21 CFR Part 178

[Docket No. 93F-0243]


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 4,5,6,7-
tetrachloro-2-[2-(4,5,6,7-tetrachloro-2,3-dihydro-1,3-dioxo-1H-inden-2-
yl)-8-quinolinyl]-1H-isoindole-1,3(2H)-dione (C. I. Pigment Yellow 
138), as a colorant for all food-contact polymers. This action is in 
response to a petition filed by BASF Corp.


[[Page 2114]]

DATES: Effective January 25, 1996; written objections and requests for 
a hearing February 26, 1996.

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: 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 18, 1993 (58 FR 43898), FDA announced that a food 
additive petition (FAP 3B4383) had been filed by BASF Corp., 8 Campus 
Dr., Parsippany, NJ 07054. 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 4,5,6,7-tetrachloro-2-[2-
(4,5,6,7-tetrachloro-2,3-dihydro-1,3-dioxo-1H-inden-2-yl)-8-
quinolinyl]-1H-isoindole-1,3(2H)-dione (C.I. Pigment Yellow 138, CAS 
Reg. No. 30125-47-4), as a colorant for all food-contact polymers.
    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, minute 
amounts of carcinogenic polychlorinated dibenzo-p-dioxins (PCDD's) have 
been detected as impurities in tetrachlorophthalic anhydride, one of 
the reactants used to produce the additive (C. I. Pigment Yellow 138). 
Residual amounts of reactants and manufacturing aids, such as PCDD's, 
are commonly found as contaminants in chemical products, including food 
additives.

I. Determination of Safety

    Under section 409(c)(3)(A) of the Federal Food, Drug, and Cosmetic 
Act (the act) (21 U.S.C. 348(c)(3)(A)), the so-called ``general safety 
clause'' of the statute, 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 additives anticancer or Delaney clause (section 
409(c)(3)(A) 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 to 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, C. I. 
Pigment Yellow 138, will result in exposure to the additive of no 
greater than 1.8 parts per billion (ppb), which equates to an estimated 
daily intake (EDI) of 5.4 micrograms per person per day (g/p/
d) (Ref. 1). The agency has also calculated the EDI of the migrating 
impurities associated with the colorant under the most severe 
conditions of the colorant's intended use (phenol, tetrachlorophthalic 
anhydride, 8-aminoquinaldine, and the monocondensation product) and the 
probable concentrations of these migrants from the colorant's use in 
contact with food. The agency estimated the potential daily intakes of 
the four impurities to be 13, 10, 5.4, and 10 nanograms/p/d, 
respectively (Ref. 1). The additive may also contain small amounts of 
carcinogenic impurities (PCDD's).
    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. 2), and the agency has not 
required such testing here. However, the agency has reviewed the 
available toxicological data from acute toxicity studies on the 
additive. No adverse effects were reported in these studies.
    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 risk presented by the 
carcinogenic chemicals (PCDD's) that may be present as impurities in 
the additive. This risk evaluation of PCDD's has two aspects: (1) 
Assessment of the worst-case exposure to the impurities 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.

A. PCDD's

    FDA has estimated the worst-case exposure to PCDD's from the 
petitioned use of the additive as discussed below. Because little is 
known about the toxicity of PCDD's except 2,3,7,8-tetrachlorodibenzo-p-
dioxin (TCDD), the agency utilized the toxicity equivalency factor 
(TEF) method (Ref. 3) to relate the toxicity of the PCDD's in terms of 
an equivalent amount of toxicologically well characterized TCDD, and 
used the TEF's adopted by the North Atlantic Treaty Organization (Ref. 
4) (see 59 FR 17384, April 12, 1994). Summing the equivalent EDI's for 
each PCDD present as an impurity gives the total exposure to PCDD's in 
terms of a total equivalent EDI for TCDD of 1.4 x 10-4 picogram 
(pg)/p/d (Ref. 1).
    Using data from a 2-year chronic toxicity and carcinogenicity study 
by Kociba et al. (Ref. 5) on TCDD fed to rats, the agency estimated the 
upper-bound level of lifetime human risk from exposure to TCDD toxic 
equivalents resulting from the use of C. I. Pigment Yellow 138 as a 
food contact colorant for polymers. The results of the bioassay on TCDD 
showed that the material was carcinogenic for rats under the conditions 
of the study in that the test material caused significantly increased 
incidences of hepatocellular carcinomas and adenomas as well as 
squamous cell carcinomas of the lung, hard palate, nasal turbinates, 
and tongue. FDA further concluded that given the paucity of TCDD 
bioassay data, the Kociba et al. bioassay provided the appropriate 
basis on which to calculate an estimate of the upper-bound level of 
lifetime carcinogenesis risk from exposure to TCDD toxic equivalents 
stemming from the use of the subject additive (C. I. Pigment Yellow 
138) as a colorant in food-contact polymers.
    The agency used a linear-at-low-dose extrapolation method from the 
doses used in the Kociba et al. bioassay and the tumor incidence data 
based upon the original classification of tumors found in that study to 
estimate the upper-bound risk presented by the very low levels of TCDD 
toxic equivalents encountered under actual conditions of the use of the 
additive as colorant in polymers. This procedure is not likely to 
underestimate the actual risk from very low doses and may in fact 
exaggerate it because the extrapolation models used are designed to 
estimate the maximum risk consistent with the data. In so doing, FDA 
estimated a carcinogenic unit risk of 16  x  10-6 for an intake of 
1 pg/kilogram (kg) body weight/d of TCDD toxic equivalents (Ref. 6).

[[Page 2115]]

    As noted, the carcinogenic unit risk assessed above by FDA was 
based on the original tumor incidence data from the Kociba bioassay 
(Ref. 5). Following FDA's risk assessment discussed above, however, a 
group of pathologists, the Pathology Working Group (PWG), reanalyzed 
the slides of the liver tumors observed in the Kociba bioassay using 
the National Toxicology Program's 1986 classification system for liver 
tumors (Ref. 7). FDA has reviewed the results of this reanalysis and 
agrees with the classification of the tumors made by PWG. Using the 
results of this revised reading of the Kociba study slides, FDA 
estimates a carcinogenic unit risk of 9  x  10-6  for an intake of 
1 pg TCDD equivalents/kg body weight/d (Ref. 8). Using this 
carcinogenic unit risk and an upper-bound total exposure to PCDD's 
present in the additive in terms of a total equivalent EDI for TCDD of 
1.4  x  10-4 pg/p/d, FDA estimates that the upper-bound limit of 
risk of cancer would be 2.1  x  10-11 from the proposed use of the 
subject additive (Ref. 9). Because of the numerous conservative 
assumptions used in calculating the exposure estimate, the actual 
lifetime averaged individual exposure to PCDD's is expected to be 
substantially less than the worst-case exposure, and therefore, the 
calculated upper-bound limit of risk would be less. Thus, the agency 
concludes that there is a reasonable certainty that no harm from 
exposure to PCDD'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 PCDD's as impurities in the additive. The 
agency finds that specifications are not necessary for the following 
reasons: (1) Because low levels of PCDD'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 small levels; and (2) the upper-bound limits of lifetime risk 
from exposure to these impurities, even under worst-case assumptions, 
are very low, less than 2.1 in 100 billion for PCDD's.

III. Conclusion

    FDA has evaluated data in the petition and other relevant material 
and concludes that the proposed use of the additive as a colorant in 
food-contact polymers is safe. Based on this information, the agency 
has also concluded that the additive will have the intended technical 
effect. Therefore, 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 21 CFR 
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. 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. Memoranda from the Chemistry Review Branch (HFS-247) to the 
Indirect Additives Branch (HFS-216) concerning FAP 3B4383--BASF 
Corp.--exposure to the food additive and its component 
(polychlorinated dibenzo-p-dioxins, PCDD's) dated January 21, 1994, 
April 19, 1994, and March 10, 1995.
    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, pp. 24-33, 1985.
    3. EPA 560/5-90-014, Background Document to the Integrated Risk 
Assessment for Dioxins and Furans from Chlorine Bleaching in Pulp 
and Papermills, pp. 3-13, July, 1990.
    4. Pilot Study on International Information Exchange on Dioxins 
and Related Compounds, Report No. 178, December, 1988.
    5. Kociba, R. J. et al., ``Results of a Two Year Chronic 
Toxicity and Oncogenicity Study of 2,3,7,8-Tetrachlorodibenzo-p-
dioxin in Rats,'' Toxicology and Applied Pharmacology, 46:279-303, 
1978.
    6. Report of the Quantitative Risk Assessment Committee, 
``Carcinogenic Risk Assessment for Dioxins and Furans in Foods 
Contacting Bleached Paper Products,'' April 20, 1990.
    7. ``2,3,7,8-Tetrachlorodibenzo-p-dioxin in Sprague-Dawley 
Rats,'' Pathco, Inc., March 13, 1990.
    8. Report of the Quantitative Risk Assessment Committee of the 
Center for Food Safety and Applied Nutrition, FDA, ``Upper-Bound 
Lifetime Carcinogenic Risk From Exposure to Dioxin Congeners From 
Foods Contacting Paper Products With Dioxin Levels Not Exceeding 2 
ppt,'' January 27, 1993.
    9. Memorandum, Report of the Quantitative Risk Assessment 
Committee of the Center for Food Safety and Applied Nutrition, FDA, 
``Estimation of upper-bound lifetime risk from polychlorinated 
dibenzo-p-dioxins in C. I. Pigment Yellow 138,'' May 24, 1994.

VI. Objections

    Any person who will be adversely affected by this regulation may at 
any time on or before February 26, 1996, 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.

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:


[[Page 2116]]

    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 paragraph (e) in the table 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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  *                    *                    *                    *      
                   *                    *                    *          
4,5,6,7-Tetrachloro-2-[2-(4,5,6,7-  For use only at levels not to exceed
 tetrachloro-2,3-dihydro-1,3-dioxo-  1 percent by weight of polymers.   
 1H-inden-2-yl)-8-quinolinyl]-1H-    The finished articles are to       
 isoindole-1,3(2H)-dione (C. I.      contact food only under conditions 
 Pigment Yellow 138, CAS Reg.        of use C through H, as described in
 No.30125-47-4).--                   Table 2 of Sec.  176.170(c) of this
                                     chapter; provided further that the 
                                     finished articles shall not be     
                                     filled at temperatures exceeding   
                                     158  deg.F (70  deg.C).            
  *                    *                    *                    *      
                   *                    *                    *          
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    Dated: January 17, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-1144 Filed 1-24-96; 8:45 am]
BILLING CODE 4160-01-F