[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