[Federal Register Volume 62, Number 142 (Thursday, July 24, 1997)]
[Rules and Regulations]
[Pages 39770-39773]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-19428]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 176
[Docket No. 93F-0428]
Indirect Food Additives: Paper and Paperboard Components
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 -
(dinonylphenyl)--hydroxy-poly(oxy-1,2-ethanediyl), containing
7 to 24 moles of ethylene oxide per mole of dinonylphenol, as a
component of defoaming agents used in styrene-butadiene coatings for
paper and paperboard intended to contact food. This action is in
response to a food additive petition filed by PPG Industries, Inc.
DATES: Effective July 24, 1997; written objections and requests for a
hearing by August 25, 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: Andrew J. Zajac, Center for Food
Safety and Applied Nutrition (HFS-215), Food and Drug Administration,
200 C St. SW., Washington, DC 20204, 202-418-3095.
SUPPLEMENTARY INFORMATION:
I. Background
In a notice published in the Federal Register of January 5, 1994
(59 FR 590), FDA announced that a food additive petition (FAP 3B4363)
had been filed by PPG Industries, Inc., One PPG Pl., Pittsburgh, PA
15272 (formerly 440 College Park Dr., Monroeville, PA 15146). The
petition proposed to amend the food additive regulations in
Sec. 176.200 Defoaming agents used in coatings (21 CFR 176.200) and
Sec. 176.210 Defoaming agents used in the manufacture of paper and
paperboard (21 CFR 176.210) to provide for the use of -
(dinonylphenyl)--hydroxy-poly(oxy-1,2-ethanediyl), containing
7 to 24 moles of ethylene oxide per mole of dinonylphenol, as a
defoaming agent used in the production of paper and paperboard and
coatings for paper and paperboard intended to contact food. The
petitioner has subsequently withdrawn the request for approval of the
use of the additive in the production of paper and paperboard and has
requested that approval of the additive be limited to use in styrene-
butadiene polymer coatings for paper and paperboard intended to contact
food.
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, it has
been found to contain minute amounts of unreacted ethylene oxide and
minute amounts of 1,4-dioxane as impurities resulting from its
manufacture. These chemicals have been shown to cause cancer in test
animals. Residual amounts of impurities are commonly found as
constitutents of chemical products, including food additives.
[[Page 39771]]
II. 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 additives 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 intended use of
the additive, Scott v. FDA, 728 F.2d. 322 (6th Cir. 1984).
III. Safety of Petitioned Use of the Additive
FDA estimates that the petitioned use of the additive, -
(dinonylphenyl)--hydroxy-poly(oxy-1,2-ethanediyl), containing
7 to 24 moles of ethylene oxide per mole of dinonylphenol, will result
in exposure to no greater than 25 parts per billion (ppb) of the
additive in the daily diet (3 kilogram (kg)) or an estimated daily
intake (EDI) of 75 micrograms per person per day (g/person/
day) (Refs. 1 and 2).
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. 3), 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 resulting from the petitioned use of
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 ethylene oxide and 1,4-dioxane, the carcinogenic chemicals
that may be present as impurities in the additive. The risk evaluation
of ethylene oxide and 1,4-dioxane has two aspects: (1) Assessment of
exposure to the impurities from the petitioned use of the additive; and
(2) extrapolation of the risk observed in the animal bioassays to the
conditions of exposure to humans.
A. Ethylene oxide
FDA has estimated the exposure to ethylene oxide from the
petitioned use of the additive as a component of defoaming agents used
in styrene-butadiene coatings for paper and paperboard to be no more
than 0.25 part per trillion (pptr) in the daily diet (3 kg), or 0.75
nanogram (ng)/person/day (Refs. 1 and 2). The agency used data from a
long-term rodent bioassay on ethylene oxide conducted for the Institute
of Hygiene, University of Mainz, Germany (Ref. 4), to estimate the
upper-bound limit of lifetime human risk from exposure to this chemical
resulting from the petitioned use of the additive. The author reported
that the test material caused significantly increased incidence of
squamous cell carcinomas in situ of the forestomach and carcinoma in
situ of the glandular stomach in female rats.
Based on the agency's estimate that exposure to ethylene oxide will
not exceed 0.75 ng/person/day, FDA estimates that the upper-bound limit
of lifetime human risk from the petitioned use of the subject additive
is 1.5 x 10-9, or 1.5 in a billion (Ref. 5). Because of the
numerous conservative assumptions used in calculating the exposure
estimate, the actual lifetime-averaged individual exposure to ethylene
oxide is likely to be substantially less than the estimated exposure,
and therefore, the probable lifetime human risk would be less than the
upper-bound limit of lifetime human risk. Thus, the agency concludes
that there is reasonable certainty that no harm from exposure to
ethylene oxide would result from the petitioned use of the additive.
B. 1,4-Dioxane
FDA has estimated the exposure to 1,4-dioxane from the petitioned
use of the additive as a component of defoaming agents used in styrene-
butadiene coatings for paper and paperboard to be no more than 0.13
pptr of the daily diet (3 kg), or 0.39 ng/person/day (Refs. 1 and 2).
The agency used data from a long-term rodent bioassay on 1,4-dioxane
conducted by the National Cancer Institute (Ref. 6), to estimate the
upper-bound limit of lifetime human risk from exposure to this chemical
resulting from the petitioned use of the additive. The authors reported
that the test material caused significantly increased incidence of
squamous cell carcinomas in male and female rats and hepatocellular
tumors in female rats and male and female mice.
Based on the agency's estimate that exposure to 1,4-dioxane will
not exceed 0.39 ng/person/day, FDA estimates that the upper-bound limit
of lifetime human risk from the petitioned use of the subject additive
is 1.4 x 10-11, or 14 in a trillion (Ref. 5). Because of the
numerous conservative assumptions used in calculating the exposure
estimate, the actual lifetime-averaged individual exposure to 1,4-
dioxane is likely to be substantially less than the estimated exposure,
and therefore, the probable lifetime human risk would be less than the
upper-bound limit of lifetime human risk. Thus, the agency concludes
that there is reasonable certainty that no harm from exposure to 1,4-
dioxane would result from the petitioned use of the additive.
C. Need for Specifications
The agency has also considered whether specifications are necessary
to control the amount of ethylene oxide and 1,4-dioxane 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 ethylene oxide and 1,4-dioxane may be expected to remain as
impurities following production of the additive, the agency would not
expect the impurities to become components of food at other than
extremely low levels; and (2) the upper-bound limits of lifetime human
risk from exposure to the impurities, even under worst-case
assumptions, are very low (less than 1.5 in 1 billion).
IV. Conclusion
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 component of defoaming agents used in
styrene-butadiene coatings for paper and paperboard intended for
contact with food is safe, and that the additive will achieve its
intended technical effect. Therefore, the agency concludes that the
regulations in Sec. 176.200 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
[[Page 39772]]
documents any materials that are not available for public disclosure
before making the documents available for inspection.
V. 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. No comments were received during the 30-day comment
period specified in the filing notice for comments on the environmental
assessment submitted with the petition.
VI. Objections
Any person who will be adversely affected by this regulation may at
any time on or before August 25, 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.
VII. 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 June 19, 1995, from the Chemistry Review
Branch (HFS-247), to the Indirect Additives Branch (HFS-216)
entitled ``FAP 3B4363 (MATS No. 695; M 2.3 and M 2.4)-PPG
Industries, Inc. Dinonylphenol-ethylene oxide adduct for use as a
component of defoaming agents used in paper coatings and in the
manufacture of paper and paperboard. Submissions dated 7-12-94, 10-
4-94, and 11-1-94.''
2. Memorandum dated July 11, 1996, from the Chemistry Review
Branch (HFS-247), to the Indirect Additives Branch (HFS-216)
entitled ``FAP 3B4363 (MATS No. 695; M 2.4.1)-PPG Industries, Inc.
Dinonylphenol-ethylene oxide adduct for use as a component of
defoaming agents used in paper coatings. Telefax submissions dated
9-22-95 and 3-7-96.''
3. 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.
4. Dunkelberg, H., ``Carcinogenicity of Ethylene Oxide and 1,2-
Propylene Oxide Upon Intragastric Administration to Rats,'' British
Journal of Cancer, 46:924, 1982.
5. Memorandum dated July 24, 1996, from Indirect Additives
Branch (HFS-216), to Sara H. Henry, Executive Secretary,
Quantitative Risk Assessment Committee (HFS-308), entitled
``Estimation of the upper-bound lifetime risk from ethylene oxide
and 1,4-dioxane - FAP 3B4363.''
6. ``Bioassay of 1,4-Dioxane for Possible Carcinogenicity,''
National Cancer Institute, NCI-CG-TR-80, 1978.
List of Subjects in 21 CFR Part 176
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
176 is amended as follows:
PART 176--INDIRECT FOOD ADDITIVES: PAPER AND PAPERBOARD COMPONENTS
1. The authority citation for 21 CFR part 176 continues to read as
follows:
Authority: Secs. 201, 402, 406, 409, 721 of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 321, 342, 346, 348, 379e).
2. Section 176.200 is amended in the table in paragraph (d)(3) by
alphabetically adding a new entry under the headings ``List of
substances'' and ``Limitations'' to read as follows:
Sec. 176.200 Defoaming agents used in coatings.
* * * * *
(d) * * *
(3) * * *
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List of substances Limitations
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* * * * * *
*
-(Dinonylphenyl)--hydroxy-poly(oxy- For use only in defoaming agents for the production of
1,2-ethanediyl), containing 7 to 24 moles of ethylene styrene-butadiene coatings at a level not to exceed
oxide per mole of dinonylphenol (CAS Reg. No. 9014-93- 0.05 percent by weight of the finished coating.
1).
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*
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[[Page 39773]]
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Dated: June 10, 1997.
William K.Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-19428 Filed 7-23-97; 8:45 am]
BILLING CODE 4160-01-F
