[Federal Register Volume 60, Number 177 (Wednesday, September 13, 1995)]
[Rules and Regulations]
[Pages 47478-47480]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-22637]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
21 CFR Part 175
[Docket No. 93F-0276]
Indirect Food Additives: Adhesives and Components of Coatings
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 ethoxylated primary
linear alcohols of greater than 10 percent ethylene oxide by weight
having molecular weights of 390 to 7,000 for use as components of food
packaging adhesives. This action is in response to a petition filed by
Petrolite Corp.
DATES: Effective September 13, 1995; written objections and requests
for a hearing October 13, 1995.
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 September 17, 1993 (58 FR 48659), FDA announced that a food
additive petition (FAP 3B4390) had been filed by Petrolite Corp., 369
Marshall Ave., St. Louis, MO 63119-1897. The petition proposed to amend
the food additive regulations in Sec. 175.105 Adhesives (21 CFR
175.105) to provide for the safe use of ethoxylated primary linear
alcohols of greater than 10 percent ethylene oxide by weight having
molecular weights of 390 to 7,000 for use as components of food
packaging adhesives.
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 1,4-dioxane and
ethylene oxide, carcinogenic impurities, resulting from the manufacture
of the additive. Residual amounts of reactants and manufacturing aids,
such as 1,4-dioxane and ethylene oxide, 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 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, ethoxylated
primary linear alcohols of no greater than 10 percent ethylene oxide by
weight having molecular weights of 390 to 7,000, will result in
exposure to the additive of no greater than 50 parts per billion (ppb)
in the daily diet (Ref. 1).
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 that may be present as impurities in the
additive,
[[Page 47479]]
1,4-dioxane and ethylene oxide. This risk evaluation of 1,4-dioxane and
ethylene oxide 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. 1,4-Dioxane
FDA has estimated the hypothetical worst-case exposure to 1,4-
dioxane from the petitioned use of the additive in the manufacture of
adhesives to be 0.25 part per trillion of the daily diet or 750
picogram (pg)/person/day (Ref. 1). The agency used data from a
carcinogenesis bioassay on 1,4-dioxane conducted by the National Cancer
Institute (Ref. 3), to estimate the upper-bound lifetime human risk
from exposure to this chemical stemming from the proposed use of the
additive (Ref. 3). The results of the bioassay on 1,4-dioxane
demonstrated that the material was carcinogenic for female rats under
the conditions of the study. The test material caused significantly
increased incidence of squamous cell carcinomas and hepatocellular
tumors in female rats.
Based on the estimated worst-case exposure of 750 pg/ person/day,
FDA estimates that the upper-bound limit of individual lifetime risk
from the use of the subject additive is 2.7 x 10-11, or 2.7 in
100 billion (Ref. 4). Because of the numerous conservative assumptions
used in calculating the exposure estimate, the actual lifetime averaged
individual exposure to 1,4-dioxane 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 1,4-dioxane would
result from the proposed use of the additive.
B. Ethylene Oxide
FDA estimated that the hypothetical worst-case exposure to
ethylene oxide from the potential use of the additive in the
manufacture of adhesives to be 0.05 part per trillion of the daily diet
or 150 pg/person/day (Ref. 1). The agency used data from a
carcinogenesis bioassay on ethylene oxide conducted by the Institute of
Hygiene, University of Mainz, Germany, to estimate the upper-bound
level of lifetime human risk from exposure to ethylene oxide stemming
from the proposed use of the additive (Ref. 5). The results of the
bioassay on ethylene oxide demonstrated that the material was
carcinogenic for female rats under the conditions of the study. The
test material caused significantly increased incidence of squamous cell
carcinomas of the forestomach and carcinomas in situ of the glandular
stomach.
Based on a potential exposure of 150 pg/person/day, FDA estimates
that the upper-bound limit of individual lifetime risk from the
potential exposure to ethylene oxide from the use of the subject
additive is 2.8 x 10-10, or 2.8 in 10 billion (Ref. 4). Because
of the numerous conservative assumptions used in calculating the
exposure estimate, actual lifetime-averaged individual exposure to
ethylene oxide is likely 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 ethylene oxide would result
from the proposed use of the additive.
C. Need for Specifications
The agency has also considered whether specifications are
necessary to control the amount of 1,4-dioxane and ethylene oxide as
impurities in the additive. The agency finds that specifications are
not necessary for the following reasons: (1) Because of the low level
at which 1,4-dioxane and ethylene oxide 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 2.7 in 100 billion for 1,4-dioxane and less
than 2.8 in 10 billion for ethylene oxide, respectively.
III. Conclusion
FDA has evaluated the data in the petition and other relevant
material and concludes that the proposed use of the additive in
adhesives is safe. Based on this information, the agency has also
concluded that the additive will have the intended technical effect.
Therefore, Sec. 175.105 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. Objections
Any person who will be adversely affected by this regulation may at
any time on or before October 13, 1995, 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 3B4390--
Petrolite Corp.--exposure to the food additive and its component
(1,4-dioxane and ethylene oxide), November 5, 1993.
[[Page 47480]]
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. ``Bioassay of 1,4-Dioxane for Possible Carcinogenicity,''
National Cancer Institute, NCI-CG-TR-80, 1978.
4. Memorandum, Report of the Quantitative Risk Assessment
Committee, June 30, 1994.
5. Dunkelberg, H., ``Carcinogenicity of Ethylene Oxide and 1,2-
Propylene Oxide Upon Intragastric Administration to Rats,'' British
Journal of Cancer, 46:924, 1982.
List of Subjects in 21 CFR Part 175
Adhesives, 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 175 is amended as follows:
PART 175--INDIRECT FOOD ADDITIVES: ADHESIVES AND COMPONENTS OF
COATINGS
1. The authority citation for 21 CFR part 175 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 175.105 is amended in the table in paragraph (c)(5) by
alphabetically adding a new entry under the heading ``Substances'' to
read as follows:
Sec. 175.105 Adhesives.
* * * * *
(c) * * *
(5) * * *
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Substances Limitations
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* * * * *
Ethoxylated primary linear alcohols
of greater than 10 percent
ethylene oxide by weight having
molecular weights of 390 to 7,000
(CAS Reg. No. 97953-22-5).
* * * * *
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Dated: September 1, 1995.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 95-22637 Filed 9-12-95; 8:45 am]
BILLING CODE 4160-01-F
