[Federal Register Volume 64, Number 221 (Wednesday, November 17, 1999)]
[Rules and Regulations]
[Pages 62583-62585]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-29915]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 178
[Docket No. 98F-0492]
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 expanded safe use of N,N-bis
(2-hydroxyethyl) alkyl (C13-C15) amine as an
antistatic agent in polypropylene homo- and copolymers intended for
contact with food. This action is in response to a petition filed by
ICI PLC.
DATES: This regulation is effective November 17, 1999; written
objections and requests for a hearing by December 17, 1999.
ADDRESSES: Submit written objections to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Ellen M. Waldron, Center for Food
Safety and Applied Nutrition (HFS-215), Food and Drug Administration,
200 C St. SW., Washington, DC 20204, 202-418-3089.
SUPPLEMENTARY INFORMATION: In a notice published in the Federal
Register of July 7, 1998 (63 FR 36699), FDA announced that a food
additive petition (FAP 8B4602) had been filed by ICI PLC, c/o ICI
Surfactants, P.O. Box 8340, Wilmington, DE 19803-8340. The petition
proposed to amend the food additive regulations in Sec. 178.3130
Antistatic and/or antifogging agents in food-packaging materials (21
CFR 178.3130) to provide for the expanded safe use of N,N-bis (2-
hydroxyethyl) alkyl (C13-C15) amine as an
antistatic agent in polypropylene homo- and copolymers intended for
contact with food.
In its evaluation of the safety of this food additive, FDA has
reviewed the safety of the additive itself, the starting materials
used, 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, which are
carcinogenic impurities resulting from the manufacture of the additive.
Residual amounts of impurities, such as 1,4-dioxane and ethylene oxide,
are commonly found as contaminants in chemical products, including food
additives.
I. Determination of Safety
Under the general safety standard 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 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
standard 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).
II. Safety of Petitioned Use of the Additive
FDA estimates that the petitioned use of the additive, N,N-bis (2-
hydroxyethyl) alkyl (C13-C15) amine, will result
in exposure to no greater than 23 parts per billion (ppb) of the
additive in the daily diet (3 kilograms (kg)) or an estimated daily
intake of 69 micrograms per person per day (g/p/d) (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 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 standard, considering all available data and using risk
assessment procedures to estimate the upper-bound limit of lifetime
human risk presented by 1,4-dioxane and ethylene oxide, the
carcinogenic chemicals that may be present as impurities in the
additive. This risk evaluation of 1,4-dioxane and ethylene oxide 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. 1,4-Dioxane
FDA has estimated the exposure to 1,4-dioxane from the petitioned
use of the additive as an antistatic agent in polypropylene homo- and
copolymers intended for contact with food to be no more than 0.09 ppb
in the daily diet (3 kg), or 0.28 g/p/d (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
limit of lifetime human risk from exposure to this chemical resulting
from the petitioned use of the additive. The results of the bioassay on
1,4-dioxane
[[Page 62584]]
demonstrated that the material was carcinogenic for female rats under
the conditions of the study. The authors reported that the test
material caused significantly increased incidence of squamous cell
carcinomas and hepatocellular tumors in female rats.
Based on the agency's estimate that exposure to 1,4-dioxane will
not exceed 0.28 g/p/d, FDA estimates that the upper-bound
limit of lifetime human risk from the petitioned use of the subject
additive is 9.8 x10-9, or 9.8 in one 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 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 a reasonable certainty that no harm from
exposure to 1,4-dioxane would result from the petitioned use of the
additive.
B. Ethylene Oxide
FDA has estimated the exposure to ethylene oxide from the
petitioned use of the additive as an antistatic agent in polypropylene
homo- and copolymers intended for contact with food to be no more than
2 parts per trillion in the daily diet (3 kg) or 6 nanograms (ng)/p/d
(Ref. 1). The agency used data from a carcinogenesis bioassay on
ethylene oxide, conducted for the Institute of Hygiene, University of
Mainz, Germany (Ref. 5), to estimate the upper-bound limit of lifetime
human risk from exposure to this chemical resulting from the petitioned
use of the additive. The results of the bioassay on ethylene oxide
demonstrated that the material was carcinogenic for female rats under
the conditions of the study. The authors reported that the test
material caused significantly increased incidence of squamous cell
carcinomas of the forestomach and carcinomas in situ of the glandular
stomach.
Based on the agency's estimate that exposure to ethylene oxide
will not exceed 6 ng/p/d, FDA estimates that the upper-bound limit of
lifetime human risk from the petitioned use of the subject additive is
1.1 x 10-8, or 1.1 in 100 millon (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 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 the exposure to
ethylene oxide 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 amounts of 1,4-dioxane and ethylene oxide
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 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 human risk from exposure to 1,4-dioxane and ethylene
oxide, are very low, 9.8 in a billion and 1.1 in 100 million,
respectively.
III. Conclusion
FDA has evaluated data in the petition and other relevant
material. Based on this information, the agency concludes that the
proposed use of the additive in food-contact articles is safe, that the
additive will achieve its intended technical effect, and therefore,
that the regulations in Sec. 178.3130 should be amended as set forth
below in this document.
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 previously considered the environmental effects of
this rule as announced in the notice of filing for FAP 8B4602 (63 FR
36699). No new information or comments have been received that would
affect the agency's previous determination that there is no significant
impact on the human environment and that an environmental impact
statement is not required.
V. Paperwork Reduction Act of 1995
This final rule contains no collections of information. Therefore,
clearance by the Office of Management and Budget under the Paperwork
Reduction Act of 1995 is not required.
VI. Objections
Any person who will be adversely affected by this regulation may
at any time on or before December 17, 1999, 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 from the Chemistry Review Team (HFS-246) to the
Division of Petition Control (HFS-215) entitled ``FAP 8B4602 (MATS
#976 M2.1): ICI Surfactants; Submission of 4/7/99. N,N-Bis(2-
Hydroxyethyl) Alkyl (C13-C15) Amine as an
Antistatic Agent in Polypropylene Used in Contact With Fatty Foods
Hot Filled or Pasteurized Above 66 deg.C,'' dated May 28, 1999.
2. 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.
3. ``Bioassay of 1,4-Dioxane for Possible Carcinogenicity,''
National Cancer Institute, NCI-CG-TR-80, 1978.
4. Memorandum from the Division of Petition Control (HFS-215)
to Executive Secretary, Quantitative Risk Assessment Committee (HFS-
308) entitled ``Estimate of the Upper bound Lifetime Risk From
Residual 1,4-Dioxane (DO) and Ethylene
[[Page 62585]]
Oxide (EO) in N,N-bis (2-Hydroxyethyl) Alkyl (C13-
C15) Amine Intended for Use as an Antistatic Agent in
Polypropylene Homo- and Copolymers Contacting Food: FAP 8B4602,''
dated June 8, 1999.
5. Dunkelberg, H., ``Carcinogenicity of Ethylene Oxide and 1,2-
Propylene Oxide Upon Intragastric Administration to Rats,'' British
Journal of Cancer, 46: 924-933, 1982.
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: 21 U.S.C. 321, 342, 348, 379e.
2. Section 178.3130 is amended in the table in paragraph (b) by
revising the entry for N,N-bis (2-hydroxyethyl) alkyl (C13-
C15) amine under the heading ``Limitations'' to read as
follows:
Sec. 178.3130 Antistatic and/or antifogging agents in food-packaging
materials.
* * * * *
(b) * * *
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List of substances Limitations
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* * * *
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N,N-bis(2-hydroxyethyl)alkyl (C13- For use only:
C15) amine (CAS Reg. No. 70955-14- 1. As an antistatic agent at
5). levels not to exceed 0.2 percent
by weight in molded or extruded
high-density polyethylene (having
a density 0.95 g/cm3
and polypropylene containers that
contact food only of the types
identified in Sec. 176.170(c) of
this chapter, Table 1, under types
I, VI-B, VII-B, and VIII, under
the conditions of use E through G
described in Table 2 of Sec.
176.170(c) of this chapter,
provided such foods have a pH
above 5.0.
2. As an antistatic agent at
levels not to exceed 0.1 percent
by weight in molded or extruded
polypropylene homopolymers and
copolymers that contact food only
of the types identified in Sec.
176.170(c) of this chapter, Table
1, under Types II, III, IV, V, VII-
A, and IX, under the conditions of
use C through G described in Table
2 of Sec. 176.170(c) of this
chapter.
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Dated: November 4, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 99-29915 Filed 11-16-99; 8:45 am]
BILLING CODE 4160-01-F
