[Federal Register Volume 63, Number 219 (Friday, November 13, 1998)]
[Rules and Regulations]
[Pages 63406-63408]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-30296]
[[Page 63406]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 176
[Docket No. 96F-0401]
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 polyamide-
ethyleneimine-epichlorohydrin resin for use as a retention aid in the
manufacture of paper and paperboard intended for use in contact with
dry food. This action is in response to a petition filed by BASF Corp.
DATES: The regulation is effective November 13, 1998; written
objections and requests for a hearing by December 14, 1998.
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: Vir D. Anand, Center for Food Safety
and Applied Nutrition (HFS-215), 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 October 31, 1996 (61 FR 56242), FDA announced that a food
additive petition (FAP 6B4501) had been filed by BASF Corp., 11501
Steele Creek Rd., Charlotte, NC 28273. The petition proposed to amend
the food additive regulations in Sec. 176.180 Components of paper and
paperboard in contact with dry food (21 CFR 176.180) to provide for the
safe use of polyamide-ethyleneimine-epichlorohydrin resin for use as a
retention aid in the manufacture of paper and paperboard intended for
use in contact with dry 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, 1,4-
dioxane, epichlorohydrin, and ethyleneimine, carcinogenic impurities
resulting from the manufacture of the additive. Residual amounts of
reactants and manufacturing aids, such as ethylene oxide, 1,4-dioxane,
epichlorohydrin, and ethyleneimine 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, polyamide-
ethyleneimine-epichlorohydrin resin will result in exposure to no
greater than 50 parts per billion (ppb) of the additive in the daily
diet (3 kilogram (kg)) or an estimated daily intake (EDI) of 0.15
milligram per person per day (mg/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 proposed use of the
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 ethylene oxide, 1,4-dioxane, epichlorohydrin,
and ethyleneimine, carcinogenic chemicals that may be present as
impurities in the additive. This risk evaluation of ethylene oxide,
1,4-dioxane, epichlorohydrin, and ethyleneimine has two aspects: (1)
Assessment of the exposure to the impurities from the proposed use of
the additive; and (2) extrapolation of the risk observed in 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 in the manufacture of paper and
paperboard to be no greater than 50 parts per quadrillion (ppq) of the
daily diet (3 kg) or no more than 150 picogram (pg)/p/d (Ref. 1). The
agency used data from a carcinogenesis bioassay on ethylene oxide
conducted by the Institute of Hygiene, University of Mainz, Germany
(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 ethylene oxide demonstrated
that ethylene oxide 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 the agency's estimate that the exposure to ethylene oxide
will not exceed 150 pg/p/d, FDA estimates that the upper-bound limit of
lifetime human risk from the proposed use of the subject additives 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, 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 proposed use of the additive.
B. 1,4-Dioxane
FDA has estimated the exposure to 1,4-dioxane from the petitioned
use of the additive in the manufacture of paper and paperboard to be no
more than 55 parts per trillion (ppt) of the daily diet (3 kg) or 0.2
microgram (g/p/d (Ref. 1)). The agency used data from a
carcinogenesis bioassay on 1,4-dioxane, conducted by the National
Cancer
[[Page 63407]]
Institute (Ref. 5), to estimate the upper-bound limit of lifetime human
risk from exposure to this chemical resulting from the proposed use of
the additive. 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 agency's estimate that exposure to 1,4-dioxane will
not exceed 0.2 g/p/d, FDA estimates that the upper-bound limit
of lifetime human risk from the proposed use of the subject additive is
6.9 x 10-9, or 6.9 in 1 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 reasonable certainty that no harm from exposure to 1,4-
dioxane would result from the proposed use of the additive.
C. Epichlorohydrin
FDA has estimated the exposure to epichlorohydrin from the
petitioned use of the additive in the manufacture of paper and
paperboard to be no more than 100 ppq of the daily diet (3 kg) or no
more than 300 pg/p/d (Ref. 1). The agency used data from a Japanese
carcinogenesis bioassay (Ref. 6), on epichlorohydrin fed to rats via
their drinking water to estimate the upper-bound limit of lifetime
human risk from exposure to this chemical resulting from the proposed
use of the additive. The results of the bioassay demonstrated that
epichlorohydrin was carcinogenic under the conditions of the study. The
test material caused significantly increased incidences of stomach
papillomas and carcinomas in the rats.
Based on the agency's estimate that exposure to epichlorohydrin
will not exceed 300 pg/p/d, FDA estimates that the upper-bound limit of
lifetime human risk from the proposed use of the subject additive is
1.4 x 10-11 (or 1.4 in 100 billion) (Ref. 4). Because of the
numerous conservative assumptions used in calculating the exposure
estimate, the actual lifetime-averaged individual exposure to
epichlorohydrin 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 epichlorohydrin would result from the proposed use of the additive.
D. Ethyleneimine
FDA has estimated the exposure to ethyleneimine from the petitioned
use of the additive in the manufacture of paper and paperboard to be no
greater than 2.5 ppq of the daily diet (3 kg) or no greater than 7.5
pg/p/d (Ref. 1). The agency used data from a carcinogenesis bioassay on
ethyleneimine conducted by the National Cancer Institute (Ref. 7), to
estimate the upper-bound limit of lifetime human risk from exposure to
ethyleneimine resulting from the proposed use of the additive. The
results of the bioassay on ethyleneimine demonstrated that the material
was carcinogenic for male and female mice under the conditions of the
study. The test material caused significantly increased incidence of
lung and liver neoplasia in both male and female mice.
Based on the agency's estimate that exposure to ethyleneimine will
not exceed 7.5 pg/p/d, FDA estimates that the upper-bound limit of
lifetime human risk from the proposed use of the subject additive is
2.6 x 10-9 (or 2.6 in 1 billion) (Ref. 4). Because of the
numerous conservative assumptions used in calculating the exposure
estimate, the actual lifetime-averaged individual exposure to
ethyleneimine 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 ethyleneimine would result from the proposed use of the additive.
E. Need for Specifications
The agency has also considered whether specifications are necessary
to control the amount of ethylene oxide, 1,4-dioxane, epichlorohydrin,
and ethyleneimine present 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 ethylene oxide, 1,4-dioxane,
epichlorohydrin, and ethyleneimine 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 risk
from exposure to ethylene oxide, 1,4-dioxane, epichlorohydrin, and
ethyleneimine are very low, 2.8 in 10 billion, 6.9 in 1 billion, 1.4 in
100 billion, and 2.6 in 1 billion, respectively.
III. 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 retention aid in the production of
paper and paperboard is safe, and that the additive will achieve its
intended technical effect. Therefore, the agency concludes that the
regulations in Sec. 176.180 should be amended as set forth as follows.
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 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. Paperwork Reduction Act of 1995
This final rule contains no collection 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 14, 1998, file with the Dockets
Management Branch (address above) written objection 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
[[Page 63408]]
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 objection 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 Branch, FDA, to the
Indirect Additives Branch, FDA, concerning ``FAP 6B4501 (MATS M2.0 &
2.1): BASF Corp., ``Safe Use of Polymin SB as a Retention Agent in
the Manufacture of Paper and Paperboard to be Made Into Dry Food
Containers,'' dated September 18, 1996.
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. Dunkelberg, H., ``Carcinogenicity of Ethylene Oxide and 1,2-
Propylene Oxide Upon Intragastric Administration to Rats,'' British
Journal of Cancer, 46: pp. 924-933, 1982.
4. Memorandum from the Indirect Additives Branch, FDA, to the
Executive Secretary, Quantitative Risk Assessment Committee, FDA,
concerning ``Estimation of Upper-bound Lifetime Risk From
Ethyleneimine, Epichlorohydrin, Ethylene Oxide and 1,4-dioxane in an
Aqueous Solution of Either One or a Mixture of the Following Two
Polymers;
Formate salt form: Hexanedioic acid with N-(2-aminoethyl)-1,3-
propanediamine, aziridine, (chloromethyl)oxirane, 1,2-ethanediamine,
N,N''-1,2-ethanediylbis[1,3-propanediamine] formic acid and
-hydro--hydroxypoly(oxy-1,2-ethanediyl) [CAS Reg.
No. 114133-44-7].
Sulfate salt form: Hexanedioic acid with N-(2-aminoethyl)-1,3-
propanediamine, aziridine, (chloromethyl)oxirane, 1,2-ethanediamine,
N,N''-1,2-ethanediylbis[1,3-propanediamine] and -hydro-
-hydroxypoly(oxy-1,2-ethanediyl), sulfate salt [CAS Reg.
No. 16768-43-5].''Subject of Food Additive Petition No. 6B4501 (BASF
Corp.), dated October 17, 1996.
5. ``Bioassay of 1,4-Dioxane for Possible Carcinogenicity,''
National Cancer Institute, NCI-CG-TR-80, 1978.
6. Konishi, Y. et al., ``Forestomach Tumors Induced by Orally
Administered Epichlorohydrin in Male Wistar Rats,'' Gann 71:922-923,
1980.
7. Innes, J. R. M. et al., ``Bioassay of Pesticide Chemicals for
Tumorigenicity in Mice: A Preliminary Note,'' Journal of National
Cancer Institute, 42:1101, 1969.
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: 21 U.S.C. 321, 342, 346, 348, 379e.
2. Section 176.180 is amended in the table in paragraph (b)(2) by
alphabetically adding an entry under the heading ``List of substances''
to read as follows:
Sec. 176.180 Components of paper and paperboard in contact with dry
food.
* * * * *
(b) * * *
(2) * * *
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List of substances Limitations
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* * * * * *
*
Polyamide-ethyleneimine-epichlorohydrin resin is
prepared by reacting equimolar amounts of adipic acid
and three amines (21 mole percent of 1,2-
ethanediamine, 51 mole percent of N-(2-aminoethyl)-1,3-
propanediamine, and 28 mole percent of N, N'-1,2-
ethanediylbis(1,3-propanediamine)) to form a basic
polyamidoamine which is modified by reaction with
ethyleneimine (5.5:1.0 ethyleneimine:polyamidoamine).
The modified polyamidoamine is reacted with a
crosslinking agent made by condensing approximately 34
ethylene glycol units with (chloromethyl)oxirane,
followed by pH adjustment with formic acid or sulfuric
acid to provide a finished product as a formate (CAS
Reg. No. 114133-44-7) or a sulfate (CAS Reg. No.
167678-43-5), having a weight-average molecular weight
of 1,300,000 and a number-average molecular weight of
16,000.
* * * * * *
*
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Dated: November 2, 1998.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 98-30296 Filed 11-12-98; 8:45 am]
BILLING CODE 4160-01-F