[Federal Register Volume 61, Number 99 (Tuesday, May 21, 1996)]
[Rules and Regulations]
[Pages 25392-25395]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-12762]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
21 CFR Part 176
[Docket No. 92F-0313]
Indirect Food Additives: Paper and Paperboard Components
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is amending the food
additive regulations to provide for the safe use of diethanolamine as a
boiler water additive in paper mill boilers used in the manufacture of
paper and paperboard intended for use in contact with aqueous and fatty
food. This action is in response to a food additive petition filed by
Betz Laboratories, Inc.
DATES: Effective May 21, 1996; written objections and requests for a
hearing by June 20, 1996.
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: Diane E. Robertson, Center for Food
Safety and Applied Nutrition (HFS-216), Food and Drug Administration,
200 C St. SW., Washington, DC 20204, 202-418-3089.
[[Page 25393]]
SUPPLEMENTARY INFORMATION:
I. Background
In a notice published in the Federal Register of September 14,
1992 (57 FR 41944), FDA announced that a food additive petition (FAP
2B4329) had been filed by Betz Laboratories, Inc., 4636 Somerton Rd.,
Trevose, PA 19053-6783. The petition proposed to amend the food
additive regulations in Sec. 176.170 Components of paper and paperboard
in contact with aqueous and fatty foods (21 CFR 176.170) to provide for
the safe use of diethanolamine as a boiler water additive in paper mill
boilers.
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 may
contain minute amounts of 1,4-dioxane and ethylene oxide, which are
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.
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 proposed 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,
diethanolamine, will result in exposure to no greater than 5 parts per
billion (ppb) of the additive in the daily diet (3 kilograms (kg)) or
an estimated daily intake (EDI) of 15 micrograms per person per day
(/person/day) (Ref. 1) and that the cumulative dietary
concentration of the additive from all regulated uses is conservatively
58 ppb in the daily diet or an EDI of 170 /person/day.
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 a small
increase in dietary exposure 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 risk presented by 1,4-
dioxane and ethylene oxide, 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 the worst-case
exposure to these 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
paper to be 0.6 part per quadrillion (ppq) of the daily diet (3 kg), or
2 picograms (pg)/person/day (Ref. 3). The agency used data from a
carcinogenesis bioassay on 1,4-dioxane conducted by the National Cancer
Institute (Ref. 4), to estimate the upper-bound limit of lifetime human
risk from exposure to this chemical resulting from the proposed use of
the additive (Ref. 4). 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 to 1,4-dioxane of 2 pg/
person/day, FDA estimates that the upper-bound limit of lifetime human
risk from the use of the subject additive is 6.9 x 10-14, or 6.9
in 100 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 expected to be
substantially less than the worst-case exposure, and therefore, the
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 has estimated the hypothetical worst-case exposure to ethylene
oxide from the petitioned use of the additive in the manufacture of
paper to be 0.6 ppq of the daily diet (3 kg), or 2 pg/person/day (Ref.
3). The agency used data from a carcinogenesis bioassay on ethylene
oxide conducted for the Institute of Hygiene, University of Mainz,
Germany to estimate the upper-bound limit of lifetime human risk from
exposure to ethylene oxide resulting from the proposed use of the
additive (Ref. 6). 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 the estimated worst-case exposure to ethylene oxide of 2
pg/person/day, FDA estimates that the upper-bound limit of lifetime
human risk from the use of the subject additive is 3.7 x 10-12, or
3.7 in 1 trillion (Ref. 5). 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
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 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 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
[[Page 25394]]
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
6.9 in 100 trillion for 1,4-dioxane and less than 3.7 in 1 trillion for
ethylene oxide, respectively.
IV. Conclusion
FDA has evaluated the data in the petition and other relevant
material and concludes that the proposed use of the additive in paper
mill boilers used in the manufacture of paper and paperboard products
intended for use in contact with aqueous and fatty food is safe. Based
on this information, the agency has also concluded that the additive
will have the intended technical effect. Therefore, Sec. 176.170 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.
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.
VI. Objections
Any person who will be adversely affected by this regulation may at
any time on or before June 20,1996, 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.
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 September 8, 1993, from the Chemistry Review
Branch (HFS-247), to the Indirect Additives Branch (HFS-216)
concerning ``FAP 2B4329 (MATS No. 654; M 2.1). Submission of 6/5/92;
Betz Laboratories. Diethanolamine in papermill boilers.''
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. Memorandum dated April 28, 1994, from the Chemistry Review
Branch (HFS-247) to the Indirect Additives Branch (HFS-216)
concerning ``FAP 2B4329 (MATS No. 654; M 2.4): Diethanolamine. Paper
mill boiler additive. Betz Laboratories-Submission of 4/8/94.''
4. ``Bioassay of 1,4-Dioxane for Possible Carcinogenicity,''
National Cancer Institute, NCI-CG-TR-80, 1978.
5. Memorandum, Report of the Quantitative Risk Assessment
Committee, October 28, 1994.
6. 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 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 176.170 is amended in the table in paragraph (a)(5) by
revising the entry for ``Diethanolamine'' under the heading
``Limitations'' to read as follows:
Sec. 176.170 Components of paper and paperboard in contact with
aqueous and fatty foods.
* * * * *
(a) * * *
(5) * * *
------------------------------------------------------------------------
List of Substances Limitations
------------------------------------------------------------------------
* * * *
* * *
Diethanolamine....................... For use only:
1. As an adjuvant to control pulp
absorbency and pitch content in
the manufacture of paper and
paperboard prior to the sheet-
forming operation.
2. In paper mill boilers.
* * * *
* * *
------------------------------------------------------------------------
[[Page 25395]]
* * * * *
Dated: May 15, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-12762 Filed 5-20-96; 8:45 am]
BILLING CODE 4160-01-F
