[Federal Register: June 25, 2002 (Volume 67, Number 122)]
[Rules and Regulations]
[Page 42714-42717]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr25jn02-5]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 173
[Docket No. 89F-0452]
Secondary Direct Food Additives Permitted for Direct Addition to
Food for Human Consumption; Materials Used as Fixing Agents in the
Immobilization of Enzyme Preparations
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 dimethylamine-
epichlorohydrin and acrylamide-acrylic acid resins, individually or
together, as fixing agents for the immobilization of glucose isomerase
enzyme preparations. This action is in response to a petition filed by
Enzyme Bio-Systems Ltd.
DATES: This rule is effective June 25, 2002. Submit written objections
and requests for a hearing by July 25, 2002.
ADDRESSES: Submit written objections and requests for a hearing to the
Dockets Management Branch (HFA-305), Food and Drug Administration, 5630
Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic
objections to http://www.fda.gov/dockets/ecomments.
FOR FURTHER INFORMATION CONTACT: Rosalie M. Angeles, Center for Food
Safety and Applied Nutrition (HFS-206), Food and Drug Administration,
5100 Paint Branch Pkwy., College Park, MD 20740, 202-418-3107.
SUPPLEMENTARY INFORMATION:
I. Background
In a notice published in the Federal Register of November 17, 1989
(54 FR 47828), FDA announced that a food additive petition (FAP 9A4175)
had been filed by Enzyme Bio-Systems Ltd., International Plaza, Route
9W, Englewood Cliffs, NJ 07632. The petition proposed to amend the food
additive regulations to provide for the safe use of dimethylamine-
epichlorohydrin copolymer (DEC) and acrylamide-acrylic acid resin (AAR)
as fixing agents for immobilizing glucose isomerase enzyme.
DEC and AAR will be used, individually or together, to immobilize
glucose isomerase enzymes for the purpose of converting glucose to a
mixture of glucose and fructose for the production of high fructose
corn syrup (HFCS). The glucose isomerase immobilized with the
petitioned polymers may be used as a substitute for one or more of the
immobilized glucose isomerases currently in use.
In its evaluation of the safety of the petitioned substances, FDA
has reviewed the safety of the additives and the chemical impurities
that may be present in them resulting from the manufacturing processes.
Although the petitioned polymers have not been shown to cause cancer,
they may contain minute amounts of carcinogenic impurities resulting
from their manufacture. DEC may contain traces of unreacted
epichlorohydrin and its degradation product, 1,3-dichloro-2-propanol.
AAR may contain minute amounts of the unreacted monomer, acrylamide.
These chemical impurities have been shown to cause cancer in test
animals. Residual amounts of reactants and their impurities commonly
are found as contaminants of chemical products, including food
additives.
II. 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 evaluated properly under the general safety
standard using risk assessment procedures to determine whether there is
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 the Petitioned Use of the Additives
FDA has estimated that the petitioned use of the additives, DEC and
AAR, will result in a daily intake of 210 micrograms per person per day
([mgr]g/p/d) and 83 [mgr]g/p/d, respectively (Ref. 1).
FDA has evaluated the safety of DEC and AAR under the general
safety
[[Page 42715]]
standard and concludes that the estimated dietary exposure to the
additives resulting from the petitioned uses is safe. In reaching this
conclusion, FDA reviewed all available toxicological data and used risk
assessment procedures to estimate the upper-bound limit of lifetime
human risk presented by the carcinogenic impurities that may be present
in the petitioned additives. The chemical impurities considered are
acrylamide in AAR and epichlorohydrin and 1,3-dichloro-2-propanol in
DEC.
The risk evaluation of the carcinogenic impurities has two aspects:
(1) Assessment of exposure to the impurities from the petitioned use of
the additives; and (2) extrapolation of the risk observed in the animal
bioassays to the conditions of exposure to humans.
A. Acrylamide
FDA has estimated the upper-bound exposure to acrylamide from the
petitioned use of AAR to be 2 nanograms per person per day (ng/p/d),
corresponding to a dietary concentration of 0.67 part-per-trillion
(pptr) in the daily diet (3 kg) (Ref. 2). This estimate is
conservative, as it does not account for the removal of impurities,
including acrylamide, from the crude HFCS during the purification
process.
1. Acrylamide as a Neurotoxin
Acrylamide is a recognized neurotoxin. To derive the safe exposure
level to acrylamide as a neurotoxin, the agency used a study by J. D.
Burek et al. (Ref. 3). FDA, using an uncertainty factor of 1,000
(equivalent to a safety factor), determined the acceptable daily intake
of acrylamide with respect to neurotoxicity to be 12 [mgr]g/p/d based
on the neurotoxicity evaluation and absence of a neurotoxic effect
(Refs. 4 and 5). Therefore, based on the agency's estimate that the
exposure to acrylamide will not exceed 2 ng/p/d, FDA concludes that the
exposure to acrylamide from the petitioned use of AAR does not pose a
neurotoxic risk.
2. Acrylamide as a Carcinogen
To estimate the upper-bound limit of lifetime human risk from
exposure to acrylamide as a carcinogen resulting from the petitioned
use of AAR, the agency used published data from a long-term rat
bioassay on acrylamide, conducted by Johnson et al., in addition to
unpublished data from this bioassay in the agency's files (Refs. 6 and
7). The authors of this bioassay reported that acrylamide administered
to rats via drinking water is associated with statistically significant
increased incidences of thyroid follicular adenomas and testicular
mesotheliomas in male rats, and of mammary tumors (adenomas or
adenocarcinomas, fibromas or fibroadenomas, adenocarcinomas alone),
central nervous system tumors (brain astrocytomas, brain or spinal cord
glial tumors), and uterine tumors (adenocarcinomas) in female rats.
Based on the agency's estimate that exposure to acrylamide will not
exceed 2 ng/p/d, FDA estimates that the upper-bound limit of lifetime
human risk from exposure to acrylamide from the petitioned use of the
subject additive is 2.2 x 10-8 or 22 in 1 billion (Ref. 8).
Considering that this estimated upper-bound risk is based on very
conservative assumptions, the agency believes that the probable
lifetime human risk would be significantly less than the estimated
upper-bound limit of lifetime human risk. Therefore, the agency
concludes that there is reasonable certainty that no harm from exposure
to acrylamide would result from the petitioned use of AAR.
B. Epichlorohydrin
FDA has estimated the exposure to epichlorohydrin from the
petitioned use of DEC to be 2.1 ng/p/d or 0.7 pptr of the daily diet
(Refs. 1 and 9). This estimate is conservative, as it does not account
for the removal of residual impurities, including epichlorohydrin,
during the processing of the crude HFCS.
The agency used data from a carcinogenesis bioassay conducted by
Konishi et al. (Ref. 10), on rats fed epichlorohydrin via their
drinking water, to estimate the upper-bound limit of lifetime human
risk from exposure to this chemical resulting from the petitioned use
of DEC. The authors reported that the test material caused
significantly increased incidence of stomach papillomas and carcinomas
in rats.
Based on the agency's estimate that exposure to epichlorohydrin
will not exceed 2.1 ng/p/d, FDA estimates that the upper-bound limit of
lifetime human risk from exposure to epichlorohydrin resulting from the
petitioned use of the subject additive is 9.5 x 10-11 or 95
in 1 trillion (Ref. 8). Considering that this upper-bound estimated
risk is based on very conservative assumptions, the agency believes
that the probable lifetime human risk would be significantly less than
the estimated upper-bound limit of lifetime human risk. Therefore, FDA
concludes that there is reasonable certainty that no harm from exposure
to epichlorohydrin would result from the petitioned use of DEC.
C. 1,3-Dichloro-2-propanol (DCP)
DCP is the product of epichlorohydrin degradation in water. The
current regulation for the use of DEC resin establishes a residual
limit for DCP at 1,000 ppm in the DEC resin (21 CFR 173.60 (b)(3)). The
agency has estimated that exposure to DCP from the petitioned use for
DEC will not exceed 210 ng/p/d (Refs. 1 and 9). This estimate is
conservative, as it does not account for the removal of residual
impurities, including DCP, during the processing of the crude HFCS.
The agency used data from a 1986 drinking water bioassay in rats
(Ref. 11) to estimate the worst case upper-bound lifetime cancer risk
from exposure to DCP from the petitioned use of DEC. This risk was
calculated as 1.2 x 10-7 or 12 in 100 million (Refs. 12 and
13). Considering that this upper-bound estimated risk is based on very
conservative assumptions, the agency believes that the probable
lifetime human risk would be significantly less than the upper-bound
limit of lifetime human risk. Therefore, FDA concludes that there is
reasonable certainty that no harm from exposure to DCP would result
from the petitioned use of DEC.
D. Need for Specifications
The agency also has considered whether specifications are necessary
to control the amount of acrylamide present as an impurity in AAR and
epichlorohydrin and DCP in DEC. The agency finds that specifications
are not necessary for the following reasons:
1. The agency would not expect these impurities to become
components of food at other than extremely low levels because of the
low levels at which acrylamide, epichlorohydrin, and DCP may be
expected to remain as impurities following production and purification
of the additives and HFCS, and
2. The upper-bound limits of lifetime human risk from exposure to
acrylamide, epichlorohydrin, and DCP are very low, 2.2 x
10-8, 9.5 x 10-11, and 1.2 x 10-7
respectively.
IV. Conclusions
FDA has evaluated data in the petition and other relevant material.
Based on this information, the agency concludes that: (1) The proposed
use of the additives as fixing agents in the immobilization of glucose
isomerase enzyme preparations is safe, (2) that the additives will
achieve their intended technical effect, and therefore, (3) the
regulations in Sec. 173.357 (21 CFR 173.357) should be amended as set
forth below.
In accordance with Sec. 171.1(h) (21 CFR 171.1(h)), the petition
and the
[[Page 42716]]
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. 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.
V. Environmental Impact
The agency has determined under 21 CFR 25.32(j) that this action is
of a type that individually or cumulatively does not have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
VI. 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.
VII. Objections
Any person who will be adversely affected by this regulation may at
any time file with the Dockets Management Branch (see ADDRESSES)
written objections by July 25, 2002. 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 are be submitted and are to 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.
VIII. References
The following references have been placed on display in the Dockets
Management Branch (see ADDRESSES) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
1. Memorandum dated November 22, 1989, from the Food and Color
Additives Review Section to the Direct Additives Branch, ``FAP
9A4175: Enzyme Bio-Systems Ltd. Dimethylamine-Epichlorohydrin Resin
(DEC) and Acrylic Acid-Acrylamide Resin (AAR) as Fixing Agents for
Glucose Isomerase Immobilized Enzyme Preparations. Submission of 9-
25-89.''
2. Memorandum dated August 17, 1998, from the Division of
Product Policy, Scientific Support Branch, Chemistry and
Environmental Review Team (CERT) to the Division of Petition
Control, ``FAP 9A4175 (MATS[numsign] 438)--Enzyme Bio-Systems Ltd.
Exposure to Acrylamide Monomer from the Use of Acrylic Acid-
Acrylamide Resin (AAR) as a Fixing Agent for Glucose Isomerase
Immobilized Enzyme Preparations. Division of Petition Control (DPC,
HFS-215) Verbal Request dated 8-4-98.''
3. Burek, J. D., R. R. Albee, J. E. Beyer, et al., ``Subchronic
Toxicity of Acrylamide Administered to Rats In the Drinking Water
Followed by Up to 144 Days of Recovery,'' Journal of Environmental
Pathology and Toxicology, 4:157-182, 1980.
4. Memorandum dated September 9, 1997, from the Division of
Health Effects Evaluation to the Division of Product Policy,
``Acrylamide, New Information and Re-evaluation of the Neurotoxicity
Potential and Tentative ADI of Acrylamide as a Migrant.''
5. Memorandum dated January 24, 2000, from the Division of
Health Effects Evaluation to the Division of Product Policy, ``Final
Safety Evaluation of Acrylamide-Acrylic Acid Resin (AAR) and
Dimethylamine-epichlorohydrin Resin (DEC) as Fixing Agents for
Immobilized Glucose Isomerase Used in Foods. Memo of Div. of Product
Manufacture and Use, Chemistry and Environmental Review Team (CERT)
4/28/99, Received 5/5/99. QRAC Concurrence of Estimation of the
Upper Bound Lifetime Risk from Residual Epichlorohydrin and
Acrylamide (S. Henry Memo Dated Dec. 20, 1999).''
6. Johnson, K. A., S. J. Gorzinski, K. M. Bodner, R. A.
Campbell, C. H. Wolf, M. A. Friedman, and R.W. Mast, ``Chronic
Toxicity and Oncogenicity Study on Acrylamide Incorporated in the
Drinking Water of Fischer 344 Rats,'' Toxicology and Applied
Pharmacology, 85:154-168, 1986.
7. Memorandum of Conference, FDA, CFSAN, Washington, DC Cancer
Assessment Committee Meeting on Acrylamide, February 13 and June 6,
1985, and May 31, 1996.
8. Memorandum dated May 7, 1999, from the Regulatory Policy
Branch to the Quantitative Risk Assessment Committee, ``Estimation
of the Upper-Bound Lifetime Risk from Residual Epichlorohydrin and
Acrylamide Monomers in Dimethylamine-Epichlorohydrin and Acrylic
Acid-Acrylamide Resins, Respectively, for Use as Fixing Agents in
Immobilizing Glucose Isomerase Enzyme Preparation: Use Requested in
Food Additive Petition No. 9A4175 from Enzymes Bio-Systems Ltd.''
9. Memorandum dated August 7, 1997, from the Division of Product
Policy to Division of Petition Control, ``FAPs 9A4175, 3B3677,
6B3940, 3B3696, 9B4131, 9B4132 and 9B4133. DPC Request to Identify
and Address Unresolved Issues in the Pending Acrylamide Petitions.''
10. Konishi, Y. et al., ``Forestomach Tumors Induced by Orally
Administered Epichlorohydrin in Male Wistar Rats,'' Gann, 71:922-
923, 1980.
11. Research and Consulting Co., AG, Project 017820, Report
Parts 1-4, February 24, 1986: 104-Week Chronic Toxicity and
Carcinogenicity Study with 1,3-Dichloropropan-2-ol in the Rats; Food
Master File 000543, Vol. 11.
12. Memorandum dated August 24, 1998, from the Executive
Secretary, Cancer Assessment Committee, to the Chairman, Cancer
Assessment Committee, ``FAP 9A4175: Worst-Case Cancer Risk
Assessment for 1,3-dichloropropanol (DCP).''
13. Memorandum dated March 25, 1999, from Division of Health
Effects Evaluation to the Executive Secretary, Cancer Assessment
Committee, ``Expedited Risk Assessment for 1,3-dichloropropanol Memo
of August 24, 1998. Accepting Risk Estimate for Regulation of FAP
9A4175.''
List of Subjects in 21 CFR Part 173
Food additives.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
173 is amended as follows:
PART 173--SECONDARY DIRECT FOOD ADDITIVES PERMITTED IN FOOD FOR
HUMAN CONSUMPTION
1. The authority citation for 21 CFR part 173 continues to read as
follows:
Authority: 21 U.S.C. 321, 342, 348.
2. Section 173.357 is amended in the table in paragraph (a)(2) by
alphabetically adding entries for ``Acrylamide-acrylic acid resin'' and
``Dimethylamine-epichlorohydrin resin'' to read as follows:
Sec. 173.357 Materials used as fixing agents in the immobilization of
enzyme preparations.
* * * * *
(a) * * *
(2) * * *
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Substances Limitations
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Acrylamide-acrylic acid resin: Complying May be used as a fixing
with Sec. 173.5(a)(1) and (b) of this material in the
chapter. immobilization of glucose
isomerase enzyme
preparations for use in the
manufacture of high fructose
corn syrup, in accordance
with Sec. 184.1372 of this
chapter.
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* * * * *
Dimethylamine-epichlorohydrin resin: May be used as a fixing
Complying with Sec. 173.60(a) and (b) material in the
of this chapter. immobilization of glucose
isomerase enzyme
preparations for use in the
manufacture of high fructose
corn syrup, in accordance
with Sec. 184.1372 of this
chapter.
* * * * *
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Dated: June 17, 2002.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-15901 Filed 6-24-02; 8:45 am]
BILLING CODE 4160-01-S