[Federal Register Volume 67, Number 122 (Tuesday, June 25, 2002)]
[Rules and Regulations]
[Pages 42714-42717]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-15901]


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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) * * * 

------------------------------------------------------------------------
                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.
                  *        *        *        *        *
------------------------------------------------------------------------

* * * * *

    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