[Federal Register Volume 61, Number 28 (Friday, February 9, 1996)]
[Rules and Regulations]
[Pages 4871-4874]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-2747]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 173
[Docket No. 92F-0447]
Secondary Direct Food Additives Permitted in Food for Human
Consumption; Periodic Acid and Polyethylenimine
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 periodic acid (PA)
and polyethylenimine (PEI) as fixing agents for the immobilization of
glucoamylase enzyme preparations from Aspergillus niger for use in the
manufacture of beer. This action is in response to a petition filed by
Enzyme Bio-Systems, Ltd.
DATES: Effective February 9, 1996; written objections and requests for
a hearing by March 11, 1996.
ADDRESSES: Submit written objections to the Dockets Management Branch
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr.,
Rockville, MD 20857.-
FOR FURTHER INFORMATION CONTACT: Andrew D. Laumbach,- Center for Food
Safety and Applied Nutrition (HFS-217), Food and Drug Administration,
200 C St. SW., Washington, DC 20204, 202-418-3071.
SUPPLEMENTARY INFORMATION: In a notice published in the Federal
Register of December 1, 1993 (58 FR 63381), FDA announced that a food
additive petition (FAP 1A4288) had been filed by Enzyme Bio-Systems,
Ltd., 2600 Kennedy Dr., Beloit, WI 53511, proposing that the food
additive regulations be amended to provide for the safe use of periodic
acid and polyethyleneimine as fixing agents for immobilizing those
enzymes that are generally recognized as safe (GRAS) or approved as
food additives.
In a letter of February 2, 1994 (Ref. 1), the petition was amended
by the petitioner to provide for the use of PA and PEI as fixing agents
for the immobilization of glucoamylase enzyme preparations from A.
niger for use in the manufacture of light beer. The Bureau of Alcohol,
Tobacco, and Firearms, the Federal agency responsible for the
regulation of alcoholic beverages such as beer, has informed FDA that
the term ``light,'' with respect to the description of beer, is not
defined by regulation or any other regulatory standards (Ref. 2).
Accordingly, FDA has omitted the term ``light'' in the regulation
responding to this petition because there are no applicable Federal
standards defining ``light beer.''
Although the filing notice refers to polyethyleneimine as one of
the two petitioned additives under agency evaluation, it became
apparent during the review of the petition that the name of the
additive should be changed to be consistent with the name of the
substance that is currently listed in Sec. 173.357(a)(2) (21 CFR
173.357(a)(2)), ``polyethylenimine reaction product with 1,2-
dichloroethane.'' While the name of the additives differ, the additives
share the same Chemical Abstract Service (CAS) Registry Number (CAS
Reg. No. 68130-97-2) and are thus considered chemically identical by
the agency. The petitioner has agreed to the name change. Therefore,
the petitioned additive is identified as a PEI reaction product with
1,2-dichloroethane (DCE) in the regulation set forth below. However,
for purposes of discussion, this preamble will use the term
``polyethylenimine'' to refer to the additive, PEI reaction product
with 1,2-dichloroethane.
Glucoamylase enzyme preparation from A. niger is the substance
that is to be immobilized with the fixing agents set forth in the
regulation below; the regulatory status of that enzyme preparation is
not addressed by this action. The agency is, however, concurrently
evaluating this particular enzyme preparation, along with a variety of
other enzymes from other sources, in its review of petition GRASP
3G0016 (Docket No. 84G-0257) for the affirmation of the GRAS status of
certain enzymes. (Eight enzyme preparations included in GRASP 3G0016
were recently affirmed as GRAS (60 FR 32904, June 26, 1995).) The
petition GRASP 3G0016 contains published data and information to
support the view that the enzyme preparation glucoamylase from A. niger
has had a long history of use prior to 1958 in the preparation of food
as well as fermentable materials that are used in the production of
alcoholic beverages (Refs. 3 and 4). Further, FDA is not aware of any
data or information showing that glucoamylase from A. niger poses a
safety concern. Finally
[[Page 4872]]
FDA acknowledges that under the Federal Food, Drug, and Cosmetic Act
(the act), a food manufacturer may market a substance for use in food
on the basis of the manufacturer's independent determination that the
substance is GRAS and thus exempt from the definition of food additive
in section 201(s) of the act (21 U.S.C. 321(s)).
In this scientific and legal context, FDA believes that it is
appropriate to proceed with a final rule approving the use of PEI and
PA as fixing agents for immobilizing glucoamylase from A. niger for
use in the manufacture of beer even though the agency has not completed
the GRAS affirmation process for all of the enzymes that are the
subject of GRASP 3G0016, including glucoamylase enzyme preparation.
In its evaluation of PA and PEI for the proposed use, FDA reviewed
the safety of the additives and the chemical impurities that may be
present in the additives resulting from the manufacturing processes.
Although neither PA nor PEI has been shown to cause cancer, PEI may
contain minute amounts of unreacted ethylenimine (EI) and 1,2-
dichloroethane because these reactants are used in the manufacture of
the additive. EI and 1,2-dichloroethane have been shown to be
carcinogens in bioassays with mice and rats (Refs. 5, 6, and 7). The
presence of such impurities is not unique to this additive. Residual
amounts of reactants and manufacturing aids are commonly found as
contaminants in chemical products, including food additives.
I. Determination of Safety
Under section 409(c)(3)(A) of the act (21 U.S.C. 348(c)(3)(A)), the
so-called ``general safety clause,'' a food additive cannot be approved
for a particular use unless a fair evaluation of the data and
information 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 anticancer or Delaney clause (section 409(c)(3)(A)) of the act)
further provides that no food additive shall be deemed to be 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 constituents of the additive. That is, where an additive 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. (See Scott v. FDA, 728 F.2d 322 (6th Cir. 1984).)
II. Evaluation of Safety of Petitioned Use of the Additives
FDA estimates that the petitioned use of the additives PA and PEI
to fix glucoamylase enzyme preparations would result in mean exposures
to these additives of 0.7 micrograms per person per day (g/
person/day) for iodate, which is formed from the decomposition of PA
(Ref. 8), and no greater than 330 g/person/day for PEI (Ref.
9).
FDA does not ordinarily consider chronic toxicological testing to
be necessary to determine the safety of additives whose use will result
in such low exposure levels (Ref. 10), and the agency has not required
such testing here. The agency has reviewed the available toxicological
data from acute toxicity studies on the additives. No adverse effects
were reported in these studies (Ref. 11).
FDA has evaluated the safety of PEI under the general safety
clause, considering all available data and using risk assessment
procedures to estimate the upper-bound limit of risk presented by EI
and DCE that may be present as impurities in the additive. This risk
evaluation of EI and DCE 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 probable exposure to humans.
A. Ethylenimine (EI)
Using estimates of the average intake of beer, FDA estimates the
potential exposure to EI from the petitioned use of PEI as an
immobilizing agent for glucoamylase enzyme preparations from A. niger
used in the production of beer to be 0.33 nanograms (ng)/person/day
(Ref. 9). To estimate the risk from EI (Ref. 5), the agency used data
from a carcinogen bioassay with the B6C3F1 strain of mice using the
oral route of exposure. EI treatment caused an increased incidence of
both lung and liver tumors that were neoplastic (Ref. 5).
Based on a potential exposure of 0.33 ng/person/day, FDA estimates
that the upper-bound limit of individual lifetime risk from the
potential exposure to EI from the use of PEI is 1.2 x 10-7 , or
less than 1.2 in 10 million (Refs. 12 and 13). Because of the numerous
conservative assumptions used in calculating the exposure estimate,
actual lifetime averaged individual exposure to EI is expected to be
substantially less than the worst-case exposure, and therefore, the
calculated upper-bound limit of risk would be less. Thus, the agency
concludes that there is a reasonable certainty that no harm will result
from the proposed use of the additive as a result of exposure to EI.
B. 1,2-Dichloroethane (DCE)
Again, using estimates of average intake of beer, FDA estimates the
potential exposure to DCE to be 0.33 ng/person/day (Ref. 9). The agency
used data from two bioassays sponsored by the National Cancer Institute
to estimate risk; the bioassays showed that DCE is carcinogenic to mice
and rats at multiple tissue sites (Ref. 6). Based on the potential
exposure of 0.33 ng/person/day, FDA estimates that the upper-bound
limit of individual lifetime risk from the potential exposure to DCE
from the use of PEI is 6.4 x 10-11, or less than 6.4 in 100
billion (Refs. 12 and 13). Because of the numerous conservative
assumptions used in calculating this exposure estimate, actual lifetime
averaged individual exposure to DCE is expected to be substantially
less than the worst-case exposure, and therefore, the calculated upper-
bound limit of risk would be less. Thus, the agency concludes that
there is a reasonable certainty that no harm will result from the
proposed use of PEI as a result of exposure to DCE.
C. Need for Specifications
The agency has also considered whether specifications are necessary
to control the amount of EI and DCE impurities in PEI. The agency finds
that specifications for PEI are necessary, and that the specifications
in Sec. 173.357(a)(2) should be retained. The PA does not require
specifications for its use (Ref. 14) because it does not contain
impurities that need to be controlled.
III. Conclusions
FDA has evaluated data in the petition and other relevant material
and concludes that the proposed use of PA and PEI as fixing agents for
the immobilization of glucoamylase enzyme preparations from A. niger
used in the manufacture of beer is safe (Ref. 15). Based on this
information, the agency has also concluded that the additives will
function as intended. Therefore, Sec. 173.357(a)(2) should be amended
as set forth below.
FDA is also amending Sec. 173.357(a)(2) to revise the division name
and address listed in the regulation as a source of methods
incorporated by reference. The change results from a reorganization of
[[Page 4873]]
the Center for Food Safety and Applied Nutrition announced in a final
rule published in the Federal Register of April 1, 1993 (58 FR 17091).
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
In the notice of filing for this petition that published in the
Federal Register of December 1, 1993, FDA gave interested parties an
opportunity to submit comments on the petitioner's environmental
assessment by January 3, 1994, to the Dockets Management Branch
(address above). FDA received no comments in response to that notice.
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. Objections
Any person who will be adversely affected by this regulation may at
any time on or before March 11, 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.
VI. 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. Letter from McKenna & Cuneo to the Direct Additives Branch
(HFS-217), amending the filing of Food Additive Petition No. 1A4288,
February 2, 1994.
2. Memorandum from Wine and Beer Branch, Bureau of Alcohol,
Tobacco, and Firearms to the Direct Additives Branch (HFS-217),
regarding regulations for ``light'' beer, October 6, 1994.
3. Underkofler, L. A., R. R. Barton, and S. S. Rennert,
``Microbiological Process Report--Production of Microbial Enzymes
and their Applications,'' Applied Microbiology, 6:212-221, 1958.
4. Beckhorn, E. J., M. D. Labbee, and L. A. Underkofler,
``Production and Use of Microbial Enzymes for Food Processing,''
Journal of Agricultural Food Chemistry, 13:30-34, 1965.
5. Memorandum from the Quantitative Risk Assessment Committee to
the Office of Toxicological Sciences (HFS-100), concerning risk
estimate for ethyleneimine, August 22, 1985.
6. Memorandum from the Cancer Assessment Committee, Color and
Cosmetics Evaluation Branch (HFF-158) to Division of Food and Color
Additives (HFF-330), Preliminary Risk Assessment on 1,2-
Dichloroethane (DCE) Migrating from Food and Beverage Contact Paper,
June 23, 1982.
7. Memorandum from Quantitative Risk Assessment Committee to the
Office of Toxicological Sciences (HFF-100), Epichlorohydrin, 1,2-
Dichloroethane, and 2,4-Toluenediamine in Reverse Osmosis Membranes
(FAP 6B3955), February 2, 1988.
8. Memorandum from the Chemistry Review Branch (HFS-247) to the
Direct Additives Branch (HFS-217), concerning letter dated October
20, 1993, and submission dated October 27, 1993, from McKenna &
Cuneo, January 11, 1994.
9. Memorandum from the Chemistry Review Branch (HFS-247) to the
Direct Additives Branch (HFS-217), Enzyme Bio-Systems Ltd.,
Submission of September 12, 1991; February 17, 1993.
10. Kokoski, C. J., ``Regulatory Food Additive Toxicology'', in
Chemical Safety Regulation and Compliance, edited by Homburger, F.
and J. K. Marquis, S. Karger, New York, NY, pp. 24-33, 1985.
11. Memorandum from the Additive Evaluation Branch (HFF-158) to
the Direct Additives Branch (HFF-217), concerning evaluation of Food
Additive Petition No. 1A4288, February 25, 1992.
12. Memorandum from the Chemistry Review Branch (HFS-247) to the
Direct Additives Branch (HFS-217), Exposure estimate for QRAC
evaluation, February 8, 1994.
13. Memorandum from the Direct Additives Branch (HFS-217) to the
Quantitative Risk Assessment Committee (HFS-308), Estimation of the
upper-bound lifetime risk for ethyleneimine (EI) and 1,2-
dichlorethane (DCE) for uses requested in FAP 1A4288 (Enzyme Bio-
Systems Ltd.), April 15, 1994.
14. Memorandum from the Chemistry Review Branch (HFS-247) to the
Direct Additives Branch (HFS-217) concerning Food Additive Petition
No. 1A4288, April 5, 1994.-
15. Memorandum from the Additives Evaluation Branch No. 1 (HFS-
226) to the Direct Additives Branch (HFS-217), final evaluation
memorandum, May 31, 1994.
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: Secs. 201, 402, 409 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 321, 342, 348).
2. Section 173.357 is amended in the table in paragraph (a)(2)
under the headings ``Substances'' and ``Limitations'' by alphabetically
adding a new entry for ``periodic acid'' and by revising the entry for
``polyethylenimine reaction product with 1,2-dichloroethane'' to read
as follows:
Sec. 173.357 Materials used as fixing agents in the immobilization of
enzyme preparations.
* * * * *
(a) * * *
(2) * * *
[[Page 4874]]
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Substances Limitations
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*
Periodic acid (CAS Reg. No. 10450-60-9).
Polyethylenimine reaction product with 1,2-dichloroethane May be used as a fixing material in the
(CAS Reg.No. 68130-97-2) is the reaction product of immobilization of glucoamylase enzyme preparations
homopolymerization of ethylenimine in aqueous from Aspergillus niger for use in the manufacture
hydrochloric acid at 100 deg.C and of cross-linking with of beer.
1,2-dichloroethane. The finished polymer has an average May be used as a fixing material in the
molecular weight of 50,000 to 70,000 as determined by gel immobilization of:
permeation chromatography. The analytical method is 1. Glucose isomerase enzyme preparations for use in
entitled ``Methodology for Molecular Weight Detection of the manufacture of high fructose corn syrup, in
Polyethylenimine,'' which is incorporated by reference in accordance with Sec. 184.1372 of this chapter.
accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies 2. Glucoamylase enzyme preparations from
may be obtained from the Division of Petition Control, Aspergillus niger for use in the manufacture of
Center for Food Safety and Applied Nutrition (HFS-215), beer. Residual ethylenimine in the finished
200 C St. SW., Washington, DC 20204, and may be examined polyethylenimine polymer will be less than 1 part
at the Center for Food Safety and Applied Nutrition's per million as determined by gas chromatography-
Library, 200 C St. SW., rm. 3321, Washington, DC, or at mass spectrometry. The residual ethylenimine is
the Office of the Federal Register, 800 North Capitol St. determined by an analytical method entitled
NW., suite 700, Washington, DC. ``Methodology for Ethylenimine Detection in
Polyethylenimine,'' which is incorporated by
reference in accordance with 5 U.S.C. 552(a) and 1
CFR part 51. Residual 1,2-dichloroethane in the
finished polyethylenimine polymer will be less than
1 part per million as determined by gas
chromatography. The residual 1,2-dichloroethane is
determined by an analytical method entitled,
``Methodology for Ethylenedichloride Detection in
Polyethylenimine,'' which is incorporated by
reference in accordance with 5 U.S.C. 552(a) and 1
CFR part 51. Copies may be obtained from the
Division of Petition Control, Center for Food
Safety and Applied Nutrition (HFS-215), 200 C St.
SW., Washington, DC 20204, or may be examined at
the Center for Food Safety and Applied Nutrition's
Library, 200 C St. SW., rm. 3321, Washington, DC,
or the Office of the Federal Register, 800 North
Capitol St. NW., suite 700, Washington, DC.
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Dated: January 17, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-2747 Filed 2-8-96; 8:45 am]
BILLING CODE 4160-01-F
