[Federal Register Volume 59, Number 138 (Wednesday, July 20, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-17577]
[[Page Unknown]]
[Federal Register: July 20, 1994]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 173
[Docket No. 78G-0027]
Secondary Direct Food Additives Permitted in Food for Human
Consumption; Cellulose Triacetate
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending its food
additive regulations to provide for the safe use of cellulose
triacetate as an immobilizing agent for lactase for use in reducing the
lactose content of milk. This action is in response to a petition filed
by Vitenco, Inc.
DATES: Effective July 20, 1994; written objections and requests for a
hearing by August 19, 1994.
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: F. Owen Fields, Center for Food Safety
and Applied Nutrition (HFS-207), Food and Drug Administration, 200 C
St. SW., Washington, DC 20204, 202-254-9528.
SUPPLEMENTARY INFORMATION: In a notice published in the Federal
Register of March 17, 1978 (43 FR 11266), FDA announced that a
generally recognized as safe (GRAS) affirmation petition (GRASP 7G0088)
had been filed by Vitenco, Inc., 594 Marett Rd., Lexington, MA 02173,
requesting that lactase from Kluyveromyces (Saccharomyces) lactis
entrapped in cellulose triacetate fibers be affirmed as GRAS for use in
reducing the lactose content of milk. Subsequent to the filing of this
petition, FDA affirmed, in response to a separate petition (GRASP
6G0077), that lactase enzyme from K. lactis is GRAS for this use (21
CFR 184.1388) (49 FR 47384 at 47387, December 4, 1984). Therefore, this
document deals only with the use of cellulose triacetate as an
immobilizing agent and with any potential contaminants that might be
introduced into food from this use.
Although the information submitted in GRASP 7G0088 allows the
agency to conclude that the use of cellulose triacetate as an
immobilizing agent is safe, the petition did not establish that the
critical data are generally available as required by 21 CFR 170.30(b).
Consequently, the agency has evaluated those portions of the petition
that relate to cellulose triacetate as a food additive (rather than as
a GRAS affirmation) petition and is issuing this decision in accordance
with 21 CFR 170.38(c)(1).
I. Determination of Safety
Under section 409(c)(3)(A) of the Federal Food, Drug, and Cosmetic
Act (the act) (21 U.S.C. 348(c)(3)(A)), the so-called ``general safety
clause,'' a food additive cannot be listed for a particular use unless
a fair evaluation of the evidence 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 Delaney anticancer provision of the general safety clause of
the act (section 409(c)(3)(A)) further 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 constituents of 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 (see Scott v. FDA, 728 F.2d 322 (6th
Cir. 1984)).
II. Evaluation of Safety of the Petitioned Use of the Additive
The requested use of cellulose triacetate is as an immobilizing
agent for the enzyme lactase in the production of reduced lactose milk.
Cellulose triacetate containing physically entrapped lactase enzyme is
added to milk that is to be treated; enzymatic digestion of lactose is
allowed to occur; and the immobilizing agent and entrapped enzyme are
then quantitatively removed from the treated milk. Data submitted by
the petitioner demonstrate that when cellulose triacetate is used as an
immobilizing agent, it does not affect the milk in which it is used in
any way. The data in the petition also demonstrate that no detectable
cellulose triacetate is present in the final product intended for human
consumption. Based on these factors, FDA concludes that the ingredient
itself is safe under these conditions of use.
FDA, in its evaluation of the safety of this additive, has reviewed
not only the safety of the additive itself but also the safety of the
chemical impurities that may be present in the additive from the
manufacturing process. Residual amounts of reactants and manufacturing
aids are commonly found as contaminants in chemical products, including
food additives.
Methylene chloride is used as a solvent in the initial stages of
manufacture of cellulose triacetate-immobilized lactase. Subsequent to
the use of methylene chloride, the resultant fibers are completely
dried to eliminate any remaining volatile contaminants (such as
residual methylene chloride). Furthermore, before it is used in food,
the product is washed several times to ensure removal of any such
residual contaminants. Data submitted by the petitioner demonstrate
that methylene chloride could not be detected in the final product
immediately prior to its use in food at a detection limit of 0.5 parts
per million (ppm).
Nevertheless, the agency has used risk assessment procedures to
estimate the upper-bound risk presented by methylene chloride, a
carcinogenic chemical, that may be present as an impurity in the
additive. This risk evaluation has two aspects: (1) Assessment of the
hypothetical worst-case exposure to the impurity from the proposed use
of the additive; and (2) extrapolation of the risk observed in the
animal bioassays to the conditions of hypothetical worst-case human
exposure.
FDA has estimated the hypothetical worst-case exposure to methylene
chloride from the proposed use to be 6.0 nanograms per person per day
(ng/p/day) (Ref. 1). This estimate is based on the assumption that
methylene chloride is present in the additive at its detection limit,
although it was not actually detected in any of the samples tested.
Using risk assessment procedures, FDA used data from the National
Toxicology Program report (Ref. 2) of a bioassay on methylene chloride
to calculate the potency, or unit risk, from exposure to this chemical
(Ref. 3). The results of the bioassay on methylene chloride
demonstrated that the material was carcinogenic for mice under the
conditions of the study. The test material induced benign and malignant
neoplasms in both the liver and lung of both sexes when administered by
the inhalation route.
The agency also evaluated data from a second study in mice of the
same strain as used in the inhalation study. In this study, methylene
chloride was administered in the drinking water of the mice (Ref. 4).
In this second study, there was no significant increase in the
incidence of neoplasms at any site examined. However, assuming that
methylene chloride would induce neoplasia at a dose just above the
highest level tested in the drinking water study, a maximum potency can
be estimated. This estimate is approximately the same as the potency
calculated from the data of the inhalation study, providing confidence
that using the inhalation study for upper bound risk assessment is not
likely to underestimate any potential risk due to ingested methylene
chloride (Ref. 3).
Based on a calculated hypothetical worst-case potential exposure of
6.0 ng/p/day, FDA estimates that the upper-bound limit of individual
lifetime risk from the potential exposure to methylene chloride
resulting from the use of cellulose triacetate as an immobilizing agent
in the production of reduced lactose milk to be 4.4x10-11, or
approximately 4 in 100 billion (Ref. 5). Because there is no evidence
to suggest, or any reason to believe, that methylene chloride will be
present in the final product at the assumed level, the calculated
estimate of the upper-bound limit of risk is likely to be substantially
higher than any actual risk. Thus, the agency concludes that there is a
reasonable certainty of no harm from the exposure to methylene chloride
that might result from the proposed use of cellulose triacetate as an
immobilizing agent in the production of reduced lactose milk.
III. Conclusion on Safety
Having evaluated data in the petition and other relevant material,
the agency concludes that the proposed use of the food additive is
safe, and that the regulations in Sec. 173.357 (21 CFR 173.357) should
be amended as set forth below.
The agency has considered whether a specification is necessary to
control the amount of methylene chloride in the food additive. The
agency finds that a specification is not necessary for the following
reasons: (1) The steps utilized in the manufacture of cellulose
triacetate that are intended to remove contaminants such as methylene
chloride (drying to completion and washing of the resin to remove
volatile and nonvolatile components, respectively, either of which
could interfere with the intended enzymatic reaction) are a necessary
part of the manufacturing process. Therefore, the agency would not
expect this impurity to become a component of food at other than
extremely small levels; (2) when the additive is manufactured under
these conditions, methylene chloride could not be demonstrated to be
present in the additive at a level of detection of 0.5 ppm; and (3) the
upper-bound limit of lifetime risk from exposure to this impurity, even
when calculated by using several worst-case assumptions, is extremely
low, less than 4.4 in 100 billion.
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.
IV. Environmental Impact
The agency has carefully considered the potential environmental
effects of this action and 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 August 19, 1994, file with the Dockets Management
Branch (address above) written objections thereto. Each objection shall
be separately numbered, and each numbered objection shall specify the
particular 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. Memorandum from Gregory Cramer, Regulatory Food Chemistry
Branch, to L. Lin, Direct Additives Branch, dated July 7, 1986.
2. ``Technical Report on the Toxicology and Carcinogenesis
Studies of Dichloromethane (Methylene Chloride) in F344/N Rats and
B6C3F1 Mice,'' NTP Draft Report, NTP-TR-306, National Institute of
Health Publication No. l 85-2562, 1985.
3. Memorandum from the Quantitative Risk Assessment Committee,
dated November 15, 1985.
4. National Coffee Association, ``24-Month Oncogenicity Study of
Methylene Chloride in Mice--Final Report,'' Hazelton Laboratories
America, Inc., Vienna, VA, November 30, 1983.
5. Memorandum from the Quantitative Risk Assessment Committee
dated October 30, 1992.
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) by
alphabetically adding a new entry under the headings ``Substances'' and
``Limitations'' 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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Cellulose triacetate................. May be used as a fixing material
in the immobilization of lactase
for use in reducing the lactose
content of milk.
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Dated: July 13, 1994.
Michael R. Taylor,
Deputy Commissioner for Policy.
[FR Doc. 94-17577 Filed 7-19-94; 8:45 am]
BILLING CODE 4160-01-F