[Federal Register Volume 59, Number 24 (Friday, February 4, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-2474]
[[Page Unknown]]
[Federal Register: February 4, 1994]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
21 CFR Part 172
[Docket No. 92F-0055]
Food Additives Permitted for Direct Addition to Food for Human
Consumption; Dimethyl Dicarbonate
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 dimethyl
dicarbonate as a yeast inhibitor in ready-to-drink tea beverages. This
action is in response to a petition filed by Miles, Inc. (formerly
Mobay Corp.).
DATES: Effective February 4, 1994; written objections and requests for
a hearing by March 7, 1994.
ADDRESSES: Written objections may be sent to the Dockets Management
Branch (HFA-305), Food and Drug Administration, rm. 1-23, 12420
Parklawn Dr., Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Rosalie M. Angeles, 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:
I. Background
In a notice published in the Federal Register of March 10, 1992 (57
FR 8460), FDA announced that a food additive petition (FAP 2A4310) had
been filed by Miles, Inc., Mobay Rd., Pittsburgh, PA 15205-9741,
proposing that the food additive regulations in Sec. 172.133 Dimethyl
dicarbonate (21 CFR 172.133) be amended to provide for the safe use of
dimethyl dicarbonate as a yeast inhibitor in ready-to-drink tea
beverages.
As discussed in more detail below, FDA has evaluated data in the
petition and other relevant material and concludes that the proposed
use of dimethyl dicarbonate (DMDC) in ready-to-drink tea beverages is
safe.
II. 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 approved 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 anticancer or Delaney clause of the Food Additives Amendment
(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, not to constituents of the
additive. That is, where an additive itself has not been shown to cause
cancer, but contains a carcinogenic impurity, such 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 Dimethyl Dicarbonate in Ready-to-Drink Tea Beverages
Dimethyl dicarbonate is currently permitted as a yeast inhibitor in
wine and wine substitutes (dealcoholized wine and low alcohol wine)
under Sec. 172.133. In the final rules establishing this regulation (53
FR 41325, October 21, 1988; and 58 FR 6088, January 26, 1993) the
agency concluded that, because dimethyl dicarbonate decomposes almost
immediately after addition to beverages, there will be virtually no
exposure of the consumer to the additive from its use in wine and wine
substitutes.
Data submitted in the petition concerning the use of the additive
in tea beverages are consistent with these findings in wine and wine
substitutes. Specifically, data from a study on the hydrolysis of
dimethyl dicarbonate in tea showed no detectable amount of the additive
after 4 hours (limit of analytical detectability = 40 parts per billion
(ppb)) (Ref. 1). Based on these data, the agency concludes that there
will be virtually no consumer exposure to dimethyl dicarbonate from the
use of the additive in ready-to-drink tea beverages. Therefore, FDA
concludes that dimethyl dicarbonate itself presents no hazard to the
consumer.
IV. Safety of Substances That May Be Present in Tea Beverages Due
to the Use of the Additive
Dimethyl dicarbonate is unstable in aqueous solution and breaks
down almost immediately after addition to beverages. In aqueous
liquids, the principal breakdown products are methanol and carbon
dioxide. Methyl ethyl carbonate, as well as carbomethoxy amino- and
hydroxy-adducts of amines, sugars, and fruit acids may also be formed
in minor amounts. Dimethyl carbonate is present as an impurity in
dimethyl dicarbonate. Dimethyl dicarbonate also may react with traces
of ammonia or ammonium ions to form trace quantities of methyl
carbamate, a compound that has been shown to cause cancer in laboratory
animals (Ref. 2).
In approving the use of dimethyl dicarbonate in wine and wine
substitutes, the agency, in accordance with 21 CFR 171.1, reviewed the
safety not only of dimethyl dicarbonate but also of its decomposition
products in aqueous beverages. The same analysis from that review was
applied by the agency in reviewing the petitioned use of dimethyl
dicarbonate in ready-to-drink tea beverages. The results of the
agency's analysis of the additive's use in wine and wine substitutes
were discussed extensively in the Federal Register of October 21, 1988,
and January 26, 1993, final rules, which are referenced; that analysis
applies equally to the evaluation of the petitioned use of DMDC.
Aspects of the safety evaluation of the decompostion products that may
result from the use of dimethyl dicarbonate in ready-to-drink tea
beverages that were not discussed previously are discussed below.
A. Minor Reaction Products
In its previous evaluation of the safety of minor breakdown
products of dimethyl dicarbonate in aqueous solutions, the agency
concluded that there is no evidence of added risk from exposure to
those minor products. For this petition, the agency also evaluated
results from an acute toxicity study on a series of putative adducts
(N-carbomethoxy conjugates of trigallic acid, glycine, glutamic acid,
alanine, proline, asparagine, cysteine, phenylalanine, arginine,
leucine, and monocysteine) that may be formed by dimethyl dicarbonate
when added to ready-to-drink tea beverages. Results of the study showed
that LD50 for each of the adducts in mice or rats ranged between
4,600 and >15,000 milligrams per kilogram body weight (mg/kg body
weight), thereby indicating the low order of acute toxicity of those
substances (Ref. 3).
B. Methanol
FDA previously estimated that the total human exposure to methanol
from consumption of food that naturally contains methanol and of wine
or wine substitutes that are treated with dimethyl dicarbonate to be 50
to 60 mg per person per day (mg/person/day) (58 FR 6088). The tolerable
(safe) level for methanol is 7.1 to 8.4 mg/kg body weight (426 to 504
mg/person/day for a 60-kg adult) based on reports of studies in human
subjects (Ref. 4). The agency estimates that the methanol exposure from
the petitioned use of dimethyl dicarbonate in ready-to-drink tea would
be 40 mg/person/day at tea intake of 332 grams(g)/person/day (90th
percentile) (Ref. 1). This would increase the human exposure to
methanol to 90 to 100 mg/person/day (to approximately one-fifth of the
tolerable safe level). The agency, therefore, concludes that there is
an adequate margin of safety between the methanol consumption from the
use of dimethyl dicarbonate and the amount of methanol that can be
safely ingested (Ref. 4).
C. Methyl Carbamate
Methyl carbamate, a carcinogen, was detected in wines treated with
dimethyl dicarbonate; based on a quantitative risk assessment, the
agency concluded that there was a reasonable certainty of no harm from
exposure to methyl carbamate in wines and wine substitutes (58 FR 6088
at 6090).
Methyl carbamate was not detected in dimethyl dicarbonate-treated
ready-to-drink tea, using an analytical method with a limit of
detection of 5 ppb. Assuming that methyl carbamate could be present at
2.5 ppb (one-half the limit of detection) and using an estimated value
for intake of tea beverages (332 g/person/day (90th percentile)), FDA
estimates that the exposure to methyl carbamate from the petitioned use
of dimethyl dicarbonate would be no more than 0.8 microgram/person/day
(Ref. 1) for individuals consuming ready-to-drink tea at the 90th
percentile level. Using the same principles and quantitative risk
assessment procedure that were applied to the wine and wine
substitutes, as discussed in the Federal Register of October 21, 1988,
and January 26, 1993, final rules, and the exposure to methyl carbamate
estimated above, FDA estimates that the upper-bound limit of individual
lifetime risk from potential exposure to methyl carbamate from the use
of dimethyl dicarbonate in ready-to-drink tea is 7.8 x 10-9, or
less than 1 in 128 million (Refs. 3, 5, and 6).
Therefore, the agency concludes that there is a reasonable
certainty of no harm from the exposure to methyl carbamate that may
result from the use of up to 250 ppm of dimethyl dicarbonate in ready-
to-drink tea beverages.
D. Conclusion On Safety
FDA has evaluated all of the data in the petition pertaining to the
use of dimethyl dicarbonate in ready-to-drink tea beverages and
concludes that the additive is safe for its proposed use.
To ensure the safe use of the additive in ready-to-drink tea
beverages, FDA, under 21 U.S.C. 348(c)(1)(A), is amending
Sec. 172.133(c)(2) to require directions on the food additive label
limiting the level of use of the additive in tea beverages to 250 ppm.
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 March 7, 1994, 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 from the Food and Color Additives Review Section
to the Direct Additives Branch, ``FAP 2A4310: Mobay Corp. Dimethyl
Dicarbonate (DMDC) for Use in Ready-to-Drink Tea Beverages.
Submission of 12-20-91,'' dated July 29, 1992.
2. NTP Technical Report on the Toxicology and Carcinogenesis
Studies of Methyl Carbamate in F344/N Rats and B6C3F1 Mice, NTP,
U.S. Department of Health and Human Services, Report No. 328, 1986.
3. Memorandum from the Additives Evaluation Branch to the Direct
Additives Branch, ``Dimethyl Dicarbonate as a Yeast Inhibitor in
Ready-to-Drink Tea Beverages at levels up to 250 ppm. FCARS memo
dated July 29, 1992,'' dated September 3, 1992.
4. Memorandum from the Standards and Monitoring Branch to the
Division of Regulatory Guidance, ``Methanol in Brandy,'' dated
August 3, 1989.
5. Memorandum from the Additives Evaluation Branch to the Direct
Additives Branch, ``Memo of the Quantitative Risk Assessment
Committee, Nov. 16, 1992, and Final Toxicological Evaluation of
Dimethyl Dicarbonate (DMDC) for Use in Ready-to-Drink (RTD) Tea
Beverages,'' dated January 4, 1993.
6. Report of the Quantitative Risk Assessment Committee,
``Dimethyl Dicarbonate (DMDC) for Use in Ready-to-Drink Tea
Beverages. FAP 2A4310 (Mobay Corp.),'' dated November 16, 1992.
List of Subjects in 21 CFR Part 172
Food additives, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
172 is amended as follows:
PART 172--FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR
HUMAN CONSUMPTION
1. The authority citation for 21 CFR part 172 continues to read as
follows:
Authority: Secs. 201, 401, 402, 409, 701, 721 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 341, 342, 348, 371,
379e).
2. Section 172.133 is amended by revising the introductory text and
paragraphs (b) and (c)(2) to read as follows:
Sec. 172.133 Dimethyl dicarbonate.
Dimethyl dicarbonate (CAS Reg. No. 4525-33-1) may be safely used in
food in accordance with the following prescribed conditions:
* * * * *
(b) The additive is used or intended for use as follows:
(1) Inhibitor of yeast in wine, dealcoholized wine, and low alcohol
wine, under normal circumstances of bottling where the viable yeast
count has been reduced to 500 per milliliter or less by current good
manufacturing practices such as flash pasteurization or filtration. The
additive may be added to wine, dealcoholized wine, or low alcohol wine
in an amount not to exceed 200 parts per million (ppm).
(2) Inhibitor of yeast in ready-to-drink teas, under normal
circumstances of bottling or canning where the viable yeast count has
been reduced to 500 per milliliter or less by current good
manufacturing practices such as heat treatment, sterile filtration, or
both. The additive may be added to teas in an amount not to exceed 250
ppm.
(c) * * *
(2) Directions to provide that not more than 200 ppm of dimethyl
dicarbonate will be added to the wine, dealcoholized wine, or low
alcohol wine and not more than 250 ppm of dimethyl dicarbonate will be
added to the ready-to-drink tea.
* * * * *
Dated: January 25, 1994.
Michael R. Taylor,
Deputy Commissioner for Policy.
[FR Doc. 94-2474 Filed 2-3-94; 8:45 am]
BILLING CODE 4160-01-F