[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