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CFSAN/Office of Food Additive Safety
March 16, 2006
Mr. Eric F. Greenberg
Eric F. Greenberg, P.C.
3500 Three First National Plaza
Re: GRAS Notice No. GRN 000180
Dear Mr. Greenberg:
The Food and Drug Administration (FDA) is responding to the notice, dated August 10, 2005, that you submitted on behalf of Mitsubishi-Kagaku Foods Corporation (Mitsubishi) in accordance with the agency's proposed regulation, proposed 21 CFR 170.36 (62 FR 18938; April 17, 1997; Substances Generally Recognized as Safe (GRAS); the GRAS proposal). FDA received the notice on August 11, 2005, filed it on August 16, 2005, and designated it as GRAS Notice No. GRN 000180. Mitsubishi also submitted additional information on November 18, 2005, January 6, 2006, and January 30, 2006.
The subject of the notice is volatile oil of mustard (VOM). Mitsubishi refers to the substance as allyl isothiocyanate (AIT) and considers AIT to be synonymous with VOM. For the purpose of this letter, FDA describes the subject of the notice as "volatile oil of mustard (Brassica spp.)" or "VOM." FDA uses the term "allyl isothiocyanate" or "AIT" to denote the major chemical component of VOM. The notice informs FDA of the view of Mitsubishi that VOM is GRAS, through scientific procedures, for use as a shelf-life extension agent or anti-spoilage agent in all foods packaged in polymers, at levels of 30-50 parts per million (ppm) (equivalent to 122-203 micrograms per Liter (µg/L)(1)) of VOM in air within a food package.
Mitsubishi states that the ingredient that is the subject of GRN 000180 is the same substance as the subject of an earlier GRAS notice for volatile oil of mustard (Brassica spp.), GRN 000133, submitted by Carex, Inc. (Carex). In response to GRN 000133, FDA issued a "no questions" letter on January 5, 2004. Mitsubishi states in GRN 000180 that the assets of Carex are now owned by Mitsubishi. Mitsubishi proposes to expand the list of the foods categories that would be packaged in an atmosphere containing VOM.
As part of its notice, Mitsubishi includes a signed statement of a panel of individuals (Mitsubishi's GRAS panel) who evaluated the data and information that are the basis for Mitsubishi's GRAS determination. Mitsubishi considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Mitsubishi's GRAS panel agrees with Mitsubishi's conclusion that the intended use of VOM is GRAS.
Mitsubishi provides information about the chemical identity and quantitative composition of VOM. The substance is derived from seeds of brown mustard and contains predominantly AIT (greater than 93 percent). AIT has the empirical formula C4H5NS with a molecular weight of 99.16. The Chemical Abstracts Service Registry Number (CAS Reg. No.) for AIT is 57-06-7. Mitsubishi notes its method of manufacture for VOM is the same as Carex described in GRN 000133. Mitsubishi states that VOM meets the specifications of the Food Chemicals Codex (4th edition).(2)
Mitsubishi proposes to use VOM for shelf-life extension or anti-spoilage protection of all foods packaged in polymers, which is broadly interpreted to include plastic and paperboard packaging. Mitsubishi notes that VOM may be used in foods that are packaged for use in the home, in food service establishments, or in farm fields for packing of raw agricultural commodities. VOM is incorporated into a food preservation system that releases the substance into airspace within storage bags and other containers. Mitsubishi states that VOM's ability to retard the growth of a wide range of common bacteria, fungi, molds and yeast has been well established and was summarized in GRN 000133. Because fully aerobic conditions are maintained under the intended conditions of use, Mitsubishi considers that its intended use of VOM will not increase the risk of outgrowth of Clostridium botulinum.
Mitsubishi describes two delivery technologies, each delivering similar levels of VOM (122-203 µg/L) into the air within the atmosphere of the food container. In the first method, a patch, made of polyethylene (or other conventional polymer) and containing VOM at a specified level (up to 5.4 mg VOM ), will be affixed to a flexible polymer by means of an adhesive or by heat-sealing. Mitsubishi states that the adhesive will comply with FDA's regulations concerning adhesive components (21 CFR 175.105). In the second method, the VOM will be contained within layers of flexible film. In either method, the VOM will be maintained within microcapsules that dissolve when the humidity within the package reaches 70% or above, thereby releasing the VOM. Small amounts of VOM may deposit on the surface of the food or be absorbed into the food item. If the VOM is absorbed by the food or escapes through the packaging material, then the patch will release more VOM in order to maintain a steady state concentration of 122-203 µg/L in the packaging atmosphere. According to Mitsubishi, the proposed use of VOM is self-limiting and below that at which organoleptic changes occur.
Mitsubishi describes a generally available review, by the Select Committee on GRAS Substances (the Select Committee),(3) to support its view that VOM is GRAS for use as a shelf-life extension agent or anti-spoilage agent in foods. In a 1975 report, the Select Committee concluded that there was no evidence in the available information on allyl isothiocyanate and brown mustard that demonstrated, or suggested reasonable grounds to suspect, a hazard to the public when consumed at levels that were then current or that might reasonably be expected in the future. Mitsubishi also describes published studies, and generally available reports by the International Agency for Research on Cancer (IARC), that discuss limited evidence for the carcinogenicity of AIT in experimental animals. Mitsubishi discusses several of the studies relevant to this issue and provides its reasons for concluding that AIT is unlikely to be a human carcinogen. Mitsubishi notes that there is general recognition of the safety of VOM at current exposure levels in the human diet through a variety of foods and food ingredients, including cruciferous vegetables, mustard and other common food items. Mitsubishi states that the proposed anti-spoilage uses of VOM would add a small increment to the existing exposure to AIT, and that the resultant cumulative intakes are safe. Mitsubishi concludes that use of VOM as a shelf-life extension or anti-spoilage agent in packaged foods is GRAS.
Consultation with USDA
During its evaluation of GRN 000180, FDA consulted with the Labeling and Consumer Protection Staff of the Food Safety and Inspection Service of the United States Department of Agriculture (USDA). Under the Federal Meat Inspection Act and the Poultry Products Inspection Act, FSIS is responsible for determining the efficacy and suitability of food ingredients and additives in meat and poultry products as well as prescribing safe conditions of use. Suitability relates to the effectiveness of the ingredient in performing the intended purpose of use and the assurance that the conditions of use will not result in an adulterated product, or one that misleads consumers.
In correspondence with FDA, FSIS stated that Mitsubishi's GRAS notice was incomplete in its original submission. FSIS requested that FDA advise Mitsubishi to seek regulatory guidance from FSIS, Labeling and Consumer Protection Staff, about the use of VOM in meat and poultry products. Mitsubishi should direct such an inquiry to Dr. Robert Post, Director, Labeling and Consumer Protection Staff, Office of Policy, Program, and Employee Development, Food Safety and Inspection Service, 1400 Independence Ave., S.W., Suite 602, Annex, Washington, DC 20250-3700. The telephone number for that office is (202) 205-0279 and the telefax number is (202) 205-3625.
Standards of Identity
In the notice, Mitsubishi states its intention to use VOM in several food categories, including foods for which standards of identity exist in Title 21 of the Code of Federal Regulations. We note that an ingredient that is lawfully added to food products may be used in a standardized food only if it is permitted by the applicable standard of identity.
Based on the information provided by Mitsubishi, as well as other information available to FDA, the agency has no questions at this time regarding Mitsubishi's conclusion that VOM is GRAS under the intended conditions of use. The agency has not, however, made its own determination regarding the GRAS status of the subject use of VOM. As always, it is the continuing responsibility of Mitsubishi to ensure that food ingredients that the firm markets are safe, and are otherwise in compliance with all applicable legal and regulatory requirements.
In accordance with proposed 21 CFR 170.36(f), a copy of the text of this letter, as well as a copy of the information in your notice that conforms to the information in proposed 21 CFR 170.36(c)(1), is available for public review and copying on the homepage of the Office of Food Additive Safety (on the Internet at http://www.cfsan.fda.gov/~lrd/foodadd.html).
Laura M. Tarantino, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
cc: Dr. Robert Post, Director
Labeling and Consumer Protection Staff
Office of Policy, Program and Employee Development
Food Safety and Inspection Service
1400 Independence Ave., SW, Suite 602, Annex
Washington, DC 20250-3700
(1)FDA calculated the intended use levels, expressed by the notifier in ppm units, in units of µg/L VOM in air based on the conversion factor for AIT cited in a 1999 International Agency for Research on Cancer (IARC) review: mg/m3 = 4.06 x ppm.
(2)FDA notes that the FCC (5th edition, unchanged from 4th edition) lists two Brassica spp. (Brassica nigra and Brassica juncea) as sources of mustard oil. FCC specifications for mustard oil include the following: not less than 93% as C3H5NCS (AIT), refractive index (between 1.524 and 1.534 at 20 degrees Celsius), and specific gravity (between 1.008 and 1.019 at 25 degrees Celsius). Mitsubishi's specification for specific gravity (between 1.014 and 1.022 at 15 degrees Celsius) differs slightly from that of the FCC.
(3)Several years ago, FDA contracted with the Life Sciences Research Office (LSRO) of the Federation of American Societies for Experimental Biology as part of its comprehensive review of GRAS and prior sanctioned food ingredients. To aid in that review, LSRO established the Select Committee on GRAS Substances.