Agency Response Letter
GRAS Notice No. GRN 000133

Dr. John A. Todhunter
SRS International Corporation
1901 L Street, N.W.
Washington, D.C.
20036

Re: GRAS Notice No. GRN 000133

Dear Dr. Todhunter:

The Food and Drug Administration (FDA) is responding to the notice, dated June 27, 2003, that you submitted on behalf of Carex, Inc. (Carex) 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 June 30, 2003, filed it on July 10, 2003, and designated it as GRAS Notice No. GRN 000133.

The subject of the notice is volatile oil of mustard (Brassica spp.). For the purpose of this letter, FDA refers to volatile oil of mustard (Brassica spp.) using the abbreviation "VOM." The notice informs FDA of the view of Carex that VOM is GRAS, through scientific procedures, for use as a shelf-life extension agent or anti-spoilage agent in meat, fish, shellfish, and poultry products and in baked pies at levels that would typically be 150 micrograms per liter of air in a food container system.

Carex provides information about the chemical identity and composition of VOM. The substance is derived from the seeds of brown mustard (Brassica juncea) and contains predominantly allyl isothiocyanate (AIT) (greater than or equal to 93 percent). AIT has the empirical formula C₄H₅NS with a molecular weight of 99. The Chemical Abstract Service Registry Number (CAS Reg. No.) for AIT is 57-06-7.

Carex describes its method of manufacture for VOM in accordance with current international hygienic standards and current good manufacturing practices. Brown mustard seeds are pressed to remove non-volatile oils. The residue of pressed seeds is macerated with warm, deionized water and allowed to stand for one hour, releasing sinigrin (a beta-glucopyranoside) from the seed and hydrolyzing it to AIT by the action of an endogenous enzyme (myrosinase). The macerate is then steam distilled to yield the volatile fraction.

Carex provides specifications for food-grade VOM, citing the Food Chemicals Codex (FCC) (but without specifying the edition). Carex states that its food grade VOM will contain a minimum of 93 percent allyl isothiocyanate and cites specifications for arsenic, heavy metals, and phenols. Carex's specification for the minimum percentage of allyl isothiocyanate is in compliance with both the 4th edition of FCC and the 5th edition of FCC. Carex also provides quality control specifications for specific gravity (between 1.014 and 1.022 at 15 degrees Celsius) and for refractive index (between 1.523 and 1.529 at 20 degrees Celsius).⁽¹⁾

Carex proposes to use VOM as a shelf-life extension agent or anti-spoilage agent in meat, fish, shellfish, and poultry products and in baked pies at levels that would typically be 150 micrograms per liter of air in a food container system. Carex describes two methods by which VOM would be applied to food in packages or display cases using a gas-permeable matrix to contain the VOM. In the first method, VOM would be incorporated into one of the layers (i.e., the adhesive or structural layer) of a plastic film, paper tape, or labeling film; the film would either be affixed inside a package or display case or used as a film wrap for food. In the second method, VOM would be impregnated into a "packet" of cellulose beads and enclosed within a gas permeable multilayer film container. In either method, the VOM-containing matrix generates and sustains the desired VOM air concentration inside the packaging or display case. Because fully aerobic conditions are maintained under the intended conditions of use, Carex considers that its intended use of VOM will not increase the risk of outgrowth of anaerobic pathogens such as C. botulinum.²

Carex notes that oil of mustard (Brassica spp.) is listed as GRAS for its intended use in food when used at levels that do not exceed good manufacturing practices (21 CFR 182.20). In a meeting on May 16, 2003, between representatives of FDA and representatives of Carex, FDA and Carex discussed FDA's view that oil of mustard has historically been used primarily as a flavoring agent. Carex provides data to support its estimates that the levels of VOM in food products that are packaged with VOM would be below those used for flavoring and considers that the flavor or odor of VOM would make the intended use of VOM self-limiting.

Carex describes a generally available review, by the Select Committee on GRAS Substances (the Select Committee)³, that Carex considers to be consistent with its view that VOM is GRAS as a shelf-life extension agent or as an anti-spoilage agent. 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. Carex 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. Although Carex discusses several of the studies in some detail, and provides its reasons for concluding that AIT is unlikely to be a human carcinogen, Carex largely relies on the 1975 report by the Select Committee, coupled with its estimate that the levels of VOM in food products that are packaged in a VOM-containing atmosphere would be below those used for flavoring, to conclude that VOM is GRAS as a shelf-life extension agent or as an anti-spoilage agent.

Use in Meat and Poultry Products

During its evaluation of GRN 000133, FDA consulted with the Labeling and Consumer Protection Staff of the Food Safety and Inspection Service (FSIS) 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 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.

FSIS advised that GRN 000133 did not provide sufficient data and information to enable FSIS to determine the efficacy and suitability of VOM for the intended use as a shelf-life extension agent or anti-spoilage agent in meat and poultry products. Specifically, FSIS advised that Carex should evaluate the microbial and organoleptic properties of meat and poultry that are subject to the VOM-containing packaging systems under the proposed conditions of use. FSIS requires submission of these data from Carex, together with Carex's interpretation of the data, for FSIS' evaluation. The data should show that the substance is being used at the lowest level necessary to achieve the intended technical effect in the specific meat and poultry products to which the application is desired, is effective in preventing spoilage or extending the shelf life of meat and poultry products, and does not lead to objectionable organoleptic changes in meat or poultry products that are packaged in the VOM-containing atmosphere. The data should also show that the VOM-containing atmosphere will not mask normal spoilage indicators so that a spoiled product may appear fresh, and show that the use of VOM will not create a situation where consumers could be mislead (e.g., by concealing damage or inferiority).⁴

FSIS requested that FDA advise Carex to seek regulatory guidance from FSIS, Labeling and Consumer Protection Staff, about the use of VOM in meat and poultry products. Carex should direct such an inquiry to Dr. Robert Post, Director, Labeling and Consumer Protection Staff, Office of Policy, Program Development and Evaluation, Food Safety and Inspection Service, 1400 Independence Ave., S.W., Suite 602, Annex, Washington, DC 20250-3700. The telephone number for his office is (202)205-0279 and the telefax number is (202)205-3625.

Standards of Identity

In the notice, Carex states its intention to use VOM in several food categories 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. If Carex has any questions about the use of VOM in standardized foods that would be marketed in the United States, Carex should contact the staff in the Office of Nutritional Products, Labeling and Dietary Supplements, Division of Food Labeling and Standards, 5100 Paint Branch Parkway, College Park, MD 20740. Carex can also reach this Division by telephone at (301)436-2371.

Conclusions

Based on the information provided by Carex, as well as other information available to FDA, the agency has no questions at this time regarding Carex'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 Carex 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).

Sincerely,    /s/ Laura M. Tarantino, Ph.D. Acting Director 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 Development and Evaluation
Food Safety and Inspection Service
1400 Independence Ave., SW, Suite 602, Annex
Washington, DC 20250-3700

---

⁽¹⁾FDA notes that the FCC is now in its fifth edition and that there have been some changes over time. In particular, as of the 4th supplement to the 3rd edition of the FCC (1994), the monograph for "mustard oil" no longer contains a description of synthetic allyl isothiocyanate and specifications for arsenic, heavy metal, and phenol content. The FCC 4th and 5th editions list two Brassica spp. (Brassica nigra and Brassica juncea) as sources of mustard oil. The specifications for mustard oil in the FCC (4th and 5th editions) for specific gravity (between 1.008 and 1.019 at 25 degrees Celsius) and refractive index (between 1.524 and 1.534 at 20 degrees Celsius) differ slightly from Carex's quality control specifications.

⁽²⁾In telephone conversations on September 15, 2003 and November 24, 2003, representatives of FDA informed representatives of Carex that the agency could not proceed with its evaluation of GRN 000133 without clarifications such as correcting a systematic error associated with Carex's estimate of dietary exposure to VOM. In these conversations, representatives of FDA also advised representatives of Carex that GRN 000133 neglected to explain how the use of VOM as an anti-spoilage agent would not inadvertently create conditions favorable to the outgrowth of pathogenic microorganisms such as C. botulinum. In amendments dated November 6, 2003, and November 24, 2003, Carex provided amendments that addressed these and other points.

⁽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.

⁽⁴⁾These comments from FSIS are from FSIS' review of Carex's original submission of GRN 000133. Due to Carex's delay in sending its amendments to GRN 000133, FDA did not request an updated consultation from FSIS.