Agency Response Letter
GRAS Notice No. GRN 000128

Mr. Robert H. Sindt
Attorney at Law
1850 M Street, N.W., Suite 400
Washington, D.C. 20036

Re: GRAS Notice No. GRN 000128

Dear Mr. Sindt:

The Food and Drug Administration (FDA) is responding to the notice, dated May 15, 2003, that you submitted on behalf of Rhodia Inc. (Rhodia) 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 May 19, 2003, filed it on May 21, 2003, and designated it as GRAS Notice No. GRN 000128.

The notice informs FDA of the view of Rhodia that skim milk or dextrose cultured with Propionibacterium freudenreichii subsp. shermanii is GRAS, through scientific procedures, for use as an antimicrobial agent in cheeses, sauces, salad dressings, sausages, soups, deli salads, salsas, pasta, tortillas, muffins, cereal bars, sour cream, yogurt, and hash brown potatoes at a maximum level of 2 percent (weight/weight) in the finished product. Rhodia estimates that dietary intake of these cultured products would be 1.7 grams per person per day (g/p/d) at the mean and 3.7 g/p/d at the 90th percentile.

Rhodia provides information about the identity, composition and characteristics of P. freudenreichii-cultured skim milk (Chemical Abstract Service Registry Number (CAS Reg. No.) 223557-80-0) and P. freudenreichii-cultured dextrose (CAS Reg. No. 275817-43-1). Rhodia produces these substances as liquid or dry fermentation products of the culture of skim milk or dextrose with P. freudenreichii. Rhodia notes that the main organic acids present in P. freudenreichii-cultured skim milk or dextrose are propionic acid and acetic acid, with much lower levels of lactic acid and butyric acid, and that the proportion of these organic acids in its cultured products is roughly similar to that of Swiss cheese. Rhodia also notes that it began marketing its cultured skim milk product for use as a microbial growth inhibitor in a variety of food products in 1983.

Rhodia discusses generally available information about the microorganism used to ferment skim milk or dextrose. P. freudenreichii subsp. shermanii is non-pathogenic, non-toxigenic, and has a long history of safe use in food production. P. freudenreichii subsp. shermanii is used to produce the characteristic qualities in Swiss and Emmentaler cheese and is described generically as propionic acid-producing bacteria (propionibacteria) in the standards of identity for these cheeses (21 CFR 133.195). P. freudenreichii and other propionibacteria have been used in food as “probiotics” (i.e, viable microorganisms purported to affect the composition of gut microflora). Rhodia notes that P. freudenreichii is distinct from the other propionibacteria in its morphology, thermotolerance, narrow range of fermented carbohydrates, peptidoglycan composition, and absence of hemolytic activity.

Rhodia provides information about the handling of its P. freudenreichii cultures. Cultures are maintained frozen in 1 milliliter vials at -80 degrees Centigrade. Each seed lot in the culture bank is fully characterized to ensure the identity of the seed strain. Concentrated starter for the industrial fermentation is produced from the seed vials. To ensure purity of the inoculum, the medium used for starter production is sterilized, and all starter batches are thoroughly analyzed for possible contaminants prior to use.

Rhodia manufactures its P. freudenreichii-cultured skim milk or dextrose in accordance with Good Manufacturing Practices (21 CFR 110). Rhodia manufactures these products using specific time- and temperature-controlled fermentation of skim milk or dextrose with P. freudenreichii subsp. shermanii. For the culture fluid, Rhodia may supplement the skim milk or dextrose with small quantities of yeast extract and sodium acetate. The mixture is sterilized and cooled to the incubation temperature and its pH is lowered. The mixture is then inoculated and allowed to incubate until it reaches the fermentation endpoint. After incubation, the pH of the culture is neutralized, followed by standardization with skim milk solids (cultured skim milk) or maltodextrin (cultured dextrose). The cultured material is pasteurized, condensed, re-pasteurized and either marketed as this liquid product or dried to obtain a powdered product. Both Rhodia and an independent certified laboratory test the P. freudenreichii-cultured skim milk or dextrose for microbiological integrity using methods that comply with standard Methods for the Examination of Dairy Products of the American Public Health Association. Rhodia provides food grade specifications for the final product, including common microbiological specifications

Rhodia cites a published article that discusses evidence of inhibition of certain food-spoilage microorganisms, including Pseudomonas putida and several yeast strains, by the cultured dextrose product. The publication also discusses studies conducted with Propionibacteria freudenreichii-cultured dextrose including a bacterial reverse mutation assay, a subchronic oral toxicity assay and an oral antigencity study. Rhodia concludes that the studies support the premise that their dextrose product shows no evidence of mutagenicity, toxicity, or allergenicity. Rhodia recognizes that cultured skim milk contains milk solids and, thus could elicit an allergic reaction in consumers who are sensitive to milk. Rhodia states its cultured skim milk product and any foods that contain it are clearly labeled to identify included dairy products.

As part of its notice, Rhodia includes the report of a panel of individuals (Rhodia’s GRAS panel) who evaluated the data and information that are the basis for Rhodia’s GRAS determination. Rhodia considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Rhodia’s GRAS panel concluded that P. freudenreichii-cultured skim milk or dextrose is safe and suitable for use in food as a microbial growth inhibitor.

Use in Meat and poultry products

During its evaluation of GRN 000128, 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 states that the ingredients have a long history of use in the production of meat and poultry products that are permitted to contain dairy ingredients, and that this history is documented in correspondence dating from 1987. FSIS further states that Rhodia has found that the substances effectively inhibit the growth of certain spoilage organisms, e.g., Gram negative psychrophiles, yeasts, and molds at levels from 0.1 to 2.0 percent in foods.

FSIS advised FDA that they have no objection to the use of cultured skim milk or cultured dextrose in the production of meat and poultry sausages (including those with standards) that permit the use of antimicrobial agents, but states that the ingredients will need to be listed by their common or usual name, i.e., “cultured skim milk,” or “cultured dextrose,” in meat and poultry products in which they are used as ingredients. FSIS advises that Rhodia should contact FSIS if they have further questions. Rhodia should direct its 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, Rhodia states its intention to use P. freudenreichii-cultured skim milk or dextrose in several food categories, including foods for which standards of identity exist, located 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 Rhodia has any questions about the use of this P. freudenreichii-cultured skim milk or dextrose in standardized foods that would be marketed in the United States, Rhodia should contact the staff in the Office of Nutritional Products, Labeling and Dietary Supplements (ONPLDS), Division of Standards and Labeling Regulations, 5100 Paint Branch Parkway, College Park, MD 20740. Rhodia can also reach this division by telephone at (301)436-2371.

Conclusions

Based on the information provided by Rhodia, as well as other information available to FDA, the agency has no questions at this time regarding Rhodia’s conclusion that P. freudenreichii-cultured skim milk or dextrose 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 P. freudenreichii-cultured skim milk or dextrose. As always, it is the continuing responsibility of Rhodia 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 Rhodia’s 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