Agency Response Letter GRAS Notice No. GRN 000284
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CFSAN/Office of Food Additive Safety
August 28, 2009
Gary L. Yingling
K & L Gates, LLP
1601 K Street NW
Washington, DC 20006-1600
Re: GRAS Notice No. GRN 000284
Dear Mr. Yingling:
The Food and Drug Administration (FDA) is responding to the notice, dated March 06, 2009, that you submitted on behalf of DSM Food Specialties (DSM) 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 March 10, 2009, filed it on March 12, 2009, and designated it as GRAS Notice No. GRN 000284.
The subject of the notice is bakers yeast mannoprotein. The notice informs FDA of the view of DSM that bakers yeast mannoprotein is GRAS, through scientific procedures, for use as a stabilizing agent in wines, at levels ranging from 50–400 milligrams per liter (mg/L), to prevent tartaric acid precipitation.
21 CFR 101.4 states that all ingredients must be declared by their common or usual name. In addition, 21 CFR 102.5 outlines general principles to use when establishing common or usual names for nonstandardized foods. Our use of “bakers yeast mannoprotein” in this letter should not be considered an endorsement or recommendation of that term as an appropriate common or usual name for the purpose of declaring the substance in the ingredient statement of foods that contain that ingredient. Issues associated with labeling and the appropriate common or usual name of a food are the responsibility of the Office of Nutrition, Labeling, and Dietary Supplements in the Center for Food Safety and Applied Nutrition.
DSM describes the identity and composition of bakers yeast mannoprotein. Bakers yeast (Saccharomyces cerevisiae) mannoprotein contains a family of glycosylated proteins and peptides of varying structures and molecular weights (20–450 kilodaltons (kDa)) present in the yeast cell wall and periplasm. The polysaccharide chains of mannoprotein consist almost exclusively of α-1→6 linked mannose units with short α-1→2 and α-1→3 linked side chains. Some of these side chains may have phosphodiester linkages to other mannosyl residues. The carbohydrate content of bakers yeast mannoprotein is at least 60 percent; no less than 70 percent of the carbohydrate is mannose. DSM produces bakers yeast mannoprotein in two forms: a spray dried powder and a colloidal solution (containing approximately 20 percent dry matter).
DSM describes the method of manufacture of bakers yeast mannoprotein from food-grade yeast extract. The steps include micro-filtration of the yeast extract to remove high molecular weight proteinaceous material followed by ultrafiltration (UF) to concentrate the mannoprotein (greater than 20 kDa). The UF-concentrate is treated with the enzyme phosphodiesterase to hydrolyze residual yeast RNA, followed by a diafiltration step to remove low molecular weight moieties such as salts, amino acids, nucleotides, and sugars. The dilute mannoprotein fraction is then concentrated by UF, followed by ultra-high temperature (UHT) treatment (130–150 degrees Celsius) to inactivate residual enzyme. The UF concentrate is cooled and polish filtered to remove insoluble proteinaceous material formed during the UHT treatment. After filtration, the clear solution is either (1) spray dried and packed as a powder or (2) stabilized with 14 grams per liter of sodium bisulfite as a preservative and packed as a colloidal solution. Both finished products are stored at 4 degrees Celsius.
DSM provides chemical and purity specifications for food-grade bakers yeast mannoprotein, including specifications for ash, nitrogen (as a measure of protein content), carbohydrates, fraction of mannose in carbohydrates, heavy metals, and microbes. DSM provides results of the compositional analysis of four batches of bakers yeast mannoprotein meeting DSM’s food-grade product specifications. DSM further notes that its specifications are consistent with those established by the Organisation Internationale du Vin, Resolution OENO 26/2004.
Bakers yeast mannoprotein is intended for use in all types of wines, including white, rosé, red, and sparkling wines, at levels ranging from 50–400 mg/L, with addition before or after the final filtration of the wine but prior to bottling. The amount to be added is determined by the winemaker and depends on, among other factors, the amount of tartaric acid and mannoprotein naturally present in the wine.
DSM calculates the current estimated daily intake (EDI) of mannoprotein in foods taking into consideration the levels of mannoprotein naturally present in wine, beer, breads and pastries, yeast extract spreads, and dietary supplements. Using the combined results of USDA’s 1994 and 1995 Continuing Survey of Food Intake by Individuals and 1994 and 1995 Diet and Health Knowledge, DSM reports a background EDI of mannoprotein of 3.6 grams per person per day (g/p/d) from these foods. DSM calculates a maximum additional EDI of 0.02 g/p/d mannoprotein from the intended addition of bakers yeast mannoprotein to wines.
As part of its safety evaluation, DSM describes published data on the natural occurrence of bakers yeast mannoprotein in a variety of foods, including wine, beer, breads and pastries, and yeast extract spreads (e.g., marmite). The notifier discusses published scientific literature establishing the safety of bakers yeast in food and food ingredient production. DSM uses published literature and nuclear magnetic resonance analysis to show that the carbohydrate moiety of bakers yeast mannoprotein is substantially equivalent to naturally occurring mannoprotein in S. cerevisiae and in commercially-available food products manufactured with S. cerevisiae.
DSM states that the toxicity of bakers yeast mannoprotein has not been specifically evaluated in animal safety studies. However, the notifier discusses the results of unpublished safety studies of its bakers yeast extract, which is used as the starting material for the manufacture of bakers yeast mannoprotein. No safety concerns were raised in acute toxicity studies in mice, rats, guinea pigs, and rabbits; subacute toxicity studies in rats; or genotoxicity studies conducted on Salmonella typhimurium, Escherichia coli, and mice.
Mannoprotein is naturally occurring in wine due to the alcohol fermentation with yeast in the wine manufacturing process. The notifier conducted a literature search and states that no reports were found to date addressing allergenic or other negative effects due to oral intake of mannoprotein via wine or other sources like bread, beer and yeast. On the basis of this literature review, DSM concludes that it is unlikely the bakers yeast mannoprotein will result in sensitization or allergies due to consumption through wine.
Section 301(ll) of the Federal Food, Drug, and Cosmetic Act (FFDCA)
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the Federal Food Drug and Cosmetic Act (FFDCA) to, among other things, add section 301(ll). Section 301(ll) of the FFDCA prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FFDCA, a biological product licensed under section 351 of the Public Health Service Act, or a drug or a biological product for which substantial clinical investigations have been instituted and their existence made public, unless one of the exemptions in section 301(ll)(1)-(4) applies. In its review of DSM’s notice that bakers yeast mannoprotein is GRAS for use as a stabilizing agent in wines to prevent tartaric acid precipitation, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing bakers yeast mannoprotein. Accordingly, this response should not be construed to be a statement that foods that contain bakers yeast mannoprotein, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by DSM, as well as other information available to FDA, the agency has no questions at this time regarding DSM’s conclusion that bakers yeast mannoprotein 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 bakers yeast mannoprotein. As always, it is the continuing responsibility of DSM 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 responding to GRN 000284, as well as a copy of the information in this notice that conforms to the information in the GRAS exemption claim (proposed 21 CFR 170.36(c)(1)), is available for public review and copying via the FDA home page at http://www.fda.gov. To view or obtain an electronic copy of the text of the letter, follow the hyperlinks from the “Food” topic to the “Food Ingredients and Packaging” section to the “Generally Recognized as Safe (GRAS)” page where the GRAS Inventory is listed.
Mitchell A. Cheeseman, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition