Agency Response Letter GRAS Notice No. GRN 000353
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CFSAN/Office of Food Additive Safety
March 1, 2011
George A. Burdock, Ph.D.
801 N. Orange Avenue
Orlando, FL 32801
Re: GRAS Notice No. GRN 000353
Dear Dr. Burdock:
The Food and Drug Administration (FDA) is responding to the notice, dated July 14, 2010, that you submitted on behalf of Alltech 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 September 1, 2010, filed it on September 2, 2010, and designated it as GRAS Notice No. GRN 000353.
The subject of the notice is high-selenium yeast. The notice informs FDA of the view of Alltech that high-selenium yeast is GRAS, through scientific procedures, for use as an ingredient in yogurts, breads, instant cereals, breakfast and granola-type bars, soups, beverages, pastas, crackers, salty snacks, pretzels, and popcorn at levels of 5 to 60 milligrams per kilogram (mg/kg); and, in medical foods such that the daily intake will not exceed 19.2 mg per day (mg/day).
Our use of “high-selenium yeast” 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. Title 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. 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 (ONLDS) in the Center for Food Safety and Applied Nutrition.
As part of its notice, Alltech includes the report of a panel of individuals (Alltech’s GRAS panel) who evaluated the data and information that are the basis for Alltech’s GRAS determination. Alltech considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Alltech’s GRAS panel evaluated information relevant to the identity and composition of high-selenium yeast; method of manufacture and specifications for the high-selenium yeast product; estimated daily intakes of high-selenium yeast and selenium; safety studies for high-selenium yeast, and observations of the effects of selenium on human health. Based on this review, Alltech’s GRAS panel concluded that high-selenium yeast is GRAS for its intended uses.
Alltech discusses the identity and composition of high-selenium yeast. Alltech describes the product as a dried (non-viable) baker’s yeast, Saccharomyces cerevisiae strain CNCM I-3060. Alltech states that the product consists of dried yeast containing selenoproteins which incorporate selenomethionine and selenocysteine. The product also contains residual food-grade fermentation medium.
Alltech describes the method of manufacture for the high-selenium yeast product. Alltech states that S. cerevisiae strain CNCM I-3060 is cultivated in a selenium-enriched fermentation medium and the fermentation process follows a typical batch-fed operation that is commonly used to produce baker’s yeast. Alltech states that following fermentation, the high-selenium yeast biomass is harvested and dried.
Alltech provides specifications for the high-selenium yeast product. Alltech states that the specifications include a content of ≥2000 mg of total selenium/kg of high-selenium yeast, of which ≥98 percent is organic selenium (65 percent selenomethionine, 33 percent other organic selenium). Alltech’s specifications also include limits for arsenic, lead, cadmium, and mercury, as well as microbiological specifications.
Alltech calculates the estimated daily intake (EDI) of high-selenium yeast and selenium for the U.S. population using the intended food categories and use levels described in GRN 000353 and food consumption data from the USDA’s National Health and Nutrition Examination Survey/What We Eat in America (NHANES/WWEIA 2003-2004). The mean and 90th percentile consumption of high-selenium yeast per person are 8.8 and 17.4 mg/day, respectively, which results in a mean and 90th percentile consumption of selenium of 17.6 and 34.8 microgram per day (µg/day). The notifier calculates a cumulative EDI for selenium from the intended uses of high-selenium yeast and dietary selenium of 123.3 and 246.2 µg/day at the mean and 90th percentile, respectively. The notifier concludes that medical food products may contain high-selenium yeast such that the daily intake will not exceed 19.2 mg/day. Alltech states that medical foods containing high-selenium yeast are intended to be used by a select population of individuals who are under the supervision of a physician, and that these medical foods are typically formulated to replace one or more meals throughout the day. Alltech calculates a mean and 90th percentile consumption of selenium from conventional foods, intended uses of high-selenium yeast, and dietary supplements of 323.2 and 446.2 µg/day, respectively (assuming that the dietary supplements contain 200 µg selenium). Alltech states that in the unlikely event that an individual consumes conventional foods enriched with high-selenium yeast at 90th percentile levels, medical foods containing high-selenium yeast, and dietary supplements containing 200 µg selenium on a daily basis, the 90th percentile consumption of selenium would be 484.6 µg/day. Alltech states that this level is higher than the upper limit of 400 µg/day selenium established by the Institute of Medicine, but lower than the No Observed Adverse Effect Level for clinical selenosis of 800 µg/day selenium.
Alltech discusses the safety of high-selenium yeast. Alltech summarizes published animal studies that investigated the potential acute and subchronic toxicity, reproductive and developmental toxicity, inhalation toxicity, and genotoxicity of high-selenium yeast. Based on the results of these studies, the authors conclude that high-selenium yeast is not toxic or genotoxic.
Alltech also discusses published studies that describe the effects of selenium on human health. Alltech discusses a human clinical study in which healthy men and women received 600 µg/day of selenium for 12 weeks. Alltech also discusses a human study in which participants received 800 µg/day of selenium for 16 weeks. The results of both studies showed no adverse treatment-related effects.
Alltech states that the results of the published studies discussed above support the safety of addition of 200 µg selenium/day (approximately 3.3 µg selenium/kg bw/day) to the human diet.
FDA notes that some of the human health studies cited in GRN 000353 are also cited in GRN 000260, the subject of which was high-selenium yeast. In GRN 000260, the notifier explicitly discussed and dismissed concerns regarding selenium and diabetes; Alltech discusses and dismisses these concerns in GRN 000353. FDA also notes that in GRN 000353, Alltech discusses studies that were published after FDA responded to GRN 000260. These studies in humans address potential effects of selenium consumption on human health. Alltech indicates that the results of these studies do not raise concerns regarding the safety of high-selenium yeast for the intended uses.
Standards of Identity
In the notice, Alltech states its intention to use high-selenium yeast 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.
Potential Labeling Issues
In describing the biological effects of high-selenium yeast in human clinical studies as part of the information that Alltech relies on to conclude that high-selenium yeast is GRAS under the conditions of its intended use, Alltech raises a potential issue under the labeling provisions of the Federal Food, Drug, and Cosmetic Act (FFDCA). Under section 403(a) of the FFDCA, a food is misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FFDCA lays out the statutory framework for the use of labeling claims that characterize the level of a nutrient in a food or that characterize the relationship of a nutrient to a disease or health-related condition. If products that contain high-selenium yeast bear any claims on the label or in labeling, such claims are the purview of ONLDS. The Office of Food Additive Safety neither consulted with ONLDS on this labeling issue nor evaluated the information in your notice to determine whether it would support any claims made about high-selenium yeast on the label or in labeling.
In its notice, Alltech informs FDA that one intended use of high-selenium yeast is use in medical foods. Section 5(b) of the Orphan Drug Act (ODA) defines a medical food as a food that is formulated to be consumed or administered enterally under the supervision of a physician and that is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation. Section 403(q) of the FFDCA lays out the statutory framework for nutrition labeling of food products. Section 403(r) of the FFDCA lays out the statutory framework for health claims and nutrient content claims. Under section 403(q)(5)(A)(iv) of the FFDCA and FDA's implementing regulations in 21 CFR 101.9(j)(8), the requirements for nutrition labeling do not apply to medical foods as defined in section 5(b) of the ODA. Under section 403(r)(5)(A) of the FFDCA and FDA's implementing regulations in 21 CFR 101.13(q)(4)(ii) and 21 CFR 101.14(f)(2), the requirements for nutrient content claims and health claims, respectively, do not apply to medical foods as defined in section 5(b) of the ODA. For your information, FDA's response to Alltech’s notice that high-selenium yeast is GRAS for use in medical foods does not address the question of whether any particular food product that contains high-selenium yeast as an ingredient would be a medical food within the meaning of section 5(b) of the ODA and, thus, would be exempt from the requirements for nutrition labeling, nutrient content claims, and health claims.
Section 301(ll) of the FFDCA
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the 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 Alltech’s notice that high-selenium yeast is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing high-selenium yeast. Accordingly, this response should not be construed to be a statement that foods that contain high-selenium yeast, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Alltech, as well as other information available to FDA, the agency has no questions at this time regarding Alltech’s conclusion that high-selenium yeast 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 high-selenium yeast. As always, it is the continuing responsibility of Alltech 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 000353, 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 at www.fda.gov/grasnoticeinventory.
Mitchell A. Cheeseman, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition