Agency Response Letter GRAS Notice No. GRN 000260
CFSAN/Office of Food Additive Safety
March 9, 2009
Robert S. McQuate, Ph.D.
GRAS Associates, LLC
20482 Jacklight Lane
Bend, OR 97702-3074
Re: GRAS Notice No. GRN 000260
Dear Dr. McQuate:
The Food and Drug Administration (FDA) is responding to the notice, dated September 3, 2008, that you submitted on behalf of Cypress Systems, Inc. (CSI), 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 10, 2008, filed it on September 12, 2008, and designated it as GRAS Notice No. GRN 000260.
The subject of the notice is high-selenium yeast. The notice informs FDA of the view of CSI that high-selenium yeast is GRAS, through scientific procedures, for use as an ingredient in baked products, non-alcoholic beverages, breakfast cereals, grain products and pastas, milk products, processed fruit and fruit juices, processed vegetables and vegetable juices, commercial soups and soup mixes, and medical foods at levels yielding 5 micrograms (μg) selenium per serving.(1)
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 "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. 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, CSI includes the report of a panel of individuals (CSI's GRAS panel) who evaluated the data and information that are the basis for CSI's GRAS determination. CSI considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. CSI's GRAS panel evaluated information relevant to the identity and composition of high-selenium yeast, selenium toxicity, dietary exposure to selenium from high-selenium yeast, substantial equivalence of the yeast component to conventional yeast, and potential for allergenicity. Based on this review, CSI's GRAS panel concluded that high-selenium yeast, produced in accordance with good manufacturing practices and complying with appropriate food-grade specifications, is GRAS under the conditions of its intended use.
CSI discusses the identity and characteristics of high-selenium yeast. Food-grade high-selenium yeast produced from Saccharomyces cerevisiae (also known as baker's yeast) is a dry powder containing 1,140 – 1,260 μg of selenium per gram of yeast, present as a mixture of four chemically characterized organoselenium forms which account for approximately 85 percent of the selenium content.(2) The predominant form of selenium in the mixture is identified as selenomethionine (84 percent); the three other characterized forms of selenium are present at low levels and include γ-glutamyl-Se-methyl-Se-cysteine (0.5 percent), Se-adenosyl-Se-homocysteine (0.5 percent), and selenite (0.1 percent). The notifier states that comparison of chemical composition and yeast performance parameters establish that standard baker's yeast and high-selenium yeast are virtually the same except for the presence of increased levels of selenium in substitution for sulfur within the high-selenium yeast.
CSI describes the manufacturing methods for high-selenium yeast. High-selenium yeast is produced using S. cerevisiae as the yeast into which inorganic selenium, as sodium selenite, is incorporated. The continuous fermentation utilizes a medium with minimal sulfur and methionine levels to enhance selenium incorporation into the yeast. The chilled mineralized yeast cream is inactivated when pasteurized through a high temperature sterilization system to achieve food grade standards and subsequently spray dried to yield a uniformly homogeneous dry powder.
CSI provides specifications for food-grade high-selenium yeast with target levels for selenium (1,140 – 1,260 μg selenium per gram of yeast).(3) Specifications also include physical/chemical target levels for protein, phosphorus, moisture, extraneous material, and inorganic selenium, as well as limitations on microbial contaminants and heavy metals.
CSI calculates an estimated daily intake (EDI) for selenium from the consumption of high-selenium yeast when added to foods in accordance with the intended conditions of use. CSI determines, on the basis of an estimated maximum number of daily servings of foods within each of the designated food categories, that the EDI would be less than 100 μg of selenium per person per day.
CSI discusses the safety of selenium and high-selenium yeast. The notifier provides summaries of published literature reviews and primary literature. The cited publications include consideration of both animal and human studies and consist of (1) evaluations of bioavailability, as well as absorption, distribution, metabolism and excretion of the relevant forms of selenium found in high-selenium yeast; (2) determinations of safe upper limits for selenium intake; and (3) evaluations of potential genotoxicity, reproductive toxicity, and teratogenicity associated with selenium (both inorganic and organic forms) and high-selenium yeast. The notifier further discusses the results of published epidemiological and clinical studies as corroborative evidence of the safe upper limits of selenium for human populations. CSI reports that the literature generally agrees that the safe upper limit of selenium intake is in the range of 300 to 400 μg selenium per day. On the basis of human experiences and associated testing, pertinent animal test results, anticipated human consumption levels, and germane supporting information, CSI concludes that high-selenium yeast, produced in accordance with good manufacturing practices and complying with appropriate food-grade specifications, is GRAS under the conditions of its intended use.
The notifier discusses a possible association between type-2 diabetes and selenium intake as well as possible allergenicity to the yeast used in the production of high-selenium yeast. The notifier concludes that there is a lack of evidence in the published scientific literature to support such associations and that consumption of high-selenium yeast does not constitute a safety concern for type-2 diabetes or for allergenicity.
Standards of Identity
In the notice, CSI 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
Under section 403(a) of the Federal Food, Drug, and Cosmetic Act (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. In describing the intended use of high-selenium yeast and in describing the information that CSI relies on to conclude that high-selenium yeast is GRAS under the conditions of its intended use, CSI raises a potential issue under these labeling provisions of the FFDCA. If products that contain high-selenium yeast bear any claims on the label or in labeling, such claims are the purview of the ONLDS in the Center for Food Safety and Applied Nutrition. 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, CSI 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 CSI'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 CSI's notice that high-selenium yeast is GRAS for use in the intended food categories, 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 CSI, as well as other information available to FDA, the agency has no questions at this time regarding CSI'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 CSI 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 000260, 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.
Laura M. Tarantino, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
(1)CSI states that foods intended for infants and toddlers, such as infant formulas or foods formulated for babies or toddlers, are excluded from the intended uses.
(2)CSI notes that 15 percent of the selenium content is uncharacterized due to analytical limitations. However, CSI concludes that numerous published human studies using high-selenium yeast, without apparent toxicity or noted adverse effects, overrides the compositional uncertainties. On this basis, CSI concludes that the compositional uncertainties do not impact safety considerations.
(3)CSI notes that commercial baker's yeast typically contains less than 5 μg of selenium per gram of yeast.