Agency Response Letter GRAS Notice No. GRN 000282
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CFSAN/Office of Food Additive Safety
August 11, 2009
Sweet Green Fields, LLC
4164 Meridian Street
Bellingham, WA 98226
Re: GRAS Notice No. GRN 000282
Dear Mr. McMurtry:
The Food and Drug Administration (FDA) is responding to the notice, dated January 15, 2009, that you submitted 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 February 17, 2009, filed it on February 18, 2009, and designated it as GRAS Notice No. GRN 000282.
The subject of the notice is rebaudioside A purified from the leaves of Stevia rebaudiana (Bertoni) Bertoni. The notice informs FDA of the view of Sweet Green Fields, LLC (Sweet Green Fields) that rebaudioside A is GRAS, through scientific procedures, for use as a general-purpose sweetener in foods, excluding meat and poultry products, provided that food standards of identity do not preclude such use, at levels determined by current good manufacturing practices.
The rebaudioside A that is the subject of GRN 000282 is a highly purified component of the leaves of the stevia plant. As such, FDA notes that the GRAS notice for the use of a specific purified component of stevia, such as rebaudioside A, and FDA’s response do not necessarily apply to the uses of other stevia products.
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. Our use of “rebaudioside A” or “rebaudioside A purified from the leaves of S. rebaudiana (Bertoni) Bertoni” in this letter should not be considered an endorsement or recommendation of any of these terms 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.
As part of its notice, Sweet Green Fields includes a summary of conclusions of a panel of individuals (Sweet Green Fields’ GRAS panel) who evaluated the data and information that are the basis for Sweet Green Fields’ GRAS determination. Sweet Green Fields considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Sweet Green Fields’ GRAS panel evaluated the identity, method of manufacture, product specifications, and the potential exposure resulting from the intended uses of rebaudioside A as well as published and unpublished studies on rebaudioside A and related substances. Based on this review, Sweet Green Fields’ GRAS panel concluded that rebaudioside A, produced consistent with current good manufacturing practice and meeting appropriate purity and food grade specifications, is GRAS, by scientific procedures, under the conditions of its intended use.
Sweet Green Fields provides information about the identity, method of manufacture, and specifications for rebaudioside A. Rebaudioside A (CAS Reg. No. 58543-16-1), a glycoside of steviol, is identified as 19-O-beta-glucopyranosyl-13-O-(beta-glucopyranosyl(1-2)-beta-glucopyranosyl(1-3))-beta-glucopyranosyl-13-hydroxykaur-16-en-19-oic acid.(1) Rebaudioside A is one of a group of known steviol glycosides, which differ by the number of glycoside moieties and bonding order. Rebaudioside A is obtained from the leaves of S. rebaudiana (Bertoni) Bertoni. The leaves are dried and extracted with water, followed by filtration of the extract. Resin chromatography and filtration processes are used to isolate the steviol glycosides from the clarified leaf extract. The resulting glycosides preparation is crystallized with a water-ethanol solvent mixture. The crystals are then rinsed with ethanol, followed by purging of the ethanol and drying to yield the final rebaudioside A product. Sweet Green Fields provides specifications for rebaudioside A that include the content of rebaudioside A (≥97% by weight (w/w)) and limits for other steviol glycosides (≤3% w/w), moisture (<6%), ash (< 0.2%), residual ethanol (≤0.5%), lead (≤1 milligrams per kilogram (mg/kg)), arsenic (≤1 mg/kg), and microbial contaminants (within specified limits).
Sweet Green Fields estimates the intake of rebaudioside A resulting from its intended use in foods. Sweet Green Fields used dietary exposure data for sweetener use in various countries from a published study (Ref. 1). This study performed an intake assessment of rebaudioside A which shows the overall projected intakes by mean and high percentile consumers in different subpopulations. The projected rebaudioside A exposures are based on sweetener substitution (expressed as sucrose equivalents in mg/kg body weight per day (mg/kg bw/d)) and assume a relative sweetness for rebaudioside A that is 200 times that of sucrose. Sweet Green Fields notes that in the general adult population, the predicted rebaudioside A exposure from consumption of foods containing Rebaudioside A would be 1.3 mg/kg bw/d for consumers at the mean and 3.4 mg/kg bw/d for high percentile consumers.
Sweet Green Fields discusses published and unpublished studies pertaining to the safety evaluation of rebaudioside A, including studies on rebaudioside A, stevioside, steviol, and crude stevia extracts. Among the published studies considered were acute toxicity studies in rats, mice, and hamsters; subchronic toxicity studies in rats; chronic toxicity/carcinogenicity studies in rats; and reproductive/developmental toxicity studies in rats and hamsters. Sweet Green Fields also considers published clinical studies and published absorption, distribution, metabolism and excretion studies in animals and humans. Additional studies that Sweet Green Fields discusses include published and unpublished in vitro and in vivo genotoxicity studies. Based on its consideration of all these studies, Sweet Green Fields concludes that rebaudioside A is safe for its intended use in foods.
To further support its view that rebaudioside A is safe for the intended use, Sweet Green Fields describes recent decisions by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the Food Standards Australia New Zealand (FSANZ) on the safety of steviol glycosides, one of which is rebaudioside A, for use in food as sweeteners. Sweet Green Fields notes that in 2008, JECFA established an acceptable daily intake (ADI) for steviol glycosides of 0-4 mg/kg bw/d (expressed as steviol) and FSANZ established an ADI for steviol glycosides of 4 mg/kg bw/d (expressed as steviol).
Section 301(ll) of the Federal Food, Drug, and Cosmetic Act (FFDCA)
The Food and Drug Administration Amendments Act of 2007, that 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 Sweet Green Fields’ notice that rebaudioside A is GRAS for use as a general-purpose sweetener in foods, excluding meat and poultry products, provided that food standards of identity do not preclude such use, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing rebaudioside A. Accordingly, this response should not be construed to be a statement that foods that contain rebaudioside A, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Sweet Green Fields, as well as other information available to FDA, the agency has no questions at this time regarding Sweet Green Fields’ conclusion that rebaudioside A purified from S. rebaudiana (Bertoni) Bertoni 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 rebaudioside A purified from S. rebaudiana (Bertoni) Bertoni. As always, it is the continuing responsibility of Sweet Green Fields 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 000282, 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
(1)FDA notes that rebaudioside A may alternatively be defined as 13-[(2-O-β –D-glucopyranosyl-3-O-β–D-glucopyranosyl-β-D-glucopyranosyl)oxy] kaur-16-en-18-oic acid β-D-glucopyranosyl ester.
1. Renwick, A.G. 2008. The use of a sweetener substitution method to predict dietary exposures for the intense sweetener rebaudioside A. Food and Chemical Toxicology 46:S61-S69.