Agency Response Letter GRAS Notice No. GRN 000638
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See also Generally Recognized as Safe (GRAS).
CFSAN/Office of Food Additive Safety
July 10, 2016
Susan Cho, Ph.D.
6309 Morning Dew Court
Clarksville, MD 21029
Re: GRAS Notice No. GRN 000638
Dear Dr. Cho:
The Food and Drug Administration (FDA) is responding to the notice, dated March 7, 2016, that you submitted on behalf of Hunan Huacheng Biotech, Inc. (HHB) 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 11, 2016, filed it on April 7, 2016, and designated it as GRAS Notice No. GRN 000638.
The subject of the notice is rebaudioside A purified from the leaves of Stevia rebaudiana (Bertoni) Bertoni (rebaudioside A). The notice informs FDA of the view of HHB that rebaudioside A is GRAS, through scientific procedures, for use as a general purpose sweetener in foods, excluding infant formula and meat and poultry products, at levels determined by good manufacturing practices (GMP), as well as use as a table top sweetener.
Our use of “rebaudioside A,” “steviol glycosides,” or “SGs” 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 each ingredient must be declared by its 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 and Food Labeling in the Center for Food Safety and Applied Nutrition.
As part of its notice, HHB includes the statement of a panel of individuals (HHB’s GRAS panel) that evaluated the data and information that are the basis for HHB’s GRAS determination. HHB considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. HHB’s GRAS panel evaluated information describing the identity and composition, manufacturing process and specifications, and estimated dietary exposure to rebaudioside A, as well as published and unpublished studies supporting the safety of rebaudioside A. Based on this review, HHB’s GRAS panel concludes that rebaudioside A produced in accordance with GMP and meeting appropriate purity and food grade specifications, is GRAS, by scientific procedures, under the conditions of its intended use.
HHB provides information about the identity for rebaudioside A. Rebaudioside A (CAS Reg. No. 58543-16-1), a glycoside of steviol, is identified 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. Rebaudioside A is one of a group of known steviol glycosides (SGs), which differ from each other by the number of glycoside moieties and bonding order.
HHB provides information about the manufacturing process for rebaudioside A. Rebaudioside A is obtained from the leaves of S. rebaudiana through extraction and multiple purification steps. The leaves are first dried, crushed, and extracted in hot water. The extract is centrifuged to precipitate impurities, and the mixture is then filtered. The filtrate is passed through an adsorption resin to trap the steviol glycoside components. Subsequently, SGs are absorbed onto a resin and eluted with ethanol. The ethanol extract is decolored using activated carbon. The extract is cooled under specified conditions to crystallize SGs with rebaudioside A remaining in solution and the crystals removed by filtration. The filtrate is concentrated, aqueous methanol or ethanol added, and the solution is then filtered. The filtrate is cooled to crystallize SGs, including rebaudioside A, and the crystals obtained by filtration. The crystals are dissolved in aqueous methanol or ethanol and recrystallized to obtain rebaudioside A. Following filtration, rebaudioside A is washed in water, filtered, dried under vacuum, and ground to obtain the final rebaudioside A product.
HHB provides specifications for rebaudioside A that include the minimum content of rebaudioside A (≥ 97%) and limits for moisture (≤ 6% w/w), lead (≤ 1 milligram per kilogram (mg/kg)), arsenic (≤ 1 mg/kg), residual methanol (≤ 200 mg/kg), residual ethanol (≤ 5000 mg/kg), and limits on microbial contaminants. HHB states that rebaudioside A meets the specifications for SGs established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) at its 73rd meeting in 2010 and the Food Chemical Codex specifications for rebaudioside A (FCC, 7th Edition). HHB provides the results of five batch analyses to demonstrate that rebaudioside A meets specifications.
HHB provides an estimate of the dietary exposure to rebaudioside A resulting from its intended use in food. HHB discusses the results of a published study in which the author estimated dietary exposure to rebaudioside A in different subpopulations (Ref. 1). In this study, published data on intake of intense sweeteners were converted to sucrose equivalents using estimates of sweetness relative to sucrose. Based on the relative sweetness of rebaudioside A, which is 200 to 300 times that of sucrose, HHB reports that the intended use of rebaudioside A would yield upper percentile (≥ 90th percentile) dietary exposures (expressed as steviol equivalents) that range from 1.12 to 1.48 mg/kg body weight/day (bw/d) for adults and 1.48 to 1.64 mg/kg bw/d for children. HHB states that the use of rebaudioside A in food is self-limiting due to organoleptic factors and consumer taste considerations.
HHB summarizes published studies pertaining to the metabolic fate of rebaudioside A and other SGs. HHB points to previously reviewed in vitro and in vivo mutagenicity/genotoxicity studies; published acute, subchronic, and chronic toxicity studies; as well as published reproductive and developmental toxicology studies in relation to their safety determination for rebaudioside A. To further support its view that rebaudioside A is GRAS for the intended use, HHB summarizes recent decisions by JECFA and other governmental bodies on the safety of rebaudioside A and other SGs for use in food as a sweetener. HHB notes that JECFA has established an acceptable daily intake (ADI) for SG of 4 mg/kg bw/d (expressed as steviol). This ADI was based on a no observed adverse effect level of 970 mg/kg bw/d (383 mg/kg bw/d, as steviol) from a two year rat study, and the application of a one hundred-fold safety factor for intra- and inter-species differences. Based on all the available scientific information, HHB concludes that rebaudioside A is GRAS for its intended use in foods.
Standards of Identity
In the notice, HHB states its intention to use rebaudioside A 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.
Section 301(ll) of the Federal Food, Drug, and Cosmetic Act (FD&C Act)
Section 301(ll) of the FD&C Act prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FD&C Act, 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 HHB’s notice that rebaudioside A is GRAS for the intended 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 HHB, as well as other information available to FDA, the agency has no questions at this time regarding HHB’s conclusion that rebaudioside A is GRAS under the intended conditions of uses. The agency has not, however, made its own determination regarding the GRAS status of the subject uses of rebaudioside A. As always, it is the continuing responsibility of HHB 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 000638, 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.
Dennis M. Keefe, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
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.