Agency Response Letter GRAS Notice No. GRN 000389
CFSAN/Office of Food Additive Safety
Jan 18, 2012
Robert S. McQuate, Ph.D.
GRAS Associates, LLC
20482 Jacklight Lane
Bend, OR 97702-3074
Re: GRAS Notice No. GRN 000389
Dear Dr. McQuate:
The Food and Drug Administration (FDA) is responding to the notice, dated July 11, 2011, that you submitted on behalf of Compound Solutions, Inc. (Compound Solutions) 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 this notice on July 18, 2011, filed it on July 26, 2011, and designated it as GRN No. 000389. In a letter dated December 5, 2011, Chengdu Wagott Pharmaceuticals Co., Ltd. (Wagott) informed FDA that it would assume responsibility for the notice and that further correspondence should still be directed to Dr. Robert McQuate.
The subject of the notice is steviol glycosides with stevioside as the principal component (hereinafter referred to as SG-S).SG-S is obtained from the leaves of Stevia rebaudiana (Bertoni) Bertoni. The notice informs FDA of the view of Wagott that SG-S is GRAS, through scientific procedures, for use as a general purpose sweetener in foods, excluding meat and poultry products, at levels determined by good manufacturing practices, as well as use as a table top sweetener. Wagott notes that purified steviol glycosides have been the subject of other GRAS notices and that FDA responded to these GRAS notices informing the notifiers that, at the time of its response, the agency had no questions regarding their conclusions that the purified steviol glycosides that are the subject of their respective notices are GRAS for their intended use as a sweetener in food.
The SG-S that is the subject of GRN 000389 is a highly purified preparation of stevioside from the leaves of the stevia plant. As such, FDA notes that a GRAS notice for the use of a specific purified preparation from stevia, such as SG-S, and FDA's response do not necessarily apply to the uses of other stevia products.
Our use of "SG-S," "steviol glycosides," or "purified steviol glycosides with stevioside as the principal component" 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, Labeling, and Dietary Supplements in the Center for Food Safety and Applied Nutrition.
As part of its notice, Wagott includes the report of a panel of individuals (Wagott's GRAS panel) who evaluated the data and information that are the basis for Wagott's GRAS determination. Wagott considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Wagott's GRAS panel evaluated the identity, method of manufacture, product specifications, and the potential exposure resulting from the intended uses ofSG-S as well as published and unpublished studies related to the safety evaluation of SG-S. Based on this review, Wagott's GRAS panel concluded that SG-S, produced consistent with good manufacturing practice and meeting appropriate purity and food grade specifications, is GRAS, by scientific procedures, under the conditions of its intended use.
Wagott provides information about the identity and composition of SG-S. Wagott describes SG-S as a white to off-white hygroscopic powder composed of ≥95% (on a dried weight basis) steviol glycosides, a group of structurally-related sweet compounds that are natural constituents of the stevia leaf. Stevioside (CAS Reg. No. 57817-89-7) is the principal steviol glycoside component of SG-S and accounts for ≥90% of its total steviol glycosides content of ≥95%. Other steviol glycosides, including rebaudioside A (CAS Reg. No. 58543-16-1), rebaudioside C (CAS Reg. No. 63550-99-2), and dulcoside A (CAS Reg. No. 64432-06-0), may also be present. Wagott provides information about the manufacturing process and specifications for SG-S. SG-S is obtained from the leaves of S. rebaudiana (Bertoni) Bertoni through extraction and multiple purification steps. The leaves are first dried, crushed, and washed by soaking in water. The extract liquid is filtered by ultrafiltration, the solids are discarded, and the filtrate is concentrated by reverse osmosis membrane separation. The concentrated extract is followed by adsorption onto polar resin to trap the steviol glycoside components. The glycosides are eluted with methanol, and concentrated using an external circulation evaporator. The resulting preparation is then decolored with active carbon, filtered and the eluate is spray dried or vacuum dried. The dried power is dissolved in ethanol/water and filtered, followed by temperature controlled crystallization. The preparation is rinsed with ethanol and spray dried, and then is subjected to re-crystallization in ethanol to yield the final SG-S product. Wagott provides specifications for SG-S that include the content of total steviol glycosides (≥95% by weight (w/w)) and limits for moisture (≤5% w/w), lead (≤1 milligrams per kilogram (mg/kg)), arsenic (≤1 mg/kg), residual methanol (≤200 mg/kg), residual ethanol (≤5000 mg/kg) and microbial contaminants (within specified limits). Wagott states that the SG-S product meets or exceeds the specifications for steviol glycosides established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) at its 73rd meeting in June 2010.
Wagott estimates the intake of SG-S resulting from its intended use in foods. Wagott largely relies on the consumer intake estimates provided by JECFA. JECFA used the WHO Global Environmental Monitoring System-Food Contamination Monitoring and Assessment Programme database to prepare international estimates of exposure to steviol glycosides (as steviol). JECFA assumed that steviol glycosides would replace all dietary sugars, at the lowest reported relative sweetness ratio for steviol glycosides and sucrose which is 200:1. Based on this assumption, the estimated daily intakes (EDIs) of steviol glycosides (as steviol) ranged from 1.3 mg per kg body weight per day (mg/kg bw/d) to 3.5 mg/kg bw/d. JECFA concluded that the replacement estimates were highly conservative and that a more probable EDI of steviol glycosides (as steviol) would be 20 - 30% of these values or 1.0 to 1.5 mg/kg bw/d. Wagott states that the use of SG-S in food is self-limiting due to organoleptic factors and consumer taste considerations.
Wagott discusses published and unpublished studies pertaining to the safety evaluation of SG-S, 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. Wagott also considers published clinical studies and published and unpublished absorption, distribution, metabolism, and excretion studies in animals and humans. Additional studies that Wagott discusses include published in vitro and in vivo mutagenicity/genotoxicity studies. Based on its consideration of all these studies, Wagott concludes that SG-S is safe for its intended use in foods.
To further support its view that SG-S is safe for the intended use, Wagott describes recent decisions by JECFA, the Food Standards Australia New Zealand (FSANZ) and the European Food Safety Authority (EFSA) on the safety of steviol glycosides for use in food as sweeteners. Wagott notes that JECFA established an acceptable daily intake (ADI) for steviol glycosides of 0 - 4 mg/kg bw/d (expressed as steviol) and FSANZ and EFSA established an ADI for steviol glycosides of 4 mg/kg bw/d (expressed as steviol). Wagott notes that, in EFSA's view, conservative estimates of steviol glycosides exposures in European adults and children suggest that it is likely that the ADI would be exceeded at the maximum use levels proposed by the petitioners whose submission was reviewed by EFSA. 
Standards of Identity
In the notice, Wagott states its intention to use SG-S 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)
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FD&C Act to, among other things, add section 301(ll). 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 Wagott's notice that SG-S is GRAS for the intended use, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing SG-S. Accordingly, this response should not be construed to be a statement that foods that contain SG-S, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Wagott, as well as other information available to FDA, the agency has no questions at this time regarding Wagott's conclusion that SG-S 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 SG-S. As always, it is the continuing responsibility of Wagott to ensure that food ingredients 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 000389, 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
 FDA considered EFSA's exposure estimate in the context of an overall safety assessment for steviol glycosides. In FDA's view, EFSA's estimate is based on conservative assumptions. FDA addresses EFSA's exposure estimate more fully in a memorandum (Memorandum from M. Dinovi, HFS-255, to the Administrative File, GRN 000337, November 11, 2011).