Agency Response Letter GRAS Notice No. GRN 000388
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CFSAN/Office of Food Additive Safety
January 9, 2012
Robert S. McQuate, Ph.D.
GRAS Associates, LLC
20482 Jacklight Lane
Bend, OR 97702-3074
Re: GRAS Notice No. GRN 000388
Dear Dr. McQuate:
The Food and Drug Administration (FDA) is responding to the notice, dated July 7, 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 8, 2011, filed it on July 13, 2011, and designated it as GRN No. 000388. 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 rebaudioside A purified from the leaves of Stevia rebaudiana (Bertoni) Bertoni (rebaudioside A). The notice informs FDA of the view of Wagott that rebaudioside A 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 rebaudioside A has 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 rebaudioside A that is the subject of their respective notices is GRAS for its intended use as a sweetener in food.
The rebaudioside A that is the subject of GRN 000 is a highly purified component of 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 rebaudioside A, and FDA's response do not necessarily apply to the uses of other stevia products.
Our use of "rebaudioside A" or "rebaudioside A purified from the leaves of Stevia rebaudiana (Bertoni) Bertoni" 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 ofrebaudioside A as well as published and unpublished studies related to the safety evaluation of rebaudioside A. Based on this review, Wagott's GRAS panel concluded that rebaudioside A, produced under good manufacturing practice is GRAS under the conditions of its intended use.
Wagott provides information about the identity, methods of manufacture, and specifications for its 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, which differ by the number of glycoside moieties and bonding order. Rebaudioside A 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 rebaudioside A product. Wagott provides specifications for rebaudioside A that include the content of rebaudioside A (≥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 rebaudioside A 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 rebaudioside A resulting from its intended use in foods. Wagott largely relies on the consumer intake estimates provided by JECFA. In addition to the JECFA intake estimates, Wagott considered the anticipated human exposure levels as determined in both GRN 000252 and GRN 000253. Wagott notes that the multiple approaches tend to converge to yield estimated daily intakes (EDIs) for rebaudioside A in the range of 0.4 - 1.6 mg/kg body weight per day (mg/kg bw/d), expressed as steviol equivalents. Furthermore, Wagott reports that if adjustments are made for the 400-fold increased sweetness of rebaudioside A alone compared to the mixed steviol glycosides sweetness factor of 200-fold relative to sucrose (JECFA), the EDI of rebaudioside A, based on the JECFA determined EDIs for steviol glycosides, would likely be about 0.5 to 0.8 mg/kg bw/d (expressed as steviol). Wagott states that the use of rebaudioside A 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 rebaudioside A, including studies on stevioside, rebaudioside A, steviol, and crude stevia extracts. Among the published studies considered were subchronic toxicity studies in rats and reproductive/developmental toxicity studies in rats. 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 rebaudioside A is safe for its intended use in foods.
To further support its view that rebaudioside A 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 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)
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 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 Wagott, as well as other information available to FDA, the agency has no questions at this time regarding Wagott's conclusion that rebaudioside A 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. 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 000388, 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).