Agency Response Letter GRAS Notice No. GRN 000380
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CFSAN/Office of Food Additive Safety
November 28, 2011
Robert S. McQuate, Ph.D.
GRAS Associates, LLC
20482 Jacklight Lane
Bend, OR 97702-3074
Re: GRAS Notice No. GRN 000380
Dear Dr. McQuate:
The Food and Drug Administration (FDA) is responding to the notice, dated May 5, 2011, that you submitted on behalf of GLG Life Tech Corporation (GLG Life Tech) 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 May 12, 2011, filed it on June 1, 2011, and designated it as GRN No. 000380.
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 GLG Life Tech 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. GLG Life Tech notes that 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 000380 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 component of 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 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. 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, GLG Life Tech includes the report of a panel of individuals (GLG Life Tech's GRAS panel) who evaluated the data and information that are the basis for GLG Life Tech's GRAS determination. GLG Life Tech considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. GLG Life Tech's 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 related to the safety evaluation of rebaudioside A. Based on this review, GLG Life Tech's GRAS panel concluded that rebaudioside A, produced under good manufacturing practice is GRAS under the intended conditions of use.
GLG Life Tech provides information about the identity, method 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 extracted with purified water. The extract is precipitated with ferric chloride and calcium hydroxide and filtered, followed by adsorption onto a resin. The resin is washed with ethanol and the resulting solution is decolorized with activated carbon and concentrated by evaporation. It is again decolorized with activated carbon, filtered and spray-dried. The spray-dried preparation is combined with similarly processed additional extracts, dissolved in ethanol and/or methanol, crystallized and filtered. The resulting preparation is subjected to further crystallization steps, filtered and spray-dried to yield the final rebaudioside A product. GLG Life Tech provides specifications for its rebaudioside A that include the content of rebaudioside A (≥95% by weight (w/w)) and limits for 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). GLG Life Tech 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 69th meeting in June 2008.
GLG Life Tech estimates the intake of rebaudioside A resulting from its intended use in foods. GLG Life Tech largely relies on the consumer intake estimates provided by JECFA. In addition to the JECFA intake estimates, GLG Life Tech considered the anticipated human exposure levels as determined in both GRN 000252 and GRN 000253. GLG Life Tech 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, GLG Life Tech 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). GLG Life Tech states that the use of rebaudioside A in food is self-limiting due to organoleptic factors and consumer taste considerations.
GLG Life Tech 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 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, mice, and hamsters. GLG Life Tech also considers published and unpublished clinical studies and published and unpublished absorption, distribution, metabolism, and excretion studies in animals and humans. Additional studies that GLG Life Tech discusses include published in vitro and in vivo mutagenicity/genotoxicity studies. Based on their consideration of all these studies, GLG Life Tech 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, GLG Life Tech 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, one of which is rebaudioside A, for use in food as sweeteners. GLG Life Tech 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). GLG Life Tech 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, GLG Life Tech 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 GLG Life Tech'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 GLG Life Tech, as well as other information available to FDA, the agency has no questions at this time regarding GLG Life Tech'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 GLG Life Tech 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 000380, 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 9, 2011).