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CFSAN/Office of Food Additive Safety
September 9, 2010
Benjamin L. England
Benjamin L. England & Associates, LLC
6420 Dobbin Road, Suite E
Columbia, MD 21045
Re: GRAS Notice No. GRN 000329
Dear Mr. England:
The Food and Drug Administration (FDA) is responding to the notice, dated March 5, 2010, that you submitted on behalf of GLG Life Tech, Ltd. (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 this notice on March 9, 2010, filed it on March 12, 2010, and designated it as GRN No. 000329.
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 current good manufacturing practices. GLG Life Tech notes that rebaudioside A has recently been the subject of other GRAS notices, including GRN 000252, and incorporates by reference the information contained in GRN 000252. GLG Life Tech also notes 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 000329 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.
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 Stevia 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.
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 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 through extraction and multiple purification steps. The leaves are dried and extracted with water. The extract is precipitated with ferric chloride and calcium hydroxide and filtered. The filtered extract is pumped into an adsorption resin exchange tank. Upon saturation, the resin is washed with a water/ethanol mixture solvent. The resulting solution is decolorized with activated carbon and concentrated by evaporation at 80°C. It is then decolorized with activated carbon again and filtered. The resulting filtrate is spray dried and subjected to crystallization and recrystallization steps in ethanol/water, followed by filtration. The resulting crystal product is dissolved and then concentrated by evaporation at 80°C, filtered, and spray/vacuum dried to yield the final rebaudioside A product. GLG Life Tech provides specifications for its rebaudioside A that include the content of rebaudioside A (≥ 97% by weight (w/w)) and limits for lead (≤ 1 milligrams per kilogram (mg/kg)), arsenic (≤ 1 mg/kg), residual ethanol (≤ 0.5%), residual methanol (≤ 0.2%) and microbial contaminants (within specified limits). GLG Life Tech states that the rebaudioside A product meets 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 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 showing 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. GLG Life Tech 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. GLG Life Tech states that the use of rebaudioside A in food is largely self-limiting due to its organoleptic properties.
GLG Life Tech 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 subchronic toxicity studies in rats; chronic toxicity/carcinogenicity studies in rats; and reproductive/developmental toxicity studies in rats and hamsters. GLG Life Tech also considers published 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 vivo mutagenicity/genotoxicity studies. Based on its 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 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. GLG Life Tech 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).
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 (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 GLG Life Tech’s notice that rebaudioside A is GRAS for use as a general-purpose sweetener in foods, excluding meat and poultry products, 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 000329, 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
- 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.
1FDA 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.