Agency Response Letter GRAS Notice No. GRN 000304
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CFSAN/Office of Food Additive Safety
March 22, 2010
Robert S. McQuate, Ph.D.
GRAS Associates, LLC
20482 Jacklight Lane
Bend, OR 97702-3074
Re: GRAS Notice No. GRN 000304
Dear Dr. McQuate:
The Food and Drug Administration (FDA) is responding to the notice, dated September 15, 2009, that you submitted on behalf of the firms Sunwin International Neutraceuticals, Inc., WILD Flavors, Inc. and Sunwin USA, LLC (hereinafter referred to as “Sunwin, WILD and Sunwin”) 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 September 18, 2009, filed it on September 24, 2009, and designated it as GRN No. 000304.
The subject of the notice is purified steviol glycosides with rebaudioside A and stevioside as the principal components (hereinafter referred to as SG-RS). SG-RS is obtained from the leaves of Stevia rebaudiana (Bertoni) Bertoni. The notice informs FDA of the view of Sunwin, WILD and Sunwin that SG-RS 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 practice. Sunwin, WILD and Sunwin note that certain purified steviol glycosides have recently been the subject of six GRAS notices, GRN 000252, GRN 000253, GRN 000275, GRN 000278, GRN 000282 and GRN 000287. They also note that FDA responded to these GRAS notices informing the notifiers that, at the time of its response, the agency had no questions regarding their conclusion that the purified steviol glycosides that is the subject of their respective notices is GRAS for its intended use as a sweetener in food.
The SG-RS that is the subject of GRN 000304 is a highly purified preparation of rebaudioside A and 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-RS, 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 “SG-RS,” “steviol glycosides” or “purified steviol glycosides with rebaudioside A and stevioside as the principal components” 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.
As part of their notice, Sunwin, WILD and Sunwin include the report of a panel of individuals (Sunwin, WILD and Sunwin’s GRAS panel) who evaluated the data and information that are the basis for Sunwin, WILD and Sunwin’s GRAS determination. Sunwin, WILD and Sunwin consider the members of their GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Sunwin, WILD and Sunwin’s GRAS panel evaluated the identity, method of manufacture, product specifications, and the potential exposure resulting from the intended uses of SG-RS as well as published and unpublished studies related to the safety evaluation of SG-RS. Based on this review, Sunwin, WILD and Sunwin’s GRAS panel concluded that SG-RS, 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.
Sunwin, WILD and Sunwin provide information about the identity, method of manufacture, and specifications for SG-RS. Sunwin, WILD and Sunwin describe SG-RS as a white to off-white powder composed of greater than 95% (on a dried weight basis) steviol glycosides, a group of structurally-related sweet compounds that are natural constituents of the stevia leaf. Rebaudioside A (CAS Reg. No. 58543-16-1) and stevioside (CAS Reg. No. 578 17-89-7) are the principal steviol glycoside components of SG-RS and account for ≥ 90% of its total steviol glycosides content. SG-RS is obtained from the leaves of S. rebaudiana (Bertoni) Bertoni through extraction and multiple purification processes. Dried leaves are subjected to water and/or ethanol extraction steps, followed by a flocculation process to remove non-soluble plant material and filtration. An adsorption resin is used to trap the steviol glycosides of the leaf extract. The resin is washed with food grade ethanol or methanol to release the glycosides. The resulting solution is decolorized using a separate adsorption resin that removes the colored plant material. The decolorized solution is concentrated by vacuum distillation, filtered and spray-dried. The dried concentrate is added to a tank with food grade ethanol or methanol and agitated, followed by centrifugation or filtration. The resulting solid and liquid portions are separately processed further by successive recrystallization with food grade ethanol or methanol to obtain a stevioside preparation and a rebaudioside A preparation. These preparations are then dried in an oven and dry-blended to yield the final SG-RS product. Sunwin, WILD and Sunwin provide specifications for SG-RS that include, in addition to total steviol glycosides content (> 95% by weight (w/w)), limits on 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). Sunwin, WILD and Sunwin state that the SG-RS 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.
Sunwin, WILD and Sunwin estimate the intake of SG-RS resulting from its intended use in foods. They largely rely 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) ranged from 1.3 milligrams per kilogram 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 on a steviol basis. Sunwin, WILD and Sunwin state that the use of SG-RS in food is self-limiting due to organoleptic factors and consumer taste considerations.
Sunwin, WILD and Sunwin discuss published and unpublished studies pertaining to the safety evaluation of SG-RS, 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, mice and hamsters. Sunwin, WILD and Sunwin also consider published and unpublished clinical studies and published and unpublished absorption, distribution, metabolism and excretion studies in animals and humans. Additional studies that they discuss include published in vitro and in vivo mutagenicity/genotoxicity studies. Based on their consideration of all these studies, Sunwin, WILD and Sunwin conclude that SG-RS is safe for its intended use in foods.
To further support their view that SG-RS is safe for the intended use, Sunwin, WILD and Sunwin describe 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. They note 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, Sunwin, WILD and Sunwin state their intention to use SG-RS 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 Sunwin, WILD and Sunwin’s notice that SG-RS 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 SG-RS. Accordingly, this response should not be construed to be a statement that foods that contain SG-RS, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Sunwin, WILD and Sunwin, as well as other information available to FDA, the agency has no questions at this time regarding Sunwin, WILD and Sunwin’s conclusion that SG-RS 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-RS. As always, it is the continuing responsibility of Sunwin, WILD and Sunwin to ensure that food ingredients these firms market 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 000304, 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
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition