Food

Agency Response Letter GRAS Notice No. GRN 000287

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CFSAN/Office of Food Additive Safety

August 28, 2009

Steven E. Weinberger
General Counsel
Wisdom Natural Brands
1203 W. San Pedro Street
Gilbert, AZ 85233

Re: GRAS Notice No. GRN 000287

Dear Mr. Weinberger:

The Food and Drug Administration (FDA) has received the notice, dated February 27, 2009, that you submitted 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 16, 2009, filed it on March 17, 2009, and designated it as GRN No. 000287.

The subject of the notice is purified steviol glycosides with rebaudioside A and stevioside as the principal components (hereinafter referred to as SG-RS in this letter). SG-RS is obtained from the leaves of Stevia rebaudiana (Bertoni) Bertoni. The notice informs FDA of the view of Wisdom Natural Brands (Wisdom) that SG-RS is GRAS, through scientific procedures, for use as a general-purpose sweetener in foods, excluding meat and poultry products and infant formulas, at levels determined by current good manufacturing practice. Wisdom notes that rebaudioside A has recently been the subject of two GRAS notices, GRN 000252 and GRN 000253, and that, on December 17, 2008, FDA responded to these GRAS notices informing the notifiers that the agency had no questions at that time regarding their conclusion that the rebaudioside A 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 000287 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 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 its notice, Wisdom includes the report of a panel of individuals (Wisdom’s GRAS panel) who evaluated the data and information that are the basis for Wisdom’s GRAS determination. Wisdom considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Wisdom’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, Wisdom’s GRAS panel concluded that SG-RS, produced consistent with current good manufacturing practice and meeting appropriate purity and food grade specifications, is GRAS, by scientific procedures, under the conditions of its intended use.

Wisdom provides information about the identity and composition of SG-RS. SG-RS is obtained from the leaves of S. rebaudiana (Bertoni) Bertoni using an aqueous extraction process. Wisdom describes the SG-RS product as a white to off-white powder composed of not less than 97% (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 Wisdom's SG-RS product and account for 86–90% of the steviol glycoside content. Other steviol glycosides, including rebaudioside C (CAS Reg. No. 63550-99-2) and dulcoside A (CAS Reg. No. 64432-06-0), may also be present.

Wisdom provides information about the manufacturing process and specifications for SG-RS. Leaves from S. rebaudiana (Bertoni) Bertoni are extracted with membrane-deionized water, followed by filtration of the extract. Large and low molecular weight impurities are then removed from the filtered extract using a mechanical separation process. The resulting extract is subjected to a food-grade ion exchange resin to achieve the minimum glycoside specification. The extract is then concentrated, pasteurized and spray-dried to yield the final SG-RS product. Wisdom provides specifications for SG-RS that include, in addition to total steviol glycosides content (>95% by weight (w/w)), limits on moisture (<6%), ash (<1%), lead (<1 milligrams per kilogram (mg/kg)), arsenic (<1 mg/kg), and microbial contaminants (within specified limits). Wisdom states 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 68th meeting in June 2007.(1)

Wisdom estimates the intake of SG-RS resulting from its intended use in foods. Wisdom intends to incorporate SG-RS into a broad selection of foods though does not provide specific consumption estimates (i.e., numbers of servings or specific use levels) for the individual food categories. Instead, Wisdom relies on the consumer intake estimates for steviol glycosides provided by JECFA and the Food Standards Australia New Zealand (FSANZ) and intake estimates for rebaudioside A as determined in both GRN 000252 and GRN 000253. JECFA assumed that steviol glycosides would replace all dietary sweeteners, at the lowest reported relative sweetness ratio for steviol glycosides and sucrose which is 200:1. Wisdom notes that estimated daily intakes (EDI) for steviol glycosides as determined by JECFA ranged from 1.3 milligrams per kilogram body weight per day (mg/kg bw/day) to 3.5 mg/kg bw/day (expressed as steviol) and that JECFA concluded that the replacement estimates were highly conservative and that a more probable dietary intake of steviol glycosides would be 20–30% of these values or 1.0 to 1.5 mg/kg bw/day (expressed as steviol). Wisdom notes that FSANZ determined the EDI for steviol glycosides would be 0.3 and 1.0 mg/kg bw/day (expressed as steviol) for the mean and 90th percentile consumer, respectively. Wisdom notes that GRN000252 provides an EDI for rebaudioside A of 0.7 mg/kg bw/day and 1.6 mg/kg bw/day (expressed as steviol) at the mean and 90th percentile, respectively. Wisdom also notes that GRN000253 provides an EDI for rebaudioside A of 0.4–1.1 mg/kg bw/day (expressed as steviol). Wisdom states that the use of SG-RS in food is self-limiting due to organoleptic factors and consumer taste considerations.

Wisdom discusses 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 and hamsters; chronic toxicity/carcinogenicity studies in rats; and reproductive/developmental toxicity studies in rats and hamsters. Wisdom also considers published clinical studies and published and unpublished absorption, distribution, metabolism and excretion studies in animals and humans. Additional studies that Wisdom discusses include published in vitro and in vivo genotoxicity studies. Based on its consideration of all these studies, Wisdom concludes that SG-RS is safe for its intended use in foods.

To further support its view that SG-RS is safe for the intended use, Wisdom describes recent decisions by JECFA and FSANZ on the safety of steviol glycosides for use in food as sweeteners. Wisdom 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, Wisdom states its 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 Wisdom’s notice that SG-RS is GRAS for use as a general-purpose sweetener in foods, excluding meat and poultry products and infant formulas, 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).

Conclusions

Based on the information provided by Wisdom, as well as other information available to FDA, the agency has no questions at this time regarding Wisdom’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 Wisdom to ensure that food ingredients that 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 000287, 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.

Sincerely,

Mitchell A. Cheeseman, Ph.D.
Acting Director
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition


(1)FDA notes that, at its 69th meeting, JECFA slightly modified the specifications with respect to solubility and limit for the solvent ethanol.