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CFSAN/Office of Food Additive Safety
July 9, 2010
Robert S. McQuate, Ph.D
GRAS Associates, LLC
20482 Jacklight Lane
Bend, OR 97702-3074
Re: GRAS Notice No. GRN 000323
Dear Dr. McQuate:
The Food and Drug Administration (FDA) is responding to the notice, dated February 3, 2010, that you submitted on behalf of PureCircle USA, Inc. (PureCircle) 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 February 5, 2010, filed it on February 18, 2010, and designated it as GRN No. 000323.
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 PureCircle 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 good manufacturing practice, as well as use as a table top sweetener. PureCircle notes that certain purified steviol glycosides have recently 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 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 000323 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 its notice, PureCircle includes the report of a panel of individuals (PureCircle’s GRAS panel) who evaluated the data and information that are the basis for PureCircle’s GRAS determination. PureCircle considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. PureCircle’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, PureCircle’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.
PureCircle provides information about the identity and composition of SG-RS. PureCircle describes 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. 57817-89-7) are the principal steviol glycoside components of SG-RS and account for ≥81% of its total steviol glycosides content. Other steviol glycosides, including rebaudioside C (CAS Reg. No. 63550-99-2), dulcoside A (CAS Reg. No. 64432-06-0), rubusoside (CAS Reg. No. 63849-39-4), steviolbioside (CAS Reg. No. 41093-60-1), rebaudioside B (CAS Reg. No. 58543-17-2), rebaudioside D (CAS Reg. No. 63279-13-0), and rebaudioside F (CAS Reg. No. 438045-89-7), may also be present.
PureCircle provides information about the manufacturing process and specifications for SG-RS. SG-RS is obtained from the leaves of S. rebaudiana (Bertoni) Bertoni through extraction and multiple purification processes. The leaves are crushed and extracted with water at 50-60 °C, followed by filtration of the extract. The filtrate is treated with calcium hydroxide to achieve removal of particulate material and some of the plant pigments. The resulting suspension is maintained at ambient temperature for about 30 minutes, filtered and desalted using ion-exchange resins. The resulting solution is passed through an adsorption resin to trap the steviol glycoside components. After a wash with deionized water, the resin is washed with an aqueous solution of ethanol to release the trapped steviol glycosides. The resulting solution is decolorized using activated carbon and filtered. It is then evaporated, desalted, and nanofiltered to concentrate the glycosides. The resulting concentrate is spray-dried to yield the final SG-RS product. PureCircle provides specifications for SG-RS that include, in addition to total steviol glycosides content (≥95% by weight (w/w)), limits on rebaudioside C (≤15% w/w), rubusoside (≤2% w/w), steviolbioside (≤2% w/w), rebaudioside B (≤2% w/w), rebaudioside D (≤2.5% w/w), rebaudioside F (≤3% w/w), dulcoside A(≤2% w/w), 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). PureCircle notes that these specifications are comparable to the specifications for steviol glycosides established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) at its 69th meeting in June 2008.
PureCircle estimates the intake of SG-RS resulting from its intended use in foods. PureCircle largely relies 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) of steviol glycosides (as steviol) 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. PureCircle states that the use of SG-RS in food is self-limiting due to organoleptic factors and consumer taste considerations.
PureCircle 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; chronic toxicity/carcinogenicity studies in rats; and reproductive/developmental toxicity studies in rats, mice and hamsters. PureCircle also considers published and unpublished clinical studies and published and unpublished absorption, distribution, metabolism and excretion studies in animals and humans. Additional studies that PureCircle discusses include published in vitro and in vivo mutagenicity/genotoxicity studies. Based on their consideration of all these studies, PureCircle 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, PureCircle 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. PureCircle 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 its notice, PureCircle 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 PureCircle’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).
Based on the information provided by PureCircle, as well as other information available to FDA, the agency has no questions at this time regarding PureCircle’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 PureCircle 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 000323, 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