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CFSAN/Office of Food Additive Safety
July 1, 2013
Robert S. McQuate, Ph.D.
GRAS Associates, LLC
20482 Jacklight Lane
Bend, OR 97701-3074
Re: GRAS Notice No. GRN 000456
Dear Dr. McQuate:
The Food and Drug Administration (FDA) is responding to the notice, dated January 7, 2013, 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 the notice on January 10, 2013, filed it on January 23, 2013, and designated it as GRAS Notice No. GRN 000456.
The subject of the notice is rebaudioside D purified from the leaves of Stevia rebaudiana (Bertoni) Bertoni (rebaudioside D). The notice informs FDA of the view of PureCircle that rebaudioside D is GRAS, through scientific procedures, for use as a general purpose sweetener in foods, excluding infant formula and meat and poultry products, at levels determined by good manufacturing practices, as well as use as a table top sweetener.
The rebaudioside D that is the subject of GRN 000456 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 D, and FDA’s response do not necessarily apply to the uses of other stevia products.
Our use of “rebaudioside D purified from the leaves of Stevia rebaudiana (Bertoni) Bertoni.” “rebaudioside D,” “steviol glycosides,” or “SGs” 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 its 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, PureCircle includes a statement from 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 rebaudioside D as well as published and unpublished studies related to the safety evaluation of rebaudioside D. Based on this review, PureCircle’s GRAS panel concluded that rebaudioside D, produced under good manufacturing practice is GRAS under the conditions of its intended use.
PureCircle provides information about the identity, method of manufacture, and specifications for rebaudioside D. Rebaudioside D (CAS Reg. No. 63279-13-0), 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, 2-O-β-D-glucopyranosyl-β-D-glucopyranosyl ester. Rebaudioside D is one of a group of known steviol glycosides (SGs), which differ from each other by the number of glycoside moieties and bonding order. Rebaudioside D is obtained from the leaves of S. rebaudiana (Bertoni) Bertoni through extraction and multiple purification steps. Initially the dried leaves are extracted in water and then calcium hydroxide is added to precipitate impurities. The resulting mixture is separated by filtration. The extract is then deionized by ion-exchange resins, subjected to an adsorption resin and eluted with aqueous ethanol. The resulting solution is decolorized with activated carbon and filtration. The filtered product is concentrated by evaporation to remove ethanol, the remaining aqueous solution is deionized again using ion-exchange resins and then spray dried. The resulting powdered product is recrystallized in aqueous methanol and then dried, sifted and packaged to produce a final product of ≥95% rebaudioside D purity. PureCircle provides specifications for rebaudioside D that include the content of rebaudioside D (≥95% by weight (w/w)), total ash (<1%), loss on drying (<6%), lead (<1 milligram/kilogram (mg/kg)), arsenic (<1 mg/kg), residual methanol (≤200 mg/kg), residual ethanol (≤3000 mg/kg), and microbial contaminants (within specified limits). PureCircle states that rebaudioside D meets the specifications for SGs established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) at its 73rd meeting in 2010.
PureCircle provides an estimate of dietary exposure to rebaudioside D resulting from its intended use in foods. PureCircle utilized the methodology reported in GRN 000301, where the notifier used dietary exposure data for sweeteners from a published study to predict dietary exposures for the intense sweetener rebaudioside A (Ref. 1). In this study, published data on intake of intense sweeteners were converted to sucrose equivalents using estimates of sweetness relative to sucrose. PureCircle determined the relative sweetness of rebaudioside D to be 270 times that of sucrose and states that based on this sweetness intensity factor, the maximum estimated dietary exposure (expressed as steviol equivalents) in adults is 0.94 mg/kg body weight per day (mg/kg bw/day) and in children is 1.03 mg/kg bw/day. PureCircle states that the use of rebaudioside D in food is self-limiting due to organoleptic factors and consumer taste considerations.
PureCircle discusses published and unpublished studies pertaining to the metabolic fate and safety evaluation of rebaudioside D. Based on these studies, PureCircle concludes that the final metabolic fate of rebaudioside D is the same as other SGs such as rebaudioside A, stevioside and mixed SGs. As such, PureCircle discusses published and unpublished studies pertaining to the safety evaluation of rebaudioside A, stevioside, steviol, and mixed SGs. Among the studies PureCircle considers are published and unpublished studies on absorption, metabolism and excretion of SGs in humans, hamsters, and rats, subchronic toxicity studies in rats, hamsters and dogs, chronic toxicity studies in rats, reproductive/developmental toxicity studies in rats, mice, and hamsters, and clinical studies. PureCircle summarizes the previous evaluation of published and unpublished in vitro and in vivo mutagenicity/genotoxicity studies. PureCircle provides and discusses unpublished studies on acute oral toxicity in rats. PureCircle also reports the results of an unpublished 28-day study on rebaudioside D and rebaudioside A in Sprague-Dawley rats, an in vitro model of digestion comparing rebaudioside A and rebaudioside D, and the 48-hour digestion of rebaudioside A and rebaudioside D in human fecal homogenates. PureCircle concludes that these corroborative studies both support the safety of rebaudioside D and its comparability to rebaudioside A in toxicity and pharmacokinetics. Based on its consideration of all these studies, PureCircle concludes that rebaudioside D is GRAS for its intended use in foods.
To further support its view that rebaudioside D is GRAS for the intended use, PureCircle summarizes recent decisions by JECFA, the Food Standards Australia New Zealand (FSANZ), Health Canada, the European Food Safety Authority (EFSA), and other countries, on the safety of SGs for use as a sweetener in food. PureCircle notes that JECFA took final action in 2010 modifying SGs specifications to allow rebaudioside D to be considered as part of the minimum composition (≥95% SGs). PureCircle also notes that JECFA established an acceptable daily intake (ADI) for SGs of 0–4 mg/kg bw/d (expressed as steviol) and FSANZ and EFSA established an ADI for SGs of 4 mg/kg bw/d (expressed as steviol). PureCircle also notes that in 2010 EFSA reassessed the dietary exposure to SGs.(1)
Standards of Identity
In the notice, PureCircle states its intention to use rebaudioside D 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 PureCircle’s notice that rebaudioside D is GRAS for the intended use, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing rebaudioside D. Accordingly, this response should not be construed to be a statement that foods that contain rebaudioside D, 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 rebaudioside D 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 D. As always, it is the continuing responsibility of PureCircle 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 000456, 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
1. 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.
(1)FDA notes that EFSA had expressed concern that the ADI would likely be exceeded at the maximum use levels proposed by the petitioners whose submission was reviewed by EFSA. FDA considered EFSA’s exposure estimate in the context of an overall safety assessment for SGs. 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).