Agency Response Letter GRAS Notice No. GRN 000418
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CFSAN/Office of Food Additive Safety
June 7, 2012
Sangeeta Patel, Ph.D.
Product Solutions Research, Inc.
2112 Baywood Lane
Davis, CA 95618
Re: GRAS Notice No. GRN 000418
Dear Dr. Sangeeta Patel:
The Food and Drug Administration (FDA) is responding to the notice, dated January 31, 2012, that you submitted on behalf of MiniStar International, Inc. (MiniStar) 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 February 1, 2012, filed it on February 3, 2012, and designated it as GRAS Notice No. GRN 000418.
The subject of the notice is rebaudioside A derived from Stevia rebaudiana (Bertoni) Bertoni (rebaudioside A). The notice informs FDA of the view of MiniStar that rebaudioside A is GRAS, through scientific procedures, for use as a general purpose sweetener in foods excluding meat and poultry products and infant formula, at levels determined by good manufacturing practice. MiniStar notes that rebaudioside A has 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 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 000418 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.
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 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, MiniStar includes a statement from a panel of individuals (MiniStar’s GRAS panel) who evaluated the data and information that are the basis for MiniStar’s GRAS determination. MiniStar considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. MiniStar’s GRAS panel evaluated the identity, method of manufacture, product specifications, and the potential exposure resulting from the intended uses of rebaudioside A as well as published and unpublished studies related to the safety evaluation of rebaudioside A. Based on this review, MiniStar’s GRAS panel concluded that rebaudioside A, produced under good manufacturing practice is GRAS under the intended conditions of use.
MiniStar 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 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. Rebaudioside A is one of a group of known steviol glycosides, which differ from each other 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, crushed and subjected to extraction with hot water. Ferrous sulfate and calcium oxide are added to the extract solution to precipitate plant substances followed by filtration. The filtrate is passed through adsorption resin to trap the steviol glycoside components, the glycosides adsorbed on the resin are eluted with ethanol and the extract is desalted by passing through ion exchange resin and decolored using active carbon. The extract is then evaporated at high temperature and the concentrate decolored a second time using active carbon and spray dried to yield the final rebaudioside A product. MiniStar provides specifications for rebaudioside A that include the content of rebaudioside A (≥ 98% by weight (w/w)), total ash (< 1%), loss on drying (6%), lead (< 1 part per million (ppm)), arsenic (< 1 ppm), residual methanol (< 200 ppm), residual ethanol (< 5000 ppm), and microbial contaminants (within specified limits). MiniStar 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 73rd meeting in 2010.
MiniStar estimates the intake of rebaudioside A resulting from its intended use in foods. MiniStar states that the foods are the same as those provided by Merisant in GRN 000252 and Cargill in GRN 000253 and the use level is proportional to those notices. MiniStar states that taking into account that rebaudioside A is about twice as sweet as mixed steviol glycosides, and JECFA (2006) estimates on a per user basis, the estimated daily intake (EDI) of rebaudioside A is 2.0 and 4.7 milligrams per kilogram body weight per day (mg/kg bw/d) for the mean and 90th percentile user, respectively.(1) MiniStar states that the use of rebaudioside A in food is self-limiting due to organoleptic factors and consumer taste considerations.
MiniStar discusses published and unpublished studies pertaining to the safety evaluation of rebaudioside A, including published and unpublished studies on pharmacokinetics and metabolism in humans and rats, subchronic toxicity studies on rats and dogs, reproductive/developmental toxicity studies in rats, clinical studies, and MiniStar notes the previous evaluation of published and unpublished in vitro and in vivo mutagenicity/genotoxicity studies. MiniStar also provides and discusses unpublished studies on acute oral toxicity in rats, acute dermal toxicity in rats, skin irritation in rabbits and ocular irritation in rabbits. Based on its consideration of all these studies, MiniStar 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, MiniStar summarizes recent decisions by JECFA, the Food Standards Australia New Zealand (FSANZ) and the European Food Safety Authority (EFSA) on the safety of steviol glycosides for use in food as sweeteners. MiniStar notes that JECFA established an acceptable daily intake (ADI) for steviol glycosides of 0 - 4 mg/kg bw/d (expressed as steviol) and FSANZ and EFSA established an ADI for steviol glycosides of 4 mg/kg bw/d (expressed as steviol). MiniStar notes that, in EFSA's view, conservative estimates of steviol glycosides exposures in European adults and children suggest that it is likely that the ADI would be exceeded at the maximum use levels proposed by the petitioners whose submission was reviewed by EFSA.(2)
Standards of Identity
In the notice, MiniStar 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 (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 MiniStar’s notice that rebaudioside A is GRAS for the intended use, 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 MiniStar International, Inc., and other information available to FDA, the agency has no questions at this time regarding MiniStar’s conclusion that rebaudioside A derived from Stevia rebaudiana (Bertoni) Bertoni 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 derived from Stevia rebaudiana (Bertoni) Bertoni. As always, it is the continuing responsibility of MiniStar 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 00 0418, 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)The notifier did not express the EDI in steviol equivalents. Based on the ratio of molecular weights (318 : 966.4), the EDIs of 2 and 4.7 mg/kg bw/d (mean and 90th percentile) for rebaudioside A are 0.7 and 1.5 mg/kg bw/d on a steviol equivalents basis, respectively.
(2)FDA considered EFSA’s exposure estimate in the context of an overall safety assessment for steviol glycosides. 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).