Agency Response Letter GRAS Notice No. GRN 000461
CFSAN/Office of Food Additive Safety
August 14, 2013
Robert S. McQuate, Ph.D.
GRAS Associates, LLC
20482 Jacklight Lane
Bend, OR 97702-3074
Re: GRAS Notice No. GRN 000461
Dear Dr. McQuate
The Food and Drug Administration (FDA) is responding to the notice, dated February 5, 2013, that you submitted on behalf of Almendra Ltd. (Almendra) 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 14, 2013, filed it on March 1, 2013, and designated it as GRAS Notice No. GRN 000461.
The subject of the notice is rebaudioside A purified from the leaves of Stevia rebaudiana (Bertoni) Bertoni (rebaudioside A). The notice informs FDA of the view of Almendra 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 practices, as well as use as a table top sweetener. Almendra 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 000461 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 purified from the leaves of Stevia rebaudiana (Bertoni) Bertoni” or “rebaudioside A, “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, Almendra includes a statement from a panel of individuals (Almendra’s GRAS panel) who evaluated the data and information that are the basis for Almendra’s GRAS determination. Almendra considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Almendra’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, Almendra’s GRAS panel concluded that rebaudioside A, produced under good manufacturing practice is GRAS under the conditions of its intended use.
Almendra provides information about the identity, method of manufacture, and specifications for 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 (SGs), 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 dry stevia leaves are extracted in hot water with continuous agitation. Non-soluble material is precipitated with ferric chloride, aluminum chloride and/or lime, and then removed by filtration. The filtrate is subjected to adsorption resin chromatography to trap the SG components, and then the SGs are eluted with ethanol. The ethanol is removed using membrane filtration and spray drying. The product at this stage consists of 40–60% rebaudioside A and ≥ 90% total SGs. The product is re-dissolved in food grade ethanol and heated. The glycosides are then allowed to crystallize. The crystals are removed by centrifugation and filtration. The product undergoes a second crystallization step in ethanol, including centrifugation and filtration. The crystallized precipitate is collected, dried in a vacuum oven, tested for compliance with specifications, and then packed. Almendra provides specifications for rebaudioside A that include the content of rebaudioside A (≥ 97% by weight (w/w)), total ash (≤ 0.1%), loss on drying (≤ 3%), lead (≤ 0.1 milligrams/kilogram (mg/kg)), arsenic (≤ 0.02 mg/kg), residual methanol (≤ 200 mg/kg), residual ethanol (≤ 500 mg/kg), and microbial contaminants (within specified limits). Almendra states that the rebaudioside A product meets the specifications for SGs established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) at its 69th meeting in 2008 and comply with the Food Chemical Codex specifications for rebaudioside A (2010).
Almendra provides an estimate of dietary exposure to rebaudioside A resulting from its intended use in foods. Almendra 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. Almendra estimated the minimum relative sweetness of rebaudioside A to be 200 times that of sucrose and states that based on this sweetness intensity factor and the maximum intended use of rebaudioside A (expressed as steviol equivalents)would yield a daily exposure of 1.47 mg/kg body weight (bw)/day in adults and 1.63 mg/kg bw/day in children. Almendra states that the use of rebaudioside A in food is self-limiting due to organoleptic factors and consumer taste considerations.
Almendra discusses published and unpublished studies pertaining to the safety evaluation of rebaudioside A, including studies on stevioside, rebaudioside A, steviol, and crude stevia extracts. Among the studies Almendra considered were published and unpublished studies on pharmacokinetics and metabolism in humans, rats, chickens, and dogs, subchronic toxicity studies on rats and dogs, reproductive/developmental toxicity studies in rats, mice, and hamsters, and clinical studies. Almendra notes the previous evaluation of published and unpublished in vitro and in vivo mutagenicity/genotoxicity studies. Based on its consideration of all these studies, Almendra concludes that rebaudioside A is GRAS for its intended use in foods.
To further support its view that rebaudioside A is GRAS for the intended use, Almendra summarizes recent decisions by JECFA, the Food Standards Australia New Zealand (FSANZ), the European Food Safety Authority (EFSA), Health Canada and the Codex Committee on Food Additives on the safety of SGs for use in food as a sweetener. Almendra notes that JECFA established an acceptable daily intake (ADI) for SGs of 0–4 mg/kg bw/day (expressed as steviol) and FSANZ and EFSA established an ADI for SGs of 4 mg/kg bw/day (expressed as steviol). Almendra notes that, in EFSA's view, conservative estimates of SG 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.1
Standards of Identity
In the notice, Almendra 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 Almendra’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 Almendra, as well as other information available to FDA, the agency has no questions at this time regarding Almendra’s conclusion that rebaudioside A 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. As always, it is the continuing responsibility of Almendra 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 000461, 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.
1FDA 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).