Agency Response Letter GRAS Notice No. GRN 000473
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CFSAN/Office of Food Additive Safety
December 2, 2013
Sidd Purkayastha, Ph.D.
915 Harger Road, Suite 250
Oak Brook, IL 60523
Re: GRAS Notice No. GRN 000473
Dear Dr. Purkayastha:
The Food and Drug Administration (FDA) is responding to the notice, dated April 24, 2013, 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 the notice on May 10, 2013, filed it on May 23, 2013, and designated it as GRN No. 000473.
The subject of the notice is steviol glycosides with rebaudioside M (also known as rebaudioside X) as the principal component (hereinafter referred to as SG-RM). SG-RM is obtained from the leaves of Stevia rebaudiana (Bertoni) Bertoni. The notice informs FDA of the view of PureCircle that SG-RM 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.
The SG-RM that is the subject of GRN 000473 is a highly purified preparation of rebaudioside M 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-RM, and FDA’s response do not necessarily apply to the uses of other stevia products.
Our use of “SG-RM,” “steviol glycosides,” or “purified steviol glycosides with rebaudioside M as the principal component” 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 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-RM as well as published and unpublished studies related to the safety evaluation of SG-RM. Based on this review, PureCircle’s GRAS panel concluded that SG-RM, 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-RM. PureCircle describes SG-RM as a white to off-white hygroscopic powder composed of ≥95% (on a dried weight basis) steviol glycosides, a group of structurally-related sweet compounds that are natural constituents of the stevia leaf. Rebaudioside M (CAS Reg. No. 1220616-44-3) is the principal steviol glycoside components of SG-RM and accounts for >50% of its total steviol glycosides content. Other steviol glycosides, including rebaudioside A (CAS Reg. No. 58543-16-1), rebaudioside B (CAS Reg. No. 58543-17-2), and rebaudioside D (CAS Reg. No. 63279-13-0), are also present. PureCircle provides information about the manufacturing process and specifications for SG-RM. SG-RM is obtained from the leaves of S. rebaudiana (Bertoni) Bertoni through extraction and multiple purification steps. The leaves are first dried, crushed, and extracted in hot water. Impurities (e.g., pigments and pectin) are precipitated with calcium oxide and then removed by filtration. The aqueous extract is subjected to deionization and adsorption resin chromatography and the steviol glycosides are eluted with ethanol. The ethanol solution is decolorized with activated carbon and deionized by ion exchange chromatography. The ethanol is removed by evaporation and the product is spray dried. The resulting powdered product is dissolved in methanol and subjected to recrystallization to preferentially purify rebaudioside M. PureCircle provides specifications for SG-RM that include the content of total steviol glycosides (≥95% by weight (w/w)), total ash (<1%), lead (<1 milligrams per kilogram (mg/kg)), arsenic (<1 mg/kg), residual methanol (<0.02%) and residual ethanol (<0.3%). Specifications also include limits on microbial contaminants, including total plate count (<1,000 colony forming units per gram) and negative test results for yeast, mold, and total coliforms. PureCircle states that although SG-RM is not one of the nine steviol glycosides listed in the specifications for steviol glycosides established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) at its 73rd meeting in June 2010, rebaudioside M has a similar structure to other steviol glycosides. PureCircle concludes that since rebaudioside M is a steviol glycoside, the purity specification of not less than 95% total steviol glycosides for SG-RM is consistent with the definition for purity established by JECFA.
PureCircle provides an estimate of the dietary exposure to SG-RM 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 estimated the minimum relative sweetness of SG-RM to be 200 times that of sucrose and states that based on this sweetness intensity factor and the maximum intended use of SG-RM would yield a daily exposure (expressed as steviol equivalents) of 1.11 mg/kg body weight (bw)/day in adults and 1.22 mg/kg bw/day in children. PureCircle states that the use of SG-RM in food is self-limiting due to organoleptic factors and consumer taste considerations.
PureCircle discusses the metabolic fate of rebaudioside M and concludes that it is similar to other steviol glycosides, and thus the safety evaluation of stevioside and rebaudioside A may be extrapolated to steviol glycosides in general and rebaudioside M specifically. In support of this conclusion, PureCircle includes the results of a new unpublished in vitro metabolism study that shows rebaudioside M is hydrolyzed to steviol (similar to the metabolism of rebaudioside A) when incubated in human intestinal fecal homogenate. PureCircle states that these results demonstrate that as all steviol glycosides, including rebaudioside M, share the same steviol backbone, they are similarly degraded by fecal microbes to steviol in the gastrointestinal tract. PureCircle also 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 other published and unpublished studies PureCircle considered were those on pharmacokinetics and metabolism in rats and humans; subchronic toxicity in rats and dogs; reproductive/developmental toxicity in rat, mice, and hamsters; and clinical studies. PureCircle notes the previous evaluation of published and unpublished in vitro and in vivo mutagenicity/genotoxicity studies. Based on its consideration of all these studies, PureCircle concludes that SG-RM is GRAS for its intended use in foods.
To further support its view that SG-RM is GRAS for the intended use, PureCircle describes recent decisions by JECFA, the Food Standards Australia New Zealand (FSANZ), the European Food Safety Authority (EFSA) and Health Canada on the safety of steviol glycosides for use in food as sweeteners. PureCircle notes that JECFA established an acceptable daily intake (ADI) for steviol glycosides of 0 – 4 mg/kg bw/day (expressed as steviol) and FSANZ and EFSA established an ADI for steviol glycosides of 4 mg/kg bw/day (expressed as steviol). PureCircle 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.(1)
Standards of Identity
In the notice, PureCircle states its intention to use SG-RM 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 SG-RM is GRAS for the intended use, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing SG-RM. Accordingly, this response should not be construed to be a statement that foods that contain SG-RM, 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-RM 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-RM. As always, it is the continuing responsibility of PureCircle to ensure that food ingredients 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 000473, 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 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).