Agency Response Letter GRAS Notice No. GRN 000448
CFSAN/Office of Food Additive Safety
May 3, 2013
Robert McQuate, Ph.D.
GRAS Associates, LLC
20482 Jacklight Lane
Bend, OR 97702-3074
Re: GRAS Notice No. GRN 000448
Dear Dr. McQuate:
The Food and Drug Administration (FDA) is responding to the notice, dated September 27, 2012, that you submitted on behalf of Daepyung Co., Ltd. (Daepyung) 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 October 18, 2012, filed it on November 5, 2012, and designated it as GRAS Notice No. GRN 000448.
The subject of the notice is enzyme-modified steviol glycosides (EMSG). EMSG is obtained by enzyme treatment of steviol glycosides (SGs) purified from the leaves of Stevia rebaudiana (Bertoni) Bertoni. The notice informs FDA of the view of Daepyung that EMSG 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, as well as for use as a table top sweetener. Daepyung notes that EMSG 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 EMSG that is the subject of their respective notices is GRAS for its intended use as a sweetener in food. Additionally, within the notice, Daepyung incorporates by reference information in Food Master File 000849. In a letter dated September 18, 2011, Daepyung and GRAS Associates, LLC state that they relinquish confidentiality of the file as of the date of submission of the GRAS notice.
The EMSG that is the subject of GRN 000448 is made from 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 EMSG, and FDA’s response do not necessarily apply to the uses of other stevia products.
Our use of “enzyme-modified steviol glycosides,” “EMSG,” “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, Daepyung includes a statement from a panel of individuals (Daepyung’s GRAS panel) who evaluated the data and information that are the basis for Daepyung’s GRAS determination. Daepyung considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Daepyung’s GRAS panel evaluated the identity, method of manufacture, product specifications, and the potential exposure resulting from the intended uses of EMSG as well as published and unpublished studies related to the safety evaluation of EMSG. Based on this review, Daepyung’s GRAS panel concluded that EMSG, produced under good manufacturing practice is GRAS under the conditions of its intended use.
Daepyung provides information about the identity and composition of EMSG. Daepyung describes EMSG as an off-white to white powder composed of ≥ 95% α-D-glucosylated SGs and unreacted SGs. The α-D-glucosylated SGs are generated by treatment of SGs extract preparations with a food-grade α-glycosyltransferase enzyme in the presence of dextrin. The α-D-glucosylated SGs have glucose side chains that have been extended, generally with 1 to 3 additional glucose moieties, as compared to the naturally occurring SGs. These additional glucose residues are attached by stereo- and regio-specific 1,4-α-D-glycosidic bonds, whereas the glucose in naturally occurring SGs is attached by β-glycosidic bonds.
Daepyung provides information about the method of manufacture, and specifications for EMSG. EMSG is obtained from the leaves of S. rebaudiana (Bertoni) Bertoni through extraction and multiple purification steps followed by treatment with an α-glycosyltransferase enzyme and repurification. In this process, the leaves are first dried, and then extracted in water. Ferric chloride and calcium hydroxide are added to the extract solution to precipitate impurities followed by filtration. The filtrate is passed through an ion-exchange resin to trap the glycoside components, the glycosides are eluted with ethanol or methanol and the result is deionized and then decolorized with activated carbon. The product is further purified by recrystallization using aqueous ethanol or methanol and then centrifuged, and then recrystallized again and then filtered, concentrated, sterilized and spray dried. The dried product is dissolved in water and reacted with a food grade α-glucanotransferase enzyme in the presence of dextrin as a glucose source. At this step, a glycosylation reaction takes place adding glucose moieties to the SGs, resulting in the formation of 1,4-α-D-glucosylated SGs constituents in the preparation. The enzyme is deactivated and the product is then subjected to an adsorption resin and eluted with methanol or ethanol, concentrated, filtered, sterilized, and spray dried. Daepyung provides specifications for EMSG that include the content of total SGs (≥ 95% by weight (w/w)), total ash (≤ 1%), loss on drying (≤ 6%), lead (≤ 1 milligram per kilogram (mg/kg)), arsenic (≤ 1 mg/kg), residual methanol (≤ 200 mg/kg), residual ethanol (≤ 5000 mg/kg), and microbial contaminants (within specified limits).
Daepyung provides an estimate of dietary intake of EMSG resulting from its intended use in foods. Daepyung 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. Daepyung determined the relative sweetness of EMSG to be 100 times that of sucrose and states that based on this sweetness intensity factor, the maximum estimated use of EMSG would yield an estimated daily intake in healthy adults (expressed as steviol equivalents) of 2.17 mg/kg body weight per day (bw/d). Daepyung states that the use of EMSG in food is self-limiting due to organoleptic factors and consumer taste considerations.
Daepyung discusses published and unpublished studies pertaining to the metabolic fate and safety evaluation of EMSG. Based on these studies, Daepyung concludes that the final metabolic fate of EMSG is the same as naturally occurring SGs with a negligible amount of glucose released in the intestines. As such, Daepyung discusses published and unpublished studies pertaining to the safety evaluation of SGs, predominantly studies on stevioside. Among the studies Daepyung considers are published and unpublished studies on absorption, metabolism and excretion of SGs in humans and rats, subchronic toxicity studies on rats and hamsters, chronic toxicity studies in rats, reproductive/developmental toxicity studies in rats, mice, and hamsters, and clinical studies. Daepyung notes the previous evaluation of published and unpublished in vitro and in vivo mutagenicity/genotoxicity studies. Daepyung 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, Daepyung concludes that EMSG is GRAS for its intended use in foods.
To further support its view that EMSG is GRAS for the intended use, Daepyung 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 in food as a sweetener. Daepyung 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). Daepyung also notes that in 2010 EFSA reassessed the intake of SGs.1
Standards of Identity
In the notice, Daepyung states its intention to use EMSG 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 Daepyung’s notice that EMSG is GRAS for the intended use, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing EMSG. Accordingly, this response should not be construed to be a statement that foods that contain EMSG, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Daepyung, as well as other information available to FDA, the agency has no questions at this time regarding Daepyung’s conclusion that EMSG 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 EMSG. As always, it is the continuing responsibility of Daepyung 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 000448, 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 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).