Agency Response Letter GRAS Notice No. GRN 000493
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CFSAN/Office of Food Additive Safety
May 30, 2014
Robert S. McQuate, Ph.D.
GRAS Associates, LLC
20482 Jacklight Lane
Bend, OR 97702-3074
Re: GRAS Notice No. GRN 000493
Dear Dr. McQuate:
The Food and Drug Administration (FDA) is responding to the notice, dated November 25, 2013, that you submitted on behalf of GLG Life Tech Corporation 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 December 18, 2013, filed it on December 23, 2013, and designated it as GRAS Notice No. GRN 000493.
The subject of the notice is steviol glycosides with rebaudioside A and stevioside as the principal components (hereinafter referred to as SG-RS). SG-RS is obtained from the leaves of Stevia rebaudiana (Bertoni) Bertoni. The notice informs FDA of the view of GLG that SG-RS is GRAS, through scientific procedures, for use as a general purpose sweetener in foods, excluding meat and poultry products, at levels determined by good manufacturing practices, as well as use as a table top sweetener. GLG notes that purified steviol glycosides have 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 purified steviol glycosides that are the subject of their respective notices are GRAS for their intended use as a sweetener in food.
The SG-RS that is the subject of GRN 000493 is a highly purified preparation of rebaudioside A and stevioside 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-RS, and FDA's response do not necessarily apply to the uses of other stevia products.
Our use of "SG-RS," "steviol glycosides," or "purified steviol glycosides with rebaudioside A and stevioside as the principal components" 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 non-standardized 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, GLG includes the report of a panel of individuals (GLG's GRAS panel) who evaluated the data and information that are the basis for GLG's GRAS determination. GLG considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. GLG's GRAS panel evaluated the identity, method of manufacture, product specifications, and the potential exposure resulting from the intended uses of SG-RS as well as published and unpublished studies related to the safety evaluation of SG-RS. Based on this review, GLG's GRAS panel concluded that SG-RS, 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.
GLG provides information about the identity and composition of SG-RS. GLG describes SG-RS as a white to off-white, hygroscopic crystal, granule or 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. GLG describes four preparations that contain differing proportions of steviol glycosides. Rebaudioside A (CAS Reg. No. 58543-16-1) and stevioside (CAS Reg. No. 57817-89-7) are the principal steviol glycoside components of SG-RS. The percentages of rebaudioside A in the four SG-RS preparations are 50, 60, 80, and 85%, respectively. The respective stevioside concentrations are 25%, 15%, not specified (NS), and NS. Other steviol glycosides, including rebaudioside C (CAS Reg. No. 63550-99-2) and dulcoside A (CAS Reg. No. 64432-06-0), may also be present.
GLG also provides information about the manufacturing process and specifications for SG-RS. SG-RS is obtained from the leaves of S. rebaudiana (Bertoni) Bertoni through extraction and multiple purification steps. The leaves are extracted in water, which is then re-extracted with ethanol and/or methanol. The steviol glycosides are crystallized, and then concentrated using filtration. The concentrate is dissolved in purified water, subjected to additional filtration, decolorization, and concentration steps prior to sterilization and spray drying. GLG provides specifications for SG-RS that include the content of total steviol glycosides (≥95% by weight (w/w)), and limits for moisture (≤4% w/w), lead (<1 milligrams per kilogram (mg/kg)), arsenic (<1 mg/kg), residual methanol (<200 mg/kg), and residual ethanol (<5000 mg/kg). Specifications also include limits on microbial contaminants. GLG states that SG-RS meets the specifications for steviol glycosides established by the FAO/WHO Joint Expert Committee on Food Additives (JECFA) at its 73rd meeting in 2010.
GLG concludes that based on published stability studies conducted on steviol glycosides and the results of stability tests conducted on GLG’s SG-RS over a period 24 months, SG-RS is stable under the intended conditions of use.
GLG provides an estimate of the dietary exposure to SG-RS resulting from its intended use in foods. GLG 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. GLG estimated the minimum relative sweetness of the four, notified SG-RS preparations to be 280, 320, 360, and 380 times that of sucrose. Based on these sweetness intensity factors and the maximum intended use of SG-RS, GLG estimates the maximum daily exposure (expressed as steviol equivalents) as 0.83 to 1.24 milligrams per kilogram body weight per day (mg/kg bw/d) in adults and 0.92 to 1.37 mg/kg bw/d in children. GLG states that the use of SG-RS in food is self-limiting due to organoleptic factors and consumer taste considerations.
GLG discusses published and unpublished studies pertaining to the safety evaluation of SG-RS, including studies on rebaudioside A, stevioside, steviol, and crude stevia extracts. Among the published studies considered were acute toxicity studies in rats, mice, and hamsters; subchronic toxicity studies in rats and hamsters; chronic toxicity/carcinogenicity studies in rats; and reproductive/developmental toxicity studies in rats and hamsters. GLG also considers published clinical studies and published and unpublished absorption, distribution, metabolism, and excretion studies in animals and humans. Additional studies that GLG discusses include published in vitro and in vivo mutagenicity/genotoxicity studies, and human clinical studies. Based on its consideration of all these studies, GLG concludes that SG-RS is GRAS for its intended use in foods.
To further support its view that SG-RS is GRAS for the intended use, GLG describes 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. GLG 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). GLG 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, GLG states its intention to use SG-RS 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 GLG's notice that SG-RS is GRAS for the intended use, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing SG-RS. Accordingly, this response should not be construed to be a statement that foods that contain SG-RS, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by GLG, as well as other information available to FDA, the agency has no questions at this time regarding GLG’s conclusion that SG-RS 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-RS. As always, it is the continuing responsibility of GLG 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 000493, 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 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).