Agency Response Letter GRAS Notice No. GRN 000348
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CFSAN/Office of Food Additive Safety
July 14, 2011
Robert S. McQuate, Ph.D
GRAS Associates, LLC
20482 Jacklight Lane
Bend, OR 97702-3074
Re: GRAS Notice No. GRN 000348
Dear Dr. McQuate:
The Food and Drug Administration (FDA) is responding to the notice, dated August 6, 2010, that you submitted on behalf of GLG Life Tech, Ltd. (GLG Life Tech) 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 this notice on August 9, 2010, filed it on August 16, 2010, and designated it as GRN No. 000348.
The subject of the notice is stevioside purified from the leaves of Stevia rebaudiana (Bertoni) Bertoni (stevioside). The notice informs FDA of the view of GLG Life Tech that stevioside is GRAS, through scientific procedures, for use as a general purpose sweetener in foods, excluding meat and poultry products and infant formulas, at levels determined by good manufacturing practice, as well as use as a table top sweetener.
The stevioside that is the subject of GRN 000348 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 stevioside, and FDA’s response do not necessarily apply to the uses of other stevia products.
Our use of “stevioside” or “stevioside 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, GLG Life Tech includes the report of a panel of individuals (GLG Life Tech’s GRAS panel) who evaluated the data and information that are the basis for GLG Life Tech’s GRAS determination. GLG Life Tech 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 Life Tech’s GRAS panel evaluated the identity, method of manufacture, product specifications, and the potential exposure resulting from the intended uses of stevioside as well as published and unpublished studies on stevioside and related substances. Based on this review, GLG Life Tech’s GRAS panel concluded that stevioside, 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 Life Tech provides information about the identity, method of manufacture, and specifications for its stevioside. Stevioside (CAS Reg. No. 57817-89-7), a glycoside of steviol, is identified as 13-[(2-O-β–D-glucopyranosyl-β–D-glucopyranosyl)oxy] kaur-16-en-18-oic acid β-D-glucopyranosyl ester. Stevioside is one of a group of known steviol glycosides, which differ by the number of glycoside moieties and bonding order. Stevioside is obtained from the leaves of S. rebaudiana (Bertoni) Bertoni with high stevioside content through extraction and multiple purification steps. The leaves are first extracted with purified water. The extract is precipitated with ferric chloride and calcium hydroxide and filtered, followed by adsorption onto a resin. The resin is washed with ethanol and the resulting solution is decolorized with activated carbon and concentrated by evaporation. It is again decolorized with activated carbon, filtered and spray-dried. The spray-dried preparation is combined with similarly processed additional extracts, dissolved in ethanol and/or methanol, crystallized and filtered. The resulting preparation is subjected to further crystallization steps, filtered and spray-dried to yield the final stevioside product. GLG Life Tech provides specifications for its stevioside that include the content of stevioside (≥95% by weight (w/w)) and limits for lead (≤1 milligrams per kilogram (mg/kg)), arsenic (≤1 mg/kg), residual methanol (<200 mg/kg), residual ethanol (<5000 mg/kg) and microbial contaminants (within specified limits). GLG Life Tech states that the stevioside product meets or exceeds the specifications for steviol glycosides established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) at its 69th meeting in June 2008.
GLG Life Tech estimates the intake of stevioside resulting from its intended use in foods. GLG Life Tech largely relies on the consumer intake estimates for steviol glycosides provided by JECFA. GLG Life Tech notes that JECFA determined the estimated daily intake (EDI) of steviol glycosides to be 5 mg/kg body weight per day (mg/kg bw/d), expressed as steviol equivalents, and states that this EDI is also applicable to its stevioside. GLG Life Tech notes that the JECFA estimate is based on the assumption of 100% replacement of steviol glycosides for all sugars. GLG Life Tech further notes that JECFA concluded that the replacement estimates were highly conservative and that the calculated intake of steviol glycosides (as steviol) would more likely be 20-30% of the calculated value or 1.0 to 1.5 mg/kg bw/d.
GLG Life Tech discusses published and unpublished studies pertaining to the safety evaluation of stevioside, including studies on stevioside, rebaudioside A, steviol, and crude stevia extracts. Among the published studies considered were acute toxicity studies in rats, mice, and hamsters, subchronic toxicity studies in rats, chronic toxicity/carcinogenicity studies in rats, and reproductive/developmental toxicity studies in rats, mice, and hamsters. GLG Life Tech also considers published and unpublished clinical studies and published and unpublished absorption, distribution, metabolism, and excretion studies in animals and humans. Additional studies that GLG Life Tech discusses include published in vitro and in vivo mutagenicity/genotoxicity studies. Based on their consideration of all these studies, GLG Life Tech concludes that stevioside is safe for its intended use in foods.
GLG Life Tech notes that certain purified steviol glycosides have recently 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 conclusion that the purified steviol glycosides that is the subject of their respective notices is GRAS for its intended use as a sweetener in food.
To further support its view that stevioside is safe for the intended use, GLG Life Tech describes recent decisions by JECFA, the Food Standards Australia New Zealand (FSANZ) and the European Food Safety Authority (EFSA) on the safety of steviol glycosides, one of which is stevioside, for use in food as sweeteners. GLG Life Tech 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). GLG Life Tech 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 Life Tech states its intention to use stevioside 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 (FFDCA)
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FFDCA to, among other things, add section 301(ll). Section 301(ll) of the FFDCA prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FFDCA, 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 Life Tech’s notice that stevioside is GRAS for the intended use, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing stevioside. Accordingly, this response should not be construed to be a statement that foods that contain stevioside, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by GLG Life Tech, as well as other information available to FDA, the agency has no questions at this time regarding GLG Life Tech’s conclusion that stevioside 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 stevioside. As always, it is the continuing responsibility of GLG Life Tech 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 000348, 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.
Mitchell A. Cheeseman, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
1. Food and Chemical Toxicology 46:S61-S69. European Food Safety Authority. 2011. Revised exposure assessment for steviol glycosides for the proposed uses as a food additive. EFSA Journal: 9(1):1972.
2. 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, following a request from the European Commission, carried out a revised exposure assessment for steviol glycosides in children and adults from its use as a food additive (Ref. 1). In the revised assessment, the exposure estimate calculation uses the same methodology that was used by EFSA in its prior opinion on steviol glycosides but with revised use levels and food consumption data for children and the adult population. The mean dietary exposure to steviol glycosides (as steviol equivalents) for European children (1 to 14 years of age) ranged from 0.4 to 6.4 mg/kg bw/day, and from 1.7 to 16.3 mg/kg bw/day at the 95th percentile. Due to observed overestimations of consumption levels of non-alcoholic flavored drinks (soft drinks) by children at the 95th percentile within certain datasets, EFSA concluded that a correction factor was necessary. The corrected exposure estimate at the 95th percentile ranges from 1.0 to 12.7 mg/kg bw/day for children. For adults (UK population) mean dietary exposure to steviol glycosides (as steviol equivalents) were calculated to be 1.9 to 2.3 mg/kg bw/day and from 5.6 to 6.8 mg/kg bw/day for high level consumers (97.5th percentile). EFSA concluded that the main contributors to the total anticipated exposure to SGs are non-alcoholic flavored drinks (soft drinks) for both populations.
FDA further notes that studies conducted in the U.S., Canada, Australia, New Zealand, and Europe estimated the intakes of aspartame and other high intensity sweeteners using post-market surveillance data. Intake modeling methods are commonly used to estimate the consumption of a particular food or food ingredient. However, a realistic, but conservative approach is to estimate the intake of a sweetener based on the data reported in published studies. Estimates of intake for different sweeteners can be calculated based on adjustments for relative sweetness intensity. In a published study by Renwick (Ref. 2), the estimated intake of rebaudioside A, one of the primary steviol glycosides, was determined assuming a relative sweetness of 200 times that of sucrose. The consumption data were primarily from studies that used specifically designed food diaries combined with actual use levels or approved levels in different foods and beverages. These data were aggregated to provide an estimate of potential consumption of rebaudioside A.