Agency Response Letter GRAS Notice No. GRN 000354
CFSAN/Office of Food Additive Safety
July 15, 2011
Robert S. McQuate, Ph.D
GRAS Associates, LLC
20482 Jacklight Lane
Bend, OR 97702-3074
Re: GRAS Notice No. GRN 000354
Dear Dr. McQuate:
The Food and Drug Administration (FDA) is responding to the notice, dated August 24, 2010, that you submitted on behalf of Guilin Layn Natural Ingredients Corporation (Guilin Layn) 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 31, 2010, filed it on September 3, 2010, and designated it as GRN No. 000354.
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 Guilin Layn that rebaudioside A 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. Guilin Layn notes that rebaudioside A has recently been the subject of several 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 000354 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” or “rebaudioside A 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 their 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, Guilin Layn includes the report of a panel of individuals (Guilin Layn’s GRAS panel) who evaluated the data and information that are the basis for Guilin Layn’s GRAS determination. Guilin Layn considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Guilin Layn’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 on rebaudioside A and related substances. Based on this review, Guilin Layn’s GRAS panel concluded that rebaudioside A, produced consistent with good manufacturing practice and meeting appropriate purity and food grade specifications, is GRAS under the conditions of its intended use.
Guilin Layn provides information about the identity, method of manufacture, and specifications for its 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, which differ 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 leaves are crushed using a size 20 mesh and washed by soaking in purified water for 20 minutes. After removal of the wash water, the leaves are extracted twice with deionized water at 95-99°C. The extract liquid is concentrated first under vacuum and then by centrifugation. The concentrated extract is passed through an adsorption resin to trap the steviol glycoside components. The glycosides are eluted with either 60% ethanol or 80% methanol, centrifuged and concentrated. The resulting preparation is then passed through a strong base anion resin for decolorization, and the eluate is dried under vacuum. The dried powder is subjected to crystallization in methanol/deionized water, followed by re-crystallization in ethanol/water. The re-crystallized preparation is then dried under vacuum and passed through an 80 mesh screen to yield the final rebaudioside A product. Guilin Layn provides specifications for rebaudioside A that include the content of rebaudioside A (≥97% by weight (w/w)) and limits for moisture (≤5% w/w), lead (<0.5 milligrams per kilogram (mg/kg)), arsenic (<0.05 mg/kg), residual methanol (<200 mg/kg), residual ethanol (<2000 mg/kg) and microbial contaminants (within specified limits). Guilin Layn states that the rebaudioside A 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.
Guilin Layn estimates the intake of rebaudioside A resulting from its intended use in foods. Guilin Layn largely relies on the consumer intake estimates provided by JECFA. In addition to the JECFA intake estimates, Guilin Layn considered the anticipated human exposure levels as determined in both GRN 000252 and GRN 000253. Guilin Layn notes that the multiple approaches tend to converge to yield estimated daily intakes (EDIs) for rebaudioside A in the range of 0.4 - 1.6 mg/kg body weight per day (mg/kg bw/d), expressed as steviol equivalents. Furthermore, Guilin Layn reports that if adjustments are made for the 400-fold increased sweetness of rebaudioside A alone compared to the mixed steviol glycosides sweetness factor of 200-fold relative to sucrose (JECFA), the EDI of rebaudioside A, based on the JECFA determined EDIs for steviol glycosides, would likely be about 0.5 to 0.8 mg/kg bw/d (expressed as steviol). Guilin Layn states that the use of rebaudioside A in food is self-limiting due to organoleptic factors and consumer taste considerations.
Guilin Layn discusses published and unpublished studies pertaining to the safety evaluation of rebaudioside A, 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, chronic toxicity/carcinogenicity studies in rats, and reproductive/developmental toxicity studies in rats and hamsters. Guilin Layn also considers published clinical studies and published and unpublished absorption, distribution, metabolism and excretion studies in animals and humans. Additional studies that Guilin Layn discusses include published in vitro and in vivo mutagenicity/genotoxicity studies. Based on its consideration of all these studies, Guilin Layn concludes that rebaudioside A is safe for its intended use in foods.
To further support its view that rebaudioside A is safe for the intended use, Guilin Layn 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 rebaudioside A, for use in food as sweeteners. Guilin Layn 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). Guilin Layn also 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, Guilin Layn 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 (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 Guilin Layn’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 Guilin Layn, as well as other information available to FDA, the agency has no questions at this time regarding Guilin Layn’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 Guilin Layn 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 000354, 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.