Agency Response Letter GRAS Notice No. GRN 000367
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CFSAN/Office of Food Additive Safety
July 8, 2011
Robert S. McQuate, Ph.D
GRAS Associates, LLC
20482 Jacklight Lane
Bend, OR 97702-3074
Re: GRAS Notice No. GRN 000367
Dear Dr. McQuate:
The Food and Drug Administration (FDA) is responding to the notice, dated December 10, 2010, that you submitted on behalf of Sinochem Qingdao Co., Ltd. (Sinochem) 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 December 29, 2010, filed it on January 11, 2011, and designated it as GRN No. 000367.
The subject of the notice is purified 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 Sinochem that SG-RS 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 practices, as well as use as a table top sweetener. Sinochem notes that purified steviol glycosides have 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 purified steviol glycosides that are the subjects of their respective notices are GRAS for their intended use as a sweetener in food.
The SG-RS that is the subject of GRN 000367 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 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, Sinochem includes the report of a panel of individuals (Sinochem’s GRAS panel) who evaluated the data and information that are the basis for Sinochem’s GRAS determination. Sinochem considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Sinochem’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, Sinochem’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.
Sinochem provides information about the identity and composition of SG-RS. Sinochem describes SG-RS 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 A (CAS Reg. No. 58543-16-1) and stevioside (CAS Reg. No. 57817-89-7) are the principal steviol glycoside components of SG-RS and account for ≥85% of its total steviol glycosides content. 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.
Sinochem 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 screened by use of a sieve to remove foreign materials, such as stems and twigs and sand, followed by extraction with deionized water. Ferrous sulfate and calcium hydroxide are added to the extract solution to precipitate plant substances such as pectin and pigment, followed by filtration steps. The resulting solution is passed through an adsorption resin to trap the steviol glycoside components. The glycosides are subsequently eluted with ethanol. The ethanol is partially evaporated and the concentrated extract is passed through an ion exchange resin to remove minerals. The concentrate is then subjected to filtration steps and spray-dried to yield the final SG-RS product. Sinochem provides specifications for its SG-RS that include the content of total steviol glycosides (≥95% by weight (w/w)) and limits for lead (≤91 milligrams per kilogram (mg/kg)), arsenic (≤91 mg/kg), residual ethanol (<5000 mg/kg) and microbial contaminants (within specified limits). Sinochem states that the SG-RS product meets or exceeds the specifications for steviol glycosides established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) at its 73rd meeting in June 2010.
Sinochem estimates the intake of SG-RS resulting from its intended use in foods. Sinochem largely relies on the consumer intake estimates provided by JECFA. JECFA used the WHO Global Environmental Monitoring System-Food Contamination Monitoring and Assessment Programme database to prepare international estimates of exposure to steviol glycosides (as steviol). JECFA assumed that steviol glycosides would replace all dietary sugars, at the lowest reported relative sweetness ratio for steviol glycosides and sucrose which is 200:1. Based on this assumption, the estimated daily intakes (EDIs) of steviol glycosides (as steviol) ranged from 1.3 milligrams per kilogram body weight per day (mg/kg bw/d) to 3.5 mg/kg bw/d. JECFA concluded that the replacement estimates were highly conservative and that a more probable EDI of steviol glycosides (as steviol) would be 20 - 30% of these values or 1.0 to 1.5 mg/kg bw/d. Sinochem states that the use of SG-RS in food is self-limiting due to organoleptic factors and consumer taste considerations.
Sinochem 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, chronic toxicity/carcinogenicity studies in rats, and reproductive/developmental toxicity studies in rats and hamsters. Sinochem also considers published clinical studies and published and unpublished absorption, distribution, metabolism and excretion studies in animals and humans. Additional studies that Sinochem discusses include published in vitro and in vivo mutagenicity/genotoxicity studies. Based on its consideration of all these studies, Sinochem concludes that SG-RS is safe for its intended use in foods.
To further support its view that SG-RS is safe for the intended use, Sinochem 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 for use in food as sweeteners. Sinochem 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). Sinochem 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, Sinochem 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 (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 Sinochem’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 Sinochem, as well as other information available to FDA, the agency has no questions at this time regarding Sinochem’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 Sinochem 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 000367, 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.