Agency Response Letter GRAS Notice No. GRN 000369
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CFSAN/Office of Food Additive Safety
October 11, 2011
Zhucheng Haotian Pharm Co., Ltd.
C/O Shanghai Freemen Americas, LLC
377 Hoes Lane, Suite 204
Piscataway, NJ 08854
Re: GRAS Notice No. GRN 000369
Dear Mr. Tchang:
The Food and Drug Administration (FDA) is responding to the notice, dated November 22, 2010, that you submitted on behalf of Zhucheng Haotian Pharm Co., Ltd. and Shanghai Freemen Lifescience Co., Ltd. (Zhucheng and Shanghai) 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 29, 2010, filed it on January 12, 2011, and designated it as GRN No. 000369.
The subject of the notice is rebaudioside A purified from the leaves of Stevia rebaudiana (Bertoni) Bertoni. The notice informs FDA of the view of Zhucheng and Shanghai 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. Zhucheng and Shanghai note that rebaudioside A has 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 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 000369 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 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 their notice, Zhucheng and Shanghai include the report of a panel of individuals (Zhucheng and Shanghai's GRAS panel) who evaluated the data and information that are the basis for Zhucheng and Shanghai's GRAS determination. Zhucheng and Shanghai consider the members of their GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Zhucheng and Shanghai'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 studies on rebaudioside A and related substances. Based on this review, Zhucheng and Shanghai's GRAS panel concluded that rebaudioside A, produced consistent with good manufacturing practice, is GRAS by scientific procedures, under the conditions of its intended use.
Zhucheng and Shanghai provide 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 extracted with de-ionized and filtered water for 1 hour. The extract is precipitated with ferrous sulfate and calcium hydroxide followed by filtration onto an adsorption absorption resin. The resin is washed with ethanol and the resulting ethanol-water solution is concentrated by filtration. The resulting preparation is passed through an ion-exchange resin for desalination and decolorization. The eluate is then concentrated using an evaporation apparatus followed by filtration. The filtrate is diluted with de-ionized and filtered water followed by spray drying. The spray-dried powder is dissolved in ethanol/water and re-crystallized. The re-crystallized preparation is centrifuged and washed in ethanol/water. The centrifuged preparation is then dried by microwave and forced hot-air to yield the final rebaudioside A product. Zhucheng and Shanghai provide specifications for rebaudioside A that include the content of rebaudioside A (≥97% by weight (w/w)), lead (≤0.1 parts per million (ppm)), arsenic ≤0.1 ppm, cadmium ≤0.1 ppm, mercury ≤0.1 ppm, residue on ignition (≤0.2%), residual methanol (≤ 200 ppm), residual ethanol (≤ 3000 ppm), and microbial contaminants (within specified limits). Zhucheng and Shanghai state that the rebaudioside A product meets the specifications for steviol glycosides established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) at its 69th meeting in June 2008.
Zhucheng and Shanghai estimate the intake of rebaudioside A resulting from its intended use in foods. Zhucheng and Shanghai rely on the consumer intake estimates described in a published study by Renwick (Ref. 1). This study performed an intake assessment of rebaudioside A which shows the overall projected intakes by mean and high percentile consumers in different subpopulations. The projected rebaudioside A exposures are based on sweetener substitution (expressed as sucrose equivalents in milligram/kilogram body weight per day (mg/kg bw/d)) and assume a relative sweetness for rebaudioside A that is 200 times that of sucrose. Zhucheng and Shanghai note that in the general adult population, the predicted rebaudioside A exposure from consumption of foods containing Rebaudioside A would be 1.3 mg/kg bw/d for consumers at the mean and 3.4 mg/kg bw/d for high percentile consumers. Zhucheng and Shanghai state that the use of rebaudioside A in food is self-limiting due to its organoleptic properties.
Zhucheng and Shanghai discuss 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. Zhucheng and Shanghai also consider published clinical studies and published and unpublished absorption, distribution, metabolism and excretion studies in animals and humans. Additional studies that Zhucheng and Shanghai discuss include published in vitro and in vivo mutagenicity/genotoxicity studies. Based on their consideration of all these studies, Zhucheng and Shanghai conclude that rebaudioside A is safe for its intended use in foods. To further support their view that rebaudioside A is safe for the intended use, Zhucheng and Shanghai note that that JECFA established an acceptable daily intake (ADI) for steviol glycosides of 0 - 4 mg/kg bw/d (expressed as steviol) and the Food Standards Australia New Zealand (FSANZ) established an ADI for steviol glycosides of 4 mg/kg bw/d (expressed as steviol).
Standards of Identity
In the notice, Zhucheng and Shanghai state their 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 (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 Zhucheng and Shanghai'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 Zhucheng and Shanghai, as well as other information available to FDA, the agency has no questions at this time regarding Zhucheng and Shanghai'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 Zhucheng and Shanghai to ensure that food ingredients the firms market 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 000369, 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. 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.