Agency Response Letter GRAS Notice No. GRN 000278
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CFSAN/Office of Food Additive Safety
July 20, 2009
Robert S. McQuate, Ph.D
GRAS Associates, LLC
20482 Jacklight Lane
Re: GRAS Notice No. GRN 000278
Dear Dr. McQuate:
The Food and Drug Administration (FDA) has received the notice, dated January 19, 2009, that you submitted on behalf of Blue California, 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)). FDA received this notice on January 21, 2009, filed it on January 22, 2009, and designated it as GRN No. 000278.
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 Blue California that rebaudioside A is GRAS, through scientific procedures, for use as a sweetener in baked products, beverages (non-alcoholic), breakfast cereals, coffee and tea, confections and frostings, dairy product analogs, fats and oils, frozen dairy desserts, fruit and water ices, milk (whole and skim), milk products, processed fruits and fruit juices, processed vegetables and vegetable juices, snack foods, soft candy, sugar substitutes, sweet sauces, toppings and syrups, meal replacement food products, and medical foods at levels determined by good manufacturing practices, as well as use as a table top sweetener. Blue California notes that rebaudioside A has recently been the subject of two GRAS notices, GRN 000252 and GRN 000253, and that, on December 17, 2008, FDA responded to these GRAS notices informing the notifiers that the agency had no questions at that time regarding their conclusion that the rebaudioside A that is the subject of their respective notice is GRAS for its intended use as a sweetener in food.
The rebaudioside A that is the subject of GRN 000278 is a highly purified component of the stevia plant. As such, FDA notes that the 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.
Title 21 CFR 101.4 states that all ingredients 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. 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 any of these terms as an appropriate common or usual name for the purpose of declaring the substance in the ingredient statement of foods that contain that ingredient. 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, Blue California includes the report of a panel of individuals (Blue California’s GRAS panel) who evaluated the data and information that are the basis for Blue California’s GRAS determination. Blue California considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Blue California’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, Blue California’s GRAS panel concluded that rebaudioside A, produced consistent with current good manufacturing practice and meeting appropriate purity and food grade specifications, is GRAS, by scientific procedures, under the conditions of its intended use.
Blue California provides information about the identity, method of manufacture, and specifications for 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 Stevia rebaudiana (Bertoni) Bertoni by extraction with hot water and ethanol and is concentrated with an adsorption resin that traps the steviol glycosides. The resin is washed with ethanol to release the glycosides. The extract is concentrated and then undergoes several filtration and purification steps using membrane technology that sorts by molecular size. Blue California notes that the filters and membranes used meet FDA requirements for food contact materials. The final powdered rebaudioside A product is obtained by spray-drying. Blue California 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 (<0.5 mg/kg), residual ethanol (≤1000 mg/kg) and microbial contaminants (within specified limits). Blue California 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) in its 69th meeting in June 2008.
Blue California estimates the intake of rebaudioside A resulting from its intended use in foods. Blue California intends to incorporate rebaudioside A into a broad selection of foods and does not provide specific consumption estimates (i.e., numbers of servings or specific use levels) for the individual food categories. Instead, Blue California largely relies on the consumer intake estimates provided by JECFA. In addition to the JECFA intake estimates, Blue California considered the anticipated human exposure levels as determined in both GRN 000252 and GRN 000253. Blue California notes that the multiple approaches tend to converge to yield estimated daily intakes (EDIs) for steviol glycosides in the range of 1.3 - 4.7 mg/kg body weight per day (mg/kg bw/d). Furthermore, Blue California reports that adjustment 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 would likely be about 1.5 to 2.3 mg/kg bw/d. Blue California states that the use of rebaudioside A in food is self-limiting due to organoleptic factors and consumer taste considerations.
Blue California discusses published and unpublished studies about the absorption, distribution, metabolism, and excretion of stevioside, rebaudioside A, steviol glycoside mixtures, and steviol in animals and humans. Blue California states that the most recent studies on toxicokinetics and metabolism of rebaudioside A, stevioside, and steviol were carried out for comparative purposes to determine whether toxicological studies conducted previously with stevioside would be applicable to the structurally-related glycoside rebaudioside A. Blue California notes that the overall data from these studies show that rebaudioside A and stevioside are metabolized via the same intermediates and hydrolysis pathways.
Blue California discusses published and unpublished studies related to the safety evaluation of rebaudioside A, including an unpublished subchronic toxicity study of rebaudioside A in Beagle dogs and various published animal studies conducted with rebaudioside A, stevioside, steviol, and crude stevia extracts. The published animal studies Blue California discusses include 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. Additional published studies that Blue California discusses include in vitro and in vivo genotoxicity studies.
Blue California discusses published clinical studies on rebaudioside A and stevioside in diabetics and nondiabetics, and in hypertensive, normotensive, and hypotensive subjects. Blue California concludes that rebaudioside A will have no effect on blood pressure and glucose metabolism in humans at the consumption levels expected from its use in food as a sweetener.
In its discussion of the published literature, Blue California also considers reports on stevia or stevia derived substances that raised safety concerns about the use of such substances as food ingredients. Blue California states that there are now a sufficient number of properly conducted studies for the safety evaluation of rebaudioside A and other purified steviol glycosides and concludes that its rebaudioside A product is safe under the conditions of its intended use.
To further support its view that rebaudioside A is safe for the intended use, Blue California describes recent decisions by JECFA and the Food Standards Australia New Zealand (FSANZ) on the safety of steviol glycosides, one of which is rebaudioside A, for use in food as sweeteners. Blue California notes that in 2008, JECFA established an acceptable daily intake (ADI) for steviol glycosides of 0–4 mg/kg bw/d (expressed as steviol) and FSANZ established an ADI for steviol glycosides of 4 mg/kg bw/d (expressed as steviol).
Standards of Identity
In the notice, Blue California 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.
In its notice, Blue California informs FDA that one intended use of rebaudioside A is use in medical foods. Section 5(b) of the Orphan Drug Act (ODA) defines a medical food as a food that is formulated to be consumed or administered enterally under the supervision of a physician and that is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation. Section 403(q) of the Federal Food, Drug, and Cosmetic Act (FFDCA) lays out the statutory framework for nutrition labeling of food products. Section 403(r) of the FFDCA lays out the statutory framework for health claims and nutrient content claims. Under section 403(q)(5)(A)(iv) of the FFDCA and FDA's implementing regulations in 21 CFR 101.9(j)(8), the requirements for nutrition labeling do not apply to medical foods as defined in section 5(b) of the ODA. Under section 403(r)(5)(A) of the FFDCA and FDA's implementing regulations in 21 CFR 101.13(q)(4)(ii) and 21 CFR 101.14(f)(2), the requirements for nutrient content claims and health claims, respectively, do not apply to medical foods as defined in section 5(b) of the ODA. For your information, FDA's response to Blue California’s notice that rebaudioside A is GRAS for use in medical foods does not address the question of whether any particular food product that contains rebaudioside A as an ingredient would be a medical food within the meaning of section 5(b) of the ODA and, thus, would be exempt from the requirements for nutrition labeling, nutrient content claims, and health claims.
Section 301(ll) of the Federal Food, Drug, and Cosmetic Act (FFDCA)
The Food and Drug Administration Amendments Act of 2007, that 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 Blue California’s notice that rebaudioside A is GRAS for use as a sweetener in various food categories as well as use as a table top sweetener, 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 Blue California, as well as other information available to FDA, the agency has no questions at this time regarding Blue California’s conclusion that rebaudioside A purified from the leaves of S. rebaudiana (Bertoni) Bertoni 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 purified from the leaves of S. rebaudiana (Bertoni) Bertoni. As always, it is the continuing responsibility of Blue California 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 000278, 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 via the FDA home page at http://www.fda.gov. To view or obtain an electronic copy of the text of the letter, follow the hyperlinks from the “Food” topic to the “Food Ingredients and Packaging” section to the “Generally Recognized as Safe (GRAS)” page where the GRAS Inventory is listed.
Laura M. Tarantino, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition