Agency Response Letter GRAS Notice No. GRN 000220
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CFSAN/Office of Food Additive Safety
November 19, 2007
Melvin S. Drozen and John F. Foley
Keller and Heckman, LLP
1001 G Street, N.W.
Suite 500 West
Washington, DC 20001
Re: GRAS Notice No. GRN 000220
Dear Messrs. Drozen and Foley:
The Food and Drug Administration (FDA) is responding to the notice, dated March 28, 2007, that you submitted on behalf of San-Ei Gen F.F.I. Inc. (San-Ei Gen) 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 March 29, 2007, filed it on April 3, 2007, and designated it as GRAS Notice No. GRN 000220.
The subject of the notice is alpha-glycosyl isoquercitrin. The notice informs FDA of the view of San-Ei Gen that alpha-glycosyl isoquercitrin is GRAS, through scientific procedures, for use as an antioxidant in non-alcoholic beverages including soft drinks, fruit juices, vegetable juices, and flavored milk products; in wine coolers (<7% alcohol); shochu-based flavored beverages(1) (<7% alcohol); frozen dairy products; gelatins and puddings; jams and jellies; soft candy; cakes; cookies; pastries and pies; and powdered or canned soup; at a maximum level of 150 milligrams per kilogram (mg/kg), and in chewing gum at a maximum level of 1500 mg/kg.
As part of its notice, San-Ei Gen includes the report of a panel of individuals (San-Ei Gen's GRAS panel) who evaluated the data and information that are the basis for San-Ei Gen's GRAS determination for the use of alpha-glycosyl isoquercitrin as an antioxidant in certain foods. San-Ei Gen considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. San-Ei Gen's GRAS panel reviewed the starting materials, method of manufacture, product specifications, supporting analytical data, intended use levels in specified foods, and consumption estimates for all intended uses. San-Ei Gen's GRAS panel assessed the safety of alpha-glycosyl isoquercitrin by evaluating the absorption, distribution, metabolism, and excretion studies, and toxicological studies (published and unpublished) including in vitro genotoxicity, acute, subacute, subchronic, and chronic testing in rodent species as well as an assessment of the available scientific literature on related compounds. Based on this review, San-Ei Gen's GRAS panel concluded that alpha-glycosyl isoquercitrin that meets its established food grade specifications is GRAS under the conditions of its intended use.
San-Ei Gen describes the identity and method of manufacture of alpha-glycosyl isoquercitrin. alpha-Glycosyl isoquercitrin is a yellow to yellow-brown water soluble powder having a distinctive odor, with an average molecular weight of 800 Daltons. The starting product, rutin (quercetin-3-rhamnoglucoside), isolated from the buds and flowers of Sophora japonica (Pagoda tree), is first enzymatically converted to isoquercitrin using rhamnosidase (also referred to as naringinase by the notifier). Subsequently, an aqueous solution of isoquercitrin and dextrin is treated with cyclodextrin glucanotransferase to add glucose units, forming alpha-glycosyl isoquercitrin. The resulting solution is heated to inactivate the enzymes, filtered and evaporated under vacuum. The residue is dissolved in ethanol, and impurities are removed by crystallization. Finally, the ethanol solution is evaporated under vacuum to yield alpha-glycosyl isoquercitrin.
San-Ei Gen provides specifications for the food-grade alpha-glycosyl isoquercitrin. The specifications include limits on lead (≤ 2 mg/kg), arsenic (≤ 2 mg/kg), and quercetin (≤ 1%). San-Ei Gen provides the analysis of five batches of dried product showing a mean percent purity of 94.7%. San-Ei Gen states that minor constituents include quercetin, sodium sulfate, and higher glycosides of alpha-glycosyl isoquercitrin. Test values for identity, purity, as well as possible contaminants (lead, arsenic, and quercetin) conform to the food-grade product specifications. Values for quercetin, a key manufacturing residue, were below the specification limit (< 1%) for the samples analyzed. The maximum content of quercetin was 0.24% and the minimum was 0.05%. San-Ei Gen states that quercetin is one of the decomposition products of alpha-glycosyl isoquercitrin and is used as an indicator of adherence to good manufacturing practices.
San-Ei Gen calculated an estimated daily intake (EDI) of 173 mg per person per day (mg/p/d) of alpha-glycosyl isoquercitrin from the intended food uses. This EDI is based on soft drink consumption at the 90th percentile (1016 g/p/d, users-only) because exposure to alpha-glycosyl isoquercitrin from these drinks dominates the potential intake in the overall population. The notifier includes beverages, non-alcoholic soft drinks (carbonated beverages, fruit drinks, flavored milk products), wine coolers, and shochu-based flavored beverages (<7% alcohol) in the category of “soft drinks.” The notifier derived the EDI by combining food consumption data from the USDA Continuing Survey of Food Intakes by Individuals (CSFII, 1994-1996, 1998) with the maximum intended use levels of alpha-glycosyl isoquercetrin.
San-Ei Gen summarizes published and unpublished toxicological studies supporting the safe use of alpha-glycosyl isoquercitrin in foods. Specifically, they report the results of a mutation assay, a 2-year rodent carcinogenicity study, as well as rat studies of acute, subacute, subchronic and chronic periods of exposure via oral administration of alpha-glycosyl isoquercitrin. San-Ei Gen reports that the mutagenicity test was negative. In the 2-year rat carcinogenicity study, the notifier states that no alpha-glycosyl isoquercitrin-related clinical signs of toxicity were observed at levels up to 1.5% of the diet (489 mg/kg bw/d). In the acute, subacute, and subchronic toxicity studies conducted with rats, San-Ei Gen reports that there were no histopathological changes as a result of ingesting alpha-glycosyl isoquercitin.
San-Ei Gen notes studies with quercetin, an anticipated metabolite and minor impurity of alpha-glycosyl isoquercitrin, reporting positive and negative genotoxicity data and evidence of carcinogenic activity based on rodent carcinogenicity. After reviewing the published literature and sponsoring a re-analysis of primary data from a rodent study, San-Ei Gen concludes that quercetin is not a carcinogenic risk to humans.
Standards of Identity
In the notice, San-Ei Gen states its intention to use alpha-glycosyl isoquercitrin 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.
Based on the information provided by San-Ei Gen, as well as other information available to FDA, the agency has no questions at this time regarding San-Ei Gen's conclusion that alpha-glycosyl isoquercitrin 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 alpha-glycosyl isoquercitrin. As always, it is the continuing responsibility of San-Ei Gen 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 000220, as well as a copy of the information in this notice that conforms to the information in the proposed GRAS exemption claim (proposed 21 CFR 170.36(c)(1)), is available for public review and copying on the homepage of OFAS (on the Internet at http://www.cfsan.fda.gov/~lrd/foodadd.html).
Laura M. Tarantino, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
(1)Shochu is a distilled alcoholic beverage similar to vodka, which is indigenous to Japan. It usually contains about 25% alcohol, and is often mixed with plum or other fruit juices to make a cocktail-type beverage that would contain less than 7% alcohol.