Agency Response Letter GRAS Notice No. GRN 000338
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CFSAN/Office of Food Additive Safety
November 5, 2010
Robert S. McQuate, Ph.D.
GRAS Associates, LLC
20482 Jacklight Lane
Bend, OR 97702-3074
Re: GRAS Notice No. GRN 000338
Dear Dr. McQuate:
The Food and Drug Administration (FDA) is responding to the notice, dated May 5, 2010, 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); the GRAS proposal). FDA received the notice on May 5, 2010, filed it on May 11, 2010, and designated it as GRAS Notice No. GRN 000338.
The subject of the notice is L-theanine extracted from tea leaves (Camellia sinensis). The notice informs FDA of the view of Blue California that L-theanine is GRAS, through scientific procedures, for use as an ingredient in fruit juices and drinks, non-herbal teas, sports beverages, bottled waters, chocolate bars and chews, hard candies, breath mints, and chewing gum at levels up to 250 milligrams (mg) per serving.
Our use of “L-theanine” 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 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. 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 (ONLDS) 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 form 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 manufacturing method, product specifications, intended use-levels in foods, estimated dietary exposure, and published and unpublished data and other information related to animal toxicology and human studies with L-theanine. Based on this review, Blue California’s GRAS panel concluded that L-theanine is GRAS under its intended conditions of use.
Blue California discusses the chemical identity of L-theanine. L-theanine is a natural constituent in tea leaves and a species of mushroom (Xerocomus badius1). L-theanine is a water-soluble amino acid also known as N-ethyl-L-glutamine or γ-glutamylethylamide and is identified by the CAS Registry Number 3081-61-6.
Blue California states that L-theanine is manufactured in accordance with current good manufacturing practices. Blue California describes the production of L-theanine from green tea leaves (C. sinensis). The production steps include extraction of crude L-theanine by incubation of cleaned tea leaves with hot deionized water, followed by concentration, centrifugation, and separation onto a resin column. L-theanine is eluted from the resin, separated from the tea polyphenols using microfiltration, isolated by crystallization, and purified through membrane ultrafiltration to 98 percent purity. In GRN 000338, Blue California notes that the method for purity analysis is the same method described in GRN 000209 for L-theanine synthesized enzymatically. Blue California describes all manufacturing aids as food grade and regulated for use in food production. Blue California provides food grade specifications for its L-theanine, including L-theanine content (≥98 percent), arsenic (<2 mg per kilogram (mg/kg)), lead (<1 mg/kg), microbial limits for yeast and molds (<100 colony forming units per gram), and for Escherichia coli and Salmonella (both negative).
Blue California states that L-theanine is intended for use as an ingredient in a variety of food products. Using results from the 1999-2002 National Health and Nutrition Examination Survey, Blue California estimates the respective mean and 90th percentile consumption of L-theanine in these foods as 11.3 and 24.2 mg per kg body weight per day (mg/kg bw/d). As a comparison, Blue California notes that the intake of L-theanine in the United States for tea consumers at the 90th percentile is 13.75 mg/kg bw/d.
For its safety determination on L-theanine, Blue California relies on the data provided in GRN 000209 and additional published studies. Blue California discusses published information in GRN 000209 related to the absorption, distribution, metabolism and excretion of L-theanine, and published and unpublished acute, subacute, subchronic, and chronic oral toxicity studies in rats and in mice. In these studies, L-theanine showed no statistically significant treatment-related adverse effects or biologically important changes in pathology, organ weights or ratios, or histological changes following oral administration of L-theanine at levels up to 5 percent of the diet (~6300 mg/kg bw/d). In addition, Blue California discusses subacute, subchronic and chronic studies, published subsequently to those cited in GRN 000209, that support the earlier data from GRN 000209. The notifier further notes L-theanine was found to be non-mutagenic and non-genotoxic in published studies using bacterial reverse mutation assays. Blue California describes several published studies designed to evaluate the biological effects of L-theanine consumed by human subjects as single-servings at levels between 50-250 mg in the presence or absence of caffeine (50-150 mg). Although most of these human studies were not formally designed to evaluate safety, Blue California noted that no serious adverse effects were reported.
Standards of Identity
In its notice, Blue California states its intention to use L-theanine as an ingredient 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.
Potential Labeling Issues
In describing the biological effects of L-theanine in human clinical studies as part of the information that Blue California relies on to conclude that L-theanine is GRAS under the conditions of its intended use, Blue California raises a potential issue under the labeling provisions of the Federal Food, Drug, and Cosmetic Act (FFDCA). In addition, in describing the intended uses of L-theanine, Blue California lists sports beverages; this food category often contains health or nutrient content claims. Under section 403(a) of the FFDCA, a food is misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FFDCA lays out the statutory framework for the use of labeling claims that characterize the level of a nutrient in a food or that characterize the relationship of a nutrient to a disease or health-related condition. If products that contain L-theanine bear any claims on the label or in labeling, such claims are the purview of the ONLDS. The Office of Food Additive Safety (OFAS) neither consulted with ONLDS on this labeling issue nor evaluated the information in your notice to determine whether it would support any claims made about L-theanine on the label or in labeling.
Section 301(ll) of the 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 Blue California's notice that L-theanine is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing L-theanine. Accordingly, this response should not be construed to be a statement that foods that contain L-theanine, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Blue California and other information available to FDA, the agency has no questions at this time regarding Blue California’s conclusion that L-theanine is GRAS under the intended conditions of use. The agency has not, however, made its own determination regarding the GRAS status of L-theanine. As always, it is the continuing responsibility of Blue California 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 000338, 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.
Mitchell A. Cheeseman, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
1The notifier refers to Xerocomus badius, which has since been reclassified as Boletus badius.