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CFSAN/Office of Food Additive Safety
April 30, 2010
Robert G. Bursey, Ph.D.
Ajinomoto Corporate Services, LLC
1120 Connecticut Avenue, N.W., Suite 1010
Washington, DC 20036
Re: GRAS Notice No. GRN 000308
Dear Dr. Bursey:
The Food and Drug Administration (FDA) is responding to the notice, dated October 27, 2009, that you submitted 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 October 30, 2009, filed it on November 2, 2009, and designated it as GRAS Notice No. GRN 000308.
The subject of the notice is L-leucine. The notice informs FDA of the view of Ajinomoto Aminoscience, LLC (Ajinomoto) that L-leucine is GRAS, through scientific procedures, for use as an ingredient in non-milk and milk based meal replacements, sports and isotonic beverages, vitamin enhanced waters, and meal replacement bars, at levels of 0.5 to 3 grams per serving.
As part of its notice, Ajinomoto includes the report of a panel of individuals (Ajinomoto’s GRAS panel) who evaluated the data and information that are the basis for Ajinomoto’s GRAS determination. Ajinomoto considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Ajinomoto’s GRAS panel evaluated published and unpublished documentation on L-leucine, including manufacturing method, product specifications, intended use-levels in specified food products, estimated dietary exposure, and available toxicological and human studies. Based on this review, Ajinomoto’s GRAS panel concluded that L-leucine, meeting appropriate food-grade specifications and manufactured according to current good manufacturing practice (cGMP), is safe for the intended conditions of use.
Ajinomoto provides information about the chemical identity of, and specifications for L-leucine. L-leucine is a branched-chain amino acid found in the diet as a component of protein. The chemical name of L-leucine is (2S)-2-amino-4-methylpentanoic acid or L-2-amino-4-methylvaleric acid. The Chemical Abstract Service Number for L-leucine is 61-90-5 and the empirical formula is C6H13NO2. Ajinomoto describes L-leucine as white crystals or a crystalline powder that has a slightly bitter taste. L-leucine is freely soluble in formic acid, sparingly soluble in water, and relatively insoluble in ethanol. Ajinomoto states that L-leucine is a high purity ingredient (≥ 98.5 percent) that is manufactured in accordance with cGMP, meets appropriate food-grade standards, and conforms to the specifications established by the Food Chemicals Codex.
Ajinomoto states that L-leucine is obtained from a bacterial strain derived from Escherichia coli K-12. Ajinomoto describes how the final production strain is modified through a series of selection steps using conventional mutagenic techniques and amplification of E. coli genes that encode the L-leucine biosynthetic enzymes. Ajinomoto also states that no foreign DNA is introduced to the final production strain. Ajinomoto further notes that E. coli K-12 (as well as bacterial strains derived from E. coli K-12) are considered to be non-pathogenic and non-toxigenic, and cites as examples similar strains that are listed in 21 CFR 184.1685 and in GRAS Notice No. 000155.
Ajinomoto describes the manufacture of L-leucine by fermentation using the modified E. coli K-12, as described above. Following fermentation, the bacterial culture is sterilized by heating to 120 degrees Celsius for not less than ten minutes. Ajinomoto states that subsequent steps involved in the manufacturing process for L-leucine consist of filtration, decolorization, concentration, crystallization, separation, and step-wise purification to consistently produce a product that meets food-grade specifications.
Ajinomoto intends to use L-leucine as an ingredient in non-milk and milk based meal replacements, sports and isotonic beverages, vitamin enhanced waters and meal replacement bars at levels of 0.5 to 3 grams per serving. Ajinomoto reports that the estimated dietary intake of L-leucine from the intended food uses in the total U.S. population for all-users is 1.9 grams per day (28 milligrams per kilogram body weight per day (mg/kg bw/d)) at the mean and 4.1 grams per day (64 mg/kg bw/d) at the 90th percentile. Additionally, Ajinomoto cites the Institute of Medicine (2005) report “Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids,” which states that the mean and 90th percentile total population background dietary intakes of L-leucine in the U.S. are estimated to be 6.08 grams per day and 8.90 grams per day, respectively.
In the notice, Ajinomoto discusses the safety of L-leucine. Specifically, Ajinomoto discusses studies that include rat subchronic and teratology toxicology studies, as well as, human clinical studies. Ajinomoto notes that in the published rat subchronic study, there were no toxicologically significant findings and the No Observable Adverse Effect Level was reported to be 5.0 percent of the diet (calculated to be 3333 and 3835 mg/kg bw/d for males and females, respectively). Ajinomoto states that the available published information supports the safety of L-leucine under the intended conditions of use.
Potential Labeling Issues
Under section 403(a) of the Federal Food, Drug, and Cosmetic Act (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. In the information that Ajinomoto relies on to conclude that L-leucine is GRAS under the conditions of its intended use, Ajinomoto raises a potential issue under these labeling provisions of the FFDCA. If products that contain L-leucine bear any claims on the label or in labeling, such claims are the purview of the Office of Nutrition, Labeling and Dietary Supplements (ONLDS) in the Center for Food Safety and Applied Nutrition. The Office of Food Additive Safety 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-leucine 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 Ajinomoto’s notice that L-leucine is GRAS, through scientific procedures, for use an ingredient in non-milk and milk based meal replacements, sports and isotonic beverages, vitamin enhanced waters, and meal replacement bars, at levels of 0.5 to 3 grams per serving, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing L-leucine. Accordingly, this response should not be construed to be a statement that foods that contain L-leucine, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Ajinomoto, as well as other information available to FDA, the agency has no questions at this time regarding Ajinomoto’s conclusion that L-leucine 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 L-leucine. As always, it is the continuing responsibility of Ajinomoto 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 000308, 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