Agency Response Letter GRAS Notice No. GRN 000312
CFSAN/Office of Food Additive Safety
June 6, 2010
Bruce K. Bernard, Ph.D.
SRA International, Inc.
5235 Ragged Point Road
Cambridge, MD 21613
Re: GRAS Notice No. GRN 000312
Dear Dr. Bernard:
The Food and Drug Administration (FDA) is responding to the notice, dated December 30, 2009, that you submitted on behalf of Ajinomoto USA, Inc. (Ajinomoto) 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 30, 2009, filed it on January 5, 2010, and designated it as GRAS Notice No. GRN 000312.
The subject of the notice is synthetic dihydrocapsiate. The notice informs FDA of the view of Ajinomoto that synthetic dihydrocapsiate is GRAS, through scientific procedures, for use as an ingredient in a variety of food categories, as described in Table 1 (below), to provide 3 milligram (mg) per standard serving,1 with the exception of chewing gum which would be at a level of 10 mg per serving. Ajinomoto notes that synthetic dihydrocapsiate was recently the subject of their notice to FDA (GRN 000249), for use as an ingredient in a variety of food categories to provide 1 mg per standard serving. Ajinomoto further notes that, FDA responded to this notice with a "no questions" letter on March 9, 2009. In GRN 000312, Ajinomoto has increased the intended use level from 1 mg per standard serving (in GRN 000249) to 3 mg per standard serving, and has expanded the intended food categories as noted in Table 1.
|Food Category||Use Level in milligrams per kilogram (mg/kg)*|
|*Use levels in table derived from the intended use of 3 mg synthetic dihydrocapsiate per standard serving size|
|Bars – Breakfast and meal replacement||75|
|Beverage concentrates (as powder) (low calorie)||138.9|
|Beverages soft drinks (sugar free)||12.5|
|Chewing gum (sugarless)||3333.3|
|Cookies (low fat, fat free)||100|
|Creamer||93.8 - 200|
|Frozen desserts (ice pops, fruit bars)||35.3|
|Frozen desserts (dairy)||12.5 – 33.3|
|Fruit-ades, drinks, and powders (low calorie)||12.5|
|Fruit juice (fresh orange juice)||12.5|
|Gelatin/pudding (low calorie)||20.4 – 25|
|Hard candy (dietetic)||75 – 1500|
|Crackers (low fat and fat free)||100|
|Meal replacement beverages||12.5 – 100|
|Non-carbonated water (low calorie)||12.5|
|Nutritional meal (e.g., Ensure)||12.5|
|Oatmeal - instant (low sugar)||12.5|
|Protein based meat alternative (from vegetable and/or dairy)||12.5 – 428.6|
|Ready-to-eat meals - frozen diet (excludes meat, poultry, seafood)||12.5|
|Ready-to-eat meals - soup||12.3|
|Ready-to-eat cereals (cold)||54.5 – 200|
|Salad dressings (low calorie)||100 – 200|
|Snack foods (low calorie) - popcorn (low fat, fat free, low sodium) - rice cake (puffed, cracker-type)||100|
|Sweeteners (low calorie)||750|
|Tea, liquid (low sugar or sugar free)||12.5|
|Yogurt – fruit (low fat and fat free)||13.3|
|Yogurt – Chocolate, Vanilla, Plain (low fat and fat free)||13.3|
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 "synthetic dihydrocapsiate" 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. 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, 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 the identity, method of manufacture, metabolism, the potential exposure resulting from the intended food uses of synthetic dihydrocapsiate, and published studies, as well as historical dietary intake of dihydrocapsiate. Based on this review, Ajinomoto's GRAS panel concluded that synthetic dihydrocapsiate that meets its established food grade specifications and used in accordance with current good manufacturing practice is GRAS under the conditions of its intended use.
Ajinomoto provides information about the identity, method of manufacture, and specifications for food grade synthetic dihydrocapsiate. Ajinomoto describes synthetic dihydrocapsiate as a viscous colorless to yellowish oil that contains more than 94 percent dihydrocapsiate. Dihydrocapsiate, ((4-hydroxy-3-methoxybenzyl) 8-methylnonanoate), has the molecular formula C18H28O4, and a molecular weight of 308.41, with the Chemical Abstracts Service Registry Number 205687-03-2. Ajinomoto states that the method of manufacture of synthetic dihydrocapsiate involves the esterification of vanillyl alcohol (V-OH) and 8-methylnonanoic acid (MNA) catalyzed by an immobilized lipase preparation. The esterification is followed by filtration, extraction with n-hexane, and evaporation. Ajinomoto also describes the manufacturing process for the starting materials V-OH and MNA. MNA is prepared from isobutyl bromide and 6-bromohexanoic acid ethyl ester through a Grignard coupling reaction and deprotection process to give a carboxylic acid. V-OH is prepared from vanillin by reduction, followed by evaporation of the solvent (tetrahydrofuran). Specifications include limits on lead (less than 1 mg/kg), arsenic (less than 1 mg/kg), cadmium (less than 1 mg/kg), V-OH (less than 1 percent), other reaction byproducts (less than 2 percent), and residual solvents, n-hexane and tetrahydrofuran (less than 5 mg/kg).
Ajinomoto estimates the daily intake of the synthetic dihydrocapsiate ingredient based on the intended use levels listed in Table 1. Ajinomoto provides an estimated mean consumption (eaters only) of synthetic dihydrocapsiate to be 0.175 milligram per kilogram body weight per day (mg/kg bw/d) and 0.37 mg/kg bw/d at the 90th percentile. Ajinomoto also notes that dihydrocapsiate occurs naturally in a variety of edible chili peppers (Capsicum species) at various concentrations and is consumed as part of the diet. FDA notes that Ajinomoto's estimated daily intake (EDI) above, calculated using the new food categories and use levels listed in Table 1, is higher than the EDI that Ajinomoto estimated in GRN 000249 (mean consumption 0.03 mg/kg bw/d and 0.068 mg/kg bw/d at the 90th percentile).
Ajinomoto discusses the safety of the synthetic dihydrocapsiate ingredient. Ajinomoto notes that dihydrocapsiate occurs naturally in edible non-pungent as well as pungent chili peppers that are consumed worldwide as part of the diet. In its safety evaluation, Ajinomoto discusses published data on synthetic dihydrocapsiate from acute, subchronic, and genetic toxicity studies in rats and mice, teratology studies in rats and rabbits, and data from a rat pharmacokinetic study. Ajinomoto concludes that oral administration of synthetic dihydrocapsiate, up to 300 mg/kg bw/d to rats for 13-weeks, did not elicit any adverse effects. Ajinomoto also discusses supportive data from published acute, subchronic, and chronic toxicity, two-generation reproduction, teratology, and mutagenicity studies in rats using CH-19 Sweet extract.2 In addition, Ajinomoto discusses a published safety assessment and pharmacokinetics study in which healthy male volunteers consumed a single oral dose of CH-19 Sweet extract (containing 3.96 or 7.92 mg of dihydrocapsiate); Ajinomoto notes that no adverse effects were reported. Based on the data and information it discusses, Ajinomoto concludes that synthetic dihydrocapsiate is safe under the conditions of its intended use.
Standards of Identity
In the notice, Ajinomoto states its intention to use synthetic dihydrocapsiate 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
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 describing the intended uses of synthetic dihydrocapsiate and in describing the information that Ajinomoto relies on to conclude that synthetic dihydrocapsiate 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 synthetic dihydrocapsiate bear any claims on the label or in labeling, such claims are the purview of ONLDS. 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 synthetic dihydrocapsiate 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 synthetic dihydrocapsiate is GRAS for use as an ingredient in a variety of food categories, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing synthetic dihydrocapsiate. Accordingly, this response should not be construed to be a statement that foods that contain synthetic dihydrocapsiate, 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 synthetic dihydrocapsiate 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 synthetic dihydrocapsiate. 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 000312, 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
1Reference amounts customarily consumed (21 CFR 101.12)
2CH-19 Sweet extract is the concentrated oil, extracted from CH-19 Sweet, a non-pungent cultivar of Capsicum annuum L., containing the capsinoids dihydrocapsiate, capsiate, and nordihydrocapsiate.