Agency Response Letter GRAS Notice No. GRN 000360
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CFSAN/Office of Food Additive Safety
May 16, 2011
Katsuhiro Osajima, Ph.D.
Senmi Ekisu Co., Ltd.
779-2 Noda, Hirano-Cho
Re: GRAS Notice No. GRN 000360
Dear Dr. Osajima:
The Food and Drug Administration (FDA) is responding to the notice, dated October 29, 2010, 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 November 9, 2010, filed it on November 18, 2010, and designated it as GRAS Notice No. GRN 000360.
The subject of the notice is hydrolyzed sardine protein. The notice informs FDA of the view of Senmi Ekisu Co., Ltd. (Senmi Ekisu) that hydrolyzed sardine protein is GRAS, through scientific procedures, for use as a food ingredient in beverages, breakfast cereals, frozen dairy desserts and mixes, milk and milk products, fish products, pastas, hard and soft candy, soups and soup mixes, processed fruits and vegetables, and fruit and vegetable juices. The proposed use level is up to 0.6 grams (g)/serving. Senmi Ekisu states that the intended use of hydrolyzed sardine protein does not include any meat, poultry, or egg products or meat- or poultry-containing products that are under the jurisdiction of the United States Department of Agriculture.
As part of its notice, Senmi Ekisu includes the report of a panel of individuals (Senmi Ekisu’s GRAS panel) who evaluated the data and information that are the basis for Senmi Ekisu’s GRAS determination. Senmi Ekisu considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Senmi Ekisu’s GRAS panel evaluated the method of manufacture, product specifications, intended uses, estimates of dietary exposure, and the available scientific literature pertaining to the safety of hydrolyzed sardine protein. Based on this review, Senmi Ekisu’s GRAS panel concluded that hydrolyzed sardine protein produced under current good manufacturing practice and meeting appropriate food grade specifications, is GRAS under the intended conditions of use.
Senmi Ekisu describes the identity and composition of hydrolyzed sardine protein. Hydrolyzed sardine protein is a yellowish white powder obtained by enzymatic hydrolysis of raw muscle tissue from sardines. The composition of hydrolyzed sardine protein consists of greater than 85% peptides of two, three, four, or five amino acids. Senmi Ekisu provides the amino acid profile for hydrolyzed sardine protein.
Senmi Ekisu provides a detailed manufacturing process for hydrolyzed sardine protein. The process begins with the heating of pulverized frozen sardine flesh to inactivate the autolytic enzymes. The pH is adjusted with sodium hydroxide and protease is added to hydrolyze the protein. The hydrolysis is terminated by heat and the addition of hydrochloric acid. Subsequently, the hydrolysate is filtered and centrifuged to remove remaining bones and flesh residues, then treated with diatomaceous earth and activated charcoal. Following another filtration step, the precursor peptide product is fractionated via column chromatography. The desired fraction is sterilized by heat-treatment, filtered, and finally spray-dried to obtain the hydrolyzed sardine protein. Senmi Ekisu states that all processing aids are used in compliance with appropriate federal regulations.
Senmi Ekisu provides specifications for hydrolyzed sardine protein, including peptides (not less than 85%), moisture (not more than 8%), lead (not more than 0.1 milligrams/kilogram (mg/kg)), and limits on microorganisms. In addition, the notifier provides the results of analyses of five lots for several environmental contaminants, including mercury and pesticides. Senmi Ekisu notes that the levels of contaminants were either below the limit of detection or below U.S. federal action levels or guidelines. As a result, Senmi Ekisu determined that specifications for environmental contaminants are not warranted at this time.
Senmi Ekisu provides estimated daily intakes of hydrolyzed sardine protein using 2003-2004 NHANES data, based on proposed food uses in the U.S. On an eaters-only basis, the mean and 90th percentile estimates of intake for hydrolyzed sardine protein are 1.3 grams per person per day (g/p/d) and 2.8 g/p/d, respectively. Senmi Ekisu compared the estimated daily intake of hydrolyzed sardine protein (in terms of peptides) with the background protein intake from all dietary sources and the background protein intake from sardines. Senmi Ekisu explains that the 90th percentile intakes for background protein from all dietary sources (114 g/p/d) and for protein from sardines (9.2 g/p/d) are both higher than that from the proposed uses of hydrolyzed sardine protein (2.4 g/p/d).
Senmi Ekisu discusses published information to support the safety of hydrolyzed sardine protein. These studies include acute and subchronic toxicity studies in Sprague-Dawley (Crj:CD) rats as well as mutagenicity and genotoxicity studies. Senmi Ekisu notes that the toxicity studies were performed using a pre-fractionated product that is closely related to hydrolyzed sardine protein and concludes that it is an appropriate article for the toxicity tests. Senmi Ekisu states that the No Observed Adverse Effect Level (NOAEL) for the two subchronic toxicity studies in rats was 5 g/kg body weight per day (bw/d) (the highest dose level tested) for the precursor product, which corresponds to 1.6 g/kg bw/d of the commercial hydrolyzed sardine protein.
Senmi Ekisu considered the potential allergenicity of sardine peptides. This was evaluated in guinea pigs using two standard tests, the active systemic anaphylaxis test and the passive cutaneous anaphylaxis test. The results were negative. Senmi Ekisu indicated that under the intended conditions of use in food, they do not anticipate that their hydrolyzed sardine protein product would produce allergenic reactions in humans.
In addition to the safety studies in animals, Senmi Ekisu discusses eight human clinical studies that included safety-related endpoints (biochemical, hematological, and urinalysis parameters). The dosing ranged from 1.5 g/d for four weeks up to 6 g administered as a bolus dose. No adverse effects were reported for any of the studies.
Standards of Identity
In the notice, Senmi Ekisu states its intention to use hydrolyzed sardine protein 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 clinical studies in support of the safe use of hydrolyzed sardine protein, Senmi Ekisu notes some results with potential health benefits. 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. If products that contain hydrolyzed sardine protein 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 hydrolyzed sardine protein on the label or in labeling.
The Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA) amends the FFDCA to require that the label of a food that is or contains an ingredient that bears or contains a “major food allergen” declare the presence of the allergen (section 403(w)). FALCPA defines a “major food allergen” as one of eight foods or food groups (i.e., milk, eggs, fish, Crustacean shellfish, tree nuts, peanuts, wheat, and soybeans) or a food ingredient that contains protein derived from one of those foods. Issues associated with labeling food are the responsibility of ONLDS.
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 Senmi Ekisu’s notice that hydrolyzed sardine protein is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing hydrolyzed sardine protein. Accordingly, this response should not be construed to be a statement that foods that contain hydrolyzed sardine protein, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Senmi Ekisu, as well as other information available to FDA, the agency has no questions at this time regarding Senmi Ekisu’s conclusion that hydrolyzed sardine protein 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 hydrolyzed sardine protein. As always, it is the continuing responsibility of Senmi Ekisu 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 000360, 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 at www.fda.gov/grasnoticeinventory.
Mitchell A. Cheeseman, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition