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CFSAN/Office of Food Additive Safety
May 11, 2007
Bruce K. Bernard, Ph.D., President
SRA International Inc.
5235 Ragged Point Road
Cambridge, MD 21613
Re: GRAS Notice No. GRN 000199
Dear Dr. Bernard:
The Food and Drug Administration (FDA) is responding to the notice, dated May 5, 2006, that you submitted on behalf of Calpis Co. Ltd. (Calpis), 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, 2006, filed it on May 9, 2006, and designated it as GRAS Notice (GRN) Number 000199. FDA also received amendments dated July 19, October 6, November 1, and November 6, 2006.
The subject of the notice is "concentrated hydrolyzed milk protein."(1) The notice informs FDA of the view of Calpis that concentrated hydrolyzed milk protein is GRAS, through scientific procedures, for use as an ingredient in orange juice, yogurt (including yogurt drinks), nutrition bars and margarine spread.
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 the term "concentrated hydrolyzed milk protein" 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 Nutritional Products, Labeling, and Dietary Supplements (ONPLDS) in the Center for Food Safety and Applied Nutrition (CFSAN).
Calpis' concentrated hydrolyzed milk protein is manufactured either through milk fermentation (FM) or an enzymatic hydrolysis of casein (CH). Concentrated hydrolyzed milk protein manufactured through FM is prepared from pasteurized reconstituted skim milk fermented with Lactobacillus helveticus. Concentrated hydrolyzed milk protein manufactured through CH is prepared from pasteurized casein solution using an Aspergillus oryzae protease. In both methods, a concentrated liquid is produced that is then filtered and dried. Calpis notes that all ingredients used in both manufacturing processes for concentrated hydrolyzed milk protein are food grade materials.
Calpis presents results of its analyses of multiple lots of concentrated hydrolyzed milk protein manufactured through FM and CH. The information provided to characterize the concentrated hydrolyzed milk protein includes appearance (white to yellow coloration), acidity, protein content (8.1% in the FM produced and 81% in the CH produced), moisture content, ash content, powder density, and the level of peptides that Calpis identified as milk derived tripeptides (MDT), L-valyl-L-prolyl-L-proline (VPP) and L-isoleucyl-L-prolyl-L-proline (IPP). FM and CH produced concentrated hydrolyzed milk protein contain ˜0.2% and ˜0.6% MDT, respectively. In addition, the notifier provides analyses for lead and cadmium (lead is reported to be less than 0.05 milligrams per kilogram (mg/kg), cadmium less than 0.01 mg/kg). In the notice, and in an amendment to the notice dated November 1, 2006, Calpis also provides microbial specifications for yeast, molds, aerobic count, and coliforms and certificates of analysis for Salmonella, Bacillus cereus, Clostridium perfringens, Campylobacter, Yersinia enterocolytica and Staphylococcus aureus as well as a discussion of their good manufacturing practices to demonstrate the absence of other microbial pathogens.
Calpis estimates that, under the intended conditions of use, the mean daily intake for the U.S. population of concentrated hydrolyzed milk protein in the form of FM and CH products would be 3.0 grams/person/day (g/p/d) and 6.9 g/p/d, respectively.
Calpis concludes that there is evidence of safety establishing that concentrated hydrolyzed milk protein, when used as intended, will reasonably be expected to be safe. Calpis summarizes the results of published genotoxicity tests with concentrated hydrolyzed milk protein in the form of FM and CH products and reports the absence of any mutagenic potential. Calpis also summarizes the results of published animal studies including reproductive and developmental studies. Calpis reports the absence of treatment-related adverse effects in a 28-day study in rats that received up to 4,000 milligrams per kilogram of body weight per day (mg/kg-bw/d) of concentrated hydrolyzed milk protein in the form of FM product. Some effects were reported by Calpis in a 13-week gavage study in rats where up to 1,000 mg/kg-bw/d of concentrated hydrolyzed milk protein in the form of CH product was administered. Calpis states that these effects showed no dose-response relationships and thus are unrelated to the administration of concentrated hydrolyzed milk protein in the form of CH product. In reproductive and developmental toxicity studies performed in rats that received up to 2,000 mg/kg-bw/d of concentrated hydrolyzed milk protein in the form of FM product, Calpis reports the absence of treatment-related adverse effects on mating behavior, fertility and fetal development.
In addition to the data from genotoxicity and animal studies, Calpis reviewed published human studies. Calpis states that no adverse effects were reported.
In its notice, Calpis states its intention to use concentrated hydrolyzed milk 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.
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 information that Calpis relies on to conclude that concentrated hydrolyzed milk protein is GRAS under the conditions of its intended use, Calpis raises a potential issue under these labeling provisions of the FFDCA. If products that contain concentrated hydrolyzed milk protein bear any claims on the label or in labeling, such claims are the purview of ONPLDS. The Office of Food Additive Safety (OFAS) neither consulted with ONPLDS on this labeling issue nor evaluated the information in your notice to determine whether it would support any claims made about concentrated hydrolyzed milk 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 foods are the responsibility of ONPLDS.
Based on the information provided by Calpis, as well as other information available to FDA, the agency has no questions at this time regarding Calpis' conclusion that concentrated hydrolyzed milk protein is GRAS under the intended conditions of use, as an ingredient in orange juice, yogurt (including yogurt drinks), nutrition bars, and margarine spread. The agency has not, however, made its own determination regarding the GRAS status of concentrated hydrolyzed milk protein. As always, it is the continuing responsibility of Calpis 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 000199, 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 the Office of Food Additive Safety (on the Internet at http://www.cfsan.fda.gov/~lrd/foodadd.html).
Sincerely,
Laura M. Tarantino, Ph.D.
Director
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
(1)In its initial submission, Calpis designated the substances that are the subject of this notice as "bovine milk-derived tripeptides (MDT), L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline." In a letter dated October 6, 2006, Calpis amended the subject of the notice to be concentrated hydrolyzed milk protein.
