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CFSAN/Office of Food Additive Safety
September 29, 2011
James T. Heimbach, Ph.D., F.A.C.N.
923 Water Street
P.O. Box 66
Port Royal, VA 22535
Re: GRAS Notice No. GRN 000377
Dear Dr. Heimbach:
The Food and Drug Administration (FDA) is responding to the notice, dated March 28, 2011, that you submitted on behalf of Cargill, Incorporated (Cargill) 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 April 4, 2011, filed it on April 6, 2011, and designated it as GRAS Notice No. GRN 000377.
The subject of the notice is Bifidobacterium animalis subsp. lactis strain Bf-6. The notice informs FDA of the view of Cargill that B. animalis subsp. lactis strain Bf-6 is GRAS, through scientific procedures, for use as an ingredient in foods. The intended foods include: dairy foods such as fluid milks, yogurt, milk-based desserts and gravies and cheeses; dry seeds, nuts, and nut butters; grain products such as flour, yeast breads, quickbreads, cakes, cookies, pies, pastries, crackers, pancakes, waffles, French toast, crepes, pasta, cooked and ready-to-eat cereals, grain mixtures, and meat substitutes; fruits and fruit beverages; dark-green vegetables, olives, pickles, relishes, and vegetable soups; salad dressings; sugars and sugar substitutes, syrups, honey, molasses, jellies, jams, preserves, gelatin desserts, ices, and popsicles, candies, and chewing gum; and carbonated soft drinks, sports drinks, energy drinks, and water at a maximum level of 1011 colony forming units (cfu) per serving.
Cargill includes the report of a panel of individuals (Cargill's GRAS Panel) who evaluated the data and information that are the basis for Cargill's GRAS determination. Cargill considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Cargill's GRAS panel discusses identity, specifications, method of manufacture, dietary exposure and safety, and concludes that B. animalis subsp. lactis strain Bf-6 is GRAS under the intended conditions of use.
Cargill discusses the characteristic properties of B. animalis subsp. lactis and cites published literature supporting the nonpathogenic and nontoxigenic nature of different strains of the organism. Cargill states that B. animalis subsp. lactis strains are commonly considered to be members of the broad classification of lactic acid bacteria (LAB). Cargill states that similar to other LAB, B. animalis subsp. lactis strains are naturally found in the human gastrointestinal system. Cargill describes the identity of B. animalis subsp. lactis strain Bf-6. Cargill states that this strain was initially isolated from the feces of a healthy human and has been sold commercially since 1993.
Cargill describes the methods used to produce B. animalis subsp. lactis strain Bf-6, noting it is manufactured in a growth medium composed of food-grade components (i.e., purified water, nonfat dry milk, dextrose, yeast, polysorbate 80). Cargill states that, after fermentation, the B. animalis subsp. lactis strain Bf-6 cultures are concentrated, and the organism is sold as the cell concentrate or as dried, cryoprotected pellets. Cargill states that microbiological purity and compliance with specifications are verified for each lot of B. animalis subsp. lactis strain Bf-6 before release.
Cargill states that B. animalis subsp. lactis strain Bf-6 will be used in a number of foods at levels between 109 and 1011 cfu/serving (usually at less than 1010 cfu/serving), and that the levels will decline over the shelf-life of the product. Cargill also states that the average individual eats about 20 servings per day of all food combined, and would need to eat between 10 and 20 servings of foods containing B. animalis subsp. lactis strain Bf-6 at levels of 5 x 109 to 1010 cfu/serving to ingest 1011 cfu. Cargill notes that it is unlikely that half or more of the foods eaten will contain B. animalis subsp. lactis strain Bf-6; therefore, ingestion of B. animalis subsp. lactis strain Bf-6 will be less than 1011 cfu/day. Based on this analysis, Cargill makes a conservative estimate for the potential daily intake of B. animalis subsp. lactis strain Bf-6 of 1011 cfu/day.
Cargill discusses data from published studies to demonstrate the safety of B. animalis subsp. lactis strain Bf-6. In its discussion, Cargill includes in vitro tests, genetic sequencing, and bioinformatic analyses for B. animalis subsp. lactis strain Bf-6. Cargill discusses animal studies conducted in rats and mice. Cargill also considers studies conducted in adult humans. Cargill reports that the results of these studies show that B. animalis subsp. lactis strain Bf-6 has little potential for transferable antibiotic resistance, does not display harmful metabolic or hemolytic activities, and does not contain genes that encode known virulence factors. Cargill states that the results of human studies support its finding that B. animalis subsp. lactis strains can be consumed at levels up to 1011 cfu/day with no adverse effects. Cargill also cites published studies that highlight a lack of genetic and phenotypic diversity among strains of this subspecies. Based on the results of these published studies and the history of use of the Bifidobacterium species, including strains of B. animalis subsp. lactis, Cargill concludes that B. animalis subsp. lactis strain Bf-6 is safe for its intended uses in foods.
Standards of Identity
In the notice, Cargill states its intention to use B. animalis subsp. lactis strain Bf-6 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.
The Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA) amends the Federal Food, Drug, and Cosmetic Act (FD&C Act) 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 the Center for Food Safety and Applied Nutrition's Office of Nutrition, Labeling and Dietary Supplements (ONLDS).
Potential Labeling Issues
In describing the clinical studies in support of the safe use of B. animalis subsp. lactis strain Bf-6, Cargill notes some results with potential health benefits. Section 403(a) of the FD&C Act, a food is misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FD&C Act 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 B. animalis subsp. lactis strain Bf-6 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 B. animalis subsp. lactis strain Bf-6 on the label or in labeling.
Section 301(ll) of the FD&C Act
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FD&C Act to, among other things, add section 301(ll). Section 301(ll) of the FD&C Act prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FD&C Act, 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 Cargill's notice that B. animalis subsp. lactis strain Bf-6 is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing B. animalis subsp. lactis strain Bf-6. Accordingly, this response should not be construed to be a statement that foods that contain B. animalis subsp. lactis strain Bf-6, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Cargill, as well as other information available to FDA, the agency has no questions at this time regarding Cargill's conclusion that B. animalis subsp. lactis strain Bf-6 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 B. animalis subsp. lactis strain Bf-6. As always, it is the continuing responsibility of Cargill 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 000377, 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 http://www.fda.gov/grasnoticeinventory.
Mitchell A. Cheeseman, Ph.D.
Office of Food Additive Safety
Center for Food Safety
and Applied Nutrition