Agency Response Letter GRAS Notice No. GRN 000268

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CFSAN/Office of Food Additive Safety

July 8, 2009

Claire L. Kruger, Ph.D.
6430 Rockledge Drive
Suite 503
Bethesda, MD 20817

Re: GRAS Notice No. GRN 000268

Dear Dr. Kruger:

The Food and Drug Administration (FDA) is responding to the notice, dated November 19, 2008, that you submitted on behalf of Morinaga Milk Industry Co., Ltd. (Morinaga) 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 this notice on November 20, 2008, filed it on November 21, 2008, and designated it as GRAS Notice No. GRN 000268.

The subject of the notice is Bifidobacterium longum strain BB536. The notice informs FDA of the view of Morinaga that B. longum strain BB536 is GRAS, through scientific procedures, for use as an ingredient in breads/baked goods, cereals, dairy products/dairy-based foods and dairy substitutes, fruit products, candy, chewing gum, cocoa powder, condiment sauces, flavored beverage syrups, fruit flavored powder beverage mixes, gelatin desserts, gravies, margarine, peanut and other nut butter/spreads, snack foods, weaning foods at a maximum level of 1x1010 colony forming units (cfu) per serving(1) and in milk based powdered infant formula at a level of 1x1010 cfu per gram of infant formula powder that is intended for consumption for term infants aged 9 months and older.

Morinaga includes the report of a panel of individuals (Morinaga’s GRAS Panel) who evaluated the data and information that are the basis for Morinaga’s GRAS determination. Morinaga considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food.

Morinaga discusses the identity and characteristic properties of B. longum strain BB536. Morinaga states that Bifidobacteria are naturally occurring bacteria and are a normal part of the human gut microflora. Bifidobacteria comprise up to 25 percent of the cultivatable fecal bacteria in adults and up to 80 percent in infants. Morinaga further states that B. longum strain BB536 was initially isolated from a healthy infant. Morinaga states that B. longum strain BB536 is nonpathogenic, nontoxigenic, lacks any antibiotic resistance genes, does not contain any plasmids, does not display harmful metabolic activities, and is non-hemolytic. Morinaga also discusses the organism’s taxonomy, physiology, and prior use in food in other countries.

Morinaga describes the inoculating and subculturing methods used to prepare the starter cultures needed to produce the variety of B. longum strain BB536 formulations. Morinaga states that after fermentation, the B. longum strain BB536 cultures are concentrated, washed with sterilized cooled water, reconcentrated, mixed, frozen, and powdered. The powder is then mixed with either corn starch, tapioca starch, or potato starch as a carrier. Finished formulations containing B. longum strain BB536 have different properties and are used in different food products.

Morinaga estimates the daily intake for the B. longum strain BB536 ingredient. For the food uses other than follow-on infant formula, Morinaga uses food consumption data from the Department of Health and Human Services’ 2003-2004 National Health and Nutrition Examination Survey (NHANES, 2003-2004) to determine the mean estimated daily intake (EDI) of B. longum strain BB536 to be 7.5 x 1010 cfu per day (cfu/d) and the 90th percentile intake to be 1.2 x 1011 cfu/d for ages 2 years and older. For the use in infant formula, Morinaga determines the EDI based on two subpopulations, namely infants 9 to 12 months and 12 to 23 months. The mean and 90th percentile is 7.4 x 1010 cfu/d and 12 x 1010 cfu/d, respectively, for infants 9 to 12 months; Morinaga reports the mean and 90thpercentile to be 6.4 x 1010 cfu/d and 9.2 x 1010 cfu/d, respectively, for 12 to 23 months. Morinaga states that loss of viability of the organism necessitates the addition of 1 to 10 times the target B. longum strain BB536 concentration in order to maintain the desired target level throughout shelf-life.

Morinaga discusses the safety of the B. longum strain BB536 ingredient. Morinaga discusses data from published and unpublished studies that include antibiotic susceptibility studies, genetic sequencing, studies in animal models, and studies in human subjects using the B. longum strain BB536. Morinaga states that the complete genome of B. longum strain BB536 has been sequenced and analyzed to address any potential safety risks. Based on these studies and genomic data, Morinaga concludes that the intended uses for B. longum strain BB536 have been shown to be safe and that there is no evidence in the available information demonstrating that there is a potential hazard to the public when B. longum strain BB536 is used in the intended applications.

Standards of Identity

In the notice, Morinaga states its intention to use B. longum strain BB536 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 label claims

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 use of B. longum strain BB536 and in describing the information that Morinaga relies on to conclude that B. longum strain BB536 is GRAS under the conditions of its intended use, Morinaga raises a potential issue under these labeling provisions of the FFDCA. If products that contain B. longum strain BB536 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 B. longum strain BB536 on the label or in labeling.

Intended use in infant formula

Under section 412 of the FFDCA, a manufacturer of a new infant formula must make a submission to FDA, providing required assurances about the formula, at least 90 days before the formula is marketed. Morinaga should be aware that FDA’s response to Morinaga’s GRAS notice does not alleviate the responsibility of any infant formula manufacturer who intends to market an infant formula that contains B. longum strain BB536 to make the submission required by section 412.

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 Morinaga’s notice that B. longum strain BB536 is GRAS for use in various food categories, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing B. longum strain BB536. Accordingly, this response should not be construed to be a statement that foods that contain B. longum strain BB536, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).


Based on the information provided by Morinaga, as well as other information available to FDA, the agency has no questions at this time regarding Morinaga’s conclusion that B. longum strain BB536 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. longum strain BB536. As always, it is the continuing responsibility of Morinaga 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 000268, 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 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.


Laura M. Tarantino, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition

(1)Serving sizes for the intended uses correspond to the Reference Amounts Customarily Consumed (21 CFR 101.12).

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