Agency Response Letter
GRAS Notice No. GRN 000196

Claire L. Kruger, Ph.D.
ENVIRON International Corporation
Suite 300
4350 North Fairfax Drive
Arlington, VA 22203

Re: GRAS Notice No. GRN 000196

Dear Dr. Kruger:

The Food and Drug Administration (FDA) is responding to the notice, dated March 3, 2006, that you submitted on behalf of Snow Brand Milk Products Co., Ltd. (Snow Brand) 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 March 6, 2006, filed it on March 8, 2006, and designated it as GRAS Notice No. GRN 000196.

For the purposes of this letter FDA describes the subject of the notice as "bovine milk basic protein fraction" (BMBPF). The notice informs FDA of the view of Snow Brand that BMBPF is GRAS, through scientific procedures, for use as an ingredient of food providing between 10 and 40 milligrams(mg) per serving of BMBPF in several food categories described in Table 1 below.

As part of its notice, Snow Brand includes the report of a panel of individuals (Snow Brand's GRAS panel) who evaluated the data and information that are the basis for Snow Brand's GRAS determination. Snow Brand considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Snow Brand's GRAS panel discusses the intended use of BMBPF, the history of safe exposure, and unpublished corroborative information.

Table 1
Intended uses of BMBPF

Food Category	Serving Size1	BMBPF (mg/serving)
Cottage cheese	110 grams (g)	10
Imitation milk (including rice and soy milk)	240 milliliters (mL)	40
Juice (100% citrus and citrus blends, prune and vegetable juices)	240 mL	40
Meal replacement bar	40 g	40
Meal replacement drink	240 mL	40
Milk (skim, 1%, kefir - fluid and dry forms)	240 mL	40
Processed cheese	30 g	30
Salad dressing 2	30 g	10
Yogurt 3	225 g	40
1 Reference Amounts Customarily Consumed (21 CFR 101.12). 2 Excludes mayonnaise and mayonnaise-type dressings. 3 Excludes frozen yogurt.

Snow Brand provides composition information based on batch analyses indicating that BMBPF is composed primarily of the proteins lactoferrin (LF) and lactoperoxidase (LPO), with residual proteins, carbohydrate, ash and moisture accounting for approximately 5% of BMBPF. Snow brand also identifies the other proteins present in BMBPF at concentrations less than 0.1% including, cystatin C, high mobility group (HMG)-like protein, and kininogen fragment 1-2.

BMBPF is produced from pasteurized bovine skim milk that is applied to a cation exchange chromatographic column, removing acid milk proteins and lactose. The basic proteins remaining on the column are eluted from the resin using sodium chloride. The resulting eluate is concentrated and dialyzed to produce BMBPF solids. These BMBPF solids are then crushed and packaged.

Snow Brand provides specifications for the major protein constituents, fat, carbohydrate, ash, moisture, heavy metals, environmental and microbiological contaminants, and physical properties. Snow Brand also provides batch analysis data supporting compliance with these specifications. Snow Brand indicates that their product complies with the food grade specifications described in the notice and that their production process consistently yields a product suitable for addition to food.

Snow Brand provides an estimated daily intake (EDI) for BMBPF. Snow Brand provides the mean and 90th percentile, 2-day average of its product EDI for multiple segments of the population as well as for the population as a whole older than 2 years. For the population older than two years of age, Snow Brand reports the mean and 90th percentile, 2-day average EDI of BMBPF to be approximately 47 and 100 mg/person/day, respectively.

Snow Brand provides estimates of the number of servings (8 ounce) of fluid milk that would correspond to the mean exposure to BMBPF based on the relative concentrations of the components of BMBPF in milk. Snow Brand notes, based on the concentration of LF and LPO in milk and concentrations of these constituents in BMBPF, the mean exposure to the constituents of BMBPF from the intended use is no more than the equivalent of 2.7 servings of milk per day for the population older than two years of age. Snow Brand states that these exposure estimates indicate that the uses of BMBPF described in the notice will not result in exaggerated exposure to other protein components relative to background exposure from dairy products.

Snow Brand discusses the safety of these components of BMBPF: LF, LPO, cystatin C, kininogen fragment 1-2, and HMG-like protein. Snow Brand notes that bovine LF has been the subject of three completed GRAS notifications (GRN 000069, GRN 000077, GRN 000130). Snow Brand also discusses published studies relevant for evaluating the allergenic potential of bovine LF. With regard to the other components of BMBPF, Snow Brand discusses their presence in milk and provides unpublished information describing the in vitro digestibility of the protein and bioinformatic analyses comparing the component to known allergenic sequences. Snow Brand indicates that these studies support the conclusion that the consumption of BMBPF will not result in an increased risk of allergic reaction.

Snow Brand provides a discussion of unpublished studies supporting the safety of BMBPF including in vitro mutagenicity, rodent oral toxicity and teratogenicity, and human clinical trials. Snow Brand states that the mutagenicity study indicated no evidence of mutagencity. Further, the rodent toxicity and teratogenicity studies noted no treatment-related adverse events at levels up to 2000 mg/kilogram of body weight of BMBPF. Snow Brand also reports the results of two unpublished clinical studies indicating that BMBPF was well-tolerated at levels up to 300 mg/day.

Standards of Identity

In its notice, Snow Brand states its intention to use BMBPF 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 use of BMBPF and in describing the information that Snow Brand relies on to conclude that BMBPF is GRAS under the conditions of its intended use, Snow Brand raises a potential issue under these labeling provisions of the FFDCA. If products that contain BMBPF bear any claims on the label or in labeling, such claims are the purview of the Office of Nutritional Products, Labeling, and Dietary Supplements (ONPLDS) in the Center for Food Safety and Applied Nutrition. 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 BMBPF on the label or in labeling.

Allergen 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 ONPLDS.

Conclusion

Based on the information provided by Snow Brand, as well as other information available to FDA, the agency has no questions at this time regarding Snow Brand's conclusion that BMBPF 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 BMBPF. As always, it is the continuing responsibility of Snow Brand 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 000196, 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