Agency Response Letter
GRAS Notice No. GRN 000197

David R. Joy
Keller and Heckman, LLP.
1001 G Street N.W.
Washington, DC 20001

Re: GRAS Notice No. GRN 000197

Dear Mr. Joy:

The Food and Drug Administration (FDA) is responding to the notice, dated March 23, 2006, that you submitted on behalf of Degussa Food Ingredients, GmbH (Degussa) 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 23, 2006, filed it on March 24, 2006, and designated it as GRAS Notice No. GRN 000197. Degussa provided additional information in support of this notification on May 10, 2006.

For the purposes of this letter FDA describes the subject of the notice as "phosphatidylserine" (PS). The notice informs FDA of the view of Degussa that its PS product is GRAS, through scientific procedures, for use as an ingredient in multiple food categories including yogurt (excluding fat-free yogurt), milk (powdered milk and ready-to-drink milk), meal replacements, cereal bars, powdered beverages, chewing gum, and breakfast cereals at a level intended to provide 20 milligrams (mg) of PS per serving.

Degussa's PS product is soy lecithin enzymatically modified to contain approximately 90 percent PS by weight. PS (1,2-diacyl-sn-glycerol-(3)-L-phosphoserine, CAS Reg. No. 84776-79-4) consists of a glycerophosphate skeleton conjugated with 2 fatty acids (phosphatidic acid), and L-serine via a phosphodiester linkage. The two acyl groups may vary, and according to Degussa the most abundant acyl group in their PS product is linoleic acid. As part of its notice, Degussa provides composition information for its PS product.

Degussa describes the method of manufacture for its PS product. Degussa's product is prepared by a process in which a high phosphatidylcholine soy lecithin fraction is treated with L-serine and an enzyme that catalyzes the formation of phosphatidylserine from available substrates. After enzymatic treatment, the resulting PS preparation is purified, including a series of aqueous washing steps that remove the residual enzyme.

Degussa states that the reagents used in the manufacture of the PS product are food grade as per the specifications presented in the Food Chemicals Codex and that their product is manufactured in accordance with good manufacturing practices. Degussa provides information on the composition of their product, including expected levels of other phospholipids, triglycerides, fatty acids, and moisture content. Degussa also provides specifications for its product, including limits for lead and other heavy metals, and microbiological specifications.

Degussa's PS product is intended for use as an ingredient in food. For the total U.S. population, Degussa provides an estimated daily intake (EDI) of PS from its proposed uses of 26.4 milligrams per person per day (mg/person/day) at the mean and 52.2 mg/person/day at the 90^th percentile. For children, ages 7 to 12 years, the mean and 90^th percentile EDI of PS is 20.8 and 45.0 mg/person/day, respectively. For adults, ages 50 years and older, the mean and 90^th percentile EDI of PS is 28.0 and 52.4 mg/person/day, respectively.

With regard to its conclusion about the safe use of PS, Degussa notes that PS is a naturally-occurring structural component of virtually all biological membranes, and as such is a normal constituent of food. Degussa states that PS is found in small quantities in some animal food stuffs, principally organ meats from dietary sources (such as brain, liver and kidney), fish, and some legumes. Degussa reports a calculated average intake of 130 mg/person/day. This estimate was calculated based on the known PS content of certain foods and United States Department of Agriculture's Continuing Survey of Food Intake by Individuals (CFSII).

Degussa summarizes several published studies supporting the safe use of PS in foods. Degussa discusses published acute and long term (26-weeks) toxicity studies in rats and dogs using bovine cortex derived PS (BC-PS), as well as studies assessing tolerance by humans. The notifier declares that their product and BC-PS are the same except for differences in the degree of saturation of the acyl groups. Degussa notes that the animal toxicity studies did not report significant toxicity at up to 1000 mg per kilogram of body weight per day. Degussa notes that the human clinical trials indicated that PS was well-tolerated at doses from 200 to 600 mg per day. Furthermore, based on published rodent studies, Degussa notes that PS is metabolized to safe and endogenous products and that approximately 70 percent of dietary PS is eliminated in urine and feces.

Allergen Labeling

The Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA) amends the Federal Food, Drug, and Cosmetic 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 Nutritional Products, Labeling, and Dietary Supplements.

Standards of Identity

In the notice, Degussa states its intention to use PS 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.

Conclusion

Based on the information provided by Degussa, as well as other information available to FDA, the agency has no questions at this time regarding Degussa's conclusion that PS 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 PS. As always, it is the continuing responsibility of Degussa 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 000197, 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