Agency Response Letter
GRAS Notice No. GRN 000223

Edward A. Steele
EAS Consulting Group, LLC
1940 Duke Street
Suite 200
Alexandria, Virginia 22314

Re: GRAS Notice No. GRN 000223

Dear Mr. Steele:

The Food and Drug Administration (FDA) is responding to the notice, dated May 15, 2007, that you submitted on behalf of Enzymotec Ltd. (Enzymotec) 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 15, 2007, filed it on May 22, 2007, and designated it as GRAS Notice No. GRN 000223.

The subject of the notice is phosphatidylserine. The notice informs FDA of the view of Enzymotec that phosphatidylserine is GRAS, through scientific procedures, for use as an ingredient in flavored milk, milk drinks, milk substitutes (i.e., soy milk), milk-based meal replacements, yogurt, breakfast bars, and fruit flavored drinks at levels of 100 milligrams (mg) per serving; and in breakfast cereals and milk (i.e., regular milk, buttermilk, and dry reconstituted milk) at 50 mg per serving.

As part of its notice, Enzymotec includes the report of a panel of individuals (Enzymotec's GRAS panel) who evaluated the data and information that are the basis for Enzymotec's GRAS determination. Enzymotec considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Enzymotec's GRAS panel evaluated estimates of dietary exposure, the method of production, and product specifications as well as published studies. Based on this review, Enzymotec's GRAS panel concluded that phosphatidylserine that meets its established food grade specifications is GRAS under the conditions of its intended use.

Enzymotec describes the identity and composition of phosphatidylserine. Phosphatidylserine (1,2-diacyl-sn-glycerol-3-L-phosphoserine, CAS Reg. No. 84776-79-4) consists of a glycerophosphate skeleton conjugated with two fatty acids and L-serine via a phosphodiester linkage. Enzymotec's product is specified to contain approximately 73% phosphatidylserine and lyso-phosphatidylserine. The product contains other phospholipids and glycerides naturally occurring in soy lecithin. These other phospholipids include phosphatidic acid, phosphatidylethanolamine, and associated lysophospholipids.

Enzymotec describes the method of manufacture for phosphatidylserine. Phosphatidylserine is manufactured from high phosphatidylcholine-enriched soybean lecithin. The phosphatidylcholine-enriched lecithin is enzymatically transphosphatidylated with L-serine using phospholipase D, which catalyses the substitution of the choline head-group with serine to form phosphatidylserine. Following the enzymatic reaction, phosphatidylserine is separated from the reaction mixture, purified and dried.

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

Enzymotec provides an estimated daily intake (EDI) of phosphatidylserine. Enzymotec incorporates by reference previous GRAS notices for phosphatidylserine (GRN 000186 and GRN000197) and indicates that the intended uses of their phosphatidylserine product are substitutional. Mean and 90th percentile two-day average intakes of phosphatidylserine by the United States population, all ages, (60% of survey population) are estimated to be approximately 25 mg/person/day and 45 mg/person/day, respectively. The 90th percentile all-person and all-user intakes of phosphatidylserine from all intended food-uses by the total population were 70 mg/person/day and 99 mg/person/day, respectively.

Regarding the safe use of phosphatidylserine, Enzymotec notes that phosphatidylserine is a naturally-occurring structural component of virtually all biological membranes in plants and animals. Enzymotec states that phosphatidylserine is found in small quantities in foods such as meats, eggs, soy products, certain legumes and milk. Enzymotec references GRN 000197 that reports a calculated average intake of 130 mg/person/day with light eaters of meat and fish consuming about 100 mg/person/day and vegans consuming less than 50 mg/person/day. This estimate was calculated based on the known phosphatidylserine content of certain foods and United States Department of Agriculture's Continuing Survey of Food Intake by Individuals.

Enzymotec summarizes published toxicological studies supporting the safe use of phosphatidylserine in foods. Enzymotec discusses published acute and long term (26-weeks) toxicity studies in rats and dogs using bovine cortex derived phosphatidylserine, as well as published studies assessing tolerance by humans. Enzymotec notes that the animal toxicity studies did not report significant toxicity at up to 1000 mg/kilogram body weight/day. In human studies, Enzymotec reports oral administration of phosphatidylserine at levels from 200 to 600 mg/day without any significant adverse effects. Enzymotec further notes that approximately 60% of dietary phosphatidylserine is excreted in the feces with a small percentage eliminated in urine. Approximately 40% of phosphatidylserine is metabolized with lysophosphatidylcholine and lysophosphatidylserine as the main metabolites.

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 (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, Enzymotec states its intention to use phosphatidylserine 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.

Conclusions

Based on the information provided by Enzymotec, as well as other information available to FDA, the agency has no questions at this time regarding Enzymotec's conclusion that phosphatidylserine is GRAS under the intended conditions. The agency has not, however, made its own determination regarding the GRAS status of the subject use of phosphatidylserine. As always, it is the continuing responsibility of Enzymotec 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 000223, 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

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