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U.S. Department of Health and Human Services

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Agency Response Letter GRAS Notice No. GRN 000186

CFSAN/Office of Food Additive Safety
July 20, 2006

Diane McEnroe
Sidley, Austin, Brown and Wood, LLP.
787 Seventh Avenue
New York, NY 10019

Re: GRAS Notice No. GRN 000186

Dear Ms. McEnroe:

The Food and Drug Administration (FDA) is responding to the notice, dated December 9, 2005, that you submitted on behalf of Lipogen Products (9000) Ltd. (Lipogen) 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 December 12, 2005, filed it on December 14, 2005, and designated it as GRAS Notice No. GRN 000186. Lipogen provided additional information in support of this notification on April 17, 2006, and May 8, 2006.

The subject of the notice is soy lecithin enzymatically modified to contain increased phosphatidylserine (soy lecithin PS). The notice informs FDA of the view of Lipogen that soy lecithin PS is GRAS, through scientific procedures, for use as an ingredient in multiple food categories as described in Table 1 below.

As part of its notice, Lipogen includes the report of a panel of individuals (Lipogen's GRAS panel) who evaluated the data and information that are the basis for Lipogen's GRAS determination. Lipogen considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Based on published and unpublished short and long term animal toxicity studies and human clinical trials, Lipogen's GRAS panel concludes that ingestion of soy lecithin PS from the intended uses would be of no health concern.

Table 1
Soy Lecithin PS Use Levels
Food category*Soy Lecithin PS use level (% w/w)
Breads and Rolls0.05 to 0.083
Biscuits0.083
Crackers0.083
Waffles0.05
Carbonated Beverages0.05
Meal Replacements (Liquid)0.05
Ready-to-Eat Breakfast Cereals0.083
Cheese0.25
Cheese Spreads0.25
Coffee0.05
Tea0.05
Ketchup0.50
Soy-Based Milk0.05
Margarine0.25
Mayonnaise0.50
Fat-based Spreads0.25
Pasta0.05
Grain-based Bars0.05
Commercial Jams0.25
Milk0.05
Milk Drinks0.05
Yogurt0.05
Peanut Sreads0.25
Tofu0.25
Soy-based Meat Substitutes0.05
Fruit Juices0.05
Salty Snacks0.05
Chocolates0.05

*Lipogen notes in a communication dated April 17, 2006, that soy lecithin PS is not intended to be used in products such as baby foods or infant formula that are specifically marketed for use by infants.

Phosphatidylserine (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 L-serine moiety differentiates phosphatidylserine from other common phospholipids like phosphatidylcholine or phosphatidylethanolamine, containing choline or ethanolamine bound via the phosphodiester bond, respectively. Lipogen intends to market both powder and liquid versions of its soy lecithin PS product. Both versions are specified to contain greater than 19 percent phosphatidylserine. In addition to the phosphatidylserine component, the products contain other phospholipids and glycerides naturally occurring in soy lecithin at levels of less than 81 percent for the powdered product and less than 63 percent for the liquid product. The liquid product will also contain soy oil at a level of less than 19 percent.

Lipogen describes the method of manufacture for soy lecithin PS. The process involves the enzymatic transphosphatidylation of phosphatidylcholine and phosphatidylethanolamine from soy lecithin via cabbage-derived phospholipase D in the presence of exogenous, food-grade L-serine to form an increased proportion of phosphatidylserine. Phospholipase D [EC 3.1.4.4] is obtained via a water-based extraction from cabbage. In addition, following the enzymatic conversion, the reaction is terminated by bringing the reaction mixture to a temperature of 70 degrees C, which is expected to denature the enzyme. Any residues, including residual serine, free choline and ethanolamine are removed as a result of the washing procedure. Silicon dioxide (less than 1 percent) and vitamin C (less than 2 percent) are added as formulation aids to the final products at levels consistent with those permitted for use in foods.

Lipogen states that all reagents used in the manufacture of soy lecithin PS (liquid or powder) are food grade as per the specifications presented in the Food Chemicals Codex. The product is manufactured in accordance with good manufacturing procedures. Specifications for soy lecithin PS includes limits on composition of phospholipids, lead, and microbiological contamination.

Lipogen provides an estimated daily intake (EDI) of soy lecithin PS from its proposed uses in GRN 000186. Lipogen reports that the mean and 90th percentile, 2-day average EDI of soy lecithin PS by the U.S. population, as 0.71 and 1.19 grams/person/day, respectively. On a body weight basis, Lipogen estimates the mean and 90th percentile intakes of phosphatidylserine product are determined to be 12.8 and 23.5 milligrams/kilogram body weight/day.

Based on the composition of soy lecithin PS (approximately 20 percent phosphatidylserine), Lipogen estimates the resultant mean and 90th percentile EDI for phosphatidylserine to be approximately 140 milligrams/person/day and 240 milligrams/person/day, respectively. In addition to this exposure to phosphatidylserine estimated from the use of its notified substance, Lipogen notes that phosphatidylserine is a normal component of plant and animal cell membranes. As such, it is a typical constituent of the human diet present in soy products, eggs, meats, certain legumes and human breast milk. Lipogen notes that a published study estimates that consumers of meat consume approximately 80 milligrams of naturally-occurring phosphatidylserine per day.

Lipogen summarizes multiple published and unpublished studies examining the toxicity of soy lecithin PS and its phosphatidylserine component. Lipogen states that the safety of the phosphatidylserine component of soy lecithin PS is confirmed by a series of published short and long term animal toxicity studies, and tolerance by humans in clinical trials. Lipogen notes the absence of treatment-related adverse effects in these studies. Furthermore, Lipogen discusses an unpublished absorption study in humans with soy lecithin PS and published studies on absorption, distribution, metabolism and elimination studies with phosphatidylserine in rodents. Based on these reports, Lipogen states that the bioavailability of the ingested phosphatidylserine is limited due to extensive hydrolysis in the intestine prior to absorption, and that the absorbed phosphatidylserine and other components of soy lecithin PS are transported and metabolized like phospholipids in the diet.

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, Lipogen states its intention to use soy lecithin 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 Lipogen, as well as other information available to FDA, the agency has no questions at this time regarding Lipogen's conclusion that soy lecithin 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 soy lecithin PS. As always, it is the continuing responsibility of Lipogen 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 000186, 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