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U.S. Department of Health and Human Services

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Agency Response Letter GRAS Notice No. GRN 000279

CFSAN/Office of Food Additive Safety

July 25, 2009

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

Re: GRAS Notice No. GRN 000279

Dear Mr. Steele:

The Food and Drug Administration (FDA) is responding to the notice, dated January 22, 2009, that you submitted on behalf of 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 January 27, 2009, filed it on January 30, 2009, and designated it as GRAS Notice No. GRN 000279.

The subject of the notice is phosphatidylserine derived from fish (fish PS). The notice informs FDA of the view of Enzymotec that fish PS is GRAS, through scientific procedures, for use as an ingredient in breakfast cereals, dairy product analogs, grain products and pastas, milk products, and processed fruits and fruit juices at levels intended to provide 30 milligrams (mg) of phosphatidylserine per serving; and, as an ingredient of medical foods at levels that would not exceed 300 mg of phosphatidylserine per day.

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 states that the most common fatty acids of fish PS are palmitic, oleic, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Enzymotec notes that phosphatidylserine is a naturally occurring, ubiquitous component of plants and animals and is a normal constituent of the human diet.

Enzymotec describes the method of manufacture and specifications for fish PS. Fish PS is manufactured from ethanol-extracted lecithin derived from herring and whiting fish biomass. Fish PS is then produced through enzymatic transphosphatidylation of the fish lecithin with L-serine using a phospholipase D enzyme. Ethanol, hexane, and ethyl acetate are utilized during the enzymatic reaction and in subsequent purification steps. These solvents are removed by multiple vacuum evaporation steps in the process. Following the enzymatic reaction, the product is purified and mixed with silicon dioxide and antioxidant ingredients to produce the finished free-flowing powder. Enzymotec states that all reagents used in the manufacture of fish PS are food grade. Enzymotec provides specifications for fish PS that include the composition of phospholipids, and limits on arsenic, mercury, cadmium, lead, residual solvents, microbiological contamination as well as pesticides, dioxins, and PCBs.

Enzymotec provides an estimated daily intake (EDI) from its intended uses of fish PS based on use levels resulting in 30 milligrams per serving and food consumption data from the 1994-1996, and 1998 USDA Continuing Survey of Food Intakes by Individuals (CSFII). Enzymotec reports the mean EDI as 39 milligrams per person per day (mg/p/d) and the 90th percentile as 79 mg/p/d For comparison, Enzymotec cites reported estimates of phosphatidylserine intake from naturally occurring sources as ranging from 75 mg/p/d to 184 mg/p/d. Enzymotec notes that the EDI of EPA and DHA combined from the intended uses of fish PS is 35 mg/p/d at the 90th percentile.

Enzymotec summarizes published safety studies supporting the safe use of phosphatidylserine in foods. Enzymotec discusses published acute and long-term safety studies in rats and dogs with no toxicity up to 1000 milligrams per kilogram body weight per day; published reproductive studies in rat and rabbit models which show no effect on embryonic or fetal development, as well as published studies assessing tolerance by humans. In human studies not formally designed to investigate the safety of phosphatidylserine, Enzymotec reports that consumption of phosphatidylserine at levels from 200 to 800 mg/p/d did not result in any notable adverse effects. In addition, the notifier points out published reports which show no genotoxic or clastogenic activity in multiple in vitro analyses.

Enzymotec notes that these safety studies were conducted using phosphatidylserine derived from a variety of sources, including bovine cortex and soy. Enzymotec notes that the primary difference in phosphatidylserine derived from differing sources is the composition of the fatty acid component of phosphatidylserine. Enzymotec notes that these differences are unlikely to affect safety since ingested phosphatidylserine is metabolized in a similar fashion regardless of source. Further, Enzymotec states that the fatty acid composition of fish PS would not be expected to pose any safety concerns.

Enzymotec includes a discussion of the safety of the fatty acid components of fish PS. Enzymotec comments on the safe levels of exposure to EPA and DHA. Enzymotec notes that the EDI of EPA and DHA from the intended uses of fish PS is significantly lower than the 3 gram per day limit FDA recognized previously (21 CFR 184.1472).

Allergen Labeling

The Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA) amends the Federal Food, Drug, and Cosmetic Act (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 the Office of Nutrition, Labeling, and Dietary Supplements (ONLDS) in the Center for Food Safety and Applied Nutrition (CFSAN).

Standards of Identity

In the notice, Enzymotec states its intention to use fish 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.

Potential Labeling Issues

Under section 403(a) of the 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 fish PS and in describing the information that Enzymotec relies on to conclude that fish PS is GRAS under the conditions of its intended use, Enzymotec raises a potential issue under these labeling provisions of the FFDCA. If products that contain fish PS bear any claims on the label or in labeling, such claims are the purview of ONLDS. 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 fish PS on the label or in labeling.

Medical Foods

In its notice, Enzymotec informs FDA that one intended use of fish PS is use in medical foods. Section 5(b) of the Orphan Drug Act (ODA) defines a medical food as a food that is formulated to be consumed or administered enterally under the supervision of a physician and that is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation. Section 403(q) of the FFDCA lays out the statutory framework for nutrition labeling of food products. Section 403(r) of the FFDCA lays out the statutory framework for health claims and nutrient content claims. Under section 403(q)(5)(A)(iv) of the FFDCA and FDA's implementing regulations in 21 CFR 101.9(j)(8), the requirements for nutrition labeling do not apply to medical foods as defined in section 5(b) of the ODA. Under section 403(r)(5)(A) of the FFDCA and FDA's implementing regulations in 21 CFR 101.13(q)(4)(ii) and 21 CFR 101.14(f)(2), the requirements for nutrient content claims and health claims, respectively, do not apply to medical foods as defined in section 5(b) of the ODA. For your information, FDA's response to Enzymotec’s notice that fish PS is GRAS for use in medical foods does not address the question of whether any particular food product that contains fish PS as an ingredient would be a medical food within the meaning of section 5(b) of the ODA and, thus, would be exempt from the requirements for nutrition labeling, nutrient content claims, and health claims.

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

Conclusions

Based on the information provided by Enzymotec, the agency has no questions at this time regarding Enzymotec’s conclusion that fish 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 fish PS. 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 000279, 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 http://www.fda.gov. 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.

Sincerely,

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