Agency Response Letter GRAS Notice No. GRN 000311
CFSAN/Office of Food Additive Safety
June 15, 2010
Edward A. Steele
EAS Consulting Group
1940 Duke Street
Alexandria, VA 22314
Re: GRAS Notice No. GRN 000311
Dear Mr. Steele:
The Food and Drug Administration (FDA) is responding to the notice, dated December 14, 2009, 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 December 28, 2009, filed it on January 5, 2010, and designated it as GRAS Notice No. GRN 000311.
The subject of the notice is krill-based phosphatidylserine (krill PS). The notice informs FDA of the view of Enzymotec that krill 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 a use level intended to provide 30 milligrams (mg) of phosphatidylserine per serving; and, as an ingredient in medical foods at levels that would not exceed 300 mg of phosphatidylserine per day.
Enzymotec describes krill PS as a mixture of polar lipids derived from krill (a crustacean) with phosphatidylserine as the principle phospholipid present. Phosphatidylserine (1,2-diacyl-sn-glycero-(3)-phospho-L-serine, 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 krill PS are eicosapentaenoic acid (EPA), palmitic acid, and docosahexaenoic acid (DHA). 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 for krill PS. The source material for the production of krill PS is lecithin from krill (Euphausia superba), which is obtained by solvent extraction from krill biomass. Enzymotec notes that solvents are removed by vacuum evaporation. Phosphatidylserine is produced through enzymatic transphosphatidylation of krill lecithin with L-serine using a phospholipase D enzyme. After the product is purified from the reaction medium, it is blended with silicon dioxide to produce a free-flowing powder. Small quantities of antioxidants are also added. The final product is a brown to red colored powder. Enzymotec notes that all processing aids and ingredients used in the manufacture of krill PS are of food grade quality as specified in the 5th Edition of the Food Chemicals Codex. Enzymotec provides specifications for krill PS that include phosphatidylserine (55 percent), total phospholipids content (80 percent), as well as limits on arsenic, mercury, cadmium, lead, residual solvents (including a specification for hexane), microbiological contamination as well as pesticides, dioxins, and PCBs.
Enzymotec calculated the estimated daily intake (EDI) for the intended food uses of krill PS for users only as 39 milligrams per person per day (mg/p/d) and 79 mg/p/d at the mean and the 90th percentile, respectively. 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 also gave the resulting 90th percentile combined intake of EPA and DHA from the intended uses of krill PS as 33 mg/p/d.
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 with no toxicity at the highest dose tested, which was 1000 milligrams per kilogram body weight per day (mg/kg bw/d) of phosphatidylserine. A dose of 1000 mg/kg bw/d would be equivalent to approximately 10 grams of phosphatidylserine per day in an average 10 kilogram experimental dog. Enzymotec also describes published reproductive studies in rats and rabbits that show no effect on embryonic or fetal development, as well as published studies assessing tolerance by humans. In human studies, Enzymotec reports oral administration of phosphatidylserine at levels from 200 to 800 mg/p/d without any adverse effects. In addition, the notifier points out published reports that show that no genotoxic or clastogenic activity was found when phosphatidylserine was investigated in multiple in vitro assays.
Enzymotec discusses the safety of the fatty acid components of krill PS, focusing on the EPA and DHA content of krill PS. Enzymotec notes that the EDI of EPA and DHA from the intended uses of krill PS is significantly lower than the 3 gram per person per day limit FDA recognized previously (21 CFR 184.1472). Finally, the notifier discusses possible impurities/contaminants as well as allergenicity as they relate to the source (krill) of the phosphatidylserine. Based on its review of published toxicological studies, the known metabolism of phosphatidylserine, the specifications provided for krill PS, and estimates of exposure to krill PS, Enzymotec concludes that the intended uses of krill PS described are safe.
Standards of Identity
In the notice, Enzymotec states its intention to use krill 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 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 krill PS and in describing the information that Enzymotec relies on to conclude that krill 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 krill PS bear any claims on the label or in labeling, such claims are the purview of the Office of Nutrition, Labeling, and Dietary Supplements (ONLDS) in the Center for Food Safety and Applied Nutrition. 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 krill PS on the label or in labeling.
Potential Requirement for a Color Additive Petition
In its notice, Enzymotec describes krill PS as a brown to red colored powder. As such, the use of krill PS in food products may constitute the use of a color additive under section 201(t)(1) of the FFDCA and FDA's implementing regulations in 21 CFR Part 70. Under section 201(t)(1) and 21 CFR 70.3(f), the term color additive means a material that is a dye, pigment, or other substance made by a process of synthesis or similar artifice, or extracted, isolated, or otherwise derived from a vegetable, animal, mineral, or other source, and that is capable (alone or through reaction with another substance) of imparting color when added or applied to a food; except that such term does not include any material which the Secretary,1 by regulation, determines is used (or intended to be used) solely for a purpose or purposes other than coloring. Under 21 CFR 70.3(g), a material that otherwise meets the definition of color additive can be exempt from that definition on the basis that it is used or intended to be used solely for a purpose or purposes other than coloring, as long as the material is used in a way that any color imparted is clearly unimportant insofar as the appearance, value, marketability, or consumer acceptability is concerned. Given the construct of section 201(t)(1) of the FFDCA and 21 CFR 70.3(f) and (g), the use of a substance that is capable of imparting color may constitute use as a color additive in addition to use as a food additive or GRAS substance. For example, beta-carotene is both approved for use as a color additive (21 CFR 73.95) and affirmed as GRAS for use as a nutrient supplement (21 CFR 184.1245); in some food products, beta-carotene is used for both purposes. Importantly, if the use of krill PS constitutes use as a color additive within the meaning of section 201(t)(1) of the FFDCA and FDA's implementing regulations in 21 CFR 70.3(f) and (g), section 721(a) of the FFDCA requires premarket review and approval of that use by FDA. Under section 402(c) of the FFDCA, a food product that contains an unapproved color additive would be deemed adulterated.2
In a telephone conference on June 1, 2010, between FDA and Enzymotec’s agent, Mr. Edward Steele, FDA requested that Enzymotec present its view on whether any of the intended uses of krill PS would be exempt from the definition of a color additive. In an amendment dated June 3, Enzymotec presented its rationale for concluding that all of the intended uses of krill PS would be exempt from the definition of color additive under section 201(t) of the FFDCA and FDA's implementing regulations in 21 CFR 70.3(f) and (g). Importantly, FDA's response to GRN 000311 does not include any comment by FDA about Enzymotec's view on this issue. If, after receipt of this letter, Enzymotec has any further questions about this issue, we recommend that Enzymotec contact the Division of Petition Review in the Office of Food Additive Safety.
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 ONLDS.
In its notice, Enzymotec informs FDA that one intended use of krill 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 krill PS is GRAS for use in medical foods does not address the question of whether any particular food product that contains krill 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 krill PS is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing krill PS. Accordingly, this response should not be construed to be a statement that foods that contain krill PS, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
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 krill 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 krill 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 000311, 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.
Mitchell A. Cheeseman, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
1The Secretary of the Department of Health and Human Services
2We note that section 721(b)(4) of the FFDCA provides that a color additive shall be deemed to be safe and suitable for the purpose of listing under section 721(b) of the FFDCA while there is in effect a published finding of the Secretary declaring that the substance is exempt from the definition of “food additive” because of its being generally recognized by qualified experts as safe for its intended use as provided in section 201(s) of the FFDCA. Importantly, FDA’s response to GRN 000110 does not constitute a “finding of the Secretary” within the meaning of section 721(b)(4) of the FFDCA.