Agency Response Letter GRAS Notice No. GRN 000419
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CFSAN/Office of Food Additive Safety
November 20, 2012
Michael Falk, Ph.D.
Life Sciences Research Organization
9650 Rockville Pike
Bethesda, MD 20814
Re: GRAS Notice No. GRN 000419
Dear Dr. Falk:
The Food and Drug Administration (FDA) is responding to the notice, dated January 25, 2012, that you submitted on behalf of ChemiNutra, Inc. (ChemiNutra) 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 February 3, 2012, filed it on February 14, 2012, and designated it as GRAS Notice No. GRN 000419.
The subject of the notice is L-alpha-glycerylphosphorylcholine (L-α-GPC). The notice informs FDA of the view of ChemiNutra that L-α-GPC is GRAS, through scientific procedures, as a source of choline in conventional beverage and beverage bases, including coffee, tea, milk (fluid), powdered milk, flavored milk/milk drinks, carbonated beverages, powdered beverages, meal replacement liquids, foods including yogurt, grain-based bars, protein bars, ready-to-eat breakfast cereals, and snack foods including chocolates, candies, and chewing gum at levels ranging from 10-100 milligrams of L-α-GPC per serving.
Our use of L-α-GPC in this letter should not be considered an endorsement or recommendation of that term as an appropriate common or usual name for the purpose of declaring the substance in the ingredient statement of foods that contain that ingredient. Title 21 CFR 101.4 states that each ingredient must be declared by its common or usual name. In addition, 21 CFR 102.5 outlines general principles to use when establishing common or usual names for nonstandardized foods. Issues associated with labeling and the appropriate common or usual name of a food or food ingredient are the responsibility of the Office of Nutrition, Labeling, and Dietary Supplements (ONLDS) in the Center for Food Safety and Applied Nutrition (CFSAN).
As part of its notice, ChemiNutra includes a report from a panel of individuals (ChemiNutra’s GRAS panel) who evaluated the data and information that are the basis for ChemiNutra’s GRAS determination. ChemiNutra considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. ChemiNutra’s GRAS panel considered the identity, manufacturing process, potential exposure resulting from the intended uses and published and unpublished safety studies. Based on this review, ChemiNutra’s panel concluded that L-α-GPC, produced with current good manufacturing practices and meeting appropriate specifications, is GRAS, based on scientific procedures, under the intended conditions of use.
ChemiNutra describes the identity of L-α-GPC as a white to off-white powder and a derivative of phosphatidylcholine. The CAS registry number for L-α-GPC is 28319-77-9.
ChemiNutra describes the manufacturing process for L-α-GPC starting from soy lecithin extract containing 35-38 percent phosphatidylcholine. The notifier describes a transesterification procedure of the soy lecithin extract that removes free fatty acids to produce L-α-GPC and fatty acid esters. L-α-GPC is then separated from the fatty acid esters, extracted, crystallized and dissolved prior to microfiltration and packaging. ChemiNutra discusses three different L-α-GPC products, including two concentrations of the ingredient with different flow agents and a powdered form without any flow agents. ChemiNutra provides specifications for all three L-α-GPC products, including identity, limits for microbial contaminants and heavy metals, and flow agents. ChemiNutra states that the products are manufactured using food grade materials and in accordance with current good manufacturing practices.
ChemiNutra discusses dietary exposure of L-α-GPC and estimates mean and 90th percentile daily intakes to be 108 mg per person per day (mg/p/d) and 196 mg/p/d, respectively, based on the intended uses at the maximum intended use levels. These estimates were calculated using consumption data from the National Health and Nutrition Examination Survey (2005-2006), for the U.S. population of 2 years and older. ChemiNutra also estimates a cumulative daily intake of choline to be 1718 mg/p/d for users, by combining background food and dietary supplement uses of choline and choline from the intended uses of L-α-GPC described above. The tolerable upper limit in adults is 3500 mg/p/d of choline as established by the Institute of Medicine in 1998.
ChemiNutra discusses published safety data on L-α-GPC. These include acute, subchronic, and chronic toxicity studies in Swiss mice, Sprague-Dawley rats, and Beagle dogs as well as mutagenicity studies. ChemiNutra also discusses corroborative unpublished teratogenicity and pharmacology studies in rats and rabbits. ChemiNutra states that in Beagle dogs (the most sensitive species) no adverse events were seen at 300 mg per kilogram body weight per day (mg/kg bw/d). This was the highest dose level tested. ChemiNutra further refers to published corroborative data of L-α-GPC consumption in humans at up to 1200 mg/p/d for six months. ChemiNutra notes that the study authors considered the observed adverse events (e.g., gastrointestinal complaints and headache seen in both treatment and control groups) to be mild and non-serious. Additionally, the authors note that no patients were withdrawn from the study because of the adverse effects. ChemiNutra cites this information to further demonstrate the safety of L-α-GPC at its intended use level.
Standards of Identity
In the notice, ChemiNutra states its intention to use L-α-GPC 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
In describing the human studies in support of the safe use of L-α-GPC, ChemiNutra notes some results with potential health benefits. Under section 403(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), a food is misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FD&C Act 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.
If products that contain L-α-GPC bear any therapeutic claims on the label or in labeling regarding the cure, mitigation, treatment, or prevention of disease, such claims are the purview of ONLDS in CFSAN. The Office of Food Additive Safety (OFAS) neither consulted with ONLDS on this labeling issue nor evaluated the information in your notice to determine whether it would support any claims made on the label or in labeling.
The Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA) amends the FD&C 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. L-α-GPC may require labeling under FALCPA because it may contain protein derived from soy lecithin. Although issues associated with labeling food are the responsibility of ONLDS, issues associated with FALCPA exemptions are the responsibility of the Food Allergen Coordinator in OFAS.
Section 301(ll) of the FD&C Act
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FD&C Act to, among other things, add section 301(ll). Section 301(ll) of the FD&C Act prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FD&C Act, 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 ChemiNutra’s notice that L-α-GPC is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing L-α-GPC. Accordingly, this response should not be construed to be a statement that foods that contain L-α-GPC, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by ChemiNutra, as well as other information available to FDA, the agency has no questions at this time regarding ChemiNutra’s conclusion that L-α-GPC 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 L-α-GPC. As always, it is the continuing responsibility of ChemiNutra 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 000419, 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 at www.fda.gov/grasnoticeinventory.
Dennis M. Keefe, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition