Agency Response Letter GRAS Notice No. GRN 000625
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See also Generally Recognized as Safe (GRAS).
CFSAN/Office of Food Additive Safety
August 18, 2016
David Bechtel, Ph.D.
Intertek Scientific and Regulatory Consultancy
100 Davidson Avenue, Suite 102
Somerset, NJ 08873
Re: GRAS Notice No. GRN 000625
Dear Dr. Bechtel:
The Food and Drug Administration (FDA) is responding to the notice, dated February 1, 2016, that you submitted on behalf of Nascent Health Sciences, LLC (Nascent) 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 2, 2016, filed it on February 29, 2016, and designated it as GRAS Notice No. GRN 000625.
The subject of the notice is pyrroloquinoline quinone (PQQ) disodium salt. The notice informs FDA of the view of Nascent that PQQ disodium salt is GRAS, through scientific procedures, for use as an ingredient in energy, sport, and isotonic drinks, non-milk based meal replacement beverages, and water (bottled, enhanced, fortified) at a maximum level of 8 milligrams (mg) per serving.
As part of its notice, Nascent includes the statement of a panel of individuals (Nascent's GRAS panel) that evaluated the data and information that are the basis for Nascent's GRAS determination. Nascent considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Nascent's GRAS panel evaluated the identity, estimates of dietary exposure, method of production, and product specifications as well as published and unpublished studies supporting the safety of PQQ disodium salt. Based on this review, Nascent's GRAS panel concluded that PQQ disodium salt that meets its established food grade specifications is GRAS under the conditions of its intended use.
Nascent provides information about the identity and composition of PQQ disodium salt. PQQ disodium salt is a reddish-brown, crystalline powder that contains ≥98% PQQ disodium salt. PQQ disodium salt is designated by the CAS Registry number of 122628-50-6, has a molecular formula of C14H4N2Na2O8, and a molecular weight of 374.17.
Nascent describes the method of manufacture for PQQ disodium salt. First, ethyl 6-amino-5-methoxy-1H-indole-2-carboxylate is reacted with dimethyl oxoglutaconate in dichloromethane and the crystalline product separated by filtration. The crystalline product is treated with copper acetate monohydrate in dichloromethane, followed by hydrogen chloride gas, and then treated with sodium bicarbonate. Excess dichloromethane is removed by evaporation, diethyl ether added, and the solid product removed by filtration and dried. This product is reacted with aqueous ceric ammonium nitrate with acetonitrile then added. The reaction mixture is filtered and the filtrate solution extracted with dichloromethane. The extract solution is treated with anhydrous sodium sulfate, dried under vacuum, combined with toluene and ethyl acetate, and the crystalline product removed by filtration and dried. The crystalline product is treated with aqueous sodium hydroxide and then sodium chloride and silicon dioxide are added. The mixture is filtered, the pH of the filtrate adjusted with hydrochloric acid, and filtered again. Ethanol and water are added and PQQ disodium salt is obtained by filtration and drying.
Nascent provides specifications for PQQ disodium salt that includes the minimum content of PQQ disodium salt (≥ 98%). Specifications also include limits on moisture (≤ 12%), residual ethanol (≤ 0.5%), lead (≤ 0.5 mg per kilogram (kg)), arsenic (≤1.0 mg/kg), cadmium (≤1.0 mg/kg), and mercury (≤0.1 mg/kg), and microbial contaminants. Nascent provides the results of six batch analyses to demonstrate that PQQ disodium salt produced by the manufacturing process above meets specifications. Nascent also provides the results of a study conducted to examine the stability of PQQ disodium salt and concludes that PQQ disodium salt is stable for up to two years when stored at room temperature.
Nascent provides an estimate of the dietary exposure to PQQ disodium salt based on the intended uses in food using food consumption data from the National Health and Nutrition Examination Survey (NHANES, 2011-2012). Nascent reports that the mean and 90th percentile, users-only, dietary exposure to the general population to be 26.5 and 61.4 mg/person/day (0.4 and 0.9 mg/kg body weight (bw)/day), respectively. Nascent notes that PQQ disodium salt is also used as a dietary supplement at levels up to 20 mg/person/day, which is equivalent to 0.33 mg/kg bw/day for a 60 kg individual.
Nascent discusses published safety studies of PQQ disodium salt. In a 90-day study, rats received up to 400 mg PQQ disodium salt/kg bw/day by gavage. No adverse effects were reported in this study. Nascent notes that 14-day, 28-day, and 13-week gavage studies on PQQ disodium salt showed no toxicity at up to 100 mg/kg bw/day.
Nascent also discusses corroborative unpublished toxicological test reports. These include a teratogenicity study conducted in rats that showed no effects on embryo survival and development, fetal gross malformations, and fetal bone and organ development. Additionally, results of a bacterial reverse mutation assay, sperm malformation assay, and bone micronucleus assay showed that PQQ disodium salt is non-mutagenic and non-genotoxic under the test conditions.
Nascent summarizes six published efficacy studies in humans that include limited safety and tolerance information. No adverse effects were reported in these studies.
Based on the totality of the data and information described above, Nascent concludes that PQQ disodium salt is GRAS for its intended use in food at the proposed levels.
Potential Labeling Issues
In describing the intended use of PQQ disodium salt and in describing the information that Nascent relies on to conclude that PQQ disodium salt is GRAS under the conditions of its intended use, Nascent raises a potential issue under the labeling provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act). Under section 403(a) of the 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 PQQ disodium salt bear any claims on the label or in labeling, such claims are the purview of the Office of Nutrition and Food Labeling (ONFL), in the Center for Food Safety and Applied Nutrition. The Office of Food Additive Safety neither consulted with ONFL on this labeling issue nor evaluated the information in your notice to determine whether it would support any claims made about PQQ disodium salt on the label or in labeling.
Section 301(ll) of the FD&C Act
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 Nascent's notice that PQQ disodium salt is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing PQQ disodium salt. Accordingly, this response should not be construed to be a statement that foods that contain PQQ disodium salt, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Nascent, as well as other information available to FDA, the agency has no questions at this time regarding Nascent's conclusion that PQQ disodium salt 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 PQQ disodium salt. As always, it is the continuing responsibility of Nascent 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 000625, 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