Agency Response Letter GRAS Notice No. GRN 000641
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See also Generally Recognized as Safe (GRAS).
CFSAN/Office of Food Additive Safety
October 14, 2016
Zhejiang Hisun Pharmaceutical Co. Ltd.
46 Waisha Road, Jiaojiang District
Taizhou City, Zhejiang Province
Re: GRAS Notice No. GRN 000641
Dear Ms. Huang:
The Food and Drug Administration (FDA) is responding to the notice, dated February 25, 2016, that you submitted 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 March 21, 2016, filed it on April 12, 2016, and designated it as GRAS Notice No. GRN 000641.
The subject of the notice is pyrroloquinoline quinone (PQQ) disodium salt. The notice informs FDA of the view of Zhejiang Hisun Pharmaceutical Co. Ltd. (Zhejiang Hisun) that PQQ disodium salt is GRAS, through scientific procedures, for use as an ingredient in energy, sport, and isotonic drinks at levels up to 5 milligrams (mg) per serving and in fortified water beverages at levels up to 20 mg per serving.
As part of its notice, Zhejiang Hisun includes the statement of a panel of individuals (Zhejiang Hisun’s GRAS panel) that evaluated the data and information that are the basis for the notifier’s GRAS determination. Zhejiang Hisun considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Zhejiang Hisun’s GRAS panel evaluated information describing the identity and composition, manufacturing process and specifications, and estimated dietary exposure, as well as published studies supporting the safety of PQQ disodium salt. Zhejiang Hisun’s GRAS panel concludes that PQQ disodium salt produced in accordance with good manufacturing practices is GRAS when used under the intended conditions of use.
Zhejiang Hisun provides information about the identity and composition of PQQ disodium salt. PQQ disodium salt is a reddish-brown, crystalline powder that contains ≥85% 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.
Zhejiang Hisun provides a description of the method of manufacture for PQQ disodium salt, which is produced through a fermentation process utilizing Hyphomicrobium denitrificans. Zhejiang Hisun states that H. denitrificans (ATCC 51888) is neither pathogenic nor toxigenic and does not contain antibiotic resistance genes. Zhejiang Hisun notes that all materials and processing aids used in the manufacture of PQQ disodium salt are food-grade. Zhejiang Hisun describes the production of the H. denitrificans culture, growth media, and a two-step fermentation process. The H. denitrificans culture is added to sterilized broth and fermented under specific conditions. The resulting mycelium suspension is then subjected to a second fermentation step under similar conditions. After fermentation is complete, PQQ is isolated by a series of filtration steps followed by resin adsorption and elution with a sodium phosphate buffer solution. Hydrochloric acid is added to the solution to adjust pH, followed by the addition of sodium chloride. The product crystallizes and is recovered by filtration. The product is dissolved in aqueous sodium hydroxide and filtered. Ethanol is added to the filtrate and the pH is adjusted using hydrochloric acid. A second crystallization step is initiated and the resulting mixture is filtered to obtain crystallized PQQ disodium salt. The product is finally dried under vacuum, milled, and sieved.
Zhejiang Hisun provides specifications for PQQ disodium salt that includes the minimum content of PQQ disodium salt (≥ 85 % by weight). Specifications also include limits on water (≤ 12 %), residual ethanol (≤ 0.5 %), lead (≤ 1 mg per kilogram (kg)), arsenic (≤ 1.5 mg/kg), cadmium (≤ 0.3 mg/kg), mercury (≤ 0.2 mg/kg), as well as limits on microbial contaminants. Zhejiang Hisun provides the results of three batch analyses to demonstrate that PQQ disodium salt meets specifications. Zhejiang Hisun also provides the results of a study that demonstrates PQQ disodium salt is stable for up to two years when stored at room temperature.
Zhejiang Hisun provides an estimate of the dietary exposure to PQQ disodium salt based on the intended uses in food and food consumption data from the National Health and Nutrition Examination Survey (NHANES, 2011-2012). Zhejiang Hisun estimates the mean and 90th percentile, users-only, dietary exposure to the general population at 12.8 and 27.8 mg/person/day (0.21 and 0.48 mg/kg body weight (bw)/day), respectively.
Zhejiang Hisun summarizes published safety studies of PQQ disodium salt. In a 90-day study, rats received up to 400 mg/kg bw/day by gavage. No adverse effects were reported in this study. Zhejiang Hisun also discusses 14-day, 28-day, and 13-week gavage studies that showed no toxicity at up to 100 mg/kg bw/day.
Zhejiang Hisun also discusses published and unpublished corroborative genotoxicity studies including reverse mutation assays in bacteria, chromosome aberration tests, and in vivo micronucleus assays that showed PQQ is non-mutagenic and non-genotoxic.
Zhejiang Hisun discusses placebo-controlled, double-blinded safety studies in humans. No adverse effects were reported at up to 60 mg PQQ/day for four weeks, the highest dose tested. Zhejiang Hisun summarizes published additional human studies that included only limited safety information. In these studies, the highest level tested was 21 mg/day for 3 days and the longest duration was 24 weeks at the level of 20 mg/day. No adverse effects were reported in any of these studies.
Based on the totality of the data and information described above, Zhejiang Hisun 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 Zhejiang Hisun relies on to conclude that PQQ disodium salt is GRAS under the conditions of its intended use, Zhejiang Hisun raises a potential issue under the labeling provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act). This issue consists of physiological effects of PQQ disodium salt that Zhejiang Hisun views as “beneficial.” 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 Zhejiang Hisun’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 Zhejiang Hisun, as well as other information available to FDA, the agency has no questions at this time regarding Zhejiang Hisun’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 Zhejiang Hisun 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 000641, 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