Agency Response Letter GRAS Notice No. GRN 000614

Recently Published GRAS Notices and FDA Letters

CFSAN/Office of Food Additive Safety

April 12, 2016

Mary Murphy, MS, RD
Exponent, Inc.
1150 Connecticut Avenue, NW
Suite 1100
Washington, DC 20036

Re: GRAS Notice No. GRN 000614

Dear Ms. Murphy:

The Food and Drug Administration (FDA) is responding to the notice, dated December 8, 2015, 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 December 9, 2015, filed it on December 15, 2015, and designated it as GRAS Notice No. GRN 000614.

The subject of the notice is chromium polynicotinate. The notice informs FDA of the view of Exponent, Inc. (Exponent) that chromium polynicotinate is GRAS, through scientific procedures, for use as an ingredient in enhanced water beverages at a maximum use level of 575 micrograms per liter (µg/l).

As part of its notice, Exponent includes a statement from a panel of individuals (Exponent’s GRAS panel) that evaluated the data and information that are the basis for Exponent’s GRAS determination. Exponent considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Exponent’s GRAS panel reviewed the identity and composition, method of manufacture, specifications, and intended use and dietary exposure to chromium polynicotinate, as well as publicly available studies supporting the safety of chromium polynicotinate. Based on this review and the totality of scientific evidence, Exponent’s GRAS panel concluded that chromium polynicotinate, produced in accordance with current good manufacturing practice (cGMP) and meeting described specifications, is GRAS under the intended conditions of use.

Exponent provides information on the identity and composition of chromium polynicotinate. Exponent describes chromium polynicotinate as an oxygen-coordinated, niacin-bound trivalent chromium complex. Exponent states that chromium polynicotinate is a mixture of chromium dinicotinate and chromium trinicotinate, with the latter being the predominant form.¹

Exponent describes the method of manufacture of chromium polynicotinate produced in accordance with cGMP. Chromium polynicotinate is synthesized from niacin and chromium chloride in an aqueous solution. Sodium hydroxide is used as a processing aid to adjust the pH. After drying and grinding, the final product contains chromium polynicotinate and sodium chloride.

Exponent provides specifications for chromium polynicotinate. Specifications include moisture (<8 %), chromium (≥100 milligrams per gram (mg/g)), niacin (≥600 mg/g), arsenic (<1 µg/g), cadmium (<0.3 µg/g), lead (<0.5 µg/g), and mercury (<0.3 µg/g), as well as limits for potential microbial contaminants. Specifications for chromium, niacin, and water in the final product add up to less than 78%. Exponent states that the remainder of the final product is sodium chloride. Data from five nonconsecutive batch analyses of chromium polynicotinate demonstrate that the product meets specifications.

Exponent estimates the dietary exposure to chromium polynicotinate using food consumption data included in the 2011-2012 National Health and Nutrition Examination Survey (NHANES). Exponent calculates the mean and 90th percentile dietary exposures to chromium polynicotinate for users-only in the U.S. population aged two years and older to be 202 µg/person/day (p/d) (or 3.1 µg/kilogram body weight per d (kg bw/d) at the mean, and 342 µg/p/d (or 5.6 µg/kg bw/d) at the 90th percentile.

Exponent discusses published studies in rats and humans addressing the oral bioavailability and safety of chromium polynicotinate. Exponent concludes from these studies that the oral bioavailability of chromium is low (0.5-2%), irrespective of the chromium compound administered, including chromium polynicotinate. Based on published sub-chronic, two-generation reproduction, and developmental toxicity studies on chromium polynicotinate, Exponent concludes that orally consumed chromium polynicotinate is well tolerated and does not cause adverse effects up to a dose of 5.86 mg/kg bw/day. Exponent cites published studies showing that chromium polynicotinate is not mutagenic or genotoxic.

Based on the available scientific evidence, Exponent concludes that chromium polynicotinate is GRAS under the conditions of its intended use.

Potential Labeling Issues

In describing the intended use of chromium polynicotinate and in describing the information that Exponent relies on to conclude that chromium polynicotinate is GRAS under the conditions of its intended use, Exponent 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 chromium polynicotinate 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 chromium polynicotinate 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 Exponent’s notice that chromium polynicotinate is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing chromium polynicotinate. Accordingly, this response should not be construed to be a statement that foods that contain chromium polynicotinate, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).

Conclusions

Based on the information provided by Exponent, as well as other information available to FDA, the agency has no questions at this time regarding Exponent’s conclusion that chromium polynicotinate 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 chromium polynicotinate. As always, it is the continuing responsibility of Exponent 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 000614, 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.

Sincerely,

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

^[1] Chromium dinicotinate and chromium trinicotinate are complexes of one molecule of chromium ion with two and three niacin (nicotinic acid) molecules, respectively.