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CFSAN/Office of Food Additive Safety
August 5, 2013
Associate Director Scientific Affairs
The Ester C Company
6735 Inter-Cal Way
Prescott, AZ 86301
Re: GRAS Notice No. GRN 000451
Dear Ms. Combs:
The Food and Drug Administration (FDA) is responding to the notice, dated July 25, 2012, 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 6, 2012, filed it on December 12, 2012, and designated it as GRAS Notice No. GRN 000451.
The subject of the notice is calcium ascorbate with added threonate. The notice informs FDA of the view of The Ester C Company (Ester C Co.) that calcium ascorbate with added threonate is GRAS, through scientific procedures, as a source of ascorbic acid (vitamin C) in beverages and beverage bases, breakfast cereals, chewing gum, coffee and tea, grain products, processed fruits and fruit juices, and medical foods at levels of up to 500 milligrams (mg) of vitamin C per serving. Ester C Co. intends that the use of calcium ascorbate with added threonate is substitutional in foods and beverages that are already fortified with vitamin C.
As part of its notice, Ester C Co. includes a statement from a panel of individuals (Ester C Co.’s GRAS panel) that evaluated the data and information that are the basis for Ester C Co.’s GRAS determination. Ester C Co. considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Ester C Co.’s GRAS panel considered the identity and method of production, estimates of dietary exposure, and product specifications as well as published and unpublished safety studies. Based on this review, Ester C Co.’s GRAS panel concluded that calcium ascorbate with added threonate that meets its established food grade specifications and produced consistent with current good manufacturing practices (cGMP) is GRAS under the conditions of its intended use.
Ester C Co. provides information about the identity and method of production of calcium ascorbate with added threonate. The ingredient is a free flowing powder comprising 95.5% calcium ascorbate dihydrate, 1.2% calcium threonate, 1.1% calcium carbonate, and not more than 2.0% moisture by weight. Ascorbic acid is first dissolved in water at 140°F in an industrial mixer. Calcium threonate is added to the solution, which is neutralized by adding calcium carbonate. The reaction is then carried out under steam pressure (> 100°F). Ester C Co. states that hydroxymethyl furanone forms as a byproduct during manufacturing. The process is completed by drying, blending and milling of the product. Ester C Co. states that processing aids are not used and a purification step is unnecessary. Ester C Co. states that the ingredient meets the requirements established under cGMP, and all raw materials used during the manufacturing process are food grade.
Ester C Co. provides specifications for the final product. Specifications include ascorbic acid (76.6% ±2.43), calcium (9.18% ±1.13), threonic acid (1.15% ±0.30), hydroxymethyl furanone (0.045% ±0.015); and limits for lead (≤ 1 mg/kilogram (kg)), moisture (≤ 2%), and microbial contaminants. Ester C Co. provides analyses of five non-consecutive lots of the product that comply with specified ranges of ascorbic acid, calcium, threonate, and hydroxymethyl furanone.
Ester C Co. estimates the dietary exposure to the components of calcium ascorbate with added threonate from all intended food uses (excluding medical foods). Ester C Co. considers that the exposure from the intended use in medical foods would be no higher than that from the typical U.S. diet. It estimates vitamin C exposure for users-only at 286 mg per person per day (mg/p/d) at the mean and 620 mg/p/d at the 90th percentile. In comparison, Ester C Co. estimates that the mean and 90th percentile dietary exposure for the total U.S. population to vitamin C from its natural occurrence in the diet are 106 mg/p/d and 150 mg/p/d, respectively. The respective users-only, mean and 90th percentile estimates of exposure to the other components of calcium ascorbate with added threonate are as follows: calcium, 34 mg/p/d and 74 mg/p/d; threonate, 4 mg/p/d and 9 mg/p/d; and hydroxymethyl furanone, 168 micrograms (μg)/p/d and 364 μg/p/d.
Ester C Co. discusses published information to support the safety of calcium ascorbate with added threonate. Specifically, Ester C Co. describes published information pertaining to absorption, distribution, metabolism, and elimination of calcium ascorbate and ascorbic acid, as well as calcium, threonic acid, and hydroxymethyl furanone. Ester C Co. notes that threonate is one of the known oxidative products of ascorbic acid metabolism. Hydroxymethyl furanone can also be a biological metabolite of ascorbic acid. In addition, Ester C Co. discusses published and unpublished acute, subchronic and chronic toxicity studies on calcium ascorbate with added threonate, threonate, or calcium threonate in various animal models including rat, mice, guinea pig, and dog that indicated the intended use levels were safe. Ester C Co. cites a published reproductive and developmental study in mice on calcium threonate that showed no adverse effects from treatment. Additionally, Ester C Co. discusses published in vitro genotoxicity studies for calcium ascorbate with added threonate, calcium threonate, or hydroxymethyl furanone that did not indicate any safety concerns. Further, Ester C Co. summarizes the toxicity data on hydroxymethyl furanone including subchronic and chronic oral toxicity studies in rats and mice and mutagenicity and genotoxicity studies.
Ester C Co. also discusses human studies using different formulations of calcium ascorbate with added threonate to demonstrate that adverse events would not be expected at the intended use levels. Ester C Co. states that although the addition of threonate enhances the absorption of vitamin C in humans and animals, the resulting daily exposure to vitamin C is below the Tolerable Upper Intake Level of 2,000 mg/p/d established by the Institute of Medicine (IOM) and is not expected to be of concern to human health. Ester C Co. further notes that the daily exposure to vitamin C in the total U.S. population is above the Recommended Dietary Allowance (RDA) of 90 mg/p/d for adult men and 75 mg/p/d for adult women established by the IOM and that background dietary exposure alone is sufficient in achieving the RDA.
Finally, Ester C Co. discusses safety evaluations for ascorbic acid and/or calcium ascorbate by the Joint FAO/WHO Expert Committee on Food Additives, the Food and Nutrition Board of the IOM, and the United Kingdom Expert Group on Vitamins and Minerals. The European Food Safety Authority has also evaluated ascorbic acid and/or calcium ascorbate individually as well as with calcium threonate.
Standards of Identity
In the notice, Ester C Co. states its intention to use calcium ascorbate with added threonate 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 discussing the intake of calcium ascorbate with added threonate as a dietary source of the essential nutrient vitamin C, Ester C Co. references the intended use of the ingredient as a source of vitamin C. Section 403(r) of the Federal Food, Drug, and Cosmetic Act (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 calcium ascorbate with added threonate bear any claims on the label or in labeling, such claims are the purview of the Office of Nutrition, Labeling and Dietary Supplements (ONLDS). 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 calcium ascorbate with added threonate on the label or in labeling.
In its notice, Ester C Co. informs FDA that one intended use of calcium ascorbate with added threonate 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 FD&C Act lays out the statutory framework for nutrition labeling of food products. Section 403(r) of the FD&C Act lays out the statutory framework for health claims and nutrient content claims. Under section 403(q)(5)(A)(iv) of the FD&C Act 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 FD&C Act 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 Ester C Co.’s notice that calcium ascorbate with added threonate is GRAS for use in medical foods does not address the question of whether any particular food product that contains calcium ascorbate with added threonate 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 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 Ester C Co.’s notice that calcium ascorbate with added threonate is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing calcium ascorbate with added threonate. Accordingly, this response should not be construed to be a statement that foods that contain calcium ascorbate with added threonate, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Ester C Co., as well as other information available to FDA, the agency has no questions at this time regarding Ester C Co.’s conclusion that calcium ascorbate with added threonate 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 calcium ascorbate with added threonate. As always, it is the continuing responsibility of Ester C Co. 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 000451, 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