Agency Response Letter
GRAS Notice No. GRN 000136

John S. Eldred
Keller and Heckman LLP
1001 G Street, N. W.
Suite 500 West
Washington, D.C. 20001

Re: GRAS Notice No. GRN 000136

Dear Mr. Eldred:

The Food and Drug Administration (FDA) is responding to the notice, dated August 13, 2003, that you submitted on behalf of Purac Biochem b.v. (Purac) 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 August 18, 2003, filed it on August 19, 2003, and designated it as GRAS Notice No. GRN 000136.

The subject of the notice is calcium gluconate. The notice informs FDA of the view of Purac that calcium gluconate is GRAS, through scientific procedures, for use as a nutrient supplement in a variety of food products. FDA has previously affirmed that calcium gluconate is GRAS for use as a firming agent, formulation aid, sequestrant, stabilizer or thickener, and as a texturizer in accordance with 21 CFR 184.1(b)(1) at levels not to exceed current good manufacturing practices (21 CFR 184.1199). In essence, GRN 000136 describes additional uses of calcium gluconate that were not considered in the rulemaking that established 21 CFR 184.1199.

Purac describes generally available information about the chemical identity and properties of calcium gluconate, also called D-gluconic acid calcium salt (2:1). Calcium gluconate exists in both an anhydrous form (empirical formula C₁₂H₂₂O₁₄Ca) and as a monohydrate (empirical formula C₁₂H₂₂O₁₄CaH₂O). Each form is an odorless, white, free-flowing powder that is soluble in water, insoluble in alcohol and most organic solvents, and stable in air.

Purac describes the method of manufacture for calcium gluconate, which involves the production of gluconic acid as an interim product that is subsequently processed to calcium gluconate. Purac describes three processes for the production of gluconic acid. In the traditional process, glucose is converted to gluconic acid by standard aerobic fermentation. In an alternative process, glucose is converted to gluconic acid by use of glucose oxidase and catalase (to degrade hydrogen peroxide). In a third process, the starting material is either sodium gluconate or glucono-delta-lactone, rather than glucose. In this third process, sodium gluconate is converted to gluconic acid by use of a cation exchange resin and glucono-delta-lactone is converted to gluconic acid by hydrolysis. Regardless of the method that Purac uses to produce gluconic acid, calcium gluconate is prepared from the gluconic acid by the addition of calcium carbonate or calcium hydroxide. The calcium gluconate solution may be crystallized and dried to yield calcium gluconate (monohydrate) or dried without crystallization to yield anhydrous calcium gluconate. Purac provides specifications for the anhydrous and monohydrate forms of calcium gluconate and notes that these specifications comply with those in the Food Chemicals Codex, 4th ed. (1996) and in the U.S. Pharmacopeia (2003).

Purac describes the intended use of calcium gluconate as a nutrient supplement in food products that include, but are not limited to, milk, soft-drinks, juices, "near waters,"⁽¹⁾ dairy products, soy products, baked goods, and confectionery. Purac estimates that this use of calcium gluconate would supply 250 milligrams per person per day (mg/p/d) of calcium in the daily diet. Purac notes that the National Academy of Sciences has recommended 1000 - 1300 mg/p/d as an adequate intake for adults, with an "upper limit" of 2500 mg/p/d to limit the potential for adverse effects that can be associated with excessive consumption of calcium, such as kidney stones, hypercalcemia, renal insufficiency, and the possibility of reduced absorption of other minerals.

Purac summarizes the results of published human studies that evaluated parameters such as the absorption of calcium from calcium gluconate, and cites a published review that compares the percent calcium absorption from several calcium salts and milk in humans. From the published review, Purac concludes that the average absorption of calcium from calcium gluconate is similar to that of milk.

Purac describes several generally available reports relevant to the safety of calcium gluconate, which is readily ionized to calcium and gluconic acid. A 1975 report by the Select Committee on GRAS Substances (the Select Committee)⁽²⁾ concluded that there was no evidence in the available information on a number of calcium salts (including calcium gluconate) that demonstrates, or suggests reasonable grounds to suspect, a hazard to the public when used at levels that were current at the time or might reasonably be expected in the future. Likewise, a 1978 report by the Select Committee concluded that there was no evidence in the available information on a number of gluconate salts⁽³⁾ that demonstrates, or suggests reasonable grounds to suspect, a hazard to the public when used at levels that were current at the time or might reasonably be expected in the future. The 1978 report of the Select Committee noted that gluconate is a normal product of glucose oxidation in mammals and that the amount of gluconic acid produced endogenously is several fold greater than the amount likely to be consumed from use of gluconate salts as food ingredients. A 1999 report by the Joint Food and Agriculture Organization/World Health Organization's (FAO/WHO) Expert Committee on Food Additives (JECFA) regarding various gluconate salts, including calcium gluconate, established an Acceptable Daily Intake (ADI) of "not specified" for the calcium salt of gluconic acid.⁽⁴⁾

Based on the information provided by Purac, as well as other information available to FDA, the agency has no questions at this time regarding Purac's conclusion that calcium gluconate is GRAS for use as a nutrient supplement in various foods. The agency has not, however, made its own determination regarding the GRAS status of the subject use of calcium gluconate. As always, it is the continuing responsibility of Purac to ensure that food ingredients that the firm markets are safe, and are otherwise in compliance with all applicable legal and regulatory requirements.

In the notice, Purac states its intention to use calcium gluconate in several food categories, including foods for which standards of identity exist 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.

In accordance with proposed 21 CFR 170.36(f), a copy of the text of this letter, as well as a copy of the information in Purac's notice that conforms to the information in proposed 21 CFR 170.36(c)(1), is available for public review and copying on the homepage of the Office of Food Additive Safety (on the Internet at http://www.cfsan.fda.gov/~lrd/foodadd.html).

Sincerely,    /s/ George H. Pauli, Ph.D. Acting Director Office of Food Additive Safety Center for Food Safety      and Applied Nutrition

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⁽¹⁾"Near waters" is a category of water-based soft drinks that are not defined by FDA and do not meet the standard of identity for bottled water as stated in 21 CFR 165.110. Purac describes "near waters" or "enhanced waters" as waters that are fortified with minerals, vitamins, herbs, electrolytes, or other such ingredients.

⁽²⁾Several years ago, FDA contracted with the Life Sciences Research Office (LSRO) of the Federation of American Societies for Experimental Biology as part of its comprehensive review of GRAS and prior sanctioned food ingredients. To aid in that review, LSRO established the Select Committee on GRAS Substances.

⁽³⁾ The gluconate salts explicitly addressed in the 1978 report of the Select Committee included sodium gluconate, potassium gluconate, magnesium gluconate, and zinc gluconate.

⁽⁴⁾ JECFA describes "ADI not specified" as a term applicable to a food component of very low toxicity for which the total dietary intake of the substance does not, in the opinion of the Committee, represent a hazard to health.