Agency Response Letter GRAS Notice No. GRN 000420
CFSAN/Office of Food Additive Safety
August 10, 2012
James T. Heimbach
923 Water Street
P.O. Box 66
Port Royal, Virginia 22535
Re: GRAS Notice No. GRN 000420
Dear Dr. Heimbach:
The Food and Drug Administration (FDA) is responding to the notice, dated February 3, 2012, that you submitted on behalf of Innophos, Inc. (Innophos) 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 13, 2012, filed it on February 14, 2012, and designated it as GRAS Notice No. GRN 000420.
The subject of the notice is calcium acid pyrophosphate. The notice informs FDA of the view of Innophos that calcium acid pyrophosphate is GRAS, through scientific procedures, for use as a leavening agent in baked products.
As part of its notice, Innophos includes the report of a panel of individuals (Innophos’ GRAS panel) who evaluated the data and information that are the basis for Innophos’ GRAS determination. Innophos considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Innophos’ GRAS panel evaluated estimates of dietary exposure, method of production, and product specifications as well as published and unpublished studies. Based on this review, Innophos’ GRAS panel concluded that calcium acid pyrophosphate that meets its established food grade specifications is GRAS under the conditions of its intended use.
Innophos provides information about the chemical identity and specifications for calcium acid pyrophosphate. Calcium acid pyrophosphate is identified by CAS registry number 14866-19-4 and the empirical formula is CaH2P2O7. Specifications for calcium acid pyrophosphate include limits on heavy metals.
Innophos describes the method of manufacture for calcium acid pyrophosphate. The process begins by reacting calcium oxide with phosphoric acid, potassium hydroxide and aluminum trioxide in the presence of heat. Sulfuric acid is used as a processing aid to seed the crystallization. The resulting precipitate is dried in a rotary dryer and the resulting material is screened and packaged. The final product consists of approximately 75% calcium acid pyrophosphate and 25% monocalcium phosphate. Monocalcium phosphate (calcium phosphate) is listed at 21 CFR 182.1217 as GRAS for use in food in accordance with good manufacturing practices.
The intended use of calcium acid pyrophosphate is as a leavening agent in baked products. Calcium acid pyrophosphate will be used as a 1:1 replacement for sodium acid pyrophosphate. Therefore, Innophos estimates there will be no change in the consumer intake of phosphorus resulting from the intended use. The estimated daily intake of calcium acid pyrophosphate provided in the notice is 15 milligrams per kilogram of body weight per day (mg/kg bw/d), based on a published exposure estimate for sodium acid pyrophosphate.
Innophos reviews the safety of calcium acid pyrophosphate and its constituents, describing numerous published and unpublished studies on the safety of inorganic phosphate compounds and discussing the conclusions of the Joint FAO/WHO Expert Committee on Food Additives (JECFA) regarding the safety of inorganic phosphate salts. JECFA concluded that inorganic phosphate salts, including ammonium, calcium, magnesium, potassium, and sodium salts of phosphate, do not differ significantly in toxicity, and the toxicity associated with their oral intake is low. No inorganic calcium phosphate salt tested produced mutagenic or teratogenic effects in any study. Based on the occurrence of specific renal effects in rats, JECFA set a maximum tolerable daily intake for all sources of phosphorus at 70 mg/kg bw/d. Innophos concludes, given estimates that the intended use will not increase exposure to phosphorus, that the evidence supports the safety of the intended uses of calcium acid pyrophosphate.
Standards of Identity
In the notice, Innophos states its intention to use calcium acid pyrophosphate 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.
Section 301(ll) of the Federal Food, Drug, and Cosmetic Act (FD&C Act)
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the Federal Food Drug and Cosmetic Act (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 Innophos’ notice that calcium acid pyrophosphate is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing calcium acid pyrophosphate. Accordingly, this response should not be construed to be a statement that foods that contain calcium acid pyrophosphate if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Innophos, as well as other information available to FDA, the agency has no questions at this time regarding Innophos’ conclusion that calcium acid pyrophosphate 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 acid pyrophosphate. As always, it is the continuing responsibility of Innophos 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 00 0420, 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