Agency Response Letter GRAS Notice No. GRN 000383
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CFSAN/Office of Food Additive Safety
December 2, 2011
Chemische Fabrik Budenheim KG
D 55257 Budenheim
Re: GRAS Notice No. GRN 000383
Dear Mr. Janssen:
The Food and Drug Administration (FDA) is responding to the notice, dated May 3, 2011, 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 May 23, 2011, filed it on June 8, 2011, and designated it as GRAS Notice No. GRN 000383.
The subject of the notice is magnesium dihydrogenpyrophosphate (MDPP). The notice informs FDA of the view of Chemische Fabrik Budenheim KG (Budenheim) that MDPP is GRAS, through scientific procedures, for use as a stabilizer, leavening agent, and acidifying agent in self-rising flour, noodles (oriental style), batters and breading, processed cereals, and bakery products at a level ranging from 2 grams per kilogram (g/kg) to 15 g/kg.
Budenheim describes the chemical identity and characteristic properties of MDPP. MDPP (anhydrous form) is identified by the CAS Registry Number 20768-12-1, and has an empirical formula H2MgP2O7. Budenheim describes MDPP as a fine white powder, soluble in water, with melting and boiling points above 1000 degrees Celsius. Budenheim states that under aqueous conditions, MDPP disassociates into magnesium, hydrogen, and diphosphate ions. The diphosphate ions hydrolyze to orthophosphate in the acidic conditions of the stomach.
Budenheim states that MDPP is manufactured from magnesium hydroxide and phosphoric acid. Magnesium hydroxide is diluted and added to phosphoric acid until an approximate molar ratio of 1:2 between magnesium and phosphorus is reached. Hydrogen peroxide is then added to oxidize the reaction ingredients. The resulting slurry is processed in a drum-dryer until a loss on ignition of below 12 percent is achieved. The resulting granules are milled to a fine powder and packaged. Budenheim states that water and remaining hydrogen peroxide are evaporated during the drying process. Budenheim notes that trace amounts of sodium, potassium, or calcium may naturally occur in the raw material, or may be intentionally added to adjust the crystalline structure of the final product. Budenheim also notes that only food-grade ingredients are used during the manufacture of MDPP.
Budenheim provides specifications for the food-grade MDPP, including specifications for lead and arsenic (<1 milligram (mg)/kg), respectively. Budenheim notes that the high production temperatures render microbial contamination very unlikely and, thus, microbial specifications are unnecessary.
Budenheim states that 20-30 percent of the sodium in bakery products comes from sodium-containing leavening agents. Budenheim uses sodium acid pyrophosphate as an example of a commonly used leavening agent in their intake estimates. Budenheim makes a conservative daily intake estimate with the assumption that MDPP will completely replace sodium acid pyrophosphate in food.
Budenheim, using data from the 2005-2006 NHANES survey, provides estimated daily intakes (EDI) for magnesium and phosphorus when MDPP is used as a substitute. Budenheim states that the EDI for magnesium will be 315.3 mg/day (d) at the mean, and 709.4 mg/d at the 97.5th percentile, resulting in an approximate increase in supplemental intake of magnesium of 34.2 mg/d at the mean, and 61.9 mg/d at the 97.5th percentile, by the United States (U.S.) population. Budenheim also states that the EDI for phosphorus will be 1329.3 mg/d at the mean and 2936 mg/d at the 97.5thpercentile, resulting in an approximate increase of 16.3 mg/d at the mean and 16.1 mg/d at the 97.5th percentile, in intake of phosphorus by the U.S. population. Budenheim explains that the mean EDI for magnesium is still within the recommended daily allowance of 310-420 mg for magnesium, and the EDI for phosphorus is under the Upper Limit of 4000 mg for the U.S. population.
Budenheim discusses safety data on magnesium and phosphorus, since MDPP dissociates into magnesium and phosphate ions under the conditions of use. Budenheim notes that MDPP is similar to magnesium phosphate, which is already affirmed GRAS. Magnesium phosphate (mono-, di-, and tri-basic) is listed for use as a nutrient supplement and pH control agent under 21 CFR 184.1434. Budenheim also notes that other expert bodies, the Joint FAO/WHO Expert Committee on Food additives (JECFA) and the European Food Safety Authority (EFSA), have issued opinions on the safety of phosphorus. JECFA established a group maximum tolerable daily intake of 70 mg/kg body weight, expressed as phosphorus from all food sources. Budenheim cited a published human study in which post menopausal female volunteers consumed 250 mg/d magnesium (in addition to normal dietary sources of magnesium) for two years. Budenheim states that the no observed adverse effect level derived from this study is 250 mg/day (supplemental). Budenheim considered published human studies, subchronic, chronic, and reproductive studies in animals on magnesium and phosphorus, and EFSA's opinion paper on phosphorus, and concludes that MDPP, produced according to good manufacturing practice, is GRAS under the conditions of its intended use.
Standards of Identity
In the notice, Budenheim states its intention to use MDPP in food, 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 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 Budenheim's notice that MDPP is GRAS under the intended conditions of use, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing MDPP. Accordingly, this response should not be construed to be a statement that foods that contain MDPP, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Budenheim, as well as other information available to FDA, the agency has no questions at this time regarding Budenheim's conclusion that MDPPis 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 MDPP. As always, it is the continuing responsibility of Budenheim 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 000383, 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