Agency Response Letter GRAS Notice No. GRN 000271
CFSAN/Office of Food Additive Safety
May 29, 2009
Mark F. Nelson, Ph.D.
Director of Scientific & Regulatory Affairs
Nestlé USA, Inc.
800 North Brand Boulevard
Glendale, CA 91203-1244
Re: GRAS Notice No. GRN 000271
Dear Dr. Nelson:
The Food and Drug Administration (FDA) is responding to the notice, dated November 17, 2008, 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 4, 2008, filed it on December 12, 2008, and designated it as GRAS Notice No. GRN 000271.
The subject of the notice is ferrous ammonium phosphate. The notice informs FDA of the view of Nestlé USA, Inc. (Nestlé) that ferrous ammonium phosphate is GRAS, through scientific procedures, for use in various food categories as a source of dietary iron for food enrichment and fortification purposes consistent with iron supplementation guidelines. Nestlé states their intent to use ferrous ammonium phosphate as a direct replacement for other iron fortificants currently in use in existing categories of fortified foods in the U.S. Nestlé intends to use ferrous ammonium phosphate as a food ingredient in beverages and beverage bases (non-milk based meal replacements, powdered chocolate and malt beverages, sport beverages), grain products and pastas (fortified cereal bars, instant noodles, meal replacement bars), milk and milk products (milk-based meal replacements, powdered milk, milk beverages) and soups and soup mixes (bouillon cubes/powders) at levels between 11 to 18 milligrams per serving (mg/serving).
As part of its notice, Nestlé includes the report of a panel of individuals (Nestlé’s GRAS panel) who evaluated the data and information that are the basis for Nestlé’s GRAS determination. Nestlé considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Nestlé’s GRAS panel evaluated estimates of dietary exposure, method of production, and product specifications, as well as published and unpublished safety studies. Based on this review, Nestlé’s GRAS panel concluded that ferrous ammonium phosphate manufactured consistently with current good manufacturing processes and meeting its established food grade specifications is GRAS under the conditions of its intended use.
Nestlé describes the chemical identity and composition of ferrous ammonium phosphate. Ferrous ammonium phosphate is identified by the Chemical Abstracts Service Registry Number 10101-60-7. The empirical formula of ferrous ammonium phosphate is FeNH4PO4, and the molecular weight of the anhydrous salt is 168.85. Nestlé states that ferrous ammonium phosphate is an inorganic salt of iron (II), ammonium, and phosphate ions that are consistent with a 1:1:1 composition containing a small amount of water of crystallization. Nestlé states that ferrous ammonium phosphate can be considered almost anhydrous because the stoichiometric fraction of the water of crystallization is typically around 0.1 and always less than 0.3.
Nestlé states that ferrous ammonium phosphate is prepared by reacting ammonium hydroxide, iron powder, and phosphoric acid in demineralized water. The reaction product is dried, milled, and then passed through a sieve and a magnetic separation unit to remove any excess starting materials and insoluble salts. The ferrous ammonium phosphate is manufactured in accordance with current good manufacturing processes. Product batch analyses show that the product meets the food grade specifications established by Nestlé. The specifications include parameters for physical appearance, identification, and limits on sulfate, arsenic, lead, and other metals.
Nestlé discusses the estimated dietary intake of ferrous ammonium phosphate. Nestlé states that the consumption estimates are based on a use level for ferrous ammonium phosphate that provides 30 percent of the 18 mg daily value (DV) for iron.1 However, Nestlé intends to add ferrous ammonium phosphate to foods to provide iron levels within 10 to 20 percent of the DV. Nestlé used their own derived data and the Reference Amounts Customarily Consumed per eating occasion (21 CFR 101.12) to determine serving sizes of foods to which they intend to add ferrous ammonium phosphate. To calculate ferrous ammonium phosphate intake, Nestlé used food codes chosen from the National Health and Nutrition Examination Survey 2003-2004 and the Continuing Survey of Food Intakes by Individuals 1994-1996, 1998. Nestlé grouped the food codes in food-use categories according to 21 CFR 170.3. Nestlé estimates that the mean ferrous ammonium phosphate intake by the total U.S. population from all intended food uses would be 13 mg per person per day (mg/p/d) or 0.2 mg per kilogram body weight per day (mg/kg bw/d). Nestlé estimates that the 90th percentile all-user intake of ferrous ammonium phosphate is 29 mg/p/d or 0.6 mg/kg bw/d. Nestlé states that ferrous ammonium phosphate has a maximum iron content of 30 percent. Therefore, Nestlé estimates that the mean iron intake by the total U.S. population from all intended food-uses of ferrous ammonium phosphate is 3.8 mg/p/d or 0.074 mg/kg bw/d. Nestlé estimates that the 90th percentile all-user iron intake by the total U.S. population from all intended food-uses of ferrous ammonium phosphate is 8.8 mg/p/d or 0.181 mg/kg bw/d. Nestlé states that the specified food-uses for ferrous ammonium phosphate are not intended to be marketed to infants or children less than 4 years of age.
Nestlé states that ferrous ammonium phosphate readily dissociates to iron (II), ammonium, and phosphate ions in the stomach. Therefore, Nestlé discusses the safety of ferrous ammonium phosphate based on the well-established safety of these constituents. Nestlé cites published studies conducted with iron (II), ammonium, and phosphate, including studies of acute, chronic, subchronic, reproductive, and developmental toxicity, as well as mutagenicity and genotoxicity in experimental animals. Nestlé states that the results of these studies do not raise concerns about the safety of ferrous ammonium phosphate’s constituents in experimental animals.
Nestlé also discusses published and unpublished studies in which the safety of ferrous ammonium phosphate, ferrous iron, and phosphate were assessed in human volunteers. Nestlé cites published ferrous iron supplementation studies and published phosphate supplementation studies. Nestlé states that the results of these studies do not raise concerns about the safety of ferrous ammonium phosphate, ferrous iron, or phosphate in humans. Nestlé also provides the results of an unpublished study in which the safety of ferrous ammonium phosphate was assessed. Regarding the safety of ammonium ions in humans, Nestlé cites a published report and states that that there is no evidence that suggests that ammonium ions at the intended use level induces toxicity in humans, given that the endogenous exposure to ammonium is 4000 mg/day.2
Nestlé also discusses international scientific bodies’ evaluations of iron, phosphorus, ammonium salts and ammonium intakes in humans. Nestlé states that the Institute of Medicine, the European Food Safety Authority, and the Food and Agriculture Organization of the United Nations and the World Health Organization Joint Expert Committee on Food Additives (JECFA) have evaluated the safety of iron and phosphorus. Nestlé also states that JECFA and the World Health Organization have evaluated the safety of ammonium salts. Nestlé states that the scientific bodies have concluded that the risks of adverse effects from intake of iron, phosphorus, ammonium salts or ammonium ions by normal individuals are low.
Standards of Identity
In the notice, Nestlé states its intention to use ferrous ammonium phosphate 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 Label Claims
Under section 403(a) of the Federal Food, Drug, and Cosmetic Act (FFDCA), a food is misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FFDCA 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. In describing the intended use of ferrous ammonium phosphate and in describing the information that Nestlé relies on to conclude that ferrous ammonium phosphate is GRAS under the conditions of its intended use, Nestlé raises a potential issue under these labeling provisions of the FFDCA. If products that contain ferrous ammonium phosphate bear any claims on the label or in labeling, such claims are the purview of the Office of Nutrition, Labeling, and Dietary Supplements (ONLDS) in the Center for Food Safety and Applied Nutrition. 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 ferrous ammonium phosphate on the label or in labeling.
Section 301(ll) of FFDCA
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FFDCA to, among other things, add section 301(ll). Section 301(ll) of the FFDCA prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FFDCA, 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 Nestlé’s notice that ferrous ammonium phosphate is GRAS for use in various foods, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing ferrous ammonium phosphate. Accordingly, this response should not be construed to be a statement that foods that contain ferrous ammonium phosphate, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Nestlé, as well as other information available to FDA, the agency has no questions at this time regarding Nestlé’s conclusion that ferrous ammonium phosphate 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 ferrous ammonium phosphate. As always, it is the continuing responsibility of Nestlé 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 000271, 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 via the FDA home page at http://www.fda.gov. To view or obtain an electronic copy of the text of the letter, follow the hyperlinks from the “Food” topic to the “Food Ingredients and Packaging” section to the “Generally Recognized as Safe (GRAS)” page where the GRAS Inventory is listed.
Laura M. Tarantino, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
1The 18 mg DV for iron is found on FDA’s website within the document entitled “A Food Labeling Guide,” revised April 2008.
2Available from http://www.inchem.org/documents/ehc/ehc/ehc54.htm, accessed May 27, 2009.