Agency Response Letter GRAS Notice No. GRN 000178
CFSAN/Office of Food Additive Safety
January 11, 2006
Edwin C. Bisinger, Jr.
Manager, Regulatory Toxicology Department
Akzo Nobel Chemicals
525 West Van Buren Street
Chicago, IL 60607
Re: GRAS Notice No. GRN 000178
Dear Dr. Bisinger:
The Food and Drug Administration (FDA) is responding to the notice, dated July 15, 2005, 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 July 19, 2005, filed it on July 21, 2005, and designated it as GRAS Notice No. GRN 000178.
The subject of the notice is sodium iron (III) ethylenediaminetetraacetate. For the purpose of this letter, we describe the subject of the notice as " sodium iron EDTA (NaFeEDTA)." The notice informs FDA of the view of Akzo Nobel Chemicals (Akzo Nobel) that NaFeEDTA is GRAS, through scientific procedures, for use as a source of dietary iron for fortification purposes in soy, fish, teriyaki, and hoisin sauces at a level of 0.024 percent iron by weight, and in sweet and sour sauce at a level of 0.012 percent iron by weight.
As part of its notice, Akzo Nobel includes the report of a panel of individuals (Akzo Nobel's GRAS panel) who evaluated the data and information that are the basis for Akzo Nobel's GRAS determination. Akzo Nobel considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. According to Akzo Nobel's GRAS panel, NaFeEDTA meeting food grade specifications is safe for its intended use.
Akzo Nobel describes the chemical identity of NaFeEDTA. Akzo Nobel's NaFeEDTA ingredient exists in the trihydrate form, with the empirical formula C10H12FeN2O8Na·3H2O and formula weight 421.1. NaFeEDTA is identified by the Chemical Abstracts Service (CAS) Registry Number 15708-41-5.
NaFeEDTA is prepared by reacting sodium EDTA with an iron salt under acidic conditions. The ingredient is manufactured to meet the Joint WHO/FAO Expert Committee on Food Additives (JECFA) food grade specifications, containing between 12.5 and 13.5 percent (by weight) iron and between 65.5 and 70.5 percent (by weight) EDTA. Purity specifications for NaFeEDTA include limits on lead, arsenic, and water-insoluble matter.
Akzo Nobel provides estimates for consumption of NaFeEDTA and its constituents (iron, EDTA) using food consumption data from the USDA 1994-1996 Continuing Survey of Food Intake by Individuals (CSFII) and the 1998 Supplemental Children's Survey. Akzo Nobel estimates that in the eaters-only group (7.9% of the total United States population), their intended uses of NaFeEDTA would result in an iron intake of 2.17 milligrams per person per day (mg/p/d) at the mean and 5.10 mg/p/d at the 90th percentile, corresponding to an EDTA intake of 11.21 mg/p/d at the mean and 26.3 mg/p/d at the 90th percentile. Akzo Nobel states that male adults (aged 19-50) have the highest estimated eaters-only mean iron intake (2.68 mg/p/d), while young children (aged 1-8) had the lowest estimated eaters-only mean iron intake (0.98 mg/p/d).
Akzo Nobel considered the contribution of their intended use of NaFeEDTA to the total dietary intake of iron from all sources. Akzo Nobel calculates that the mean iron intake of the eaters-only population in the United States is 16.76 mg/p/d prior to NaFeEDTA fortification and 18.93 mg/p/d after fortification. Akzo Nobel also notes that Kraft Foods Global submitted a GRAS notice (GRN 000152) for the use of NaFeEDTA as an iron fortificant in powdered meal replacement, flavored milk, and fruit-flavored beverages. Akzo Nobel calculates that the combined intake of iron from intended food uses in GRN 000152 and GRN 000178 would be 6.37 mg/p/d at the mean and 13.3 mg/p/d at the 90th percentile, while the combined intake of EDTA from the intended food uses of GRN 000152, GRN 000178, and currently regulated uses of EDTA would be 40.76 mg/p/d at the mean and 84.8 mg/p/d at the 90th percentile.
Akzo Nobel notes that NaFeEDTA has been used in studies in developing countries for the iron fortification of foods. No adverse effects were reported in humans participating in long-term NaFeEDTA fortification studies in which fish and soy sauces, sugar, and curry powder were fortified with NaFeEDTA providing levels of 4 to 15 mg/p/d of iron (0.067 to 0.25 milligrams per kilogram of bodyweight per day (mg/kg bw/d)). Akzo Nobel also notes that numerous human absorption trials have been conducted with iron from other sources. In general, these trials provided iron levels ranging from 0.2 to 80 mg/p/d in various foods, with no adverse effects reported.
Akzo Nobel cites a provisional maximum tolerable intake of 0.8 mg/kg bw/d for iron supplements (or 50 mg for a 60 kg individual) presented by JECFA (1983), and a tolerable upper limit of 45 mg/p/d of iron from all sources presented by the Institute of Medicine (IOM, 2001).(1) Akzo Nobel considers that the intended use of NaFeEDTA will not raise any concerns relative to the maximum iron intakes proposed by JECFA and IOM.
Akzo Nobel describes results from published studies examining the toxicity of NaFeEDTA and the safety of NaFeEDTA for food fortification purposes. These studies include an acute toxicity study with NaFeEDTA in rats, a subchronic toxicity study with NaFeEDTA in rats, and a mutagenicity study with NaFeEDTA. Akzo Nobel concludes that no toxicologically significant effects of NaFeEDTA were observed in these studies.
Akzo Nobel describes generally available published documents on the safety of EDTA and its salts, as well as published chronic toxicity studies in dogs and rats, published reproductive and developmental studies in rats, and published carcinogenicity studies in rats and mice. Akzo Nobel also discusses published studies relevant to the potential for adverse effects of EDTA on the absorption of essential minerals in humans, including a study with NaFeEDTA in rats and studies with NaFeEDTA and EDTA in humans. Akzo Nobel concludes that these studies support the view that Akzo Nobel's intended use of NaFeEDTA is safe and would not interfere with the absorption of minerals such as calcium, copper, zinc, and magnesium.
Potential Labeling Issues
Section 403(a) of the Federal Food, Drug, and Cosmetic Act (FFDCA) provides that a food shall be deemed to be misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FFDCA establishes the statutory framework for health claims. In describing information that the notifier relies on to conclude that NaFeEDTA is GRAS under the conditions of its intended use, Akzo Nobel raises issues under these labeling provisions of the FFDCA. These issues include absorption of iron from dietary NaFeEDTA and its effects on iron status. They are the purview of the Office of Nutritional Products, Labeling, and Dietary Supplements (ONPLDS) in the Center for Food Safety and Applied Nutrition. The Office of Food Additive Safety neither consulted with ONPLDS on these labeling issues nor evaluated the information in Akzo Nobel's notice to determine whether it would support any claims made about NaFeEDTA on the label or in labeling.
Based on the information provided by Akzo Nobel, as well as the information in GRN 000178 and other information available to FDA, the agency has no questions at this time regarding Akzo Nobel's conclusion that NaFeEDTA 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 NaFeEDTA. As always, it is the continuing responsibility of Akzo Nobel 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, as well as a copy of the information in your 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).
Laura M. Tarantino, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
(1)JECFA considered the use of NaFeEDTA as a nutritional supplement in foods acceptable when used in supervised food fortification programs that would provide iron intakes of approximately 0.2 mg/kg bw/day from fortified food. Akzo Nobel states that this restriction to use in supervised fortification programs at an iron intake of 0.2 mg/kg bw/d was a result of the request received from the Codex Alimentarius Commission for an evaluation for this specific purpose.