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U.S. Department of Health and Human Services

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Agency Response Letter GRAS Notice No. GRN 000152

CFSAN/Office of Food Additive Safety
December 9, 2004

Edward A. Steele
Vice President - Food, Dietary Supplement, & Cosmetic Consulting
AAC Consulting Group
7361 Calhoun Place
Suite 500
Rockville, MD 20855

Re: GRAS Notice No. GRN 000152

Dear Mr. Steele:

The Food and Drug Administration (FDA) is responding to the notice, dated June 3, 2004, that you submitted on behalf of Kraft Foods Global (Kraft) 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 this notice on June 9, 2004, filed it on June 15, 2004, and designated it as GRAS Notice No. GRN 000152.

The subject of the notice is sodium iron (III) ethylenediaminetetraacetate (NaFe+3EDTA). 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 Kraft that NaFeEDTA is GRAS, through scientific procedures, for use as a source of dietary iron for food fortification purposes in powdered meal replacement, flavored milk, and fruit-flavored beverages at a use level not to exceed 2.5 milligrams (mg) of iron per 200 milliliters (mL) of reconstituted beverage. Kraft intends NaFeEDTA for iron fortification in areas of the world with a high prevalence of iron deficiency.

As part of its notice, Kraft includes the report of a panel of individuals (Kraft's GRAS panel) who evaluated the data and information that are the basis for Kraft's GRAS determination. Kraft considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Kraft's GRAS panel evaluated estimates of dietary exposure, the method of manufacture, specifications for the ingredient, and published studies on NaFeEDTA or its constituents (iron and EDTA). Kraft's GRAS panel concluded that NaFeEDTA meeting food-grade specifications is GRAS for its intended use.

Kraft describes the chemical identity of NaFeEDTA. NaFeEDTA (Chemical Abstracts Service Registry Number 15708-41-05) exists in the trihydrate form, with the empirical formula C10H12FeN2NaO8·3H2O; it is also known by the chemical names sodium feredetate, sodium iron (III) EDTA, and sodium ferric EDTA. NaFeEDTA is a pale yellow powder that is very water-soluble at pH 7. Kraft notes that NaFeEDTA is relatively stable and is suitable for use in foods that are stored for long periods of time or prepared at high temperatures.

NaFeEDTA is prepared by reacting sodium EDTA with an iron chloride salt under acidic conditions, followed by filtering and drying, in accordance with current good manufacturing practice. 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.

Kraft intends NaFeEDTA for iron fortification of powdered meal replacement, flavored milk, and fruit-flavored beverages in areas of the world with a high prevalence of iron deficiency. The intended level of fortification is 2.5 mg iron per 200 mL of reconstituted beverage; the beverage powder would contain 0.02 percent iron and 0.1 percent EDTA by weight. Reconstitution of 12.5 grams (g) of beverage powder with 200 mL of water would result in 2.5 mg iron per 200 mL of beverage, or a final concentration of 0.00125 percent iron (0.00125 g iron per 100 mL beverage).

Kraft estimates that the intended uses would result in a mean intake of 31.4 milligrams of NaFeEDTA per person per day (mg/p/d).(1) Kraft also estimates that the intended uses of NaFeEDTA would result in an iron intake of 4.2 mg/p/d at the mean and 8.2 mg/p/d at the 90th percentile and an EDTA intake of 21.8 mg/p/d at the mean and 43.0 mg/p/d at the 90th percentile.(2) Kraft provides estimates of intake for various age groups, including infants 0-2 years of age. Kraft notes that infants and children consume more food and drink than adults on a body weight basis, but states that realistic estimates of NaFeEDTA intake for young children correspond to an iron intake that remains within JECFA's recommended limit of intake for iron in supervised fortification programs (0.2 milligrams per kilogram of bodyweight per day (mg/kg bw/day).

Kraft notes that JECFA evaluated the use of NaFeEDTA as a nutritional supplement in foods in both 1993 and again in 1999. JECFA's provisional 1993 conclusion expressed concern about overfortification of NaFeEDTA and did not recommend its availability for general use by individuals. Consistent with this approach, Kraft intends to restrict the use of NaFeEDTA for iron fortification of powdered meal replacement, flavored milk, and fruit-flavored beverages to areas of the world with a high prevalence of iron deficiency.(3) JECFA's 1999 evaluation confirmed the provisional 1993 conclusion that "sodium iron EDTA could be considered safe for use in supervised food fortification programmes, when public health officials had determined the need for iron supplementation in the diet of a population," at iron intakes of approximately 0.2 mg/kg bw/d. Kraft notes that the restriction to use in supervised food fortification programs is included because the original request for evaluation of NaFeEDTA by JECFA from the Codex Committee for Food Additives and Contaminants was for this specific purpose alone.

Kraft describes results from studies that support the safety of NaFeEDTA for food fortification purposes. These studies include published human studies with NaFeEDTA, published and unpublished acute and subchronic (60-day, 90-day) animal toxicity studies with NaFeEDTA, and a published mutagenicity study with NaFeEDTA. No adverse effects specific to NaFeEDTA were found. Kraft concludes from these studies that the safety of NaFeEDTA, as judged by the acute toxicity of the elemental iron content, is similar to that of ferrous sulfate. Kraft also concludes that the tissue distribution and deposition of iron is similar for orally-administered NaFeEDTA and ferrous sulfate.

Kraft cites generally available published documents on the safety of EDTA and its salts. Because the majority of NaFeEDTA dissociates in the gastrointestinal tract to produce free iron and EDTA, Kraft considers studies with calcium and sodium salts of EDTA to be relevant to the safety of NaFeEDTA. Kraft notes that extensive published studies in humans and other organisms have been conducted with EDTA and its salts, and that these studies have shown that EDTA is poorly absorbed and is essentially not metabolized. Kraft cites several published toxicity studies conducted with calcium disodium EDTA (CaNa2EDTA) and trisodium EDTA (Na3HEDTA), including studies reviewed by JECFA in its safety evaluations, and discusses some of these studies in detail. The notice also includes a discussion of a carcinogenicity study with Na3HEDTA. In some rat studies, teratogenic effects were reported when EDTA was administered at very high doses (1000-1500 mg/kg bw/day) and zinc was restricted in the diet. No other adverse effects were observed in any of the studies. Kraft states that these studies contribute to the conclusion that NaFeEDTA is safe for its intended uses.

Iron Exposure

Kraft discusses the estimated contribution of NaFeEDTA to total dietary iron in populations where the ingredient would be used. Kraft provides examples of Latin American countries where iron deficiency anemia occurs in 30 to 70 percent of susceptible subpopulations (e.g., young children and women of childbearing age). Further, Kraft notes that iron intake in iron deficient populations, while not precisely known, may be assumed to be substantially less than the recommended dietary allowance (RDA) for iron.(4) Kraft estimates that the intended uses of NaFeEDTA would contribute an amount of iron equivalent to approximately 25 percent of the dietary intake of iron in those populations, assuming that typical iron intake is approximately 10 mg/p/d and one 200-mL serving (delivering 2.5 mg of iron) is consumed per day.

Kraft discusses the potential for iron overload from the intended uses of NaFeEDTA. Kraft cites published studies including long-term human studies in developing countries where NaFeEDTA was provided as an iron fortificant and a study of NaFeEDTA toxicity in rats. No adverse effects were seen in any of the studies, and Kraft notes that in the rat study the amount consumed was 50 times greater than the estimated 90th percentile intake of iron resulting from the intended uses of NaFeEDTA. Kraft states that these studies support its conclusion that the intended uses will not cause iron overload.

Kraft also discusses the levels of iron intake associated with acute toxicity in humans. Kraft notes that iron poisoning symptoms may occur from iron overload caused by acute ingestion of as little as 25 mg/kg bw/d of iron, with clinically significant iron poisoning occurring at iron doses of 60 mg/kg bw/d. Kraft estimates that a dose of 60 mg/kg bw/d of iron would be equivalent to consumption of approximately 100 liters (L) of reconstituted beverage containing 2.5 mg iron per 200 mL reconstituted soft drink. Kraft states that this estimate also supports the conclusion that the intended uses of NaFeEDTA will not cause toxicity in normal individuals.

Finally, Kraft discusses the intended uses of NaFeEDTA relative to the tolerable upper limit (UL) of intake for iron (45 mg/p/d for adults) established by the Institute of Medicine (IOM).(5) Kraft notes that the UL is based on gastrointestinal effects and considers that these effects constitute a self-limiting factor with respect to consumption of an iron-fortified beverage. Kraft further notes that an individual would need to consume 2.8 L of an iron-fortified beverage to reach the UL for iron, an amount that is well beyond the estimated intake from Kraft's intended uses. For iron deficient populations, where iron intake is presumed to be below the RDA, Kraft concludes that the risk of exceeding the UL is minimal given the intended uses of NaFeEDTA.

EDTA Exposure

Kraft discusses the contribution of NaFeEDTA to total dietary intake of EDTA in light of the JECFA acceptable daily intake (ADI) for EDTA of 2.5 mg/kg bw/d. Kraft states that EDTA intake resulting from the intended uses of NaFeEDTA would be 1.0 mg/kg/day of EDTA at the 90th percentile. Kraft notes that even if NaFeEDTA were used in populations already consuming EDTA-containing foods, the resulting total exposure to EDTA would not exceed the JECFA ADI for EDTA. In support of this statement, Kraft cites a published 1993 estimate of daily intake of EDTA in the U.S. from uses then currently regulated by FDA, where estimated daily intake (EDI) of EDTA was 0.22 mg/kg bw/day and 0.43 mg/kg bw/day at the 50th and 90th percentiles, respectively.(6)

Kraft discusses the potential for adverse effects of EDTA on the absorption of essential minerals in humans. Kraft acknowledges that, in large doses, EDTA may interfere with the absorption or retention of minerals but states that moderate doses of EDTA are generally considered to be innocuous. In support of this view, Kraft cites published long-term human studies with NaFeEDTA conducted in developing countries, published animal studies on EDTA and NaFeEDTA, and JECFA's evaluations of both EDTA and NaFeEDTA. Kraft concludes that the intended uses of NaFeEDTA 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 lays out 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, Kraft raises issues under these labeling provisions of the FFDCA. These issues include absorption of iron from dietary NaFeEDTA and its effects on iron status, and 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 Kraft's notice to determine whether it would support any claims made about NaFeEDTA on the label or in labeling.

Conclusions

Based on the information provided by Kraft, as well as other information available to FDA, the agency has no questions at this time regarding Kraft's conclusion that NaFeEDTA is GRAS when used as a source of dietary iron for food fortification purposes in powdered meal replacement, flavored milk, and fruit-flavored beverages in areas of the world with a high prevalence of iron deficiency. 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 Kraft 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).

Sincerely,
Laura M. Tarantino, Ph.D.
Director
Office of Food Additive Safety
Center for Food Safety
     and Applied Nutrition


(1)FDA estimates that NaFeEDTA exposure from Kraft's intended uses would be approximately 63 mg/p/d at the 90th percentile.

(2)FDA notes that Kraft's estimates, based on food consumption data from the USDA 1994-1996 Continuing Survey of Food Intake by Individuals (CSFII) and the 1998 Supplemental Children's Survey, may not be directly relevant to Kraft's target population with a high prevalence of iron deficiency. However, these estimates do provide some information on the level of exposure to be expected from use of NaFeEDTA in the specific food categories chosen by Kraft.

(3)Iron overload may be a greater problem in the United States than iron deficiency. FDA notes that the stated restriction on the intended uses of NaFeEDTA would minimize the risk of overfortification both within and outside the United States.

(4)The RDA for iron varies with age and gender, ranging from 6 mg/p/d for adult men 19-70+ years of age to 18 mg/p/d of iron for menstruating women 19-50 years of age. The RDAs for infants (7-12 months), children, adolescents, and teens are in this range. An RDA has not been set for infants 0-6 months of age.

(5)The UL for iron established by the IOM is 45 mg/p/d for adults (= 19 y) and adolescents (14-18 y) and 40 mg/p/d for infants (0-12 months) and children (1-13 y). FDA notes that, by definition, the UL represents the highest level of daily iron intake that is likely to pose no risk of adverse health effects in almost all individuals. Individuals with hereditary hemochromatosis, liver disease, or iron loading abnormalities are exceptionally sensitive to the effects of iron overload, and were not considered in the IOM's derivation of a UL for the general population.

(6)Calcium disodium EDTA (CaNa2EDTA) and disodium EDTA (Na2H2EDTA) are approved as direct food additives under 21 CFR 172.120 and 21 CFR 172.135, respectively.