The present opinion deals only with the safety of ferric sodium EDTA as a source of iron and with the bioavailability of iron from this source. The safety of iron itself, in terms of the amounts that may be consumed, is outside the remit of this Panel.

Information has been provided on the bioavailability of iron from ferric sodium EDTA based on iron fortification studies in humans. From these studies the Panel deduced that iron is liberated from the complex and that it is bioavailable. The studies further show that iron in the form of ferric sodium EDTA is 2 to 3 times more bioavailable than iron in the form of ferrous sulfate and that it is efficiently incorporated into haemoglobin.

The Panel notes that the absorption of iron from ferric sodium EDTA is regulated physiologically by the body��s iron status, in a manner similar to that for other iron compounds and that dietary iron fortification with ferric sodium EDTA is not expected to result in iron overload in iron-repleted individuals.

The Panel also notes that studies have been conducted to investigate the effect of ferric sodium EDTA on the absorption and metabolism of other nutrients in food (i.e. zinc, copper, calcium, manganese, and magnesium) in animals (rat) and in humans (fortification studies) and that no influence has been observed.

The Panel notes that two 90-day studies with ferric sodium EDTA it the rat have been provided. From the data provided the Panel derives an overall NOAEL of 250 mg ferric sodium EDTA/kg bw/day.

From a 61-day feeding study in the rat a NOAEL of 84.3 mg/kg bw/day of ferric sodium EDTA (providing 11.2 mg iron/kg bw/day) could be derived. The Panel notes that based on the results of this study, the JECFA concluded in 2000, that administration of ferric sodium EDTA in the diet would not result in a greater uptake of iron once nutritional requirements for iron were met.

The Panel notes that in vitro mutagenicity assays conducted in S. typhimurium (7 strains) and E. coli (2 strains) were negative, while in an in vitro mouse lymphoma assay a weak positive response in the presence of moderate cytotoxicity was observed. However, similar results were observed with other iron compounds in this in vitro mouse lymphoma assay and the effects observed with sodium iron (III) EDTA could probably be attributed to iron rather than to EDTA. Additionally, an in vivo mouse micronucleus assay was negative. Furthermore, in an EU Risk Assessment Report on EDTA, it is concluded that ��EDTA and its sodium salts have a low mutagenic potential at extremely high doses. On the basis of the various negative findings and the assumption of a threshold mode-of action for aneugens, it can be concluded that EDTA and its sodium salts are not mutagenic for humans.�� Thus, the Panel considers that from the information available there is no safety concern with respect to genotoxicity of ferric sodium EDTA as a source of iron added for nutritional purposes to foodstuffs.

No chronic toxicity or carcinogenicity studies have been conducted with ferric sodium EDTA; however, several studies have been conducted with other EDTA salts (e.g. trisodium EDTA, calcium disodium EDTA and disodium EDTA). Ferric sodium EDTA, like other EDTA-metal complexes, dissociates in the gut to a bioavailable form of iron and an EDTA salt; hence, toxicology studies of other EDTA salts are relevant when considering the safety of ferric sodium EDTA. From these studies it can be concluded that EDTA salts do not raise concern with respect to carcinogenicity.

From data on developmental studies conducted in the rat using similar EDTA salts, such as disodium EDTA, trisodium EDTA, tetrasodium EDTA, and calcium disodium EDTA, no compound-related mortality, reproductive, or teratogenic effects were reported.

From a developmental toxicity study on ferric sodium EDTA in the rat the Panel derived a NOAEL of 200 mg/kg bw/day.

Ferric sodium EDTA has been used in numerous field trials on iron fortification of foods in developing countries. From these studies it appears that no adverse effects were reported in humans subjected to long-term ferric sodium EDTA fortification trials.

The Panel notes that photodegradation of EDTA can give rise to the formation of formaldehyde. The EFSA AFC Panel examined formaldehyde when used as a preservative during the manufacture and preparation of food additives and concluded that there was no evidence indicating that formaldehyde is carcinogenic by the oral route. Therefore the Panel considers that the potential formation of formaldehyde as a degradation product of EDTA is not expected to pose a safety concern in humans under the proposed conditions of use of ferric sodium EDTA.

The petitioner indicates that ferric sodium EDTA will be used in PARNUTS to provide 22.3 mg iron/day for a 60 kg adult and 11.1 mg iron/day for a 30 kg child. To provide these levels of iron, equivalent values of ferric sodium EDTA of about 168 mg/day and 84 mg/day respectively will be needed.

In the case of food supplements, the petitioner did not indicate precise use levels, but states that these are similar to that of other forms of iron currently approved for use in food supplements. The petitioner expects the iron intake from the use of ferric sodium EDTA not to exceed 22.3 mg/day for a 60 kg adult or 11.1 mg/day for a 30 kg child. Equally to the use of ferric sodium EDTA as a source of iron in PARNUTS, to provide these levels of iron in the case of food supplements, equivalent values of ferric sodium EDTA of about 168 mg/day and 84 mg/day respectively will be needed.

The Panel notes that the EVM has stated that for guidance purposes only, a supplemental intake of approximately 17 mg iron/day (equivalent to 0.28 mg/kg bw/day for a 60 kg adult) would not be expected to produce adverse effects in the majority of people. An amount of 17 mg iron/day would be provided by 128.3 mg ferric sodium EDTA providing 89 mg EDTA, equivalent to about 1.5 mg EDTA/kg bw/day for an adult and 5.9 mg EDTA/kg bw/day for children weighing 15 kg.

Based on these intake values the Panel calculated the resulting intake of EDTA if all iron were to be provided by ferric sodium EDTA. In the case of PARNUTS the exposure to EDTA would amount to about 116 mg/day for adults and to about 58 mg/day for children. In the case of food supplements the exposure to EDTA would also amount to 116 mg/day for adults and to about 58 mg/kg bw/day for children. The Panel notes that in both cases the exposure to EDTA will be about 1.9 mg EDTA/kg bw/day for adults and 3.9 mg EDTA/kg bw/day for children weighing 15 kg.

In the case of food fortification, assuming the use levels of ferric sodium EDTA as provided by the petitioner, the total exposure to EDTA would be 11.3 mg/day for children (15 kg) and 24.6 mg/day for male adults on average, and 24.6 mg/day and 58.5 mg/day, respectively, at the 95th percentile. On a body weight basis, this is equivalent to 0.8 and 0.4 mg/kg bw/day at the average, and 1.7 and 1.0 mg/kg bw/day at the 95th percentile.

The Panel notes that no ADI for EDTA has been set but that the JECFA established an ADI for calcium disodium EDTA of 2.5 mg/kg bw/day, which can be calculated to amount to 1.9 mg EDTA/kg bw/day. Calcium disodium EDTA is the only currently approved EDTA derivative in the EU.

If assumed that ferric sodium EDTA as a source for iron would be consumed from all three sources (PARNUTS, fortified foods and supplements), the combined exposure to EDTA would be 8.6 mg/kg bw/day for children and 4.2 mg/kg bw/day for adults on average and to 9.5 mg/kg bw/day for children and 4.8 mg/kg bw/day for adults at the 95th percentile. This exceeds the value for EDTA of 1.9 mg/kg bw/day derived from the ADI established for calcium disodium EDTA. The Panel cannot estimate the probability that an individual is exposed to all products where ferric sodium EDTA is intended to be added as a source for iron although it considers this as rather unlikely.

The exposure to sodium resulting from ferric sodium EDTA intended to provide 22.3 mg iron/day (equivalent to 165 mg ferric sodium EDTA) would result in an additional exposure to 9 mg sodium/day. Compared to the typical dietary exposure to sodium in the average range of 4,500-11,000 mg/day across Europe, this additional exposure is considered to be irrelevant even under concurrent exposure to ferric sodium EDTA from different sources.

The Panel concludes that iron is bioavailable from ferric sodium EDTA and that the use of ferric sodium EDTA as a source of iron in food is of no safety concern as long as it does not lead to an exposure to EDTA above 1.9 mg EDTA/kg bw/day.

The Panel further concludes that ferric sodium EDTA as a source of iron at the proposed use level in fortified food for the general population would not be of safety concern.

The Panel notes that when ferric sodium EDTA is used in PARNUTS or food supplements at levels which provide 22.3 mg iron/day for an adult and 11.1 mg iron/day for a child, the corresponding exposure to EDTA would be 1.9 mg EDTA/kg bw/day for adults and 3.9 mg/kg bw/day for children.

Published: 18 January 2010