Potassium [[N,N'-ethylenebis[N-(carboxymethyl)glycinato]](4-)-N,N',O,O',ON,ON']ferrate(1-)

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result:

In summary, most iron absorbed after EDTA-FeK is ingested is released to the physiological mucosal uptake system before absorption.

Only a very small fraction of the EDTA-FeK complex (less than 1%) is absorbed intact, and it is completely excreted in the urine.

An additional small fraction (probably less than 5%) of the EDTA moiety itself is absorbed, presumably bound to other metals in the gastrointestinal

tract, and it is also completely excreted in the urine. Although the absorption of the EDTA moiety from administered EDTA-FeK has not been measured directly in humans, physicochemical considerations indicate that EDTA absorption from EDTA-FeK would be similar to that from other metal complexes, such as EDTA-CaNa2 and Cr-EDTA. As described above, poor absorption of the intact EDTA-FeK can be inferred from measurements of urinary radio iron excretion after the oral administration of Na59-FeEDTA.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

Toxicokinetics EDTA-FeNa; the same is expected for EDTA-FeK (see read across document in section 13).

 

INACG and WHO have written extensive reviews on the ADME of EDTA-FeNa based on available literature. For their full review see attachments.

There are no indications from literature that, upon ingestion, EDTA or EDTA-FeNa or any other metal‑EDTA complex‑ion, will give rise to bioaccumulation. All metal‑EDTA complex-ions are highly soluble in water and when absorbed these are rapidly and completely removed by the kidneys from the blood circulation.

The total amount of iron in the human body is ca. 4 g. In general 1 mg iron per day will be lost. Females because of their monthly period, will additionally loose ca. 30 mg, which is on average also 1 mg per day. These losses will be replenished via the food intake. A normal diet contains ca. 10 to 15 mg Fe per day. The iron uptake from the gut is directly related to the to the body’s need; in case of shortage uptake from the gut will increase. 

 

Only a very small fraction of the EDTA-FeNa complex (less than 1%) in humans is absorbed intact from the gut, and due to its high water solubility it is completely excreted in the urine. Poor absorption of the intact EDTA-FeNa can be inferred from measurements of urinary radio-labeled iron excretion after the oral administration of Na⁵⁹FeEDTA.

 

After EDTA-FeNa has been ingested, the absorption of iron from ferric sodium EDTA is regulated through the same physiological mechanisms as other forms of iron. Following oral administration, the iron from ferric sodium EDTA is separated from the iron EDTA complex in the lumen of the gut by the intestinal cells of the duodenum and small intestine. As indicated above, the mucosa cells will only pick up the non-complexed ferric ions that are needed by the body, and this amount will be transported to the blood plasma where it will be coupled to transferrin, like all other absorbable iron in food. This iron joins the general non-haem iron pool that is finally incorporated into the circulating haemoglobin. The iron component of ferric sodium EDTA is subsequently handled systemically like any other source of iron; the safety and maximum tolerable intake of which has been reviewed and evaluated by a number of distinguished scientific committees such as JECFA, WHO, UK EVM, SCF, IOM and EFSA. Non-absorbed iron will be excreted via the feces.

 

With regard to the EDTA-moiety, following dissociation from ferric sodium EDTA, most of this EDTA is promptly excreted in the feces, while less than 5% is absorbed. The absorbed fraction is presumably bound to other metals in the gastrointestinal tract, and it is also completely excreted in the urine because of high water solubility. Although the absorption of the EDTA moiety from administered EDTA-FeNa has not been measured directly in humans, physicochemical considerations indicate that EDTA absorption from EDTA-FeNa would be similar to that from other metal complexes, such as EDTA-CaNa2 and EDTA-CrNa.

 

Traces of ferric-EDTA complex‑ions that might possibly be formed in the blood circulation out of absorbed EDTA molecules that are present in the form of e.g. calcium‑EDTA complex‑ions and out of ferric ions that have not been bound to transferrin, will also rapidly be removed by the kidneys.

 

The EDTA moiety does not undergo biotransformation. Evidence for this conclusion comes from studies which indicate that EDTA moieties are excreted unchanged into the urine following ingestion of EDTA-CaNa2. Biotransformation of iron does by definition not occur: ferric ions (from whatever source in the food) can only be converted into ferrous ions, and back.

 

The use of EDTA-FeNa as a food fortificant has no measurable effect on the nutrition or metabolism of calcium, copper, zinc, or magnesium. In some situations, fortifying foods with EDTA-FeNa may even have a beneficial effect on zinc nutrition by improving zinc absorption. EDTA-FeNa improves iron balance by supplying iron in a form hardly affected by dietary inhibitors such as phytic acid and additionally improves the absorption of nonhaem iron from other iron sources in the meal e.g. from vegetables and cereals.

 

Overall, based on the data available, for EDTA-FeNa, intestinal absorption was estimated to be maximally 5%, based on the EDTA-moiety as iron uptake will be guided by the body’s iron need. Dermal absorption of EDTA-FeNa was also based on EDTA (RAR, 2004, see robust summary), viz. 0.001%. Because of its high water solubility and because of the larger molecular structure, dermal absorption of EDTA-FeNa would certainly not be higher than that of EDTA. Based on the particle size distribution of EDTA-FeNa, it is expected that 90% of the inhaled substance will be deposited in the upper respiratory tract, which will finally be taken up orally. Of this, only 5% will be absorbed in the gastrointestinal tract and become available systematically, i.e. 0.9 x 0.05 = 0.045 (4.5%). The other 10% may reach the alveoli and it is assumed that this will be absorbed completely (worst case). Therefore, the total inhalation absorption factor will be 0.045 + 0.10 = 0.145 (14.5%). 

 

Discussion on bioaccumulation potential result:

With regard to EDTA:

According to the dissociation equilibrium of edetic acid, administration of different sodium salts will result in dependence on the intestinal pH-value to the formation of various anionic species of EDTA. In whatever salt EDTA is administered it is likely to chelate metal ions in vivo. It can be assumed that the oral and dermal absorption of sodium salts of EDTA and of the free acid is comparable to the low absorption of CaNa2EDTA. Calcium salts of EDTA are poorly absorbed from the gastrointestinal tract (2 to 18% within 24 h), a maxium of 5% was detected in the urine. Only 0.001% is absorbed after dermal application. Intravenously injected EDTA is excreted within 24 h in the urine, 50% of the substance in the first h and 90% within 7 h.

With regard to EDTA-FeNa:

After ingestion, based on the data available, a low bioaccumulation potential for EDTA-FeNa is concluded (see also section 7.1).

For EDTA-FeNa, intestinal absorption was estimated to be 5%, and dermal absorption 0.001%. Based on the particle size distribution of EDTA-FeNa, it is expected that 90% of the inhaled substance will be deposited in the upper respiratory tract, which will finally be taken up orally. Of this, only 5% will be absorbed in the gastrointestinal tract and become available systematically, i.e. 0.9 x 0.05 = 0.045 (4.5%). The other 10% may reach the alveoli and it is assumed that this will be absorbed completely (worst case). Therefore, the total inhalation absorption factor will be 0.045 + 0.10 = 0.145 (14.5%). Neither the iron nor the EDTA moiety of EDTA-FeNa undergoes biotransformation.