Magnesium, EDTA cobalt copper iron manganese zinc complexes

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
In rat as well as in human studies CaNa2EDTA and Na2EDTA is poorly absorbed from GI tract and the absorbed part rapidly excreted by urine, therefore one can rule out the danger of bioaccumulation. However, administration of EDTA salts results in an increased excretion of necessary ions like Zn, Mn or Ca.
Short description of key information on absorption rate: 
- CaNa2EDTA does not penetrate the skin.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

5

Absorption rate - dermal (%):

0.001

Additional information

Some poorly reported toxicokinetic studies using the disodium salt of EDTA have been performed. Additionally studies using Ca and Na salts of EDTA are available. According to the dissociation equilibrium of edetic acid, administration of different sodium salts will result in the formation of various anionic species of EDTA in dependence on the intestinal pH value. In whatever salt EDTA is administered it is likely to chelate metal ions in vivo. Therefore the studies using CaNa2EDTA have been used as read-across. It can be assumed that the systemic absorption from the intestinal tract is low. The obtained data can be used to predict that dermal absorption should be even lower. Additionally absorbed EDTA does not undergo any biotransformation and is excreted unchanged.

In toxicokinetic studies on humans as well as rats the CaNa2 and Na salts of EDTA are poorly absorbed from the gastrointestinal tract (2 -18% in rats; less than 5% in humans) CaNa2EDTA does not penetrate the skin, only 0.001% were absorbed within 24 h of administration. Intravenously applied EDTA is rapidly excreted in urine (humans 50% within the first hour 98% within 24 h; rats: 95%- 98% within 6 h). These data were also confirmed by the independent evaluation of the MAK Commission for the Investigation of Health Hazards of Chemical Compounds in the work area (MAK, 46. Lieferung, 2009).

  

Oral

Studies with EDTA-CaNa2 and EDTA-Na2H2 indicate that these complexes are poorly absorbed in mammals after oral administration (Foreman and Trujillo, 1954; Foremanet al., 1953; Yang and Chan, 1964). For each of these materials, approximately 1-5% and

90-99 % of the administered dose was detected in urine and feces, respectively, within

24-48 hours. Experiments with the EDTA-CaNa2 in rats and man showed that at the low

pH of the stomach, calcium dissociates from EDTA, leading to precipitation of EDTA in the stomach and re-dissolution at pH levels encountered in the small intestine (Foremanet al., 1953; Foreman and Trujillo, 1954). Because ions complexed to EDTA dissociate from EDTA in the GI tract, and EDTA is poorly absorbed, mammalian toxicity data for all EDTA-containing chelants are expected to be similar, with subtle differences arising from the ability of the complexes to dissociate under pH’s encountered in the GI tract.

With regard to EDTA-FeNa, the iron remains complexed with the EDTA under the acidic conditions in the stomach. The strength of the complex is reduced as the pH rises in the upper small intestine, allowing release of some of the iron for absorption (Heimbachet al., 2000). Once ingested, the absorption of iron is regulated through the same physiological mechanisms as for other forms of dietary iron (Heimbachet al., 2000) and would include uptake of uncomplexed iron from the lumen of the gut as needed by the body, and transported to the blood and plasma coupled to transferrin. Zinc absorption was significantly increased and retention and elimination enhanced in rats fed a zinc deficient diet fortified with EDTA-FeNa compared with the same diet without EDTA-FeNa (Hurrellet al., 1993). Enhanced zinc absorption was found from low bioavailability diets supplemented with EDTA-FeNa (Davidssonet al., 1994). In this same study, there was no effect on calcium absorption and no effect on retention of zinc or calcium. In another study, manganese absorption and urinary excretion were unchanged in adults receiving a diet fortified with EDTA-FeNa (Davidssonet al., 1998).

 

Two additional studies on the toxicokinetics of CaNa2EDTA after i.p. application are available. In one study rats got 10 injections of 300 - 436 mg/kg bw/day 14 C labeled CaNa2EDTA. 66 - 92% of the administered dose were recovered in urine while generally less than 5% were excreted by feces. 24 h after the last injection kidneys showed less than 0.1% of the radioactivity (Doolan, 1967). In the other study, 18 rats got a single i. p. application of 400 mg/kg bw 14[C]CaNa2EDTA. Within 22 h 80% of the radioactivity were excreted in urine, while the concentration in kidney homogenate was approximately 0.1 - 0.2% during this time period (Miller, 1986).

 

The available evidence indicates that EDTA-complexes are not or are scarcely metabolized but are excreted as chelated complexes via the urine following glomerular filtration and tubular secretion.

  

Dermal

After application of 14C-labelled EDTA-CaNa2 to the skin of healthy young adult men, no radioactivity was detected in the blood, and that found in urine accounted for a maximum of only 0.001% of the administered dose (Foreman and Trujillo, 1954).

 

The effects of sc application of CaNa2EDTA on Zn, Cu and Mn metabolism were investigated in female dogs. CaNa2EDTA was applied with a dose of 280 mg/kg bw/ every 6 hours for 54 h. Urine was collected every 6 h and the Zn, Cu and Mn content analysed. CaNa2EDTA application increased the urinary excretion of Zn, Cu and Mn significantly (Ibim 1992).

  

Overall

Toxicokinetic data with different read across substances are available, which are ingredients of the target substance.Dermal application of radiolabeled EDTA-CaNa2 to human skin showed that 0.001% was found in the urine and none was found in the blood. Studies with EDTA-CaNa2 and EDTA-Na2H2 indicate that these complexes are poorly absorbed in mammals after oral administration. EDTA and its salts are eliminated from the body, 95% via the kidneys and 5% by the bile, along with the metals and free ionic calcium which was bound in transit through the circulatory system. In whatever salt EDTA is administered, it is likely to chelate metal ionsin vivo.