Sodium feredetate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Additional information

Based on read across with other EDTA compounds such as EDTA-CaNa2 and EDTA-MnNa2 it is concluded that reproductive effects were not present at levels up to 250 or 500 mg/kg bw, respectively. This was also concluded by Heimbach et al. (2000) and in the RAR on EDTA-H4 and EDTA-Na4 (2004). Heimbach et al. (2000) concluded that EDTA compounds are not reproductive toxicants when fed with a nutrient sufficient diet or minimal diets supplemented with Zn. Because in this case animals were treated with EDTA-FeNa and not with an empty chelate such as EDTA-H4 or EDTA-Na4, binding of zinc will even be less.

Short description of key information:
Studies with levels up to 250 mg/kg bw EDTA-CaNa2 did not give any indication for effects on reproduction. A study on EDTA-MnNa2 showed decreased sperm motility at a level of 1500 mg/kg bw but not at 500 mg/kg bw. In the latter study, no changes were found on female reproduction.

Effects on developmental toxicity

Description of key information

Studies with levels up to ca. 1000 mg/kg bw EDTA-compounds did not give any indication for effects on development; higher levels revealed developmental effects including malformations. A study on EDTA-MnNa2 showed a decreased number of females with liveborn pups, a decreasd number of (live) pups and an increased post-implantation loss at a level of 1500 mg/kg bw but not at 500 mg/kg bw. 

Additional information

It was concluded that with regard to EDTA-compounds, that the mechanism by which EDTA induced developmental toxicity at high levels of EDTA was the binding of zinc by EDTA resulting in zinc deficiency during embryonic development (Heimbach et al., 2000; RAR, 2004). With regard to EDTA-MnNa2, binding of Zn will even be less. However, at a very high level of 1500 mg/kg bw EDTA-MnNa2 was developmental toxic, most probably due to the effect of manganese as other manganese compounds had also shown developmental effects. Such changes were not seen with the zinc chelate of EDTA (RAR, 2004) and are therefore also not expected for iron i.e. EDTA-FeNa. In contrast, Fe-shortage in dams (fed with 7.5 mg Fe per kg diet instead of 50 mg Fe per kg diet) resulted in greater pup mortaility, smaller pup size, and pups with larger hearts, and with smaller kidneys and spleens. The only available study on EDTA-FeNa was disregarded because of several severe limitations; however, no developmental effects were seen at 200 mg/kg bw (nominal); the effects seen at 800 mg/kg bw (nominal) such as delayed ossification were considered to be due to maternal toxicity at that level. Overall, despite all the study limitations, no teratogenic effects were observed in this study.

Justification for classification or non-classification

As EDTA and the zinc chelate of EDTA obviously lack a specific teratogenic potential (RAR, 2004), it is expected that this applies to EDTA-FeNa too. In addition, because malformations caused by EDTA compounds have been demonstrated at relatively high oral dose levels (i.e. 1000 mg/kg bw and above) and a steep dose response relationship can be assumed (RAR, 2004), no classification for reprotoxicity is needed.