Ferric ammonium citrate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Additional information

It is considered that based on the following points, a weight-of-evidence approach can be taken for reproductive and developmental endpoints, rather than proposing to conduct further, new experimental animal tests to fulfil the Annex requirements: • the ubiquitous nature of citrate and iron in the environment, and the ubiquitous nature of ferric citrate in the circulation; • the fact that iron is an essential element; • iron and citrate both play an important role in biological processes, with iron homeostasis being under strict control, and citrate is involved in the metabolism of eukaryote cells, being ubiquitous in living organisms; • iron has been given to pregnant women for many years without an effect on pregnancy outcome; • available experimental animal data have not revealed any adverse effects on reproduction parameters and development. From the weight-of-evidence approach the following conclusion can be reached: Results from recent guideline oral screening studies performed on ferrous chloride and ferrous sulfate gave NOAELs for reproductive and developmental effects of ≥500 mg/kg body weight/day or ≥1000 mg/kg body weight/day (no adverse effects were observed), respectively. These findings are considered to be relevant to ferric as well as ferrous salts, as oxidation of ferrous to ferric occurs in the low pH of stomach before ingested iron is absorbed into the body. In humans, iron supplementation of about 5.8 to 11.7 mg/kg bw/day (for a 60kg individual) is routinely prescribed throughout pregnancy with no adverse effects on pregnancy outcome. Evidence of adverse effects on male testes has only been observed at acutely toxic, overload doses, at which some of the experimental animals died.

Short description of key information:

There are no guideline experimental data relating to the potential for adverse effects on fertility of the reaction mass of ammonium iron (III) citrate and ammonium sulfate. Due to the ubiquitous nature of the constituents of the registered substance,  the reproductive and developmental endpoints are waived.

Results from recent guideline oral screening studies performed on iron dichloride (NIER, 2004) and iron sulfate (MHLW, 2003) gave NOAELs for reproductive and developmental effects of ≥500 mg/kg body weight/day or ≥1000 mg/kg body weight/day (no adverse effects were observed), respectively. These findings are considered to be relevant to ferric as well as ferrous salts, as oxidation of ferrous to ferric occurs in the low pH of stomach before ingested iron is absorbed into the body.

Effects on developmental toxicity

Description of key information

Due to the ubiquitous nature of the constituents of the reaction mass of ammonium iron (III) citrate and ammonium sulfate the reproductive and developmental endpoints are waived.

Additional information

It is considered that based on the following points, a weight-of-evidence approach can be taken for reproductive and developmental endpoints, rather than proposing to conduct further, new experimental animal tests to fulfil the Annex requirements: • the ubiquitous nature of citrate and iron in the environment, and the ubiquitous nature of ferric citrate in the circulation; • the fact that iron is an essential element; • iron and citrate both play an important role in biological processes, with iron homeostasis being under strict control, and citrate is involved in the metabolism of eukaryote cells, being ubiquitous in living organisms; • iron has been given to pregnant women for many years without an effect on pregnancy outcome; • available experimental animal data have not revealed any adverse effects on reproduction parameters and development. From the weight-of-evidence approach the following conclusion can be reached: Results from recent guideline oral screening studies performed on ferrous chloride and ferrous sulfate gave NOAELs for reproductive and developmental effects of ≥500 mg/kg body weight/day or ≥1000 mg/kg body weight/day (no adverse effects were observed), respectively. These findings are considered to be relevant to ferric as well as ferrous salts, as oxidation of ferrous to ferric occurs in the low pH of stomach before ingested iron is absorbed into the body. In humans, iron supplementation of about 5.8 to 11.7 mg/kg bw/day (for a 60kg individual) is routinely prescribed throughout pregnancy with no adverse effects on pregnancy outcome. Evidence of adverse effects on male testes has only been observed at acutely toxic, overload doses, at which some of the experimental animals died.

Justification for classification or non-classification

Based on a weight of evidence based approach on data available for other iron salts, and the ubiquitous nature of the the consituent ions of the reaction mass of ammonium iron (III) citrate and ammonium sulfate, no classification is required for the reproductive and developmental endpoints in accordance with current regulation (EC 1272/2008).