Ferric ammonium citrate

Endpoint summary

Description of key information

No data are available for the acute toxicity of the reaction mass of ammonium iron (III) citrate and ammonium sulfate.

The key study for acute oral toxicity is read across from ferric chloride, which reports an LD50 value equivalent to 440 mg Fe/kg bw in a reliable study conducted according to an appropriate protocol (Hosking 1970). Based on the known composition of the reaction mass of ammonium iron (III) citrate and ammonium sulfate of 12.1% ferric ion and 0.1% ferrous ion, the LD50 for  the reaction mass of ammonium iron (III) citrate and ammonium sulfate is calculated to be 3600 mg/kg, based on the available read across data.

The data for acute inhalation and acute dermal toxicity are waived.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 600 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

No data are available for acute toxicity of the reaction mass of ammonium iron (III) citrate and ammonium sulfate. The key study for acute oral toxicity is therefore read across from ferric chloride, which reports an LD₅₀value equivalent to 440 mg Fe/kg bw in a reliable study conducted according to an appropriate protocol (Hosking 1970). Based on the known composition of the reaction mass of ammonium iron (III) citrate and ammonium sulfate of 12.1% ferric ion and 0.1% ferrous ion, the LD₅₀for the reaction mass of ammonium iron (III) citrate and ammonium sulfate is estimated to be 3600 mg/kg. Given that the ferric citrate complex may remain intact and that the intestinal absorption of ferric citrate may be higher than that of the read across substance due to the role of citrate as an iron carrier, the estimated LD₅₀of 3600 mg/kg bw is well above the classification limit and is considered sufficiently cautious to base an assessment of acute oral toxicity upon of the registered substance. For similar reasons, penetration through the skin is also unlikely. Both the registered substance and the read across substance (ferric chloride) contain ferric ions when in aqueous solution, and the key study has been chosen to examine the potential for acute toxicity of the ferric ion. The chloride counter ion of the read-across substance is not expected to contribute to the potential for acute toxicity, as it is ubiquitous in nature and forms part of a normal diet. The non-ferric chemical species that are part of the registered substance are ammonium and citrate. Neither ammonium nor citrate ions are expected to contribute to the potential for acute toxicity of the registered substance. Information on the lack of acute toxicity of ammonia and its salts is available in the public domain. Information on the lack of potential for acute toxicity of citrate is also available in the public domain and moreover citrate is involved in the metabolism of eukaryote cells.

A supporting study on the acute oral and dermal toxicity of ammonium sulfate is also included, reporting LD₅₀values of >2000 mg/kg bw in mice and rats for both acute oral and dermal toxicity (Yamanaka, 1990), which further supports the lack of acute toxicity of the registered substance.

The acute inhalation and acute dermal toxicity endpoints are waived based on a weight-of-evidence approach rather than proposing to conduct further, new experimental animal tests to fulfil the Annex requirements. The ubiquitous nature of iron and citrate in the environment and the fact that iron and citrate play important roles in biological processes, with their homeostasis being under strict control make further testing counterintuitive. The ferric citrate complexation is known to be thermodynamically stable, and given penetration through the lung, systemic toxicity would be unlikely due to the ubiquitous nature of ferric citrate in circulation. Furthermore, the exposure profile of the registered substance comprises the obligatory use of full respiratory protection for loading / charging operations. Similarly, penetration through the skin is unlikely. Due to the ubiquitous nature of the constituents of the registered substance and the intrinsic mechanisms in place for the regulation of citrate and iron homeostasis, further testing would be unjustified. Additional information on basis of read across approach and justification for data waiving is given in an expert report (Peter Fisk Associates, 2012) attached in Section 13 of the IUCLID dossier.

Justification for classification or non-classification

Based on the available information and the ubiquitous nature of the consituent ions of the registered substance, no classification is proposed for acute toxicity of the reaction mass of ammonium iron (III) citrate and ammonium sulfate in accordance with current regulation (EC 1272/2008).