Iron tris(2-ethylhexanoate)

Endpoint summary

Description of key information

NOAEL on REPEATED DOSE TOXICITY >= 300 mg/kg bw

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subacute

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The toxic effects on Sprague Dawley rats after repeated dosing by oral route with the test item, as well as any effects of the test item on male and female reproductive performance, such as gonadal function, mating behaviour, conception, parturition

and early lactation of the offspring were investigated. The vehicle was corn oil. All doses (0, 75, 150 and 300 mg/kg/day) were administered at a constant volume of 5mL/kg body weight.

Males of the main groups were treated for 14 days prior to pairing and during pairing with females until the day before necropsy, for a total of 32/33 days. Males of the recovery group were treated for a total of 28 days. Females of the main groups were treated for 14 days prior to pairing, during pairing and throughout the gestation and lactation periods until Day 13 post partum, for a total of 42 to 63 days. Females of the recovery groups were treated for a total of 63 days.

The following investigations were performed in all groups (main and recovery): body weight, clinical signs (including neurotoxicity assessment, motor activity and sensory reactivity to stimuli), food consumption, clinical pathology investigations (haematology and clinical chemistry in five animals/sex/main group randomly selected and in all recovery

animals), post mortem macroscopic observations, organ weights. In addition, for main phase groups only (parental animals), oestrous cycle evaluation for parental females (1 week before dosing, during pre-mating and mating phases, prior to necropsy), mating performance, thyroid hormone determination (parental main phase males) and litter data were performed. Clinical signs, anogenital distance, external and internal examination and thyroid weight at necropsy were recorded for pups. Thyroid hormone levels were also determined in 1 pup/sex/group randomly selected at Day 14 post partum.

Routine histopathological examination was performed only in main control and high dose groups (five animals/sex/group randomly selected). It included identification of the stages of the spermatogenic cycle in five males.

The following parameters have been observed under this experimental conditions:

Mortality and Clinical signs: no treatment-related clinical signs were observed in the males from the main phase and in

those from the recovery phase, during treatment and recovery periods.

Neurotoxicity assessment: no treatment-related alterations in motor activity, grip strength, landing footsplay and sensory reactivity to stimuli were observed in any treatment group at the examination performed at the end of treatment.

Body weight and body weight gain: very slight reductions in body weight were observed in the high dose females of the recovery group. Reductions gradually recovered during the recovery period.

No significant changes in body weight and body weight gain were observed in the treated male animals and in the main group females.

Food consumption: no changes of toxicological relevance, which could be considered adverse, were observed in food consumption during the study.

Haematology: slight decrease of erythrocytes was recorded in males dosed at 150 and 300mg/kg/day. Due to the minimal severity, this change was considered to be not adverse. No changes were recorded on the recovery phase.

Coagulation: no changes of toxicological relevance were observed.

Terminal body weight and organ weights: terminal body weight unaffected by treatment in both sexes. Absolute and relative organ weights were comparable in all groups.

Macroscopic observations: no remarkable differences were noted at post mortem examination in treated animals

sacrificed at the end of treatment and recovery period, when compared with controls.

Microscopic observations: no treatment-related changes were noted in animals sacrificed at the end of the treatment

period.

No adverse effects indicating systemic toxicity were observed in male or female animals from main and recovery groups at any of the dose levels investigated (75, 150 and 300 mg/kg/day).

Based on the results of the present study, the NOAEL (No Observed Adverse Effect Level) for general toxicity was considered to be 300 mg/kg/day for males and females.

Justification for classification or non-classification

According to the CLP Regulation (EC) No. 1272/2008, substances are classified as specific target organ toxicants following repeated exposure, and are placed in one of two categories, depending on the nature and severity of the effect(s) observed. Substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following repeated exposure, are classified in Category 1 for target organ toxicity (repeat exposure). Classification in Category 1 is applicable when significant toxic effects are observed in a 90-day repeated-dose animal study at low concentrations (< 10 mg/kg bw/day in oral studies, and < 20 mg/kg bw/day in dermal studies) (CLP Regulation (EC) No. 1272/2008: Annex 1, Part 3, Table 3.9.2).

Substances which can be presumed to have the potential to be harmful to human health following repeated exposure, based on evidence from animal studies, are classified in Category 2. Classification in Category 2 is applicable when significant toxic effects are observed in a 90-day repeated-dose animal study at generally moderate exposure concentrations (10 to 100 mg/kg bw/day in oral studies, and 20 to 200 mg/kg bw/day in dermal studies) (CLP Regulation (EC) No. 1272/2008: Annex 1, Part 3, Table 3.9.3).

Equivalent guidance values for an equivalent 28-day study period raises the concentration values for classification by three-fold: classification in category 1 is applicable at low concentrations (< 30 mg/kg bw/day in oral studies; < 60 mg/kg bw/day in dermal studies) and in Category 2 at generally moderate concentrations (30 to 300 mg/kg bw/day in oral studies, 60 to 600 mg/kg bw/day in dermal studies).

Based on the short-term, repeated dose toxicity study (combined with reproductive and developmental toxicity) according to the OECD Guildeline 422 (2016), the test item did not produce adverse toxicity in male or female rats when administered at 300 mg/kg bw/day. Therefore, no classification of the test item is warranted for specific target organ toxicity – repeated exposure according to the CLP Regulation (EC) No. 1272/2008.