Iron tris(2-ethylhexanoate)

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEL on FERTILITY and REPRODUCTION >= 300 mg/kg bw

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

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 results obtained under test conditions are the following:

- Repeated oral administration of the tested substance to rats by gavage at the dose levels of 75, 150 and 300 mg/kg bw/day did not cause any mortality.

- Fertility and developmental part of the study

Oestrous cycle, reproductive parameters, pairing combination and mating performance: no treatment-related anomalies were noted in the pre-coital interval of the treated females. Absence or reduced oestrous cycles number were seen in the females of mid- and high dose groups (dosed at 150 and 300 mg/kg/day) during the pre-mating phase of the study. The number of copulation plugs was similar between control and treated groups.

The copulatory indices were 100% for controls, low and mid-dose groups (dosed at 75 and 150 mg/kg/day), 90% for high dose animals (dosed at 300 mg/kg/day).

The fertility indices were 100% for controls and low dose animals (dosed at 75 mg/kg/day) and 90% for animals dosed at 150 and 300 mg/kg/day.

Implantation, pre-birth loss data and gestation length of females: no significant differences were observed for these parameters between the treated groups and the controls. All pregnant dams gave birth between Days 21 and 23 post coitum.

Litter data at birth, on Day 1 and on Day 4 post partum of females and sex ratio of pups: no significant differences in total litter size, live litter size, mean pup loss and mean pup weights were observed among the treated dams and the controls at birth and on Days 1, 4 and 13 post partum.

A dose-related reduction of the percentage of males at birth, statistically significant in the high dose group (receiving 300 mg/kg/day) was observed in comparison to controls.

Clinical signs of pups: there were no compound-related effects.

Necropsy findings in decedent pups and in pups sacrificed on Day 4 post partum: necropsy did not reveal any treatment-related effect.

No effects which could be considered adverse were observed on male and female reproductive performance, such as gonadal function, mating behaviour, conception, parturition and early lactation of the offspring at any of the dose levels investigated.

Therefore, the NOAEL (No Observed Adverse Effect Level) for fertility and reproduction parameters was considered to be 300 mg/kg/day for males and females.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

According to CLP Regulation (EC) No 1272/2008, reproductive toxicity includes adverse effects on sexual function and fertility in adult males and females, as well as developmental toxicity in the offspring.

For the purpose of classification for reproductive toxicity, substances may be allocated to one of two categories. Within each category, effects on sexual function and fertility, and on development, are considered separately.

- Category 1: Known or presumed human reproductive toxicant. Substances are classified in Category 1 for reproductive toxicity when they are known to have produced an adverse effect on sexual function and fertility, or on development in humans or when there is evidence from animal studies, possibly supplemented with other information, to provide a strong presumption that the substance has the capacity to interfere with reproduction in humans. The classification of a substance is further distinguished on the basis of whether the evidence for classification is primarily from human data (Category 1A) or from animal data (Category 1B).

- Category 2: Suspected human reproductive toxicant. Substances are classified in Category 2 for reproductive toxicity when there is some evidence from humans or experimental animals, possibly supplemented with other information, of an adverse effect on sexual function and fertility, or on development, and where the evidence is not sufficiently convincing to place the substance in Category 1.

Based on the available information, no effect on fertility and development was observed therefore no calssification is warrented according to the CLP Regulation (EC No 1272/2008).