Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

The NOAEL (No Observed Adverse Effect Level) for general toxicity and for fertility and reproduction parameters was considered to be 450 mg/kg body weight/day for males and females.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
450 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available (further information necessary)
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In order to provide information on toxicity as well as any possible effects of the test item on male and female reproductive performance, a study was performed according to the OECD Guideline. 421 (2016).

The effects of the test item on male and female reproductive performance such as gonadal function, mating behaviour, conception, development of conceptus, parturition and early lactation of the offspring were investigated, when administered daily by oral gavage to male (up to 36 days) and female (from 51 to 54 days) Sprague Dawley SD rats. The vehicle was water softened by reverse osmosis.

All doses (50, 150 and 450 mg/kg body weight/day) were administered at a constant volume of 10 ml/kg body weight. The treatment groups were composed by 10 males and 10 females.

The following investigations were performed on parental animals of all groups: mortality check, clinical signs, body weight, body weight gain, food consumption and mating performance, thyroid hormone determination only for parental males, litter data, macroscopic observations, organ weights and histopathological examination. Clinical signs, anogenital distance, external and internal examination of pups at necropsy were also recorded.

In addition, thyroid hormone levels were determined in 1 pup/sex/group randomly selected at Day 14 post partum. Histopathological evaluation of reproductive organs/tissues was performed on all control and high dose males and females, as well as on all abnormalities detected during post mortem observation. The identification of the stages of the spermatogenic cycle was performed in all males of the control and high dose groups.

The following results were obtained:

Mortality: one female from the high dose group was found dead on Day 12 of the pre-mating phase of the study. The cause of death was attributed to a misdosing represented by dark red soft contents in the thoracic cavity and red foamy contents in trachea and oesophagus.

Fate of females: the number of pregnant females, with live pups on Day 14 post partumwas: 10, 10, 10 and 9 in control, low (50 mg/kg/day), mid- (150 mg/kg/day) and high dose (450 mg/kg/day) groups, respectively.

Clinical signs: no relevant clinical signs were observed during the study. Slight to marked red staining and/or red faeces in the cage tray of animals from all treatedgroups were observed during the study.

Body weight and body weight gain: throughout the study, no difference in body weights was recorded in animals of both sexes compared to the control group.

Food consumption: no effects on food consumption were observed in both sexes.

Thyroid hormone determination: in adult males no differences in hormone levels were described between the control and the treated parentalmales.

Oestrous cycle, reproductive parameters, pairing combination and mating performance: oestrous cycle, pre-coital intervals, copulatory index and fertility index did not show intergroup differences.

Implantation, pre-birth loss data and gestation length of females: no significant differences were observed for implantation, pre-implantation loss, pre-birth/post implantation loss and gestation length between the treated groups and the controls. Allpregnant dams gave birth on Day 22 post coitum(mean value).

Litter data of females and sex ratio of pups: no significant differences in total litter size, live litter size, mean pup loss, sex ratio and meanpup weights were observed among the treated dams and the controls.

Terminal body weight and organ weights: no relevant changes were observed on terminal body weight, absolute and relative organ weights of treated animals, when compared to the controls.

Macroscopic observations: no remarkable differences were noted at post mortem examination in treated animals, when compared to the controls.

Microscopic observations: no treatment-related changes were observed in treated animals, when compared to the controls.

No effects on sexual function and fertility and lactation were observed at any of the dose levels investigated.

Effects on developmental toxicity

Description of key information

The NOAEL (No Observed Adverse Effect Level) for general toxicity and for fertility and reproduction parameters was considered to be 450 mg/kg body weight/day for males and females.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
450 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

In order to provide information on toxicity as well as any possible effects of the test item on male and female reproductive performance, a study was performed according to the OECD Guideline. 421 (2016).

The effects of the test item on male and female reproductive performance such as gonadal function, mating behaviour, conception, development of conceptus, parturition and early lactation of the offspring were investigated, when administered daily by oral gavage to male (up to 36 days) and female (from 51 to 54 days) Sprague Dawley SD rats. The vehicle was water softened by reverse osmosis.

All doses (50, 150 and 450 mg/kg body weight/day) were administered at a constant volume of 10 ml/kg body weight. The treatment groups were composed by 10 males and 10 females.

Clinical signs, anogenital distance, external and internal examination of pups at necropsy were recorded.

In addition, thyroid hormone levels were determined in 1 pup/sex/group randomly selected at Day 14 post partum.

The following results were obtained:

Thyroid hormone determination: in male and female pups performed on Day 14post partum Hormone levels in treated pups were similar to controls.

Clinical signs of pups: there were no compound-related effects. Pre-weaning clinical signs were comparablebetween treated and control groups.

Anogenital distance and nipple count: no differences in the anogenital distance (normalised value) were seen between the controland the treated groups both for male and female pups. No nipples were observed in any pup.

Necropsy findings in pups: necropsy findings in decedent pups and in pups sacrificed on Days 4 and 14 post partum did not reveal any treatment-related effect.

Pups thyroid weights: no relevant changes were observed in the pups thyroid weights.

No effects in developmental parameters were observed at any of the dose levels investigated.

Justification for classification or non-classification

According to CLP Regulation (EC 1272/2008), 3.7 Reproductive toxicity section, reproductive toxicity includes adverse effects on sexual function and fertility in adult males and females, as well as developmental toxicity in the offspring.

The available experimental data are adequate for classification and labelling and the substance does not meet the criteria to be classified for reproductive toxicity, according to CLP Regulation (EC 1272/2008).