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Key value for chemical safety assessment

Effects on fertility

Description of key information

No toxic effects of the test substance were seen after repeated dose and on reproduction/development in Sprague Dawley rats. Hence, the NOAEL (No Observed Adverse Effect Level) for both general toxicity and reproduction/developmental toxicity was considered to be above 1000 mg/kg body weight/day for males and females of the parental and Fl generation.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
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

A combined repeat-dose/reproductive screening study was performed to obtain information on the possible toxic effects on Sprague Dawley rats of both sexes, after repeated dosing with the structural analogue, as well as any effects of the test item on male and female reproductive performance, such as gonadal function, conception, parturition and early lactation. Recovery from any treatment-related effects was also investigated during a period of 2 weeks.

The test item, formulated in sesame oil, was administered orally, by gavage, at the dosages of 62.5, 250 and 1000 mg/kg body weight/day.

Reproductive/Developmental toxicity

Thein vivoparameters did not show signs of toxicological importance. Green staining of the tail was mainly recorded in high dose animals receiving 1000 mg/kg body weight/day and occasionally in the mid-dose group (250 mg/kg body weight/day), and was related to the colour of the test item (dark green textile dye). In addition, green staining in the cage tray was recorded likely due to the compound excreted with urine and/or faeces.

Furthermore, neurotoxicity assessment including functional tests such as hindlimb landing foot splay, sensory reactivity tostimuliincluding grip strength and motor activity did not show differences of toxicological relevance between control and treated groups in the animals of both sexes.

There were no relevant effects on body weight or food consumption. The significant differences of body weight gain recorded before pairing in females of the high dose group on Day 8 (decrease) and on Day 15 (increase) of study, respectively, were considered to represent biological variability and hence not to be of toxicological importance.

No findings of toxicological relevance were recorded at haematological and biochemistry investigations.

Concerning the reproductive parameters, no relevant differences were found in terms of mating performance including the pre-coital interval (number of days paired to sperm positive day) and the copulatory evidence (the positive identification of mating i.e. the presence of sperm and/or copulation plugin situor in the cage). The resulting copulatory index, calculated as the percentage of animals mated respect to those paired, was comparable between groups.

No significant differences were found in terms of number of implantation sites and/or corpora lutea between the groups. All dams had comparable length of gestation and gave birth on Day 22 post coitum as mean value Furthermore, sex ratio calculated as the percentage of males in the litter did not differ between the groups.

No effects were seen onbodyweight of pups at birth and on Day 4 post partum and no abnormalities were detected in pups sacrificed at term. Similar findings were found in decedent pups of all groups.

The macroscopic observation of organs did not show relevant findings. The changes observed such as green staining of tail or green content of stomach were attributed to the colour of the test item, while enlarged liver in rats of both sexes or reduced thymus in control and treated females are suggested to be incidental and/or due to physiological pregnancy changes, often seen in this kind of study in some treated Sprague Dawley rats of the same age. No remarkable alterations in the organ weights were found that could be considered treatment-related.

No treatment-related changes were noted at histopathological examination including the evaluation of the spermatogenic cycle.

Repeated dose - Recovery groups

Thein vivoparameters did not reveal signs of toxicity. No signs of toxicological importance were recorded at daily clinical observation including the neurotoxicity assessment. Green staining of the tail was also recorded in the animals dosed at 1000 mg/kg body weight/day during treatment and recovery phases as well as green staining in the cage tray was recorded during the treatment phase. Body weight and food consumption did not significantly differ between groups during treatment and recovery phases.

At clinical pathology investigation, changes recorded during the dosing phase showed reversibility. Other significant differences of slight leucopenia in males or increased mean corpuscular haemoglobin concentration in females were considered incidental findings of no toxicological importance.

No treatment-related changes were recorded at macroscopic examination, including organ weights.

Histopathological evaluation was not conducted as no adverse findings were noted in main group animals.

In conclusion, no toxic effects were seen after repeated dose and on reproduction/development in Sprague Dawley rats.

On the basis of the results obtained in this study, the NOAEL (No Observed Adverse Effect Level) for both general toxicity and reproduction/developmental toxicity was considered to be above 1000 mg/kg body weight/day for males and females of the parental and Fl generation.

Justification for classification or non-classification