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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Under the conditions of a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, the oral administration by gavage of the test item to Wistar rats revealed adverse findings in parental animals and progeny at 600 and 2000/1000 mg/kg bw/d. Thus, the no observed adverse effect level (NOAEL) for general systemic toxicity was 200 mg/kg bw/d in both sexes of parental animals. The no observed adverse effect level (NOAEL) for fertility was at 2000 mg/kg bw/d in male and at least at 1000 mg/kg bw/d in female Wistar rats. The no observed adverse effect level (NOAEL) for reproductive performance was 200 mg/kg bw/d in male and female Wistar rats. The NOAEL for developmental toxicity in the F1 progeny was 200 mg/kg bw/d.

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP and guideline study.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Discussion

In this Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in Wistar Rats the test item was administered orally by gavage to groups of 10 male and 10 female Wistar rats (F0 animals) at dose levels of 0 (test group 0, vehicle control), 200 (test group 1), 600 (test group 2) and 2000/1000 mg/kg bw/d (test group 3). Based on severe clinical findings, the dose of test group 3 was reduced from 2000 mg/kg bw/d to 1000 mg/kg bw/d in females on study day 37 (around delivery). The duration of treatment covered a 2 weeks pre-mating period, 2 weeks mating period in both sexes, approximately 7 days post-mating in males, the entire gestation period as well as up to 13 days of the lactation period in females, and up to one day prior to the day of schedule sacrifice of the animals.

Analyses confirmed the overall accuracy of the prepared concentrations and the homogeneity of the test substance in the vehicle. The stability of these preparations was demonstrated over a period of 7 days under ambient conditions. Regarding clinical examinations, during pre-mating and mating in males and females of all test groups no treatment-related findings were observed. During gestation, in test group 3 (2000/1000 mg/kg bw/d), four females showed adverse signs including semiclosed eyelid, tremors, reduced nutritional and general poor conditions, as well as hypothermia. Finally, 3 of them were found dead on gestational day 21 and 24. During gestation, in test group 2 (600 mg/kg bw/d) 2 females showed adverse signs including general poor conditions and hypothermia. Finally, 1 of them was sacrificed moribund on gestational day 22. During gestation, food consumption, and body weight (change) of the female animals in all test groups showed no adverse changes. During lactation, in test group 3 (2000/1000 mg/kg bw/d), two females showed adverse signs including reduced nutritional and general poor conditions, tremors, as well as pale skin. Finally, 1 of them were found dead on lactation day 1. The animals in this test group had a decreased food consumption (-25%) and decreased body weight gain (-62%). During gestation, in test group 2 (600 mg/kg bw/d) only 1 females showed one adverse sign, general poor conditions, on lactation day 0 only. During lactation, food consumption, and body weight (change) of the female animals in test groups 1 (200 mg/kg bw/d) and 2 (600 mg/kg bw/d) showed no treatment-related, adverse changes. In the subsequent investigations including the detailed clinical observation (DCO), the functional observational battery (FOB) and measurement of motor activity (MA) no treatment related, adverse differences to control were observed at any dose level. Concerning clinical pathology no treatment-related, adverse effects were observed up to a dose of the compound of 2000 mg/kg bw/d (in females reduced dose to 1000 mg/kg bw/d, beginning at study day 37).

In the heart of females of test group 2 and 3 (600 and 1000/2000 mg/kg bw/d) multifocal myocardial necrosis (up to severe) were seen, which are assumed to caused death in four females in test group 3 (1000/2000 mg/kg bw/d) and the moribund state in one test group 2 (600 mg/kg bw/d) female. This finding was regarded to be treatment-related and adverse.

The fertility, was not impaired in male or female parental animals of all test groups (200, 600, and 2000/1000 mg/kg bw/d). Regarding reproductive performance, in test group 3 (2000/1000 mg/kg bw/d) the gestational (50%) and live birth (58.3%) indices were decreased. This was correlated with increased numbers of stillborn pups (41.7%), litters with pups all stillborn (28.6%). Furthermore, one female of this test group showed insufficient maternal care and did not nurse the pups properly. Comparable findings at a lower incidence were observed in test group 2 (600 mg/kg bw/d): decreased gestation (80%) and live birth (86.5%) indices, increased number of stillborn pups (13.5%), litters with stillborn pups (44.4%) and litters with all pups stillborn (11.1%). Furthermore, in this test group one female showed insufficient maternal care and another one did not nurse the pups properly. The observations in both test groups were assessed as treatment-related and adverse. Regarding developmental toxicity, an increased incidence of mortality of fetuses/pups were observed towards the end of gestation and at delivery in test group 2 (600 mg/kg bw/d) and 3 (2000/1000 mg/kg bw/d). However, all vital pups did not show any treatment-related finding in both test groups. No developmental toxicity was observed in test group 1 (200 mg/kg bw/d).

The most logical relation of maternal and pup findings was seen in the following: The maternal toxicity of test group 2 (600 mg/kg bw/d) and test group 3 (2000/1000 mg/kg bw/d) manifested i.a. in multifocal myocardial necrosis (up to severe) are of highest concern and considered to have caused death and moribund state in dams. The time point of its observation was gestational day 21-24, the time of delivery in rats. It was assumed that the treatment-related impaired heart of dams was unable to cope with the increased burden to the blood circulation system during labor. In consequence, the dams died or became moribund because they were unable to deliver or those dams managed to deliver under adverse conditions had increased number of stillborn pups. Since neither the number of postimplantation loss nor the anomalies of surviving pups were increased as well as viability index and survival index were not affected, it was assessed that the increased perinatal loss, with increased number of still born pups and subsequently lower gestation index, was most likely caused by maternal toxicity rather than due to direct effects of the test substance to the developing fetus/pup.

 

Conclusion

Under the conditions of this Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, the oral administration by gavage of the test item to Wistar rats revealed adverse findings in parental animals and progeny at 600 and 2000/1000 mg/kg bw/d. Thus, the no observed adverse effect level (NOAEL) for general systemic toxicity was 200 mg/kg bw/d in both sexes of parental animals. The no observed adverse effect level (NOAEL) for fertility was at 2000 mg/kg bw/d in male and at least at 1000 mg/kg bw/d in female Wistar rats. The no observed adverse effect level

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

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As a result the substance is not considered to be classified for reproductive or developmental toxicity under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776.