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Administrative data

Description of key information

In a GLP-compliant OECD 422 study male parental animals showed no signs of toxicity up to the highest dose level administered. In parental females, the gestation index (reduced to 66.7%) as well as the live birth index (58.1% due to the reduced number of females with live pups on the day of birth) were clearly affected at 1000 mg/kg body weight. The number of dams with stillborn pups was significantly increased at 1000 mg/kg and in 2 litters all pups were stillborn. The mean value of perinatal loss was significantly increased (47.2%) as well. The reason for the increased perinatal deaths as well as for dystocia were unknown but one effect might also cause the other. Therefore, at a critical internal dose level, the test substance (or a metabolite) affects either fetal life or the process of birthing or both. Thus, the no observed adverse effect level (NOAEL) for general systemic toxicity was 1000 mg/kg bw/d for male and 300 mg/kg bw/d for female Wistar rats.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
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 test article was given daily as a suspension to groups of 10 male and 10 female Wistar rats (F0 animals) by gavage at dose levels of 0 mg/kg body weight/day (mg/kg bw/d; test group 0), 100 mg/kg bw/d (test group 1), 300 mg/kg bw/d (test group 2) and 1000 mg/kg bw/d (test group 3). Corn oil served as vehicle, control animals were dosed daily with the vehicle only. The duration of treatment covered a 2-week premating period and mating in both sexes (mating pairs were from the same test group) as well as entire gestation and lactation period in females up to one day prior to the day of schedule sacrifice of the animals. During clinical examinations signs of general systemic toxicity were not observed in male animals of test groups 1-3 (100, 300 and 1000 mg/kg bw/d) during the entire study period. The same was true for female animals of test groups 1 and 2. However, two female animals of test group 3 (1000 mg/kg bw/d) showed piloerection and pale skin during end of gestation and early lactation, each one additional individual showed either one finding, only. The observed effects were most likely a consequence of dystocia, the labored birthing process.

Fertility indices for male and female animals were not impaired by test-substance administration even at a dose level of 1000 mg/kg bw/d. However, the gestation index (reduced to 66.7%) as well as the live birth index (58.1% due to the reduced number of females with live pups on the day of birth) were clearly affected in test group 3. In test group 3, the mean duration of gestation was 23.3 days and significantly increased when compared to the controls. The postimplantation loss in test group 3 was clearly outside the historical range. The number of dams with stillborn pups was significantly increased in test group 3 and in 2 litters all pups were stillborn. The mean number of stillborn pups/litter was also significantly increased. Mean value of perinatal loss was significantly increased (47.2%) in test group 3. All findings with regard to reproductive performance and developmental toxicology were assessed to be related to treatment since they occurred in a dose-dependent manner. The reason for the increased perinatal deaths as well as for dystocia were unknown but one effect might also cause the other. Concerning clinical pathology, no treatment-related, adverse effects were observed up to a dose of the compound of 1000 mg/kg bw/d. Regarding pathology, there were no treatment-related organ weighs changes. Macroscopically, a dose-dependent yellow discoloration of the adipose tissue was noted in males of test groups 2 and 3 (300 and 1000 mg/kg bw/d) and in females of all test groups. This finding was consistent with the color of the test-substance but had no histopathological correlate. Therefore, it was judged as treatment-related but not adverse per se since only bioavailability was demonstrated. All other histopathological findings occurred either individually or were biologically equally distributed over control and treatment groups. They were considered incidental or spontaneous in origin and without any relation to treatment. Taken together, the discoloration of adipose tissue obviously corresponds with duration of treatment and dose level since low-dose male animals did not show the discoloration (treated for 4 weeks), but females did (treated for about 8 weeks). These observations support the hypothesis of systemic bioavailability and lead to the conclusion that the test substance accumulates by time and dose. At a critical internal dose level, the test substance (or a metabolite) affects either fetal life or the process of birthing or both.

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 signs of toxicity in female animals at a dose level of 1000 mg/kg bw/d. No effects were observed in male animals at any dose level. Thus, the no observed adverse effect level (NOAEL) for general systemic toxicity was 1000 mg/kg bw/d for male and 300 mg/kg bw/d for female Wistar rats.

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for the purpose of classification under Regulation (EC) No.1272/2008. Based on the data, classification for repeated dose toxicity is not warranted under Regulation (EC) No.1272/2008.