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EC number: 944-528-8 | CAS number: -
Oral (OECD 422), rat: NOAEL fertility ≥ 200 mg/kg bw/day
The test substance was tested in a combined repeated dose oral toxicity study with the reproduction/developmental toxicity screening study according to OECD Guideline 422 and in compliance with GLP (2013). Eleven Han Wistar rats per sex and dose were treated via gavage with the test substance at concentrations of 10, 40 and 200 mg/kg bw/day, respectively. The control group received the vehicle corn oil. Male animals were treated for at least 28 days, starting 2 weeks before the mating period and a maximum of 14 days during mating. Females were treated 2 weeks before mating and throughout gestation until the F1 generation reached Day 3 post partum. Since a low fertility was observed after the mating period further animals were added to the study. Six males and females each were added to control and 40 mg/kg bw/day dose group and 8 animals each to the 10 mg/kg bw/day dose group. It was noted at the end of the study that the automatic light cycle of 12 h on / 12 h off was not functional. Therefore, the all animals were subjected to 24 h light.
In parental animals, no test substance-related findings were observed on reproductive organs in males and females at any dose group. In particular, the qualitative examination of the stages of spermatogenesis in the testis did not reveal any test substance-related abnormalities in the integrity of the various cell types present within the different stages of the sperm cycle. Furthermore, no test substance-related microscopic findings, including following evaluation of the uterus or evaluation of follicles and corpora lutea in the ovaries, were noted in females. Increased infertility was observed at all dose levels. Of the original females, 3 were not pregnant in the control group, 7 at 10 mg/kg bw/day, 3 at 40 mg/kg bw/day and 2 at 200 mg/kg bw/day. This was considered to have been directly influenced by the disturbance of the light/dark cycle, resulting in 24 h light, which is known to have an impact on the estrous cycle. Since no dose-dependent reduction of fertility was observed, an effect of the test substance could be excluded. At 200 mg/kg bw/day, the mean pre-coital time was increased (5.6 days compared to 2.7 days in the control group). However, taking into account that the mating performance and the fertility figures (percentage mating, fertility index and conception rate) of the high dose group was comparable to the control group or even higher, the prolonged pre-coital time should not be considered to be an adverse effect. The pre-coital time increase might also be influenced by the disturbance of the light/dark cycle. No effects on further reproductive parameters (corpora lutea count, implantation sites, litter size, gestation index and duration) were observed, compared with the control animals. The post-implantation loss was generally high at all dose levels. However, at 200 mg/kg bw/day mean post-implantation loss was increased compared to the control group (mean 5.7 per litter compared to 2.5 in the control group). This was partly due to one female (16 losses), which died during the lactation period due to a bacterial infection. Therefore, this increase was not considered to be test substance-related.
Therefore, a NOAEL for parental fertility of ≥ 200 mg/kg bw/day was derived for male and female rats.
Short description of key information: Oral (OECD 422), rat: NOAEL fertility ≥ 200 mg/kg bw/day Justification for selection of Effect on fertility via oral route: The reliable GLP compliant OECD Guideline study was chosen.
Oral (OECD 422), rat: NOAEL developmental ≥ 200 mg/kg bw/day
There were no adverse effects on early postnatal pup development (including the number of dead and living pups, postnatal loss, viability index and sex ratio) with treatment up to 200 mg/kg bw/day. Furthermore, body weight and external macroscopic examination did not reveal treatment-related findings.
Thus the NOAEL for developmental toxicity/teratogenicity is considered to be ≥ 200 mg/kg bw/day.
The available data on toxicity to reproduction of the test substance do not meet the criteria for classification according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification. No adverse effects were noted up to the limit dose in an OECD 422 guideline study.
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