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Detection of mating was not confirmed for one female dosed at 300 mg/ kg bw/ day which had implantation sites. The mating date of this animal could not be determined. For one female dosed at 100 and one female dosed at 300 mg/ kg bw/ day, which delivered live offspring, detection of mating was not confirmed but pregnancy was confirmed by palpation. The mating date of these animals was estimated at 21 days prior to the actual delivery date. This day was designated day 0 postcoitum. There were 3/10 couples treated at 300 mg/kg and 3/10 couples treated at 1000 mg/kg without offspring. This was within historical control limits of the laboratory and thus not found to be adverse. No abnormalities were seen in the reproductive organs, which could account for their lack of offspring. Spermatogenic staging profiles were normal for all males examined.
The mating index, fertility and conception indices, precoital time, and number of corpora lutea and implantation sites were unaffected by treatment. The numbers of litters were 10, 10, 7 and 7 at 0, 100, 300 and 1000 mg/kg, respectively. Lower numbers of corpora lutea and implantations were noted at 300 mg/kg. The differences from the control group were not statistically significant and there was no dose-related response. Therefore, these findings were not attributed to treatment.
No signs of difficult or prolonged parturition were noted among the pregnant females, except for one female at 1000 mg/kg bw/ day which had a parturition period between one and two days. This single occurrence of prolonged parturition was considered not to be related to treatment because it was seen for only one female which had a litter of normal size and healthy pups. Examination of cage debris of pregnant females revealed no signs of abortion or premature birth. No deficiencies in maternal care were observed.
EARLY POSTNATAL PUP DEVELOPMENT
The numbers of dead and living pups at first litter check, postnatal loss, viability index and sex ratio were unaffected by treatment, and clinical signs, body weight and external macroscopy did not reveal treatment-related findings. At 300 mg/kg the mean number of living pups at first litter check was statistically significantly lower than in the control group. This difference was not attributed to treatment because there was no dose-related response and values were within normal limits.
At the first litter check, two pups of the control group, two pups at 300 mg/kg bw/ day and four pups (all of one litter) at 1000 mg/kg bw/ day were found dead. During lactation, one pup of the control group and one pup at 300 mg/kg bw/ day went missing, and one pup of the control group died spontaneously. Pups missing were most likely cannibalised. No toxicological relevance was attributed to these dead/missing pups since the mortality incidence did not show a dose-related trend and remained within the historical range.
CLINICAL SIGNS PUPS
Pups that went missing or died during lactation showed no clinical signs. Clinical signs in surviving pups were limited to scabs on the head in one pup of a litter of the control group. This was reported to be a normal background finding in pups of this age.
BODY WEIGHT PUPS
Body weights of pups were not adversely affected by treatment. At 1000 mg/kg bw/ day mean body weights of male and female pups were higher compared to controls at days 1 and 4 of lactation. The pups in one litter at 1000 mg/kg bw/ day were heavier than those in control litters because the pups of this litter were born on day 23 post-coitum. The pup weights in the other litters at 1000 mg/kg bw/ day were within normal limits, therefore the higher mean pup weights at 1000 mg/kg bw/ day were considered not to be related to treatment.
Surviving pups showed no macroscopic abnormalities. Incidental macroscopic findings of pups that were found dead consisted of beginning autolysis. The nature and incidence of these finding remained within the range considered normal for pups of this age, and were therefore considered to be of no toxicological relevance.
An oral OECD 422 study was performed with rats according to OECD/ EC guidelines and GLP principles. L 130 was administered by daily oral gavage to male and female Wistar Han rats at dose levels of 100, 300 and 1000 mg/kg bw/day (10 rats/sex/dose level). Males were exposed for 2 weeks prior to mating, during mating, and up to termination (for 32 days). The females were exposed for 2 weeks prior to mating, during mating, during post-coitum, and at least 4 days of lactation (for 42-56 days). Accuracy and homogeneity of formulations were confirmed by analyses. No parental toxicity was observed up to the highest dose level tested (1000 mg/kg bw/ day) as evidenced by the absence of clinical signs of toxicity or adverse changes in functional observational results, body weight (gain), food consumption, haematology and clinical biochemistry parameters, organ weights, macroscopic findings, and microscopic findings.
No treatment-related changes were noted in any of the developmental parameters investigated in this study (i.e. gestation index and duration, parturition, maternal care and early postnatal pup development consisting of mortality, clinical signs, body weight and macroscopy). In the 300 and 1000 mg/kg dose groups, there were 7 females with living pups. At 300 mg/kg, out of ten females one was not pregnant and two had implantation sites only. At 1000 mg/kg, out of ten females two were not pregnant and one had implantation sites only. This finding was considered a chance finding and not treatment related, as the offspring at 300 and 1000 mg/kg was healthy and litter size was normal. Furthermore, the numbers of litters at 300 and 1000 mg/kg showed no dose-related response. Therefore, it was concluded that the test substance did not affect the number of females with living pups and that enough offspring was produced to assure a meaningful evaluation of possible developmental (from implantation onwards) toxicity of the test substance. It was therefore concluded that no developmental toxicity was observed up to the highest dose level tested. In conclusion, the maternal and developmental NOAELs of L 130 were determined to be at least 1000 mg/kg bw/day , based on absence of adverse effects seen at the highest dose level.
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