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EC number: 427-650-1 | CAS number: -
This study is read across to a structural analogue (SA03), which is considered structurally equivalent to the substance to be registered. Justification is attached below under "attached background material".
In the combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in rats (Kubaszky, 2011), the test item administered daily by oral gavage to Wistar rats did not result in test item related mortality or systemic adverse effects.
There were no statistically significant differences between the Control and test item-treated groups with regard to reproductive ability or in the mating or gestation indices, or effects considered adverse or toxicologically significant in correlation with the test item administration. Test item administration was considered to have no impact on the duration of the mating period. Successful coitus (sperm positive vaginal smears and/or vaginal plugs) generally occurred within up to 6 days of pairing (cohabitation). No test item effect on the duration of pregnancy or abnormalities in the gestation outcome ascribed to the treatment were observed. No external abnormalities ascribed to treatment were detected at the clinical or external macroscopic examinations of the pups.
In this study, at the 1000 mg/kg bw/day dose level, the intrauterine mortality, post-natal mortality and subsequently the total mortality were higher than control. However, only the post-natal mortality attained statistical significance. These effects were considered to be possibly related to the test item administration although a role of the individual variability could not be excluded.
At 1000 mg/kg bw/day, the mean number of viable pups was -26.1% lower than control on PND0 and -30.4% lower on PND4, attaining statistical significance when evaluated for the total number of pups. These results correlated with the higher post-natal and total mortality observed in the High dose dams.
There were no effects considered adverse on the offspring weight or weight gain at up to and including 250 mg/kg bw/day. At 1000 mg/kg bw/day, when evaluated per litter basis, there were no statistically significant differences to control, however, the mean litter weights were lower than control on both PND0 and PND4. When evaluated for all pups, the mean body weights were statistically significant, slightly lower up to -7% than control: on PND0, 6.39 g vs. 6.88 g, and on PND4, 10.36 g vs. 11.03 g. As the differences were minor and the dose response was not clear, a test item related adverse effect on the offspring development following administration of 1000 mg/kg bw/day to the parental generation in the conditions of this study could not be ascertained, although it could not be excluded.
Under the conditions of this study, based on histopathological changes in the kidney and stomach, the no observed adverse effect level (NOAEL) for the test item for parental toxicity effects is considered to be 62.5 mg/kg bw/day. For reproductive toxicity, the no observed effect level (NOEL) for parental/adult effects is considered to be 1000 mg/kg bw/day for the males and 250 mg/kg bw/day for the females, due to the higher intrauterine, postnatal and total foetal mortality at 1000 mg/kg bw/day, correlated with a NOEL of 250 mg/kg bw/day for F1 offspring, based on a possible test item-related slight effect on pup-survival and birth weight at 1000 mg/kg bw/day.
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