Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
250 mg/kg bw/day
Additional information

In the combined repeated dose toxicity study with the reproduction/developmental toxicity screening test, TIS-M was administered daily 7 days per week by oral gavage to Wistar (CRL:(WI)BR) rats at 3 dose levels, 50, 250 and 1000 mg/kg bw/day (12 males and 12 females per dose group). A control group (12 males and 12 females) received the vehicle only (dried sunflower oil). Males were dosed for 28 days and females were dosed for 14 days pre-mating, for up to 14 days mating period, through gestation and up to and including the day before necropsy (at least 4 days post-partum dosing). Females showing no-evidence of copulation were sacrificed 24 to 26 days after the last day of the mating period.


No test item-related pathological findings were noted in the reproductive organs in the parental animals, or in the F1 Generation. There were no differences considered test-item related between the control and TIS-M treated groups with regard to reproductive ability or in the mating, fertility and gestation indices. All the parturitions were normal, with the exception of one female (dosed at 50 mg/kg bw/day), which was pre-terminally euthanized in poor clinical condition and showed total foetal mortality at necropsy on Day 38. Enlargement of the spleen and placental haemorrhage were found at necropsy. Due to the isolated incidence, the observations noted in this female were considered incidental and unrelated to treatment.


At 1000 mg/kg bw/day, the number of live born, total number of viable pups, as well as the number of viable pups (calculated as litter means) were lower than control; this was a statistically significant effect potentially related to TIS-M administration. The mean litter weights, pups body weight and/or body weight gain for all pups or per litter showed statistically significant lower values compared to controls in the F1 generation following administration of TIS-M to the parental generation at the 250 and 1000 mg/kg bw/day doses. In addition, a statistically significant lower mean number of implantation sites was noted at 1000 mg/kg bw/day compared to control, which was considered possibly related to TIS-M administration. Therefore, for reproductive toxicity, the NOAEL was considered to be 1000 mg/kg bw/day for the males and 250 mg/kg bw/day for the females, based on the statistically significant lower mean number of implantation sites and litter mean number of live born. For offspring survival and growth rate, the NOAEL for TIS-M was considered to be 50 mg/kg bw/day.

The following information is taken into account for any hazard / risk assessment:

Value used for CSA:

NOAEL (male parents): 1000 mg/kg bw/day

NOAEL (female parents): 250 mg/kg bw/day

NOAEL (offspring): 50 mg/kg bw/day

Short description of key information:
Summary of reproduction/developmental toxicity

Effects on developmental toxicity

Description of key information
Summary of reproduction/developmental toxicity
Effect on developmental toxicity: via oral route
Dose descriptor:
50 mg/kg bw/day
Additional information

A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test was conducted as detailed above. See Discussion under Effects on Fertility.

Justification for classification or non-classification

The above study has been ranked reliability 1 according to the Klimisch et al system. This ranking was deemed appropriate because the study was conducted to GLP and in compliance with agreed protocols. Sufficient dose ranges and numbers are detailed; hence it is appropriate for use based on reliability and animal welfare grounds.

The above results triggered no classification under the Dangerous Substance Directive (67/548/EEC) and the CLP Regulation (EC No 1272/2008). No classification for reproductive/developmental effects is therefore required.

Additional information