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Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

A reproduction/developmental toxicity screening study was performed under GLP and according to OECD guideline 421 (WIL Research Laboratories, LLC, 2011). The test substance, in sterile water for injection, was administered orally by gavage once daily to 3 groups of Crl:CD(SD) rats, each group consisting of 12 males and 12 females. Dosage levels were 5, 25, and 100 mg/kg bw/day administered at a dosage volume of 10 mL/kg. A concurrent control group of 12 rats/sex received the vehicle (sterile water for injection) on a comparable regimen. Males and females were approximately 11 weeks of age at the beginning of test substance administration. Males received at least 14 daily doses prior to mating and were dosed throughout the mating period through 1 day prior to euthanasia for a total of 28 doses. Females received 14 daily doses prior to pairing and were dosed through lactation day 3 for a total of 39-51 doses; females with no evidence of mating or that failed to deliver were dosed through the day prior to euthanasia (post-mating or post-cohabitation day 25) for a total of 40-52 doses. All animals were observed twice daily for mortality and moribundity. Clinical observations, body weights, and food consumption were recorded at appropriate intervals. All F0 females were allowed to deliver and rear their pups until lactation day 4. F1 clinical observations and body weights were recorded on PND 1 and 4. Necropsies were performed on F1 pups that were found dead. Surviving pups were euthanized on PND 4 and discarded without examination. F0 males were euthanized following completion of the mating period and F0 females were euthanized on lactation day 4. Complete necropsies were conducted on all F0 animals, and selected organs were weighed. Selected tissues were examined microscopically from all F0 animals in the control and high-dose groups.

Test substance-related total litter loss was noted for 2 females in the 100 mg/kg/day on lactation day 1. All males and all other females survived to the scheduled necropsies. No test substance-related clinical findings were observed at any dosage level. Mean body weights, body weight gains, and food consumption were unaffected by test substance administration during the entire treatment period for the 5, 25, and 100 mg/kg bw/day group males and during the pre-mating and gestation periods for the 5, 25, and 100 mg/kg bw/day group females. During lactation, lower mean body weights and body weight gains with corresponding reduced mean food consumption were noted in the 100 mg/kg bw/day group females, although the effects on mean body weight and body weight gain were not statistically significant when compared to controls. Mean lactation body weights, body weight gains, and food consumption in the 5 and 25 mg/kg bw/day group females were similar to the control group.

There were no test substance-related effects on male and female mating and fertility indices, male copulation index, or female conception index. The mean number of days between pairing and coitus and mean gestation lengths in the 5, 25, and 100 mg/kg bw/day groups were similar to those in the control group.

There were no test substance-related gross observations. However, there were higher absolute and relative liver weights in the 25 and 100 mg/kg bw/day group males that were considered related to test substance administration. Exacerbation of vacuolation/hypertrophy of basophilic cells in the anterior pituitary gland, graded as minimal to mild in severity, in the 5, 25, and 100 mg/kg bw/day group males was observed. This effect occurred in all test groups (including the control group), did not show a dose-related response and was only observed in males (females did not show this effect while being exposed longer). Furthermore, the absolute and relative weights of the pituitary glands were unchanged. Based on these findings, the effects on the pituitary glands do not need to be taken into account for establishing the NOAEL for parental toxicity for the OECD 421 study.

The mean numbers of corpora lutea and implantation sites were unaffected by test substance administration. However, a higher mean number of unaccounted-for sites was noted in the 100 mg/kg bw/day group compared to the control group.

A lower mean live litter size was observed in the 100 mg/kg bw/day group. The effect was not statistically significant but was below the mean historical control value for the strain of rat in the testing laboratory. Reduced mean postnatal survival (including total litter loss) from birth to PND 4 was also noted in the 25 and 100 mg/kg bw/day groups. Test substance-related clinical findings of a body that was cool to the touch and small stature were noted for the 100 mg/kg bw/day group pups. Lower mean body weights (up to 10.8% and 27.7%) were noted in the 25 and 100 mg/kg bw/day pups, respectively, during PND 1 and 4. No test substance-related effects on the number of pups born, the percentages of males at birth at any dosage level, and live litter size in the 5 and 25 mg/kg bw/day groups, and mean pup body weights or body weight gains and postnatal survival in the 5 mg/kg bw/day group were noted.

In conclusion, under the conditions of this screening study, 100 mg/kg bw/day was considered to be the NOAEL for effects on fertility due to the lack of effects on reproductive parameters in this study.

The NOAEL for neonatal toxicity was 5 mg/kg bw/day based on clinical findings of a body that was cool to the touch and small stature at 100 mg/kg bw/day and on reduced postnatal survival and lower mean male and female pup body weights in the 25 and 100 mg/kg bw/day groups.

The NOAEL for systemic toxicity was 5 mg/kg bw/day based on lower mean body weights, body weight gains and food consumption (significantly affected) during lactation days 1-4 in the 100 mg/kg bw/day group females and higher absolute and relative liver weights in the 25 and 100 mg/kg bw/day group males.


Short description of key information:
Under the conditions of the available reproduction/developmental toxicity screening study, 100 mg/kg bw/day was considered to be the NOAEL for effects on fertility due to the lack of effects on reproductive parameters in this study. The NOAEL for neonatal toxicity was 5 mg/kg bw/day based on clinical findings of a body that was cool to the touch and small stature at 100 mg/kg bw/day and on reduced postnatal survival and lower mean male and female pup body weights in the 25 and 100 mg/kg bw/day groups.
The NOAEL for systemic toxicity was 5 mg/kg bw/day based on lower mean body weights, body weight gains and food consumption (significantly affected) during lactation days 1-4 in the 100 mg/kg bw/day group females and higher absolute and relative liver weights in the 25 and 100 mg/kg bw/day group males.

Justification for classification or non-classification

Based on the postnatal developmental toxicity (lower live litter size and reduced postnatal survival) observed in an oral reproduction/developmental toxicity screening study, the substance has to be classified according to EU Directive 67/584/EEC as Xn, Repr. Cat. 3 - R63 (Possible risk of harm to the unborn child). In accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, the substance has to be classified for Reproduction toxicity, Cat. 2 - H361 (Suspected of damaging fertility or the unborn child).