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Effects on fertility

Description of key information
No teratogenic effects and no effect on fertility could be observed in segment I (fertility and reproduction), segment II (Teratology) studies and segment III (perinatal and postnatal) studies in different species.
Cases have been reported that use of pharmaceutic active substances acting directly on the renin-angiotensin system like (test substance) during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury and can cause fetal and neonatal morbidity and even death to the developing fetus when administered to pregnant women.

Toxicity to reproduction: other studies

Additional information

Segment I (fertility and reproduction) and segment III (perinatal and postnatal) studies in rats and segment II (Teratology) studies in rats, mice and rabbits have been performed (Bradley, 1995, Expert Report on the Toxicological and Pharmacological Documentation).

In the segment I study, rats were treated with test substance doses of 10, 50 and 200 mg/kg bw/d via gavage for 90 days (males) or from day 14 to 20 (females). No effects on fertility and reproductive performance were observed in F0 and F1 generation. No effects on F1 development, especially on kidney development were noticed.

Segment II studies were performed in rats, rabbits and mice. Mice and rats were treated on days 6 through 15 with 60, 200 and 600 mg/kg bw/d of the test substance by gavage. No embryotoxic, fetotoxic and teratogenic effects were observed in both species. In rats, the maternal body weight gain was decreased at 200 and 600 mg/kg bw/d and fetal weights were reduced at 600 mg/kg bw/d.

In a range-finding study, rabbits were treated on days 6 through 18 with doses of 2.5, 15, 30, 45, 50 and 150 mg/kg bw/d. At 15 mg/kg bw/d and above, litter losses and deaths occurred. In the main study, rabbits were treated with test substance doses of 2, 5 and 10 mg/kg bw/d via gavage on days 6 through 18 or days 7 through 19. No teratogenicity occurred. An increased incidence of low fetal weights was observed. Fetotoxicity in rabbits at 5 mg/kg and above was characterized by litter loss and abortion and was closely associated with maternal toxicity.

In the segment III study, rats were treated with 60, 200 and 600 mg/kg bw/d by gavage on days 15 through 20. At 600 mg/kg bw/d, reduced maternal body weight gain and slightly reduced post natal F1 survival and development were observed. At 600 mg/kg bw/d, slightly reduced pup survival and development together with reduced maternal body weight gain was observed. No effects were observed on kidney development.

Cases have been reported that use of pharmaceutic active substances acting directly on the renin-angiotensin system like the test substance during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury and can cause fetal and neonatal morbidity and even death to the developing fetus when administered to pregnant women.

For precautionary reasons with regard to Responsible Care the substance has to be considered as toxic to Reproduction based on the criteria of the CLP Regulation (EC) No 1272(2008).

Justification for classification or non-classification

Because of the known "Class effect" of substances based on renin-angiotensin system and the adverse effect on the developing fetus the substance is classified as a Reproductive Substance Category 2

Additional information