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Key value for chemical safety assessment

Effects on fertility

Additional information

The test substance was administered in aqueous solution by gavage to 2 groups of rats, each consisting of 10 males and 20 females. Doses used were 2 and 4 mg/kg bw/day. The drug was well tolerated by the low dose group. Five females in high dose group, however, died during the study due to perforated ulceration of the intestines and/or peritonitis. Fertility of both males and females was not detectably affected by medication. Prolonged gestation and dystocia were observed in the high dose females while evidence of embryotoxicity (increased frequency of intra-uterine resorption in females sacrificed on day 13 of gestation and/or decreased numbers of offspring in full-term litters and reduced average weight of male and female neonates) was observed in dams treated with 2 and 4 mg/kg bw/day. However, the subsequent post-natal growth and survival of pups derived from drug-treated parents were comparable to that of controls.


Short description of key information:
No prohibitive effects on fertility of the parent animals was detected.

Effects on developmental toxicity

Description of key information
No teratogenic effects were observed in Segment II studies with rats, rabbits and mice and in Segment III studies in rats.
Additional information

The test substance was administered orally to pregnant rats through the whole period of gestation in doses of 2, 4, and 10 mg/kg bw/day. At the high-dose level a marked toxic effect in the dams was observed as mainly expressed by the intercurrent death of fifteen out of twenty animals. In all dams of the latter dose group ulcerations of stomach were observed. The reduced gain in body weight may be partially caused by a considerable loss of foetal mean weight. The foetuses displayed marked signs of toxicity, too, as indicated by an increase in the number of foetal deaths. In the intermediate dose group only a slight foetotoxic effect was noted (reduced mean weight). In the low-dose group neither dams nor the foetuses were affected. No teratogenic effects were observed.

No teratogenic effects were observed in Segment II studies with rabbits and mice.

In a Segment III study (pre- and postnatal) female rats were intubated with the test substance at dose levels of 2 or 4 mg/kg bw/day during the last trimester of pregnancy and throughout the lactation period. Seventeen of 20 dams in the low dose group and 8 of 20 dams in the high dose group survived to termination of the study. Ulceration of the intestines and/or peritonitis was observed at necropsy in 3 of 20 dams in the low dose group and in 16 of 20 dams in the high dose group. Not unexpectedly, dose-related reductions in average maternal feed intake and body weight gain were observed in medicated dams. The gestation period was prolonged slightly in both drug-treated groups. A marked increase in the frequency of stillbirths was also observed in the high dose group but was attributable to maternal toxicity. Postnatally, offspring mortality in litters of surviving dams were comparable to control values.

In conclusion, this study indicates that under the designated experimental conditions, daily oral doses of 2 mg/kg bw/day of the test substance, administered during the last trimester of pregnancy and lactation, is the maximum tolerated dose, and in some cases exceeds maximum tolerability for pregnant and lactating rats. However, even at a dose level of 4 mg/kg bw/day, which caused the death of 60% of the dams, offspring viability in litters of surviving dams was not reduced, indicating that no toxic factor was passed through the milk and that milk secretion was not impaired.

Toxicity to reproduction: other studies

Additional information

Peroral and parenteral studies were carried out with 10 - 21 different treatment schedules in rats, mice and rabbits, respectively. No prohibitive effects on fertility of the parent animals nor on the pre-, peri- and postnatal development of the offspring was detected.

However, it is well known, that the test substance shows the effect of prostaglandin inhibition on the fetal cardiovascula system (premature closure of the ductus arteriosus). This is a Class Effect and the same finding was seen with a great number of other NSAIDS (non steroidal anti-inflammatory drugs). The test substance should be avoided in late pregnancy (Third Trimester).

Justification for classification or non-classification

Taking the animal test results and the Class Effect of the premature closure of the ductus arteriosus into consideration, the test substance has been classified in Hazard Class "Reproductive Toxicity", CAT 2 and H361d (Suspected of damaging the unborn child).

Additional information