Methylprednisolone

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Additional information

A fertility study was carried out in rats and dose were given daily subcutaneous doses of 0, 0.004, 0.02 or 0.1 mg/kg bw/day of methylprednisolone aceponate. Treatment of the males commenced 60 days prior to mating. Treatment of females commenced 14 days prior to mating and continued up to day 7 of gestation. The dams were killed on day 21 of gestation and the foetuses examined. There was no effect on fertility. Parental body weight gain and food consumption were reduced at 0.02 mg/kg bw and above and there were significant increases in the number of dead foetuses at these dose levels. The NOEL was 0.004 mg/kg bw/day.

Effects on developmental toxicity

Additional information

In a peri/post-natal study, female rats were given daily subcutaneous doses of 0, 0.04, 0.2 or 1 mg/kg bw/day of methylprednisolone aceponate from day 17 of gestation up to day 21 post partum. The dams were allowed to litter naturally and the offspring were monitored for growth and functional development. At 1 mg/kg bw, maternal body weight gain and pup weights were reduced but there were no effects on behaviour or development of the pups. The NOEL was 0.2 mg/kg bw/day.

Female rats were given daily subcutaneous doses of 0, 0.1, 0.3 or 1 mg/kg bw/day of methylprednisolone aceponate from days 7 to 17 of gestation. Two thirds of the dams were killed on day 21 of gestation and the uterine contents examined. The remaining dams were allowed to deliver naturally and rear the offspring. The top dose of 1 mg/kg bw cased reduced maternal body weight gain and food consumption, reduced foetal weight and an increase in delayed ossification. Foetal weights were also reduced at 0.3 mg/kg bw. At 1 mg/kg bw, there was a small but significantly increased incidence of foetuses with ventricular septal defect. In the group allowed to litter naturally, pup body weight was reduced and opening of the eyelids was delayed in the group administered 1 mg/kg bw/day. The NOELs were 0.1 mg/kg bw/day for foetotoxicity and 0.3 mg/kg bw/day for maternal toxicity and teratogenicity.

A very brief report of a teratogenicity study in rabbits was available. Pregnant female rabbits were given intramuscular injections of 0, 0.004, 0.02, 0.1, 0.15 or 0.25 mg/kg bw/day of methylprednisolone acetate from days 7 to 18 of gestation. Resorption rates were significantly increased and foetal viability was significantly reduced in the 0.15 and 0.25 mg/kg bw groups. The incidence of malformations was significantly increased at 0.1 mg/kg bw and above. The malformations included hydrocephaly, limb defects and spina bifida.

Groups of mated female mice were given a single intramuscular injection of 330 mg/kg bw methylprednisolone sodium succinate or the same dose the acetate, or the solvent vehicle on day 10 of gestation. Treatment with the acetate produced a decrease in the number of viable foetuses and significant increases in the numbers of foetuses born with their eyes open and foetuses with cleft palate. No cases of cleft palate were observed following treatment with the sodium succinate; instead, there was a significant increase in the incidence of foetal exencephaly.

Glucocorticoids may cause fetal damage when administered to pregnant women. One retrospective study of 260 women who received pharmacologic dosages of glucocorticoids during pregnancy revealed 2 instances of cleft palate, 8 stillbirths, 1 spontaneous abortion, and 15 premature births. Another study reported 2 cases of cleft palate in 86 births. Occurrence of cleft palate in these studies is higher than in the general population but could have resulted from the underlying diseases as well as from the steroids. Other fetal abnormalities that have been reported following glucocorticoid administration in pregnant women include hydrocephalus and gastroschisis. Women should be instructed to inform their physicians if they become or wish to become pregnant while receiving glucocorticoids. If glucocorticoids must be used during pregnancy or if the patient becomes pregnant while taking one of these drugs, the potential risks should be carefully considered.

Justification for classification or non-classification

Animal studies and human studies showed clear evidence of an adverse effect on reproduction and on development.

Therefore in accordance with Regulation (EC) No. 1272/2008 Table 3.7.1 (a), this substance should be classified as Category 1A for reproductive toxicity endpoint.