Insulin Human Methyl Ester

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Data on fertility and development is only available on the active pharmaceutical ingredient Human insulin in connection with subcutaneous injections (S.C.). The effects seen in relation to maternal toxicity, fertility and development are overall considered as a consequence of the hypoglycaemic mode of action of the substance and as secondary effects of the maternal toxicity.

Effects on developmental toxicity

Description of key information

In a study examining fertility and embryofoetal development in rats dosed with 0, 100U/kg human insulin dosed twice daily by s.c. administration (corresponding to 0; 7.60 mg/kg/day) the males were dosed from 4 weeks before mating and females from 2 weeks before mating untill day 15 of pregnancy. Reduced blood glucose levels were observed in relation to the dosing and one male rat died presumably due to severe hypoglycaemia. No effects on mating performance or pregnancy rate was observed, but slightly increased pre-and postimplantation losses was seen and a slight increase of foetuses with small orbital sockets was noted . Slightly reduced sperm count and slight histopathological changes in testes were found in males. The findings in the study was considered most likely to be induced by hypoglycaemia.

A study examining peri- and postnatal toxicity toxicity study was conducted with human insulin in female rats using dose levels of 0, 100U/kg dosed twice daily by s.c. administration (corresponding to 0; 7.60 mg/kg/day) from D6 of gestation to D20 after parturation. The administration of human insulin did not result in any effects on fertility or development. Hypoglycaemia was observed in the adult animals including a few lethal outcomes.

A developmental toxicity study in rabbits dosed with 0; 0.5; 1.5; 5 U/kg/ twice daily from day 6 to day 18 of pregnancy by s.c. injection (corresponding to 0; 0.04; 0.11; 0.38 mg/kg/d) resulted in an increase in early embryonic death and reduction of litter size at highest dose level and at all dose levels in a higher proportion of skeletal abnormalities. Blood glucose levels were affected in a dose-related manner and effects in relation to fertility and development were suggested to be secondary effects of lowered maternal blood glucose levels.

The findings from these studies are considered relevant forhuman insulin methylesteras well as this substance also bind 100% to the insulin receptor and thus has the potential to induce a hypoglycaemic response. The data does not indicate any need for CLP-classification for fertility or development as the effects seen is primarily considered secondary to maternal toxicity. Also, the dosing has been performed with s.c. administration which make interpretation for more relevant exposure routes in terms of classification very difficult.

Justification for classification or non-classification

In a study examining fertility and embryofoetal development in rats dosed with 0, 100U/kg human insulin dosed twice daily by s.c. administration (corresponding to 0; 7.60 mg/kg/day) the males were dosed from 4 weeks before mating and females from 2 weeks before mating untill day 15 of pregnancy. Reduced blood glucose levels were observed in relation to the dosing and one male rat died presumably due to severe hypoglycaemia. No effects on mating performance or pregnancy rate was observed, but slightly increased pre-and postimplantation losses was seen and a slight increase of foetuses with small orbital sockets was noted . Slightly reduced sperm count and slight histopathological changes in testes were found in males. The findings in the study was considered most likely to be induced by hypoglycaemia.

A study examining peri- and postnatal toxicity toxicity study was conducted with human insulin in female rats using dose levels of 0, 100U/kg dosed twice daily by s.c. administration (corresponding to 0; 7.60 mg/kg/day) from D6 of gestation to D20 after parturation. The administration of human insulin did not result in any effects on fertility or development. Hypoglycaemia was observed in the adult animals including a few lethal outcomes.

A developmental toxicity study in rabbits dosed with 0; 0.5; 1.5; 5 U/kg/ twice daily from day 6 to day 18 of pregnancy by s.c. injection (corresponding to 0; 0.04; 0.11; 0.38 mg/kg/d) resulted in an increase in early embryonic death and reduction of litter size at highest dose level and at all dose levels in a higher proportion of skeletal abnormalities. Blood glucose levels were affected in a dose-related manner and effects in relation to fertility and development were suggested to be secondary effects of lowered maternal blood glucose levels.

The findings from these studies for human insulin are considered relevant for human insulin methylester as well as this substance also bind 100% to the insulin receptor and thus has the potential to induce a hypoglycaemic response. Howver, the data does not indicate any need for CLP-classification for fertility or development as the effects seen is primarily considered secondary to maternal toxicity. Also, the dosing has been performed with s.c. administration which make interpretation for more relevant exposure routes in terms of classification very difficult.