Registration Dossier
Registration Dossier
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 944-548-7 | CAS number: -
Endpoint summary
Administrative data
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 insulin aspart in connection with subcutaneous injections. 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.
In a study examining fertility and embryofoetal development in rats dosed with 0, 5, 25, 100U/kg dosed twice daily by s.c. administration (corresponding to 0; 0.38; 1.90; 7.60 mg/kg/day) the males were dosed from 4 weeks before mating and females from 2 weeks before mating until 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 post -implantation losses was seen at the highest dose level and a slight dose-related increase of foetuses with small orbital sockets was noted . Slightly histopathological changes in testes were found in males at the two highest dose levels. The findings in the study was considered most likely to be induced by hypoglycaemia.
The findings from these studies are considered relevant for Insulin aspart ethyl ester as 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 questionalbe.
Effects on developmental toxicity
Description of key information
Data on fertility and development is only available on the active pharmaceutical ingredient insulin aspart in connection with subcutaneous injections. 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.
A two-generation reproductive toxicity study was conducted with insulin apart in rats using dose levels of 0, 5, 25, 100U/kg dosed twice daily by s.c. administration (corresponding to 0; 0.38; 1.90; 7.60 mg/kg/day). The administration of insulin apart did not result in any effects on fertility or development. Hypoglycaemia was observed at all dose levels in adult animals. Maternal toxicity was observed at the two highest dose levels that was considered to be linked to the induction of hypoglycaemia. Six of 28 females died at highest dose levels on day 20 to 23 of gestation. The lowest dose level of 0.38 mg/kg/d was concluded as NOAEL for maternal toxicity.
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 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 for Insulin aspart ethyl ester as 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
Based on weight of evidence Insulin aspart precusor is not to be classified for reproductive toxicity according to the CLP-criteria.
Additional information
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
