Insulin Aspart Ethyl Ester

Endpoint summary

Description of key information

The oral administration of MI3 at dose levels of 0, 100, 300, 1000 mg/kg/d to Wistar rats produced no evidence of toxicity and no sign of effects could be attributed to the treatment. I.e. due to structural similarity to insulin aspart ethyl ester the oral NOAEL of 1000 mg/kg/d is considered relevant for this substance as well in realtion to effects not mediated via insulin receptor binding as MI3 doses not bind to the insulin receptor.

In a 26 week inhalation study female and male rats were subjected to 0.5 h of daily inhalation exposure to insulin aspart aerosols in the concentration range of 344 – 2074 mg/m³for 26 weeks. Increased female mortality was observed within the first 4 weeks at a concentration level of 1796 mg/m³. The lethal outcome was found to be due to severe hypoglycaemia. Such effects were not found at an exposure level of 805 mg/m3 that can be considered as a NOAEC. This NOAEC that is in connection with the substance insulin aspart (an active pharmaceutical ingredient) that bind to the insulin receptor may be used as NOAEC for inuslin aspart ethyl ester that has been shown to bint to the human insulin receptor as well.

See read-across template and justification attached in section 13

 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

1 796 mg/m³

Species:

rat

System:

other: Mortality

Organ:

not specified

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Justification for classification or non-classification

STOT RE applies if repeated or long-term exposure is associated to morbidity, death or significant functional changes in organ systems (CLP-regulation, item 3.9.2.7.3). The criteria for STOT RE category 2 classification from a 28D inhalation study is the observation of severe effects at concentration levels not higher than 600 mg/m³ for exposure 6h/day for the substance in the form of particle exposure (classification in category 1 would apply for exposure levels below 60 mg/m³). In the inhalation study with insulin aspart the severe effects/death occurred from repeated exposure during ½ hour of exposure per day at a concentration level of 1796 mg/m³. If the inhaled amount of insulin aspart during ½ hour exposure should be scaled to a 6 h exposure period (exposure of 6 h normally used in 28D inhalation study) this would then correspond to 1796 mg/m³x 0.5h/ 6 h = 150 mg / m³i.e. clearly below the classification cut-off limit of 600 mg/m³. Based on this insulin aspart should be classified with STOT RE2; H373 (May cause damage to organs (blood sugar regulation) through prolonged or repeated exposure (inhalation)). Due to the close similarities bewteen Insulin aspart (S1) and Insulin aspart ethyl ester, the target substance should therefore also be classified as STOT RE2; H373. Only the inhalational route is considered for the classification as absorption of insulin aspart ethyl ester by dermal and oral exposure route is not considered relevant.