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Administrative data

Description of key information

The oral administration of MI3 at dose levels of 0, 100, 300, 1000 mg/kg/d to Wistar rats during 28 days(OECD TG 407 study)produced no evidence of toxicity and no sign of effects could be attributed to the treatment. The low toxicity from repeated oral administration is most likely due to a very low degree of oral absorbtion which would apply for human insulin methylester as well.

Female and male rats were during 26 weeks subjected to 0.5 h of daily inhalation exposure to human insulin at concentrations of 1162 mg/m3(females) and 1979 mg/m3 (males). The exposure resulted in hypoglycaemia, however, not to an extent causing any adverse outcome.

Other groups of rats were exposed to insulin aspart* in the concentration range of 344 – 2074 mg/m3for 26 weeks. Increased mortality was observed within the first 4 weeks at the highest concnetration (3 females and 2 males). Altogether 6 females (at 1796 mg/m3a) and 3 males (at 2074 mg/m3 ) died at the highest dose level of insulin aspart. Lethality were noted to be due to severe hypoglycaemia. The NOAEC for insulin aspart was 804 mg/m3. The lack of effects observed using human insulin may be because the most susceptible sex (females) was exposed to a considerable lower exposure level compared to the insulin aspart study. Hence similar effects would be expected for human insulin at higher exposure levels.

*insulin aspart is an API nearly identical to human insulin as proline in position 28 of the amino acid chain in human insulin is replaced by aspartic acid in insulin aspart

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
Study duration:
subchronic
Species:
rat
System:
other: Mortality
Organ:
not specified

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Justification for classification or non-classification

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 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 and the structural similarities between human insulin, insulin aspart and Inuslin Human methyl ester, Insulin Human methyl ester should be classified with STOT RE2; H373 (May cause damage to organs (blood sugar regulation) through prolonged or repeated exposure (inhalation)).