3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate

Endpoint summary

Description of key information

Partly cited from SIAR for SIAM 23 (Jeju, Korea, October 17-20, 2006):
"No repeated-dose toxicity tests are available for the oral and dermal route of exposure.
A subacute inhalation study (0.24, 1.05, and 4.1 mg/m3; 6 hours/day, 5 days/week, 4 weeks; OECD TG 412) with male and female Wistar rats indicates the respiratory tract to be the target organ. Clinical signs of respiratory tract irritation (nostrils: red encrustations, stridor, nasal discharge, breathing sounds, hypothermia) are restricted to the high concentration rats." The LOAEC is 1.05 mg/m3 (histopathological changes in nasal cavity and larynx). "At 4.1 mg/m3 also the pharynx, trachea, and lungs are affected but the lesions are reversible within the four weeks of recovery with regard to the lung and trachea. However, lesions in the nasal cavity, the pharynx, and the larynx still occurred in some animals with minimal or slight degree. The most relevant systemic effects were a slight decrease in body weight gain in the high dose group and an increased leukocyte count in the peripheral blood in mid and high dose groups." The NOAEC is 0.24 mg/m3.
A subchronic 13 week inhalation study demonstrates that rats exposed up to 1.1 mg/m3 of the test substance Isophorone Diisocyanate did not display any substance-induced clinical effects, changes in reflexes and body temperature, conclusively affected body weights or food/water consumption. There was no evidence of hematological effects. Clinical pathology and urinanalysis were unobtrusive. There were no statistically significant or conclusive dose-dependend changes in absolute or relative organ weights. The histopathological evaluation of the nasal cavity and the larynx revealed minimal or slight epithelial changes at 1.1 mg/m3. After a four week recovery period minimal epithelial metaplasia could still be detected; however clear evidence of recovery existed. This study demonstrated that the test substance was tolerated without any systemic adverse effects or clinical findings suggestive of respiratory tract irritation at any exposure level. Taking all findings into account, 0.27 mg/m3 constitutes a No-Observed-Adverse-Effect-Concentration (NOAEC).

Additional information

Partly cited from SIAR for SIAM 23 (Jeju, Korea, October 17-20, 2006):

 

"No repeated dose toxicity studies are available for the oral and dermal routes of exposure."

 

Subacute 28 day inhalation study

 

"In a study performed according to OECD TG 412, groups of ten male and ten female Wistar rats were exposed for six hours/day on five days/week for four consecutive weeks to target 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate concentrations of 0.25, 1 or 4 mg/m³ (corresponding to analytical means of 0.24; 1.05; 4.1 mg/m³). Exposure was dynamic directed-flow nose-only and vapor saturation was reported to be about 4 – 11 mg/m³ at 20 – 25°C. A concurrent control group was exposed to air only, under otherwise identical conditions. Recovery was studied after approximately four further weeks in two additional, identical groups, one of them a control group, the other one exposed to the highest test concentration.

No mortality was observed in this study. No treatment-related effects were observed in urinalysis, ophthalmoscopic examination, clinical chemistry, gross pathology and examination of reflexes. Clinical signs were mild and transient signs of respiratory tract irritation (nostrils: red encrustations, stridor, nasal discharge, breathing sounds, hypothermia) in most rats only at 4.1 mg/m³ (signs in 18/20 males, 18/20 females). Body weights were slightly decreased in the high dose group (day 28: males ‑5.1%, statistically significant; females ‑3.4%, not significant) and returned rapidly to normal during the recovery period. The only relevant hematological finding was an increased leukocyte count in the peripheral blood in mid (males +46%, significant; females +82%, not significant) and high dose (males +55%, significant; females +16%, not significant) groups. Other statistical significances (none in high dose animals except prothrombin time for females +7.6%) were considered to be of no pathodiagnostic relevance. Statistically significant findings in high dose group organ weights were a reduced absolute liver weight in females (‑9.7%) and an increased relative lung weight in males (+12.6%). Only the latter finding was conclusive. Histopathology revealed in rats exposed at 1.05 and 4.2 mg/m³a significantly increased incidence of inflammatory as well as epithelial changes occurring in the airways of the entire respiratory tract (nasal cavity, pharynx, larynx, trachea, lungs) with typical anterior-posterior gradient in intensity. Recovery after the post observation period was incomplete in nasal cavity, pharynx, larynx, and complete in trachea and lung. The lesions were thus considered to be reversible with no evidence of fibroproliferative effects. There was no effect on extrapulmonary organs. Determination of the rectal temperatures indicated hypothermia in the high dose group, which was statistically significant on day 0 (males 34.6 vs. 37.4°C in control, females 35.6 vs. 37.3°C) but not towards the end of the exposure period (day 22)." The NOAEC (histopathological changes in nasal cavity and larynx) was 0.24 mg/m³ (Bayer AG, 2003).

 

Subchronic 90 day inhalation study

 

A subcronic 13 week inhalation study with Isophorone Diisocyanate has been conducted in young adult Wistar rats (Pauluhn, 2008). 10 male and 10 female rats per group were exposed (dynamic directed-flow, nose-only) 6 hours/day on five days/week for 13 weeks to following concentrations of the test substance: 0 (air control), 0.05, 0.27 and 1.1 mg/m3. Additional animals of the control and high-level exposure group (10/sex/group) were allowed to recover over an exposure-free time period of approximately 4 weeks. This subchronic 13 week inhalation study demonstrates that rats exposed up to 1.1 mg/m3 of the test substance did not display any substance-induced clinical effects, changes in reflexes and body temperature, conclusively affected body weights or food/water consumption. There was no evidence of hematological effects. Clinical pathology and urinanalysis were unobtrusive. There were no statistically significant or conclusive dose-dependend changes in absolute or relative organ weights. The histopathological evaluation of the nasal cavity and the larynx revealed minimal or slight epithelial changes at 1.1 mg/m3. After a four week recovery period minimal epithelial metaplasia could still be detected; however clear evidence of recovery existed. This study demonstrated that the test substance was tolerated without any systemic adverse effects or clinical findings suggestive of respiratory tract irritation at any exposure level. Taking all findings into account, 0.27 mg/m3 constitutes a No-Observed-Adverse-Effect-Concentration (NOAEC).

Justification for classification or non-classification

Regarding repeated dose toxicity the substance 3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate is not classified according to the criteria of EC Directive 67/548/EEC.