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Cited from SIAR for SIAM 23 (Jeju, Korea, October 17-20, 2006):
"Assessment of the acute inhalation toxicity data indicates that effects caused by exposure to respirable aerosols of 3 isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate were confined predominantly to the respiratory tract. Clinical signs (serous nasal discharge, bradypnea, stridor) indicated respiratory distress. There are two studies according to OECD TG 403 with LC50-values (4 h, rat) of approximately 40 mg/m3 and 31 mg/m3, respectively. Special investigations with male rats revealed airway rather than pulmonary irritation, which became evident after exposure of a concentration causing some lethality (25 mg/m3, 1 x 6 h). The dermal LD50 determined in compliance with OECD TG 402 was > 7000 mg/kg bw for rats. Non-specific, transient signs of intoxication (sedation, ataxia) and obvious skin irritation at the application site were reported. The available studies revealed a low oral toxicity with LD50-values (rat) of 4814 - 5490 mg/kg bw. Toxic symptoms after oral administration included decreased activity, piloerection, and diarrhea."

Key value for chemical safety assessment

Additional information

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

Studies in Animals


"3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate is a liquid with a low vapor pressure under ambient conditions. Based on these characteristics, 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate is expected to occur at temperatures close to room temperature as vapor at low concentrations and as liquid aerosol droplets at higher concentrations. With the vapor, exposure of the respiratory tract should be relatively uniform. In contrast, exposure to 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate aerosols may result in an unequal distribution and higher local concentrations in the respiratory tract at the site of deposition which depends on particle size.

These considerations lead to some requirements for adequately testing the inhalation toxicity of 3‑isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate. The particle-size distribution of aerosols generated in inhalation studies should allow exposure of all relevant regions of the respiratory tract, since damage to and/or deposition in any region of the respiratory tract may induce lethality. An aerosol bracketing a particle-size mass distribution of mass median aerodynamic diameter (MMAD) 1 to 4 µm, as recommended by Society of Toxicology (1992) and a geometric standard deviation (GSD) in the range of 1.5 to 3.0 µm therefore appear to be appropriate for LC50determination. Only two of the available inhalation LC50studies give consideration to these exposure and analysis requirements, which are essential for a reliable quantitative assessment of inhalation toxicity. These studies will be presented here in more detail.

Particular attention was paid to the location of effects in the study of Pauluhn (2004). Both the concentration- and time dependence of parameters in the bronchoalveolar lavage fluid (BALF) following a single 6 hours exposure to the aerosolized 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate was analyzed. Male rats were exposed in direct-flow nose-only exposure chambers to conditioned air or target concentrations of 2, 8, and 25 mg 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate/m3(analytical: 2.09; 7.5; 26 mg/m3). The test substance was applied as an aerosol with high respirability (MMAD 1.6 µm; GSD approx. 1.8 µm) at the high level group. No particle size analyses were performed in the low and mid dose group because these concentrations were in the range of the vapor saturation concentration of 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate. BALF was analyzed for protein as an index of air-blood barrier permeability. Lactate dehydrogenase (LDH) was taken as indicator of cell injury. These endpoints were determined on postexposure days 1, 3, and 7. Clinical signs of respiratory distress were observed at 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate concentrations> 8 mg/m3. 2/18 rats died at 25 mg/m3. At 8 mg/m3and higher body weight retardation was observed, which was statistically significant only in the high dose group (21% below control on day 7). Rectal temperature was statistically significantly decreased at 8 and 25 mg/m3(6.2 and 9.1°C below control, respectively). Lung weights were increased only in the high dose group (25 mg/m3) not until at day 7 (+24.3%) as were protein (+291%; also significant on day 1, not on day 3) and LDH (+151%) in BALF. The time course of changes can be associated with features reminiscent of upper airway rather than pulmonary irritation."

The inhalation LC50of3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate(purity > 99%) was determined by Bayer AG (1995) by exposing Wistar rats in six groups, each containing 5 males and 5 females according to the method of OECD TG 403. "Each group was nose only exposed to conditioned air or aerosol concentrations of the test substance. After exposure (4 hours) the animals were observed for four weeks. The actual mean concentrations of3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanatewere 20.4, 53.3, 73.8, 104.6 and 410.3 mg/m3. The test substance aerosol exhibited a particle-size indicating that this aerosol was of adequate respirability (83% of the particle mass was< 3 µm; MMAD approx. 1.6 – 2.1 µm; GSD approx. 1.7 µm). Rats exposed to >= 20.4 mg/m3experienced signs of respiratory tract distress (i.e. tachypnea, bradypnea, stridor). Body weight gain and rectal temperature were depressed significantly in all exposed groups. Exposure to a concentration of 53.3 mg/m3induced mortality in 6 of 10 animals. This mortality was observed between days 16 and 28. Exposure to concentrations of >= 73.8 mg/m3was lethal for all exposed animals and increased exposure concentrations clearly induced a speeding up of mortality.With the exception of a less collapsed lung and some focal discolorations of the lung, which are sporadically observed, survivors showed no substance-induced macroscopic, extrapulmonary alterations. Animals that died during or following exposure showed nose/muzzle with red incrustations, mucous membrane of nose with reddening, pleural cavity filled with liquid, lung less collapsed emphysematous, and spongy, which are considered to reflect local irritant effects to the respiratory tract." The LC50(4 h) stated in this study (Bayer AG, 1995) is approximately 40 mg/m3for both sexes.

"In the OECD TG 403 study of RCC (1988), a four-hour LC50of3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate(purity > 99%)to male and female Wistar rats of 31 mg/m3was determined. The no-observed-effect level was less than 18 mg/m3. The animals were exposed flow-past nose-only to3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate aerosol and observed for up to 17 days after exposure. Applied analytical concentrations were 18, 22, 70 and 450 mg/m3. The data on particle size distribution showed that all particles were below 4.6 µm and approximately 90% w/w of the particles had diameters< 2.13 µm at the three lowest exposure concentrations. The predominant clinical signs werebreathing difficulty, piloerection and stagger.Necropsy findings were red foci on lung lobes, or reddish lungs (in decedent animals only). There was no body weight gain during the first week.


A test performed according to OECD TG 402 with male and female rats (Hüls AG, 1985) demonstrated the low acute dermal toxicity of 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate. No animal (= 0/10) died after 24 hours occlusive application of 7000 mg/kg. Non-specific transient signs of intoxication (sedation, ataxia) and obvious skin irritation at the application site were observed in all animals.


Kimmerle (1968) reported LD50values (with 14 days post observation period) of > 2645 mg/kg bw each for 15 male Wistar rats and for 15 male CF1 mice. In the study with rats no animal died and no signs of intoxication or change of behavior could be observed at any dose up to 2645 mg/kg bw. In the study with mice two animals died at 2645 mg/kg bw on the first day, symptoms of intoxication were uncharacteristic. While in this study unspecified oil was used as vehicle, no vehicle was employed in the other oral toxicity studies:

Similarly low acute oral toxicities in Wistar rats were determined by IBR (1976) and Thyssen (1976), with LD50values of 4814 mg/kg bw and above. Clinical signs observed in the former study were a decrease in activity, diarrhea, piloerection, in the higher dose groups also tremor, the symptoms beginning 20 minutes after dosing and lasting for about 24 hours. Growth rates were transiently reduced but returned to normal by the end of the post exposure observation period. Mortalities occurred within 3 days after dosing. Necropsy findings were reddening of stomach and intestinal mucosa of dead animals, and loss of hair at the perineum of survivors."

Justification for classification or non-classification

The substance 3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate is classified according to the criteria of EC Directive 67/548/EEC (Annex I) as follows: "Toxic by inhalation" (T, R 23)