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

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1993-11-24 to 1994-01-05

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study with acceptable restrictions: exposure concentrations spaced suboptimal

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1995

Report date:

1995

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

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

EC Number:

223-861-6

EC Name:

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

Cas Number:

4098-71-9

Molecular formula:

C12H18N2O2

IUPAC Name:

5-isocyanato-1-(isocyanatomethyl)-1,3,3-trimethylcyclohexane

Details on test material:

Isophorone diisocyanate of Bayer AG, batch no. 1.5/3-28, purity > 99 %

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Strain: SPF bred Wistar rats, strain Hsd/Win:WU (formerly BOR:WISW  (SPF-Cpb))
- Source: Harlan-Winkelmann, Borchen, Germany
- Age: 2-3 months
- Weight at study initiation: 193 g (males mean), 177 g (females mean), weights did not exceed ± 10 per cent of the mean for each sex and group
- Animal housing: The animals were acclimatized to the animal room conditions for at least 5 days before use. Cages and water bottles were changed twice a week while unconsumed feed was changed once per week.
- before the start of the study the health status of each animal was assessed. Animals were
subsequently assigned to exposure groups at random.
- Environmental conditions:
Room temperature: 22±2°C
Relative humiditv: approx. 50%
Dark/light cycle: 12 h/12 h; artificial light from 6.00 a.m. to 6. 00 p.m. Central European Time
Illumination: aooroximately 13-14 watt/m2 floor area
Ventilation: aooroximately 10 air changes per hour
- Both food and water were available ad libitum.

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

- Controls: air
- Type of exposure: nose-only using the dynamic directed-flow principle
- nominal concentration (calculated from the ratio of the quantity of  test substance sprayed into the baffle and the total throughput of air  through 
the inhalation chamber): 115, 289, 462, 379, 1514 mg/m3
- gravimetric concentration: 18, 55, 85, 105, 410 mg/m3
- Particle size:    Mass Median Aerodynamic Diameter (MMAD) 1.6 - 2.1 µm   geometric standard deviation: approx. 1.7 µm
- Type or preparation of particles: aerosol, generated using a  two-component nozzle with conditioned compressed air (15 litres of air/min; dispersion pressure approx. 600 kPa)

Analytical verification of test atmosphere concentrations:

yes

Remarks:

HPLC, UV detection (Chamber samples were taken in the vicinity of the breathing zone of the animals)

Duration of exposure:

4 h

Concentrations:

0; 20.4; 53.3; 73.8; 104.6; 410.3 mg/m3 (analytical)

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- post-exposure observation period: 4 weeks
- rectal temperature: 15 to 30 min after exposure
- mortality: time recorded as precisely as possible 
- clinical signs: appearance and behaviour of each rat was examined several times on day of exposure and twice daily  (morning and evening) thereafter (morning only on weekends), assessments from restraining tubes were made only if unequivocal signs occured (e.g. spasms, abnormal movements, severe respiratory signs)
- body weight: before exposure, on days 3 and 7, thereafter weekly, at death if applicable
- all surviving rats were sacrificed at the end of the observation period using sodium
pentobarbital; irrespective of the day of death, all rats were given a gross-pathological examination.

Statistics:

CALCULATION OF LC50: Since only test concentration (53.3 mg/m3) was  within 0 % and 100 % lethality, the geometric mean of the next  
concentrations (20.4 and 73.8 mg/m3) was chosen

Results and discussion

Preliminary study:

not applicable

Effect levels

Sex:

male/female

Dose descriptor:

LC50

Effect level:

ca. 40 mg/m³ air

Exp. duration:

4 h

Mortality:

Analytical concentration: number of death animals and time point of lethalities (males/females):
0 mg/m3 (control): no mortalities/no mortalities;
20.4 mg/m3: no mortalities / no mortalities;
53.3 mg/m3: 3 (16 d - 28 d) / 3 (11 d - 25 d);
73.8 mg/m3: 5 (1 d - 12 d) / 5 (3 d - 9 d);
104.6 mg/m3: 5 (1 d - 10 d) / 5 (1 d - 20 d);
410.3 mg/m3: 5 (<= 4 h) / 5 (<= 4 h - 6 h)

  

Clinical signs:

other: control: no signs;  20.4 mg/m3: reduced motility, piloerection, ungroomed coat, bradypnea,  labored breathing, rales, sluggishness, nose and/or muzzle with red  incrustations, reddening of nose   additional observations in higher dose groups: tachypnea

Remarks:

Body weight:

- Body weights: Significant depression in b.w. gain in all exposed groups 

Gross pathology:

- Survivors: Except for a less collapsed lung and some focal  discolorations of the lung, which was only sporadically observed,  survivors showed no 
substance
-induced macroscopic alterations.
- Animals that died within the exposure / observation period: Nose and/or  muzzle with red incrustations, mucous membrane of nose with 
reddenings;  pleural cavity filled with liquid; lung less collapsed, with dark-red  foci or diffusely black-red, emphysematous, spongy, and with escape of  liquid at the cut part; small intestine with reddenings and yellowish  and/or reddish content; liver pale, spotted, and with distinct lobular  pattern; 
spleen pale; kidneys pale, pelvis of kidneys with reddenings. Findings of the nose/muzzle, pleural cavity, and lung are considered to  reflect irritant 
effects to the respiratory tract. POTENTIAL TARGET ORGANS: respiratory tract (severe irritation)
-SEX-SPECIFIC DIFFERENCES: not ascertained

Any other information on results incl. tables

no remarks

Applicant's summary and conclusion

Conclusions:

Treatment related mortality and other sublethal symptoms were observed in rats within the 4 week post-exposure period for the concentrations used in this acute inhalation toxicity study. The LC50 (inhalative) was calculated to be approximately 40 mg/m3 air in rats. Under the conditions of this study 3-Isocyanatomethyl-3.5.5-trimethylcyclohexyl isocyanate is very toxic for rats after inhalative exposure.

Executive summary:

The inhalation LC50 of 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate (purity > 99%) was determined 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 of 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate were 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/m3 experienced 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/m3 induced mortality in 6 of 10 animals. This mortality was observed between days 11 and 28. Exposure to concentrations of 73.8 mg/m3 was 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 is approximately 40 mg/m3 for both sexes.