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Toxicological information

Acute Toxicity: inhalation

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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 guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
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 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)

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
Analytical verification of test atmosphere concentrations:
yes
Remarks:
HPLC, UV detection
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: several times on day of exposure and twice daily  (morning and evening) thereafter (morning only on weekends)
- body weight: before exposure, on days 3 and 7, thereafter weekly, at death if applicable
- gross pathology of all animals after sacrifice of surviving animals
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:
- Time of death:     Concentration: No. and time span (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
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 LC50of3-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 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 of³ 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 is approximately 40 mg/m3for both sexes.