Registration Dossier

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Administrative data

Description of key information

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

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
No data on purity of test substance
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
; if relevant deviations exist they are described under materials and methods or as appropriate entries in this endpoint study record
Principles of method if other than guideline:
Method based on "Appraisal of the safety of chemicals in foods, drugs and cosmetics" by the staff of the Division of Pharmacology, FDA (1959), complies with OECD Guideline 401 (1981)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS:
- Source: Winkelmann, Paderborn (Germany)
- Weight at study initiation: 110-140 g
- diet: Ssniff Intermast; Diet deprived 16 hours before oral application of test substance
- Water ad libitum

ENVIRONMENTAL CONDITIONS:
- Room temperature 22°C;
- Air humidity 45-55%;
- Light 12 hours per day
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
- Doses: calculated from volume
- Doses per time period: single dose (gavage)
Doses:
4.21; 5.29; 6.67; 8.40; 10.58 g/kg bw
No. of animals per sex per dose:
5 male and 5 female per dose
Control animals:
no
Details on study design:
- Volume administered or concentration: undiluted test substance, 3.98;  5.00; 6.30; 7.94; 10.00 ml/kg bw   * 1.058g/ml = 4.21; 5.29; 6.67; 8.40; 10.58 g/kg bw
- Post dose observation period: 14 days
EXAMINATIONS: 
central nervous system, lung, heart, heart sac, stomach,  large intestine, small intestine, liver, spleen, kidneys, serosa, lymph  nodes, gonads, perineum
Statistics:
- LD50 calculation: according to Litchfield and Wilcoxon, in connection  with the Gauß integral
Preliminary study:
not applicable
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
4 814 mg/kg bw
95% CL:
>= 4 295 - <= 5 396
Remarks on result:
other: 95% CL in mg/kg bw
Mortality:
- Time of death: within 3 days
- Number of deaths at each dose 14 days after substance application:    3.98 ml/kg: 2/10 ;  5.00 ml/kg: 8/10 ; 6.30 ml/kg: 10/10; 7.94 ml/kg: 10/10; 10.00 ml/kg: 10/10      
- LD50 (24 hours) = 7.10 ml/kg = 7512 mg/kg   confidence interval: 6.02 - 8.38 ml/kg  
- LD50 (7 days, 14 days) = 4.55 ml/kg = 4814 mg/kg   confidence interval: 4.06 - 5.10 ml/kg
Clinical signs:
decrease in activity, diarrhea, piloerection, in higher  dose groups also tremor (beginning 20 min after dosing, lasting 24 hours) - .
Body weight:
Growth rates returned to normal by the end of the post exposure  observation period
Gross pathology:
NECROPSY FINDINGS: reddening of stomach and intestinal mucosa of dead  animals, loss of hair at perineum of survivors

table of results see under attached background material

Conclusions:
Treatment related mortality and other sublethal symptoms were observed in rats within the 14 day post-dosing period for the doses used in this acute oral toxicity study. The LD50 (oral) was calculated to be 4814 mg/kg bw in rats. Under the conditions of this study the acute toxicity of test item after oral exposure in rats was very low
Executive summary:

The test item was applied once to 5 dose-groups of rats (5 male and 5 female Wistar rats per dose-group) in doses of 3.98 ml/kg bw; 5.00 ml/kg bw; 6.30 ml/kg bw; 7.94 ml/kg bw and 10.00 ml/kg bw of undiluted test item. The observation period was 14 days. At the highest dose (10.00 ml/kg bw) all animals died within 24 hours after oral application of the test item. Clinical signs were reddening of stomach and intestinal mucosa in dead animals.


In all doses groups a decrease in activity, disturbances of coordination, diarrhoea, piloerection, and in higher dose groups (>= 7.94 ml/kg bw) also tremor was observed beginning 20 min after dosing and lasting 24 hours. A loss of hair at perineum was observed among the survivors at the end of the study. Subsequently the surviving animals showed normal behaviour again throughout the observation period. According to this study the LD50 value (oral) was determined to be 4814 mg/kg bw in rats for the test item 3-Isocyanatomethyl-3.5.5-trimethylcyclohexyl isocyanate. Therefore under the conditions of this study the acute toxicity of 3-Isocyanatomethyl-3.5.5-trimethylcyclohexyl isocyanate after oral application in rats is very low.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
4 814 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

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
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
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
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.
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
Preliminary study:
not applicable
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

no remarks

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.

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1987-08-27 to 1987-10-05
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study with acceptable restrictions: no air control animals; exposure concentrations spaced suboptimal
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPP 81-3 (Acute inhalation toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: U.K. B4 (Inhalation Toxicity of Pesticidal Chemicals)
Deviations:
no
Principles of method if other than guideline:
other: Sachsse et al. (1973, 1976)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ORGANISMS: 
Wistar rat, KFM-Han., outbred, SPF quality
- Source: KFM Kleintierfarm Madoerin AG, Füllinsdorf (Switzerland)
- Age at study initiation: males 10-11 weeks, females 13-14 weeks
- Weight at study initiation: males 221.8-326.8 g, females 202.2-266.4 g
- Animals were randomly selected at time of delivery in groups of five
- Animals were aclimatized for 6 days (group 1), 3 days (group 2 & 3) and 15 days (group 4), respectively
- Food and water ad libitum
- Environmental conditions: Standard Laboratory Conditions:
Air-conditioned with 10-15 air changes per hour, and continuously monitored
environment with temperature 22° +/-3° C, relative humidity 40-70 %, 12 hours
artificial fluorescent light/12 hours dark period.
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
ADMINISTRATION: 
- Type of exposure: flow-past nose-only inhalation
- gravimetric concentrations: 14, 23, 69, 548 mg/m3
- Particle size:  18 mg/m3: 100 % <= 4.6 µm; 99.7 % <= 3 µm; 92.4 % <= 2.13 µm; 22 mg/m3: 100 % <= 4.6 µm; 99.3 % <= 3 µm; 94.4 % <= 2.13 µm;  70 mg/m3: 100 % <= 4.6 µm; 97.2 % <= 3 µm; 87.1 % <= 2.13 µm; 450 mg/m3: 100 % <= 4.6 µm; 81.3 % <= 3 µm; 61.1 % <= 2.13 µm
- Type or preparation of particles: Hospitak No. 950 nebulizer and  dilution system (clean air), symmetrical top-down flow of aerosol to  animals' 
noses and further
EXAMINATIONS:
- Analysis of test atmosphere:   Sampling close to the animals' noses with Gelman A/E 47 mm diameter  glass fiber filters; monitoring of relative 
aerosol concentration using a  RAM-1 light scattering type aerosol monitor.   In addition, collection of test atmosphere in three bottles filled with  
ethyl acetate and cooled with dry ice, subsequent analysis with gas  chromatography
- Particle size (gravimetric): Once during each exposure
- Concentration (gravimetric): At regular intervals during each exposure
- Concentration (analytic): Three times during each exposure
- Oxygen content, humidity, temperature: Once during each exposure
- Air flow rate: Monitored indirectly during the exposure period
Analytical verification of test atmosphere concentrations:
yes
Remarks:
GC
Duration of exposure:
4 h
Concentrations:
18; 22; 70; 450 mg/m3 (analytical)
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
EXAMINATIONS:
- Post dose observation period (including day of exposure as day 1): 18 mg/m3: 17 days 22 mg/m3: 21 days 70 mg/m3: 27 days 450 mg/m3: 24 hours (all dead)
- Mortality/viability: At least four times on test day 1 and twice daily thereafter.
- Body weights 18 mg/m3: test days 1, 7, 14 22 mg/m3: test days 1, 8, 15, 21 70 mg/m3: test days 1, 7, 14 450 mg/m3: test day 1
- Symptoms: At least four times on test day 1 and twice daily thereafter. During exposure only grossly abnormal signs could be noted, due to the animals being in restraint tubes. General behavior, motor susceptibility, body position, motility, respiration, skin / fur, eyes, and nose were characterized in addition to potential emaciation, poor condition, salivation, crying, diarrhea and distended abdomen.
- Necropsies of all animals
Statistics:
LoGIT-Model was used to calculate the LC50
Preliminary study:
not applicable
Sex:
male/female
Dose descriptor:
LC50
Effect level:
31 mg/m³ air
95% CL:
>= 28 - <= 35
Exp. duration:
4 h
Sex:
male/female
Dose descriptor:
other: NOEL
Effect level:
< 18 mg/m³ air
Exp. duration:
4 h
Mortality:
- Time of death: The LC50 is based on observation for 27 days.  One female  of the 22 mg/m3 group died on day 19.   
18 mg/m3: no mortalities   
22 mg/m3: 3/5 males on test days 2, 8, and 9; 1/5 females on test day  19.   
70 mg/m3: 5/5 males overnight (day 1/2), 4/5 females between test days  5 and 9; 1 female survived in poor condition until test day 27.   
450 mg/m3: 3/5 males and 3/5 females during exposure, all other animals  within 24 hours after begin of exposure.
Clinical signs:
other: All groups: Breathing difficulty, piloerection and stagger following  exposure (for several days); no body weight gain during first week.   22 mg/m3: Salivation, sedation.   >= 22 mg/m3: Nose bleeding 
Body weight:
see "Attached background material"
Gross pathology:
NECROPSY FINDINGS: Red foci on all lung lobes, or reddish lungs were  observed in all decedent animals except in 4 females of the 22 mg/m3  group. No abnormal findings were observed in surviving animals. POTENTIAL TARGET ORGANS: Respiratory tract
Other findings:
no
no further remarks
Conclusions:
Treatment related mortality and other sublethal symptoms were observed in rats within the post-exposure period for the concentrations used in this acute inhalation toxicity study. The LC50 (inhalative) was calculated to be 31 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:

In this study a four-hour LC50 of 3-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 isocyanateaerosol 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.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
31 mg/m³

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1985-02-04 to 1985-02-18
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study with acceptable restrictions: Kind of limit test with unusual dose, no rationale for dose selection reported
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ORGANISMS:
- Source: Winkelmann, Borchen (Germany)
- Weight at study initiation: males 265 g, females 208 g (mean)
- Housing conditions: room temperature 20°C (+/- 1°C); humidity: 60% (+/- 5%); light: 12h per day; air exchange: 15-fold per hour; access to water: ad libitum; diet: R10 diet for rats (Ssniff, Soest)
- Randomisation: By reference to an arbitrary number table on distribution into the test cages
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
ADMINISTRATION: 
- Occlusion: yes
- Removal of test substance: with warm water after 24 hours
Duration of exposure:
24 hours
Doses:
7000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
EXAMINATIONS: 
- Clinical observation and mortality: for 6 hours on day of exposure,  daily thereafter
- Body weights: Before exposure and on days 1, 7 and 14 after treatment
- Gross pathology: After observation period (14 days)
- LD 50 is generally determined according to Litchfield and Wilcoxon
Statistics:
median of body weights were calculated
Preliminary study:
not applicable
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 7 000 mg/kg bw
Remarks on result:
other: 95% CL not applicable
Mortality:
MORTALITY:  - Number of deaths at each dose: no deaths
Clinical signs:
CLINICAL SIGNS: 5/5 females and 5/5 males showed signs of intoxication  for up to 72 hours: After 24 hours most animals showed piloerection,  
sedation, ataxia, hypothermia, hunched position, irritations at  application site. 
Body weight:
Reduced body weight was observed after 1 week.
Gross pathology:
NECROPSY FINDINGS: hyperemia of stomach and intestinal mucosa, pale  kidneys with dark spots, incrustation and cicatrization at application  site 
(number of affected animals not reported)
Other findings:
no further findings

Increase in body weight (means) in g:



  • before administartion (fasting): 236.4 g

  • 24h after administration: 236.6 g

  • 1 week after administration: 230.6 g

  • 2 weeks after administration: 248.2 g
     


Conclusions:
Sublethal symptoms of intoxication but no treatment related mortality was observed within the 14 day post-dosing period with the dose used in this study. Under the conditions of this acute dermal toxicity test the LD50 (dermal) was calculated to be > 7000 mg/kg bw in male and female rats. Therefore under the conditions of this study the acute toxicity of 3-Isocyanatomethyl-3.5.5-trimethylcyclohexyl isocyanate after dermal application in rats is very low.
Executive summary:

A test performed according to OECD TG 402 with male and female rats (Hüls AG, 1985) demonstrated the low acute dermal toxicity of3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate. The treated animals showed signs of toxicity for up to 72 hours. There was a temporary inhibitive influence on the increase in body weight. Dissection at the end of the experiment showed hyperaemia of the gastric and small intestinal mucosa as well as very pale-coloured kidneys with dark flecks. The application area showed incrustations and scars on the skin. 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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
7 000 mg/kg bw

Additional information

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


Studies in Animals


 


Inhalation


"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 LC50 determination. Only two of the available inhalation LC50 studies 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/mand 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/m(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 LC50 of 3-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 of 3-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/mexperienced 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/minduced mortality in 6 of 10 animals. This mortality was observed between days 16 and 28. Exposure to concentrations of >= 73.8 mg/mwas 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/mfor both sexes.


"In the OECD TG 403 study of RCC (1988), a four-hour LC50 of3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate (purity > 99%) to male and female Wistar rats of 31 mg/mwas determined. The no-observed-effect level was less than 18 mg/m3. The animals were exposed flow-past nose-only to 3-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 were breathing 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.


 


Dermal


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.


 


Oral


Kimmerle (1968) reported LD50 values (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 LD50 values 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

Based on data (LC50 values for acute inhalation toxicity were determined as 31.0 and approximately 40 mg/mair) the test substance has to be considered as very toxic for rats after inhalative exposure. According to the criteria given by the CLP regulation the classification criteria for acute inhalation toxicity category 1 are fulfilled.


 


The substance 3-Isocyanatomethyl-3,5,5 -trimethylcyclohexyl isocyanate is listed in Annex VI of regulation 1272/2008.


Based on the available data the current Annex VI entry should be modified from Acute Tox. 3 (Minimum classification) with H 331 to Acute Tox. 1 with H 330.