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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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented study report which meets basic scientific principles; the test conduct was similar to the OECD TG 403.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1985
Report Date:
1985

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- 20 male and 20 female animals
- Source: Central Institute for breeding of Laboratory Animals TNO, Zeist, the Netherlands
- Mean weight at study initiation: males 172 g, females 143 g.
- Diet: ad libitum (Institute' s stock diet for rats)
- Water: ad libitum (bottled unfluoridated tap water)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21°C +/-1
- Humidity (%): 30-70%

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: H 1000 multitiered inhalation chamber (Hazleton Systems Inc., USA)
- Exposure chamber volume: 2.3 m³
- Method of holding animals in test chamber: individually, whole body exposure
- System of generating particulates/aerosols: 2 steel/glass air nebuliser, equipped with a baffle for separation of large particles (thermostated at about 70°C). Deposited test substance was not re-circulated through the nebuliser, which is usual for this type of generator. Upon entering the exposure chamber, additional air was mixed with the aerosol resulting in a total air flow of 4-11 m³/hour.
- Method of particle size determination: The particle size distribution was determined by means of a cascade impactor.
- Temperature, humidity, pressure in air chamber: 19.5 ± 1°C, 30-70%.

TEST ATMOSPHERE
- Brief description of analytical method used:
1. Gravimetry: by a glass fiber filter (type SM 134 00 from Sartorius). The first sample was taken 45 minutes after start of the exposure and subsequent samples were taken at about one hour intervals.
2. Spectrophotometry:
a. Calculation from the oil-red concentration determined by spectrophotometry after sampling of the test atmosphere by means of a G-4 filter and an impinger. Samples were taken simultaneously with those indicated under 1.
b. Calculation from the oil red concentration, determined by spectrophotometry after sampling of the test atmosphere by means of a cascade impactor during each exposure period one such a sample was taken.
3. HPLC: Calculation from the monomeric HDI concentration determined by HPLC after sampling of the test atmosphere by means of an impinger. The first sample was taken 60 minutes after the start of the exposure and subsequent samples were taken at approximate one hour intervals.
- Samples taken from breathing zone: yes

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: in all samples about 100 % of the particles had a diameter smaller than 5 µm.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.):
Group 465 mg/m³: 1.8µm/1.9µm
Group 413 mg/m³: 1.8µm/1.9µm
Group 301 mg/m³: 1.8µm/1.8µm
Group 256 mg/m³: 1.7µm/1.6µm
Analytical verification of test atmosphere concentrations:
yes
Remarks:
Gravimety, HPLC of monomer, spectrophotometry
Duration of exposure:
4 h
Concentrations:
values obtained by gravimetry: 465 mg/m³, 413 mg/m³, 301 mg/m³, 256 mg/m³
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
Groups of male and female rats were exposed one single time for a period of four hours to an atmosphere in which a specific concentration of test substance aerosol was maintained.
During the exposure and the observation period the animals were controlled for mortality and reactions to treatment daily. Observed abnormalities were recorded. Body weights were recorded at days 0, 1, 2, 4, 7 and 14.
Gross pathology was performed on survivors and animals which were found dead during the study period.
Statistics:
Probit analysis method of Finney.

Results and discussion

Effect levelsopen allclose all
Sex:
male/female
Dose descriptor:
LC50
Effect level:
402 mg/m³ air (analytical)
Based on:
test mat.
95% CL:
244 - 560
Exp. duration:
4 h
Sex:
female
Dose descriptor:
LC50
Effect level:
423 mg/m³ air (analytical)
Based on:
test mat.
95% CL:
225 - 797
Exp. duration:
4 h
Sex:
male
Dose descriptor:
LC50
Effect level:
388 mg/m³ air (analytical)
Based on:
test mat.
95% CL:
177 - 848
Exp. duration:
4 h
Mortality:
Mortality was 50% at 465 mg/m³, 70% at 413 mg/m³, 30% at 301 mg/m³ and 0% at 256 mg/m³
No mortality occurred during exposure; all animals that died, died within 2 days after termination of the exposure period.
Clinical signs:
other: During the exposure period the animals were quiet and kept their eyes closed. No abnormalities were observed during the observation period. The fur of the back skin of the animals was slightly pink coloured at the end of the exposure period.
Body weight:
Both males and females lost body weight or gained hardly weight during the first 24 hours of the observation period. After day 2, body weight gain turned back to normal.
Gross pathology:
Gross examination of animals that died during the experimental period revealed hydrothorax and/or haemorrhagic lungs. Haemorrhagic lungs were observed also in one male rat of the 465 mg/m³ group that was killed at the end of the observation period.
No treatment related abnormalities were observed in the animals of the other groups, killed at the end of the observation period.

Any other information on results incl. tables

Analytical results:

Data obtained by gravimetry were approx. 25% higher than those obtained by spectrophotometry.

In all samples about 100 % of the particles had a diameter smaller than 5 µm.

Table 1: Mean concentration of test substance in test atmospheres [mg/m3], particle size distribution MMAD +/-GD [µm] and mortality [%]:

 [mg/m3]   Gravimetry     Spectophotometry  HPLC Particle size distribution   Mortality
 treatment group    G4 filter cascade impactor       
 A  465 403  387 291   1.8 +/-1.9 50
 B  413 308  313  317   1.8 +/-1.9 70 
 256 193 240  not detectable   1.7 +/-1.6 0
 D  301 238  313  not detectable

 1.8 +/-1.8 

30

Applicant's summary and conclusion