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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:
January 30 - February 28, 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study has been performed according to OECD guideline and according to GLP principles. Purity not given.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1980
Report Date:
1980

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): TAKENATE 500; 1,3-bis(isocyanatomethyl)benzene
- Physical state: colourless mobile liquid

Test animals

Species:
rat
Strain:
other: CD albino (A Caesarean derived strain of Sprague-Dawley)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River UK, Manston Road, Margate, Kent
- Age at study initiation: no data
- Weight at study initiation: 194-274 g
- Fasting period before study: no data
- Housing: 5 rats per cage, cages were made of polypropylene and had detachable wire mesh tops and floors
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-25
- Humidity (%): 39
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: none
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The whole body exposure chambers were of square section and were fitted with pyramidal tops. The chambers were made of Perspex. Each chamber was divided by wire mesh partitions to provide 10 separate animal compartments.
- Exposure chamber volume: approximately 0.13 m3
- Method of holding animals in test chamber: the rats were placed into separate animal compartments of the exposure chamber
- Airflow: 30 litres per minute
- System of generating particulates/aerosols: The aerosol generator was designed to produce and maintain an atmosphere containing a high proportion (>85%) of respirable droplets. All parts of the generator were made of stainless steel. The test substance was supplied to the generatot from a syringe driven at a constant rate by a syringe pump.
- Method of particle size determination: May multistage liquid impinger with 0.04M dibenzylamine solution as the trapping agent. The air sample was taken at a flow rate of 10 litres per minute and the collection characteristics of the May impinger at this flow rate were as follows:
Stage 1 - particles greater than 5.5 µm mean aerodynamic diameter (a.d.)
Stage 2 - particles between 5.5 and 2.0 µm mean a.d.
Stage 3 - particles less than 2.0 µm mean a.d.
- Temperature, humidity, pressure in air chamber: The temperature was recorded at 30 minute intervals during the exposure.

TEST ATMOSPHERE
- Sampling: 5 samples/exposure into a gas absorption trap.
- Analysis of samples: HPLC-UV (216 nm)
- Samples taken from breathing zone: yes

Analytical verification of test atmosphere concentrations:
yes
Remarks:
(see section "details on inhalation exposure")
Duration of exposure:
4 h
Remarks on duration:
continuous whole body exposure
Concentrations:
Atmosphere concentrations of TAKENATE 500: 58.3, 198.8, 224.7 and 358.0 mg/m^3 of chamber air.
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The rats were observed continuously during exposure and at least twice daily during the observation period. All rats were weighed daily.
- Necropsy of survivors performed: yes
- Other examinations performed: food and water consumption, lung weight.
Statistics:
The LC50 was calculated by the log probit method of Miller and Tainter.

Results and discussion

Effect levelsopen allclose all
Sex:
male
Dose descriptor:
LC50
Effect level:
175 mg/m³ air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: whole body exposure
Sex:
female
Dose descriptor:
LC50
Effect level:
187 mg/m³ air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: Finney, 1971, Probit method; whole body exposure
Mortality:
control: 0/10
58.3 mg/m^3: 0/10
198.8 mg/m^3: 2/10
224.7 mg/m^3: 9/10 (includes 2 rats killed for humane reasons. Deaths due to exposure taken as 8/10 instead of 7/10, because an animal had the same symptoms as spontaneously dying animals)
358.0 mg/m^3: 10/10
Clinical signs:
Signs that the aerosol of TAKENATE 500 was irritant to the mucous membranes and respiratory system were evident in all groups during exposure. The severity of the reactions and the rapidity of onset were related to the exposure level.
During the observation period rales, (sounds of varied character heard on ausculation of the chest), laboured breathing and sneezing were observed for up to 14 days following exposure. Brown staining and red-brown to black encrustation around the eyes and on the snout were observed for up to 11 days.
The appearance and behaviour of rats in the control was normal during the exposure and during the observation period.
Body weight:
A moderate or marked decrease in bodyweight was observed at 58.3 and 198.8 mg/m^3, respectively, over a period of 3-6 days after exposure.
224.7 and 358.0 mg/m^3: Progressive decrease in bodyweight prior to death with the exception of the surviving rat in 224.7 mg/m^3. This rat gained weight from day 9 of the observation period.
Gross pathology:
No macroscopic abnormalities at control and 58.3 mg/m^3.
Abnormalities seen in rats that died as a result of exposure were oedema, congestion and hepatisation of the lungs and distended gas filled stomachs and intestines. Abnormalities in surviving rats were limited to small areas of consolidation sub-pleural and dark red foci in the lung.
The adrenals of one rat at 224.7 mg/m^3 were pale and enlarged and those of two other rats at this dose level were enlarged.
Other findings:
- Food and water consumption: Food and water consumption was reduced to approximately 40-50% of normal at 58.3 mg/m^3 for 3-4 days following exposure and, subsequently, food and water consumption was normal. Little or no food was consumed at 198.8 mg/m^3 for 5 days following exposure and water consumption was reduced to approximately 30% of normal. Normal food and water consumption was resumed over the next 4-5 days.
The rats that died as a result of exposure to higher concentrations of TAKENATE 500 consumed little or no food and water prior to death. Normal food and water consumption was observed for the surviving rat at 224.7 mg/m^3 from day 12 of the observation period. Food and water consumption was normal for the control.

- Lung weight to bodyweight ratio: The lung weight to bodyweight ratio was within normal limts for surviving rats and for the rats killed during the observation period. High values (>1) were found for rats dying during or within 2-3 days of exposure. The high value for one rat at 224.7 mg/m^3 is due to decreased bodyweight rather than increased lung weight.

Any other information on results incl. tables

The mean percentage by weight of respirable particles (aerodynamic diameter <5.5 µm) was 88.5% (S.D. 0.95%)

Applicant's summary and conclusion

Interpretation of results:
other: Acute toxicity Category 2 (Fatal if inhaled)
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
In an acute inhalation study in rats, conducted in accordance with OECD 403 and GLP, a 4h-LC50 of 0.17 mg/L (males) and 0.19 mg/L (females) was determined.
Executive summary:

In an acute inhalation study in rats, conducted in accordance with OECD 403 and GLP, a 4h-LC50 of 0.17 mg/L was determined. The rats (5 males and 5 females per dose) were exposed by whole body. The mean achieved doses were 58.3, 198.8, 224.7 and 358.0 mg/m^3 of chamber air. Two of the 10 animals in the 198.8 mg/m^3 group, nine of the 10 animals in the 224.7 mg/m^3 group (includes 2 rats killed for humane reasons) and all animals of the highest dose group died during exposure. The rats in the other dose group survived. Exposure to TAKENATE 500 in an aerosol form produced irritant effects to the mucous membranes, the skin and the respiratory system of the rat.