1,3-bis(1-isocyanato-1-methylethyl)benzene

Specific investigations: other studies

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

specific investigations: other studies

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From Jul. 16, 1988 to Oct. 14, 1988

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

other: American Standard Test Method E981-84 (ASTM, 1984)

Deviations:

no

Principles of method if other than guideline:

The testing protocol was based on American Standard Test Method E981-84 (ASTM, 1984).

GLP compliance:

not specified

Type of method:

in vivo

Endpoint addressed:

respiratory irritation

Species:

mouse

Strain:

Swiss Webster

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Sprague Dawley, Inc., Indianapolis, IN
- Age at study initiation: 7-8 wk
- Housing: 2/cage,wire mesh cages
- Diet: Pellet feed (Pro Lab RHM #3000, Agway, Inc.), ad libitum
- Water: Tap water (Municipal Authority of Westmoreland County. Greensburg, PA), ad libitum
- Acclimation period: At least 7 d


ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12h dark/12h light


IN-LIFE DATES: From: Jul. 16, 1988 To: Oct. 14, 1988

Route of administration:

inhalation

Vehicle:

unchanged (no vehicle)

Details on exposure:

RANGE FINDING TESTS: Groups of 2-4 animals were exposed to increasing concentrations of test material until a sensory irritation wave pattern was observed (i.e., a lengthening of the expiratory phase of breathing) and concentration was then determined analytically and used as the target concentration for the first exposure.

Animal exposure details:
- Technique: Head only
- Exposure chamber: Plethysmographs
- Volume of the chamber: 2.3 L
- Air flow rate: 36 L/min
- Frequency of data recording: 15 sec
- Acclimatization in chamber: 10-15 min
- Preexposure period: 10 min
- Exposure period: 3 h
- Recovery period: 10 min (only clean air was introduced into the exposure system during recovery period)

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

- The analytical method for m-TMXDI was an adaptation of the HPLC Standard Method.
- HPLC was performed using a Waters liquid chromatograph equipped with an SP8400 ultraviolet/visible detector and a Spectra-Physics SP4290 Integrator.
- The reverse phase HPLC method is summarized below.
- Column: Adsorbosphere TMS 10 U (250 x 4.6 mm)
- Mobile phase: 60 % acetonitrile, 40 % of 1 % triethylamine in water (pH to 3.0 with phosphoric acid)
- Flow rate: 2.0 mL/min
- Volume of injection: 10 microliters
- Wavelength: 254 nm
- Detector range: 0.02
- Chart speed: 1 cm/min
- Retention time: 4.25 minutes
- Chart attenuation: 64

Duration of treatment / exposure:

3 h/exposure

Frequency of treatment:

Single

Post exposure period:

No data

Remarks:

Doses / Concentrations:
0.48, 1.1, 1.3 and 2.5 ppm
Basis:
nominal conc.

No. of animals per sex per dose:

Four

Control animals:

no

Details on study design:

None

Details on results:

- Chamber exposure concentrations: The mean concentrations (± SD) generated for the 4 mouse exposures were 0.48 (± 0.07), 1.1 (± 0.06), 1.3 (± 0.31) and 2.5 (± 0.30) ppm.
- Clinical observations and mortality: Periocular wetness was observed in 75-100 % of animals in all but the 0.48 ppm group immediately following exposure
- Mortality was observed in 1 animal of the highest concentration group on Day 4
- Body weights: Mean body weight gains were observed in all exposure groups but 1.3 ppm group.
- Respiratory rate: Decrease in respiratory rate was observed with maximal depression for all concentration groups was achieved within 30 min following the start of the exposure. The maximal decrease in respiratory rate was sustained throughout the duration of the exposure period. The concentrations of test material vapor which produced a 50 percent decrease in respiratory rate were determined to be 1.7 ppm
- Tidal Volume: No effect on tidal volume occurred in test animals.
- Minute volume and theoretical dose available for deposition: The minute volumes for mice exposed to approximately 0.5 and 1.4 ppm test material was 40.7 and 25.7 mL/min respectively. The estimates of the total amount of test material inhaled during an exposure to 0.5 and 1.4 ppm were calculated to be 35 and 63 µg respectively. The dose available for deposition in the upper respiratory tract for animals exposed to approximately 0.5 ppm was calculated to be 0.07 µg/min/cm2. The dose available for deposition in the alveolar region for animals exposed to approximately 1.4 ppm was calculated to be 0.00051 µg/min/cm2.

Table1. Mean percent decrease in respiratory rate, tidal volume of mice at each exposure concentration

m-TMXDI concentration (ppm)	Mean maximal % decrease in respiratory Rate	Mean Maximal Percent Change in Tidal Volume
0.48	6	-13
1.1	36	-2
1.3	46	3
2.5	60	1

 

Conclusions:

Under the conditions of the test, the concentrations of test material vapor which produced a 50% decrease in respiratory rate, RD50, was found be 1.7 ppm.

Executive summary:

A study was conducted to investigate the respiratory response and sensory irritation potential of test material in male Swiss Webster mice. The procedure was based on American Standard Test Method (ASTM) E981-84 and prior research investigating respiratory intake of sensory irritants.

Test animals (4/group) were exposed (head-only) to test material vapour for 3 h at a concentration of 0.48, 1.1, 1.3 or 2.5 ppm. Sensory irritation was assessed by monitoring the decrease in respiratory rate which resulted during exposure to the test material.

Clinical signs of toxicity occurring at concentrations of 1.1 ppm and higher included periocular wetness, decreased motor activity and/or an unkempt appearance. The incidence of these clinical signs generally increased with the exposure concentration and typically lasted only several days.

Exposure to the test material depressed respiratory rate and, as a result, minute volume in test animal. Tidal volume was not affected. The dose available for deposition in the nasal cavity exposed to approximately 0.5 ppm was calculated to be 0.07 µg/min/cm²and the dose available for deposition in the alveoli for mice exposed to approximately 1.4 ppm was calculated to be 5.1 µg/min/cm².

 

Under the conditions of the test, the concentrations of test material vapour which produced a 50% decrease in respiratory rate, RD50, was found be 1.7 ppm.

 

Reference 2

Endpoint:

specific investigations: other studies

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From Jul. 16, 1988 to Oct. 14, 1988

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Reason / purpose for cross-reference:

reference to other study

Qualifier:

equivalent or similar to guideline

Deviations:

no

Principles of method if other than guideline:

The testing protocol was based on American Standard Test Method E981-84 (ASTM, 1984).

GLP compliance:

not specified

Type of method:

in vivo

Endpoint addressed:

respiratory irritation

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Sprague Dawley, Inc., Indianapolis, IN
- Age at study initiation: 7-8 wk
- Housing: 4/cage, wire mesh cages
- Diet (e.g. ad libitum): Pellet feed (Pro Lab RHM #3000, Agway, Inc.), ad libitum
- Water (e.g. ad libitum): Tap water (Municipal Authority of Westmoreland County. Greensburg, PA), ad libitum
- Acclimation period: At least 7 d


ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12h dark/12h light


IN-LIFE DATES: From: Jul. 16, 1988 To: Oct. 14, 1988

Route of administration:

inhalation

Vehicle:

unchanged (no vehicle)

Details on exposure:

RANGE FINDING TESTS: Groups of 2-4 animals were exposed to increasing concentrations of test material until a sensory irritation wave pattern was observed (i.e., a lengthening of the expiratory phase of breathing) and concentration was then determined analytically and used as the target concentration for the first exposure

Animal exposure details:
- Technique: Head only
- Exposure chamber: Plethysmographs
- Volume of the chamber: 5.1 L
- Air flow rate: 36 L/min
- Frequency of data recording: 15 sec
- Acclimatization in chamber: 30 min
- pre-exposure period: 10 min
- Exposure period: 3 h
- Recovery period: 10 min (only clean air was introduced into the exposure system during recovery period).

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Instrumentation and method:
- The analytical method for m-TMXDI was an adaptation of the HPLC Standard Method.
- HPLC was performed using a Waters liquid chromatograph equipped with an SP8400 ultraviolet/visible detector and a Spectra-Physics SP4290 Integrator.
- The reverse phase HPLC method is summarized below.
- Column: Adsorbosphere TMS 10 U (250 x 4.6 mm)
- Mobile phase: 60 % acetonitrile, 40 % of 1 % triethylamine in water (pH to 3.0 with phosphoric acid)
- Flow rate: 2.0 mL/min
- Volume of injection: 10 mL
- Wavelength: 254 nm
- Detector range: 0.02
- Chart speed: 1 cm/min
- Retention time: 4.25 minutes
- Chart attenuation: 64

Duration of treatment / exposure:

3 h/exposure

Frequency of treatment:

Single

Post exposure period:

No data

Remarks:

Doses / Concentrations:
0.56, 0.84, 1.4 or 2.2 ppm
Basis:
nominal conc.

No. of animals per sex per dose:

Four

Control animals:

no

Details on study design:

None

Examinations:

Not applicable

Positive control:

Not applicable

Details on results:

- Chamber exposure concentrations: The mean concentrations (± SD) generated for the 4 rat exposures were 0.56 (± 0.10), 0.84 (± 0.09), 1.4 (± 0.18) and 2.2 (± 0.43) ppm.
- Clinical observations: Perinasal encrustation was observed in 50-100 % of rats in all exposure concentration groups immediately following exposure. Other clinical observations 0.84, 1.4 and 2.2 ppm group included lacrimation, periocular and perinasal encrustation, periocular and perinasal wetness, subcutaneous red discoloration around the eyes, audible breathing and/or reddened ears. Mortality occurred in 1 rat of the 0.84 ppm group on Day 2 post-exposure.
- Body weights: Mean body weight gains were observed in all exposure groups except for 2.2 ppm group.
- Respiratory rate: Decrease in respiratory rate was observed with maximal depression for all concentration groups was achieved within 30 min following the start of the exposure. The maximal decrease in respiratory rate was typically only sustained for several minutes. The concentrations of test material vapor which produced a 50 % decrease in respiratory rate was determined to be 3.7 ppm (the concentration-response curve was extended beyond the range of exposure concentrations in order to extrapolate the RD50)
- Tidal volume: Small decreases in tidal volume occurred in test animals which was typically sustained in the rats and did not return to preexposure levels during the recovery period
- Minute volume and theoretical dose available for deposition: The minute volumes for mice exposed to approximately 0.5 and 1.4 ppm test material were 129.5 and 110.6 mL/min respectively. The estimates of the total amount of test material inhaled during an exposure to 0.5 and 1.4 ppm were calculated to be 112 and 271 µg respectively. The dose available for deposition in the upper respiratory tract for animals exposed to approximately 0.5 ppm was calculated to be 0.05 µg /min/cm2. The dose available for deposition in the alveolar region for animals exposed to approximately 1.4 ppm was calculated to be 3.9 X 10(-4) µg/min/cm2.

Table1. Mean percent decrease in respiratory rate, tidal volume at each exposure concentration

m-TMXDI concentration (ppm)-X	Mean maximal % decrease in respiratory Rate-Y	Mean Maximal Percent Change in Tidal Volume
0.56	30	37
0.84	26	25
1.4	40	22
2.2	44	26

Conclusions:

Under the conditions of the test, the concentrations of test material vapor which produced a 50% decrease in respiratory rate (RD50), was found be 3.7 ppm.

Executive summary:

A study was conducted to investigate the respiratory response and sensory irritation potential of the test material in male Sprague Dawley rat. The procedure was based on American Standard Test Method (ASTM) E981-84 and prior research investigating respiratory intake of sensory irritants.

Test animals (4/group) were exposed (head-only) to test material vapour for 3 h at a concentration of 0.56, 0.84, 1.4 or 2.2 ppm. Sensory irritation was assessed by monitoring the decrease in respiratory rate which resulted during exposure to test material.

Rats exposed to 0.56 ppm of test material vapor exhibited only perinasal encrustation. However, at higher concentrations, ocular and nasal irritation, audible breathing, subcutaneous red discolouration around the eyes, and reddened ears were noted. The incidence of these clinical signs generally increased with the exposure concentration and typically lasted only several days. Exposure to test material depressed respiratory rate and, as a result, minute volume in test animal. The tidal volume of test animals decreased moderately during exposure however, the decrease in tidal volume was not determined to be concentration-dependent. The dose available for deposition in the nasal cavity at 0.5 ppm was calculated to be 0.05 µg /min/cm². The dose available for deposition in the alveoli at 1.4 ppm was calculated to be 3.9 µg /min/ cm².

 

Under the conditions of the test, the concentrations of test material vapour which produced a 50 % decrease in respiratory rate (RD50), was found be 3.7 ppm.

 

Additional information

Respiratory irritation (mice and rats)

A study was conducted to investigate the respiratory response and sensory irritation potential of test material in male Swiss Webster mice. The procedure was based on American Standard Test Method (ASTM) E981-84 and prior research investigating respiratory intake of sensory irritants. Test animals (4/group) were exposed (head-only) to test material vapour for 3 h at a concentration of 0.48, 1.1, 1.3 or 2.5 ppm. Sensory irritation was assessed by monitoring the decrease in respiratory rate which resulted during exposure to the test material. Clinical signs of toxicity occurring at concentrations of 1.1 ppm and higher included periocular wetness, decreased motor activity and/or an unkempt appearance. The incidence of these clinical signs generally increased with the exposure concentration and typically lasted only several days. Exposure to the test material depressed respiratory rate and, as a result, minute volume in test animal. Tidal volume was not affected. The dose available for deposition in the nasal cavity exposed to approximately 0.5 ppm was calculated to be 0.07 µg/min/cm2and the dose available for deposition in the alveoli for mice exposed to approximately 1.4 ppm was calculated to be 5.1 µg/min/cm2. Under the conditions of the test, the concentrations of test material vapour which produced a 50% decrease in respiratory rate, RD50, was found be 1.7 ppm (Burleigh-Flayer, 1992).

A study was conducted to investigate the respiratory response and sensory irritation potential of the test material in male Sprague Dawley rat. The procedure was based on American Standard Test Method (ASTM) E981-84 and prior research investigating respiratory intake of sensory irritants. Test animals (4/group) were exposed (head-only) to test material vapour for 3 h at a concentration of 0.56, 0.84, 1.4 or 2.2 ppm. Sensory irritation was assessed by monitoring the decrease in respiratory rate which resulted during exposure to test material. Rats exposed to 0.56 ppm of test material vapor exhibited only perinasal encrustation. However, at higher concentrations, ocular and nasal irritation, audible breathing, subcutaneous red discolouration around the eyes, and reddened ears were noted. The incidence of these clinical signs generally increased with the exposure concentration and typically lasted only several days. Exposure to test material depressed respiratory rate and, as a result, minute volume in test animal. The tidal volume of test animals decreased moderately during exposure however, the decrease in tidal volume was not determined to be concentration-dependent. The dose available for deposition in the nasal cavity at 0.5 ppm was calculated to be 0.05 µg /min/cm2. The dose available for deposition in the alveoli at 1.4 ppm was calculated to be 3.9 µg /min/ cm2. Under the conditions of the test, the concentrations of test material vapour which produced a 50 % decrease in respiratory rate (RD50), was found be 3.7 ppm (Burleigh-Flayer, 1992).