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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:
2000/07/17-2000/07/31
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: According to or similar to guideline study OECD 403: GLP.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Cross-reference
Reason / purpose:
read-across: supporting information
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
2000/07/17-2000/07/31
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: According to or similar to guideline study OECD 403: GLP.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Reason / purpose:
read-across source
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
no
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Inc.
- Age at study initiation: 9-10 weels
- Weight at study initiation: Males: 299-325 g; Females: 221-244g
- Fasting period before study:
- Housing: single housed
- Diet (e.g. ad libitum): PMI Feeds
- Water (e.g. ad libitum): ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 64-72
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
The animals were individually housed within a 150-liter stainless steel and acrylic whole body inhalation exposure chamber. The chamber operated under slight negative pressure to the room, at an airflow of approximately 30 liters per minute. The exposure period was 4 hours, plus time for equilibration (theoretical T99 = 23 minutes). Chamber airflow, temperature, and relative humidity were monitored continuously throughout the exposure and recorded approximately every 30 minutes.

The concentration of solvent in the test atmosphere was monitored continuously during the exposure by means of a high temperature total hydrocarbon analyzer. The instrument was calibrated using a gravimetric procedure.

Test Atmosphere Generation: The test material was volatilized at 160 deg C. The resulting vapors were drawn into the exposure chamber by the supply air moving countercurrent to the liquid flow.

Exposure Concentrations: Nominal concentrations were determined by subtracting the weight of the syringe from the weight of the syringe plus test material. Analytical concentrations were determined through the use of a calibrated infrared monitor. Chamber concentrations were recorded every 30 minutes. Uniformity of the test atmosphere was conducted by sampling the concentration of the four corners of the exposure chamber.

Analytical verification of test atmosphere concentrations:
yes
Remarks:
4951 mg/m3; maximum attainable vapor
Duration of exposure:
4 h
Concentrations:
4951 mg/m3 (analytical); 5250 mg/m3 (nominal); maximum attainable vapor
No. of animals per sex per dose:
5 males; 5 females
Control animals:
no
Details on study design:
Experimental Evaluation
The animal population as a whole was observed for mortality and obvious signs of toxicity at approximately 1 5-minute intervals during the first hour of exposure and once each hour thereafter throughout the exposure. Detailed individual animal observations were recorded pre-exposure, post-exposure upon removal from the chamber, and once daily for 14 days post-exposure. Body weights were recorded prior to exposure (Day 0), and on Days 7 and 14 post-exposure.

Termination
After the Day 14 observations, all surviving animals were sacrificed by exsanguination from the abdominal aorta while under sodium pentobarbital anesthesia (administered intraperitoneal). A gross necropsy which included an examination of the external surface of the body, the cranial, thoracic, abdominal cavities and their contents, and complete examination of the respiratory tract (primarily the external surfaces) was performed on all animals.
Statistics:
Statistical analyses included the calculations of means and standard deviations for body weight and body weight change by sex (Snedecor and Cochran, 1989).
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 4 951 mg/m³ air (analytical)
Exp. duration:
4 h
Remarks on result:
other: maximum attainable vapor concentration
Mortality:
All rats survived to the end of the experimental observation.
Clinical signs:
All rats appeared normal during the exposure and during the 14 day post-exposure period.
Body weight:
No effects noted
Gross pathology:
All animals were free of any pathological symptoms at their postmortem examination.
Interpretation of results:
other: Not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The LC50 for acute inhalation exposure to MRD-00-586 vapor is greater than the highest obtainable vapor concentration (4951 mg/m3). Classification as an acute inhalation toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.
Executive summary:

MRD-00-586 was administered via individual inhalation chambers for four hours to ten rats at the maximum attainable vapor concentration of 4951 mg/m3 for four hours to assess acute inhalation toxicity. There were no mortality or gross pathological alterations noted in any of the animals.  Based on the conditions of this study, the LC50 for acute inhalation exposure to MRD-00-586 vapor is greater than the highest obtainable vapor concentration (4951 mg/m3).  Classification as an acute inhalation toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report Date:
2005

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Inc.
- Age at study initiation: 9-10 weels
- Weight at study initiation: Males: 299-325 g; Females: 221-244g
- Fasting period before study:
- Housing: single housed
- Diet (e.g. ad libitum): PMI Feeds
- Water (e.g. ad libitum): ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 64-72
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
The animals were individually housed within a 150-liter stainless steel and acrylic whole body inhalation exposure chamber. The chamber operated under slight negative pressure to the room, at an airflow of approximately 30 liters per minute. The exposure period was 4 hours, plus time for equilibration (theoretical T99 = 23 minutes). Chamber airflow, temperature, and relative humidity were monitored continuously throughout the exposure and recorded approximately every 30 minutes.

The concentration of solvent in the test atmosphere was monitored continuously during the exposure by means of a high temperature total hydrocarbon analyzer. The instrument was calibrated using a gravimetric procedure.

Test Atmosphere Generation: The test material was volatilized at 160 deg C. The resulting vapors were drawn into the exposure chamber by the supply air moving countercurrent to the liquid flow.

Exposure Concentrations: Nominal concentrations were determined by subtracting the weight of the syringe from the weight of the syringe plus test material. Analytical concentrations were determined through the use of a calibrated infrared monitor. Chamber concentrations were recorded every 30 minutes. Uniformity of the test atmosphere was conducted by sampling the concentration of the four corners of the exposure chamber.

Analytical verification of test atmosphere concentrations:
yes
Remarks:
4951 mg/m3; maximum attainable vapor
Duration of exposure:
4 h
Concentrations:
4951 mg/m3 (analytical); 5250 mg/m3 (nominal); maximum attainable vapor
No. of animals per sex per dose:
5 males; 5 females
Control animals:
no
Details on study design:
Experimental Evaluation
The animal population as a whole was observed for mortality and obvious signs of toxicity at approximately 1 5-minute intervals during the first hour of exposure and once each hour thereafter throughout the exposure. Detailed individual animal observations were recorded pre-exposure, post-exposure upon removal from the chamber, and once daily for 14 days post-exposure. Body weights were recorded prior to exposure (Day 0), and on Days 7 and 14 post-exposure.

Termination
After the Day 14 observations, all surviving animals were sacrificed by exsanguination from the abdominal aorta while under sodium pentobarbital anesthesia (administered intraperitoneal). A gross necropsy which included an examination of the external surface of the body, the cranial, thoracic, abdominal cavities and their contents, and complete examination of the respiratory tract (primarily the external surfaces) was performed on all animals.
Statistics:
Statistical analyses included the calculations of means and standard deviations for body weight and body weight change by sex (Snedecor and Cochran, 1989).

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 4 951 mg/m³ air (analytical)
Exp. duration:
4 h
Remarks on result:
other: maximum attainable vapor concentration
Mortality:
All rats survived to the end of the experimental observation.
Clinical signs:
All rats appeared normal during the exposure and during the 14 day post-exposure period.
Body weight:
No effects noted
Gross pathology:
All animals were free of any pathological symptoms at their postmortem examination.

Applicant's summary and conclusion

Interpretation of results:
other: Not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The LC50 for acute inhalation exposure to MRD-00-586 vapor is greater than the highest obtainable vapor concentration (4951 mg/m3). Classification as an acute inhalation toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.
Executive summary:

MRD-00-586 was administered via individual inhalation chambers for four hours to ten rats at the maximum attainable vapor concentration of 4951 mg/m3 for four hours to assess acute inhalation toxicity. There were no mortality or gross pathological alterations noted in any of the animals.  Based on the conditions of this study, the LC50 for acute inhalation exposure to MRD-00-586 vapor is greater than the highest obtainable vapor concentration (4951 mg/m3).  Classification as an acute inhalation toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.