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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:
1995/07/28-1995/09/08
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: According to or similar to guideline study OECD 403: GLP

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1998
Report Date:
1998

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:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: Crl: CDBR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Kingston Facility, Stone Ridge, New York
- Age at study initiation: Group 1, approximately 6-7 weeks; Group 2, approximately 8-9 weeks
- Weight at study initiation: Group 1 males, 182 to 208 grams; Group 1 females, 171 to 184 grams; Group 2 males, 315 to 339 grams; Group 2 females, 220 to 232 grams
- Fasting period before study: none
- Housing: Single housed during study period, suspended stainless steel and wire mesh
- Diet (e.g. ad libitum): Certified Rodent Diet #5002 from PMI Feeds, Inc. Richmond, Indiana, ad libitum during non-exposure periods. Food was withheld while animals were in chamber.
- Water (e.g. ad libitum): Automatic watering system, ad libitum during non-exposure periods. Water withheld while animals were in chamber.
- Acclimation period: At least 12 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 68-76 degrees F in animal room; 70-74 degrees F in exposure chamber
- Humidity (%): 40-70% relative humidity in animal room; 58-73% relative humidity in exposure chamber
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark


IN-LIFE DATES: From: 1995-08-08 To: 1995-09-08

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 150 liter stainless steel and acrylic whole-body inhalation exposure chamber
- System of generating particulates/aerosols: The test material was generated using a single-barrel Laskin nebulizer and a 3-neck round-bottom flask as a reservoir for the liquid test material. Compressed air was supplied to the nebulizer at approximately 3.5-4.0 psi back-pressure, producing a liquid droplet aerosol atmosphere within the 3-neck flask. The aerosol mixed with additional room air which was drawn through a glass mixing vessel prior to entering the exposure chamber.
- Method of particle size determination: The particle size distribution was determined once during each exposure using a Sierra Instruments Model 210 Cascade Impactor. Pre-weighed glass fiber filters were used to collect the aerosol on each stage. A bulk estimation technique was employed to characterize the particle size distribution of the atmosphere. The change in weight of the filter for each stage was measured and the cumulative percent of the sample collected on each stage was calculated. This information plus the stage constants for the impactor were used to calculate the 15.9%, 50.0%, and 84.1% particle sizes (equivalent aerodynamic diameter), the geometric standard deviation, and the estimated percent of the aerosol less than or equal to 1, 10, and 15 microns in size.
- Temperature, humidity, pressure in air chamber: Chamber airflow, temperature, and relative humidity were monitored continuously throughout the exposure and recorded approximately every 30 minutes.


TEST ATMOSPHERE
- Brief description of analytical method used: Analytical chamber concentrations were determined during each hour of the exposure by drawing a known volume of the test atmosphere through a sample train consisting of pre-weighed teflon (PTFE) (Group 1) or glass fiber (Group 2) filters for non-volatile aerosol and a charcoal sorbent tube for volatile hydrocarbons.

From Group 1, the filters were first weighed for gravimetric determination of total non-volatile aerosol; the analytical procedure then specified analyis of both filters and sorbent tubes by GC/FID for total and individual hydrocarbons. However, the filters were not weighed until 8 days after the exposure and it appeared that a significant portion of the collected test material had volatilized from the fibers. Exposure was repeated with a second group of animals.

From Group 2, non-volatile aerosol was collected on a glass-fiber filter and the gravimetric determination was performed immediately following sample collection. The filters and sorbent tube were analyzed by GC/FID, and total hydrocarbons and individual hydrocarbons (full scan) were reported as the sum of the gravimetric aerosol and total hydrocarbon vapor results.

PARTICLE SIZE DATA
-Mass median equivalent aerodynamic diameter (50% size): Group 1 and Group 2, 3.7 microns
-Geometric standard deviation: Group 1, 2.9; Group 2, 2.5
-Percent <= 15 microns: Group 1, 91%; Group 2, 93.5%
-Percent <= 10 microns: Group 1, 83%; Group 2, 85.9%
-Percent <= 1 micron: Group 1, 10.6%, Group 2, 8.3%
Analytical verification of test atmosphere concentrations:
yes
Remarks:
gravimetrically (aerosol); GC/FID (vapor)
Duration of exposure:
4 h
Concentrations:
Group 1: estimated aerosol concentration of 5247 mg/m3
Group 2: analytical chamber concentration of 5266 mg/m3 (5213 mg/m3 aerosol, 53 mg/m3 vapor)
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: At 15 minute intervals during the first hour of exposure and once each hour thereafter through the termination of exposure.
- Necropsy of survivors performed: yes
Statistics:
Statistical analyses included means and standard deviations of body weight and body weight change by group and sex.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5 266 mg/m³ air (analytical)
Exp. duration:
4 h
Remarks on result:
other: No mortality occurred.
Mortality:
No mortality in either Group 1 or Group 2.
Clinical signs:
During exposure, animals in both Group 1 and Group 2 exhibited material on fur, decreased activity and closed eyes. Some animals in Group 2 displayed clear nasal discharge.

Upon removal from chamber, animals in both groups displayed decreased activity, test material on fur, fur wet and matted, and anogenital staining. Two animals in Group 1 exhibited clear ocular discharge and one animal in Group 2 displayed clear nasal discharge.
Body weight:
All animals displayed increased in body weight over their initial (Day 0) values, with the exception of two females in Group 2 that had slight weight losses.
Gross pathology:
All Group 1 animals were free of abnormalities at the gross postmortem evaluation.

In Group 2, 4 males/1 female exhibited red foci and/or slight discoloration on the lungs, 1 male displayed dark red nasal turbinates, 1 male had smaller than normal right kidney, and 3 males/1 female exhibited alopecia and/or scabs on the dorsal surface, extremities and/or head.

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LC50 for acute inhalation exposure (aerosol atmosphere) of MRD-95-247 is greater than 5266 mg/m3 (5213 mg/m3 aerosol, 53 mg/m3 vapor). This finding does not warrant classification of MRD-95-247 as an acute inhalation toxicant under the new Regulation (EC) 1272/2008 on classification, labeling, and packaging of substances and mixtures (CLP) or under the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.
Executive summary:

To assess acute inhalation toxicity, MRD-95 -247 was administered via individual whole-body inhalation chambers for four hours to two groups of ten Crl:CDBR rats at either an estimated aerosol concentration of 5247 mg/m3 or an analytical concentration of 5266 mg/m3 (5213 mg/m3 aersol, 53 mg/m3 vapor). Animals were observed for fourteen days following exposure. No mortality was observed, and all animals that received the estimated aerosol concentration of 5247 mg/m3 were free of gross pathological abnormalities. In the second group (5266 mg/m3 aerosol), 4 males and 1 female exhibited red foci on the lungs, one male displayed dark red nasal turbinates, and 3 males and 1 female had alopecia and/or scabs on the dorsal surface, extremities, and/or head. Based on the conditions of this study, the LC50 for acute inhalation exposure to an aerosol atmosphere of MRD-95 -247 is greater than 5266 mg/m3.

This finding does not warrant classification of MRD-95-247 as an acute inhalation toxicant under the new Regulation (EC) 1272/2008 on classification, labeling, and packaging of substances and mixtures (CLP) or under the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.