Registration Dossier

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 13 October 1989 to 28 March 1990
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted in accordance with generally accepted scientific principles, possibly with incomplete reporting or methodological deficiencies, which do not affect the quality of the relevant results.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report Date:
1990

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
EPA OPP 81-3 (Acute inhalation toxicity)
Principles of method if other than guideline:
Atmospheric concentrations and particle size did not meet agency requirements. Due to the small size of the test materal, grinding with a Jet mill would not have increased the percentage of particles less than 1 um in size. Although higher concentrations could be obtained with the Wright dust generator at higher settings, the reservoir would have to be removed and replaced with a newly packed reservoir. This would take 5-10 minutes during which time the animals would not be exposed to test material.
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Molecular weight (if other than submission substance): 326

- Physical state: powder
- Analytical purity: 99.8%

- Lot/batch No.: AGR 240043

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston NY
- Age at study initiation: 11-13 weeks
- Weight at study initiation: males = 257 g, females = 145 g
- Fasting period before study:
- Housing: two per cage in stainless steel wire cages
- Diet (e.g. ad libitum): Purina Certified Rodent Chow #5002, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: one week


ENVIRONMENTAL CONDITIONS

- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: no data
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:Stainless steel and glass 157 liter Rochester-type chambers (50cm wide x 50 cm deepx 50 cm high with pyramid top and bottom)


- Source and rate of air: airflow maintained at 30 ml per minute

- System of generating particulates/aerosols:Aerosolized using a Wright Dst Feeder.
- Method of particle size determination: mass concentration of aerosol present in the chamber was determined gravimetrically at least four times durin the 4-hour exposure period by drawing samples from a vertical stainless steel tube which projected into the animal breathing zone. Exposure concentrations were calculated based from these determinations using a time-weighted average method. Aerodynamic particle size was determined three times during the exposure period by drawing samples from the animal breathing zone through a six-stage Cascade Impactor.

- Temperature, humidity, pressure in air chamber: Air supplied to the chambers was controlled by a system designed to maintain temperature and relative humidity at 22 degrees C and 50 %, respectively.


TEST ATMOSPHERE
- Brief description of analytical method used: Air flow was measured using manometer calibrated with a gas meter prior to start of study.
- Samples taken from breathing zone: yes
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
4 h
Concentrations:
1.2 mg/L for a 4-hour period
No. of animals per sex per dose:
5 females and 5 males exposed to the highest attainable concentration of test material (1.2 mg/l) for a single 4-hour period.
Control animals:
not specified
Details on study design:
Groups of 5 males and 5 female rats were exposed to the highest practically attainable concentration (~1.2 mg/liter) of the test material for a single 4-hour period. Whole body exposures occurred under dynamic air flow conditions. Animals were observed daily and weighed on test days 1, 2, 4, 8, 11, and 15. All animals were necropsied on test day 15. Inhalation was selected as the route of administration since it is a potential route for human exposure.
Statistics:
Means and standard deviations of animal body weights, chamber temperatures and relative humidities, and chamber airflows were calculated for descriptive purposes.

Results and discussion

Preliminary study:
no information
Effect levels
Sex:
male/female
Dose descriptor:
other: no observed effect
Effect level:
1.2 mg/L air
Exp. duration:
4 h
Remarks on result:
other: maximum achievable concentration in air.
Mortality:
no mortality
Clinical signs:
no clinically visible effects
Body weight:
Average body weights on day 2 were decreased slightly from pre-exposure values, but thereafter the animals achieved expected gains in body weight.
Gross pathology:
No grossly visible lesions noted in animals necropsied at the end of the 14 day post-exposure period.
Other findings:
no information

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: not specified
Conclusions:
All animals survived the 4-hour exposure and 14 day post-exposure period with no clinically visible effects.
Executive summary:

The purpose of this study was to determine the acute toxicity of inhaled XRD-498. Groups of male and female Fischer 344 rats were exposed to approximately 1.2 mg/liter XRD-498 aerosol (the highest attainable concentration) for 4 hours under dynamic airflow conditions. The mass median aerodynamic diameter and geometric standard deviation for the two exposures were 3.8 um +_ 2.2 and 3.4 um +_ 2.2, respectively. The animals were weighed at selected intervals during the 2 -week post-exposure period and observed daily. All animals were necropsied at the end of the 2 week post-exposure period. All animals survived the 4 -hour exposure and 14 -day post-exposure period with no clinically visible effects. The average body weight on test day 2 was decreased slightly (2%) from pre-exposure values but thereafter the animals achieved expected body weight gains. There were no exposure-related grossly visible lesions noted in the animals necropsied at the end of the 14 -day post-exposure period.