Registration Dossier

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
4.8.2000-18.8.2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2000
Report Date:
2000

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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male
Details on test animals and environmental conditions:
Quarantine and Animal Selection
Rats were quarantined after arrival for 6 days prior to testing. During the quarantine period, rats were weighed and observed for clinical signs of disease 3 times. Rats were obtained from the general population of stock rats released from quarantine and were selected for use on this study from those rats exhibiting a normal pattern of weight gain and no overt signs of disease.

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Mass median aerodynamic diameter (MMAD):
7 µm
Geometric standard deviation (GSD):
2.4
Remark on MMAD/GSD:
Animals were exposed to H-24515 at a concentration of 8.0 mg/L. The mass median aerodynamic diameter (MMAD) of the aerosol particles collected during an inhalation exposure is generally targeted to be 1-4 μm. The dust atmospheres generated during this study were considered to be only moderately respirable in rats since the MMAD was 7.0 μm. However, 66% of the atmosphere was less than 10 μm.
Although attempts at grinding the test substance differently (e.g., sieving) and various generation systems were tried during the method development phase of the study, the physical properties of the test substance (e.g., granular texture) and safety concerns (e.g., explosivity), made it difficult to generate an atmosphere with a MMAD that was less than 7.0 μm. The atmospheres generated during this study were considered to be the best that could be generated, and acceptable for a hazard evaluation.
Details on inhalation exposure:
Atmosphere Generation
Chamber atmospheres of H-24515 were generated by suspending the particulate test substance in air with a Fluid Energy Processing model 00 Jet-O-Mizer jetmill. The test substance was metered into the jetmill with a K-Tron model T-20 twin screw volumetric feeder. Nitrogen was introduced into the bin feeder to prevent moisture absorption by the test substance. Filtered, houseline air (37 L/min) introduced into the jetmill carried the resulting atmosphere into a 1.5 L glass cyclone elutriator and then into the exposure chamber. Chamber concentrations of H-24515 were controlled by varying the test substance feed rate to the jetmill.
Test atmospheres were exhausted through a high-capacity particle filter followed by an MSA charcoal/HEPA filter cartridge prior to discharge into the fume hood.

Chamber Construction and Design
The exposure chamber was constructed of glass (cylindrical) with a nominal internal volume of 29 L. A dispersion plate inside the chamber promoted uniform chamber distribution of the test atmosphere.

Exposure Mode
During exposure, rats were individually restrained in perforated plastic cylinders with conical nosepieces. The restrainers were inserted into the polymethylmethacrylate faceplate of the exposure chamber so that only the nose of each rat extended into the chamber.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
8.0 mg/L
Range: 5.2-11 mg/L (s.d. 2.0, n=9)
No. of animals per sex per dose:
6
Control animals:
no

Results and discussion

Effect levels
Key result
Sex:
male
Dose descriptor:
other: ALC / approximate lethal concentration
Effect level:
> 8 mg/L air
Exp. duration:
4 h
Mortality:
All rats exposed to H-24515 survived the exposure and subsequent 14-day recovery period.
Clinical signs:
No abnormalities were observed in rats during the exposure. Immediately following the exposure and one day postexposure, most rats exposed to H-24515 exhibited stained/wet fur and nasal/ocular discharge. Stained fur and nasal/ocular discharge continued to be observed in some rats up to 3 days following exposure.
Body weight:
In addition, all rats had slight to severe weight loss (4 to 13% of initial body weight) on the day following the exposure, but had normal weight-gain patterns by the second day of recovery and experienced an overall weight gain by the end of recovery period.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Under the conditions of this study, the approximate lethal concentration (ALC) for H-24515 was greater than 8.0 mg/L. Because of the low respirability of the test atmosphere, this study should be considered a hazard evaluation of the test substance, rather than an accurate toxicity evaluation. However, H-24515, as tested, is considered to be no worse than very low in toxicity on an acute inhalation basis (ALC greater than 2.0 mg/L).
Executive summary:

One group of 6 male Crl:CD®(SD)IGS BR rats was exposed nose-only for a single, 4-hour period to H-24515 in air. The test atmosphere was generated by suspension of H-24515 particulate in air. Gravimetric analysis was used to measure the concentration of the test substance in the exposure chamber. Rats were weighed and observed for clinical signs of toxicity during a 14-day recovery period.

Rats were exposed to a dust atmosphere of H-24515 at a concentration of 8.0 mg/L. The mass median aerodynamic diameter (MMAD) for the dust generated in the exposure chamber was 7.0 μm, with 66% of the particles less than 10 μm.

All rats exposed to H-24515 survived the exposure and subsequent 14-day recovery period. Stained/wet fur and nasal/ocular discharge were observed in rats up to 3 days following exposure. In addition, all rats had slight to severe weight loss (4 to 13% of initial body weight) on the day following the exposure, but had normal weight-gain patterns by the second day of recovery and experienced an overall weight gain by the end of recovery period.

Under the conditions of this study, the approximate lethal concentration (ALC) for H-24515 was greater than 8.0 mg/L. Because of the low respirability of the test atmosphere, this study should be considered a hazard evaluation of the test substance, rather than an accurate toxicity evaluation. However, H-24515, as tested, is considered to be no worse than very low in toxicity on an acute inhalation basis (ALC greater than 2.0 mg/L).