Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
Not reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: A non-GLP study performed to sound scientific principles with a sufficient level of detail to assess the quality of the submitted data. Study not extensive enough to fully address the repeated-dose toxicity of the substance.

Data source

Reference
Reference Type:
publication
Title:
Inhalation Experiments with Tantalum Oxide Dust
Author:
Nemetschek-Gansler H, Nemerschek T, Polley H, Wesch H, Renovanz H D & Franz H
Year:
1975
Bibliographic source:
Pneumonologie 152: 299-309

Materials and methods

Principles of method if other than guideline:
10 day repeated exposure inhalation to the test material for 10 hours each day. Inbred male Sprague-Dawley rats were used. Macroscopic and microscopic analysis was performed. The nominal concentration in the inhalation chamber was 150 mg/m³.

Dust application followed the protocol set out by Polley (1963, 1965).
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
Ta2O5
Physical state: powder
Particle size: ~ 2µ

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Housing: In groups in large cages. Individual for exposure.

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure:
not specified
Vehicle:
not specified
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
The dust atmosphere was produced by generators, where tantalum oxide compacts were constantly pushed against a rotating grinding wheel and pulverized. A constant dose and grain spectrum was formed.

EQUIPMENT
- Cleavage-channel dust-measuring instrument
- Recording dust photometer
- Tyndalloscope.

TEST CONDITIONS
- Temperature in dust channel: ~ 22ºC
- Humidity: 80-90%
- Carbon dioxide concentration: < 0.15%.
- Oxygen depletion: constantly < 1%, measured with a Draefer-Bio Marine apparatus.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
10 hours/day
Frequency of treatment:
10 days
Doses / concentrations
Dose / conc.:
150 mg/m³ air (nominal)
Remarks:
Approximately 150 mg/m³

No. of animals per sex per dose:
A total of 18 males were used in test. The animals were examined in groups of 2 or 3.
Control animals:
yes

Examinations

Observations and examinations performed and frequency:
EXAMINATIONS
- Animals were sacrificed for examination at the following time points:
> day 1 (3 rats)
> day 12 (3 rats)
> day 25 (3 rats)
> day 46 (2 rats)
> day 67 (2 rats)
> day 77 (2 rats)
> day 112 (3 rats)
- Clinical signs were recorded
Sacrifice and pathology:
Histopathology of lungs, quantitative dust examinations and ray bronchographs. Histology was performed using Light Microscopy Examination and Electron-Microscopic Examination.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Physical damage caused by the dust particles.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Physical damage caused by the dust particles.
Histopathological findings: neoplastic:
not examined
Details on results:
GROSS PATHOLOGY
Of the animals killed up to day 46 after termination of inhalation there was one animal in each group with extended haemorrhagic infarcts of both lobes. These infarcts are probably caused by a cytotoxic lesion of the alveolar capillaries caused by the enormously high dust loading.

HISTOPATHOLOGY
Light Microscope:
A dust deposition with a time-dependent tendency to fall off, both with respect to the dust deposits as well as the density of the dust in the cells. In the haemorrhagically infarcted areas, however, there was noticed a clear falling-out of dust elimination. In addition the dust was retained over a longer period than in animals which were only exposed to dust once. In those animals killed 1 day after the termination of the experiment the dust cells were irregularly spread throughout the lung that is they were found in the alveolar as well as in the intrabronchial area. There were no indications of formation of dust granulomas; the collagen content of the tissue appeared normal. The bronchial and bronchiolar ciliated epithelium showed defects of various sizes up to the day 46 after termination of the experiment. However, tissue that was withdrawn later did not show these defects. The impression is merely that of a hyperplastic reaction. In the peribronchial lymph nodes only a few dust cells of little significance were observed.

Electron Microscope:
Showed numerous monocytes in the alveolar capillaries and the alveolar septa.
No symptoms of a significant lesion of the dust cells can be seen.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Of the animals killed up to day 46 after termination of inhalation there was one animal in each group with extended haemorrhagic infarcts of both lobes. These infarcts are probably caused by a cytotoxic lesion of the alveolar capillaries caused by the enormously high dust loading.
Executive summary:

 

10 day repeated exposure inhalation to the test material for 10 hours each day. Inbred male Sprague-Dawley rats were used (18 animals in total). Macroscopic and microscopic analysis was performed. The nominal concentration in the inhalation chamber was 150 mg/m³. Animals were sacrificed at different time points in groups of 2 or 3 to the following schedule:

day 1 (3 rats)

day 12 (3 rats)

day 25 (3 rats)

day 46 (2 rats)

day 67 (2 rats)

day 77 (2 rats)

day 112 (3 rats)

 

Of the animals killed up to day 46 after termination of inhalation there was one animal in each group with extended haemorrhagic infarcts of both lobes. These infarcts are probably caused by a cytotoxic lesion of the alveolar capillaries caused by the enormously high dust loading.