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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:
11 October 2000 - 1 November 2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted to GLP in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report Date:
2001

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
other: EEC (Annex II, point 5.2.3)
Deviations:
no
Qualifier:
according to
Guideline:
other: J-MAFF
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
Ta2O5
Tantalum Pentoxide Grade LT

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River UK Limited, Manston Road, Margate, Kent, England
- Age at study initiation: Males approximately 7 weeks; Females approximately 8 weeks.
- Weight at study initiation: Males: 256 - 298 g; Females: 204 - 237 g
- Fasting period before study:
- Housing: The holding cages were made of stainless steel sheet and wire mesh and were suspended on a movable rack
- Diet (e.g. ad libitum): ad libitum. While in their cages all rats had free access to an excess amount of food, SDS rat and mouse diet (RM1 (E) SQC expanded pellet).
- Water (e.g. ad libitum): ad libitum. While in their cages all rats had free access to tap water supplied by Anglian Water. Tap water was available from individual polypropylene bottles that were emptied and re-filled daily.
There was no information available to indicate to the Study Director the presence, in the food or water, of any non-nutrient substance likely to influence the outcome of this study. The results of chemical analyses on batches of diet and water supplied to the animals during this study are lodged in the Huntingdon Life Sciences Archives.
- Acclimation period: 7 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.5 – 20.5 °C
- Humidity (%): 39 – 65 % relative
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12 hours light (06:00 - 18:00 GMT) and 12 hours dark per 24 hours.

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
EXPOSURE SYSTEM
Dust generator:
A Wright Dust Feed mechanism (WDF) (WRIGHT, B.M. (1950) A new dust-feed mechanism, J.Sc.Instr. 27,12) was used to produce the test atmosphere containing a particulate aerosol generated from Ta2O5.
The WDF was designed to produce and maintain atmospheres containing a particulate aerosol by suspending material scraped from the surface of a compressed powder in a stream of dry air. The concentration of particulate aerosol in the air is determined by the rate at which the scraper blade is advanced into the compressed powder.
Two models of a 'belt-driven' WDF are used for acute inhalation exposures, each with a different gearing mechanism and designated as 'Slow' or 'Fast'. The 'Fast WDF' was used for generation of the test atmosphere. A baffle, designated as 'narrow' and a jet were fitted to the WDF to break-up aggregates emitted from the aerosol generator.

Aerosol conditioning:
The test atmosphere was passed through a vertical glass elutriator to reduce, by sedimentation, the amount of non-respirable particulate in the test atmosphere.
The snout-only exposure chambers used for the exposures were of cylindrical form (30 cm diameter, 45 cm height) and made of aluminium alloy. The internal surfaces of the chamber have a conformal chemically resistant coating. The chambers have an enclosed volume of approximately 30 litres. The rats were held for exposure in moulded polycarbonate restraining tubes, which were attached at evenly spaced ports in the cylindrical section of the chamber, and were designed to allow only the snout to project into the chamber. Each rat was restrained in a forward position by an adjustable foamed plastic stopper, which also provided a seal for the tube.
The conditioned test atmosphere entered through a port at the top centre of the chamber and passed out through a port at the base section below the level of the rats.
The exposure system was positioned inside a large cabinet equipped with an extract fan exhausting to atmosphere through an absolute filter.

PROCEDURE
The test material was used hand ground using a pestle and mortar, prior to use, in order to produce a powder suitable for generation of the test aerosol.

A sample of the test substance was packed into the container of the Wright Dust Feed mechanism (WDF) using a hydraulic bench press to assist packing. An even density of the test substance was achieved by packing the container in stages and applying a force of 2.0 ton to compress the powder. The applied force was sufficient to prevent disintegration of the packed powder during the generation procedure.

A supply of clean, dry air was passed through an electronic neutraliser. The neutralised air was connected to the generator and the supply pressure was adjusted to give a flow rate of 25 litres/minute, measured at the generator outlet. An in-line flow meter was used to monitor the generator air supply throughout the exposure. The exhaust airflow was calibrated and adjusted to produce a slightly negative pressure.
The WDF was positioned vertically on a stand at the side of the exposure chamber and the output was connected to the top inlet port of the chamber via the elutriation column. A speed controller setting of '80% of the maximum speed' 4 of the WDF was selected, as a result of preliminary generation trials, to generate a concentration of total particulate at the maximum practicable concentration.
Each rat was placed into a separate restraining tube and the tubes were then attached to the exposure chamber.
The powder container of the WDF was advanced manually until a trace of suspended dust was seen to emerge from the WDF outlet. The gearing on the generator was then engaged and the generator motor switched on to start the exposure (a setting of '80 % of maximum' is the maximum operational speed of a 'Fast' Wright dust feed).

After an equilibration period of 3 minutes (3 minutes is the theoretical time required for the concentration of aerosol to reach 90 % of its final value under the conditions of exposure employed) the exposure was timed for 4 hours. The WDF canister was replaced with packed canisters as required during the exposure. The generator was then switched off and the chamber was allowed to clear before the rats were removed for examination.

CHAMBER ATMOSPHERE ANALYSIS
Chamber concentration:
Nine samples of air were removed from the test chamber during exposure in order to determine the concentration of the test aerosol. In the first instance, samples were obtained following equilibration and at approximately hourly intervals thereafter. Additional samples were obtained as necessary to monitor the chamber concentration in order to ensure satisfactory aerosol generation.
Each air sample was withdrawn, at a rate of 2 litres/minute, through a pre-weighed glass fibre filter mounted in an open face filter holder. The volume of air sampled was measured using a wet-type gas meter. The filters were re-weighed following sampling for gravimetric analysis of the test aerosol.
Particle size distribution
Two air samples were taken during the exposure at a sampling rate of 2 litres/minute using a Marple cascade impactor to determine particle size distribution. The samples were taken at 105 and 205 minutes into exposure. The volume of air sampled was measured using a wet-type gas meter.
The amount of material collected on the stages of the sampler was determined gravimetrically. The particle size distribution of the test atmosphere was assessed using linear regression analysis. The probit of the cumulative percentage of the total particles collected, smaller than the cut-point of each stage, was plotted against the logarithm of the cut-point of each stage.

NOMINAL CONCENTRATION
The nominal concentration of the test substance in the exposure chamber was calculated from the total mass of Ta2O5 dispersed by the dust generator and the total volume of air flowing through the exposure system during the period of generation.

CHAMBER AIR TEMPERATURE AND RELATIVE HUMIDITY
The air temperature in the exposure chamber was measured using an alcohol-in-glass thermometer and the relative humidity was measured using a Casella type T6900 relative humidity meter. The temperature and relative humidity were recorded at the start of exposure and then at 30-minute intervals during the 4-hour exposure.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
The mean chamber concentration of total particulate was 3.89 mg/L and was considered to be the maximum practicable concentration.
No. of animals per sex per dose:
5 male and 5 female
Control animals:
yes
Details on study design:
OBSERVATIONS
Mortality:
Throughout the study, all cages were checked at least twice daily, once in the morning and again towards the end of the normal working day, for dead or moribund animals.

Clinical signs:
The rats were observed intermittently for signs of reaction to the test substance during exposure and at least twice daily throughout the observation period.
The clinical signs were recorded at the end of the chamber equilibration period, at 0.25, 0.5 and 1.0 hours then at hourly intervals during the exposure. Clinical signs were recorded immediately following exposure and then at 1.0 and 2.0 hours post-exposure.
During the observation period, the clinical signs were recorded once in the morning and then as necessary following a later check for survival.

Bodyweight:
All rats were weighed at least twice during the week prior to exposure, prior to exposure (Day 0), weekly during the observation period and on the day of death.

Water consumption:
A visual inspection of water bottles was conducted daily.

TERMINAL STUDIES
At the end of the 14-day observation period, the rats were killed by intraperitoneal injection of pentobarbitone sodium followed by exsanguination from the brachial blood vessels.
All rats were subjected to a detailed macroscopic examination. The lungs (including the larynx and trachea) were removed, dissected clear of surrounding tissue, weighed and the weights recorded.
Tissues were discarded following necropsy.
Statistics:
CALCULATIONS
In order to minimise the cumulative errors, which result from repeated rounding of numbers, some of the data in this report have been calculated using unrounded data and only rounded for reporting. Consequently any further calculation using the data as presented will include rounding errors in the last significant figure, possibly leading to small apparent discrepancies with other data in the report.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LC0
Effect level:
> 3.89 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
There were no unscheduled deaths.
Clinical signs:
other: Clinical signs: - During the exposure - Exaggerated breathing was observed in all test rats from 2 hours into exposure. - Soiling of the fur with excreta was observed in all test and control group rats from 1 hour into exposure and was considered to be as
Body weight:
There were no treatment related effects.
Gross pathology:
There were no treatment-related findings noted at necropsy.
Small dark areas on the lungs were noted for a female test rat. This finding was considered to be incidental.
Other findings:
Lung weights:
The lung weights of male test rats were higher than control values. In the absence of any similar finding is the female animals, this was considered to be incidental and not treatment-related.

Any other information on results incl. tables

CHAMBER ATMOSPHERE CONDITIONS

 

Table 1: Chamber concentration of Ta2O5

Group

Sample

Time taken

(h:min)

Gravimetric concentration (mg/L)

Nominal concentration*

(mg/L)

2

(Test)

1

2

3

4

5

6

7

8

9

0:10

0:20

0:40

0:50

1:15

2:15

3:20

3:50

3:54

3.60

4.30

4.11

4.30

3.93

4.03

4.96

2.85

2.97

 

Mean

sd

3.89

0.007

49.6

sd = standard deviation

*Calculated from the total mass of the test substance dispersed by the generator (301.2 g) and the total volume of air supplied to the exposure system (6075 litres).

 

The mean chamber concentration of total particulate was 3.89 mg/L and was considered to be the maximum practicable concentration.

The nominal concentration was 49.6 mg/L. The mean chamber concentration was 7.8 % of the nominal concentration and reflects losses of the test material due to impaction, deposition and cohesion due to static within the exposure system. When generating Tantalum pentoxide, agglomeration due to static was considered to be a significant factor in particulate losses within the aerosol generation system. The use of a neutralised air supply to the WDF was necessary to achieve the concentrations attained. The relatively low efficiency observed in this study is not unusual for the exposure system and test compound employed.

 

Table 2: Particle size distribution

Group

Sample

Time taken

(h:min)

Stage

Cut-off size (µm)

Amount collected (mg)

2

(Test)

PSD 1

1:45

1

2

3

4

5

6

7

8

Filter

21.30

14.80

9.80

6.00

3.50

1.55

0.93

0.52

0.00

0.00

0.00

0.03

0.09

0.61

1.31

0.09

0.01

0.00

Total

2.14

PSD 2

3:25

1

2

3

4

5

6

7

8

Filter

21.30

14.80

9.80

6.00

3.50

1.55

0.93

0.52

0.00

0.01

0.00

0.03

0.19

0.84

1.21

0.03

0.00

0.01

Total

2.32

 

Table 3: Calculations

Cut-off size (µm)

% less than size (cumulative)

PSD 1

PSD 2

Combined

21.30

14.80

9.80

6.00

3.50

1.55

0.93

0.52

100.0

100.0

98.6

94.4

65.9

4.7

0.5

0

99.6

99.6

98.3

90.1

53.9

1.7

0.4

0.4

99.7

99.7

98.4

92.1

59.6

3.1

0.4

0.2

MMAD (µm)

σg

% respirable (<7 µm)

3.2

1.62

95

3.5

1.80

88

3.4

1.77

90

MMAD = Mass Mean Aerodynamic Diameter

σg = Geometric standard deviation

 

The mass median aerodynamic diameter (MMAD) of the test aerosol was 3.4 µm and was within the acceptable range (1 - 4 µm) for an acute inhalation study. Approximately 90 % of the particulate were considered of a respirable size (< 7 µm in aerodynamic diameter).

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LC0 (4-hour) for the test substance is in excess of 3.89 mg/L in air, the maximum practicable concentration.
Executive summary:

The acute toxicity of the test substance was examined in a 4-hour inhalation study using male and female Sprague-Dawley rats. The study design was in compliance with EEC (Annex II, point 5.2.3), OECD 403, US EPA (Health Effects Test Guidelines, OPPTS 870.1300, Acute Inhalation Toxicity, 5 August 1998) and J-MAFF test guidelines for acute inhalation studies. The study was conducted to GLP standard.

The LC0 (4-hour) for the test substance is in excess of 3.89 mg/L in air, the maximum practicable concentration.