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Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2010-03-24 - 2010-04-27
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report date:
2010

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Mullite
EC Number:
215-113-2
EC Name:
Mullite
Cas Number:
1302-93-8
Molecular formula:
Al6O13Si2
IUPAC Name:
tris(oxo[(oxoalumanyl)oxy]alumane); bis(silanedione)

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Animal maintenance and environmental control
Hygiene: Optimal hygienic conditions.
Room number: EI1-11.
Room temperature: Range = 20.2 to 20.9 °C
Relative humidity: Range = 47.0 to 62.4 %.
Air exchange: About 12 / h.
Light: Artificial light from 6 a.m. to 6 p.m.
Cages: Single caging in Makrolon cages type III (39 cm x 23 cm x 18 cm). Wire mesh lids.
Bedding material: Aspen wood chips, Fa. ABEDD Dominik Mayr KEG, A-8580 Köflach, autoclaved. Random samples of the bedding material are analysed for contaminants by the supplier. Changes 1 / week.
Environmental enrichment: Nibbling wood bricks (10 cm x 2 cm x 2 cm) and nesting material, both from the same material and source as the bedding material, were offered to the animals once a week.
Water: Tap water, acidified with HCl to pH >3, from an automatic watering system, ad libitum. Random samples of the water are analysed by the "AGES", 1226 Vienna, Austria, to check, if the water fulfils the requirements for drinking water for humans (exception: the pH).
Feed: Ssniff R/M-H maintenance diet for rats and mice (item V1534-300) ad libitum, supplied by Ssniff Spezialdiäten GmbH, 59494 Soest, Germany. Analysis of the feed for ingredients and contaminants is performed randomly by Ssniff.
Identification: Labelling with felt-tipped pen on the tail and on the cage.
Acclimatisation: At least 5 days.

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
Chamber
The test substance was administered in a 'nose-only' inhalation apparatus (TSE Systems GmbH, Bad Homburg, Germany; article no. 504101). It consisted of a two chamber system. The apparatus was 30 cm in diameter and 27 cm in height, resulting in a total volume of 19 litres. In the twenty openings of the outer chamber, the inhalation tubes with the animals were situated. As only ten animals were administered, only the openings in the upper row were used. Neither feed nor water was offered to the animals during the exposure.
The air (17.2 L/min) was inserted via the central opening in the bottom, it escaped via the upper central opening and via the animal tubes.
The inhalation chamber was situated in a fume cupboard.

Dust generation
A dust generator acc. to Budiman, from TSE Systems GmbH, Bad Homburg, Germany, was used.

Air
The air was obtained from a central pressure pump. The relative humidity was reduced to about 10 %. The air was filtered oil-free and distributed within the Research Centre. In the Toxicology Department the pressure was reduced.

Preparation and administration of the test substance
The test substance powder was pressed to a powder cake. Portions of 20 g each were filled into a steel cylinder with 46 mm inner diameter and pressed with a force of 10 tons. These steel cylinders with the powder cake were used for the filling of the dust generator.

Actual concentration of the test substance
The amount of test substance was measured by gravimetric analysis.
The dust was collected 8 times during the exposure in plastic pipette-tips filled with cotton-wool which were inserted into the inhalation facility through a separate hole between two inhalation tubes. The site of collection was within the outer chamber. The inner diameter of the tips was 7 mm. Accurately measured volumes of air with the dust were collected at a rate of 1.7 litres per minute which means a velocity of 0.75 m/sec in the tips. The exact amount of collected air was measured by a gas meter (Labor Experimentiergaszähler, size 00, 2 to 120 L/h, Ritter Apparatebau GmbH, D-44892 Bochum).
Each filter-tip was dried and weighed before sampling. After sampling dry air (< 10 % humidity) was passed through them until the weight was constant. The difference in the weights before and after sampling divided by the volume of air sampled is the concentration of the dust.

Nominal concentration of the test substance
The nominal chamber concentration was calculated as the weight of test substance used divided by the air flow through the chamber.

Size distribution of the dust
The size of the dust particles was analysed with a cascade impactor (Berner-Impaktor Type LPI4/0,06/2 from Hauke KG, Gmunden, Austria). It contains nine steps with cut-off- diameters from 0.06 µm to 16 µm. The cut-off diameters were obtained from the manufacturer.
5.65 litres/minute of the test substance - air mixture were passed through the impactor within 1 minute and the amount which sediment in the individual steps was determined gravimetrically. The site of collection was the same as for the analysis.
For the calculation of the mean particle size (mass median aerodynamic diameter, MMAD), the probit of the fraction of masses smaller then the cut-off diameters was plotted against the logarithm of the cut-off diameters and the linear regression of this graph was calculated, preferring the data around 50 %. The diameter, where the regression gives a probit of 5 (corresponding to a fraction of 50 %) is the mass median diameter. The quotient of the diameter at a probit of 6 (corresponding to a fraction of 84 %) to the MMAD is the geometric standard deviation (GSD).
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
The mean concentration of "White Fused Mullite" was 2190 mg/m3 or 2.19 mg/L.
No. of animals per sex per dose:
5 males and 5 females
Control animals:
no

Results and discussion

Preliminary study:
Preliminary experiments
Before starting the test, the following experiments were made to obtain more information about the test substance:
• It was tried to produce a dust with an actual concentration of 5 mg test substance per litre.
• Two rats were exposed during the dust generation to obtain first results about the toxicity of the test substance.

Results:
The highest possible dust concentration which could be produced was about 2.5 mg/L. A higher feed rate of the scraper is not possible when a 4 hour operation was required.
Two rats which were exposed to this dust for 4 hours did not show signs of toxicity.
The particle size of the dust was higher than 4 µm. But as the limit concentration of 5 mg/L was not reached, no separator for large particles was used as this would decrease also the smaller particles.
Therefore it was decided to expose the first group with the highest technically feasible dust concentration.
Effect levelsopen allclose all
Sex:
male
Dose descriptor:
LC50
Effect level:
> 2.19 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Sex:
female
Dose descriptor:
LC50
Effect level:
> 2.19 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
All animals survived till the end of the study.
Clinical signs:
other: All animals were normal during the 14 days of the observation period.
Body weight:
The mean body weights at the day of the exposure were 341 g for males and 236 g for females. Most animals lost weight the first day after the exposure. This is caused by the restraining of the animals in the inhalation tubes. All animals gained weight one and two weeks after the exposure.
Gross pathology:
Necropsy: Nothing abnormal was seen in any of the animals.
Histopathology: All animals with the exception of one female were affected. All findings can be explained by the response of the lungs to high amounts of test substance dust and borderline tissue damage. The findings were general of low degree of severity.

Applicant's summary and conclusion

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The inhalation exposure of rats to "White Fused Mullite" at the maximal technically feasible concentration of 2.19 mg/L (2.19 g/cm3) did not produce signs of toxicity. All animals survived and no adverse effects were observed during the 14-day observation period. Histologically adaptive reactions to the test substance dust and borderline signs of tissue damage were seen in the lungs.
The LC50, per inhalation, four hours exposure, of "White Fused Mullite" for male and female rats is therefore greater than 2.19 mg per litre air (2.19 g/m3) which is the highest technically feasible dust concentration.
Executive summary:

The inhalation exposure of rats to "White Fused Mullite" at the maximal technically feasible concentration of 2.19 mg/L (2.19 g/m3) did not produce signs of toxicity. All animals survived and no adverse effects were observed during the 14-day observation period. Histologically adaptive reactions to the test substance dust and borderline signs of tissue damage were seen in the lungs.

The LC50, per inhalation, four hours exposure, of "White Fused Mullite" for male and female rats is therefore greater than 2.19 mg per litre air (2.19 g/m3) which is the highest technically feasible dust concentration.

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