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Diss Factsheets

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
01 Sep 2005 - 02 Nov 2005
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report date:
2005

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Qualifier:
according to guideline
Guideline:
other: Annex to the commission directive 92/69/EEC for 17. Amendment of the Council directive 67/548/EEC, Part B, B.2. Acute Toxicity, Inhalation.
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes

Test material

Constituent 1
Test material form:
solid: nanoform, no surface treatment
Details on test material:
- State of aggregation: solid, powder
- Particle size distribution (TEM): 29.1 nm (D50)
- Mass median aerodynamic diameter (MMAD): not specified
- Geometric standard deviation (GSD): not specified
- Shape of particles: plate
- Surface area of particles: 89 m²/g
- Crystal structure: crystalline
- Coating: no
- Surface properties: not applicable
- Density: 1566 kg/m³ at 20°C
- Moisture content: refer to IUCLID chapter 1
- Residual solvent: refer to IUCLID chapter 1
- Activation: not applicable
- Stabilisation: not applicable
Specific details on test material used for the study:
- Physical state: Powder / black
- Storage condition of test material: Room temperature
- CAS No. cis 41635-87-4, trans 6859-32-1
- Analytical purity: 99.9%
- Expiration date of the lot/batch: unlimited at room temperature

Test animals

Species:
other: rat, HanRcc:Wist (SPF)
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd Laboratory Animal Services, Fuellinsdorf, Switzerland
- Age at study initiation: approx. 9 weeks for males and approx. 10 weeks for females
- Weight at study initiation: mean (males): 265.1 +/-20.5 g; mean (females): 199.1 +/- 8.1 g
- Housing: single housing in cages type DK III (Becker, Germany) without bedding
- Diet: KLIBA mouse / rat Iaboratory diet 10 mm pellets "GLP", Kliba SA, Kaiseraugst, Basel Switzerland, ad libitum
- Water: drinking water ad libitum
- Acclimation period: at least 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24°C
- Humidity (%): 30 - 70%
- Air changes (per hr): The animals were kept in fully air-conditioned rooms
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
other: inhalation: dust aerosol
Type of inhalation exposure:
nose/head only
Vehicle:
other: 1 % of Aerosil 200 to improve dust aerosol formation
Mass median aerodynamic diameter (MMAD):
>= 1.8 - <= 2.1 µm
Geometric standard deviation (GSD):
>= 3 - <= 3.1
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Head-nose inhalation system INA 20 (glass-steel construction, BASF)
- Exposure chamber volume: 55 l
- Method of holding animals in test chamber: The animals were restrained in glass tubes and their snouts projected into the inhalation system.
- Source and rate of air: A supply air flow (compressed air) of 1.5 m3/h was used for the exposure. An air change of about 27 times per hour can be calculated by dividing the supply air flow by the volume of the inhalation system.
- System of generating particulates/aerosols: dosing-wheel dust generator (Gericke/BASF); the exposure system was located inside an exhaust cabin in an air-conditioned laboratory.
- Method of particle size determination: Cascade impactor measurements (Stack Sampler Mark III (Andersen))
- Treatment of exhaust air: The lower amount of exhaust air, which was adjusted by means of a separate exhaust air system, achieved a positive pressure inside the exposure system. This ensured that the mixture of test substance and air was not diluted with Iaboratory air in the breathing zones of
the animals.
- Temperature, humidity: 22-3 +/- 0.2°C, 56.2 +/- 0.4%,

TEST ATMOSPHERE
Test substance preparation:
The test substance was stirred in its container before a sample for dust generation was taken. The test substance was desagglomerated in a mixer under addition of 1 % (w/w) of Aerosil 200 before introduction into the dust generator, in order to improve dust aerosol formation.

- Brief description of analytical method used: Gravimetric determination. Sampling equipment: vacuum pump (Millipore). Preweighed filters were placed into the filtration equipment. By means of the vacuum pump metered volumes of the dust were drawn through the filter. For each sample the dust aerosol concentration in mg/I was calculated from the difference between the preweight of the filter and the weight of the filter after sampling, with reference to the sample volume of the inhalation atmospheres.
- Samples taken from breathing zone: yes

TEST ATMOSPHERE (if not tabulated)
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): Sample 1: 1.8 µm; Sample 2: 2.1 µm / Sample 1: 3.1; Sample 2: 3.0

Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Remarks on duration:
plus equilibration time of the inhalation systems (about 10 min)
Concentrations:
5.1 mg/l (nominal concentration: 24.7 mg/l)
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The body weight of the animals was determined just prior to exposure (day 0), weekly thereafter and at the end ot the observation period. A check for overt clinical signs of toxicity or mortality as well as a check for the presence of feed and drinking water was made twice a day on workdays and once daily on weekends and public holidays. Detailed clinical observations were recorded for each animal separately several times during exposure and at least once on each workday ot the observation period.
- Necropsy of survivors performed: yes
Statistics:
The binomial test was used for statistical evaluation.
The calculation ot the particle size distribution was carried out in the inhalation laboratory on the basis ot mathematical methods for evaluating particle measurements.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.1 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
not determinable
Mortality:
One of five female but no male animals died.
Clinical signs:
other: Clinical signs of toxicity comprised visually accelerated respiration, pulmonary respiration sounds, squatting posture, piloerection, smeared and contaminated fur, black colored faeces. Findings were observed from hour 0 of exposure until including study
Body weight:
The mean body weights of all surviving male and female animals increased throughout the study period.
Gross pathology:
Gross pathological abnormalities of the organs were noted neither in the female animal that died during exposure nor in those necropsied at termination of the post exposure observation period. Contaminated fur was observed in all animals. In the female animal that died during exposure, smeared fur around the snouts was observed additionally.

Any other information on results incl. tables

Under the conditions of this study the LC50 for male and female rats after dust inhalation was > 5.1 mg/l. Although 1 female animal died during exposure, the tested high concentration is judged to be sufficient to demonstrate the low order acute toxicity of the test substance and no further concentration was tested.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this study the LC50 for male and female rats after dust inhalation was > 5.1 mg/l.
Executive summary:

For determination of the acute inhalation toxicity (single 4-hour-exposure) of the test substance as dust, a GLP-compliant study in male and female Wistar rats was performed according to OECD-Guideline method 403, as well as EEC and EPA guidelines. A measured concentration of 5.1 mg/l was tested (Limit test). Cascade impactor measurements resulted in particle size distributions with mass median aerodynamic diameters (MMADs) of 1.8 and 2.1 um, which were well within the respirable range. At the tested concentration, one of five female but no male animals died during exposure. Clinical signs of toxicity comprised visually accelerated respiration, pulmonary respiration sounds, squatting posture, piloerection, smeared and contaminated fur, black colored faeces. Findings were observed from hour 0 of exposure until including study day 14. Moreover, attempts to escape were observed in all animals at the very beginning of the exposure (hour 0). The mean body weights of all surviving male and female animals increased throughout the study period. Gross pathological abnormalities of the organs were noted neither in the female animal that died during exposure nor in those necropsied at termination of the post exposure observation period. Contaminated fur was observed in all animals. In the female animal that died during exposure, smeared fur around the snouts was observed additionally. Under the conditions of this study the LC50 for male and female rats after dust inhalation was > 5.1 mg/l. Although 1 female animal died during exposure, the tested high concentration is judged to be sufficient to demonstrate the low order acute toxicity of the test substance and no further concentration was tested.