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Diss Factsheets

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2011-01-25 to 2011-03-31
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
The minor deviations from the guidline do not effect the reliability of the study.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report date:
2013

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
Version / remarks:
2009
Deviations:
yes
Remarks:
The demanded values of MMAD= 1-4 µm & GSD= 1.5-3.0 were slightly exceeded: MMAD: 4.004, 4.418; GSD: 3.51, 3.58. The rationale for selecting the test concentration was not stated.
GLP compliance:
yes (incl. QA statement)
Remarks:
signed 2009-11-17
Test type:
acute toxic class method
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Cobalt sulphide
EC Number:
215-273-3
EC Name:
Cobalt sulphide
Cas Number:
1317-42-6
Molecular formula:
CoS
IUPAC Name:
Cobalt(2+) sulfide
Test material form:
solid: particulate/powder
Details on test material:
- Appearance: grey powder
- Storage conditions: Stored desiccated and under an inert gas or vacuum to prevent oxidation
Specific details on test material used for the study:
Particle size parameter were determined with a CILAS 715 (non-GLP determination): d(0.1) = 4.86 μm; d(0.5) = 33.85 μm (median); d(0.9) = 89.28 μm

Test animals

Species:
rat
Strain:
Sprague-Dawley
Remarks:
Crl: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Females nulliparous and non-pregnant: not specified
- Age at study initiation: males: approx. 8 weeks, females: approx. 9 weeks
- Weight at study initiation: males: 240 - 268 g, females: 217 - 236 g
- Fasting period before study: 16 h
- Housing: groups of 2 - 3 animals by sex in MAKROLON cages (type III plus); bedding material: granulated textured wood (Granulat A2, J. Brandenburg, 49424 Goldenstedt, Germany)
- Historical data: not stated
- Diet: ad libitum, ssniff® R/M-H V1534 (ssniff Spezialdiäten GmbH, 59494 Soest, Germany)
- Water: tap water ad libitum
- Acclimation period: at least 5 days. The animals were acclimatised to the test apparatus for approx. 1 hour on 2 days prior to testing. The restraining tubes did not impose undue physical, thermal or immobilization stress on the animals.


ENVIRONMENTAL CONDITIONS
- Temperature: 22 °C ± 3 °C
- Humidity: 55 % ± 15 %
- Air changes: 12/h
- Photoperiod (hrs dark / hrs light): 12/12 (150 lux at approx. 1.50 m room height)

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
clean air
Mass median aerodynamic diameter (MMAD):
>= 4.004 - <= 4.418 µm
Geometric standard deviation (GSD):
>= 3.51 - <= 3.58
Remark on MMAD/GSD:
The mass median aerodynamic diameter (MMAD) was determined as 4.004 μm (main study) or 4.418 μm (satellite animals). The Geometric Standard Deviations (GSD) of the MMAD were calculated as 3.51 (main study) or 3.58 (satellite animals). No smaller MMASs or GSDs could be obtained with the test item supplied.
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: dynamic inhalation apparatus (RHEMA-LABORTECHNIK, 65719 Hofheim/Taunus, Germany) (air changes/h (≥ 12 times)) with a nose-only exposure of the animals according to KIMMERLE & TEPPER.
- Exposure chamber volume: 40 L
- Method of holding animals in test chamber: the animals were hold in pyrex tubes in a way that the animals’ noses were placed at the edge of the chamber in a radial position.
- Source and rate of air (airflow): entrance: 900 L/h; exit: 800 L/h; air changes: 22.5/h. At the bottom of the exposure chamber, the air was sucked off at a lower flow rate than it was created by the dust generator in order to produce a homogenous distribution and a positive pressure in the exposure chamber. A manometer and an air-flow meter (ROTA Yokogawa GmbH & Co. KG, 79664 Wehr/Baden, Germany) were used to control the constant supply of compressed air and the exhaust, respectively. Flow rates were checked hourly and corrected if necessary.
- Method of conditioning air: The generator was fed with compressed air (5.0 bar) from a compressor (ALUP Kompressorenfabrik, 73257 Köngen, Germany). The air was taken from the surrounding atmosphere of the laboratory room and filtered using an in-line disposable gas-filter.
- System of generating particulates/aerosols: rotating brush dust generator (RBG 1000, PALAS GmbH Partikel und Lasermesstechnik, 76229 Karlsruhe, Germany).
- Method of particle size determination: particle size distribution was determined twice daily by a cascade impactor according to MAY (MAY, K. R. Aerosol impaction jets, J.Aerosol Sci. U6U, 403 (1975), RESEARCH ENGINEERS Ltd., London N1 5RD, UK).
The dust from the exposure chamber was drawn through the cascade impactor for 5 minutes at a constant flow rate of 5 L/min. The slides were removed from the impactor and weighed on an analytical balance (SARTORIUS, type 1601 004, precision 0.1 mg). Deltas of slides’ weight were determined.
The mass median aerodynamic diameter (MMAD) was estimated by means of nonlinear regression analysis. The 32 μm particle size range and the filter (particle size range < 0.5 μm) were not included in the determination of the MMAD in order not to give undue weight to these values.
The Geometric Standard Deviation (GSD) of the MMAD was calculated from the quotient of the 84.1%- and the 50%-mass fractions, both obtained from the above mentioned non-linear regression analysis.
In addition, a sample of approx. 10 g test material was taken from the exposure chamber to determine the median physical particulate size with a CILAS 715 by My- Tec, 91325 Adelsdorf, Germany. This determination was non-GLP.
- Treatment of exhaust air: the exhaust air was drawn through gas wash-bottles.
- Temperature, humidity: Temperature (20.5°C ± 0.1°C (main study) or 20.1°C ± 0.1°C (satellite group)) and humidity (60.8% ± 0.1% (main study) or 60.5% ± 0.1% (satellite group)) were measured once every hour with a climate control monitor (testo 175-HZ data logger).
- Oxygen, carbon dioxide: The oxygen content in the inhalation chamber was 21%. It was determined at the beginning and at the end of the exposure with a DRÄGER Oxygen-analysis test set (DRÄGER Tube Oxygen 67 28 081). Carbon dioxide concentration did not exceed 1%.


TEST ATMOSPHERE
- Brief description of analytical method and equipment used: the actual dust concentration in the inhalation chamber was measured gravimetrically with an air sample filter (Minisart SM 17598 0.45 μm) and pump (Vacuubrand, MZ 2C7) controlled by a rotameter. A probe was placed close to the animals' noses and air was drawn through the air sample filter at a constant flow of air of 5 L/min for 1 minute. The filters were weighed before and after sampling (accuracy 0.1 mg).
- Samples taken from breathing zone: yes, once every hour during the exposure
- Time needed for equilibrium of exposure concentration before animal exposure: 15 min. (t95 approximately 8 min.)


TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: d(0.1) = 4.86 μm; d(0.5) = 33.85 μm (median); d(0.9) = 89.28 μm
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): main study: MMAD: 4.004 µm, GSD: 3.51; satellite study: MMAD: 4.418 µm, GSD: 3.58.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
see above `Details on inhalation exposure´
Duration of exposure:
4 h
Remarks on duration:
Exposition started by locating the animals’ noses into the exposure chamber after equilibration of the chamber concentration for at least 15 minutes.
Concentrations:
5.09 mg/L (main study);
5.09 mg/L (satellite study)
No. of animals per sex per dose:
3 males and 3 females (main study); 3 males and 3 females (satellite study)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: During and following exposure, observations were made and recorded systematically; individual records were maintained for each animal. Careful clinical examinations were made at least twice daily until all symptoms subsided, thereafter each working day. Observations on mortality were made at least once daily (in the morning starting on test day 2).
- Frequency of weighing: Individual weights of animals were determined once during the acclimatisation period, before and after the exposure on test day 1, on test days 3, 8 and 15.
- Necropsy of survivors performed: yes
- Examinations performed:
Cageside observations included, but were not limited to: changes in the skin and fur, eyes, mucous membranes, respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour patter, observation of tremor, convulsions, salivation, diarrhoea, lethargy, sleep and coma and indications of respiratory irritation such as dyspnoea, rhinitis etc.

Changes in weight were calculated and recorded when survival exceeded one day.

Necropsy of all main study and satellite animals (3 + 3 males and 3+3 females) was carried out and all gross pathological changes were recorded.

Histophatology: All animals were subjected to the same level of histopathological examination. Attention was paid to alterations that might be indicative of respiratory irritation, such as hyperaemia, oedema, minimal inflammation, thickened mucous layer.
The following organs of all animals were fixed in 10% (nose, i.e. head without brain, eyes and lower jaw) or 7% (other organs) buffered formalin for histopathological examination:
- Nose (5 levels of the nasal turbinates): The tip and Level 1 of the nose were taken from a cut just anterior to the incisor teeth. With tip removed, Level 2 was taken approximately 2 mm posterior to free tip of the incisor teeth. Level 3 was cut through the incisive papilla. Level 4 was cut through the middle of the second palatal ridge, which is located just anterior to the molar teeth. Level 5 was cut through the middle of the molar teeth. All sections were embedded face down to yield a section from the anterior section, except the nose tip was embedded posterior surface down.
- Larynx
- Trachea
- Lungs (five levels)
Paraffin sections were prepared of all above mentioned organs and stained with haematoxylin-eosin.
Statistics:
Since no animal died prematurely, the calculation of an LC50 was not required.

Results and discussion

Preliminary study:
not specified
Effect levels
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.09 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: LC50 cut-off value is 'unclassified'.
Mortality:
No mortality occured.
Clinical signs:
other: Slight tremor (day 1, 0- 30 min. post exposure), slight ataxia, slight dyspnoea (reduced frequency of respiration with increased volume) (day 1 & 2), slightly reduced motility (day 2) in all male and female animals.
Body weight:
No influence in body weight gain was observed.
Gross pathology:
no pathologically noteworthy findings.
Other findings:
Histopathology: Macroscopic changes in the nasal cavity and lungs
- Nose level 1-5: mild congestion in 5/6 terminal sacrificed animals and all interim sacrificed animals.
- Nose level 1: respiratory epithelium with mild focal vacuolization in 1/6 subepithelial terminal sacrificed animals.
- Nose level 3-5: minimal to moderate focal lympho-histiocytic infiltration of respiratory epithelium in 3/6 terminal sacrificed animals and all interim sacrificed animals.
- Nose level 5: mild lymphocytic follicle in 5/6 terminal sacrificed animals and 4/6 interim sacrificed animals
- Nose level 3-5: minimal to moderate (focal) artefacts/degeneration of the olfactory epithelium was observed in all terminal and all interim sacrificed animals.
- Nose level 4-5: minimal to moderate (focal) mucus in the lumen in all terminal sacrificed animals and 5/6 interim sacrificed animals.
- Nose level 5: minimal to moderate (focal) vacuolization of the olfactory epithelium in 4/6 terminal sacrificed animals and 4/6 interim sacrificed animals.
- Trachea: minimal focal lympho-histiocytic infiltration in 2/6 terminal sacrificed and 1/6 interim sacrificed animals.
- Trachea: minimal to mild focal/multifocal loss of epithelial cells in 5/6 terminal sacrificed animals and 5/6 interim sacrificed animals.
- Lung: mild alveolar pulmonary oedema in 1/6 terminal sacrificed animals.
- Lung: minimal to mild (focal/multifocal) inflammatory perivascular oedema in all animals.
- Lung: minimal to mild pneumonic foci in 3/6 terminal sacrificed animals and 1/6 interim sacrificed animals.
- Lung: mild congestion in 5/6 terminal sacrificed animals and all interim sacrificed animals.
- Lung: mild focal haemorrhage in 1/6 terminal sacrificed animals.
- Lung: minimal to mild focal alveolar pulmonary emphysema in 1/6 terminal sacrificed animals and 3/6 interim sacrificed animals.
- Lung: minimal infiltration mixed cells, perivascular in 2/6 interim sacrificed animals)

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Under the present test conditions, the LC50 value for rats following inhalation of Cobalt sulphide for 4 hours was determined to be: LC50 > 5.09 mg Cobalt sulphide/L air (gravimetric concentration).
Based on the results of the histopathological and macroscopic investigations, Cobalt sulphide does not require classification for respiratory irritation.
According to the EC Regulation 1272/2008 and subsequent regulations, the test material does not require classification for `acute inhalation toxicity´ or `specific target organ toxicity - single exposure´.
Executive summary:

Rats were exposed to a dry aerosol of Cobalt sulphide at a gravimetrically determined concentration of 5.09 ± 0.06 mg/L air (main study – 14-day sacrifice) or 5.09 ± 0.05 mg/L air (satellite animals – 24-hour sacrifice) for 4 hours by inhalation using a dynamic nose-only exposure chamber. The aerosol was generated with the aid of a dry, rotating brush dust generator.

The generated aerosol particulates of the main study and satellite animals had a mass median aerodynamic diameter (MMAD) and a Geometric Standard Deviation (GSD) of MMAD: 4.004 μm (GDS: 3.51) and MMAD: 4.418 μm (GSD: 3.58), respectively as determined with a cascade impactor. No smaller MMADs and GSDs could be obtained with the test item supplied.

No premature death occurred.

Slight tremor (day 1, 0- 30 min. post exposure), slight ataxia, slight dyspnoea (reduced frequency of respiration with increased volume) (day 1 & 2), slightly reduced motility (day 2) in all male and female animals occurred. However, this effect is considered to be an overall clinical sign of general toxicity common to dust exposure, but not necessarily test item related.

Discoloration of the lungs were observed in 2/3 male and 3/3 female animals of the main study and in all animals of the satellite study.

The histomorphological examination of the satellite animals of the five lung localisations, the five levels of the nose, the trachea and the larynx revealed mild morphological changes in form of an inflammatory reaction in level 4 and 5 of the noses and in all five levels of the lungs which are considered to be test item related. The changes observed had almost normalised 14 days after exposure.

The minimal lympho-histological infiltration in the lungs, nose, trachea and larynx, and the pneumonic foci in the lungs were considered as coincidental findings or normal immunological reaction in healthy rats.

Since the detailed histopathology of the respiratory tract revealed no pathologically noteworthy findings, Cobalt sulphide is not considered to be irritating to the respiratory system.