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Toxicological information

Acute Toxicity: inhalation

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Administrative data

acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
12 July 2010 to 26 July 2010
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP and guideline study. Rated as Klimisch 2 because it is a read-across study.

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
according to guideline
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
GLP compliance:
yes (incl. QA statement)
signed by Amt für Arbeitsschutz, Arbeitnehmerschutz Hamburg (2009-11-12)
Test type:
acute toxic class method
Limit test:

Test material

Constituent 1
Reference substance name:
Constituent 2
Reference substance name:
dibismuth trioxide
dibismuth trioxide
Constituent 3
Reference substance name:
Dibismuth trioxide
EC Number:
EC Name:
Dibismuth trioxide
Details on test material:
- Name of test material (as cited in study report): Dibismuth trioxide (technical grade)
- Molecular formula: Bi2O3
- Molecular weight: 465.96 g/mol
- Physical state: solid, yellow powder
- Storage condition of test material: at room temperature in closed containers

Test animals

other: CD / Crl: CD(SD)
Details on test animals or test system and environmental conditions:
- Source: Charles River Laboratories, D-97633 Sulzfeld
- Age at study initiation: 50 days (males), 64 days (females)
- Weight at study initiation: 229-242 g (males) and 236-240 g (females)
- Fasting period before study: Feeding was discontinued approx. 16 hours before exposure.
- Housing: During the 14-day observation period the animals are kept by sex in groups of 2 - 3 animals in MAKROLON cages (type III plus).
- Diet: Commercial diet, ssniff® R/M-H V1534 served as food.
- Water: ad libitum, tap water
- Acclimation period: At least 5 adaptation days and animals were acclimatised to the test apparatus for approx. 1 hour on 2 days prior to testing.

- Temperature (°C): 22 +/- 3
- Humidity (%): 55 +/- 15
- Photoperiod: 12 hours dark/light cycle

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Details on inhalation exposure:
- Exposure apparatus: The study was carried out using a dynamic inhalation apparatus (air changes/h (≥ 12 times)) with a nose-only exposure of the animals according to KIMMERLE & EBEN. The apparatus consists of a cylindrical exposure chamber which holds the animals in pyrex tubes at the edge of the chamber in a radial position.
- Exposure chamber volume: 40 L
- Source and rate of air: Air was taken from the surrounding atmosphere of the laboratory room and filtered using an in-line disposable gas-filter. 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 (inflow 900 L/h, outflow 800 L/h, 22.5 air changes per hour).
- System of generating particulates/aerosols: The dust of the test material was generated with a rotating brush dust generator. The generator was fed with compressed air (5.0 bar) from a compressor.
- Treatment of exhaust air: The exhaust air was drawn through gas wash-bottles.
- Temperature, humidity, pressure in air chamber: Temperature (26.5°C ± 0.8°C) and humidity (69.2% ± 1.4%) were measured once every hour with a climate control monitor.

- Brief description of analytical method used: The actual dust concentration in the inhalation chamber was measured gravimetrically with an air sample filter and pump, controlled by a rotameter. Dust samples were taken once every hour during the exposure.
- Samples taken from breathing zone: yes; 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).

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: An analysis of the particulate size distribution was carried out twice during the exposure period using a cascade impactor. 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. Delta of slides’ weight were determined.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): The mass median aerodynamic diameter (MMAD) was estimated by means of non-linear regression analysis to be 2.700µm. The Geometric Standard Deviation (GSD) of the MMAD was calculated as 2.95 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 Malvern Sizer by Malvern, 71083 Herrenberg, Germany.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration: according to guideline
Analytical verification of test atmosphere concentrations:
Before initiating the study with the animals, a pre-test was carried out with the exposure system in order to verify that under the experimental settings chosen, the limit concentration of 5 mg/L air could be achieved by gravimetric analysis.
Duration of exposure:
4 h
5.00 mg/L air (nominal concentration)
5.07 mg/L air (measured concentration)
No. of animals per sex per dose:
One concentration of 3 males and 3 females (limit test)
Control animals:
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 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) to minimize loss of animals to the study, e.g. necropsy or refrigeration of those animals found dead and isolation or sacrifice of weak or moribund animals. 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. Changes in weight were calculated and recorded when survival exceeded one day. At the end of the test, all animals were weighed and sacrificed.
- Necropsy of survivors performed: yes
- Other 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, as well as somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremor, convulsions, salivation diarrhoea, lethargy, sleep and coma. The animals were also observed for possible indications of respiratory irritation such as dyspnoea, rhinitis etc.
Necropsy of all animals was carried out and all gross pathological changes were recorded. No microscopic examination was carried out as no pathological findings were noted at necropsy.
no data

Results and discussion

Effect levels
Dose descriptor:
Effect level:
> 5.07 mg/L air
Based on:
test mat.
Exp. duration:
4 h
No mortality occurred.
Clinical signs:
other: Under the present test conditions, a 4-hour inhalation exposure to dibismuth trioxide at a concentration of 5.07 mg/L air revealed slight ataxia and slight dyspnoea in 2 or 3 male and 3 female rats.
Body weight:
All animals gained the expected body weight throughout the study period.
Gross pathology:
No findings.
Other findings:
No other findings were observed.

Applicant's summary and conclusion

Interpretation of results:
not classified
Migrated information Criteria used for interpretation of results: EU
Under the conditions of this study, the 4 -hour inhalation LC50 of dibismuth trioxide is >5.07 mg/L air, and hence, the LC50 cut-off value unclassified. According to the Globally Harmonized Classification System (GHS) the test item should be classified in the hazard category 'unclassified'.
Executive summary:

The aim of the present experiment was to obtain information on the acute toxicity and respiratory irritation, following a single 4-hour inhalation exposure of rats to dibismuth trioxide.

Rats were exposed to a dry aerosol of dibismuth trioxide at a gravimetricly determined concentration of 5.07±0.09 mg dibismuth trioxide/L air 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.

In the inhalation chamber, close to the animals' noses, the generated aerosol particulates had a mass median aerodynamic diameter (MMAD) of 2.700 µm as determined with a cascade impactor. The Geometric Standard Deviation (GSD) of the MMAD was calculated as 2.95. No smaller MMAD could be obtained with the test item supplied.

Under the present test conditions, a 4 -hour inhalation exposure to dibismuth trioxide at a concentration of 5.07 mg/L air (determined by gravimetric analysis) caused no mortality, and the body weight changes of all animals revealed throughout the study period normal gains.

A 4 -hour inhalation exposure to dibismuth trioxide at a concentration of 5.07 mg/L air revealed slight ataxia and slight dyspnoea on test day 1 immediately after end of exposure until 3 hours post exposure in 2 or 3 male and 3 female animals.

Under the conditions of this study, the 4 -hour inhalation LC50of dibismuth trioxide is >5.07 mg/L air, and hence, the LC50cut-off value is unclassified.