Dibismuth trioxide

Endpoint summary

Description of key information

Dibismuth trioxide is not acute toxic via oral, dermal or inhalation route.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

no data available

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well described publication.

Justification for type of information:

Please see read-across justification attached below.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Japan, Inc.
- Age at study initiation: At the start of administration, animals were 5 weeks old
- Weight at study initiation: 128-154 g, 113-127 g, 154-176 g and 128-147 g, respectively
- Fasting period before study: the animal was fasted for about 18 hours prior to dosing
- Diet: The animals were fed a pellet diet (MF, Oriental Yeast Co., Ltd.)
- Water: ad libitum; tap water inradiated by UV rays after passing through a 5-µm filter
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 55 +/- 15
- Air changes (per hr): about 12 changes per hour
- Photoperiod: 12 hours dark/light cycle

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: The dosing volume was set at 10 mL/kg, and the dose volume for individual animals was calculated based on the body weight measured just before dosing.

No further details are given.

Doses:

2000 mg/kg

No. of animals per sex per dose:

five male and five female rats

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes.
- Other examinations performed: clinical signs, body weight, organ weights, histopathology,
- Frequency of observations and weighing: Clinical signs of the animals were observed four times on the dose day and thereafter once a day. The body weights of all animals and the gross weights of the feeders were measured before dosing and on days 4, 8, and 15 (the day of administration was designed as day 1).

Statistics:

A multiple comparison test to analyse statistical significance in the numerical data (body weight, food consumption, haematology, blood chemistry, and organ weights) was used. Statistical significance in graded categorical data (urinalysis, necropsy findings and histopathological findings) was analysed by a x b chi-square test. A significance level of 5% and 1% was set lor all statistical analysis.

Preliminary study:

Since there were no deaths during a preliminary study doses of 1000 and 2000 mg/kg (one rat of each sex at each dose), a dosage of 2000 mg/kg was set for this study.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was observed.

Clinical signs:

other: No abnormal clinical signs in any animals were found.

Gross pathology:

No histopathological abnormalities attributed to bismuth were observed.

Other findings:

No further findings are reported.

Based on the results, the lethal dose 50% mortality rate (LD50) dosage was greater than 2000 mg/kg for both sexes.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Based on the results, the lethal dose 50% mortality rate (LD50) dosage was greater than 2000 mg/kg for both sexes.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Klimisch 2 study.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

from 2010-07-12 till 2010-07-26

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP and guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

signed by Amt für Arbeitsschutz, Arbeitnehmerschutz Hamburg (2009-11-12)

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

other: CD / Crl: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- 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.

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

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- 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.

TEST ATMOSPHERE
- 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:

yes

Remarks:

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

Concentrations:

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:

no

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.

Statistics:

no data

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.07 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

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.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

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 unclassified.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

5 070 mg/m³ air

Quality of whole database:

Klimisch 1 study.

Additional information

A publication is available in which the acute toxicity in rats with bismuth (mean particle diameter was 10 µm) was tested (Sano, 2005). No deaths occurred at a dose of 2000 mg/kg body weight. Therefore the LD₅₀ is considered to be >2000 mg/kg bw for both sexes.

Read across from bismuth metal to dibismuth trioxide is possible based on similar water solubility.

In an acute inhalation toxicity test in rats with dibismuth trioxide (d₅₀ approximately 6 µm), no deaths occurred. The LC₅₀ was determined to be >5.07 mg/L air.

An acute dermal toxicity study with dibismuth trioxide is considered to be scientifically unjustified.

Justification for selection of acute toxicity – oral endpoint
Only one study available.

Justification for selection of acute toxicity – inhalation endpoint
Only one study available.

Justification for selection of acute toxicity – dermal endpoint
Conduct of an acute dermal toxicity study for the substance in question is unjustified since dermal uptake is considered negligible (cf. Annex VIII section 8.5 Column 2 of regulation (EC) 1907/2006).

Justification for classification or non-classification

In an acute oral toxicity test in rats with bismuth, the LD₅₀was determined to be >2000 mg/kg bw. Read across from bismuth metal to dibismuth trioxide is possible based on similar water solubility.

An acute dermal toxicity study with bismuth metal is considered to be scientifically unjustified.

In an acute inhalation toxicity test in rats with dibismuth trioxide the LC₅₀was determined to be >5.07 mg/L air.

The available information indicates that dibismuth trioxide is not acutely toxic or harmful. Therefore, classification of dibismuth trioxide for acute toxicity is not warranted.