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Description of key information

REACH Annex VII column 2 states that testing by the inhalation route is appropriate if exposure of humans via inhalation is likely. Forming insoluble particulate matter, the inhalation route was considered the most appropriate exposure pathway for bismuth silicate. A reliable (Klimisch 1), GLP compliant, OECD Guideline 436 study was conducted for the test item (Haferkorn 2016). CD/Crl(SD) rats (3 male; 3 female) were exposed to an aerosol dust of bismuth silicate at a gravimetrically determined concentration of 5.07±0.01 mg/L air for 4 hours by inhalation, via nose-only exposure. The dust particles had a Mass Median Aerodynamic Diameter (MMAD) of 1.617 µm and a Geometric Standard Deviation (GSD) of 2.14. Under the present test conditions, 4-hour inhalation exposure induced slight dyspnoea until 3 hours post exposure in all rats. No other clinical signs of toxicity, mortality or pathological changes at necropsy, were observed in the treated rats. Under the present test conditions, the LC50 value for rats following inhalation of bismuth silicate for 4 hours was determined as >5.07 mg/L air.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because a study on acute toxicity by the inhalation route is available
Endpoint conclusion
Endpoint conclusion:
no study available

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:
7 July 2016 - 13 October 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
REACH Annex VII column 2 states that testing by the inhalation route is appropriate if exposure of humans via inhalation is likely. Forming insoluble particulate matter, the inhalation route was considered the most appropriate exposure pathway for bismuth silicate.
Qualifier:
according to
Guideline:
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
Version / remarks:
Adopted September 7, 2009
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.52 (Acute Inhalation Toxicity - Acute Toxic Class Method)
Version / remarks:
Commision Regulation (EC) No. 260/2014 method B.52, published in the Official Journal of the European Union, dated March 19, 2014
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No. of test material: sponsor lot# 231/08/15
- Expiration date of the lot/batch: March 2020
- Purity test date: 21 January 2016

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Composition: Bismuth oxide (Bi2O3) 83.35%; Silicon oxide (SiO) 16.63%.
- Particle size parameters: Diameter (D) 10% = 0.54 µm; D50% = 1.81 µm; D90% = 5.23 µm
- Physical characteristics: Powder
- Storage condition of test material: At ambient temperature (10 - 25°), container kept tightly closed and stored in a dry and well-ventilated place.
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: males approx. 8 weeks and females approx. 9 weeks
- Weight at study initiation: males (262 - 292 g); females (243 - 258 g)
- Fasting period before study: Feeding was discontinued 16 hours before exposure
- Housing: MAKROLON cages (type III plus)
- Diet: Commercial diet, ssniff R/M-H V1534 ad libitum
- Water: tap water ad libitum
- Acclimation period: At least 5 adaption days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3°C
- Humidity (%): 55 ± 15%
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12:12 hours dark/light cycles at 150 lux

IN-LIFE DATES: From: To: not reported
Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
clean air
Mass median aerodynamic diameter (MMAD):
1.617 µm
Geometric standard deviation (GSD):
2.14
Remark on MMAD/GSD:
The generated dust particles had a mass median aerodynamic diameter (MMAD) of 1.617 µm, as determined with a cascade impactor. The Geometic Standard Deviation (GSD) of the MMAD was 2.14. The measured MMAD/GSD are as expected, considering the particle size determined prior to experimentation (Diameter (D) percentage cumulative size: D10% = 0.54 µm; D50% = 1.81 µm; D90% = 5.23 µm).
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: RHEMA-LABORTECHNIK dynamic inhalation apparatus (6579 Hofheim/Taunus, Germany)
- Exposure chamber volume: 28.5 L
- Method of holding animals in test chamber: Animals held in pyrex tubes at edge of the chamber in radial position for nose-only exposure.
- Source and rate of air: The generator was fed with compressed air (5.0 bar) from a compressor (ALUP Kompressorenfabrik, 73257 Köngen, Germany). At the bottom of the exposure chamber, the air was sucked off at a lower flow rate, in order to produce a homogenous distribution and positive pressure in the exposure chamber (inflow 900 L/h, outflow 800 L/h). A manometer and air-flor meter (ROTA Yokogawa GmbH & Co. KG), were used to control supply and exhaust, respectively. Flow rates were checked hourly.
- System of generating particulates/aerosols: rotating brush dust generator
- Method of particle size determination: Cascade impactor 6.0 L/min (Article No. 700800-CI-060), TSE Systems GmbH, 61352 Bad Homburg, Germany)
- Temperature, humidity, pressure in air chamber: Temperature (21.1°C ± 0.1°C) and humidity (59.5% ± 0.2%) were measured once every hour with a climate control monitor (testo 175-HZ data logger).

TEST ATMOSPHERE
- Brief description of analytical method used: The dust from the exposure chamber was drawn through the cascade impactor for 1 minute 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).
- Samples taken from breathing zone: yes. Dust samples were taken once every hour during the exposure. For that purpose, 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.

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution:1.617
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 2.14
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Remarks on duration:
In accordance with OECD Guideline 436
Concentrations:
Nominal concentration: 5 mg/L
Measured concentration: 5.07 mg/L
No. of animals per sex per dose:
3 males, 3 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: During and following exposure, clinical examinations were made daily. Individual weights of animals were determined once during the acclimatisation period, before the exposure on test day 1, on test days 2, 4, 8 and 15. Changes in weight were calculated and recorded at 1 day, and at the end of the test.
- Necropsy of survivors performed: yes. Necropsy of all animals was carried out and all gross pathological changes were recoded for each animal, with particular attention to any changes in the respiratory tract.
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: 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.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
< 5.07 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
not determinable due to absence of adverse toxic effects
Mortality:
No mortality was observed
Clinical signs:
other: Under the present test conditions, a 4-hour inhalation exposure to Bismuth silicate at a concentration of 5.07 mg/L air induced slight dyspnoea until 3 hours post exposure in all rats. This effect was considered to be an clinical signs of general toxicity
Body weight:
No influence in body weight gain was noted.
Gross pathology:
No pathological findings were observed at necropsy in any of the male or female rats (n=6).
Interpretation of results:
GHS criteria not met
Conclusions:
Under the present test conditions, the LC50 value for rats following inhalation of Bismuth silicate for 4 hours was determined as >5.07 mg/L air. According to the Globally Harmonised Classification System (GHS), the test item does not require classification for acute inhalation toxicity.
Executive summary:

CD/Crl(SD) rats (3 male; 3 female) were exposed to an aerosol dust of bismuth silicate at a gravimetrically determined concentration of 5.07±0.01 mg/L air for 4 hours by inhalation, via nose-only exposure. The dust particles had a Mass Median Aerodynamic Diameter (MMAD) or 1.617 µm and a Geometic Standard Deviation (GSD) or 2.14. Under the present test conditions, 4-hour inhalation exposure induced slight dyspnoea until 3 hours post exposure in all rats. No other clinical signs of toxicity, mortality or pathological changes at necropsy, were observed in the treated rats.

Under the present test conditions, the LC50 value for rats following inhalation of bismuth silicate for 4 hours was determined as >5.07 mg/L air. Conducted according to OECD 436 and GLP, the study was considered reliable without restriction (Klimisch 1).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
5 mg/m³

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Under REACH Annex VII, an acute toxicity study via the oral route of exposure is required. Column 2 of Annex VII permits waiving of acute oral toxicity testing if a study on acute toxicity by the inhalation route is available. Exposure to bismuth silicate via the oral route is unlikely, considering the low bioaccessibility, and a guideline-compliant inhalation study is available (OECD 436), therefore further testing is not recommended.

Previously REACH Annex VIII required an acute toxicity study using a second route of administration, but, as of 1st June 2016, point 8.5 of Annex VIII has been updated. According to section 8.5.3, the acute toxicity by dermal route does not need to be conducted if: the substance does not meet the criteria for classification for acute toxicity or STOT SE by the oral route and no systemic effects have been observed in in vivo studies with dermal exposure (e.g. skin irritation, skin sensitisation) or, in the absence of an in vivo study by the oral route, no systemic effects after dermal exposure are predicted on the basis of non-testing approaches (e.g. read across, QSAR studies). There was no evidence of systemic toxicity in the in vivo LLNA assay for bismuth silicate and the substance was not classifiable in the acute inhalation study. In line with the recent amendments to the guidance, no further testing is required.

Justification for classification or non-classification

Forming insoluble particulate matter, the inhalation route was considered the most appropriate exposure pathway for bismuth silicate. Significant exposure via the oral and dermal pathways was considered unlikely, due to limited bioaccessibility. An acute inhalation study via the acute toxic class method (OECD 436) was conducted. Under the present test conditions, the LC50 value for rats following inhalation of bismuth silicate for 4 hours was determined as >5.07 mg/L air. Conducted according to OECD 436 and GLP, the study was considered reliable without restriction (Klimisch 1) and sufficient to determine classification. According to the Globally Harmonised Classification System (GHS) and EU CLP criteria, the test item does not require classification for acute inhalation toxicity.