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EC number: 231-177-4 | CAS number: 7440-69-9
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: inhalation
Administrative data
- Endpoint:
- sub-chronic toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- no data available
- Reliability:
- 3 (not reliable)
- Rationale for reliability incl. deficiencies:
- other: Route of exposure is not relevant for risk assessment.
Data source
Reference
- Reference Type:
- publication
- Title:
- A 13-week toxicity study of bismuth in rats by intratracheal intermittent administration
- Author:
- Sano, Y.; et al.
- Year:
- 2 005
- Bibliographic source:
- J Occup Health 2005 ; 47: 242-248
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Conduction of a 13-week intratracheal intermittent bismuth dose toxicity study.
- GLP compliance:
- no
- Limit test:
- no
Test material
- Reference substance name:
- Bismuth
- EC Number:
- 231-177-4
- EC Name:
- Bismuth
- Cas Number:
- 7440-69-9
- Molecular formula:
- Bi
- IUPAC Name:
- bismuth
- Details on test material:
- - Name of test material (as cited in study report): Bismuth
- Physical state: solid
- Analytical purity: 99.99%
- Particle size diameter: 1-2 µm
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crj:CD(SD)IGS
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Rats were obtained from Charles River Japan, Inc.
- Age at study initiation: 6 weeks old
- Weight at study initiation: 197-229 g
- Diet: ad libitum; the animals were fed a pellet diet (MF, Oriental Yeast Co., Ltd.)
- Water: tap water ad libitum
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 55 +/- 15
- Photoperiod: 12 hours dark/light cycle
Administration / exposure
- Route of administration:
- other: intratracheal instillation
- Vehicle:
- other: 0.5% carboxymethylcellulose sodium solution
- Remarks on MMAD:
- MMAD / GSD: no data
- Details on inhalation exposure:
- Bismuth was weighed in to amounts of 0.032, 0.16 and 0.8 g and mixed with 20 mL of the vehicle for the dosing suspensions. The dose volume was set at 0.5 m//kg and the individual dose volume was calculated on the basis of the body weight measured just before administration on each administration day.
- Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- no data
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- Considering the accumulation of bismuth in the lungs by repeated administration and its effects on the physical condition of the animals, it was decided that the dose interval should be once a week to keep a steady-state concentration of bismuth in the lungs, because in the single dose study, the bismuth concentration in the lungs decreased rapidly in each treatment group up to 8 days after administration, but thereafter it did not fluctuate largely.
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
20 mg/kg
Basis:
nominal conc.
- Remarks:
- Doses / Concentrations:
4 mg/kg
Basis:
nominal conc.
- Remarks:
- Doses / Concentrations:
0.8 mg/kg
Basis:
nominal conc.
- No. of animals per sex per dose:
- The dosing suspensions were intratracheally administered to the 12 animals of each dosing group.
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The highest dose level was chosen as 20 mg/kg, since the result of a single dose toxicity study (Sano, 2005) showed that 20 mg/kg did not cause death.
- Positive control:
- No positive control substance was tested.
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: No data
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical signs of the animals were observed twice a day (before and after administration) throughout the dosing period, and once a day in the morning during the other period.
BODY WEIGHT: Yes
- Time schedule for examinations: The body weights of all animals were measured once a week.
FOOD CONSUMPTION:
- Time schedule for examinations: The gross weights of the feeders were measured once a week.
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data
WATER CONSUMPTION: No data
OPHTHALMOSCOPIC EXAMINATION: No data
HAEMATOLOGY: Yes
- Time schedule for collection of blood: On days of the scheduled necropsy, the animals were anesthetised; thereafter, blood samples were collected via the posterior vena cava.
- Anaesthetic used for blood collection: Yes (identity); intraperitoneal injection of sodium thiopental
- Parameters examined: For haematology, the erythrocyte count (RBC), haemoglobin concentration (Hb), haematocrit value (Ht), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), reticulocyte count, platelet count (PLT), prothrombin Time (PT), activated partial thromboplastin time (APTT), leukocyte count (WBC), and differential leukocyte count were measured.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: On days of the scheduled necropsy, the animals were anesthetised; thereafter, blood samples were collected via the posterior vena cava.
- Parameters examined: For blood chemistry, the aspartatate aminotransferase (ASAT), alanine arninotransferase (AI-,aT), y-glutamyltrasferase (1GT), alkaline phosphatase (ALP), total bilirubin, blood urea nitrogen (BUN), creatinine, glucose, total cholesterol, triglycerides, total protein, albumin, A/G ratio, calcium, inorganic phosphorus, sodium (Na), potassium (K), and chlorine (Cl) were measured.
URINALYSIS: Yes
- Time schedule for collection of urine: Fresh urine samples from all the surviving animals were collected on the day before scheduled necropsy.
- Metabolism cages used for collection of urine: No data
- Parameters examined: pH, protein, glucose, ketone bodies, bilirubin, occult blood, and urobilinogen were measured.
NEUROBEHAVIOURAL EXAMINATION: No data - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes; After the blood sampling, all animals were sacrificed by exsanguinations via the abdominal aorta, and then subjected to necropsy. The following organs of all animals were weighed: brain, liver, kidney, spleen, and testis. Relative organ weights were calculated from body weights on each necropsy day.
HISTOPATHOLOGY: Yes; Histopathological examinations on the lung, liver, kidney, spleen, brain, and testis from the control and 20 mg/kg groups and gross lesions from all animals including the control group. The organs except for testes were fixed by 10% neutral phosphate-buffered formalin solution. The testes were fixed in Bouin's solution. The haematoxylin and eosin stained specimens were prepared according to the standard procedure and then microscopically examined. Furthermore, PAS stained specimens of the kidneys from three animals were prepared to confirm the change of the glomerulus. Berlin blue stained specimens of the spleen from three animals were prepared to confirm that the brown pigments found in the spleen were hemosiderin. - Other examinations:
- No further examinations were made.
- Statistics:
- A multiple comparison test to analyse statistical significances in the numerical data (body weight, food consumption, haematology, blood chemistry,
and organ weights) was used. If there was statistical significances in the data between groups, Dunnett's test or Dunnett type rank-sum test was conducted. Statistical significance in graded categorical data (urinalysis, necropsy findings and histopathological findings) was analyzed by a x b chi-square test. If statistically significant data were found, Cochran-Armitage trend test was conducted. Significance levels of 5% and 1% were chosen for all statistical analyses.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- not specified
- Details on results:
- CLINICAL SIGNS AND MORTALITY
No abnormal clinical signs attributable to bismuth administration were observed in any treated group during the testing period. Two animals of the control group, two animals of the 20 mg/kg group, one animal of the 4 mg/kg group, and one animal of the 0.8 mg/kg group died. A possible cause of death in these animals was excessive anaesthesia at administration or suffocation just after the administration associated with the intratracheal dose.
Loss of hair was observed in one and two animals in the 4 and 20 mg/kg groups, respectively.
BODY WEIGHT AND WEIGHT GAIN
Suppression of body weight gain was observed at Day 29 and thereafter in the 20 mg/kg group, but it was not statistically significant.
FOOD CONSUMPTION
No abnormal food consumption attributable to bismuth administration were observed in any treated group during the testing period.
FOOD EFFICIENCY
no data
WATER CONSUMPTION
no data
OPHTHALMOSCOPIC EXAMINATION
no data
HAEMATOLOGY
A slight increase in erythrocyte count and MCHC were observed in the 20 mg/kg group, and slight increases in haemoglobin concentration and haematocrit value were observed in the 4 mg/kg and higher groups. Higher rates of segmented neutrophil were observed in the 4 mg/kg and higher groups, and lower rates of lymphocytes were observed in the 0.8 mg/kg and higher groups.
CLINICAL CHEMISTRY
An increase in urea nitrogen was observed in the 20 mg/kg group. A decrease in ASAT in the 4 mg/kg group was observed, however, this was considered to be an incidental change, because it was not observed in the high dose group.
URINALYSIS
There were no significant differences between the control group and any treated group in the urinalysis.
NEUROBEHAVIOUR
no data
ORGAN WEIGHTS
The absolute and relative lung weights increased in the 0.8 mg/kg and higher groups. Increases in the relative brain and kidney weights were observed in the 20 mg/kg group, however, it was considered to be an incidental change related to decreased body weight, since suppression of body weight gain was also observed in the 20 mg/kg group and there was no difference in the absolute organ weight.
GROSS PATHOLOGY
Pathological changes attributed to bismuth administration were observed in the lungs and bronchial lymph nodes. In the lungs, a brown patch was observed in 3, 4 and 8 animals of the 0.8, 4 and 20 mg/kg groups, respectively. Black patches originating from the colour of bismuth and collapses were observed in all animals of the 4 and 20 mg/kg groups. Furthermore, enlargement of bronchial lymph nodes was observed in 6, 5 and 10 animals of the 0.8, 4 and 10 mg/kg groups, respectively. A brown patch in the lungs also observed in one animal in the control group, and slight focal inflammatory cell infiltration with small haemorrhage was observed in this lesion microscopically.
A white patch in the liver was observed in 1, 2 and 3 animals of the 0.8, 4 and 20 mg/kg groups, respectively. Although, it was not statistically significant, there was a dose dependent trend of increase in number of animals which had a white patch. This necropsy finding was possibly related to bismuth. As an incidental change, abnormal lobulation of the liver and cyst in the kidney were observed in one animal of the 0.8 mg/kg group. In the necropsy of 4 of 6 animals that died during the administration period, the following changes were observed in one animal of the 4 mg/kg group: dilatation and haemorrhage of the urinary bladder, possibly related to death, and other changes such as renal pelvic dilatation, ascites, small sized thymus and spleen, and black patch, dark red change and collapse of the lungs. The cause of death in this animal may have been anuria; it was considered to be an incidental mortality, since it occurred in only one animal.
HISTOPATHOLOGY: NON-NEOPLASTIC
Histopathological changes attributed to bismuth were observed in the lungs, bronchial lymph nodes and kidneys. Focal inflammatory cell infiltration in the lungs was observed in all animals in the 0.8 mg/kg and higher groups. The incidence of lesions increased dose-dependently. In the lesions of inflammatory cell infiltration, hyperfrophy of alveolar epithelial cells was observed in the 0.8 mg/kg and higher groups, and hyperplasia of bronchial epithelial cells was observed in the 4 mg/kg and higher groups. Inflammatory cell infiltration in the 0.8 mg/kg and higher groups, hypertrophy of alveolar epithelium in the 4 mg/kg and higher groups, and hyperplasia of bronchial epithelial cell in the 20 mg/kg group showed statistically significant differences, as compared with the control group. Aggregation of foamy cells was observed in all groups including the control group and increased significantly in the 20 mg/kg group. Microscopic accumulation of bismuth was observed in all animals of the 4 and 20 mg/kg groups, and showed statistically significant differences as compared with the control group. In enlarged bronchial lymph nodes observed macroscopically, hyperplasia of the para-cortical area was observed, and increased pigment-laden phagocytic cells including the test substance was observed in 3 and 10 animals of the 4 and 20 mg/kg groups, respectively. In other changes, hyaline droplet of the proximal tubular epithelium in the kidney was observed in all groups including the control group, and its incidence decreased significantly in the 20 mg/kg group. The kidneys of representative animals of the control and 20 mg/kg groups were stained by PAS method, since a change in the glomerulus was suspected. In the result, there were no changes in the glomerulus and the hyaline droplets were PAS negative. Additional examination of the liver was conducted, since an effect of bismuth on the liver was suspected. Focal fatty degeneration of hepatic cells was observed in 1 and 2 animals of the 4 and 20 mg/kg groups, respectively. Brown pigment of the spleen was confirmed to be a hemosiderin pigment by Berlin blue staining.
OTHER FINDINGS
The kinetics of bismuth can be described with a one-compartment pharmacokinetic model, since the logarithms of the lung concentrations of bismuth versus time plotted for each dosing group yield straight lines. From the slope of these lines, we calculated the half life of bismuth elimination
from the lungs as 4.47, 3.25, 2.10 days for the doses of 20, 100, 500 mg/kg, respectively.
Effect levels
- Dose descriptor:
- other:
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: see 'Remark'
- Remarks on result:
- not measured/tested
- Remarks:
- Effect level not specified (migrated information)
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- The author concluded that dose-dependent, but not specific adverse effects, were attributable to bismuth inhalation in the rat.
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