Dibismuth trisulphide

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2005

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: No GLP, according to OECD

Data source

Reference

Reference Type:

publication

Title:

Oral Toxicity of Bismuth in Rat: Single and 28-Day repeated Administration Studies

Author:

Yuri Sano, Hirochi Satoh, Momoko Chiba, Masahide Okamoto, Koji Serizawa, Hiroshi Nakashima and Kazuyiki Omae

Year:

2005

Bibliographic source:

Journal of Occupational Health

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Chemical Substances Control Law (1986)

Deviations:

not specified

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Bismuth

EC Number:

231-177-4

EC Name:

Bismuth

Cas Number:

7440-69-9

Molecular formula:

Bi

IUPAC Name:

bismuth(3+)

Test material form:

not specified

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

Test animals:
-Crj: CD(SD) IGS rats (SPF) 36 female rats for the 28-d repeated oral dose toxicity study from Charles River Japan, Inc.
Age of animals: 5 weeks old
-Body weight range at starting of administration: 128-154g, 154-176g and 128-147g, repectively
- Diet: Pellet diet (MF, Oriental Yeast Co., Ltd.)
- Water: ad libitum, tap water irradiated by UV rays after passing through a 5µm filter
- Acclimatisation time: 7 days quarantine and acclimatization period

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 °C
- Humidity (%): 55 % ± 15%
- Air changes (per hr): about 12 air exchanges/hour
- Lighting for 12 hours per day (7:00 to 19:00)

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

Prior to the 28-d oral toxicity study, a preliminary dose-finding study entitled "A Fourteen-Day Repeated Oral Toxicity Preliminary Study in Rats"
(dose Ievels: 0, I 00, 500, and 1,000 mg/kg; number of animals, 3 males and 3 females per group) and found no changes attributable to the test
substance in clinical signs, body weights, hematology, organ weights (brain, thymus, liver, kidney, adrenal glands, spieen, testis, and ovary),
on necropsy. On account of these findings, the highest dose Ievel was set at 1,000 rrig/kg, and the medium and lower dose Ievels were set at 200 and 40 mg/kg, respectively.
Thereafter, oral administration (gavage) was performed once a day in the morning throughout the 28-d dosing period according to the Chemical
Substances Control Law ( 1986), to 6 rats of each sex in the 200 and 40 mg/kg groups and to 12 rats of each sex in the control and 1,000
mg/kg groups. The dosing volume (10 ml/kg) for individual animals was calculated based upon the mostrecent body weight. Moreover, 6 rats in the control and 1,000 mg/kg groups were given to a 14-d recovery period after the completion of the dosing period.

Duration of treatment / exposure:

28 days

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
40, 200 and 1,000 mg/kg
Basis:
actual ingested

No. of animals per sex per dose:

6 rats of each sex in the 200 and 40 mg/kg groups and 12 rats of each sex 1,000 mg/kg groups

Control animals:

yes

Details on study design:

Testing Procedure
Prior to the 28-d oral toxicity study, we conducted a preliminary dose-finding study entitled "A Fourteen-Day Repeated Oral Toxicity Preliminary
Study in Rats" (dose Ievels: 0, I 00, 500, and 1,000 mg/kg; number of animals, 3 males and 3 females per group) and found no changes
attributable to the test substance in clinical signs, body weights, hematology, organ weights (brain, thymus, liver kidney, adrenal glands, spieen,
testis, and ovary), on necropsy. On account of these findings, the highest dose Ievel was set at 1,000 mg/kg, and the medium and lower dose Ievels were set at 200 and 40 mg/kg, respectively. Thereafter, oral administration (gavage) was performed once a day in the morning throughout the 28-d dosing period according to the Chemical Substances Control Law ( 1986), to 6 rats of each sex in the 200 and 40 mg/kg groups and to 12 rats of
each sex in the control and 1,000mg/kg groups. The dosing volume (10 ml/kg) for individual animals was calculated based upon the most recent
body weight. Moreover, 6 rats in the control and 1,000 mg/kg groups were given to a 14-d recovery period after the completion of the dosing
period.

Positive control:

not required

Examinations

Observations and examinations performed and frequency:

For the 28-d repeated-dose toxicity study, the parameters described below were examined. Clinical signs, body weight, andfood consumption:
Clinical signs of the animals were observed four times on the dose day and thereafter once a day in the acute oral toxicity study, and twice a day
(before and after administration) throughout the dosing period, and once a day in the morning during the recovery period in the 28-d repeated-
dose toxicity study. The body weightof all animals and the gross weights of the feeders were measured before dosing and on days 4, 8, and 15 (the day of administrationwas designed as day 1) in the acute oral toxicity study, and once a week in the 28-d repeateddose toxicity study.
Hematology and blood chemistry:
On days of the scheduled necropsy, the animals were anesthetized by intraperitoneal injection of sodium thiopental
(Ravonal, Tanabe Seiyaku Co., Ltd.). Thereafter, blood samples were collected via the posterior vena cava. For hematology, we measured the
erythrocyte count (RBC), hemoglobin concentration (Hb), hematocrit value (Ht), mean corpuscular volume (MCV), mean corpuscular hemoglobin
(MCH), mean corpuscular hemoglobin concentration (MCHC), reticulocyte count, p1 atdet~.:uu nt (PLT), prulhrumbiu time (PT), aclivated partial
thromboplastin time (APTT), leukocyte count (WBC), and differential leukocyte count. For blood chemistry, we used the obtained serum samples to
measure the aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), y-glutamyltransferase (y G T), 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). Urinalysis: Fresh urine samples from s ix males and six females in each group were
collected on day 27, and the following test items were measured: pH, protein, glucose, ketone bodies, bilirubin, occult blood, urobilinogen.
No changes attributed to bismuth were found in the examinations during the dosing period. Therefore, examinations were not conducted during the recovery period.
Pathological and histopathological examination:
After the blood sampling, all animals were sacrificed by exsanguinat ion via the abdominal aorta and then subjected to necropsy. The fol lowing
organs of all animals were weighed: brain, liver, kidney, adrenal glands g land, thymus, spieen, testis, and ovary. Relativeorgan weights were
calculated from body weights on each necropsy day. Histopathological examination was performed on the heart, liver, spieen, kidneys, and
adrenals obtained from the animals of the control and I ,000 mg/kg groups, and on gross lesions of any group. The hematoxylin and eosin
staining specimens were prepared according to the standard procedure and then microscopically examined. No -changes attributed to bismuth
were found. Therefore, histopathological examination of argans and tissues except for gross lesions in the animals of the recovery group was not
conducted.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

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 examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

There were no changes in clinical signs , body we ights, foodconsumption, hematology, urinalysis, organ weights, necropsy, or histopathological
findings in the 28-d repeated oral dose toxicity study. As a result of these findings, we determined the no-observed-effect Ievel (NOEL) of bismuth to be 1000 mg/kg for males and females and calculated on dibismuth trisulphide the no-observed-effect Ievel (NOEL) was 2460 mg/kg for males and females.

Effect levels

1

Dose descriptor:

NOEL

Effect level:

1 230 other: mg/kg bw/day

Based on:

other: calculated for dibismuth trisulfide

Sex:

male/female

2

Dose descriptor:

NOEL

Effect level:

1 000 other: mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The NOEL for bismuth was determined to be 1000 mg/kg bw for males and females. Since bismuth and dibismuth trisulfide are both almost insoluble inorganic compounds and exhibite comparable properties the results from bismuth were used used via read-across as supporting data. The calculated LD50 for dibismuth trisulfide is above 1230 mg/kg bw.

Executive summary:

There were no changes in clinical signs , body weights, food consumption, hematology, urinalysis, organ weights, necropsy, or histopathological findings in the 28-d repeated oral dose toxicity study with bismuth. As a result of these findings, the NOEL for bismuth was determined to be 1000 mg/kg for males and females. Since bismuth and dibismuth trisulfide are both almost insoluble inorganic compounds and exhibite comparable properties the results from bismuth were used used via read-across as supporting data. The calculated LD50 for dibismuth trisulfide is above 1230 mg/kg bw.