Dibismuth trisulphide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Statement

Adequacy of study:

key study

Study period:

2013-04-22

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Expert Statement

Data source

Reference

Reference Type:

other: Expert Statement

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Test guideline

Qualifier:

no guideline required

Test material

Test material information

Constituent 1

Reference substance name:

Dibismuth trisulphide

EC Number:

215-716-0

EC Name:

Dibismuth trisulphide

Cas Number:

1345-07-9

Molecular formula:

Bi2S3

IUPAC Name:

dibismuth trisulphide

Test material form:

solid: crystalline

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

ASSESSMENT OF ABSORPTION

Assessment of potential absorption via oral/inhalation/dermal route according to REACH Guidance R7c is provided in Table 1, 2 and 3, respectively. Additional literature data on insoluble bismuth compounds is provided if available.

For detailed information please refer to the attached Statement.

2.1 ORAL ABSORPTION

The oral absorption of bismuth compounds depends on the solubility in the gastrointestinal tract. Therefore, insoluble bismuth compounds, e.g. dibismuth trisulfide, are poorly absorbed (Billon et al., 1976; Dresow et al., 1991; Thomas et al., 1977; Thomas et al., 1983; Lechat and Kisch, 1986).
Bismuth bioavailability from 205Bi-labeled compounds given to human volunteers showed a low bioavailability of 0.005 – 0.038 % depending on the compound (Dresow et al., 1992).
The site(s) of Bi absorption are unknown (Slikkerveer and de Wolff, 1996).

Taken together, based on the physical form and low water solubility, but mainly on the absence of toxicity in acute and repeated dose oral toxicity studies, oral absorption of dibismuth trisulfide is assumed to be very low. This conclusion is confirmed by the literature on oral absorption of insoluble bismuth compounds.

2.2 DERMAL ABSORPTION

Adequate data on uptake following dermal exposure are not available.

Taken together, the physical state, the molecular weight, the water solubility, the vapour pressure, but mainly the absence of toxicity in acute dermal animal testing and the absence of irritating or corrosive and sensitizing potential the dermal absorption of dibismuth trisulfide is assumed to be very low.

2.3 RESPIRATORY ABSORPTION

Adequate data on uptake following respiratory exposure are not available.

Taken together, the low vapour pressure and the tendency of dibismuth trisulfide particles to agglomerate and deposit do not favour the respiratory uptake, whereas the particle size and the low water solubility favour the assumption that particle can be absorbed on different stages of the stages of the respiratory tract and via the gastrointestinal tract. However, the absence of toxicity in acute inhalation toxicity and acute and repeated dose oral toxicity studies, the respiratory and oral absorption of dibismuth trisulfide is assumed to be very low.

Details on distribution in tissues:

ASSESSMENT OF DISTRIBUTION

For detailed information please refer to the attached Statement.

Inorganic bismuth compounds are considered to be not able to penetrate the blood-brain barrier (Clarkson, 1979). Bismuth compounds induce the synthesis of a metal-binding protein, affecting its accumulation in the kidney (Zidenberg-Cherr et al., 1989).

Taken together, based on the low water solubility, but mainly based on the absence of target organs or signs of toxicity in a repeated dose toxicity study with the Read-Across substance bismuth in rats up to the limit concentration, distribution was considered minimal. Data from literature indicates accumulation in the kidney, however this is not considered to be relevant since the absorption of poorly water-soluble inorganic bismuth compounds is considered to be low.

Details on excretion:

ASSESSMENT OF EXCRETION

For detailed information please refer to the attached Statement.

Literature summarize that bismuth elimination from the body takes place by urinary and faecal routes (Slikkerveer and de Wolff, 1996).

Since the oral absorption of dibismuth trisulfide is very low, therefore the estimated favoured excretion route is the faecal route. However, very small quantities of absorbed and therefore dissolved parts are excreted via urine.

Metabolite characterisation studies

Details on metabolites:

It is discussed inconsistent if bismuth compounds are methylated within mammalian tissue (Clarkson, 1979; Hirner and Rettenmeyer, 2010).

Any other information on results incl. tables

References

 

Billon, J. P., Gernez, G., Gourdin, J. C., Martin, C., and Palliere, M. (1976) [Some physico-chemical properties of bismuth salts used in pharmacy].Ann Pharm Fr.34, 161-71.

 

Clarkson, T. W. (1979) Effects - General principles underlying the toxic action of metals. In Handbook on the Toxicology of Metals (L. Friberg, G. F. Nordberg and V. B. Vouk, eds.), Vol. 1, pp. 99-117. Elsevier/North-Holland Biomedical Press, Amsterdam.

Dresow, B., Nielsen, P., Fischer, R., Wendel, J., Gabbe, E. E., and Heinrich, H. C. (1991) Bioavailability of bismuth from²⁰⁵Bi-labelled pharmaceutical oral Bi-preparations in rats.Arch. Toxicol.65, 646-650.

Dresow, B., Fischer, R., Gabbe, E. E., Wendel, J., and Heinrich, H. C. (1992) Bismuth absorption from 205Bi-labelled pharmaceutical bismuth compounds used in the treatment of peptic ulcer disease.Scand. J. Gastroenterol.27, 333-336.

Hirner, A.V., Rettenmeyer, A.W. (2010) Methylated metal(loid) species in humans. Met ions Life Sci. 7: 465-521

Slikkerveer, A., and de Wolff, F. A. (1996) Toxicity of bismuth and its compounds. InToxicology of Metals(L. W. Chang, L. Magos and T. Suzuki, eds.), pp. 439-454. CRC Lewis Publishers, New York.

 

Thomas, D., and al, e. (1977) InClinical Chemistry and Clinical Toxicology of Metals(S. Brown and J. Savory, eds.), pp. 293-296. Elsevier/North Holland Biomedical Press, Amsterdam.

 

Thomas, D., Sobecki, S., Hartley, T., Coyle, P., and Alp, M. (1983) Variable absorption and excretion of bismuth and its potential for toxicity. InChemical Toxicology and Clinical Chemistry of Metals(S. Brown and J. Savory, eds.), pp. 391-394. Academic Press, London.

Lechat, P., and Kisch, R. (1986) [Bismuth encephalopathy: a reappraisal of risk factors]. Gastroenterol Clin Biol. 10, 562-569

Zidenberg-Cherr, S., Clegg, M.S., Parks, N.J., and Keen, C.L. (1989). Localization of bismuth radiotracer in rat kidney following exposure to bismuth. Biol Trace Elem Res., 19 (3): 185-194.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Based on the physical form and low water solubility, but mainly on the absence of toxicity in acute and repeated dose oral toxicity studies, oral absorption of dibismuth trisulfide is assumed to be very low. This conclusion is confirmed by the literature on oral absorption of insoluble bismuth compounds.

The physical state, the molecular weight, the water solubility, the vapour pressure, but mainly the absence of toxicity in acute dermal animal testing and the absence of irritating or corrosive and sensitizing potential the dermal absorption of dibismuth trisulfide is assumed to be very low.

The low vapour pressure and the tendency of dibismuth trisulfide particles to agglomerate and deposit do not favour the respiratory uptake, whereas the particle size and the low water solubility favour the assumption that particle can be absorbed on different stages of the stages of the respiratory tract and via the gastrointestinal tract. However, the absence of toxicity in acute inhalation toxicity and acute and repeated dose oral toxicity studies, the respiratory and oral absorption of dibismuth trisulfide is assumed to be very low.

Based on the low water solubility, but mainly based on the absence of target organs or signs of toxicity in a repeated dose toxicity study with the Read-Across substance bismuth in rats up to the limit concentration, distribution was considered minimal. Data from literature indicates accumulation in the kidney, however this is not considered to be relevant since the absorption of poorly water-soluble inorganic bismuth compounds is considered to be low.

There is no direct indication of bioaccumulation potential of dibismuth trisulfide in lung, adipose tissue, bone or stratum corneum. However, literature describes that bismuth compounds may accumulate in the kidney. Taking into account that absorption of dibismuth trisulfide is considered to be very low, accumulation is not considered to be relevant.

Since the oral absorption of dibismuth trisulfide is very low, therefore the estimated favoured excretion route is the faecal route. However, very small quantities of absorbed and therefore dissolved parts are excreted via urine.

For detailed information please refer to the attached statement.

Executive summary:

Based on the physical form and low water solubility, but mainly on the absence of toxicity in acute and repeated dose oral toxicity studies, oral absorption of dibismuth trisulfide is assumed to be very low. This conclusion is confirmed by the literature on oral absorption of insoluble bismuth compounds.

 

The physical state, the molecular weight, the water solubility, the vapour pressure, but mainly the absence of toxicity in acute dermal animal testing and the absence of irritating or corrosive and sensitizing potential the dermal absorption of dibismuth trisulfide is assumed to be very low.

 

The low vapour pressure and the tendency of dibismuth trisulfide particles to agglomerate and deposit do not favour the respiratory uptake, whereas the particle size and the low water solubility favour the assumption that particle can be absorbed on different stages of the stages of the respiratory tract and via the gastrointestinal tract. However,the absence of toxicity in acute inhalation toxicity and acute and repeated dose oral toxicity studies, the respiratory and oral absorption of dibismuth trisulfide is assumed to be very low.

 

Based on the low water solubility, but mainly based on the absence of target organs or signs of toxicity in a repeated dose toxicity study with the Read-Across substance bismuth in rats up to the limit concentration, distribution was considered minimal. Data from literature indicates accumulation in the kidney, however this is not considered to be relevant since the absorption of poorly water-soluble inorganic bismuth compounds is considered to be low.

 

There is no direct indication of bioaccumulation potential of dibismuth trisulfide in lung, adipose tissue, bone or stratum corneum. However, literature describes that bismuth compounds may accumulate in the kidney. Taking into account that absorption of dibismuth trisulfide is considered to be very low, accumulation is not considered to be relevant.

 

Since the oral absorption of dibismuth trisulfide is very low, therefore the estimated favoured excretion route is the faecal route. However, very small quantities of absorbed and therefore dissolved parts are excreted via urine.

For detailed information please refer to the attached statement.