Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Short description of key information on bioaccumulation potential result: 
Oral absorption: The assumption appears justified that upon oral uptake the systemic uptake is low for bismuth. An oral absorption factor of 1% will be taken forward for risk characterisation purposes as a conservative assumption.
Inhalation absorption: Considering the very low oral bioavailability and the minimal predicted deposition in the respiratory tract, it is proposed to take forward an inhalation absorption factor of 1% for the purpose of risk characterisation, thus rendering corrections when extrapolating route-to-route (oral-inhalation) unnecessary.
 

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
1
Absorption rate - dermal (%):
0.1
Absorption rate - inhalation (%):
1

Additional information

General read-across concept:

In vitro bioaccessibility data or in vivo toxicokinetic data for a comparative assessment of relative bioavailability of various bismuth substances are not available, thus water solubility (although a poor surrogate) is adopted as a rough measure of bioavailability, for which the following data are available:

 

bismuth substance

water solubility

reference

bi metal

1.87 mg/L

Paulus, 2010; see specific IUCLID-file, section 4.8

dibismuth trioxide

5.89 mg/L

Paulus, 2010; see specific IUCLID-file, section 4.8

bismuth trinitrate

998.4 mg/L

Paulus, 2010; see specific IUCLID-file, section 4.8

 

Based on the above, tentative read-across groups of poorly soluble bismuth substances (metal, trioxide) and highly soluble substances (trinitrate) will be assumed for the purposes of this dossier. 

 

Oral absorption

There are some publications that allow an assessment of the oral bioavailability of bismuth metal in rats, which are however somewhat of age. In the following, the results from two review articles (Slikkerveer, A.; de Wolff, F.A. (1989) and Tillman, L.A.; et al. (1996)) that were considered to contain relevant and reliable data are summarised:

 

Systemic bioavailability from bismuth compounds such as tripotassium dicitrato bismuthate (De-Nol), bismuth subsalicylate and ranitidine bismuth citrate is low. Less than 1% of the bismuth dose administered is absorbed.

 

The normal concentration of bismuth in blood is between 1 and 15µg/L, but absorption from oral preparations produces a significant rise. Transient peak plasma bismuth concentrations greater than 50 µg/L are observed 30-60 minutes after dosing with tripotassium dicitrato bismuthate in some patients, but are not associated with any toxic effects.

 

The distribution of bismuth in the organs is largely independent of the compound administered: the concentration in kidney is always highest. Elimination from the body takes place by the urinary and faecal routes. Elimination from blood displays multi-compartment pharmacokinetics. After discontinuation of treatment with bismuth preparations its excretion in urine may continue for up to 3 months, by which time blood bismuth concentrations have declined to pre-treatment values.

 

In conclusion, the assumption appears justified that upon oral uptake the systemic uptake is low for bismuth. An oral absorption factor of 1% will be taken forward for risk characterisation purposes as a conservative assumption.

 

Reviews:

Slikkerveer, A.; de Wolff, F.A. (1989); Pharmacokinetics and toxicity of bismuth compounds; Med. Toxicol. Adverse Drug Exp. 4, 303-323

Tillmann; L.A.; et al. (1996); Review article: safety of bismuth in the treatment of gastrointestinal diseases; Aliment Pharmacol Ther 10, 459-467

Bierer, D.W. (1990); Bismuth subsalicylate: history, chemistry, and safety; Reviews of Infectious Diseases 12, 3-8

Krigman, M.R.; et al. (1985); Matal toxicity in the nervous system; Monographs in Pathology 26, 58-100

 

 

Inhalation absorption

No data on inhalation absorption and distribution are available for bismuth metal or bismuth compounds.

Nevertheless, after completion of a testing programme on dustiness testing and particle size analysis of the airborne fraction on commercially available forms of bismuth metal powder, dibismuth trioxide and bismuth (III) trinitrate pentahydrate, the collected information can be used to estimate inhalation absorption factors based on a prediction of deposition patterns in the respiratory tract (MPPD model), in accordance with guidance developed under HERAG.

The fate and uptake of deposited particles depends on the clearance mechanisms present in the different parts of the airway. In the head region, most material will be cleared rapidly, either by expulsion or by translocation to the gastrointestinal tract. A small fraction will be subjected to more prolonged retention, which can result in direct local absorption. More or less the same is true for the tracheobronchial region, where the largest part of the deposited material will be cleared to the pharynx (mainly by mucociliary clearance) followed by clearance to the gastrointestinal tract, and only a small fraction will be retained (ICRP, 1994). Once translocated to the gastrointestinal tract, the uptake will be in accordance with oral uptake kinetics.

 

In consequence, the material deposited in the head and tracheobronchial regions would be translocated to the gastrointestinal tract, where it would be subject to gastrointestinal uptake at a ratio of 1%. The material that is deposited in the pulmonary region may be assumed by default to be absorbed to 100%. This absorption value is chosen in the absence of relevant scientific data regarding alveolar absorption although knowing that this is a conservative choice. Thus, the following predicted inhalation absorption factors can be derived for bismuth metal, dibismuth trioxide and bismuth (III) trinitrate pentahydrate. For further information on particle size and dustiness refer to the individual IUCLID-files section 4.5.

 

Absorption factors, bismuth metal, dibismuth trioxide and bismuth (III) trinitrate pentahydrate

test item

absorption factors via inhalation [%]

Bismuth metal

0.50

Dibismuth trioxide

0.59

Dibismuth trioxide nanosize

0.33

Bismuth (III) trinitrate pentahydrate

0.38

 

Considering the very low oral bioavailability and the minimal predicted deposition in the respiratory tract, it is proposed to take forward an inhalation absorption factor of 1% for the purpose of risk characterisation, thus rendering corrections when extrapolating route-to-route (oral-inhalation) unnecessary.

 

Dermal absorption

In the absence of measured data on dermal absorption, previous guidance primarily directed at organic chemicals with a defined lipophilicity and corresponding percutaneous transfer potential, suggests the assignment of either 10% or 100% default dermal absorption rates. In contrast, the currently available scientific evidence on dermal absorption of metal cations (predominantly based on the experience from previous EU risk assessments) yields substantially lower figures, which can be summarised briefly as follows:

 

Measured dermal absorption values for metal cations or inorganic metal substances in studies corresponding to the most recent OECD test guidelines are typically 1 % or even less. Therefore, the use of a 10 % default absorption factor is not scientifically supported for such ionic species. This is corroborated by conclusions from previous EU risk assessments (Ni, Cd, Zn), which have derived dermal absorption rates of 2 % or far less (but with considerable methodical deviations from existing OECD methods) from liquid media.

 

However, considering that under industrial circumstances many applications involve handling of dry powders, substances and materials, and since dissolution is a key prerequisite for any percutaneous absorption, a factor 10 lower default absorption factor may be assigned to such “dry” scenarios where handling of the product does not entail use of aqueous or other liquid media. This approach was taken in the in the EU RA on zinc. A reasoning for this is described in detail elsewhere (Cherrie and Robertson, 1995), based on the argument that dermal uptake is dependent on the concentration of the material on the skin surface rather than it’s mass.

 

Consistent with the methodology proposed in HERAG guidance for metals (HERAG fact sheet - assessment of occupational dermal exposure and dermal absorption for metal cations and inorganic metal substances; EBRC Consulting GmbH / Hannover /Germany; August 2007), the following default dermal absorption factors for metal cations have therefore been proposed (reflective of full-shift exposure, i.e. 8 hours):

 

From exposure to liquid/wet media: 1.0 %

From dry (dust) exposure: 0.1 %

 

Given that the primary cause between the lack of percutaneous transfer is considered to be the ionic nature, it is proposed to assume similar behaviour for bismuth ions, and to adopt the above stated dermal absorption factors forbismuth metal and bismuth compounds.

Remark: Detailed information used for this summary are provided in the attached report "derivation of oral, dermal and inhalation absorption factors for bismuth metal and bismuth compounds", including a list with the primary literature.

 

Discussion on bioaccumulation potential result:

Oral absorption

There are some publications that allow an assessment of the oral bioavailability of bismuth metal in rats, which are however somewhat of age. Information from two review articles(Slikkerveer, A.; de Wolff, F.A. (1989) and Tillman, L.A.; et al. (1996)) that were considered to contain relevant and reliable data are summarised.

For details please refer to the endpoint summary for toxicokinetics, metabolism and distribution.

 

Inhalation absorption

No data on inhalation absorption and distribution are available for bismuth metal or bismuth compounds.

Nevertheless, after completion of a testing programme on dustiness testing and particle size analysis of the airborne fraction on commercially available forms of bismuth metal powder, dibismuth trioxide and bismuth (III) trinitrate pentahydrate, the collected information can be used to estimate inhalation absorption factors based on a prediction of deposition patterns in the respiratory tract (MPPD model), in accordance with guidance developed under HERAG.

For details please refer to the endpoint summary for toxicokinetics, metabolism and distribution.