Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
calculation (if not (Q)SAR)
Remarks:
Migrated phrase: estimated by calculation
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
A written assessment of toxicokinetic behaviour is considered appropriate for the substance. The substance displays only minor toxicological effects in any of the studies proposed, and is deemed to be be not harmful for health effects. As such, it is deemed inappropriate in terms of animal welfare to conduct a toxicokinetic assessment when no harmful effects are predicted based on known toxicology. A written assessment has therefore been prepared to address this endpoint.

Data source

Materials and methods

Principles of method if other than guideline:
A written assessment based on the toxicological profile of the substance.

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Name: Bismuth subnitrate

Test animals

Species:
other: not applicable
Details on test animals and environmental conditions:
Not applicable

Administration / exposure

Route of administration:
other: not applicable
Details on exposure:
Not applicable
Duration and frequency of treatment / exposure:
Not applicable
Doses / concentrations
Remarks:
Doses / Concentrations:
Not applicable
No. of animals per sex per dose:
Not applicable
Positive control:
Not applicable
Details on study design:
Not applicable
Details on dosing and sampling:
Not applicable

Results and discussion

Preliminary studies:
Not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Not applicable
Details on distribution in tissues:
Not applicable
Details on excretion:
Not applicable

Metabolite characterisation studies

Details on metabolites:
Not applicable

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: low bioaccumulation potential based on review of study results
The bismuth portion of pharmaceutical preparations of bismuth subnitrate is poorly absorbed from the gastrointestinal tract with an oral bioavailability reported to be < 0.01%. There are very few data on the dermal absorption of bismuth, however, absorption via this route is expected to be low. In humans, ingested nitrate is rapidly absorbed (oral bioavailability is at least 92%) from the proximal small bowel and is distributed throughout the body. Based on particle size distribution data and modelling of deposition in the respiratory tract, it is estimated that between 1.0% and 12.9% of bismuth subnitrate may be absorbed via inhalation.

The small amount of bismuth that is absorbed is distributed to various organs with the highest concentration expected to be in the kidney. Bismuth can cross the blood-brain barrier. The results of a study in guinea pigs with radiobismuth suggest poor placental transfer of bismuth (< 1%). Excretion of absorbed bismuth is via the urinary and faecal routes. The distribution half-life of bismuth is 1 to 4 hours, the plasma half-life is 5 to 11 days and the urinary excretion half-life lasts between 21 to 72 days. Unabsorbed bismuth is excreted in the faeces. Nitrates are rapidly converted in the liver to denitrated metabolites and inorganic nitrites, which are then excreted in urine. Approximately 60% to 70% of an ingested nitrate dose is excreted in urine within the first 24 hours.
Executive summary:

A toxicokinetics assessment was conducted for bismuth subnitrate using available data including data from the published literature.

Absorption:The bismuth portion of pharmaceutical preparations of bismuth subnitrate is poorly absorbed from the gastrointestinal tract with an oral bioavailability reported to be < 0.01%. There are very few data on dermal absorption of bismuth, however, absorption via this route is expected to be low. In humans, ingested nitrate is rapidly absorbed from the proximal small bowel (oral bioavailability is at least 92%).Based on particle size distribution data and modelling of deposition in the respiratory tract, it is estimated that between 1.0% and 12.9% of bismuth subnitrate may be absorbed via inhalation.

Distribution: The small amount of bismuth that is absorbed is distributed to various organs with the highest concentration expected to be in the kidney. The results of a study in guinea pigs with radiobismuth suggest poor placental transfer of bismuth (< 1%), however, bismuth can cross the blood-brain barrier. The distribution half-life of bismuth is 1 to 4 hours and the plasma half-life is 5 to 11 days. Nitrate is distributed throughout the body; it does not accumulate in the body. Hydroxide ions are normal constituents of the body fluids and therefore are likely to be widely distributed in the body.

Elimination: Excretion of absorbed bismuth is via the urinary and faecal routes and the urinary excretion half-life lasts between 21 to 72 days. Unabsorbed bismuth is excreted in the faeces. Nitrates are rapidly converted in the liver to denitrated metabolites and inorganic nitrites, which are then excreted in urine. Approximately 60% to 70% of an ingested nitrate dose is excreted in urine within the first 24 hours.