Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics, other
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

Constituent 1
Chemical structure
Reference substance name:
Bismuth oxide salicylate
EC Number:
238-953-1
EC Name:
Bismuth oxide salicylate
Cas Number:
14882-18-9
Molecular formula:
C7H5BiO4
IUPAC Name:
2-hydroxy-4H-1,3,2-benzodioxabismin-4-one
Details on test material:
Name: Bismuth subsalicylate

Test animals

Species:
other: not applicable
Details on test animals or test system 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 / concentration:
Not applicable
Positive control reference chemical:
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
Bismuth subsalicylate in pharmaceutical preparations is converted to bismuth carbonate and sodium salicylate in the small intestine. The bismuth portion of bismuth subsalicylate is poorly absorbed from the gastrointestinal tract with an oral bioavailability reported to be < 0.005%. There are very few data on the dermal absorption of bismuth, however, absorption via this route is expected to be low. In contrast, the salicylate portion of bismuth subsalicylate is well absorbed via the oral route with a bioavailability > 90%. Salicylates are also absorbed percutaneously. Based on particle size distribution data and modelling of deposition in the respiratory tract, it is estimated that between 2.9% to 9.2% of bismuth subsalicylate is 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. Salicylates are widely distributed through the body with an elimination half-life that is dependent on level of exposure; half-life may be prolonged to 22 hours with ingestion of toxic doses. Elimination is via metabolism in the liver with urinary excretion of conjugated metabolites and free salicylic acid. The elimination of salicylates at therapeutic doses follows first order kinetics, which may change to zero order kinetics with toxic doses due to saturation of 2 of the 5 possible pathways of elimination. Alkalinisation of the urine increases the urinary excretion rate of salicylates.
Executive summary:

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

Absorption: The bismuth portion of bismuth subsalicylate is poorly absorbed from the gastrointestinal tract with an oral bioavailability reported to be < 0.005%. There are very few data on the dermal absorption of bismuth, however, absorption via this route is expected to be low. In contrast, the salicylate portion of bismuth subsalicylate is well absorbed via the oral route with a bioavailability of > 90%. Salicylates are also absorbed percutaneously. Based on particle size distribution data and modelling of deposition in the respiratory tract, it is estimated that between 2.9% and 9.2% of bismuth subsalicylate 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 indicate 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. Salicylates are widely distributed through the body with an elimination half-life that is dependent on level of exposure; the half-life may be prolonged to 22 hours with ingestion of toxic doses.

 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.Elimination of salicylate is via metabolism in the liver with urinary excretion of conjugated metabolites and free salicylic acid. The elimination of salicylates at therapeutic doses follows first order kinetics, which may change to zero order kinetics with toxic doses due to saturation of 2 of the 5 possible pathways of elimination. Alkalinisation of the urine increases the urinary excretion rate of salicylates.