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Diss Factsheets

Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
not reported
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment

Data source

Reference
Reference Type:
publication
Title:
Intestinal uptake site, enterohepatic circulation, and excretion of tetra- and trialkyltin compounds in mammals
Author:
Iwai H, Wada O, Arakawa Y, & Ono T
Year:
1982
Bibliographic source:
Journal of Toxicology and Environmental Health 9:41-49

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Tetrabutyltin, along with other alkyltins, was investigated for intestinal uptake sites, distribution in organs, enterohepatic circultions, and excretion into feces, urine and bile.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Tetrabutyltin
EC Number:
215-960-8
EC Name:
Tetrabutyltin
Cas Number:
1461-25-2
Molecular formula:
C16H36Sn
IUPAC Name:
tetrabutylstannane
Constituent 2
Reference substance name:
Bu4Sn
IUPAC Name:
Bu4Sn
Details on test material:
- Analytical purity: >98 %
- Source: Tokyo Kasei Kogyo Co., Ltd., Tokyo
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
Three male Wistar rats weighing 400-450 g were used for one group. Two male Japanese white rabbits weighing 3 kg were used also.

Administration / exposure

Route of administration:
other: oral (unspecified) and subcutaneous
Vehicle:
other: sesame oil
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): 5 times at 12-hour intervals
- Mixing appropriate amounts with (Type of food): administered orally in sesame oil

PREPARATION OF DOSING SOLUTIONS:
For oral administration:
Tetrabutyltin (10 mg/kg) was dissolved in sesame oil was administered orally to the rats five times at 12-h intervals.

For subcutaneous administration:
Tetrabutyltin (10 mg/kg) was dissolved in 2 mL ethanol and saline (2:1) solution was administered sc to three rats twice at 2-h intervals.

For bile collection: 51 mg tetrabutyltin in 6 mL ethanol and saline solution were infused into the intestine of a rabbit. A polyethylene cannula was inserted into the bile duct and the bile was collected in a test tube.

For feces and urine collection: Tetrabutyltin (10 mg/kg) was dissolved in ethanol and administered sc to three rats.


Duration and frequency of treatment / exposure:
For oral administration: 5 times at 12-hour intervals
For subcutaneous administration: 2 times at 2 hour intervals
For bile collection: once
For feces and urine collection: once
Doses / concentrationsopen allclose all
Dose / conc.:
10 other: mg/kg
Remarks:
oral administration
Dose / conc.:
10 other: mg/kg
Remarks:
subcutaneous administration
Dose / conc.:
51 other: mg
Remarks:
bile collection
Dose / conc.:
10 other: mg/kg
Remarks:
feces and urine collection
No. of animals per sex per dose / concentration:
For oral administration: 3 male rats
For subcutaneous administration: 3 male rats
For bile collection: rabbit
For feces and urine collection: 3 male rats
Control animals:
not specified
Positive control reference chemical:
No information
Details on study design:
For oral administration: 3 male rats were administered tetrabutyltin five times at 12-h intervals. Four hours after the last dose, all rats were sacrificed and the organs (gastrointestinal tract, liver, kidney, blood and brain) were removed. The gastrointestinal tract was cut open and rinsed in succession with saline, 70 % ethanol, and 100 % ethanol to avoid contamination by the contents of the lumen. The small intestine was divided into duodenum for the upper fourth, ileum for the lower fourth, and jejunum for the rest.

For subcutaneous administration: Tetrabutyltin was dissolved in 2 mL ethanol and salin solution and administered subcutaneously to three rats at twice 2h intervals. One hour after the last injection, the animals were sacrificed and their organs (small intestine contents, liver, and blood) were examined.

For bile collection: 51 mg of tetrabutyltin was dissolved in 6 mL of ethanol and saline solution and infused into the intestine of a rabbit. A polyethylene cannula was inserted into the bile duct and the bile was collected in a test tube. Amounts of tetrabutyltin were measured as a function of time after the infusion.

For feces and urine collection: Tetrabutyltin was dissolved in ethanol and administered subcutaneously to three rats. The rats were housed in separate metabolic cages and feces and urine were collected for 3 days.
Details on dosing and sampling:
Alkyltins were extracted from samples with ethyl acetate after the homogenised samples were acidified with HCl. Further purification was performed by concentration of the extracted solution followed by stepwise elution on a silica gel column with n-hexane for R4Sn. Eluates were concentrated and the amounts of R4Sn were determined by gas chromatography. Silica gel for column chromatography was washed before use. Gas chromatography was performed with Shimadzu model GC-6A Instrument. A 200 cm x 3 mm glass column containing 10 % PEG-20M was used for the analysis of tetrabutyltin. Tetrabutyltin was detected with a flame ionization detector. The temperature of the injection and detector ports was 180 degrees C and the program rate was 4 degrees Celsius/minute. Extraction and analysis of alkyltins were carried out by previously reported methods. Alkyltins were extracted from samples with ethyl acetate after the homogenized samples were acidified with HCl. Further purification was performed by concentration of the extracted solution, followed by stepwise elution on a silica gel column with n-hexane for tetrabutyltin. Eluates were concentrated and the amount of tetrabutyltin were determined by gas chromatography. Recoveries through all procedures of tetrabutyltin added to various tissues ranged from 97 to 104 %.
Statistics:
No information

Results and discussion

Preliminary studies:
No information

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Tetrabutyltin was mainly taken up in the jejunum and duodenum. The kidney and liver retained tetrabutyltin. Almost no retention of the compounds was observed in the brain and blood. Relatively large amounts of Bu3Sn+ were found in the small and large intestines and the brain.
Details on distribution in tissues:
The concentration of tetrabutyltin in the wall of the gastrointestinal tract after oral administraion increased in the order of duodenum, jejunum, and ileum. The liver retained tetrabutyltin. Almost no retention was observed in the brain and blood.
Transfer into organs
Transfer type:
other: passive diffusion
Observation:
distinct transfer
Details on excretion:
After a single subcutaneous injection of tetrabutyltin (10 mg/kg) in rats, tetrabutyltin could not be detected in feces or urine. However, although the amounts were very small (0.07 - 0.16 % of the dose), Bu3Sn+ was found in feces and urine, suggesting that absorbed tetrabutyltin is dealkylated in the body and the metabolites are mainly excreted in urine and feces in the rats. The most lipid-soluble tetrabutyltin that escapes dealkylation in organs is excreted into the bile and futher metabolized in the intestine or reabsorbed there.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Metabolites include Bu3Sn+

Any other information on results incl. tables

When Bu4Sn was administered, the amount of Bu4Sn excreted into urine and feces was not detected, but Bu3Sn+ was detected in both the feces at 0.16 % of the dose and in the urine at 0.12 % of the dose of Bu4Sn.

Applicant's summary and conclusion

Conclusions:
The route, rate and amount of excretion of tetrabutyltin depends on the velocity of dealkylation, doses, physical and chemical properties, and route of administration of the compound.
Executive summary:

The intestinal uptake site, enterohepatic circulation, and excretion into bile, feces and urine of tetrabutyltin was investigated after oral, subcutaneous, or intestinal administration of the compounds to rats and rabbits. Assays of tetrabutyltin in the biological materials were carried out by gas chromatography. The main uptake sites in the small intestine were the jejunum and duodenum for tetrabutyltin. Tetrabutyltin was detected in the small intestine and contents of the intestinal lumen after subcutaneous injection of these compounds in rats. Tetrabutyltin is transported in the body through enterohepatic circulation. The route, rate and amount of excretion of tetrabutyltin depends on the velocity of dealkylation, doses, physical and chemical properties, and route of administration of the compound.