Tributyltin chloride

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

Not specified

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Similar to OECD 417 but with deviations. No GLP, but peer reviewed.

Objective of study:

toxicokinetics

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

yes

Remarks:

See principles of method if other than guideline

Principles of method if other than guideline:

Main deviations:
- Not enough animals used.
- No information on feeding and housing conditions.
- Different vehicles used for different routes of entry.

GLP compliance:

not specified

Radiolabelling:

no

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.

Route of administration:

other: Oral & subcutaneous

Vehicle:

other: Oral: sesame oil; subcutaneous: ethanol & saline (2:1)

Duration and frequency of treatment / exposure:

Oral: five times at 12 h intervals.
Subcutaneous: twice at a 2 h intervals.

Dose / conc.:

3 other: mg/kg

Remarks:

Oral

Dose / conc.:

10 other: mg/kg

Remarks:

Oral

Dose / conc.:

5 other: mg/kg

Remarks:

Subcutaneous

Dose / conc.:

10 other: mg/kg

Remarks:

Subcutaneous

No. of animals per sex per dose / concentration:

3 rats.

Control animals:

yes, concurrent vehicle

Details on dosing and sampling:

Oral Doses of the test material (10 mg/kg each) dissolved in sesame oil were simultaneously administered orally to the rats five times at 12 h intervals. Another group of rats received simultaneously the test material (3 mg/kg each) dissolved in sesame oil at the same time intervals. Rats of the control group were given only sesame oil at these time 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.

Subcutaneous Doses of the test material (10 mg/kg each) dissolved in 2 mL ethanol and saline (2:1) solution were administered sc to three rats twice at a 2 h interval. Doses of the test material (5 mg/kg each) were administered to another group of rats in the same way. One hour after the last injection, the animals were sacrificed and their ogans [small intestine (contents of small intestine), liver, and blood] examined.

Faeces and Urine of Rats: Test material (l0 mg/kg each) dissolved in ethanol were administered sc to three rats. Test material (5 mg/kg each); dissolved in ethanol were administered to another three rats. Each group of rats, were housed in a separate metabolic cage. Faeces and urine were collected for 3d.

Preliminary studies:

No data

Type:

absorption

Results:

The main uptake sites in the small intestine were the ileum and the jejunum

Type:

distribution

Results:

See figure 3

Type:

excretion

Results:

The test material (5 mg/kg) administered sc were detected in higher concentrations in urine than in faeces. This result may be explained by the chemical properties of the test material, which are less susceptible to metabolism and more soluble in water.

Details on absorption:

The main uptake sites in the small intestine were the ileum and the jejunum.

Details on distribution in tissues:

When the test material was orally administered, their concentrations in the gastrointestinal tract increased in the order of jejunum, duodenum, and ileum.
A moderately high amount of TBT+ was found in the brain after oral administration of the test material.
When the test material was injected sc, TBT+ was recovered in the small intestine and contents of the lumen (Fig. 5).

Details on excretion:

The test material (5 mg/kg) administered sc were detected in higher concentrations in urine than in feces. This result may be explained by the chemical properties of the test material, which are less susceptible to metabolism and more soluble in water.

Metabolites identified:

not specified

Details on metabolites:

No data

Conclusions:

The main uptake sites in the small intestine were the ileum and the jejunum.
When the test material was orally administered, their concentrations in the gastrointestinal tract increased in the order of jejunum, duodenum, and ileum.
A moderately high amount of TBT+ was found in the brain after oral administration of the test material. When the test material was injected sc, TBT+ was recovered in the small intestine and contents of the lumen.
The test material (5 mg/kg) administered sc were detected in higher concentrations in urine than in faeces. This result may be explained by the chemical properties of the test material, which are less susceptible to metabolism and more soluble in water.

Executive summary:

The intestinal uptake site, enterohepatic circulation, and excretion into faeces, and urine of alkyltins were investigated after oral and sc administration of the test material to rats. Assays of trialkyltins in biological materials were carried out by gas chromatography.

The main uptake sites in the small intestine were the ileum and jejunum for trialkyltins. When the test material was injected sc, TBT+ was recovered in the small intestine and contents of the lumen (Fig. 5). These facts suggest that trialkyltins are transported in the body through enterahepatic circulation.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

Not specified

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: No guideline available. No GLP, but peer reviewed.

Objective of study:

distribution

Qualifier:

no guideline followed

Principles of method if other than guideline:

The distribution of tributyltin (TBT) and its metabolites, dibutyltin (DBT) and monobutyltin (MBT), was examined in the liver, brain and fat tissues in a two-generation reproductive toxicity study of the test material in rats using dietary supplementation at concentrations, of 5, 25 and 125 ppm.

GLP compliance:

not specified

Radiolabelling:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Wistar rats (Kud: Wistar) were used and 12 rats of each sex, 9 weeks of age, were purchased from Kyudo Co., Ltd., Tosu, Japan as parents of F1 generation.
A closed-formula diet was used CE-2 (Clea Japan Inc., Tokyo, Japan) as a base diet to formulate the test material diets.

Route of administration:

oral: feed

Vehicle:

not specified

Duration and frequency of treatment / exposure:

The test material diet was given to female rats of F0 generation at the copulation day (postnatal day (PND) 78-81) and was continued until the end of the experiment. F1 generation male and female rats were mated starting on PND 92 with a cohabitation period of 14 days. Males and females were sacrificed at different ages in the F1 generation. Because the primary purpose of this study is to evaluate the reproductive toxicity of the test material, the F1 males were sacrificed 14 days after the cohabitation period to restore the sperm count, that is, the F1 male rats were sacrificed on PND 119. Given a 21-day gestation followed by a 22-day lactation, the F1 female rats were sacrificed on the first day of the estrous stage from PND 148 in this study. The F2 rats were sacrificed on PND 91 for males and on the first day, of the estrous stage from PND 91 for females.

Dose / conc.:

5 ppm

Dose / conc.:

25 ppm

Dose / conc.:

125 ppm

No. of animals per sex per dose / concentration:

4-16 (see tables 1 & 2)

Control animals:

not specified

Details on study design:

A two-generation reproductive toxicity study of the test material was carried out using dietary concentrations of 5, 25 and 125 ppm.

Details on dosing and sampling:

The test material concentration was analysed in the diet using the same methods for analysing concentrations in fat tissue and confirmed that the base diet contained <0.02 ppm-0.06 ppm test material.

The test material diet was given to female rats of F0 generation at the copulation day (postnatal day (PND) 78-81) and was continued until the end of the experiment. F1 generation male and female rats were mated starting on PND 92 with a cohabitation period of 14 days. Males and females were sacrificed at different ages in the F1 generation. Because the primary purpose of this study is to evaluate the reproductive toxicity of the test material, the F1 males were sacrificed 14 days after the cohabitation period to restore the sperm count, that is, the F1 male rats were sacrificed on PND 119. Given a 21-day gestation followed by a 22-day lactation, the F1 female rats were sacrificed on the first day of the estrous stage from PND 148 in this study. The F2 rats were sacrificed on PND 91 for males and on the first day, of the estrous stage from PND 91 for females. In the F2 generation, one male and one female were selected from one litter and examined. One F1 female in the 125 ppm group delivered only female pups and therefore the number of males in this group was less than that of females in the F2 generation. The rats were euthanised through the inhalation of carbon dioxide, and the liver, brain, and abdominal fat were removed and stored at -80 °C until analysis. We divided this study into three blocks and it required more than one year to complete this study. Therefore, the tissues were stored for a period of a few months to 18 months before analysis. The liver and fat of all animals were analysed. For the analysis of the brain, four to five animals in each group of each sex were randomly selected. The brains of the remaining animals were used for evaluating the toxic effect of the test material on the brain.

Approximately 1 g of the abdominal fat from each individual was homogenised in 1 M HCl methanol solution using a Polytron homogeniser (Model PCU11, Kinematica, Switzerland) and spiked with 1 µg of triphenyltin chloride (Tokyo Kasei Kogyo Co., Ltd., Tokyo) as an internal standard.
The concentrations of butyltin compounds in fat tissue were measured by gas chromatography equipped with a flame photometric detector (GC-8APFP, Shimadzu, Japan) and calculated based on the extraction efficiency of triphenyltin. The detection limits of TBT, DBT, and MBT were 0.069, 0.086, and 0.114 nmol/g-tissue, respectively.

Approximately 1 g of the liver or brain from each individual was homogenised with 300 to 500 % (w/w) diatom earth (Hyflo Super-Cel, Wako, Japan) using mortar and pestle. Each sample was spiked with 1 µg of each deuterium butyltin derivative (TBT-d27, DBT-d18, and MBT-d9, Hayashi Junyaku Kogyo, Tokyo, Japan) and then extracted with 0.1 % tropolone in benzene using an accelerated solvent extraction system (ASE 200, Dionex, USA). The extracts were concentrated to 3 mL under N2 and ethylated using sodium tetraethylborate (Strem Chemicals, USA). Following the addition of 10 mL of 1M KOH in hexane, the mixture was shaken and the organic layer was cleaned up with Sep-pak florisil cartridges (Waters, USA): The resulting sample was concentrated to 1 mL and analysed on a gas chromatograph equipped with a mass spectrometer (6890 gas chromatograph, 5973 mass spectrometer, Hewlett-Packard, USA). The target ions (m/z) in each compound are as follows: TBT, 263; DBT, 261; MBT, 235; TBT-d27, 318; DBT-d18, 279; and MBT-d9, 244. The concentrations of butyltins were calculated from the ratio of the area under the peaks of each butyltin compound and its derivative. The detection limits of TBT, DBT and MBT were 0.010, 0.013 and 0.017 nmol/g-tissue, respectively.

Statistics:

Factorial ANOVA was used to test the significance of the gender difference of the tissue concentrations of TBT, DBT and MBT. Dietary concentration of the test material (5, 25 and 125 ppm), gender (male or female), and generation (F1 or F2) were used as factors. The results were interpreted as significant when p was less than 0.01.

Preliminary studies:

n/a

Type:

distribution

Results:

The results of this study suggest tissue-dependent distribution of TBT, DBT and MBT and gender-dependent distribution of the three metabolites in the liver of rats.

Details on absorption:

n/a

Details on distribution in tissues:

The concentrations of TBT, DBT and MBT in the liver, brain and fat tissues of rats fed a test material diet in the F1 and F2 generations are presented in Tables 1 and 2, respectively. In the 0 ppm group, the concentrations of butyltin compounds were below the detection limit in all brain and fat samples, and only MBT and DBT were detected in a few liver samples (DBT was detected in only one sample). The maximum MBT concentration in the liver in this group was 0.2 nmol/g. In the liver, irrespective of test material diet concentration, gender or generation, the highest concentration of metabolite was consistently MBT, followed by DBT, and then TBT. In the 125 ppm test material group, the mean MBT concentration in the liver reached approximately 10 nmol/g in males and 6-7 nmol/g in females in the F1 and F2 generations. In contrast, in the brain, TBT was consistently present at the highest concentration across both genders and generations, nearly always followed by DBT and MBT. Some exceptions were noted at the lowest test material diet concentration. In the brains of rats given the 125 ppm diets, the concentrations of TBT, DBT and MBT ranged from 15-20, 2-4, and 0.5-1.5 nmol/g, respectively. In fat tissue, the concentrations of TBT, DBT, and MBT showed similar relationships to those observed in the brain, although the concentrations were much lower and were below the detection limit in some samples, particularly at the lowest test material diet concentration.
The differences in the concentrations of TBT, DBT and MBT by gender in the liver and brain of F1 and F2 rats fed test material diets are shown in Figs. 1 and 2, respectively. The male-to-female ratio of butyltin compound concentrations of rats from the same litter was calculated and expressed as a percentage. In the liver, except for the rats in the 5 ppm group in the F1 generation, the male/female ratio of TBT concentration was approximately 70 %, while the ratios of DBT and MBT were higher than 100 %. The male/female ratio of MBT concentration was highest, reaching approximately 200-300 %, although the confidence intervals are also large. In contrast, there was no remarkable gender difference in the concentrations of TBT, DBT and MBT in the brain.
Figure 3 shows the generational difference (F2/F1 ratio) in the concentrations of TBT, DBT and MBT in the liver and brain of female rats which were in the parent and child relationship. In neither of the organs, no apparent difference was found in the concentrations of TBT and its metabolites between the F1 and F2 generations. The F2/F1 ratio of MBT concentration was high in the brain, although the confidence intervals are very large.
Table 3 shows the result of factorial ANOVA of the tissue concentrations of TBT, DBT and MBT in the liver and brain. Three animals of the 5 ppm group with MBT concentrations in the brain below the detection limit were excluded from the data set in this analysis. The dietary concentration of the test material significantly affected the tissue concentration of the three butyltin compounds in the liver and brain. Gender also significantly affected the tissue concentrations in the liver but did not significantly affect the tissue concentrations in the brain. Generation did not significantly affect the concentrations of the three butyltin compounds in either of the organs. An interaction between dietary test material concentration and gender was found to affect the TBT concentration in the liver and an interaction between dietary test material concentration and generation was found to affect the MBT concentration in the brain.

Details on excretion:

n/a

Metabolites identified:

yes

Details on metabolites:

MBT, DBT & TBT.

Conclusions:

The results of this study suggest tissue-dependent distribution of TBT, DBT and MBT and gender-dependent distribution of the three metabolites in the liver of rats.

Executive summary:

The distribution of tributyltin (TBT) and its metabolites, dibutyltin (DBT) and monobutyltin (MBT), was examined in the liver, brain and fat tissues in a two-generation reproductive toxicity study of the test material in rats using dietary supplementation at concentrations, of 5, 25 and 125 ppm. In the liver, irrespective of the test material dietary concentration, gender or generation, the highest concentration of metabolite was consistently MBT, followed by DBT, and then TBT. In contrast, TBT was consistently present at the highest concentration in the brain, nearly always followed by DBT and MBT. In fat tissues, the concentrations of the three butyltin compounds showed similar relationships to those observed in the brain, although the concentrations were much lower. In the liver, the concentration of TBT was higher in females, and those of DBT and MBT were higher in males. Factorial ANOVA also suggested the effect of gender on the concentrations of the three butyltin compounds in the liver. The results of this study suggest tissue-dependent distribution of TBT, DBT and MBT and gender-dependent distribution of the three metabolites in the liver of rats.

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

Not specified

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted in accordance with generally accepted scientific principles, possibly with incomplete reporting or methodological deficiencies, which do not affect the quality of the relevant results.

Objective of study:

distribution

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

The aim of the study was to examine these metabolites and determine the metabolic fate of TBT to evaluate the biological effect of TBT pollution on mammals. It is conceivable that the products of hydroxylation at positions 1 and 2 of the butyl moiety are unstable under acidic conditions and they form dibutyltin acetate and 1-butanol from the former and dibutyltin acetate and 1-butene from the latter, respectively. Unfortunately, this experiment was not designed to detect such metabolites, and therefore only probable oxygenated derivatives at positions 3 and 4 of the alkyl moiety of TBT and DBT were studied. DBT and its oxygenated derivatives are thought to be produced partly by biochemical degradation and partly by chemical degradation of the products formed by hydroxylation at position 1 or 2 of TBT or its oxygenated products under the acidic condition used. Because it was impossible to distinguish them, results of the analysis were expressed as the total amount obtained by both biochemical and chemical degradation. For the sake of brevity, each metabolite is referred to in this paper as if it exists only in the structure indicated, but this does not mean to imply exact identity of these compounds in rats.

Samples and authentic standards were tetraalkylated prior to analysis by a gas-liquid chromatography equipped with a flame photometric detector (GC/FPD) or by gas chromatography/mass spectrometry (GC/MS) to make analysis easier and to avoid changing their chemical characteristics.

GLP compliance:

no

Radiolabelling:

no

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

Rats were 9 weeks old at treatment. They were housed at 23 ± 2 °C and 50 % relative humidity. After treatment animals were housed in metabolic cages.

Route of administration:

oral: gavage

Vehicle:

soya oil

Details on exposure:

The test material was dissolved in soybean oil and orally administered (po) at a dose of 2 mg/kg after 12 h of fasting.

Duration and frequency of treatment / exposure:

Single administration

Dose / conc.:

2 mg/kg bw (total dose)

No. of animals per sex per dose / concentration:

No data

Control animals:

no

Details on study design:

The rats were housed in metabolic cages and given access to food and water ad libitum; sacrifice was by decapitation 6 h and 1, 2, 3, 4, 5, 6, and 7 days after the administration.

Details on dosing and sampling:

Male Wistar rats received a single oral dose of the test material in soybean oil at the dose of 2 mg/kg b.w. after 12 hrs fasting. Sacrifice was by decapitation 6 hrs, 1, 2, 3, 4, 5, 6 and 7 days after the administration. Liver, kidney, spleen, brain and blood were excised or collected. Urine was collected for every 24-h period. Di-n-butyl(3-hydroxybutyl)tin chloride (IV), di-n-butyl(3-oxobutyl)tin chloride (V), di-n-butyl(4-hydroxybutyl)tin chloride (VI) and di-n-butyl(3-carboxypropyl)tin chloride (X) were also dissolved in soybean oil and injected intraperitoneally at 4 mg/kg bw. Liver, kidney, spleen, brain and blood were removed 1 day after administration. Urine was collected for 24 hrs. Samples were extracted, purified, concentrated, tetraalkylated and analysed by gas-liquid chromatography equipped with a flame photometric detector (GC/FPD) or by gas chromatography/mass spectrometry (GC/MS).

Extraction of organotin compounds from organs and purification involved the organotin compounds being extracted using HCl-treated silica gel and eluted directly with a mixture of n-hexane and ethyl acetate (2:1 v/v) without prewashing with n-hexane. The eluate was evaporated to dryness under reduced pressure, and the residue was dissolved in ether (3 mL) and transferred to a screw-capped glass tube. Methylmagnesium bromide (2 mL) was added to the tube. The mixture was shaken gently and allowed to stand for 2 h at room temperature. Then water (10 mL) was added dropwise to the mixture cooled in an ice bath, and anhydrous sodium sulphite (0.2 g) and saturated ammonium chloride solution (4 mL) were added. The mixture was shaken vigorously with n-hexane (10 mL) and centrifuged. The organic layer was removed, and the aqueous layer was extracted with additional n-hexane (5 mL). The combined organic layer was dried over anhydrous sodium sulphate and carefully concentrated at 40 °C to 1-10 mL. The standard solutions for GC/FPD were prepared as described above after treatment of stock solutions of authentic standards with HCl. Recovery of organotin compounds added to the organs was 101-104 % for the substance, 77.5-106 % for II (di-n-butyltin dichloride), 71.1- 102.0 % for III (n-butyl-trichloride), 76.8-105.0 % for IV (di-n-butyl(3-hydroxybutyl)tin chloride), 90.6-116 % for V (di-n-butyl(3-oxobutyl)tin chloride), 72.2-93.1 % for VI (di-n-butyl(4-hydroxybutyl)tin chloride), 69.2-78.9 % for VII (n-butyl(3-hydroxybutyl)tin dichloride), 96.2-105.0 % for VIII (n-butyl(3-oxobutyl) tin dichloride), 66.1-78.7 % for IX (n-butyl(4-hydroxybutyl)tin dichloride), 69.6-80.5 % for X (di-n-butyl(3-carborypropy1)tin chloride), and 68.1-94.3 % for XI (n-butyl(3-carboxypropyl)tin dichloride). Detection limits in the liver were 0.003 µg/g for the test material, 0.002 µg/g for II, 0.006 µg/g for III, 0.007 µg/g for IV, 0.006 µg/g for V, 0.005 µg/g for VI, 0.006 µg/g for VII, 0.006 µg/g for VIII, 0.005 µg/g for IX, 0.015 µg/g for X, and 0.014 µg/g for XI.

Type:

metabolism

Results:

Tri-n-butyltin chloride is metabolised to many oxidised forms as well as the simply dealkylated products. The principal metabolites in blood and brain are simply dealkylated species, but in liver and kidenys are oxidised products.

Type:

distribution

Results:

Only the dealkylated metabolites were present in the blood and brain. Hydroxylated metabolites were found in other organs (liver, kidney, and spleen) and in urine.

Type:

excretion

Results:

M-5, M-2, M-1, M-3,M-4, M-6, M-7 and unknown peaks were observed in urine extracts.

Details on distribution in tissues:

The test material (M-5) and its simple dealkylated metabolites M-2 and M-1 were present in every organ, blood, and urine 6 h after administration and
decreased gradually after the maximum, 6 h^-1 day, except brain. In brain, the test material was present at a far higher level than M-2 and M-1 and showed slight accumulation.
In contrast to the observation that only the dealkylated metabolites were present in the blood and brain, M-3, a hydroxylated metabolite, was found in other organs (liver, kidney, and spleen) and in urine. The decrease in M-3 level in the kidney was slower than in the liver and spleen.
M-7 was the principal metabolite in the liver but it was not observed in the blood. The concentration of M-7 in the liver increased until 2 days after treatment and then decreased slowly.

Metabolites identified:

yes

Details on metabolites:

Metabolites were identified and quantified by comparing their retention times (RTs) on the GC/FPD chromatograms after their derivatisation to tetraalkyltin compounds by methylmagnesium bromide. The identification of metabolites by authentic standards was confirmed by GUMS, GC/MS/SIM, or HPLC.
Identified metabolites were the following:
M- 1 = n-butyltin trichloride (III)
M-2 = di-n-butyltin dichloride (II)
M-3 = n-butyl(3-hydroxybuty1)tin dichloride (VII)
M-4 = n-butyl(3-oxobuty1)tin dichloride (VIII)
M-5 = tri-n-butyltin chloride (the substance - I)
M-6 = n-butyl(4-hydroxybuty1)tin dichloride (IX)
M-7 = n-butyl(3-carboxypropy1)tin dichloride (XI); di-n-butyl(3-hydroxybuty1)tinc hloride (IV); di-n-butyl(3-oxobuty1)tin chloride (V); di-n-butyl(4-hydroxybuty1)tinc hloride (VI)
M-8 = di-n-butyl(3-carboxyropy1)tin chloride (X)

Conclusions:

The test material is metabolised in male rats to many oxidised forms as well as the simply dealkylated products. The principal metabolites in blood and brain are simply dealkylated species, di-n-butyltin and mono-n-butyltin compounds, but in liver and in kidney n-butyl(3-carboxypropyl)tin and n- butyl(3-hydroxybutyl)-tin compounds are dominant. These metabolites are not detected in blood and brain but are present in high concentration in liver and kidney for a long time in spite of the fairly rapid decrease in di-n-butyltin and mono n-butyltin compound levels in blood.

Executive summary:

The test material was orally administered to male rats, and the metabolites were investigated. After being divided into organs, blood, and urine, the samples were homogenised and extracted. After purification, the extracts were alkylated with methylmagnesium bromide and the resulting tetraalkylated tin compounds were quantified by gas-liquid chromatography with a flame photometric detector.

Analytical results showed that n-butyl(3-carboxypropyl)tin compound in the liver and n-butyl(3 -hydroxybutyl)tin compound in the kidney were the main products, respectively. The former metabolite showed slight accumulation in the liver and kidney and the latter in the kidney. n-Butyl(4-hydroxybutyl)- and n-butyl(3-oxobutyl)tin compounds were detected only in the urine in small amounts. Trialkyltin metabolites were not found in any organs, blood, and urine. Depending on the results of administration of possible intermediates, it was found that n-butyl(3-carboxypropyl)tin compound was formed not only from di-n-butyl(3-carboxypropyl)tin chloride and di-n-butyl(4-hydroxybutyl)tin chloride but also from di-n-butyl(3-hydroxybutyl)tin chloride. The metabolic fate of the test material was postulated.

Additional information

Supporting information is available for this endpoint:

- In the Iwai et al (1982) paper, the intestinal uptake site, enterohepatic circulation, and excretion into feces, and urine of alkyltins were investigated after oral and sc administration of the compounds to rats. Assays of trialkyltins in biological materials were carried out by gas chromatography. The main uptake sites in the small intestine were the ileum and jejunum for trialkyltins. When the test material was injected sc, TBT+ was recovered in the small intestine and contents of the lumen. These facts suggest that trialkyltins are transported in the body through enterahepatic circulation. A reliability rating of 4 was assigned to this study, according to the criteria of Klimisch, 1997.

- In the Omura et al (2004) paper, the distribution of the test material and its metabolites, dibutyltin (DBT) and monobutyltin (MBT), was examined in the liver, brain and fat tissues in a two-generation reproductive toxicity study of the test material in rats using dietary supplementation at concentrations, of 5, 25 and 125 ppm. The results of this study suggest tissue-dependent distribution of TBT, DBT and MBT and gender-dependent distribution of the three metabolites in the liver of rats. A reliability rating of 2 was assigned to this study, according to the criteria of Klimisch, 1997.

- In the Matsuda et al (1993) paper, the test material was orally administered to male rats, and the metabolites were investigated. After being divided into organs, blood, and urine, the samples were homogenised and extracted. After purification, the extracts were alkylated with methylmagnesium bromide and the resulting tetraalkylated tin compounds were quantified by gas-liquid chromatography with a flame photometric detector. The test material is metabolised in male rats to many oxidised forms as well as the simply dealkylated products. The principal metabolites in blood and brain are simply dealkylated species, di-n-butyltin and mono-n-butyltin compounds, but in liver and in kidney n-butyl(3-carboxypropyl)tin and n- butyl(3-hydroxybutyl)-tin compounds are dominant. These metabolites are not detected in blood and brain but are present in high concentration in liver and kidney for a long time in spite of the fairly rapid decrease in di-n-butyltin and mono n-butyltin compound levels in blood. A reliability rating of 2 was assigned to this study, according to the criteria of Klimisch, 1997.