Bis(tributyltin) oxide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Nov 1977 to Feb 1978

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1984

Report date:

1984

Materials and methods

Objective of study:

absorption

distribution

excretion

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

113Sn-labelled tributyltinoxide was given to rats (190 to 210 g) as an aqueous suspension in doses of 5 mg/kg by the intragastric and the intraduodenal route. Following preliminary studies to determine the rate of absorption and the rate of elimination (female/male animals), the distribution and the elimination of the 113Sn-labelled substance was examined in four experimental groups (male animals).
Organ and tissue specimens were removed from animals 24 hours after termination of treatment (after the last dose). In group IV, the urine was measured in daily fractions and the faeces in weekly fractions.

GLP compliance:

yes

Remarks:

40 CFR Part 792

Test material

Test material information

Constituent 1

Reference substance name:

Bis(tributyltin) oxide

EC Number:

200-268-0

EC Name:

Bis(tributyltin) oxide

Cas Number:

56-35-9

Molecular formula:

C24H54OSn2

IUPAC Name:

tributyl[(tributylstannyl)oxy]stannane

Details on test material:

Tested formulation: ES 1873 Ra
Manufacturer: Isotope Chemistry Dept, Schering
Manufacturer of formulation of test articles: Galenics Dept, Schering
Formulation: Aqueous suspension of 750 mg % Tween 60 and 1 % ethanol containing 1 mg/ml tributyltin oxide

Radiolabelling:

yes

Remarks:

(113 Sn)

Test animals

Species:

rat

Strain:

other: Wistar-han

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: male rats were reported to weigh between 190 to 210 grams
- Individual metabolism cages: yes
- Diet: ad libitum (Altromin rat pellets/standard diet tpf 1324)
- Water: ad libitum (tap water)

Rats were barrier sustained.

Administration / exposure

Route of administration:

other: intragastric and intraduodenal route

Vehicle:

other: Tween and ethanol

Details on exposure:

Aqueous suspension of 750 mg % Tween 60 and 1 % ethanol containing 1 mg/ml tributyltin oxide. Doses of 5 mg/kg were given

Duration and frequency of treatment / exposure:

Group 1: single dose
Group 2: once-daily dose for 3 days
Group 3: once-daily dose for 7 days
Group 4: once-daily dose for 14 days

Doses / concentrations

Dose / conc.:

5 mg/kg bw/day

No. of animals per sex per dose / concentration:

5 males/4 females
For the most part the animal experiments were carried out in male rats. Studies on absorption of the substance were conducted in female animals.

Control animals:

no

Details on study design:

The substance was administered to the animals intragastrically as a suspension. In addition to the preliminary measurements to determine the rate of absorption and the elimination half-life following a single administration, another four experimental gropus were studied for the distribution and elimination of the 113 Sn-labelled substance following a single dose and repeated daily dose of 5 mg/kg.

Details on dosing and sampling:

After administration of the substance, the animals were kept in metabolic cages to measure the percentage of administered dose eliminated in the urine and in the feces. They were allowed food and water ad libitum. In Group 4, the elimination of the 113Sn-labelled dose equivalents administered was determined in the sample of urine collected over the week. In each of the groups 1-3, excreta were pooled, leaving one urine and one fecal sample for each animal. 24 hours after the last dose of the substance the animals were bled to death under ether narcosis, and the organs and tissues were removed.
For the 113Sn measurement a maximum of 15 g of biological material was used in each case. Specimens of a total weight of > 15 g were first homogenised with distilled water. All specimens were measured individually. Counting was done in a gamma-scintillation spectrometer (Packard Model 5285) set at the 125J energy spectrum.

Statistics:

Calculated means ± standard deviation in % of a single dose per total organ or in micrograms per gram of fresh tissue. Percentage in the blood was calculated on the basis of a total volume of 68 ml/kg. Of fatty tissue, the skin, the bone marrow, the lymph nodes, the spinal cord, and the skeletal muscle, only aliquots were used, so that the carcass contained most of the radioactivity of these tissues. The results of the measurments in % of a single dose per total organ were calculated for these specimens on one gram of fresh tissue.
The 113Sn measurements relate to the total radioactivity. The radioactivity in the study was not differentiated into unchanged substance and possible metabolites. To determine the half-life, the slope of the line was calculated using the following:

bxy = ((Σx*y) -((Σx*y)/n))/(Σx² - ((Σx/n)²)

Results and discussion

Preliminary studies:

No information

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Only about 20% of i.g. tributyltinoxide administered in dosed of 5 mg/kg is absorbed

Main ADME results 2

Type:

excretion

Results:

Biphasic elimination at an average half-life of 12 ± 1 h and 3 ± 0.7 days

Toxicokinetic / pharmacokinetic studies

Details on absorption:

When given intraduodenal doses of 5 mg/kg to rats with acute biliary and urethral catheters, TBTO was absorbed to only about 20%. After 24 hours, the amount of absorbed substance eliminated by the kidneys corresponded to 1.3 ± 0.6% of the administered dose (% adm. dose) and the amount excreted with the bile, to 6.4 ± 1.9 % adm. dose. The percentage of dose found in the body was 7.8 ± 1.5%.
Compared to intragastric single dosing in intact animals, there was no marked difference in neither the amount measured in the urine 24 hours post dosing nor in the amount recovered after the same time in the faeces and in the bile plus intestinal tract, respectively.

Details on distribution in tissues:

24 hours after administration of a single dose, an average of 11.9 ± 1.9% of the dose was measured in the animal body (excluding GIT). This corresponds to a concentration of the 0.66 ± 0.07 ug of 113 Sn dose equivalents/g fresh tissue. The determinations carried out in the tissues revealed that about 50% of the radioactivity recovered in the animal was present in the liver and 10% in the kidney. Compared to the levels measured in the blood, the concentration of radioactive substance detected in the liever and in the kidneys was on average 70 and 80 times higher, respectively.

After repeated daily dosing, a steady state between absorption and elimination of the labelled compound could not be demonstrated until the end of the 14-day treatment.

A comparison of the 113Sn concentrations in the tissue specimens of groups II-IV with the corresponding data of treatment group I (single dose) showed a marked accumulation in all speciments as well as in the whole animal. After 14-days of treatment (group IV) the average accumulation factors were calculated to range between 2.1 and 7.4. The degree of accumulation (KNF) was as follows:
heart, bone marrow, liver 2-3
blood, lungs, nodes, kidneys, pancreas 3-4
spleen adrenal glands, thyroid gland 4-5
fatty tissue, brain, skin, spinal cord, skeletal muscle, thymus 5-6
testis, carcass >7 (7.4)

The autoradiograph of the 24 hour dose presented as illustration 1 in the attached illustration figure 3 demonstrates that there is an above average concentration of radioactivity in the colon and stomach (high density areas). In the liver and small intestine the concentration of radioacitive substance is noticeably less than that of the stomach or the colon. In other areas no differentiation of tissue structures is detectable; however the section of the kidney is missing. The sutoradiogram of the distribution of radioactivity taken on day 3 and 7 after adminsitration is similar to that taken 24 hours post dosing. In the gastric region the distribution is easily differentiated between the stomach wall and the contents. In the kidney (Illustration 3 of figure 3 renal cortex), radioactivity can clearly be detected.

Details on excretion:

Following a single i.g. (5 mg/kg) adminsitration the ratio of dose equivalents eliminated in the urine and the faeces was about 1:14. Up to day 7 post administration, an average of 6.5 ± 1.6% of the dose was recovered in the urine and 88.1 ± 7.7% of the dose in the faeces. At that time 3.5 ± 0.4% of the administered dose could still be detected in the body, excluding the gastro-intestinal tract. It could be demonstrated with the experimental results obtained in rats with acute biliary and urethral fistulas, that on an average about 80% of the dose administered by the intestinal route was not absorbed. Thus the amount eliminated through the hepatic system via faeces could be about 10 to 15% of the administered dose. In conclusion, the ratio of absorbed substance eliminated with the urine and with the faeces is around 1:3.
Daily measurements of the renal elimination (intact animals) showed a biphasic course and a half life of 12 ± 1 hour (period of day 1 to day 3 post administration) and 3.0 ± 0.7 days (day 4 to day 7 post dosing) (phase 1 excluded animal no. 2; phase II excluded animal no.1; no unequivocally first order kinetics of excretion). Within the seven-day experimental period, and average of 93% of the radioactivity recovered in the urine was eliminated during phase I and 7% during phase II.
In the experimental animals with acute biliary and urethal fistulas, biliary elimination of the administered dose during the period from 2-24 hours post administration was found to be monophasic, with a half-life of 4.4 ± 1.9 hours.

With repeated daily doses for up to 14 days, 96.0 ± 2.4% of the total dose administered was recovered in the urine and the faeces between the begining of the experiment and 24 hours after the last dose. Up to day 3 of the treatment there was a marked increase in the daily amount of the dose eliminated by the kidneys, from an average of 6 to 15% of the single dose administered. In the course of the study (day 3 to day 14 of the treatment) it was measured that on average about 13 ± 2% of a single dose was recovered daily in the renal excretion.

Metabolite characterisation studies

Metabolites identified:

not specified

Any other information on results incl. tables

Group Treatment (Days) % Radioactivity Recovered in Animal Accumulation Factor Liver Kidneys Carcass Other organs Liver Kidneys Carcass Other Organs I 1 54 10 34 5 II 3 44 9 43 4 1.5 1.5 2.3 1.3-4.9 III 7 36 8 52 4 2.3 2.1 4.8 1.4-5.2 IV 14 29 8 59 4 2.8 3.5 7.4 2.1-7.4

Applicant's summary and conclusion

Conclusions:

Only about 20% of i.g. tributyltinoxide administered of 5 mg/kg is absorbed. The concentration of radioactive substance measured in the body after a two-week treatment is about four times higher than after a single dose; the accumulation factor in organs and tissues is 2-7. A steady state between absorption and elimination of the substance was not reached during the 14-day period. There is sustained gastric secretion of radioacitivity, which could be of importance with regard to the percentages of administered dose that are excreted.

Executive summary:

The purpose of this study to characterize the pharmacokinetic properties of the substance (absorption, distribution, accumulation, elimination) in rats. Rats were administered 113 Sn-labelled tributyltin oxide as an aqueous suspension in doses of 5 mg/kg by the intragastric and the intraduodenal route. The distribution and elimination of the radio-labelled substance was studied in four experimental groups:

Group 1: single dose

Group 2: once-daily dose for 3 days

Group 3: once-daily dose for 7 days

Group 4: once-daily dose for 14 days

Organ and tissue specimens were removed in each case 24 hours after termination of treatment. Only about 20% of i.g. tributyltinoxide administered of 5 mg/kg is absorbed. The concentration of radioactive substance measured in the body after a two-week treatment is about four times higher than after a single dose; the accumulation factor in organs and tissues is 2-7. A steady state between absorption and elimination of the substance was not reached during the 14-day period. There is sustained gastric secretion of radioactivity, which could be of importance with regard to the percentages of administered dose that are excreted.