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Toxicological information

Basic toxicokinetics

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Administrative data

basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
no guideline available at the timeframe of the test, no glp information, well documented study; only examination of 14C, The hydrolysis in the stomach of rat is not clarified, it seems plausible that the solubility of the dichloride compond ist 1000 times higher in the stomach of rat than the hydrolysis product (oxide) from diacetylacetone compound.

Data source

Reference Type:

Materials and methods

Objective of study:
Test guideline
no guideline available
Principles of method if other than guideline:
Tissue distribution studies
The tissue distribution of radioactivity was determined in male rats
weighing 80--100 g following a single i.v. or oral (by gavage) administration
of 1.2 and 6.3 mg [~C]DOTC/kg body weight, respectively. Groups of 3
animals were killed by decapitation at 1, 2, 4 and 7 days after the administration,
and blood was collected in heparinized tubes. The animals were
dissected immediately to sample and weigh the organs and tissues. Duplicate
or triplicate 50--100-mg samples of most organs and tissues were cut,
weighed, and transferred to liquid scintillation vials to examine their content
of radioactivity. For the smaller organs, e.g. adrenal, pituitary glands etc. the
radioactivity of the total organ was measured. To each vial 1 ml of the
tissue solubilizer Soluene 350 (Packard Instruments, Packard Dekker
B.V., The Netherlands) was added and allowed to stand for one night at
50--60°C. After solubilization, samples of liver, kidney, heart, lung and
blood were decolourized by adding 0.5 ml of isopropanol followed by 0.5
ml of a 30% solution of H202, to reduce colour quenching. After adding
10 ml scintillation fluid to each vial the content of radioactivity was determined
in a Mark II (Nuclear Chicago) liquid scintillation counter and corrected
for background. Counting efficiency was determined by the external
standard technique. The tissue radioactivity was expressed in dpm/mg tissue.
From these data the relative accumulation index of radioactivity in each of
the organs and tissues was calculated according to the equation: R t = (Ct/Ht).
In this equation R t stands for the relative accumulation of radioactivity at
time t (days); C t for radioactivity in dpm/mg tissue at time t, and H t for the
radioactivity in dpm/mg tissue which was calculated by dividing the total
radioactivity in the sampled organs and tissues by their total weight at time
t (see Table I and III). The weights of blood, muscle and fat tissues were
estimated to contribute to 8, 45 and 8% of the total body weight, respectively
Excretion studies
Groups of 3 male rats weighing 100--120 g were given a single i.v. or a
single p.o. dose (by gavage) of 1.2 mg and 2 mg [14C] DOTC/kg body weight,
respectively. Then for 25 days urine and feces of each animal were dally
collected separately and their r a d i o a c t i v i t i e s were measured. Triplicate
50-pl aliquots of urine from the individual animals were transferred to
s c i n t i l l a t i o n vials and 1 ml Soluene-350 was added. The fecal samples of the
individual animals were dried at 50--60°C, weighed, and ground to a fine
powder with a mortar and pestle. Then t r i p l i c a t e 10--20-mg samples from
the individual animals were transferred to s c i n t i l l a t i o n vials and rehydrated
with 0.1 ml water (1 h) before adding 1 ml Soluene-350. The vials of urine
and fecal samples were closed and incubated overnight at 50--60°C. To reduce
GLP compliance:
not specified

Test material

Constituent 1
Reference substance name:
di-n-octyltin dichloride
di-n-octyltin dichloride
Test material form:
solid - liquid: suspension
migrated information: dispersion
Details on test material:
14C-labeled di-n-octyltin dichloride from Schering AG, Berlin.
Chemical purity > 98% , contaminated with about 1%

Test animals


Administration / exposure

Route of administration:
other: i.v. and oral (gavage)
other: ethanol, Tween 80 and phosphate buffered physiological saline
Duration and frequency of treatment / exposure:
Duration and frequency of treatment:
Frequency: 1 time dose
Experiment 1 – distribution:
1, 2, 4 and 7 days
Experiment 2 – Excretion / absorption
25 days
Doses / concentrations
Doses / Concentrations:
Experiment 1 – distribution:
a) i.V., 1.2 mg / kg bw
b) oral (gavage), 6.3 mg / kg bw
Experiment 2 – Excretion / absorption
a) i.V., 1.2 mg / kg bw
b) oral (gavage), 2 mg / kg bw
No. of animals per sex per dose / concentration:
3 male animals per dose / administration / timeframe
Control animals:
yes, concurrent no treatment

Results and discussion

Preliminary studies:

Toxicokinetic / pharmacokinetic studies

Details on absorption:
From the oral dose 84.5 ± 5.1 % (6.3 mg/ kg bw dose) and 79.6 + 4.5% (2 mg / kg bw dose) of the radioactivity was recovered from the feces in the first two days. So there was an absorption of 15.5 respective 20.4 % of the radioactive labeled 14C. Assuming the fetal excretion is approximately identical in the oral and in die i.v. experiment (values form i.v.: 12.1 and 9.6 %; mean ) 10.9) there can calculate an absorption between 17.4 and 22.9 % via absorption = administered oral dose - fecal excretion + 10.9%.
Details on distribution in tissues:
The highest concentration of radioactivity in tissue was found in liver and kidney. Also in the endocrine organs adrenals, thyroid glands and pituitary gland, the radioactivity tissue was somewhat higher than in the other organs and tissues determined. Although thymic atrophy is the most sensitive criterion of DOTC toxicity in rats, as it is also shown by the decrease in relative thymus weight in this study low levels of radioactivity were observed in this organ.
Transfer into organsopen allclose all
Test no.:
Transfer type:
blood/brain barrier
slight transfer
Test no.:
Transfer type:
secretion via gastric mucosa
distinct transfer
Test no.:
Transfer type:
secretion via gastric mucosa
distinct transfer
Details on excretion:
see details on absorption
Toxicokinetic parametersopen allclose all
Test no.:
Toxicokinetic parameters:
half-life 1st: 8.3 d (i.v.)
Test no.:
Toxicokinetic parameters:
half-life 1st: 8.9 d (oral)

Metabolite characterisation studies

Metabolites identified:
Details on metabolites:

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

Any other information on results incl. tables

see attachment in due to publication by ECHA and copyright

Applicant's summary and conclusion

Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
Only 20% of 14C in DOTC was absorbed, Half life time between 8.3 and 8.9 days,
Slight increase of 14C accumulation in brain and adipose tissue in due to rate constant; decrease of thymus weight.
DOTC induced thymus atropy is not caused by selective accumulation of this compound in the thymus.
Executive summary:

"Absorption and distribution

In orally treated rats (Wistar derived) only a small part of the dioctyltindichloride (DOTC)

was absorbed as approximately 80 % of the 14C-labelled DOTC radioactivity was already

excreted in the feces during the first day after administration. This is in accordance with the

observation that after i.v. administration of 1.2 mg 14C-labelled DOTC/kg b.w./day the tissue

radioactivity was about 3 - 4 times higher than after oral administration with 6.3 mg 14CDOTC/

kg b.w./day. Absorption was calculated to be approximately 20 % of the dose.

The highest amount of radioactivity was found in liver and kidney, and to a lesser degree in

adrenal, pituitary and thyroid glands. The lowest activity was recovered from blood and brain.

No selective accumulation was observed in the thymus, although thymus atrophy is the most

sensitive parameter of DOT toxicity in rats. It was suggested that DOT is rapidly distributed

and diffuses poorly into the brain


After a single oral dose of 14C-labelled DOTC (6.3 mg/kg b.w./day) a time dependent

decrease in radioactivity was found for all tissues investigated, except for the kidney. At day

25 after exposure, a total of about 10 % of the administered radioactivity was excreted in the

urine, while 89 % of the dose was excreted in the feces. So at this time about 99.9 % of the

oral administered radioactivity was recovered from excreta. A half-life value of 8.9 days was

estimated from the fecal excretion of radioactivity. The urinary excretion of radioactivity

appeared to be independent of the body burden, since the daily urinary excretion of

radioactivity was nearly constant during the 25 days experimental period after both oral and

i.v. administration."

Source: Question N° EFSA-Q-2003-110