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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
Not available
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Not a GLP study; no analytical verification of adminstered doses; incomplete description of methodology; no derived half-lifes or other quantitative measures developed
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Distribution and elimination of tin taken up into the organism in the form of organo-tin compounds
Author:
Mazaev, VT, ZJ Tikhonova, and TG Shlepnina
Year:
1976
Bibliographic source:
Journal of Hygiene, Epidemiology, Microbiology and Immunology. 20(4): 392-395.

Materials and methods

Objective of study:
other: Absorption, Distribution, Excretion
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Tetraoctyltin was administered to albino rats at an oral dose of 4000 mg/kg and an intraperitoneal dose of 66 mg/kg. Rats were sacrificed at 3hrs, and 1, 4, 7, and 10 days after exposures and tissue samples analyzed for tin. Elimination pathways were also studied.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Tetraoctyltin
EC Number:
222-733-7
EC Name:
Tetraoctyltin
Cas Number:
3590-84-9
Molecular formula:
C32H68Sn
IUPAC Name:
tetraoctylstannane
Constituent 2
Reference substance name:
TOT
IUPAC Name:
TOT
Details on test material:
- Name of test material (as cited in study report): Tetraoctyltin (TOT)
- Substance type: Monoconstituent
Radiolabelling:
no

Test animals

Species:
rat
Strain:
other: Albino
Sex:
not specified
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Not stated
- Age at study initiation: Not stated
- Weight at study initiation: Not stated
- Fasting period before study: Not stated
- Housing: In elimination study, rats were kept in metabolic cages where urine and faeces could be collected separately
- Individual metabolism cages: Not clear
- Diet (e.g. ad libitum): Not stated
- Water (e.g. ad libitum): Not stated
- Acclimation period: Not stated


ENVIRONMENTAL CONDITIONS
- Temperature (°C): Not stated
- Humidity (%): Not stated
- Air changes (per hr): Not stated
- Photoperiod (hrs dark / hrs light): Not stated

Administration / exposure

Route of administration:
other: Unspecified oral route; intraperitoneal injection
Vehicle:
not specified
Details on exposure:
No data
Duration and frequency of treatment / exposure:
Once, single dose
Doses / concentrations
Remarks:
Doses / Concentrations:
Oral exposure: 4000 mg/kg
Interperitoneal exposure: 1000 mg/kg
No. of animals per sex per dose / concentration:
Not stated
Control animals:
not specified
Details on study design:
- Dose selection rationale: The given LD50 of tetraoctyltin for rats was 50,000 mg/kg; both oral and intraperitoneal exposures were selected to be less than this exposure level.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, liver, kidney, brain, femoral bone, and muscle tissues
- Time and frequency of sampling: 3-5 animals sacrificed at each of the following time intervals- 3hrs, 1d, 4d, 7d, and 10d after exposure. Urine and faeces for elimination studies were collected on days 2, 5, 7, and 10


METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled (delete / add / specify): N/A, metabolism
- Time and frequency of sampling: N/A
- From how many animals: (samples pooled or not) N/A
- Method type(s) for identification (e.g. GC-FID, GC-MS, HPLC-DAD, HPLC-MS-MS, HPLC-UV, Liquid scintillation counting, NMR, TLC): While metabolites were not specifically measured, quantititative analysis of tin was carried out via Hilger's spectrometer of intermediate dispersion (therefore, measured tin would equal parent compound and tin-containing metabolites).

Statistics:
Mean and standard deviation

Results and discussion

Preliminary studies:
Preliminary studies suggested rat LD50s of 50,000 mg/kg for tetraoctyltin and 66 mg/kg for diethyl tin dichloride.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The degree of absorption was dependant on the size of the molecule. The larger tetraoctyltin reached levels comparable to that of the smaller diethyl tin dichloride, although TOT was administered at a much higher dose (e.g. 15 to 60 times higher)
Details on distribution in tissues:
The distribution of tin in rat tissues was dependant on route-of-exposure, e.g. differed between oral and intraperitoneal routes. After oral administration, the majority of tin was detected in the liver, while the kidneys accumulated most of the tin following intraperitoneal injection. In both cases, the smallest amount of tin was detected in the brain. See table of results below.
Transfer into organs
Test no.:
#1
Transfer type:
blood/brain barrier
Observation:
not determined
Details on excretion:
Tin elimination by the rats was a slow process, and up to 98% of it was excreted in the faeces. However, there was some evidence of accumulation of tin compounds by exposed rats

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
No additional information.

Any other information on results incl. tables

Table 1: Tissue tin concentrations (mg/100g tissue) in albino rats following oral exposure to 4000 mg/kg tetraoctyltin

Time after dose administration

Liver

Kidneys

Muscles

Brain

Bones

Mean±SD

n

Mean±SD

n

Mean±SD

n

Mean±SD

n

Mean±SD

n

3 hrs

0.505± 0.2637

3

1.783± 0.8907

5

0.085± 0.0188

3

0.037± 0.0171

4

0.309± 0.0048

4

1 day

0.637± 0.3699

3

0.137± 0.0694

4

0.283± 0.1541

3

0.034± 0.0078

4

0.315± 0.0328

4

4 days

0.413± 0.2282

4

0.066± 0.0080

4

0.090± 0.0265

4

N/A

4

0.338± 0.0169

4

7 days

0.424± 0.0805

5

0.133± 0.0404

4

0.078± 0.0072

5

0.025± 0.0078

5

0.309± 0.1322

5

10 days

0.390± 0.0898

4

0.490± 0.1245

5

0.188± 0.1063

5

0.050± 0.0115

5

N/A

 

Table 2: Tissue tin concentrations (mg/100g tissue) in albino rats following interperitoneal exposure to 1000 mg/kg tetraoctyltin

Time after dose administration

Liver

Kidneys

Muscles

Brain

Bones

 

Mean±SD

n

Mean±SD

n

Mean±SD

n

Mean±SD

n

Mean±SD

n

3 hrs

N/A

--

19.566± 1.9520

3

0.323± 0.0103

3

0.247± 0.1084

4

0.273± 0.0788

3

1 day

0.349± 0.0788

4

13.988± 2.4270

4

0.211± 0.0583

4

--

--

14.825± 2.3300

4

4 days

N/A

--

15.634± 3.8790

5

0.358± 0.0622

5

0.033± 0.4428

4

5.744± 1.9630

5

7 days

0.560± 0.1849

3

10.514± 2.5850

5

0.169± 0.0188

5

0.132± 0.0499

3

2.776± 0.4780

5

10 days

1.558± 0.5339

3

7.900± 0.1468

3

2.005± 0.1301

3

0.325± 0.1321

3

0.195± 0.0856

3

0.021± 0.0020

6

0.027± 0.0089

10

0.018± 0.0029

5

0.019± 0.0067

7

0.117± 0.0380

10

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
Distribution of tin among tissues was dependant on route of exposure. Some evidence of bioaccumulation was observed, but in general tetraoctyltin was both less toxic and less likely to bioaccumulate than the smaller diethyl tin dichloride.
Executive summary:

Some conclusions can be drawn from the experiments. The steeper increase in the concentration of tin in the organs after intraperitoneal administration as compared with oral administration testifies to difficult absorption of OTC [organotin compounds] in the gastrointestinal tract. The degree of absorption depends on the size of the molecule: in spite of the large amount of tin administered in the compostion of tetraoctyltin, the concentrations in the organs were of the same order as after the administration of DETDC [diethyl tin dichloride]. The distribution of tin in the organs is uneven: after oral administration, larger quantities of tin are detected in the liver, after intraperitoneal administration in the kidneys. The smallest amount of tin is found in the brain.

The elimination of tin is a slow process. An overwhelming quantity of tin (up to 98%) is eliminated in the faeces. The difference in the quantity of tin eliminated in the faeces after oral and intraperitoneal administration can be explained by the transit passage of tin through the intestinal tract, but it is not so large as reported by Soner (1955). Obviously, the low toxicity of macromolecular OTC can be explained partly by the passage of part of the OTC as transit through the intestine and partly by the slower absorption rate of the substance in the gastrointestinal tract. This consideration does not preclude the possibility of difficult passage of OTC through other membranes of the organism, which cannot be demonstrated in the present experiment. The prolonged retention of tin in the organism observed in all experiments can serve as one of the indices of cumulative properties of organo-tin compounds.

From the hygenic point of view, macromolecular compounds should be preferred in the selection of organo-tin stabilizers for polyvinyl chloride.