2-ethylhexyl 10-ethyl-4,4-dimethyl-7-oxo-8-oxa-3,5-dithia-4-stannatetradecanoate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Dimethyltin Dichloride: Investigations into its Gastrointestinal Absorption and Transplacental Transfer

Author:

Noland. E.A., P.T. McCauley and R.J. Bull

Year:

1983

Bibliographic source:

Journal of Toxicology and Environmental Heealth, 12:89-98

Materials and methods

Objective of study:

absorption

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

In Phase I the female animals were randomly assigned to one of three groups, two of which received the test compounds in their drinking water. The exposure began 2 weeks prior to breeding and continued through breeding and gestation. At birth and prior to the first nursing, the pups were removed from the dam.
In Phase II, a cross-fostering study was conducted. Except for the omission of the stannous chloride group, the animals were treated as in Phase 1.
In Phase III, a tracer study, 19-d pregnant dams were dosed by stomach tube. Dams were sacrificed by decapitation. The fetuses were removed in order to take their blood and brain samples.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Dimethyltin dichloride

EC Number:

212-039-2

EC Name:

Dimethyltin dichloride

Cas Number:

753-73-1

Molecular formula:

C2H6Cl2Sn

IUPAC Name:

dimethyltin dichloride

Constituent 2

Reference substance name:

Stannae, dichlorodimethyl-

IUPAC Name:

Stannae, dichlorodimethyl-

Details on test material:

- Name of test material (as cited in study report): dimethyltin dichloride
- Molecular formula (if other than submission substance): C2H6Cl2Sn
- Molecular weight (if other than submission substance): 219.67 g/mol
- Smiles notation (if other than submission substance): C[Sn](C)(CL)CL
- Stability under test conditions: stable

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles Rivers breeding laboratory
- Age at study initiation: 70 days at arrival
- Housing: one per cage with sawdust bedding
- Diet (e.g. ad libitum): Purina Lab Chow; ad libitum
- Water (e.g. ad libitum): ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 deg C
- Humidity (%): 54%

Administration / exposure

Route of administration:

other: Phase 1: drinking water ; Phase II: drinking water; Phase III: gavage

Vehicle:

unchanged (no vehicle)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Phase II and II- drinking water; Phase III- 0.9 M NaCl solution containing 100 uCi DMDC/L



VEHICLE
- Justification for use and choice of vehicle (if other than water): Phase I and II- drinking water; Phase III- NaCl
- Concentration in vehicle: 0.9 M NaCl solution containing 100 uCi DMDC/L
- Amount of vehicle (if gavage): 0.8 mL/100 g bw

Duration and frequency of treatment / exposure:

Phase I and II- 2 weeks prior to breeding and continued through breeding and gestation.
Phase III- 5 min, 15 min, 30 min, 1 h, 2 h, 6 h and 24 h

Phase I and II- in drinking water
Phase III- single dose

Doses / concentrations

Remarks:

Doses / Concentrations:
40 mg tin/L in solution as dimethyltin dichloride
Nominal in water

No. of animals per sex per dose / concentration:

Phase I and II- 13 females
Phase III- 28 females

Control animals:

yes, concurrent vehicle

Positive control reference chemical:

Not applicable

Details on study design:

- Dose selection rationale: data from previously conducted tests
- Rationale for animal assignment (if not random): random

Details on dosing and sampling:

Phase I and II- Since there was no method available specific for measurement of organotin in biological fluids, the tissues were analyzed for total tin content. The tissues were analyzed for tin by flameless atomic absorption technology. The determinations were performed on a Perkin-Elmer atomic absorption spectrophotometer model 305A, euipped with an electrodeless discharge lamp, model HGA2100 grpahite furnace control, model HGA 74 graphite furnace, model AS1 autosampler, and a model 56 2-mV recorder. The samples were prepared for analysis by digestion in nitric acid and perchloric acid on a hotplate. To minimize interferences, the samples were treated with ammonium molybdate and then analyzed by the method of standard additions. Phase III- Brains and 5-mL blood samples were taken for analysis. The fetuses were removed in order to take their brain and blood samples. Four samples from each litter were pooled to make one composite sample. Samples were prepared for counting via oxidation in a Packard Model B0306 sample oxidizer with 3 mL OXI-SCINT and 17 mL OXI-AMIN scintillation fluid. Samples were counted in a Beckman Model LS8100 scinitillation counter. All samples were adjusted for quench and normalized.

Examinations
Maternal examinations
BODY WEIGHT: Yes
- Time schedule for examinations: throughout study

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: throughout the study


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice - prior to first nursing
- Organs examined: brain and blood samples

Fetal examinations
Blood samples were taken by carotid artery puncture and brains were remved

Statistics:

Data for the first phase were analyzed using Kruskal-Wallis test, and the means were compared with a non-parametric multiple comparisons procedure based on Kruskal-Wallis ranked sums (Hollander and Wolfe, 1973) Data for the cross-fostering phase were analyzed using an anlysis of variance (ANOVA) (Hollander and Wolfe, 1973). Drinking water consumption data were analyzed using a two-way nested ANOVA.

Results and discussion

Preliminary studies:

Not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Phase I- In the dam's blood there were significant differences among dosage groups. The tin content of blood from the test substance was significantly higher than that of the controls. Dams drank significantly less than controls.
Phase II- The level of tin in the blood of dams was significantly higher than the controls.
Phase III- The highest measured level of label in the dam blood was recorded at 1 h, while the level in the brain continued to increase through 24 h when measurements were stopped.

Phase I- The tin content in blood from pups of dams given the test substance was significantly higher than blood from control pups.
The tin content from the brains of pups of dams administered the test substance was significantly higher than controls.
Phase II- The highest levels of tin in blood at any time in any age group were demostrated at birth in gestationally exposed animals. By 10 d postnatal age, blood tin levels decreased rapidly in both prenatally exposed groups. Pups exposed only postnatally (CT/DM)had blood levels of tin significantly lower than the DM/DM and the DM/CT animals. Tin levels in the brains of prenatally exposed pups were again highest at birth and different from controls. At 10 d, the DM/DM pups demostrated significantly higher levels of tin in the brain than the other groups. The DM/CT group was also different from the other groups. At 21 d, the DM/DM group was significantly higher than the CT/DM group, which was higher than either the CT/CT or DM/CT group.
Phase III- The label in pup blood reached its highest measured level at 6 h, and in the brain the highest concentration measured was the last sample taken at 24 h after exposure. The level of DPM/g in dam brain at 24 h post dosing were equivalent to DPM/g in pup brain at 6 h post dose.

Details on distribution in tissues:

Phase III- The highest measured level of label in the dam blood was recorded at 1 h, while the level in the brain continued to increase through 24 h when measurements were stopped.

Phase I- The tin content from the brains of pups of dams administered the test substance was significantly higher than controls.
Phase II- Tin levels in the brains of prenatally exposed pups were again highest at birth and different from controls. At 10 d, the DM/DM pups demostrated significantly higher levels of tin in the brain than the other groups. The DM/CT group was also different from the other groups. At 21 d, the DM/DM group was significantly higher than the CT/DM group, which was higher than either the CT/CT or DM/CT group.
Phase III- The label in pup blood reached its highest measured level at 6 h, and in the brain the highest concentration measured was the last sample taken at 24 h after exposure. The level of DPM/g in dam brain at 24 h post dosing were equivalent to DPM/g in pup brain at 6 h post dose.

Transfer into organs

Transfer into organs 1

Test no.:

#1

Transfer type:

blood/placenta barrier

Observation:

distinct transfer

Remarks:

The tin content in blood from pups of dams given dimethyltin chloride was significantly higher than blood from the other groups.

Transfer into organs 2

Test no.:

#1

Transfer type:

blood/brain barrier

Observation:

distinct transfer

Remarks:

The tin content from the brains of pups of dams was significantly higher the other groups.

Transfer into organs 3

Test no.:

#2

Transfer type:

blood/placenta barrier

Observation:

distinct transfer

Remarks:

The highest levels of tin in blood at any time were demonstrated at birth in gestationally exposed animals.

Transfer into organs 4

Test no.:

#2

Transfer type:

blood/brain barrier

Observation:

distinct transfer

Remarks:

Tin levels in the brains of prenatally exposed pups were highest at birth and different from controls.

Transfer into organs 5

Test no.:

#3

Transfer type:

blood/placenta barrier

Observation:

distinct transfer

Remarks:

The label in the pup blood reached its highest measured level at 6 h.

Transfer into organs 6

Test no.:

#3

Transfer type:

blood/brain barrier

Observation:

distinct transfer

Remarks:

The label in the pup brain reached its highest concentration measured at 24 h.

Metabolite characterisation studies

Metabolites identified:

not measured

Applicant's summary and conclusion

Conclusions:

The results of this study have demostrated that tin from dimethyltin dichloride is absorbed by the rat dam, undergoes transplacental transfer, and arrives in the brain of the prenatal animal. From this data it can be inferred that the methyl substitution on the tin enhances the gastrointestinal absorption and subsequent transplacental transfer of tin.
The cross-fostering experiment demonstrates that the bulk of the tin is transferred from the pups prenatally. There is a 50% decrease in the amount of tin in the blood of the DM/DM pups 10 d after birth, and another 50% decrease from that level at 21 d, despite the increased water consumption of the dam. The level of tin in the brain of gestationally exposed pups was highest at birth. During the postnatal period, the tin from dimethyltin follows roughly the same pattern of decreasing concentration in pup brain and pup blood.
When the test substance was administered by intubation, the label was readily absorbed into both dam blood and brain and fetal blood and brain. However, at 6 h post dosing, fetal blood 14 C levels are only 16% of dam blood levels, yet fetal brain 14C levels are 167% of dam brain 14C concentrations.
This study shows that dimethyltin dichloride is absorbed in the gastrointestinal tract of the dam much more rapidly than Sn2+, and consequently that higher concentrations of tin are found in pup blood and brain from dimethyltin dichloride than from Sn2+ dosing. And that the majority of the tin received as dimethyltin is transferred to the pups during gestation rather than lactation. Dosing of the dam results in both tin and methyl carbon absorption by the dam , transplacental transfer to fetal blood, and localization in fetal brain.

Executive summary:

Studies were conducted with female Sprague-Dawley rats to determine whether dimethyltin dichloride was absorbed by the dam and transferred across the placenta to fetal blood and brain tissue. This was accomplished in three phases: 1- a comparison of absorption of organic and inorganic tin from drinking water; 2- a comparison of prenatal and postnatal levels of tin in the pups in cross-fostering studies and; 3- a¹⁴C dimethyltin dichloride tracer study to determine whether organic tin passed to the pup intact. Major findings included: the organic test substance is absorbed in the gastrointestinal tract of the dam much more rapidly than Sn^{2 +}. The more rapid absorption of the test substance results in higher concentration of tin in fetal blood and brain. In fetuses that receive tin as the dimethyltin dichloride, both tin and the methyl carbon are absorbed by the dam and transferred to the blood and brain of the fetuses