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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
not reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
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. The study has been read across from supporting substances, CAS Numbers 77-58-7, 78-04-6 and 818-08-6.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report date:
2004

Materials and methods

Objective of study:
other: to simulate the hydrolytic action by mammalian gastric contents and to determine if the tin-ligand bond breaks, leading to formation of the corresponding alkyltin chloride and release of the ligand.
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
In three separate experiments, each of the test substances, dibutyltin dilaurate (DBTL, CAS # 77-58-7), dibutyltin maleate (DBTM, CAS # 78-04-6) and dibutyltin oxide (DBTO, CAS # 818-08-6) were individually tested under low pH (-1-2) conditions (0.07 N HC1) at 37 °C in order to simulate the hydrolytic action by mammalian gastric contents.
The hypothesis was that in the hydrochloric acid solution the tin-ligand bond breaks, leading to formation of the corresponding alkyltin chloride and simultaneous liberation of the ligand.
GLP compliance:
not specified

Test material

Constituent 1
Reference substance name:
Dibutyltin oxide
EC Number:
212-449-1
EC Name:
Dibutyltin oxide
Cas Number:
818-08-6
IUPAC Name:
dibutyl(oxo)stannane
Constituent 2
Reference substance name:
Dibutyltin dilaurate
EC Number:
201-039-8
EC Name:
Dibutyltin dilaurate
Cas Number:
77-58-7
IUPAC Name:
dibutyltin dilaurate
Constituent 3
Reference substance name:
Dibutyltin maleate
EC Number:
201-077-5
EC Name:
Dibutyltin maleate
Cas Number:
78-04-6
IUPAC Name:
dibutyltin maleate
Constituent 4
Reference substance name:
Dibutyltin Dimaleate
IUPAC Name:
Dibutyltin Dimaleate
Constituent 5
Reference substance name:
Dioctyltin oxide
EC Number:
212-791-1
EC Name:
Dioctyltin oxide
Cas Number:
870-08-6
IUPAC Name:
dioctyl(oxo)stannane
Details on test material:
- Name of test material (as cited in study report): Dibutyltin oxide (DBTO)
- Molecular formula (if other than submission substance): (C4H9)2SnO
- Molecular weight (if other than submission substance): 248.92
- Analytical purity: 99.2%
- Lot No: 1704

- Name of test material (as cited in study report): Dibutyltin dilaurate (DBTL)
- Molecular formula (if other than submission substance): (C4H9)2Sn(C12H23O2)2
- Molecular weight (if other than submission substance): 631.55
- Analytical purity: 98.2%
- Lot No: 0020

- Name of test material (as cited in study report): dibutyltin maleate
- Molecular formula (if other than submission substance): (C4H9)2SnC4H2O4
- Molecular weight (if other than submission substance): 348.04
- Analytical purity: 99.65%
- Lot/batch No.: 0010
Radiolabelling:
no

Test animals

Species:
other: n/a
Strain:
other: n/a
Details on test animals or test system and environmental conditions:
No test animals used - simulated gastric hydrolysis.

DBTO, DBTL and DBTM was tested under low pH (~1-2) conditions (0.07 N HCl) at 37 degrees Celsius in order to simulate the hydrolytic action by mammalian gastric contents. The degree of hydroloysis for the test substance was studied by determination of the amount of DBTC formed after 0.5, 1, 2, and 4 hours, uusing GC-FPD.

Administration / exposure

Route of administration:
other: n/a
Vehicle:
other: DBTM/DBTL: Acetonitrile; DBTO: insoluble in solvent; thoroughly mixed with 811.17 mg of lactose in mortar
Details on exposure:
Preparation of samples:

DBTM
A stock solution of DBTM in acetonitrile (1.63 mg/ml) was freshly prepared by dissolving 40.76 mg of the test substance in 25.0 ml acetonitrile.
No correction for the purity of DBTM (98.5%) was used; the amount of free maleic acid given was determined by infrared EHMA and therefore considered as not sufficiently reliable.
Into a series of 4 polypropylene vessels, 150 µl of the stock solution of DBTM (1.63 mg/ml) was added to 25 ml of 0.07 N HCl (already at 37°C). In this way, the concentration of DBTM in the final 0.07 N HCI solution was 9.78 mg/l. The solution was stirred for predetermined periods at 37 °C. The temperature was maintained using an oven. A sample was taken from one of the polypropylene vessels after 0.5, 1.0, 2.0 and 4.0 hours, respectively. Once a vessel had been sampled, no other sample was collected from that vessel.
To the sample 75 µl of internal standard solution (TPT, 1.58 mg/ml) was added.
350 µl of the sample was transferred into a GC injection vial and 100 µl to a HPLC injection vial.
The amounts of DBTC and maleic anhydride were determined by GC-FPD and HPLC-UV respectively and calculated.


DBTL
A stock solution of DBTL in acetonitrile (5.15 mg/ml) was freshly prepared by dissolving 128.83 mg test substance in 25.0 ml distilled diethylether.
No correction for the purity of DBTL (98.2%) was used; the amount of free lauric acid could not be determined by the sponsor.
Into a series of 4 polypropylene vessels, 50 µl of the stock solution of DBTL (5.15 mg/ml) was added to 25 ml of 0.07 N HCl (already at 37°C). In this way, the concentration of DBTL in the final 0.07 N HC1 solution was 10.31 mg/l. The solution was stirred for predetermined periods at 37 °C. The temperature was maintained using an oven. A sample was taken from one of the polypropylene vessels after 0.5, 1.0, 2.0 and 4.0 hours, respectively. Once a vessel had been sampled, no other sample was collected from that vessel.
To the sample 75 µl of internal standard solution (TPT, 1.58 mg/ml) was added.
350 µl of the sample was transferred into a GC injection vial. The remaining solution was extracted with 25 ml distilled diethylether. 5 ml of ether extract was transferred to a polypropylene tube. 500 µl of diazomethane was added. After 10 min. reaction, the 100 µl of the methylated extract was transferred to a GC injection vial.
The amount of DBTC and lauric acid were analyzed by GC-FPD and GC-MS respectively and calculated.


DBTO
Due to the insolubility of DBTO in any solvent, DBTO had to weighed and directly transferred to the vessels. To increase the accuracy of weighing and to gain a better distribution of the particle size, 202.10 mg DBTO was 'diluted' by thoroughly mixing with 811.17 mg lactose in a mortar.
No correction for the purity of DBTO (99.2%) was used.
Into a series of 4 PTFE vessels, 50 mg (accurately weighed) of the DBTO/lactose mixture (0.199 mg/mg) was added to 1000 ml of 0.07 N HCl (already at 37°C). In this way, the concentration of DBTO in the final 0.07 N HCl solution was approximately 10 mg/l. The solution was stirred for predetermined periods at 37 °C. The temperature was maintained using an oven. A sample was taken from one of the Teflon vessels after 0.5, 1.0, 2.0 and 4.0 hours, respectively. Once a vessel had been sampled, no other sample was collected from that vessel.
350 µl of the sample was transferred into a GC injection vial. The amount of DBTC was analyzed by GC-FPD and calculated.

All of the experiments were performed in duplicate.


Duration and frequency of treatment / exposure:
4 hours
Doses / concentrations
Remarks:
Doses / Concentrations:
50 mg of DBTO/lactose mixture (0.199 mg/mg) was addd to 1000 ml of 0.07 N HCl.

50 µl of the stock solution of DBTL (5.15 mg/ml) was added to 25 ml of 0.07 N HCl.

150 µl of the stock solution of DBTM (1.63 mg/ml) was added to 25 ml of 0.07 N HCl
No. of animals per sex per dose / concentration:
n/a
Control animals:
other: n/a
Positive control reference chemical:
n/a
Details on study design:
n/a
Details on dosing and sampling:
A sample was taken from one of the Test vessels after 0.2, 1, 2, and 4 hours. Once a vessel was sampled, no other sample was collected from that vessel.
Statistics:
For DBTM/DBTL, both the chloride formed of the organotin moiety as well as the respective ligands were determined.

DBTM:
DBTC measurements were calculated using the formula: 150 (µl) * 1.63 (mg/ml)/25 ml * Mw(DBTC)/Mw(DBTM)
Maleic acid and maleic acid anhydride measurement: 150 (µl) * 1.63 (mg/ml)/25 ml * Mw(maleic anhydride)/Mw(DBTM)

DBTL:
DBTC measurements were calculated using the formula: 50 (µl) * 5.15 (mg/ml)/25 ml * Mw(DBTC)/Mw(DBTL)
Maleic acid and maleic acid anhydride measurement: 50 (µl) * 5.15 (mg/ml)/25 ml * Mw(lauric acid)/Mw(DBTL)

For DBTO, the percentage of hydrolyzed organotin test substance based on the DBTC measurements was calculated as described below:
0.20 (mg/mg)/1000 ml * Mw(DBTC)/Mw(DBTO)

The half-life of the simulated gastric analysis was obtained from the graphs by estimating the time in which 50% of the maximal level was reached.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
No information available.
Details on distribution in tissues:
No information available.
Details on excretion:
No information available.
Toxicokinetic parametersopen allclose all
Toxicokinetic parameters:
other: Half life for DBTO was 3.5 hours
Toxicokinetic parameters:
other: Half life for DBTM/DBTL was <0.5 hours

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
The percentage of hydrolyzed organotin test substance was determined. DBTC in solution can be formed upon complete hydrolysis of DBTO/DBTM/DBTL.

Any other information on results incl. tables

DBTM

See table 5 and figure 1 attached.

From the graphical representation, it is clear that hydrolysis was rapid. The half-life of DBTM was < 0.5 hours; already at 0.5 hours the percentage of simulated gastric hydrolysis had reached a plateau level of 100% of the theoretical level. This supports the conclusion that all of the DBTM had hydrolyzed to DBTC and maleic anhydride by the first analysis time point, 0.5 hours.

DBTL

See table 6 and figure 2 attached.

From the graphical representation, it is clear that the simulated gastric hydrolysis of DBTL to DBTC was rapid. The percentage of hydrolysis was 87.8% after 2 hours. The half-life was < 0.5 hours; already at 0.5 hours the percentage of simulated gastric hydrolysis had reached a plateau level of 82% of the theoretical level. This supports the conclusion that most of the DBTL had hydrolyzed to DBTC in 2 hours.

As the levels of lauric acid were too low due to analytical problems, the measurement of the ligand was not further used for the data evaluation.

DBTO

See table 7 and figure 3 attached.

From the graphical representation, approximately 80% hydrolysis to DBTC occurred in 2 hours and the percent hydrolysis to DBTC in 4 hours was 87%. The half-life of DBTO was 3.5 hours.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: DBT may be hydrolyzed to a great extent in simulated mammalian gastric contents
The hydrolysis of DBTM and DBTL to DBTC plus the ligands was rapid. The calculated percentages of hydrolysis were 100.1 % after 0.5 hours for DBTM and 87.8% after 2 hours for DBTL. The half-life of DBTM and DBTL under simulated gastric hydrolysis conditions was < 0.5 hours. DBTO hydrolyzed to 87.3% after 4 hours, with a half-life at 3.5 hours.
Executive summary:

In three separate experiments, each of the test substances, dibutyltin dilaurate (DBTL, CAS # 77-58-7), dibutyltin maleate (DBTM, CAS # 78-04-6) and dibutyltin oxide (DBTO, CAS # 818-08-6) were individually tested under low pH (-1-2) conditions (0.07 N HC1) at 37 °C in order to simulate the hydrolytic action by mammalian gastric contents.

The hypothesis was that in the hydrochloric acid solution the tin-ligand bond breaks, leading to formation of the corresponding alkyltin chloride and simultaneous liberation of the ligand.

The degree of hydrolysis for the test substances DBTM, DBTL and DBTO was studied by determination of the amount of DBTC formed after 0.5, 1.0, 2.0 and 4.0 hours, using GC-FPD.

Where possible the ligand was also analyzed. The analytical approach to the individual ligands, maleate, laurate, and oxide, was different due to the unique chemical properties of each.

The hydrolysis of DBTM and DBTL to DBTC plus the ligands was rapid. The calculated percentages of hydrolysis were 100.1 % after 0.5 hours for DBTM and 87.8% after 2 hours for DBTL. The half-life of DBTM and DBTL under simulated gastric hydrolysis conditions was < 0.5 hours. DBTO hydrolyzed to 87.3% after 4 hours, with a half-life at 3.5 hours.

It was not possible to carry out the simulated gastric hydrolysis study for dioctyltin oxide (DOTO, CAS # 870-08-6). From the information available, it was concluded that DOTO only partially hydrolyzed in the test system and the estimated percentage of hydrolysis was 20 to 55%.