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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
experimental study
Adequacy of study:
key study
Study period:
02.02.2016 - 15.02.2016
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report Date:
2016

Materials and methods

Objective of study:
metabolism
Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: OECD TG 111, Hydrolysis as Function of pH Value
Deviations:
yes
Remarks:
In the present study only the hydrolytical behaior under simmulated gastric conditions at pH 1.2 has been investigated
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Details on test material:
Since DOTTG turned out to be very poorly soluble in water and organic solvents, a solution of DOTTG in DOTE (CAS 15571-58-1) was used for the experiment.
After stirring DOTTG in DOTE at 40 °C for 16 hours and separating the liquid phase, a 8.1 % solution of DOTTG in DOTE was obtained
Specific details on test material used for the study:
Since DOTTG turned out to be very poorly soluble in water and organic solvents, a solution of DOTTG in DOTE was used for the experiment.
After stirring DOTTG in DOTE at 40 °C for 16 hours and separating the liquid phase, a 8.1 % solution of DOTTG in DOTE was obtained.
Since DOTTG is solely manufactured in situ together with DOTE in typical concentrations of 2-3 % (max 10 %), this solution gets closest to the marketed form of DOTTG.
Radiolabelling:
no

Results and discussion

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
The in-vitro metabolite of DOTTG under simulated gastric conditions Dioctyltin chloro thioglycolic acid (DOTCTA)

Any other information on results incl. tables

The result of the DOTTG in-vitro metabolism under the simulated gastric conditions is displayed in table 1:The characteristic signal for DOTTG at -46 ppm completely disappeared during the incubation time, which shows that the substance did completely hydrolyze. The ring-opening reaction with HCl leads to the Dioctyltin-monochloro-thioglycolic acid (DOTCTA) which is similar to DOTCE, the hydrolysis product of DOTE. The difference between both species is the ester function in the ligand of DOTCE and the acid function in DOTCTA. The impact on the substitution of the central tin atom is expected to be, if any, marginal. In the present study we could determine a single signal which can be assigned to both, the esterified and un-esterified species.

Table 1: Hydrolysis of DOTTG in DOTE solution

Test iten; DOTTG in DOTE solution

Imp*)

DOTE

MOTE

DOTCE

DOTTG

 

 

103.14

74.28

67.4

34.27

-46

 

ppm

3.5

78

4.3

1.4

12.8

 

Mol %

Incubated Test Item (4h, 37 °C, pH 1.2)

Imp*)

DOTE

MOTE

DOTCE DOTCTA

DOTTG

MOTCE

 

102.9

73.2

66.9

32.95

 

-12.7

ppm

0.6

26.1

2.3

68.2

--

2.8

Mol %

The signal at ~ 103 ppm is assigned to an impurity which is most likely a sulfur bridged bis(dioctyltin thiogylcolate) which is formed during synthesis of DOTE

No signal typical for DMTC was detected.

 

Tin in aqueous solution:

In order to detect tin containing breakdown products, which may be better soluble in water, the extracted water phase has been acidified and analyze by AAS.

The content of tin in the aqueous pahse was below the detection limit of 5 ppm.

Mass balance:

The recovered mass after incubation and extraction was found to be

0.99 g (99%).

Applicant's summary and conclusion

Conclusions:
In-vitro metabolism of DOTTG in DOTE can be monitored using 119Sn-NMR Spectroscopy by the decrease in the relative intensity of the respective 119Sn-NMR signals at ~ 77 ppm (DOTE) and -46 ppm (DOTTG) the increase of the signal at ~ 33 ppm characteristic to DOTEC / DOTCTA
DOTC was not detected in any of the metabolized DOTTG/DOTE samples.
Executive summary:

The study showed that under the simulated gastric conditions (0.1 M HCl / pH 1.2 / 37 °C) DOTTG in DOTE solution completely hydrolyses under the conditions of the study. The hydrolysis product is Dioctyltin chloro thioglycolic acid (DOTCTA) similar to Dioctyltin chloro 2-ethylhexylthioglycolate (DOTCE), which has been shown to be the only metabolite of DOTE (CAS 15571 -58 -1) under simulated gastric conditions.

Both substances produce a signal at the same chemical shift in 119Sn-NMR, due to the similar substitution pattern of the central tin atom.No Dioctyltindichloride (DOTC) was detected as a product of a simulated gastric hydrolysis.