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Link to relevant study record(s)

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

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%).

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.

Description of key information

Hydrolysis

The hydrolysis of DOTTG is highly differentiated depending on the circumstances

1 Exposure to HCl, low pH

the investigations on alky tin compounds in general and on DOTTG in particular aim to simulate the gastric hydrolysis as an important step in metabolism.

1.1 Pure substance

The pure substance reacts with HCl in in a ring opening reaction to DOTC-TA, followed by a reaction with a second molecule HCl to DOTC (Naßhan 2019)

DOTTG + HCl --> DOTCE-TA | DOTCE-TA +HCl --> DOTC

1.2 DOTTG in DOTE solution

DOTTG is manufactured and marketed only in a max 10 % DOTE (DOTI) solution.

The degradation product DOTC formed by reaction with HCl reacts with the excess DOTE rapidly to DOTEC, the electronically stabilized monochloro-thioester with a cyclic structure close to the DOTTG structure. (Naßhan 2019)

DOTTG +2 HCl --> DOTC | DOTC + DOTE --> 2 DOTEC

1.3 DOTTG while acting as a PVC stabilizer in a mixture with DOTE and MOTE

During the stabilization process of PVC, DOTTG is exposed to HCl from the degradation of PVC. DOTTG is completely transformed to DOTEC during this process. (Frenkel 2016).

DOTTG + PVC --> DOTC | DOTC + DOTE --> DOTEC

2 Exposure to water, pH 4-9

The studies done on organotins at higher pH pursue the goal to demonstrate the stability during manufacturing process, which includes contact to water and to simulate the exposure and behavior in the environment.

2.1 Dioctyltins in ACN/water solution

Dioctyltins hydrolyse in acetonitrile/water solutions to form dioctyltin oxide. It was determined that contact of these dioctyltins with water alone produces the oxide

The formation of the ligand EHTG could be observed unequivocally, whereas the formation of DOTO was postulated. The DOTO signal intensity remained constant in the experiment, which was attributed to the very low solubility of DOTO. (Yoder 2003)

The study shows, that dioctyltins in solution react rapidly with water to form Dioctyltin oxide and the ligand. The scenario is relevant for any dissolved dialkyltin compounds which are dissolved in water, e.g. during sewage treatment.

2.2 Alkyltin substances as neat substances

Hydrolysis studies at pH 4-7 with neat substances have been conducted with Dimethyl, Dibutyl and Dioctyltin substituted organotin substances with thiobonds, namely:

DMTE (Dimethyltin bis(2-ethylhexylthioglycolate) CAS-No.: 57583-35-4)

DBT-MPTD (Diisotridecyl 3,3'-[(dibutylstannylene)bis(thio)]dipropionate- / CAS 84896-44-6)

DOTE (2-ethylhexyl 10-ethyl-4,4-dioctyl-7-oxo-8-oxa-3,5-dithia-4-stannatetradecanoate), CAS 15571-58-1

All substances remained stable when the neat substances were exposed to buffer solutions for 5 days / 50 °C. 119Sn-NMR spectroscopy was used to determine the (unchanged) organotin species.

The scenario of neat organotin substances is relevant for the manufacturing of this compouns since they are manufactured in contact with water.

3 Ligands:

The ligand which is released during hydrolysis of dialkyltin thioglycolates (Yoder 2003) is Ethylhexyl thioglycolate (EHTG)

It is is self-classified as Aquatic Acute 1 and Aquatic Chronic 1.

The ligand of DOTTG, Thioglycolic acid is not classified for the environment and thus does not pose any additional risk for the environment when released from DOTTG by hydrolysis

It degrades in water by fast oxidation to dithiodiglycolate.

Based on the physico-chemical properties of thioglycolic acid and salts (high solubility and low Log P), it is considered that they are not expected to adsorb to suspended solids, sediments and soils and are mobile in soil

Thioglycolic acid and its main oxidation product, the diammonium dithiodiglycolate, it can be considered that thioglycolic acid and its salts are ready biodegradable and do not raise concern in terms of persistency.

Thioglycolic acid and its salts are highly soluble in water (> 1000 g/L at 20°C) (Sablowski, 2007b; reliability 2) and have a partition coefficient octanol-water equal to -2.99 at 22°C and pH 7. Therefore thioglycolic acid is not expected to bioaccumulate according to technical guidance documents

 

 

 

 

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
1
Absorption rate - inhalation (%):
100

Additional information