2-ethylhexyl 10-ethyl-4-[[2-[(2-ethylhexyl)oxy]-2-oxoethyl]thio]-4-octyl-7-oxo-8-oxa-3,5-dithia-4-stannatetradecanoate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

06.07.2016-11.01.2017

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

according to guideline

Guideline:

other: OECD 111

GLP compliance:

no

Remarks:

Inhouse study

Test material

Test material information

Constituent 1

Reference substance name:

2-ethylhexyl 10-ethyl-4-[[2-[(2-ethylhexyl)oxy]-2-oxoethyl]thio]-4-octyl-7-oxo-8-oxa-3,5-dithia-4-stannatetradecanoate

EC Number:

248-227-6

EC Name:

2-ethylhexyl 10-ethyl-4-[[2-[(2-ethylhexyl)oxy]-2-oxoethyl]thio]-4-octyl-7-oxo-8-oxa-3,5-dithia-4-stannatetradecanoate

Cas Number:

27107-89-7

Molecular formula:

C38H74O6S3Sn

IUPAC Name:

2-ethylhexyl 10-ethyl-4-({2-[(2-ethylhexyl)oxy]-2-oxoethyl}sulfanyl)-4-octyl-7-oxo-8-oxa-3,5-dithia-4-stannatetradecan-1-oate

Test material form:

liquid

Details on test material:

- Appearance: Pale yellow liquid
- Storage Conditions: Cool and dry (+2 to +8 °C)

Radiolabelling:

no

Administration / exposure

Details on study design:

BUFFER
Commercially available solutions purchased from VWR International GmbH
pH 1.2 HCl 0.1 M

METHOD
Tier 1 Testing (pH 1.2):
1 g (1.18 mMol) test item was added to 100 ml of buffer solution in a 250 ml Erlenmeyer flask. The flask was closed with a stopper and heated in a heating cabinet for 5 days (120 hours) at 50°C. The mixture was stirred by a magnetic stirrer using a 40*7 mm stir bar at approx. 100 rpm. The test was carried out at pH 1.2 and 37 °C

After the pre-determined reaction time, the solution was allowed to cool down to room temperature; the reaction mixture was extracted with 20 ml hexane, the phases were separated using a separatory funnel. The organic phase was transferred into a pre-weighed flask and the solvent was removed in a rotary evaporator (<40 °C, 10 mbar). The weight difference was recorded for the mass balance, and the samples were analyzed by 119Sn-NMR.

Tier 2 Testing (pH 1.2/37°C)
1 g (1.3 mMol) Test Item was added to 100 ml of 0.1 M hydrochloric acid that was preheated to 37 °C in an 250 ml Erlenmeyer flask with ground. For the initial time of the experiment (15 seconds), the reaction products were extracted with hexane immediately according to the below-described procedure. For longer exposure/hydrolysis times, the flask was closed with a stopper and heated in a heating cabinet for 1, 2, 4, 8, 24, and 48 hours at 37°C. The mixture was stirred by a magnetic stirrer using a 40*7 mm stir bar at approx. 100 rpm.

After the pre-determined reaction time, the solution was allowed to cool down to room temperature; each reaction mixture was extracted with 20 ml hexane; the phases were separated using a separatory funnel. The organic phase was transferred into a pre- weighed flask, and the solvent was removed in a rotary evaporator (<40 °C, 10 mbar). The weight difference was recorded for the mass balance, and the samples were analyzed by 119Sn-NMR.

The experiments were run in duplicate.

DETAILS ON ANALYTICAL METHODS
The 119Sn-NMR has been chosen to analyze the test item as well as the breakdown products of the test item, since it combines several unique aspects of analyzing tin substances.
• 119Sn-NMR detects all tin-containing substances in a sample qualitatively and quantitatively at the same time.
• 119Sn-NMR is a direct and non-destructive method. It does not require any sample digestion or derivatization. Thus it avoids errors associated with a) the sample derivatization and b) misinterpretation of the results associated with analyzing and quantifying the derivatives.
• The 119Sn spectra signals are highly selective. They directly represent the corresponding tin compounds. Chemical shifts of differently substituted tin atoms are highly characteristic of the specific atom coordination.
• The 119Sn-NMR spectroscopy is very sensitive and reliable. Its detection limit was established to be 0.5% (see Annex 6).
• The 119Sn-NMR method has been used for decades by the industry as a standard analytical method on tin compounds for the purpose of quality control, process development and research.

Apparatus: Bruker Advance 200
Temperature: Ambient temperature
Sample preparation: 370 µl/330µl toluene-d8 (10 mg/ml CrAcAc)
Documentation: The test conditions and spectra obtained were documented as raw data and the printouts

AAS: Analytik Jena ContrAA 300

Results and discussion

Any other information on results incl. tables

The DT50 of the substance at pH 1.2 and at 37°C was determined to be < 1 minute.

Applicant's summary and conclusion

Conclusions:

Under the simulated gastric conditions (0.1 M HCl / pH 1.2 / 37 °C) MOTE was hydrolyzed to (Monooctyltin chloro bis(2-ethylhexyl mercaptoacetate) (MOTCE2), its monochloro ester.
It can be concluded that MOTCE2 is the only metabolite of MOTE that was formed in the simulated mammalian gastric environment. No Dichloro etster (MOTC2E) or MOTC was formed under the conditions of this study.

Executive summary:

Under the simulated gastric conditions (0.1 M HCl / pH 1.2 / 37 °C) MOTE was hydrolyzed to (Monooctyltin chloro bis(2-ethylhexyl mercaptoacetate) (MOTCE2), its monochloro ester.

It can be concluded that MOTCE2 is the only metabolite of MOTE that was formed in the simulated mammalian gastric environment. No Dichloro etster (MOTC2E) or  MOTC was formed under the conditions of this study.