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

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

16 January 2015 to 03 March 2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

reference to same study

Objective of study:

metabolism

Qualifier:

according to guideline

Guideline:

other: EU Method C.7 (Degradation: Abiotic Degradation: Hydrolysis as a Function of pH

Deviations:

not applicable

GLP compliance:

no

Species:

other: Not applicable to in vitro simulated gastric pH testing

Strain:

other: Not applicable to in vitro simulated gastric pH testing

Sex:

not specified

Details on test animals or test system and environmental conditions:

Not applicable to in vitro simulated gastric pH testing

Route of administration:

other: Not applicable to in vitro simulated gastric pH testing

Vehicle:

unchanged (no vehicle)

Details on exposure:

Analytical Method:
119Sn-NMR spectroscopy:
The 119Sn-NMR has been chosen to analyse the test material as well as the breakdown products of the test material since it combines several unique aspects of analysing 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 derivatisation. Thus it avoids errors associated with a) the sample derivatisation and b) misinterpretation of the results associated with analysing and quantifying 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 %
- 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 / 330 µL toluene-d8 (10 mg/mL CrAcAc)
AAS: Analytik Jena ContraAA 300

Temperature of the measurements: Ambient temperature (outside the apparatus); test temperature 50 °C / 37 °C.
The test material was dissolved in buffer solutions for specific pH values and kept at 50 °C for 5 days assessing the environmental date and to 0.1 M HCl pH 1.2 at 37 °C for 4 h simulating the metabolism under gastric conditions.

Buffers:
The buffer systems were selected according to the guidelines. The chosen buffers provided the required pH values. Commercially available solutions were used:
pH 1.2: HCl 0.1 M
pH 4.0: HCl / NaCl / Citric acid
pH 7.0: Na2HPO4 / NaH2PO4
pH 9: H3BO3 / KCl / NaOH

Gastric pH testing (pH 1.2 / 37 °C)
The test material was used without a co-solvent or a detergent.
1 g (1.3 mMol) test material was added to 100 mL of 0.1 < aqueous solution of hydrochloric acid that was pre-heated to 37 °C in a 250 mL Erlenmeyer flask with ground.
The flask was closed with a stopper and heated on a heating cabinet for 4 h at 37 °C. The mixture was stirred by a magnetic stirrer using a 40 x 7 mm stir bar at approximately 100 rpm.
After the pre-determined exposure time, the solution was allowed to cool down to room temperature; extracted 2 times with 25 mL hexane; the phases were separated using a separatory funnel. The organic phase was transferred into a flask, and the solvent was removed in a rotary evaporator (< 40 °C, 10 mbar). The sample was analysed by 119Sn-NMR spectroscopy.

Duration and frequency of treatment / exposure:

4 h

Dose / conc.:

1.3 other: mmol/L

Control animals:

no

Details on study design:

Not applicable to in vitro simulated gastric pH testing

Details on dosing and sampling:

Not applicable to in vitro simulated gastric pH testing

Metabolites identified:

yes

Details on metabolites:

Hydrolysis at pH 1.2: A sample of the test material was added to an excess of a 0.1 M hydrochloric acid at 37 °C for 4 h. The 119Sn-NMR spectrum of the recovered reaction product showed that the test material is partially hydrolysed to MMTEC. Both substances were present in equilibrium in a ca. 70/30 MMTE / MMTEC mol % ratio.
MMTEC a product of hydrolysis, has been identified based on the 119Sn-NMR signal at -12.7 ppm. The substance was already present in the non-treated test material as an impurity of ca. 4 % (NMR).
No signal corresponding to MMTC (typically present at 133 ppm) was detected.

Conclusions:

Under simulated gastric conditions (0.1 M HCl / pH 1.2 / 37 °C) the test material was partially hydrolysed to its monochloro ester.
It can be concluded that the monochloro ester is the only metabolite of the test material that was formed in the simulated mammalian gastric environment. 

Executive summary:

The hydrolysis of the test material was assessed according to OECD Test Guideline 111 and EU Method C.7. Quantitative ^119Sn-NMR spectroscopy has been used as a valuable analytical tool to directly identify and quantify all organotin components, which are formed as a result of hydrolysis of the tested substance.

The study shows that under the simulated gastric conditions (0.1 M HCl / pH 1.2 / 37 °C) the test material was partially hydrolysed to its monochloro ester.

It can be concluded that the monochloro ester is the only metabolite of the test material that was formed in the simulated mammalian gastric environment. No MMTC was formed under the conditions of the study.

Description of key information

The study shows that under the simulated gastric conditions (0.1 M HCl / pH 1.2 / 37 °C) the test material was partially hydrolysed to its monochloro ester.

It can be concluded that the monochloro ester is the only metabolite of the test material that was formed in the simulated mammalian gastric environment.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

No experimental studies of the absorption, distribution, metabolism or elimination of 2-ethylhexyl 10-ethyl-4-[[2-[(2-ethylhexyl)oxy]-2-oxoethyl]thio]-4-methyl-7-oxo-8-oxa-3,5-dithia-4-stannatetradecanoate (synonym: MMTE; EC Number 260-828-5; CAS Number 57583-34-3) in mammals are available. However, the physical chemical properties and the existing toxicity studies on the substance have been used to infer, as far as possible, its potential toxicokinetics.

 

The substance MMTE is a clear liquid, with a molecular weight (MW) of 743.71 g/mol. Water solubility was not determined because the substance was believed to be hydrolytically unstable (although this is being further considered in light of some of the recent new data). The partition coefficient (Log Kow/Log Pow) was also not determined but generated by a property-estimation software (e.g., KOWWIN version 1.67), by a calculation method based on the theoretical fragmentation of the molecule into substructures for which reliable log Pow increments are known. The log Pow obtained by summing the fragment values and the correction terms for intramolecular interactions was estimated to be 11.0. However, because this substance was believed not to exist in contact with water, the log Pow of the expected/stable daughter product (2-ethylhexylthioglycolate) was also calculated and was determined to be 3.68. The vapour pressure of MMTE was determined to be 0.38 Pa at 25 °C.

 

In an in vitro study simulating gastric conditions (0.1 M HCl / pH 1.2 / 37 °C) the test material was partially hydrolysed to its monochloro ester. The monochloro ester is the only metabolite of the test material that was formed in the simulated mammalian gastric environment.

 

Absorption

Toxicity studies with MMTE showed that oral absorption does occur; in rats the LD50 was 880 mg/kg bw and the NOAEL in a dietary 90-d study was 2000 ppm, approximately 163 mg/kg bw/day. For human health risk assessment purposes, oral absorption of MMTE is assumed to be complete (100 %).

The high molecular weight (MW 743.71 g/mol) and high estimated Log Pow values indicate that micellar solubilisation would play a major role for absorption by inhalation. In the absence of any quantitative data, for human health risk assessment purposes absorption by inhalation of MMTE is assumed to be 100 %.

As the molecular weight of MMTE is > 500 g/mol and the estimated Log Pow values are in general > 4, a default value of 10 % dermal absorption is considered appropriate for human health risk assessment.

 

Distribution

The fact that following repeated oral (dietary) exposure lesions were observed in the central nervous system indicates that, notwithstanding the high molecular weight, wide distribution occurs. Micellar solubilisation and preferential partition to tissues with high lipid content are expected to occur.

 

Metabolism and Excretion

In an in vitro study simulating gastric conditions the only identifiable breakdown product was the monochloro ester; the stable daughter product 2-ethylhexylthioglycolate is also expected to occur.

Excretion is expected to occur mainly via the faeces.

The potential for bioaccumulation is considered to be low.