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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
Reason / purpose for cross-reference:
reference to same study
Objective of study:
metabolism
Qualifier:
according to guideline
Guideline:
other: OECD 111
GLP compliance:
no
Remarks:
Inhouse study
Radiolabelling:
no
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

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

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.

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Guideline:
other: no guideline followed
Principles of method if other than guideline:
Monooctyltin tris(2-ethylhexylmercaptoacetate, CAS no. 27107-89-7 was tested under low pH (1-2) conditions at 37°C in order to simulate the possible hydrolytic action on mammalian gastric contents.
GLP compliance:
no
Radiolabelling:
no
Type:
other: in vitro gastric hydrolysis test
Conclusions:
Under the conditions of the study, the estimated half-life was 0.28 hours. The data show that, within 0.5 hour most of the available EHMA ligands have been released and there is approximately 88% hydrolysis of the test substance. 
Executive summary:

This study was performed using a MOT(2-EHMA):DOT(2-EHMA) mixture (60.88%:35.67%). Under acidic conditions, the tin-EHMA bond is expected to break, forming the corresponding alkyltin chloride MOTC and free EHMA ligands, which may then hydrolyze further forming thioglycolic acid (TGA) and 2-ethylhexanol (EH). Previous simulated gastric reaction studies have indicated that organotin stabilizers undergo rapid conversion (on the order of minutes to hours) to the alkyltin chloride species when exposed to low pH (<2) conditions similar to mammalian gastric systems. These studies have also demonstrated a distinct relationship between the methyl, butyl, and octyltin organotin species, as all three followed the same pattern of conversion to their chloride derivatives under similar low pH conditions.

The simulated gastric reaction study of the MOT(2-EHMA):DOT(2-EHMA) mixture was performed by spiking a sample of the test substance into 0.07 M HCl that had been thermostated to 37 deg. C. The pH of the solution was <2. Samples were collected at 0.5, 1, 2, and 4 hours and analyses for the expected reaction products EHMA and EH were conducted using gas chromatography with flame ionization detection (GC-FID). The concentration of the test substance in the 0.07 M HCl solution was 9.2 mg/l. The experiment was conducted in duplicate.

Results (as % conversion to MOTC) for MOT(2-EHMA), by sample collection time:

0.5-h: 88%
1-h: 88%
2-h: 88%
4-h: 89%

t1/2 (estimated) = 0.28 hours.

The data show that, within 0.5 hour most of the available EHMA ligands have been released and there is approximately 88% hydrolysis of the test substance. 

Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Qualifier:
according to guideline
Guideline:
OECD Guideline 428 (Skin Absorption: In Vitro Method)
GLP compliance:
yes
Radiolabelling:
no
Species:
other: rat and human epidermis
Type of coverage:
other: occluded and unoccluded
Vehicle:
ethanol
Duration of exposure:
24 hour(s)
Doses:
Absorption was determined via both occluded and unoccluded applications to human and rat epidermis (100 µl/cm²; equivalent to a dose of 17,007 µg tin/cm²).
Details on study design:
Absorption of tin compouds was measured (not DOTE only).

HUMAN EPIDERMIS: A dose of 17,007 ug tin/cm² was determined to alter the barrier function of the epidermis.  From the occluded and unoccluded applications, the rates of tin absorption over the 0-24 h exposure period were below the limit of quantification (0.001 ug/cm²/h).  In terms of  percent applied tin, 0.0001% was absorbed from the occluded dose,  and  0.0001% was absorbed from the unoccluded dose after  24 hours of exposure.

RAT EPIDERMIS: Absorption of tin through rat epidermis was much faster than through human epidermis.  From the occluded application, the  maximum rate of tin absorption (0.035 ug/cm²/h) occurred during 16-24 hours of exposure, and the mean rate of tin absorption over the whole  24-h exposure period was 0.021 ug/cm²/h.  From the unoccluded application, the maximum rate of tin absorption occurred during 12-24 hours of  exposure and was 0.033 ug/cm²/h.  The mean rate of tin absorption over the whole  24-h exposure period was 0.025 ug/cm²/h.  In terms of percent applied tin, 0.003% was absorbed from the occluded dose, and 0.004% was  absorbed from the unoccluded dose after 24 hours of exposure.  The overall recovery of tin from the test system after 24-h exposure was low and may be due to adsorption of the test substance to the glass  equipment used.  The recovery was 45.5% (human) and 25.2% (rat) of theapplied occluded doses, and 29.6% (human) and 30.5% (rat) were  recovered from the unoccluded test systems.  Of the recovered tin, 2.1% (human) and 5.5% (rat) were obtained from the surface of the epidermis and donor chamber.  The mean amounts of tin  absorbed by 24 hours were 0.010 ug/cm² (unoccluded) and 0.011 ug/cm² (occluded) through human epidermis and 0.641 ug/cm² (unoccluded)  and 0.547ug/cm² (occluded) through rat epidermis.  These results show that the absorption of tin from dioctyltin bis(2-ethylhexylmercaptoacetate) through rat epidermis significantly  overestimated absorption from human epidermis.  By 24 hours only a small amount of the applied tin (3% in human and 1% in the rat) is  associated with the epidermis and is not regarded as systemically available.

The recovery was 45.5% (human) and 25.2% (rat) of the applied occluded doses, and 29.6% (human) and 30.5% (rat) were recovered from the unoccluded test systems.

Conclusions:
Bioaccumulation potential cannot be judged based on study results.
Absorption of tin from DOT(EHMA) through rat epidermis significantly overestimates absorption through human epidermis.
Executive summary:

A dermal absorption study was carried out with DOT(2 -EHMA). Absorption of tin compounds was determined via both occluded and unoccluded applications to human and rat epidermis.

Of the recovered tin, 2.1% (human) and 5.5% (rat) were obtained from the surface of the epidermis and donor chamber.  The mean amounts of tin absorbed by 24 hours were 0.010 ug/cm² (unoccluded) and 0.011 ug/cm² (occluded) through human epidermis and 0.641 ug/cm² (unoccluded) and 0.547ug/cm² (occluded) through rat epidermis.

The results show that the absorption of tin from dioctyltin bis(2-ethylhexylmercaptoacetate) through rat epidermis significantly over-estimated absorption from human epidermis.  By 24 hours only a smallamount of the applied tin (3% in human and 1% in the rat)  is associated with the epidermis and is not regarded as systemically available.

Description of key information

Key value for chemical safety assessment

Additional information

- Basic toxicokinetics

Schilt (2004)

This study was performed using a MOT(2-EHMA):DOT(2-EHMA) mixture (60.88%:35.67%). Under acidic conditions, the tin-EHMA bond is expected to break, forming the corresponding alkyltin chloride MOTC and free EHMA ligands, which may then hydrolyze further forming thioglycolic acid (TGA) and 2-ethylhexanol (EH). Previous simulated gastric reaction studies have indicated that organotin stabilizers undergo rapid conversion (on the order of minutes to hours) to the alkyltin chloride species when exposed to low pH (<2) conditions similar to mammalian gastric systems. These studies have also demonstrated a distinct relationship between the methyl, butyl, and octyltin organotin species, as all three followed the same pattern of conversion to their chloride derivatives under similar low pH conditions.  The simulated gastric reaction study of the MOT(2-EHMA):DOT(2-EHMA) mixture was performed by spiking a sample of the test substance into 0.07 M HCl that had been thermostated to 37 deg. C. The pH of the solution was <2. Samples were collected at 0.5, 1, 2, and 4 hours and analyses for the expected reaction products EHMA and EH were conducted using gas chromatography with flame ionization detection (GC-FID). The concentration of the test substance in the 0.07 M HCl solution was 9.2 mg/l. The experiment was conducted in duplicate.  Results (as % conversion to MOTC) for MOT(2-EHMA), by sample collection time:  0.5-h: 88% 1-h: 88% 2-h: 88% 4-h: 89%  t1/2 (estimated) = 0.28 hours.  The data show that, within 0.5 hour most of the available EHMA ligands have been released and there is approximately 88% hydrolysis of the test substance. 

Under the conditions of the study, the estimated half-life was 0.28 hours. The data show that, within 0.5 hour most of the available EHMA ligands have been released and there is approximately 88% hydrolysis of the test substance. 

Naßhan (2017)

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.

- Dermal absorption

Ward (2003)

A dermal absorption study was carried out with DOT(2-EHMA). Absorption of tin compounds was determined via both occluded and unoccluded applications to human and rat epidermis.

Of the recovered tin, 2.1% (human) and 5.5% (rat) were obtained from the surface of the epidermis and donor chamber.  The mean amounts of tin absorbed by 24 hours were 0.010 ug/cm² (unoccluded) and 0.011 ug/cm² (occluded) through human epidermis and 0.641 ug/cm² (unoccluded) and 0.547ug/cm² (occluded) through rat epidermis.

The results show that the absorption of tin from dioctyltin bis(2-ethylhexylmercaptoacetate) through rat epidermis significantly over-estimated absorption from human epidermis.  By 24 hours only a smallamount of the applied tin (3% in human and 1% in the rat)  is associated with the epidermis and is not regarded as systemically available.