Diisooctyl 2,2'-[(dioctylstannylene)bis(thio)]diacetate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

22 January 2016 to 05 April 2016

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

(non-GLP)

Reason / purpose for cross-reference:

other: read-across target

Objective of study:

metabolism

Qualifier:

according to guideline

Guideline:

other: OECD 111

GLP compliance:

no

Radiolabelling:

no

Conclusions:

The study showed that DOTE at pH 9, 7 and 4 can be considered hydrolytically stable. After 5 days at 50°C less than 10% DOTE was hydrolysed (t 0.5 25°C > 1 year).
Under the simulated gastric conditions (0.1 M HCl / pH 1.2 / 37 °C) DOTE was hydrolysed to DOTEC, its monochloride ester.
It can be concluded that DOTEC is the only metabolite of DOTE that was formed in the simulated mammalian gastric environment. No DOTC was formed under the conditions of this study.

Executive summary:

The study showed that DOTE at pH 9, 7 and 4 can be considered hydrolytically stable. After 5 days at 50 °C less than 10% DOTE was hydrolysed (t 0.5 25°C > 1 year).

Under the simulated gastric conditions (0.1 M HCl / pH 1.2 / 37 °C) DOTE was hydrolysed to DOTEC, its monochloride ester.

It can be concluded that DOTEC is the only metabolite of DOTE that was formed in the simulated mammalian gastric environment. No DOTC was formed under the conditions of this study.

Reference 2

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted on read-across material

Justification for type of information:

Read-across to structurally similar substance Dioctyltin bis (2-ethylhexylmercaptoacetate) (DOTE) (CAS No. 15571-58-1), see attached justification.

Reason / purpose for cross-reference:

read-across source

The study showed that DOTE at pH 9, 7 and 4 can be considered hydrolytically stable.  After 5 days at 50 °C less than 10% DOTE was hydrolysed (t 0.5 25 °C > 1 year).

Under the simulated gastric conditions (0.1 M HCl / pH 1.2 / 37 °C) DOTE was hydrolysed to DOTEC, its monochloride ester.

It can be concluded that DOTEC is the only metabolite of DOTE that was formed in the simulated mammalian gastric environment. No DOTC was formed under the conditions of this study.

Reference 3

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

15 April 2014 to 20 June 2014

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

other: read-across target

Objective of study:

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

Hydrolysis at pH 4.0, 7.0 and 9.0
The test material was stirred in buffer solution, at room temperature, for a period of 72 hours. At the end of the exposure period the reaction mixture was analysed by ¹¹⁹Sn-NMR.

Hydrolysis at pH 1.2 (simulated gastric environment)
The test material was exposed to 0.1 N HCl (pH 1.2) at 40 °C for 72 hours with 0.1 % detergent and slight stirring. At the end of the exposure period the reaction mixture was analysed by ¹¹⁹Sn-NMR.

GLP compliance:

no

Remarks:

However, the study was conducted in compliance with DIN, EN, ISO, OECD and EEC Regulations.

Radiolabelling:

no

Species:

other: not applicable - in vitro experiment

The sample of test material that was analysed by ¹¹⁹Sn-NMR andwas found to have a chemical shoift of 74 ppm (DOTE) and 67 ppm (MOTE) at intensities of DOTE / MOTE of 97 / 3.

> pH 4.0 Hydrolysis Results

¹¹⁹Sn-NMR:

74 ppm DOTE

67.7 ppm MOTE

(intensity DOTE / MOTE = 98 / 2)

TOC:

NPOC = 0.09467 mg/L

> pH 7.0 Hydrolysis Results

¹¹⁹Sn-NMR:

69 ppm DOTE

62.5 ppm MOTE

(intensity DOTE / MOTE = 98 / 2)

TOC:

NPOC = 0.01632 mg/L

> pH 9.0 Hydrolysis Results

¹¹⁹Sn-NMR:

74.2 ppm DOTE

67.7 ppm MOTE

(intensity = 97 / 3)

TOC:

NPOC = 0.06666 mg/L

> pH 1.2 Hydrolysis Results

¹¹⁹Sn-NMR:

71.54 ppm DOTE (22)*

65.65 ppm MOTE (1)

31.01 ppm DOTECl (95)

-16.12 ppm MOTE2Cl (1)

*) number in brackets are relative intensities

 

TOC:

NPOC = 0.04928 mg/L

The separated water phase did not contain significant amounts of organic carbon. So it can be concluded that none of the organotin species would have been lost via the aqueous phase.

There was no peak in the region of 133 ppm (DOTC) in any of the media analysed.

Conclusions:

Under the conditions of the study the test material did not degrade in aqueous environments at pH 4 and above. In a gastric environment DOTECl is the only metabolite of DOTE. No dioctlytindichloride was formed under the conditions of this study.

Executive summary:

The hydrolysis of the test material was investigated in buffer solutions (pH 4.0, 7.0 and 9.0) at room temperature, as well as in a simulated mammalian gastric environment. 1 g of test material was exposed to either 100 mL of the appropriate buffer solution or simulated gastric fluid (0.1 N HCl, pH 1.2 and 0.1 % detergent) and for a period of 72 hours. The buffer solutions were stirred at room temperature while the gastric media was stirred at 40 °C.

After the stirring time two phases were observed. 10 mL of each reaction mixture was removed for TOC analysis. The remainder of each reaction mixture was extracted with 20 mL of hexane and the phases separated with separatory funnel. The solvent was removed in a rotary evaporator and the sample analysed by ¹¹⁹Sn-NMR.

Under the conditions of the study the test material did not degrade in aqueous environments at pH 4 and above. In a simulated gastric environment the test material formed a degradation product, which could characterised by ¹¹⁹Sn -NMR most likely as Oc₂Sn(EHTG)Cl, the monochloride derived from DOTE. It is (besides the unreacted DOTE) the main product (~75:25) of the reaction. No NMR-signals were found for the dichloride derived from DOTE (DOTC).

TOC analysis was applied to exclude losses of potentially water soluble organotin species. The analyses showed that no organic matter was dissolved in the aqueous phases of the experiment.

It can therefore be concluded that DOTECl is the only metabolite of DOTE which is formed in a simulated mammalian gastric environment. No dioctlytindichloride was formed under the conditions of this study.

Reference 4

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted on read-across material

Justification for type of information:

Read-across to structurally similar substance Dioctyltin bis (2-ethylhexylmercaptoacetate) (DOTE) (CAS No. 15571-58-1), see attached justification.

Reason / purpose for cross-reference:

read-across source

The sample of test material that was analysed by ¹¹⁹Sn-NMR andwas found to have a chemical shoift of 74 ppm (DOTE) and 67 ppm (MOTE) at intensities of DOTE / MOTE of 97 / 3.

> pH 4.0 Hydrolysis Results

¹¹⁹Sn-NMR:

74 ppm DOTE

67.7 ppm MOTE

(intensity DOTE / MOTE = 98 / 2)

TOC:

NPOC = 0.09467 mg/L

> pH 7.0 Hydrolysis Results

¹¹⁹Sn-NMR:

69 ppm DOTE

62.5 ppm MOTE

(intensity DOTE / MOTE = 98 / 2)

TOC:

NPOC = 0.01632 mg/L

> pH 9.0 Hydrolysis Results

¹¹⁹Sn-NMR:

74.2 ppm DOTE

67.7 ppm MOTE

(intensity = 97 / 3)

TOC:

NPOC = 0.06666 mg/L

> pH 1.2 Hydrolysis Results

¹¹⁹Sn-NMR:

71.54 ppm DOTE (22)*

65.65 ppm MOTE (1)

31.01 ppm DOTECl (95)

-16.12 ppm MOTE2Cl (1)

*) number in brackets are relative intensities

 

TOC:

NPOC = 0.04928 mg/L

The separated water phase did not contain significant amounts of organic carbon. So it can be concluded that none of the organotin species would have been lost via the aqueous phase.

There was no peak in the region of 133 ppm (DOTC) in any of the media analysed.

Reference 5

Endpoint:

dermal absorption in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

other: read-across target

Qualifier:

according to guideline

Guideline:

other: OECD 402

Deviations:

yes

Remarks:

Additional determination of dermal absorption of the test item (DOTL)

Principles of method if other than guideline:

Additional determination of dermal absorption of the test item (DOTL), via Sn in plasma

GLP compliance:

yes

Radiolabelling:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Duration of exposure:

24h

Doses:

2000 mg/kg bw

No. of animals per group:

5 female, 5 male

Control animals:

no

Signs and symptoms of toxicity:

no effects

Dermal irritation:

no effects

Key result

Time point:

3 h

Dose:

2000 mg/kg

Parameter:

percentage

Absorption:

0 %

Key result

Time point:

24 h

Dose:

2000 mg/kg

Parameter:

percentage

Absorption:

0 %

Conversion factor human vs. animal skin:

Not relevant, since no absorption was detected

Conclusions:

The study proves, that no Dioctyltin dilaurate has been absorbed via the dermal route.

Reference 6

Endpoint:

dermal absorption in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted on read-across material

Justification for type of information:

Read-across to structurally similar substance.

Reason / purpose for cross-reference:

read-across source

Key result

Time point:

3 h

Dose:

2000 mg/kg

Parameter:

percentage

Absorption:

0 %

Key result

Time point:

24 h

Dose:

2000 mg/kg

Parameter:

percentage

Absorption:

0 %

Reference 7

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

Not specified

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

Reason / purpose for cross-reference:

other: read-across target

Qualifier:

according to guideline

Guideline:

OECD Guideline 428 (Skin Absorption: In Vitro Method)

Version / remarks:

OECD Draft Guideline for Dermal Delivery and Percutaneous Absorption: In Vitro Method [OECD TG 428]

Deviations:

no

GLP compliance:

yes

Radiolabelling:

no

Species:

other: rat and human epidermis

Type of coverage:

other: occluded and unoccluded applications

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).

Control animals:

no

Details on study design:

Absorption of tin compouds was measured (not DOTE only).

Key result

Time point:

24 h

Dose:

17007 µg tin/cm²

Parameter:

rate

Absorption:

0.025 other: µg/cm²/h

Remarks on result:

other: Absorption of tin from DOT(EHMA) through rat epidermis significantly overestimates absorption through human epidermis.

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 µg/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 µg/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 µg/cm²/h.  From the unoccluded application, the maximum rate of tin absorption occurred during 12-24 hours of  exposure and was 0.033 µg/cm²/h.  The mean rate of tin absorption over the whole  24-h exposure period was 0.025 µg/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 material 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 µg/cm² (unoccluded) and 0.011 µg/cm² (occluded) through human epidermis and 0.641 µg/cm² (unoccluded)  and 0.547 µg/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:

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 tins 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 µg/cm² (unoccluded) and 0.011 µg/cm² (occluded) through human epidermis and 0.641 µg/cm² (unoccluded) 

and 0.547 µg/cm² (occluded) through rat epidermis.

The 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.

Reference 8

Endpoint:

dermal absorption in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted on read-across material

Justification for type of information:

Read-across to structurally similar substance Dioctyltin bis (2-ethylhexylmercaptoacetate) (DOTE) (CAS No. 15571-58-1), see attached justification.

Reason / purpose for cross-reference:

read-across source

Key result

Time point:

24 h

Dose:

17007 µg tin/cm²

Parameter:

rate

Absorption:

0.025 other: µg/cm²/h

Remarks on result:

other: Absorption of tin from DOT(EHMA) through rat epidermis significantly overestimates absorption through human epidermis.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

0.004

Absorption rate - inhalation (%):

100

Additional information

Introduction

Physico-chemical properties of diisooctyl 2,2'-[(dioctylstannylene)bis(thio)]diacetate (synonym: DOTI; EC Number: 247-666-0; CAS Number: 26401-97-8) and the results of in vitro and in vivo studies conducted with the substance and the read-across structurally-related substance 2-ethylhexyl 10-ethyl-4,4-dioctyl-7-oxo-8-oxa-3,5-dithia-4-stannatetradecanoate (synonym: DOTE; EC Number: 239-622-4; CAS Number: 15571-58-1) have been used to determine, as far as possible, a toxicokinetic profile for DOTI.

Physicochemical properties

DOTI is a mono-constituent organotin substance that consists of a tin as central metal element with two octyl-ligands. The read-across substance DOTE is also an organotin compound that has the identical structure elements as the target substance in respect of the tin-alkyl moiety. In addition, they are isomers only slightly differing in the structure of the C-8 alcohol of the mercaptoester ligand.

DOTI (molecular weight approximately 752 g/mol) is a yellowish liquid at room temperature with a freezing point of <-21°C. Its relative density and vapour pressure at 20°C are 1.08 and 229 78 Pa, respectively. The partition coefficient (log Kow) is 15.3542 and it is insoluble in water (QSAR prediction 1.22x 10 ^-12 mg/L at 25°C).

Absorption

Oral absorption

Several acute oral toxicity studies have been conducted with DOTI or the read-across substance DOTE and the calculated LD₅₀values were generally reported to be between 1000 and 2000 mg/kg bw. In the most recent study (performed in 1984 to FIFRA and TSCA guidelines), dose-related mortalities occurred at doses of 600 to 2500 mg DOTI /kg bw and macroscopic changes were evident at necropsy. Signs of toxicity were seen in most groups, which were almost entirely subsided by Day 7.

In a 90-day oral (dietary) toxicity study in the rat (broadly equivalent to OECD 408), the read-across substance DOTE caused mortality, decreased body weight gain, decreased food intake and changes in clinical pathology, organ weights and histopathology. The NOEL was defined as 10 ppm (equivalent to 0.5 mg/kg/day using a default factor of 0.05) with the LOAEL being 25 ppm based on thymus changes. Although both rat and dog studies on DOTI are available, which show NOEL/NOAEL values between 25 ppm and 150 ppm, these studies are generally of poor quality and are therefore considered less reliable than the available data on the read-across substance DOTE. 

In vivo mouse micronucleus studies on DOTI showed test substance-related toxicity to the bone marrow; reproductive toxicity studies in the rat confirmed DOTI caused changes in organ weights, histopathology and body weights with NOEL reported to be 20 ppm (approximately 1.5 mg/kg bw/day).

The available in vivo data, indicate that oral absorption of DOTI / DOTE does occur. DOTI’s The physico-chemical properties of DOTI (moderate MW, water insolubility and high lipophilic nature) would suggest absorption is likely to be limited to micellular solubilisation rather than passive diffusion). Therefore, in the absence of any other information, for the purposes of human DNEL setting, 100% oral absorption is assumed for human health risk assessment purposes.

Dermal absorption

An acute dermal toxicity study on DOTE reported an LD₅₀of >2000 mg/kg and neither DOTE nor DOTI were reported to be skin irritants. DOTE is not a skin sensitizer.

The absorption of DOTE was measured in vitro through both occluded and unoccluded human and rat epidermis. The absorption through rat epidermis was much faster than through human epidermis. With human epidermis, a dose of 17,007 µg tin/cm²was 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 µg/cm²/h). In terms of percent applied tin, 0.0001% was absorbed from the occluded and unoccluded doses after 24 hours of exposure. With rat epidermis, the maximum rate of tin absorption (0.035 µg/cm²/h) for the occluded application occurred during 16-24 hours of exposure, and the mean rate of tin absorption over the whole 24-h exposure period was 0.021 µg/cm²/h. From the unoccluded application, the maximum rate of tin absorption occurred during 12-24 hours of exposure and was 0.033 µg/cm²/h. The mean rate of tin absorption over the whole 24-h exposure period was 0.025 µg/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. These results show that the absorption of tin from DOTE through rat epidermis significantly overestimated absorption from human epidermis.

For the purposes of human DNEL setting, the most precautionary, experimentally determined absorption value, i.e. 0.004% dermal absorption, is used for human health risk assessment purposes.

Inhalation absorption

In an acute inhalation toxicity study, a 7 hour exposure to DOTI (as an 80:20 mix of DOTI:MOTI (CAS 26401-86-5) as steam saturated in air), there were no mortalities and overall DOTI was considered to be of low inhalation hazard

The physico-chemical properties of DOTI (liquid at room temperature and highly lipophilic) would suggest that any inhaled liquid could be extensively absorbed across the respiratory tract epithelium. Therefore, in the absence of any other information, for the purposes of DNEL setting, 100% inhalation absorption is assumed for human health risk assessment purposes.

Distribution, Metabolism and Elimination

No in vivo information is available to describe the distribution, metabolism or elimination of DOTI.

The relatively high molecular weight of DOTI would suggest a somewhat limited distribution, however given it is highly lipophilic and water insoluble, there is the potential for preferential partition to fatty/adipose tissues upon repeated exposure.

Recentin vitrotoxicokinetics studies under simulated mammalian gastric conditions, using 119-Sn-NMR to identify the reaction products, clearly show Dioctyltinchlor 2-ethylhexymercaptoacetate (DOTCE) is the only identifiable hydrolysis product. No DOTC could be detected under the conditions of the studies

Bioaccumulation is considered unlikely to occur.

Conclusions

Based on in vitro and in vivo data from studies performed with DOTI or the read-across substance DOTE, oral absorption is estimated at 100%, inhalation absorption is estimated at 100% and dermal absorption is estimated at 0.004%. 

The potential for bioaccumulation is considered low.