Bis(dodecylthio)dioctylstannane

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

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 2

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 DOTE (Dioctyltin bis(2-ethylhexyl thioglycolate)) (CAS 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.

Reference 3

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

21 September 2016 to 20 September 2017

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study / Non GLP

Qualifier:

according to guideline

Guideline:

other: OECD 111

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: EU Method C.7

Deviations:

no

GLP compliance:

no

Radiolabelling:

not specified

HYDROLYSIS AT PH 4,7 AND 9

- Samples of the test material were added to the respective buffer solutions at 50 °C for 5 days (120 h). At No pH value the 119Sn-NMR spectra of the extracted reaction products show signs of hydrolysis.

- The half-life time of the test material under the conditions of the study is > 1 year. The test material is considered as hydrolytically stable

HYDROLYSIS AT PH 1.2

- 1 g (1.3 mMol) of the test material was added to an excess 0.1 M Hydrochloric Acid at 37°C for 4 hours and extracted with hexane after cooling down to room temperature. The 119Sn-NMR spectrum of the organic extract shows a decrease of the products peak and an increase of the breakdown product, the monochloride of the substance DOT(-SLau)Cl.

- A small side sharp side peak in the broad signal for the monochloride appears at 144 ppm and cannot be reliably quantified or assigned to a organotin substance. The chemical shift points to a disulfur bridged organotin compound. No signal for DOTC could be identified in the 119Sn spectrum.

- The composition of the test material hydrolysate at pH 1.2 based on 119Sn-NMR analysis was:

DOT(-SLau)2 30 Mol% and DOT(-SLau)Cl 70 Mol%.

- In order to assure no DOTC has been formed, the NMR sample was spiked with DOTC. The spectra showed a further reaction between the residual dioctyltin-di-thiolaurate and the dioctyltin dichloride resulting in additional dioctyltin-monochloro mono thiolaurate according to the following equation:

Oc2Sn(S-Lau)2 + Oc2SnCl2 = 2 Oc2Sn(SLau)Cl

MASS BALANCE RECIVERY RATES

pH 4: 100 %

pH 7: 98 %

pH 9: 100 %

pH 1.2: 103 %

ATOMIC ABSORPTION SPECTOMETRY

- The aqueous phases of the low pH hydrolysis has been analysed after extraction with hexane by AAS and contained less than 5 mg/L Sn.

Conclusions:

Under the conditions of this study, the test material was is hydrolytically stable at pH 4, 7 and 9. At pH 1.2 the only identifiable breakdown product was the monochloride of the test material chloro, dodecylthio dioctylstannane (DOT-SLau Cl). It appears besides the unreacted test material. DOTC was not detected in the organic extract. The high recovery of substances in the hexane extract and the low tin content of the aqueous phase (< 5 mg/L) indicate that no reaction products remained in the aqueous phase of the experiment.

Executive summary:

The hydrolysis of the test material as a function of pH was investigated in accordance with the standardised guidelines OECD 111 and EU Method C.7.

The stability of the test material was investigated at pH 4, 7 and 9 and pH 1.2 using NMR spectroscopy.

The study showed that the test material was hydrolytically stable at pH 9, 7 and 4. After 5 days of hydrolysis at 50°C less than 10 % of the test material was hydrolysed (t 0.5 at 25°C > 1 year).

At simulated gastric conditions (0.1 M HCl /pH 1.2 /37°C/ 4 h) the only identifiable breakdown product was the monochloride of the test material chloro, dodecylthio dioctylstannane (DOT-SLau Cl). It appears besides the unreacted test material. DOTC was not detected in the organic extract.

A spiking experiment confirmed non-presence of DOTC in the reaction mixture and showed that DOTC reacts with the test material forming it’s monochloride.

The high recovery of substances in the hexane extract and the low tin content of the aqueous phase (< 5 mg/L) indicate that no reaction products remained in the aqueous phase of the experiment.

Description of key information

Hydrolysis of the registered substance at pH 1.2

Under the conditions of the study (0.1 M HCl /pH 1.2 /37°C/ 4 h) the only identifiable breakdown product was the monochloride of the test material chloro, dodecylthio dioctylstannane (DOT-SLau Cl). It appears besides the unreacted test material. DOTC was not detected in the organic extract. The high recovery of substances in the hexane extract and the low tin content of the aqueous phase (< 5 mg/L) indicate that no reaction products remained in the aqueous phase of the experiment.

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 bis(dodecylthio)dioctylstannane (synonym DOT-SLau EC Number: 244-841-3, CAS Number: 22205 -30 -7) and the results of in vitro and in vivo studies conducted with the substance and two read-across, structurally-related substances  diisooctyl 2,2'-[(dioctylstannylene)bis(thio)]diacetate (synonym: DOTI; EC Number: 247-666-0; CAS Number: 26401-97-8) and 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 DOT-SLau.

Read-across Justification

The target substance Bis(dodecylthio)dioctylstannane (DOT SLau CAS: 22205-30-7, EC: 244-841-3) is a mono-constituent organotin substance that consists of a tin as central metal element with two octyl-ligands. The source substances DOTE (Dioctyltin bis(2-ethylhexyl thioglycolate)) (CAS 15571-58-1) and DOTI (Diisooctyl 2,2'-[(dioctylstannylene)bis(thio)]diacetate) (CAS 26401-97-8) are also organotin compounds and have the identical structure elements as the target substance in respect of the tin-alkyl moiety.

According to WHO IPCS CIRCAD (2006) organotin compounds are characterized by a tin–carbon bond and have the general formula RxSn(L)(4−x), where R is an organic alkyl or aryl group and L is an organic (or sometimes inorganic) ligand. The organotin moiety is significant toxicologically. The anionic ligand influences physicochemical properties but generally has little or no effect on the toxicology.

Since the target substance and the source substances share the identical organotin moiety, and the organotin moiety is generally recognized as the relevant toxophore of organotins and the toxicity estimates (AE) respectively toxicity limits for organotins are expressed as tin, the overall ecotoxicity/systemic toxicity of the target can be interpolated by assessing the (eco-)toxicity of the source (WHO IPCS CIRCAD, 2006, BAUA AGS TRGS 900, 2014, Summer KH, Klein D and Greim H, 2003).

The purity of the source and target substance are expected to be high, based on the manufacturing method. The impurity profile is not expected to have strong effects on substance properties and any impurity of (eco-)toxicological relevance of the source substances is expected to be present in the target substance. Consequently, the hazard profiles of the source substances, including those of their impurities, are intrinsically covered. Differences in impurities are not expected and thus do not have an impact on the (eco-)toxic properties.

The bioavailability of all substances varies in a predictable manner and is assumed to be dependent on the water solubility. The prediction of the effects of the target substance is based on the relationship between solubility and (eco-)toxicity or on a worst-case basis.

The result of the simulated gastric hydrolysis study on our substance shows close similarities with the hydrolysis study conducted on DOTE, in that both materials breakdown to form the monochloride versions of the substance as the only breakdown products, which further backs up their similarities and the read across.

Hydrolysis of the registered substance at pH 1.2

The hydrolysis of the test material as a function of pH was investigated in accordance with the standardised guidelines OECD 111 and EU Method C.7.

The stability of the test material was investigated at pH 4, 7 and 9 and pH 1.2 using NMR spectroscopy.

The study showed that the test material was hydrolytically stable at pH 9, 7 and 4. After 5 days of hydrolysis at 50°C less than 10 % of the test material was hydrolysed (t 0.5 at 25°C > 1 year).

At simulated gastric conditions (0.1 M HCl /pH 1.2 /37°C/ 4 h) the only identifiable breakdown product was the monochloride of the test material chloro, dodecylthio dioctylstannane (DOT-SLau Cl). It appears besides the unreacted test material. DOTC was not detected in the organic extract.

A spiking experiment confirmed non-presence of DOTC in the reaction mixture and showed that DOTC reacts with the test material forming it’s monochloride.

The high recovery of substances in the hexane extract and the low tin content of the aqueous phase (< 5 mg/L) indicate that no reaction products remained in the aqueous phase of the experiment.

In addition hydrolysis data on DOT(2 -EHMA) (CAS 15571 -58 -1) has also been included as read across. The hydrolysis of the test material as a function of pH was investigated in accordance with the standardised guidelines OECD 111 and EU Method C.7. The stability of the test material was investigated at pH 4, 7 and 9 and pH 1.2 using NMR spectroscopy.

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 hydrolyzed (t 0.5 25°C > 1 year).

Under the simulated gastric conditions (0.1 M HCl / pH 1.2 / 37 °C) DOTE was hydrolyzed 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.

Physicochemical properties

DOT-SLau is a mono-constituent organotin substance that consists of a tin as central metal element with two octyl-ligands. The read-across substance DOTE and DOTI are also organotin compounds that have the identical structure elements as the target substance in respect of the tin-alkyl moiety. In vitro hydrolysis data under simulated gastric conditions confirmed that both DOT-SLau and the read-across substance DOTE show close similarities, as the only breakdown products observed were the monochloride versions of DOT-SLau (DOT-SLau Cl) or DOTE (DOTC), respectively.

DOT-SLau (molecular weight approximately 748 g/mol, molecular formula C₄₀H₈₄S₂Sn) is a colourless liquid at room temperature with a freezing point of -8°C and a boiling point of >250°C. Its relative density and vapour pressure at 25°C are 0.97 and 0 Pa (experimental value of 3.29 x10^-13), respectively. The partition coefficient (log Kow) is estimated to be 20.349 and it is insoluble in water (WSKOW v1.42, US EPA prediction 7.03 x10^-17mg/L at 25°C).

Absorption

Oral absorption

Several acute oral toxicity studies have been conducted with the read-across substances DOTE and DOTI, with calculated LD₅₀values generally reported to be between 2000 and 4000 mg/kg bw for DOTE or 1000 and 2000 mg/kg bw for DOTI. In the most recent study on DOTI (performed in 1984 to FIFRA and TSCA guidelines and identified as the key study for oral toxicity), dose-related mortalities occurred at doses of 600 to 2500 mg DOTI /kg bw and macroscopic changes were evident at necropsy. Due to the results of the key study on the read across substance DOTI, DOT-SLau has been proposed as Acute Toxicity (oral) category 4.

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 (equivalent to 1.3 mg/kg bw/d) based on thymus changes. Due to the results of the key study on the read across substance DOTE, DOT-SLau has been proposed as STOT RE category 1.

In vivo mouse micronucleus studies on the read-across substance DOTI showed 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 the NOEL reported to be 20 ppm (approximately 1.5 mg/kg bw/day).

The available in vivo data, indicate that oral absorption of the read across substances DOTI and DOTE does occur. The physico-chemical properties of DOT-SLau (moderate MW, water insolubility and high lipophilic nature) would suggest absorption is likely to be limited to micellar 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 (OECD 402) on the read-across substance DOTE reported an LD₅₀of >2000 mg/kg and neither DOT-SLau or the read-across substances DOTE and DOTI are reported to be skin irritants. The read-across substance DOTE is not a skin sensitizer.

The absorption the of read-across substance DOTE was measured in vitro through human and rat epidermis both under occluded and unoccluded conditions. 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). With rat epidermis, the mean rate of tin absorption over the whole 24-h exposure period was 0.021 µg/cm²/h for the occluded application and 0.025 µg/cm²/h for the unoccluded application. In terms of percent tin applied, 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 DOT-SLau human health risk assessment purposes.

Inhalation absorption

In an acute inhalation toxicity study with the read-across substance DOTI, 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 DOT-SLau (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 DOT-SLau.

The relatively high molecular weight of DOT-SLau 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.

A hydrolysis study with DOT-SLau under simulated mammalian gastric conditions, clearly showed DOT-SLau Cl to be the only identifiable hydrolysis product,therefore suggesting limited or no biotransformation.

The molecular weight of >300 g/mol of DOT-SLau indicates that excretion is more likely to occur via the bile.

The partition coefficient for DOT-SLau was a predicted value and therefore in the absence of experimental log Kow data, the potential for bioaccumulation is considered low.

Conclusions

Based on in vitro and in vivo data from studies performed with DOT-SLau or the read-across substances DOTE or DOTI, 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.

References

BAUA (Bundesanstalt für Arbeitsschutz und Arbeitsmedizin (Federal Institute for Occupational Safety and Health)) AGS (Ausschuss für Gefahrstoffe (Committee on Hazardous Substances)) TRGS (Technical Rules for Hazardous Substances) 900 (2014). Begründung zu n-Octylzinnverbindungen, April 2014.

Summer KH, Klein D, Griem H (2003). Ecological and toxicological aspects of mono- and disubstituted methyl-, butyl-, octyl-, and dodecyltin compounds - Update 2002. GSF National Research Center for Environment and Health, Neuherberg, for the Organotin Environmental Programme (ORTEP) Association.

World Health Organization (WHO) International Programme on Chemical Safety (IPCS) Concise International Chemical Assessment Document (CICAD) 73 Mono- and disubstituted methyltin, butyltin, and octyltin compounds (2006). Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organization, and the World Health Organization, and produced within the framework of the Inter-Organization Programme for the Sound Management of Chemicals. World Health Organization ISBN 978 92 4 153073.