8,8-dioctyl-1,4-dioxa-7,9-dithia-8-stannacycloundecane-5,11-dione

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:

key study

Study period:

22 January 2016 to 05 April 2016

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

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:

Interpretation of results (migrated information): other:
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 at 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 at 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:

experimental study

Adequacy of study:

key study

Study period:

21 September 2016 to 07 November 2017

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

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

- The 119Sn spectrum of the unhydrolysed test material shows a signal group between  88 – 100 ppm which can be attributed to different species of DOT-EGMA which is a UVCB substance. The main peak appears at 88 ppm, attributed to DOT-EGMA, the smaller side peaks represent different coordinations of the bi-funtional ligand EGMA with the dioctyltin unit. A sharp signal at ~ -45 ppm is attributed to DOTTG which is present in UVCB substance as side reaction product or breakdown product. The integrals of the spectrum show a ration of 86:12 Mol %  DOT-EGMA : DOTTG

- At pH 4 and 7 the 119Sn-NMR spectra of the hydrolysates show a shift of intensities from the signal group between 88-100 ppm towards the DOTTG peak at -45 ppm. The difference in intensities is between 16 and 21 %.

- At pH 9 a further shift of intensities occurs together with the broadening of the DOTTG signal.  Two additional broad signals of minor intensity show at -0.6 ppm and -53 ppm.

- The broadening of peaks in this area indicates the formation of a DOTO complex resp. a solution of DOTO in DOTTG.

- The formation of such DOTO complex structures have been postulated for the breakdown of other Organotin carboxylates.

HYDROLYSIS AT PH 1.2

- In the 119Sn-NMR spectrum of the organic extract the signal group between 88-100 ppm decreased in intensity to 12 Mol %.

- New peaks appear at 49 ppm, 42 and 41 ppm. They are typical for the monochloroesters of thiocarboxylates.

- The peak representing DOTTG at -45 ppm increased in intensity from 12 to 30 Mol%. This supports that also a breakdown of the EGMA ligand occurs.

- Some smaller peaks between -40 and 0 ppm can not be assigned unequivocally to an organotin species.

- No DOTC was formed under the conditions of the study

MASS BALANCE RECOVERY RATES

pH 4: 73 %

pH 7: 80 %

pH 9: 92 %

pH 1.2: 85 %

ATOMIC ABSORPTION SPECTOMETRY

- The aqueous phase of the low pH hydrolysis has been analysed after extraction with hexane by AAS and contained < 5mg/L Sn. So the formation of an organotin substance better soluble in water than in hexane can be excluded.

Conclusions:

After 5 days of hydrolysis at 50 °C at pH 4, 7 ,9 there is an increase of DOTTG in the extracted hydrolysate. This suggests that the breakdown of the test material includes the hydrolysis of the EGMA ligand.
At pH 9 the DOTTG peak is broadened, which suggests the formation of DOTO.
At simulated gastric conditions (0.1 M HCl /pH 1.2 /37 °C/ 4 h) the extracted test material decreased to 17 Mol %. The DOTTG content of the extracted hydrolysate increased from 12 to 30 Mol%. Three new signals at 41, 42 and 49 ppm are typical for the monochloroesters of thiocarboxylates.
No signals have been formed during simulated gastric hydrolysis which can be attributed to DOTC.
The tin content in the aqueous phase of the hydrolysis remained under the detection limit of < 5 mg/L in AAS. Thus the formation of a water soluble organotin species can be excluded.

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 test material is a UVCB type substance resulting from the reaction of a bi-functional ligand to with Dioctyltin unit allowing all different kind of coordinations. Thus the interpretation of the hydrolytical behaviour of this test material is rough and has to consider groups of possible UVCB constituents.

After 5 days of hydrolysis at 50 °C at pH 4, 7 ,9 there is an increase of DOTTG in the extracted hydrolysate. This suggests that the breakdown of the test material includes the hydrolysis of the EGMA ligand.

At pH 9 the DOTTG peak is broadened, which suggests the formation of DOTO.

At simulated gastric conditions (0.1 M HCl /pH 1.2 /37 °C/ 4 h) the extracted test material decreased to 17 Mol %. The DOTTG content of the extracted hydrolysate increased from 12 to 30 Mol%. Three new signals at 41, 42 and 49 ppm are typical for the monochloroesters of thiocarboxylates.

No signals have been formed during simulated gastric hydrolysis which can be attributed to DOTC.

The tin content in the aqueous phase of the hydrolysis remained under the detection limit of < 5 mg/L in AAS. Thus the formation of a water soluble organotin species can be excluded.

Reference 3

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

supporting study

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:

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 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.

Description of key information

Hydrolysis of the registered substance at pH 1.2

At simulated gastric conditions (0.1 M HCl /pH 1.2 /37 °C/ 4 h) the extracted test material decreased to 17 Mol %. The DOTTG content of the extracted hydrolysate increased from 12 to 30 Mol%. Three new signals at 41, 42 and 49 ppm are typical for the monochloroesters of thiocarboxylates.

No signals have been formed during simulated gastric hydrolysis which can be attributed to DOTC.

The tin content in the aqueous phase of the hydrolysis remained under the detection limit of < 5 mg/L in AAS. Thus the formation of a water soluble organotin species can be excluded.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

1

Absorption rate - inhalation (%):

100

Additional information

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 test material is a UVCB type substance resulting from the reaction of a bi-functional ligand to with Dioctyltin unit allowing all different kind of coordinations. Thus the interpretation of the hydrolytical behaviour of this test material is rough and has to consider groups of possible UVCB constituents.

After 5 days of hydrolysis at 50 °C at pH 4, 7 ,9 there is an increase of DOTTG in the extracted hydrolysate. This suggests that the breakdown of the test material includes the hydrolysis of the EGMA ligand.

At pH 9 the DOTTG peak is broadened, which suggests the formation of DOTO.

At simulated gastric conditions (0.1 M HCl /pH 1.2 /37 °C/ 4 h) the extracted test material decreased to 17 Mol %. The DOTTG content of the extracted hydrolysate increased from 12 to 30 Mol%. Three new signals at 41, 42 and 49 ppm are typical for the monochloroesters of thiocarboxylates.

No signals have been formed during simulated gastric hydrolysis which can be attributed to DOTC.

The tin content in the aqueous phase of the hydrolysis remained under the detection limit of < 5 mg/L in AAS. Thus the formation of a water soluble organotin species can be excluded.

In addition hydrolysis data on DOT(2 -EHMA) (CAS 15571 -58 -1) has also been included as read across.

Although this is a UVCB substance read across from DOTE [Dioctyltin bis(2-ethylhexyl thioglycolate) (CAS 15571-58-1)] can be justified by structural analogy, based on the fact both substances are dioctyltins with two thiogylocolate ligands. The result of the simulated gastric hydrolysis study is complex (as would be expected based on the UVCB composition of the substance), but it shows close similarities with the study conducted on DOTE  in that both materials breakdown to form the monochloride versions of the substance as their likely only breakdown products, which further backs up their similarities and the the 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.

Read across from DOTE (Dioctyltin bis(2-ethylhexyl thioglycolate)) (CAS 15571-58-1) and DOTI (Diisooctyl 2,2'-[(dioctylstannylene)bis(thio)]diacetate) (CAS 26401-97-8) can be justified by structural analogy, based on the fact both substances are dioctyltin with two thiogylocolate ligands. In addition 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 the read across.

Toxicokinetic Assessment of the UVCB substance:reaction product of dioctyltin oxide and glycoldimercaptoacetate

Introduction

The substance is a UVCB, it is the reaction product of:

·        dioctyltin oxide and

·        glycoldimercaptoacetate

Constituents of the reaction product

The material is a UVCB (substance of Unknown or Variable composition, Complex reaction products or Biological materials) and due to the issues with characterisation only DOT-EGMA and one other component (CAS 15535-79-2, present at approximately 12%) have been determined the other, almost 50%, remains unknown.

Reaction product (a): DOT-EGMA:

Present in the substance at 40%.

EC 273-920-5

CAS 69226-44-4

IUPAC name: 8,8-dioctyl-1,4-dioxa-7,9-dithia-8-stannacycloundecane-5,11-dione

Reaction product (b): 2,2-dioctyl-1,3,2-oxathiastannolan-5-one (‘Compound B’):

Present in the substance at 12%.

EC 239-581-2

CAS 15535-79-2

IUPAC name: 2,2-dioctyl-1,3,2-oxathiastannolan-5-one

Referred to as ‘Compound B’ in this document, for convenience.

 

The substance as a whole is referred to as the UVCBin this document.

 

Since limited data are available forDOT-EGMA, read-across has been used to the data from two structurally similar substances DOTE (CAS 15571-58-1) and DOTI (CAS 26401-97-8). 

Physico-chemical data and results ofin vitroandin vivostudies with DOT-EGMA, DOTE and DOTI have been used to determine the toxicokinetic profile of the UVCB as detailed below.

	Target Substance	Source Substance 1	Source Substance 2
Chemical Name	UVCB substance: reaction product of dioctyltin oxide & glycoldimercaptoacetate	DOTE Dioctyltin bis(2-ethylhexyl thioglycolate	DOTI Diisooctyl 2,2’-[(dioctylstannylene)bis(thio)]diacetate
CAS No	Contains: 40% DOT-EGMA (CAS 69226-44-4) 12% Compound B (CAS 15535-79-2)	15571-58-1	26401-97-8
EC No	DOT-EGMA (273-920-5) Compound B (239-581-2)	239-622-4	247-666-0

 

Physicochemical properties

The molecular weight (MW) of DOT-EGMA and Compound B are 553.412 and 435.25 g/mol, respectively. The UVCB has a melting point of 29 °C and is a solid at room temperature with a waxy consistency.

The water solubility of the components was calculated to be 1.737 × 10^-5mg/L at 25 °C for DOT-EGMA (practically insoluble) and 1.473 mg/L at 25 °C for Compound B (very slightly soluble).

The log Pow value of the components was calculated to be 8.5 for DOT-EGMA and 3.6 for Compound B, meaning that both substances are expected to be lipophilic. The vapour pressure of the components was calculated to be 2.95 × 10^-11Pa at 25°C for DOT-EGMA and 2.64 × 10^-6Pa at 25°C for Compound B, meaning that both substance are considered to have low volatility.

Oral absorption

The high molecular weight in combination with the low water-solubility and high octanol/water partition coefficient indicate that DOT-EGMA is unlikely to be readily absorbed from the gut.

Anin vitrohydrolysis study (Nasshan H., 2017) on DOT-EGMA was conducted. The test material is a UVCB resulting from a complex reaction that allows many different coordinations and interpretation of the hydrolytic behaviour of the material is therefore also complex. After 5 days of hydrolysis at 50°C at pH 4, 7 and 9 there is an increase in DOTTG suggesting there is hydrolysis of the EGMA ligand. At pH 9 DOTO appears to form. At simulated gastric conditions (pH 1.2) there is evidence that the test material breaks down with the formation of DOTTG and there is evidence for the formation of the typical monochloroesters of thiocarboxylates but no DOTC or water soluble organotin species. It is possible the hydrolysis products are readily absorbed from the gut.

In addition data on DOTE, also known as DOT(2-EHMA), CAS 15571-58-1 has been included. A study on the hydrolysis of DOTE as a function of pH (with simulated gastric hydrolysis) (Naßhan, 2015) and anin vitrometabolism study on DOTE (Naßhan, 2014) are available. Although this is a UVCB substance,read-across from DOTE can be justified by structural analogy;both substances are dioctyltins with two thiogylocolate ligands. The result of the simulated gastric hydrolysis study is complex (as would be expected based on the UVCB composition of the substance), but it shows close similarities with the study conducted on DOT-EGMAin that both materials breakdown to form the monochloride versions of the substance as their likely only breakdown products, which issupportive ofthe read across. The hydrolysis ofDOTE asa 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 thesimulated gastric conditions (pH 1.2) 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, as was the case for DOT-EGMA.

The available information on DOTE regarding acute oral toxicity supports limited oral absorption, as the reported LD₅₀values for DOTE are generally higher than a limit dose of 2000 mg/kg bw (Anonymous, 1976, 1982, 1992).

Some oral absorption is demonstrated by results of various repeat dose studies oral (dietary route) conducted in 1963 and 1970 with DOTI or DOTE in combination with other substances. In a 13-week oral rat and 14-week oral dog study (1970) with DOTI, there were no notable effects were seen at the highest dose (150 ppm for rat and dog). In a 30-day oral dog and 30-day oral rat study (1963) systemic effects were noted in dogs at 225 and 675 ppm and in rats at 75 and 225 ppm. In a 13-week oral rat study (1970) using a mixture of DOTE, MOTE and TOTE (97: 0.3: 2.7) (CAS 15571 -58 -1, CAS 27107-89-7 and CAS 61912-55-8) systemic effects were also noted at 25 ppm. In another 13-week oral rat study (1974) using a mixture of DOTE and TOTE (70:30) (CAS 15571-58-1 and CAS 27107-89-7) systemic effects including increased thymus weights were noted above 25 ppm.

As a worst-case estimate, for human health risk assessment purposes oral absorption of DOT-EGMA is considered to be 100%.

Dermal absorption

No information is available on dermal absorption of the components of the UVCB or the UVCB itself.

In a dermal absorption study on DOTE absorption was determinedviaboth occluded and unoccluded applications to human and rat epidermis according to OECD Guideline 428 (Ward, R.J., 2003). In human epidermis, for occluded and unoccluded applications rates of tin absorption over the 0-24 hour exposure period were below the limit of quantification (0.001 ug/cm²/h) and 0.0001 % of the applied material was absorbed after 24 hours of exposure. In rat epidermis, for occluded and unoccluded applications, the maximum rate of tin absorption (0.033 to 0.035 ug/cm²/h) occurred during 12-24 hours of exposure, and the mean rate of tin absorption over the whole 24-hour exposure period was 0.021 to 0.025 ug/cm²/h. In terms of percent applied tin, 0.003 to 0.004 % was absorbed after 24 hours of exposure. The mean amounts of tin absorbed by 24 hours were up to 0.011 ug/cm²through human epidermis and up to 0.641 ug/cm²through rat epidermis. These results show that absorption is much faster through rat epidermis compared to human epidermis and therefore the absorption of tin from DOTE through rat epidermis significantly overestimates absorption through human epidermis.

Based on physicochemical data available for the UVCB and its components, it is concluded that the UVCB is lipophilic and practically not soluble in water. Therefore the rate of transfer between the stratum corneum and the epidermis is expected to be slow and will limit absorption across the skin.

This is further supported by the lack of any skin irritating or corrosive properties, as determined inin vitrostudies with DOT-EGMA (Lacey, F.E., 2017 and 2018), the lack of any sensitisation potential as determined in a fully compliant Local lymph Node Assay (OECD 422B – BrdU-ELISA) performed with the read-across substance DOTE (Patel, K., 2016), and the acute dermal LD₅₀greater than 2000 mg/kg bw also determined with the read-across substance DOTE (Anonymous, 1992). The test substance was DOTE and octyltin tris(2-EHMA) (90:10 % w/w).

Therefore, for human health risk assessment and using a really conservative approach, dermal absorption is estimated 1%.

Inhalation absorption

No information is available on inhalation toxicity of the substance, or on 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 (study Günzel P 1978).

The UVCB is a solid with a waxy consistency that is not particulate in nature. It is therefore unlikely that the UVCB would reach the lower tract of the respiratory system, as the proportion of the test material having an inhalable particle size of <100 μm, a thoracic particle size of <10.0 μm or a respirable particle size of <5.5 μm is expected to be practically zero. Furthermore DOT-EGMA has a high molecular weight and is practically insoluble in water and Compound B (CAS 15535-79-2) is very slightly soluble.

In the absence of any quantitative data, and using a really conservative approach, for human health risk assessment purposes absorption by inhalationofDOT-EGMAis assumed to be 100%.

Distribution

No data are available on DOT-EGMA.

A molecule of this size would typically be considered to have a somewhat limited distribution. Given the high estimated log Pow and the low water solubility there is the potential for preferential partition, upon repeated exposure, to tissues with high lipid content.

Results of the oral repeat dose studies oral (dietary route) conducted in 1963 and 1970 with DOTI or DOTE in combination with other substances suggest that once absorbed it is widely distributed within the body, as the target organs, in studies where effects were seen, were the thymus, kidney and liver.

Metabolism and Elimination

In an in vitro hydrolysis study (Nasshan H., 2017) on DOT-EGMA involving simulated gastric conditions (pH 1.2) there is evidence that the test material breaks down with the formation of DOTTG and there is evidence for the formation of the typical monochloroesters of thiocarboxylates but no DOTC or water soluble organotin species.

Undersimulated gastric conditions the read-across substance,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, as was the case for DOT-EGMA.

Unchanged DOT-EGMA and the monochloroester are expected to be excreted mainlyviathe faeces. A bioaccumulation study in fish with a structurally related substance determined aBCF of >100. No upper limit appears to have been verified hence it is not possible to estimate the extent of elimination of the material from fatty tissues.

Conclusion

Based on in vitro and in vivo data from studies performed with DOT-EGMA, and the source substances DOTE and DOTI, for risk assessment purposes DOT-EGMA is considered to be absorbed orally, dermally andviainhalation at 100 %, 1 % and 100%, respectively.

The potential for bioaccumulation is low, and absorption of unhydrolyzed DOT-EGMA is expected to be low and any potentially absorbed amount to be completely excreted in faeces.

 

Read-across Justification

The target substance Reaction Products of Dioctyltin Oxide and Glycoldimercaptoacetate is a UVCB 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 is complex (as would be expected based on the UVCB composition of the substance), but it shows close similarities with the hydrolysis study conducted on DOTE and thus backs up the read across.

 

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.