Triisooctyl 2,2',2''-[(octylstannylidyne)tris(thio)]triacetate

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:

29 January 2015 to 17 February 2015

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 Guideline 111 (Hydrolysis as a Function of pH)

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

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). The 119Sn-NMR spectra of the reaction products show only slight signs of hydrolysis. The NMR peak characteristic to the MOTE molecule at about 70 ppm decreased from 91.8 Mol % in the untreated staring material to a minimal value of 85.7 Mol % in the pH 4 buffer solution. In all cases the degree of hydrolysis was lower than 10 %. Thus, the higher tier testing was not considered for these pH-value buffers.

HYDROLYSIS AT PH 1.2

- A sample of the test material was added to an excess 0.1 M Hydrochloric Acid at 37 °C for 5 days (120 h). The 119Sn-NMR spectrum of the recovered reaction product (Annex 2) showed that MOTE is hydrolysed to MOTEC. Both substances were present in an equilibrium in a 25/75 MOTE/DOTCE mol. % ratio.

- MOTEC, a product of hydrolysis, has been identified based on the 119 Sn-NMR signal.  Pure DOTCE substance was synthesised via two different synthetic routes.

- Besides the MOTE hydrolysis product (DOTCE), the spectrum showed minor peaks corresponding to MOTE hydrolysis component (MOTE was present as an impurity in MOTE), which was MOTE2C at -14.7 ppm.  Other signals appeared at 77.5 ppm (0.6 Mol % attributed to the TOTE that was present as an impurity in MOTE) and 143.4 (1.2 Mo l% / not identified).

No signal corresponding to DOTC (typically present at 133 ppm) was detected.

MASS BALANCE

- For each tested pH value, a 1g (1.3 mmol) sample of the test material was added to the respective buffer solution.  After the required hydrolysis period of 5 days amounts of the hydrolysate were recovered via hexane extraction from the aqueous phase.

- Recovery rates:

pH 4: 100 %

pH 7: 100 %

pH 9: 100 %

pH 1.2: 92 % (The recovered amount was corrected assuming a 75 % reaction with HCl)

- The mass balance showed a high recovery of the initial material of the test material after hydrolysis over the required period (5 days) and the extraction with hexane.  It demonstrates high reliability of the chosen experimental design of the study.

TIER 2 TESTING AT PH 1.2

- Additional 1 g (1.33 mmol) samples of the test material were hydrolysed over 6 different time periods (from 15 seconds to 48 hours) in an excess of 0.1 M Hydrochloric Acid at 37 °C.  The recorded 119Sn-NMR spectra detected DOTCE (? = 32.7 ppm) as the only product of MOTE hydrolysis. MOTE which was present in the sample as impurity hydrolysed to MOTE2C (? = -14.5 ppm).  No DOTC (? = 133 ppm) signal was detected in the hydrolysate.

- Kinetics of the hydrolysis was studied measuring intensities of the NMR-signals for MOTE and MOTEC. The sum of both signal intensities was about the same (within 3 %).  The kinetics of the first and the second test series were nearly identical.

- After 15 seconds of contact with the preheated buffer (an aqueous solution of hydrochloric acid), the test material was worked up immediately.  The 119Sn-NMR showed that the MOTE signal was reduced by about 50 % of its initial signal intensity.  Conversion of MOTE continued during 1 hour of hydrolysis to about 25 % of the initial signal intensity, whereas the DOTCE signal increased proportionally at the same rate.  

- The MOTE concentration then increased slightly to 35 and 41 % after 2 and 8 hours, respectively.  The MOTE signal intensity was then decreased to about 25 % of the initial value after 48 hours of exposure and has not change much after 120 hours.  It may represent an equilibrium state between MOTE and DOTCE, since the same MOTE/DOTCE ratio was measured at 120 hours of exposure during Tier 1 experiments.

MASS BALANCE

- For each tested 1g (1.3 mmol) sample of MOTE, the test material was added to a preheated (to 37 °C) solution of hydrochloric acid.  After completing the respective hydrolysis period, 94 to 100 % of the test material were recovered via the hexane extraction from the aqueous phase.

- The mass balance showed high recovery of the initial amount of the test material. It demonstrates high reliability of the chosen experimental design of the study.

TOC MEASUREMENT

- TOC (NPOC) was used to determine organic carbon content attributed to water-soluble breakdown products of MOTE that might be formed and present in the aqueous phases under the conditions of the experiment after recovering the test material.  

- Results can be seen in Table 1. The table shows a low content of organic carbon remaining in the aqueous phases after completion of the simulated gastric hydrolysis under Tier 2 test conditions (rows from W54-101-A1 to W54-101-F2). The NPOC values range from 81.8 to 239.6 mg/L.  Since the test material contained a total of 57.4 % of organic carbon, these values represent from 1.4 to 4.2 % of the available organic carbon.  Certain organic carbon content values of Tier 1 tests were higher, due to the presence of organic material in the buffer solution (W54-100A) and/or the longer hydrolysis/exposure time (W54-100D). Hydrolysis products that have higher [compared with MOTE (< 0.1 mg/l) and other organotin compounds] water solubility are 2-EHTG (4.73 mg/L) (a ligand of MOTE) and its breakdown products, such as 2-ethylhexanol (0.9 mg/l) and thiogylcolic acid (> 1000 g/L).

Conclusions:

It can be concluded that DOTCE is the only tin-containing metabolite of DOTE that is formed under the simulated mammalian gastric environment. No DOTC was formed and detected under the conditions of this study.

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 MOTE is hydrolytically stable at pH 9, 7 and 4. After 5 days of hydrolysis at 50 °C less than 10% MOTE was hydrolysed (t 0.525 °C> 1 year). Amount of hydrolysed MOTE was increased at lower pH values from 1.85 % at pH 9 to 5.33 % at pH 7 and 7.01 % at pH 4. At the simulated gastric conditions (0.1 M HCl/pH 1.2 /37 °C) 75% MOTE was hydrolysed to it’s monochloride (DOTCE). No formation of DOTC was detected under the conditions of the study.

Hydrolysis of MOTE can be monitored by the decrease in the relative intensity of the respective 119Sn-NMR signal at 73.4 ppm and the increase of the DOTCE signal at 33.3 ppm. The sum of both intensities agrees well with MOTE signal intensity of the untreated test material. DOTC could not be identified in any of the hydrolysed MOTE samples and DOTC= 133 ppm using the 119Sn-NMR spectroscopy. Detection limit for DOTC has been experimentally found to be 0.5% w/w. It was shown in that when spiked with DOTC, MOTE signal present in a partially hydrolysed MOTE sample containing DOTCE, disappeared but still no peak characteristic to DOTC was detected. These results provide direct evidence that DOTC readily reacts with MOTE and forms DOTCE. Similar behaviour of MOTE was described in a study focused on the fate of MOTE in a polyvinylchloride (PVC) film. In that study MOTE was also converted to DOTCE due to the exposure to HCl that is formed as a result of the thermal degradation of PVC. No DOTC was detected until all MOTE has been transformed into DOTCE.

TOC analysis has been conducted to ensure completeness of the analysis and recover all organic carbon in aqueous phases including all possible water-soluble organotin substances and their breakdown components. The analyses detected some organic carbon content (from 1.4 to 4.2 % of the total available organic carbon) in the aqueous phases of the experiments. These traces of organic carbon could be attributed to 2-EHTG (a hydrolysed ligand of DOTE) and its breakdown products EH and TGA. 

Therefore, it can be concluded that DOTCE is the only tin-containing metabolite of DOTE that is formed under the simulated mammalian gastric environment. No DOTC was formed and detected 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 Octyltin tris(2-ethylhexylmercaptoacetate) (MOTE) (EC Number 248-227-6 and CAS No 27107-89-7) based on structural similarity and hydrolytical behaviour, see attached justification.

Reason / purpose for cross-reference:

read-across source

Conclusions:

It can be concluded that DOTCE is the only tin-containing metabolite of DOTE that is formed under the simulated mammalian gastric environment. No DOTC was formed and detected under the conditions of this study.

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 MOTE is hydrolytically stable at pH 9, 7 and 4. After 5 days of hydrolysis at 50 °C less than 10% MOTE was hydrolysed (t 0.525 °C> 1 year). Amount of hydrolysed MOTE was increased at lower pH values from 1.85 % at pH 9 to 5.33 % at pH 7 and 7.01 % at pH 4. At the simulated gastric conditions (0.1 M HCl/pH 1.2 /37 °C) 75% MOTE was hydrolysed to it’s monochloride (DOTCE). No formation of DOTC was detected under the conditions of the study.

Hydrolysis of MOTE can be monitored by the decrease in the relative intensity of the respective 119Sn-NMR signal at 73.4 ppm and the increase of the DOTCE signal at 33.3 ppm. The sum of both intensities agrees well with MOTE signal intensity of the untreated test material. DOTC could not be identified in any of the hydrolysed MOTE samples and DOTC= 133 ppm using the 119Sn-NMR spectroscopy. Detection limit for DOTC has been experimentally found to be 0.5% w/w. It was shown in that when spiked with DOTC, MOTE signal present in a partially hydrolysed MOTE sample containing DOTCE, disappeared but still no peak characteristic to DOTC was detected. These results provide direct evidence that DOTC readily reacts with MOTE and forms DOTCE. Similar behaviour of MOTE was described in a study focused on the fate of MOTE in a polyvinylchloride (PVC) film. In that study MOTE was also converted to DOTCE due to the exposure to HCl that is formed as a result of the thermal degradation of PVC. No DOTC was detected until all MOTE has been transformed into DOTCE.

TOC analysis has been conducted to ensure completeness of the analysis and recover all organic carbon in aqueous phases including all possible water-soluble organotin substances and their breakdown components. The analyses detected some organic carbon content (from 1.4 to 4.2 % of the total available organic carbon) in the aqueous phases of the experiments. These traces of organic carbon could be attributed to 2-EHTG (a hydrolysed ligand of DOTE) and its breakdown products EH and TGA. 

Therefore, it can be concluded that DOTCE is the only tin-containing metabolite of DOTE that is formed under the simulated mammalian gastric environment. No DOTC was formed and detected under the conditions of this study.

Reference 3

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 4

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.
Read-across performed on structurally similar substance data for the substance (DOTI) and the read-across substance (DOTE) can be used for the registration as they are isomers differing only slightly in the structure of the C-8 alcohol of the mercaptoester ligand.

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:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

0.004

Absorption rate - inhalation (%):

100

Additional information

Toxicokinetic Assessment of the Substance
Triisooctyl 2,2’,2”-[(octylstannylidyne)tris(thio)] triacetate(MOTI)
(CAS Number 26401-86-5; EC Number 247-665-5)

Introduction

No experimental data on absorption, distribution, metabolism and excretion are available for triisooctyl 2,2’,2”-[(octylstannylidyne)tris(thio)] triacetate (CAS Number 26401-86-5; EC Number 247-665-5), also known as MOTI. Limited toxicity data are available for MOTI, and therefore read-across has been used to the data from two structurally similar substances:

-      octyltin tris(2-ethylhexylmercaptoacetate) (MOTE,CAS Number:27107-89-7;EC Number:248-227-6) and

-      dioctyltin bis(2-ethylhexylmercaptoacetate) (DOTE,CAS Number:15571-58-1;EC Number:239-622-4). 

Toxicity and hydrolysis data on MOTE and DOTE in combination with the toxicity and physicochemical data on MOTI were used to provide the toxicokinetic profile of MOTI.

Physicochemical properties

The substanceMOTIis a clear liquid with a molecular weight of 841.9 g/mol. The relative density was determined to be 1.08 at 20°C and the melting point is <-21°C at 101.3 kPa. The vapour pressure of MOTIis calculated to be 319 Pa at 25°C. Therefore,MOTIis considered to be of low volatility and not available for inhalation as a vapour.

The partition coefficient log Pow is calculated to be 14.1 and the water solubility is very low, 3.67 × 10^-12mg/L at 25 °C. Therefore,MOTIis a highly lipophilic substance which is poorly soluble in water. 

The substance is not readily biodegradable. Hydrolysis data from the Source substance MOTE, suggest that MOTI is hydrolytically stable at pH 9, 7 and 4, but hydrolyses under low pH conditions simulating the gastric environment.

Oral absorption

The relatively high molecular weight, high Log Pow and low water solubility would limit absorption of the intact molecule from the gastrointestinal tract. Data on the read-across substance MOTE shows that these molecules are hydrolytically unstable at low pH, and therefore MOTI is expected to hydrolyse to the itsmonochloride esterin the aqueous conditions of the gastrointestinal tract. It is also possible that the labile ligands can be displaced by other anions in the medium. The displaced thioester ligands can also undergo further hydrolysis of the ester linkage to form thyioglycolic acid andisooctan-1-ol. These hydrolysis products will be more readily absorbed.

Evidence of oral absorption was seen in an acute oral toxicity study in the rat (similar to OECD 401) in which rats were administered a single oral dose of MOTI at 3590, 4640 or 7750 mg/kg. Clinical signs of toxicity of dyspnoea, sedation, exophthalmos, curved position and ruffled fur were seen which became more accentuated as the dose increased. No abnormalities were seen at necropsy (Bathe, 1973). Supporting evidence of systemic toxicity was also seen in a previous acute oral toxicity studies in the rat at 4000 mg/kg (Gunzel and Richter, 1969) and 2.2-7.5 mL/kg (Klimmer, 1969). In a study (largely following EPA OPP 81-1), rats were administered a single oral dose of MOTI at 600, 800, 1200, 1700 and 2500 mg/kg. No mortality was seen at the lowest dose level but increasing numbers of animals died at higher dose levels, and those that died showed substantial weight loss. At necropsy, changes were seen in the lungs, liver and gastrointestinal tract (Auletta, 1984). The repeat-dose data in rats dosed with MOTI showed slight increases in kidney weights, with histopathological changes observed in some studies, indicating systemic exposure. A very slight dose-related increase in adrenal weights was observed in one study. 

In addition,data on the read-across substance MOTEalso provides some evidence of systemic toxicity, and thereby of absorption. Rats were administered a single oral dose of MOTE at 50, 300 or 2000 mg/kg. Clinical signs included hunching, ataxia, blepharospasm, protrusion of eyes, piloerection and an abdominal lump, no treatment-related changes were found at post-mortem (Prinsen, 2012). 

Oral absorption does take place, but the exact extent cannot be determined, therefore, for risk assessment purposes the extent of oral absorption of MOTI is considered to be 100% for human health risk assessment purposes.

Dermal absorption

MOTI has a relatively high molecular weight, with a high log Pow value of14.1and very low water solubility. All these factors indicate the rate of transfer between the stratum corneum and the epidermis will be slow, and therefore dermal penetration is expected to be low. 

Data on the read-across substance MOTE report an acute dermal LD₅₀of > 2000 mg/kg (Prinsen, 2010) and no skin sensitisation potential (Patel, 2016). Data on the read-across substance DOTE, report no skin irritation (Hagermann 1992) or skin sensitisation (Hagermann 1993) potential.

Anin vitrodermal absorption study on human and rat skin is available with DOTE. The results of this study show that 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.

In conclusion, the most precautionary, experimentally determined, absorption value of 0.004% is proposed for human health risk assessment purposes.

Inhalation absorption

The low vapour pressure of MOTI indicates that the substance cannot generate an inhalable vapour. Furthermore, inhalation exposure to MOTI is unlikely under normal conditions of use. For any MOTI that is inhaled, the high log Pow and low water solubility of MOTI means that MOTI may be absorbed by micellar solubilisation. 

In the absence of any experimental data on toxicity following inhalation exposure, a worst-case value of 100% is proposed for inhalation for human health risk assessment purposes.

Distribution

MOTI has a relatively high molecular weight, high Log Pow and is of low water-solubility. Consequently, absorption of parent MOTI is expected to be low, and any absorbed MOTI will not be widely distributed.

MOTI is expected to hydrolyseto itsmonochloride ester,thyioglycolic acid andisooctan-1-ol in the aqueous conditions of the gastrointestinal tract, and therefore the distribution of the hydrolysis products is also considered. 

Results of acute oral toxicity studies with MOTI show evidence of distribution to thelungs and liver, and the repeat dose studies show evidence of distribution to thekidneys. Given the high log P_OWand low water solubility, micellular solubilisation may play a major role for absorption, and preferential partition to tissues with high lipid content. Data on the read-across substance MOTE showed no effects on bone marrow in the rat micronucleus assay, therefore there is no evidence for distribution of MOTE to bone marrow(Reus, 2012).

A bioaccumulation study has been performed in fish with the read-across substance DOTE. This substance hydrolyses rapidly in water to DOTO (dioctyl tin oxide). The substance is not expected to bioconcentrate, and a BCF of <100 was determined. No upper limit appears to havebeen verified hence it is not possible to estimate the extent of elimination of the material from fatty tissues(Bouwman, 2010).

2-Mercaptoacetic acid is a low molecular weight, highly water-soluble molecule, and therefore is expected to be widely distributed once absorbed. On the basis of its physical properties, it is not expected to partition into fat.

Isooctan-1-ol is a low molecular weight, water insoluble molecule with an estimated log Pow of 2.7. Due to the low water solubility, isooctane-1-ol is expected to be poorly absorbed, but the lipophilicity means that any absorbed dose is likely to partition into fatty tissues.

Metabolism

MOTI is expected to hydrolyse to itsmonochloride ester, thioglycolic acid and isooctan-1-olin the acidic conditions of the gastrointestinal tract. Hydrolysis at physiological pH is expected to be very limited.

2-Mercaptoacetic acid is a low molecular weight, highly water-soluble molecule, and therefore is expected to be readily excreted unchanged, however it may also undergo oxidation to the dimer 2,3-dimercaptosuccinic acid and/or conjugation with cysteine. 2-Mercaptoacetic acid is a naturally occurring product of sulphur metabolism and is assumed to be an endogenous constituent of human urine(Kusmierek & Bald, 2008). Refer to the IUCLID dossier for 2-mercaptoacetic acid (CAS no. 68-11-1). 

Isooctan-1-ol is of low water solubility, therefore is likely to be oxidised to the aldehyde and then to the carboxylic acid to facilitate excretion.

In the bacterial mutation assays inS. typhimuriumandE. coliconducted with a 67:33 % mixture of MOTE and DOTE, there were no significant reproducible increases in the observed numbers of revertant colonies in any of the test strains used, either in the presence or absence of S9-mix(Arni, 1981). Hence no conclusions can be drawn about the metabolism of MOTI from this study.

Similarly, no conclusions can be drawn about the metabolism of MOTI from thein vitrocytogenicity test conducted with MOTE(de Vogel, 2010).

Elimination

Unabsorbed or unchanged MOTI is expected to be excreted mainly in the faeces. 

The hydrolysis productmonochloride esterofMOTI isexpected to be excreted mainlyviathe faeces.

The hydrolysis product 2-mercaptoacetic acid is a small polar, water soluble compound and will therefore be excreted predominantlyviathe urine, either unchanged or following further metabolism/conjugation.

The hydrolysis product isooctan-1-ol is a small, water-insoluble compound and is therefore expected to be excreted mainly unchanged in the faeces.

Conclusions

Oral, dermal and inhalation absorption of MOTI are considered to be 100%, 0.004% and 100%, respectively. 

There is no potential for bioaccumulation.

MOTI is hydrolytically unstable at low pH and will be readilyhydrolysed to itsmonochloride ester, thioglycolic acid and isooctan-1-olin the gut. Only2-mercaptoacetic acid is expected tobewidely distributed within the body and will be excreted in the urine either unchanged or as the disulphide dimer or as the cysteine conjugate. Themonochloride ester of MOTIand isooctan-1-olwill be excreted mainly unchanged in the faeces. 

Basic Toxicokinetics

Read-across to Octyltin tris(2-ethylhexylmercaptoacetate) (MOTE) CAS No27107-89-7

The study presented is a Simulated gastric hydrolysis study (Schilt & Zondervan van den beuken, 2004) which was conducted in order to simulate the behaviour of the substance in mammalian gastric systems.

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 hydrolyse 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 ionisation 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. 

Dermal Absorption

Read-across from supporting substance (DOTE, CAS 15571-58-1)

The absorption of the read across substance DOT(2 -EHMA) was measured in vitro (Ward 2003) though both occluded and unoccluded human and rat epidermis. Reading-across from this substance was considered appropriate, because both substances are liquid, with a high molecular weight (>500 g/mol), and may be too large to be absorbed though the skin. Moreover, their vapour pressure are very low.

The absorption through rat epidermis was much faster than through human epidermis:

HUMAN EPIDERMIS: A dose of 17,007 µg 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 substance to the glass equipment used. 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. 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.

Read-across Justification

The target substance Triisooctyl 2,2’,2”-[(octylstannylidyne)tris(thio)] triacetate (MOTI) (EC Number 247-665-5 and CAS 26401-86-5) is a mono-constituent organotin substance that consists of a tin as central metal element with one octyl-ligands. The source substances Octyltin tris(2-ethylhexylmercaptoacetate (MOTE) (EC Number 248-227-6 and CAS No 27107-89-7) 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 differing only slightly in the structure of the C-8 alcohol of the mercaptoester ligand.

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