Dibutyltin oxide

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

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

Principles of method if other than guideline:

Male Swiss-Webster mice were administered orally with [14C]Bu2Sn(OAc)2. The urine and faeces of the animals were examined for metabolites of the parent compound. Tissues were also examined for uptake at 138 hours post dosing.

GLP compliance:

not specified

Radiolabelling:

yes

Remarks:

6.3 mCi/mmol

Species:

mouse

Strain:

Swiss Webster

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Horton Laboratories, Oakland, Calif
- Housing: Metabolism cages

Route of administration:

oral: gavage

Vehicle:

other: methoxytriglycol

Details on exposure:

VEHICLE
- Amount of vehicle (if gavage): 125 µl

Duration and frequency of treatment / exposure:

A single dose

Remarks:

Doses / Concentrations:
1.1 mg/kg

No. of animals per sex per dose / concentration:

No data

Control animals:

not specified

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces and tissues
- Time and frequency of sampling: Tissues were collected 138 hours post dosing

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled : urine, faeces, tissues
- Method type(s) for identification: Urine, faeces, and 14C02 were collected and quantitated to determine the radiocarbon content. The urine was diluted with water and extracted with chloroform (2 x 1 vol) before and after acidification to pH 1-2 by addition of HC1. The faeces were dried and pulverized for determination of total radiocarbon content (combustion) or extraction by a multistep procedure. Thus, aliquots of the faeces (40-100 mg) were homogenized in chloroform (5 ml) with a Polytron homogenizer (Kinematica GmbH, Lucerne, Switzerland), and the homogenate was centrifuged and filtered to give the chloroform-soluble fraction. The precipitate and residue on the filter paper were combined and homogenized (Polytron) in methanol (5 ml) for recovery of the methanol-soluble fraction as above. Finally, the centrifugal precipitate and filter residues were moistened with a few drops of water, acidified to pH 1-2 by addition of HC1, and re-extracted with methanol as above to give the acid methanol extract and unextractable residue (analyzed by combustion). Tissue residues were analyzed by combustion on sacrifice of the animals at 138 h after treatment. In separate experiments with each labelled compound, the 1-[14C] butene expired within 24 h after treatment was trapped and analyzed. Also, the liver was removed 3 h after treatment, immediately frozen on dry ice, and then homogenized in water (10 ml) and the homogenate extracted with chloroform (5 x 35 ml), followed by a second chloroform extraction (5 x 35 ml) after acidification of the aqueous phase to pH 1-2 with HCl.

Details on distribution in tissues:

For [14C]Bu2Sn(OAc)2 in tissues, the highest level was detected in the brain (0.13 ppm equivalents), intermediate in heart, kidney, liver, and lung (0.058-0.082 ppm), and the lowest in the other tissues examined (0.008-0.053 ppm). These results do not differentiate [14C] butyltin derivatives retained in the tissues from metabolites formed by cleavage of the tin-carbon bond and reincorporation of the carbon fragments into tissue components.

Details on excretion:

After administration of [14C]Bu2Sn(OAc)2, the faeces contained a large amount of unmetabolized compound and some [14C]BuSnX3. Large amounts of polar and unextractable metabolites was noted.

Metabolites identified:

yes

Details on metabolites:

[14C]Bu2Sn(OAc)2 in mice undergoes extensive in vivo cleavage at the tin-carbon bond and further oxidation of the liberated carbon fragment(s) to l4CO2, the amount being equivalent within 90 h after oral treatment to destannylation of 14% of the [14C]Bu2Sn(OAc)2 dose. In addition, expired l-[14C]butene is equivalent to 0.2% of the administered [14C]Bu2Sn(OAc)2. A portion of the urinary radiocarbon may consist of conjugates that no longer retain a tin-carbon bond. Thus, it is clear that the butyltin compounds are extensively absorbed and metabolized by pathways that, in at least their initial steps, are similar to or identical with those for the MO reactions. After administration of [14C]Bu2Sn(OAc)2, the faeces contained a large amount of unmetabolized compound and some [14C]BuSnX3. Large amounts of polar and unextractable metabolites was noted.

Conclusions:

Metabolism of Bu2Sn(OAc)2 yields BuSnX3, possibly by both nonenzymatic destannylation and by a- and β-carbon hydroxylation and decomposition of the hydroxy derivatives. The unidentified polar metabolites are probably formed by two or more sites of hydroxylation at different butyl groups. Bu3SnX and Bu2SnX2 bind extensively in some tissue fractions, making analysis difficult analysis and a plausible explanation for the relatively low metabolite yields.

Executive summary:

Male Swiss-Webster mice were administered orally with [14C]Bu2Sn(OAc)2. The urine and faeces of the animals were examined for metabolites of the parent compound. Tissues were also examined for uptake at 138 hours post dosing.

Metabolism of Bu2Sn(OAc)2 yields BuSnX3, possibly by both nonenzymatic destannylation and by a- and β-carbon hydroxylation and decomposition of the hydroxy derivatives. The unidentified polar metabolites are probably formed by two or more sites of hydroxylation at different butyl groups. Bu3SnX and Bu2SnX2 bind extensively in some tissue fractions, making analysis difficult analysis and a plausible explanation for the relatively low metabolite yields.

Reference 2

Endpoint:

basic toxicokinetics 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 dibutyltin acetate.

Reason / purpose for cross-reference:

read-across source

Details on distribution in tissues:

For [14C]Bu2Sn(OAc)2 in tissues, the highest level was detected in the brain (0.13 ppm equivalents), intermediate in heart, kidney, liver, and lung (0.058-0.082 ppm), and the lowest in the other tissues examined (0.008-0.053 ppm). These results do not differentiate [14C] butyltin derivatives retained in the tissues from metabolites formed by cleavage of the tin-carbon bond and reincorporation of the carbon fragments into tissue components.

Details on excretion:

After administration of [14C]Bu2Sn(OAc)2, the faeces contained a large amount of unmetabolized compound and some [14C]BuSnX3. Large amounts of polar and unextractable metabolites was noted.

Metabolites identified:

yes

Details on metabolites:

[14C]Bu2Sn(OAc)2 in mice undergoes extensive in vivo cleavage at the tin-carbon bond and further oxidation of the liberated carbon fragment(s) to l4CO2, the amount being equivalent within 90 h after oral treatment to destannylation of 14% of the [14C]Bu2Sn(OAc)2 dose. In addition, expired l-[14C]butene is equivalent to 0.2% of the administered [14C]Bu2Sn(OAc)2. A portion of the urinary radiocarbon may consist of conjugates that no longer retain a tin-carbon bond. Thus, it is clear that the butyltin compounds are extensively absorbed and metabolized by pathways that, in at least their initial steps, are similar to or identical with those for the MO reactions. After administration of [14C]Bu2Sn(OAc)2, the faeces contained a large amount of unmetabolized compound and some [14C]BuSnX3. Large amounts of polar and unextractable metabolites was noted.

Reference 3

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

no information

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

significant methodological deficiencies

Objective of study:

other: to simulate the hydrolytic action by mammalian gastric contents and to determine if the tin-ligand bond breaks, leading to formation of the corresponding alkyltin chloride and release of the ligand.

Principles of method if other than guideline:

DBTO was tested under low pH (~1-2) conditions (0.07 N HCl) at 37 °C in order to simulate the hydrolytic action by mammalian gastric contents. The degree of hydroloysis for the test substance was studied by determination of the amount of a product considered as DBTC formed after 0.5, 1, 2, and 4 hours, using GC-FPD.

GLP compliance:

not specified

Radiolabelling:

no

Species:

other: No species were used - simulated gastric hydrolysis

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

DBTO was tested under low pH (~1-2) conditions (0.07 N HCl) at 37 °C in order to simulate the hydrolytic action by mammalian gastric contents. The degree of hydroloysis for the test substance was studied by determination of the amount of a product considered as DBTC formed after 0.5, 1, 2, and 4 hours, using GC-FPD.

Route of administration:

other: test to simulate mammalian gastric contents

Vehicle:

other: insoluble in solvent; 'diluted' by thoroughly mixing with 811.17 mg of lactose

Details on exposure:

No information available.

Duration and frequency of treatment / exposure:

No information available.

Remarks:

Doses / Concentrations:
50 mg of DBTO/lactose mixture (0.199 mg/mg) was added to 1000 ml of 0.07 N HCl.

No. of animals per sex per dose / concentration:

No information available.

Control animals:

no

Positive control reference chemical:

No further information required.

Details on study design:

Into a series of 4 PTFE vessels, 50 mg (accurately weighed) of the DBTO/lactose mixture (0.199 mg/mg) was added to 1000 ml of 0.07 N HCl (already at 37 degrees Celsius). In this way, the concentration of DBTO in the final 0.07 N HCl solution was approximately 10 mg/L. The solution was stirred, and the temperature was maintained using an oven.

Details on dosing and sampling:

A sample was taken from one of the Teflon vessels after 0.2, 1, 2, and 4 hours. Once a vessel was sampled, no other sample was collected from that vessel. Experiments were performed in duplicate.

Statistics:

The percentage of hydrolyzed organotin test substance based on the measurement of a product considered as DBTC was calculated as follows: The total amount of the hydrolysis product considered as DBTC in solution that can be formed upon complete hydrolysis of the test substance was approximately 12 mg/l (DBTO) was weighed and thus varied slightly per sample. This level was calculated using the following formula:

50 (mg) * 0.20 (mg/mg)/1000 ml * Mw(DBTC)/Mw(DBTO).

Preliminary studies:

The mean percentage of hydrolysis of DBTO is summarized in Table 7 (see below). Under chemical conditions intended to simulate mammalian gastric contents, as described in this report, DBTO was hydrolyzed to a great extent. Approximately 80% hydrolysis occurred in 2 hours and percent hydrolysis in 4 hours was 87%. The half life of DBTO was 3.5 hours.

Details on absorption:

No information available.

Details on distribution in tissues:

No information available.

Details on excretion:

No information available.

Toxicokinetic parameters:

half-life 1st: 3.5 hours

Metabolites identified:

yes

Details on metabolites:

The percentage of hydrolyzed organotin test substance was determined. The formed metabolite was not clearly identified in this study.

 

Table 7. Summary of the results of the simulated gastric hydrolysis of DBTO
Time	Mean percentage of hydrolysis (calculated as DBTC values based on assumption that DBTC was formed) %
0.5	42.6
1	64.8
2	80.3
4	87.3

Conclusions:

DBTO may be hydrolyzed to a great extent in simulated mammalian gastric contents.
Under chemical conditions intended to simulate mammalian gastric contents, for DBTO the percent hydrolysis was 87.3% and the half life was 3.5 hours.

Executive summary:

This study aimed to assess the hydrolysis of various organotin compounds including DBTO under simulated gastric conditions. Dibutyltin oxide was tested under pH 1 -2 conditions (0.07 N HCl) at 37 degrees C in order to simulate the hydrolytic action by mammalian gastic contents. The degree of hydrolysis was tested by GC-FPD. 

As DBTO could not be dissolved in any solvent without chemically converting the test substance, DBTO was introduced to the test system in a "dry" diluted form (diluted with lactose). The hypothesis was that in the hydrochloric acid solution the tin-ligand bond breaks. leading to the formation of the corresponding alkyltin chloride and simultaneous liberation of the ligand. Thus, the hydrolysis product was considered as DBTC in this study, however the product was not analytically identified in this study.

Overall, the study reports that under these conditions, DBTO hydrolyzed to 87.3% after 4 hours, with a half-life at 3.5 hours. However, due to the chosen analytical method, no conclusion can be drawn on the identity of the hydrolysis product.

Reference 4

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

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

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted on read-across material.

Justification for type of information:

Read-across to structurally similar substance dibutyltin acetate.

Reason / purpose for cross-reference:

read-across source

Type:

metabolism

Results:

Unlabeled Bu2SnX2 undergoes NADPH-dependent conversion to BuSnX3 (TLC cochromatography in D & E) no other products detected with rabbit microsomes, while [14C]Bu2SnX2 yields one polar NADPH-dependent metabolite and no BuSnX3with rat microsome.

Metabolites identified:

yes

Details on metabolites:

[14C]Butyltin Derivatives and Rat Liver Microsome-NADPH System:-
Metabolites of [I4C]-Bu2Sn(OAc)2 were analysed in a series of chromatographic systems that resolve all of the authentic unlabeled compounds and therefore allow tentative metabolite identification by cochromatography and quantitation by lsc. [14C]Bu2Sn(OAc)2 yields one NADPH-dependent metabolite (free, polar) in a small amount but the formation of BuSnX3does not appear to be dependent on NADPH fortification.
Unlabeled n-Alkyltin Derivatives and Rabbit Liver Microsome-NADPH System:-
Unlabeled Bu2SnX2 undergoes NADPH-dependent conversion to BuSnX3 (TLC cochromatography in D and E) but no other products are detected with rabbit microsomes, while [14C]Bu2SnX2 yields only one polar NADPH-dependent metabolite and no BuSnX3with rat microsomes.

Reference 5

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

supporting study

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

Principles of method if other than guideline:

The metabolic fate of dibutyltin acetate was examined in a microsomal monooxygenase metabolism system (MO) derived from either rat or rabbit livers. Comparative data was also provided on other alkyltins in the MO system.

GLP compliance:

not specified

Radiolabelling:

yes

Remarks:

Bu2Sn(OAc)2: 6.3 Ci/mmol

Vehicle:

ethanol

Remarks:

Doses / Concentrations:
0.003 µmol of [14C]butyltin derivative
0.5 µmol of unlabeled compound

Type:

metabolism

Results:

Unlabeled Bu2SnX2 undergoes NADPH-dependent conversion to BuSnX3 (TLC cochromatography in D & E) no other products detected with rabbit microsomes, while [14C]Bu2SnX2 yields one polar NADPH-dependent metabolite and no BuSnX3with rat microsome.

Metabolites identified:

yes

Details on metabolites:

[14C]Butyltin Derivatives and Rat Liver Microsome-NADPH System:-
Metabolites of [I4C]-Bu2Sn(OAc)2 were analysed in a series of chromatographic systems that resolve all of the authentic unlabeled compounds and therefore allow tentative metabolite identification by cochromatography and quantitation by lsc. [14C]Bu2Sn(OAc)2 yields one NADPH-dependent metabolite (free, polar) in a small amount but the formation of BuSnX3does not appear to be dependent on NADPH fortification.
Unlabeled n-Alkyltin Derivatives and Rabbit Liver Microsome-NADPH System:-
Unlabeled Bu2SnX2 undergoes NADPH-dependent conversion to BuSnX3 (TLC cochromatography in D and E) but no other products are detected with rabbit microsomes, while [14C]Bu2SnX2 yields only one polar NADPH-dependent metabolite and no BuSnX3with rat microsomes.

Properties and Optimization of Monooxygenase System.

Rat liver microsomal preparations were used with ¹⁴C-labeled substrates and rabbit liver microsomes with unlabeled substrates, unless noted otherwise. With both rat and rabbit preparations, a small amount of soluble fraction (optimum 40-100 mg fresh liver weight equivalent) increases the activity of the microsome-NADPH system although the soluble fraction is not active by itself or with NADPH. There is a considerable variation in the activity of different enzyme preparations from the same species, for unknown reasons. It is necessary in all cases to fortify the microsomal preparations with NADPH to obtain detectable metabolism of the organotin and organolead substrates. (The rat liver microsome-NADPH system acting on [¹⁴C]Bu3SnOAc is totally inhibited by carbon monoxide and to a large extent by 4(5)-a-naphthylimidazole, which suggests that a cytochrome P450 dependent monooxygenase system is responsible for metabolism of the organometallic substrates.)

Conclusions:

Metabolism of Bu2Sn(OAc)2 yields BuSnX3, possibly by both nonenzymatic destannylation and by a- and β-carbon hydroxylation and decomposition of the hydroxy derivatives. The unidentified polar metabolites are probably formed by two or more sites of hydroxylation at different butyl groups. Bu3SnX and Bu2SnX2 bind extensively in some tissue fractions, making analysis difficult analysis and a plausible explanation for the relatively low metabolite yields.

Executive summary:

The metabolic fate of dibutyltin acetate was examined in a microsomal monooxygenase metabolism system (MO) derived from either rat or rabbit livers. Comparative data was also provided on other alkyltins in the MO system.

Metabolism of Bu2Sn(OAc)2 yields BuSnX3, possibly by both nonenzymatic destannylation and by a- and β-carbon hydroxylation and decomposition of the hydroxy derivatives. The unidentified polar metabolites are probably formed by two or more sites of hydroxylation at different butyl groups. Bu3SnX and Bu2SnX2 bind extensively in some tissue fractions, making analysis difficult analysis and a plausible explanation for the relatively low metabolite yields.

Reference 6

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: Toxicokinetic assessment

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The toxicokinetic profile of Dibutyltin oxide (CAS 818-08-6) was assessed based on existing toxicity studies and the physico-chemical properties of the substance.

Objective of study:

absorption

distribution

excretion

metabolism

toxicokinetics

Qualifier:

no guideline available

Principles of method if other than guideline:

The toxicokinetic profile of Dibutyltin oxide (CAS 818-08-6) was assessed based on existing toxicity studies and the physico-chemical properties of the substance.

Type:

absorption

Results:

For risk assessment purposes, an absorption rate of 100 % is assumed for the oral and inhalation routes and 50 % for the dermal route, following worst-case considerations.

Type:

other: Distribution and accumulation

Results:

DBTO is likely to distribute in cells, particularly in fatty tissue, where it may accumulate to a greater extent. The potential of DBTO to accumulate might be reduced due to probable chemical conversion in the GI and the liver.

Type:

metabolism

Results:

Data on metabolic fate of dibutyltin acetate (CAS: 1067-33-0) provide indications that DBTO might form metabolites. However, detailed information on the metabolic pathway of DBTO are not available.

Type:

excretion

Results:

The nonpolar/lipophilic nature of DBTO indicates it might be excreted to a certain extend via bile. Polar metabolites that may be formed are likely to be excreted in the urine. Regarding the skin, DBTO is likely to be sloughed off with skin cells.

Details on absorption:

In general, absorption of a substance is possible when the substance is able to cross biological membranes. In case where no transport mechanisms are involved, this process requires a substance to be soluble, both in lipid and in water, and is also dependent on its molecular weight. In this regard, substances which are sufficiently soluble in water, with molecular weights (MW) below 500 g/mol and Log P values between -1 and 4 are favorable for absorption. Generally, the absorption of substances which are surfactants or irritants may be enhanced due to damage to cell membranes.

Oral absorption
Considering the absorption potential of DBTO, the following assumptions can be made based on its physico-chemical parameters. DBTO has a relatively low molecular weight (248.94 g/mol), which generally favors absorption. However, due to its lipophilic nature and rather low water solubility, absorption of DBTO may be limited by the inability to dissolve readily in the gastrointestinal (GI) fluid and hence make contact with the mucosal surface. The absorption of DBTO will be enhanced if the substance undergoes micellular solubilization; a process by which highly lipophilic substances are taken up via micelles (aggregates of surface-active molecules that reduce surface tension) into the lymphatic system and bloodstream, bypassing the liver. In addition, the absorption of DBTO may be increased due to its irritant properties and thus its ability to damage cell membranes.

In an in vitro study by Schilt and Zondervan-van den Beuken (TNO, 2004), it was reported that DBTO undergoes metabolic transformation under simulated gastric conditions (pH 1-2 with 0.07 N HCl at 37 °C); hydrolysis was determined to be 87.3 % and the half-life was 3.5 hours. However, due to the use of the highly unspecific GC-FPD analytical method (gas chromatography with flame photometric detector), the results obtained are of low reliability and no conclusion can be drawn on the identity of the hydrolysis product. Nevertheless, the study provides indications that DBTO may undergo a chemical transformation and may as such be present in the gastrointestinal tract only for a limited period of time. The identity of potentially formed metabolite(s) from DBTO is unknown, thus assessment of expected GI absorption and contribution to the toxicological properties of DBTO is not possible.

In general, signs of systemic toxicity after exposure indicate the systemic availability and absorption of a substance or its metabolites, if toxicological activity is to be expected.
In the available OECD TG 422 study on DBTO in rats, offspring of the highest dose group were smaller in size and showed reduced growth, indicating that DBTO or its metabolite(s) were systemically absorbed by the dams. Also, in a pilot study of a prenatal developmental toxicity in rats treated orally with DBTO, effects indicative of systemic absorption were observed, including clinical findings, effects on body weight, reduced food intake, and macroscopic findings (smaller thymus and reduced body fat percentage). The fact that a lymphoid organ is affected supports the assumption that absorption as micelles is likely.

In sum, in the absence of reliable experimental data on quantitative absorption rates of DBTO or its metabolite(s), the oral absorption is considered to be 100 % for risk assessment purposes following worst-case assumptions.

Absorption by inhalation
Due to a very low vapour pressure of 0.004 kPa at 25°C, inhalation in the form of vapour is not expected for DBTO. As the substance is a solid powder, exposure via inhalation might occur. To estimate the presence of inhalable/respirable particles, the particle size distribution of DBTO should be considered. As a rough approximation for deriving deposition patterns, the following assumptions can be made for humans:

Particles with aerodynamic diameters
< 100 μm are potentially inhaled,
< 50 μm may reach the thoracic region,
< 15 μm may reach alveolar region of the respiratory tract.

Particle size data of DBTO show that a portion of 59.6 % of its particles are smaller than 100 μm and therefore potentially inhalable. Only very small shares are expected to reach the alveolar region of the respiratory tract (6.45 x 10^-2 % < 10 µm, 4.89 x 10^-2 % < 5.5 µm). If deposited in the alveolar region, DBTO may be taken up by alveolar macrophages as the substance will not be able to dissolve. Macrophages will then either translocate particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues.

Deposited DBTO particles, especially those which settle in the tracheo-bronchial region, would mainly be cleared from the lungs by the mucociliary mechanism and swallowed.

In sum, based on its inert properties and rather large particle size, the inhalation exposure of DBTO is generally expected to be low. However, In the absence of any specific inhalation data, the respiratory absorption factor is set at 100 % following a worst-case consideration.

Dermal Absorption
To cross the skin, a substance must first penetrate the stratum corneum and may subsequently reach the viable epidermis and the dermis where the vascular network is located. The penetration of a substance into deeper skin layers and reaching the systemic circulation enables the substance to become systemically available.

Since the molecular weight of the registrered substance is in the range of > 100 and < 500, dermal absorption is generally considered possible. Due to the lipophilicity (log P > 4), also the uptake into the stratum corneum is possible. However, the uptake via skin may be strongly hindered by the rate of transfer between the stratum corneum and the epidermis.
The assumption that dermal uptake is limited is supported considering the relatively low water solubility of 2.55 mg/L; between 1-100 mg/L dermal absorption is anticipated to be low to moderate. In addition, dry particulates will have to dissolve into the surface moisture of the skin prior to uptake. Since the registered substance is a solid with relatively low water solubility, this requisite process takes place only to a limited extent.

An available acute dermal toxicity study according to OECD 402 and GLP (Sanders, 2010) revealed no toxic effect of the registration substance in rats following dermal exposure over a 24-hour period at a level of 2000 mg/kg (LD50 > 2000 mg/kg bw/d). In the available acute oral study on the other hand, all animals died in the dose group of 2000 mg/kg body weight. Animals revealed clinical signs like lethargy, diarrhea, wet perineum and nasal discharge followed by death (LD50 = 500 mg/kg bw). The observation that the test substance did not induce any toxic effects when applied dermally at the same dose, at which it led to mortality in the oral study, clearly demonstrates that the dermal absorption is far below the oral absorption (LD 50 > 2000 mg/kg bw vs. LD50 = 500 mg/kg bw). This reduced dermal absorption is also in line with the assumption that the absorption via skin is limited based on physico-chemical properties.

In sum, dermal absorption of DBTO is in principle possible due to the small molecule size, but it can be assumed that the rate is very low since it is a solid with high lipophilicity and relatively low water solubility. Although dermal absorption is generally considered to be low due to physico-chemical properties and available toxicological studies, it may be increased due to the irritant potential of the substance, as it was shown that DBTO is a skin irritant (Skin Irrit. 2) and some damage to the upper layers of the skin associated with irritation may enhance penetration. Therefore, instead of an absorption rate of 10 % (which is for example assumed for larger molecules and with log P outside the range [-1, 4]) for DBTO, an increased absorption rate of 50% is considered for further assessments for precautionary reasons.

Details on distribution in tissues:

In general, the principle the smaller the molecule, the wider the distribution applies once the substance is absorbed. For lipophilic molecules (log P > 0), it can be assumed that they are rather distributed into cells (intracellular concentration > extracellular concentration), especially in fatty tissues. The protein binding ability of a substance might limit the amount of a substance available for distribution.

In case of DBTO, the rather small molecular weight of 248.94 g/mol indicates a wide distribution. However, considering its high lipophilicity (Log P value > 5) and the rather poor water solubility (2.55 mg/L), the absolute systemic bioavailability of absorbed DBTO is expected to be restricted.
As a lipophilic molecule, DBTO is likely to distribute into cells and the intracellular concentration may be higher than the extracellular concentration, particularly in fatty tissues.

The protein binding affinity of DBTO was assessed by the profiling methods of the OECD QSAR Toolbox (v4.5, please refer to Annex I “The profiling results of the target chemical”). The chemical has no structural alerts linked to high reactivity with biomolecules (proteins and DNA). Thus, the amount of substance available for distribution is not considered to be limited due to protein binding.
No predictions can be made about the distribution of potential DBTO metabolite(s).

Details on excretion:

In general, the major routes of excretion for substances from the systemic circulation are the urine and/or the faeces (via bile). Substances that are excreted in the urine tend to be water-soluble and of low molecular weight (below 300), whereas substances that are excreted in the bile tend to be amphipathic (containing both polar and nonpolar regions) and have higher molecular weights.

DBTO is a relatively small molecule with a molecular weight of 248.94 g/mol and possesses a low to moderate water solubility. No data of the potential metabolites of DBTO are available. No conclusion can be drawn regarding the excretion of DBTO (and its metabolites) via urine. Due to its nonpolar/lipophilic nature, one could suggest that DBTO is excreted to a certain extend via bile, although it has a small molecular weight. Nonetheless, a conclusion can’t be drawn because metabolism data is missing. If polar metabolites are formed by chemical transformation, as indicated by experimental data from dibutyltin acetate, excretion via the urine is likely.

Regarding dermal exposure, if the penetration of DBTO is restricted to the stratum corneum, DBTO is considered to be sloughed off with skin cells.

Metabolites identified:

not specified

Remarks:

Identity of potentially formed metabolite(s) from DBTO is unknown.

Conclusions:

The absorption rate of dibutyltin oxide is assumed to be 100% via the oral and inhalation route following a worst-case consideration. Regarding dermal absorption, a rate of 50% is assumed for precautionary reasons. The substance is expected to be distributed into the cells, especially fatty tissue based on its high lipophilicity. Accumulation in the body is assumed to be reduced due to metabolic transformation processes, while in deeper, fatty skin layers it is expected. Excretion is assumed to happen to a certain extend via bile due to the substance's nonpolar/lipophilic nature. Regarding the skin, it is considered to be sloughed off with skin cells.

Executive summary:

Dibutyltin oxide was evaluated regarding its toxicokinetic behaviour.

DBTO is a solid powder with relatively large particles (59.6% <100 µm, 6.45x10^-2 % <10 µm, 4.89x10^-2 % <5.5 µm). It has a small molecular weight (248.94 g/mol), low vapour pressure (4x10^-6 Pa), rather low water solubility (2.55 mg/L) and high lipophilicity (estimated log P > 5). DBTO has been shown to have a skin irritant potential. It has an acute toxic potential after oral administration (LD50 of 500 mg/kg body weight) but not after dermal application (LD50 > 2000 mg/kg). The effects after repeated oral administration are evidence of the systemic bioavailability of DBTO and/or its metabolites.

Based on its physico-chemical properties and findings in toxicological studies, it can be assumed that the highest absorption potential can be expected from oral exposure. However, in the absence of quantitative data, oral and inhalation absorption rate is set to 100 % and the dermal absoprtion is considered to be 50% for precautionary reasons. 

An in-vitro study indicates that DBTO may be hydrolysed at a pH compatible with stomach acid to form other butyltin derivatives. However, the hydrolysis product(s) was/were not further identified in this study.

Due to its nonpolar/lipophilic nature, one could suggest that dibutyltin oxide is excreted to a certain extend via bile. Nonetheless, a conclusion can’t be drawn because metabolism data is missing. If polar metabolites are formed by chemical transformation, as indicated by experimental data from dibutyltin acetate, excretion via the urine is more likely than via the faeces.

Description of key information

Short description of key information on bioaccumulation potential result:

The following studies have been submitted to address the basic toxicokinetics endpoint:

 

Schilt, R & Zondervan-van den Beuken EK (2004) Dibutyltin dilaurate (DBTL, CAS# 77-58-7), Dibutyltin maleate (DBTM, CAS# 78-04-6), Dibutyltin oxide (DBTO, CAS# 818-08-6) and Dioctyltin oxide (DOTO, CAS# 870-08-6): Simulated gastric hydrolysis. 2004-07-12

Kimmel et al (1977) Bioorganotin Chemistyr. Metabolism of Organotin Compounds in Microsomal Monooxygenase Systems and in Mammals. J. Agric. Food Chem. 25(1): 1-9. (Presented as two separate summaries)

 

The study Schilt & Zondervan-van den Beuken (2004) was conducted with DBTO, whereas both Kimmel studies were performed on dibutyltin di(acetate) as rea-across substance. Unfortunately, the study Schilt & Zondervan-van den Beuken (2004) had to be assigned a reliability score of 3 due to major methodological deficiencies. The studies by Kimmel et al. were assigned a reliability score of 2.

 

Due to the very limited experimental data available to draw direct conclusions on the toxicokinetic behaviour (absorption, distribution, metabolism and excretion), a qualitative toxicokinetic assessment was performed according to ECHA Guideline R7c (ECHA, 2017).

Key value for chemical safety assessment

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

No toxicokinetic study on the substance DBTO is available. Therefore, the basic toxikokinetics of DBTO were assessed according to the "Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.7c: Endpoint specific guidance" (ECHA, 2017).

 

 

An in-vitro study indicates that DBTO may be hydrolysed at a pH compatible with stomach acid to form other butyltin derivatives. However, the hydrolysis product(s) was/were not further identified in this study.

 

The EFSA/SPCFC review suggests that oral absorption of tributyl and dibutyltins is incomplete (41% unmetabolised DBTacetate recovered from the faeces of mice). Existing dermal penetration data for organotin compounds indicates dermal absorption to be low.

 

In the absence of quantitative data on DBTO, the absorption rate after inhalation and oral intake is set to 100% and dermal absorption to 50% for risk assessment purposes, assuming the worst case.

 

Discussion on bioaccumulation potential result:

Most studies presented were performed to a good standard and included a good level of detail in the reporting of the methods and the results.

 

The two Kimmel et al (1977) studies summarised were published within the same report.

The first study presented investigated the metabolic fate of dibutyltin acetate examined in a microsomal monooxygenase metabolism system (MO) derived from either rat or rabbit livers. Comparative data was also provided on other alkyltins in the MO system. Metabolism of Bu₂Sn(OAc)₂ yields BuSnX₃, possibly by both nonenzymatic destannylation and by a- and β-carbon hydroxylation and decomposition of the hydroxy derivatives. The unidentified polar metabolites are probably formed by two or more sites of hydroxylation at different butyl groups. Bu₃SnX and Bu₂SnX₂ bind extensively in some tissue fractions, making analysis difficult and providing a plausible explanation for the relatively low metabolite yields.

The second study investigated the metabolism of Bu₂Sn(OAc)₂ which yields BuSnX₃, possibly by both nonenzymatic destannylation and by a- and β-carbon hydroxylation and decomposition of the hydroxy derivatives. The unidentified polar metabolites are probably formed by two or more sites of hydroxylation at different butyl groups. Bu₃SnX and Bu₂SnX₂ bind extensively in some tissue fractions, making analysis difficult and providing a plausible explanation for the relatively low metabolite yields.

 

The study Schilt & Zondervan-van den Beuken (2004) aimed to assess the hydrolysis of various organotin compounds including DBTO under simulated gastric conditions. Dibutyltin oxide was tested under pH 1 -2 conditions (0.07 N HCl) at 37 degrees C in order to simulate the hydrolytic action by mammalian gastic contents. The degree of hydrolysis was tested by GC-FPD. As DBTO could not be dissolved in any solvent without chemically converting the test substance, DBTO was introduced to the test system in a "dry" diluted form (diluted with lactose). The hypothesis was that in the hydrochloric acid solution the tin-ligand bond breaks. leading to the formation of the corresponding alkyltin chloride and simultaneous liberation of the ligand. Thus, the hydrolysis product was considered as DBTC in this study, however the product was not analytically identified in this study. Overall, the study reports that under these conditions, DBTO hydrolyzed to 87.3% after 4 hours, with a half-life at 3.5 hours. However, due to the chosen analytical method, no conclusion can be drawn on the identity of the hydrolysis product.