Zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate)

Endpoint summary

Additional information

Summary and discussion of the toxicokinetic behaviour

 

The toxicokinetic profile of the substance zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate), is evaluated by use of the physical chemical properties which were integrated with data from acute and repeated-dose toxicity animal studies to create a prediction of the toxicokinetic behaviour.

The substance is a zinc dialkyldithiophosphate (ZDDP) and meets the definition of a UVCB substance based on analytical characterization.

This substance has an average molecular weight of 548 g/mol, a water solubility of >1000 mg/L, log Kow of <3, and a vapour pressure of <4.4x10² Pa at 20 °C.

 

Significance of the route of exposure:

Oral exposure:

According to the identified uses of the substance, human exposure via the oral route is not expected. No consumer uses have been identified for zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate). The substance is solely used by workers and professionals for occupational purposes.

Dermal route:

The dermal route is considered a principle route for occupational exposure.

Inhalation route:

The inhalation route is not considered a principle route for occupational exposure.

Besides, the test material has a low vapour pressure of <4.4x10² Pa, ECHA guidance substances with low volatility have a vapour pressure of less than 500 Pa (ECHA 2012). Therefore, under normal use and handling conditions, and based on the identified uses of the substance (there are no spraying uses), respiratory absorption of the test material in the form of vapours, gases, or mists is not expected to be significant.

 

Absorption:

The absorption of zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) is assessed using the available toxicity data from animal models together with model calculations for this substance and/or structural analogues.

Oral Route:

Absorption of a chemical substance after oral intake occurs in the gastrointestinal tract (GI) and is depends on the physical properties, including mainly molecular size but also lipid solubility and dissolution rate. Since a log Kow value between 0 and 4 and MW values <500 are the most suitable for GI absorption, zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) can be expected to participate in endogenous passive absorption within the mammalian GI tract based on its water solubility of >1000 mg/L and the Log Kow of >3, respectively. Consequently, an Human intestinal absorption (HIA) of 89.1% is predicted by OECD QSAR ToolBox 2.3.0.

This is supported by the results obtained from animal toxicity tests, where systemic effects like diarrhoea, tremors, increasing weakness, dyspnoea and mortality were only noted at concentration of >2000 mg/kg bw after single oral administration. Taken together the data indicate that absorption of zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate by the GI tract is expected, but occurs by simple diffusion.

Dermal Route:

In general, the physicochemical properties have a decisive influence on the penetration of molecules through the skin. Based on the available information, a dermal absorption can be expected for zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) as it has an average MW of 548 and a log Kow of <3. This assumption is confirmed by (Q)SAR, which calculates the dermal penetration coefficient (Kp) or Pd (the permeability of the skin) by using empirical formulas based on the relevant physicochemical properties (Danish EPA (Q)SAR database, 2013).

This dermal absorption by zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) is supported by results from animal studies, where systemic effects were noted after dermal application, indicating a bioavailability of the substance. Consequently, the dermal absorption of zinc O,O',O'-tetrabutyl bis(phosphorodithioate) is expected to be moderate and thus, based on a conservative assumption, a dermal absorption rate of 50% is used in the assessment.

Inhalation Route: 

The potential of respiratory uptake of zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) was evaluated in a study with the structural analogue CAS 84605-29-8. Ten Sprague-Dawley rats which were exposed to a concentrated vapour with the nominal concentration of 2.3 mg/L air for 4 hours. Since no animals died following exposure, the LC50 was determined to be >2.3 mg/L air. While diarrhoea was noted in one rat following exposure, all remaining rats appeared normal. These observations suggested the uptake in the upper respiratory tract, but the lack of severe toxicity effects in the majority of animals indicated limited absorption and/or a low systemic toxicity. Due to the structural similarity of zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) and CAS 84605-29-8, the result can be expected for zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate).

 

Distribution:

Distribution within the body through the circulatory system depends on the MW, the lipophilic character, and water solubility. Based on its physical properties zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) may therefore be transported through the circulatory system, thus potentially traverse cellular barriers and distribute to distant organs other than site of exposures. This argument is supported by the observations obtained from various toxicity tests. In the acute toxicity studies apathy, severe diarrhoea, tremors, increasing weakness, dyspnoea and collapse with gastrointestinal inflammation were seen at high doses.

However, no substance-related lesions were found indicating the absence of accumulation within tissue. Due to the structural similarity of zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) and CAS 84605-29-8, the same result could be expected for zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate).

 

Metabolism:

Metabolism of zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) is assessed using the available toxicity data from animal models together with model calculations for this substance and/or structural analogues. The idealized chemical structure shows a few functional groups which are assumed to be candidate substrate(s) for various enzymatic reactions.

Oral/inhalative route: 

The liver metabolism simulator (OECD QSAR ToolBox 2.3.0) predicted 29 metabolites resulting from hydroxylation/dehydrogenation mediated by P450 at –CH3 and CH2 groups of the butyl ester group, followed by oxidations of alcohols. The resulting metabolites possess functional groups (acids) that can undergo conjugation reactions catalyzed by Phase II enzymes.

Dermal route:

According to skin metabolism simulator of the OECD QSAR ToolBox 2.3.0 two metabolites were identified for zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate).

Since intestinal microflora is actively involved in metabolic processes, the microbial metabolism simulator modelling was used (OECD QSAR ToolBox 2.3.0). 12 possible metabolites were identified, which resulted from an oxidative desulfuration or reduction process or a hydrolysis reaction mediated by esterase.

Excretion:

Based on the absorption and metabolism, it is expected that of zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) will undergo biotransformation rather than excretion. If these metabolites were not assimilated into normal cellular metabolic pathways, they were expected to readily undergo routine renal and/or biliary excretion based the predicted structures. While the absorption after inhalation is expected to be limited, only a small fraction of zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) is expected to be exhaled unchanged due to its low vapour pressure.

 

Conclusion:

Zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) has an average molecular weight of 548 g/mol, a water solubility of >1000 mg/L, log Kow of <3, and a vapour pressure of <4.4x10² Pa at 25 °C. The dermal adsorption is predicted to be moderate (50%), which is supported by the systemic effects observed in the acute dermal toxicity studies. Intestinal adsorption is regarded to be effective as also supported by the existing acute oral toxicity studies. The liver and microbial metabolism simulator predicted metabolites of zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) which could be further metabolized and/or excreted showing a low index of inherent toxicity for this substance, and/or its metabolite(s).

The results seen in animals studies together with model calculations indicate that zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) is bioavailable, but does not show any bioaccumulative potential.

 

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within CSR