2-Propenoic acid, methyl ester, reaction products with mixed O,O-bis(branched and linear pentyl and iso-Bu) phosphorodithioates

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Toxicokinetic assessment using physico-chemical properties and toxicological study data.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Toxicokinetic assessment using reliable physico-chemical properties and toxicological study data.

Materials and methods

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

The toxicokinetic profile of the test item was predicted using the physical chemical properties of the substance, the data obtained from acute and repeated-dose toxicity studies, as well as information gained from genotoxicity assays.

Test material

Test material information

Constituent 1

Test material form:

liquid

Specific details on test material used for the study:

The test item is a UVCB with an average molecular weight of 238. The substance is poorly water soluble at 5.4 x 10-4g/L, with an estimated octanol/water partition coefficient, log Pow>3.42, and a low vapour pressure (9.6 x 10-4Pa @ 25°C). The surface tension of the substance has not been determined because of the low water solubility and the substance is considered not to dissociate at environmental pH.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

- Oral Route: The physical chemical properties described above indicate that the substance has a molecular size which may be expected to be absorbed within the mammalian gastrointestinal tract, should that material be ingested. Being lipophilic with a Log Pow of >3.42, the substance may be expected to cross gastrointestinal epithelial barriers, and the evidence from the repeated dose toxicity study indicates that absorption did occur because there were dose-related increases in liver organ weights. An acute oral gavage toxicity study identified no evidence of toxicity (LD50 >2000 mg/kg bw). The repeat dose and reproductive screening toxicology study using the oral route gave a NOAEL of 750 mg/kg bw/day. The absence of adverse findings following oral dosing is probably due to a low index of inherent toxicity for this substance, and/or its metabolite(s).- Dermal Route: Regarding the dermal absorption of the substance, its rate of uptake into the stratum corneum and its rate of transfer between the stratum corneum and the epidermis are likely to be slow considering the MW, the log Pow, and its low water solubility. These assumptions were supported by the absence of observed systemic effects following dermal application of the substance in the acute dermal toxicity study at up to 2000 mg/kg bw.- Inhalation Route: The potential for inhalation toxicity was not studied directly in a toxicology study using the inhalation route. However, the physical nature of the substance (a liquid) with a low vapour pressure (9.6 x 10-4Pa) that indicates a very low propensity to enter atmospheric air in a respirable form. Thus, respiratory absorption under normal use, and based on the life-cycle information of this substance, is expected to be inconsequential.

Details on distribution in tissues:

Systemic distribution of the substance can be predicted from the physical chemical properties of this substance. The log Pow and poor water solubility suggests that this substance, upon systemic absorption, may be transported through the circulatory system in association with a carrier molecule such as a lipoprotein or other macromolecules. The lipophilic character and MW of the substance suggests that a major proportion of the substance will readily traverse cellular barriers and distribute into fatty tissues. There is evidence of systemic exposure and histopathological changes in repeated dose studies, but not of cumulative toxicity, as would be manifested by an accumulation of the substance or metabolites in tissues.

Details on excretion:

The characteristics of the substance suggest that this molecule may undergo phase I and phase II metabolic transformation. The resulting metabolic by-products are expected to undergo routine renal and or biliary excretion.

Metabolite characterisation studies

Details on metabolites:

The substance is a UVCB and like most xenobiotics, it may be expected to undergo phase I oxidation/reduction, esterase-catalyzed hydrolysis and subsequent Phase II conjugation. Acute and repeated-dose toxicity testing provided no evidence that the substance was metabolized into toxic metabolites. Data from bacterial mutagenicity and a chromosomal aberration test in mammalian cells, in which the substance was subjected to rat hepatic microsomal enzyme systems did not show any evidence of genotoxic activity from the substance or its metabolites. Furthermore, the in vitro toxicity of the substance was slightly reduced in the presence of metabolic enzymes. This may indicate that the metabolites may be less toxic than the substance itself but more likely that the presence of protein may bind the substance, or protect the cells, such that the toxicity is reduced.

Applicant's summary and conclusion

Conclusions:

The toxicokinetic profile of the test item was predicted using the physical chemical properties of the substance, the data obtained from acute and repeated-dose toxicity studies, as well as information gained from genotoxicity assays.- Physico-chemical properties: the test item is a UVCB with an average molecular weight of 238. The substance is poorly water soluble at 5.4 x 10-4g/L, with an estimated octanol/water partition coefficient, log Pow>3.42, and a low vapour pressure (9.6 x 10-4Pa @ 25°C). The surface tension of the substance has not been determined because of the low water solubility and the substance is considered not to dissociate at environmental pH.Absorption- Oral Route: The physical chemical properties described above indicate that the substance has a molecular size which may be expected to be absorbed within the mammalian gastrointestinal tract, should that material be ingested. Being lipophilic with a Log Pow of >3.42, the substance may be expected to cross gastrointestinal epithelial barriers, and the evidence from the repeated dose toxicity study indicates that absorption did occur because there were dose-related increases in liver organ weights. An acute oral gavage toxicity study identified no evidence of toxicity (LD50 >2000 mg/kg bw). The repeat dose and reproductive screening toxicology study using the oral route gave a NOAEL of 750 mg/kg bw/day. The absence of adverse findings following oral dosing is probably due to a low index of inherent toxicity for this substance, and/or its metabolite(s).- Dermal Route: Regarding the dermal absorption of the substance, its rate of uptake into the stratum corneum and its rate of transfer between the stratum corneum and the epidermis are likely to be slow considering the MW, the log Pow, and its low water solubility. These assumptions were supported by the absence of observed systemic effects following dermal application of the substance in the acute dermal toxicity study at up to 2000 mg/kg bw.- Inhalation Route: The potential for inhalation toxicity was not studied directly in a toxicology study using the inhalation route. However, the physical nature of the substance (a liquid) with a low vapour pressure (9.6 x 10-4Pa) that indicates a very low propensity to enter atmospheric air in a respirable form. Thus, respiratory absorption under normal use, and based on the life-cycle information of this substance, is expected to be inconsequential. DistributionSystemic distribution of the substance can be predicted from the physical chemical properties of this substance. The log Pow and poor water solubility suggests that this substance, upon systemic absorption, may be transported through the circulatory system in association with a carrier molecule such as a lipoprotein or other macromolecules. The lipophilic character and MW of the substance suggests that a major proportion of the substance will readily traverse cellular barriers and distribute into fatty tissues. There is evidence of systemic exposure and histopathological changes in repeated dose studies, but not of cumulative toxicity, as would be manifested by an accumulation of the substance or metabolites in tissues. MetabolismThe substance is a UVCB and like most xenobiotics, it may be expected to undergo phase I oxidation/reduction, esterase-catalyzed hydrolysis and subsequent Phase II conjugation. Acute and repeated-dose toxicity testing provided no evidence that the substance was metabolized into toxic metabolites. Data from bacterial mutagenicity and a chromosomal aberration test in mammalian cells, in which the substance was subjected to rat hepatic microsomal enzyme systems did not show any evidence of genotoxic activity from the substance or its metabolites. Furthermore, the in vitro toxicity of the substance was slightly reduced in the presence of metabolic enzymes. This may indicate that the metabolites may be less toxic than the substance itself but more likely that the presence of protein may bind the substance, or protect the cells, such that the toxicity is reduced. ExcretionThe characteristics of the substance suggest that this molecule may undergo phase I and phase II metabolic transformation. The resulting metabolic by-products are expected to undergo routine renal and or biliary excretion.

Executive summary:

The toxicokinetic profile of the test item was predicted using the physical chemical properties of the substance, the data obtained from acute and repeated-dose toxicity studies, as well as information gained from genotoxicity assays.  

- Physico-chemical properties: The test item is a UVCB with an average molecular weight of 238. The substance is poorly water soluble at 5.4 x 10-4g/L, with an estimated octanol/water partition coefficient, log Pow>3.42, and a low vapour pressure (9.6 x 10-4Pa @ 25°C). The surface tension of the substance has not been determined because of the low water solubility and the substance is considered not to dissociate at environmental pH.  

Absorption  

- Oral Route: The physical chemical properties described above indicate that the substance has a molecular size which may be expected to be absorbed within the mammalian gastrointestinal tract, should that material be ingested. Being lipophilic with a Log Pow of >3.42, the substance may be expected to cross gastrointestinal epithelial barriers, and the evidence from the repeated dose toxicity study indicates that absorption did occur because there were dose-related increases in liver organ weights. An acute oral gavage toxicity study identified no evidence of toxicity (LD50 >2000 mg/kg bw). The repeat dose and reproductive screening toxicology study using the oral route gave a NOAEL of 750 mg/kg bw/day. The absence of adverse findings following oral dosing is probably due to a low index of inherent toxicity for this substance, and/or its metabolite(s).    

- Dermal Route: Regarding the dermal absorption of the substance, its rate of uptake into the stratum corneum and its rate of transfer between the stratum corneum and the epidermis are likely to be slow considering the MW, the log Pow, and its low water solubility. These assumptions were supported by the absence of observed systemic effects following dermal application of the substance in the acute dermal toxicity study at up to 2000 mg/kg bw.  

- Inhalation Route: The potential for inhalation toxicity was not studied directly in a toxicology study using the inhalation route. However, the physical nature of the substance (a liquid) with a low vapour pressure (9.6 x 10-4Pa) that indicates a very low propensity to enter atmospheric air in a respirable form. Thus, respiratory absorption under normal use, and based on the life-cycle information of this substance, is expected to be inconsequential.  

Distribution  

Systemic distribution of the substance can be predicted from the physical chemical properties of this substance. The log Pow and poor water solubility suggests that this substance, upon systemic absorption, may be transported through the circulatory system in association with a carrier molecule such as a lipoprotein or other macromolecules. The lipophilic character and MW of the substance suggests that a major proportion of the substance will readily traverse cellular barriers and distribute into fatty tissues. There is evidence of systemic exposure and histopathological changes in repeated dose studies, but not of cumulative toxicity, as would be manifested by an accumulation of the substance or metabolites in tissues.  

Metabolism  

The substance is a UVCB and like most xenobiotics, it may be expected to undergo phase I oxidation/reduction, esterase-catalyzed hydrolysis and subsequent Phase II conjugation. Acute and repeated-dose toxicity testing provided no evidence that the substance was metabolized into toxic metabolites. Data from bacterial mutagenicity and a chromosomal aberration test in mammalian cells, in which the substance was subjected to rat hepatic microsomal enzyme systems did not show any evidence of genotoxic activity from the substance or its metabolites. Furthermore, the in vitro toxicity of the substance was slightly reduced in the presence of metabolic enzymes. This may indicate that the metabolites may be less toxic than the substance itself but more likely that the presence of protein may bind the substance, or protect the cells, such that the toxicity is reduced.  

Excretion  

The characteristics of the substance suggest that this molecule may undergo phase I and phase II metabolic transformation. The resulting metabolic by-products are expected to undergo routine renal and or biliary excretion