Reaction products of slack wax (petroleum), oxidized, esterified with n-butanol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

Expert statement

Type of information:

other: Expert statement

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert statement

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline required

Version / remarks:

Expert statement

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Reaction products of slack wax (petroleum), oxidized, esterified with n-butanol

EC Number:

945-889-4

Molecular formula:

Too Complex

IUPAC Name:

Reaction products of slack wax (petroleum), oxidized, esterified with n-butanol

Test material form:

other: waxy solid

Details on test material:

- Physical state: brown waxy solid
- Analytical purity:100%
- Expiration date of the lot/batch: 13 July 2017
- Storage condition of test material: room temperature in the dark

Specific details on test material used for the study:

The test item is a complex mixture of esters and amides containing a minor amount of unreacted test substance, 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.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Absorption

Oral Route
The physical chemical properties described above indicate that the majority of the components of the substance have an average molecular size greater than that which may be expected to be easily absorbed within the mammalian gastrointestinal tract, should that material be ingested. Being highly lipophilic but with a Log Pow of >10, the substance may be expected not to easily cross gastrointestinal epithelial barriers, and the high average MW may also significantly restrict absorption, at least of a major proportion of this UVCB. It may participate in micellar transport into the hepatic portal system along with other lipophilic substances (e.g., dietary fats), although this is considered unlikely because of the absence of ionic properties.

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 1000 mg/kg bw/day. The absence of adverse findings following oral dosing may be due to limited gastrointestinal absorption of the test material after dosing, or a very low index of inherent toxicity for this substance, and/or its metabolite(s). However, the absence of systemic effects indicates the likely absence of, or very low, potential for absorption of the substance, or its metabolites, or at least the majority of the components of this UVCB substance.

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 both the high average MW and the log Pow >10. Moreover, it is assumed that the dermal uptake of the substance is also limited because of 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 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 waxy solid), its’ very low vapour pressure (0.555 Pa) indicate 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:

Distribution

Systemic distribution of substance can be predicted from the physical chemical properties of this substance. The very high 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 another macromolecule. The lipophilic character of the substance, with high Log Pow, low water solubility and high average MW suggests that a major proportion of the substance will not readily traverse cellular barriers or distribute into fatty tissues. There is no evidence of systemic toxicity and/or histopathological changes or increasing severity of clinical observations from repeated dose studies, nor of cumulative toxicity, as would be manifested by an accumulation of the substance or its’ metabolites in body tissues.

Details on excretion:

Excretion

The structural characteristics (esters and amides) of the substance suggest that this it 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:

Metabolism

Like most xenobiotics, the substance 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, mammalian cell mutagenicity, and a mammalian cell chromosomal aberration, 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 unchanged by the presence of the microsomal enzyme system.

Applicant's summary and conclusion

Conclusions:

Toxicokinetic assessment of Slack wax (petroleum), oxidized, Bu ester

The toxicokinetic profile of Slack wax (petroleum), oxidized, Bu ester, a complex mixture of esters and amides containing a minor amount of unreacted test substance, 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

Slack wax (petroleum), oxidized, Bu ester is a UVCB with a molecular weight range of 86.13 to about 733.32 g/mol although with very little present at the extremes of the range. The substance is a brown waxy solid and is poorly water soluble. The water solubility is loading rate dependent and the majority of the components are considered to be insoluble in water. The octanol/water partition coefficient is very high, estimated log Pow >10.0 (which is >4, the bioaccumulation limit), and a low vapour pressure of 0.555 Pa @ 25oC. The surface tension of the substance was dependent on the loading rate (66.5±2.0 mN/m at a loading rate of 0.11 g/L and 56.2±1.0 mN/m for the 1.1 g/L loading rate; the substance is considered to be surface active. The majority of the components of the substance are considered not to dissociate at environmental pH.

Absorption

Oral Route
The physical chemical properties described above indicate that the majority of the components of the substance have an average molecular size greater than that which may be expected to be easily absorbed within the mammalian gastrointestinal tract, should that material be ingested. Being highly lipophilic but with a Log Pow of >10, the substance may be expected not to easily cross gastrointestinal epithelial barriers, and the high average MW may also significantly restrict absorption, at least of a major proportion of this UVCB. It may participate in micellar transport into the hepatic portal system along with other lipophilic substances (e.g., dietary fats), although this is considered unlikely because of the absence of ionic properties.

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 1000 mg/kg bw/day. The absence of adverse findings following oral dosing may be due to limited gastrointestinal absorption of the test material after dosing, or a very low index of inherent toxicity for this substance, and/or its metabolite(s). However, the absence of systemic effects indicates the likely absence of, or very low, potential for absorption of the substance, or its metabolites, or at least the majority of the components of this UVCB substance.

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 both the high average MW and the log Pow >10. Moreover, it is assumed that the dermal uptake of the substance is also limited because of 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 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 waxy solid), its’ very low vapour pressure (0.555 Pa) indicate 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 substance can be predicted from the physical chemical properties of this substance. The very high 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 another macromolecule. The lipophilic character of the substance, with high Log Pow, low water solubility and high average MW suggests that a major proportion of the substance will not readily traverse cellular barriers or distribute into fatty tissues. There is no evidence of systemic toxicity and/or histopathological changes or increasing severity of clinical observations from repeated dose studies, nor of cumulative toxicity, as would be manifested by an accumulation of the substance or its’ metabolites in body tissues.

Metabolism

Like most xenobiotics, the substance 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, mammalian cell mutagenicity, and a mammalian cell chromosomal aberration, 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 unchanged by the presence of the microsomal enzyme system.

Excretion

The structural characteristics (esters and amides) of the substance suggest that this it 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:

Toxicokinetic assessment of Slack wax (petroleum), oxidized, Bu ester

 

The toxicokinetic profile of Slack wax (petroleum), oxidized, Bu ester, a complex mixture of esters and amides containing a minor amount of unreacted test substance, 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

 

Slack wax (petroleum), oxidized, Bu ester is a UVCB with a molecular weight range of 86.13 to about 733.32 g/mol although with very little present at the extremes of the range. The substance is a brown waxy solid and is poorly water soluble. The water solubility is loading rate dependent and the majority of the components are considered to be insoluble in water. The octanol/water partition coefficient is very high, estimated log Pow >10.0 (which is >4, the bioaccumulation limit), and a low vapour pressure of 0.555 Pa @ 25oC. The surface tension of the substance was dependent on the loading rate (66.5±2.0 mN/m at a loading rate of 0.11 g/L and 56.2±1.0 mN/m for the 1.1 g/L loading rate; the substance is considered to be surface active. The majority of the components of the substance are considered not to dissociate at environmental pH.

 

Absorption

 

Oral Route

The physical chemical properties described above indicate that the majority of the components of the substance have an average molecular size greater than that which may be expected to be easily absorbed within the mammalian gastrointestinal tract, should that material be ingested. Being highly lipophilic but with a Log Pow of >10, the substance may be expected not to easily cross gastrointestinal epithelial barriers, and the high average MW may also significantly restrict absorption, at least of a major proportion of this UVCB. It may participate in micellar transport into the hepatic portal system along with other lipophilic substances (e.g., dietary fats), although this is considered unlikely because of the absence of ionic properties.

 

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 1000 mg/kg bw/day. The absence of adverse findings following oral dosing may be due to limited gastrointestinal absorption of the test material after dosing, or a very low index of inherent toxicity for this substance, and/or its metabolite(s). However, the absence of systemic effects indicates the likely absence of, or very low, potential for absorption of the substance, or its metabolites, or at least the majority of the components of this UVCB substance.

 

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 both the high average MW and the log Pow >10. Moreover, it is assumed that the dermal uptake of the substance is also limited because of 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 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 waxy solid), its’ very low vapour pressure (0.555 Pa) indicate 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 substance can be predicted from the physical chemical properties of this substance. The very high 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 another macromolecule. The lipophilic character of the substance, with high Log Pow, low water solubility and high average MW suggests that a major proportion of the substance will not readily traverse cellular barriers or distribute into fatty tissues. There is no evidence of systemic toxicity and/or histopathological changes or increasing severity of clinical observations from repeated dose studies, nor of cumulative toxicity, as would be manifested by an accumulation of the substance or its’ metabolites in body tissues.

 

Metabolism

 

Like most xenobiotics, the substance 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, mammalian cell mutagenicity, and a mammalian cell chromosomal aberration, 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 unchanged by the presence of the microsomal enzyme system.

 

Excretion

 

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