Hydrocarbon waxes (petroleum), oxidized, Me esters

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

other: expert opinion

Adequacy of study:

key study

Study period:

12 August 2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2019

Report date:

2019

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The following assessment of the toxicokinetic profile of registered substance is based on the physical chemical properties and toxicity data on the substance. No experimentally derived ADME data are available for this substance.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Confidential

IUPAC Name:

Confidential

Test material form:

solid

Details on test material:

- Appearance / physical state: Dark brown paste
- Storage conditions: Room temperature in the dark

Administration / exposure

Details on study design:

Analytical characterizations show that this substance meets the definition of a UVCB. This substance is a paste at ambient laboratory temperature (20°C). This material shows a much broader molecular weight range with carbon numbers from about 5 to 65. This substance is a UVCB due primarily to the variation in molecular weight of the constituent esters.

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Absorption via the oral, dermal and inhalation routes expected to be limited by physico-chemical properties and use patterns

Main ADME results 2

Type:

distribution

Results:

Cmax in the plasma of the venous blood predicted to be 0.06 mg/L

Main ADME results 3

Type:

metabolism

Results:

Unlikely to be metabolically activated to toxic intermediates

Main ADME results 4

Type:

excretion

Results:

Half-life predicted to be 30 hours

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Dermal route
Dermal absorption of the substance is likely to be slow considering high molecular weight and very high log Pow >10. Moreover, it is assumed that the dermal uptake of the substance is also limited because of its very low water solubility. ECHA endpoint specific guidance chapter R.7C indicates that substances with a molecular weight <100 are favored for absorption and if water solubility is <1 mg/L and the Log Pow is >6, then the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Consequently, absorption via the dermal route is expected to be very low, which is supported by the lack of toxicity in acute dermal and skin irritation tests.

Oral route
Absorption in the gastrointestinal tract is predominantly influenced by the water solubility, ionization state, lipophilicity, and molecular weight of a chemical. The physical chemical properties described above indicate that the majority of the constituents 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 the material be ingested. Being highly lipophilic with a Log Pow of >10, the substance may be expected to not easily cross gastrointestinal epithelial barriers, and the high molecular weight may also significantly restrict absorption, at least of a major proportion of this UVCB. The results of an acute oral toxicity, 14-day range finder, 28-day repeat dose, and reproductive developmental screen studies indicate no evidence of systemic toxic effects. In vitro studies with bacteria show that the substance is not toxic to Salmonella typhimurium, either with or without metabolic activation. In mammalian cell genotoxicity assays in vitro the substance was shown to be non-toxic in the absence or presence of metabolic activation enzymes (S9 mix).

Inhalation route
The substance is a paste and has a very low vapor pressure, therefore the potential for inhalation exposure via vapor is considered to be highly unlikely.

Details on distribution in tissues:

Once this substance (or at least the absorbable components) is absorbed, it is expected to be circulated via the blood to the liver and other tissues. The results of a toxicokinetic simulation system (PK-Sim©) (attached) predict that the Cmax in the plasma of the venous blood is 0.06 mg/L.

Details on excretion:

The results of a toxicokinetic simulation system (PK-Sim©) (attached) predict that half-life is 30 hours. Overall, exposure to the parent substance, and subsequent metabolism and metabolites was without obvious adverse toxicological consequences in any of the acute or subacute in vivo studies.

Metabolite characterisation studies

Metabolites identified:

no

Details on metabolites:

In-vivo metabolism data were not available. However, AMES testing with and without S9 fractions gave similar negative results in terms of revertants and toxicity. These results suggest the substance is unlikely to be metabolically activated to toxic intermediates.

Applicant's summary and conclusion

Conclusions:

Assessment of the toxicokinetic profile of the registered substance is based on the physical chemical properties and toxicity data on the substance. The potential for exposure to this substance is limited by its use and physical chemical properties. Absorption via the dermal route is expected to be very low. The substance is not expected to easily cross gastrointestinal epithelial barriers via the oral route, and the high molecular weight may also significantly restrict absorption, at least of a major proportion of this UVCB. The substance is a paste and has a very low vapor pressure, therefore the potential for inhalation exposure via vapor is considered to be highly unlikely. The substance is expected to be distributed via the blood to the liver and other tissues (Cmax in the plasma of the venous blood predicted to be 0.06 mg/L). Available information suggests that the substance is unlikely to be metabolically activated to toxic intermediates. Results of a toxicokinetic simulation system (PK-Sim©) predict that substance half-life is 30 hours.

Executive summary:

The following assessment of the toxicokinetic profile ofregistered substanceis based on the physical chemical properties and toxicity data on the substance. No experimentally derived ADME data are available for this substance.

 

Analytical characterizations show that this substance meets the definition of a UVCB. This substance is a paste at ambient laboratory temperature (20°C).This material shows a much broader molecular weight range with carbon numbers from about 5 to 65. This substance is a UVCB due primarily to the variation in molecular weight of the constituent esters.

 

Physical Chemical Properties

Molecular weight, water solubility, log Pow, and vapor pressure are key physical chemical properties for assessing the toxicokinetics of a substance. This substance is a paste and, for the purposes of toxicokinetic assessment, the molecular weight (average) is assumed to be 293.9 g/mol. This substance is sparingly soluble in water (4.34 x 10^-03g TOC/L at 20.0±0.5°C), highly lipophilic (partition coefficient: > 1.0 x 10¹⁰, Log₁₀P_ow>10) and has a low vapour pressure (1.91 Pa at 25°C).

 

Exposure routes

The potential for exposure to this substance is limited by its use and physical chemical properties. The dermal contact route is considered to be the primary route of occupational exposure. Inhalation exposure is expected to be limited because this substance has a negligible vapour pressure. Because of the use pattern oral exposure is not an anticipated route of exposure, either to workers or the general public.

 

Absorption

 

Dermal route

Dermal absorption of the substance is likely to be slow considering high molecular weight and very high log Pow >10. Moreover, it is assumed that the dermal uptake of the substance is also limited because of its very low water solubility. ECHA endpoint specific guidance chapter R.7C indicates that substances with a molecular weight <100 are favored for absorption and if water solubility is <1 mg/L and the Log Pow is >6, then the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Consequently, absorption via the dermal route is expected to be very low, which is supported by the lack of toxicity in acute dermal and skin irritation tests.

 

Oral route

Absorption in the gastrointestinal tract is predominantly influenced by the water solubility, ionization state, lipophilicity, and molecular weight of a chemical. The physical chemical properties described above indicate that the majority of the constituents 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 the material be ingested. Being highly lipophilic with a Log Pow of >10, the substance may be expected to not easily cross gastrointestinal epithelial barriers, and the high molecular weight may also significantly restrict absorption, at least of a major proportion of this UVCB. The results of an acute oral toxicity, 14-day range finder, 28-day repeat dose, and reproductive developmental screen studies indicate no evidence of systemic toxic effects.In vitrostudies with bacteria show that the substance is not toxic to Salmonella typhimurium, either with or without metabolic activation. In mammalian cell genotoxicity assaysin vitrothe substance was shown to be non-toxic in the absence or presence of metabolic activation enzymes (S9 mix).

 

Inhalation route

The substance is a paste and has a very low vapor pressure, therefore the potential for inhalation exposure via vapor is considered to be highly unlikely.

 

Distribution

Once this substance (or at least the absorbable components) is absorbed, it is expected to be circulated via the blood to the liver and other tissues. The results of a toxicokinetic simulation system (PK-Sim^©) (attached) predict that the Cmax in the plasma of the venous blood is 0.06 mg/L.

 

Metabolism

In-vivo metabolism data were not available. However, AMES testing with and without S9 fractions gave similar negative results in terms of revertants and toxicity. These results suggest the substance is unlikely to be metabolically activated to toxic intermediates.

 

Elimination

The results of a toxicokinetic simulation system (PK-Sim©) (attached) predict that half-life is 30 hours. Overall, exposure to the parent substance, and subsequent metabolism and metabolites was without obvious adverse toxicological consequences in any of the acute or subacute in vivo studies.