Fatty acids, C14-18 and C16-18-unsatd., 2-phenoxyethyl esters, maleated

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: expert statement

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Well documented expert statement based on a series of physicochemical, environmental and toxicology studies with WS400109 in general performed according to technical guidelines and in compliance with GLP in internationally recognized contract research organizations.

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2012

Report date:

2012

Materials and methods

Objective of study:

absorption

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

Expert statement based on a series of physicochemical, environmental and toxicology studies with WS400109. Technical guidelines followed in these experimental studies are cited in the respective endpoint study records.

GLP compliance:

no

Remarks:

Considered unnecessary for expert statement

Test material

Test material information

Constituent 1

Details on test material:

- Name of test material: WS400109
Further details on the test material used in the experimental studies referred to are presented in the respective endpoint study records.

Radiolabelling:

no

Test animals

Species:

other: Detailed in endpoint study records of in-vivo studies referred to in the present expert statement

Strain:

other: Detailed in endpoint study records of in-vivo studies referred to in the present expert statement

Sex:

male/female

Details on test animals or test system and environmental conditions:

Detailed in the endpoint study records of in-vivo studies referred to in the present expert statement.

Administration / exposure

Route of administration:

other: Detailed in endpoint study records of in-vivo studies referred to in the present expert statement

Vehicle:

other: Detailed in endpoint study records of in-vivo studies referred to in the present expert statement, if appropriate

Details on exposure:

Detailed in endpoint study records of in-vivo studies referred to in the present expert statement.

Duration and frequency of treatment / exposure:

Detailed in endpoint study records referred to in the present expert statement.

Doses / concentrations

Remarks:

Doses / Concentrations:
Detailed in endpoint study records of in-vivo studies referred to in the present expert statement.

No. of animals per sex per dose / concentration:

Detailed in endpoint study records of in-vivo studies referred to in the present expert statement.

Control animals:

other: Detailed in endpoint study records referred to in the present expert statement, if applicable

Positive control reference chemical:

Detailed in endpoint study records referred to in the present expert statement, if applicable

Details on study design:

Detailed in endpoint study records referred to in the present expert statement, if applicable

Details on dosing and sampling:

Detailed in endpoint study records referred to in the present expert statement, if applicable

Statistics:

Detailed in endpoint study records referred to in the present expert statement, if applicable. Not applicable for the present expert statement.

Results and discussion

Preliminary studies:

Not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Moderate partition coefficient values (Log10Pow ≥ -1 ≤ 4) with molecular weights < 500 are favourable for gastrointestinal absorption [ECHA 2008]. The test material, WS400109, is a complex mixture of components and a number of its components (ca. 80% by chromatographic area) have a Log10Pow > 4.1 at 25°C. In general, its molecular weight range is ca. 370-900, but for ca. 3.7% of it a molecular weight of ca. 100 has been identified. The water solubility of WS400109 is < 1 mg/L at 20°C (pH 4.9 - 6.5). Therefore, in general, absorption of WS400109 after oral uptake is expected to be limited, but in view of the above partition coefficient data and some of the components with a molecular weight < 500, some gastro-intestinal absorption of WS400109 or components thereof after oral uptake cannot be entirely discounted. After repeated oral gavage administration of WS400109 for 5 weeks to male and female rats, a number of haematology and biochemical blood plasma parameters differed statistically significantly from concurrent controls, but these changes were toxicologically irrelevant and it has remained unclear, whether or not they reflect systemic absorption of WS400109 or components of it.

After topical administration to intact skin, the transfer of WS400109 from the stratum corneum to the lower epidermis and dermis is expected to be limited, because of its low water solubility and to some extent the molecular weight [ECHA 2008]. However, some dermal absorption of WS400109 or a fraction of it must have occurred in a Local Lymph Node Assay (LLNA) with mice, because topical administration of undiluted WS400109 to the ears caused increases in ear thickness (> 25%) and of non-irritating test concentrations a dose-related sensitization response.

No data is available on absorption after inhalation. Inhalation of any vapour from WS400109 is an unlikely route of human exposure, because the substance has a very low vapour pressure (7 x 10E-3 Pa at 25°C) and decomposes without boiling at high temperatures (> ca. 215°C) [ECHA 2008]. Exposure of humans to an inhalable aerosol of WS400109 may be unlikely, because it is a viscous liquid (viscosity medium in degree) probably limiting its availability as an inhalable aerosol.

Reference: ECHA 2008, Chapter R.7c: Endpoint specific guidance

Details on distribution in tissues:

There is no indication in the available study results regarding the metabolism or distribution of WS400109 or components thereof.

Details on excretion:

There is no indication in the available study results regarding the excretion of WS400109 or components thereof.

Metabolite characterisation studies

Metabolites identified:

not specified

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
No specific study was performed on the absorption, distribution, metabolism and/or excretion (ADME) of WS400109. In general, absorption and systemic availability of WS400109 after oral or topical administration are expected to be limited, because of its low water solubility (< 1 mg/L), rather high lipohilicity (for ca. 80% by chromatographic area Log10Pow > 4.1) and, to some extent, its molecular weight (ca. 370 – 900). However, some absorption and systemic availability of WS400109 or components of this complex mixture cannot be entirely discounted, because a number of its components may have a partition coefficient value (Log10Pow) ≤ 4.1 and/or for some the molecular weight is only moderate, i.e. ca. 100 or ca. 370 to < 500.

Effects clearly indicative of absorption and systemic availability of WS400109, components or metabolites of it have not been evident after oral administration to rodents in the available toxicity studies. However, some dermal absorption of WS400109 or a fraction of it after topical administration has been concluded from an irritation response (increased ear thickness) to undiluted WS400109 and from a dose-related sensitization response to non-irritating test concentrations attained in a Local Lymph Node Assay (LLNA) in mice.

Availability of WS400109 under a vapour state is unlikely, because of its low vapour pressure and decomposition without boiling (above ca. 215°C), and its availability as an inhalable aerosol may be unlikely, because it is a viscous liquid.

All available study results gave no indication regarding the metabolic pathway, distribution or excretion of WS400109. Bioaccumulation was not investigated.