Registration Dossier

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 WS400123 or a formulation of it, in general performed according to technical guidelines and in compliance with GLP in internationally recognized contract research organizations.
Cross-reference
Reason / purpose:
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 WS400123 or a formulation of it. 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

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material: WS400123 or formulation of it
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 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:
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:
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, WS400123, is a complex mixture of components and has a Log10Pow < +1 at pH 4, 7 or 9 at 25°C, a molecular weight range of ca. 300 – 600 and a water solubility of 2.5 mg/L at 20°C (pH 7). Therefore, low to moderate gastro-intestinal absorption of WS400123 or components thereof cannot be entirely discounted after oral uptake. After repeated oral administration of WS400123 for 5 weeks to male and female rats in a toxicity study combined with reproductive/developmental toxicity screening (OECD 422), mean haematocrit, haemoglobin concentration and erythrocyte count were statistically significantly lower in both sexes at 300 and/or 1000 mg/kg/day than in concurrent controls. Although these differences were not of toxicological significance (absence of any correlating in life or histopathological findings), they may be an indication of systemic absorption of WS400123 or a small fraction of it after oral administration.

The above physicochemical properties of WS400123 are considered also to favour only low dermal absorption after topical administration [ECHA 2008]. However, in view of the sensitization response attained in a Local Lymph Node Assay (LLNA) in mice at non-irritating test concentrations of WS400123, some dermal absorption must have occurred. This may have been only a small fraction of the administered test material.

No data is available on absorption after inhalation. Inhalation of any vapour from WS400123 is an unlikely route of human exposure, because the substance has a very low vapour pressure (1 x 10-3 Pa at 25°C) and decomposes without boiling at high temperatures (> ca. 150°C). Exposure of humans to an inhalable aerosol of WS400123 is also unlikely, because it is a highly viscous liquid 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 WS400123 or components thereof.
Details on excretion:
There is no indication in the available study results regarding the excretion of WS400123 or components thereof.

Metabolite characterisation studies

Metabolites identified:
not specified

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results log Pow < 1
No specific study was performed on the absorption, distribution, metabolism and/or excretion (ADME) of WS400123.

Low to moderate absorption and systemic availability of WS400123 or components of this complex mixture after oral or topical administration cannot be entirely discounted, because of its, possibly moderate, partition coefficient value (Log10Pow < 1), low water solubility (2.5 mg/L) and, to some extent, its molecular weight (ca. 300 – 600). Reductions in mean haematocrit, haemoglobin concentration and erythrocyte count after 5 weeks of oral gavage treatment at 300 and/or 1000 mg/kg/day in rats may be an indication of systemic absorption of WS400123 or a small fraction of it after oral administration. Some dermal absorption has been concluded from the sensitization response attained in a Local Lymph Node Assay (LLNA) in mice at non-irritating test concentrations of WS400123.

Availability of WS400123 under a vapour state is unlikely, because of its low vapour pressure and decomposition without boiling (above ca. 150°C) and its availability as an inhalable aerosol is unlikely, because it is a highly viscous liquid.

All available study results gave no indication regarding the metabolic pathway, distribution or excretion of WS400123. Bioaccumulation was not investigated, but in view of its Log10Pow < 1, WS400123 is not considered to be bioaccumulative.