Registration Dossier

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: see 'Remark'
Remarks:
Well documented expert statement from an internationally recognized contract research organization. This expert statement has been based on a series of physicochemical and toxicology studies with WS400517 or formulations 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:
2011

Materials and methods

Principles of method if other than guideline:
Expert statement based on a series of physicochemical and toxicology studies with WS400517 or formulations of it. Technical guidelines followed in these experimental studies are cited in the respective endpoint study records.

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material: WS400517 or formulations of it
Further details on the test material used in the experimental studies referred to are presented in the respective endpoint study records.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
WS400517 is a complex mixture of components. The rather high molecular weight (897) and low water solubility (< 1 mg/L at 20°C) of WS400517 would be expected to limit its absorption across the skin after topical administration and to limit its absorption after oral administration [ECHA, Chapter R.7c: Endpoint specific guidance]. Consequently the above physicochemical properties of WS400517 are considered to limit its systemic availability both, after topical and after oral administration. This is consistent with the absence of toxicologically relevant signs of irritation in skin irritation studies with formulations of WS400517 in the rabbit and in a Local Lymph Node Assay (LLNA) in mice and with the absence of any sensitization response in the latter study. In addition, in a repeat dose oral toxicity study combined with reproductive/developmental toxicity screening, in which rats received WS400517 at 100, 300 or 1000 mg/kg/day, findings indicative of absorption were not evident after 4 treatment weeks.

No data is available on absorption after inhalation. In view of on average only 0.3 mass percent of the particles of WS400517 < 10 µm, inhalable particles predominantly will settle in the nasopharyngeal region [additional comment by the submitter derived from Endpoint study record 7.2.2]. The high molecular weight and low water solubility of WS400517 lower the potential for absorption and might slightly enhance penetration to the lower respiratory tract [ECHA, R.7c]. Thus WS400517 may behave rather like inert material. Inhalation of any vapour from WS400517 is an unlikely route of human exposure, because the substance has a very low vapour pressure (< 10E-27 Pa at 25°C, calculated value) and decomposes without boiling at high temperatures (>ca. 230°C).
Details on distribution in tissues:
There is no indication in the available study results regarding the metabolism or distribution of WS400517 or components thereof.
Details on excretion:
There is no indication in the available study results regarding the excretion of WS400517 or components thereof.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
No specific study was performed on the absorption, distribution, metabolism and/or excretion (ADME) of WS400517. Its systemic availability after topical, oral or inhalation administration is expected to be limited, because of its high molecular weight and low water solubility. This is consistent with the absence of any relevant adverse effects attributable to WS400517 in all in vitro mutagenicity and in vivo toxicity studies. Thus WS400517 may behave rather like inert material. The particle size distribution of WS400517 led to the conclusion that inhalable particles predominantly will settle in the nasopharyngeal region. Its limited absorption might slightly enhance penetration to the lower respiratory tract. Availability of WS400517 under a vapour state is unlikely, because of its low vapour pressure, and because at high temperatures (> ca. 230°C) the substance decomposes without boiling.

All available study results gave no indication regarding the metabolic pathway, distribution or excretion of WS400517. Based on the above summarised findings and on the low water/octanol partition coefficient (log Pow = 2.2) WS400517 has a low bioaccumulation potential, if any.