Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Expert statement
Adequacy of study:
key study
Study period:
2013-02-14
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Expert statement in the absence of toxicokinetic studies.

Data source

Reference
Reference Type:
other: Expert statement
Title:
Unnamed
Year:
2013
Report Date:
2013

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Expert statement
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: liquid

Test animals

Species:
other: Expert statement
Strain:
other: Expert statement
Details on test animals and environmental conditions:
Not applicable.

Administration / exposure

Route of administration:
other: Expert statement
Vehicle:
other: Expert statement
Details on exposure:
Not applicable.
Duration and frequency of treatment / exposure:
Not applicable.
Doses / concentrations
Remarks:
Doses / Concentrations:
Not applicable.
No. of animals per sex per dose:
Not applicable.
Positive control:
Not applicable.
Details on study design:
Not applicable.
Details on dosing and sampling:
Not applicable.
Statistics:
Not applicable.

Results and discussion

Preliminary studies:
Not applicable.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
After oral administration the substance is assumed to dissolve in the gastrointestinal fluids and absorption via aqueous pores or carriage across membranes with the bulk passage of water might occur as indicated by the high water solubility. In addition, absorption of the substance via passive diffusion might be favoured due to the log Pow value of -0.24. The LD50 evaluated in an oral acute toxicity study and the pathological and histopathological findings after repeated oral administration indicate that the compound becomes bioavailable after oral administration.
The test item is solidified or highly viscous at room temperature and the vapour pressure of the test item at 20 °C is estimated to be low. Therefore, inhalation of dust or vapour is unlikely. However, if the test item becomes available for inhalation, the test item might cross the respiratory tract epithelium by passive diffusion or active transport via aqueous pores as indicated by the small molecular weight and the physic-chemical properties of the substance. This assumption is supported by the results of the acute inhalation toxicity studies in which mortality and signs of systemic toxicity were observed.
Dermal absorption of hex-3-yne-2,5-diol is estimated to be low as uptake into the stratum corneum is limited by a high water solubility and a log Pow value below 0. No signs of systemic toxicity were observed in the available acute dermal toxicity studies. However, since the available LLNA revealed a skin sensitising effect, penetration through the skin has to occur to a certain extend.
Taken together, experimental data indicate bioavailability of the test substance via oral and inhalation route and to a certain extend also via dermal route.
Details on distribution in tissues:
A wide distribution of the test substance in the organism is expected due to its low molecular weight and high water solubility. This assumption is supported by the adverse effects observed in the stomach, spleen, liver, kidney and bone marrow in the available combined repeated dose toxicity study with the reproduction/developmental toxicity screening test. Based on the low log Pow value no bioaccumulation of the test substance is expected.
Details on excretion:
Due to the low molecular weight, the high water solubility (>500 g/L) and the presumed metabolism hex-3-yne-2,5-diol and/or its metabolites are expected to be excreted via urine.

Metabolite characterisation studies

Details on metabolites:
The test substance might be oxidised to hex-3-yne-2,5-dion. A reduction of the triple bond by NAD(P)H-linked reductase is further considered resulting in corresponding alkene- and alkane-derivatives as already shown by Kitamura S. et al. (2002). In order to facilitate excretion conjugation of the parent compound and/or its metabolites with endogenous substrates is expected.
The test item did not induce gene mutations neither in the Ames test nor in the HPRT test in mammalian cells in the absence and in the presence of a metabolic activation system, respectively. However, there are indications of genotoxicity of the test item and/or its metabolites from the present cytogenetic test (BASF SE, 2012). In the presence of a metabolic activation system hex-3-yne-2,5-diol or rather its metabolites were shown to be clastogenic in vitro. Based on these data metabolic activation could not be excluded.

Bioaccessibility

Bioaccessibility testing results:
Based on the results of acute and repeated dose toxicity studies as well as on the structure, the molecular weight and the phys./chem. properties, the test substance can be considered to be bioavailable via oral, inhalation and possibly also via dermal route.

Applicant's summary and conclusion