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: Expert statement in the absence of toxicokinetic studies.

Data source

Reference
Reference Type:
other: Expert statement
Title:
Unnamed
Year:
2012
Report Date:
2012

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:
Due to the vapor pressure (4.2 hPa) the main exposure/absorption route for CHVE is inhalative.
Details on distribution in tissues:
No data.
Details on excretion:
Due to the low molecular weight, the chemical structure, the vapor pressure and its presumed metabolism, CHVE and/or its metabolites are expected to be excreted via exhalation and via the urine.

Metabolite characterisation studies

Details on metabolites:
CHVE might be metabolized by formation of acetaldehyde and cyclohexanone. Potential hydrolysis in the organism could result in cyclohexanol and acetaldehyde.

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, CHVE can be considered to be bioavailable.

Any other information on results incl. tables

Cyclohexylvinylether (CHVE; CAS-No. 2182-55-0) is a clear, colorless liquid with a density of 0.891 g/cm2 ,a boiling point of 152 °C and a molecular weight of 126.2 g/mol. CHVE has a vapor pressure of 4.2 hPa (20°C) and is of limited water solubility (0.33 g/L).

The main exposure/absorption route for CHVE is inhalative.

In an acute oral toxicity study with CHVE in rats (BASF, 1964) the LD50was determined to be 3100 mg/kg body weight (bw). The clinical signs of toxicity were staggering, dyspnoea and narcosis, necropsy showed no abnormalities. A later acute oral toxicity study in Wistar rats (Bioassay, 2012) showed no mortality up to a dose of 2000 mg/kg bw. Signs of toxicity were impaired and poor general state, dyspnoea, staggering, piloerection, atonia and narcosis. In an acute inhalation toxicity study with an atmosphere that was saturated by CHVE vapor (about 5000 ppm), 2 of 12 animals died after 3 hours and 5 of 12 animals died after 8 hours of exposure (BASF, 1964). The clinical signs of toxicity were irritation of the mucosa with dyspnoea more or less severe in relation to the time of exposure, only slowly reversible narcosis and necropsy findings: distinct pulmonary congestion and congestion of the liver after prolonged inhalation. In another acute inhalation toxicity study (BASF, 2012) with male and female Wistar rats the LC50was estimated to be > 22 mg/L (no mortality). Clinical signs of toxicity comprised depressed and labored respiration, intermittent respiration, unsteady gait and piloerection. In a reproductive toxicity screening study with Wistar rats (OECD 421; BASF, 2012), CHVE was administered via inhalation at concentrations of 0, 100, 500 and 1500 mg/ m3. Main signs of toxicity were observed in males including increased liver weight, centrilobular hepatocellular hypertrophy and increased lung weight at the high dose as well as degeneration of the olfactory epithelia in the nasal cavity at high and mid dose. Repeated dose toxicity of CHVE was evaluated in Wistar rats which were head-nose exposed to dynamic inhalation atmosphere for 6 hours on 5 days per week for 90 days (BASF SE, 2012). The targeted concentrations were 100 mg/m3, 500 mg/m3and 1500 mg/m3. Treatment related effects at the high dose were increased alkaline phosphatase and triglyceride levels as well as absolute and relative liver weights. Histopathology revealed centrilobular hepatocellular hypertrophy and necrosis. Furthermore, the CHVE treated groups showed a degeneration and regeneration of the olfactory epithelium.

Based on the results of these studies as well as on the structure, the molecular weight and the phys./chem. properties, CHVE can be considered to be bioavailable.

CHVE might be metabolized by formation of acetaldehyde and cyclohexanone. Potential hydrolysis in the organism could result in cyclohexanol and acetaldehyde. A comparable metabolism could be shown for other vinylethers, i.e. isobutylvinylether (IBVE, CAS 109‑53‑5) in in vitro studies (BASF, 2006). In these studies IBVE was incubated in gastric acid simulans or in subcellular fraction of rat liver and it could be shown that IBVE hydrolyzed fast in these systems.

There are no indications of genotoxicity of CHVE and its metabolites from the present mutation and cytogenetic tests (Ames-test +/- S9 (BASF SE, 2012), in vitro (BASF SE, 2012) and in vivo (BASF SE, 2012) cytogenetics). Due to the low molecular weight, the chemical structure, the vapor pressure and its presumed metabolism, CHVE and/or its metabolites are expected to be excreted via exhalation and via the urine.

Based on the results of the repeated dose toxicity studies in rats and the overall assessment of the available data, accumulation of CHVE can be excluded.

Applicant's summary and conclusion