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Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
absorption
excretion
metabolism
Principles of method if other than guideline:
Urinary excretion of metabolites was evaluated in 2 chinchilla doe rabbits after a single dose of radiolabelled test material.
GLP compliance:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source of test material: British Drug House Limited
- Density: 1.465
- Boiling point: 161-162 °C
Radiolabelling:
yes
Remarks:
14C
Species:
rabbit
Strain:
Chinchilla
Details on species / strain selection:
not specified
Sex:
female
Details on test animals and environmental conditions:
Kept on constant diet (60 g of diet 41, Associated Flour Millers Ltd and 100 mL of water daily)
Route of administration:
oral: gavage
Vehicle:
water
Duration and frequency of treatment / exposure:
single dose application
Remarks:
Doses / Concentrations:260 mg/kg bw
No. of animals per sex per dose:
2
Control animals:
no
Preliminary studies:
Cyclohexanol administered orally by gavage to rabbits was readily absorbed. The substance was highly conjugated with glucuronic acid and excreted mainly via the urine (in the two experimental animals, 68 and 75% of the dose was found as radioactivity in the urine). The main metabolites were cyclohexyl glucuronide (about 60% of administered dose) and trans-cyclohexane-1:2-diol glucoronide (about 6% of administered dose). Negligible amounts of cyclohexanol were found in the expired air.
Toxicokinetic parameters:
other: no data
Metabolites identified:
yes
Details on metabolites:
Cyclohexyl glucuronide (about 60%), trans-cyclohexane-1:2-diol glucuronide (about 6%)
Conclusions:
Cyclohexanol administered orally by gavage to rabbits was readily absorbed. The substance was highly conjugated with glucuronic acid and excreted mainly via the urine (in the two experimental animals, 68 and 75% of the dose was found as radioactivity in the urine). The main metabolites were cyclohexyl glucuronide (about 60% of administered dose) and trans-cyclohexane-1:2-diol glucoronide (about 6% of administered dose). Negligible amounts of cyclohexanol were found in the expired air.

Description of key information

Cyclohexanol is readily absorbed and excreted as the glucuronic acid conjugate or is further metabolised to 1,2-cyclohexanediol or 1,4-cyclohexanediol and then excreted. At higher doses in both animals and humans the predominant metabolite in urine is the glucuronide conjugate of cyclohexanol. In humans at lower doses, typically seen following occupational exposure, the predominant metabolites are 1,2-cyclohexanediol (excreted as glucuronide), 1,4-cyclohexanediol (unconjugated) and low yields of cyclohexanol. Furthermore, the elimination kinetics of the metabolites cyclohexanol, 1,2-cyclohexanediol and 1,4-cyclohexanediol exhibit almost identical patterns, regardless of whether exposure was performed with cyclohexane, cyclohexanone or cyclohexanol (Mráz et al. 1994 and Mráz et al. 1998).

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Basic toxicokinetics

Humans - inhalation

The toxicokinetics and metabolism of cyclohexanol were studied in 8 human volunteers (4/sex) exposed by inhalation to 236 mg/m³ cyclohexanol for 8 h. The retention in the respiratory tract and the total absorbed dose were determined and the urine which was collected over a 72h-period was analysed for cyclohexanol, 1,2- and 1,4-cyclohexanediol (free and conjugated).

Barely 1% of the absorbed dose (8.46 ± 1.85 mmol) was excreted as cyclohexanol, whereas the major metabolite was 1,2-cyclohexanediol (19.1 +/- 3.8%) followed by 1,4-cyclohexanediol (8.4 +/- 1.4%). The excretion of cyclohexanol in urine peaked at the end of exposure; thereafter, cyclohexanol decayed rapidly with an estimated half-life of 1.5 h reflecting a rapid clearance of cyclohexanol which to a large extent is due to its rapid oxidization to cyclohexanediols. The excretion curves of 1,2- and 1,4-cyclohexanediol reached the maximum at a few hours post exposure with elimination half-lives of 14.3 ± 1.2 h and 18 ± 2.5 h, respectively.

The rate-limiting step in the elimination of cyclohexanol (14-18 h) thus appears to be associated with the elimination, rather than formation, of cyclohexanediols. Whereas the 1,2-cyclohexanediol metabolite is excreted as a conjugate to glucoronic acid, the 1,4-cyclohexanediol is eliminated freely.

No difference was found between the groups of men and women with regard to the metabolic yields and elimination half-lives of the metabolites. The decay of the diols followed a one phase log linear elimination course providing no evidence of significant absorption of cyclohexanol into deep compartments. The disposition of cyclohexanediols in fat is negligible (partition coefficient olive oil/ blood <= 0.1) (Mráz et al 1994 and Mráz et al 1998).

The toxicokinetic and metabolism of cyclohexane and cyclohexanone were investigated using a similar study protocol.

Animals

Other limited data on specific aspects of toxicokinetics of cyclohexanol in animals exist:

Chinchilla rabbits given 260 mg/kg bw of labelled cyclohexanol excreted 65% of the dose in the urine as glucuronides and 6% of the dose as trans-cyclohexane-1,2-diol glucuronide. 68-75% of the radioactivity was excreted in the urine (Elliot et al., 1959).

In another study (Martis et al., 1980) a single dose of 323 mg/kg of cyclohexanol was applied intravenously to a dog. Blood and urine samples were collected at predetermined intervals for a period of 24 hours. Cyclohexanol was found to clear from the body rapidly (elimination half-life of 99 min). The plasma concentration curve showed a mono exponential decline.

 

Dermal absorption

Little quantitative data on absorption of cyclohexanol in animals are available. Fiserova-Bergerova et al. (1990) estimated dermal uptake of 2520 mg cyclohexanol per hour over a surface area of 2000 cm2 skin using the calculated dermal flux rate of 1.26 mg x cm-2 x h-1 (model calculation).