Uptake, metabolism and elimination of cyclohexanone in humans

Abstract

The metabolism and toxicokinetics of cyclohexanone (CH-one), an important solvent and chemical intermediate, have been studied in volunteers during and after 8-h exposures to CH-one vapour at a concentration of 101, 207 and 406 mg.m-3. The pulmonary ventilation in these experiments was typically 11 l.min-1 and retention in the respiratory tract was 58%. After exposure to CH-one, 207 mg.m-3, the metabolic yields of cyclohexanol (CH-ol), 1,2- and 1,4-cyclohexanediol (CH-diol) as determined in urine by a gas chromatographic method involving hydrolysis of glucuronide conjugate were 1.0% +/- 0.3%, 39% +/- 5% and 18% +/- 2% (n = 8), respectively. Peak excretion of CH-ol was achieved at the end of the exposure period, after which it decayed rapidly. Elimination of 1,2- and 1,4-CH-diol reached maximum values a few hours following exposure, with subsequent elimination half-times of 16 +/- 2 and 18 +/- 4 h, respectively. Repeated exposure to CH-one vapour (around 200 mg.m-3) for five consecutive days (8 h/day) resulted in cumulative excretion of CH-diols. The permeation rate of CH-one liquid through the skin was 0.037-0.069 mg.cm-2.h-1 (n = 3), indicating that the contribution of percutaneous absorption to total CH-one occupational intake is of minor importance. CH-diols are recommended as biomarkers of exposure to CH-one.

Scientific Opinion on Flavouring Group Evaluation 9, Revision 3 (FGE.09Rev3): Secondary alicyclic saturated and unsaturated alcohols, ketones and esters containing secondary alicyclic alcohols from chemical group 8 and 30, and an ester of a phenol derivative from chemical group 25

“…Cyclohexanol and cyclohexanone were found in the urine of these workers, indicating that the same metabolic pathways are also found in humans (Governa et al, 1987). A recent study in humans shows that the main metabolite in urine after cyclohexanone or cyclohexanol exposure is not cyclohexanolglucuronide as in rabbit and rats, but 1,2-cyclohexanediol-glucuronide (Mráz et al, 1994;Mráz et al, 1998).…”

Cyclohexanone [BAT Value Documentation, 2010]

“…Only the values at the end of the shift are important for threshold limit evaluation. In addition, Mraz et al (1994) have shown that, during an exposure lasting several days, an increase in diol excretion occurs which is 60 % higher on day 3 than on day 1. According to calculations in the BEI documentation of the ACGIH (ACGIH 2004), the corresponding excretion values in the post-shift samples after an exposure to 20 ml cyclohexanone/m 3 are 58 mg 1,2-cyclohexanediol/l urine on day 1 and 82 mg/l urine on day 3.…”

“…Three field studies (Kawai et al 1999;Ong et al 1991a, b) and three laboratory studies from one working group (Mraz et al 1994(Mraz et al , 1998(Mraz et al , 1999 are available for the evaluation of a correlation, which is mainly based on two investigations. Kawai et al (1999) investigated 24 workers who had been exposed to a solvent mixture with cyclohexanone as a component.…”

“…The fact that the external cyclohexanone exposure in this study is only recorded sporadically is a limiting factor. Mraz et al (1994Mraz et al ( , 1998 conducted exposure studies in inhalation chambers with 8 volunteers, who were exposed to cyclohexanone concentrations of 25 ml/m 3 , 50 ml/m 3 and 100 ml/m 3 for 8 hours. Investigations were carried out under rest.…”

Scientific Opinion on Flavouring Group Evaluation 9, Revision 5 (FGE.09Rev5): Secondary alicyclic saturated and unsaturated alcohols, ketones and esters containing secondary alicyclic alcohols from chemical group 8 and 30, and an ester of a phenol derivat

“…A recent study in humans shows that the main metabolite in urine after cyclohexanone or cyclohexanol exposure is not cyclohexanol-glucuronide as in rabbit and rats, but 1,2-cyclohexanediolglucuronide (Mráz et al, 1994;Mráz et al, 1998).…”