1,2- and 1,4-Cyclohexanediol: major urinary metabolites and biomarkers of exposure to cyclohexane, cyclohexanone, and cyclohexanol in humans

Abstract

The metabolism and toxicokinetics of cyclohexane (CH) and cyclohexanol (CH-ol), important solvents and chemical intermediates, were studied in volunteers after 8-h periods of inhalation exposure at concentrations of 1010 and 236 mg m(-3), respectively (occupational exposure limits: CH, 1050 mg m(-3); CH-ol, 200 mg m(-3)). Of the dose of absorbed parent compounds, the yields of urinary CH-ol and 1,2- and 1,4-cyclohexanediol (CH-diol) were 0.5%, 23.4%, and 11.3%, respectively, after exposure to CH and 1.1%, 19.1%, and 8.4%, respectively, after exposure to CH-ol as determined by a gas chromatography method involving hydrolysis of glucuronide conjugates. The metabolic patterns of CH and CH-ol were very similar to that of cyclohexanone (CH-one) studied in the laboratory previously. For all three compounds, peak excretion of CH-ol occurred at the end of the exposure period, after which it decayed rapidly. Excretion curves of 1,2- and 1,4-CH-diol reached maximal values within 0-6 h postexposure, with subsequent elimination half-lives being 14-18 h. The rate-limiting step in the elimination of CH compounds from the organism is renal clearance of CH-diols. Determination of CH-diols in end-of-shift urine samples is recommended as a useful new method of biomonitoring of CH, CH-ol, and CH-one at the workplace. However, due to accumulation of CH-diols in the body during repeated exposure, quantitative relationships between the exposure and the level of CH-diols have to be adjusted according to the day of sampling during the working week.

Cyclohexan [BAT Value Documentation in German language, 2003]

“…Mráz et al 1994Mráz et al , 1998Mutti et al 1981;Ong et al 1991;Perbellini et al 1980;Perbellini und Brugnone 1980;Perico et al 1999;Walter et al 1999;Yasugi et al 1994). Als Grundlage zur Evaluierung eines BAT-Wertes für Cyclohexan lassen sich insbesondere die Feldstudie von Perico et al (1999), ein Simulationsmodell des gleichen Autors, basierend auf Daten von Perbellini et al (1988) und Mráz et al (1994, sowie Laborstudien von Mráz et al (1998), bzw. Walter et al (1999) heranziehen.…”

Cyclohexane [BAT Value Documentation, 2005]

“…Cyclohexanol and the two diols are excreted in man both in glucuronidized and also in free, non-conjugated form (Trabs 1999). As a result of further oxidative biotransformation the amount of cyclohexanol renally excreted is small; only about 10 % of the amount of 1,2-cyclohexanediol excreted (Mráz et al 1998, Trabs 1999, Walter et al 1999. The resulting elimination half-times for 1,2-cyclohexanediol were found to be on average 17.0 ± 5.2 hours (Mráz et al 1998) and 15.8 ± 1.9 hours (Trabs 1999, Walter et al 1999.…”

“…As a result of further oxidative biotransformation the amount of cyclohexanol renally excreted is small; only about 10 % of the amount of 1,2-cyclohexanediol excreted (Mráz et al 1998, Trabs 1999, Walter et al 1999. The resulting elimination half-times for 1,2-cyclohexanediol were found to be on average 17.0 ± 5.2 hours (Mráz et al 1998) and 15.8 ± 1.9 hours (Trabs 1999, Walter et al 1999. The half-time for 1,4-cyclohexanediol determined by Mráz et al 1998 is of a comparable order of magnitude, while Trabs determined a half-time that was around twice as high, with an average value of 31.5 hours (Trabs 1999).…”

“…The resulting elimination half-times for 1,2-cyclohexanediol were found to be on average 17.0 ± 5.2 hours (Mráz et al 1998) and 15.8 ± 1.9 hours (Trabs 1999, Walter et al 1999. The half-time for 1,4-cyclohexanediol determined by Mráz et al 1998 is of a comparable order of magnitude, while Trabs determined a half-time that was around twice as high, with an average value of 31.5 hours (Trabs 1999). This indicates that both metabolites accumulate.…”

“…This indicates that both metabolites accumulate. Cyclohexanol, however, was found to be eliminated with mean half-times of 4.6 hours (Trabs 1999, Walter et al 1999) and 1.5 hours (Mráz et al 1998). For the monitoring of occupationally exposed persons, the cyclohexane metabolites 1,2-cyclohexanediol and 1,4-cyclohexanediol should therefore be determined at the end of the shift after several previous shifts.…”