Cyclohex-1,4-ylenedimethanol

Endpoint summary

Additional information

1,4-Cyclohexanedimethanol is an isomeric mixture of about of 70 % trans- and 30 % cis-isomers. The metabolic fate and disposition of the test material was investigated in a non-guideline study conducted according to generally acceptable scientific standards of the time. In one phase of the study, groups of four adult male or female Charles River CD-COBS rats received a single dose of 40 (males only) or 400 (both sexes) mg/kg bw [14C] 1,4-cyclohexanedimethanol by oral gavage. Urine, feces and expired air were collected for 48 hours. At necropsy, brain, heart, lung, kidney, fat, liver and carcasses were processed for radioactivity. The test material was rapidly absorbed, metabolized and eliminated with most of the radioactivity recovered in urine (89-96%), feces (1.2-3.0%), and cage washings (1.02-6.61%) by 48 hours. Up to 73% of the dose was excreted in urine by 4 hours. Respiratory [14C] CO2 accounted for only 0.01-0.05% of the dose. Less than 0.5% of the administered radioactivity was retained in the tissues, organs and carcass. Total radioactivity recovered accounted for 97.9-99.7% of the dose. Total excretion of radioactivity did not appear to be dose or sex related; however, females exhibited a slightly slower excretion rate than males but this may be related to the differences in radioactivity recovered in the cage washes. Urine from this phase of the study was treated under a variety of conditions to characterize and identify metabolites. 

To determine the half life of 1,4-cyclohexanedimethanol in blood, additional groups of 3-4 male rats were administered 400 mg/kg bw of non-radioactive test material by oral gavage and blood samples were removed at 0.25- 4 hours after dosing. Blood plasma was extracted with diethyl ether to characterize and identify blood metabolites.  Metabolites in blood and urine were identified by flame ionization gas chromatography and gas chromatography-mass spectrometry. In addition to the parent compound 1,4-cyclohexanedimethanol (both cis- and trans-isomers), cis- and trans-isomers of 4-hydroxymethylcyclohexanecarboxylic acid were detected in the blood. The half-life of 1,4-cyclohexanedimethanol in blood from male rats dosed with 400 mg/kg bw of the test material was about 13 minutes. Unchanged 1,4-cyclohexanedimethanol was not detected in the urine. The major metabolites identified in the urine were cyclohexanedicarboxylic acid (68%) and 4-hydroxymethylcyclohexanecarboxylic acid (31%). The cis-trans ratio of the metabolites excreted in the urine was the same as the ratio of the original dose. Less than 2% of the radioactivity in urine was not fully characterized.

The metabolic pathway for 1,4-cyclohexanedimethanol appears to consist of a series of oxidation reactions that ultimately yield cyclohexanedicarboxylic acid. Methanol groups on the parent compound appear to be oxidized to aldehyde groups which are further oxidized to carboxyl groups. The partial oxidation product, 4-hydroxymethylcyclohexanecarboxylic acid, was identified in both urine and blood while the terminal oxidation product, cyclohexanedicarboxylic acid, was identified in the urine. Urinary ether extraction studies suggest a small amount of radioactivity may be attributed to a glycine conjugate of one or more of the oxidation products of 1,4-cyclohexanedimethanol. 

The results of this study indicate that, at dose levels up to 400 mg/kg bw, orally administered 1,4-cyclohexanedimethanol is rapidly absorbed from the gastrointestinal tract, metabolized, and excreted by male and female rats. Almost all of the orally administered radiolabeled material was excreted in the urine by 48-hours with small amounts recovered in feces and expired air. Less than 0.5% of the dose was retained in the tissues and carcass. Based on the study results, 1,4-cyclohexanedimethanol has a low potential to bioaccumulate.