1,4-bis[(vinyloxy)methyl]cyclohexane

Endpoint summary

Additional information

1,4-bis[(vinyloxy)methyl]cyclohexane (CAS 17351-75-6) is a non-volatile (vapour pressure 0.014 hPa), lipophilic, poorly water soluble substance (log Po/w 3.65 at 20 °C; 24.5 mg/l at 20 °C).There is no study available concerning absorption, metabolism and excretion.

It can be assumed that 1,4-bis[(vinyloxy)methyl]cyclohexane is readily absorbed in the gastrointestinal tract. Due to the double bond in direct neighborhood to the ether bond, the ether bond is not resistant to enzymatic cleavage in the liver or to hydrolysis in the gastric fluid yielding acetaldehyde formed from the vinyl group and 1,4 cyclohexanediol. Acetaldehyde is also naturally occurring in human metabolism and therefore will be utilized by the human body. In humans, 1,4 clohexandiol is excreted mainly unchanged via kidneys. Thus, there is no bioaccumulation of 1,4-bis[(vinyloxy)methyl]cyclohexane expected.

Concerning log Po/w dermal absorption is to be anticipated which is proven by the skin sensitizing properties of the compound. However due to the reactivity of the molecule the amount beings systemically available is expected to be low. Inhalation is not a relevant route of exposure for this non-volatile vinyl ether.

Due to the overwhelming amount of literature there are only some key literature given to cover the main aspects of the supposed metabolism.

Sone et al. showed that the vinyl moiety of various aliphatic and aryl vinyl ethers was subject to microsomal oxidation resulting in the respective epoxides. The authors demonstrated that the oxidation rates by hepatic microsomes from PCB-pretreated rats were significantly higher for various aryl vinyl ethers (range: 8.2 – 14.6 nmol/mg protein/min) than for the two tested aliphatic vinyl ethers (EVE and n-butyl vinyl ether). The oxidation rates were 2.9 nmol/mg protein/min) for EVE, and 5.1 nmol/mg protein/min for n-butyl vinyl ether, respectively. Because of their instability, the epoxides of EVE and n-butyl vinyl ether could not be isolated. Epoxid stability strongly correlates with mutagenicity in strain TA100 with metabolic activation. Because no mutagenicity was discovered in TA 100 with metabolic activation it was concluded that the corresponding epoxides are unstable.

Rapid complete hydrolysis (100%) of IBVE to form isobutanol and acetaldehyde was shown to occur in simulated gastric fluid (SCF, 1998). Similarly, IBVE hydrolyzed completely within minutes to acetaldehyde and isobutanol when it was incubated with simulated gastric fluid at a pH of 1.5 in another study (BASF AG, 1994). In the latter study, hydrolysis was only approximately 20 % in simulated saliva (pH about 9) at all sampling intervals from 0 through 4 hours after the incubation was started, and approximately 40 % after 1, 2, and 4 hours of incubation with intestinal fluid (pH 7.5). In all simulants, remarkable concentrations of acetaldehyde were found even when no or minor hydrolysis occurred, which, according to the study authors, may be due to the production of acetaldehyde during the derivatization step prior to the analysis by liquid chromatography. The results show that acetaldehyde is a main hydrolysis product of IBVE; no conclusions could however be drawn on the rate of acetaldehyde formation during the ongoing hydrolysis (BASF AG, 1994).

In a study originally investigated the metabolism of cyclohexane and cyclohexanone after inhalation 4 subjects ingested 232 mg each of the two main metabolites 1,2- and 1,4 cyclohexandiol (Mráz, 1998). Volunteers who ingested 1,2- and 1,4-CH-diol excreted 57% and 76% of the delivered dose, respectively, over the following 72 h. 1,2-CH-diol appeared in urine as glucuronide (>=95%), whereas 1,4-CH-diol was excreted unconjugated. On the basis of the assumption that the monoexponential elimination as observed during the first 72-h period would be maintained until complete removal from the body, the total urinary recovery of CH-diols did not exceed 60% and 80%, respectively. The authors concluded that this indicates that CH-diols undergo further metabolism, albeit to a minor extent. However, the contribution of incomplete absorption is not clear.

Refernces used:

BASF AG (1994). Hydrolysis tests of vinyl isobutylether. Study report dated 21 December 1994.

Mráz J, Gálová E, Nohová H, and Vítková D (1998) 1,2- and 1,4 Cyclohexandiol: major urinary metabolites and biomarkers of exposure to cyclohexane, cyclohexanone and cyclohexanol in humans. Int Arch. Occ Environ Health 71, 560-565.

SCF (1998). Opinion of the Scientific Committee on Food on an additional list of monomers and additives for food contact materials, adopted the 19 March 1998. Annex II to document XXIV/1269/98, European Commission, Bruxelles.

Sone T, Isobe M, and Takabatake E (1989). Comparative studies on the metabolism and muta­genicity of vinyl ethers. J. Pharmacobio-Dyn. 12, 345-351.