2-methylcyclohexyl acetate

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Additional information

The common characteristic structural element of cyclic acetates is the acetate unit bound to a mono-, bi- or tri- cyclic alcohol, and the only substituents at the alcohol moiety are alkyl groups. It is assumed that unsubstituted monocyclic esters (e.g. cyclohexyl acetate) are rapidly hydrolysed to cyclohexanol and the component aliphatic carboxylic acids by classes of enzymes recognised as carboxylesterases [1] [2] [3], the most important of which are the beta-esterases. In mammals, these enzymes occur in most tissues [4] [3] but predominate in the hepatocytes [3].

Several studies have been performed on 2-methylcyclohexyl acetate’s analogues confirming the fast hydrolysis of cyclohexyl analogues. In a study conducted by Salzer [5],cis-andtrans-1-methylene-4-isopropenylcyclohexan-2-yl acetate were shown to be rapidly hydrolysed in vitro in the presence of rat liver homogenate. In accordance with Emberger [6], the structurally related ethylene glycol and propylene glycol carbonate esters of (-)-2isopropyl-5-methylcyclohexanol were completely hydrolysed after incubation for 1 hour with rat liver homogenate and according to White et al. [1], it was observed that esters of cyclohexanol were also readily hydrolysed in rat liver homogenate.

As indicated above, 2-methylcyclohexyl acetate is subjected to action of carboxylesterase and will undergo hydrolysis to yield 2-methylcyclohexanol. The major metabolic pathway involves conjugation of 2-methylcyclohexanol excreted primarily as the glucuronic acid conjugates [7] [8] [9] [10] [11]. This metabolic pathway can be derived from studies with t-butylcyclohexane and various cyclohexanol derivatives. Also it is shown that to a very minor extent, alicyclic ketones and secondary alcohols containing an alkyl side-chain undergo oxidation of the side-chain to form polar poly-oxygenated metabolites that are also excreted as the glucuronide or sulfate conjugates mainly in the urine.

Although it has been suggested that lipophilic alcohols or ketones with sterically hindered functional groups would undergo more extensive oxidation of alkyl ring substituents [12], studies on 2-, 3-, or 4-methylcyclohexanol, 2-isopropyl-5methylcyclohexanol, 3,5,5-trimethylcyclohexanol, and even 2-, 3-, or 4-tert-butylsubstituted cyclohexanol or cyclohexanones revealed that conjugation of the cyclohexanol moiety by glucuronic acid is the predominant excretion pathway regardless of the size or position of the ring substituent. In the studies conducted by Lington and Bevan and Topping, it was shown that the metabolic fate of alkyl-substituted cyclohexanol and cyclohexanone derivatives is similar to that of the un-substituted homologues [7] [8].

According to the scientific studies conducted with several analogue substances (see details on Rationale for read-across approach, attached to Section 13), the metabolic fate of the target substance 2-methylcyclohexyl acetate is subjected to the action of carboxylesterase and will undergo hydrolysis to yield 2-methylcyclohexanol. In the next metabolic step 2-methylcyclohexanol, in the same way as the analogue substance 2-isopropyl-5-methylcyclohexanol (menthol), is conjugated with glucuronic acid to yield the corresponding glucuronide that is excreted mainly in the urine. The analogue cyclic acetates are also assumed to be rapidly hydrolysed to the alcohol and the carboxylic acid.

References:

[1] White D. A., Heffron A., Miciak B., Middleton B., Knights S. and Knights D. (1990) Chemical synthesis of dual radiolabelled cyclandelate and its metabolism in rat hepatocytes and mouse J774 cells. Xenobiotica 20, 71.

[2] Ford D.M. and Moran E.J. (1978) Preliminary indications of in vitro hydrolysis of two flavor chemical esters. Private communication to FEMA. Submitted to WHO by the Flavor and Extract Manufacturers Association of the United States, Washington, DC, U.S.A.

[3] Heymann E. (1980) Carboxylesterases and amidases. In Enzymatic Basis of Detoxication. Edited by W. B. Jakoby. 2nd ed. pp. 291-323. Academic Press, New York.

[4] Anders M.W. (1989) Biotransformation and bioactivation of xenobiotics by the kidney. In Intermediary Xenobiotic Metabolism in Animals. Edited by D. H. Hutson, J. Caldwell, and G. D. Paulson. pp. 81-97. Taylor and Francis, New York.

[5] Salzer D. (1998) In Vitro Hydrolysis test cis and trans-p-1(7),8-menthadien-2-yl acetate. Private communication to FEMA. Submitted to WHO by the Flavor and Extract Manufacturers Association of the United States, Washington, DC, U.S.A.

[6] Emberger D. (1994) In vitro hydrolysis test on menthyl propyleneglycol carbonate. Private communication to FEMA. Submitted to WHO by the Flavor and Extract Manufacturers Association of the United States, Washington, DC, U.S.A.

[7] Lington A.W. and Bevan C. (1994) Alcohols in Patty’s Industrial Hygiene and Toxicology, 4th ed. Edited by Clayton and Clayton, Volume IID pp.2585-2760. John Wiley & Sons, Inc., New York.

[8] Topping D.C, Morgott, D.A., David R.M. and O’Donoghue J.L. (1994) Ketones in Patty’s Industrial Hygiene and Toxicology, 4th ed. Edited by Clayton and Clayton, Volume IIC pp.1739-1878. John Wiley & Sons, Inc., New York.

[9] Cheo K.L., Elliott T. H. and Tao R. C. C. (1967) The metabolism of the isomeric tertbutylcyclohexanones. Biochem. J. 104, 198-204.

[10] Elliott T.H., Tao R. C. C. and Williams R.T. (1965) Studies in detoxication. The metabolism of isomeric methylcyclohexanones. Biochemistry Journal 95, 59-65.

[11] Yamaguchi T., Caldwell J. and Farmer P.B. (1994) Metabolic fate of [3H]-l-menthol in the rat. Drug Metabolism and Disposition 22, 616-624.

[12] Nelson S. D., McClanahan R. H., Thomassen D., Gordon W. P. and Knebel N. (1992) Investigations of mechanisms of reactive metabolite formation from (R)-(+)pulegone. Xenobiotica 22, 1157-1164.