2-isopropyl-5-methyl-cyclohexanone

Endpoint summary

Description of key information

d-Isomenthone is reduced in the rabbit to d-isomenthol and excreted in urine as glucuronide.
l-Menthone is reduced in the rabbit to d-neomenthol and excreted in urine as glucuronide.
Menthone has low skin permeability coefficient Ps=0.40±0.01x10^-3 cm/h

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The investigation of menthone and isomenthone metabolism by Williams (1940) showed that both ketones undergo a reduction to the respective menthols. For example, l-menthone is reduced to d-neomenthol, whereas d-isomenthone is reduced to d-isomenthol. In addition, Miyazawa and Nakanishi (2006) showed that l-menthone in human liver microsomes could metabolise not only to d-neomenthol, but also to 7-hydroxymenthone. No other primary major metabolites of menthone and isomenthone were tested. Thereafter, these menthols conjugate to glucuronic acid and excreted as urinary glucuronides. The extent of conjugation of d-neomenthol is therefore of the same order as that of d-menthol and d-isomenthol. These three d-menthanols are structural isomerides and it appears that this structural variation has no influence on their conjugation with glucuronic acid in the body, although in purely chamical reactions they show considerable differences (Williams, 1940). The rates of glucuronidation for 0.5 mM d-menthol, l-menthol and d-neomenthol were 43, 41 and 51 pmol/min/mg protein, respectively (RIFM Expert Panel et al, 2008). A study in 4 male volunteers showed that urinary excretion of menthol conjugated with glucuronide in the 14 h time period has an average recovery of 40 % of the oral dose of 180 mg of peppermint oil. In another study, one subject dosed with 1 g of menthol excreted in 6 h urine pool 79 % of the dose of menthol as menthol glucuronide (Bhatia et al, 2008). In humans, rats and rabbits, menthol is effeiciently metabolized not only to menthol glucuronide but also to hydroxylated metabolites. Oxidation of the methyl and isopropyl groups of menthol has been reported to provide major metabolites in the rat after administration for up to 20 days. Therefore the major pathways of menthol metabolism are: 1) conjugation of the alcohol with glucuronic acid, 2) side-chain oxidation yielding polar metabolites, which may be conjugated and excreted (MacDougall et al, 2003; RIFM Expert Panel et al, 2008). An oral pharmacokinetic study in 12 volunteers showed that after 100 mg/menthol capsule administration, the plasma half-life of menthol glucuronide averaged 56.2 minutes (95 % confidence interval 51.0-61.5) (Bhatia et al 2008). It could be concluded, that oral exposure to menthol does not conduct to this accumulation in the body due to very short plasmatic half-life.

Gabbanini et al (2009) investigated the diffusion kinetic of menthone through SkinEthic(R) reconstructed human epidermis (RHE) and have found the low permeability coefficient Ps=0.40±0.01x10^-3 cm/h. A percutaneous absorption study in humans showed that after dermal patch containing 37.44 mg menthol application (2 to 8 patches), the mean terminal plasmatic half-live was 4.7±1.6 h. It could be concluded that daily or even twice-daily application of dermal patches is unlikely to result in substantial accumulation because the terminal half-live is relatively short (Bhatia et al, 2008).