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Description of key information

4-tert-butylcyclohexyl acetate is bioavailable via oral route. Limited absorption and systemic exposure via inhalation and dermal routes is anticipated. The substance will cross cellular barriers and will be distributed into fatty tissues. 4-tert-butylcyclohexyl acetate is expected to be readily hydrolyse and to be mainly excreted in urine.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

There is no specific requirement to generate toxicokinetic information in REACH. Therefore, the toxicokinetic profile of 4-tert-butylcyclohexyl acetate (i.e. absorption, distribution, metabolism and elimination) was derived from the relevant available information. The physical chemical characteristics of the substance, the results obtained from acute and repeated-dose toxicity studies, as well as information gained from genotoxicity assays were used to predict the toxicokinetic behavior of 4-tert-butylcyclohexyl acetate.

Physico chemical properties:

4-tert-butylcyclohexyl acetate is a multi-constituent substance, composed of cis- and- trans isomers, both having a relatively low molecular weight of 198.3 g/mol. The substance is highly lipophilic based on its octanol/water partition coefficient (log Kow = 4.8). The cis-isomer is slightly water soluble (<39.6 mg/L, LOQ), and not volatile (vapour pressure = 7.9 Pa at 25°C). No significant difference is anticipated for the multi-constituent substance.


The physical chemical characteristics described above suggest that 4-tert-butylcyclohexyl acetate is of adequate molecular size to participate in endogenous absorption mechanisms within the mammalian gastrointestinal tract. Being lipophilic, 4-tert-butylcyclohexyl acetate may be expected to cross gastrointestinal epithelial barriers even if the absorption may be limited by the inability of the substance to dissolve into gastro-intestinal fluids and hence make contact with the mucosal surface. Moreover, the absorption will be enhanced if 4-tert-butylcyclohexyl acetate undergoes micellular solubilisation by bile salts. Substances absorbed as micelles will enter the circulation via the lymphatic system, bypassing the liver. It is also expected that the acidic conditions of the stomach will promote hydrolysis to 4-tert-butylcyclohexanol, which has an approximately two-times higher water solubility (<100 mg/L) and lower log Kow (3.06) than the parent, which should make it more readily absorbed than the parent molecule. 4-tert-butylcyclohexanol is also the anticipated primary metabolite of the parent molecule, see below.

This assumption is supported by the observation of mortality and signs of systemic toxicity at and above 1872 mg/kg bw in the acute oral gavage toxicity study conducted on 4-tert-butylcyclohexyl acetate. A pre-natal/developmental toxicity study identified a NOAEL of 160 mg/kg bw/day based on one maternal mortality, body weight losses, reduced body weight gains and feed consumption values observed at 640 mg/kg bw/day. Similar findings were not observed in the 28-day conducted on the cis-isomer.

The observation of systemic effects indicates the oral bioavailability of 4-tert-butylcyclohexyl acetate and/or its metabolites.

Regarding dermal absorption, 4-tert-butylcyclohexyl acetate being lipophilic (log Kow = 4.8), the rate of uptake into the stratum corneum is expected to be high while the rate of penetration is likely to be limited by the rate of transfer between the stratum corneum and the epidermis. However, 4-tert-butylcyclohexyl acetate being identified as a skin sensitizer, some uptake must occur although it may only be a small fraction of the applied dose. Enhanced skin penetration is not expected since 4-tert-butylcyclohexyl acetate is not a skin irritant or corrosive. These assumptions are supported by the absence of systemic effects following single-dose dermal application of 4-tert-butylcyclohexyl acetate, up to 4680 mg/kg bw which would suggest a limited systemic absorption through cutaneous barriers.

The potential for inhalation toxicity was not evaluated in vivo. However, the vapour pressure of cis-4-tert-butylcyclohexyl acetate (7.9 Pa at 25°C) indicated an absence of volatility and therefore no exposure by inhalation is anticipated. Thus, at ambient temperature, no respiratory absorption of 4-tert-butylcyclohexyl acetate is expected under normal use and handling of the substance


Systemic distribution of 4-tert-butylcyclohexyl acetate can be predicted from its physical chemical characteristics. Considering that the substance is highly lipophilic (log Pow >4) and slightly water soluble, it is suggested that, upon systemic absorption, 4-tert-butylcyclohexyl acetate may be transported through the circulatory system in association with a carrier molecule such as a lipoprotein or other macromolecule. Afterwards, based on its lipophilic character, the substance will readily cross cellular barriers or will be distributed into fatty tissues with a low potential to accumulate.

Metabolism and excretion:

4-tert-butylcyclohexyl acetate is expected to be readily hydrolysed to its corresponding alcohol, 4-tert-butylcyclohexanol, and the resulting acid, acetic acid, by carboxylesterases. Subsequently the major metabolic pathway is the conjugation of 4-tert-butylcyclohexanol with glucuronic acid to yield the corresponding glucuronide that is mainly excreted in the urine. Since alkyl-substituted cyclohexanols are interconvertible with their corresponding ketones in vivo, the metabolic pathways from studies on cyclohexanone derivatives are directly relevant to the hazard assessment of cyclohexanol derivatives. To a very minor extent, alicyclic ketones 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. (FFHPVC, 2003)

Following dermal exposure, highly lipophilic substances, such as 4-tert-butylcyclohexyl acetate, that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with skin cells.