4-tert-butylcyclohexanol

Endpoint summary

Description of key information

No studies are available. The molecular structure, molecular weight, water solubility and octanol-water partition coefficient of 4-tert-butylcyclohexanol favours oral and dermal absorption. 4-tert-Butylcyclohexanol may be able to cross the blood-brain barrier. It is assumed, that 4-tert-butylcyclohexanol is metabolised if at all only to a limited extent, and it is expected to be excreted via the urine/feces.

Additional information

The following remarks on the toxicokinetics of 4-tert-butylcyclohexanol are based on physicochemical properties as well as on data obtained in a basic dataset. There are no experimental toxicokinetic studies of the compound available and generation of new data is not required as the assessment of the toxicokinetic behaviour of a substance should be performed to the extent that can be derived from the relevant available information (REACh Annex VIII, Section 8.8.1).

 

4-tert-Butylcyclohexanol has a molecular weight of 156.17 g/mol. It is a viscid solid at room temperature and melts in the range from 56 °C (> 94% of cis form) to 83 °C (> 99% of trans form) (Krestinina et al_1984; Eliel and Rerick_1960). The vapour pressure of 4-tert-butylcyclohexanol was determined to be 6 Pa at 25 °C (2011-0116-DKB). The estimated partition coefficient log P is 3.23 at 25 °C (89-0514-DKP) and its water solubility is 264 mg/L at 20 °C (2012-0120-DGP).

 

Absorption

The observation of systemic toxicity following exposure by any route is an indication for substance absorption; however, this will not provide any quantitative information. In general, absorption is likely because of the predominant lipophilic character as well as the low molecular weight of 4-tert-butylcyclohexanol.

A single dose oral toxicity test of 4-tert-butylcyclohexanol in rats revealed a LD50 value of 4200 mg/kg bw (Denine_1973). Mortality was observed in dose groups receiving the test substance in concentrations starting at 2500 mg/kg bw. Immediate stimulation following ataxia was the only clinical sign reported. In a subacute oral toxicity study in rats, the animals showed partly severe clinical symptoms after treatment at a dose of 300 mg/kg bw/day and effects on motoractivity and changes in body weight were observed at this dose level (98-0184-DGT). These observations indicate that absorption of the compound via the gastrointestinal tract (at least to some extent) has evidently occurred. Water solubility is moderate with 264 mg/L; therefore, dissolving of the compound in the gastrointestinal fluids will be possible but limited.

The gastrointestinal absorption is reported as 100% for a dose of 1 mg (Danish EPA Database, 2004).

Concerning dermal acute toxicity no detailed information is available. In a study in rats a LD50 value greater than 5000 mg/kg bw was determined. No mortality occurred and no signs of toxicity were reported. However, the study is not considered sufficient for assessment.

To gain more information on dermal absorption, the permeability of the skin can be calculated based on the physico-chemical properties of 4-tert-butylcyclohexanol. The dermal permeability constant Kp of 4-tert-butylcyclohexanol was estimated to be 0.0395 cm/h using the QSAR published by Potts and Guy (1992) considering the log P of 3.23 and the molecular weight of 156.17 g/mol. Furthermore, the maximum flux Imax (Imax = Kp [cm/h] x water solubility [mg/cm³]) was calculated similar to the approach taken by Kroes et al. (2007) and resulted in a value of 10.44 µg/cm²/h for 4-tert-butylcyclohexanol. This flux value represents a high dermal absorption potential and can be assigned to a dermal absorption of 80% (Mostert and Goergens, 2011). Therefore, the dermal bioavailability can be considered high.

 

4-tert-butylcyclohexanol is a solid of low vapour pressure (6 Pa at 25 °C). In an inhalation risk test with 4-tert-butylcyclohexanol no mortality and no systemic effects were noted in rats exposed to a saturated vapour atmosphere (at 20 °C) for 8 h (BASF, 1975). In addition, the state of substance can be described as pasty or viscid and therefore the development and inhalation of dust is unlikely. Thus inhalation is considered to be of no concern as the vapour pressure is very low and the formation of aerosols is considered negligible.

 

Rarely, exogenous compounds (e. g. similar to a nutrient) may be taken up via a carrier mediated or active transport mechanism. However, prediction in this direction is not generally possible. Active transport (efflux) mechanisms also exist to remove exogenous substances from gastrointestinal epithelial cells thereby limiting entry into the systemic circulation. From physicochemical data, identification of substances ready for efflux is not possible.

 

Distribution

Some information or indication on the distribution of the compound in the body might be derived from the available physico-chemical and toxicological data. Once a substance has entered the systemic circulation, its distribution pattern is likely to be similar for all administration routes. However, first pass effects after oral exposure influence the distribution pattern and distribution of metabolites is presumably different to that of the parent compound. The smaller a molecule, the wider is its distribution throughout the body. As no target organ could be identified after the toxicological studies, distribution throughout the body cannot be predicted or presumed. Membrane-crossing substances with a moderate log P and molecular weight, as it is the case for 4-tert-butylcyclohexanol, will be able to cross the blood-brain and blood-testes barrier and reach the central nervous system (CNS) or testes, respectively. Due to the effects in neurobehaviour in the oral repeated dose study, crossing of the blood-brain barrier of the test compound is likely. There is no indication of effects on spermatogenesis, thus, no conclusion regarding blood-testes barrier penetration can be drawn.

 

Bioaccumulation

Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, highly lipophilic (log P > 4) compounds tend to have longer half-lives. Thus, they potentially accumulate within the body in adipose tissue, especially after frequent exposure (e.g. at daily work) and the body burden can be maintained for long periods of time. After the stop of exposure, the substance will be gradually eliminated dependent on its half-life. During mobilization of fat reserves, e.g. under stress, during fasting or lactation, release of the substance into the serum or breast milk is likely, where suddenly high substance levels may be reached.

After dermal exposure, highly lipophilic compounds may persist in the stratum corneum, as systemic absorbance is hindered.

Substances with log P values of ≤ 3 would be unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace but may accumulate during continuous exposures. 4-tert-butylcyclohexanol is rather lipophilic with a log P of 3.23 and thus accumulation in adipose tissue during 8 h-workday scenarios cannot be excluded, but is not likely to be strong. 

 

Metabolism

Prediction of compound metabolism based on physico-chemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo. An important role plays the liver where many metabolites may arise. 9 possible liver metabolites were predicted with the OECD Toolbox 3.0, three thereof with a certain hazard potential as they contain a Schiff base structure. However, no elevated toxicity was observed after oral treatment, nor were there evidence for differences in toxic potencies due to metabolic changes in in vitro genotoxicity tests. No difference could be seen with respect to the addition of metabolic activation in an Ames test (2012-0124-DGM), a chromosome aberration test (97-0366-DGM), or a mouse lymphoma assay (2012-0126-DGM) with 4-tert-butylcyclohexanol (i.e. no increased mutagenicity or cytotoxicity in treatments with metabolic activation). There is, thus, no indication for reactive metabolites of 4-tert-butylcyclohexanol. A publication is available (Henningsen et al., 1987) dealing with the metabolism of t-butylcyclohexane. 4-tert-Butylcyclohexanol was found as its main metabolite excreted via urine. Thus, it can be assumed that 4-tert-butylcyclohexanol is not strongly metabolised further.

 

Excretion

Only limited conclusions on excretion of a compound can be drawn based on physico-chemical data. Due to metabolic changes, the finally excreted compound may have few or none of the physico-chemical properties of the parent compound. In addition, conjugation of the substance may lead to very different molecular weights of the final product. 4-tert-butylcyclohexanol and its potential metabolites have a molecular weight lower than 500 g/mol, thus, excretion via faeces/urine is likely. As mentioned above, the results presented in the publication by Henningsen et al. (1987) supports the assumption of excretion of 4-tert-butylcyclohexanol via urine.

 

References:

Danish EPA Database, 2004: http://130.226.165.14/

 

Kroes et al., 2007. Application of the threshold of toxicological concern (TTC) to the safety evaluation of cosmetic ingredients.Food Chem Toxicol 45:2533-2562

 

Henningsen, G.M. et al.,The metabolism of t-butylcyclohexane in Fischer-344 male rats with hyaline droplet nephropathy. Toxicology Letters 39: 313-318 (1987)

 

Mostert and Goergens (2011) Dermal DNEL setting: using QSAR predictions for dermal absorption for refined route-to-route extrapolation. The Toxicologist: 107

 

Potts, R.O. and Guy, R.H., Predicting skin permeability. Pharm. Res. 9: 663-669 (1992)