1-isopropyl-4-methylcyclohexane

Endpoint summary

Description of key information

 The toxicokinetic assessment is based on the test results and a(n) (theoretical) evaluation of uptake, distribution, metabolism and excretion.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

10

Additional information

Toxicokinetic assessment

Introduction

p-Menthane is obtained as a cis/trans mixture by the catalytic hydrogenation of limonene, terpinols, and p-cymene[1]. Raney nickel, platinum, or copper and aluminum oxides are used as catalyst during the production process.This process takes place outside the EU.

P-menthane in its primary form consists of an aliphatic ring-structure (cyclohexane) with an isopropyl group and a methyl group (on 1 and 4 positions). The chemistry of these compounds is very well described and in general alkanes and cycloalkanes (with the exception of cyclo-propane) are not very reactive. The structure can be in cis- or trans-configuration (structure see under chapter 1).

 

Toxicokinetics

 

No data on absorption, distribution excretion and metabolism of the test substance is available. P-menthane is a liquid with a molecular weight of 140 Da, low water solubility and a logKow of 5.6. Physicochemical parameters are summarised in the table below.

 

Table physico-chemical properties of p-menthane

Molecular weight	140.27
State of the substance at 20°C and 101,3 kPa	Liquid
Vapour pressure	260 Pa at 20 °C
Water solubility	0.62 mg/L at 20 °C
Partition coefficient n-octanol/ water	5.6

 

Although extensive data are available on cyclohexane, that may be considered a structural analogue for p-menthane, these data were not taken into account to assess the absorption potential of p-menthane, because of the very different physico-chemical properties of cyclohexane (vapour pressure 12400 Pa, water solubility 52 mg/L and logKow 3.4). However after absorption, metabolism may be similar for both compounds (see section on metabolism). Excretion characteristics will again differ as for cyclohexane a high proportion of the administrated dose is excreted via the respiratory tract. This is not expected for p-menthane that has a much lower volatility.

 

Absorption

Based on the molecular weight, it is expected that p-menthane can be taken up via the gastro-intestinal tract. This is confirmed by the presence of some systemic effects seen in the repeated dose-reproduction study and the 90-day study. The low water solubility however, is expected to lead to suboptimal conditions for absorption, as the bioavailability in the gastro-intestinal tract will be low. The logKow favours uptake in the biological membranes, but transfer into the blood is expected to be limited by the solubility. Therefore, it is assumed that uptake via the oral route will be limited to 10% (default in absence of data).

The molecular weight is <500 and the logKow is above 4; therefore, dermal uptake may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum may be high. Dermal absorption is set at a default value of 10% in absence of data. The fact that no systemic effects were reported in the acute dermal toxicity study and the substance is not sensitising are indications for limited bioavailability after dermal application.

The vapour pressure of p-menthane indicates a potential for exposure, but the low water solubility may limit the amount transported via breathing and thus, decreases the potential of p-menthane to be absorbed in the alveoli. In view of the uses of the test substance, it is not expected that aerosols with respirable particles will be formed. Therefore, in absence of data inhalation, absorption is set at 10%. 

 

Metabolism and excretion

 

No data are available on p-menthane, but for the analogue structures cyclohexane and isopropylcyclohexane some data are available, which are summarized below.

 

Cyclohexane:

Metabolic studies of the microsomal mixed-function oxidase (monooxidase) system in liver confirm hydroxylation of cyclohexane to cyclohexanol. Cyclohexanol is the primary metabolite of cyclohexane; however, in addition, lesser amounts of cyclohexanone and 1,2-cyclohexane-diol have been identified. Cyclohexyl metabolites are conjugated to glucuronides for excretion, but at high doses sulfate conjugation may also occur[2].

 

Isopropylcyclohexane:

The metabolism of isopropylcyclohexane in rats includes oxidation to the alcohol on the isopropyl side-chain and on the ring (1:2), identified in urine. Ring-metabolites included cis- and trans-4-isopropylcyclohexanol with the trans-isomer being the major overall metabolite. In addition, 2‐cyclohexylpropanoic acid, 2‐cyclohexyl‐1,3‐propanediol, 2t‐hydroxy‐4t‐isopropylcyclohexanol, 2c‐hydroxy‐4c‐isopropyl‐cyclohexanol, and 2c‐hydroxy‐4t‐isopropylcyclohexanol were reported[3]. No information on possible conjugation of these metabolites is available and the mass balance is not reported in the publication. There is no information on presence of the parent compound or metabolites in exhaled breath.

 

p-menthane:

It is expected that the metabolism of p-menthane will show similarities to that of cyclohexane and isopropyl cyclohexane. This would mean that oxidation and/or hydroxylation of the ring structure and the substituent groups is expected. However, it cannot be assessed on theoretical grounds what the influence of the methyl group on the primary oxidation site and thus the primary metabolite.

After oxidation, conjugation of the alcohol group with glucuronic acid is expected and concomitant rapid excretion.

 

Conclusion

It is expected that limited amounts of p-menthane are absorbed via the oral, dermal and inhalation route. After uptake it is expected that the compound is rapidly excreted after hydroxylation/oxidation and conjugation with glucuronic acid.

[1]V. N. Ipatieff, H. Pines, E. E. Meisinger, J. Am. Chem. Soc. 71 (1949) inUllmann's Encyclopedia of Industrial Chemistry

[2]EPA Toxicological review of cyclohexane, 2003

[3]G. M. Henningsena, R. A. Salomona, K. O. Yua, I. Lopez, J. Roberts & M. P. Servec, Metabolism of nephrotoxic isopropylcyclohexane in male Fischer 344 rats, Journal of Toxicology and Environmental Health, Volume 24, Issue 1, 1988