Cyclohexane, 1,4-bis(ethoxymethyl)-

Endpoint summary

Description of key information

Based on physicochemical characteristics, particularly water solubility and octanol-water partition coefficient, absorption by the dermal and oral route is expected, while inhalation seems unlikely. This assumption is further supported by the results of the oral, inhalation and dermal acute toxicity studies, revealing some/no systemic effects. Bioaccumulation of the test substance is not considered critical, as it is expected that the substance is metabolized in the human body leading to metabolites with lower logPow and higher water solubility to facilitate excretion. Phase I and II metabolism within liver cells is likely and excretion will presumably occur after renal passage via urine.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

The test substance is a colourless liquid at room temperature with a molecular weight of 200.32 g/mol. The substance is soluble in water (569 mg/L at 20 °C). The log Pow was determined to be in the range of 4.0 – 4.3. The test substance has a low vapour pressure of 0.01 hPa at 20 °C. The test substance is a multi-constituent substance consisting mostly of the two diastereomers (cis: ca. 30 % (w/w), trans: ca. 70 % (w/w)).

 

Absorption

Generally, oral absorption is favoured for molecular weights below 500 g/mol. The moderate water solubility of 569 mg/L enables the substance to dissolve in the gastrointestinal fluids. In combination with the low molecular weight of approximately 200 g/mol the test substance can pass through aqueous pores or can be carried through the epithelial barrier by the bulk passage of water. The log Pow value of 4.3 indicates a highly lipophilic compound and uptake might occur by micellular solubilisation. On the other hand a log Pow of 4.0 is a borderline value, therefore passive diffusion might also occur. Taken together, the physiochemical properties indicate that the test substance becomes bioavailable following the oral route. This assumption is confirmed by the results of the acute and repeated dose toxicity studies. These studies showed impaired general state of the animals, body weight loss and reduced food consumption after oral treatment.

 

Due to the low vapour pressure of the test substance it is unlikely that the substance will be available as a vapour to a large extend, but if it is the case absorption via inhalation route might be possible due to the moderate water solubility. In combination with the water solubility the log Pow range indicates both possible uptake directly across the respiratory tract epithelium by passive diffusion and by micellular solubilisation. As no mortality occurred after exposure of rats to the substance’s aerosol and all observed effects were local, a very limited uptake of the test substance via inhalation is assumed.

 

Dermal absorption might take place, favoured by the water solubility and also by the size of the molecule. The log Pow range indicates a high uptake of the substance into the stratum corneum. In addition it shows a possible limitation of the penetration rate by the rate of transfer between the stratum corneum and the epidermis, thereby limiting the dermal absorption of the test substance up to a certain degree. As the test substance was found to be not skin irritating and not sensitising no direct conclusion from these endpoints can be made for dermal absorption. The absence of effects could be due to lack of harmfulness of the substance or it could be due to the limitation of dermal absorption, resulting in the inability of the substance to pass into the lower parts of the epidermis and into the dermis to induce inflammatory/ immune cell responses.

 

Distribution

As mentioned above, some physicochemical properties of the test substance partially favour systemic absorption following oral and dermal uptake. The systemic absorption is also demonstrated by the adverse effects on general state, body weight and food consumption of the animals after oral treatment.

Direct transport through aqueous pores is likely to be an entry route to the systemic circulation. After being absorbed into the body the test substance is most likely distributed into the interior part of cells due to its lipophilic properties (log Pow 4.0 – 4.3) and in turn the intracellular concentration may be higher than extracellular concentration particularly in adipose tissues.

The logPow of the test substance may indicate a possible bioaccumulation potential. A logPow of 4.0 is a borderline value with the most likely uptake mechanism into cells is passive diffusion. Due to the lipophilic tendency, the test substance may be bioaccumulative in individuals that are frequently exposed. Nevertheless, it is expected that the substance is metabolized in the human body leading to metabolites with lower logPow and higher water solubility to facilitate excretion and consequently bioaccumulation is not considered critical. 

 

Metabolism

The genotoxicity studies indicated no remarkable differences with regard to genotoxicity and cytotoxicity in the presence or absence of metabolic activation systems. No changes were observed for blood chemistry, in the liver and kidneys after repeated oral exposure to the test substance. This indicates that no specific metabolism or interaction mechanism of the test substance and proteins occurs. Therefore it is likely that common protein interaction such as cytochrome P450 oxidases interaction during Phase I metabolism introduce a reactive or polar group in the test substance. Those might be further processed into polar compounds during the metabolism in Phase II.

 

Excretion

The test substance will be excreted most likely in a metabolised form.

The likely excretion pathway of the test substance is via urine. As substances with a molecular weight below 300 g/mol are prone for this pathway and the substance’s molecular weight is 200.32 g/mol, therefore favoring renal excretion.