1,1'-(1-phenylethane-1,1-diyl)bis[4-(heptyloxy)benzene]

Endpoint summary

Description of key information

There are no specific studies available on the ADME of 4,4’-(1-phenylethane-1,1-diyl)bis(heptyloxybenzene). However, data is available from the physico-chemical parameters, in vitro and in vivo toxicology studies and these have been employed to predict the ADME for this substance.

 

Absorption

Oral route: The physico-chemical characteristics of 4,4’-(1-phenylethane-1,1-diyl)bis(heptyloxybenzene) suggest that it is unlikely that the substance would be absorbed via the gastro-intestinal tract. Typically high oral bioavailability is associated with low molecular weight and high water solubility. The MW of this substance is just below 500 and it is not soluble in water. The reported Log P value of over 7.02 indicates that permeability will be decreased. A pKa (dissociation constant) in water has not been determined. However, dose-dependent myofiber necrosis (adverse effect) was observed in the heart of male parental animals in a 28-day repeat-dose oral toxicity study in rats. This shows that there is sufficient systemic absorption occurring following oral exposure to cause an effect.

 

Dermal route: A substance with low water solubility and a Log P value of over 7.02 could be considered incapable of systemic absorption through the dermal route. 4,4’-(1-phenylethane-1,1-diyl)bis(heptyloxybenzene) is a liquid with a MW 486.35, a Log P value of over 7.02 and is insoluble in water at less than 4.4x10-7 g/L. These parameters suggest that the substance is unlikely to be absorbed via the skin. This is because the substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. However, clinical effects were reported in an acute dermal toxicity study, which indicates that there is sufficient absorption of the substance occurring following dermal route exposure to cause an effect. 4,4’-(1-phenylethane-1,1-diyl)bis(heptyloxybenzene) is not classified as a skin sensitiser nor is it a dermal irritant based on in vivo data. The low irritancy potential of 4,4’-(1-phenylethane-1,1-diyl)bis(heptyloxybenzene) might be attributed to low skin penetration. Irritation usually occurs as a result of skin penetration giving rise to an inflammatory response (irritation). The lack of sensitisation potential of 4,4’-(1-phenylethane-1,1-diyl)bis(heptyloxybenzene) may indicate poor absorption by the skin, therefore unlikely to enter the systemic circulation. It is worth noting that these data do not provide conclusive evidence for the absorption potential via the dermal route of exposure. The lack of sensitisation and irritation effects along with the high dermal LD50 could be the result of low toxicological activity rather than poor skin absorption/penetration. However, clinical effects were observed following dermal exposure and this indicates that there is sufficient absorption occurring via this route.

 

Inhalation route: 4,4’-(1-phenylethane-1,1-diyl)bis(heptyloxybenzene) is not expected to be highly volatile given that vapour pressure is very low at 25°C. Therefore, significant exposure as a vapour is unlikely. However, in the absence of further information absorption via this route should be assumed to be 100%.

 

Ocular route: 4,4’-(1-phenylethane-1,1-diyl)bis(heptyloxybenzene) is not irritating to the eyes as evidenced by findings from an in vitro test for ocular exposure. This may be indicative of no ocular absorption. Equally, this could also be as a result of the low toxicological activity of 4,4’-(1-phenylethane-1,1-diyl)bis(heptyloxybenzene) via this route of exposure.

 

Distribution

There are no studies available to evaluate the systemic distribution of 4,4’-(1-phenylethane-1,1-diyl)bis(heptyloxybenzene). There is no indication as to the systemic distribution of 4,4’-(1-phenylethane-1,1-diyl)bis(heptyloxybenzene) from the dermal toxicity studies available. In a 28-day repeat dose oral toxicity study in rats treatment-related adverse effects were observed in the heart indicating that the substance is able to distribute into cardiac tissue following oral exposure. There may be some distribution of the substance to the brain following dermal exposure given that there were some adverse effects (e.g. flat posture, ptosis, lethargy) of the nervous system reported in an acute dermal toxicity study. It is unclear whether 4,4’-(1-phenylethane-1,1-diyl)bis(heptyloxybenzene) would be distributed to other organs. The substance is lipophilic (log P of over 7.02) and thus may be able to distribute to fatty tissues. The absence of toxicity in other tissues could be attributed to the lack of toxicity exerted in those organs investigated or equally be as a result of a lack of tissue distribution.

 

Metabolism

There are no studies available to evaluate the metabolism of 4,4’-(1-phenylethane-1,1-diyl)bis(heptyloxybenzene). However, 4,4’-(1-phenylethane-1,1-diyl)bis(heptyloxybenzene) did not induce mutagenicity or genotoxicity in in vitro studies both in the presence and absence of a metabolic activation system. This could be indicative of a lack of metabolism of the substance, however this could also be taken to mean that both the substance and any metabolites that are formed are not mutagenic or genotoxic.

 

Excretion

There are no studies available to evaluate the excretion of 4,4’-(1-phenylethane-1,1-diyl)bis(heptyloxybenzene). Typically small organic compounds are more likely to be excreted in the urine with biliary excretion more likely for high MW compounds either because of biotransformation by phase 2 conjugation or because the parent substance is innately large (>500 MW). Therefore it is possible that 4,4’-(1-phenylethane-1,1-diyl)bis(heptyloxybenzene) may be excreted predominantly via the urine given that its MW is below 500. However, there is no conclusive evidence for this and it will depend on the extent of metabolism.

 

Summary and conclusions

The MW of 4,4’-(1-phenylethane-1,1-diyl)bis(heptyloxybenzene) is 486.35, it is not water soluble and has a Log P of over 7.02 (lipophilic). The MW and physico-chemical properties of4,4’-(1-phenylethane-1,1-diyl)bis(heptyloxybenzene)indicate that it is unlikely to be absorbed via the oral and dermal routes of exposure.Repeated dose (oral) exposure to4,4’-(1-phenylethane-1,1-diyl)bis(heptyloxybenzene) resulted in treatment-related adverse effects in the heart tissue. This confirms that there is sufficient systemic absorption via the oral route of exposure with distribution to the heart. Treatment-related clinical effects were observed in experimental animals following dermal exposure, which indicates that there is some skin absorption occurring. The physical chemical properties of the substance indicates that it is has the potential to distribute to other organs, but in the absence of any adverse effects in the other tissues in the subacute toxicity study makes it difficult to conclude definitively. The absence of irritation (moderate) or sensitization effects could be the result of a lack of significant skin penetration/absorption, but equally this could be due to the low toxicological activity of the substance. Exposure via the inhalation route to4,4’-(1-phenylethane-1,1-diyl)bis(heptyloxybenzene)is unlikely given that the substance has a very low vapour pressure. However, in the absence of further information any absorption via this route should be assumed to be 100%. There is no evidence regarding the metabolism, metabolite fate or excretion of4,4’-(1-phenylethane-1,1-diyl)bis(heptyloxybenzene). Excretion via the kidneys is considered likely based on the Log P and relatively low MW of the constituents of the substance. The high Log P indicates that bioaccumulation is likely.