Cyclohexane-1,2,4-triyltris(ethylene)

Endpoint summary

Description of key information

No toxicokinetic studies are available. The toxicokinetics of TVCH was assessed based on physico-chemical dataand the toxicological profile.

The molecular weight, water solubility, octanol/water partition coefficient and QSAR predictions favours oral and inhalative absorption, whereas dermal absorption is considered to be very low. TVCH may be distributed throughout the body in a moderate way. It is assumed that TVCH does not build reactive metabolites.

Additional information

General

No experimental data on absorption, distribution, metabolism and excretion of TVCH (1,2,4 -Trivinylcyclohexan) are available.

According to REACH, the human health hazard assessment shall consider the toxicokinetic profile (Annex I). However, generation of new data is not required as the assessment of the toxicokinetic behaviour of the substance should be performed to the extent that can be derived from the relevant available information (REACH Annex VIII, 8.8.1).

Qualitative information on toxicokinetic behaviour can be derived taking into account the information on the chemical properties of the compound as well as data obtained in a basic data set. Furthermore, the behavior of the formed metabolites within the body should be taken in account.

 

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.

Results from available toxicity tests show that TVCH is irritating to the skin and a skin sensitizer. Furthermore, transient narcotic effects were observed after single oral administration of very high doses. No information on inhalatory toxicity is available. From these data it can be concluded that the substance is at least slightly absorbed and systemically available after oral administration.

To be absorbed, the substance has to cross biological membranes, either by active transport mechanisms or - as being the case for most compounds - by passive diffusion. The latter is dependent on compound properties such as molecular weight, lipophilicity, and water solubility. In general, low molecular weight (MW ≤ 500) and moderate lipophilicity (log Pow values of - 1 to + 4) are favourable for membrane penetration and thus absorption. The molecular weight of TVCH is relatively low with 162.27 g/mol, favouring oral absorption of the compound; however, the substance is highly lipophilic (log Kow of 6.0) and water solubility is low (< 350 µg/L at 20°C) indicating that absorption by passive diffusion may be limited. For highly lipophilic substances uptake by micellular solubilisation may be of particular importance, particularly for those that are poorly soluble in water (1 mg/L or less) (ECHA Guidance R.7c, Chapter R7.12.2.1).

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.

Dermal uptake is expected to be moderate at this molecular weight level (< 100: dermal uptake high; > 500: no dermal uptake). However, for dermal uptake, sufficient water solubility is needed for the partitioning from the stratum corneum into the epidermis. Therefore, at the water solubility level of below 1 mg/L, dermal uptake is likely to be low. The log Pow of 6.0 supports this estimation; at values above 6 the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. As a conclusion, based on the high log P outside the range of - 1 to 4, a default value of 10% skin absorption can be used for risk assessment (ECHA Guidance R.7c, Chapter R7.12.2.1).

For respiratory uptake it can be considered that generally liquids would readily diffuse/dissolve into the mucus lining. Thereby, lipophilic substances with moderate log P values (between - 1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. However, any lipophilic compound may be taken up by micellular solubilisation. This mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4) like TVCH, which are poorly soluble in water (1 mg/L or less) and that would otherwise be poorly absorbed (ECHA Guidance R.7c, Chapter R7.12.2.1).

Moreover, QSAR predictions were taken into account. QSAR predictions obtained from the Danish (Q)SAR database (2009) for TVCH the gastrointestinal absorption to be about 100% for a 1 mg dose, whereas dermal uptake is predicted to be very low (0.000667 mg/cm2/event).

It can be summarized that the low molecular weight of TVCH of 162.27 g/mol would allow direct absorption through membranes, however, passive diffusion is most probably very limited by the high lipophilicity and the low water solubility. It this therefore assumed that oral and respiratory uptake might roughly be in the same moderate range; whereas dermal absorption is considered to be very low. 

 

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. The molecular weight of 162.27 g/mol of TVCH indicates a moderate distribution in the body. Through its high lipophilie (log Pow = 6.0), TVCH is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissue.

The limited results of the toxicity studies identify narcotic effects after single exposure at high doses. The QSAR predictions obtained from the Danish (Q)SAR database (2009) for TVCH calculates a Log brain/blood partition coefficient of 1.162. That means that TVCH is supposed to be very well able to cross the blood-brain barrier and reach the central nervous system (CNS), which is supported by the observed narcotic effects.

 

Bioaccumulation

Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, highly lipophilic (log Pow > 4) compounds tend to have longer biological 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 (log Piw between 4 and 6) compounds may persist in the stratum corneum, as systemic absorbance is hindered.

With the log Pow value of 6.0, TVCH is highly lipophilic and thus will tend to concentrate in adipose tissue during workplace exposure.

 

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. It is even more difficult to predict the extent of metabolism along different pathways and species differences possibly existing.

Evidence for differences in toxic potencies due to metabolic changes can be derived for instance from in vitro genotoxicity tests conducted with or without metabolic activation. Regarding the in vitro genotoxicity of TVCH, studies in mammalian cells regarding gene mutation (OECD 476) and chromosome aberration (OECD 473) revealed a negative outcome with metabolic activation by S9-mix, so that a toxification effect was not observed.

 

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.

 

Literature

Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7c: Endpoint specific guidance, European Chemicals Agency, ECHA-17 -G-11-EN, June 2017.