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Description of key information

No toxicokinetic studies are available. The toxicokinetics of DINCD was assessed based on physico-chemical data, the toxicological profile and available metabolism studies from the literature.

The molecular weight, water solubility and octanol/water partition coefficient favours oral absorption, whereas dermal and inhalative absorption is considered to be low. DINCD may be distributed throughout the body in a moderate way. It is assumed that DINCD does not build reactive metabolites. It is assumed that DINCD is hydrolyzed by esterase enzymes to cyclohexane-1,4-dicarboxylic acid and the respective alcohol moieties and further oxidised metabolites.

Key value for chemical safety assessment

Additional information

Toxicokinetic statement to 1,4-Cyclohexanedicarboxylic acid,

1,4-diisononyl ester (DINCD)

 

No experimental data on absorption, distribution, metabolism and excretion of DINCD are available.

According to REACH Regulation (EC) No 1907/2006, 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). The assessment of the likely toxicokinetic behaviour of the substance was provided to the extent that can be derived from the relevant available information at the time of the assessment. The assessment is based on the Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, June 2017).

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.

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The observation of systemic toxicity following exposure by any route is an indication for substance absorption; however, this will not provide any quantitative information.The major routes by which toxicants enter the body are via the lungs, the gastrointestinal tract (both being absorption surfaces by nature), and the skin.

Acute oral and dermal toxicity, skin sensitization, eye and skin irritation as well as subacute oral toxicity was not observed with DINCD. No information on inhalatory toxicity is available. Thus, data from toxicity studies do not give any indication for the extend of absorption.

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, or water solubility.As biological membranes are built as layers consisting of lipid as well as aqueous phases a process like this requires a substance to be soluble both in lipid and water.In general, log P values of -1 to +4 are favorable for membrane penetration and thus absorption.

The molecular weight of DINCD is relatively moderate with 422,6 g/mol. Dermal uptake can be seen to be low at this molecular weight level (<100: dermal uptake high; >500: no dermal uptake). This is supported by the determined water solubility value being <25 µg/l. Also for dermal uptake, sufficient water solubility is needed for the partitioning from the stratum corneum into the epidermis. The measured log P of 9,4-10,6 of DINCD indicates that the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin.

All in all, it is expected that DINCD will be poorly absorbed via dermal route.

In addition, the respiratory absorption is expected to be very low, because DINCD is low volatile due to its vapor pressure of < 0,1 hPA at 20°C.

The molecular weight of DINCD (< 500) show that the gastro-intestinal tract provides a route of absorption, following oral administration, before entering the circulatory system via the blood. Indeed, the absorption of highly lipophilic substances like DINCD (log P > 4) may be limited by the inability to dissolve into GI fluids and hence make contact with the mucosal surface.

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. The rate of distribution and the target tissues will be determined by the blood flow through the organ, the ability of the substance to cross membranes and capillaries, and its relative affinity for the various tissues. 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.

Since DINCD is very lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration. The substance may potentially accumulate in the adipose tissue due to the high log octanol/water partition coefficient value.

The smaller a molecule, the wider is its distribution throughout the body.The molecular weight of 422,6 g/mol of DINCD indicates a moderate distribution in the body. The results of the toxicity studies identify no target organ toxicity. In addition, no effects on spermatogenesis were observed in the combined repeated dose toxicity study, thus no conclusion regarding blood-testes barrier penetration can be drawn.The lack of evidence to suggest the test item is a skin sensitizer suggests that it does not bind to carrier proteins in the circulatory system.

 

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. 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 (log P between 4 and 6) may persist in the stratum corneum, as systemic absorbance is hindered. With the log P value of 9,4 - 10,6, DINCD is highly lipophilic and thus likely to accumulate in adipose tissue during 8h-working day scenarios.

At present, a study is performed to investigate the biological half-live of DINCD in rat serum after intravenous application over different times. This study gives details of how long the compound will stay in that system until it is lost by mainly excretion, degradation or metabolism. This resulted in the amount of a substance eliminated from the blood in unit time, is the product of clearance (the volume of blood cleared per unit time) and concentration (the amount of a compound per unit volume).

 

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 DINCD, all studies (Ames test, chromosome aberration and mouse lymphoma mutation assay), revealed a negative outcome with metabolic activation, which does not show a toxification effect.

For the analogue substance di-isononyl cyclohexane-1,2-dicarboxylate (DINCH) a lot of metabolism data exists. In a human metabolism study with DINCH, cyclohexane-1,2-dicarboxylic acid was identified as the major urinary metabolite (Fromme et al., 2016). Koch et al. (2007) and Silva et al. (2012) assume that in principle the metabolism of DINCH is similar to DINP and other high molecular weight (HMW) phthalates. According to that, a potential metabolite of DINCD is cyclohexane-1,4-dicarboxylic acid and further oxidized metabolites. Unfortunately, there is no publicly available toxicokinetic data to cyclohexane-1,4-dicarboxylic acid.

Another analogue substance class are terephthalate esters. Ball and co-workers (2012) described a metabolic pathway of terephthalate esters in a category approach. Ball et al. (2012) concluded that the category members are all hydrolyzed by esterase enzymes to TPA and the respective alcohol moieties.

No experimental data on metabolism of DINCD is available, for which reason a further assessment is not possible.

 

Excretion

Only limited conclusions on excretion of a compound can be drawn based on physico-chemical properties of the compound and its various metabolites. 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.

Since no information regarding the metabolism of DINCD is available, no prediction of excretion routes is possible.

Due to its high molecular weight, poor water solubility, an urinary excretion of the parent compound DINCD will be very low.Therefore, biliary excretion may be a significant route for this material. As there is evidence of hepatic metabolism this does not, however, rule out urinary excretion.

The main reason for xenobiotic metabolism is to render the product more water-soluble thereby facilitating urinary excretion. Any test item that is not absorbed will be excreted in the faeces.

 

 

Literature

Fromme H., Schütze A., Lahrz T., Kraft M., Fembacher L., Siewering S., Burkardt R., Dietrich S., Koch H.M., Völkel W., Non-phthalate plasticizers in German daycare centers and human biomonitoring of DINCH metabolites in children attending the centers (LUPE 3), Int J Hyg Environ Health, 219(1):33-9, 2016.

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

Koch H.M., Angerer, J., Di-iso-nonylphthalate (DINP) metabolites in human urine after a single oral dose of deuterium-labelled DINP, Int. J. Hyg. Environ Health 210 (1), 9–19, 2007.

Silva M.J., Furr J., Preau J.L.J., Samandar E., Earl Gray L., Calafat A.M., Identification of potential biomarkers of exposure to di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), an alternative for phthalate plasticizers. J Expo Sci Environ Epidemiol, 22 (2), 204–211, 2012.