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Toxicokinetics

Physical chemical properties

The substance is a liquid with a molecular weight of 358.475 g/mol and is almost insoluble in water (0.052 mg/L at 20 °C). The Log P value is >6.5 (at 23 °C, pH 6.1). The substance has a low vapour pressure below 1E-4Pa at room temperature. These physico-chemical properties of the substance will enable qualitative judgements of the toxicokinetic behaviour (Guidance on information requirements and chemical safety assessment Chapter R.7.c: Endpoint specific guidance, R.7.12 Guidance on Toxicokinetics).

Absorption

GI absorption

The relatively low molecular weight (< 500) of the substance is favourable for absorption, however the substance is highly lipophilic which indicates poor absorption. Considering the high Log P value (Log P > 4) combined with the high hydrophobicity (water solubility < 1 mg/L), absorption by micellular solubilization may be of particular importance. Furthermore, the substance was found to be irritating to the skin (Henkel, 1991), which may enhance absorption because of damage to cell membranes. No mortality was observed in rats following a single oral exposure to 2000.0 mg/kg bw (administrated by gavage, using 2% carboxymethyl cellulose and 0.5% cremophor as vehicle). However, all animals showed reduced activity in the first 3 hours following exposure, indicating systemic availability (Henkel, 1986). No further data on oral administration are available for the substance. However, Article 13 of the REACH legislation states that, in case no appropriate animal studies are available for assessment, information should be generated whenever possible by means other than vertebrate animal tests, i.e. applying alternative methods such as in vitro tests, QSARs, grouping and read-across. A two generation reproduction toxicity study is available with the structural analogue dicyclohexyl phthalate (CAS No. 84-61-7), which differs from the target substance only by two methyl groups on each cyclohexylgroup. Based on the structural similarity ADME properties are expected to be similar.In the two generation reproduction toxicity study dicyclohexyl phthalate was continuously administrated to rats via the feed (at doses of 24.0, 1200.0 and 6000.0 ppm) for at least 90 days. Adverse effects included a reduced food consumption and compound intake, reduced body weights, and histopathologic effects. These findings support the conclusion that the target substance is systemically available following oral administration.

Respiratory absorption

The substance is a lipophilic liquid and may therefore readily diffuse/dissolve into the mucus lining the respiratory tract followed by direct absorption across the respiratory tract epithelium. Furthermore, considering the potential for absorption via the GI tract, absorption via the respiratory tract is likely. However, considering the low vapour pressure below 1 E-4 Pa resulting in a saturated vapour concentration of 0.015 mg/m³, the substance is virtually unavailable for respiration in the vapour phase. Exposure could only arise during tasks with aerosol formation.

Dermal absorption

The molecular weight of the substance (358.475 g/mol) is below 500, and therefore despite the high lipophilicity (Log P value >6.5), a default value of 100% skin absorption is recommended by Chapter R.7.c. However, as mentioned in Table R.7.12-3, the substance must be sufficiently water soluble in water to partition from the stratum corneum into the epidermis. Considering the low water solubility of the substance (0.052 mg/L at 20 °C), dermal absorption is expected to be low. However, the substance caused skin sensitization in mice, so dermal uptake can occur, even only at trace amounts.

Metabolism

In vivo data regarding metabolism is not available for the substance. Using the QSAR toolbox, it was predicted that in vivo (rat) the substance is mainly cleared by hydrolysis of the parent compound. For all isomers the respective acid (ortho-phthalic acid) is a common metabolite, while the alcohols differ for each isomer (e.g. 1-methylcyclohexanol or 4-methylcyclohexanol). Phtalates are known to be prone touridine 5'-diphosphoglucuronyl transferase (UGT)-catalyzed conjugation to form glucuronide-conjugated monoesters (Bang et al., 2011). Cyclohexanol can be oxidized by alcohol dehydrogenases to the respective carbonyl compounds, as was also predicted by the QSAR toolbox for4-methylcyclohexanol.

Excretion

The substance is a hydrophobic liquid with a molecular weight of 358.475 g/mol. Characteristics favouring urinary excretion include good water solubility and a low molecular weight (below 300 in the rat). Urinary excretion is therefore not expected for the substance itself. The metabolites can be excreted as such in the urine or faeces, however excretion is highly increased following glucuronide conjugation of the phthalic acid. 

Accumulation

The substance is poorly water soluble and is highly lipophilic (Log P value of >6.5). Based on these physicochemical characteristics, accumulation in the alveolar region of the lung is not expected. In contrast, the high Log P value favours concentration of the substance in the stratum corneum, while the poor water solubility highly limits systemic absorption. The substance will eventually be cleared from the stratum corneum as this is sloughed off. The high log P value also favours concentration of the substance in the adipose tissue, and the potential for accumulation is dependent on the exposure and half-life of the substance. There is no substance-specific data available on the biological half-live. In general, it is assumed that substances with high Log P values have long biological half-lives, and that daily exposure to substances with a Log P value higher than 4 could result in a build-up of that substance within the body. However, since phthalates are known to be prone to extensive metabolism (Meeker et al., 2009), a shorter half-live is to be expected, which leads to the final assessment of ‘low bioaccumulation potential’.

 

References

Bang, D. Y., Lee, I. K., & Lee, B.-M. (2011).Toxicological Characterization of Phthalic Acid.Toxicological Research,27(4), 191–203.

Meeker, J. D., Sathyanarayana, S., & Swan, S. H. (2009). Phthalates and other additives in plastics: human exposure and associated health outcomes.Philosophical Transactions of the Royal Society B: Biological Sciences,364(1526), 2097–2113.