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EC number: 205-617-0 | CAS number: 144-15-0
There is data available on the physico-chemical properties. The substance is a colourless liquid. The molecular weight of tris(2-ethylhexyl) 2-(acetyloxy)propane-1,2,3-tricarboxylate is 570.8 g/mol. The melting point is reported as -55°C. It has a high boiling point of 267°C. Tris(2-ethylhexyl) 2-(acetyloxy)propane-1,2,3-tricarboxylate is little soluble in water (< 0.05 mg/L at 20°C). The value for LogPow has been reported to be 5.7. The vapour pressure of calculated 0.0318 Pa is considered to be very low. Hydrolysis (as a function of pH) has not been determined.
The citrate substances are not acutely toxic, when administered to rats orally or dermally (oral LD50>2000 mg/kg bw, dermal LD50 >2000 mg/kg bw, respectively). It is not a skin irritant and not eye irritating. Reliable data indicate that this substance to not bear a potential to cause allergic reactions. Additionally, the available data on genetic toxicity do not indicate a potential for mutagenicity in studies according to OECD 471.
It is also important to consider the potential for a substance to accumulate or to be retained within the body. Lipophilic substances have the potential to accumulate within the body (mainly in the adipose tissue), if the dosing interval is shorter than 4 times the whole body half-life. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, substances with high LogPow values tend to have longer half-lives. On this basis, there is the potential for highly lipophilic substances (LogPow >4) to accumulate in biota which are frequently exposed. Highly lipophilic substances (LogPow between 4 and 6) that come into contact with the skin can readily penetrate the lipid rich stratum corneum but are not well absorbed systemically. Although they may persist in the stratum corneum, they will eventually be cleared as the stratum corneum is sloughed off. A turnover time of 12 days has been quoted for skin epithelial cells.
Accordingly, the experimentally determined LogPow value, the water solubility and the predicted behaviour concerning absorption, the logPow value of tris(2-ethylhexyl) 2-(acetyloxy)propane-1,2,3-tricarboxylate might indicate a potential for accumulation, but this is unlikely because of the limited absorption of tris(2-ethylhexyl) 2-(acetyloxy)propane-1,2,3-tricarboxylate.
Route specific toxicity may result from several phenomena, such as hydrolysis within the gastrointestinal or respiratory tracts, also metabolism by gastrointestinal flora or within the gastrointestinal tract epithelia (mainly in the small intestine), respiratory tract epithelia (sites include the nasal cavity, tracheo-bronchial mucosa [Clara cells] and alveoli [type 2 cells]) and skin.
Hydrolysis does apply for tris(2 -ethylhexyl)2 -(acetyloxy)propane-1,2,3 -tricarboxylate. Esterases are enzymes known for their broad substrate specificity and therefore tris(2-ethylhexyl) 2-(acetyloxy)propane-1,2,3-tricarboxylate is expected to be cleaved releasing ethylhexanol as a major intermediate metabolism product. Further metabolites should be acetyl mono (di) ethylhexyl citrate, acetyl citrate, citric and acetic acid.
Metabolism is very likely to occur via the Cytochrome P450 group of metabolising enzymes, as it has been predicted with the TOXTREE modelling tool (Chemservice S.A., 2011, report-no. CSL-DCD-178). The chemicals have been identified to bear primary, secondary and tertiary sites and more than 4 sites for metabolism by the Cytochrome P450 group of metabolising enzymes. The primary, secondary and tertiary sites of metabolism are predicted to be subject to aliphatic hydroxylation.
To identify all possible sites for phase 1 reactions, the molecular structures were investigated in detail. The acetyl- and the methyl groups of ethyl- or butyl-rests are possibly subject to oxidative desalkylation and as a consequence the molecular weight and the length of the molecule would decrease. Additionally, as specified above, the carbon atoms in the chain (in the center and in periphery) are possibly subject to aliphatic hydroxylation, possibly yielding multiple hydroxyl groups, which is facilitating the elimination. The introduced hydroxyl-groups can, however, also be subject to further phase I metabolism by alcohol dehydrogenase to a ketone, which in turn might be metabolised to a carboxylic acid.
In conclusion, it is most likely that the substance of interest will be subject to extensive metabolism by esterases and cytochrome P450 enzymes and break-down in the beta-oxidation or citric acid cycle or in cases subsequent glucuronidation.
The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces (via bile and directly from the gastrointestinal mucosa). For non-polar volatile substances and metabolites exhaled air is an important route of excretion. Substances that are excreted favourable in the urine tend to be water-soluble and of low molecular weight (below 300 in the rat) and be ionized at the pH of urine. Most will have been filtered out of the blood by the kidneys though a small amount may enter the urine directly by passive diffusion and there is the potential for reabsorption into the systemic circulation across the tubular epithelium. Substances that are excreted in the bile tend to be amphipathic (containing both polar and nonpolar regions), hydrophobic/strongly polar and have higher molecular weights and pass through the intestines before they are excreted in the faeces and as a result may undergo entero-hepatic recycling which will prolong their biological half-life. This is particularly a problem for conjugated molecules that are hydrolysed by gastrointestinal bacteria to form smaller more lipid soluble molecules that can then be reabsorbed from the GI tract. Those substances less likely to recirculate are substances having strong polarity and high molecular weight of their own accord. Other substances excreted in the faeces are those that have diffused out of the systemic circulation into the GIT directly, substances which have been removed from the gastrointestinal mucosa by efflux mechanisms and non-absorbed substances that have been ingested or inhaled and subsequently swallowed. Non-ionized and lipid soluble molecules may be excreted in the saliva (where they may be swallowed again) or in the sweat. Highly lipophilic substances that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with skin cells.
Concerning the above mentioned behaviour predicted for its metabolic fate, it is not very likely that the parent substance will be excreted unchanged.
Based on its chemical structure and its molecular weight, the substance is assumed to be excreted (if not metabolised completely in beta-oxidation and citric cycle) as metabolites (i.e. conjugates with glucuronic acid) via urine and to a lower extent via bile. However, it has to be kept in mind, that metabolites conjugated to glucuronic acid, can be subject to entero-hepatic recycling, and therefore might re-enter the system.
In order to assess the toxicological behaviour of tris(2-ethylhexyl) 2-(acetyloxy)propane-1,2,3-tricarboxylate, the available experimental and predicted physico-chemical data have been evaluated. Unchanged tris(2-ethylhexyl) 2-(acetyloxy)propane-1,2,3-tricarboxylate is expected to be poorly absorbed after oral exposure (based on molecular weight, water solubility and LogPow value and experimentally derived data). This prediction for tris(2-ethylhexyl) 2-(acetyloxy)propane-1,2,3-tricarboxylate can not be reconsidered based on the acute toxicity data available for this substance, as the results do not clearly indicate that the rapid absorption noted is based on absorption of the unchanged compound. The absorption of any metabolite of the substances of interest is, however, fast and complete. Concerning the absorption after exposure via inhalation, as the chemical has a low vapour pressure, it is clear, that the substance is poorly available after inhalation. Given its lipophilicity (LogPow 5.7) - if absorbed - it is expected to be absorbed directly across the respiratory tract epithelium. The substance is expected to be also poorly absorbed following dermal exposure into the stratum corneum and to a certain extent into the epidermis, due to its molecular weight and its LogPow. In addition, the systemic toxicity via the skin is assumed to be low and this has been proven with the results of the acute dermal toxicity study with tris(2-ethylhexyl) 2-(acetyloxy)propane- 1,2,3-tricarboxylate, which showed no mortality after dermal application of 2000 mg/kg bw in rats. Concerning the distribution in the body, the chemical is expected to be better distributed into the cells, since it is a lipophilic substance. The experimentally determined LogPow value, the water solubility and predicted behaviour concerning absorption,. the LogPow value of tris(2-ethylhexyl) 2-(acetyloxy)propane-1,2,3-tricarboxylate might indicate a potential for accumulation, but this is unlikely because of the limited absorption of unchanged tris(2-ethylhexyl) 2-(acetyloxy)propane-1,2,3-tricarboxylate. The substance is expected to be extensively metabolised by esterases and cytochrome P450 enzymes and break-down in the beta-oxidation or citric acid cycle or in cases subsequent glucuronidation.The substance is assumed to be excreted (if not metabolised completely in beta-oxidation and citric cycle) as metabolites (i.e. conjugates with glucuronic acid)via urine and to a lower extent via bile.
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