Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

Hydrolysis by esterases is regarded as an important first step in the oral absorption of ortho-phthalates. The potential for such hydrolysis to occur with this trimellitate (TEHTM (also known as TOTM)) has been examined in an in-vitro study using a rat gut homogenate. There was no evidence of hydrolysis occurring while the corresponding phthalate, di(2 -ethylhexyl)phthalate (DEHP), was significantly hydrolysed. A more recent study utilizing porcine liver esterase also showed that the trimellitate was stable against enzymatic hydrolysis in-vitro. However, the diesters, 1,2 -DEHTM, 1,4 -DEHTM and 2,4 -DEHTM were shown to be distinctly and selectively hydrolysed by porcine liver esterase at the para position, resulting in the monoesters, 1-MEHTM and 2 -MEHTM, as the main hydrolysis products.

 

The absorption, distribution, metabolism and elimination of TOTM have been investigated in the rat following oral administration of a single dose. Recovery of the administered dose was 94% with approximately 75% eliminated unchanged in the faeces, 16.3% found in the urine and 1.9% in expired air. Residual radioactivity in the carcass after 6 days was <0.6% of the administered dose. Findings indicate that TOTM may be partially hydrolysed in the gastro-intestinal tract to 2-ethylhexanol and the corresponding di-ester and, following further hydrolysis, the mono-ester. Only 2-ethylhexanol and a single isomer of mono-(2-ethylhexyl)trimellitate appear to be absorbed. Following absorption, 2-ethylhexanol was extensively metabolised with metabolites eliminated in the urine and as expired 14CO2.There was no evident metabolism of mono-(2-ethylhexyl)trimellitate, this being eliminated unchanged. Urinary excretion of radioactivity was bi-phasic with half-lives of 3.1 and 42 hours.

The metabolism and excretion kinetics of TEHTM following administration of a single oral dose has recently been studied in humans. TEHTM was shown to be absorbed and regioselectively hydrolysed to its diesters di-2-(ethylhexyl) trimellitates (1,2-DEHTM, 2,4-DEHTM) with maximum blood concentrations occurring 3-hours post-exposure, and further hydrolysis to the monoester isomers mono-2-(ethylhexyl) trimellitates (1-MEHTM, 2-MEHTM) with peak blood concentrations 5-hours post-exposure. Biphasic elimination kinetics of urinary metabolites was observed. The most dominant urinary metabolite was 2-mono-(2-ethylhexyl) trimellitate (2-MEHTM), followed by a number of specific secondary metabolites.

Approximately 5.8% of the orally administered dose was recovered in urine over a 72 hour period.

 

When barriers to absorption are by-passed by intravenous administration, TEHTM has been found to distribute mainly in the liver, lungs and spleen. Excretion of the substance or its metabolites over 14 days was slow with 21.3% and 2.8% of the administered dose found in the faeces and urine respectively, suggesting a half-life of approximately 40 days. While data from the intravenous route may suggest a possible concern for potential bioaccumulation, the substance is poorly absorbed by the oral route and the kinetics of urinary elimination suggests a far shorter half-life, indicating a lower potential for bioaccumulation.

 

In summary, available toxicokinetic studies show that TEHTM is poorly absorbed through the gastro-intestinal tract following oral administration. If absorbed it is eliminated relatively rapidly, mainly via the urine as polar metabolites. When barriers to absorption are by-passed elimination is rather slower and occurs mainly in the faeces, presumably via biliary excretion.