Bis(2-ethylhexyl) terephthalate

Endpoint summary

Additional information

The metabolic fate and disposition of di (2-ethylhexyl) terephthalate are well understood. An in vivo absorption and metabolism study conducted by the oral route with di (2-ethylhexyl) terephthalate according to generally acceptable scientific standards was available for review. Adult male Sprague-Dawley rats received a single dose of 100 mg/kg bw [14^C] di (2-ethylhexyl) terephthalate mixed in corn oil by oral gavage. Urine, feces, expired air, and cage washings were collected for up to 144 hours. At necropsy, brain, heart, lungs, liver, spleen, kidneys, small and large intestines, testes, and samples of abdominal fat as well as carcasses were processed for radioactivity. Tissues were also processed to determine percentage of acetone-extractable radioactive material while carcasses were processed with acetone as well as hexane. The test material was rapidly absorbed, metabolized and eliminated with most of the radioactivity recovered in urine (31.9±10.9% of the dose), feces (56.5±12.1%), and expired 14^CO2 (3.6±0.9%). The rate of excretion of radioactivity in urine was observed to reach a peak at about 8-10 hours after dosing with a similar pattern observed in the feces. The time course for the excretion of radioactivity indicated that more than 95 and 99% of the total urinary and fecal radioactivity was excreted by 24 and 48 hours, respectively. There was evidence for a slow elimination process that resulted in small amounts of radioactivity being excreted up to 144 hours (estimated to be less than 0.1% of the total urinary and fecal excretion). Less than 2% of the administered radioactivity was retained in the carcass at the time of sacrifice. At sacrifice, very low levels of 14^C were found in the tissues, and most had relative levels lower than the carcass values. The only exceptions were the liver, probable site of continued residual metabolism, and abdominal fat. Most of the 14^C found in abdominal fat was acetone extractable. Total average radioactivity recovered accounted for 93.0±2.2% of the administered dose. Urine and feces were treated and analyzed under a variety of conditions to characterize and identify metabolites. The major components of the fecal extracts were di (2-ethylhexyl) terephthalate (36.6% of the dose), mono-(2-ethylhexyl) terephthalate (2.5%), the glucuronic acid conjugate of 2-ethyl-5-hydroxyhexanoic acid, and several uncharacterized radiolabeled metabolites that were more polar than di (2-ethylhexyl) terephthalate. The predominant metabolites in urine were unlabeled terephthalic acid (equivalent to 51% of the dose on a molar basis), 2-ethylhexanol, and phase I metabolites of 2-ethylhexanol and mono-(2-ethylhexyl) terephthalate. Based on hydrolytic evidence, about 60% of the radioactivity in urine was extracted after treatment with HCl, and about 17% and 12% of the urinary radioactivity was present as glucuronic and sulfuric acid conjugates, respectively.

  

These findings indicate that about 63% of the administered dose of di (2-ethylhexyl) terephthalate was hydrolyzed to 2-ethylhexanol, mono-(2-ethylhexyl) terephthalate and terephthalic acid and that these compounds were absorbed from the gastrointestinal tract while the remainder of the dose (36%) was excreted unchanged in the feces. 2-Ethylhexanol and mono-(2-ethylhexyl) terephthalate were largely metabolized and excreted in urine and feces. The major hydrolytic product was unlabeled terephthalic acid and the major excretory products were terephthalic acid and di (2-ethylhexyl) terephthalate, together accounting for 87% of the dose. The excretion of unchanged di (2-ethylhexyl) terephthalate is presumed to be due to limited solubility or the availability of di (2-ethylhexyl) terephthalate to hydrolytic enzymes. Only a small portion of dose was excreted as mono-(2-ethylhexyl) terephthalate or oxidative metabolites of mono-(2-ethylhexyl) terephthalate.  Di (2-ethylhexyl) terephthalate is metabolized differently than its isomer, di (2-ethylhexyl) phthalate. While di (2-ethylhexyl) terephthalate is hydrolyzed predominantly to terephthalic acid, di (2-ethylhexyl) phthalate is hydrolyzed largely to mono-(2-ethylhexyl) phthalate.

  

A supporting in vitro study conducted with rat gut homogenates (Fox et al., 1983) also found that di (2-ethylhexyl) terephthalate was hydrolyzed to yield 2-ethylhexanol and terephthalic acid, both of which may be absorbed from the gastrointestinal tract. The in vitro disappearance half-life of di (2-ethylhexyl) terephthalate under these test conditions was 53.3 minutes.

  

In an in vitro dermal absorption study conducted according to OECD Guideline 428, the mean absorption rate of di (2-ethylhexyl) terephthalate through dermatomed human skin was 0.103±0.053 μg/cm^2/hr with a corresponding permeability constant of 8.39 x 10^-8 cm/hr. The mean damage ratio (1.14±0.23) for this study was not different from that expected from exposure to physiological saline indicating that the test material did not cause significant damage to the skin. Based on criteria established by Marzulli et al. (1969), di (2-ethylhexyl) terephthalate would be considered an “extremely slow” penetrant relative to other chemical species.