Ester reaction products of 1,4-Benzenedicarboxylic acid with C11-14 iso-alcohols, C13-rich

Endpoint summary

Description of key information

No data on the toxicokinetics, absorption, distribution, metabolism, or excretion (ADME) in animals or in humans have been reported for the submission substance (i. e. CAS No. 162030-42-4). However, there are in vivo and in vitro ADME and toxicokinetic studies have been carried out for the structurally analogous, di-2-ethylhexyl terephthalate (DEHT) (CAS No. 6422-86-2), which can provide read-across assessment.  

The systemic absorption and metabolism of DEHT was studied in vivo by administering [¹⁴C-ethylhexyl labelled] DEHT in corn oil by oral gavage (100 mg/kg) to 10 adult male SD rats (Barber et al., 1994). Urine, feces and expired air were collected daily for 144 hours and analyzed for the presence of radioactivity and metabolites. At study termination, ca. 93% of the total administered radioactivity was recovered. Most of the recovered radioactivity was found in the feces (56.5%) and urine (31.9%), while 3.6% was isolated in expired air (as¹⁴CO₂) and 1.4% remained with the carcass. Urinary and fecal recovery rates peaked by 10 hours with > 95% of the total excreted amount recovered within 24 hours (> 99% by 48 hours). The mean amount of non-metabolized [¹⁴C]-DEHT recovered in the feces was 36.6% of the total dose and the percentage of the total DEHT dose recovered in the urine as terephthalic acid (TPA) was 50.5%. In total, 90.7% of the dose was accounted for as either unchanged DEHT in feces, unlabelled TPA in urine, or as¹⁴CO₂in expired air. Mass balance analysis estimated the amount of mono(2-ethylhexyl)terephthalate (MEHT) formed to be a maximum of only 9.3% of the orally administered dose. 

 

In summary, DEHT was rapidly absorbed orally to the extent of about 36.9%. Distribution or retention in the tissues was determined to be about 1.4% at study termination. Metabolism occurred primarily via initial hydrolysis of both alkyl esters group to terephthalic acid and 2-ethylhexyl alcohol and further metabolism, conjugation and excretion of metabolites in the urine. The remainder of the radioactive dose passed through the GI tract as unabsorbed, unchanged DEHT and was recovered in the feces (56.5%) or was eliminated as¹⁴CO₂in expired air. 

 

In addition, the in vitro metabolic hydrolysis rate of DEHT to free 2-ethylhexanol (2-EH) was determined using rat intestinal homogenates (Barber et al., 1994). The half-life for disappearance of the di-ester parent molecule (i.e., DEHT) was 53.3 minutes. More importantly, the stoichiometry of the reaction at termination showed that 1.97 moles of 2-EH were formed per mole of DEHT, indicating complete hydrolysis to terephthalic acid (TPA). In contrast, the stoichiometry of the reaction with DEHP (the ortho-phthalate analog) was one mole of 2-EH formed per mole of DEHP, indicating incomplete hydrolysis to mono-(2-ethylhexyl) phthalate (MEHP). 

Overall, the read-across assessment of the toxicokinetic ADME studies with the DEHT surrogate indicates that: (1) the submission substance is not likely to be extensively absorbed via the oral or dermal routes; (2) the submission substance is expected to undergo rapid metabolism, further conjugation and subsequent excretion in the urine and feces. precluding any significant bioaccumulation in the tissues; (3) the submission substance is expected to undergo complete hydrolysis of both alkyl ester groups to terephthalic acid with little formation of the monoalkyl terephthalate metabolite; (4) the submission substance is expected to show similar toxicokinetic and metabolism profile to that reported for DEHT. These findings are consistent with the low order of toxicity exhibited by the submission substance or the related DEHT surrogate (see OECD SIAP, 2003).

Discussion on absorption rate:

No information has been reported in humans for the submission substance, CAS No. 162030-42-4. However, in vitro dermal absorption studies have been performed with the related terephthalate analog, DEHT (CAS No. 6422-86-2) using human skin which could provide some useful read-across information for the submission substance. Guerin and Taylor (2002) applied excess DEHT to human skin using in vitro percutaneous glass diffusion cells and determined the dermal absorption rate for DEHT to be 0.103 ± 0.052 μg/cm2/hr. These findings indicate that DEHT was very slowly absorbed through human skin. Based on this absorption rate, it was estimated that if excess DEHT was to be in contact with an area of skin equivalent to both hands (approximately 720 cm²surface area, 70 kg human) continuously for 1 hr, the calculated systemically absorbed dose would be 1.06 μg/kg. Hence, overall bioavailability was considered relatively low or minimal via dermal route of exposure for DEHT. 

Based on read-across, dermal absorption of the submission substance would similarly be expected to be low or minimal. This is consistent with the fact that the submission substance has a higher MW than DEHT and would generally be expected to be less dermally absorbed than a lower MW analog like DEHT.