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

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Reliability rating was 2 because study was conducted in accordance with generally accepted scientific principles for ADME radiolabel studies. Results from study published in peer-reviewed journal, Xenobiotica 24: 441-450 (1994).

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1994

Report date:

1993

Materials and methods

Test guideline

Qualifier:

no guideline available

Guideline:

other: followed generally accepted radioactivity ADME techniques

Principles of method if other than guideline:

General ADME study was carried out using radiolabelled chemical to investigate ADME as well as hydrolysis of the ester groups in the parent chemical.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Bis(2-ethylhexyl) terephthalate

EC Number:

229-176-9

EC Name:

Bis(2-ethylhexyl) terephthalate

Cas Number:

6422-86-2

Molecular formula:

C24H38O4

IUPAC Name:

bis(2-ethylhexyl) terephthalate

Constituent 2

Reference substance name:

Di-2-ethylhexyl terephthalate

IUPAC Name:

Di-2-ethylhexyl terephthalate

Radiolabelling:

yes

Remarks:

C14 labelled in 2-ethylhexyl portion

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

[14C-ethylhexyl labelled] DEHT in corn oil by oral gavage (100 mg/kg) to 10 adult male SD rats

Duration and frequency of treatment / exposure:

144 hrs

Doses / concentrations

Dose / conc.:

100 other: mg/kg

Remarks:

Doses / Concentrations:
single oral dose (100 mg/kg) with radiolabelled [14C-ethylhexyl labelled] DEHT

No. of animals per sex per dose / concentration:

10 male rats

Control animals:

no

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

DEHT is rapidly absorbed orally to the extent of about 36.9% based on radioactivity recovery in urine, residual carcass, expired CO2

Details on distribution in tissues:

Low bioaccumulation potential expected since only 1.4% radioactivity found in residual carcass

Details on excretion:

Radioactivity was excreted in the urine (31.9%) as terephthalic acid and other conjugated metabolites. The remainder of the radioactivity was found in the feces (56.5%) or as CO2 (3.6%) in expired air.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Metabolic hydrolysis of DEHT occurs extensively with both ester groups to yield 2-ethylhexyl alcohol and terephthalic acid and their glucuronide or sulfate conjugates. Unchanged DEHT material was found unabsorbed and unchanged in the feces (56.5%). Mono-2-ethylhexyl terephthalate was estimated to be no more than 9.3% of the radiolabelled dose.

In vitro rat intestinal homogenate study (Barber et al, 1994):
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).

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
Main findings of this ADME study indicate that both ester groups DEHT was extensively hydrolyzed to terephthalic acid and very little (ca 9.3 %) of the mono ester metabolite detected. This differs from di-2-ethylhexyl phthalate in which one only of its two diester group is hydrolyzed to the monoester phthalate metabolite, which is predominant metabolite detected. Hence, the terephthalate material undergoes complete hydrolysis of both ester groups in the gut which limits absorption of the parent material.

Executive summary:

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).