Registration Dossier

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

basic toxicokinetics
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
year of publication: 1994
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented publication/study report which meets basic scientific principles

Data source

Reference Type:
Report Date:

Materials and methods

Objective of study:
Test guideline
no guideline followed
Principles of method if other than guideline:
In vitro assay:
- Hydrolysis of unlabelled/radioactive labelled DEHT by rat gut homogenate
In vivo assay:
- Metabolism of DEHT in the Sprague-Dawley rat after single gavage administration of 100 mg/kg radioactive DEHT [14^C]
GLP compliance:
not specified

Test material

Details on test material:
- Name of test material (as cited in study report): di(2-ethylhexyl) terephthalate (DEHT)
Unlabelled test material
- Analytical purity: >98%

Radioactive labelled test material:
- Radiochemical purity: 97.7%
- Specific activity:8.39 mCi/mmol
- Locations of the label: [Hexyl-2-14^C]DEHT
- Stability under test conditions: yes, throughout the course of the study (proofed by periodically analysis)
other: in vitro assay: unlabelled/radioactive; in vivo: radioactive labelled 14^C-DEHT

Test animals

Details on test animals and environmental conditions:
- strain: Crl:CD*(SD)BR
- Source: Charles River Breeding Laboratories (Wilmington, MA, USA)
- Weight at study initiation: 200-300 g
- Fasting period before study: 16 hours
- Housing: prior to dosing single housing in suspended wire-mesh cages.
- Individual metabolism cages: yes ( After administration of test substance the rats were housed in glass metabolism cages.)
- Diet: Ralston Purina Laboratory rodent chow #5001, ad libitum (except for fasting period)
- Water: ad libitum
- Acclimation period: no data

- Temperature (°C): 21.1 +/- 0.9
- Humidity (%): 50 +/- 20%
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
corn oil
Details on exposure:
in vitro: vehicle methanol
in vivo: vehicle corn oil, single administration via gavage
Duration and frequency of treatment / exposure:
in vitro: single application
in vivo: singla gavage adminsitration
Doses / concentrations
Doses / Concentrations:
in vitro: no data
in vivo: 100 mg/kg
No. of animals per sex per dose:
in vitro: not applicable
in vivo: 10 males
Control animals:

Results and discussion

Main ADME resultsopen allclose all
in vivo: 65 % of administered 100 mg/kg were absorbed
in vitro: 1.97 moles of 2-EH are produced from 1 mole bis(2-ethylhexyl) terephthalate (DEHT)
in vitro: half-life for disapperance of DEHT homogenates of rat small intestines is 53.3 minutes
Excretion occurs mainly via faeces (56.5 %) and urine (31.9 %), to a minor extend in expired air (3.1 %). 1.4% remained in carcasse (total recovery approx. 93%). Excretion is rapid (peak 10 h after administration >95 %; > 99 % by 48 h).

Toxicokinetic / pharmacokinetic studies

Details on absorption:
36.6% of the dose recovered (corresponding to ca. 34 mg/kg) were excreted unchanged and thus rendered unabsorbed via the faeces. In reverse approximately 65% of the administered 100 mg/kg were absorbed.
Details on distribution in tissues:
1.4% of radioactivity from the dose administered was found in the carcasses.
Relative contents of radioactivity in brain, heart, large and small intestines, lunge, kidneys, spleen and testes are leass than or maximally equal to radioactivity found in the carcasses. With the notable exception of abdominal fat and liver (approximately 4-times the relative radioactivity content of the carcasses).
Details on excretion:
The mean total recovery of 14^C was 93.0 +/- 2.2%.
Most of the radioactivity was eliminated in the feces (56.5 +/- 12.1%); either unchanged/unabsorbed as DEHT (36.6%) or as metabolites (e.g. mono-(2-ethylhexyl) terephthalate (MEHT, 2.5%)) and polar metabolites.
In the urine (31.9 +/- 10.9%) as metabolic products of MEHT and 2-EH or in expired air (small amount as 14^CO2, 3.6 +/- 0.9%).

Excretion was fast and by 24 and 48 hours more than 95 and 99% of the total urinary and fecal radioactivity were excreted, respectively. Urinary and fecal excrection reached a peak at about 8 to 10 hours after administration. No further details on expiration of radioctive material was provided.

Metabolite characterisation studies

Metabolites identified:
Details on metabolites:
major metabolites in urine: terephthalic acid (TPA) and 2-Ethylhexanol (2-EH) and theirs respective metabolites and conjugates (glucuronide and sulphate)

Applicant's summary and conclusion

in vitro assay:
When hydrolysis of DEHT was investigated using homogenates of small intestines from rats major findings included:
- 1 mole DEHT produces 1.97 moles of 2-EH
- half-life times of DEHT is 53.3 minutes
in vivo assay:
When metabolism of 14^C-DEHT was investigated after adminsitration of 100 mg/kg by gavage to male rats the major findings included:
- that in a rough approximation only about 50% of DEHT are absorbed
- except for slightly higher contents of 14^C DEHT metabolites in abdominal fat and liver, distribution between tissues examined is even
- excretion is rapid (>95% by 10 to 24 h) and occurs mainly via faeces (56.5 %) and urine (31.9 %), to a minor extend in expired air (3.1 %) and only 1.4% remain in the carcasse
Executive summary:

In this vitro assay hydrolyis of DEHT by rat gut homogenates was examined. Therefore homogenates from small intestines of fasted male Sprague-Dawley rats were prepared. The test substance was dissolved in methanol and was then incubated at 37°C for up to 30 minutes with these gut homogenates. Periodically samples were drawn and the intestinal enzymes were inactivated. Under conditions of this study it was determined that DEHT is rapidly metabolised to 2 -ethylhexanol (2 -EH) and terephthalic acid (TPA). The disappearance half-life of DEHT was determined to be 53.3 minutes.

To investigate metabolism of DEHT under in vivo conditions 10 fasted male Sprague-Dawley rats were administered 100 mg/kg 14^C DEHT by single gavage. For up to 144 hours urine, feces and expired air were collected periodically. Radioactive concentration was determined in all excreta as well as selected tissues and the carcass. In feces and urine characterisation of metabolites from the test chemical was performed. The results of the study showed that excretion mainly occurs via faeces (56.5 %) and urine (31.9 %), to a minor extend in expired air (3.1 %) and carcasse (1.4 %; total recovery approx. 93%). Urinary and fecal excretion is rapid and reaches a peak 10 h after administration (>95 %; > 99 % by 48 h).

Major excretory products are TPA in the urine and unchanged [14^C]DEHT in the feces. Only a small amount is excreted as

mono(2 -ethylhexyl)terephthalate. More than 90% of the [14^C]DEHT recovered

was found either in faeces (36.6%), urine (50.5%) or in expired air (3.6%). In faeces only unchanged DEHT was detected, whereas in urine and expired air only indicators of complete metabolism were found (unlabelled TPA and 14^CO2, respectively).

Indirect conclusion on absorbtion suggests that only about 65 % from the original 100 mg DEHT/kg are absorbed (i.e. 36.6% of the dose recovered (corresponding to ca. 34 mg/kg) were excreted unchanged and thus rendered unabsorbed via the faeces. In reverse approximately 65% of the administered 100 mg/kg were absorbed).