Registration Dossier

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: Acceptable, well documented publication comparable to guideline study

Data source

Reference
Reference Type:
publication
Title:
Toxicokinetics of phthalic acid: the common final metabolite of phthalic acid esters in rats.
Author:
Lim, D.S. et al.
Year:
2007
Bibliographic source:
J Toxicol Environ Health A. 2007 Aug;70(15-16):1344-9.

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Principles of method if other than guideline:
The toxicokinetic properties of phthalic acid after oral administration at 20, 100, or 500 mg/kg to rats was investigated.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Phthalic acid (PA) and monomethyl phthalate (mMP)
- Source: Sigma Aldrich, Munich, Germany
To minimize the possibility of contamination by phthalates during sample handling and analysis, all glassware used in this study was prewashed with methanol.
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Samtako, Inc. (Seoul, Korea)
- Age at study initiation:
- Weight at study initiation:
- Fasting period before study:
- Housing:
- Individual metabolism cages: yes
- Diet (ad libitum): standard rat diet
- Water (ad libitum):
- Acclimation period: one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +/-2
- Humidity (%): 50 +/- 10
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Duration and frequency of treatment / exposure:
single dose
Doses / concentrations
Remarks:
Doses / Concentrations:
20, 100, or 500 mg/kg
No. of animals per sex per dose:
3
Control animals:
no
Details on dosing and sampling:
For oral toxicokinetic studies, three groups of rats (n = 3) were administered a single dose of 20, 100, or 500 mg/kg PA by gavage in
corn oil. For each dosage group, studies were conducted over 3 d, and plasma samples were collected at 30 min, 1, 2, 3, 4, 6, 8, 12, and 24 h post administration.
Pooled urine from each rat was collected in a glass vial from 0–4, 4–8, 8–12, 12–16, and 16–24 h after dosing.
At sacrifice rats were anesthetized with ether, and blood was collected from the abdominal aorta.

Results and discussion

Preliminary studies:
The HPLC procedure described adequately separated PA and the internal standard (mMP) in rat plasma and urine. Extraction recoveries were greater than 90% for all analytes in both plasma and urine. Linear calibration curves (n = 3) were obtained over the concentration range of 0.1–10 μg/mL in plasma for PA (y = 0.28x + 0.01, R2 = .997), and over the concentration range 1–100 μg/mL in urine (y = 0.28x + 0.01, R2 = .997). The limit of quantification was 100 ng/mL for PA in plasma and urine.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
PA was absorbed rapidly after oral administration, and peak plasma concentrations were attained 30 min after administration.
Details on distribution in tissues:
The apparent distribution volume in the steady state indicates that PA is distributed extensively into tissues. The total systemic clearance of PA was moderate and significantly less than hepatic blood flow (approximately 3.91 h/kg).
Details on excretion:
The main route of elimination following a single p.o. dose of PA was in urine. After administering oral doses of 20, 100, or 500 mg/kg, PA was excreted in urine within 24 h. A larger percentage (13–26%) of PA was excreted in urine following a single oral administration of PA (20–500 mg/kg).
Our results show that PA plasma levels in rats declined in a biphasic fashion after oral administration.
Urine analysis after the oral administration at 500 mg/kg indicated that only about 13% of unchanged PA is excreted in urine.
Toxicokinetic parametersopen allclose all
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: 5.46 ± 1.13 h (upon oral administration of 20 mg/kg PA as single dose)
Test no.:
#1
Toxicokinetic parameters:
AUC: 44.69 ± 2.56 μg/h/mL (upon oral administration of 20 mg/kg PA as single dose)
Test no.:
#1
Toxicokinetic parameters:
Cmax: 4.92 ± 0.78 µg/mL (upon oral administration of 20 mg/kg PA as single dose)
Test no.:
#1
Toxicokinetic parameters:
Tmax: 0.83 ± 0.29 h (upon oral administration of 20 mg/kg PA as single dose)
Test no.:
#3
Toxicokinetic parameters:
half-life 1st: 5.10 ± 1.19 h (upon oral administration of 500 mg/kg PA as single dose)
Test no.:
#3
Toxicokinetic parameters:
AUC: 146.90 ± 9.33 µg/h/mL (upon oral administration of 500 mg/kg PA as single dose)
Test no.:
#3
Toxicokinetic parameters:
Cmax: 20.49 ± 3.64 µg/mL (upon oral administration of 500 mg/kg PA as single dose)
Test no.:
#3
Toxicokinetic parameters:
Tmax: 0.67 ± 0.29 h (upon oral administration of 500 mg/kg PA as single dose)

Metabolite characterisation studies

Metabolites identified:
no

Any other information on results incl. tables

After administering PA at 20, 100, or 500 mg/kg po, t1/2 values for PA in plasma were determined to be 6.46 ± 1.13, 5.19 ± 3.56, and 5.10 ± 1.19 h, respectively, and Ke values to be 0.11 ± 0.02, 0.17 ± 0.09, and 0.14 ± 0.03/h, respectively. AUC increased with increasing PA dose, and mean AUC0-tvalues in plasma were 44.69 ± 2.56, 107.64 ± 31.77, and 146.90 ± 9.33 μg/h/ml, respectively. CL/F was relatively constant, from 97.43 ± 4.20 to 721.07 ± 51.81 ml/h, as was Vz/F, from 903.28 ± 125.28 to 5264.86 ± 993.65 ml. A comparison of the dose-dependent toxicokinetics of PA (see Figure 1 and Table 1) indicated that a fivefold increase in PA dose (20–500 mg/kg) resulted in a 4.16-fold increase in Cmax (4.92–20.49 μg/ml) and a 3.29-fold increase in AUC (44.69–146.90 μg/ml/h). These results suggest that PA kinetics are nearly proportional over this dose range.

Applicant's summary and conclusion