Disodium phthalate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: No OECD guideline or GLP defined.

Data source

Reference

Reference Type:

publication

Title:

Toxicokinetics of Phthalic Acid: The Common Final Metabolite of Phthalic Acid Esters in Rats

Author:

Lim DS, Shin BS, Yoo SD, Kim HS, Kwack SJ, Ahn MY, Lee BM

Year:

2007

Bibliographic source:

Journal of Toxicology and Environmental Health, Part A, 70: 1344–1349

Materials and methods

Objective of study:

toxicokinetics

Principles of method if other than guideline:

The toxicokinetic profiles of phthalic acid (PA) were studied in rats after orally administering doses 20, 100, or 500 mg/kg. Concentrations of PA were determined in serum or urine by high performance liquid chromatography (HPLC).

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Phthalic acid

EC Number:

201-873-2

EC Name:

Phthalic acid

Cas Number:

88-99-3

IUPAC Name:

phthalic acid

Radiolabelling:

not specified

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Samtako, Inc. (Seoul, Korea)
- Age at study initiation: Seven-week-old male rats.
- Housing: After dosing, animals were housed in metabolic cages.
- Diet (e.g. ad libitum): standard rat diet (Samtako, Inc.), ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: One week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2°C
- Humidity (%): 50 ± 10%
- Photoperiod (hrs dark / hrs light): 12-h light/dark cycle

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Duration and frequency of treatment / exposure:

Single administration of the test substance

Doses / concentrations

Remarks:

Doses / Concentrations:
20, 100, or 500 mg/kg

No. of animals per sex per dose / concentration:

Three males per dose

Control animals:

no

Details on dosing and sampling:

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 postadministration.

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.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The test substance was absorbed rapidly after an oral dose of 500 mg/kg with peak concentration (Cmax) in blood (3.5 ± 0.33 ug/ml) at 30 min postadministration. After oral administration, the dose-normalized area under the curve (AUC) (146.90 ± 9.33 mg/h/ml) for 500 mg/kg was significantly greater than at 20
mg/kg (44.69 ± 2.56 mg/h/ml).

Details on distribution in tissues:

The plasma concentrations of the test substance showed a biexponential increase following oral administration of doses ranging from 20 to 500 mg/kg. The terminal elimination half-lives (t1/2) of test substance at dosages of 20, 100, or 500 mg/kg were 6.46 ± 1.13, 5.19 ± 3.56, and 5.10 ± 1.10 h, respectively, total clearances (Cl/F) of test substance at 20, 100, or 500 mg/kg were 97.43 ± 4.20, 215.01 ± 55.42, and 721.07 ± 51.81 ml/h, and apparent distribution volumes of test substance in the steady state (Vz/F) at 20, 100, or 500 mg/kg were 903.28 ± 125.28, 1419.87 ± 527.53, and 5264.86 ± 993.65 ml, respectively.

Details on excretion:

The main route of elimination following a single p.o. dose of test substance was in urine. After administering oral doses of 20,100, or 500 mg/kg bw, the test substance was excreted in urine within 24h. A larger percentage (13-26%) of test substance was excreted in urine following a single oral administration (20-500 mg/kg bw). The results show that test substance plasma levels in rats declined in a biphasic fashion after oral administration. The apparent distribution volume in the steady state indicates that test substance is distributed extensively into tissues. The total systemic clearance of test substance was moderate and significantly less than hepatic blood flow (approximately 3.91 h/kg). The test substance was absorbed rapidly after oral administration, and peak plasma concentrations were attained 30 min after administration. Urine analysis after the oral administration at 500 mg/kg indicated that only about 13% of unchanged test substance is excreted in urine. In conclusion, the present investigation demonstrates that test substance concentrations in rat plasma declined following oral administration with a mean terminal elimination half-life of about 5-6h

Toxicokinetic parameters

Toxicokinetic parameters 1

Toxicokinetic parameters:

half-life 1st: 5-6 h [20 mg/kg]

Toxicokinetic parameters 2

Toxicokinetic parameters:

Tmax: 0.83 ± 0.29 (h) [20 mg/kg]

Toxicokinetic parameters 3

Toxicokinetic parameters:

Cmax: 4.92 ± 0.78 (µg/ml) [20 mg/kg]

Toxicokinetic parameters 4

Toxicokinetic parameters:

AUC: (µg-h/ml) 44.69 ± 2.56 [20 mg/kg]

Toxicokinetic parameters 5

Toxicokinetic parameters:

half-life 1st: 5.19 ± 3.56 (h) [100 mg/kg]

Toxicokinetic parameters 6

Toxicokinetic parameters:

Tmax: 1.00 ± 0.87 (h) [100 mg/kg]

Toxicokinetic parameters 7

Toxicokinetic parameters:

Cmax: 15.87 ± 1.68 (µg/ml) [100 mg/kg]

Toxicokinetic parameters 8

Toxicokinetic parameters:

AUC: (µg-h/ml) 107.64 ± 31.77 [100 mg/kg]

Toxicokinetic parameters 9

Toxicokinetic parameters:

half-life 1st: 5.10 ± 1.19 (h) [500 mg/kg]

Toxicokinetic parameters 10

Toxicokinetic parameters:

Tmax: 0.67 ± 0.29 (h) [500 mg/kg]

Toxicokinetic parameters 11

Toxicokinetic parameters:

Cmax: 20.49 ± 3.64 (µg/ml) [500 mg/kg]

Toxicokinetic parameters 12

Toxicokinetic parameters:

AUC: (µg-h/ml) 146.90 ± 9.33 [500 mg/kg]

Metabolite characterisation studies

Metabolites identified:

not specified

Any other information on results incl. tables

Concentration of Phthalic Acid (PA) in Urine Samples After Its Oral Administration to Male Rats:

Time interval (h)	Conc. (µg/ml)	Urine Volume (ml)	PA #1 (total amount excreted, µg)	Conc. (µg/ml)	Urine Volume (ml)	PA #2 (total amount excreted, µg)	Conc.(µg/ml)	Urine Volume (ml)	PA #3 (total amount excreted, µg)
PA-500 mg/kg
0 -4	12492.67	1.0	12492.67	5814.89	2.0	11629.77	7306.40	2.0	14612.79
4 -8	9410 .84	2.4	22586.01	12149.83	2.0	24299.65	11642.85	1.8	20957.13
8 -12	6386.03	2.4	15326.47	5611.77	2.5	14029.43	5648.68	1.8	10167.62
12 -16	3713.82	1.8	6684.87	5319.60	2.0	10639.20	4379.18	1.8	7882.52
16 -24	3311.50	2.0	6622.99	1228.05	4.0	4912.18	1047.12	4.0	4188.48
PA-100 mg/kg
0 -4	4154.18	2.0	8308.35	5629.77	1.0	5629.77	4869.44	2.0	9738.87
4 -8	6369.44	2.0	12738.87	5639.02	2.5	14097.55	5425.86	2.5	13564.64
8 -12	1441.43	2.0	2882.86	2122.93	2.5	5307.33	1880.74	3.0	5642.21
12 -16	549.18	3.0	1647.54	1402.85	2.0	2805.70	681.56	2.5	1703.90
16 -24	170 .06	3.0	510.17	529.60	2.0	1059.19	248.59	4.5	1118.64
PA-20 mg/kg
0 -4	558.15	2.0	1116.3	503.30	2.0	1006.59	443.29	2.0	886.58
4 -8	375.97	2.5	939.92	313.06	2.5	782.65	380.94	2.0	761.87
8 -12	248.87	2.0	497.74	119.10	4.0	476.39	172.43	2.5	431.07
12 -16	138.78	2.5	346.94	158.34	2.0	316.68	70.28	4.0	281.10
16 -24	81.80	3.0	245.39	29.17	8.0	233.37	133.37	2.0	266.73

Applicant's summary and conclusion

Executive summary:

The toxicokinetic profiles of phthalic acid (PA) were studied in rats after orally administering doses 20, 100, or 500 mg/kg. Concentrations of PA were determined in serum or urine by high performance liquid chromatography (HPLC). The plasma concentrations of PA showed a biexponential increase following oral administration of doses ranging from 20 to 500 mg/kg. The terminal

elimination half-lives (t1/2) of PA at dosages of 20, 100, or 500 mg/kg were 6.46 ± 1.13, 5.19 ± 3.56, and 5.10 ± 1.10 h, respectively,

total clearances (Cl/F) of PA at 20, 100, or 500 mg/kg were 97.43 ± 4.20, 215.01 ± 55.42, and 721.07 ± 51.81 ml/h, and apparent distribution volumes of PA in the steady state (Vz/F) at 20, 100, or 500 mg/kg were 903.28 ± 125.28, 1419.87 ± 527.53, and 5264.86 ± 993.65 ml, respectively. PA was absorbed rapidly after an oral dose of 500 mg/kg with peak concentration (Cmax) in blood (3.5 ± 0.33 µg/ml) at 30 min postadministration. After oral administration, the dose-normalized area under the curve (AUC) (146.90 ± 9.33 mg/h/ml) for 500 mg/kg was significantly greater than at 20 mg/kg (44.69 ± 2.56 mg/h/ml). Urine analysis indicated that 13 ± 0.45% of the administered PA dose (at 500 mg/kg, p.o.) was recovered unchanged in urine within 24 h.