Phthalic acid

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: No OECD guideline or GLP defined. No purity of test substance defined.

Objective of study:

other: absorbtion, excretion

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.

GLP compliance:

not specified

Radiolabelling:

not specified

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Route of administration:

oral: gavage

Vehicle:

corn oil

Duration and frequency of treatment / exposure:

single administration of test substance

Remarks:

Doses / Concentrations:
20, 100, or 500 mg/kg bw by gavage in corn oil.

No. of animals per sex per dose / concentration:

3

Control animals:

not specified

Preliminary studies:

no data

Details on absorption:

The test substance was absorbed rapidly after an oral dose of 500 mg/kg bw with peak concentration (Cmax) in blood (3.5+/- 0.33 µg/ml) at 30 min postadministration.

Details on distribution in tissues:

Apparent distribution volumes pf the test substance in the steady state (Vz/F) at 20, 100, or 500 mg/kg bw were 903.28+/- 125.28, 1419.87+/-527.53, and 5264.86+/- 993.65 ml, respectively.

Transfer type:

other: no data

Observation:

other: no data

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 of PA (20-500 mg/kg bw). The results show that PA plasma levels in rats declined in a biphasic fashion after oral administration. 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). PA 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 PA is excreted in urine. In conclusion, the present investigation demonstrates that PA concentrations in rat plasma declined following oral administration with a mean terminal elimination half-life of about 5-6h.

Toxicokinetic parameters:

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

Toxicokinetic parameters:

Tmax: 0.83 +/- 0.29 (h) [20 mg/kg]

Toxicokinetic parameters:

Cmax: 4.92 +/- 0.78 (µg/ml) [20 mg/kg]

Toxicokinetic parameters:

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

Toxicokinetic parameters:

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

Toxicokinetic parameters:

Tmax: 1.00 +/- 0.87 (h) [100 mg/kg]

Toxicokinetic parameters:

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

Toxicokinetic parameters:

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

Toxicokinetic parameters:

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

Toxicokinetic parameters:

Tmax: 0.67 +/- 0.29 (h) [500 mg/kg]

Toxicokinetic parameters:

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

Toxicokinetic parameters:

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

Metabolites identified:

not specified

Details on metabolites:

no data

Toxicokinetic Parameters in Plasma Determined by Noncompartmental Analysis of the Time Course of Phthalic Acid (PA) Following the Oral Administration of 20, 100, or 500 mg/kg PA as a Single Dose.

Parameters	Mean +SD
20mg/kg
Tmax (h)	0.83 +0.29
Cmax (µg/ml)	4.92 +0.78
Ke (1/h)	0.11 +0.02
t1/2 (h)	5.46 +1.13
AUC (µg-h/ml)	44.69 +2.56
Vz/F (ml)	903.28 +125.28
CL/F (ml/h)	97.43 +4.20
AUMC (µg-h²/ml)	438.92 +74.15
MRT (h)	9.79 +1.21
100 mg/kg
Tmax (h)	1.00 +0.87
Cmax (µg/ml)	15.87 +1.68
Ke (1/h)	0.17 +0.09
t1/2(h)	5.19 +3.56
AUC (µg-h/ml)	107.64 +31.77
Vz/F (ml)	1419.87 +527.53
CL/F (ml/h)	215.01 +55.42
AUMC (µg-h²/ml)	1003.41 +747.31
MRT (h)	8.58 +3.83
500 mg/kg
Tmax (h)	0.67 +0.29
Cmax (µg/ml)	20.49 +3.64
Ke (1/h)	0.14 +0.03
t1/2(h)	5.10 +1.19
AUC (µg-h/ml)	146.90 +9.33
Vz/F (ml)	5264.86 +993.65
CL/F (ml/h)	721.07 +51.81
AUMC (µg-h²/ml)	1344.52 +325.99
MRT (h)	9.09 +1.63

Tmax- time to reach peak plasma concentration,

Cmax-maximum plasma concentration,

Ke- Rate constant associated with the terminal phase,

t_1/2- elimination half-life in plasma,

AUC- area under the concentration-time curve,

Vz/F- apparent distribution volume,

CL/F- total body clearance,

MRT- mean residence time.

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

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 (t_1/2) 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 post administration. After oral administration, the dose-normalized area under the curve (AUC) (146.90 +9.33 µg/h/ml) for 500 mg/kg was significantly greater than at 20 mg/kg ( 44.69 +2.56 µg/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.

Description of key information

Phthalic acid administered orally to the rat is rapidly absorbed by the gastrointestinal tract with peak plasma concentrations after 30 minutes and a short terminal half-life of 5-6 h. PA is not retained in the organs or tissues and is almost quantitatively excreted in feces and urine as unchanged PA. The main excretion route was the feces followed by urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

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 post administration. After oral administration, the dose-normalized area under the curve (AUC) (146.90+9.33 µg/h/ml) for 500 mg/kg was significantly greater than at 20 mg/kg (44.69+2.56 µg/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 (Lim, 2007).

In a toxicokinetic study following a single oral dose of carbonyl labeled phthalic acid to rats 95% of the radioactivity was recovered as phthalic acid in the feces and urine. The distribution between the feces and the urine was relatively independent of the dose level with 70-80% of the radioactivity in the feces and 20 -25% in the urine. No metabolites of phthalic acid could be detected in the feces or the urine but a small amount of the phthalic acid was converted to carbon dioxide (0.11 – 0.15%). Four hours after dosing approximately 2% of the radioactivity was distributed throughout the organs and tissues with most of this radioactivity detected in the liver, kidney, spleen and testes. No radioactivity could be detected in these organs twenty-four hours after dosing. (Williams, 1974).

These results indicate that phthalic acid administered orally to the rat is rapidly absorbed by the gastrointestinal tract with peak plasma concentrations after 30 minutes and a short terminal half-life of 5-6 h. PA is not retained in the organs or tissues and is almost quantitatively excreted in feces and urine as unchanged PA. The main excretion route was the feces followed by urine.

No experimental data on PA is available for some toxicological endpoints. For these endpoints read across with phthalic anhydride is proposed due to the rapid hydrolysis of phthalic anhydride to the phthalic acid. In an in vitro hydrolysis test the rate of hydrolysis of phthalic anhydride was determined at different pHs at 25°C in water/buffer containing a small amount of acetonitrile. Phthalic anhydride hydrolyses rapidly in the presence of water forming phthalic acid. Half-life for phthalic anhydride was 30.5 seconds at pH 7.24. At pH 6.8 the half-life of phthalic anhydride in water was prolonged to 61 seconds (Andrés, 2001).