Tetrachlorophthalic anhydride

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable publication which meets basic scientific principles

Data source

Reference

Reference Type:

publication

Title:

Effect of tetrachlorophthalic anhydride on hepatic microsomal metabolism in rats and mice.

Author:

Ridley WP, Warren J

Year:

1988

Bibliographic source:

J Toxicol Environ Health. 24: 217-227

Materials and methods

Objective of study:

other: hepatic microsomal metabolism

Principles of method if other than guideline:

The capacity for induction of microsomal metabolic enzymes by tetrachlorophthalic anhydride (TCPA) was evaluated in male Sprague-Dawley rats. The rats (6/dose group) were orally dosed for 7 days with the test substance suspended in corn oil at dose rates of 25, 100, 250, and 500 mg/kg bw. Phenobarbital was used as positive control, negative control animals were treated with vehicle or remained untreated. Paralysis time was monitored following i.p. injection of zoxazolamine (75-100 mg/kg bw) and hexobarbital (150-200 mg/kg bw). Concentration of microsomal cytochrome P-450, acitivities of aminopyrine N-demethylase and aniline hydroxylase were determined in liver homogenates.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Tetrachlorophthalic anhydride

EC Number:

204-171-4

EC Name:

Tetrachlorophthalic anhydride

Cas Number:

117-08-8

Molecular formula:

C8Cl4O3

IUPAC Name:

tetrachloro-1,3-dihydro-2-benzofuran-1,3-dione

Details on test material:

- Name of test material (as cited in study report): Tetrachlorophthalic anhydride
- Analytical purity: 99.8%
- Impurities (identity and concentrations): 0.2% hexachlorobenzene

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories
- Weight at study initiation: 150-260 g
- Housing: single
- Diet (e.g. ad libitum): certified Purina Rat Chow pellets
- Water (e.g. ad libitum): tap water


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 25±2
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Tetrachlorophthalic anhydride (TCPA) dosing suspensions were prepared by grinding crystalline TCPA to a fine powder in a mortar, sifting it through a fine wire screen and adding the resulting material to corn oil with continuous stirring. Animals were dosed by oral intubation with TCPA at a dose volume of 4-5 ml/kg bw.

Duration and frequency of treatment / exposure:

single

Doses / concentrations

Remarks:

Doses / Concentrations:
25, 100, 250, and 500 mg/kg bw

No. of animals per sex per dose / concentration:

6

Control animals:

yes, concurrent vehicle

Positive control reference chemical:

Phenobarbital

Details on study design:

- Dose selection rationale: Dose levels for TCPA were selected based on the results of preliminary studies. In the rat, over the 7-d dosing period, mortality was observed at 5000 mg/kg bw (5 out of 8 animals died) and at 1500 mg/kg bw (3 out of 8 animals died). Therefore, 500 mg/kg bw was the highest dose level used in the rat. At both 500 and 250 mg/kg bw in the rat, weight gain was significantly lower in the treated groups when compared with the control. No difference in weight gain between treated and control rats was observed at 100 and 25 mg/kg bw.

Statistics:

Phenobarbital treatment groups were compared with the control by Student’s t-test, and multiple TCPA treatment groups were compared with the control by Dunnett's test.

Results and discussion

Any other information on results incl. tables

Following treatment, a dose-dependent reduction in the zoxazolamine paralysis time occurred over the dose range 100-500 mg/kg bw. At 100, 250 and 500 mg/kg bw of TCPA, the extent of paralysis was 75%, 66% and 44% of control, respectively. No significant difference in paralysis time between the control and treated groups was found at a TCPA dose level of 25 mg/kg bw for two experimental runs. No effect on the hexobarbital sleep time was observed at any test level.

Phenobarbital caused a significant increase in the microsomal protein levels and the liver to body weight ratio, while TCPA at dose levels of 25-500 mg/kg-d produced no change in these parameters.

TCPA was found to produce statistically significant increases in hepatic aminopyrine N-demethylase, aniline hydroxylase, and cytochrome P-450 in the rat at 500 mg/kg bw (Table 1). In addition statistically significant increases were seen in aniline hydroxylase and cytochrome P-450 at 25 mg/kg bw but not at 250 mg/kg bw.

Table 1. Effects of Phenobarbital and TCPA on the Activities of Liver Microsomal Enzymes^a

Test substance	Dose level (mg/kg bw)^b	Cytochrome P-450^c	Aminopyrine N-demethylase^d	Aniline hydroxylase^e
Control	-	1.26 ± 0.09	1.94 ± 0.38	0.86 ± 0.15
Phenobarbital	80	2.22 ± 0.61^f	5.18 ± 0.85^f	1.50 ± 0.19^f
Control	-	1.35 ± 0.11	2.04 ± 0.60	0.86 ± 0.09
TCPA	25	1.47 ± 0.21	2.05 ± 0.37	1.13 ± 0.10
TCPA	250	1.60 ± 0.22	2.32 ± 0.47	1.05 ± 0.20
Control	-	1.30 ± 0.06	3.77 ± 0.47	1.08 ± 0.12
TCPA	25	1.59 ± 0.16^h	3.54 ± 0.40	1.42 ± 0.25^h
TCPA	500	1.70 ± 0.24^g	5.09 ± 1.14^h	1.54 ± 0.23^g

^aValues expressed as mean ±SD.

^bPhenobarbital was dosed ip for 4 d; TCPA was dosed orally for 7 d.

^cIn nmol P-450/mg microsomal protein.

^dIn nmol formaldehyde/min/mg microsomal protein.

^eIn nmol p-aminophenol/min/mg microsomal protein.

^fSignificantly different from the control, p < 0.01, by Student's t-test.

^gSignificantly different from the control' p < 0.01, by Dunnett's test.

^hSignificantly different from the control, p < 0.05, by Dunnett's test.