4-fluoroaniline

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: Peer reviewed publication.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1984

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

no guideline available

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

4-fluoroaniline

EC Number:

206-735-5

EC Name:

4-fluoroaniline

Cas Number:

371-40-4

Molecular formula:

C6H6FN

IUPAC Name:

4-fluoroaniline

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Sittingbourne Research Centre, Shell Research Limited
- Weight at study initiation: 220-267 g (test for methaemoglobin content), 216-309 g (test for isolation and identification of the metabolites), 218- 281 g (test for metabolite excretion)
- Fasting period before study: Overnight and the following morning
- Housing: Glass metabolism cages
- Individual metabolism cages: No, two per cage
- Diet: free access to food 1 h after dosing
- Water: ad libitum

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS
Test substance: Prepared no more than 24 h before administration

VEHICLE
- Amount of vehicle: Dose in 2 mL per kg of corn oil

Doses / concentrations

Remarks:

Doses / Concentrations:
14, 28, 56, 112 mg/kg bw (0.13, 0.25, 0.5, 1 mmol/kg)

No. of animals per sex per dose / concentration:

4

Control animals:

yes, concurrent vehicle

Positive control reference chemical:

4-Chloroaniline (1 mmol/kg)

Details on study design:

Two different approaches were investigated: Analysis of urinary metabolites and determination of methaemoglobin content in blood.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: Blood
- Time and frequency of sampling: 1 h before, and at 1, 2, 4, 6, 8 and 24 h after dosing
- Limit detection of exposure: 5 mg/kg bw, when methaemoglobinaemia is greatest

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: Urine
- Time and frequency of sampling: 0 to 24 h
- From how many animals: 10
- Method type for identification NMR
- Limits of detection: The limit of detection of the analytical method was of the order of 0.1 µg/mL expressed as parent fluoroanilie.

Results and discussion

Main ADME results

Type:

metabolism

Results:

Identified metabolite: ortho-sulphate of 2 amino-5-fluorophenol

Toxicokinetic / pharmacokinetic studies

Details on excretion:

The excretion of urinary conjugated aminophenols in the male rat after oral administration is rapid.
Only very low concentrations of these urinary metabolites were detected on the second day after dosing.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

At all doses the maximum methaemoglobinaemia occurs rapidly, within 1 or 2 h, indicating that both absorption and metabolism to the oxidised derivatives (Kiese and Uehleke 1961; Kampffmeyer and Kiese 1964) is rapid.

The test substance is a potent inducers of methaemoglobinaemia in the rat.
The amount of methaemoglobin induced is proportional to the dose administered and varies rapidly with the time since dosing.
39% of the test substance dose is metabolised by rats to the corresponding o-sulphate of 2 amino-5-fluorophenol, which is excreted in the urine.