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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
other information
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given (comparable to guidelines)

Data source

Reference
Reference Type:
publication
Title:
Tissue distribution, subcellular localization and covalent binding of 2-chloroaniline and 4-chloroaniline in Fischer 344 rats
Author:
Dial, LD et al.
Year:
1998
Bibliographic source:
Toxicology, 131: 109-119

Materials and methods

Objective of study:
distribution
excretion
Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method B.36 (Toxicokinetics)
Deviations:
yes
Remarks:
; purity not reported, no metabolites identified, limited investigation of absorption
Principles of method if other than guideline:
Radiolabeled 2-chloroaniline hydrochloride (0.5 or 1 mmol/ kg bw) was injected i.p in male Fisher 344 rats tissue distribution an faecal and urinary radioactivity output were determinded 3 h post-dose. An additional third group received 1 mmol/ kg bw and tissue distribution as well as radioactivity output were determined after 24 h.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
2-chloroaniline
EC Number:
202-426-4
EC Name:
2-chloroaniline
Cas Number:
95-51-2
Molecular formula:
C6H6ClN
IUPAC Name:
2-chloroaniline
Details on test material:
- Name of test material (as cited in study report): 2-chloroaniline hydrochloride

- Analytical purity: test substance was converted to the resepective hydrochloride and purified

- Radiochemical purity (if radiolabelling): not reported
- Specific activity (if radiolabelling): 24.83 mCi/mmol
- Locations of the label (if radiolabelling): U
Radiolabelling:
yes
Remarks:
[14C]-2-chloroaniline

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hilltop Lab Animals (Scottdale, PA)
- Weight at study initiation: 200-260 g
- Fasting period before study: no
- Housing: in standard plastic cages prior to experiment
- Individual metabolism cages: yes, one day prior and then throughout the study
- Diet: prior to experiment ad libitum, fasted during experiment
- Water: ad libitum
- Acclimation period: 1 week acclimation to animal fascility and one day to the metabolism cages


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 40-55
- Photoperiod (hrs dark / hrs light): 12/12


Administration / exposure

Route of administration:
intraperitoneal
Vehicle:
water
Duration and frequency of treatment / exposure:
single
Doses / concentrations
Remarks:
Doses / Concentrations:
0.5 mmol/ kg/ bw, 1 mmol/kg bw
No. of animals per sex per dose / concentration:
4 male rats per dose
Control animals:
no
Positive control reference chemical:
no
Details on study design:
no data
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, erythrocytes, plasma, kidney (cortex, medulla), liver, spleen
- Time and frequency of sampling: after 3 h and 24 h

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine and faeces
- Time and frequency of sampling: 3h and 24 h
- From how many animals: 4, pooled
- Method type(s) for identification: Liquid scintillation counting, NMR
- Other: only detection and quantification no identification of metabolites

Statistics:
values were expressed as means +- standard error.
Annova followed by Dunnett's or Newman-Keuls analysis
p<0.05

Results and discussion

Preliminary studies:
no data

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
accumulation mainly in the liver (compared to total dose) but also in kidney, namely the medulla (compared to organ weight), with the highest radioactivity observed in the cytosolic fraction, covalent binding of radioactivity was observed in hepatic microsomes. radioactivity after 3 h was more evident in plasma than in erythrocytes.
Details on excretion:
primarily renally excreted (53 %), <1% excretion in the faeces within 24 h p.a. in the high dose group (1 mmol/kg bw)

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
no qualitative determination of metabolites

Any other information on results incl. tables

In general, 2-chloroaniline derived radioactivity was excreted faster, reached peak tissue concentrations earlier, disappeared from tissues faster and had less covalent binding in target tissue at 24 h than 4-chloroaniline-derived radioactivity.

Applicant's summary and conclusion