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Diss Factsheets

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 4-chloroaniline hydrochloride (0.5 or 1 mmol/ kg bw) was injected i.p in male Fisher 344 rats tissue distribution and 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:
1-amino-2-chlorobenzene
Details on test material:
- Name of test material (as cited in study report): 4-chloroaniline hydrochloride

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

- Radiochemical purity (if radiolabelling): not reported
- Specific activity (if radiolabelling): 8.9 mCi/mmol
- Locations of the label (if radiolabelling): U
Radiolabelling:
yes
Remarks:
[14C]-4-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:
Target organs

In the 0.5 mmol/kg 4-chloroaniline treatment group, liver and kidney medulla had the highest tissue concentrations of radioactivity at 3 hours, while the liver had the highest percentage of injected dose in total tissue (whole organ or kidney section). Plasma radioactivity derived from 4-chloroaniline than in erythrocytes.

Increasing the 4-chloroaniline dose to 1 mmol/kg had little effect on increasing tissue concentrations of 4-chloroaniline-derived radioactivity except in liver.

In blood, erythrocyte concentrations were unchanged (µmol/mL) or decreased (percentage of injected dose/mL), while plasma radioactivity tended to increase, but the increase was not significant.

24 hour post-treatment with 4-chloroaniline 1.0 mmol/kg , kidney, liver, plasma and erythrocyte values of 4-chloroaniline-derived radioactivity were not altered from 3 h values, but splenic concentrations were increased.

Subcellular distribution and covalent binding

In kidney, 4-chloroaniline was located first in cytosolic compartment at 3h post-treatment, regarless of the dose administered. At 24 h post-treatment 4-chloroaniline treatment group only the cytosolic compartment had decreased radioactivity to the corresponding h values. Covalent binding of metabolites were present in liver and kidney
Details on excretion:
30% of the administered radioactivity was excreted in the corresponding 4-chloroaniline group. Fecal excretion accounted for less than 1% of adminisstered radioactivity in both groups at all time points.

Metabolite characterisation studies

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

Applicant's summary and conclusion