N-(4-aminophenyl)aniline

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study, comparable to guideline study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Reference 2

Reference Type:

publication

Title:

Oral and dermal absorption studies in Sprague-dayley rats with 4-aminodiphenylamine

Author:

Healy CE et al.

Year:

1993

Bibliographic source:

The Toxicologist 13, 1993

Materials and methods

Objective of study:

toxicokinetics

Principles of method if other than guideline:

Method: other: see Test Condition

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

N-(4-aminophenyl)aniline

EC Number:

202-951-9

EC Name:

N-(4-aminophenyl)aniline

Cas Number:

101-54-2

Molecular formula:

C12H12N2

IUPAC Name:

N1-phenylbenzene-1,4-diamine

Details on test material:

IUCLID4 Test substance: other TS: purity: 98,3% (C14-labeled)

Radiolabelling:

yes

Remarks:

14C

Test animals

Species:

rat

Strain:

other: CRL:CD(R) (SD) rats

Sex:

female

Administration / exposure

Route of administration:

other: Oral gavage; Intravenous injection; dermal

Vehicle:

other: Corn oil / Propylene glycol; dermal: ethanol; intravenous: emulphor/ethanol mixture

Duration and frequency of treatment / exposure:

7 days for oral administration, 7 days for i.v. administration, 3 days for dermal administration

Doses / concentrations

Remarks:

Doses / Concentrations:
Females: 2 mg/kg/bw via intravenous injection and skin
200 mg/kg/bw via oral gavage

No. of animals per sex per dose / concentration:

4/dose/application

Control animals:

not specified

Results and discussion

Preliminary studies:

2 groups of 4 females for method development

Main ADME results

Main ADME results 1

Type:

absorption

Results:

20 % dermal absorption

Main ADME results 2

Type:

excretion

Results:

Approximately 80% of the oral/corn  oil dose, 88% of the oral/propylene glycol dose, 80% of the iv dose, and   15% of the dermal dose were eliminated in the urine and feces

Toxicokinetic / pharmacokinetic studies

Details on absorption:

20 % dermal absorption

Details on excretion:

Approximately 80% of the oral/corn  oil dose, 88% of the oral/propylene glycol dose, 80% of the iv dose, and  
15% of the dermal dose were eliminated in the urine and feces

Any other information on results incl. tables

RS-Freetext:
The total 4-ADPA derived radioactivity recovered in the test animal  

Groups 3-6 ranged from 82.0% to 93.9% of the administered dose. 

The  majority of the test material was eliminated in the feces. The  

urine:feces ratio was approximately 1:2. Propylene glycol caused a  significant 

increase in the amount of activity excreted in the urine as  compared to corn oil,which may be a result of increased absorption.  There was little difference in 

fecal elimination of 4-ADPA derived  activity regardless of the method of 

treatment, and very little 4-ADPA  remained in the carcass. The body burden 

of animals administered 4-ADPA  via IV injection was significantly greater 

than all other routes of  administration. For dermal administration, 

the majority of activity  remained at the site of application. Nearly 42% of 

the administered dose  was removable with alcohol swabbing. 20% was associated 

with the skin,  and 8% was associated with the metal cap used to cover the site 

of  application. Approximately 23% of the absorbed dermal dose was eliminated  

in the urine, and 56% in the feces. This indicates that there was little  

difference between oral, iv or dermal administration with respect to the  

amount eliminated in the urine and feces. 
ABSORPTION: Absorption of 4-ADPA in propylene glycol was approximately  

1.4 times greater than that of 4-ADPA in corn oil. Based upon urinary  

elimination, about 17% of the dose was absorbed through the skin. The  

total amount of absorbed 4-ADPA derived activity which was detected in  

the urine, feces, carcass, blood, and in the cage washings of  dermally-treated

 animals was about 20% of the administered dose. The  vehicle produced a 

significant effect on blood levels. 4-ADPA/corn oil  reached a maximum 

concentration of 0.5% of the administered dose two  hours after gavage. 

In contrase, peak blood concentrations of  4-ADPA/propylene glycol were 

almost double that of corn oil vehicle, and  was not reached until 24 hours 

after dosing. These results indicate that  the rate of absorbtion of 

4-ADPA/propylene glycol was faster, and the  total amount absorbed was greater 

than that of 4-ADPA/corn oil.  
BLOOD CLEARANCE:  The halflife of 4-ADPA in the blood was calculated as  

11.6 days for 4-ADPA/corn oil and 13.7 days for 4-ADPA/propylene glycol.  

Plasma clearance after iv injection consisted of a short alpha phase with  

a halflife <1 day, followed by a much longer beta phase of 12 days. There  

was about a 1.8 fold increase in the area under the blood elimination  

curve from animals that received 4-ADPA/propylene glycol compared to  

those treated with 4-ADPA/corn oil. The bioavailability of material in  

the 4-ADPA/corn oil animals was about 54% of those administered  

4-ADPA/propylene glycol.  
WHOLE BODY ELIMINATION:  Treatment had little effect on the profile of  

total urinary and fecal elimination. Approximately 80% of the oral/corn  

oil dose, 88% of the oral/propylene glycol dose, 80% of the iv dose, and  

15% of the dermal dose were eliminated in the urine and feces combined  

over the 7 day observation period.

Applicant's summary and conclusion

Executive summary:

The absorption and elimination of 4-ADPA were evaluated in female CD® rats. Groups of four female rats received single doses of 14C labeled 4-ADPA by the oral (gavage), dermal or intravenous routes. In order to investigate whether the vehicle has an influence on the absorption of 4-ADPA from the gastro-intestinal tract, one group was given the test substance (200 mg/kg bw) in corn oil, and another group received the same dose in propylene glycol. In-life blood samples were taken from each animal 2 hours after dosing, and then in 24-hours intervals until sacrifice. Samples of urine and feces were collected from each animal at 24-hour intervals. The body burden of 14C at the end of the 7day observation period was determined by analyzing blood and carcasses. The use of propylene glycol caused a significant increase in the amount of 4-ADPA derived radioactivity excreted in the urine as compared to corn oil, which, according to the authors, may have been the result of an about 1.4 times greater absorption of 4-ADPA from the propylene glycol preparation as compared to the corn oil preparation. Peak blood concentrations of 4-ADPA derived radioactivity from the propylene glycol vehicle were almost double that of corn oil vehicle, and were not reached until 24 hours after dosing. The half-life of 4-ADPA in the blood was calculated as 11.6 days for 4-ADPA derived radioactivity from the corn oil preparation and 13.7 days for ADPA derived radioactivity from propylene glycol preparation. Plasma clearance after intravenous injection (2 mg/kg bw) consist of a short alpha-phase with a half-life of less than one day, followed by much longer beta phase of 12 days. The bioavailability of 4-ADPA in the 4-ADPA/corn oil animals was only about 54 % of those administered 4-ADPA in propylene glycol. About 20 % of the applied dermal dose (2 mg/kg bw in ethanol) was absorbed through the skin. Approximately 80 % of the oral dose in corn oil, 88% of the oral dose in propylene glycol, 80% of the intravenous and 15 % of the dermal dose were eliminated in the urine and feces (combined) over the 7 day observation period. Independent of the route of administration, the majority of the test substance derived radioactivity was eliminated in the feces (urine: feces ratio 1:2) (Monsanto 1991).