N-(4-aminophenyl)aniline

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: limitations in documentation and study design (e.g. only one sex is treated; only the 4-ADPA concentration in the diet is given); acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Acute and short-term toxicity studies on p-aminodiphenylamine.

Author:

Singh RL, Khanna SK, Shanker R, Singh GB

Year:

1986

Bibliographic source:

Vet Hum Toxicol 28: 219 - 223

Materials and methods

Principles of method if other than guideline:

Method: other subchronic toxicity study

GLP compliance:

not specified

Limit test:

no

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: commercial grade from Koch-Light Laboratories Ltd.

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: 4-ADPA contained in diet

Duration of treatment / exposure:

90 d

Frequency of treatment:

continuously in diet

Doses / concentrations

Remarks:

Doses / Concentrations:
1,000, 2,500, 5,000, 7,500 ppm (approximately 100, 250, 500 and 750 mg/kg bw/day)
Basis:
nominal in diet

No. of animals per sex per dose:

12 males

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: no

Results and discussion

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: erythrocyte sedimentation rate increased, no other effects

2

Dose descriptor:

LOAEL

Effect level:

250 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: haematological changes, changes in liver enzymes

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

RS-Freetext:
TOXIC RESPONSE/EFFECTS BY DOSE LEVEL:

- Mortality and time to death: no information relating to mortality  reported 

- Clinical signs: not reported

- Body weight gain: reduction at higher dose; overall
weight gain 11.7 % at 5,000 ppm, 0 % at 7,500 ppm in
comparison to 36 % in controls (no further details)

- Food consumption: reduction from 10th week onward until
end of study: The average reduction in the last 4 weeks was documented to  

be -13 % at 5,000 ppm, -26 % at 7,500 ppm; no
effect for lower dosages

- Clinical chemistry:
Serum: from 2,500 ppm GOT and GPT significantly increased
(p<= 0.01); from 5,000 ppm acid and alkaline phosphatase
significantly increased (p<= 0.01); at 2,500 and 5,000 ppm
cholesterol significantly increased (p<= 0.01)
Liver: from 5000 ppm dose-dependent decrease of acid and
alkaline phosphatase which became statistically significant (p <= 0.05)  

at 7500 ppm, at 7500 ppm esterified cholesterol significantly decreased  

(p <= 0.05) but no pronounced change in the total cholesterol 

Testis: marginal depletion of 25% for of LDH and hyaluronidase at 5000 and 7500ppm; 

from 5,000 ppm significant effect for hyaluronidase (p<0.05) 
Accessory sex organs: Alkaline phosphatase of seminal vesicles, acid  

phosphatase in ventral prostates, and fructose in coagulating glands and  

dorso-lateral prostates did not reveal any consistent change over matched  

controls

-Haematology: statistically significant increase in erythrocyte 

at 1000 ppm: erythrocytes sedimentation rate increased

sedimention rate and MCH at 2500 and 7500 ppm; from 2,500 ppm RBC and Hb  

significantly decreased and MCV significantly increased (p<0.01); at  

7,500 ppm packed cellular volume (hematocrit) significantly decreased (p<0.01)

-Organ weights: Average relative organ weights of heart, lung, spleen,  

testis and kidney remained unaffected; an increase of about +35 % both at  

5,000 ppm and 7500 ppm is described for the liver

- Histopathology:
Liver: from 5,000 ppm degenerative changes of hepatocytes,
plasma cell reaction in portal triad areas; normal
appearance at lower dosages
Testis: 7,500 ppm patchy degeneration of seminiferous
tubules, no multinucleated giant cells,
interstitial tissue had normal vascularity and Leydig cells; no damage at  

lower dosages

Applicant's summary and conclusion

Conclusions:

CL-Freetext:
No effects were observed at 1000 ppm. Body weight retardation parallel to reduced food intake was observed from 5,000 ppm onwards.
The haematological changes observed from 2500 ppm onwards suggest anemia. Hepatotoxicity is evident
from increased liver weight (>= 5000 ppm), changes in marker enzymes in the serum (>= 2500 ppm) and histopathological changes (>= 5000 ppm). Decreased hyaluronidase in testis (>= 5000 ppm) and degeneration of seminiferous tubules (7500 ppm) were observed at dose levels which are in the magnitude of the acute LD50-value (7500 ppm correspond to 555-750 mg/kg bw/day).

Executive summary:

In a 90-day study, groups of 12 male Wistar rats were orally exposed to dietary concentrations of 1000, 2500, 5000 or 7500 ppm 4-ADPA (approximately 100, 250, 500 (435), 750 (555) mg/kg bw/d). No information is given with regard to mortality and clinical signs. For these two highest doses only a decrease in body weight gain (11.7% at 5000 ppm, 0% at 7500 ppm in comparison to 36% in controls) in parallel to a reduced food intake was described (decrease of 13% at 5000 ppm and 26% at 7500 ppm corresponding to calculated doses approximately 435 and 555 mg/kg bw/day). Haematological changes observed at =2500 ppm (approximately 250 mg/kg bw/d; reduction of erythrocytes and haemoglobin, increased MCV) suggest anaemia. Unchanged organ weights and no findings in microscopic examination of heart, lung, spleen, adrenals and kidneys as well as unchanged accessory sex gland weight revealed no adverse effects to these organs. Hepatotoxicity was evident from increased liver weight (35% both at 5000 and 7500 ppm) and changes in marker enzymes in serum at =2500 ppm (approximately 250 mg/kg bw/d). Histopathological findings as degenerative changes of hepatocytes from 5000 ppm (approximately 435-500 mg/kg bw/d) and plasma cell reaction in portal triad area also showed a hepatotoxic effect of 4-ADPA, whereas the livers presented normal appearance at doses of 2500 ppm and lower. At 7500 ppm (approximately 555-750 mg/kg bw/d) degeneration of seminiferous tubules in testes as well as decreased hyaluronidase activity in testes which started at 5000 ppm (approximately 435 ¿ 500 mg/kg bw/d) were described. There were no multinucleated cells and interstitial tissue had normal vascularity and Leydig cells. No histological damage was seen at lower doses and testes weight was unaffected over the whole dose range (Singh 1986). For the 90-day feeding of 4-ADPA to male rats a NOAEL of 1000 ppm, corresponding to a dose of approximately 100 mg/kg bw/d is derived with regard to haematology parameters and changes in liver enzymes as first indication of an impact on this organ (Singh 1986).