N-(4-aminophenyl)aniline

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP and guideline study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1989

Report date:

1989

Reference 2

Reference Type:

publication

Title:

Developmental toxicity studies in rats with 4-aminodiphenylamine (4-ADPA) and 4-nitrodiphenylamine (4-NDPA).

Author:

Bannister RM, Brewster DW, Rodwell DE, Schroeder RE, Barnett JW Jr

Year:

1992

Bibliographic source:

The Toxicologist 12: 103

Reference 3

Reference Type:

secondary source

Title:

Unnamed

Year:

1989

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

EPA OTS 798.4900 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes

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: purity 98.6 %

Test animals

Species:

rat

Strain:

other: Sprague-Dawley derived CD

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

yes

Details on mating procedure:

mating ratio 1:1

Duration of treatment / exposure:

day 6-15 of gestation

Frequency of treatment:

once daily

Duration of test:

termination on GD 20

No. of animals per sex per dose:

24 dams

Control animals:

yes, concurrent vehicle

Details on study design:

Sex: female
Duration of test: day 20 of gestation

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

LOAEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Effect levels (fetuses)

1

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: fetotoxicity

2

Dose descriptor:

LOAEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: fetotoxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

RS-Freetext:
MATERNAL TOXIC EFFECTS BY DOSE LEVEL: 
- Mortality and day of death: none
- Number pregnant per dose level: 100 %, 91.7 %, 91.7 %, 
  100 % (0, 10, 50, 100 mg/kg bw/d)
- Number of resorptions: no effects
- Number of implantations: no effects
- Pre and post implantation loss: no effects
- Number of corpora lutea: no effects
- Duration of Pregnancy: no effects
- Body weight: 100 mg/kg: weight gain significantly lower 
  during early dosing (GD 6-11 and entire gestation period 
  GD 6-15); on GD 11-13 and 13-15 and pre- and
  post-treatment weight gain comparable to controls;
  corrected body weight on GD 20 (gravid uterine weight 
  subtracted) was comparable among all groups.
- Food consumption: significantly reduced at 100 mg/kg
  during early dosing on GD 6-11, 26 % lower than control
  value; for all other time intervals and doses comparable
  to controls
- Description, severity, time of onset and duration of
  clinical signs:
  excessive salivation in all groups with dose   relationship:
  2/24, 8/24, 17/24, 24/24;
  100 mg/kg: staining of the skin/fur in the anogenital
  region and/or soft stool with increasing frequency during
  dosing period
- Hematological findings incidence and severity: no data
- Clinical biochemistry findings incidence and severity: no 
  data 
- Gross pathology incidence and severity: no effects
- Organ weight changes: 100 mg/kg: gravid uterine weight 
  significantly reduced
FETAL DATA: 
- Litter size and weights: litter size no effect; 
  fetal weight: 100 mg/kg: significant reduction for both 
  sexes and all fetuses
- Number viable: 100 % at 0, 50 and 100 mg/kg; at 10 mg/kg: 
  14/15 in 1 litter, all other litters 100 %
- Sex ratio: no effects
- Grossly visible abnormalities: 
- non significant increase of external variations in       

fetuses resp.  litters: 0 %, 0 %, 0.3 % resp. 4.3% (1/315    fetuses evaluated resp.  1/23 litters evaluated), 1.0 %      resp. 4.5% (3/300 fetuses evaluated  resp. 1/22 litters     evaluated:  glassy shiny 
- appearance due to thin skin of these developmentally 
  retarded fetuses)
- non significant increase of external abnormalities in     fetuses resp.  litters:
  0 % (0/334), 0 % (0/308), 0.3 % resp. 4.3% (1/315:     

fetuses  evaluated resp. 1/23 litters evaluated:     edematous), 1.0 % resp. 13.6%
  (3/300 fetuses evaluated resp. 3/22 litters evaluated:      micrognathia, exencephaly, absence of eye bulge, 
  edema in cervical and thoracic region)
- Soft tissue abnormalities: 
  non significant increase of visceral malformations in       fetuses  resp. litters: 
  0 % (0/174), 0.6 % resp. 4.5% (1/160 fetuses evaluated   resp. 1/22  litters evaluated); 0 % (0/165); 2.5 % resp.     13.6% (4/157 fetuses  evaluated resp. 3/22 litters   evaluated) (all dissimilar malformations);
  visceral variations: 
  Fetal incidences (the groups differ significantly (p <=   0.05); the  response is linearly related to the dose   levels (p <= 0.05):
  4.6 % (8/174), 1.3 % (2/160), 5.5 % (9/165), 
  9.6 % (15/157) (specific changes within historical 
  control range)
  Litter incidence (no statistical differences among   groups)
  33.3% (8/24), 9.1% (2/22), 34.8% (8/23), 27.3% (6/22)
- Skeletal abnormalities: 
  skeletal malformations: significant increase at 100 mg/kg
  both on a per litter and a per fetus basis: 0.6 % resp.   4.2% (1/159  fetuses evaluated resp. 1/24 litters     evaluated, wavy rib), 0 % resp.  0% (0/147 fetuses   evaluated resp. 0/22 litters evaluated), 0 % resp. 0%    (0/150 fetuses evaluated resp. 0/23 litters), 27.6 %   resp. 63.6%  (40/145 fetuses evaluated resp. 14/22 litters   evaluated);  
  types of defects: wavy rib (26 resp. 12), fused rib,     vertebral  defects
  skeletal variations: significant decrease at 10 mg/kg, 
  significant increase at 100 mg/kg on per fetus basis; the   statistical  evaluation on per litter basis was not tested   due to lack of variance :  87.4 % resp. 100 % (139/159   fetuses evaluated resp. 24/24 litters  evaluated), 
  76.2 % resp. 100 % (112/147 fetuses evaluated resp. 22/22   litters  evaluated), 84.7 % resp. 100 % (127/150 fetuses   evaluated resp. 23/23  litters evaluated), 97.2 % resp.   100 % (141/145 fetuses evaluated resp.  22/22 litters   evaluated);
  at 100 mg/kg generally increased retardation of 
  ossification as a fetotoxic effect
STATISTICAL RESULTS: 
maternal effects: 100 mg/kg: significant reduction of body
weight gain during GD 6-11 resulting from significant
reduction of food consumption; significant reduction of
gravid uterine weight.
fetal effects: 100 mg/kg: significant reduction of fetal
weight for both sexes and all fetuses; significant increase
of skeletal malformations and variations (most prevalent findings were  wavy ribs, fused ribsm vertebral defects and ossification variations)

Applicant's summary and conclusion

Conclusions:

CL-Freetext:
Signs of maternal toxicity at 100 mg/kg bw were significantly depressed weight gain and food consumption during the early dosing period (GD 6-11) and a significant reduction of gravid uterine weight. A significant reduction of fetal weight and an increased incidence of skeletal malformations (e.g. wavy ribs, fused ribs, vertebral defects and ossification variations) were considered to be associated with maternal toxicity. Increased incidences of fetotoxic or developmental effects were not observed in the absence of maternal toxicity (at 10 or 50 mg/kg bw and day).

Executive summary:

In another developmental toxicity study by the same laboratory, groups of 24 pregnant CD® rats were exposed to 10, 50 or 100 mg/kg bw/d by gavage from gestational day 6 to 15. Reported clinical signs were excessive salivation in all groups with a dose relationship and in the highest dose group staining of the skin/fur in the anogenital region and soft stool with increasing frequency during the dosing period. At 100 mg/kg bw/d, the weight gain was significantly decreased and the food consumption of dams was 26% lower than that of the controls during early dosing on gestation day 6 to 11. The significant reduction in weight gain and the decrease in food consumption were considered clear signs of maternal toxicity. Mean number of viable foetuses, implantation sites and number of corpora lutea were comparable for the treatment and the control groups. A significant reduction in foetal weights in the high dose animals was indicative of a fetotoxic effect. An increased incidence of skeletal malformations and variations were restricted to the high dose group. The most prevalent findings were wavy ribs, fused ribs, vertebral defects and ossification variations. These findings were considered to be associated with maternal toxicity. At dose levels where no overt toxicity was seen, similar rib and vertebral defects were not seen. The NOAEL both for maternal and developmental effects was 50 mg/kg bw/d (Monsanto Co 1989).