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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study under GLP condition

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
2007
Report Date:
2007
Reference Type:
publication
Title:
Reproductive and developmental toxicity screening study of 4-aminophenol in rats.
Author:
Harada T, Kimura E, Hirata-Koizumi M, Hirose A, Kamata E, Ema M
Year:
2008
Bibliographic source:
Drug Chem Toxicol.2008;31(4):473-86.

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
not specified
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 4-aminophenol
- Physical state: white or pale-yellow crystalline powder
- Analytical purity: 99.00%
- Lot/batch No.: Lot No.044K0101 (Tokyo Chemical Industry Co., Ltd.)
- Storage condition of test material: The test material was sealed up, and it was saved in the cool and dark space
- Other: The purity and stability of the chemical were verified by analysis before the study.

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan, Inc., Atsugi
- Age at study initiation: (P) 10 weeks old
- Housing: Rats were housed individually, except during the acclimation, mating, and nursing periods. From Day 0 of pregnancy to the day of sacrifice, individual dams and litters were reared by using wooden chips (White Flake; Charles River Japan, Inc.) as bedding.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 25 ± 2 ℃
- Humidity (%): 55 ± 5 %
- Air changes (per hr): 10 - 20 times/hr
- Photoperiod (hrs dark / hrs light): 12 hrs dark /12 hrs light

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.5% carboxymethylcellulose-Na solution
Details on exposure:
Dosing volume: 10 mL/kg
Stability (test solutions): The stability of formulations in the dark at room temperature has been confirmed for up to 6 h.
Frequency of preparation: The formulations were prepared just before use and were used within 6 h.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: 2 weeks
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
(P) Male: 49 days (from 14 days before mating to the day before sacrifice through the mating period)
(P) Female: 40 - 60 days (from 14 days before mating to 3 days after delivery through the mating and gestation periods)
Frequency of treatment:
once-daily
No. of animals per sex per dose:
12 animals/sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
The dosage levels were determined based on the results of a previous 28-day repeated-dose toxicity study in rats given 4-aminophenol by gavage at 0 (vehicle), 4, 20, 100, or 500 mg/kg/day (See repeated dose toxicity_001). At 500 mg/kg/day, the death in 1 male with renal necrosis, decreases in body-weight gain, food consumption, erythrocyte count, hematocrit value (Ht) and hemoglobin content (Hb), increased relative weight of the liver and spleen, basophilic tubules in the kidney, and brown urine were observed. At 100 mg/kg/day, brown urine and basophilic tubules in the kidney were also observed. No toxicological effects were detected at 4 and 20 mg/kg/day.
- Rationale for animal assignment (if not random):
Body weight-balanced randomization

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations:
Male: Twice a week
Female:
Premating period: Twice a week
Mating period: Twice a week
Pregnancy period: Days 0, 7, 14 and 20
Lactation period: Days 1 and 4

FOOD CONSUMPTION: Yes
Male:
Premating period: Twice a week
Female:
Premating period: Twice a week
Pregnancy: Days 1, 7, 14 and 20
Lactation: Days 1 and 4"

WATER CONSUMPTION: No
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No
- Number of late resorptions: No
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: No
- Skeletal examinations: No
- Head examinations: No
Statistics:
Statistical analyses were conducted by Mann-Whitney U-test, Fischer’s exact probability test, Dunnett’s test, and Kruskal-Wallis rank sum test.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
2 females died at 500 mg/kg/day.
Decreased food consumption, and brown urine in females at 100 and 500 mg/kg/day were observed.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
At 500 mg/kg/day, the body weight of live male and female pups were significantly lowered on PND 0 and were decreased on PND 4.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion