3-aminophenol

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Justification for type of information:

Data is from a study report.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1982

Report date:

1982

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: Combined 90 Day Feeding Study to assess teratogenicity

Principles of method if other than guideline:

The above test chemical was tested in a 90 days feeding study followed by teratology study.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

3-aminophenol

EC Number:

209-711-2

EC Name:

3-aminophenol

Cas Number:

591-27-5

Molecular formula:

C6H7NO

IUPAC Name:

3-aminophenol

Details on test material:

- Name of test material (as cited in study report): m-aminophenol
- Molecular formula (if other than submission substance): C6H7NO
- Molecular weight (if other than submission substance):109.13
- Substance type: Organic
- Physical state: solid
- Analytical purity: 99.93%
- Lot/Batch number: 49

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Taconic farms, Germantown, N.Y. 12526.
- Age at study initiation: No data available
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: All animals were housed individually in suspended wire mesh bottom cages except during mating.
- Diet (e.g. ad libitum): basal laboratory chow ad libitum.
- Water (e.g. ad libitum): Fresh tap water ad libitum
- Acclimation period: Twelve days

ENVIRONMENTAL CONDITIONS
- Temperature (°F):70 ± 1.13 deg F
- Humidity (%): 55.8 ± 4.6%

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: Feed

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: overnight
- Proof of pregnancy: Each female was checked in the morning for the presence of a sperm plug in the vagina or beneath the cages. Mating was verified by the microscopic examination of a vaginal washing for the presence of sperm cells
- After 1 days of unsuccessful pairing cohabitation continued for 3 more days.
- Further matings after 3 days of unsuccessful mating:: If mating had not occured after 3 days of cohabitation, females were separated from males and re-assigned to new males 2 days later.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No Data Available

Duration of treatment / exposure:

18 weeks

Frequency of treatment:

Daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 80, 200 and 700 mg/kg bw/day (average actual doses received)

No. of animals per sex per dose:

Twenty-five females per treatment group. A total of 100 females were used.

Control animals:

yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:

Parental animal: observation and examination
Each female was observed daily for condition (live, dead, moribund) and for signs of toxicity. Body weights were recorded on days 0, 6, 9, 12, 15 and 20 of gestation.

Oestrous cyclicity (parental animals):

No Data Available

Sperm parameters (parental animals):

No Data Available

Litter observations:

The number of live fetuses and dead fetuses were recorded when pregnant females were sacrificed.

Postmortem examinations (parental animals):

Each females uterus and ovaries were exposed. Early and late resorptions were recorded as well as the total number of corpora lutea on both ovaries.
Following removal of all fetuses each females abdominal and thoracic cavity were examined for grossly abnormal tissues or organs.

Postmortem examinations (offspring):

Each live fetuses were removed, gently dried, weighed and examined for external gross malformations and sex determination. Dead fetuses were preserved in 10% Neutral Buffered Formalin.
Approximately 1/3 of the live fetuses were preserved in Bouin's solution while the remaining 2/3 were eviscerated and stored in alcohol. These fetuses were later on stained with Alizarin Red-S.

Statistics:

All statistical analysis compared the treatment groups with the control with a minimal level of significance set at p<0.05. Analysis of variance followed by a Student's t-test to isolate significant differences was used to compare body weights, fetal weights, corpora lutea, total implants and live fetuses. The number of resorptions (early and late), dead fetuses and post-implantations losses were compared by the Mann-Whitney U-test. The number of litters with malformations was compared with Fishers Exact test. Fetal sex ratios were compared by Chi-square (with Yates correction factor).

Reproductive indices:

No Data Available

Offspring viability indices:

No Data Available

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

not examined

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Reduction in body weight were recorded in the two highest doses.
When changes in body weight were determined between days 0, 6, 9, 12, 15 and 20, the animals exposed to 700 mg/kg per day showed significantly less gain as compared to control.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

The females in the 700 mg/kg dosage group also consumed less food.

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

effects observed, treatment-related

Description (incidence and severity):

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
There was no significant effect on any parameter related to reproductive performance, except in the average number of corpora lutea which was marginally but statistically lower at 700 mg/kg (mean 12.2) as compared to controls (mean 14.2).

Effect levels (P0)

1

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

2

Dose descriptor:

LOAEL

Effect level:

700 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

Results: F1 generation

General toxicity (F1)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

mortality observed, non-treatment-related

Description (incidence and severity):

VIABILITY (OFFSPRING)
Only one fetus in the control group was found to be dead when pregnant females were sacrified on day 20 of gestation.

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

GROSS PATHOLOGY (OFFSPRING)
There were no visceral malformations noted. A low incidence of full 14th ribs was noted at 200 and 700 mg/kg. However, the lack of other malformations and the presence of full 14th ribs in historical controls indicates that this is probably not a toxicologically significant effect.

Histopathological findings:

not specified

Other effects:

no effects observed

Description (incidence and severity):

No significant effect on the number of live fetuses or fetal sex ratio between the treatment groups.

Developmental neurotoxicity (F1)

Behaviour (functional findings):

not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not specified

Effect levels (F1)

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

700 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

body weight and weight gain

gross pathology

other: sex ratio

Overall reproductive toxicity

Reproductive effects observed:

yes

Lowest effective dose / conc.:

700 mg/kg bw/day (actual dose received)

Treatment related:

yes

Relation to other toxic effects:

reproductive effects as a secondary non-specific consequence of other toxic effects

Dose response relationship:

not specified

Relevant for humans:

not specified

Applicant's summary and conclusion

Conclusions:

The no observed adverse effect level (NOAEL) was condsidered to be 200 mg/kg/day when female rats were exposed to the test chemical during gestation.

Executive summary:

In this reproductive and developmental toxicity study, male and female Sprague-Dawley rats were exposed to 3-aminophenol by diet for 90 days prior to mating (males and females) and from day 0-20 of gestation (females) at approx. 0, 80, 200, 700 mg/kg bw/day. There was a marked decrease in body weight throughout the treatment period in males (before mating) and in females (before mating and during gestation) at 700 mg/kg as compared to controls. This was accompanied by a significant decrease in food consumption in both male and females. At 200 mg/kg, the body weight was slightly lower in females before mating and during gestation, as compared to the controls. The mean number of corpora lutea per dam was significantly lower at 700 mg/kg (mean, 12.2) as compared to controls (mean 14.2). This effect was of doubtful significance as there were no adverse effects on any other parameter of reproduction at 700 mg/kg, as evident by no significant effect on the number of resorptions, the number of live fetuses, fetal sex ratio or fetal body weight. No visceral malformations were noted. A low incidence of supernumerary 14th ribs was noted at 200 mg/kg (1 fetus out of 239) and at 700 mg/kg (6 fetuses out of 262). This effect was of doubtful clinical significance due to lack of other malformations and due to supernumerary 14th ribs in historical control data. The no observed adverse effect level (NOAEL) was condsidered to be 200 mg/kg/day when female rats were exposed to the test chemical during gestation.