3-aminophenol

Repeated dose toxicity: dermal

Administrative data

Endpoint:

chronic toxicity: dermal

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 study report

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1979

Report date:

1979

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

Lifetime chronic toxicity/carcinogenisis study in rats were performed using the dermal application of test material m-aminophenol

GLP compliance:

not specified

Limit test:

no

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

Constituent 2

Reference substance name:

m-aminophenol

IUPAC Name:

m-aminophenol

Details on test material:

- Name of test material (as cited in study report): formula P-25 and Formula P-26
- Substance type:organic
- Physical state:
P-25 : thick gray liquid
P-26 : Thick brown liquid

Test animals

Species:

rat

Strain:

other: Charles river

Sex:

male/female

Details on test animals or test system and environmental conditions:

Details on test animal
TEST ANIMALS
- Source: Charles River
- Age at study initiation: No data available
- Weight at study initiation: Male weighing from 62 to 204 grams; Females weighing from 61 to 192 grams
- Fasting period before study: No data available
- Housing: The rats were housed individually in hanging wire mesh cages and maintained in a temperatures, humidity and light controlled environment.
- Diet (e.g. ad libitum): Ground Purinas Laboratory Chow, ad libitum
- Water (e.g. ad libitum): Water was available at libitum
- Acclimatization period: No data available

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%): No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available

Administration / exposure

Type of coverage:

open

Vehicle:

other: No vehicle was used

Details on exposure:

TEST COMPOUND
The fully prepared formulas (P-25 and P-26) were recieved from Cosmair, Inc., New York.

TEST SITE
- Time intervals for shavings or clipplings: The hair on the neck and back of each rat was clipped with an electric clipper (at least 24 hours prior to compound administration) as necessary during the study

COMPOUND ADMINISTRATION
The dyes were applied as evenly as possible to assure skin contact and to avoid run off.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

24 months (lifetime)

Frequency of treatment:

twice a week

Doses / concentrations

Remarks:

Doses / Concentrations:
Each topical application (0.5 ml/rat) contained 3-aminophenol at approx. 0.59 mg/kg (P-26) or 2.65 mg/kg (P-25).
Basis:

No. of animals per sex per dose:

600 rats in total, divided as below:
Control 1: 60 males, 60 females
Control 2: 60 males, 60 females
Control 3: 59 males, 60 females
P-25: 60 males, 60 females
P-26: 60 males, 60 females

Control animals:

other: Yes, untreated but clipped on the same regime as the treated rats but no compund was added.

Details on study design:

No data

Positive control:

No data

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations:Individual body weights were recorded weekly for the first 14 weeks and monthly thereafter

FOOD CONSUMPTION:
Sex group food consumption was recorded weekly.

FOOD EFFICIENCY: No
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data available

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
- Time schedule for examinations: No data available

OPHTHALMOSCOPIC EXAMINATION: No
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At 3, 12, 18 and 24 months
- Anaesthetic used for blood collection: No data available
- Animals fasted: Yes
- How many animals: 5 males and 5 females in each group.
- Parameters examined: Hemoglobin, hematocrit, total erythrocyte, total and differential leucocyte counts, total platelet and reticulocyte count.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At 3, 12, 18 and 24 months
- Animals fasted: Yes
- How many animals: 5 males and 5 females in each group.
- Parameters examined: Fasting glucose, urea nitrogen, serum alkaline phosphate, serum glutamic oxalacetic, pyruvic transaminase activities and serum creatinine.

URINALYSIS: Yes
- Time schedule for collection of urine: At 3, 12, 18 and 24 months
- Metabolism cages used for collection of urine: No data available
- Animals fasted: Yes
- Parameters examined: Volume, pH, specific gravity, description of color and appearance, and qualitative test for albumin, glucose, bilirubin and occult blood. Microscopic examinations of sediment was also performed.

NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available

OTHER: no data availble

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
After twelve months of treatment, five male and five female rats from each group were sacrificed by decapitation and necropsied. At necropsy, representative tissues from each rat were collected in buffered neutral 10% .formalin. All~ rats of a sex were sacrificed and necropsied when the survival for that sex reached 20%.. Any rats which died or were sacrificed in extremis during the course of the study also were necropsied and, unless precluded by autolysis, representative tissues were retained in formalin.

HISTOPATHOLOGY: Yes
The following tissues from all rats sacrificed after twelve months of treatment and at study termination were sectioned and stained with hematoxylin and eosin, and were then examined microscopically: skin neck (thyroid level), lung, gastrointestinal tract , spleen, pancreas, liver, pituitary, kidneys, urinary bladder, ureters, bone marrow, lymph node, adrenalsgonads ,brain, skeletal muscle, eyes and all tumor masses.

Other examinations:

No data

Statistics:

All statistical analyses compared the treatment groups with each control group. The body weights and hematological and biochemical parameters were compared by analysis of variance (one-way classification). Then Bartlett's test for hemogeneity of variance was applied to the respective parameters. The appropiate t-test (for equal or unequal variance) was used to judge the significance of differences between the means, based upon Dunnett's multiple comparison tables.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

The most common incidental finding noted for some control and treated rats were localized hair loss, ocular discharge, and masses.

Dermal irritation:

no effects observed

Mortality:

mortality observed, non-treatment-related

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The terminal body weight was marginally lower (9.4% lower) among females in the 2.65 mg/kg dose group compared to control group.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food consumption was slightly higher at 0.59 and 2.65 mg/kg compared to concurrent control groups.

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

At 2.65 mg/kg, one male rat at 12 months of study showed slight decrease in total erythrocytes, hemoglobin and hematocrit with increases in reticulocytes, neutrophils and platelets compared to control group. Also at 2.65 mg/kg, one female rat at 24 months of study showed moderate increases in total leukocytes and a marked decrease in lymphocytes. At 0.59 mg/kg, two male and two females at 24 months of study showed slight to moderate decreases in total erythrocytes, hemoglobin and hematocrit. Two of these four animals also showed moderate increases in reticulocyte counts.
Based on the low incidences and the lack of a dose-related trend, these effects are not attributed to 3-aminophenol exposure.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

At 2.65 mg/kg, one female at 24 months of study showed slight urea nitrogen and a marked increase in alkaline phosphatase activity and another female at 24 months of study showed moderate increases in the urea nitrogen level, serum glutamic-oxaloacetic transaminase and alkaline phosphatase activities.
At 0.59 mg/kg, one male rat at 18 months of study showed slight increases in urea nitrogen levels and a moderate increase in serum glutamic-oxaloacetic transaminase activity. At 0.59 mg/kg at 24 months of study, one male showed slight increases urea nitrogen levels and serum glutamic-oxaloacetic transaminase acitivty and a moderate increase in alkaline phosphatase activity whereas another male at 24 months of study showed a moderate increase in urea nitrogen level and a slight increase in the creatinine level.
Based on the low incidences and the lack of a dose-related trend, these effects are not attributed to 3-aminophenol exposure

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Description (incidence and severity):

There were no gross lesions attributed to the compound at necropsy in any experimental rats at the 12 or 24 months of study or in rats which died or were sacrificed extremis during the course of the study.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Non-neoplastic lesions were observed in various organs and tissues of rats from the control and experimental groups. These changes appeared to reflect normal background incidence of histopathology for rats of this strain and age routinely observed at this laboratory and were not considered to be compound related.

Histopathological findings: neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

The most common neoplasm or neoplasm-like lesion observed in rats from all sex groups was pituitary adenoma, the incidence of the neoplasm was generally greater in female rats then in males in the control and experimental groups. However, statistically significant variations of the tumor did occur in males between various control and experimental groups. The incidence of the tumor was significantly greater in male rats from groups Control 2, Control 3 and at 2.65 mg/kg than in males from group Control 1. Conversely, the incidence of the tumor was significantly less in male rats treated at 0.59 mg/kg than in males from groups Control 2 and Control 3. The statistically significant variations in incidence of pituitary adenomas between rats of different control groups as well as their statistically significant decrease in an experimental group when compared with two ontrol groups tended to discount in aging rats of this strain at this laboratory. The incidence of mammary lobular hyperplasia was statistically significantly greater in female rats from group Control 3 at 0.59 mg/kg when compared with group Control 1 females. Again, the occurrence of statistically significant variations between control groups as well as between a control and an experimental group discounted the biological significance of these findings. The incidence of skin fibromas in female rats fram groups Control 2, Control 3 at 0.59 mg/kg was statistically significantly less than those of group Control 1 females. This finding was considered to be of no biological significance but demonstrated the variations in incidence of neoplasms that may occur between rats of a given group. No other statistically significant variations in neoplasms or neoplasm-like lesions occurred. Actuarial (life table) analyses did not show significant variations in incidences of tumor bearing animals in either of the treated groups when compared with each of the three control groupa by sex. A number of other neoplasms or neplasm-like lesions of relatively low incidences were observed in various organs and tissues of rats from the control and experimental groups. These changes appeared to reflect normal background incidence of histopathology for rats of this strain and age routinely observed at this laboratory and were not considered to be compound related.

Other effects:

not specified

Details on results:

HISTOPATHOLOGY: NEOPLASTIC

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

0.59 other: mg/kg bw per week

Based on:

test mat.

Sex:

male/female

Basis for effect level:

behaviour (functional findings)

body weight and weight gain

clinical biochemistry

clinical signs

dermal irritation

food consumption and compound intake

haematology

histopathology: neoplastic

histopathology: non-neoplastic

mortality

urinalysis

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

NOAEL for the test chemical was found at the 0.59 mg/kg when rats were exposed to the test chemical by the dermal route two times per week for 2 years.

Executive summary:

In this study by L’Oreal (1979) male and female Charles river rats were exposed by dermal route two times per week for 24 months to hair dye formulations P-26 or P-25. Each topical application contained a 3-aminophenol concentration of approximately 0.59 mg/kg (for P-26) and 2.65 mg/kg (for P-25). The terminal body weight was marginally lower (9.4% lower) in the females in the P-25 treatment group as compared to the controls. Food consumption was slightly higher in the treated rats as compared to the controls. No gross lesions were considered to be compound-related. In the P-25 treatment group, hyperkeratosis and/or acanthosis of the stomach mucosa was considered to be possibly compound-related. Hepatocellular hypertrophy/hyperplasia or formation of hyperplastic/hypertrophic nodules in the livers of the rats in the P-25 treatment group (most notably in males) was also considered to be possibly compound-related. The incidence of liver hematopoiesis in both sexes in the P-25 treatment group was moderately higher as compared to the controls. This effect was of doubtful clinical significance due to absence of increased incidence of hematopoiesis in other blood forming organs. The incidence of testicular seminiferous tubular atrophy or degeneration in male rats in the P-25 and P-26 treatment groups was also of doubtful clinical significance due to historical control data of the laboratory. There were no significant changes in hematology parameters, blood biochemistry or in urine. There were also no significant changes in general behavior or food intake. NOAEL for the test chemical was found at the 0.59 mg/kg dose level.