3-aminophenol

Endpoint summary

Description of key information

Repeated dose toxicity - Oral

In a study by L’Oreal (1996), female 6-week-old Sprague-Dawley rats were exposed to 3-aminophenol daily for 13 weeks at 0, 20, 70, 200 and 600 mg/kg bw/day by oral gavage administration. No effects were observed at 20 mg/kg. From 70 mg/kg, there was a dose-related increase in thyroid hyperactivity in both male and females based on microscopic evaluation. At 70 mg/kg, the increase in thyroid function was observed in 2 (of the 10) males and in 2 (of the 10 females). This effect was not considered toxicologically relevant, due to the well-established relationship between increased thyroid hyperactivity and increased functional demand of the liver due to chemical dosing. In comparison to the controls, marked hemosiderosis was noted in the rats treated at 200 mg/kg. This was accompanied by slight changes in biochemistry parameters, i.e. slightly higher total protein levels in blood, slightly lower glucose levels in blood and slightly lower red blood cell count in blood. Based on the data, NOAEL for the test chemical was considered at 70 mg/kg bw/day in this 13 -weeks study. Serious effects occured at 600 mg/kg bw/day.

Repeated dose toxicity - Inhalation

3-aminophenol (CAS no. 591-27-5)has very a low vapor pressure of0.248 Pa at 25°C. The particle size distribution was determined to be in the range of 500 micrometer to 1000 micrometer. The normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely. Therefore this end point for repeated dose toxicity by inhalation route is considered for waiver

Repeated dose toxicity - Dermal

In a 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. No serious effects occured at the highest dose level of 2.65 mg/kg.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

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:

guideline study with acceptable restrictions

Justification for type of information:

Data is from study report

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

The objective of this study was to evaluate the potential toxicity of the test substance, m-aminophenol (batch No. 4090202), when administered daily by gavage to Sprague- Dawley rats for 13 weeks.
The test substance is a dye precursor.

GLP compliance:

not specified

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
- Age at study initiation: Animals were approximately six weeks old
- Weight at study initiation: had a mean body weight of 190 g for the males (178 g to 207 g) and 173 g for the females (156 g to 190 g).
- Fasting period before study:
- Housing: The animals were housed in suspended wire-mesh cages and each cage contained two rats of the same sex and group. A metallic tray was placed under each cage and contained autoclaved sawdust (SICSA, 94142 Alfortville, France).
- Diet (e.g. ad libitum): The animals had access to AO4 C pelleted diet,
- Water (e.g. ad libitum): The animals had access to bottles containing tap water filtered using a 0.22 micron filter (Millipore S.A., 78140 Velizy, France).
- Acclimation period: A six day acclimatization period to the conditions of the study preceded the beginning of the treatment period.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2 deg C
- Humidity (%): 50 ± 20%
- Air changes (per hr): about 12 cycles/hour of filtered, non-recycled air.
- Photoperiod (hrs dark / hrs light):12h/12h (07:00 - 19:00)

Route of administration:

oral: gavage

Vehicle:

other: 0.5 % aqueous methylcellulose

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
The test substance was administered as a suspension in the vehicle.
Prior to use the vehicle was degassed by sonification for at least ten minutes and was bubbled with nitrogen for two or three minutes; this vehicle was then kept under an argon atmosphere and away from light until use. The test substance was ground to fine powder using a mortar and pestle, suspended in the
vehicle in order to achieve a concentration of 120 mg/ml, and homogenized using a magnetic stirrer. The 4, 14 and 40 mg/ml preparations were prepared by direct dilution of the 120 mg/ml preparation.
The preparations were rapidly inserted in glass sealed bottles under an argon atmosphere. On the basis of stability data, the preparations were made for up to seven days of treatment, except for the 40 mg/ml preparation which was prepared on the day of dosing or the day preceding dosing. The preparations were stored at +4'C, away from light, pending utilization. They were delivered to the animal room each day and maintained under continuous stirring during the dosing procedure.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

PRINCIPLE OF METHODS
Samples of the preparations to be analysed are diluted to a target concentration of 20 microg/mL, using degrassed stabilised solvent. The content of meta-aminophenol is subsequently determined by HPLC with UV detection at 282 nm.

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
20, 70, 200 or 600 mg/kg/day
Basis:
no data

No. of animals per sex per dose:

10 males and 10 females per dose; in total 50 males and 50 females were used.

Control animals:

yes, concurrent vehicle

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical signs were observed for each animal at least once a day, at the same approximate daily time.

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: once a week

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
The quantity of food consumed by the animals of each cage was recorded once a week (over a seven day period) until the end of the study.

FOOD EFFICIENCY: Yes
- 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: Yes

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

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: at the beginning of treatment period and week 13
- Dose groups that were examined: control, 200 and 600 mg/kg/day bw

HAEMATOLOGY: Yes
- Time schedule for collection of blood: approximately 24 hours after treatment
- Anaesthetic used for blood collection: Yes (light ether anaesthesia)
- Animals fasted: Animals were deprived of food and placed in metabolism cages over atleast 14 hours
- Parameters examined: Erythrocytes (RBC), Haemoglobin (HB), mean cell volume (MCV), Packed cell volume (PCV), mean cell haemoglobin concentration (MCHC), mean cell haemoglobin (MHC), thromocytes (PLAT), leucocytes (WBC), differential white cell count with cell morphology (neutrophils, eosinophils, basophils, lymphocytes and monocyes) and reticulocytes (RETIC).


URINALYSIS: Yes
- Time schedule for collection of urine: 13 week
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters examined: Volume, pH, specific gravity (SP.GRAV), proteins (PROT), glucose (GLUC), ketones (CETO), bilirubin (BILI), nitrates (NITR), blood, urobilinogen (UROB) and cytology (leucocytes, erythrocytes, cylinders, magnesium ammonium phosphate crystals, calcium phosphate crystals, calcium oxalate crystals and cells. In addition, appearance and and colour were recorded.


OTHER:
No data available

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
All gross observations were recorded individually. A complete macroscopic examination was performed on all animals that which was killed prematurely. All animals were sacrificed at the end of the treatment period and the weight was recorded for heart, adrenals, kidneys, liver, ovaries, spleen, testes, thymus, thyroids with parathyroids. Paired organs were weighed separately, except thyroids with parathyroids which were weighed together.

Statistics:

Body weight, food consumption, haematology, blood chemistry, urinalysis and organ weight data were subjected to statistical evaluation. The normality of the distibution of the values in each group was checked by Kolmogorov-Smirnov's test. If the distribution was normal, the homogenity of variances between the groups was assessed by Batlett's test or Fisher's test. If no signifcant heterogenicity of the variances was established, the comparison between treated and control groups was performed by Dunnett's test.
If the variance were heterogeneous, the comparison between treated and control groups was performed by Dunn'd test or by Mann Whitney's test.
If the distribution of values in the groups was not normal, the analysiswas repeated after logarithmic transformation of the values (except for organ weights).

It the logarithmic transformation failed to normalise the distribution of the values, comparison of treated and control groups was performed by Dunn's test using original values.

Clinical signs:

no effects observed

Description (incidence and severity):

No clinical signs were observed in animals given 20 mg/kg/day. Ptyalism was observed in some animals given 70 mg/kg/day and in all animals given 200 or 600 mg/kg/day. Lacrimation was observed in some animals given 600 mg/kg/day on week I only.

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Slightly lower body weight gain was noted throughout the treatment period in males given 600 mg/kg/day (-19%).

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Slightly lower food consumption was recorded in males given 600 mg/kg/day (-3% to -18% over the period week 4 to week l0). This difference from controls was considered to be treatment-related.

Food efficiency:

effects observed, treatment-related

Description (incidence and severity):

The mean efficiency of food utilization of all treated males and females was similar to that of concurrent controls.

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

not examined

Ophthalmological findings:

no effects observed

Description (incidence and severity):

No treatment-related findings were noted at the end of the treatment period.

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Signs of slight regenerative anaemia observed at 600 mg/kg.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

On week 13, the following differences from controls were recorded:
Slightly higher total protein level in males given 200 or 600 mg/kg/day, lower potassium level in females given 600 mg/kg/day, slightly higher calcium levels in animals given 600 mg/kg/day, slightly higher total bilirubin and cholesterol levels in animals given 600 mg/kg/day, slightly lower glucose level in females given 200 mg/kg/day and in animals given 600 mg/kg/day, higher cholesterol levels in animals given 600 mg/kg/day, higher inorganic phosphorus concentration in females given 600 mg/kg/day.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

Slightly lower urinary pH was noted in males given 600 mg/kg/day and slightly higher urinary volume was observed in males given 200 or 600 mg/kg/day. Colouration of urine was noted in males and females given 200 or 600 mg/kg/day. This observation was attributed to the elimination of the test substance or its metabolites, and was considered to be an indirect proof of the absorption of the test substance.

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Higher absolute and relative spleen weights (related to the higher severity of haemosiderosis) and higher absolute and relative thyroid weights (ascribed to the thyroid hyperactivity) were recorded in animals given 600 mg/kg/day. Higher absolute and relative liver weights were found in animals given 200 or 600 mg/kg/day. Higher relative kidney weights were found in animals given 200 and 600 mg/kg/day, with minimal changes of concurrent absolute weights.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Yellowish deposit on the mucosa of stomach in one male and orange coloured tail in 8/10 females were noted at 600 mg/kg/day. These discolourations were attributed to the properties of the test substance (dye precursor). Blackish colour of the spleen related to the presence of haemosiderosis was observed in some males and females at 200 mg/kg/day and in all animals at 600 mg/kg/day. Large liver (I/1O) or large thyroid glands (I/l0) were observed in males given 600 mg/kg/day.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

When compared to the controls, increase in severity and/or incidence in thyroid hyperactivity was noted in males and females given 70, 200 or 600 mg/kg/day. Haemosiderosis was found in the spleen of animals given 200 or 600 mg/kg/day. Minimal to marked brownish pigment was found in the cortical tubular epithelium of the kidneys in two males at 70 mg/kg/day, in eight males at 200 mg/kg/day and in all males and three females at 600 mg/kg/day. This was considered to be due to the presence of the test substance or its metabolites. Some other minor microscopic findings related to the dyeing properties of the test substance were noted at 200 or 600 mg/kg/day in some organs (orange or brownish pigment laden macrophages in mesenteric lymph nodes and in some parts of the gastro-intestinal tract).

Histopathological findings: neoplastic:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

70 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical biochemistry

clinical signs

food consumption and compound intake

food efficiency

gross pathology

haematology

histopathology: non-neoplastic

mortality

ophthalmological examination

organ weights and organ / body weight ratios

urinalysis

Remarks on result:

other: not specified

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

600 mg/kg bw/day (nominal)

System:

other: Overall effects involving multiple systems

Organ:

not specified

Treatment related:

yes

Dose response relationship:

not specified

Relevant for humans:

not specified

Conclusions:

NOAEL for the test chemical was considered at 70 mg/kg bw/day in this 13 -weeks study.

Executive summary:

In this study by L’Oreal (1996), female 6-week-old Sprague-Dawley rats were exposed to 3-aminophenol daily for 13 weeks at 0, 20, 70, 200 and 600 mg/kg bw/day by oral gavage administration. No effects were observed at 20 mg/kg. From 70 mg/kg, there was a dose-related increase in thyroid hyperactivity in both male and females based on microscopic evaluation. At 70 mg/kg, the increase in thyroid function was observed in 2 (of the 10) males and in 2 (of the 10 females). This effect was not considered toxicologically relevant, due to the well-established relationship between increased thyroid hyperactivity and increased functional demand of the liver due to chemical dosing. In comparison to the controls, marked hemosiderosis was noted in the rats treated at 200 mg/kg. This was accompanied by slight changes in biochemistry parameters, i.e. slightly higher total protein levels in blood, slightly lower glucose levels in blood and slightly lower red blood cell count in blood. Based on the data, NOAEL for the test chemical was considered at 70 mg/kg bw/day in this 13 -weeks study.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

70 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

K1 data from GLP certified lab

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: inhalation, other

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

Waiver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

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

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

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

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

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

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.

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

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

Critical effects observed:

not specified

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.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

0.59 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

the data is K2 level

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Data available for target chemical was reviewed to determine the toxic nature of the test chemical 3 -aminophenol. The studies are as mentioned below:

Additional repeated dose toxicity studies - Oral

In a sub-chronic toxicity study by Re et al (1984) female Sprague-Dawley rats were fed 3-aminophenol at approx. 0, 70, 200 and 700 mg/kg bw/day. Mean weekly body weights were slightly lower at 200 mg/kg (from week 3-13) and markedly lower at 700 mg/kg (from week 1-13) compared to the controls. Food intake was significantly decreased in the early weeks at 200 mg/kg and throughout the period at 700 mg/kg. Significant hemolytic effects were observed only at 700 mg/kg as evident by a lower red blood cell count, lower hemoglobin levels, a mean increase in corpuscular volume, and increased iron accumulation in spleen, liver and kidney. Compared to the controls, the absolute and relative weight of the thyroid was significantly lower at 70 and 200 mg/kg but significantly higher at 700 mg/kg. Histological evaluation of the thyroids revealed reduced follicular size and increased height of the epithelial cell lining of the follicles in 9/10 animals in the 700 mg/kg dose group and in several animals in the 200 mg/kg dose group. These histological changes (which are indicative of thyroid hyperreactivity) were not considered toxicologically relevant, due to the well-established relationship between increased thyroid hyperactivity and increased functional demand of the liver due to chemical dosing. NOAEL for the test chemical was found at 70 mg/kg bw/day in this 13 -week study. Serious effects were observed at the 700 mg/kg dose level.

In a study by Koizumi et al (2002), five-week-old Sprague-Dawley rats were exposed to 3-aminophenol daily by gastric intubation at 0, 80, 240 and 720 mg/kg/d for 28 days. At 720 mg/kg bw/day the following observations were made: depression of body weight gain, tremors, anemia, and liver, kidney and thyroid toxicity. At 240 mg/kg, slight pigmentation of the renal proximal tubular epithelium occurred but was not considered as an adverse effect due to lack of changes in related toxicological parameters. NOAEL for the test chemical was found at 240 mg/kg bw/day in this 28 -days study. Serious effects occured at the 720 mg/kg dose level.

Repeated dose toxicity - Inhalation

3-aminophenol (CAS no. 591-27-5) has very a low vapor pressure of0.248 Pa at 25°C. The particle size distribution was determined to be in the range of 500 micrometer to 1000 micrometer. The normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely. Therefore this end point for repeated dose toxicity by inhalation route is considered for waiver

Additional repeated dose toxicity study - Dermal

Repeated dose dermal toxicity study was performed to determine the dermal toxic nature of m-aminophenol. Groups of 50 male and 50 female per dose Swiss mice were treated by dermal route one time per week to hair dye formulations P-26, P25 and 7406 at 3-aminophenol concentrations of approx. 0.28, 1.25 and 9.7 mg/kg, respectively. The formulation 7406 was given for 21 months whereas the formulations P-25 and P-26 were each given for 23 months. The animals were observed for mortality, behavior, physical appearance and were subjected to gross and microscopic examination. Treatment with the test material containing formulation had no effect on survival rate compared with the three untreated controls. No significant variation in body weight and organ to body weight ratios were noted in the control and treated group animals. No unusual tumor types developed in either treatment or control groups. A few skin tumors were diagnosed in both treatment and control groups; however, they occurred at low incidence and were not treatment-related. No treatment related microscopic variations were noted in the control and treated animals. NOAEL was found at 9.7 mg/kg per day when mice were exposed to the test chemical one day per week for 21 months.

Justification for classification or non-classification

90 days oral treatment with 3-aminophenol in rats is not associated with any significant toxicity at doses that would justify a classification for STOT-RE. In a shorter repeated dose toxicity study in rats (28 days), there were no signs of significant toxicity at 240 mg/kg that would warrant a classification. Significant to severe toxicity was observed at 720 mg/kg, which is well-above the guidance value for classification. By weight of evidence, 3-aminophenol is regarded to be classified as Not Classified for STOT-RE by the oral route. Repeated dermal exposure of hair dyes containing 3-aminophenol did not produce any significant or severe toxic effects that would justify classification for STOT-RE. Therefore, 3-aminophenol is also regarded to be classified as Not Classified for STOT-RE by dermal route.