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Toxicological information

Carcinogenicity

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Description of key information

A repeated dose dermal toxicity study was performed to determine the toxic nature of N-Methyl-p-aminophenol sulfate. Male and female Swiss mice were treated one time weekly for 21 months of the formulation 7404 or 23 months of the formulation P26 containing the test material in the dose of 1% and 0.05%, respectively. 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. Therefore, NOAEL for N-Methyl-p-aminophenol sulfate was considered to be 0.28675 mg/kg and 0.0143375 mg/kg when Swiss Webster mice were exposed to formulation 7404 and P26 for 21 and 23 months, respectively.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data is from peer reviewed publication
Qualifier:
according to
Guideline:
other: see Principles of method below
Principles of method if other than guideline:
A repeated dose dermal toxicity study was performed to determine the toxic nature of N-Methyl-p-aminophenol sulfate in mice.
GLP compliance:
not specified
Specific details on test material used for the study:
- Name of test material : N-methyl-p-aminophenol sulfate- Molecular formula : C7H9NO.1/2H2O4S- Molecular weight : 344.386 g/mol- Substance type: Organic- Physical state: No data available- Impurities (identity and concentrations): No data available
Species:
mouse
Strain:
Swiss Webster
Details on species / strain selection:
No data available
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS- Source: Swiss Webster mice rom the Eppely colony - Age at study initiation: 8-10 weeks - Weight at study initiation: No data available- Fasting period before study: No data available- Housing: The animals were housed individually for the study in plastic cages with granular cellulose bedding in a controlled environment.- Diet (e.g. ad libitum): Commercial Wayne Lab-Blox pellets, ad libitum- Water (e.g. ad libitum): Tap water, ad libitum- Acclimatization period: 14 daysENVIRONMENTAL 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
Route of administration:
not specified
Vehicle:
other: Water and 6% hydrogen peroxide
Details on exposure:
TEST SITE- Area of exposure: Interscapular region- % coverage: Approximately 1 cm2- Type of wrap if used: No data available- Time intervals for shavings or clipplings: The hair clipping at the treatment site was done 24 hrs before test material applicationREMOVAL OF TEST SUBSTANCE- Washing (if done): No data available- Time after start of exposure: No data availableTEST MATERIAL- Amount(s) applied (volume or weight with unit): 0.05 ml of the 7404 and P-26 dye formulation- Concentration (if solution): 0, 0.05% (0.0143375 mg/kg Formulation P-26) or 1% (0.28675 mg/kg: Formulation 7404)- Constant volume or concentration used: 0.05 ml formulation containing an equal volume of 6% hydrogen peroxide- For solids, paste formed: No data availableVEHICLE- Justification for use and choice of vehicle (if other than water): No data available- Amount(s) applied (volume or weight with unit): No data available- Concentration (if solution): No data available- Lot/batch no. (if required): No data available- Purity: No data availableUSE OF RESTRAINERS FOR PREVENTING INGESTION: No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
21 months (Formulation 7404) or 23 months (Formulation P26)
Frequency of treatment:
Concurrently
Post exposure period:
No data available
Remarks:
Doses/Concentrations: 0, 0.05% (0.0143375 mg/kg Formulation P-26) or 1% (0.28675 mg/kg: Formulation 7404)
No. of animals per sex per dose:
Total: 500 miceControl 1: 50 males, 50 femalesControl 2: 50 males, 50 femalesControl 3: 50 males, 50 females0.0143375 mg/kg : 50 males, 50 females0.28675 mg/kg: 50 males, 50 females
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Positive control:
No data available
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes- Time schedule: Daily- Cage side observations included: Mortality, behavior and physical appearanceDETAILED CLINICAL OBSERVATIONS: No data availableDERMAL IRRITATION (if dermal study): Yes- Time schedule for examinations: DailyBODY WEIGHT: Yes- Time schedule for examinations: MonthlyFOOD CONSUMPTION: No data availableFOOD EFFICIENCY: No data availableWATER CONSUMPTION: No data availableOPHTHALMOSCOPIC EXAMINATION: No data availableHAEMATOLOGY: No data availableCLINICAL CHEMISTRY: No data availableURINALYSIS: No data availableNEUROBEHAVIOURAL EXAMINATION: No data availableOTHER: No data available
Sacrifice and pathology:
GROSS PATHOLOGY: YesAfter 7 and 9 months of treatment, 10 males and 10 females, randomly selected from each test and control group, were weighed and killed by ether inhalation and a gross necropsy was performed. For each animal the liver and kidney weights were recorded and the organ-to-body weight ratios calculated. Gross examinations were performed on all mice found dead or sacrificed in moribund condition or at termination of the study. Skin lesions were also charted weekly.HISTOPATHOLOGY: YesMicroscopic examinations were performed on all mice found dead or sacrificed in moribund condition or at termination of the study. The following were preserved and stained for microscopic pathological evaluation: skin, neck (thyroid level), lung, gastrointestinal tract, spleen, pancreas, liver, skeletal muscle, pituitary, kidney, urinary bladder, ureters, bone marrow, lymph nodes, adrenals, gonads, brain, eyes, tumors, and other pathological lesions.
Other examinations:
No data available
Statistics:
Statistical analysis of the distribution of tumor types among control and treated groups was done using Fisher's exact test.
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
Treatment with the test material containing formulation had no effect on survival rate compared with the three untreated controls.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No significant variation in body weight was noted in the control and treated group animals.
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
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No considerable variation in the organ to body weight ratios and no significant departures from the control value was noted during the study.
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
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.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
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.
Other effects:
not specified
Relevance of carcinogenic effects / potential:
No unusual tumor types developed in either treatment or control groups.
Dose descriptor:
NOAEL
Remarks:
Formulation 7404
Effect level:
0.287 other: mg/kg
Based on:
test mat.
Sex:
male/female
Basis for effect level:
mortality
body weight and weight gain
organ weights and organ / body weight ratios
histopathology: non-neoplastic
histopathology: neoplastic
Dose descriptor:
NOAEL
Remarks:
Formulation P26
Effect level:
0.014 other: mg/kg
Based on:
test mat.
Sex:
male/female
Basis for effect level:
mortality
body weight and weight gain
organ weights and organ / body weight ratios
histopathology: non-neoplastic
histopathology: neoplastic
Critical effects observed:
not specified
Conclusions:
NOAEL for N-Methyl-p-aminophenol sulfate is considered to be 0.28675 mg/kg and 0.0143375 mg/kg in Swiss Webster mice since dermal application did not induce a carcinogenic response of formulation 7404 and P26, respectively.
Executive summary:

A repeated dose dermal toxicity study was performed to determine the toxic nature of N-Methyl-p-aminophenol sulfate. Male and female Swiss mice were treated one time weekly for 21 months of the formulation 7404 or 23 months of the formulation P26 containing the test material in the dose of 1% and 0.05%, respectively. 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. Therefore, NOAEL for N-Methyl-p-aminophenol sulfate was considered to be 0.28675 mg/kg and 0.0143375 mg/kg when Swiss Webster mice were exposed to formulation 7404 and P26 for 21 and 23 months, respectively.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
0.287 mg/kg bw/day
Study duration:
chronic
Species:
mouse
Quality of whole database:
Data is from peer reviewed publication

Additional information

Carcinogenicity

A repeated dose dermal toxicity study was performed to determine the toxic nature of N-Methyl-p-aminophenol sulfate. Male and female Swiss mice were treated one time weekly for 21 months of the formulation 7404 or 23 months of the formulation P26 containing the test material in the dose of 1% and 0.05%, respectively. 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. Therefore, NOAEL for N-Methyl-p-aminophenol sulfate was considered to be 0.28675 mg/kg and 0.0143375 mg/kg when Swiss Webster mice were exposed to formulation 7404 and P26 for 21 and 23 months, respectively.

A repeated dose dermal carcinogenicity study was performed to determine the toxic nature of N-Methyl-p-aminophenol sulfate. Male and female Sprague-Dawley rats were treated with one application twice weekly for 114 weeks with formulation 7404 (1%) or formulation P26 (0.5%) in 0.5 ml. The animals were observed for overt signs of toxicity, mortality, individual body weights, group food consumption, hematological and biochemical parameters, urinalysis, and gross and histopathological parameters. p-Methylaminophenol containing formulations produced no local adverse effects and had no effect on survival rate. It did not produce any clinical signs or any changes in body weight, food consumption or clinical pathology parameters. No significant differences considered to be treatment related were observed in the biochemical studies or in the urinalysis. Non-neoplastic lesions were those commonly found in ageing rats and were considered to be spontaneous. Females treated with formulation 7404 (0.5% p-Methylaminophenol) had a significant increase in the incidence of mammary adenomas when compared to a single control group. Since this increase was confined to one of the three control groups and this treatment group showed a decrease in the number of mammary carcinomas compared to the same control group, this finding was not considered to be biologically significant. Therefore, NOAEL for N-Methyl-p-aminophenol sulfate was considered to be 1% and 0.5% when Sprague-Dawley rats were exposed to formulation 7404 and P26, respectively, for 114 weeks. Since no carcinogenic responses were observed in the current study, the target compound is not regarded to induce carcinogenicity.

Carcinogenicity was predicted for N-Methyl-p-aminophenol sulfate using the Danish QSAR database (2017). The study assumed mice as target organisms, where the endpoint for carcinogenicity was modeled in the Danish QSAR using two software systems, i.e. Leadscope and CASE Ultra. The prediction by Danish QSAR for the target compound was negative, and hence the chemical is predicted to not classify as a toxic for carcinogenicity.

Justification for classification or non-classification

Based on a (Q)SAR prediction and two experimental data available for the target chemical, N-Methyl-p-aminophenol sulfate is suspected to have carcinogenic potentials. Hence, since the amount of data is limited further investigation needs to be performed to elucidate the carcinogenic effects of the target chemical. Especially, an oral route is of interest since there is indications of repeated oral toxicity.