Bis(4-hydroxy-N-methylanilinium) sulphate

Carcinogenicity

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

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 or test system 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:

body weight and weight gain

histopathology: neoplastic

histopathology: non-neoplastic

mortality

organ weights and organ / body weight ratios

Dose descriptor:

NOAEL

Remarks:

Formulation P26

Effect level:

0.014 other: mg/kg

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

histopathology: neoplastic

histopathology: non-neoplastic

mortality

organ weights and organ / body weight ratios

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

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.

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.