Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity: Oral

Based on the prediction done (SSS Nagpur, 2017) using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose oral toxicity was predicted for the test compound N-methyl-p-aminophenol sulfate. The study assumed the use of male and female Wistar rats in a subchronic study of 3 months. No significant alterations were noted at the dose level of 56.916667938 mg/kg bw/day and thus the predicted NOAEL for N-methyl-p-aminophenol sulfate is considered to be 56.916667938 mg/kg bw/day.

Repeated dose toxicity: Inhalation

N-Methyl-p-aminophenol has very low vapor pressure (0.000000536 Pa), so the potential for the generation of inhalable vapours is very low. Also 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 and therefore this end point was considered for waiver.

Repeated dose toxicity: Dermal

A repeated dose dermal toxicity study was performed to determine the dermal toxic nature of N-methyl-p-aminophenol sulfate. The study was performed on female Charles River CD rats, where 2 ml/kg dye formulation 7404 or P-26 containing 1% and 0.05% N-methyl-p-aminophenol sulfate, respectively, was applied to the dorso-scapular area. These dye formulations contained other active ingredients in an aqueous solution and were mixed with an equal volume of 6% hydrogen peroxide prior to application. The application was made during the gestation days 1, 4, 7, 10, 13, 16 and 19. The animals were observed for clinical signs, body weight changes, dermal irritation if any and food consumption. No dye formulation related toxicity was noted. Changes in female body weights and food consumption were similar for rats in the untreated controls and all dye-treated groups. No irritation or other changes in appearance were noted except for changes in skin and hair color at the site of topical application of the dye formulation. Based on the observations made, NOAEL for N-methyl-p-aminophenol sulfate in female Charles River CD rats was considered to be 11.47 mg/kg for formulation 7404 and 0.5735 mg/kg for formulation P26, where both formulations contain the target compound.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: oral
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification
Justification for type of information:
Prediction is done using OECD QSAR Toolbox version 3.3 and the supporting QMRF report has been attached
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: Refer below principle
Principles of method if other than guideline:
Prediction is done using OECD QSAR Toolbox version 3.3, 2017
GLP compliance:
not specified
Limit test:
no
Test material information:
Composition 1
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- Impurities (identity and concentrations): No data
Species:
rat
Strain:
Wistar
Details on species / strain selection:
No data available
Sex:
male/female
Details on test animals and environmental conditions:
No data available
Route of administration:
oral: gavage
Details on route of administration:
No data available
Vehicle:
not specified
Details on oral exposure:
No data available
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data available
Duration of treatment / exposure:
3 months
Frequency of treatment:
No data available
Remarks:
No data available
No. of animals per sex per dose:
No data available
Control animals:
not specified
Details on study design:
No data available
Positive control:
No data available
Observations and examinations performed and frequency:
No data available
Sacrifice and pathology:
No data available
Other examinations:
No data available
Statistics:
No data available
Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
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:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Dose descriptor:
NOAEL
Effect level:
56.917 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No treatment-related effects were noted at the mentioned dose level
Critical effects observed:
not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 6 nearest neighbours
Domain  logical expression:Result: In Domain

((((((((((((("a" or "b" or "c" or "d" )  and "e" )  and "f" )  and "g" )  and "h" )  and "i" )  and "j" )  and "k" )  and "l" )  and ("m" and ( not "n") )  )  and ("o" and ( not "p") )  )  and "q" )  and ("r" and "s" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Phenols (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Strong binder, NH2 group AND Very strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Strong binder, NH2 group OR Very strong binder, OH group by Estrogen Receptor Binding ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Phenols, Poly by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Aliphatic Amine, secondary AND Ammonium salt AND Aryl AND Phenol AND Precursors quinoid compounds by Organic Functional groups ONLY

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Aliphatic Amine, secondary AND Ammonium salt AND Aryl AND Phenol AND Precursors quinoid compounds by Organic Functional groups ONLY

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Aliphatic Amine, secondary AND Ammonium salt AND Aryl AND Phenol AND Precursors quinoid compounds by Organic Functional groups ONLY

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Aliphatic Amine, secondary AND Ammonium salt AND Aryl AND Phenol AND Precursors quinoid compounds by Organic Functional groups ONLY

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Aliphatic Amine, secondary AND Ammonium salt AND Aryl AND Phenol AND Precursors quinoid compounds by Organic Functional groups ONLY

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Aliphatic Amine, secondary AND Ammonium salt AND Aryl AND Phenol AND Precursors quinoid compounds by Organic Functional groups ONLY

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Aliphatic Amine, secondary AND Ammonium salt AND Aryl AND Phenol AND Precursors quinoid compounds by Organic Functional groups ONLY

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Aliphatic Amine, secondary AND Ammonium salt AND Aryl AND Phenol AND Precursors quinoid compounds by Organic Functional groups ONLY

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as o-/ p-Aminophenols (Hemolytic anemia with methemoglobinemia) Rank B AND Oxyphenistain (Hepatotoxicity) Alert AND p-Aminophenols (Renal toxicity) Rank B by Repeated dose (HESS)

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Hydroquinones (Hepatotoxicity) Rank B by Repeated dose (HESS)

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as o-/ p-Aminophenols (Hemolytic anemia with methemoglobinemia) Rank B AND Oxyphenistain (Hepatotoxicity) Alert AND p-Aminophenols (Renal toxicity) Rank B by Repeated dose (HESS)

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Alcohol, olefinic attach [-OH] AND Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Amino, aliphatic attach [-NH2] AND Aromatic Carbon [C] AND Hydroxy, aromatic attach [-OH] AND Miscellaneous sulfide (=S) or oxide (=O) AND Nitrogen, hydrogen attach {v+5} AND Olefinic carbon [=CH- or =C<] AND Oxygen, one aromatic attach [-O-] AND Suflur {v+4} or {v+6} AND Sulfate, linear [-O-SO2-O-] AND Sulfite, linear [-OS(=O)O-] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.8

Domain logical expression index: "s"

Parametric boundary:The target chemical should have a value of log Kow which is <= 5.92

Conclusions:
The predicted NOAEL for  N-methyl-p-aminophenol sulfate is considered to be 56.916667938 mg/kg bw/day.
Executive summary:

Based on the prediction done (SSS Nagpur, 2017) using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose oral toxicity was predicted for the test compound N-methyl-p-aminophenol sulfate. The study assumed the use of male and female Wistar rats in a subchronic study of 3 months. No significant alterations were noted at the dose level of 56.916667938 mg/kg bw/day and thus the predicted NOAEL for  N-methyl-p-aminophenol sulfate is considered to be 56.916667938 mg/kg bw/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
56.917 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is from K2 prediction database

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: inhalation, other
Remarks:
Waiver
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:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
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
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: Refer below principle
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 using Charles River CD female rats.
GLP compliance:
not specified
Limit test:
no
Test material information:
Composition 1
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- Impurities (identity and concentrations): No data
Species:
rat
Strain:
other: Charles River CD
Details on species / strain selection:
No data available
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS- Source: No data available- Age at study initiation: No data available- Weight at study initiation: No data available- Fasting period before study: No data available- Housing: The mated female animals were housed individually in temperature- and humidity-controlled rooms.- Diet (e.g. ad libitum): Ralston Purina Laboratory Chow, ad libitum- Water (e.g. ad libitum): Water, ad libitum- Acclimatization period: No data availableENVIRONMENTAL 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:
not specified
Vehicle:
other: water and 6% hydrogen peroxide
Details on exposure:
TEST SITE- Area of exposure: The dorso-scapular area- % coverage: No data available- Type of wrap if used: No data available- Time intervals for shavings or clipplings: The hair at the site of application on the dorso-scapular area was shaved closely the day prior to application.REMOVAL 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): 2 ml/kg of the 7404 and P-26 dye formulation- Concentration (if solution): 0, 0.05% (0.5735 mg/kg: Formulation P-26) or 1% (11.47 mg/kg: Formulation 7404)- Constant volume or concentration used: No data available- 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
Details on analytical verification of doses or concentrations:
No data available
Duration of treatment / exposure:
20 days
Frequency of treatment:
Once on days 1, 4, 7, 10, 13, 16 and 19 of gestation
Remarks:
Doses/Concentrations: 0, 0.05% (0.5735 mg/kg: Formulation P-26) or 1% (11.47 mg/kg: Formulation 7404)
No. of animals per sex per dose:
Total: 120 ratsControl: 60 femalesPositive control: 20 females0.5735 mg/kg : 20 females11.47 mg/kg: 20 females
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Positive control:
Acetylsalicylic acid
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data availableDETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: No data availableDERMAL IRRITATION (if dermal study): Yes- Time schedule for examinations: No data availableBODY WEIGHT: Yes- Time schedule for examinations: On days 1, 4, 7, 10, 13, 16 and 19 day of gestationFOOD CONSUMPTION: Yes- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: YesFOOD EFFICIENCY: No data available WATER 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: YesTwenty pregnant rats from each group were sacrificed on day 20 of gestation by chloroform anesthesia, and Cesarean sections were performed. The uteri were examined, corpora lutea of pregnancy counted, and the number, distribution, and location of live, dead, and resorbed fetuses recorded. All fetuses were examined for gross anomalies, sexed, and weighed.HISTOPATHOLOGY: YesApproximately one-third the fetuses from each litter were fixed and subsequently examined for visceral anomalies by razor blade sectioning. The remaining fetuses in each litter were fixed, eviscerated, cleared, stained´with KOH-alizarin red S, and examined for skeletal anomalies.
Other examinations:
No data available
Statistics:
All statistical analyses compared the treatment groups with the control groups. The number of females exhibiting resorption sites, number of females exhibiting two or more resorptions, number of dead or resorbed fetuses, and the number of fetuses with soft-tissue or skeletal anomalies and accessory ribs was compared using chi-square test criterion with Yates' correction on 2 X 2 contingency tables or Fisher's exact probability test as appropriate to judge the significance of difference. The mean number of corpora lutea, implantation sites, live fetuses, and resorption sites was compared by analysis of variance (one-way classification) using Dunnett's multiple comparison tables to judge the significance of differences. The live fetal weights were compared by analysis of variance (hierarchal classification) using Dunnett's multiple comparison tables to judge the significance of differences.Statistically significant differences between groups were judged valid only when there were significant differences between any one of the dye treated groups and each of the three untreated control groups.
Clinical signs:
no effects observed
Description (incidence and severity):
No signs of toxicity were seen throughout the study in the treated rats.
Dermal irritation:
no effects observed
Description (incidence and severity):
Except for the changes in the color of the skin and hair at the site of dye application, no irritation or other changes in appearance were seen.
Mortality:
not specified
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Changes in female body weights were similar for rats in the untreated controls and all dye-treated groups.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Mean food consumption for all groups throughout gestation was similar in the treated and control group rats.
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:
not specified
Gross pathological findings:
no effects observed
Description (incidence and severity):
No significant changes were observed regarding soft-tissue anomalies between the dye-treated groups and the untreated control groups. Normally occurring skeletal variations were present in all groups; the most frequent variation noted was accessory ribs.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
no effects observed
Description (incidence and severity):
The dye formulations produced no significant differences in the mean number of corpora lutea, implantation sites and live fetuses, and the sex ratio when compared with the untreated control groups. No differences between groups were seen regarding the number of females exhibiting resorption sites or mean resorptions per pregnancy.
Dose descriptor:
NOAEL
Remarks:
Formulation 7404
Effect level:
11.47 other: mg/kg
Based on:
test mat.
Sex:
female
Basis for effect level:
clinical signs
mortality
dermal irritation
body weight and weight gain
food consumption and compound intake
gross pathology
Dose descriptor:
NOAEL
Remarks:
Formulation P26
Effect level:
0.574 other: mg/kg
Based on:
test mat.
Sex:
female
Basis for effect level:
clinical signs
mortality
dermal irritation
body weight and weight gain
food consumption and compound intake
gross pathology
Critical effects observed:
not specified
Conclusions:
NOAEL for N-methyl-p-aminophenol in female Charles River CD rats is considered to be 11.47 mg/kg for Formulation 7404 and 0.5735 mg/kg for formulation P26, where both formulations contain the target compound.
Executive summary:

A repeated dose dermal toxicity study was performed to determine the dermal toxic nature of N-methyl-p-aminophenol sulfate. The study was performed on female Charles River CD rats, where 2 ml/kg dye formulation 7404 or P-26 containing 1% and 0.05% N-methyl-p-aminophenol sulfate, respectively, was applied to the dorso-scapular area. These dye formulations contained other active ingredients in an aqueous solution and were mixed with an equal volume of 6% hydrogen peroxide prior to application. The application was made during the gestation days 1, 4, 7, 10, 13, 16 and 19. The animals were observed for clinical signs, body weight changes, dermal irritation if any and food consumption. No dye formulation related toxicity was noted. Changes in female body weights and food consumption were similar for rats in the untreated controls and all dye-treated groups. No irritation or other changes in appearance were noted except for changes in skin and hair color at the site of topical application of the dye formulation. Based on the observations made, NOAEL for N-methyl-p-aminophenol sulfate in female Charles River CD rats was considered to be 11.47 mg/kg for formulation 7404 and 0.5735 mg/kg for formulation P26, where both formulations contain the target compound.

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

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

Additional information

Repeated dose toxicity: Oral

Based on the prediction done (SSS Nagpur, 2017) using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose oral toxicity was predicted for the test compound N-methyl-p-aminophenol sulfate. The study assumed the use of male and female Wistar rats in a subchronic study of 3 months. No significant alterations were noted at the dose level of 56.916667938 mg/kg bw/day and thus the predicted NOAEL for N-methyl-p-aminophenol sulfate is considered to be 56.916667938 mg/kg bw/day.

A repeated dose oral toxicity study was performed to determine the toxic nature of Elon upon repeated exposure for 91-94 days. Male and female Crl: COBS®, CD®, SD, BR rats were administered the test material by intubation five days a week with a dose of 0, 30, 100 or 300 mg/kg bw. The animals were observed for mortality, morbidity, clinical signs, body weight and organ weight changes, food consumption, hematology, serum chemistry, urinalysis, gross and histopathological parameters. Compound and dose-related effects occurred primarily in the 300 and 100 mg/kg groups and sporadically in the 30 mg/kg group. The major effects were degeneration of hemoglobin in circulating erythrocytes, hemolytic anemia, hemoglobinuric nephrosis and death. Compound-related morphologic effects in erythrocytes were slight (100 mg/kg group) to moderate (300 mg/kg group) and included polychromasia, macrocytosis, anisocytosis, siderocytosis and incidence of Howell-Jolly bodies. In addition, minimal to minor hypochromasia, microcytosis, spherocytosis and incidence of target cells occurred in 3 of 22 rats observed in the 100 mg/kg group and in 8 of 20 observed in the 300 mg/kg group. Compound and dose-related effects in urine included decreased urine volume and pH, increased specific gravity, increased concentration of protein, increased incidence of red and white blood cells per high power microscopic field of urine sediment, green to brown color and a hazy appearance. Effects in the 100 mg/kg group were minimal to minor and those in the 300 mg/kg group were moderate. Hepatic extramedullary hematopoiesis and hypertrophy of hepatocytes; renal tubular pigmentation, hemoglobinuric nephrosis and regeneration; and splenic extramedullary hematopoiesis, hemosiderosis and congestion were observed. Hemoglobinuric nephrosis occurred in 36 of 40 rats in the 300 mg/kg group and in 33 of the 40 in the 100 mg/kg group. Renal tubular necrosis occurred in the 27 rats that died or became moribund during the exposure period. Regenerative tubular epithelial cells in the distal convoluted tubules occurred in 37 of the 40 rats in the 300 mg/kg group, in 36 of the 40 in the 100 mg/kg group and in 18 of the 20 males in the 30 mg/kg group. These effects were minor to moderate in the 100 mg/kg and 300 mg/kg groups, minimal to minor in the males in the 30 mg/kg group and absent in the females in the 30 mg/kg group and in both males and females in the 0 mg/kg group. Extramedullary hematopoiesis occurred in the liver and/or spleen of 25 (16 male, 9 female) of 39 rats in the 300 mg/kg group and in 21 (13 male, 8 female) of 40 in the 100 mg/kg group. They did not occur in the 30 mg/kg or 0 mg/kg groups. Hemosiderosis occurred in the liver and/or spleen in 35 of 40 rats in the 300 mg/kg group, in 35 of 39 in the 100 mg/kg group, in 17 of 20 males in the 30 mg/kg group and in 9 of 20 males in the 0 mg/kg group. Hemosiderosis did not occur in the females in the 30 and 0 mg/kg groups. Hypertrophy of hepatocytes occurred in 13 of 20 female and 3 of 20 male rats in the 300 mg/kg group and in 4 of 20 female and 1 of 20 male rats in the 100 mg/kg group. Therefore, NOAEL of Elon was considered to be 30 mg/kg bw in male and female rats since higher dosage levels induced toxic responses.

A repeated dose oral toxicity study was performed to determine the toxic nature of p-Methylaminophenol sulphate for 92 days. Ten male and 10 female Sprague Dawley rats per dose were administered the test chemical at dose levels of 0, 3, 10 or 30 mg/kg/day by an oral gavage route of exposure for 13 weeks followed by a 4-week treatment-free period. Six additional animals per sex for the high dose + control group (which were kept for a 4-week treatment free period) and 6 animals per sex in the satellite groups (3, 10 and 30 mg/Kg/day) were also included in the study. The treated animals were observed for mortality, clinical signs, and changes in body weight and food consumption, as well as functional battery observations were also made. Hematology, clinical chemistry and urinanalysis was performed and was followed by gross and histopathology. The test item was clinically well tolerated at all dose-levels and did not cause any change in haematological or blood biochemical parameters. Only a higher urinary volume and a lower specific gravity were noted in some males given 30 mg/kg/day. No effects on organ weights and no macroscopic findings were noted. Microscopic examination revealed tubular epithelial degeneration/single cell necrosis in the kidneys of animals given 30 mg/kg/day, and complete reversibility of these changes was noted at the end of the treatment-free period. Therefore, NOAEL for p-Methylaminophenol sulphate was considered to be 10 mg/kg/day when male and female Sprague-Dawley rats were orally exposed for 92 days.

Repeated dose toxicity: Inhalation

N-methyl-p-aminophenol has very low vapor pressure (0.000000536 Pa), so the potential for the generation of inhalable vapours is very low. Also 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 and therefore this end point was considered for waiver

Repeated dose toxicity: Dermal

A repeated dose dermal toxicity study was performed to determine the dermal toxic nature of N-methyl-p-aminophenol sulfate. The study was performed on female Charles River CD rats, where 2 ml/kg dye formulation 7404 or P-26 containing 1% and 0.05% N-methyl-p-aminophenol sulfate, respectively, was applied to the dorso-scapular area. These dye formulations contained other active ingredients in an aqueous solution and were mixed with an equal volume of 6% hydrogen peroxide prior to application. The application was made during the gestation days 1, 4, 7, 10, 13, 16 and 19. The animals were observed for clinical signs, body weight changes, dermal irritation if any and food consumption. No dye formulation related toxicity was noted. Changes in female body weights and food consumption were similar for rats in the untreated controls and all dye-treated groups. No irritation or other changes in appearance were noted except for changes in skin and hair color at the site of topical application of the dye formulation. Based on the observations made, NOAEL for N-methyl-p-aminophenol sulfate in female Charles River CD rats was considered to be 11.47 mg/kg for formulation 7404 and 0.5735 mg/kg for formulation P26, where both formulations contain the target compound.

A repeated dose dermal toxicity study was performed to determine the toxic nature of N-Methyl-p-aminophenol sulfate. The study was performed on male and female New Zealand White rabbits, where 1 ml/kg dye of formulation 7404 and P-26 containing 1% (5.735 mg/kg) and 0.05% (0.2867 mg/kg) N-Methyl-p-aminophenol sulfate, respectively, was applied to the back and dorso-lateral aspects of the thoracic-lumbar area (one on each side of the midline). The dye formulations contained other active ingredients in an aqueous solution and were mixed with an equal volume of 6% hydrogen peroxide prior to application. The application was made twice weekly for 13 weeks. The animals were observed for mortality, body weight changes, hematological, clinical chemistry, urine analysis, and gross and histopathology. No dye formulation-related toxicity was noted. Body weight gain of all test groups was at least equal to that of the controls. Scattered statistically significant differences in the hematologic and clinical chemistry values were noted between test and control groups at the various sampling intervals. However, these differences were not considered to be of any toxicological significance because of either the direction or continuity of the differences or the fact that they fell within the range of historical control values. No remarkable urinalysis data was noted. No dye discoloration of the urine was seen at any time during the test. Statistically significant differences in relative organ weights between a test group and the combined controls were observed where the differences were not significant when the group was compared with each control group separately. No gross and microscopic lesions were noted that were judged to be due to the administration of the hair dye formulations containing the test compound. Therefore, NOAEL for N-Methyl-p-aminophenol sulfate was found to be 5.735 mg/kg of formulation 7404 and 0.2867 mg/kg of formulation P26 in male and female New Zealand White rabbits.

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.

Justification for classification or non-classification

Based on (Q)SAR predictions and the experimental data available for the target chemical, N-Methyl-p-aminophenl sulfate is likely to exhibit a toxic nature upon repeated exposure by oral route and hence it may be considered for classification as per the criteria mentioned in CLP regulation. The available data of dermal toxicity for the target chemical showed no toxic effects and thus is indicating that the target compound may be considered as not toxic for dermal administration.