Registration Dossier

Toxicological information

Endpoint summary

Currently viewing:

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity via oral route

NOAEL was estimated to be 740 mg/kg bw when Crj: CD(SD) male and female rats were exposed with p-Methylaminophenol sulphate orally.

Link to relevant study records
Reference
Endpoint:
toxicity to reproduction
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:
Data is from OECD QSAR toolbox v3.3 and the QMRF report has been attached.
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Prediction was done using OECD QSAR toolbox v3.3, 2017
GLP compliance:
not specified
Limit test:
no
Justification for study design:
not specified
Test material information:
Composition 1
Specific details on test material used for the study:
- Name of test material: p-Methylaminophenol sulfate- IUPAC name: Bis(4-hydroxy-N-methylanilinium) sulphate- Molecular formula: C14H20N2O6S- Molecular weight: 344.386 g/mole- Smiles:CNc1ccc(cc1)O.CNc1ccc(cc1)O.OS(=O)(=O)O- Inchl: 1S/2C7H9NO.H2O4S/c2*1-8-6-2-4-7(9)5-3-6;1-5(2,3)4/h2*2-5,8-9H,1H3;(H2,1,2,3,4)- Substance type: Organic- Physical state: Solid crystalline (off white - white)
Species:
rat
Strain:
Crj: CD(SD)
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
Vehicle:
corn oil
Details on exposure:
No data available
Details on mating procedure:
No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Treatment started 14 days prior to mating, and continued daily through the premating period, mating, gestation, and until lactation day 3.
Frequency of treatment:
Daily
Details on study schedule:
No data available
Dose / conc.:
740 mg/kg bw/day (nominal)
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Positive control:
No data available
Parental animals: Observations and examinations:
No data available
Estrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
No data available
Postmortem examinations (parental animals):
No data available
Postmortem examinations (offspring):
No data available
Statistics:
No data available
Reproductive indices:
No data available
Offspring viability indices:
No data available
Clinical signs:
not specified
Dermal irritation (if dermal study):
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:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: estrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
No effect was observed on reproduction performance.
Dose descriptor:
NOAEL
Effect level:
740 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance
Critical effects observed:
no
System:
female reproductive system
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
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
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Dose descriptor:
other: not specified
Generation:
other: not specified
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: not specified
Remarks on result:
other: not specified
Reproductive effects observed:
not specified
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

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

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 OR Very strong binder, OH group by Estrogen Receptor Binding ONLY

Domain logical expression index: "c"

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

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OECD ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No superfragment by Superfragments ONLY

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as High (Class III) by Toxic hazard classification by Cramer (original) ONLY

Domain logical expression index: "g"

Similarity boundary:Target: CN{+}(c1ccc(O)cc1).O{-}S(=O)(=O)O{-}.N{+}(C)c1ccc(O)cc1
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "h"

Similarity boundary:Target: CN{+}(c1ccc(O)cc1).O{-}S(=O)(=O)O{-}.N{+}(C)c1ccc(O)cc1
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "i"

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: "j"

Referential boundary: The target chemical should be classified as 3-Methylcholantrene (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "k"

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: "l"

Referential boundary: The target chemical should be classified as Thiocarbamates/Sulfides (Hepatotoxicity) No rank by Repeated dose (HESS)

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Aliphatic Amine, secondary AND Overlapping groups AND Precursors quinoid compounds by Organic Functional groups (nested)

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Triazinetrione by Organic Functional groups (nested)

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Aliphatic Amine, secondary AND Overlapping groups AND Precursors quinoid compounds by Organic Functional groups (nested)

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Azomethine by Organic Functional groups (nested)

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.19

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is <= 6.83

Conclusions:
NOAEL was estimated to be 740 mg/kg bw when male and female Crj: CD(SD) rats were exposed to p-Methylaminophenol sulphate orally.
Executive summary:

In an prediction done by SSS (Nagpur, 2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for p-Methylaminophenol sulphate. No effect was estimated to be observed on the reproductive function. Hence, NOAEL was estimated to be 740 mg/kg bw when male and female Crj: CD(SD) rats were exposed to p-Methylaminophenol sulphate orally.

 

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
740 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is Klimicsh 2 and from QSAR Toolbox 3.3. (2017)
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
11.47 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Data is Klimisch 2 and from a peer-reviewed publication
Additional information

Reproductive toxicity via oral route

In a prediction done by SSS (Nagpur, 2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for p-Methylaminophenol sulphate. No effect was estimated to be observed on the reproductive function. Hence, NOAEL was estimated to be 740 mg/kg bw when male and female Crj: CD(SD) rats were exposed to p-Methylaminophenol sulphate orally.

A reproductive and developmental toxicity study of p-Methylaminophenol sulphate was performed in female Sprague Dawley Crl CD (SD) IGS BR rats. The test material in a 0.5% suspension of carboxymethylcellulose were administered in dose concentration 0, 5, 25 or 125 mg/kg bw/day from day 6 through day 19 post-coitum by oral gavage. Animals were checked daily for clinical signs, and food consumption and body weight were recorded at designated intervals during pregnancy. On day 20 post-coitum, the dams were sacrificed and subjected to a macroscopic examination. The gravid uterus was weighed and the fetuses were removed by hysterectomy. The litter parameters like number of corpora lutea, implantation sites, early and late resorptions, dead and live fetuses were recorded. The fetuses were weighed, sexed and subjected to external, soft tissue or skeletal examinations. No treatment-related clinical signs and premature deaths were observed. Relevant maternal changes were only observed at 25 and 125 mg/kg/day where net body weight gain was slightly reduced when compared to controls. No relevant necropsy findings were noted. The litter parameters like number of corpora lutea, implantation sites, early and late resorptions, dead and live fetuses were not affected by treatment with the test item. Also, in fetuses there were no treatment-related malformations or variations in any groups at external, soft tissue or skeletal examinations. Therefore, LOEL for maternal toxicity was considered to be 25 mg/kg/day while the dose-level of 125 mg/kg/day was considered to be the NOAEL for embryo-fetal toxicity when pregnant female Sprague Dawley rats were treated with p-Methylaminophenol sulphate orally.

A combined repeated dose and reproductive/developmental toxicity study was performed to determine the toxic nature of N-Methyl-p-aminophenol sulfate when administered by a dermal route. 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. Application was made on 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. No significant differences in the mean number of corpora lutea, implantation sites and live fetuses, and the sex ratio were observed when compared with the control groups. No differences between groups were seen regarding the number of females exhibiting resorption sites or mean resorptions per pregnancy. 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. Therefore, NOAEL for N-Methyl-p-aminophenol sulfate in the maternal generation and the F1 generation of Charles River CD rats was considered to be 11.47 mg/kg for formulation 7404 and 0.5735 mg/kg for formulation P26, when both formulations contained the target compound.

Effects on developmental toxicity

Description of key information

Developmental toxicity

LOEL for maternal toxicity was considered to be 25 mg/kg/day, and the dose-level of 125 mg/kg/day was considered to be the NOAEL for embryo-fetal toxicity when female Sprague Dawley rats were treated with p-methylaminophenol sulphate orally.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Remarks:
(Prenatal Developmental Toxicity Study)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
Data from secondary source
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
A prenatal development toxicity study of p-methylaminophenol sulphate was performed in Sprague-Dawley 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: p-Methylaminophenol sulfate- IUPAC name: Bis(4-hydroxy-N-methylanilinium) sulphate- Molecular formula: C14H20N2O6S- Molecular weight: 344.386 g/mole- Smiles:CNc1ccc(cc1)O.CNc1ccc(cc1)O.OS(=O)(=O)O- Inchl: 1S/2C7H9NO.H2O4S/c2*1-8-6-2-4-7(9)5-3-6;1-5(2,3)4/h2*2-5,8-9H,1H3;(H2,1,2,3,4)- Substance type: Organic- Physical state: Solid crystalline (off white - white)
Species:
rat
Strain:
Sprague-Dawley
Remarks:
Crl CD (SD) IGS BR)
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: p-methylaminophenol sulphate in a 0.5% suspension of carboxymethylcellulose was prepared prior to treatment.DIET PREPARATION- Rate of preparation of diet (frequency):No data available- Mixing appropriate amounts with (Type of food): No data available- Storage temperature of food: No data availableVEHICLE- Justification for use and choice of vehicle (if other than water): c
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- M/F ratio per cage: No data available- Length of cohabitation: No data available- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: The day of positive proof for sperm in the vaginal smear or sperm plug was designated as day 0 post coitum (p.c.) or gestation day 0. - After ... days of unsuccessful pairing replacement of first male by another male with proven fertility: No data available- Further matings after two unsuccessful attempts: No data available- After successful mating each pregnant female was caged (how): No data available- Any other deviations from standard protocol: No data available
Duration of treatment / exposure:
14 days (from day 6 through day 19 post-coitum)
Frequency of treatment:
Daily from day 6 through day 19 post-coitum
Duration of test:
20 days
Remarks:
Doses/Concentrations: 0, 5, 25 or 125 mg/kg bw/day
No. of animals per sex per dose:
Total: 96 ratsControl :24 females5 mg/kg bw/day: 24 females25 mg/kg bw/day: 24 females125 mg/kg bw/day: 24 females
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes - Time schedule: Daily- Cage side observations included: No data availableDETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: DailyBODY WEIGHT: Yes - Time schedule for examinations: On designated intervals during prenancyFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: On designated intervals during prenancy- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data availableWATER CONSUMPTION AND COMPOUND INTAKE(if drinking water study): No data availableOPHTHALMOSCOPIC EXAMINATION: No data availableHAEMATOLOGY: No data availableCLINICAL CHEMISTRY: No data availableURINALYSIS: No data availableNEUROBEHAVIOURAL EXAMINATION: No data availableOTHER: No data available
Ovaries and uterine content:
On day 20 post-coitum, the dams were sacrificed and subjected to a macroscopic examination. The gravid uterus was weighed and the fetuses were removed by hysterectomy.
Fetal examinations:
Upon necropsy, the fetuses were subjected to external, soft tissue or skeletal examinations.
Statistics:
No data available
Indices:
No data available
Historical control data:
No data available
Clinical signs:
no effects observed
Description (incidence and severity):
No treatment-related clinical signs were observed.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
There were no premature deaths during the study.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Relevant maternal changes were only observed at 25 and 125 mg/kg/day where net body weight gain was slightly reduced when compared to controls.
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:
no effects observed
Description (incidence and severity):
No relevant necropsy findings were recorded.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Number of abortions:
not specified
Pre- and post-implantation loss:
not specified
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
not specified
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
not specified
Other effects:
not specified
Dose descriptor:
LOEL
Effect level:
25 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
Abnormalities:
not specified
Fetal body weight changes:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified
Reduction in number of live offspring:
not specified
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Description (incidence and severity):
There were no treatment-related malformations or variations in any groups at external examination.
Skeletal malformations:
no effects observed
Description (incidence and severity):
There were no treatment-related malformations or variations in any groups at skeletal examinations.
Visceral malformations:
no effects observed
Description (incidence and severity):
There were no treatment-related malformations or variations in any groups at soft tissue examinations.
Other effects:
not specified
Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
external malformations
skeletal malformations
visceral malformations
Abnormalities:
not specified
Developmental effects observed:
no
Lowest effective dose / conc.:
125 mg/kg bw/day (nominal)
Treatment related:
not specified
Relation to maternal toxicity:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
LOEL for maternal toxicity was considered to be 25 mg/kg/day while the dose-level of 125 mg/kg/day was considered to be the NOAEL for embryo-fetal toxicity when pregnant female Sprague Dawley rats were treated with p-Methylaminophenol sulphate orally.
Executive summary:

A reproductive and developmental toxicity study of p-Methylaminophenol sulphate was performed in female Sprague Dawley Crl CD (SD) IGS BR rats. The test material in a 0.5% suspension of carboxymethylcellulose were administered in dose concentration 0, 5, 25 or 125 mg/kg bw/day from day 6 through day 19 post-coitum by oral gavage. Animals were checked daily for clinical signs, and food consumption and body weight were recorded at designated intervals during pregnancy. On day 20 post-coitum, the dams were sacrificed and subjected to a macroscopic examination. The gravid uterus was weighed and the fetuses were removed by hysterectomy. The litter parameters like number of corpora lutea, implantation sites, early and late resorptions, dead and live foetuses were recorded. The fetuses were weighed, sexed and subjected to external, soft tissue or skeletal examinations. No treatment-related clinical signs and premature deaths were observed. Relevant maternal changes were only observed at 25 and 125 mg/kg/day where net body weight gain was slightly reduced when compared to controls. No relevant necropsy findings were noted. The litter parameters like number of corpora lutea, implantation sites, early and late resorptions, dead and live fetuses were not affected by treatment with the test item. Also, in fetuses there were no treatment-related malformations or variations in any groups at external, soft tissue or skeletal examinations. Therefore, LOEL for maternal toxicity was considered to be 25 mg/kg/day while the dose-level of 125 mg/kg/day was considered to be the NOAEL for embryo-fetal toxicity when pregnant female Sprague Dawley rats were treated with p-Methylaminophenol sulphate orally.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
125 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Data is Klimisch 4 and from secondary source
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
11.47 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Data is Klimisch 2 and from a peer-reviewed publication
Additional information

Developmental toxicity

A reproductive and developmental toxicity study of p-Methylaminophenol sulphate was performed in female Sprague Dawley Crl CD (SD) IGS BR rats. The test material in a 0.5% suspension of carboxymethylcellulose were administered in dose concentration 0, 5, 25 or 125 mg/kg bw/day from day 6 through day 19 post-coitum by oral gavage. Animals were checked daily for clinical signs, and food consumption and body weight were recorded at designated intervals during pregnancy. On day 20 post-coitum, the dams were sacrificed and subjected to a macroscopic examination. The gravid uterus was weighed and the fetuses were removed by hysterectomy. The litter parameters like number of corpora lutea, implantation sites, early and late resorptions, dead and live foetuses were recorded. The fetuses were weighed, sexed and subjected to external, soft tissue or skeletal examinations. No treatment-related clinical signs and premature deaths were observed. Relevant maternal changes were only observed at 25 and 125 mg/kg/day where net body weight gain was slightly reduced when compared to controls. No relevant necropsy findings were noted. The litter parameters like number of corpora lutea, implantation sites, early and late resorptions, dead and live fetuses were not affected by treatment with the test item. Also, in fetuses there were no treatment-related malformations or variations in any groups at external, soft tissue or skeletal examinations. Therefore, LOEL for maternal toxicity was considered to be 25 mg/kg/day while the dose-level of 125 mg/kg/day was considered to be the NOAEL for embryo-fetal toxicity when pregnant female Sprague Dawley rats were treated with p-Methylaminophenol sulphate orally.

A combined repeated dose and reproductive/developmental toxicity study was performed to determine the toxic nature of N-Methyl-p-aminophenol sulfate when administered by an dermal route. 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. Application was made on 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. No significant differences in the mean number of corpora lutea, implantation sites and live fetuses, and the sex ratio were observed when compared with the control groups. No differences between groups were seen regarding the number of females exhibiting resorption sites or mean resorptions per pregnancy. 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. Therefore, NOAEL for N-Methyl-p-aminophenol sulfate in the maternal generation and the F1 generation of Charles River CD rats was considered to be 11.47 mg/kg for formulation 7404 and 0.5735 mg/kg for formulation P26, when both formulations contained the target compound.

Justification for classification or non-classification

Based on a (Q)SAR prediction and available experimental data of the target chemical, N-Methyl-p-aminophenol sulfate is not regarded as toxic for reproductive toxicity since no effects were noted on any reproductive parameters. In addition, no embryotoxicity or teratogenic effects were presented in the reviewed data and thus the target chemical is not regarded as toxic for developmental toxicity.