Bis(4-hydroxy-N-methylanilinium) sulphate

Endpoint summary

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.

Qualifier:

according to guideline

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

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 or test system 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

Oestrous 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

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous 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

Qualifier:

equivalent or similar to guideline

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

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.