4-methoxy-N-phenyl-o-toluidine

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Toxicity to reproduction

The reproductive toxicity of 4-methoxy-2-methyl-N-phenylaniline (41317-15-1)was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and NOAEL was estimated to be 952.77mg/kg bw.When male and female Sprague-Dawleyratswere exposed with 4-methoxy-2-methyl-N-phenylaniline (41317-15-1) orally. Thus, based on the above predictions and experimental study of4-methoxy-2-methyl-N-phenylaniline (41317-15-1)) and its structurally similar read across substance, No Observed Adverse Effect Level (NOAEL) was considered to be 952.77mg/kg bw Thus, comparing this value with the criteria of CLP regulation4-methoxy-2-methyl-N-phenylaniline (41317-15-1)cannot be classified as reproductive toxicant.

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:

equivalent or similar to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3, 2018

GLP compliance:

not specified

Limit test:

no

Justification for study design:

No data available

Specific details on test material used for the study:

- Name of test material: 4-methoxy-2-methyl-N-phenylaniline
- IUPAC name: 4-methoxy-2-methyl-N-phenylaniline
- Molecular formula: C14H15NO
- Molecular weight: 213.279 g/mol
- Smiles: c1(c(cc(cc1)OC)C)Nc1ccccc1
- InChl: 1S/C14H15NO/c1-11-10-13(16-2)8-9-14(11)15-12-6-4-3-5-7-12/h3-10,15H,1-2H3
- Substance type: Organic

Species:

rat

Strain:

Sprague-Dawley

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

Type of inhalation exposure (if applicable):

other: NOT_SPECIFIED

Vehicle:

not specified

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:

10 weeks

Frequency of treatment:

Daily

Details on study schedule:

No data available

Dose / conc.:

952.77 mg/kg bw/day (nominal)

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

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:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

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

Dose descriptor:

NOAEL

Effect level:

952.77 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

reproductive performance

Remarks on result:

other: overall no effects on reproductive parameters

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

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 examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

952.77 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

viability

body weight and weight gain

Remarks on result:

other: overall no developmental toxic effects observed

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

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 6 nearest neighbours
Domain  logical expression:Result: In Domain

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Alkylarylether OR Amine OR Aromatic compound OR Ether OR Secondary amine OR Secondary aromatic amine by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] OR Aliphatic Carbon [-CH2-] OR Aliphatic Carbon [-CH3] OR Aliphatic Nitrogen, two aromatic attach [-N-] OR Aromatic Carbon [C] OR Nitrogen, two or tree olefinic attach [>N-] OR Olefinic carbon [=CH- or =C<] OR Oxygen, one aromatic attach [-O-] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Alkyl arenes OR Aromatic amine OR Ether OR Overlapping groups OR Precursors quinoid compounds by Organic Functional groups (nested) ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Alkyl arenes OR Aromatic amine OR Aryl OR Ether OR Precursors quinoid compounds by Organic Functional groups ONLY

Domain logical expression index: "e"

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

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Michael addition OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Alkyl phenols OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Hydroquinones OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Polycyclic (PAHs) and heterocyclic (HACs) aromatic hydrocarbons-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated ketones OR SN1 OR SN1 >> Carbenium Ion Formation OR SN1 >> Carbenium Ion Formation >> Polycyclic (PAHs) and heterocyclic (HACs) aromatic hydrocarbons-SN1 OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine by DNA binding by OECD

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Basesurface narcotics by Acute aquatic toxicity MOA by OASIS ONLY

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CN Lipid Solubility < 0.4 g/kg AND Group CN Aqueous Solubility < 0.1 g/L by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Group All Aqueous Solubility < 0.000005 g/L OR Group All Aqueous Solubility < 0.00002 g/L OR Group All log Kow > 9 OR Group C Aqueous Solubility < 0.0001 g/L OR Group C Aqueous Solubility < 0.0005 g/L OR Group C Melting Point > 55 C OR Group C Molecular Weight > 380 g/mol by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Known precedent reproductive and developmental toxic potential AND Toluene and small alkyl toluene derivatives (8a) by DART scheme v.1.0

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Di-substituted hydrocarbons (24b) by DART scheme v.1.0

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Alkyl arenes AND Aromatic amine AND Aryl AND Ether AND Precursors quinoid compounds by Organic Functional groups ONLY

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.62

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.55

Conclusions:

In reproductive toxicity study, NOAEL was estimated to be 952.77mg/kg bw. When male and female Sprague-Dawley rats were exposed with 4-methoxy-2-methyl-N-phenylaniline (41317-15-1) orally.

Executive summary:

The reproductive toxicity of 4-methoxy-2-methyl-N-phenylaniline (41317-15-1)was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and NOAEL was estimated to be 952.77mg/kg bw.When male and female Sprague-Dawleyratswere exposed with 4-methoxy-2-methyl-N-phenylaniline (41317-15-1) orally.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

952.77 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimicsh 2 and from QSAR Toolbox 3.3. (2018)

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Reproductive toxicity

In different studies4-methoxy-2-methyl-N-phenylaniline (41317-15-1)has been investigated for reproductive toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for4-methoxy-2-methyl-N-phenylaniline (41317-15-1).The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies performed on structurally similar read across substance.

The reproductive toxicity of 4-methoxy-2-methyl-N-phenylaniline (41317-15-1)was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and NOAEL was estimated to be 952.77mg/kg bw. When male and female Sprague-Dawley rats were exposed with 4-methoxy-2-methyl-N-phenylaniline (41317-15-1)orally.

Further supported by experimental study conducted byGESTIS(IFA, Institute for Occupational Safety and Health of the German Social Accident Insurance) on structurally similar read across substance Diphenyl ether(101-84-8) .Reproductive and development toxicity study of  Diphenyl ether(101-84-8) was performed on mated female Sprague Dawley rats according to OECD Test Guideline 414. The test material73.5%Diphenyl ether  & 26.5% biphenyl mixed in corn oil at volume of 5 ml/kg were administered in dose concentration 0,50, 200, 500 mg/kg/day on gestation days 6-15by oral gavage route. .96 rats were divided as 24 rats /dose group. Animals was checked daily for clinical signs. Food consumption and body weight were recorded; the dams were sacrificed and subjected to a macroscopic examination. Approximately 1/2 of the fetuses in each litter were processed for soft-tissue evaluations while the other half for skeletal evaluations. Statistical evaluation of equality of means was made by the appropriate one-way analysis of variance technique (ANOVA) for parametric procedures and Kruskal-Wallis test for nonparametric procedures were used after applying Bartlett's test for determination of equal variance. Statistical tests for trend, using either standard regression techniques (parametric cases) or Jonckheere's test in nonparametric cases. Levels of statistical significance used were either p<0.05 or p<0.01. Two deaths occurred at 500 mg/kg. Statistically reduced maternal weight gain and food consumption were observed at 200 and 500 mg/kg/d. Excessive alopecia, salivation and/or anogenital staining was observed but no pattern of treatment relationship could be determined. No effects observed on fetal resorptions, fetal viability, postimplantation loss or total implantations. Mean litter weights in treated and control groups were similar. No significant increases were observed in incidence of malformations or variations at any treatment level. Therefore No Observed Adverse Effect Level (NOAEL) for maternal toxicity was considered to be 50 mg/kg/day, and No indications of any influence on reproductive parameters or damage to reproductive organs were found and No developmental toxic effects were seen up to the highest dose of 500 mg/kg bw. Hence the dose-level of 500 mg/kg/day was considered to be the NOAEL for embryo-foetal toxicity and reproductive toxicity .When female Sprague Dawley rats were treated with Diphenyl ether(101-84-8)orally.

Thus, based on the above predictions and experimental study of4-methoxy-2-methyl-N-phenylaniline (41317-15-1)) and its structurally similar read across substance, No Observed Adverse Effect Level (NOAEL) was considered to be 952.77mg/kg bw Thus, comparing this value with the criteria of CLP regulation4-methoxy-2-methyl-N-phenylaniline (41317-15-1)cannot be classified as reproductive toxicant

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Thus, comparing this value with the criteria of CLP regulation4-methoxy-2-methyl-N-phenylaniline (41317-15-1)cannot be classified as reproductive toxicant.