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Description of key information

Based on the prediction done 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 toxicity was predicted for 4-methoxy-2-methyl-N-phenylaniline. The study assumed the use of male and female Sprague Dawley rats in a 28 days study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for 4-methoxy-2-methyl-N-phenylaniline is predicted to be 419.804534912 mg/Kg bw/day.

Based on this value it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

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:
Data is from OECD QSAR Toolbox version 3.3 and the supporting QMRF report has been attached
Qualifier:
according to guideline
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
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:
not specified
Details on species / strain selection:
No data
Sex:
male/female
Details on test animals or test system and environmental conditions:
No data
Route of administration:
oral: feed
Details on route of administration:
No data
Vehicle:
not specified
Details on oral exposure:
No data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
Remarks:
No data
No. of animals per sex per dose:
No data
Control animals:
not specified
Details on study design:
No data
Positive control:
No data
Observations and examinations performed and frequency:
No data
Sacrifice and pathology:
No data
Other examinations:
No data
Statistics:
No data
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:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
No data
Dose descriptor:
NOAEL
Effect level:
419.805 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant alterations 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 19 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 ( not "j") )  )  and ("k" and ( not "l") )  )  and ("m" and ( not "n") )  )  and "o" )  and "p" )  and "q" )  and "r" )  and "s" )  and "t" )  and ("u" and "v" )  )

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 OASIS v.1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Michael addition OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Quinone methides OR Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR Radical >> ROS formation after GSH depletion OR Radical >> ROS formation after GSH depletion >> Quinone methides OR SN1 OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines OR SN2 OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines by DNA binding by OASIS v.1.3

Domain logical expression index: "g"

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

Domain logical expression index: "h"

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 SN1 OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine by DNA binding by OECD

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.3

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Michael Addition OR Michael Addition >> Polarised Alkenes OR Michael Addition >> Polarised Alkenes >> Polarised Alkene - alkenyl pyridines, pyrazines, pyrimidines or triazines  by Protein binding by OASIS v1.3

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as No Data by Ultimate biodeg

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as > 100 days by Ultimate biodeg

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as No Data by Ultimate biodeg

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as 0 to 1 day OR 1 to 10 days OR 10 to 100 days by Ultimate biodeg

Domain logical expression index: "o"

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

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "q"

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: "r"

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: "s"

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

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Does NOT Biodegrade Fast by Biodeg probability (Biowin 7) ONLY

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is >= 3.29

Domain logical expression index: "v"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.76

Conclusions:
The No Observed Adverse Effect Level (NOAEL) for 4-methoxy-2-methyl-N-phenylaniline is predicted to be 419.804534912 mg/Kg bw/day.
Executive summary:

Based on the prediction done using the OECD QSAR toolbox version 3.1 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose toxicity was predicted for 4-methoxy-2-methyl-N-phenylaniline. The study assumed the use of male and female Sprague Dawley rats in a 28 days study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for 4-methoxy-2-methyl-N-phenylaniline is predicted to be 419.804534912 mg/Kg bw/day.

Based on this value it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

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

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated dose toxcity: oral

Prediction model based estimation for the target chemical and data from read across chemicals has been reviewed to determine the toxic nature of 4-methoxy-2-methyl-N-phenylaniline. The studies are as mentioned below:

Based on the prediction done 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 toxicity was predicted for 4-methoxy-2-methyl-N-phenylaniline. The study assumed the use of male and female Sprague Dawley rats in a 28 days study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for 4-methoxy-2-methyl-N-phenylaniline is predicted to be 419.804534912 mg/Kg bw/day.

Repeated dose oral toxicity study (HPVIS, 2018) was performed to determine the toxic nature of Benzene, 1,1'-oxybis- . The study was performed using male and female Sprague Dawley albino rats at dose levels of0, 200, 1000, 5000 ppm (Males - 0, 11.7, 60.7 & 301.1 mg/kg/day; Females - 0, 14.5, 73.9, & 334.8 mg/kg/day). The animals were dosed by mixing the test chemical in feed for 13 weeks followed by 4 weeks recovery period. During the study period, the animals were observed for clinical signs, mortality, body weight and food consumption changes, hematology, clinical chemistry, urinalysis, organ weight changes and the animals were subjected to gross and hstopathology.None of the test or recovery animals died during the 13-week feeding or 4-week treatment/ recovery periods. No signs of test article-related clinical toxicity were observed during the 13-week treatment period, nor were any adverse signs noted during the recovery period. Mean weekly body weight and food consumption was significantly decreased in 5000 ppm males and females (301.1 mg/Kg/day – males and 334.8 mg/Kg/day-females) during entire 13-week treatment period. Statistically significant decreases in mean body weight and food consumption also were noted in the 1000 ppm (73.9 mg/Kg/day) female group during most of the study. These changes were however attributable to decreased palatability of test diet, as evidenced by statistically significant increases in food consumption and/or body weight gain during one or more weeks of recovery. No ocular manifestations of toxicity were observed. No hematological, clinical chemistry and urianalysis changes were noted at the mentioned dose level. Statistically significant differences noted if any were either not dose-related, within range of in-house historical values or occurred only in recovery animals. No absolute organ weight changes attributable to treatment were observed. The few statistically significant differences in relative weights observed in both sexes in the high dose group and mid dose females were attributed to their substantive decreased body weights seen at termination of treatment and not direct target organ toxicity. There were no gross lesions related to treatment and there were no histopathological effects related to treatment, including male and female gonads. Based on the observations made, the No observed adverse effect level (NOAEL) for Benzene, 1,1'-oxybis- is considered to be >301.1 mg/Kg/day (males) and >334.8 mg/Kg/day (females) respectively.

Repeated dose feeding study was performed to determine the toxic nature of 70 -80% struturally similar read across chemical Methyl 2-naphthyl ether (RA CAS no 93 -04 -9) and 50 -60% structurally similar read across chemical β-naphthyl ethyl ether (RA CAS no 93 -18 -5). 5 weanling rats were dosed at dose level of 2% (approximately 1000 mg/Kg bw) in the diet for 2 months. During the 2 months rats developed cataracts and the chemical was considered to be cataractogenic. Based on the observations made,the No Observed Adverse Effect Level (NOAEL) was considered to be < 1000 mg/Kg/day when 5 weanling rats treated with Methyl 2-naphthyl ether orally in feed for 2 months.

Based on the data available for the target chemical and its read across, 4-methoxy-2-methyl-N-phenylaniline is not likely to be toxic as per the criteria mentioned in CLP regulation.

Justification for classification or non-classification

Based on the data available for the target chemical and its read across, 4-methoxy-2-methyl-N-phenylaniline (CAS no 41317 -15 -1) is not likely to be toxic as per the criteria mentioned in CLP regulation.

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