Registration Dossier

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 1-(4-methoxyphenyl)acetone. The study assumed the use of male and female rats in a 28 days toxicity study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for 1-(4-methoxyphenyl)acetone is predicted to be 823.861083984 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.

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, 2018

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: 4-methoxyphenylacetone
- IUPAC name: 1-(4-methoxyphenyl)acetone
- Molecular formula: C10H12O2
- Molecular weight: 164.203 g/mole
- Smiles : c1(ccc(OC)cc1)CC(C)=O
- Inchl: 1S/C10H12O2/c1-8(11)7-9-3-5-10(12-2)6-4-9/h3-6H,7H2,1-2H3
- Substance type: Organic
- Physical state: Colorless, oily liquid

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: unspecified

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:

No data

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:

823.861 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 mentoned 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 7 nearest neighbours
Domain logical expression:Result: In Domain

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Nucleophilic addition AND Nucleophilic addition >> Addition to carbon-hetero double bonds AND Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones by Protein binding by OASIS v1.3

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Class 1 (narcosis or baseline toxicity) by Acute aquatic toxicity classification by Verhaar (Modified)

Domain logical expression index: "c"

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

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR AN2 >> Shiff base formation for aldehydes OR AN2 >> Shiff base formation for aldehydes >> Geminal Polyhaloalkane Derivatives OR AN2 >> Thioacylation via nucleophilic addition after cysteine-mediated thioketene formation OR AN2 >> Thioacylation via nucleophilic addition after cysteine-mediated thioketene formation >> Haloalkenes with Electron-Withdrawing Groups OR Radical OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA >> Organic Peroxy Compounds OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR SN1 OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Acylation involving a leaving group OR SN2 >> Acylation involving a leaving group >> Geminal Polyhaloalkane Derivatives OR SN2 >> Acylation involving a leaving group after metabolic activation OR SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives 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 >> Haloalkenes with Electron-Withdrawing Groups OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives by DNA binding by OASIS v.1.3

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 >> Arenes OR SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN2 OR SN2 >> Epoxidation of Aliphatic Alkenes OR SN2 >> Epoxidation of Aliphatic Alkenes >> Halogenated polarised alkenes by DNA binding by OECD

Domain logical expression index: "g"

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

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Acylation Involving a Leaving group OR Acylation >> Direct Acylation Involving a Leaving group >> Acetates OR Michael addition OR Michael addition >> Polarised Alkenes OR Michael addition >> Polarised Alkenes >> Polarised alkene - pyridines by Protein binding by OECD

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules (GSH) by Protein binding potency

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Highly reactive (GSH) OR Highly reactive (GSH) >> 3-Alken-2-ones (MA) by Protein binding potency

Domain logical expression index: "k"

Similarity boundary:Target: CC(=O)Cc1ccc(OC)cc1
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Aryl AND Ether AND Ketone by Organic Functional groups ONLY

Domain logical expression index: "m"

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

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as No alert found by in vitro mutagenicity (Ames test) alerts by ISS

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as alpha,beta-unsaturated aliphatic alkoxy group by in vitro mutagenicity (Ames test) alerts by ISS

Domain logical expression index: "p"

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

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as 3-Methylcholantrene (Hepatotoxicity) Alert OR Aliphatic amines (Mucous membrane irritation) Rank C OR Aliphatic/Alicyclic hydrocarbons (Alpha 2u-globulin nephropathy) Rank C OR Aromatic hydrocarbons (Liver enzyme induction) Rank C OR Chlorphentermine (Hepatotoxicity) Alert OR Halobenzenes (Hepatotoxicity) Rank A OR Halobenzenes (Renal toxicity) Rank A OR Organophosphates (Neurotoxicity) Rank A OR Perhexiline (Hepatotoxicity) Alert OR Tamoxifen (Hepatotoxicity) Alert OR Valproic acid (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "r"

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

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Non-Metals by Groups of elements

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Transition Metals by Groups of elements

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Aryl AND Ether AND Ketone by Organic Functional groups ONLY

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aromatic Carbon [C] AND Carbonyl, aliphatic attach [-C(=O)-] AND Miscellaneous sulfide (=S) or oxide (=O) AND Olefinic carbon [=CH- or =C<] AND Oxygen, one aromatic attach [-O-] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as Aryl AND Ether AND Ketone AND Overlapping groups by Organic Functional groups (nested) ONLY

Domain logical expression index: "x"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.778

Domain logical expression index: "y"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.72

Conclusions:

The No Observed Adverse Effect Level (NOAEL) for 1-(4-methoxyphenyl)acetone is predicted to be 823.861083984 mg/Kg bw/day.

Executive summary:

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 1-(4-methoxyphenyl)acetone. The study assumed the use of male and female rats in a 28 days toxicity study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for 1-(4-methoxyphenyl)acetone is predicted to be 823.861083984 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:

no adverse effect observed

Dose descriptor:

NOAEL

823.861 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is from K2 prediction database

Endpoint conclusion:

no study available

Quality of whole database:

Waiver

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Quality of whole database:

Waiver

Endpoint conclusion:

no study available

Repeated dose toxicity: Oral

Prediction model based esrimation and data from read across chemicals have been reviewed to determine the toxic nature of 1-(4-methoxyphenyl)acetone. 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 1-(4-methoxyphenyl)acetone. The study assumed the use of male and female rats in a 28 days toxicity study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for 1-(4-methoxyphenyl)acetone is predicted to be 823.861083984 mg/Kg bw/day.

The predicted data for the target chemical is further supported by the data from read across chemicals.

In a reproductive developmental toxicity study, Wistar male and female rats were treated with 50 -60% structurally and functionally similar read across chemcal Methyl Phenyl acetate (RA CAS no 101 -41 -7) in the concentration of 0, 308, 556 and 1000 mg/kg bw orally by gavage in Corn oil for 63 days. No mortality or morbidity and apparent treatment related clinical signs were observed any of the groups of animals throughout the study period. Detailed clinical examinations like Home cage observation, Handling observation and Open field observation of all animals were observed to be normal during study period. Number of rear, urine pools, fecal bolus in animals of all the test groups of both the sexes was comparable and did not show any treatment related significant difference as compared to the respective control groups. Body weight, percent body weight changes and feed consumption in animals of all the test groups of both the sexes was comparable and did not show any treatment related significant difference as compared to the respective control groups. The sensory reactivity measurements, Foot splay, fore limb and hind limb grip strength parameters and Motor activity were comparable and no treatment related changes were revealed in any of the animals of all treated groups as compare to the repective control groups. Similarly, No treatment related changes were observed inhematological and clinical chemistry parameters of treated male and female rats as compared to control. No test item related changes in estrous cyclicity and precoital interval were observed. There was statistically significant decrease in G3 (556 mg/kg body weight) as compared to control G1 (0 mg/kg body weight). This is not dose dependent hence not considered as treatment related. There was no statistically significant difference between the control and treatment groups in the maternal and pups parameters, except markedly decreased pregnancy index / fertility index in G4 (1000 mg/kg body weight), which was considered to be treatment related.In addition, no significant change in organ weight, External and visceral examination of treated and recovery groups as compared to control.Focal to multifocal minimal lymphocytic infiltration of male and female and focal minimal necrosis in male in liver, focal minimal lymphocytic infiltration of male and female and focal mild mineralization in female in kidney, multifocal minimal lymphocytic infiltration in male and female andfocal minimal histiocyte infiltration in female lungs, focal minimal lymphocytic infiltration in heart of male, focal minimal aneurysm in aorta of male, focal moderate cystic dilationof cortex of Mandibular Lymph Node in female,focal mildsquamous epitheliumhyperplasia stomach of female, focal moderate cystic dilation of cortex in Mesenteric lymph node, focalto diffuse minimal to mild extramedullary hematopoesis in spleen and mild to moderate atrophy in Thymus of female, focal to multifocal minimal to moderate Neutrophilic/lymphocytic infiltration of Trachea of male and female, unilateral accessory adrenocortical tissue of Adrenals and focal to multifocal minimal to mildretention of mature sperm,focal minimal to milddegeneration of seminiferous tubules,focal to multifocal minimalsloughing of Pachytene Spermatocyte,focal minimalsloughing of round spermatid andfocal mildinfiltration of multinucleated giant cells of Testes, multifocal mildneutrophilic/lymphocytic infiltration of Seminal Vesicles and focal moderate necrotic debris in lumen of Prostate observed in male rats, multifocal to diffuse mild reduction of stromal cells, focal moderate necrosis, multifocal mild to moderate nodular hyperplasia of Uterus and focal minimal lymphocytic infiltration of Cervix in female rats were observed. Lesions observed in liver, kidneys, lungs, heart, aorta, stomach, lymph nodes, spleen, thymus, trachea, adrenal gland and reproductive organs of high dose treated group rats are well comparable with respective control group rats and exhibited no dose relationship Therefore, No Observed Adverse Effect Level (NOAEL) is considered to be 1000 mg Methyl Phenyl acetate (CAS No.: 101-41-7) / kg body weight when Wistar male and female rats were orally treated with Methyl Phenyl acetate (CAS No.: 101-41-7).

Repeated dose oral toxicity study was performed by Taylor et al (Toxicology and Applied Pharmacology, 1964) to determine the toxic nature of 50 -60% structurally and functionally similar read across chemical anisole (RA CAS no 100 -66 -3). The study was performed using 3 male and 3 female rats. Anisole was administered to the rats daily by stomach tube for 4 days. On day 5, the animals were subjected to gross pathology and the livers were observed for macroscopic lesions. The animals did not show any macroscopic lesions during the study. One death was noted during the study. Based on the observations made, No observed adverse effect level (NOAEL) for the test compound anisole is considered to be 1230 mg/Kg.

In a study for another 50 -60% structurally and functoinally similar read across chemical, Repeated dose feeding study was performed to determine the toxic nature of Methyl 2-naphthyl ether (RA CAS no 93 -04 -9). 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, 1-(4-methoxyphenyl)acetone is not likely to classify as a toxicant as per the criteria mentioned in CLP regulation.

Based on the data available for the target chemical and its read across, 1-(4-methoxyphenyl)acetone (CAS no 122 -84 -9) is not likely to classify as a toxicant as per the criteria mentioned in CLP regulation.