4-methoxyphenylacetone

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Toxicity to reproduction

The reproductive toxicity of 1-(4-methoxyphenyl)propan-2-one (122-84-9)was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and NOAEL was estimated to be 866.66 mg/kg bw. When male and female CD-1rats were exposed with 1-(4-methoxyphenyl)propan-2-one (122-84-9) orally.

Thus, based on the above studies and predictions on1-(4-methoxyphenyl)propan-2-one (122-84-9)and its read across substances, Adverse Effect Level (NOAEL) was considered to be 866.66mg/kg bw. Thus, comparing this value with the criteria of CLP regulation1-(4-methoxyphenyl)propan-2-one (122-84-9)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 (IUPAC name): 1-(4-methoxyphenyl)propan-2-one
- Common name: 4-Methoxyphenylacetone
- Molecular formula: C10H12O2
- Molecular weight: 164.203 g/mol
- Smiles notation: 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

Species:

rat

Strain:

CD-1

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:

52 days

Frequency of treatment:

Daily

Details on study schedule:

No data available

Dose / conc.:

866.66 mg/kg bw/day (nominal)

No. of animals per sex per dose:

12

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:

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

Dose descriptor:

NOAEL

Effect level:

866.66 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Remarks on result:

other: overall no reproductive toxicity 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

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:

not measured/tested

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 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 ( not "m") )  )  and "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 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 OECD

Domain logical expression index: "d"

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 Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters OR SN1 OR SN1 >> Carbenium Ion Formation OR SN1 >> Carbenium Ion Formation >> Polycyclic (PAHs) and heterocyclic (HACs) aromatic hydrocarbons-SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN2 OR SN2 >> Episulfonium Ion Formation OR SN2 >> Episulfonium Ion Formation >> 1,2-Dihaloalkanes by DNA binding by OECD

Domain logical expression index: "e"

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

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as SN2 OR SN2 >> SN2 reaction at a sp2 carbon atom OR SN2 >> SN2 reaction at a sp2 carbon atom >> Polarised alkenes with a halogen leaving group by Protein binding by OECD

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Not known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Alkyl amide, urea, thiourea, nitroso urea, carbonate, guanidine and carbamate derivatives (21b1) OR Alkyl amide, urea, thiourea, nitroso urea, carbonate, guanidine and carbamate derivatives (21b1) >> Carbonate compounds OR C1 to C4 non-branched alkyl alcohols- sub category (25a) OR Known precedent reproductive and developmental toxic potential OR Multi-halogenated alkyl ethers (23b) OR Toluene and small alkyl toluene derivatives (8a) by DART scheme v.1.0

Domain logical expression index: "i"

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

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as (!Undefined)Group CN Lipid Solubility < 0.4 g/kg OR Group All Aqueous Solubility < 0.000005 g/L OR Group All Aqueous Solubility < 0.00002 g/L 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 by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "k"

Similarity boundary:Target: CC(=O)Cc1ccc(OC)cc1
Threshold=50%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Aliphatic/Alicyclic hydrocarbons (Alpha 2u-globulin nephropathy) Rank C OR Chlorphentermine (Hepatotoxicity) Alert OR Halobenzenes (Hepatotoxicity) Rank A OR Halobenzenes (Renal toxicity) Rank A OR Perhexiline (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Alkylarylether AND Aromatic compound AND Carbonyl compound AND Ether AND Ketone by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Alkylarylether AND Aromatic compound AND Carbonyl compound AND Ether AND Ketone by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "p"

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: "q"

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: "r"

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: "s"

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: "t"

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

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.267

Domain logical expression index: "v"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.15

Conclusions:

In reproductive toxicity study, NOAEL was estimated to be 866.66 mg/kg bw. When male and female CD-1 rats were exposed with 1-(4-methoxyphenyl)propan-2-one (122-84-9) orally.

Executive summary:

The reproductive toxicity of 1-(4-methoxyphenyl)propan-2-one (122-84-9)was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and NOAEL was estimated to be 866.66 mg/kg bw. When male and female CD-1rats were exposed with 1-(4-methoxyphenyl)propan-2-one (122-84-9) orally.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

866.66 mg/kg bw/day

Study duration:

subacute

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 studies1-(4-methoxyphenyl)propan-2-one (122-84-9)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 for1-(4-methoxyphenyl)propan-2-one (122-84-9).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 1-(4-methoxyphenyl)propan-2-one (122-84-9)was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and NOAEL was estimated to be 866.66 mg/kg bw. When male and female CD-1rats were exposed with 1-(4-methoxyphenyl)propan-2-one (122-84-9) orally.

It is supported by experimental study conducted by Sustainability Support Services (Europe) AB (reort no. 15_49_124, 2016) on 50-60% structurally similar read across substance Methyl Phenyl acetate (CAS No.: 101-41-7) Combined repeated dose repro-developmental toxicity study was to provide evaluations of general and reproduction/ developmental toxicity endpoints associated with administration of repeated doses of Methyl Phenyl acetate (CAS No.: 101-41-7) in Wistar rats according to OECD guideline 422. The animals were randomly allocated to the four main groups (13/sex/group) and two recovery groups (5/sex/group). The doses selected for main groups were; 0 (G1-control),308 mg/kg body weight (G2), 556 mg/kg body weight (G3) and 1000 mg/kg body weight (G4) daily for 64 days. The recovery groups G1-R and G4-R were dosed with similar doses of respective main groups.Vehicle corn oil to G1 and G1-R and test item to G2, G3, G4 and G4-R animals were administered by oral gavage route each day during the dosing period. No mortality and morbidity were observed any of the groups of animals throughout the study period. Animals of all dose groups were observed for Clinical signs/ symptoms daily once during the experimental period. No apparent treatment related clinical signs were observed in any of the animals throughout the treatment and recovery 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, per cent 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 were comparable and no statistically significant changes were revealed in animals of treatment groups in both the sexes. Foot splay and fore limb and hind limb grip strength parameters were comparable and no treatment related changes were revealed in any of the animals of all treated groups as compare to the respective control groups. Motor activity measurements were comparable and no changes were revealed in any of the animals of all treated groups of both the sexes as compared to control group. Estrous cycle was evaluated for checking the regularity during treatment period and in cohabitation for confirmation of pregnancy.

 

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. All haematological and clinical chemistry parameters in animals of different treated groups of both the sexes were comparable to their respective control groups. No treatment related changes were observed in any of the treatment groups.  At the end of treatment and recovery period, absolute and relative weight of organs of treated group rats of either sex did not differ significantly when compared to the respective control group rats. External and visceral examination of all male and female rats of control and all treated groups including recovery groups did not reveal any abnormality of pathological significance. Terminally sacrificed pups of all treated groups did not reveal any lesion of pathological significance in any of the group when compared with control group. Pups that died among the control and treated groups during the course of study, revealed various lesions when examined externally and internally but the observations were not considered treatment related. From the patho-morphological results presented, it is concluded that, the treatment of Methyl Phenyl acetate at 308, 556 and 1000 mg/kg body weight in male and female rats did not affect adversely and no alteration of pathological significance was observed in any of the organs including reproductive organs. 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. Further these observed lesions are common in occurrence in rodents during toxicological studies. Hence, occurrence of these lesions could be considered as spontaneous or incidental in nature and not to be attributed to the administration of the Test Item.

Based on the findings of Repeated Dose Oral Toxicity Study in combination with Reproduction/ Developmental Toxicity of Methyl Phenyl acetate (CAS No.: 101-41-7) in Wistar Rats with 14 days recovery, where in 0, 308, 556 and 1000 mg/kg body weight, doses were tested; No Observed Adverse Effect Level (NOAEL) is considered to be 556 mg/kg bw. When male and female wistar rats were treated with Methyl Phenyl acetate (CAS No.: 101-41-7) orally.

It is further supported by experimental study conducted by GESTIS (IFA, Institute for Occupational Safety and Health of the German Social Accident Insurance, 2017)on structurally and functionally 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 studies and predictions on1-(4-methoxyphenyl)propan-2-one (122-84-9)and its read across substances, Adverse Effect Level (NOAEL) was considered to be 866.66mg/kg bw. Thus, comparing this value with the criteria of CLP regulation1-(4-methoxyphenyl)propan-2-one (122-84-9)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 regulation1-(4-methoxyphenyl)propan-2-one (122-84-9)cannot be classified as reproductive toxicant.