4-methoxyphenylacetic acid

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

The reproductive toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017) with respect to the descriptor log Kow; to evaluate the toxic effects of administration of 4-methoxyphenylacetic acid (CAS No. 104-01-8) in rat by the oral route. No significant effects was observed. Therefore, the no observed adverse effect level (NOAEL) of 4-methoxyphenylacetic acid for reproductive toxicity study was considered to be 1480.5 mg/kg bw/day.

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:

Prediction is done using OECD QSAR toolbox version 3.3 and the supporting QMRF report has been attached.

Qualifier:

no guideline available

Principles of method if other than guideline:

Prediction is done using OECD QSAR Toolbox version 3.3 with respect to the descriptor log Kow.

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report):(4-methoxyphenyl)acetic acid
- Molecular formula:C9H10O3
- Molecular weight:166.175 g/mole
- Substance type:Organic

Species:

rat

Strain:

Fischer 344

Sex:

female

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Duration of the test: approx. 54 days

Frequency of treatment:

Daily

Dose / conc.:

1 480.5 mg/kg bw/day

Control animals:

not specified

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: No data
- Cage side observations checked in table [No.?] were included. Mortality was observed.

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD 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: yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

Postmortem examinations (parental animals):

GROSS NECROPSY: Yes

HISTOPATHOLOGY / ORGAN WEIGHTS: Yes

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality:

no mortality observed

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:

no effects observed

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

No significant effects was observed.

Dose descriptor:

NOAEL

Effect level:

1 480.5 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

food consumption and compound intake

gross pathology

histopathology: non-neoplastic

other: No effects observed.

Critical effects observed:

no

Remarks on result:

not measured/tested

Critical effects observed:

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

Remarks on result:

not measured/tested

Critical effects observed:

not specified

Remarks on result:

not measured/tested

Critical effects observed:

not specified

Reproductive effects observed:

no

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

Domain logical expression index: "a"

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: "b"

Referential boundary: The target chemical should be classified as Aryl OR Carboxylic acid OR Ether by Organic Functional groups ONLY

Domain logical expression index: "c"

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

Domain logical expression index: "d"

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

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Alkylarylether OR Aromatic compound OR Carbonic acid derivative OR Carboxylic acid OR Carboxylic acid derivative OR Ether by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as AN2 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 Michael addition OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Quinone methides 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 >> ROS formation after GSH depletion OR Radical >> ROS formation after GSH depletion >> Quinone methides OR 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 >> Haloalkenes with Electron-Withdrawing Groups OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 >> DNA alkylation OR SN2 >> DNA alkylation >> Vicinal Dihaloalkanes OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) >> Vicinal Dihaloalkanes by DNA binding by OASIS v.1.3

Domain logical expression index: "h"

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

Domain logical expression index: "i"

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 amides OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters OR SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines by DNA binding by OECD

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Low (Class I) by Toxic hazard classification by Cramer (original) ONLY

Domain logical expression index: "k"

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: "l"

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: "m"

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

Domain logical expression index: "n"

Similarity boundary:Target: COc1ccc(CC(O)=O)cc1
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "o"

Similarity boundary:Target: COc1ccc(CC(O)=O)cc1
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

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 Aliphatic/Alicyclic hydrocarbons (Alpha 2u-globulin nephropathy) Rank C OR Tamoxifen (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Inclusion rules not met by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Ethylenglycolethers by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as No alert found by Respiratory sensitisation

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Pro-SN2 OR Pro-SN2 >> Pro-ring opening SN2 OR Pro-SN2 >> Pro-ring opening SN2 >> Vinyl benzenes by Respiratory sensitisation

Domain logical expression index: "v"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.268

Domain logical expression index: "w"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.13

Conclusions:

The reproductive toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017) with respect to the descriptor log Kow; to evaluate the toxic effects of administration of 4-methoxyphenylacetic acid (CAS No. 104-01-8) in rat by the oral route. No significant effects was observed. Therefore, the no observed adverse effect level (NOAEL) of 4-methoxyphenylacetic acid for reproductive toxicity study was considered to be 1480.5 mg/kg bw/day.

Executive summary:

The reproductive toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017) with respect to the descriptor log Kow; to evaluate the toxic effects of administration of 4-methoxyphenylacetic acid (CAS No. 104-01-8) in rat by the oral route. No significant effects was observed. Therefore, the no observed adverse effect level (NOAEL) of 4-methoxyphenylacetic acid for reproductive toxicity study was considered to be 1480.5 mg/kg bw/day.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 480.5 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The data is Klimicsh 2 and from OECD QSAR toolbox version 3.3 (2017).

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Toxicity to reproduction

Various studies including predicted results from the validated model and experimental study has been investigated for reproductive toxicity to a greater or lesser extent for the test chemical 4-methoxyph enylacetic acid (CAS No. 104-01-8) along with its structurally similar read across substance Hexan-1-ol (CAS No. 111-27-3). The predicted data for target chemical 4-methoxyphenylacetic acid (CAS No. 104-01-8) has been compared with experimental study for target and read across substance. The studies are summarized as below:

 

The reproductive toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017) with respect to the descriptor log Kow; to evaluate the toxic effects of administration of 4-methoxyphenylacetic acid (CAS No. 104-01-8) in rat by the oral route. No significant effects was observed. Therefore, the no observed adverse effect level (NOAEL) of 4-methoxyphenylacetic acid for reproductive toxicity study was considered to be 1480.5 mg/kg bw/day.

 

In addition, a reproductive toxicity study was conducted by National Cancer Institute (1968), B6C3F1 and B6AKF1 female mice were treated with 4-Methoxyphenylacetic acid in the concentration of 0 and 215 mg/kg bw/day in 0.5% gelatin for 7 to 28 day and after dose is administered through diet at 560 ppm for 18 months. Body weight gain was observed with the increase in duration of treatment. No gross pathological changes were observed in treated female mice. In addition, No fibroadenoma and carcinoma mammary gland were observed in treated female mice as compared to control. Therefore, NOAEL was considered to be > 215 mg/kg bw when B6C3F1 and B6AKF1 female mice by using 4-Methoxyphenyl-Acetic Acid for 18 months.

 

Moreover, in an oral gavage reproductive screening study by Bingham, E. et al (Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 6:440), CD rats were dosed with 0, 200, and 1000 mg/kg of 1-hexanol (in corn oil) on days 6 to 15 of gestation. Maternal toxicity occurred at the 1000 mg/kg level as indicated by clinical signs and decreased body weight gain. No embryotoxic or teratogenic effects were observed at either dose level. Thus, under the condition of this study, the no observed adverse effect level (NOAEL) for maternal toxicity study was considered to be 200.0 mg/kg whereas NOAEL for teratogenicity study was considered to be 1000.0 mg/kg.

Based on the above mentioned studies for target substance and to its read across substance by applying weight of evidence approach and also according to CLP criteria, it can be concluded that no adverse effects on sexual function and fertility was observed, therefore the substance 4-methoxyphenylacetic acid (CAS No.- 104-01-8) 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

Based on the available data for the assessment of reproductive toxicity and following CLP Regulation EC No. 1272/2008 no classification of 4-methoxyphenyl acetic acid (CAS No.- 104-01-8) as reproductive toxicant is warranted.