4-methoxyphenylacetic acid

Endpoint summary

Description of key information

The repeated dose toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017) with log kow as the primary descriptor and considering the five closest read across substances; to evaluate the toxic effects of administration of 4-methoxyphenylacetic acid  (CAS No. 104-01-8) in rats by the oral route in a 13 weeks of exposure. No adverse effects were observed. Therefore, the no-observed adverse effect level (NOAEL) of 4-methoxyphenylacetic acid  (CAS No. 104-01-8) was estimated to be 1153.08 mg/kg bw/day (actual dose received).

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:

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 the test material: 4-methoxyphenylacetic acid
- Molecular formula: C9H10O3
- Molecular weight: 166.175 g/mol
- Substance type: Organic
- Purity: No data

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

Daily

Dose / conc.:

1 153.08 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

10 male and 10 female rats

Control animals:

not specified

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule:Not specified
- Cage side observations checked in table [No.?] were included.: Mortality was examined.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:No data

BODY WEIGHT: Yes
- Time schedule for examinations:No data

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Not specified
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not specified

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Not specified

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Not specified
- Time schedule for examinations:Not specified

OPHTHALMOSCOPIC EXAMINATION: Not specified
- Time schedule for examinations:Not specified
- Dose groups that were examined:Not specified

HAEMATOLOGY: Not specified
- Time schedule for collection of blood:Not specified
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals:Not specified
- Parameters checked in table [No.?] were examined.Not specified

CLINICAL CHEMISTRY: Not specified
- Time schedule for collection of blood:Not specified
- Animals fasted:Not specified
- How many animals:Not specified
- Parameters checked in table [No.?] were examined.Not specified

URINALYSIS: Not specified
- Time schedule for collection of urine:Not specified
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Not specified
- Parameters checked in table [No.?] were examined.Not specified

NEUROBEHAVIOURAL EXAMINATION: Not specified
- Time schedule for examinations: Not specified
- Dose groups that were examined: Not specified
- Battery of functions tested: sensory activity / grip strength / motor activity / other: Not specified

IMMUNOLOGY: Not specified
- Time schedule for examinations:Not specified
- How many animals:Not specified
- Dose groups that were examined:Not specified
- Parameters checked in table [No.?] were examined.Not specified

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Clinical signs:

no effects observed

Mortality:

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

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

1 153.08 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

gross pathology

histopathology: non-neoplastic

mortality

other: No effects observed.

Critical effects observed:

no

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

((((((((("a" or "b" or "c" or "d" or "e" )  and "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 ( not "q") )  )  and ("r" and "s" )  )

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 Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as No alert found by Protein binding alerts for Chromosomal aberration by OASIS v1.1

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Michael addition to alpha, beta-unsaturated acids and esters OR AN2 >> Michael addition to alpha, beta-unsaturated acids and esters >> alpha, beta - Unsaturated Carboxylic Acids and Esters OR AN2 >> Michael addition to the quinoid type structures OR AN2 >> Michael addition to the quinoid type structures >> N-Subsituted Aromatic Amines OR AN2 >> Michael-type addition to activated double bonds in vinyl pyridines OR AN2 >> Michael-type addition to activated double bonds in vinyl pyridines >> Ethenyl Pyridines by Protein binding alerts for Chromosomal aberration by OASIS v1.1

Domain logical expression index: "i"

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

Domain logical expression index: "j"

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 >> Carbamates  OR Acylation >> Direct acylation involving a leaving group >> Diacyl peroxides, anhydrides (sulphur analogues of diacyl peroxides)   OR Michael Addition OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-Carbonyl compounds with polarized double bonds  OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones OR Schiff base formation OR Schiff base formation >> Benzoyl Schiff base formation OR Schiff base formation >> Benzoyl Schiff base formation >> Benzoyl phosphine oxides  by Protein binding alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as H-acceptor-path3-H-acceptor by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Aliphatic halogen OR alpha,beta-unsaturated aliphatic alkoxy group OR Aromatic mono- and dialkylamine OR Hydrazine OR Monohaloalkene OR No alert found OR Oxolane OR Primary aromatic amine, hydroxyl amine and its derived esters by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "m"

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: "n"

Referential boundary: The target chemical should be classified as Alkoxy propanol derivatives OR Alpha-alkylcarboxylic acid derivatives (22c) OR Di-substituted hydrocarbons (24a) OR Di-substituted hydrocarbons (24b) OR Inorganic chemical OR Known precedent reproductive and developmental toxic potential OR Metal atoms were identified OR Not covered by current version of the decision tree by DART scheme v.1.0

Domain logical expression index: "o"

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

Domain logical expression index: "p"

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

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as 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 by DNA binding by OASIS v.1.3

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.199

Domain logical expression index: "s"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.67

Conclusions:

The no-observed adverse effect level (NOAEL) of 4-methoxyphenylacetic acid  (CAS No.-104-01-8) was estimated to be 1153.08 mg/kg bw/day (actual dose received).

Executive summary:

The repeated dose toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017) with log kow as the primary descriptor and considering the five closest read across substances; to evaluate the toxic effects of administration of 4-methoxyphenylacetic acid  (CAS No. 104-01-8) in rats by the oral route in a 13 weeks of exposure. No adverse effects were observed. Therefore, the no-observed adverse effect level (NOAEL) of 4-methoxyphenylacetic acid  (CAS No. 104-01-8) was estimated to be 1153.08 mg/kg bw/day (actual dose received).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 153.08 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

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

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 toxicity: Oral

Various repeated dose toxicity studies has been investigated to observe the adverse general toxicologycal effects occurring as a result of repeated daily dosing with, or exposure, to a substance for a specified period up to the expected lifespan of the test species. Often are the studies based on experiments and estimated data in rodents for 4-methoxyphenylacetic acid along with the study available on structurally similar read across substance benzyl Alcohol (CAS No.100-51-6). The predicted data using the OECD QSAR toolbox has also been compared with the experimental data. The studies are summarized as below:

 

The repeated dose toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017) with log kow as the primary descriptor and considering the five closest read across substances; to evaluate the toxic effects of administration of 4-methoxyphenylacetic acid  (CAS No. 104-01-8) in rats by the oral route in a 13 weeks of exposure. No adverse effects were observed. Therefore, the no-observed adverse effect level (NOAEL) of 4-methoxyphenylacetic acid  (CAS No. 104-01-8) was estimated to be 1153.08 mg/kg bw/day (actual dose received).

 

Two studies of 18 months duration on different strains of mice were reviewed.

Combined repeated dose- carcinogenicity study was conducted by NTRL, (1968) for 4-methoxyphenylacetic acid (CAS no 104 -01 -8) on male and female mice of strain B6C3F1 for 18 months. The chemical was used at dose levels of 0 or 215 mg/Kg and given daily for 18 months. Oral administration by stomach tube was initiated from 7th day of age to 28th weanling day following which the compound was mixed with the ground feed. Animals were observed daily for any abnormalities and palpated weekly at time of weighing for enlargement of liver and spleen. Animals which appeared moribund were killed for necropsy. One mice of each sex died during the 18 months experimental study period. Significant weight gain was observed with the increase in duration from 4, 26, 52 weeks to 18 months. Incidence of Type A Reticulum cell carcinoma and Hepatic carcinoma with kidney metastasis was observed in 1 male animal each and Pulmonary adenoma was noted in 2 female mice. Based on the observations made, Low Observed Adverse Effect Level (LOAEL) for 4-methoxyphenylacetic acid is 215 mg/Kg.

 

In the supporting data, the same study was conducted on male and female mice of strain B6AKF1 for 18 months. The chemical was used at dose levels of 0 or 215 mg/Kg and given daily for 18 months. Oral administration by stomach tube was initiated from 7th day of age to 28th weanling day following which the compound was mixed with the ground feed (baked diet). Animals were observed daily for any abnormalities and palpated weekly at time of weighing for enlargement of liver and spleen. Animals which appeared moribund were killed for necropsy. One mice of each sex died during the 18 months experimental study period. Significant weight gain was observed with the increase in duration from 4, 26, 52 weeks to 18 months. Incidence of Type A Reticulum cell carcinoma was observed in 1 female mice. Based on the observations made, Low Observed Adverse Effect Level (LOAEL) for 4-methoxyphenylacetic acid is 215 mg/Kg.

 

Moreover, In a gavage study by Nair B (International Journal of Toxicology, 20(Suppl. 3):23–50, 2001), technical grade Benzyl Alcohol (99% pure) in corn oil at doses of 125, 250, 500, 1000, or 2000 mg/kg was administered to groups of 10 F344/N rats and B6C3F1 mice (5 of each sex). Animals were dosed 5days a week for 16 days(total of 12doses). Feed and water were provided ad libitum.On days 8 and 9,both rats and mice of the 125-mg/kg group received doses that were 10-fold too high. All rats that received 2000 mg/kg and two of five males and three of five females that received 1000 mg/kg Benzyl Alcohol died before the end of the study. Rats of the two highest dose groups had blood around the nose and mouth, subcutaneous hemorrhages, and blood in the urinary and gastrointestinal tracts. Final body weight of male rats of the 1000 mg/kg group was 18% less than that of vehicle controls. Lethargy was observed in rats of the two highest dose groups; rough coats were noted in males of the 500-and 1000-mg/kg groups and in females of the 250- and 500-mg/kg groups. No compound-related histopathologic changes were noted.

All mice that received 2000 mg/kg and one of five males and two of five females that received 1000 mg/kg Benzyl Alcohol died before the end of the study. Lethargy and rough coats were noted in males that received ≥500 mg/kg and in females that received ≥ 1000 mg/kg. Blood in the urinary bladder was noted at necropsy in mice of the two highest dose groups. No compound related histopathologic changes were noted. Reviewing this study, the no-observable adverse-effect level (NOAEL) was observed to be 125 mg/kg for male/female rats whereas the no-observable adverse-effect level (NOAEL) of Benzyl Alcohol was observed to be ≤ 250 mg/kg for male mice and ≤ 500 mg/kg for female mice.

On the basis of evidence from above studies (for target and to its read across substance) in experimental animals, it can be presumed that there may be very little potential to be harmful to human health following repeated exposure as effects observed only on one male and 2 female mice out of 18 male and female mice. Thus, on the basis of CLP classification criteria the substance 4-methoxyphenylacetic acid (CAS No. 104-01-8) is not classified.

Repeated dose toxicity: inhalation

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance 4-methoxyphenylacetic acid, which is reported as 0.000535 mmHg. Also considering the particle size distribution of the substance the majority of the particles were found to be in the size of 150 micrometer which is much larger size range compared to the inhalable particulate matter. Thus, exposure to inhalable dust, mist and vapour of the chemical 4-methoxyphenylacetic acid is highly unlikely. Therefore this study is considered for waiver.

Repeated dose toxicity: dermal

The acute toxicity value for 4-methoxyphenylacetic acid (as provided in section 7.2.3) is >2000 mg/kg body weight. The substance was also found to be not irrtating to skin. Also, given the use of the chemical as intermediate; repeated exposure by the dermal route is unlikely. Thus, it is expected that 4-methoxyphenylacetic acid shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no dermal absorption data as well as no data available that suggests that 4-methoxyphenylacetic acid shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Justification for classification or non-classification

Based on the available data for the assessment of repeated dose toxicity by oral, inhalation and dermal route and following CLP Regulation (EC) No 1272/2008 , the substance 4-methoxyphenylacetic acid is not classified.