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EC number: 203-166-4 | CAS number: 104-01-8
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
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
- 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
- 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).
Reference
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
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.
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