Registration Dossier

Repeated dose toxicity: Oral

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 4-Hydroxyphenylacetic Acid. The study assumed the use of male and female F344 rats in a 13 weeks toxicity study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for 4-Hydroxyphenylacetic Acid is predicted to be 879.677429199 mg/Kg bw/day.

Based on this value it can be concluded that the substance is considered to be not toxic as per the criteria mentioned in CLP regulation.

Repeated dose toxicity: Inhalation

4-Hydroxyphenylacetic Acid (CAS no. 156-38-7) has very low vapour pressure (0.0074 Pa=5.5504556613e-5 mm Hg). So the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore the end point for repeated dose toxicity by inhalation route is considered for waiver.

Repeated dose toxicity: Dermal

The acute dermal toxicity value for4-Hydroxyphenylacetic Acid (CAS No. – 156-38-7)(as provided in section 7.2.3) is >2000 mg/kg body weight. The substance was also found to be not irritating and not sensitizing to the skin. Based on these considerations, the end point for repeated dermal toxicity is considered as waiver.

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:

Final Report on the Safety Assessment of Sodium m-Nitrobenzenesulfonate

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: 4-Hydroxyphenylacetic Acid
- IUPAC name: 4-Hydroxyphenylacetic Acid
- Molecular formula: C8H8O3
- Molecular weight: 152.148 g/mol
- Substance type: Organic

Species:

rat

Strain:

Fischer 344

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:

13 weeks

Frequency of treatment:

Daily

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:

879.677 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No significant effects were noted at the mentioned dose level

Critical effects observed:

not specified

The prediction was based on dataset comprised from the following descriptors: NOEL
Estimation method: Takes average value from the 6 nearest neighbours
Domain logical expression:Result: In Domain

(((((("a" or "b" or "c" or "d" ) and "e" ) and ("f" and ( not "g") ) ) and ("h" and ( not "i") ) ) and ("j" and ( not "k") ) ) and ("l" and "m" ) )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Phenols (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Class 2 (less inert compounds) by Acute aquatic toxicity classification by Verhaar (Modified)

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Acid moiety AND Phenols by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "e"

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

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.161

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.01

Conclusions:

The No Observed Adverse Effect Level (NOAEL) for 4-Hydroxyphenylacetic Acid is predicted to be 879.677429199 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 4-Hydroxyphenylacetic Acid. The study assumed the use of male and female F344 rats in a 13 weeks toxicity study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for 4-Hydroxyphenylacetic Acid is predicted to be 879.677429199 mg/Kg bw/day.

Based on this value it can be concluded that the substance is considered to be not toxic as per the criteria mentioned in CLP regulation.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

879.7 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Data is from K2 prediction database

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Repeated dose toxicity: Oral

Prediction model based estimation for the target chemical and data from read across chemicals has been reviewed to determine the toxic nature of 4 - hydroxyphenylacetic acid upon repeated exposure by oral route. 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 4-Hydroxyphenylacetic Acid. The study assumed the use of male and female F344 rats in a 13 weeks toxicity study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for 4-Hydroxyphenylacetic Acid is predicted to be 879.677429199 mg/Kg bw/day.

The above mentioned predicted data is further supported by the data from read across chemicals as mentioned below:

In a combined repeated dose- reproductive developmental toxicity study (Sustainability Support Services (Europe) AB, 2015), Wistar male and female rats were treated with functionally similar read across chemical 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).

Combined repeated dose repro-devp. screen was performed (J-check, 2018; OECD SIDS 1999) to evaluate the oral toxic nature of 70 -60% structurally siilar read across chemical 4-Hydroxybenzoic acid (RA CAS no 99 -96 -7) using rats. The chemical was given at dose levels of 0, 40, 200 or 1000 mg/Kg to 13 male and 13 female Sprague Dawley rats (Crj: CD, SPF) per group. Males were treated once daily for 42 days and females were treated with the chemical before mating period (2 weeks), during mating period (2 weeks) and in mating females throughout the pregnancy period 3 days after delivery. Male and females animals were note only observed for general condition, mortality, hematology, clinical chemistry, gross pathology and histopathology parameters but also for reproductive parameters and developmental parameters in the developing fetuses. No mortality was observed in any of the dose groups and also in the control animals. Abnormal respiratory sounds or transient salivation after administration were observed intermittently throughout the administration period in both males and females in 200 mg/Kg group. In males, suppression of body weight gain was observed with a dose of 1000 mg / kg. Based on the results of hematology and blood biochemical tests conducted in males, the reduction of lymphocyte ratio and glucose with a dose of 200 mg/kg or more, the decrease of total protein due to the dose of 1000 mg/kg and the A / G ratio An increase in GPT and GOT levels were observed. There was no effect on body weight of female, feeding amount of male and female, organ weight, autopsy and histopathological findings. These changes were significant, but not considered adverse effects. Based on these considerations, the repeated dose No observed Adverse Effect level (NOAEL) for 4-Hydroxybenzoic acid in rats is 1000 mg/Kg/day.

Repeated dose toxicity: Inhalation

4-Hydroxyphenylacetic Acid (CAS no. 156-38-7) has very low vapour pressure (0.0074 Pa=5.5504556613e-5 mm Hg). So the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore the end point for repeated dose toxicity by inhalation route is considered for waiver.

Repeated dose toxicity: Dermal

The acute dermal toxicity value for4-Hydroxyphenylacetic Acid (CAS No. – 156-38-7)(as provided in section 7.2.3) is >2000 mg/kg body weight. The substance was also found to be not irritating and not sensitizing to the skin. Based on these considerations, the end point for repeated dermal toxicity is considered as waiver.

Based on the data available for the target chemical and its read across, 4- hydroxyphenylacetic acid is not likely to be toxic upon repeated exposure by oral route as per the criteria mentioned in CLP regulation.

Based on the data available for the target chemical and its read across, 4- hydroxyphenylacetic acid (CAS no 156 -38 -7) is not likely to be toxic upon repeated exposure by oral route as per the criteria mentioned in CLP regulation.