Phenylacetic acid

Endpoint summary

Description of key information

Repeated dose toxicity: Oral

Based on the data available, the No Observed Adverse Effect Level (NOAEL) for the test chemical was considered to be 1000mg/Kg bw using male and female rats. Hence the test chemical is not likely to be toxic upon repeated exposure by oral route as per the criteria mentioned in CLP regulation.

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 test chemical  which is reported as 0.0038 mm Hg at 25 deg C.Thus, exposure to inhalable dust, mist and vapour of the test chemical is highly unlikely. Therefore this study is considered for waiver.

Repeated dose toxicity: dermal

The acute toxicity value for test chemical (as provided in section 7.2.1) was considered to be >2000 mg/kg body weight. Thus, it is expected that phenylacetic acid shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that test chemical shall exhibit repeated dose toxicity by the dermal route. hence this end point was considered for waiver

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data from peer reviewed journal

Qualifier:

equivalent or similar to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

Immunotoxicity of test chemical was assessed in CD1 mice.

GLP compliance:

not specified

Limit test:

no

Species:

mouse

Strain:

CD-1

Sex:

female

Details on test animals or test system and environmental conditions:

Details on test animal
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: 6-8 wk of age
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: group housed in polypropylene cages with hardwood chip bedding
- Diet (e.g. ad libitum): Certified Purina Rodent Chow 5002 Ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-26°C
- Humidity (%): 10-70%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12-hr light/dark cycle.

IN-LIFE DATES: From: To: no data

Route of administration:

other: intragastrically

Vehicle:

other: 1% methyl cellulose

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
Test chemical was diluted with 1% methyl cellulose

Amount of vehicle : 10ml/kg

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

5 days

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
0, 250, 500 or 1000 mg/kg bw
Basis:

No. of animals per sex per dose:

Total :120
0 mg/kg bw:30 females
250 mg/kg bw:30 females
500 mg/kg bw:30 females
1000 mg/kg bw:30 females

Control animals:

yes, concurrent vehicle

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
-observed twice each day

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
No data

FOOD EFFICIENCY: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / No data
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER:
Body weights of the mice used in the PFC assay were measured at the time of dosing initiation, exposure day 5, and at autopsy. Spleen and thymus weights were measured following removal from all animals in
the PFC assay, with organ/body weight ratios calculated using individual body weights measured at the
time of autopsy. PFC assay was carried out

Sacrifice and pathology:

GROSS PATHOLOGY: No data
HISTOPATHOLOGY: No data

Statistics:

Dunnett's test and chi-square analysis were used to evaluate mean survival time and mortality data in the host resistance assay. For continuous response data, analysis of variance (two tailed) and appropriate post-hoe comparisons using Dunnett's test were performed on natural logarithmic or Iog it transformed PFC data, For the positive control group, post-hoc comparisons were made to the naive control group using a Student's t-test. Individual groups of data were evaluated for outliers prior to statistical analysis (Dixon, 1953)

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Description (incidence):

Mortalities were observed at all the dose concentration

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

not examined

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Dose descriptor:

NOEL

Effect level:

1 000 other: mg/kg bw

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no effect observed on body weight, mortality observed in all dose group, no plaque forming cells were observed

Remarks on result:

other: No toxic effects were observed

Critical effects observed:

not specified

Conclusions:

The No observed effect level (NOEL) of test chemical in CD1 rats in a 5-day study was observed at a dose concentration of 1000 mg/kg bw.

Executive summary:

Immunotoxicity of test chemical was assessed in CD1 mice. Female CD1 mice were administered intragastrically with test chemical at a dose concentration of 0, 250 or 500, 1000mg/kg bw on a daily basis for 5 days. A host resistance assay and plaque-forming cell (PFC) response to sheep erythrocytes were carried out. The results indicated that the test chemical did not modulate the cell-mediated or humoral immune response. no cheange in body weight was observed .Hence No observed effect level (NOEL) for test chemical was considered to be 1000 mg/kg bw,.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is Klimicsh 2 and from authoritative database

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

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

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: dermal

Data waiving:

other justification

Justification for data waiving:

other:

Critical effects observed:

not specified

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

Data available form various studies for the test chemicals was reviewed to determine the toxic nature of test chemical .The studies are as mentioned below:

Study 1

Immunotoxicity of test chemical was assessed in CD1 mice. Female CD1 mice were administered intragastrically with test chemical at a dose concentration of 0, 250 or 500, 1000mg/kg bw on a daily basis for 5 days. A host resistance assay and plaque-forming cell (PFC) response to sheep erythrocytes were carried out. The results indicated that the test chemical did not modulate the cell-mediated or humoral immune response. no cheange in body weight was observed .Hence No observed effect level (NOEL) for test chemical was considered to be 1000 mg/kg bw.

Study 2

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 test substance in Wistar rats. 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. All hematological 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 test substance 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 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 test substance in Wistar Rats with 14 days recovery, where in 0, 308, 556 and 1000 mg/kg body weight, doses were tested; no test chemical related changes were observed at any of the dose level, hence the general No Observed Adverse Effect Level (NOAEL) of test substance is considered to be more than 1000 mg / kg body weight.

Study 3

A subacute study was conducted to evaluate the toxic effects of repeated administration of test chemical in male and female Sprague-Dawley rats by gavage. The test chemical was administered to 6 animals/sex/species in Corn oil at doses of 0,250,500 and 1000 mg/kg/bw/day for 28 days. All rats of 250,500 and 1000 mg/kg/bw/day dose group Survive though-out the study, test chemical  have no effect on mortality. Blood samples for Clinical Biochemistry and Haematology were collected. No abnormalities occurred that could be directly attributed to test chemical treatment. Although significant change in relative weights of liver, ovaries and lungs of female were observed in 1000 mg/kg/bw/day dose groups. No test chemical related gross pathological or histological changes were seen and findings were not test chemical dependent and hence considered to be of no toxicological importance. Therefore NOEAL for repeated dose toxicity study was considered to be 1000 mg/kg/bw/day in male and female Sprague-Dawley rats when exposed to test chemical by oral route for 28 days.

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 test chemical  which is reported as 0.0038 mm Hg at 25 deg C.Thus, exposure to inhalable dust, mist and vapour of the test chemical is highly unlikely. Therefore this study is considered for waiver.

Repeated dose toxicity: dermal

The acute toxicity value for test chemical (as provided in section 7.2.1) was considered to be >2000 mg/kg body weight. Thus, it is expected that phenylacetic acid shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that test chemical shall exhibit repeated dose toxicity by the dermal route. hence this end point was considered for waiver.

Based on the data available and applying the weight of approach, the test chemical is not likely to be toxic upon repeated exposure by oral, dermal and inhalation route of exposure and hence it is not likely to classify as a toxicant as per the criteria mentioned in CLP regulation.

Justification for classification or non-classification

Based on the data available and applying the weight of approach, the test chemical is not likely to be toxic upon repeated exposure by oral, dermal and inhalation route of exposure and hence it is not likely to classify as a toxicant as per the criteria mentioned in CLP regulation.