2-ethoxybenzoic acid

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Justification for type of information:

Data iis from HPVIS

Data source

Reference

Reference Type:

secondary source

Title:

Repeated dose oral toxicty study for test chemical

Author:

United States Enviromental Protection Agency

Year:

2018

Bibliographic source:

High Production Volume Information System, 2018

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

Repeated oral toxicity study was performed to determine the toxic nature of sodium benzoate

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Sodium Benzoate

Cas Number:

532-32-1

Molecular formula:

C7H5NaO2

IUPAC Name:

Sodium Benzoate

Details on test material:

- Name of test material: Sodium benzoate
- Molecular formula: C7H5NaO2
- Molecular weight: 144.1045 g/mol
- Substance type: Organic

Test animals

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

Administration / exposure

Route of administration:

oral: feed

Details on route of administration:

No data

Vehicle:

other: Feed

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: The test chemical was mixed with feed at dose levels of 0, 1 or 2% (approximately 0, 370 or 735 mg/kg bw/d for males and 445 or 880 mg/kg bw/d for females, respectively)

DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): No data
- Storage temperature of food: No data

VEHICLE
- Justification for use and choice of vehicle (if other than water): Feed
- Concentration in vehicle: 0, 1 or 2% (approximately 0, 370 or 735 mg/kg bw/d for males and 445 or 880 mg/kg bw/d for females, respectively)
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): No data
- Purity: No data

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

18-24 months

Frequency of treatment:

Daily

Doses / concentrations

Remarks:

0, 1 or 2% (approximately 0, 370 or 735 mg/kg bw/d for males and 445 or 880 mg/kg bw/d for females, respectively)

No. of animals per sex per dose:

Test group: 50 male and 52 female
Control group: 25 males and 43 females

Control animals:

yes, concurrent vehicle

Details on study design:

No data

Positive control:

No data

Examinations

Observations and examinations performed and frequency:

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

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): 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: No data

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: No data

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

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data

HAEMATOLOGY: No data
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

CLINICAL CHEMISTRY: No data
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

URINALYSIS: No data
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. No data

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data

OTHER: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, An interim necropsy was conducted in the middle of the study on several rats randomly selected from each group. Necropsies also were conducted at study termination.

HISTOPATHOLOGY: Yes, microscopic examination was performed

Other examinations:

No data

Statistics:

T test

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

All dead rats, with the exception of 1 female control rat, had pneumonia with abscess.

Mortality:

mortality observed, treatment-related

Description (incidence):

Mortality averaged 14.5% in all rat groups within the first 16 months of the study. After 16 months, 100 rats in total from all groups died of hemorrhagic pneumonia with edema. However, there were no reported differences in mortality between the control and treated animals

Body weight and weight changes:

no effects observed

Description (incidence and severity):

There were no reported differences in growth between the control and treated animals

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

There were no reported differences in food intake between the control and treated animals

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:

effects observed, treatment-related

Description (incidence and severity):

There also was no significant difference in benign (chromophobe adenoma of the pituitary, endometrial polyp, fibroadenoma of the mammary gland, and interstitial cell tumor of the testis) and malignant tumors (leukemia, malignant lymphoma, epidermoid carcinoma of the maxilla) in treated rats compared to controls.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

No data

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male

Basis for effect level:

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

Remarks on result:

other: No toxic effects were observed

2

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

female

Basis for effect level:

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

Remarks on result:

other: No toxic effects were observed

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The No Observed Adverse Effect Level (NOAEL) for test chemical is considered to be 735 mg/kg bw/d for males and 880 mg/kg bw/d for females, respectively.

Executive summary:

Repeated oral toxicity study was performed to determine the toxic nature of test chemical . The study was performed using male and female F344 rats for 18-24 months. The test chemical was mixed with feed at dose levels of1 or 2% (approximately 370 or 735 mg/kg bw/d for males and 445 or 880 mg/kg bw/d for females, respectively). Groups of 50 male and 52 female Fischer 344 rats were used in the study. Control rats consisting of 25 males and 43 females received basal diet alone. Rats were group housed (5 rats/cage) and monitored for clinical signs, mortality, growth, food intake, and behavior. Body weight and food intake were recorded. An interim necropsy was conducted in the middle of the study on several rats randomly selected from each group. Necropsies also were conducted at study termination. During necropsy various organ tissues were prepared for microscopic examination. Mortality averaged 14.5% in all rat groups within the first 16 months of the study. All dead rats, with the exception of 1 female control rat, had pneumonia with abscess. After 16 months, 100 rats in total from all groups died of hemorrhagic pneumonia with edema. There were no reported differences in mortality, growth or food intake among treated and control rats. There also was no significant difference in benign (chromophobe adenoma of the pituitary, endometrial polyp, fibroadenoma of the mammary gland, and interstitial cell tumor of the testis) and malignant tumors (leukemia, malignant lymphoma, epidermoid carcinoma of the maxilla) in treated rats compared to controls. Based on the observations made, theNo Observed Adverse Effect Level (NOAEL) for test substance is considered to be735 mg/kg bw/d for males and 880 mg/kg bw/d for females, respectively.