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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
Data is from J-check database

Data source

Reference
Reference Type:
review article or handbook
Title:
Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test of test substance by oral administration in rats
Author:
National Institute of Technology and Evaluation
Year:
2018
Bibliographic source:
Japan Chemicals Collaborative Knowledge Database, 2018

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
Combined repeated dose repro-devp. Screen of m-Nitrobenzoic acid in rat orally
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material: m-nitrobenzoic acid
- Molecular formula: C7H5NO4
- Molecular weight: 167.121 g/mol
- Substance type: Organic
- Purity: 99.2%

Test animals

Species:
rat
Strain:
other: Crl: CD(SD)
Details on species / strain selection:
No data
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: No data available
- Age at study initiation: 9 weeks old (initiation of dosing)
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: No data available
- Diet (e.g. ad libitum): No data available
- Water (e.g. ad libitum): No data available
- Acclimation period: No data available

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%):No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available

IN-LIFE DATES: From: To: No data available

Administration / exposure

Route of administration:
oral: gavage
Details on route of administration:
No data
Vehicle:
other: 0.1 w/v% Tween 80 +0.5 w/v% Sodium carboxymethylcellulose solution
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The test chemical was dissolved in 0.1 w/v% Tween 80 +0.5 w/v% Sodium carboxymethylcellulose solution to give dose levels of 0, 20, 100 or 500 mg/Kg/day

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

VEHICLE
- Justification for use and choice of vehicle (if other than water): 0.1w/v% Tween 80 +0.5w/v% Sodium carboxymethylcellulose solution
- Concentration in vehicle: 0, 20, 100, 500 mg/kg/day
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data available
Duration of treatment / exposure:
Males: 42 days
Females: 55 days (from 14 days before mating to day 4 of lactation)
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 20, 100, 500 mg/kg/day
Basis:
no data
No. of animals per sex per dose:
Total: 116
0 mg/kg/day: 12 male, 12 female
20 mg/kg/day: 12 male, 12 female
100 mg/kg/day: 12 male, 12 female
500 mg/kg/day: 12 male, 12 female

Recovery:
0 mg/kg/day: 5 male, 5 female
500 mg/kg/day: 5 male, 5 female
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: No data available
- Rationale for animal assignment (if not random): No data available
- Rationale for selecting satellite groups: No data available
- Post-exposure recovery period in satellite groups: 14 days
- Section schedule rationale (if not random): No data available
Positive control:
No data

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: No data available
- Cage side observations checked in table [No.?] were included. Mortality were observed

DETAILED CLINICAL OBSERVATIONS: Yes , but no detailed information available
- Time schedule: No data available

BODY WEIGHT: Yes , but no detailed information
- Time schedule for examinations: Observed during dosing period

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: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight :No data

HAEMATOLOGY: Yes
- 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. Red blood cell count, hemoglobin concentration and hematocrit value were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. A/G ratio, Pi, K, BUN, TP, Cl and ALT were examined.

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: No data
- 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:
Organ weight: Brain R, Liver R, Kidney R, Testes A/R, Epididymides A/R, Thymus A and Spleen were in males and liver R, Spleen R, Spleen A, Thymus A, Kidney A from females was weighed
Sacrifice and pathology:
HISTOPATHOLOGY: Yes
Organ examined:
Forestomach, testes, epididymides, seminiferous tubular epithelium, epididymides duct, femur bone were examined in male rats and forestomach, trabecular bone in femur bone, female genital tract were examined in female rats
Other examinations:
No data
Statistics:
No data

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
When treated with 500 mg/kg/day, Salivation was observed in male and female rats and decrease in locomotor activity, irregular respiration, prone position and drastic worsening was observed in female rat.
Mortality:
mortality observed, treatment-related
Description (incidence):
When treated with 500 mg/kg/day, 3 female rat were died.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
When treated with 500 mg/kg/day, restrained body weight gain was noted in male rats.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
A decrease in food consumption was noted on day 8 in 500 mg/Kg bw/day male and female rats
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
AT 500 mg/Kg bw/day, a decrease in red blood cell, hemoglobic and hematocrit values was noted in male and female rats
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
An increase in the A/G ration, Pi, K was noted in males and ALT increase was noted in females at 500 mg/Kh bw/day dose. However, a decrease in BUN, TP and CL was noted in male rats at 500 mg/Kg bw/day
Urinalysis findings:
no effects observed
Description (incidence and severity):
No effects were noted for urianalysis in male and female rats at any of the dose levels.
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
When treated with 500 mg/kg/day, in male rats, relative weight of Brain, Liver and Kidney increased, absolute and relative weight of Testes, Epididymides and absolute weight of Thymus decreased. During recovery, absolute and relative weigh of Testes and Epididymides were decreased in male rats.

In female rats, when treated with 500 mg/kg/day, relative Liver and Spleen weight increased and absolute Thymus weight decreased. During recovery, absolute spleen and kidney weight increased.
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
In male rats, Squamous hyperplasia, Erosion and Focal inflammatory cell infiltration in the forestomach, Small and soft testes, Small epididymides, Degeneration in seminiferous tubular epithelium in the testes, Decrease in sperm and Cell debris in the epididymides duct and increase in trabecular bone in the femur bone were observed in 500 mg/kg/day treated and in recovery period.

When treated with 100 mg/kg/day, Squamous hyperplasia in the forestomach were observed in male rats.

In female, Squamous hyperplasia, Erosion in the forestomach and an Increase in trabecular bone in the femur bone in 500 mg/kg/day treated and an Increase in trabecular bone in the femur bone in recovery period at mg/Kg/day was noted.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
20 other: mg/kg/day
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No effect on survival, clinical signs, body weight and weight gain, food consumption, haematology, clinical chemistry, organ weights and histopathology
Dose descriptor:
NOAEL
Effect level:
100 other: mg/kg/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No adverse effect on survival, clinical signs, body weight and weight gain, food consumption, haematology, clinical chemistry, organ weights and histopathology

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The no-observed- adverse-effect-level (NOAEL) for male rats was considered to be 20 mg/kg/day and NOAEL for female rats was considered to be 100 mg/kg/day when Crl:CD (SD) male and female rat were treated with test substance.
Executive summary:

In a combined repeated dose repro-devp. Screen, Crl:CD (SD) male and female rats were treated with test chemical in the concentration of 0, 20, 100, 500 mg/kg/day orally for 42 days in male rats and 55 days (from 14 days before mating to day 4 of lactation). The animal were fed the diet containing the test chemical daily and were observed for clinical signs, mortality, body weight and food consumtion changes, hematological and urine analysis, organ weight changes and histopathology. When treated with 500 mg/kg/day, Salivation was observed in male and female rats and decrease in locomotor activity, irregular respiration, prone position and drastic worsening was observed in female rat. 3 female rat died at 500 mg/Kg/day. When treated with 500 mg/kg/day, restrained body weight gain was noted in male rats. A decrease in food consumption was noted on day 8 in 500 mg/Kg/day male and female rats. At 500 mg/Kg/day, a decrease in red blood cell, hemoglobic and hematocrit values was noted in male and female rats. An increase in the A/G ration, Pi, K was noted in males and ALT increase was noted in females at 500 mg/Kg/day dose. However, a decrease in BUN, TP and CL was noted in male rats at 500 mg/Kg/day. No effects were noted for urianalysis in male and female rats at any of the dose levels. When treated with 500 mg/kg/day, in male rats, relative weight of Brain, Liver and Kidney increased, absolute and relative weight of Testes, Epididymides and absolute weight of Thymus decreased. During recovery, absolute and relative weigh of Testes and Epididymides were decreased in male rats. In female rats, when treated with 500 mg/kg/day, relative Liver and Spleen weight increased and absolute Thymus weight decreased. During recovery, absolute spleen and kidney weight increased. In male rats, Squamous hyperplasia, Erosion and  Focal inflammatory cell infiltration in the forestomach, Small and soft testes, Small epididymides, Degeneration in seminiferous tubular epithelium in the testes, Decrease in sperm and Cell debris in the epididymides duct and increase in trabecular bone in the femur bone were observed in 500 mg/kg/day treated and in recovery period. When treated with 100 mg/kg/day, Squamous hyperplasia in the forestomach were observed in male rats. In female, Squamous hyperplasia, Erosion in the forestomach and an Increase in trabecular bone in the femur bone in 500 mg/kg/day treated and an Increase in trabecular bone in the femur bone in recovery period at 500 mg/Kg/day was noted. Based on the observations made, the no-observed- adverse-effect-level (NOAEL) for male rats was considered to be 20 mg/kg/day and NOAEL for female rats was considered to be 100 mg/kg/day when Crl:CD (SD) male and female rat were treated with test chemical.