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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data is from J check

Data source

Reference
Reference Type:
other:
Title:
Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test of test chemical by oral administration in rats
Author:
National institute of technology and evaluation
Year:
2015
Bibliographic source:
Japan Chemicals Collborative Knowledge Database (J-check), 2015

Materials and methods

Test guideline
Qualifier:
according to guideline
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 reproduction / developmental toxicity Screen of test chemical was performed in rats orally

GLP compliance:
not specified
Limit test:
no
Justification for study design:
Data is from J check

Test material

Constituent 1
Chemical structure
Reference substance name:
3-nitrobenzoic acid
EC Number:
204-508-5
EC Name:
3-nitrobenzoic acid
Cas Number:
121-92-6
Molecular formula:
C7H5NO4
IUPAC Name:
3-nitrobenzoic acid
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): m-nitrobenzoic acid
- Molecular formula (if other than submission substance): C7H5NO4
- Molecular weight (if other than submission substance): 167.121
- Substance type: Organic
- Physical state: solid
- Purity : 99.2%

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Details on species / strain selection:
No data
Sex:
male/female
Details on test animals or test system 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
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: 0.1w/v% Tween 80 + 0.5w/v% Sodium carboxymethylcellulose solution
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Test chemical was dissolved in 0.1 w/v% Tween 80 + 0.5 w/v% Sodium carboxymethylcellulose solution at dose levels of 0, 20, 100 or 500 mg/Kg bw/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): 0.1 w/v% Tween 80 + 0.5 w/v% Sodium carboxymethylcellulose solution
- Concentration in vehicle: 0, 20, 100 or 500 mg/kg bw/day
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available
Details on mating procedure:
No data available
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
42 days
Frequency of treatment:
Daily
Details on study schedule:
No data available
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 20, 100 or 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:
No data
Positive control:
No data

Examinations

Parental animals: Observations and examinations:
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, animal were observed for salivation
- Time schedule: No data available

BODY WEIGHT: Yes
- 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

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

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.

OTHER:
Organ weight: Brain R, Liver R, Kidney R, Testes A/R, Epididymides A/R, Thymus A and Spleen A/R were weighed.
Oestrous cyclicity (parental animals):
Any irregularities in the estrous cycle were investigated.
Sperm parameters (parental animals):
No data
Litter observations:
Number of live offspring, clinical signs and body weight were observed.
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: No detailed data available
- Maternal animals: No data available

GROSS NECROPSY and HISTOPATHOLOGY / ORGAN WEIGHTS
The target organs for the study were Stomach, Bone, Testes, Epididymides, (Female genital tract)
Postmortem examinations (offspring):
No detailed data available
Statistics:
No data
Reproductive indices:
Gestation index, delivery index, number of corpora lutea, number of implantations, implantation index and number of offspring delivered were observed
Offspring viability indices:
Offspring viability on day 0 and 4 were observed

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Salivation was observed in 500 mg/kg bw/day treated male and female rats as compared to control and and decrease in locomotor activity, irregular respiration, prone position and drastic worsening was observed in female rat.
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, treatment-related
Description (incidence):
When treated with 500 mg/kg bw/day, three female rats died as compared to control.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Restrained body weight gain was observed in 500 mg/kg bw/day treated male rat as compared to control.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
On day 8, Decrease in the food consumption was observed in 500 mg/kg bw/day treated male and female rat as compared to control.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Description (incidence and severity):
No effects was observed in treated male and female rat as compared to control.
Behaviour (functional findings):
no effects observed
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
In male rat, Squamous hyperplasia, Erosion and Focal inflammatory cell infiltration in the forestomach, Small and soft testes, Small epididymides, Degeneration in seminiferous tubular epithelium of testes, Decrease sperm in the epididymides duct, Cell debris in epididymides duct and Increase in the trabecular bone in femur bone were observed in 500 mg/kg bw/day during treatment and recovery.

In female rat, Squamous hyperplasia and Erosion in forestomach during test and Increase in trabecular bone in femur bone during test and Recovery at in 500 mg/kg bw/day treated female rats.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
No effects were observed on estrous cycle, irregular estrous cycle, mating index, mating days until copulation, number of estrous stages without mating.
Reproductive function: sperm measures:
not specified
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
No effects were observed on estrous cycle, irregular estrous cycle, mating index, mating days until copulation, number of estrous stages without mating, fertility index, gestation period and parturition or maternal behavior of treated rat.

Reproductive performance:
Decrease in gestation index, delivery index, number of corpora lutea, number of implantation sites, implantation index and number of pups delivered were observed in 500 mg/kg bw/day treated female rats.

Details on results (P0)

Mortality:
When treated with 500 mg/kg bw/day, three female rats died as compared to control.

Clinical signs:
Salivation was observed in 500 mg/kg bw/day treated male and female rats as compared to control and and decrease in locomotor activity, irregular respiration, prone position and drastic worsening was observed in female rat.

Body weight and weight gain:
Restrained body weight gain was observed in 500 mg/kg bw/day treated male rat as compared to control.

Food consumption:
On day 8, Decrease in the food consumption was observed in 500 mg/kg bw/day treated male and female rat as compared to control.

Urinalysis:
No effects was observed in treated male and female rat as compared to control.

Hematology:
Decrease in the RBC, Hgb and Hct level were observed in 500 mg/kg bw/day treated male and female rat as compared to control.

Blood chemistry:
In male rats, Increase in the A/G ratio, Pi, K, and Decrease in Blood Urea Nitrogen, total protein and Cl level were observed in 500 mg/kg bw/day.

In female rats, Increase in ALT was observed in 500 mg/kg bw/day.

Organ weight:
In male rats, Increase in Relative brain, liver and kidney weight and Decrease in Absolute and Relative testes and epididymides weight during test and recovery and Absolute thymus weight during test were observed in 500 mg/kg bw/day.

In female, Increase in Relative liver and spleen weight during test and recovery and Absolute spleen and kidney weight in recovery and Decrease in Absolute thymus weight during test were observed in 500 mg/kg bw/day.

Histopathology:
In male rat, Squamous hyperplasia, Erosion and Focal inflammatory cell infiltration in the forestomach, Small and soft testes, Small epididymides, Degeneration in seminiferous tubular epithelium of testes, Decrease sperm in the epididymides duct, Cell debris in epididymides duct and Increase in the trabecular bone in femur bone were observed in 500 mg/kg bw/day during treatment and recovery.

In female rat, Squamous hyperplasia and Erosion in forestomach during test and Increase in trabecular bone in femur bone during test and Recovery at in 500 mg/kg bw/day treated female rats.

Reproductive function:
No effects were observed on estrous cycle, irregular estrous cycle, mating index, mating days until copulation, number of estrous stages without mating, fertility index, gestation period and parturition or maternal behavior of treated rat.

Reproductive performance:
Decrease in gestation index, delivery index, number of corpora lutea, number of implantation sites, implantation index and number of pups delivered were observed in 500 mg/kg bw/day treated female rats.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive function (oestrous cycle)
reproductive performance
other: Effects were observed at 500 mg/kg bw/day
Remarks on result:
other: effects observed at 500mg/kg bw

Target system / organ toxicity (P0)

Critical effects observed:
not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Description (incidence and severity):
No effect were observed on Clinical signs of pups
Dermal irritation (if dermal study):
not specified
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
When treated with 500 mg/kg/day, decrease in number of live pups on day 4 were observed as compared to control.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No change in body weight of pups was observed in treated rats.
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
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Description (incidence and severity):
No abnormal changes were observed in Gross pathology of pups.
Histopathological findings:
not specified
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Details on results (F1)

Mortality: When treated with 500 mg/kg/day, decrease in number of live pups on day 4 were observed as compared to control.

Clinical signs: No effect were observed on Clinical signs of pups

Body weight: No change in body weight of pups was observed in treated rats.

Food consumption: No data available

Gross pathology: No abnormal changes were observed in Gross pathology of pups.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
clinical signs
mortality
body weight and weight gain
gross pathology
other: No of pups delivered. The effects were observed at 500 mg/Kg bw/day
Remarks on result:
other: No of pups delivered. The effects were observed at 500 mg/Kg bw/day

Target system / organ toxicity (F1)

Critical effects observed:
not specified

Overall reproductive toxicity

Reproductive effects observed:
not specified
Treatment related:
not specified

Applicant's summary and conclusion

Conclusions:
The no-observed-adverse-effect-level (NOAEL) was considered to be 100 mg/kg/day for F0 and F1 generation when Crl:CD(SD) male and female rat were treated with test chemical orally.
Executive summary:

In Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test, Crl:CD (SD) male and female rats were treated with test chemical in the concentration of 0, 20, 100 and 500 mg/kg bw/day orally by gavage. In F0 generation, when treated with 500 mg/kg/day, three female rats died, Salivation in male and female rat was noted, restrained body weight gain in male rat and decrease in the food consumption on day 8 in male and female rat were observed. Similarly, Decrease in the RBC, Hgb and Hct level in male and female rat, Increase in A/G ratio, Pi, K and Decrease in Blood Urea Nitrogen, total protein, Cl level in male rat and Increase in ALT level in female rat were observed in 500 mg/kg/day. In addition, Increase in Relative brain, liver and kidney weight and Decrease in absolute and relative testes and epididymides weight during test and recovery and absolute thymus weight during test in male rat and Increase in relative liver and spleen weight during test and recovery and absolute spleen and kidney weight in recovery and Decrease in absolute thymus weight during test in female, Squamous hyperplasia, Erosion and Focal inflammatory cell infiltration in the forestomach, Small and soft testes, Small epididymides, Degeneration in seminiferous tubular epithelium of testes, decrease sperm and cell debris in epididymides duct and an increase in the trabecular bone in femur bone in male rat and squamous hyperplasia and erosion in forestomach during test and an increase in trabecular bone in femur bone during test and recovery in female rat treated with 500 mg/kg/day. Decrease in gestation index, delivery index, number of corpora lutea, number of implantation sites, implantation index and number of pups delivered in F0 female and a decrease in number of pups delivered, number of live pups on day 0 and number of live pups on day 4 were observed in F1 generation treated with 500 mg/kg bw/day female rats. Based on the observations made, the reproductive No Observed Adverse Effect Level (NOAEL) was considered to be 100 mg/kg body/day for F0 and F1 generation when Crl:CD (SD) male and female rats were treated with test chemical.