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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental 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: J-check
Title:
Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test
Author:
National Institute of Technology and Evaluation
Year:
2015
Bibliographic source:
Japan Chemicals Collaborative Knowledge Database, 2015

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD Test Guideline 422
Principles of method if other than guideline:
The 42 days feeding study was conducted on groups of 12 Males and 12 females Crl:CD(SD) rats to determine the developmental toxicity effect of test chemical
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): 3nitrobenzoic acid (NBA)
- Molecular formula (if other than submission substance): C7H5NO4
- Molecular weight (if other than submission substance): 167.121g/mole
- Substance type: Organic
- Physical state: solid
- Purity : 99.2%
- Impurities (identity and concentrations): 0.8 %

Test animals

Species:
rat
Strain:
Crj: CD(SD)
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
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 disssolved 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
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Details on mating procedure:
No data available
Duration of treatment / exposure:
Males, 42 days
Females, from 14 days before mating to day 4 of lactation
Females (satellite), 42 days
Frequency of treatment:
daily
Duration of test:
Males, 42 days
Females, from 14 days before mating to day 4 of lactation
Females (satellite), 42 days
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 20, 100 or 500 mg/kg bw/day
Basis:
no data
No. of animals per sex per dose:
Total: 116
0 mg/kg bw/day: 12 males, 12 females
20 mg/kg bw/day: 12 males, 12 females
100 mg/kg bw/day: 12 males, 12 females
500 mg/kg bw/day: 12 males, 12 females

For recovery
0 mg/kg bw/day: 5 males, 5 females
500 mg/kg bw/day: 5 males, 5 females
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
- Other: No data available

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
- Cage side observations checked in table [No.?] were included. The animals were observed for mortality

DETAILED CLINICAL OBSERVATIONS: Yes, the animals were observed for salivation
- 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: No data
- Compound intake 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

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # No data
- Organs examined: Liver, sleen, thymus and kidney weight was examined

OTHER: Histopathology of forestomach, small and soft testes, small epididymides, seminiferous tubular epithelium in the testes, sperm in the epididymides duct, Cell debris in the epididymides duct, trabecular bone in the femur bone
Ovaries and uterine content:
Implantation sites and corpora lutea were observed
Fetal examinations:
Number of pups delivered and number of live pups were examined.
Statistics:
No data available
Indices:
Gestation index, delivery index and implantation index were examined.
Historical control data:
No data available

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
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
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Maternal developmental toxicity

Number of abortions:
not specified
Pre- and post-implantation loss:
effects observed, treatment-related
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
not specified
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
not specified
Other effects:
not specified
Details on maternal toxic effects:
Maternal toxic effects:yes.
Remark: Decrease in the gestation index, delivery index, number of corpora lutea, number of implantation sites and implantation index (tendency) was noted at 500 mg/Kg/day

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.

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.

Reproductive performs:
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.

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.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: Significant alterations were noted at 500 mg/Kg/day
Remarks on result:
other: Not toxic at the mentioned dose level

Maternal abnormalities

Abnormalities:
not specified

Results (fetuses)

Fetal body weight changes:
not specified
Reduction in number of live offspring:
effects observed, treatment-related
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
not specified
Skeletal malformations:
not specified
Visceral malformations:
not specified
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes. Remark: Decrease in number of pups delivered, number of live pups on day 0 and number of live pups on day 4 in 500 mg/kg bw/day treated female rats was noted

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
100 other: mg/Kg/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Significant treatment related effects were noted at 500 mg/Kg/day

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental 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 body/day for F0 and F1 generation when Crl:CD (SD) male and female rats were treated with test chemical
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, 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