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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
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 from handbook or collection of data

Data source

Reference
Reference Type:
review article or handbook
Title:
TOXICOLOGY AND CARCINOGENESIS STUDIES OF test substance
Author:
National Toxicology Program Technical Report Series.
Year:
1988
Bibliographic source:
NTP

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: As mention below
Principles of method if other than guideline:
Repeated dose toxicity study was evaluated for test chemical in Fischer 344 male and female rats for 13 weeks by oral gavage.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 2-amino-4-nitrophenol
- Molecular Formula: C6H6N2O3
- Molecular Weight: 154.125 g/mol
- SMILES Notation: C1=CC(=C(C=C1[N+](=O)[O-])N)O
- InChI: 1S/C6H6N2O3/c7-5-3-4(8(10)11)1-2-6(5)9/h1-3,9H,7H2
- Substance type: Organic
- Physical state: solid

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:Charles River Breeding Laboratories
- Age at study initiation:7 wk
- Diet (e.g. ad libitum):NIH 07 RatRation, ad libitum
- Water (e.g. ad libitum):Automatic watering system, ad libitum
- Housing:Animals were caged in polycarbonated cages with Aspen wood chips in a controlled
environment.
ENVIRONMENTAL CONDITIONS
- Temperature (°C):21.1-24.4°C
- Humidity (%): 40%-60%
- Photoperiod (hrs dark / hrs light):12 hrs dark/light

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
Justification for use and choice of vehicle (if other than water): Corn oil
- Concentration in vehicle: 0, 62.5, 125, 250, 500 or 1000 mg/kg/day
- Amount of vehicle (if gavage): 5 ml/kg/day
- Lot/batch no. (if required): No data available
- Purity: No data available
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyses for test substance in dose mixtures by methanolic extraction and spectrophotometric quantitation were performed by the study and analytical chemistry laboratories to determine if the suspensions were formulated properly. Good agreement was generally found between the study and analytical chemistry laboratories.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
5 days per week
Doses / concentrations
Remarks:
0, 62.5, 125, 250, 500, or 1,000 mg/kg
No. of animals per sex per dose:
Total 120 animals
0 mg/kg/day 10 male and 10 female
62.5 mg/kg/day 10 male and 10 female
125 mg/kg/day 10 male and 10 female
250 mg/kg/day 10 male and 10 female
500 mg/kg/day 10 male and 10 female
1000 mg/kg/day 10 male and 10 female
Control animals:
yes, concurrent vehicle
Details on study design:
Animals were distributed to weight classes and assigned to groups according to two tables of random numbers with 5 animals per cage. Animals were identified by toe clip.

Examinations

Observations and examinations performed and frequency:
Observations and examinations performed and frequency
CAGE SIDE OBSERVATIONS: Yes,Rats were observed twice per day.
DETAILED CLINICAL OBSERVATIONS: Yes ,Clinical signs were recorded.
BODY WEIGHT: Yes,Body weights were recorded once per week for the first 12 weeks of the studies
and once per month thereafter. Mean body weights were calculated for each group.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Necropsy performed on all animals. Histologic exam performed on animals dying before the end of
the studies, on animals with gross lesions, and all vehicle control and high dose animals. Kidney was
examined in all mice and the liver was weighed at necropsy.
HISTOPATHOLOGY: Yes
Histopathologic examinations were performed on all grossly visible lesions in all dose groups.
Statistics:
Data recording:Data were recorded in the Carcinogenesis Bioassay Data System, including des criptive information on the chemicals, animals, experimental design, survival, body weight and indi vidual pathology results.

Survival analyses
The probability of survival was estimated by a product-limit procedure and is presented in the form of graphs. Animals were censored from the survival analyses at the time they were found to be missing or dead from other than natural causes.

Calculation of incidence
The incidence of neoplastic or nonneoplastic lesions is given as the ratio of the number of animals bearing such lesions at a specific anatomic site to the number of animals in which that site was examined. In most instances, the denominators include only those animals for which the site was examined histologically.
Analysis of Tumor Incidence
Three statistical methods are used to analyzetumor incidence data: life table tests, incidental tumor an alysis and Fisher exact/Cochran-Armitage trend analyses.
Historical Control Data
Although the concurrent control group is always the first and most appropriate control group used for evaluation, there are certain instances in which historical control data can be helpful in the overall assessment of tumor incidence.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Significant clinical signs such as Diarrhea and lethargy were observed for rats that received 500 and 1,000 mg/kg/day in treated group compare to control
Mortality:
mortality observed, treatment-related
Description (incidence):
Mortality observed in 2/10 male rats at 1000 mg/kg/day treated dose compare to control.
Mortality observed in 2/10 female rats at 500 mg/kg/day treated dose compare to control.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No significant change were observed in final mean body weights at dose level of 62.5, 125, 250, 500, or 1,000 mg/kg of treated group compare to control.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Liver weight to body weight ratios of rats that received 500 mg/kg were significantly greater than those of vehicle controls.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Liver
Microscopic examination of the liver did not reveal any histopathologic changes attributable to chemical exposure.
Kidney
Mild to severe mineralization of the renal cortex and mild to severe degeneration of the renal tubular epithelium were observed in male rats that received 500 or 1000 mg/kg/day and in females that received 1000 mg/kg/day.

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw (total dose)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant effect were observed at this dose
Remarks on result:
other: No toxic effects were observed

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL was considered to be 250 mg/kg/day for test chemical in Fischer 344 male and female rats for 13 weeks by oral gavage.

Executive summary:

Repeated dose toxicity study was assessed for test substance to evaluate its possible toxic effect .The test chemical was exposed to the Fischer 344 male and female rats for 13 weeks by oral gavage. The test substance was exposed at the concentration of 0, 62.5, 125, 250, 500, or 1,000 mg/kg by using corn oil as vehicle. The above mention doses were decided based on dose finding study. The animals were observed for clinical sign, mortality, body weight, organ weight, gross and histopathology. Significant clinical signs such as Diarrhea and lethargy were observed for rats that received 500 and 1,000 mg/kg/day in treated group compare to control. Mortality were also observed in 2/10 male rats at 1000 mg/kg/day treated dose compare to control .Mortality observed in 2/10 female rats at 500 mg/kg/day treated dose compare to control. No significant change were observed in final mean body weights at dose level of 62.5, 125, 250, 500, or 1,000 mg/kg of treated group compare to control. No mortality or clinical signs were observed at the 250 mg/kg/day treated dose in male and female rats compare to control. Therefore NOAEL was considered to be 250 mg/kg/day for test chemical in Fischer 344 male and female rats for 13 weeks by oral gavage.