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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
repeated dose toxicity: oral, other
Remarks:
Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test
Type of information:
experimental study
Adequacy of study:
weight of evidence
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 authoritative database

Data source

Reference
Reference Type:
review article or handbook
Title:
Repeated dose oral toxicity study of the test chemical
Author:
National Institute of Technology and Evaluation
Year:
2019
Bibliographic source:
J-check

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:
According to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Remarks:
Powder
Details on test material:
- name of the test chemical: 1,8-Dihydroxy-4-nitro-5-(phenylamino)anthracene-9,10-dione
- molecular formula: C20H12N2O6
- molecular weight: 376.32 g/mol
- substance type: Organic

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
- Age at study initiation of dosing: 10 weeks old

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
methylcellulose
Remarks:
0.5 % Methylcellulose aqueous solution
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The test chemical was dissolved in 0.5 % Methylcellulose aqueous solution to give dose level of 0, 40, 200 or 1000 mg/Kg/day.

VEHICLE
- Justification for use and choice of vehicle (if other than water): 0.5 % Methylcellulose aqueous solution
- Concentration in vehicle: 0, 40, 200 or 1000 mg/Kg/day
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The prepared solution was confirmed by UV-visible absorbance method.
Duration of treatment / exposure:
- Male: 42 days
- Female: 41 - 45 days (from 14 days before mating to day 4 of lactation)
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
0, 40, 200 or 1000 mg/Kg/day
No. of animals per sex per dose:
Test group:
0 mg/Kg/day: 7 males and 12 females
40 mg/Kg/day: 12 males and 12 females
200 mg/Kg/day: 12 males and 12 females
1000 mg/Kg/day: 7 males and 12 females

Recovery group:
0 mg/Kg/day: 5 males and 5 females
1000 mg/Kg/day: 5 males and 5 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Rationale for selecting satellite groups: 5 females
- Post-exposure recovery period in satellite groups: Females, 14 days
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. No data

DETAILED CLINICAL OBSERVATIONS: No data
- Time schedule: No data

BODY WEIGHT: Yes
- Time schedule for examinations: No data

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: No data
- 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: 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. No data

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. TP, Alb, 2-Glob

URINALYSIS: Yes
- 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

IMMUNOLOGY: No data
- Time schedule for examinations: No data
- How many animals: No data
- Dose groups that were examined: No data
- Parameters checked in table [No.?] were examined. No data

OTHER: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, no detailed data available
HISTOPATHOLOGY: Yes, no detailed data available
Other examinations:
No data
Statistics:
No data

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Colored feces were noted in male and female rats treated with 40, 200 or 1000 mg/Kg/day
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Decrease in the TP, decrease in the Alb and increase in the percentage of alpha 2-Glob (Male) in 1000 mg/Kg day treated animals. Though albumin level (mg/dL) was significantly decreased in males of the high dose group, A/G ratio was not affected.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Abnormal color of urine was observed in males and females treated with 200 or 1000 mg/Kg/day
Behaviour (functional findings):
no effects observed
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Colored aqueous content in the alimentary tract in 40 mg/Kg/day treated male animals.
Colored aqueous content in the alimentary tract (Male/Female), Mucosal discoloration of alimentary tract (Male) in 200 mg/Kg/day treated animals.
Colored aqueous content in the alimentary tract (Male/Female), Mucosal discoloration of alimentary tract (Male/Female) in 1000 mg/Kg/day treated animals.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
haematology
clinical biochemistry
urinalysis
gross pathology
histopathology: non-neoplastic
Remarks on result:
other: No significant effects were observed at 1000 mg/Kg/day

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The no observed adverse effect level (NOAEL) for the test chemical is considered to be 1000 mg/Kg/day when male and female rats were exposed to the test chemical in combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD TG422).
Executive summary:

Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD TG422) was performed to determine the toxic nature of the test chemical. The study was performed using Crl:CD (SD) male and female rats. Recovery group was also included in the study. The test chemical was dissolved in 0.5 % methylcellulose aqueous solution and used at dose level of 0, 40, 200 or 1000 mg/Kg/day. The treated animals were observed for mortality, clinical signs, changes in body weight, food consumption, urinalysis, hemotology, clinical chemistry and were subjected to gross and histopathology. No mortality was noted and no effects were observed in clinical signs, functional battery observations, body weight and food consumption changes, hematology, organ weights and histopathology. Colored feces (40, 200 and 1000 mg/Kg/day) and abnormal urine color (200 and 1000 mg/Kg/day) was noted in the treated animals. Decrease in the TP, decrease in the Alb and increase in the percentage of alpha 2-Glob (Male) in treated animals of 1000 mg/Kg/day. Though albumin level (mg/dL) was significantly decreased in males of the high dose group, A/G ratio was not affected. Colored aqueous content in the alimentary tract in 40 mg/Kgday treated male animals. Colored aqueous content in the alimentary tract (Male/Female), Mucosal discoloration of alimentary tract (Male) in 200 mg/Kg/day treated animals. Colored aqueous content in the alimentary tract (Male/Female), Mucosal discoloration of alimentary tract (Male/Female) in 1000 mg/Kg/day treated animals. Based on the observations of the study, the no observed adverse effect level (NOAEL) for the test chemical is considered to be 1000 mg/Kg/day when male and female rats were exposed to the test chemical in combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD TG422).