N-[4-[(9,10-dihydro-4-hydroxy-9,10-dioxo-1-anthryl)amino]phenyl]acetamide

Repeated dose toxicity: oral

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

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

Test material information

Constituent 1

Reference substance name:

9,10-Anthracenedione, 1,8-dihydroxy-4-nitro-5-(phenylamino)-

Cas Number:

20241-76-3

Molecular formula:

C20-H12-N2-O6

IUPAC Name:

9,10-Anthracenedione, 1,8-dihydroxy-4-nitro-5-(phenylamino)-

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 or test system 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:

body weight and weight gain

clinical biochemistry

clinical signs

gross pathology

haematology

histopathology: non-neoplastic

mortality

urinalysis

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).