2,7-Naphthalenedisulfonic acid, 4-amino-3,6-bis[2-[4-(ethenylsulfonyl)phenyl]diazenyl]-5-hydroxy-, sodium salt (1:2)

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1. Feb to 1 Mar 1990

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Compliant to OECD 407 and GLP Guideline

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1990

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Structural Analogue 01

IUPAC Name:

Structural Analogue 01

Details on test material:

see below

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hoechst AG
- Strain: Hoe:WISKf (SPF71)
- Age at study initiation: approx. 6 weeks
- Housing: 5 rats/cage
- Diet (ad libitum): Altromin 1324
- Water (ad libitum): tap water
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3
- Humidity (%): 50±20
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Preparation: daily
- Concentration in vehicle: 1.25, 5, 20%
- Amount of vehicle (if gavage): 5 ml/kg

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

Test duration: 28 days

Frequency of treatment:

Dosing regime: 7 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
62.5, 250, 1000 mg/kg/day
Basis:
nominal in water

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Positive control:

not requested

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least once daily

BODY WEIGHT: Yes
- Time schedule for examinations: twice weekly

FOOD CONSUMPTION: Yes
- Time schedule: twice per week
- Calculation: food consumption/100g bw/week

WATER CONSUMPTION : Yes
- Time schedule: once weekly

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to necropsy
- Anaesthetic used for blood collection: No data
- Animals fasted: No
- How many animals: all

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to necropsy
- Animals fasted: No
- How many animals: all

URINALYSIS: Yes
- Time schedule for collection of urine: overnight Day 26/27
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes

NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
ORGAN WEIGHTS: Yes
HISTOPATHOLOGY: Yes

Statistics:

Yes

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food efficiency:

no effects observed

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

Gross pathology: Reddish discoloration in kidneys and testes at 1000 mg/kg/day
Histopathology: In 2 females resorption vacuoles with dye in tubular epithelial cells of convoluted segment of the proximal tubulus of the renal cortex at 1000 mg/kg/day

Effect levels

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: 1000 mg/kg: Discoloration of exctreta and organs. Renal re-absorption of dye - not considered to be toxicological relevant adverse effects.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The oral administration of the test substanceat a dose of 1000 mg/kg body weight/day for 4 weeks resulted in microsopically visible re-absorption of the dye in the kidneys of two female animals. There was no evidence in clinical chemistry and histopathology of an adverse effect on the renal function. The administration of the test compound in a dose of 1000 mg/kg body weight/day did not induce any evident relevant compound-related changes in male animals. The NOAEL was therefore considered to be 1000 mg/kg bw/day.

Executive summary:

The test substance was administered orally by gavage to SPF-Wistar rats over a period of 29 days (a total of 28 applications, 7 days a week) at dose levels of 0.62.5.250 or 1000 mg kg body weight. Behavior and general state of health were examined in all study groups. Body weights and food consumption were recorded twice a week, water consumption once weekly.

Hematology, clinical chemistry and urinalysis were performed at study end. During necropsy the animals were examined for macroscopically visible abnormalities, the main organs were weighed and the organ to body weight ratios calculated. Relevant organs of the animals were processed for histopathological examination and checked for microscopically visible changes.

Body weights, hematological and clinical chemistry data, albumin and globulin values, urine data (pH-value and specific weight) as well as the absolute and relative organ weights were analyzed with the aid of a statistical program to show differences compared to control groups.

 

Behavior, general state of health, body weight development as well as food and water consumption remained unaffected by the administration of the test compound. Feces of animals of the 1000 mg/kg test group were red discolored, beginning with day 6.

There was no evidence for compound-related toxicity in hematology and clinical chemistry. Urine was red-brown discolored in all animals of the 1000 mg/kg test group.

Evaluation of absolute and relative organ weights showed no compound-related effects.

Necropsy revealed red discoloration of the kidneys in all animals of the 1000 mg/kg test group. Additionally, the testes of the male animals were red discolored. Vacuolization of the epithelial cells of the renal cortex was microscopically observed in two female animals of this test group which are considered to be a result of an increased re-absorption and subsequent deposition of the test compound.

Summarizing, the 29-day oral administration of the test substance at a dose of 1000 mg/kg body weight/day resulted in two female animals in microsopic renal findings as described above. There was no evidence in clinical chemistry and histopathology of an adverse effect on the renal function. The administration of the test compound in a dose of 1000 mg/kg body weight/day did not induce any evident relevant compound-related changes in male animals. The NOAEL was therefore considered to be 1000 mg/kg bw/day.