Registration Dossier

Administrative data

Description of key information

Summary of repeat-dose data

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals 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
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Preparation: daily
- Concentration in vehicle: 1.25, 5, 20% (w/v)
- Amount of vehicle (if gavage): 5 ml/kg
Details on analytical verification of doses or concentrations:
Test substance preparation was done daily and correct preparation verified by weighing documentation
Duration of treatment / exposure:
Test duration: 28 days
Frequency of treatment:
Dosing regime: 7 days/week
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
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

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 27/28
- 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:
Body weight and body weight gain, clinical pathology, absolute and relative organ weights, urinalysis
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):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
The feces of all test substance-treated animals was bue discolored from Day 4 onwards.
Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food efficiency
haematology
clinical biochemistry
urinalysis
behaviour (functional findings)
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
Critical effects observed:
no
Conclusions:
The oral administration of the test substance at dose levels of 62.5, 250, and 1000 mg/kg body weight/day did not result in any test substance-related toxicity. Consequently, the "no toxic effect level" was considered to be 1000 mg/kg bw/day or above.
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.

There was no evidence for compound-related toxicity in hematology and clinical chemistry. Urine was red to red-brown discolored in all animals of the 250 and 1000 mg/kg test groups.

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

Macroscopic and microscopic examination revealed no test compound-related adverse effects.

Summarizing, the 29-day oral administration of Reaktiv- Blau F-64 357 FW at dose levels of 62.5, 250, and 1000 mg/kg body weight/day did not result in any test substance-related toxicity. Consequently, the "no toxic effect level" was considered to be 1000 mg/kg bw/day or above.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Guideline study

Additional information

10 male and 10 female mixed-breed healthy albino rats with a body weight range of 100 - 130 g at study start were used in a 21 -day study with 14 oral administrations. The animals were housed separated by sex in groups of 5 animals per cage. The test substance, Remazolbrillantblau R was administered in aqueous solution 14-times within 21 days by gavage at a dose level of 500 mg/kg bw.

All animals were weighed weekly and in 5 animals/sex, the urine and blood was analysed at start and end of the study. There was a 5-day recovery period at the end of the study prior to necropsy.

Body weight gains were slightly retarded in the 500 mg/kg bw group when compared to control animals. There were no changes in behaviour in substance-treated animals. There were no haematological changes. Urinalysis showed a slightly increased protein excretion. The dye was excreted via feces and urine. At necropsy, no macroscopic changes were observed. Histopathologically, substance-related changes in the kidneys were observed, however these changes were assessed not to be adverse effects.

The No Observed Effect Level is 500 mg/kg bw/day.

Reaktiv-Blau F-64 357 FW 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.

There was no evidence for compound-related toxicity in hematology and clinical chemistry. Urine was red to red-brown discolored in all animals of the 250 and 1000 mg/kg test groups.

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

Macroscopic and microscopic examination revealed no test compound-related adverse effects.

Summarizing, the 29-day oral administration of Reaktiv-Blau F-64 357 FWat dose levels of 62.5, 250, and 1000 mg/kg body weight/day did not result in any test substance-related toxicity. Consequently, the "no toxic effect level" was considered to be 1000 mg/kg bw/day or above.

Justification for classification or non-classification

No classification necessary