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Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 19 FEB 1979 to 03 APR 1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: basic data given, comparable to guideline

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1979
Report date:
1979
Reference Type:
publication
Title:
Subacute Toxicity Studies of Selected Organic Colorants.
Author:
Leist KH
Year:
1982
Bibliographic source:
Ecotoxicology and Environmental Safety 6: 457-463
Report date:
1982

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
not applicable
GLP compliance:
no
Remarks:
study was performed previous to GLP implementation
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
2-[(4-methyl-2-nitrophenyl)azo]-3-oxo-N-phenylbutyramide
EC Number:
219-730-8
EC Name:
2-[(4-methyl-2-nitrophenyl)azo]-3-oxo-N-phenylbutyramide
Cas Number:
2512-29-0
Molecular formula:
C17H16N4O4
IUPAC Name:
2-[(4-methyl-2-nitrophenyl)diazenyl]-3-oxo-N-phenylbutanamide
Test material form:
solid: nanoform, no surface treatment

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Strain: WISKf (SPF 71)
- Source: in house breeding; Hoechst, breeding colony, Hattersheim
- Weight at study initiation: males: 73.8 +/- 2.29 g (69 g - 79 g); females: 73.6 +/- 2.41 g (69 g - 78 g)
- Fasting period before study: no
- Housing: 5 animals/sex/cage
- Diet: Standard diet Altromin 1324 (Altromin GmbH, Lage, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-28
- Humidity (%): 25-50


Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: suspension in starch mucilage
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
- the test item suspension was freshly prepared every day before dosing
- 10% test item suspension in 2% starch mucilage, which was permanently stirred during the dosing procedure
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
30 days
Frequency of treatment:
daily except on weekends, i.e. 22 doses over a period of 30 days
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 1000 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
20
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: no lethality and no signs of toxicity were observed after single oral application of 5000 mg/kg bw
Positive control:
none

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: one week before the first treatment, on the days of treatment, and two times per week (monday and thursday) during the recovery period

FOOD CONSUMPTION AND COMPOUND INTAKE (no feeding study): Yes
- Food consumption for each animal determined: Yes
- mean daily diet consumption calculated as % body weight: Yes

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: Yes

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: weekly
- Dose groups that were examined: all

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the treatment period and at the end of the recovery period
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 5 males and 5 females of each groupd
- Parameters examined: hematocrit, hemoglobin, erythrocytes count, total and differential leucocyte counts, median cell volume, median cell hemoglobin, platelet count, prothrombin time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the treatment period and at the end of the recovery period
- Animals fasted: No data
- How many animals: 5 males and 5 females of each group
- Parameters examined: serum alkaline phosphatase (SAP), serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT)

URINALYSIS: Yes
- Time schedule for collection of urine: at the end of the treatment period
- Metabolism cages used for collection of urine: yes
- Animals fasted: yes
- Parameters examined: appearance, colour, protein, glucose, hemoglobin, bilirubin, pH-value, sediment


NEUROBEHAVIOURAL EXAMINATION: No
- weekly examinations for neurologic disturbances

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (liver, spleen, adrenals, kidney)
Other examinations:
ORGAN WEIGHTS:
- liver, spleen, adrenals, kidney

Results and discussion

Results of examinations

Clinical signs:
no effects observed
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):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
SGPT: statistically significant decrease in females, fully reversible during the recovery period, no histopathological findings, therefore not regarded to be adverse
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:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
- no effects

BODY WEIGHT AND WEIGHT GAIN
- no differences between treated animals and controls

FOOD CONSUMPTION
-no effects

WATER CONSUMPTION
- no effects

OPHTHALMOSCOPIC EXAMINATION
- not examined

CLINICAL CHEMISTRY
- SGPT statistically significantly decreased in females at the end of the treatment period, effects were fully reversible at the end of the recovery period; these effects were not regarded to be adverse as no histopathological findings were observed
- no effects in males or on other endpoints in females

HAEMATOLOGY
- no pathological findings

URINALYSIS
- no effects
- no discolouration of the urine observable

NEUROBEHAVIOUR
- no neurologic disturbances

ORGAN WEIGHTS
- no effects

GROSS PATHOLOGY
- no effects

HISTOPATHOLOGY: NON-NEOPLASTIC
- no effects

Effect levels

Key result
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:
other:
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity

Key result
Critical effects observed:
not specified

Any other information on results incl. tables

The test item was excreted via faeces but not via urine (no discolouration of the urine).

Applicant's summary and conclusion

Conclusions:
The test item did not reveal any substance related toxic effects under the conditions tested. The NOAEL in this subacute oral study was 1000 mg/kg bw in male and female rats.
Executive summary:
Male and female Wistar rats (20 animals per sex and dose group) received 22 daily oral (gavage) doses of 0 or 1000 mg test item per kg bw over a period of 30 days and were partially (10 animals per sex and dose group) observed for another 14 days without treatment.

Cage side observations, food consumption, body weight development, haematology, clinical biochemistry, urine analysis, macroscopic investigations, organ weights and histopathology of selected organs did not reveal any substance related toxic effects. The NOAEL in this study was 1000 mg/kg bw.

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