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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From JAN 1974 to APR 1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given, comparable to standards; restrictions: e.g. no data on clinical biochemistry, haematology, urine analysis
Cross-reference
Reason / purpose:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1980
Report Date:
1980
Reference Type:
publication
Title:
Carcinogenicity studies on different diarylide yellow pigments in mice and rats
Author:
Leuschner F
Year:
1978
Bibliographic source:
Toxicology Letters 2: 253-260
Report Date:
1978

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: OECD Guideline 451 (Carcinogenicity Studies)
Deviations:
not applicable
Remarks:
The study was performed to test carcinogenicity of the test item. That's the reason why some details usually requested in a repeated dose toxicity study (e.g. data on clinical biochemistry, haematology) are missing.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: S. IVANOVAS GmbH & Co, Med. Versuchstierzucht KG (Kissleg, Germany)
- Age at study initiation: 38 (males) -42 (females) days
- Weight at study initiation: 100 - 109 g
- Housing: in groups of 2 or 3 animals in Macrolon cages (Type III)
- Diet: Altromin 1321 (Altromin, Lage), ad libitum
- Water: tap water, ad libitum
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 +/- 0.5
- Humidity (%): 60 +/- 3
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
1000, 3000, 9000 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
50
Control animals:
yes, plain diet
Positive control:
none

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice per day


DETAILED CLINICAL OBSERVATIONS: No


BODY WEIGHT: Yes
- Time schedule for examinations: weekly


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: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: 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 AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: daily


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: once, immediately before sacrifice
- Dose groups that were examined: all animals


HAEMATOLOGY: No


CLINICAL CHEMISTRY: No

URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No


OTHER:
at the end of the exposure period the following investigations were performed:
- audiometry (using a simple sound test)
- inspection of denture
- organ weights of 7-8 organs (heart, liver, lungs, spleen, kidney, thymus, brain, testis)
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (animals of the control and highest dose group; paraffin sections, Haematoxylin-Eosin staining):
heart, lung, liver (additionally: frozen sections with Sudan staining), kidney, spleen, adrenal, thymus, pituitary, brain, gonads, thyroid, prostate/uterus, seminal vesicle/mammary gland, stomach, duodenum, colon, salivary gland, lymph nodes, eye and optic nerve, urinary bladder, bone marrow, neoplastic lesions, bones
- histopathological investigations of animals of the lower dose groups were performed, if they died or were sacrificed in the meantime and revealed macroscopic findings
Statistics:
- variance analysis according to Peto
- Student's t-test

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:
no effects observed
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
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

Effect levels

Dose descriptor:
NOAEL
Effect level:
9 000 mg/kg diet
Sex:
male/female
Basis for effect level:
other: no substance related toxicity or carcinogenicity was observed; 9000 mg/kg diet (ppm) correspond to 533.1 mg/kg bw/day and 523.0 mg/kg bw/day in male and female rats, respectively (calculated in the study report on basis of food consumption)

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

 - no effects on behaviour, appearance, faeces, feed and drinking water uptake, eyes, hearing, dentition, mortality, body weight development

- no substance induced macroscopic or histological changes

- no substance related effects on the tumour incidence

- 1000, 3000, 9000 ppm in diet correspond to 58, 174, 533 mg/kg bw/day in male and 59, 180, 523 mg/kg bw/day in female rats, respectively

 - no 3,3'-dichlorobenzidine was detected in the urine samples (limit of detection: 3 µg/10 ml urine; 0.3 ppm)

Applicant's summary and conclusion

Conclusions:
Chronic feeding of Sprague Dawley rats with up to 9000 ppm of the test item in diet did not cause any adverse effect. The NOAEL in this study was 9000 ppm in diet (corresponding to 533.1 mg/kg bw/da and 523.0 mg/kg bw/day in male and female rats, respectively).
Executive summary:

Sprague Dawley rats (50 per sex per dose) were exposed to 1000, 3000, 9000 ppm of the test item in diet (corresponding to 58, 174, 533 mg/kg bw/day and 59, 180, 523 mg/kg bw/day in male and female rats, respectively) for 104 weeks. The test item did neither induce toxicity nor tumorigenicity. The NOAEL in this study was 9000 ppm in diet.