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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given: comparable to guidelines/standards
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1978
Report date:
1978

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Reference substance name:
4,4'-bis[4-[bis(2-hydroxyethyl)amino]-6-anilino-1,3,5-triazin-2-yl]amino]stilbene-2,2'-disulphonic acid
EC Number:
224-548-7
EC Name:
4,4'-bis[4-[bis(2-hydroxyethyl)amino]-6-anilino-1,3,5-triazin-2-yl]amino]stilbene-2,2'-disulphonic acid
Cas Number:
4404-43-7
IUPAC Name:
2,2'-ethene-1,2-diylbis[5-({4-anilino-6-[bis(2-hydroxyethyl)amino]-1,3,5-triazin-2-yl}amino)benzenesulfonic acid]
Details on test material:
- Analytical purity: 89.1%

Test animals

Species:
rat
Strain:
other: Wistar II
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Winkelmann, Borchen, Germany
- Age at study initiation: 28 - 32 days
- Weight at study initiation: mean: males: 54 g, females: 53 g
- Fasting period before study:
- Housing: single
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): once weekly
- Mixing appropriate amounts with (Type of food): Altromin R-Pulver feed (Altromin GmbH, Lage, Germany)
- Storage temperature of food: no data
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
24 months
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 1000, 10000 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
50
Control animals:
yes, plain diet

Examinations

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

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly until 27th week, afterwards every 14 days

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
- 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

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 1, 3, 6, 12 and 24 months after start of feeding study
- Anaesthetic used for blood collection: Yes (identity): ether
- Animals fasted: No data
- How many animals: 5 per sex and group, at the end 10 per sex and group
(number of erythrocytes, thrombocytes and leucocytes, reticulocytes, heamoglobin, haematocrit, MCH, MCV, thromboplastin time)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 1, 3, 6, 12 and 24 months after start of feeding study
- Animals fasted: No data
- How many animals: 5 per sex and group, at the end 10 per sex and group
(ALP, GOT, GPT, GlDH, creatinin, urea, blood glucose, cholesterin, bilirubin, protein)

URINALYSIS: Yes
- Time schedule for collection of urine: 1, 3, 6, 12 and 24 months after start of feeding study
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
(glucose, blood, protein, pH, keton, bilirubin, urobilinogen, sediment,)

NEUROBEHAVIOURAL EXAMINATION: No

OTHER FINDINGS: tumors
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Organ weights: thyroid, heart, lung, liver, spleen, kidney, adrenal, testes, ovaries
HISTOPATHOLOGY: Yes
(aorta, eyes, duodenum, jejunum, ileum, colon), femur, brain, urin bladder, heart, testes, pituitary gland, liver, lung, lymph nodes, stomach, spleen, adrenals, kidney, epididymis, N. ischiadicus, oesophagus, parotid gland, ovaries, pancreas, prostata, seminal vesicle, thyroid, skeletal muscels, sternum, trachea, uterus, as well as all macroscopic changes).
Statistics:
Mann-Whitney test, Wilcoxon test, Exact Fisher-test

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY were not affected by the test substance in all groups.

BODY WEIGHT AND WEIGHT GAIN: The body weight was transiently reduced in male animals at the dose of 10000 ppm

HAEMATOLOGY: The blood was not affected in all groups.

CLINICAL CHEMISTRY: No abnormal observations were detected.

URINALYSIS: No abnormal observations were detected.

ORGAN WEIGHTS: No abnormal observations were detected.

GROSS PATHOLOGY: No abnormal observations were detected.

HISTOPATHOLOGY: No abnormal observations were detected.

OTHER FINDINGS: Looking at type, localisation and frequency of found tumor there was no evidence of a cancerogenic activity of the test substance.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
10 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects, maximal tested dose
Dose descriptor:
NOAEL
Effect level:
542 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: overall effects, maximal tested dose
Dose descriptor:
NOAEL
Effect level:
779 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: overall effects, maximal tested dose
Dose descriptor:
NOEL
Effect level:
1 000 ppm
Based on:
test mat.
Sex:
male
Basis for effect level:
other: body weight at 10000ppm transiently reduced
Dose descriptor:
NOEL
Effect level:
10 000 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: maximal tested dose; overall effects

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion