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Diss Factsheets

Toxicological information

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
read across substance

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report date:
2002

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Version / remarks:
(adopted 27th July 1995)
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Version / remarks:
(adopted 3rd October 2008)
Deviations:
yes
Remarks:
no testing of the endocrine system
Qualifier:
according to guideline
Guideline:
other: 96/54/EEC of September 30, 1996, Part B, 1996
Qualifier:
according to guideline
Guideline:
other: Japan/MHW 1987
GLP compliance:
yes (incl. QA statement)
Remarks:
testing lab.
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Disodium 4,5-dichloro-2-[[4,5-dihydro-3-methyl-5-oxo-1-(3-sulphonatophenyl)-1H-pyrazol-4-yl]azo]benzenesulphonate
EC Number:
265-633-9
EC Name:
Disodium 4,5-dichloro-2-[[4,5-dihydro-3-methyl-5-oxo-1-(3-sulphonatophenyl)-1H-pyrazol-4-yl]azo]benzenesulphonate
Cas Number:
65212-76-2
Molecular formula:
C16H12Cl2N4O7S2.2Na
IUPAC Name:
disodium 4,5-dichloro-2-{[3-methyl-5-oxo-1-(3-sulfonatophenyl)-4,5-dihydro-1H-pyrazol-4-yl]diazenyl}benzenesulfonate

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
breeder: Charles River, Sulzfeld, Germany
age: 36 +/- 1 days
body weight: app. 153 g male, 126 g female
acclimatization period: 5d
The rats were housed singly in a fully air-conditioned room.
Central air-conditioning guaranteed a range of 20 - 24°C for temperature and of 30 - 70% for relative humidity.
The day/night rhythm was 12 hours (12 hours light from 06.00 a.m. - 06.00 p.m., 12 hours dark from 06.00 p.m. - 06.00 a.m.).
Food and drinking water (from water bottles) were available ad libitum.

in life data: start 2002-01-29 until: 2002-03-19

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
The test substance was weighed out and thoroughly mixed with a small amount of food. Then corresponding amounts of food were added to this premix in order to obtain the desired concentration, and mixing was carried out for 10 minutes in a laboratory mixer. The mixtures were prepared weekly and kept cold (+4°C). The food was changed twice a week.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The stability of the test substance in the diet was demonstrated over a period of up to 4 days at room temperature and up to 4 days in the refrigerator. As the mixtures were stored no longer than this time period, the stability was guaranteed.
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
1 500 ppm
Remarks:
corresponding to 142.3 mg/kg bw/day and 153.3 mg/kg bw/day in males and females, respectively.
Dose / conc.:
5 000 ppm
Remarks:
corresponding to 478.5 mg/kg bw/day and 529.9 mg/kg bw/day in males and females, respectively.
Dose / conc.:
15 000 ppm
Remarks:
corresponding to 1462.9 mg/kg bw/day and 1552.1 mg/kg bw/day in males and females, respectively.
No. of animals per sex per dose:
Control group: 10 animals per sex
1500 and 5000 ppm groups: 5 animals per sex
15000 ppm group: 10 animal per sex
Control animals:
yes, plain diet
Details on study design:
In a test study the test item was administered to groups of 3 male and 3 female Wistar rats at dose levels of 1000, 5000 and 15000 ppm for 2 weeks. Food consumption, water consumption, body weight and clinical signs were recorded. As no substance-related findings or signs of toxicity were observed, the following dose levels were selected for the present study: 15000 ppm as high concentration; this concentration results in an test substance intake of at least 1,000 mg/kg body weight/day which is the highest dose to be tested for non-toxic test substances in a 'limit test'; 5000 ppm: as mid dose and 1500 ppm: as low dose.
The oral route was selected since this was proven to be suitable for the detection of a toxicological hazard.
Positive control:
no

Examinations

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

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD EFFICIENCY:
- Food consumption was determined weekly over a period of 4 days and calculated as mean food consumption in grams per animal and day


HAEMATOLOGY: Yes
- Time schedule for collection of blood: day 29
- Anaesthetic used for blood collection: No
- Animals fasted: Yes
- How many animals: all

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: day 29
- Animals fasted: Yes
- How many animals: all

URINALYSIS: Yes
- Time schedule for collection of urine: day 29
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: end of the treatment period
- Dose groups that were examined: all animals
- Battery of functions tested: home cage observations, sensory activity, motor activity, open field
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Statistics of clinical pathology
Means and standard deviations of each test group were calculated for several parameters.
Further statistical analyses were performed for:
(1) CIinical pathology parameters, except differential blood count: Non-parametric one-way analysis using KRUSKAL-WALLIS test (two-sided). If the resulting p-value was equal or less than 0.05, a pairwise comparison of each dose group with the control group was performed using Wilcoxon-test (two-sided) for the equal medians.
(2) Urinalysis, except volume, colour, turbidity and specific gravity.

Statistics of pathology
Non-parametric one-way analysis using KRUSKAL-WALLIS test (two-sided). If the resulting p-value was equal or less than 0.05, a pairwise comparison of each dose group with the control group was performed using the WILCOXON test for the hyphothesis of equal medians.
For the animals of the recovery group: Pairwise comparison of each dose group with the control group was performed using the WILCOXON test (two-sided) for the hypothesis of equal medians.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
yellow discoloration of faeces
Mortality:
no mortality observed
Description (incidence):
yellow discoloration of faeces
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
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
Details on results:
In summary:
15,000 ppm (1462.9 mg/kg bw/d in males; 1552.1 mg/kg bw/d in females): no substance-related toxic effects were obtained in the main as well as recovery groups.
5,000 ppm (478.5 mg/kg bw/d in males; 529.9 mg/kg bw/d in females): no substance-related toxic effects.
1,500 ppm (142.3 mg/kg bw/d in males; 153.3 mg/kg bw/d in females): no substance-related toxic effects.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
15 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Corresponds to the highest dose tested. No adverse effects occured.
Dose descriptor:
NOAEL
Effect level:
1 462.9 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Corresponds to the highest dose tested. No adverse effects occured.
Dose descriptor:
NOAEL
Effect level:
1 552.1 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Corresponds to the highest dose tested. No adverse effects occured.

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion