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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
Study period:
1991-05-08 to 1991-05-09
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report date:
1991

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Test material form:
solid: particulate/powder
Details on test material:
Direct Red 83:1

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
The rat was selected for this study as it is a readily available rodent species historically used in safety evaluation studier and is acceptable to appropriate regulatory authorities.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Sprague-Dawley CD Strain rats
- Age at study initiation: 5 to 8 weeks
- Weight at study initiation: will not exceed ±20% of the mean weight.
- Fasting period before study:
- Housing: Groups of five by sex in polypropylene cages with stainless steel lids and grid bases suspended over trays containing absorbent paper.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C):19-25
- Humidity (%):40-75
- Air changes (per hr): at least 15 air changes/h
- Photoperiod (hrs dark / hrs light): 12 hours of continuous artificial light in each 24 hours period.

IN-LIFE DATES: From: 1991-05-08 to 1991-05-09

Administration / exposure

Route of administration:
oral: gavage
Details on route of administration:
The oral route was selected as a possible route of human exposure and the results of the study are believed to be of value in predicting the likely toxicity of the test material to man.
Vehicle:
water
Remarks:
Distilled water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The test material was prepared at the appropriate concentrations, as a solution/suspension in distilled water.
The stability and homogeneity of the test material formulations were determined and show the formulation to be stable for at least 9 days.
Formulations were therefore prepared weekly and stored at 4°C in the dark.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were taken of each test material formulation and were analysed for concentration of Direct Red 83:1 using aspectrophotometric procedure.
The results indicate that the prepared formulations were within ± 10% of the nominal concentration.

Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
The dose levels were chosen based an the results of a range-finding study.
Dose / conc.:
150 mg/kg bw/day (nominal)
Dose / conc.:
15 mg/kg bw/day (nominal)
No. of animals per sex per dose:
5 males/5 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels were chosen based an the results of a range-finding study.
- Rationale for animal assignment (if not random): random
- Fasting period before blood sampling for clinical biochemistry: Animals were not fasted prior to sampling.
- Rationale for selecting satellite groups: NA
Positive control:
not required

Examinations

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

BODY WEIGHT: Yes Individual bodyweights recorded on the day before the start of dosing (day 0) and at weekly intervals thereafter.
- Time schedule for examinations: 0 day to weekly interval

FOOD CONSUMPTION: Diet intake recorded weekly for each cage group.


WATER CONSUMPTION: Yes, monitored daily by visual inspection of water bottles. Measurement will be initiated, if a treatment related effect is suspected, at the discretion of the study director.
- Time schedule for examinations: daily

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the end of the treatment period
- Anaesthetic used for blood collection: Yes (identity) Halothane B.P. anesthesia
- Animals fasted: No data
- How many animals: all animals from group 1 to 4


URINALYSIS: Yes
Urine samples collected from all animals in groups 1 to 4 during the final week of the study by housing overnight in metabolism cages under normal hydration but without access to food. Urinalysis will be performed on satellite group animals where abnormalities are detected in the main study.
Sacrifice and pathology:
HISTOPATHOLOGY: Initially the following tissues were examined microscopically from:
a) all animals that die during the study
b) all animals in the control and high dose groups (group 1 and 4)
Heart Adrenals
Liver Target organ
Spleen Gross lesions
Kidneys Testes
These examinations were extended to animals of other dose groups including satellite groups.
Other examinations:
Hematological, blood chemical and organ weight data will be assessed using one way analysis of variance incorporating "F-max"
Statistics:
Variance incorporating "F-max" test for homogeneity variance.
The organ weights will be expressed as percentage of final bodyweight. Other statistical analyses such as students "t" test, analysis of covariance, Kruskal-Wallis analysis and Mann-Whitney "u" test may be performed if necessary.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
There were no treatment-related deaths during the study although one high dose male died during the blood sampling procedure.
Mortality:
no mortality observed
Description (incidence):
There were no treatment-related deaths during the study although one high dose male died during the blood sampling procedure.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Bodyweight gains in test animal were comparable with those seen in controls.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No adverse effect on food consumption or weekly food efficiency was detected during the study.
Food efficiency:
no effects observed
Description (incidence and severity):
No adverse effect on weekly food efficiency was detected during the study.
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
No overt intergroup differences were detected.
Ophthalmological findings:
not examined
Description (incidence and severity):
No data avalaible
Haematological findings:
no effects observed
Description (incidence and severity):
No treatment-related effects were detected
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No treatment-related effect were detected
Urinalysis findings:
no effects observed
Description (incidence and severity):
No treatment-related effect were detected
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No treatment-related effect were detected
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No treatment-related effects were detected
Histopathological findings: neoplastic:
not examined
Description (incidence and severity):
not applicable
Details on results:
CLINICAL SIGNS AND MORTALITY No clinically observable signs of toxicity were detected in test or control animals throughout the study period.

BODY WEIGHT AND WEIGHT GAIN: Bodyweight gains in test animals were comparable with those seen in controls.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study) No adverse effect on food consumption.

FOOD EFFICIENCY: no weekly food efficiency was detected during the study.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No overt intergroup differences were detected.


HAEMATOLOGY No treatment-related effects were detected

CLINICAL CHEMISTRY: No treatment-related effects were detected

URINALYSIS: No treatment-related effects were detected

NEUROBEHAVIOUR: no data available

ORGAN WEIGHTS: No treatment-related effects were detected



HISTOPATHOLOGY: NON-NEOPLASTIC: No treatment-related effects were detected


OTHER FINDINGS
Necropsy: No treatment-related effects were detected.

Effect levels

Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity

Critical effects observed:
no

Any other information on results incl. tables

Week Food efficiency * -Females

 Group number  Dose level (mg/kg/day)   Food efficiency during Week  1       2 3 4
 1 0 (control)   0.22  0.19  0.13  0.10
 2  15  0.22  0.19 0.14   0.12
 3  150  0.26  0.18  0.11  0.11
 4  1000  0.22  0.20  0.12  0.08

*Food Efficiency= Change in Mean Bodyweight (g) / Food consumption (g/rat/week)

Week Food efficiency -Males

 Group number  Dose level (mg/kg/day)   Food efficiency during Week   1        2 3 4
 1 0 (control)   0.31  0.26  0.22  0.13
 2  15  0.31  0.27 0.21  0.15
 3  150  0.32  0.27  0.22  0.17
 4  1000  0.32  0.27  0.21  0.16

Homogeneity of test material formulations

Nominal concentration (mg/L)  Sampling location  Concentration found (mg/mL)1 2 3 Mean 
 1  Top Middle Bottom 0.831 0.842 0.840 0.847 0.830 0.849 0.853 0.855 0.853 0.844 0.842 0.847
 5  Top Middle Bottom 4.48 4.45 4.44  4.44 4.50 4.52  4.52 4.55 4.56  4.48 4.50 4.51 
 25  Top Middle Bottom 23.0 23.2 23.3  23.1  22.4 22.9 23.1 23.3 22.5  23.1 23.0 22.9 
 100 Top Middle Bottom  92.8 92.9 91.6  94.2 91.4 92.2  93.6 92.9 93.0  93.5 92.4 92.3 

Stability of test material formulations

Nominal concentration (mg/L)  Concentration found initially Concentration found after Storage for 9 days(mg/mL) (expressed as % of initial)
 1  0.844 0.872 103
 5  4.50 4.46 99  
 25  23.0 22.8 99
 100 92.7 90.8  98

       

Applicant's summary and conclusion

Conclusions:
Oral administration of the test material to rats for a period of twenty-eight consecutive days by gavage, at dose levels of up to 1000 mg/kg/day did not result in any toxicologically significant changes. The no observed effect level (NOEL) is, therefore, considered to be 1000 mg/kg/day.
Executive summary:

Oral administration of the test material to rats for a period of twenty-eight consecutive days by gavage, at dose levels of up to 1000 mg/kg/day did not result in any toxicologically significant changes. The no observed effect level (NOEL) is, therefore, considered to be 1000 mg/kg/day.