Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1989
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: according GLP and guideline, purity of the test article not documented

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989
Report Date:
1988

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)BR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd., Margate
- Age at study initiation: 4 weeks
- Weight at study initiation: male 156 - 188g, female 108-141g
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 12 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 40-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5%
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): daily
- Storage temperature of food: stored in brown glass bottles and stored at ambient temperature

VEHICLE
The control article and vehicle for the test article was 0.5% (w/v) aqueous methylcel lulose.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysis of test formulations
The analyses detailed below were carried out.

Stability and homogeneity
Stability and homogeneity were determined at HUK.

Achieved concentration
Analysis of achieved concentration was performed at HUK on samples formulated in weeks 1 and 3.
Duration of treatment / exposure:
28d
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 300, 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The following dose levels were selected by the sponsor on the basis of an LD50 study performed by the client
Positive control:
no

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: day 1, weekly intervall

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: Yes

HAEMATOLOGY: Yes
- Time schedule for collection of blood: week 4
- Anaesthetic used for blood collection: Yes
- Animals fasted: Yes
- How many animals: all

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: week 4
- Animals fasted: Yes
- How many animals: all

URINALYSIS: Yes
- Time schedule for collection of urine: week 4 and week 7
- Metabolism cages used for collection of urine: No data
- Animals fasted: Yes

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
adrenals brain
kidneys liver
testes pancreas
ovaries seminal vesicles

HISTOPATHOLOGY: Yes
adrenals brain (including brain stem)
eyes (with optic nerves) femur (bone marrow)
heart kidneys
liver lungs (with mainstem bronchi)
ovaries pancreas
pituitary seminal vesicles
spleen stomach
testes thyroids (with parathyroids)
urinary bladder all gross lesions
Statistics:
Data were processed, where appropriate, to give group mean values and standard deviations.
Some tables and appendices presented in the report are computer generated.
For each parameter, the analysis was performed using a two way analysis of variance (ANOVA). Where differences were found at the 5% level of significance each treated group was compared against the control group for the given sex, using the t-test.
For haematology and clinical chemistry parameters, parametric or non-parametric methods were used where appropriate. Where ANOVA could not be performed because of variance heterogeneity, the Kruskal-Wallis test was carried out for each sex; where this was significant at the 5% level of significance, pairwise Wilcoxon Rank Sum tests were performed to compare each treated group with the control group.

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:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis 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
Details on results:
Pink faeces characteristic of the test article were noted for all treated groups from day 2 of dosing and throughout the treatment period. The pink colouration was not observed from day 2 of the treatment-free phase.

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion