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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
18 December 1996 - 24 January 1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: done under GLP and OECD method

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997
Report Date:
1997

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Principles of method if other than guideline:
The oral route was selected to accord with a possible route of human exposure. Dosages of 15, 150 and 1000 mg/kg/day were based on results from a preliminary study performed at these laboratories (Schedule No. PER/014
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
A sample ofUK-143,108, weighing approximately 5.1 kg, taken from Batch No. CPI/96/070 was received from the Sponsor on 2 October 1996. A 500 g aliquot of this batch of test material was used for this study. It was a fine white cohesive powder and was 101.3% pure (this information was supplied by the Sponsor). The sample was used as supplied.

Test animals

Species:
rat
Strain:
CD-1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent, England
- Age at study initiation: 6 weeks
- Weight at study initiation:147 g to 197 g
- Fasting period before study: overnight before blood draw
- Housing: Animals were housed inside a barriered rodent facility. Each animal room was kept at positive pressure with respect to the outside by its own supply of filtered fresh air which was passed to atmosphere and not re-circulated.
- Diet (e.g. ad libitum): An expanded rodent diet, RMl (E) SQC (Special Diets Services Ltd., Witham, Essex, England), was available without restriction, except overnight before routine blood sampling.
- Water (e.g. ad libitum): free assess to tap water
- Acclimation period: 9 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C):21°C (acceptable range l 9-25°C
- Humidity (%):acceptable range 40-70%)
- Air changes (per hr):10 air changes per hour
- Photoperiod (hrs dark / hrs light):12/24

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 1% w/v methylcellulose
Details on oral exposure:
Animals received the test material or vehicle control formulations by oral gavage at a volume-dosage of 10 ml/kg bodyweight/day. Stirring was performed before, and maintained throughout, dosing to ensure a satisfactory suspension. All animals were dosed in sequence of cage-number within each group, once each day, seven days a week. The volume administered to each animal was calculated from the bodyweight measured immediately before each administration
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Before treatment commenced the suitability of the proposed mixing procedure, and the stability of the test material in the vehicle, were determined by trial preparations made up as for Day 1 of treatment at concentrations of 1.5 mg/ml and 100 mg/ml
Duration of treatment / exposure:
Test duration: 28 days
Frequency of treatment:
Dosing regime: 7 days/week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 mg/kg
Basis:
other: gavage
Remarks:
Doses / Concentrations:
15mg/kg
Basis:
other: gavage
Remarks:
Doses / Concentrations:
150 mg/kg
Basis:
other: gavage
Remarks:
Doses / Concentrations:
1000 mg/kg
Basis:
other: gavage
No. of animals per sex per dose:
Male: 5 animals at 0 mg/kg bw/day
Male: 5 animals at 15 mg/kg bw/day
Male: 5 animals at 150mg/kg bw/day
Male: 5 animals at 1000mg/kg bw/day

Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 15 mg/kg bw/day
Female: 5 animals at 150 mg/kg bw/day
Female: 5 animals at 1000 mg/kg bw/day
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on acute oral toxicity testing results
- Rationale for animal assignment (if not random):random

Examinations

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

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to exposure and then once a week

BODY WEIGHT: Yes
- Time schedule for examinations: prior to treatment and then weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): mean weekly per cage.
- 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: No data

FOOD Conversion EFFICIENCY: mean weekly

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): visually weekly

HAEMATOLOGY: Yes
- Time schedule for collection of blood: D30
- Anaesthetic used for blood collection: Yes (identity)
- Animals fasted: Yes for 16+2 hours
- How many animals:all animals

OTHER: blood chemistry and coagulation, mortality
Sacrifice and pathology:
On Day 29 all surviving animals were killed by carbon dioxide inhalation. The sequence in which the animals were killed after completion of treatment was selected to allow satisfactory inter-group comparison

GROSS PATHOLOGY: Yes
macroscpic, organ weight and microscopic-standard organs
HISTOPATHOLOGY: Yes
--organs
Statistics:
step 1: homogeneity of intergroup vairance (Bartlett test)
step 2: equality of intergroup means (student t test)
step 3: pair wise comparison of means between the treated group and the control groups ( either Behrans-Fisher Test or Dunnett's Test)

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
One female receiving 15 mg/kg/day (No. 29) was found dead on Day 6 of the treatment period.not attributed to treatment with UK-143,108.
Mortality:
mortality observed, treatment-related
Description (incidence):
One female receiving 15 mg/kg/day (No. 29) was found dead on Day 6 of the treatment period.not attributed to treatment with UK-143,108.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
no clear effect on bodyweight gain in animals receiving UK-143,108, when compared with the Controls
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The food consumption of treated animals was generally similar to that of the Controls throughout the treatment period
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
There were no changes that could be ascribed to treatment with UK-143,108. Inter-group variations which attained statistical significance either lacked dosage­ relationship or were confined to one sex
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Although there were a few statistically significant differences from the Control values, these either lacked dosage-relationship or were confined to one sex
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Bodyweight-relative ovary weights were higher than those of the Controls for females receiving 1000 mg/kg/day largely due to one female (No. 36).
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
There were no findings that were considered to be related to the administration of UK-143,lOS.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
There were no changes associated with treatment with UK-143,108
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
There were no changes associated with treatment with UK-143,108
Details on results:
One female receiving 15 mg/kg/day (No. 29) was found dead on Day 6 of the treatment period. The animal had shown no previous signs; necropsy revealed red fluid in the thorax, red fluid and clotted blood in the abdomen and poorly defined dark areas on the thymus; organ weights were unremarkable. Due to the isolated nature, and its occurrence in the lowest dosage group, this single death is not attributed to treatment with UK-143,108

Effect levels

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

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The oral administration ofUK-143,108 at dosages of 15, 150 or 1000 mg/kg/day for four weeks produced no evidence of toxicity. Hence, according to the Classification Criteria of the Commission of the European Communities, labeling with the R48 Risk
Phase is not required. The no-observed-effect level (NOEL) as identified by this study was
considered to be 1000 mg/kg/day.