Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
20-Jan-1992 to 13-May-1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: OECD and GLP compliant.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report Date:
1992

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
other: This study was performed according to a Solvay Duphar standard operating procedure TDS 032
Deviations:
yes
Remarks:
Temperature was lower on three days of the study but not lower than 18 degrees celsius. There was a power failure on one day before the last day of the study. None of these deviations are considered to have affected the integrity of the study.
Qualifier:
according to
Guideline:
other: EEC directive, 84-449, Annex V, Part B3.
GLP compliance:
yes (incl. certificate)
Test type:
other: Single dermal dose of 2000 mg/kg
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: Solid

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Test animals
SPF-derived Hsd/Cpb:WU Wistar rats were obtained from Harlan/CPB, Zeist, The Netherlands. Male rats weighed 175-200 g and females 150-175 g at arrival.

Animal care
The rats were housed continuously in Macrolon cages with two or three animals per cage, except for the application period; then the rats were caged alone. The rats had free access to food (a standard laboratory diet RHM-TM, Hope Farms, Woerden, The Netherlands). Water was available ad libitum. The acclimatisation period was 5 days. Animals were housed in room no. 408, CDA IV, with the following animal room conditions:
Temperature
Relative humidity
Artificial light
18-25°C;
48-70%;
from 7 a.m. till 7 p.m.;
24 hours per day;
Radio-sound
Ventilation
approximately 16 air changes per hour.

Administration / exposure

Type of coverage:
occlusive
Vehicle:
other: suspended in a 1.25% tragacanth solution in distilled water
Details on dermal exposure:
The test procedure used was in accordance with EEC-Directive 84-449, Annex V, Part B3. The animals were individually identified by means of a dye marking system on the fur. The day before the application of the compound , the hair from the back and flanks of male and female rats was removed with an electric clipper. Animals with obvious skin lesions were not used. From the test material suspension, aliquots with a volume of 8 ml/kg body weight were taken, equivalent to 2000 mg/kg, and were uniformly applied over a strip of gauze of about 15 cm2. The gauze was covered with an occlusive Blenderm tape of about 5 x 10 cm, on a wider strip of plaster. The total patch with test material was applied on the back and flanks of each animal and held in place with strips of plaster.

To prevent damaging of the patches, the rats were fitted with collars during the application period. After 24 hours, the collars were removed and the gauze patches were peeled off under light ether anaesthesia. The skin was wiped to remove any remaining test substance.
Duration of exposure:
The rats were observed at 1, 3, 4, 24 and 28 hours after application and thereafter once on each day till the end of the experiment. Any sign of intoxication which could be ascertained by observation and manipulation of the rats during the 14-day observation period was recorded.
Doses:
A single dermal dose of 2000 mg/kg.
No. of animals per sex per dose:
5/sex/group
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days

Clinical signs
The rats were observed at 1, 3, 4, 24 and 28 hours after application and thereafter once on each day till the end of the experiment. Any sign of intoxication which could be ascertained by observation and manipulation of the rats during the 14-day observation period was recorded.

Body weights
The rats were weighed one day before dosing (day -1), at the day of dosing prior to dose administration (day 0), and at 2, 7 and 14 days after treatment.

Autopsy
At-the end of the experiment, the rats were killed by ether inhalation and an autopsy was performed that included inspection of the external appearance, the cervical area, the thoracic and abdominal cavities.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Since none of the rats died within the 14-day observation period, the acute dermal Lo50 was established to be greater than 2000 mg/kg in male and female rats.
Mortality:
None of the rats died during the application or observation period.
Clinical signs:
During the application period, chromodacryorrhoea and dirty noses were noticed from 1 hour after start of the application up to 24 hours after treatment in both males and females. Upon removal of the collars, these signs disappeared. No further symptoms were observed.
Body weight:
Male and female rats gained normal weights one day prior to dosing. Upon exposure to a single dermal dose of 2000 mg/kg of retroketal, females lost some weight during the first few days after treatment. Thereafter, growth was normal.
Gross pathology:
3 female rats showed a dilated uterus. No abnormalities were noted for the other female and all male rats. Dilatation of the uterus is considered to be a physiological process within the oestrus cycle, which is routinely noticed in approximately 1 out of 5 female animals. Therefore, this finding was considered to be not treatment-related.
Other findings:
During the application period, when the rats were wearing collars, chromodacryorrhoea and dirty noses were noticed in males and females. The production of red tears is a normal physiological phenomenon, but is not always noticed due to grooming. In the present study normal grooming behaviour was hindered during the application period by the collars fitted around the neck of the rats. Therefore, chromodacryorrhoea and dirty noses are not considered to be treatment-related signs.

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Dermal administration of a single dose of 2000 mg/kg of retroketal caused no mortalities among male and female rats during the 14-day observation period.

Only female rats treated with a dermal dose of 2000 mg/kg of retroketal lost some weight in the first few days after treatment. The transient weight loss observed in this study is considered to be a consequence of the study design rather than the test material. Body weight-gains of female rats were normal after the second day of the observation period.

Autopsy of the male and females rats at the end of the observation period did not reveal any macroscopic abnormality, that was considered treatment-related.