Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
10 november 1999 to 23rd November 1999
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2000
Report Date:
2000

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Details on test material:
- Appearance: Off-white powder
- Storage condition of test material: At room temperature protected from light
Specific details on test material used for the study:
Off White Powder, Purity 99.15%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Animals in the main study were in the weight range of 210 to 254 g and approximately eight to eleven weeks of age prior to dosing (Day I). All the rats were acclimatised to the experimental environment for a minimum period of six days prior to the start of the study.
The rats were allocated without conscious bias to cages within the treatment group. They were housed individually in metal cages (RS Biotech Sub-Dividable Rodent Cages - polished stainless steel (20cm high x 39cm wide x 39cm long) until Day 6 when they were returned to group housing. The cages were fitted wit grid floors to ensure rapid removal of waste material to undertrays. The cages were suspended in mobile stainless steel racks
A standard laboratory rodent diet (Special Diet Services RMl(E) SQC expanded pellet) and drinking water were provided ad libitum. The batch(es) of diet used for the study was analysed for certain nutrients, possible contaminants and micro-organisms. Results of routine physical and chemical examination of drinking water, as conducted by the supplier, are made available to Huntingdon Life Sciences Limited as quarterly summaries

Thermostatic controls were set to maintain a temperature of22 ± 3 °C. Relative humidity was not fully controlled but was anticipated to be in the range 30 - 70%. Temperature and humidity were recorded continuously using a seven day recorder. Actual measurement of these parameters revealed that animal room temperature was in the range 20.5 to 21.5°C and relative humidity was in the range 28 - 54%. Permanent daily recordings of these parameters were made and these are archived with other Departmental raw data. Lighting was controlled by means of a time switch to provide 12 hours of artificial light (0600 - 1800 hours GMT) in each 24-hour period.

Each animal was identified by cage number and ear punching. Each cage was identified by a coloured label displaying the dose level, study schedule number, animal mark and the initials of the Study Director and Home Office licensee

Administration / exposure

Type of coverage:
occlusive
Vehicle:
methylcellulose
Details on dermal exposure:
One day prior to treatment, hair was removed from the dorso-lumbar region of each rat with electric clippers taking care to avoid damaging the skin, exposing an area equivalent to approximately 10% of the total body surface area.

The test substance was applied by spreading it evenly over the prepared skin. The treatment area (approximately 50 mm x 50 mm) was covered with porous gauze held in place with a non irritating dressing, and further covered by a waterproof dressing encircled firmly around the trunk of the animal.

Treatment in this manner was performed on Day 1 (day of dosing) of the study only.

At the end of the 24 hours exposure period the dressings were carefully removed and the treated area of skin was washed with warm water 30 to 40°C to remove any residual test substance. The treated area was blotted dry with absorbent paper.



Duration of exposure:
24 hrs expsoure
Doses:
1 dose of 2000mg/kg
No. of animals per sex per dose:
5 Male and 5 Female animals per dose
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations 0.5, 1, 2, and 4 hours after dosing, then once daily. Weighing was conducted on Day 0, 7, and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

BMS 233101-01 was formulated at a maximum practical concentration of 75% w/v in 1% w/v aqueous methy]cellulose and administered at a dose volume of 2.67 ml/kg bodyweight in order to achieve the desired dose concentration

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
no indication of skin irritation up to the relevant limit dose level
Mortality:
No mortality
Clinical signs:
No clinical sign effects detected
Body weight:
Minor flucatation in body weight was observed but not treatment realated
Gross pathology:
No macroscopic abnormalities
Other findings:
Dermal reactions characterised by slight erythema only were notable in one rat on Day 2 only. There was no dermal response seen in the remaining nine rats throughout the study.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Acute letal dose was determined to be greater than 2000mg/kg,
Executive summary:

A study was performed to assess the acute dermal toxicity of BMS 233101 to the rat. 

A group often rats (five males and five females) received a single topical application of the test substance formulated at a maximum practical concentration in1%w/v aqueous methylcellulose and administered at a dosage of 2000mg/kg bodyweight

All animals were killed as scheduled at study termination (Day 15)and subjected to a macroscopic examination.

There was no clinical signs of reaction to treatment observed in any animal throughout the study.

Dermal reactions characterized by slight erythema only were notable in one rat on Day2 only.  There was no dermal response seen in the remaining nine rats throughout the study. Minor  bodyweight  fluctuations were noted in the occasional animal, however, these were not considered to be of toxicological significance in light of the majority of animals achieving satisfactory weight gains.

No macroscopic abnormalities were observed for animals killed at study termination on Day15. The acute lethal dermal dose to rats of BMS 233101-01 was demonstrated to be greater than 2000mg/kg body weight.