Reaction Mass of 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine and Toluene

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

14 September 1998 - 02 October 1998

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1998

Report date:

1998

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Test guideline 2

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine

Cas Number:

188416-28-6

Molecular formula:

C6H5BrClFN2

IUPAC Name:

6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine

Test material form:

liquid

Details on test material:

Amber Oil

Specific details on test material used for the study:

Amber to yellow liquid (5494/96/1)

Test animals

Species:

rat

Strain:

CD-1

Sex:

male/female

Details on test animals or test system and environmental conditions:

Animals were in the weight range of 2.37 to 268 g and approximately eight E0 eleven weeks of age prior to dosing (Day 1). All the rats were acclimatised to the experimental environment fOr a minimum period of five days prior to the start of the study,
The rats were allocated without conscious bias to ca ges (RS Biotech Sub-Dividable Rodent Cage - polished stainless steel, 20cm high x 39cm wide x 39cm long). The cages -were fitted with grid floors to ensure rapid removal of waste material to undeitrays which were cleaned as necessary. No more than five animals of the same sex were accommodated in each cage. The day prior to dosing and f011owing removal of hair from the treatment site, the animals wereseparated and individually housed. This measure was taken to inhibit cagemates disturbing each others dressings during the treatment period. The animals were not returned to group housing because it was considered skin reactions were too severe.

Administration / exposure

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

One day prior to treatment., hair was removed from the dorso-lumbar region of each rat with electric clippers taking case to avoid darni*13g the skin, exposing anarea equivalent to approxiniatcl y 10°0 of the total body surface area.
The test substance was applied by spreading it evenly over the prepared skin. The treatment area (approximately .50 ram N 50 mm) was covered with porous gauze held in place with a non irritating dressing, and further covered bv a ,Nitterproof dressing encircled firmly around the trunk of the animal.
Treatment in this manner was perfOrmed on Day l (day of dosing) of the study only

Duration of exposure:

2.4 hours exposure period

Doses:

2000 mg/kg

No. of animals per sex per dose:

five males and five females

Control animals:

no

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

approximate LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths in ay animal throughout the study following a single dermal application of UK 134,821 to a group of ten rats (five males and five females) at a dose level of 2000 mg/kg body weight.

Clinical signs:

other: Clinical signs of reaction to treatment characterised b y piloerection, hunched posture, waddling/unsteady and and increased sensitivity to touch. were seen in allrats. Also observed in one or more animals were abnormal respiration, pallid extremities, wa

Gross pathology:

No macroscopic) abnormalities were observed tbr animals killed at study termination on Day 29.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

There \Nere no deaths ni am animal throughout the study following a single dermal application of UK 134,821 to a group of ten rats (five males and five females) at a dose level of 2000 mg/kg

Executive summary:

A group of ten fasted rats (five males and five females) received a single topical application of the test substance administered, as supplied, at a dosage of 2000 ing/kp-, bodyweight (EEC and OECD limit dosage), All animals were killed as scheduled at study termination (Day 29) and subjected to a macroscopic examination. Clinical signs of miction to treatment characterised by piloerection, hunched posture, waddling/unsteady gait and increased sensitivity to touch, were seen in all rats. Also observed in one or more animals were abnormal respiration, pallid extremities, walking on toes, abnormal faeces, thin appearance, ungroomed appearance and protruding eyes. Recovery was complete in all instances by Day 25. Application to the skin of UK-134,821 resulted in a considerable level of dermal injury. This was first evident in ail ten rats immediately following removal of the dressings with a similar level of response persistent over the following days and weeks. To assist in identifying when reversibility of tile skin lesions might be anticipated the observation period was extended beyond the scheduled termination (Day 15). By Day 29, reactions had lessened sufficiently to indicate recovery was taking place and a decision was then taken to terminate the study. A notably low bodyweight gain was evident in one male (No 1 on Day 8) and two females (No 6 on Day 15 and No 7 on Day 8). A slight bod:yweight loss was noted in two females (No 8 on Day 8 and No 9 on Day 22). All remaining animals were considered to have achieved satisfactory bodyweight cams throughout the study. With the exception of the dermal lesions, there was no macroscopic abnormalities observed for animals killed at study termination on Day 29. The acute lethal dermal dose to rats of UK-134,821 was demonstrated to be greater than 2000 mg/kg bodyweight.