Reaction mass of (R)-2-(3-(diisopropylamino)-1-phenylpropyl)-4-(hydroxymethyl)phenol and Methylene Chloride

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

01 July 1998 - 15 July 1998

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

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:

4-chloro-6-ethyl-5-fluoropyrimidine; dichloromethane

EC Number:

929-144-0

IUPAC Name:

4-chloro-6-ethyl-5-fluoropyrimidine; dichloromethane

Test material form:

liquid

Details on test material:

Clear yellow liquid
Storage conditions: Room temperature in the dark

Specific details on test material used for the study:

Clear yellow liquid
Storage conditions: room temperature in the dark
Batch number: 5494/95/2

Test animals

Species:

rat

Strain:

other: Hsd:Sprague-Dawley(CD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

Animals were in the weight range of 227 to 260 g and approximately eight to eleven weeks of age prior to dosing (Day 1). 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. A standard laboratory rodent diet and drinking water were provided ad libitum. Thermostatic controls were set to maintain a temperature of 22 ± 3° C. Each animal was identified by cage number and ear punching.

Administration / exposure

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

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 was 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 hours

Doses:

2000 mg/kg

No. of animals per sex per dose:

A group of ten rats (five males and five females)

Control animals:

no

Details on study design:

Dermal responses
Local dermal irritation at the treatment site was assessed daily using the following numerical scoring system:
Erythema and eschar formation:
No erythema 0
Slight erythema 1
Well defined 2
Moderate erythema 3
Severe erythema (beet redness) to slight eschar formation (injuries in depth) 4

Oedema formation:
No oedema
Slight 1
Well-defined oedema (edges of area well-defined by definite raising) 2
Moderate oedema (raised approximately 1 millimetre) 3
Severe oedema (raised more than 1 millimetre and extending beyond the
area of exposure) 4

Any other lesion not covered by this scoring system was described.

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

discriminating dose

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:

Cages of rats were checked at least twice daily for mortalities. All animals were killed on Day 15 by carbon dioxide asphyxiation.

Clinical signs:

other: Hyperactivity was first evident within eight minutes following removal of the dressings and accompanied on later intervals during the study by hunched posture, waddling/unsteady gait, lethargy, partially closed eyelids, pallid extremities, walking on toes

Gross pathology:

No abnormalities were recorded at the macroscopic examination on Day 15.

Other findings:

Dermal Responses: A well-defined dermal response (erythema/oedema Grades 1 to 3) was first evident in all rats following removal of the dressings with a similar response also apparent 48 hours after dosing. By Day 4 reactions had notably ameliorated in the majority of rats and dermal reactions had resolved in all instances by Day 9.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

There were no deaths in any animal throughout the study following a single dermal application of UK- 103,444 to a group of ten rats (five males and five females) at a dose level of 2000 mg/kg bodyweight.

Executive summary:

The acute lethal dermal dose to rats of UK-103,444 was demonstrated to be greater than 2000 mg/kg bodyweight. On the basis of findings in this study and in accordance with EU hazard classification UK-103,444 will

not require labelling with the risk phrase GHS classification of acute tox. category 4, H-312: "Harmful in contact with skin"