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

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

30 June to 21 July 1998

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2001

Report date:

2001

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

no

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 No: 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 in the main study were in the weight range of 81 to 95 g and approximately five to seven weeks of age prior to dosing (Day 1). All the rats in the main study were acclimatised to the experimental environment for a period of five days prior to the start of the study. The rats were allocated without conscious bias to cages within the treatment group. They were housed in groups of up to five rats of the same sex in metal cages. A standard laboratory rodent diet and drinking water were provided ad libitum. Access to food only was prevented overnight prior to and for
approximately 4 hours after dosing. Thermostatic controls were set to maintain a temperature of 22 ± 3° C. Each animal was identified by cage number and ear punching.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

methylcellulose

Details on oral exposure:

UK-103,444 was administered, as supplied, at a dose volume of 0.386 ml/kg for the animal dosed at 500 mg/kg and subsequently in the study was formulated at various w/v concentrations in 1% w/v aqueous methylcellulose and administered at a fixed dose volume of 10 ml/kg bodyweight.

Doses:

Preliminary Study: Initially, one female rat was treated at 500 mg/kg and for further clarification two further female rats were dosed, one at 50 mg/kg and one at 200 mg/kg bodyweight.
Main Study: A group of ten rats (five males and five females) received a single oral gavage dose of the test substance at a dose level of 50 mg/kg bodyweight. This dose level was chosen after review of findings in the preliminary investigations and in compliance with the test guidelines.

No. of animals per sex per dose:

Preliminary Study: 500 mg/kg 1 female, 50 mg/kg 1 female, 200 mg/kg 1 female
Main Study: 50 mg/kg 5 males and 5 females

Control animals:

yes

Details on study design:

The appropriate dose volume of the test substance was administered to each rat by oral gavage using a microlitre and plastic cannula (18g) or a syringe and plastic catheter (8 choke). The day of dosing was designated Day 1.

Results and discussion

Preliminary study:

Treatment groups each comprising one female rat were treated at 50, 200 and 500 mg/kg bodyweight.
Study findings were as follows:
Clinical signs comprised piloerection, hunched posture, waddling/unsteady gait, walking on toes and
increased sensitivity to touch, seen in all rats. These signs were accompanied in the rats dosed at 200
and 500 mg/kg only by lethargy, abnormal respiration, partially closed eyelids and increased salivation.
In addition, abnormal faeces, increased lacrimation, ungroomed appearance, prostration, blue/cold
extremities and dark colouring to eyes were noted in the animal dosed at 500 mg/kg and pallid
extremities were noted in the animal dosed at 200 mg/kg only. Recovery was complete in the rats dosed
at 50 mg/kg and 200 mg/kg by Day 5. The rat dosed at 500 mg/kg died on Day 1.

Bodyweight gain was considered satisfactory for studies of this nature and duration.

Macroscopic examination of the decedent at 500 mg/kg revealed congestion (characterised by darkened
tissues/organs and/or injected blood vessels) in the subcutaneous tissue, brain, spleen and kidneys.
Congestion, gaseous distension and fluid contents was also observed in the stomach and along the
alimentary tract. No abnormalities were evident in the other animals killed at study termination on
Day 8.

The results from this phase of the study showed the non-lethal dose to be less than 500 mg/kg and that a
systemic response to treatment was evident at 50 mg/kg bodyweight.

Effect levels

Key result

Sex:

male/female

Dose descriptor:

discriminating dose

Effect level:

50 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths in a group of ten rats (five males and five females) following a single oral administration of UK-103,444 at a dose level of 50 mg/kg bodyweight.

Clinical signs:

other: Piloerection was observed in all rats within six minutes of dosing. This sign persisted and was accompanied on Days 1 and 2 by hunched posture, notable in all rats. Recovery of surviving rats, as judged by external appearance and behaviour, was complete i

Gross pathology:

No macroscopic abnormalities were observed for animals killed at study termination on Day 15.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The discriminating (non-lethal but clear evidence of toxicity) oral dose to rats of UK-103,444 was indicated to be 50 mg/kg bodyweight.

Executive summary:

On the basis of findings in this study and in accordance with EU hazard classification UK-103,444 will require labelling with the risk phrase of GHS classification of acute tox. category 4, H-302: "Harmful if swallowed."