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Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
4th to 22nd August 1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Deviations:
yes
Remarks:
an upper temperature range of 27.5°C for approx 24 hrs. This deviation was not considered to have affected the integrity or validity of the study.
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
yes
Specific details on test material used for the study:
TEST MATERIAL
- Batch No.of test material: 92480/N/9/1
- Expiration date of the lot/batch: Not supplied
- Purity: 95%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material:Room temperature

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: UK-220,955 was prepared at a concentration of 20% w/v in 1% w/v aqueous methylcellulose and administered at
a volume of 10 ml/kg bodyweight in the main study.

The test substance was prepared on the day of dosing.

The absorption of the test substance was not determined.
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan U.K. Ltd
- Age at study initiation: 4-7 weeks
- Weight at study initiation: 91 to 108 g
- Housing: housed in groups of up to five rats of the same sex in metal cages with wire mesh floors
- Fasting: access to food only was prevented overnight prior to and for approximately 4 hours after dosing.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 27.5°C
- Humidity (%): 42-65 %
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12 hours of artificial light (0700 - 1900 hours) in each 24-hour period.

IN-LIFE DATES: From: 0 To: 15 (All animals in the main study were killed on Day 15 by carbon dioxide asphyxiation.
Route of administration:
oral: gavage
Vehicle:
methylcellulose
Details on oral exposure:
VEHICLE
- Concentration in vehicle: UK-220,955 was prepared at a concentration of 20% w/v in 1% w/v aqueous methylcellulose.


MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg of UK-220,955 in 1% w/v aqueous methylcellulose.

- Rationale for the selection of the starting dose: after review of the results from the preliminary study using doses of 500 and 2000 mg/kg.
Doses:
2000 mg/kg
No. of animals per sex per dose:
5/sex/group
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality
Cages of rats were checked at least twice daily for any mortalities.

Clinical signs
Animals were observed soon after dosing and at frequent intervals for the remainder of Day 1. On subsequent days animals were observed once in the morning and again at the end of the
experimental day (with the exception of Day 15 - morning only.

Bodyweight
The bodyweight of each rat in the main study was recorded on Days 1, 2, 3, 4, 8 and 15

- Necropsy of survivors performed: All animals in the main study were killed on Day 15. All animals were subjected to a macroscopic examination.

- Other examinations performed: mortality, clinical signs, body weight, macroscopic pathology
Preliminary study:
One female rat was treated at 500 or 2000 mg/kg bodyweight to establish a dosing regime for the main study.
Sex:
male/female
Dose descriptor:
discriminating dose
Effect level:
ca. 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths following a single oral dose of UK-220,955 to a group of ten rats (five males and five females) at a dosage of 2000 mg/kg bodyweight.
Clinical signs:
Pilocrection was observed in all rats within four minutes of dosing. This sign persisted and was accompanied in all rats on Day 1 by abnormal faeces (characterised by soft to liquid faeces). There were no other clinical signs and recovery, as judged by external appearance and behaviour, was complete in all animals by Day 2.
Body weight:
All rats were considered to have achieved satisfactory bodyweight gains during the study.
Gross pathology:
Macroscopic examination of animals killed on Day 15 revealed no abnormalities.
Interpretation of results:
GHS criteria not met
Conclusions:
The discriminating dose to rats of UK-220,955 was demonstrated to be 2000 mg/kg bodyweight.
Executive summary:

A study was performed to assess the acute oral toxicity of UK-220,955 to the rat. The method followed was that described in EEC Methods for the determination of toxicity, Annex to Directive 92/69/EEC (OJ No. L383A, 29. 12.92), Part B, Method B.1 bis. Acute toxicity (oral) -Fixed Dose Method.

A group of ten fasted rats (five males and five females) received a single oral gavage dose of the test substance, formulated in 1 % w/v aqueous methylcellulose and administered at a dose level of 2000 mg/kg bodywcight. The dose level was chosen on the basis of preliminary study investigations. All animals were killed and examined macroscopically on Day 15, the end of the observation period.

Clinical signs of reaction to treatment included piloerection and abnormal faeces, seen in all rats. There were no other signs of reaction to treatment and recovery was complete in all animals by Day 2.

All rats were considered to have achieved satisfactory bodyvveight gains during the study.

Macroscopic examination of animals killed on Day 15 revealed no abnormalities.

The discriminating dose to rats of UK-220,955 was demonstrated to be 2000 mg/kg bodyweight.

UK-220,955 will not require labelling in accordance with GHS

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
30 July- 1 August 1997
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
yes
Remarks:
An upper temperature range of 28 oC occurred for a brief period (approximatelv 24 hours) during the study. This deviation was not considered to have affected the integrity or validity of the study.
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Batch No.of test material: 92,480/N/9/1
- Expiration date of the batch: Not supplied
- Purity test date: 95 %

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room Temperature


TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- UK-220.955 was formulated at a maximum practical concentration of 62.5% w/v in 1% aqueous methylcellulose and administered at a volume of 3.2 ml/kg body-weight.
-The test substance was prepared on the day of dosing.
-The absorption of the test substance was not determined.
-The concentration, homogeneity and stability of the test substance in the vehicle was not evaluated.
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan O.K.. Ltd.. Bicester, Oxon. England.
- Male/Female
- Age at study initiation: seven to ten weeks of age prior to dosing
- Weight at study initiation: 215 to 242g

- Housing: Housed individually in metal cages with wire mesh floors
- Diet: Special Diet Services RMI (13) SQC expanded pellet) ad libitum
- Water: ad libitum
- Acclimation period: minimum of five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-28 (°C)
- Humidity (%): 45-62%
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): I 2 hours of artificial light (0700 - 1900 hours) in each 24-hour period

IN-LIFE DATES: Day 0 to Day 15
Type of coverage:
occlusive
Vehicle:
methylcellulose
Details on dermal exposure:
TEST SITE
- Area of exposure: dorso-lumbar region, approximately 50 mm x 50 mm
- Type of wrap if used: 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.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): At the end of the 24 hours exposure period the dressings was carefully removed and the treated area of the skin was washed with warm water (30o to 40oC) and the treated area was blotted dry with absorbent paper.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 3.2 ml/kg
- Concentration (if solution): 62.5 % w/v in 1 % aqueous methylcellulose
- Constant volume or concentration used: yes

VEHICLE
- Concentration (if solution): 1 % aqueous methylcellulose
Duration of exposure:
24 hrs
Doses:
2000 mg/kg
No. of animals per sex per dose:
5/sex/dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observed soon after dosing and at frequent intervals on Day 1. Subsequently, animals were observed once in the morning and again at the end of the experimental day (with the exception of Day 15- morning only). Bodyweights were recorded on Days 1 (prior to dosing), 8 and 15.
- Necropsy of survivors performed: All animals were killed on day 15 and all were subjected to a macroscopic examination
- Other examinations performed: mortality, clinical signs, dermal responses, body weight,macroscopic examination
Sex:
male/female
Dose descriptor:
discriminating dose
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths following a single dermal application of 2000 mg/kg UK-220.955 to a group of ten rats (5/sex/dose)
Clinical signs:
No systemic response was observed in any animal throughout the study.
Body weight:
All rats were considered to have achieved satisfactory bodyweight gains throughout the study.
Gross pathology:
Macroscopic examination of animals killed on Day 15 revealed no abnormalities.
Interpretation of results:
study cannot be used for classification
Conclusions:
The acute lethal dermal dose to rats of UK-220, 955 was demonstrated to be greater than 2000 mg/kg bodyweight.
Executive summary:

A study was preformed to assess the acute dermal toxicity of UK-220 955 to the rat. The method followed was that described in EEC Methods for the determination of toxicity. Annex to Directive 92/69/EEC (OJ No. L383A. 29.12.92), Part B, Method B.3. Acute toxicity (dermal).

A group of ten rats (five males and five females) received a single dose by topical application of the test substance, formulated at a maximum practical concentration of 62.5 % w/v in 1 % aqueous methylcellulose and administered at a dose level of 2000 mg/kg bodyweight. All animals were killed and examined macroscopically on Day 15, the end of the observation period.

There were no signs of systemic reaction to treatment observed throughout the study.

Transient well-defined dermal irritation (Grade 1 or 2 erythema with up to Grade 3 oedema) was evident in four females following removal of the dressings (Day 2) and resolving in all instances by Day 4. No dermal response to treatment was observed in the remaining six animals throughout the study.

All rats were considered to have achieved satifactory bodyweight gains throughout the study.

Macroscopic examination of animals killed on Day 15 revealed no abnormalities.

The acute lethal dermal dose to rats of UK-220,955 was demonstrated to be greater than 2000 mg/kg bodyweight.

UK-220, 955 will not require labelling in accordance with GHS

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Justification for classification or non-classification