Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2006-10-23 to 2007-04-04
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study performed according to OECD Guideline 402 (Acute Dermal Toxicity) and EU Method B.3 (Acute Toxicity (Dermal)) without deviations.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007
Report Date:
2007

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Remarks:
The testing facility indicated that the protocol was followed without deviation.
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Remarks:
The testing facility indicated that the protocol was followed without deviation.
GLP compliance:
yes (incl. certificate)
Remarks:
Certificate given by the Department of Health of the Government of the United Kingdom
Test type:
other: acute dermal toxicity
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): VRT-753136 hcl
- Molecular formula: Not applicable
- Molecular weight: Not applicable
- Smiles notation: Not applicable
- InChl: Not applicable
- Structural formula attached as image file: Not applicable
- Substance type: No data
- Physical state: White powder
- Analytical purity: 100 area %
- Impurities: 0.03 area% of unknowns
- Composition of test material, percentage of components: No data
- Isomers composition: No data
- Purity test date: 2006-09-15
- Lot/batch No.: Batch number 25515/Lot No. AF6-001
- Expiration date of the lot/batch: 2008-05-01
- Stability under test conditions: No data
- Storage condition of test material: Room temperature
- Other: No data

Test animals

Species:
rat
Strain:
other: CD (Crl:CD BR IGS)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Obtained from Charles River (UK) Ltd, Margate, Kent, England.
- Age at study initiation: Approximately eight to twelve weeks of age prior to dosing (Day 1).
- Weight at study initiation: 229 to 301 g
- Fasting period before study: No data
- Housing: The cages were made of a stainless steel body with a stainless steel mesh lid and floor. The animals were housed individually from Day -1.
- Diet: The animals were allowed free access to a standard rodent diet (Rat and Mouse No. 1 Maintenance Diet).
- Water: Potable water taken from the public supply was freely available via polycarbonate bottles fitted with sipper tubes.
- Acclimation period: Six days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 23 deg C
- Humidity (%): 40-70%
- Air changes (per hr): Not applicable
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light artificial light

IN-LIFE DATES: From: 2006-11-01 To: 2006-11-15

Administration / exposure

Type of coverage:
occlusive
Vehicle:
other: purified water
Details on dermal exposure:
TEST SITE
- Area of 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.
- % coverage: Exposed an area equivalent to approximately 10% of the total body surface area.
- Type of wrap if used: 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.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The dressing was carefully removed and the treated area of skin was washed with warm water (30 - 40 deg C), to remove any residual test substance. The treated area was blotted dry with absorbent paper.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): Administered at a volume of 4 mL/kg bodyweight.
- Concentration (if solution): The test substance was formulated at a maximum practical concentration of 500 mg/mL in the vehicle
- Constant volume or concentration used: No
- For solids, paste formed: Not applicable
- A record of the weight of the formulation dispensed and the amount remaining after dosing was made. The balance of these two weights was compared with the predicted usage as a check that the doses had been administered correctly.

VEHICLE
- Amount(s) applied (volume or weight with unit): No data
- Concentration (if solution): No data
- Lot/batch no.: No data
- Purity: No data
Duration of exposure:
24 hours
Doses:
Single topical appliation of the test substance, formulated at a maximum practical concentration in purified water, at a dosage of 2000 mg/kg bodyweight (only on Day 1).
No. of animals per sex per dose:
Five males and five females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 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). The nature and severity, where appropriate, of the clinical signs and the time were recorded at each observation.
- Necropsy of survivors performed: yes
- Other examinations performed: Mortality, clinical signs, body weight, macroscopic pathology

Mortality: Cages of rats were checked at least twice daily for any mortalities.

Bodyweight: The weight of each rat was recorded on Days 1 (prior to dosing), 8 and 15. Individual weekly bodyweight changes and group mean bodyweights were calculated.

Macroscopic Pathology: All animals were subject to a macroscopic examination which consisted of opening the cranial, thoracic and abdominal cavities. The macroscopic appearance of all examined organs was recorded.
Statistics:
No data

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
There were no deaths and no systemic response to treatment in any animal.
Clinical signs:
No data
Body weight:
A low bodyweight gain was recorded on day eight for all females. All other animals were considered to have achieved satisfactory bodyweight gains throughout the study.
Gross pathology:
No data
Other findings:
- Dermal Reactions:
Very slight irritation (Grade 1 erythema) was observed in one female after bandage removal from Day 4. These reactions had resolved by Day 9. A small area of scab formation was seen in two females, one from Day 3 and one from Day 5 this was also seen in one male from Day 7. These reactions had resolved by Day 13.
- Histopathology: Macroscopic examination- No abnormalities were noted in any animal at the macroscopic examination at study termination on Day 15.

Any other information on results incl. tables

Not applicable

Applicant's summary and conclusion

Conclusions:
The acute lethal dermal dose to rats of VRT-753136 hcl was demonstrated to be greater than 2000 mg/kg bodyweight.
Executive summary:

Not applicable