Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
10 March, 2016 - 24 March, 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report Date:
2016

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
(1987)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
(2008)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Version / remarks:
(1998)
Deviations:
no
Qualifier:
according to
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000; including the most recent partial revisions.
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
Appearance: White crystalline solid
Storage conditions: At room temperature protected from light

Test animals

Species:
rat
Strain:
other: Wistar strain, Crl:WI (Han)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: Young adult animals
- Weight at study initiation: Males: 302 - 339g; females: 188 - 221g
- Housing: Individually housed in labeled Makrolon cages. During the acclimatization period the animals were group housed in Makrolon cages.
- Diet: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water: Free access to tap water.
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS Set to maintain
- Temperature (°C): 18 – 24
- Humidity (%): 40 - 70
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:
occlusive
Vehicle:
propylene glycol
Details on dermal exposure:
TEST SITE
One day before exposure (Day -1) an area of approximately 5x7 cm on the back of the animal was clipped.

The preparation was applied on an area of approx. 10% of the total body surface, i.e. approx. 25 cm² for males and 18 cm² for females. The preparation was held in contact with the skin with a dressing, consisting of a surgical gauze patch, successively covered with aluminum foil and Coban elastic bandage. A piece of Micropore tape was additionally used for fixation of the bandages in females only.

Frequency: Single dosage, on Day 1.

REMOVAL OF TEST SUBSTANCE
Washing: 24 hours, after which dressings were removed and the skin cleaned of residual test item using tap water.
Duration of exposure:
24 hours.
Doses:
2000 mg/kg


No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
VEHICLE
- Justification for choice of vehicle: The vehicle was selected based on trial preparation performed at WIL Research Europe and on test item data supplied by the Sponsor. There was no information available regarding the solubility or stability in vehicle.

Dose volume: 20 mL/kg body weight.

DOSAGE PREPARATION: The preparation (w/w) was kept at room temperature and dosed within 4 hours after adding the vehicle to the test item. Homogeneity was assessed by visual inspection of the solutions and the formulations were stirred during dosing, which ensures homogeneity sufficient for these kinds of studies.

Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/Viability: Twice daily.
Body weights: Days 1 (pre-administration), 8 and 15.
Clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15.
- Necropsy of survivors performed: At the end of the observation period, all animals were euthanatised by oxygen/carbon dioxide procedure and subjected to necropsy. Death was confirmed by checking reflexes and heartbeat. Descriptions of all internal macroscopic abnormalities were recorded.
Statistics:
None.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Hunched posture (three males and three females) and/or chromodacryorrhoea (four males and one female) were noted between Days 1 and 3.
Body weight:
The changes noted in body weight gain in males and females were within the range expected for rats used in this type of study and were therefore considered not indicative of toxicity.
Gross pathology:
Pelvic dilation of the right kidney was found in one male animal, at macroscopic post mortem examination. Since this is occasionally seen among rats of this age and strain and it was found in one animal only, this was considered not toxicologically significant. Macroscopic examination of the other animals did not reveal any abnormalities.
Other findings:
Scales and/or white staining were seen on the skin of some animals during the observation period.
These local effects were considered not to have affected the conclusion of the study.

Applicant's summary and conclusion

Interpretation of results:
not classified
Conclusions:
In an acute dermal toxicity study with rats, performed according to OECD 402 test guideline and GLP principles, an LD50 >2000 mg/kg bw was determined.
Executive summary:

BMS-587172 -01 was tested in an acute dermal toxicity study with rats, performed according to OECD 402 test guideline and GLP principles. No mortality occurred. Hunched posture (three males and three females) and/or chromodacryorrhoea (four males and one female) were noted between Days 1 and 3. Pelvic dilation of the right kidney was found in one male animal, at macroscopic post mortem examination. Since this is occasionally seen among rats of this age and strain and it was found in one animal only, this was considered not toxicologically significant. Macroscopic examination of the other animals did not reveal any abnormalities.

Based on the rsults of this study, the dermal LD50 value of BMS-587172-01 in Wistar rats was established to exceed 2000 mg/kg body weight.