Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
22 December, 2015 - 12 January, 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study has been performed according to OECD and/or EC guidelines and according to GLP principles.

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
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): BMS-587319-03
- Appearance: White powder

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 (approx. 10-11 weeks old)
- Weight at study initiation: males: 275 - 307g; females: 186 - 209g
- Housing: Individually housed in labeled 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:
A staggered start was used in this dermal study to minimize the number of animals and severe responses. Initially, three females were treated at 2000 mg/kg. Thereafter, 2 females and 5 males were treated at 2000 mg/kg, based on the interim results of the first step.

One day before exposure (Day -1) an area of approximately 5x7 cm on the back of each animal was clipped.

The test item formulation 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 test item formulation 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.

Due to the loss of the bandage, 2 females and 2 males were exposed to the test item for at least 5 hours and maximally 22 hours.
Evaluation: Since sufficient animals were exposed to the test item for the exposure period as planned, sufficient data is available for evaluation of this study.

Frequency: Single dosage, on Day 1.

Washing: Following application, dressings were removed and the skin cleaned of residual test substance using tap water.
Duration of exposure:
24 hours.
Doses:
2000 mg/kg bw


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.

Dose volume: 10 mL/kg bw

DOSAGE PREPARATION: The preparations (w/w) were 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. Adjustment was made for specific gravity (1.036) of the vehicle. No correction was made for purity of the test item.

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 sacrificed by oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded.
- Other examinations performed: none.
Statistics:
None.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Erythema, scabs and/or scales were noted on treated skin and/or flank of most of the animals exposed for 24 hours. One female showed a scar on the left flank.
Among the animals exposed for 5-22 hours, similar skin effects were noted, however at lower severity. One female showed chromodacryorrhea on the day of exposure.
Body weight:
The changes noted in body weight gain in all 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:
Reddish discolouration of the thymus, pale discolouration of the lung and/or pelvic dilation in the kidney were found at macroscopic post mortem examination in two animals exposed for 24 hours.
Reddish discolouration of the thymus was also noted in two animals exposed for 5-22 hours. At the incidence observed this was considered not toxicologically significant.

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
In an acute dermal toxicity study with male and female rats, performed according to OECD 402 test guideline and GLP principles, an LD50 >2000 mg/kg bw was determined.
Executive summary:

BMS-587319 -03 was tested in an acute dermal toxicity study with male and female rats, performed according to OECD 402 test guideline and GLP principles.

No mortality occurred. Due to the loss of the bandage, 2 females and 2 males were exposed to the test item for at least 5 hours and maximally 22 hours. Erythema, scabs and/or scales were noted on treated skin and/or flank of most of the animals exposed for 24 hours. One female showed a scar on the left flank. Among the animals exposed for 5-22 hours, similar skin effects were noted, however at lower severity. One female showed chromodacryorrhea on the day of exposure.

Reddish discolouration of the thymus, pale discolouration of the lung and/or pelvic dilation in the kidney were found at macroscopic post mortem examination in two animals exposed for 24 hours. Reddish discolouration of the thymus was also noted in two animals exposed for 5-22 hours. At the incidence observed this was considered not toxicologically significant.

Based on the results, an LD50 >2000 mg/kg bw was determined and BMS-587319 -03 does not have to be classified for acute dermal toxicity, according to Regulation (EC) No 1272/2008 on classification, labelling and packaging.