Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
14 June 2016 - 29 June 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:
May 2008, including most recent amendments
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Version / remarks:
August 1998
Deviations:
no
Qualifier:
according to
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147.
Version / remarks:
November 2000; including the most recent partial revisions.
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
; date certificate 03 November 2015
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:
Identification: BMS-589154-01
Appearance: White to off-white powder
Test item storage: At room temperature protected from light
Stable under storage conditions until 17 March 2017 (retest date)
Specific details on test material used for the study:
Test item handling: Use amber glassware or wrap container in aluminum-foil
pH (1% in water, indicative range): 4.5 – 4.4 (determined by Charles River Den Bosch)
Stability in vehicle (Propylene glycol): Stability for at least 5 hours at room temperature is confirmed over the concentration range 1 to 200 mg/mL

Test animals

Species:
rat
Strain:
other: Wistar strain, Crl:WI (Han)
Sex:
male/female
Details on test animals and environmental conditions:
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: Young adult animals (approx. 12 weeks old)
- Weight at study initiation: males 329 - 341 grams, females 194 - 219 grams.
- Housing: Individually housed in labeled Makrolon cages containing sterilized sawdust as bedding material and paper as cage-enrichment.
- 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): approx 10
- Photoperiod (hrs dark / hrs light): 12/12

Deviations from the maximum level of daily mean relative humidity occurred. Evaluation: Laboratory historical data do not indicate an effect of the deviations. The study integrity was not adversely affected by the deviation.

IN-LIFE DATES: From: 14 June 2016 to 29 June 2016

Administration / exposure

Type of coverage:
occlusive
Vehicle:
propylene glycol
Remarks:
The vehicle was selected based on trial preparation performed at Charles River Den Bosch and on test item data supplied by the Sponsor.
Details on dermal exposure:
One day before exposure (Day -1) an area of approximately 5x7 cm on the back of the animal was clipped.

TEST ITEM PREPARATION
The preparation (w/w) was kept at room temperature protected from light 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 of the vehicle. No correction was made for purity of the test item.

TREATMENT
Method: Dermal application. The test item (preparation) was stirred on a magnetic stirrer during application.
Clipping: One day before exposure (Day -1) an area of approximately 5x7 cm on the back of each animal was clipped.
Application: The test item 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 test item preparation was held in contact with the skin with a dressing, consisting of a surgical gauze patch (Surgy 1D), 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.
Washing: Following 24 hour exposure, dressings were removed and the skin cleaned of residual test substance using tap water.
Duration of exposure:
24 hours.
Doses:
2000 mg/kg (10 mL/kg) body weight

No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
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: At the end of the observation period, all animals were euthanatized by oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded.
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:
Restless behaviour, piloerection, ptosis and/or chromodacryorrhoea (snout) were noted for several animals on Day 1.
Maculate erythema, general erythema, scales and/or scabs were noted for several animals between Days 8 and 15. These local effects were considered not to have affected the conclusion of the study.
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:
No abnormalities were found at macroscopic post mortem examination of the animals.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
In an acute dermal toxicity study with BMS-589154-01 in rats, performed according to OECD/EC test guidelines, an LD50 >2000 mg/kg bw was determined.
Executive summary:

Assessment of acute dermal toxicity with BMS-589154-01 in the rat was performed according to OECD/EC guidelines and in compliance with GLP principles. BMS-589154-01 was administered to five Wistar rats of each sex by a single dermal application at 2000 mg/kg bw for 24 hours. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal euthanasia (Day 15). No mortality occurred. Restless behaviour, piloerection, ptosis and/or chromodacryorrhoea (snout) were noted for several animals on Day 1. Maculate erythema, general erythema, scales and/or scabs were noted for several animals between Days 8 and 15. These local effects were considered not to have affected the conclusion of the study. The mean body weight gain during the observation period was within the range expected for rats used in this type of study. No abnormalities were found at macroscopic post mortem examination of the animals.

The dermal LD50 value of BMS-589154-01 in Wistar rats was established to exceed 2000 mg/kg bw.

Based on these results, BMS-589154-01 does not have to be classified and has no obligatory labelling requirement for acute dermal toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2015) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).