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Description of key information

A key study was completed for acute oral toxicity according to OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method) and EU Method b.1 tris (Acute Oral Toxicity - Acute Toxic Class Method). A key study was also completed for the acute dermal toxicity according to OECD Guideline 402 (Acute Dermal Toxicity), EU Method B.3 (Acute Dermal Toxicity), EPA OPPTS 870.1200 (Acute Dermal Toxicity), and Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000; including the most recent partial revisions. Both of these studies were completed under GLP. An acute inhalation study was waived as exposure to humans via inhalation is not likely due to the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles, or droplets of inhalable size (exposure considerations).

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:
April 6 to April 26, 2005
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
Commission Directive 96/54/EC, B1 tris
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
With exception of an overnight fast before dosing and 3-4 hours after dosing, free access to mains drinking water and food was allowed. The temperature and relative humidity were set to achieve limits of 19 to 25 C and 30 to 70% respectively. The rate of air exchange was at least 15 changes per hour and the lighting was controlled by a time switch to give 12 hours continuous light and 12 hours of darkness.
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
Using all available information on the toxicity of the test material, 2000 mg/kg was chosen as the starting dose.
dose level: 2000 mg/kg
concentration: 100 mg/ml
dose volume 10 ml/g
3 females per dose, followed by a group of 3 males per dose
Doses:
Female: 2000 mg/kg bw
No. of animals per sex per dose:
Female: 2000 mg/kg bw; Number of animals: 3 then, 3 additional rats at same dose level.
Control animals:
no
Details on study design:
All animals were dosed once only by gavage, using a metal cannula attached to a graduated syringe. The volume administered was calculated according to the fasted bodyweight at the time of dosing. Treatment of animals was sequential. Sufficient time was allowed between each group to confirm the survival of the previously dosed animals. The animals were observed for deaths or overt signs of toxicity 1/2, 1, 2 and 4 hours after the final dose and subsequently once daily for fourteen days. At the end of the observation period the animals were killed using ascending concentrations of carbon dioxide. All animals were subjected to gross pathological observations. This consisted of external examination and opening of the abdominal and thoracic cavities for examination of major organs. The appearances of any macroscopic abnormalities were recorded. No tissues were retained.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:

Female: 2000 mg/kg bw; Number of animals: 6; Number of deaths: 0
Clinical signs:
Signs of toxicity related to dose levels:
There were no signs of systemic toxicity.


All animals showed expected gains in bodyweight over the
study period.
Body weight:
All animals showed expected gains in bodyweight over the study period.
Gross pathology:
Effects on organs:
No abnormalities were noted at necropsy.
Interpretation of results:
not classified
Conclusions:
The acute oral median lethal dose (LD50) of the test material in the Sprague-Dawley CD strain rat was estimated as being greater than 2000 mg/kg bodyweight.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

Acute toxicity: via inhalation route

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Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size
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:
10 March, 2016 - 24 March, 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
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
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
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.
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.
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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

Additional information

Justification for classification or non-classification

The acute oral median lethal dose (LD50) of the test material in the Sprague-Dawley CD strain rat was estimated as being greater than 2000 mg/kg bodyweight. The dermal LD50 value in Wistar rats was established to exceed 2000 mg/kg body weight. Therefore, the substance is not classified according to the EU CLP regulation.