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Description of key information

Two in-vivo key studies available for acute toxicity, oral and dermal.

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:
March 6 to April 3, 2006
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study was conducted in 2006 according to OECD Method # 423 and in accordance with GLP. The study material is well characterized.
Reference:
Composition 0
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:
acute toxic class method
Limit test:
yes
Test material information:
Composition 1
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, 300 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: 300 mg/kg and 2000 mg/kg bw
No. of animals per sex per dose:
Female: 300 mg/kg bw; number of animals: 3 female
additionally 3 females at 2000 mg/kg and 3 at 300 mg/kg dosed sequentially
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:
300 - 2 000 mg/kg bw
Based on:
test mat.
Mortality:
Female: 2000 mg/kg bw; Number of animals: 3; Number of deaths: 1 found dead, 1 killed in extremis 1 day after dosing
Female: 300 mg/kg bw; Number of animals: 6; Number of deaths: 0
Clinical signs:
Signs of toxicity related to dose levels:
there was no sign of toxicity for animals dosed at 300 mg/kg.

At 2000 mg/kg, hunched posture, lethargy, piloerection,ataxia, decreased respiration rate, laboured respiration, ptosis, pallor of the extremeties, emaciation, red/brown staining around the eyes and tiptoe gait. 1 animal was normal 6 days after dosing.


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 of the animals killed at the end of the study. For the animal that died or was killed in extremis the following was noted haemorrhagic lungs, dark or patchy pallor of the liver, dark kidneys, pale gastric mucosa and pale non-glandular region of the stomach at necropsy.
Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral median lethal dose (LD50) of the test material in the Sprague-Dawley CD strain rat was between 300 and 2000 mg/kg bodyweight.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
500 mg/kg bw

Acute toxicity: via inhalation route

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Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study technically not feasible
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

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Reference
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.
Reference:
Composition 0
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 information:
Composition 1
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
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.
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.
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.

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

Additional information

Justification for selection of acute toxicity – oral endpoint
The acute oral median lethal dose (LD50) of the test material in the Sprague-Dawley CD strain rat was between 300 and 2000 mg/kg bodyweight. An ATE of 500 mg/kg bw. Therefore, classified per CLP as acute toxicity category 4 , oral.
High exposure effects include: lethargy, abnormal posture, ataxia, labored respiration, lung toxicity, liver effects, kidney effects, mortality.

Justification for selection of acute toxicity – dermal endpoint
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. High exposure effects include: skin effects. No mortality occurred.

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 between 300 and 2000 mg/kg bodyweight. An ATE of 500 mg/kg bw. Therefore, classified per CLP as acute toxicity category 4 , oral. 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.