Registration Dossier

Administrative data

Description of key information

This study was conducted for Bristol-Myers Squibb Company. It was designed to evaluate the potential toxicity ofBMS 233101-01 when administered orally, via gastric intubation, to Sprague-Dawley CD® rats (5/sex/group) at dose levels of 15, 150, and 1000 mg/kg/day for a period of 4 weeks.  Control animals (5/sex) received the vehicle (Com Oil) at the same dose volume (5 mL/kg) as administered to the treated animals. The dose levels were selected based on the results of a 7-day range-finding study.  Data from this study may serve as a basis for classification and labeling of the test article.

 

 Physical observations, body weight measurements and feed consumption measurements were performed pretest and weekly during the study. Motor activity and functional observational battery were performed pretest and during the fourth week of dosing.  After 4 weeks of treatment, hematology and clinical chemistry evaluations were performed, all animals were euthanatized, selected organs were weighed and organ/body weight and organ/brain weight ratios calculated.  Complete macroscopic postmortem examinations and histopathological evaluation of selected tissues were conducted on all animals.

All animals survived the four weeks of dosing. There were no clinical signs of treatment noted in any group during the four weeks of dosing. There were no significant differences in body weights, feed consumption, motor activity and functional observation battery during the four weeks of dosing. There were no significant differences in hematology and clinical chemistry values. There were no significant differences in organ weights, macroscopic postmortem findings and microscopic postmortem findings.

In conclusion, the dose levels of 1000, 150 and 15 mg/kg/day of BMS 233101-01 were considered non-toxic levels, when administered daily for 4 weeks by the oral route. Therefore, the high dose level of 1000 mg/kg/day was considered a NOEL (No Observed Adverse Effect Level).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23 December 1999 to 31 January
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
yellow/off white solid; 99.15% purity
Species:
rat
Strain:
Crj: CD(SD)
Details on species / strain selection:
Supplier: Charles River Laboratories
Sex:
male/female
Details on test animals and environmental conditions:
Animals were aged 4 weeks on receipt and were 6 weeks at the initiation of dosing. Animals were acclimated for approximately 2 weeks prior to study start and were examined during the acclimation period to determine suitability
Weight at start:
Males mean weight 197g
Females mean weight 161g

Light/Dark Cycle
A twelve hour light/dark cycle controlled via an automatic timer was provided.

Temperature
Temperature was monitored and recorded twice daily and maintained within the specified range to the maximum extent possible. Excursions outside the specified range were not considered to have affected the integrity of the study because they
were minimal and of brief duration.

Desired: Actual:

18 to 26°C
21 to 27°C
Relative Humidity
Relative humidity was monitored and recorded once daily and maintained within the specified range to the maximum extent
possible.
Route of administration:
oral: gavage
Details on route of administration:
Oral, via intubation
Vehicle:
corn oil
Details on oral exposure:
Animals were dosed daily with the appropriate amounts of test articel via the oral gavage route for 29 days. Test articel adminstration continued through the day prior to necrospy.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
All dose level preperations were assayed during the 4 weeks (one sample and 2 sub samples per concentration) of dosing. Analysis was conducted to determine homogenicity, stability and concentration
Duration of treatment / exposure:
29 days
Frequency of treatment:
daily
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
15 mg/kg bw/day (nominal)
Dose / conc.:
150 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
5 animals per sex per dose
Control animals:
yes, concurrent no treatment
Details on study design:
The study was designed to evaluate the potential toxicity of BMS 233101-01 when administered orally, via gastric intubation, to Sprague-Dawley CD® rats (5/sex/group) at dose levels of 15, 150, and 1000 mg/kg/day for a period of 4 weeks.  Control animals (5/sex) received the vehicle (Com Oil) at the same dose volume (5 mUkg) as administered to the treated animals. The dose levels were selected based on the results of a 7-day range-finding study.  
Positive control:
No
Observations and examinations performed and frequency:
Animals were removed daily from there cages and examined twice pretest and once weekly during the study period. Examinations included observations of general condition, respiration, skin and fur, eys, nose, oral cavity, abdomen and external genitalia as well as evaluations for any unusual behavioral signs and clinical signs of toxic or pharmalogical effects and palpatation for tissue masses. Behavioural assessment was performed in conjuction with the physical examinations and inlcuded changes in gait, posture, response to handling, stereotypic and abnormal behaviours. During the pretest week and week 4 this examination was replaced with a full neirobehavioral examination.
Sacrifice and pathology:
Euthanasia was performed with carbon dioxide inhalation at termination of the study. Necropsy was scheduled to established to ensure that examination of the animals of both sexes was performed at simlliar times of the day.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
With the exception of alopecia noted in one group III and one group IV female there was no other clinical signs of treatment related effects
Mortality:
no mortality observed
Description (incidence):
All animals survived the 4 weeks of dosing
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No significant differences in body weights in group in the 3 test group compared to the control
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No significant differences in food consumption in the 3 test group compared to the control
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
No significant differences in hematology values in treament groups when compared to the controls
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No significant differences in clinical chemistry values in treament groups when compared to the controls
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No macroscopic findings attributed to the treatment with BMS 233101. Macroscopic findings seen were sporadic and of the type commonly found as incidenital finding in that species
Neuropathological findings:
no effects observed
Description (incidence and severity):
No reproducible significant differences in the functional observations in groups II,III and IV compared to the controls.
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
No microscopic findings attributed to the treatment with BMS 233101. MAcroscopic findings seen were sporadic and of the tpye commonly found as incidenital finding in that species
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Non-toxic at all levels tested.
Remarks on result:
other: Non-toxic
Key result
Critical effects observed:
no
Lowest effective dose / conc.:
1 000 mg/kg bw/day (nominal)
Conclusions:
In conclusion, the dose levels of 1000, 150 and 15 mg/kg/day of BMS 233101-01 were considered non-toxic levels, when administered daily for 4 weeks by the oral route. Therefore, the high dose level of 1000 mg/kg/day was considered a NOEL (No Observed Effect Level).
Executive summary:

This study was conducted for Bristol-Myers Squibb Company. It was designed to evaluate the potential toxicity of BMS 233101-01 when administered orally, via gastric intubation, to Sprague-Dawley CD® rats (5/sex/group) at dose levels of 15, 150, and 1000 mg/kg/day for a period of 4 weeks.  Control animals (5/sex) received the vehicle (Com Oil) at the same dose volume (5 mUkg) as administered to the treated animals. The dose levels were selected based on the results of a 7-day range-finding study.  

Data from this study may serve as a basis for classification and labeling of the test article.

 

 Physical observations, body weight measurements and feed consumption measurements were performed pretest and weekly during the study. Motor activity and functional observational battery were performed pretest and during the fourth week of dosing.  After4 weeks of treatment, hematology and clinical chemistry evaluations were performed, all animals were euthanatized, selected organs were weighed and organ/body weight and organ/brain weight ratios calculated.  Complete macroscopic postmortem examinations and histopathological evaluation of selected tissues were conducted on all animals.

All animals survived the four weeks of dosing.  There were no clinical signs of treatment noted in any group during the four weeks of dosing.    There were no significant differences in body weights, feed consumption, motor activity and functional observation battery during the four weeks of dosing.   There were no significant  differences in hematology and clinical chemistry values. There were no significant differences in organ weights, macroscopic postmortem findings and microscopic postmortem findings.

In conclusion, the dose levels of 1000, 150 and 15 mg/kg/day of BMS 233101-01 were considered non-toxic levels, when administered daily for 4 weeks by the oral route. Therefore, the high dose level of 1000 mg/kg/day was considered a NOEL (No Observed Effect Level).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
1

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

No effects seen up the to the highest dose tested of 1000 mg/kg