BMS 233110-01

Endpoint summary

Description of key information

The objective of the study was to determine the toxicity of the test article, BMS-233110-01, following oral (gavage) administration to the rat for 28 days. The following dose levels were selected: 0, 16.5, 55.0, and 165.0. There were no unscheduled deaths. Post dosing clinical signs included salivation and piloerection in treated animals, excessive activity occasional observations of straub tail in high dose animals. Reduced body weight gain was apparent in high dose animals and to a lesser extent in intermediate dose animals. Reduced food consumption was noted in high dose animals. There were occasional observations of aggression upon removal from the cage and a higher incidence of rough/stained fur in high dose animals. High dose males also had a reduced hind limb footsplay and forelimb and hindlimb grip strength. There was some evidence of a slight reduction in the motor activity of intermediate and high dose animals. There was a reduced plasma alanine aminotransferase in high dose animals. The plasma urea and bilirubin concentrations were increased in intermediate and high dose animals and the plasma total cholesterol concentration was increased in high dose animals. Intermediate and high dose animal had an increased adrenal weight and intermediate and high dose animals of both sexes had an increased liver weight at terminal necropsy. There were no macroscopic findings suggestive of any systemic test article toxicity.

 

Microscopically, there was minor tubular vacuolation in the kidney and minor centrilobular hypertrophy in the liver of most high dose and some intermediate dose animals. The no effect level (NOEL) was the low dose.

 

In conclusion, administration of BMS-233110-01 to rats for 28 days at dosages of 55 mg/kg/day and above was mainly associated with, reduced body weight gain and food intake, changes in plasma clinical chemistry parameters, increased adrenal and liver weight, microscopic observations of tubular vacuolation in the kidney and centrilobular hypertrophy in the liver. There was some evidence of an effect of treatment on the central nervous system. The NOEL was considered to be 16.5 mg/kg/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral, other

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

GLP compliance:

yes

Limit test:

no

Specific details on test material used for the study:

Identity of test material same as for substance defined in section 1

Species:

rat

Details on species / strain selection:

Rat, Crl:WI(Glx)

Sex:

male/female

Route of administration:

oral: unspecified

Vehicle:

arachis oil

Details on oral exposure:

Method of administration: Gavage

Duration of treatment / exposure:

Test duration: 28 days

Frequency of treatment:

Dosing regime: 7 days/week

No. of animals per sex per dose:

Male: 5 animals at 16.5 mg/kg bw/day
Male: 5 animals at 55 mg/kg bw/day
Male: 5 animals at 165 mg/kg bw/day
Female: 5 animals at 16.5 mg/kg bw/day
Female: 5 animals at 55 mg/kg bw/day
Female: 5 animals at 165 mg/kg bw/day

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Endpoint Effect level Based on Sex Basis for effect level / Remarks
NOAEL 16.5 mg/kg bw/day (nominal) original NCD unit is mg/kg/day.

Mortality:

mortality observed, treatment-related

Description (incidence):

yes:There were no unscheduled deaths. Post dosing clinical signs included salivation and piloerection in treated animals, excessive activity occasional observations of straub tail in high dose animals

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Reduced body weight gain was apparent in high dose animals and to a lesser extent in intermediate dose animals

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Reduced food consumption was noted in high dose animals

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

yes: There was a reduced plasma alanine aminotransferase in high dose animals. The plasma urea and bilirubin concentrations were increased in intermediate and high dose animals and the plasma total cholesterol concentration was increased in high dose animals.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

yes: Clinical chemistry indicated lower plasma alanine aminotransferase activity in high dose group animals

Gross pathological findings:

no effects observed

Description (incidence and severity):

no effects - There were no macroscopic findings suggestive of any systemic test article toxicity.

Details on results:

Clinical observations:
Clinical signs reported following administration included salivation and piloerection, excessive activity and occasional observations of straub tail in high dose animals.
High dose males had a reduced hindlimb footsplay and reduced forelimb and hindlimb grip strength.

Laboratory findings:
Clinical chemistry indicated lower plasma alanine aminotransferase activity in high dose group animals.

The group mean plasa urea concentration and the plasma total bilirubin concentration of intermediate and high dose animals was above controls for both males and females. The group mean plasma total cholesterol concentration of high dose males and females was above control values.

Effects in organs:
There were no dose-related macroscopic effects in organs although an effect on weight of adrenals and livers were noted for the high and intermediate groups.
Microscopic examination showed minor tubular vacuolation in the kidney and centrilobular hypertrophy in the liver in the high dose and some intermediate dose animals.

Key result

Dose descriptor:

NOAEL

Effect level:

16.5 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical biochemistry

Critical effects observed:

yes

Lowest effective dose / conc.:

55 mg/kg bw/day (nominal)

System:

other: liver, kidney and CNS

Organ:

adrenal glands

kidney

liver

Treatment related:

yes

Conclusions:

In conclusion, administration of BMS-233110-01 to rats for 28 days at dosages of 55 mg/kg/day and above was mainly associated with, reduced body weight gain and food intake, changes in plasma clinical chemistry parameters, increased adrenal and liver weight, microscopic observations of tubular vacuolation in the kidney and centrilobular hypertrophy in the liver. There was some evidence of an effect of treatment on the central nervous system. The NOEL was considered to be 16.5 mg/kg/day.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

16.5 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

1