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Diss Factsheets

Administrative data

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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2000

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
429-080-9
EC Name:
-
Cas Number:
198904-85-7
Molecular formula:
C17 H21 N3 O2
IUPAC Name:
Tert-butyl 2-[4-(2-pyridinyl) phenylmethyl] hydrazine carboxylate
Test material form:
solid: bulk
Specific details on test material used for the study:
Identity of test material same as for substance defined in section 1

Test animals

Species:
rat
Details on species / strain selection:
Rat, Crl:WI(Glx)
Sex:
male/female

Administration / exposure

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

Results and discussion

Results of examinations

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.

Effect levels

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

Target system / organ toxicity

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

Applicant's summary and conclusion

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.