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Description of key information

A 28-day repeated dose oral toxicity study on rats was carried out for substance BMS 217947-01. The study was carried out according to OECD guidance 407. Separate groups of 5 male and 5 female animals were each exposed to concentrations of 0, 15, 150 and 1000 mg/kg bw/day. No deaths were recorded during the 28-day. However, a number of adverse effects were observed at the test concentration of 1000 and 150 mg/kg/day when administered daily for 4 weeks by the oral route, based on dose-related increases in liver weights and associated hepatic and/or renal pathology. Therefore, the low dose level of 15 mg/kg/day was considered a NOEL (No Observed Effect Level).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2nd July 1999 - 21 Sept 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: done under GLP and OECD method
Qualifier:
according to guideline
Guideline:
other: OECD Guideline No. 407 "Repeated Dose 28-day Oral Toxicity Study in Rodents".
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: unspecified
Vehicle:
peanut 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 0 mg/kg bw/day
Male: 5 animals at 15 mg/kg bw/day
Male: 5 animals at 150 mg/kg bw/day
Male: 5 animals at 1000 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 15 mg/kg bw/day
Female: 5 animals at 150 mg/kg bw/day
Female: 5 animals at 1000 mg/kg bw/day
Clinical signs:
no effects observed
Description (incidence and severity):
There were no clinical signs of treatment or significant differences in body weights and feed consumption noted in any group during the four weeks of dosing. There were no significant differences in motor activity or functional observation battery during the fourth week of dosing. The procedures used for the functional observational battery were confirmed to be suitable for detecting major neurotoxic endpoints by the use of positive control substances including chloropromazine, D-amphetamine and physostigmine.
Mortality:
no mortality observed
Description (incidence):
All animals survived the four weeks of dosing.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
The only significant differences in feed consumption were increases in the 1000mg/kg male animals in weeks 2, 3 and 4 and increases in the 1000mg/kg female animals in week 4, compared to Group I during the four weeks of dosing. These were not considered toxicologically significant since increases in feed consumption are not used usually considered an adverse response to treatment.
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Significant increases in cholesterol, Globulin and Gamrna-Glutamyl Transferase levels and there were statistically significant decreases for Albumin/Globulin Ratio and Chloride observed in females treated with 1000mg/kg. There were no other toxicologically significant differences in haematology or clinical chemistry values. For the male animals, there was a statistically significant increase in the 1000mg/kg group for Total Bilirubin. None of these differences were clearly considered of toxicological significance.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
The only statistically significant difference in organ weights was an increase in absolute and/or relative (to body weight and to brain weight) liver weights for the 1000mg/kg male animals and female animals compared to controls. The observations in the liver may correlate with the microscopic pathology
Gross pathological findings:
no effects observed
Description (incidence and severity):
Other than increased liver weights, there were no macroscopic findings attributable to treatment with the test substance.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Microscopically, slight to moderate centrilobular epatocytic hypertrophy was present in most of the animals administered 1000 mg/kg/day and in 2/5 of the male and female animals administered 150 mg/kg/day. This finding is suggestive of an adaptive change resulting from the increased metabolic demand on the liver following repeated administration of a xenobiotic. The kidneys from 4/5 of the male animals administered 1000 mg/kg/day showed cytoplasmic eosinophilic droplets in the proximal tubular epithelium of the kidney. The appearance and location of these inclusions is suggestive of a2 microglobulin induced nephropathy. This is a lesion, specific to the male rat, which has been described following administration of a variety of chemicals and pharmacological agents. Accumulation of a2 microglobulin in the lysosome can lead to cell death that can stimulate restorative cell replication promoting renal carcinogenesis in male rats. It is a finding considered to have limited significance and relevance to humans. In addition males treated with 1000mg/kg of the substance displayed lymphocytolysis in the thymus gland.
Details on results:
Clinical observations:
All animals survived the four weeks of dosing. There were no clinical signs of treatment or significant differences in body weights and feed consumption noted in any group during the four weeks of dosing. There were no significant differences in motor activity or functional observation battery during the fourth week of dosing. The procedures used for the functional observational battery were confirmed to be suitable for detecting major neurotoxic endpoints by the use of positive control substances including chloropromazine, D-amphetamine and physostigmine.

Laboratory findings:
Significant increases in cholesterol levels were observed in females treated with 1000mg/kg. There were no other toxicologically significant differences in haematology or clinical chemistry values. A statistically significant increase in absolute and/or relative (to body weight and to brain weight) liver weights for the 1000 mg/kg/day dosed male and female animals compared to the control animals was observed. A significant increase in spleen weight was apparent in male rats treated with 15mg/kg. Decreases in thymus weight and increases in kidney weight were observed in males treated with the highest dose of the substance.

Effects in organs:
Other than increased liver weights, there were no macroscopic findings attributable to treatment with the test substance. Microscopically, slight to moderate centrilobular epatocytic hypertrophy was present in most of the animals administered 1000 mg/kg/day and in 2/5 of the male and female animals administered 150 mg/kg/day. This finding is
suggestive of an adaptive change resulting from the increased metabolic demand on the liver following repeated administration of a xenobiotic. The kidneys from 4/5 of the male animals administered 1000 mg/kg/day showed cytoplasmic eosinophilic droplets in the proximal tubular epithelium of the kidney. The appearance and location of these inclusions is suggestive of a2 microglobulin induced nephropathy. This is a lesion, specific to the male rat, which has been described following administration of a variety of chemicals and pharmacological agents. Accumulation of a2 microglobulin in the lysosome can lead to cell death that can stimulate restorative cell replication promoting renal carcinogenesis in male rats. It is a finding considered to have limited significance and relevance to humans. In addition males treated with 1000mg/kg of the substance displayed lymphocytolysis in the thymus gland.
Dose descriptor:
LOAEL
Effect level:
150 mg/kg bw/day (nominal)
Basis for effect level:
other: original NCD unit is mg/kg/day.
Dose descriptor:
NOEL
Effect level:
15 mg/kg bw/day (nominal)
Basis for effect level:
other: original NCD unit is mg/kg/day.
Critical effects observed:
not specified
Conclusions:
NOAEL and NOEL is < 15 mg/kg bw/day(nominal).
Executive summary:

A 28-day repeated dose oral toxicity study on rats was carried out for substance BMS 217947-01. The study was carried out according to OECD guidance 407. Separate groups of 5 male and 5 female animals were each exposed to concentrations of 0, 15, 150 and 1000 mg/kg bw/day. No deaths were recorded during the 28-day. However, a number of adverse effects were observed even at the lowest test concentration of 15 mg/kg bw/day. Therefore, a NOAEL/NOEL could not be derived and it is expected to be lower than 15 mg/kg bw/day (nominal).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Study duration:
subacute
Species:
rat

Additional information

Justification for classification or non-classification