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Diss Factsheets

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Jan 17 - Feb 28, 1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: done under GLP and OECD method

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Version / remarks:
Subacute Toxicity (oral)
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of International Trade and Industry Notification Nr.2
GLP compliance:
yes
Remarks:
21 CFR 28
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
A mixture of: bis(1S,2S,4S)-(1-benzyl-4-tert-butoxycarboxamido-2-hydroxy-5-phenyl)pentylammonium succinate; isopropyl alcohol
EC Number:
414-810-0
EC Name:
A mixture of: bis(1S,2S,4S)-(1-benzyl-4-tert-butoxycarboxamido-2-hydroxy-5-phenyl)pentylammonium succinate; isopropyl alcohol
Cas Number:
144163-85-9
Molecular formula:
Empirical formula: C25H35N2O5
IUPAC Name:
butanedioic acid; propan-2-ol; bis(tert-butyl N-[(4R)-5-amino-4-hydroxy-1,6-diphenylhexan-2-yl]carbamate)

Test animals

Species:
rat
Strain:
other: Sprague Dawley Crl:CD®BR
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Portage, Michiga
- Age at study initiation: 28 - 35 days
- Weight at study initiation: 170 - 240g at the start of treatment.
- Housing: ventilated, hanging stainless steel, wire bottomed cages.
- Diet: Certified Rodent Chow, ad libitum
- Water: ad libitum
- Acclimation period: 1 day followed by 8 days pretreatment).

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 71±6
- Humidity (%): ambient
- Photoperiod (hrs dark / hrs light):12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.2% Hydroxypropyl methyl cellulose
Details on oral exposure:
Method of administration:
Gavage
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of the dosing formulations were sent for assay analysis in weeks 1 and 4 of the test period.

At the end of the treatment period a sample of the bulk test article was sent for analysis to verify stability over the treatment period.
Duration of treatment / exposure:
Test duration: 28 - 42 days
Frequency of treatment:
Dosing regime: 7 days/week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 mg/kg
Basis:
other: gavage
Remarks:
Doses / Concentrations:
15mg/kg
Basis:
other: gavage
Remarks:
Doses / Concentrations:
150mg/kg
Basis:
other: gavage
Remarks:
Doses / Concentrations:
500mg/kg
Basis:
other: gavage
No. of animals per sex per dose:
Male: 10 animals at 0 mg/kg bw/day
Male: 5 animals at 15 mg/kg bw/day
Male: 10 animals at 150 mg/kg bw/day
Male: 10 animals at 500 mg/kg bw/day

Female: 10 animals at 0 mg/kg bw/day
Female: 5 animals at 15 mg/kg bw/day
Female: 10 animals at 150 mg/kg bw/day
Female: 10 animals at 500 mg/kg bw/day

6 males and 10 females in the 500mg/kg/day group were either found dead or euthanized in a moribund condition by day 14. Consequently, the remaining animals in this group were reduced to a daily dosage of 300mg/kg/day
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on acute oral toxicity testing results
- Rationale for animal assignment: random
Positive control:
n/a

Examinations

Observations and examinations performed and frequency:
All rats observed twice daily during pretreatment, treatment and recovery for survival and general condition.
Physical condition and behavior recorded 1-2 hrs after the daily dose at least 2 days per week during the treatment period and weekly during the recovery period at approx the same time each day.

Formulation of different test concentrations were prepared for each dosage level so that all rats received a constant volume of 10mg/kg with each treatment.

BODY WEIGHT: Yes
- Time schedule for examinations: At least twice during pretreatment and at least twice weekly during treatment and recovery for all rats in the study
Sacrifice and pathology:
All rats that died during the study were necropsied as soon as practicable. Those that became moribund or deemed unlikely to survive until the next day were euthanized and necropsied.

Up to 5 males and 5 females from each group were fasted overnight, euthanized and necropsied at the end of the treatment and recovery periods.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
On days 6-8, seven rats, 1 male and 6 females, in the 500mg/kg/day dosage group were found dead or were euthanized in a moribund condition.
Mortality:
mortality observed, treatment-related
Description (incidence):
On days 6-8, seven rats, 1 male and 6 females, in the 500mg/kg/day dosage group were found dead or were euthanized in a moribund condition.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Lower mean body weight values were observed (30-35%) in both males and females in 500-300mg/kg group compared to control group.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
No statistically significant difference to control groups among the low and mid dosage groups
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
In 500-300mg/kg grp, increses in ALP, ALT and AST activities. Increase in BUN values in some rats also.
Urinalysis findings:
no effects observed
Description (incidence and severity):
No toxicological differences with control group.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
No difference between weights observed at the end of treatment and recovery period. However, marginal incs versus control for mean absolute and relative liver wts (in males and females) on 150mg/kg/day at end of treatment period.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment-related gross observations were present in the rats that completed the study.
Details on results:
CLINICAL SIGNS:

MORTALITY: 6 males and 10 females in the 500mg/kg/day group were either found dead or euthanized in a moribund condition by day 14. Consequently, the remaining animals in this group were reduced to a daily dosage of 300mg/kg/day

Effect levels

open allclose all
Dose descriptor:
NOEL
Effect level:
15 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical biochemistry
clinical signs
haematology
mortality
organ weights and organ / body weight ratios
Remarks on result:
not measured/tested
Remarks:
Effect level not specified (migrated information)

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Recovery group animals were only assigned to group T2 after it became apparent that T3 treatment group animals would not survive completion of the treatment period. Since T2 recovery animals were not part of the original assignment to treatment, and these animals began treatment 10 days after the start of treatment for all other study animals it was decided to exclude data from the T2 recovery animals from all statistical an alysis.

Applicant's summary and conclusion

Conclusions:
The no-toxic-effect level ws considered to be 15mg base/kg/day in this study.
Executive summary:

The oral administration of Abbott-88820 at dosages of 150-500mgm/kg/day resulted in severe gaseous distension of the gastrointestinal tract and ultimately death in numerous rats. In surviving animals at a dosage of 150mg/kg/day, signs of toxicity were limited to hepatocellular.