2,5-dioxopyrrolidin-1-yl N-{[methyl[[2-(1-methylethyl)-4-thiazolyl]methyl]amino]carbonyl}-.sc.l.sc.-valinate

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

May - June 1996

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:

1996

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))

Version / remarks:

Subacute Toxicity (oral)

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Test guideline 3

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of International Trade and Industry Notification Nr.2

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

424-660-8

EC Name:

-

Cas Number:

224631-15-6

Molecular formula:

Hill formula: C18H26N4O5S CAS formula: C18H26N4O5S

IUPAC Name:

2,5-dioxopyrrolidin-1-yl (2S)-3-methyl-2-{[methyl({[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl})carbamoyl]amino}butanoate

Test animals

Species:

rat

Strain:

other: Crl:CD®BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, Nth. Carolina
- Age at study initiation: approx. 6 weeks
- Weight at study initiation: 144 - 254g. Recovery rats in the 150g/kg/day dosage group weighed 175 - 378g at their delayed start of treatment.
- Housing: ventilated, hanging stainless steel, wire bottomed cages.
- Diet: Certified Rodent Chow, ad libitum
- Water: ad libitum
- Acclimation period: 14 days ( 6 days followed by 8 days pretreatment). 28 days for the 150k/kg/day recovery group.

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

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

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. All dosage formulations were within ±6% of the intended concentrations at all time points.

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 / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0 mg/kg
Basis:
other: gavage

Doses / concentrations 2

Remarks:

Doses / Concentrations:
15mg/kg
Basis:
other: gavage

Doses / concentrations 3

Remarks:

Doses / Concentrations:
150mg/kg
Basis:
other: gavage

Doses / concentrations 4

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: 5 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: 5 animals at 150 mg/kg bw/day
Female: 10 animals at 500 mg/kg bw/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 2-3 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: Twice during pretreatment and twice weekly during treatment and recovery. All surviving rats weighed on day of necropsy.

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.
All surviving male rats in the 500mg/kg/day group were fasted overnight, euthanized and necropsied on study day 14 following 14 days of consecutive treatment.
5 males and 5 females from each of the 0, 15 and 150mg/kg/day and 4 females from the 500mg/kg/day group were also euthanized and necropsied at the end of the treatment period.

Other examinations:

Microscopic examination of designated tissues did not reveal any test article-induced target organ pathology.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

6 male and 3 female mortalities

Mortality:

mortality observed, treatment-related

Description (incidence):

6 male and 3 female mortalities

Gross pathological findings:

no effects observed

Description (incidence and severity):

No changes in microscopic pathology

Details on results:

CLINICAL SIGNS:

MORTALITY: 5 males and 2 females at dosage of 500mg base/kg/day were found dead or euthanized in a moribund condition by study day 12.Due to excessive test article-related mortality, all surviving rats in the 500mg/kg/day group were necropsied on study day 14.

1 male and 1 female at dosage of 150mg base/kg/day were found dead by study day 6.

Effect levels

Dose descriptor:

NOEL

Effect level:

15 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

mortality

Target system / organ toxicity

Critical effects observed:

not specified

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-133816 to rats caused mortality in the 150 and 500mg/kg/day dosage groups. These deaths were attributed to a test article-related induction of gaseous extension of the gastrointestinal tract and associated abnormal respiration (gasping, noisy, laboured rales). There were no changes in microscopic pathology that could be directly attributed to test article administration.