Registration Dossier
Registration Dossier
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EC number: 430-900-2 | CAS number: 192725-50-1
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- June 09 - July 07, 1999
- 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:
- 1 999
- Report date:
- 1999
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Version / remarks:
- Directive 96/54
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Qualifier:
- according to guideline
- Guideline:
- other: Annex V of EEC Directive 92/32 (7th amendment)
- GLP compliance:
- yes
- Remarks:
- OECD[C(81)30 final]
- Limit test:
- no
Test material
- Reference substance name:
- -
- EC Number:
- 430-900-2
- EC Name:
- -
- Cas Number:
- 192725-50-1
- Molecular formula:
- Hill formula: C9H16N2O3 CAS formula: C9H16N2O3
- IUPAC Name:
- 3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanoic acid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Sprague DawleyCrl:CD(SD)BR
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Italia S.p.A. CALCO (Lecco) Italy
- Age at study initiation: approx. 4 weeks
- Weight at study initiation: males; 75-85g, females; 60-70g.
- Housing: wire cages.
- Diet: 4 RF 21 GLP Top Certificate.
- Water: ad libitum
- Acclimation period: 3 weeks approx.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity: 55±10%
- 20 air changes per hour
- Photoperiod (hrs dark / hrs light):12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 0.2% Hydroxypropyl methylcellulose in water.
- Details on oral exposure:
- Method of administration:
Gavage - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- C.o.A. provided by supplier indicate contents of diet were ±5% of the declared contents.
- Duration of treatment / exposure:
- Test duration: 28 days
- Frequency of treatment:
- Dosing regime: once daily, 7 days/week
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
0 mg/kg
Basis:
other: gavage
- Remarks:
- Doses / Concentrations:
50mg/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: 5 animals at 0 mg/kg bw/day
Male: 5 animals at 50 mg/kg bw/day
Male: 5 animals at 150 mg/kg bw/day
Male: 5 animals at 500 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 50 mg/kg bw/day
Female: 5 animals at 150 mg/kg bw/day
Female: 5 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
- Positive control:
- n/a
Examinations
- Observations and examinations performed and frequency:
- All rats observed twice daily during treatment for mortality.
Daily observations for physical appearance, behavior and clinical signs were also performed.
At week 4 of treatment the animals were also examined for signs of neurological changes.
Formulation of different test concentrations were prepared for each dosage level so that all rats received a constant volume of 10mg/kg, adjusted weekly on the basis of the most recently determined body weights.
BODY WEIGHT:
- Time schedule for examinations: The day before dosing commenced and then at weekly intervals. - Sacrifice and pathology:
- At the end of the 4 week dosing period, the body weight of each animal that had been fasted overnight (about 16 hrs) was recorded before the animal was sacrificed for pathology investigation (organ weight, gross pathology and histology).
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No deaths or clinical abnormalities were seen at any dose.
- Mortality:
- no mortality observed
- Description (incidence):
- No deaths or clinical abnormalities were seen at any dose.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No treatment related effects were found.
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- No modification was seen
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- No treatment related effects were found.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- No treatment related effects were found.
- Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- No treatment related effects were found.
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- No treatment related modifications were observed.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No treatment related changes were seen.
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No treatment related effects were observed
- Details on results:
- CLINICAL SIGNS:
MORTALITY: No animals died during the study
Effect levels
- Dose descriptor:
- NOEL
- Effect level:
- 500 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: after 4 weeks of daily dosing
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- The no-toxic-effect level ws considered to be 500mg /kg/day in this study.
- Executive summary:
Abbott-164220.0 when given to Sprague Dawley rats by oral route for 4 consecutive weeks at dosages of 50, 150 and 500mg/kg/day, was well tolerated up to and including the highest dosage tested, inducing no signs of toxicity.
The dosage of 50mg/kg/day of Abbott-164220.0 may be considered the NOEL in rats after 4 weeks of consecutive daily administrations.
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