[1,1'-Biphenyl]-2-carbonitrile, 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

30 July 1996 to December 1996

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study. GLP compliance

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1996

Report date:

1996

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

[1,1’-Biphenyl]-2-carbonitrile, 4’-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-

IUPAC Name:

[1,1’-Biphenyl]-2-carbonitrile, 4’-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-

Constituent 2

Reference substance name:

4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-ene-3-yl)methyl)(1,1'-biphenyl)-2-carbonitrile

EC Number:

604-075-6

Cas Number:

138401-24-8

Molecular formula:

C25H27N3O

IUPAC Name:

4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-ene-3-yl)methyl)(1,1'-biphenyl)-2-carbonitrile

Details on test material:

- Name of test material (as cited in study report): SR 47563
- Lot/batch No.: 6R00003
- purity: considered as 100% for dose calculation
- storage: at room temperature

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 0.5% methylcellulose aqueous solution

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

28 consecutive days

Frequency of treatment:

Daily

Doses / concentrations

Remarks:

Doses / Concentrations:
100, 300 and 600 mg/kg/day (volume injected was 5 ml/kg of preparations at 20, 60 and 120 mg/mL, once daily)
Basis:
actual ingested

No. of animals per sex per dose:

5 males and 5 females per group

Control animals:

yes

Results and discussion

Effect levels

1

Dose descriptor:

LOAEL

Effect level:

100 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: microscopic examinations

2

Dose descriptor:

NOAEL

Basis for effect level:

other: The authors claim that it has not been possible to establish a NOEL in this study, probably based on the significant hepatocellular hypertrophy recorded in all treated groups.

Remarks on result:

not determinable

Remarks:

no NOAEL identified

3

Dose descriptor:

NOEL

Remarks:

(Indicated in the study as no toxic effect level)

Effect level:

100 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: mortality, body weight, food consumption, organ weight, clinical signs, blood chemistry, heamatology, coagulation, macroscopic examination

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

No dose-related body weight decrease was observed in all treated groups throughout the treatment period.

No mortality was observed at 0, 300 and 600 mg/kg. At 100 mg/kg, one female was found dead on day 7. This death was related to incorrect intubation and not to treatment.

No abdormal clinical sign related to treatment was observed in all groups.

Blood clinical biochemistry showed an increase in total protein and globulin in all treated groups, an increase of albumin in males (300 mg/kg) and in females (300 and 600 mg/kg), an increase of total cholesterol in females (300 and 600 mg/kg), a decrease of ASAT in males (300 and 600 mg/kg) and in females (600 mg/kg), an increase of creatinine in females (600 mg/kg), an increase of calcium (300 and 600 mg/kg), a decrease of potassium in females (300 and 600 mg/kg).

Most red blood cell parameters were affected in females (300 and 600 mg/kg): decrease of red blood cell count, haemoglobin, packed cell volume, mean cell haemoglobin and mean cell haemoglobin concentration.

Activated partial thromboplastin time was increased as a function of the dose levels in males (300 and 600 mg/kg) and females (all treated groups).

Absolute and relative weights of liver were markedly increased as a function of the dose level. This increase was significant in 300 and 600 mg/kg. Hepatic enlargement was the only significant macroscopic change observed during necropsy. This increase was due to hepatocellular hypertrophy. This hypertrophy was dose related.

Applicant's summary and conclusion

Conclusions:

The test substance administrated at the dose levels of 100, 300 and 600 mg/kg/day was associated with slight hepatotoxicity. SR 47563 induced a dose-related hepatocellular hypertrophy. No significant macroscopic effects were recorded at 100 mg/kg/day (indicated as no toxic effect level).
The authors further claim that it has not been possible to establish a NOEL in this study. This is probably based on the observed hystopathological finding of significant hepatocellular hypertrophy in all treated groups. Therefore, the lowest dose group is indicated here as a LOAEL.