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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2013

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Isonicotinonitrile
EC Number:
202-856-2
EC Name:
Isonicotinonitrile
Cas Number:
100-48-1
Molecular formula:
C6H4N2
IUPAC Name:
isonicotinonitrile
Specific details on test material used for the study:
Purity 99.65%

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Remarks:
Crl:CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
9 weeks old at initiation of dosing

Administration / exposure

Route of administration:
oral: gavage
Details on route of administration:
5 mL/kg dosing volume
Vehicle:
olive oil
Remarks:
dissolved
Duration of treatment / exposure:
males - 42 days dosing period
females - 42-50 days (from 14 days before mating to day 4 of lactation)
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
4 mg/kg bw/day (nominal)
Dose / conc.:
20 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Males:
7 rats/group (control and high dose groups of main study) + 5 rats/group (control and high dose groups of recovery)
12 rats/group (low and middle dose groups of main study)
Females:
12 rats/group (all groups of main study) + 5 rats/group (control and high dose groups of recovery, satellite without mating)
Control animals:
yes, concurrent vehicle

Examinations

Sacrifice and pathology:
Males: day 43 of treatment and day 15 of recovery
Females: day 5 of lactation
Females (satellite): day 15 of recovery
Offspring: day 4 after birth

Results and discussion

Results of examinations

Description (incidence and severity):
At 100 mg/kg: soiled perigenitalial region (M/F); decreased fecal volume (M/F)
Description (incidence):
At 100 mg/kg: Males = none; Females = 1/12 (gestation day 22, under parturition)
Description (incidence and severity):
At 100 mg/kg, decreased weight gain initial period (MF, RF)
Description (incidence and severity):
At 100 mg/kg, decreased in week 1, increased in week 2 (M/F)
Description (incidence and severity):
At 100 mg/kg, decreased RBC, decreased eosinophil%; increased MCH; increased MCHC (M only); increased MCV (M tendency, RM), increased RET (MF, RM), increased Plt (F only); decreased neutrophil%, increased lymphocyte% (F only)
Description (incidence and severity):
TP inc, Alb inc, A/G inc, T-Bil inc (MF), T-Cho inc, PL inc, Glu dec, BUN dec, Cl dec (M), ALP inc, K inc, TG dec, ALT dec (F)
Description (incidence and severity):
Males only - No effects in any dosage groups
Description (incidence and severity):
20 mg/kg group: liver A, R inc (M), liver R inc (F)
100 mg/kg group: liver A,R inc (MF, RM, RF); kidney A, R inc (MF); kidney A inc (RM,RF), edipidiymis A dec (M, RM[tendency]), edipidiymis R dec (M, RM[tendency])
Description (incidence and severity):
20 mg/kg dose:
Liver: centrilobular hepatocyte hypertrophy (M 1/12, F 2/12), centriolobular fatty change (M 1/12).
Kidney: eosinophilic body in proximal tubule (M 7/12).

100 mg/kg dose:
Dead female (F 1/12)
Liver: centrilobular necrosis, centriolbular fatty change, centrilobular single cell necrosis, anisonucleosis
Kidney: tubular necrosis, hyaline cast
Survivals
Liver: centrilobular hepatocyte hypertrophy (M 7/7, F 11/11, RM 1/5, RF 1/5), centrilobular fatty change (M 7/7, F 9/11, RM 2/5, RF 5/5), centrilobular single cell necrosis (F 2/11), inflammatory cell nest (F 6/11, RF 5/5), anisonucleosis (F 10/11, RF 5/5), extramedullary hemapoiesis (F 2/11)
Kidney: eosinophilic body in proximal tubule (M 7/7, RM 5/5), tubular necrosis / hyaline cast (F 1/11)
Spleen: extramedullary hematopiesis (F 2/11)
Testis: tubular atrophy (M 1/7)
Epididymis: debris of spermatic elements (M 1/7)

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
4 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
gross pathology
haematology
Key result
Dose descriptor:
NOAEL
Effect level:
4 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
gross pathology
haematology
Key result
Dose descriptor:
NOEL
Effect level:
4 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
gross pathology
haematology
Key result
Dose descriptor:
NOEL
Effect level:
4 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
gross pathology
haematology

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
100 mg/kg bw/day (nominal)
System:
other: multiple systems
Organ:
erythrocyte development
liver
testes
Treatment related:
yes

Applicant's summary and conclusion

Conclusions:
The endpoint for NOAEL/NOEL was effects on the liver including an increased liver weight in both sexes given 20 mg/kg/day and above. It was concluded that an NOAEL/NOEL for repeated dose toxicity of 4-Cyanopyridine was 4 mg/kg/day for both sexes.
Executive summary:

The endpoint for NOAEL/NOEL was effects on the liver including an increased liver weight in both sexes given 20 mg/kg/day and above.  It was concluded that an NOAEL/NOEL for repeated dose toxicity of 4-Cyanopyridine was 4 mg/kg/day for both sexes.