Isonicotinonitrile

Repeated dose toxicity: oral

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

Test material information

Constituent 1

Reference substance name:

Isonicotinonitrile

EC Number:

202-856-2

EC Name:

Isonicotinonitrile

Cas Number:

100-48-1

Molecular formula:

C6H4N2

IUPAC Name:

pyridine-4-carbonitrile

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 / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

4 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

20 mg/kg bw/day (nominal)

Doses / concentrations 4

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

1

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

2

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

3

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

4

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.