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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
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:
according 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:
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
Vehicle:
olive oil
Remarks:
dissolved
Details on exposure:
5 mL/kg dosing volume
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
Details on study design:
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

Examinations

Parental animals: Observations and examinations:
Mortality: At 100 mg/kg: Males = none; Females = 1/12 (gestation day 22, under parturition)
Clinical Signs: At 100 mg/kg: soiled perigenitalial region (M/F); decreased fecal volume (M/F)
Body weight: At 100 mg/kg, decreased weight gain initial period (MF, RF)
Food consumption: At 100 mg/kg, decreased in week 1, increased in week 2 (M/F)
Hematology: 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)
Blood chemistry: 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)
Oestrous cyclicity (parental animals):
100 mg/kg dose: prolonged estrous cycle, abnormal parturition (2/11)
Litter observations:
Decreased birth index, decrease number of live pups on postnatal days 0 and 4.
Postmortem examinations (parental animals):
Organ weight: 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), epididymis A dec (M, RM[tendency]), epididymis R dec (M, RM[tendency])
Pathology:
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)

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
At 100 mg/kg: soiled perigenitalial region (M/F); decreased fecal volume (M/F)
Mortality:
mortality observed, treatment-related
Description (incidence):
At 100 mg/kg: Males = none; Females = 1/12 (gestation day 22, under parturition)
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
At 100 mg/kg, decreased weight gain initial period (MF, RF)
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
At 100 mg/kg, decreased in week 1, increased in week 2 (M/F)
Haematological findings:
effects observed, treatment-related
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)
Clinical biochemistry findings:
effects observed, treatment-related
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)
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
effects observed, treatment-related
Description (incidence and severity):
prolonged estrous cycle
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
abnormal parturition (2/11)

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
20 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive function (oestrous cycle)
reproductive performance

Target system / organ toxicity (P0)

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
100 mg/kg bw/day (nominal)
Organ:
cauda epididymis
testes

Results: F1 generation

General toxicity (F1)

Clinical signs:
not examined
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
decreased birth index, decrease number of live pups on days 0 and 4
Gross pathological findings:
not examined

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
20 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
mortality

Overall reproductive toxicity

Key result
Reproductive effects observed:
yes
Lowest effective dose / conc.:
100 mg/kg bw/day (nominal)
Treatment related:
yes
Relation to other toxic effects:
not specified

Applicant's summary and conclusion

Conclusions:
For reproductive and developmental toxicity, the endpoint for a NOAEL/NOEL was a decreased weight of epididymis and tublar atrophy of a rat, and abnormalities of delivery and a decrease in number of pups born in the 100 mg/kg dosed group. NOAEL/NOEL = 20 mg/kg/day
Executive summary:

For reproductive and developmental toxicity, the endpoint for a NOAEL/NOEL was a decreased weight of epididymis and tublar atrophy of a rat, and abnormalities of delivery and a decrease in number of pups born in the 100 mg/kg dosed group.  NOAEL/NOEL = 20 mg/kg/day