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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
Data from secondary source

Data source

Reference
Reference Type:
secondary source
Title:
A 28 day feeding study in mice with isophthalonitrile.
Author:
HPVIS database
Year:
2006
Bibliographic source:
HPVIS, United States Environmental protection, 2006

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Reproductive Toxicity study of 1,3 Benzenedicarbonitrile was performed on rats by oral route
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (IUPAC name): 1,3-Benzenedicarbonitrile
- Common name: 1,3-Dicyanobenzene
- Molecular formula: C8H4N2
- Molecular weight: 128.134 g/mol
- Smiles notation: c1c(cccc1C#N)C#N
- InChl: 1S/C8H4N2/c9-5-7-2-1-3-8(4-7)6-10/h1-4H
- Substance type: Organic
Specific details on test material used for the study:
- Name of test material (IUPAC name): 1,3-Benzenedicarbonitrile
- Common name: 1,3-Dicyanobenzene
- Molecular formula: C8H4N2
- Molecular weight: 128.134 g/mol
- Smiles notation: c1c(cccc1C#N)C#N
- InChl: 1S/C8H4N2/c9-5-7-2-1-3-8(4-7)6-10/h1-4H
- Substance type: Organic

Test animals

Species:
rat
Strain:
not specified
Details on species / strain selection:
No data available
Sex:
male/female
Details on test animals and environmental conditions:
Details on test animals and env. conditions
TEST ANIMALS
- Source:
- Age at study initiation: 45 days
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g
- Fasting period before study:
- Housing:
- Use of restrainers for preventing ingestion (if dermal): yes/no
- Diet (e.g. ad libitum): fed PurinaB Certified Rodent Chow No. 5002 ad libitum.
- Water (e.g. ad libitum): fresh tap water ad libitum.

- Acclimation period:16 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):

IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
oral: feed
Vehicle:
not specified
Details on exposure:
Details on exposure
PREPARATION OF DOSING SOLUTIONS:
Test material mixed with fed
DIET PREPARATION
- Rate of preparation of diet (frequency): After initiation of mating on Study Day 81, diets were prepared weekly at constant concentration based on Week 11 body weight and food consumption data for the remainder of the study
- Mixing appropriate amounts with (Type of food )
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle:
- Amount of vehicle (if gavage): No data available

- Lot/batch no. (if required): No data available
- Purity: No data available
Details on mating procedure:
- M/F ratio per cage:
- Length of cohabitation: 14days
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: [no / yes (explain)]
- After successful mating each pregnant female was caged (how):
- Any other deviations from standard protocol:
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
122 days
Frequency of treatment:
Daily
Details on study schedule:
No data available
Doses / concentrations
Remarks:
0, 5, 10, 25 and 50 mg/kg/day.
No. of animals per sex per dose:
Total:250
0 mg/kg bw/day:25 male and 25 female
5 mg/kg bw/day:25 male and 25 female
10mg/kg bw/day:25 male and 25 female
25mg/kg bw/day:25 male and 25 female
50mg/kg bw/day:25 male and 25 female

Control animals:
yes, plain diet
Details on study design:
No data available
Positive control:
No data available

Examinations

Parental animals: Observations and examinations:
Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes

DETAILED CLINICAL OBSERVATIONS: Yes

Time schedule: daily


BODY WEIGHT: Yes
Time schedule for examinations: daily (Rats were mated for a total of 14 days during which no body weight measurements were recorded. )
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes Food consumption was determined weekly.

Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes ( Rats were mated for a total of 14 days during which no food consumption measurements were recorded. )
Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data available


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
Time schedule for examinations:

Oestrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
No data available
Postmortem examinations (parental animals):
Postmortem examinations (Parent Animal)
SACRIFICE :
Male animals: All surviving animals [describe when, e.g. as soon as possible after the last litters in each generation were produced.]: yes
Maternal animals: yes ( Ten animals per sex from each group were killed after at least 31 days on the test diets, and the remaining 15 of each sex per group on day 122

GROSS NECROPSY: yes
HISTOPATHOLOGY / ORGAN WEIGHTS: yes
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.:
macroscopic examination was performed
Postmortem examinations (offspring):
No data available
Statistics:
No data available
Reproductive indices:
No data available
Offspring viability indices:
No data available

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Compound-related effects on body weight and body weight gain with corresponding changes in food consumption were observed in males at 25 and 50 mg/kg/day and females at 10, 25 and 50 mg/kg/day during the 28- day feeding phase of the study.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Clinical chemistry analyses revealed significant increases in ALT in males at 10 and 50 mg/kg/day and in females at 10 mg/kg/day and higher. In addition, serum cholesterol was in 50mg/kg bw dose group males than controls.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Urine volume was higher and specific gravity was lower in males at 25 and 50 mg/kg/day and females at 50 mg/kg/day.
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathologic examinations revealed compound-related increases in the incidence of centrilobular hepatocytomegaly in males and females at 50 mg/kg/day and males at 25 mg/kg/day. Furthermore, a compound related increase in hyaline droplet formation was noted in the kidneys of males when compared to controls. No females exhibited this finding. Hyaline droplet formation in the proximal tubular epithelium of kidneys in male rats is indicative of abnormal accumulation of alpha-2 m-globulin, a protein reported to be unique to the rat
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
parental reproductive parameters appeared to be unaffected . No compound-related effects were seen on mating, fertility or gestation length .Apparent compound-related reproductive effects on offspring survival in utero were noted. This was evidenced by an increase in the number of stillborn pups with a corresponding decrease in the number of live born pups and litter size at 50 mg/kg/day. Similar effects were not observed at lower dietary concentrations,(10,25 mg/kg /day)

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
25 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
reproductive performance
Remarks on result:
other: No effects were seen on mating, fertility or gestation length
Dose descriptor:
LOEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: on the bases of an increase in the number of stillborn pups with a corresponding decrease in the number of live born pups and litter size at 50 mg/kg/day.
Remarks on result:
other: on the bases of an increase in the number of stillborn pups with a corresponding decrease in the number of live born pups and litter size at 50 mg/kg/day.

Target system / organ toxicity (P0)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Effect levels (F1)

Dose descriptor:
other: not specified
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: not specified
Remarks on result:
other: not specified

Target system / organ toxicity (F1)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Overall reproductive toxicity

Reproductive effects observed:
no
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
No Observed Adverse Effect Level (NOAEL) was considered to be 25mg/kg/day, on the bases of No compound-related effects were seen on mating, fertility or gestation length and LOAEL was considered to be 50mg/g bw , on the bases of an increase in the number of stillborn pups with a corresponding decrease in the number of live born pups and litter size at 50 mg/kg/day. When male and female rats were treated with 1,3-Benzenedicarbonitrile (626-17-5) orally.
Executive summary:

The reproductive toxicity study of1,3-Benzenedicarbonitrile (626-17-5) was performed in male and female rats. The teat material mixed with fedPurinaB Certified Rodent Chow No. 5002 in dose concentration 0, 5, 10, 25 and 50 mg/kg/day. The concentration of test material administered to the rats was adjusted weekly in order to achieve as closely as possible the desired dietary intake of treatment. The achieved dosages of test material were calculated at the end of each week based on the dietary concentrations and body weights and food consumption for that week. After initiation of mating on Study Day 81, diets were prepared weekly at constant concentration based on Week 11 body weight and food consumption data for the remainder of the study. Control animals were fed PurinaB Certified Rodent Chow No. 5002 without test substance ad libitum and fresh tap water was available ad libitum. 25 rats of each sex were assigned to each group. Ten animals per sex from each group were killed after at least 31 days on the test diets, and the remaining 15 of each sex per group were exposed to test material for a total of at least 122 days. For the one-generation reproduction phase, mating commenced of Week 11. Rats were mated for a total of 14 days during which no body weight or food consumption measurements were recorded.  

Compound-related effects on body weight and body weight gain with corresponding changes in food consumption were observed in males at 25 and 50 mg/kg/day and females at 10, 25 and 50 mg/kg/day during the 28- day feeding phase of the study. Histopathologic examinations revealed compound-related increases in the incidence of centrilobular hepatocytomegaly in males and females at 50 mg/kg/day and males at 25 mg/kg/day. Furthermore, a compound related increase in hyaline droplet formation was noted in the kidneys of males when compared to controls. No females exhibited this finding. Hyaline droplet formation in the proximal tubular epithelium of kidneys in male rats is indicative of abnormal accumulation of alpha-2 m-globulin, a protein reported to be unique to the rat. Clinical chemistry analyses revealed significant increases in ALT in males at 10 and 50 mg/kg/day and in females at 10 mg/kg/day and higher. In addition, serum cholesterol was in 50mg/kg bw dose group males than controls.

Urine volume was higher and specific gravity was lower in males at 25 and 50 mg/kg/day and females at 50 mg/kg/day. parental reproductive parameters appeared to be unaffected . No compound-related effects were seen on mating, fertility or gestation length .Apparent compound-related reproductive effects on offspring survival in utero were noted. This was evidenced by an increase in the number of stillborn pups with a corresponding decrease in the number of live born pups and litter size at 50 mg/kg/day. Similar effects were not observed at lower dietary concentrations,(10,25 mg/kg /day).Hence in the 28-day feeding phase ,LOEL was considered to be 5mg/kg bw in male rats because of the increased incidence of hyaline droplet formation in the kidneys of males at all dietary levels. The LOEL was considered to be 10mg/kg bw for females. Based on the reductions in body weight, body weight gain, food consumption and increases in ALT at 10 mg/kg/day and higher, While for the reproductive phase No Observed Adverse Effect Level (NOAEL) was considered to be 25mg/kg/day, on the bases ofNo compound-related effects were seen on mating, fertility or gestation length.and LOAEL was considered to be 50mg/g bw , on the bases of an increase in the number of stillborn pups with a corresponding decrease in the number of live born pups and litter size at 50 mg/kg/day.When male and femalerats were treated with1,3-Benzenedicarbonitrile (626-17-5)orally.