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Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
Combined repeated dose and reproduction / developmental screening for test chemical
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data is from authoritative database J-check

Data source

Reference
Reference Type:
other: Authoritative database
Title:
Combined repeated dose and reproduction / developmental screening for test chemical
Author:
Ministry of Health, Labour and Welfare", "Ministry of the Environment" and "National Institute of Technology and Evaluation
Year:
2010
Bibliographic source:
Japan chemicals collborative knowledge database (J-check),2010

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)
Principles of method if other than guideline:
Combined repeated dose and reproduction / developmental screening was performed for test chemical
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1-methylpiperazine
EC Number:
203-639-5
EC Name:
1-methylpiperazine
Cas Number:
109-01-3
Molecular formula:
C5H12N2
IUPAC Name:
1-methylpiperazine
Test material form:
liquid
Details on test material:
Name of test material (as cited in study report): 1-methyl piperazine
Molecular formula : C5H12N2
Molecular weight : 100.1638 g/mol
Substance Type: Organic
Physical State: Liquid

Test animals

Species:
rat
Strain:
other: Crl:CD (SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
Age at study initiation of dosing: 10 weeks old / - Recovery: 0, 500 mg/kg/day

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
not specified
Details on exposure:
Not specified
Details on mating procedure:
Not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Male: 42 days / - Female: 42 - 58 days (from 14 days before mating to day 5 of lactation)
Frequency of treatment:
daily
Details on study schedule:
Not specified
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
80 mg/kg bw/day (actual dose received)
Dose / conc.:
200 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
Not specified
Control animals:
yes, concurrent vehicle
Details on study design:
Not specified
Positive control:
Not specified

Examinations

Parental animals: Observations and examinations:
Clinical signs, Body weight, food consumption, Organ weights, Gross pathology, Histopathology, Hematology, Food chemistry, Urinalysis
Reproductive performance
Oestrous cyclicity (parental animals):
Not specifed
Sperm parameters (parental animals):
Not specifed
Litter observations:
Not specifed
Postmortem examinations (parental animals):
Yes
Postmortem examinations (offspring):
Not specifed
Statistics:
Not specifed
Reproductive indices:
Not specifed
Offspring viability indices:
Not specifed

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Male: Decrease in the body weight gain (500 mg/kg/day, tendency), Decrease in the rate of body weight gain (500 mg/kg/day)
Female: Decrease in the body weight (500 mg/kg/day), Decrease in the body weight gain(200, 500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the rate of body weight gain (Recovery 500 mg/kg/day)
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Male: No effect
Female: Decrease in the food consumption (200 and 500 mg/kg/day)
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Male: Decrease in the WBC (200 and 500 mg/kg/day, tendency), Decrease in the RET (500 mg/kg/day), Decrease in the percentage of Eosinophil (500 mg/kg/day)
Female: Decrease in the Hct (500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the WBC (500 mg/kg/day, tendency), Decrease in the percentage of Lymphocyte (500 mg/kg/day, tendency), Decrease in the RBC (Recovery 500 mg/kg/day), Increase in the MCHC (Recovery 500 mg/kg/day)
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Male: Decrease in the AST (200 mg/kg/day), Decrease in the ALT (200 and 500 mg/kg/day), Decrease in the creatinine (500 mg/kg/day), Decrease in the beta-glb (500 mg/kg/day)
Female: No effect
Urinalysis findings:
no effects observed
Description (incidence and severity):
No effect
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Male: No effect
Female: Atrophy of white pulp in the spleen (500 mg/kg/day)
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

Details on results (P0)

No overall adverese effects were observed on rats (male/female) including reproductive performance.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
haematology
organ weights and organ / body weight ratios
gross pathology
reproductive performance
Remarks on result:
other: No overall adverse effects

Target system / organ toxicity (P0)

Critical effects observed:
not specified
System:
other: not specified
Organ:
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:
no effects observed

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Details on results (F1)

No overall adverse effects observed.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No overall adverse effects
Remarks on result:
other: not specified

Target system / organ toxicity (F1)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified

Overall reproductive toxicity

Reproductive effects observed:
not specified
Treatment related:
not specified

Applicant's summary and conclusion

Conclusions:
The No Observed Adverse effect level (NOAEL) in relation to reproductive toxicity for the test chemical was considered to be 500 mg/Kg bw/day in male and female Crl:CD (SD) rats for both P0 and F1 generation.
Executive summary:

Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD TG422) was performed to evaluate the toxic nature of the test chemical upon repeated dosing by oral route. The test was performed on male and female Crl:CD (SD) rats at dose levels of 0, 80, 200, 500 mg/kg/day. The animals were observed for clinical signs, body weight, food consumption, urinalysis, hematological and blood biochemistry parameters, gross and histopathological changes and reproductive performance.

in male decrease in the body weight gain (500 mg/kg/day, tendency), Decrease in the rate of body weight gain (500 mg/kg/day)was observed while in female decrease in the body weight (500 mg/kg/day), Decrease in the body weight gain(200, 500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the rate of body weight gain (Recovery 500 mg/kg/day) .in Female decrease in the food consumption (200 and 500 mg/kg/day) dose grop while male decrease in the WBC (200 and 500 mg/kg/day, tendency), Decrease in the RET (500 mg/kg/day), Decrease in the percentage of Eosinophil (500 mg/kg/day)Female: Decrease in the Hct (500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the WBC (500 mg/kg/day, tendency), Decrease in the percentage of Lymphocyte (500 mg/kg/day, tendency), Decrease in the RBC (Recovery 500 mg/kg/day), Increase in the MCHC (Recovery 500 mg/kg/day)In female atrophy of white pulp in the spleen (500 mg/kg/day) was observed .No overall adverese effects were observed on rats (male/female) including reproductive performance.

 

On the basis of observations made, The No Observed Adverse effect level (NOAEL) in relation to reproductive toxicity for the test chemical was considered to be 500 mg/Kg bw/day in male and female Crl:CD (SD) rats for both P0 and F1 generation.