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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
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:
equivalent or similar to guideline
Guideline:
other: 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:
other: Liquid
Details on test material:
- Name of test material (as cited in study report):1-Methylpiperazine
- Molecular formula :C5H12N2
- Molecular weight :100.163g/mol
- Smiles notation :N1(CCNCC1)C
- InChl (if other than submission substance):1S/C5H12N2/c1-7-4-2-6-3-5-7/h6H,2-5H2,1H3
- Substance type:Organic
- Physical state: Liquid

Test animals

Species:
rat
Strain:
other: Crl:CD (SD)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
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
Duration of test:
58 days
Doses / concentrations
Remarks:
0,80,200,500mg/kg bw /day
No. of animals per sex per dose:
Not specified
Control animals:
not specified
Details on study design:
Not specified

Examinations

Maternal examinations:
Clinical signs, Body weight, food consumption, Organ weights, Gross pathology, Histopathology, Hematology, Food chemistry, Urinalysis
Reproductive performance
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other:
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: [all per litter / half per litter / #? per litter ] / No / No data
- Skeletal examinations: Yes: [all per litter / half per litter / #? per litter ] / No / No data
- Head examinations: Yes: [all per litter / half per litter / #? per litter ] / No / No data
Statistics:
Not specified
Indices:
Not specified
Historical control data:
Not specified

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

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):
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):
no effects observed
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
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Male: Decrease in the spleen weight (Absolute and Relative) (200 mg/kg/day), Increase in the spleen weight (Absolute) (Recovery 500 mg/kg/day, tendency), Increase in the spleen weight (Relative) (Recovery 500 mg/kg/day), Decrease in the testes weight (Absolute)
(Recovery 500 mg/kg/day)
Female: Decrease in the spleen weight (Absolute and Relative) (500 mg/kg/day)
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
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

Maternal developmental toxicity

Number of abortions:
not specified
Pre- and post-implantation loss:
not specified
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
not specified
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
not specified
Other effects:
not specified
Details on maternal toxic effects:
No overall adverese effects were observed on rats (male/female) including reproductive performance.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs
food consumption and compound intake
gross pathology
haematology
histopathology: non-neoplastic
organ weights and organ / body weight ratios
urinalysis
other: No overall adverese effects were observed on rats (male/female) including reproductive performance.
Remarks on result:
other: No overall adverese effects were observed on rats (male/female) including reproductive performance.

Maternal abnormalities

Abnormalities:
not specified
Localisation:
not specified

Results (fetuses)

Fetal body weight changes:
not specified
Reduction in number of live offspring:
not specified
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Skeletal malformations:
not specified
Visceral malformations:
not specified
Other effects:
no effects observed
Description (incidence and severity):
No overall adverse effects observed.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: No overall adverse effects observed.
Remarks on result:
other: No overall adverse effects observed.

Fetal abnormalities

Abnormalities:
not specified
Localisation:
other: not specified

Overall developmental toxicity

Developmental effects observed:
not specified
Treatment related:
not specified

Applicant's summary and conclusion

Conclusions:
The No Observed Adverse effect level (NOAEL) in relation to developmental 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, TheNo 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.