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Diss Factsheets

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:
4 (not assignable)

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Piperazine phosphate. Rabbit teratology study.
Author:
Ridgway P
Year:
1987
Bibliographic source:
Report to Reckitt and Coleman from Toxicol Laboratories Ltd., Ledbury, Herefordshire. (unpublished).
Reference Type:
other: study report
Title:
European Union Risk Assessment Report : Piperazine
Author:
European Chemicals Bureau
Year:
2005
Bibliographic source:
3rd Priority List Volume: 56;Final Report, 2005

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other:
Principles of method if other than guideline:
Data is from Report to Reckitt and Coleman from Toxicol Laboratories Ltd.,
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Piperazine, compound with phosphoric acid
EC Number:
217-775-8
EC Name:
Piperazine, compound with phosphoric acid
Cas Number:
1951-97-9
Molecular formula:
C4H10N2.xH3O4P
IUPAC Name:
phosphoric acid; piperazine

Test animals

Species:
rabbit
Strain:
New Zealand White

Administration / exposure

Route of administration:
other: oral intubation
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: methyl cellulose
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
The females were treated from days 6 to 18 of pregnancy
Frequency of treatment:
females were treated from days 6 to 18 of pregnancy
Duration of test:
28 days
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 225, and 500 mg piperazine phosphate per kg bw
Basis:
no data
No. of animals per sex per dose:
16 animals
Details on study design:
At 210 mg/kg/day piperazine base overt signs of toxicity were observed in the treated dams including signs of neurotoxicity as demonstrated
by excessive salivation and nervousness noted in all treated animals. Other symptoms of adverse effects were anorexia, reduced or no faeces production, reduced food intake (e.g., by 85% days 6-14) coupled with body weight loss (high dose animals lost 9% of body weight whereas controls gained 6%).
Two females were killed in extremis and one female aborted.The sacrificed females were found to have intestinal abnormalities including erosion of the mucosa of the stomach or duodenum. At 94 mg/kg/day piperazine base, there were no effects on body weight, although food consumption (-39%) and body weight gain were transiently reduced during the 4 first days of dosing. One female aborted, and five females were observed with reduced faeces production for short periods. One female died, but this was ascribed to accidental dosing into the lungs.

Examinations

Fetal examinations:
The foetuses were subjected to detailed external, visceral and skeletal examination.

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
42 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Remarks on result:
other: not specified
Dose descriptor:
LOAEL
Effect level:
94 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Remarks on result:
other: not specified

Maternal abnormalities

Abnormalities:
not specified
Localisation:
not specified
Description (incidence and severity):
not specified

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes. Remark: Fetal weight reduced and feotuses exhibited major abnormalities like umbilical hernia and cleft palate

Effect levels (fetuses)

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

Fetal abnormalities

Abnormalities:
not specified
Localisation:
other: not specified
Description (incidence and severity):
not specified

Overall developmental toxicity

Developmental effects observed:
not specified
Treatment related:
not specified

Applicant's summary and conclusion

Conclusions:
In the New Zealand rabbit, embryotoxic as well as teratogenic effects were elicited at doses that also caused overt signs of toxicity in the mother animal (maternal LOAEL 94/ NOAEL 42 mg/kg/day).

No effects were observed at 42 mg/kg/day of piperazine base.Although borderline, 94 mg/kg/day piperazine base may be considered to constitute the maternal LOAEL in this study.
Executive summary:

In the New Zealand rabbit, embryotoxic as well as teratogenic effects were elicited at doses that also caused overt signs of toxicity in the mother animal (maternal LOAEL 94/ NOAEL 42 mg/kg/day).

No effects were observed at 42 mg/kg/day of piperazine base.Although borderline, 94 mg/kg/day piperazine base may be considered to constitute the

maternal LOAEL in this study.