Piperazine, compound with phosphoric acid

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

fertility, other

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Qualifier:

according to guideline

Guideline:

other:

Principles of method if other than guideline:

Details not available

GLP compliance:

not specified

Species:

rabbit

Strain:

not specified

Sex:

female

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Details not available

Frequency of treatment:

Details not available

Remarks:

Doses / Concentrations:
100, 250 and 500 mg
Basis:
no data

No. of animals per sex per dose:

5 rabbits

Control animals:

yes

Details on study design:

A reproduction study using oral administration of doses 100, 250 and 500 mg piperazine phosphate per kg body weight by gavage.

Parental animals: Observations and examinations:

Study showed dose dependent maternal toxicity culminating at the highest dose in death of does (2), abortion (1) and increase of major abnormalities in pups (23% versus 1.7% in controls).

Litter observations:

The main abnormalities observed were cleft palate and umbilical hernia; otherwise rarely seen in the strains of rabbit used

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

dose dependent maternal toxicity culminating at the highest dose in death of does (2), abortion (1)

Study showed dose dependent maternal toxicity culminating at the highest dose in death of does (2), abortion (1)

Dose descriptor:

dose level:

Effect level:

> 100 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Piperazine in doses higher than 100 mg/kg bw/daycould provoke maternotoxicity, which can contribute to teratological effects as a consequence (at high dose levels )

Remarks on result:

other: not specified

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

The main abnormalities observed were cleft palate and umbilical hernia; otherwise rarely seen in the strains of rabbit used

The main abnormalities observed were cleft palate and umbilical hernia; otherwise rarely seen in the strains of rabbit used

Remarks on result:

not measured/tested

Reproductive effects observed:

not specified

Treatment related:

not specified

Conclusions:

Piperazine in doses higher than 100 mg/kg bw/daycould provoke maternotoxicity, which can contribute to teratological effects as a consequence (at high dose levels )

Executive summary:

In the study using 5 rabbits, a study on reproduction by oral administration of doses 100, 250 or 500 mg piperazine posphate /kg bw per gavage showed dose dependent maternal toxicity culminating at the highest dose in death, abortion and increases of major abnormalities in pups (23% versus 1.7% in controls). The main abnormalities observed were cleft palate and umbalical hernia , otherwise rarely seen in the strains of rabbits used. Piperazine in doses higher than 100 mg/kg bw/daycould provoke maternotoxicity, which can contribute to teratological effects as a consequence (at high dose levels ). Thus, it can be summarised that piperazine phosphate is likely to be reprotoxic substance at higher doses.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Additional information

The summary of the weight of evidence studies in support of piperazine phosphate being classified as a repro-toxic substance is furnished below

S. No	Dose level	Species	Effect	Source of data
1	100 mg/kg bw/day (NOAEL)	Rabbit	Maternotoxicity	The European Agency for the Evaluation of Medicinal Products Veterinary medicines and Inspections
2	125 mg/kg bw/day (NOAEL)	Sprague-Dawley Rat	Parental toxicity	European Union Risk Assessment Report : Piperazine

Short description of key information:

In the study using 5 rabbits, a study on reproduction by oral administration of doses 100, 250 or 500 mg piperazine posphate /kg bw per gavage showed dose dependent maternal toxicity culminating at the highest dose in death, abortion and increases of major abnormalities in pups (23% versus 1.7% in controls). The main abnormalities observed were cleft palate and umbalical hernia , otherwise rarely seen in the strains of rabbits used. Piperazine in doses higher than 100 mg/kg bw/daycould provoke maternotoxicity, which can contribute to teratological effects as a consequence (at high dose levels ). Thus, it can be summarised that piperazine phosphate is likely to be reprotoxic substance at higher doses.

Justification for selection of Effect on fertility via oral route:

Data has been taken from published report of the European Agency for the evaluation of medicinal products veterinary medicines and Inspections

Effects on developmental toxicity

Description of key information

Piperazine phosphate does not appear to be teratogenic in rat. However, in rabbit teratogenic effects may be elicited at a dose level that is also toxic to the mother animal. Thus, the teratogenic effect of piperazine phosphate remains inconclusive and since there is no classification in the CLP inventory suggesting "teratogenicity" for piperazine phosphate, the chemical is not considered to be teratogenic.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

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

Species:

rabbit

Strain:

New Zealand White

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

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.

Fetal examinations:

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

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

Abnormalities:

not specified

Localisation:

not specified

Description (incidence and severity):

not specified

Details on embryotoxic / teratogenic effects:

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

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

Abnormalities:

not specified

Localisation:

other: not specified

Description (incidence and severity):

not specified

Developmental effects observed:

not specified

Treatment related:

not specified

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.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

Study duration:

subacute

Species:

rat

Additional information

The summary of the weight of evidence studies in support of piperazine phosphate not being classified as a teratogenic substance is furnished below. Thus, the teratogenic effect of piperazine phosphate remains inconclusive and since there is no classification in the CLP inventory suggesting "teratogenicity" for piperazine phosphate, the chemical is not considered to be teratogenic.

S. No	Dose level	Species	Effect	Source of data
1	42 mg/kg bw/day (NOAEL)	Rabbit (New Zealand White)	Developmental toxicity	European Union Risk Assessment Report : Piperazine
2	250 to < 5000 mg/kg bw/day (nominal) (LOAEL)	Rat Crj: CD(SD)	Lower foetal weight was recorded but no evidence of teratogenecity was reported at any dose level.	Piperazine phosphate, Rat teratology study; Report to Reckitt and Coleman from Toxicol. Laboratory Limited
3	94 mg/kg bw/day (LOAEL)	Rabbit (New Zealand White)	No symptoms of teratogenecity, only maternal toxicity observed	USEPA High volume program (HPV) report

Justification for selection of Effect on developmental toxicity: via oral route:

Data has been published in the European Union Risk Assessment Report of Piperazine