Tripiperazine dicitrate

Endpoint summary

Description of key information

Repeated dose toxicity: oral

The No Observed Adverse Effect Level (NOAEL) was considered to be 100 mg/kg body weight/day when albino Wistar male and female rat exposed to Piperazine citrate. Based on the results, it can be concluded that the chemical piperazine citrate is not likely to cause repeated dose toxicity by the oral route of exposure as per CLP classification criteria.

Repeated dose toxicity: Inhalation

The use of the chemical tripiperazine dicitrate is mostly as an anti-helminthic. Thus, repeated exposure by the inhalation route is highly unlikely and hence this end point was considered for waiver and the chemical is not likely to exhibit repeated dose toxicity by the inhaltion route.

Repeated dose toxicity: Dermal

The use of the chemical tripiperazine dicitrate is mostly as an anti-helminthic. Thus, repeated exposure by the dermal route is highly unlikely and hence this end point was considered for waiver and the chemical is not likely to exhibit repeated dose toxicity by the dermal route.

Based on the available data and the applicable waivers, it can be concluded that the chemical tripiperazine dicitrate is not likely to cause repeated dose toxicity by the oral, inhalation or dermal route of exposure. Thus, the chemical is not likely to be considered for classification.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Data is from peer reviewed journal

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

Impact of Subchronic toxcity study of Piperazine Citrate on the Electrocardiogram of the rat orally.

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): Piperazine citrate - Molecular formula: C12H30N6•Cl2H16O14 - Molecular weight: 642.76 g/mole - Substance type: Organic - Physical state: Solid

Species:

rat

Strain:

other: Albino Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Details on test animalTEST ANIMALS- Source: No data available - Age at study initiation: No data available- Weight at study initiation: 200 – 250 g - Fasting period before study: No data available - Housing: No data available- Diet (e.g. ad libitum): Standard diet, ad libitum - Water (e.g. ad libitum): No data available - Acclimation period: No data available ENVIRONMENTAL CONDITIONS- Temperature (°C): No data available- Humidity (%):No data available- Air changes (per hr): No data available - Photoperiod (hrs dark / hrs light): No data available IN-LIFE DATES: From: To: No data available

Route of administration:

oral: feed

Vehicle:

other: Standard diet

Details on oral exposure:

Details on oral exposurePREPARATION OF DOSING SOLUTIONS: No data available DIET PREPARATION- Rate of preparation of diet (frequency): No data available - Mixing appropriate amounts with (Type of food): No data available - Storage temperature of food: No data available VEHICLE- Justification for use and choice of vehicle (if other than water): Standard diet - Concentration in vehicle: 0, 30, 60 and 100 mg/kg/body weight/day - Amount of vehicle (if gavage): No data available - Lot/batch no. (if required): No data available - Purity: No data available

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

16 weeks

Frequency of treatment:

Two times a day

Remarks:

Doses / Concentrations:0, 30, 60 and 100 mg/kg/body weight/day Basis:nominal in diet

No. of animals per sex per dose:

Total : 40 0 mg/kg/body weight/day: 10 sex matched rat 30 mg/kg/body weight/day: 10 sex matched rat 60 mg/kg/body weight/day: 10 sex matched rat 100 mg/kg/body weight/day: 10 sex matched rat

Control animals:

yes, concurrent vehicle

Details on study design:

- Rationale for animal assignment (if not random): On the basis of matched sex

Positive control:

No data

Observations and examinations performed and frequency:

OTHER: Effects on electrocardiogram of heart were observed.

Sacrifice and pathology:

No data available

Other examinations:

Effects on electrocardiogram of heart:Approximately 1 hour after last dose rat were anesthetized with thiopentone sodium (50mg/kg intaperitoneally) and placed in supine position with all four limbs tied onto dissectine board.Observation:Heart rat, atrial and atrioventricular conduction and cardiac dysthythmic phenomena were observed.

Statistics:

Averages were expressed as arithmetic mean ± standard error of the mean. Student t test were performed comparing the results obtained from each drug concentration with measurements from control experiments and a p value of < 0.05 taken as indicating a statistically significant difference. Analysis of variance was then performed to evaluate differences between the three test grou[p using a one-way analysis of variance.

Clinical signs:

not specified

Mortality:

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

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Details on results:

Effect on heart rate:When treated with 30 mg/kg/body weight /day, the average heart rate at the end of 15 minute was observed and no statistically significant difference were observed in treated and control rat.Atrial and atrioventricular conduction: The p wave for the 30 and 60 mg/kg body weight/day and control remained unaltered at 40 ms. P-R interval :When treated with 30, 60 and 100 mg/kg body weight/day, P-R interval was statistically significantly increased as compared to control.QTc interval: When treated with 60 and 100 mg/kg/body weight/day, statistically significant difference was observed as compared to control.J-T interval of 120 ms:Statistically significant difference was observed in 30, 60 and 100 mg/kg/body weight /day treated rat as compared to control.T wave amplitude:Statistically significant increased was observed in average T wave amplitude of 100 mg/kg/body weight/day treated rat as compared to control. R wave amplitude:Statistically significant increased was observed in average R wave amplitude of 30,60 and 100 mg/kg/body weight/day treated rat as compared to control. Cardiac dysthythmic phenomena:When treated with 30, 60 and 100 mg/kg body weight/day, statistically significant change in R, T and QRS-T complex and dose dependent electrocardiographic change were observed in treated rat as compared to control.

Key result

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effect on electrocardiogram of rat heart

Critical effects observed:

not specified

Conclusions:

The No Observed Adverse Effect Level (NOAEL) was considered to be 100 mg/kg body weight/day when albino Wistar male and female rat exposed to Piperazine citrate. Based on the results, it can be concluded that the chemical piperazine citrate is not likely to cause repeated dose toxicity by the oral route of exposure as per CLP classification criteria.

Executive summary:

In a repeated dose subchronic toxicity study, albino Wistar male and female rat were exposed to Piperazine citrate in the concentration of 30, 60 and 100 mg/kg body weight/day. The results showed that Piperazine citrate was not toxic. No toxic change were observed in Electrocardiogram of treated rat. Some significant changes were observed in atrial and atrioventricular conduction, P-R interval, QTc interval, J-T interval, T and R wave amplitude and Cardiac dysthythmic phenomena of treated rat but the changes were non toxic. No ECG abnormalities were observed at the end of study. Therefore, the No Observed Adverse Effect Level (NOAEL) was considered to be 100 mg/kg body weight/day when albinoWistar male and female rat were exposed to Piperazine citrate orally for 16 weeks. Based on the results, it can be concluded that the chemical piperazine citrate is not likely to cause repeated dose toxicity by the oral route of exposure as per CLP classification criteria.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data from K2 publication.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: dermal

Data waiving:

other justification

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity: Oral
The data from various peer reviewed journals have been summarized below to determine the toxic nature of the test compound piperazine citrate (CAS 144-29-6) upon repeated application:

 

In Key study, a repeated dose subchronic toxicity by Ghasi et al (2012) was conducted where albino Wistar male and female rat were exposed to Piperazine citrate (CAS no 144-29-6) in the concentration of 30, 60 and 100 mg/kg body weight/day. The results showed that Piperazine citrate was not toxic. No toxic change were observed in Electrocardiogram of treated rat. Some significant changes were observed in atrial and atrioventricular conduction, P-R interval, QTc interval, J-T interval, T and R wave amplitude and Cardiac dysthythmic phenomena of treated rat but the changes were non toxic. No ECG abnormalities were observed at the end of study. Therefore, the No Observed Adverse Effect Level (NOAEL) was considered to be 100 mg/kg body weight/day when albino Wistar male and female rat were exposed to Piperazine citrate orally for 16 weeks.

In another subchronic repeated dose toxicity study by Ghasi et al (2012), albino wistar rats were treated with Piperazine Citrate in the concentration of 0, 30, 60 and 100 mg/kg/day, results shows that Piperazine Citrate is toxic, toxic changes were observed as change in creatinine,sodium and potassium level in serum when treated with 60 and 100 mg/kg/day. In addition, significant changes were observed in histopathology of kidney such as vascular congestion, shrunken pyknotic and degenerated glomeruli,hyalimisation, glomerular hyaline droplets and necrosis in 60 and 100 mg/kg/day treated rats. Therefore, Low Observed Adverse Effect Level (LOAEL) was considered to be 60 mg/kg day when albino wistar rats were treated with Piperazine Citrate orally in diet for 6 weeks.

In repeated dose toxicity study by Martin et al (1963), albino male and female rat were exposed to 1, 4-Di (D-glucosyl) piperazine (DGP) (CAS no 144-29-6) in a concentration of 0, 1000, 2000 and 3000 mg/kg/day which is equivalent to Piperazine citrate in concentration of 0, 210,420 and 630 mg/kg/day. The results showed that Piperazine citrate was not toxic. No toxic changes were observed on survival, body weight and body weight gain, food consumption and gross pathology of treated rat as compared to control, therefore The No Observed Adverse Effect Level (NOAEL) was considered to be 630 mg/kg/day when albino male and female rat were exposed to Piperazine citrate orally for 10 weeks.

In a repeated dose toxicity study by Brown et al (1956), children with Trichuris trichiura Infections exposed to Piperazine citrate (CAS no 144-29-6) in the concentration of 0.4 g (400 mg/kg/day). The result shows that Piperazine citrate is not effective inTrichuris trichiurainfections. No significant reduction in egg counts of patients with light Trichuris infections was observed.Therefore, No Obsereved Effect Level (NOEL) was considered to be 0.4 g (400 mg/kg/day) when children were exposed to Piperazine citrate orally.  

In the same study by Brown et al (1956), patient with Enterobius Infections exposed to Piperazine citrate (CAS no 140-29-6) in the concentration of 1 and 2 gm (1000 and 2000 mg/kg body weight/day). The result shows that Piperazine citrate is curative in Enterobius Vermicularis Infections. Patient treated with different dose of Piperazine citrate shows 97% cure rat of Enterobius infection. Therefore, No Observed Adverse Effect Level (NOAEL) was considered to be1 gm (1000 mg/kg body weight/day) when patient were exposed to Piperazine citrate daily for 7 days. 

Repeated dose toxicity: Inhalation
The use of the chemical tripiperazine dicitrate is mostly as an anti-helminthic. Thus, repeated exposure by the inhalation route is highly unlikely and hence this end point was considered for waiver and the chemical is not likely to exhibit repeated dose toxicity by the inhaltion route.

Repeated dose toxicity: Dermal
The use of the chemical tripiperazine dicitrate is mostly as an anti-helminthic. Thus, repeated exposure by the dermal route is highly unlikely and hence this end point was considered for waiver and the chemical is not likely to exhibit repeated dose toxicity by the dermal route.

 

Based on the overall available data and the applicable waivers, it can be concluded that the chemical tripiperazine dicitrate (piperazine citrate) is not likely to cause repeated dose toxicity by the oral, inhalation or dermal route of exposure. Thus, the chemical is not likely to be considered for classification under Repeated dose toxicity as per CLP classification criteria.

Justification for classification or non-classification

Based on the overall available data and the applicable waivers, it can be concluded that the chemical tripiperazine dicitrate (piperazine citrate) is not likely to cause repeated dose toxicity by the oral, inhalation or dermal route of exposure. Thus, the chemical is not likely to be considered for classification under Repeated dose toxicity as per CLP classification criteria.