Tripiperazine dicitrate

Repeated dose toxicity: oral

Administrative data

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

Data source

Reference

Reference Type:

publication

Title:

Impact of Subchronic Administration of Piperazine Citrate on the Electrocardiogram of the rat

Author:

Samuel Ghasi, Anthovy Ogbonna, and Anthony Mbah

Year:

2012

Bibliographic source:

American Journal of Therapeutics 19, 81-87, (2012)

Materials and methods

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

Tripiperazine dicitrate

EC Number:

205-622-8

EC Name:

Tripiperazine dicitrate

Cas Number:

144-29-6

Molecular formula:

C6H8O7.3/2C4H10N2

IUPAC Name:

piperazine 2-hydroxypropane-1,2,3-tricarboxylate (3:2) (salt)

Test material form:

solid

Details on test material:

- 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

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

Test animals

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

Administration / exposure

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

Doses / concentrations

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

Examinations

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.

Results and discussion

Results of examinations

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.

Effect levels

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

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

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.