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Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics in vivo
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 per reviewed publication
Objective of study:
toxicokinetics
Qualifier:
according to
Guideline:
other: as mentioned below
Principles of method if other than guideline:
Modified colorimetric method: The aim of this study was to compare the amount of piperazine excreted in the urine over 24 hr. after oral administration of a newly developed syrup formula, equivalent to 3.5 g. piperazine hexahydrate, against a commercial syrup sample. This dose was chosen according to the normal adult dose range for the treatment of ascariasis.
Radiolabelling:
no
Species:
other: Human
Strain:
other: not applicable
Sex:
male/female
Details on test animals and environmental conditions:
Five Caucasian subjects, three men and two women ranging from 23 to 38 years of age, in normal state of health as determined by prior physical and laboratory medical examination, were used in this trial
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on exposure:
an oral dosage of 35 ml. of piperazine citrate syrup equivalent to 3.5 g. piperazine hexahydrate was administered to five Caucasian subjects
Duration and frequency of treatment / exposure:
24 hrsFrequency was a single dose
Dose / conc.:
20 other: mcg./ml
No. of animals per sex per dose:
5 (three men and two women)
Control animals:
no
Positive control:
not specified
Details on study design:
Prior to the oral administration of either syrup sample, a urine sample was collected from each individual to be used as an internal control.
Details on dosing and sampling:
not specified
Statistics:
not specified
Details on absorption:
Readily absorbed from the GI tract
Details on distribution in tissues:
not specified
Details on excretion:
Urinary excretion began 1 hr after the oral administration, and the rate was maximal between 2 and 6 hr. Excretion was nearly completed in 24 hr. Within 24 hours between 60 to 75% of the administered dose was excreted. The total urinary recovery of piperazine varied from 15 to 75%.
Toxicokinetic parameters:
other: not specified
Metabolites identified:
not specified
Bioaccessibility testing results:
not specified
Conclusions:
Piperazine citrate was readily absorbed from the GI tract. Urinary excretion began 1 hr after the oral administration, and the rate was maximal between 2 and 6 hr. Excretion was nearly completed in 24 hr. Within 24 hours between 60 to 75% of the administered dose was excreted. The total urinary recovery of piperazine varied from 15 to 75%. Thus, the bio-accumulation potential of piperazine citrate in the human body is likely to be low.
Executive summary:

A modified colorimetric method using Folin's amino acid reagent was used for the quantitative determination of piperazine in human urine. Comparative urinary excretion trials were carried out on five subjects using two different piperazine citrate syrup formulas. The aim of this study was to compare the amount of piperazine excreted in the urine over 24 hr after oral administration of a newly developed syrup formula, equivalent to 3.5 g. piperazine hexahydrate, against a commercial syrup sample. This dose was chosen according to the normal adult dose range for the treatment of ascariasis. Five Caucasian subjects, three men and two women ranging from 23 to 38 years of age, in normal state of health as determined by prior physical and laboratory medical examination, were used in this trial. Each was administered an oral dosage of 35 ml. of piperazine citrate syrup equivalent to 3.5 g. piperazine hexahydrate. At least 48 hr. elapsed between the administration of the new formula and the commercial sample. Prior to the oral administration of either syrup sample, a urine sample was collected from each individual to be used as an internal control. Urine samples were collected. whenever possible, at 1, 2.5, 4.5. 6.5, 9, 13, 20, and 24 hr. after oral administration.
Piperazine citrate was readily absorbed from the GI tract. The percentage and pattern of urinary excretion of piperazine calculated
ashexahydrate varied from individual to individual, as seen in the five subjects. Urinary excretion began 1 hr after the oral administration, and the rate was maximal between 2 and 6 hr. Excretion was nearly completed in 24 hr. Within 24 hours between 60 to 75% of the administered dose was excreted. The total urinary recovery of piperazine varied from15to75%. Thus, the bio-accumulation potential of piperazine citrate in the human body is likely to be low.

Description of key information

Piperazine citrate was readily absorbed from the GI tract. Urinary excretion began 1 hr after the oral administration, and the rate was maximal between 2 and 6 hr. Excretion was nearly completed in 24 hr. Within 24 hours between 60 to 75% of the administered dose was excreted. The total urinary recovery of piperazine varied from 15 to 75%. Thus, the bio-accumulation potential of piperazine citrate in the human body is likely to be low.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

Basic toxicokinetics:
Two different experimental studies of the test substance pieprazine citrate were reviewed for basic toxicokinetics endpoint which are summarised as follows:

In key study a modified colorimetric method using Folin's amino acid reagent was used by S. Hanna. and A. Tang, Journal of pharmaceutical sciences Vol. 62, No. 12, December 1973, for the quantitative determination of piperazine in human urine. Comparative urinary excretion trials were carried out on five subjects using two different piperazine citrate syrup formulas. The aim of this study was to compare the amount of piperazine excreted in the urine over 24 hr after oral administration of a newly developed syrup formula, equivalent to 3.5 g. piperazine hexahydrate, against a commercial syrup sample. This dose was chosen according to the normal adult dose range for the treatment of ascariasis. Five Caucasian subjects, three men and two women ranging from 23 to 38 years of age, in normal state of health as determined by prior physical and laboratory medical examination, were used in this trial. Each was administered an oral dosage of 35 ml. of piperazine citrate syrup equivalent to 3.5 g. piperazine hexahydrate. At least 48 hr. elapsed between the administration of the new formula and the commercial sample. Prior to the oral administration of either syrup sample, a urine sample was collected from each individual to be used as an internal control. Urine samples were collected. whenever possible, at 1, 2.5, 4.5. 6.5, 9, 13, 20, and 24 hr. after oral administration. Piperazine citrate was readily absorbed from the GI tract. The percentage and pattern of urinary excretion of piperazine calculatedashexahydrate varied from individual to individual, as seen in the five subjects. Urinary excretion began 1 hr after the oral administration, and the rate was maximal between 2 and 6 hr. Excretion was nearly completed in 24 hr. Within 24 hours between 60 to 75% of the administered dose was excreted. The total urinary recovery of piperazine varied from15 to75%.

In a supporting comparative studies, as cited in The MAK Collection for Occupational Health and Safety. 304 – 313; 2013, 8 healthy volunteers (3 male, 5 female) were given single oral doses of piperazine adipate or citrate equivalent to a dose of 1000 mg anhydrous piperazine. The proportion of the dose excreted in the 24-hour urine was 32.1 ± 9.5 % (adipate) and 33.2 ± 8.3 % (citrate). Three days after dosing, not even traces of piperazine were detected in the urine.

Thus from the results of the above mentioned studies it can be concluded that the bio-accumulation potential of piperazine citrate in the human body is likely to be very low as it is excreted in urine.