Piperazine, compound with phosphoric acid

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Piperazine dihydrochloride (CAS No 142-64-3) and piperazine phosphate (CAS No 1951-97-9) belong to the same catergory of piperazine salts. Both the salts have the core funational group of the parent compound Piperazine . In medicine, piperazine is used in the form of the hexahydrate or as the citrate, tartrate, phosphate (1951-97-9), dihydrochloride or adipate. Thus, piperazine dihydrochloride and piperazine phosphate can be considered as belonging to the same category of chemicals.

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1997

Reference 2

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

Objective of study:

absorption

distribution

excretion

Test guideline

Qualifier:

according to guideline

Guideline:

other:

Principles of method if other than guideline:

Data is from Covance Laboratories Ltd. Report CHE.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Piperazine dihydrochloride

EC Number:

205-551-2

EC Name:

Piperazine dihydrochloride

Cas Number:

142-64-3

IUPAC Name:

piperazine dihydrochloride

Radiolabelling:

yes

Test animals

Species:

pig

Strain:

not specified

Sex:

male/female

Administration / exposure

Route of administration:

other: gastric intubation

Vehicle:

not specified

Details on exposure:

Two male and two female pigs were administered a single dose of 14C-piperazine at a nominal dose of 300 mg/kg bw and the excretion of radiolabeled material in urine and faeces was followed for up to 7 days in two animals.

Duration and frequency of treatment / exposure:

7 days

Doses / concentrations

Remarks:

Doses / Concentrations:
300 mg/kg bw

No. of animals per sex per dose / concentration:

two male and two female pigs

Control animals:

not specified

Details on study design:

By means of thin layer chromatography (TLC), high performance liquid chromatography (HPLC), and by liquid chromatography-mass spectroscopy (LC-MS) attempts were made to characterise the labelled material present in urine, faeces, as well as in tissues, and was mostly found to initially consist of unchanged piperazine. In the urine collected 0-24 h, 82-83% of the peak activity co-chromatographed with piperazine in HPLC or TLC. By the use of LC-MS for the radioactive residues found in tissue, the validity of the results from the chromatographic analysis could be confirmed, although there were some discrepancies between the HPLC and the TLC data. The nature of the labelled conversion products derived from piperazine was not determined, and the proportion of such metabolites in the urine increased with time to reach about 40-50% of the remaining activity in the 144-168 h urine as judged by HPLC and TLC. In the kidney the fraction unidentified metabolites increased from about 20% at 12 h post dosing to 80-90% of the remaining activity at 96 h post dosing. Since carbon dioxide in exhaled air was not collected, minor metabolic conversion of piperazine to this metabolic end product cannot be excluded.

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

In the pig piperazine is readily absorbed from the gastrointestinal tract,

Main ADME results 2

Type:

excretion

Results:

The principal route of excretion of piperazine and its metabolites is via urine, with a minor fraction recovered from faeces (16%).

Toxicokinetic / pharmacokinetic studies

Details on absorption:

In the pig piperazine is readily absorbed from the gastrointestinal tract, and the major part of the resorbed compound is excreted as unchanged piperazine during the first 48 h. An oral absorption of 100 % is brought forward to the exposure assessment. Default absorption values of 100 % are assumed for dermal and inhalatory exposure.

Details on distribution in tissues:

Of the sampled tissues, the highest activity was found in kidneys and liver.

Details on excretion:

The principal route of excretion of piperazine and its metabolites is via urine, with a minor fraction recovered from faeces (16%). However, about one forth of a single administered oral dose is retained in the tissues after 7 days, some of which seems to consist of unidentified conversion products.
56% of the total activity was eliminated via urine during 7 days, out of which 46% was excreted in the first 24 h. During the time of observation, 16% was excreted in faeces, while; again, most of the dose (8%) was eliminated during the first 24 h.
However, whereas elimination of the activity in kidney was rapid, with only some 3% remaining of the 12 h value post dosing, the excretion from liver, skeletal muscle, fat and skin was considerably slower with 10, 11, 24, 25%, respectively, remaining after 7 days in comparison with the 12 h levels.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

N-mononitrosopiperazine have been identified.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
The substance, piperazine, do not have a bioaccumulation potential based on the experimental study result.

Executive summary:

In the pig piperazine is readily absorbed from the gastrointestinal tract, and the major part of the resorbed compound is excreted as unchanged piperazine during the first 48 h. An oral absorption of 100 % is brought forward to the exposure assessment.Default absorption values of 100 % are assumed for dermal and inhalatory exposure. The principal route of excretion of piperazine and its metabolites is via urine, with a minor fraction recovered from faeces (16%). However, about one forth of a single administered oral dose is retained in the tissues after 7 days, some of which seems to consist of unidentified conversion products. Besides N-mononitroso piperazine, no other metabolites have been identified.