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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
14C-piperazine dihydrochloride as aqueous solution was administered as single dose by gavage.
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Piperazine
EC Number:
203-808-3
EC Name:
Piperazine
Cas Number:
110-85-0
Molecular formula:
C4H10N2
IUPAC Name:
piperazine
Specific details on test material used for the study:
piperazine dihydrochloride / 142-64-3 / 205-551-2 was used.
Radiolabelling:
yes

Test animals

Species:
pig
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Doses / concentrations
Dose / conc.:
300 mg/kg bw/day (actual dose received)
No. of animals per sex per dose / concentration:
2 male/2 female
Control animals:
no
Details on dosing and sampling:
The excretion of radiolabeled material in urine and feaces was followed for up to 7 days in two animals, and two were sacrificed 12 and 24 h after dosing for determination of radiolabel in liver, kidney, muscle, fat and skin. By means of TLC, HPLC and LC-MS attempts were made to characterise the labelled material present in urine, feaces and tissue.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Peak plasma concentrations were attained 1 h after administration, followed by rapid disappearence from the blood.
Details on distribution in tissues:
The highest activity was found in kidneys and liver. Elimination of the activity in the kidney was rapid, with only 3% remaining of the 12h value post dosing. The elimination from the liver, skeleton, muscle, fat and skin was considerably slower with 10, 11, 24, 25% respectively remaining after 7 days in comparison with the 12 h levels
Details on excretion:
56% of the total activity was eliminated via the urine during 7 days, out of which 46% was excreted in the first 24h. During the time of observation, 16% was excreted in feaces, while; again, most of the dose, 8%, was eliminated during the first 24h.
When residues present in cage debris and washes are also included, after 7 days about one fourth of the totally administered amount can be considered as still retained in the body.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
In the urine collected 0-24 hours, 82-83% 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. The nature of the labeled 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 hour urine. In the kidney the fraction unidentified metabolites increased from about 20% at 12 hours post dosing to 80-90% of the remaining activity at 96 hours post dosing. Since carbon dioxide in exhaled air was not collected, minor metabolic conversion of piperazine to
this metabolic end product cannot be excluded.

Applicant's summary and conclusion

Conclusions:
Low bioaccumulation potential based on study results.