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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study performed under GLP. Piperazine is one constituent (ca. 15%) of the test substance.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999
Report Date:
1999

Materials and methods

Test guideline
Guideline:
other: FDA 1986, Toxicological principles for Safety Assessment of Direct Food Additives and Color Additives Used in Food
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): piperazine dihydrochloride
- Analytical purity: 52.25% as piperazine base

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: 6 weeks
- Weight at study initiation: M: 205 g F 156 g
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 36 - 74%
- Photoperiod (hrs dark / hrs light): 12 h cycle


Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet: Weekly
- Mixing appropriate amounts with: Certified Rodent Diet No. 5002
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
90 days
Frequency of treatment:
7 days/week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
400 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1200 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
2394 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
20
Control animals:
yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Twice pre-test, weekly during treatment and terminally after fasting.

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pre test: day -5 and at termination day 92

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Day 0, test day 46, and at termination day 92 and 94
- How many animals: 10/sex/group

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Day 0, test day 46, and at termination day 93 and 94
- How many animals: 10/sex/group

URINALYSIS: Yes
- Time schedule for collection of urine: Day -6, test day 43, and at termination day 87

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Histopathological findings: non-neoplastic:
no effects observed
Details on results:
BODY WEIGHT AND WEIGHT GAIN
Dose-related decreases in body weight gain, with a difference to control of 10% occurred in the high dose group.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 200 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: Decrease in body weight gain
Dose descriptor:
NOAEL
Effect level:
627 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: Recalculated to Piperazine base

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL for sub-chronic repeated dose toxicity to the rat is 627 mg/kg bw/day.
Executive summary:

In a 90-day study rats were dosed with Piperazine-dihydrochloride administred in the diet. The doses were 400, 1200 and 2394 mg/kg bw/day, administered to 20 animals/sex/dose. The only effects noted was a dose related decrease in body-weight gain. NOAEL for repeated dose toxicity to the rat was 627 mg/kg bw/day, recalculated to piperazine base.