Reaction mass of 2-Piperazin-1-ylethanol and Piperazine-1,4-diethanol and Piperazine

Repeated dose toxicity: oral

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

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

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 or test system 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 / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
400 mg/kg bw/day
Basis:
actual ingested

Doses / concentrations 2

Remarks:

Doses / Concentrations:
1200 mg/kg bw/day
Basis:
actual ingested

Doses / concentrations 3

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

1

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

2

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.