Registration Dossier

Administrative data

Description of key information

No studies are available for hydroxyethylpiperazine mixture. Studies concerning repeated dose toxicity are available from piperazine dihydrochloride (CAS 142-64-3). This corresponds to 52.25% piperazine base which is one constiutent of the hydroxyethylpiperazine mixture (piperazine CAS 110-85-0).
Oral:
rat: NOAEL = 627 mg/kg bw/day ( 90-day feeding, GLP guideline study, Dow, 1999)
dog: NOAEL = 25 mg/kg bw/day ( 90-day feeding, similar to guideline, Huntsman, 1975)
human: LOAEL = 30 mg/kg bw/day (case report from use of piperazine as antihelmintic agent, 3-7 days)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
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.
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
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


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
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
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
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.
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
Critical effects observed:
not specified
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.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
627 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
GLP guideline study

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No studies are available for hydroxyethylpiperazine mixture. Studies concerning repeated dose toxicity are available from piperazine dihydrochloride (CAS 142-64-3). This corresponds to 52.25% piperazine base which is one constiutent of the hydroxyethylpiperazine mixture (piperazine CAS 110-85-0). Therefore these studies may be used as read across in order to assess the repeated dose toxicity of hydroxehtylpiperazine mixture.

In a 90-day feeding study 20 male and 20 female Sprague-Dawley rats (GLP guideline study, Dow, 1999) were dosed daily with 400, 1200 and 2394 mg/kg bw piperazine dihydrochloride. The only effect noted was a dose related decrease in body weight gain (10% decrease compared to control). NOAEL for repeated dose toxicity to the rat was therefore set to 627 mg/kg/day, recalculated to piperazine base.

In a further 90-day feeding study with 16 beagle dogs/sex/dose the toxicity of piperazine dihydrochloride was investigated (similar to OECD 409, Huntsman, 1975). The doses 92.3, 369.2 and 3692 ppm daily did not result in any signs of systemic toxicity in any of the test animals. All dogs showed slight to moderate weight gains and food consumption was generally comparable between test and control groups. No gross or microscopic pathology attributable to the test substance were observed at termination. NOAEL for repeated dose toxicity to the dog was 25 mg/kgbw/day, recalculated to piperazine base.

In conclusion, both studies showed no adverse effect but in a developmental toxicity study with rabbits, neurotoxic effects were noted. The NOAEL in this study was 42 mg/kg bw/day. Furthermore, in the use of piperazine as antihelmintic agent, neurotoxic effects have been noted in humans (EU Risk Assessment, 2005). A LOAEL of 30 mg/kg bw/day can be established for a limited exposure of 3 to 7 days.

Since piperazine is one constituent of hydroxehtylpiperazine mixture it is assumed that this mixture has also neurotoxic potential in high doses.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
key study

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available studies are considered reliable and suitable for classification purposes under 67/548/EEC. As a result the substance is not considered to be classified for repeated dose toxicity under Directive 67/548/EEC, as amended for the 28th time in Directive 2001/59/EC.

 

Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified for repeated dose toxicity under Regulation (EC) No. 1272/2008.