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Diss Factsheets

Administrative data

Endpoint:
acute toxicity: dermal
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: see 'Remark'
Remarks:
The study conduct was guideline compliant, however with some deviations. Only 4 animals were used per dose (2 males, 2 females) instead of 5/sex; the skin was abraded, which might have an impact on the permeability of the skin; no purity data were given. Piperazine is one constituent (ca. 15%) of the test substance.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1981
Report date:
1981

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
purity not reported, skin is abraded, number of test animals is different
Principles of method if other than guideline:
OECD guideline says: at least 5 animals of the same sex per dose group. In this study: 4 animals (2 males, 2 females) are used per dose group.
OECD guideline says: care should be taken to avoid abrading the skin, which could alter its permeability. In this study: the skin of the rabbits were abraded by making 4 epidermal incisions with a clean needle through the stratum corneum.
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
no

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
Details on test material:
- Name of test material (as cited in study report): 4236-42-15
- Physical state: light yellow liquld
- Analytical purity: no data reported (responsibility of the sponsor)
- Lot/batch No.: J-82
- Stability under test conditions: no apparent change in the physical state of the test article during administration
- Storage condition of test material: no data

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Perfection Breeders, Inc., Douglassville, Pennsylvania
- Age at study initiation: adult
- Weight at study initiation: 2.010-2.250 kg
- Housing: individually in cages sized in accordance with the "Guide for the Care of Laboratory Animals" of the Institute of Laboratory Resources, National Research Council.
- Diet: Wayne Rabbit Ration, ad libitum
- Water: fresh tap water, fit for human consumption, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3°C
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12 h dark/12 h light

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: trunk (clipped free of fur)
- % coverage: min. 10%
- Type of wrap if used: rubber dam and an ace bandage


REMOVAL OF TEST SUBSTANCE
- Washing (if done): washing was done
- Time after start of exposure: 24 h


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 8 g/kg bw in the preliminary test; 7, 9 and 10 g/kg bw in the main test.
Duration of exposure:
24 h
Doses:
Preliminary test: 8000 mg/kg bw
Main test for LD50 determination: 7000, 9000 and 10000 mg/kg bw
No. of animals per sex per dose:
4 animals per dose (2 male, 2 female)
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 30 min, 2 and 4 hours after 24 h period of exposure and twice daily thereafter for 14 days.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, dermal signs
Statistics:
According to the method of Litchfield and Wilcoxon (1949) JPET 96: 99-114.

Results and discussion

Preliminary study:
Ten animals were treated with 8000 mg/kg bw; 3/10 animals died.
Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
8 300 mg/kg bw
95% CL:
7 300 - 9 400
Mortality:
Main test:
7000 mg/kg bw: 1/4 animal died.
9000 mg/kg bw 2/4 animals died.
10000 mg/kg bw: 4/4 animals died.
Clinical signs:
Cyanosis, diarrhea, salivation, mild convulsions, bleeding from mouth and nose, ataxia, loss of righting, abnormal stance, catatonia, ptosis, and decreased activity were reported. Necropsy of dying animals on study revealed black skin discoloration at application site, with hemorrhage below skin layers and skin necrosis.
Body weight:
Normal weight gain was observed in all animals.
Gross pathology:
Terminal necropsy revealed a discoloration of the tissue at application site, mottled kidneys and patchy lungs ( no visible lesions except signs of skin destruction and hemorrhage at application site).

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based upon the observations made in the Acute Dermal Toxicity Test in Rabbits, LD50 was 8300 mg/kg bw (95% confidence limits: 7300 - 9400 mg/kg bw).
Executive summary:

In an acute dermal toxicity study performed according to OECD 402, but with deviations, an LD50 value of 8300 mg/kg bw was found.