Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards, well documented and acceptable for assessment

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1967
Report Date:
1967
Reference Type:
publication
Title:
No information
Author:
Schilling, B.V. et al.
Year:
1966
Bibliographic source:
Naunyn-Schmiedeberg's Arch. Exp. Path. Pharmak. 253, 82
Reference Type:
publication
Title:
No information
Author:
Schilling, B.V. et al.
Year:
1966
Bibliographic source:
Verh. Dtsch. Ges. Path., 50. Tagung Heidelberg, 429

Materials and methods

Principles of method if other than guideline:
BASF-Test (internal BASF method)
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Aethylenimin rein
- Analytical purity: pure (no further data)

Test animals

Species:
rabbit
Strain:
not specified
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 0.01 - 0.05 % aqueous solution
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
see "Any other information on material and methods incl. tables"
Frequency of treatment:
up to 5 times a week
Doses / concentrations
Remarks:
Doses / Concentrations:
0.42, 0.83, 1.66, 3.32, 4.15 mg/kg bw (0.5, 1, 2, 5 µL/kg bw) as 0.01-0.05 % aqueous solution (Recalculation bsed on relative density at 24 °C = 0.83)
Basis:

No. of animals per sex per dose:
1 animal/dose regime
Control animals:
no
Details on study design:
Post-exposure period: no data
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: no data


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: no data


BODY WEIGHT: Yes
- Time schedule for examinations: before test start, during test, and at test termination


HAEMATOLOGY: Yes
- Time schedule for collection of blood: no data
- How many animals: all animals
- Parameters examined: leukocytes, lymphocytes, erythrocytes, granulocytes


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: no data
- How many animals: all animals
- Parameters examined: urea, serum-glutamate-pyruvate-transaminase


URINALYSIS: Yes
- Time schedule for collection of urine: no data

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
no data

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
- 4.15 mg/kg bw: 4/4 rabbits dead
- 1.66 mg/kg bw: 4/4 rabbits dead
- 0.83 mg/kg bw: 5/7 rabbits dead
- 0.42 mg/kg bw: 3/4 rabbits dead

Anorexia, atony, apathy, laboured respiration, and shortly before death abdominal and lateral position


BODY WEIGHT AND WEIGHT GAIN
Decrease of body weights


HAEMATOLOGY
Decrease in lymphocytes down to 10-15 % of normal, and an increase in granulocytes. All other values were normal.


URINALYSIS
Proteinuria was observed; both erythrocytes and, to a lesser extend, leukocytes were detected in the urine. Urea in blood was generally increased in the treated rabbits.


HISTOPATHOLOGY: NON-NEOPLASTIC
Renal papillary necrosis, hyperemia in the medulla renalis

Effect levels

Dose descriptor:
NOAEL
Remarks on result:
not determinable
Remarks:
no NOAEL identified

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

The repeated administration of ethylenimine to rabbits caused at doses of 0.83 mg/kg bw or higher anorexia, atony, and apathy, laboured respiration, and shortly before death abdominal and lateral position.

Repeated dosing (3-8 times) with 4.15 and 1.66 mg/kg bw led to the death of the treated rabbits. Haematology (haemoglobin, erythrocyte and leukocyte counts) appeared to be normal. But the differential blood count showed a decrease in lymphocytes down to 10-15 % of normal, and an increase in granulocytes. Proteinuria was observed; both erythrocytes and, to a lesser extend, leukocytes were detected in the urine. Blood ureawas generally increased in the treated rabbits. Necropsy revealed in all of the deceased rabbits of both dose groups (4.15 and 1.66 mg/kg bw ) renal papillary necrosis.

The repeated gavage administration of 0.83 mg/kg bw caused proteinurea, increased blood urea and to the excretion of erythrocytes and leukocytes in urine. Haematology (haemoglobin, erythrocyte and leukocyte counts) appeared to be normal. The repeated application of 0.83 mg/kg bw resulted in renal papillary necrosis and in one case hyperemia in the medulla renalis.

2 rabbits survived 31 gavage administrations with substance doses of 0.83 mg/kg bw without clinical signs of toxicity. After increasing the dose to 1.66 and 3.32 mg/kg bw respectively, symptoms of renal toxicity were observed.

The lowest dose (0.42 mg/kg bw) was lethal to 3/4 rabbits. Haematology was within normal ranges, except for a decrease of lymphocytes accompanied by an increase of granulocytes. Again, erythrocytes were found in urine sediment. Pathology revealed hyperemia of the medulla renalis.

Applicant's summary and conclusion