Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
disregarded due to major methodological deficiencies
Study period:
no data
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Does not meet important criteria of today standard methods: test site was abraded, coverage was not used.
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1974
Report Date:
1974

Materials and methods

Principles of method if other than guideline:
20 day dermal study in rabbits
GLP compliance:
no
Remarks:
pre-GLP
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: liquid
Details on test material:
- Name of test material (as cited in study report): Ethylene Brassylate
- Substance type: clear, colourless to slightly yellow cast, viscous liquid
- Analytical purity: no data
- Storage condition of test material: no data

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: M: 2392-3593 g; F: 2386-3581 g
- Fasting period before study: no data
- Housing: individually, in metal metabolism cages
- Diet (e.g. ad libitum): Purina Rabbit Chow ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): controlled room
- Humidity (%): controlled room
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

IN-LIFE DATES: no data

Administration / exposure

Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: backs of the rabbits, clipped free with an electric clipper and abraded twice weekly with a scalpel blade
- % coverage: no data
- Time intervals for shavings or clippings: as necessary; skin was abraded twice weekly

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.029; 0.067 or 0.667 mL/kg bw/d
- Constant volume or concentration used: no

USE OF RESTRAINERS FOR PREVENTING INGESTION: no
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
none
Duration of treatment / exposure:
20 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
30, 70 or 700 mg/ kg bw/d
Basis:
nominal per unit body weight
No. of animals per sex per dose:
6 animals per sex per dose
Control animals:
yes, concurrent no treatment
Details on study design:
none
Positive control:
yes, a positive control group of rabbits received 700 mg/kg bw/d of mineral oil (0.800 mL/kg bw/d)

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: changes in general behaviour and appearance

DETAILED CLINICAL OBSERVATIONS: No

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: prior to and 6 hours following compound application

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: No

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: All
- Parameters checked in table 7.5.3/1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: all
- Parameters checked in table 7.5.3/1 were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: no data
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No data
- Parameters checked in table 7.5.3/1 were examined.

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes. Liver, kidney, testes and ovaries were weighted.
HISTOPATHOLOGY: Yes: liver, kidneys, bone marrow and testes or ovaries were examined.
Other examinations:
none
Statistics:
T-test

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
highest serum cholesterol values in the 700 mg/kg bw/d dose group
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY:
One rabbit at the 700 mg/kg bw/d dosage level died on the 21st day of the study.

BODY WEIGHT AND WEIGHT GAIN
No effects

DERMAL IRRITATION
Dermal irritation noted for all rabbits included intradermal haemorrhaging, blanching, necrosis and sloughing of the dead tissues.
The following signs were noted for all rabbits and were generally slight to moderate and occasionally marked for rabbits at the 30 mg/kg bw/d dosage level and moderate to marked for rabbits at the 70 and 700 mg/kg bw/d dosage levels: erythema, edema, desquamation, coriaceousness and fissuring.

HAEMATOLOGY
Two rabbits showed nucleated erythrocytes and most rabbits showed slight decreases in hemoglobin concentration at the 700 mg/kg bw/d dosage level. Although within the normal range for New Zealand White rabbits in this laboratory, the total leucocyte counts for rabbits were elevated over the values for the negative control rabbits. An increase in neutrophils and a decrease in lymphocytes also were noted. These changes were probably due to the dermal irritation noted for these rabbits.

CLINICAL CHEMISTRY
The sodium values were statistically significantly lower than those of the negative control rabbits. However, the values were in the normal range for New Zealand White rabbits in this laboratory and these differences were not considered biologically significant.
Serum cholesterol values for most of the rabbits at the 700 mg/kg bw/d dosage level were higher than those of control rabbits.

URINALYSIS
No changes

ORGAN WEIGHTS
No data

GROSS PATHOLOGY
Compound related slight to marked dermal irritation at the application site and enlargement and edema of the regional lymph nodes were observed. The severity of the skin lesion was dose related and enlargement of the regional lymph nodes occurred only at the 700 mg/kg bw/d dosage level and was considered secondary to the severe skin irritation which occurred at this level. All other gross lesions in these rabbits were those which commonly occur spontaneously in this species and were not significant.

HISTOPATHOLOGY
No lesions which were considered compound-related were seen in any of the tissues examined. Lesions seen were those which commonly occur spontaneously and were not significant.

Effect levels

Dose descriptor:
LOAEL
Effect level:
30 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: local effects on the skin

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

none

Applicant's summary and conclusion

Conclusions:
Under the test conditions, the LOAEL is 30 mg/kg bw/d based on local effects on the skin.
Executive summary:

In a repeat-dose dermal toxicity study, the test material was applied to the shaved and abraded skin of 6 New Zealand White rabbits/sex/dose at dose levels of 0, 30, 70 or 700 mg/kg bw/day, during a 20-day period.

One rabbit at the 700 mg/kg bw/d dosage level died on the 21st day of the study.

Dermal irritation noted for all rabbits included intradermal haemorrhaging, blanching, necrosis and sloughing of the dead tissues.

The following signs were noted for all rabbits and were generally slight to moderate and occasionally marked for rabbits at the 30 mg/kg bw/d dosage level and moderate to marked for rabbits at the 70 and 700 mg/kg bw/d dosage levels: erythema, edema, desquamation, coriaceousness and fissuring.

Serum cholesterol values for most of the rabbits at the 700 mg/kg bw/d dosage level were higher than those of control rabbits.

Under the test conditions, the LOAEL is 30 mg/kg bw/d based on local effects on the skin.

This study does not meet important criteria of today's standard methods: the test site was abraded and an occluded dressing was not used. Therefore it was not considered reliable for the purpose of hazard evaluation.