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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
short-term repeated dose 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: reliable study report, no guideline available For justification of read-across please refer to section 13.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1988
Report Date:
1988

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
The test material was applied dermally to the clipped skin of rats daily for a period of 14 days, 5 days/week. During this period and after the last application, skin reactions as signs of irritancy were recorded according to the Draize scale.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid: viscous

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Sprague-Dawley, Inc., Indianapolis, IN, USA
- Age at study initiation: Approximately 7 weeks
- Weight at study initiation: 206.2-234.1 g
- Housing: 6/group

Administration / exposure

Type of coverage:
other: The treatment area was uncovered following the first 6 applications and covered following the last 4 applications.
Vehicle:
water
Details on exposure:
TEST SITE
- Area of exposure: dorsal area from the scapular region to just above the rump, approx. 5 cm wide

TEST MATERIAL
- Amount applied: 2.0 mL per kg body weight
- Concentration: 0, 0.03/0.6, 0.1, 0.3, 1.0 and 3.0 % (irritation was not observed during the first week of the study, animals which received a 0.03 % solution of test substance for the first five applications received a 0.6 % solution of test substance for the last five applications)
- Constant volume or concentration used: yes

DURATIN OF EXPOSURE
- Two weeks (10 applications), with the exception of the high-dose (3.0%) animals which were only dosed for 5 days due to severe skin irritation.

Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
10 applications except for the highest dose group: 5 applications, 6 hours/day
Frequency of treatment:
5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0.03/0.6, 0.1, 0.3, 1.0 and 3.0 % (animals which received a 0.03% solution of test substance for the first five applications received a 0.6% solution of test substance for the last five applications)
Basis:
other: active substance
No. of animals per sex per dose:
6
Control animals:
yes, concurrent vehicle
Positive control:
not required

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

DERMAL IRRITATION: Yes
- Time schedule for examinations: The skin of the application site was evaluated for erythema and edema six hours after the 5th application, prior to the 6th application, six hours after the 10th application, and prior to sacrifice.
Sacrifice and pathology:
HISTOPATHOLOGY: The skin at the application site was collected and fixed for possible future histopathological examination.
Other examinations:
not applicable
Statistics:
not applicable

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Dermal irritation:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
not examined
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:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
No mortality occured. Perinasal and periocular encrustation were observed in all high-dose (3.0%) animals during the first week of the study and in one animal at the 0.1% level on Day 12. Hyperactivity lasting several minutes was observed in animals in the 1.0% treatment group immediately following dose application on Day 8.

DERMAL IRRITATION
Erythema and edema were found from the 1 % dose group onwards. No erythema or edema were present in the lower dose groups.

Effect levels

Dose descriptor:
NOAEL
Effect level:
6 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male
Basis for effect level:
other: local skin effects after 2 week application calculated from the concentration of 0.3 % a.s. in water at 2 mL/kg bw/day (3 mg/mL x 2 mL/kg bw/day = 6 mg/kg bw/d) corresponding to 0.045 mg/cm2

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

It was assumed that the treated body surface was 10 %. The total surface body of rat (male and female) is 400 cm2 and the mean body weight is 300 g. Assuming that 10 % of the body surface has been exposed to the test substance, the resulting exposed area is of 40 cm2.

The NOAEC in mg/cm2 was calculated according to the following formula:

NOAEC in mg /cm2 =( Total dose applied in mg)/( Treated surface in cm2) =

(average animal weight in kg * dose in mg kg bw)/ (treated surface area in cm2)

NOAEC = (0.3 kg x 6 mg/kg bw/day) / 40cm2 = 0.045 mg/cm2

Applicant's summary and conclusion