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Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Experimental starting date: 12 February 2008 and experimental compeltion date:04 March 2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008
Report date:
2008

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
6,6'-(1-methylethylidene)bis[3,4-dihydro-3-phenyl-2H-1,3-benzoxazine
EC Number:
604-960-7
Cas Number:
154505-70-1
Molecular formula:
C31 H30 N2 O2
IUPAC Name:
6,6'-(1-methylethylidene)bis[3,4-dihydro-3-phenyl-2H-1,3-benzoxazine
Test material form:
solid

Test animals

Species:
rat
Strain:
other: HanRcc:WIST (SPF)
Sex:
male/female
Details on test animals or test system and environmental conditions:
Test System
- Animals: Rat, HanRcc: WIST(SPF)
- Rationale: Recognized by international guidelines as a recommended test system.
- Breeder: RCC Ltd, Laboratory Animal Services, Wölferstrasse 4, 4414 Füllinsdorf / Switzerland
- Number of Animals per Group: 5 males 5 females
- Age when treated: Males: 9 weeks
- Females: 11 weeks
- Identification: Unique cage number and corresponding color-coded spots on the tail. The animals were marked at acclimatization start.
- Randomization: Selected by hand at time of delivery.

Acclimatization: Under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.

Husbandry
- Room Number: 0105 / RCC Ltd, Füllinsdorf
- Conditions: Standard Laboratory Conditions. Air-conditioned with 10-15 air changes per hour, and continuously monitored environment with ranges for room temperature 22 ± 3 °C and for relative humidity between 30-70 % (values above 70 % during cleaning process possible), automatically controlled light cycle of 12 hours light and 12 hours dark, music during the daytime light period.
Accommodation: During acclimatization in groups of five per sex in Makrolon type-4 cages with standard softwood bedding. Individually in Makrolon type-3 cages with standard softwood bedding ("Lignocel", Schill AG, CH-4132 Muttenz) during treatment and observation.

- Diet: Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no. 77/07 (Provimi Kliba AG, CH-4303 Kaiseraugst/Switzerland) ad libitum.
- Water: Community tap water from Füllinsdorf ad libitum.

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
corn oil
Details on dermal exposure:
One day before treatment, the backs of the animals were clipped with an electric clipper, exposing an area of approximately 10 % of the total body surface.
Only those animals without injury or irritation on the skin were used in the test.
On test day 1, the test item was applied at a dose of 2000 mg/kg body weight evenly on the intact skin with a syringe and covered with a semi-occlusive dressing. The dressing was wrapped around the abdomen and fixed with an elastic adhesive bandage.
- Application volume/kg body weight: 4 mL
Twenty-four hours after the application the dressing was removed and the skin was flushed with lukewarm tap water and dried with disposable paper towels. Thereafter, the reaction sites were assessed.
All animals were re-shaved on test day 8 to facilitate the reading of the local reactions.
Rationale: Dermal administration was used as this is one possible route of human exposure during manufacture, handling and use of the test item.

VEHICLE
- Identification: Corn oil
- Description: Yellowish oily liquid
- Batch number: 18787208
- Source: Carl Roth GmbH & Co. D-76185 Karlsruhe / Germany
- Stability of the Vehicle: Stable under storage conditions; expiration date: October, 2009
- Storage Conditions: At room temperature (range of 20 ± 5 °C), light protected.
- Safety Precautions: Routine hygienic procedures were used to ensure the health and safety of the personnel.
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5 males and 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 1 days
- Necropsy of survivors performed: yes. All animals were killed at the end of the observation period by Carbon dioxide asphyxiation and discarded after macroscopic examinations were performed. No organs or tissues were retained.
- Other examinations performed: clinical signs, body weight.
- Frequency of observations and weighing:

- Viability / Mortality: Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15.
- Clinical Signs: Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1. Once daily during days 2-15. All abnormalities were recorded.
- Local Signs Once daily during days 2-15. All abnormalities were recorded.
- Body Weights: On test days 1 (prior to administration), 8 and 15.
Statistics:
No statistical analysis was used.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred during the study.
Clinical signs:
No clinical signs were observed during the course of the study.
Body weight:
The body weight of the animals was within the range commonly recorded for this strain and age.
Gross pathology:
No macroscopic findings were recorded at necropsy.
Other findings:
LOCAL SIGNS:

At removal of the application no local signs of irritation were observed in any animal. However, a yellowish staining produced by the test item was noted in all animals which persisted up to test day 15, the end of observation. A very slight erythema was recorded in one female on test day 8 and persisted up to test day 11. Slight scaling was recorded in all females from test day 8 to test days 13 and 15, respectively. Slight scabs were noted in two females from test day 10 to 13 or 15.

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The median lethal dose of the test item after single dermal administration to rats of both sexes, observed over a period of 14 days is:
LD50 (rat): greater than 2000 mg/kg body weight
Executive summary:

Five male and five female HanRcc:WIST (SPF) rats were treated with the test substance at 2000 mg/kg by dermal application. The test item was diluted in vehicle (corn oil) at a concentration of 0.5 g/mL and administered at a volume dosage of 4 mL/kg. The application

period was 24 hours.

The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs at approximately 30 minutes, 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-5. Local signs were noted once daily from test day 2 to 15. Mortality/viability was recorded at approximately 30 minutes, 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15. Body weights were recorded on day 1 (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically.

No deaths occurred during the study.

No clinical signs were observed during the course of the study.

At removal of the application no local signs of irritation were observed in any animal. However, a yellowish staining produced by the test item was noted in all animals which persisted up to test day 15, the end of observation. A very slight erythema was recorded in one female on test day 8 and persisted up to test day 11. Slight scaling was recorded in all females from test day 8 to test days 13 and 15, respectively. Slight scabs were noted in two females from test day 10 to 13 or 15.

The body weight of the animals was within the range commonly recorded for this strain and age.

No macroscopic findings were observed at necropsy.

The median lethal dose of the test item after single dermal administration to rats of both sexes, observed over a period of 14 days is: LD50 (rat): greater than 2000 mg/kg body weight

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