Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
26.08.2004 to 02.12.2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study was performed according to the OECD guideline 402 and in compliance with GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report date:
2004

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
yes

Test material

Constituent 1
Reference substance name:
OS Menthol Ester
IUPAC Name:
OS Menthol Ester
Constituent 2
Chemical structure
Reference substance name:
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2R,5R)-5-hydroxy-1,3-oxathiolane-2-carboxylate
EC Number:
604-569-1
Cas Number:
147126-62-3
Molecular formula:
C14H24O4S
IUPAC Name:
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2R,5R)-5-hydroxy-1,3-oxathiolane-2-carboxylate
Constituent 3
Reference substance name:
(2R, 5R)-5-Hydroxy-[1,3]oxathiolane-2- carboxy!ic acid, 2Scisopropyl-5R-methyl- 1R-cyclohexyl ester
IUPAC Name:
(2R, 5R)-5-Hydroxy-[1,3]oxathiolane-2- carboxy!ic acid, 2Scisopropyl-5R-methyl- 1R-cyclohexyl ester
Test material form:
other: White solid

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Age at study initiation: X days (at study initiation / at test item administration)
- Weight at study initiation: males 2-3 kg, females 2-3 kg
- Fasting period before study:
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 14 days
- Temperature (°C): 20°C
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
water
Details on dermal exposure:
- Area of exposure: Twenty-four hours prior to the experiment, the dorsal area of the trunk of selected rabbits will be closely shaved using electric clippers. Not less than 10% of the body surface area will be cleaned for the application of the test substance. Care must be taken to avoid abrading
the skin which could alter the permeability of the skin.
- Type of wrap if used: gauze moistened with SWFI
Duration of exposure:
24 h
Doses:
One dose level (for the Limit Test) or a minimum of 3 dose levels (for the Defined LD5o) will be tested. The dose level(s) will be calculated based on
the results of the Range Finding test to cover an estimated LD10-LD9o range and will increase on a logarithmic scale. The individual doses of the
test article will be individually calculated for each animal based on the body weight of the animal.

The calculated dose portion of the test article will be placed on sheets of gauze moistened with SWFI, and these will be placed on the shaved rabbit skin. Rubber sleeves, approximately 30 em long and 15 em in diameterat the ends, will then be wrapped around the trunk of the rabbit and secured at
the ends with adhesive tape.

Following the dosing, the rabbits will be placed back into their cages for a 24-hour exposure period. Foot jackets may be used, if required, in order to prevent the rabbits from tearing the rubber sleeves. At the end of the 24-hour exposure period, the sleeves on the rabbits will be removed, any amount of unabsorbed sample. will be documented, and the exposed skin will be cleansed by rinsing with USP Purified Water.
No. of animals per sex per dose:
-15 rabbits (5 males and-10 females) for a limit test
-35 rabbits (15 males and-20 females) for LD50 test
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations (mortality, clinical signs): at 1, 2 and 4 h after dosing and once daily thereafter
- Frequency of weighing: day 0 (prior to dosing), day 7 and day 14
- Necropsy of survivors performed: yes
- Other examinations performed: gross examination of organs at necropsy, organ weights, histopathology
Statistics:
Not applicable due to no mortalities at 2000 mg/kg bw.

Results and discussion

Preliminary study:
In one female rabbit a range finding study at 2000 mg/kg bw was carried out and based on the
Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
At the end of the study period, all animals were sacrificed and submitted for gross necropsy. The necropsy included an examination of: external surfaces of the body; all orifices; cranial cavity; external surfaces of the brain and spinal cord; nasal cavity and paranasal sinuses; thoracic, abdominal, and pelvic cavities and viscera.
Clinical signs:
All animals exhibited some skin irritation; erythema for up to approximately 3 days post exposure period and edema for 2 days. From Day 3 to approximately Day 12 after the exposure period, all animals exhibited some skin desquamation. All animals recovered back to normal by Day 13. No other
signs of toxicity were observed.
Body weight:
Mean Group Weight (kg)± S.D. (n=5)
Sex Initial Day7 Day 14
Male 2.1 ± 0.1 2.3 ± 0.1 2.5 ± 0.1
Female 2.1 ± 0.0 2.3 ± 0.1 2.5 ± 0.1
Gross pathology:
All animals were sacrificed at the end of the study and full gross necropsy was performed. No gross pathological fmdings were observed at time of necropsy.

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the results of this study, the Rabbit Dermal LD50 of the test article OS Menthol Ester was found to be in excess of 2.0 g per kg body weight.
Executive summary:

As no mortalities were observed in female rabbits dermally dosed at 2000 mg/kg bw the substance was not classified.