Cyclopropanecarboxylic acid, [(3S,4R,4aR,6S,6aS,12R,12aS,12bS)-3-[(cyclopropylcarbonyl)oxy]-1,3,4,4a,5,6,6a,12,12a,12b-decahydro-6,12-dihydroxy-4,6a,12b-trimethyl-11-oxo-9-(3-pyridinyl)-2H,11H-naphtho[2,1-b]pyrano[3,4-e]pyran-4-yl]methyl ester

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From January 28, 2009 to October 5, 2009

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

1987

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

other: JMAFF No 12 Nosan No 8147

Version / remarks:

1987

Deviations:

no

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

[(3S,4R,4aR,6S,6aS,12R,12aS,12bS)-3-(cyclopropanecarbonyloxy)-6,12-dihydroxy-4,6a,12btrimethyl-11-oxo-9-(pyridin-3-yl)-1,2,3,4,4a,5,6,6a,12a,12b-decahydro-11H,12Hbenzo[f]pyrano[4,3-b]chromen-4-yl]methylcyclopropanecarboxylate

EC Number:

815-966-6

Cas Number:

915972-17-7

Molecular formula:

C33H39NO9

IUPAC Name:

[(3S,4R,4aR,6S,6aS,12R,12aS,12bS)-3-(cyclopropanecarbonyloxy)-6,12-dihydroxy-4,6a,12btrimethyl-11-oxo-9-(pyridin-3-yl)-1,2,3,4,4a,5,6,6a,12a,12b-decahydro-11H,12Hbenzo[f]pyrano[4,3-b]chromen-4-yl]methylcyclopropanecarboxylate

Test material form:

solid

Details on test material:

- Analytical purity: 96.1 %
- Appearance: Solid yellowish
- Batch: COD-001545

Specific details on test material used for the study:

Lot number: 080722
Expiry: 29 July 2010

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Fuji (Shizuoka, Japan).
- Females nulliparous and non-pregnant: Yes
- Age at study initiation: 9 weeks at dosing
- Weight at study initiation: 271- 283 g (male); 170-180 g (female)
- Fasting period before study: A fasting period was not reported
- Housing: Housed individually in metal cages (310 mm wide x 410 mm depth x 230 mm height)
- Diet: Scertified pellet diet MF (Lot No 081015, Oriental Yeast Co; Tokyo, Japan), ad libitum
- Water: Tap water, ad libitum
- Acclimation period: 9 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 2°C
- Humidity: 50 ± 20%
- Air changes: 10x or more per hour
- Photoperiod: 12 hours of artificial light (0700 – 1900 GMT) in each 24-hour period

IN-LIFE DATES: From Feb 19, 2009 to March 5, 2009

Administration / exposure

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: Dorso-lumbar region; about 26hr prior to treatment, hair was removed with electric clippers, on the dorsal body surface area.
- Type of wrap: Surgical dressing pad moistened with 0.5 mL of distilled water, then applied to the 4 cm X 5 cm clipped skin area and occlusively held in place with surgical tape (Transpore TM).

REMOVAL OF TEST SUBSTANCE
- Washing: Residual test substance was washed off with warm water and neutral detergent
- Time after start of exposure: After 24 hours

TEST MATERIAL
- Concentration: 66.7% in 1% w/v aqueous methylcellulose
- Constant volume or concentration used: Yes

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were carefully observed for their mortalities, appearance, posture, behavior, respiration, consciousness, neurologic signs, body temperature, excretion, etc., at the time points of 1, 3 and 6 hours after administration and once daily thereafter until the termination of the observation period. Each animal was weighed on day of the administration shortly before dosing and on days 7 and 14 after administration.
- Necropsy of survivors performed: Yes
- Other examinations performed: Macroscopic examination consisted of opening the thoracic and abdominal cavities. The macroscopic appearance of all tissues including the dose sites was recorded.

Statistics:

None

Results and discussion

Preliminary study:

Not applicable

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was observed in this study.

Clinical signs:

other: No systemic clinical signs were observed during the study. There were no observed dermal responses.

Gross pathology:

Macroscopic examination revealed no abnormal findings in any of the animals at the termination of the study.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met