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: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From October 6, 2009 to March 24, 2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2010

Report date:

2010

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

2009

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: MAFF in Japan, No 12 Nosan No 8147

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

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
Description: Pale yellow green powder
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: 8 weeks
- Weight at study initiation: 229-247 g (males) and 149-167 g (females)
- Housing: Housed by sex in groups of 5 in holding cages made of stainless steel sheet and wire mesh that was suspended on a moveable rack. (240 mm wide x 400 mm depth x 180 mm height)
- Diet: SDS rat and mouse diet (RM1(E) SQC expanded pellet)
- Water: Tap water supplied by Anglian Water, ad libitum
- Acclimation period: At least 8 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3°C
- Humidity: 50 ± 20%
- Air changes (per hr): at least 100 changes
- Photoperiod (hrs dark / hrs light): 12 hours of artificial light (07.00 – 19.00 GMT) in each 24-hour period

IN-LIFE DATES: From: October 28, 2009 to: November 18, 2009

Administration / exposure

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose/head only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

4.3 µm

Geometric standard deviation (GSD):

1.89

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Turn-table type dust feeder with compressed air
- Exposure chamber volume: 31.2 L
- Method of holding animals in test chamber: Snout-only exposure chamber
- Source and rate of air: Airflow, 20 L/min
- Method of particle size determination: Gravimetrically with an electronic balance
- Treatment of exhaust air: Chamber air was exhausted through an air filter system consisting of a bag filter and was emitted to the atmosphere using a blower.
- Temperature, humidity, pressure in air chamber: 22-23°C; 45-51%,- 20 and -5 mm H2O

TEST ATMOSPHERE
- Brief description of analytical method used: HPLC
- Samples taken from breathing zone: Yes, 6 L of chamber air was drawn from the chamber sampling port using an air sampler

TEST ATMOSPHERE
- Particle size distribution: Measured three times with an Andersen type personal sampler at 1, 2 and 3 hours after the initiation of exposure.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

5.48 mg/L

No. of animals per sex per dose:

5

Control animals:

yes

Remarks:

a vehicle control group (1.31 mg/L for white carbon) was conducted with 5 males and 5 females.

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of weighing: Shortly before exposure and on 1, 3, 7 and 14 days after exposure
- Necropsy of survivors performed: Yes
- Other examinations: All animals were checked at 2 hours during the exposure. Further clinical observations were made immediately post exposure as well as 1 and 4 hours post exposure and daily thereafter.

Statistics:

Statistical methods employed are not detailed in the final report.

Results and discussion

Preliminary study:

Not applicable

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.48 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

None

Clinical signs:

other: In the test substance group, abnormal respiratory sound was noted in four males and one female. This sign began to appear immediately after the termination of exposure and disappeared by 4 hours after the termination of exposure. No signs were noted in an

Body weight:

Several males in test substance group and all animals in vehicle control group lost body weight on day 1 after exposure. On 3 days afer exposure, all animals in vehicle control group lost body weight. All animals gained body weight by 7 and 14 days after exposure.

Gross pathology:

No gross pathological abnormalities were detected in the animals that underwent necropsy at termination of the study.

Other findings:

No other findings were observed.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met