7-oxabicyclo[4.1.0]hept-3-ylmethyl 7-oxabicyclo[4.1.0]heptane-3-carboxylate

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

18 May 2010 to 9 June 2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Proprietary Guideline Study

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2010

Report date:

2010

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)

Deviations:

yes

Remarks:

Body weight was not recorded on Day 7, however additional measurements were made. This will not affect the validity of the study.

Principles of method if other than guideline:

Not relevant

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Celloxide 2021

IUPAC Name:

Celloxide 2021

Specific details on test material used for the study:

-Name of test material (as cited in study report): Celloxide 2021P
- Physical state: Yellow liquid
- Analytical purity: 96.48%
- Impurities (identity and concentrations): Not documented
- Composition of test material, percentage of components: Not documented
- Isomers composition: Not documented
- Purity test date: 6th April 2010
- Lot/batch No.: CELP-AD-038
- Expiration date of the lot/batch: 7th July 2010
- Stability under test conditions: Not documented
- Storage condition of test material: When not in use, the test article was stored in a sealed container, at 15-25ºC.

Test animals

Species:

rat

Strain:

other: HsdHanTM:WIST

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan, Bicester, UK
- Age at study initiation: approximately 11 weeks old
- Weight at study initiation: males weighed between 238 and 244 g, females weighed between 203 and 217 g
- Fasting period before study: Not documented
- Housing: The animals were housed in groups of three/sex. European softwood bedding was provided weekly to each cage. The animals were provided with wooden aspen chew blocks and rodent retreats.
- Diet (e.g. ad libitum): SQC Rat and Mouse Maintenance Diet No 1, Expanded ad libitum
- Water (e.g. ad libitum): Mains water was provided ad libitum via water bottles.
- Acclimation period: 8 days. Animals were acclimatised to the restraint procedures for 3 consecutive days prior to the exposure, for successive periods of 1, 2 and 4 hours.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 24°C
- Humidity (%): 45 to 65%
- Air changes (per hr): minimum of 15 air changes/hour
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark.

IN-LIFE DATES: From: 18 May 2010 To: 9 June 2010

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

not specified

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Restraint tubes
- Exposure chamber volume: 40L
- Method of holding animals in test chamber: Not documented
- Source and rate of air: 25L/min
- Method of conditioning air: An aerosol of the test article, Celloxide 2021P, was generated using a Jet atomiser into a flow-through (nose-only) exposure chamber (volume approximately 40 L) continuously for four hours.
- System of generating particulates/aerosols:
- Method of particle size determination: The particle size distribution of the aerosol was measured gravimetrically using a Marple Series 290 cascade impactor by sampling the aerosol from inside the chamber at a flow rate of 2L/min. The weight of test article collected on each substrate was used to calculate the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD).
- Treatment of exhaust air: No information provided
- Temperature, humidity, pressure in air chamber: Temperature: 20.2°C
Humidity: 21.9%
Oxygen Concentration: 19% (v/v)

TEST ATMOSPHERE
- Brief description of analytical method used: The chamber aerosol concentration was sampled at a flow rate of 1 L/minute on to weighed glass fibre filters. Using the collected weight and volume of air sampled, the gravimetric chamber aerosol concentration was calculated. Filter samples were collected from a sampling port representative of the animals breathing zone.
- Samples taken from breathing zone: yes

VEHICLE
- Composition of vehicle (if applicable): Not documented
- Concentration of test material in vehicle (if applicable): Not documented
- Justification of choice of vehicle: Not documented
- Lot/batch no. (if required): Not documented
- Purity: Not documented

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution:
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): Mean MMAD: 3.09 μm and GSD: 2.54

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration:

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

>= 4 h

Concentrations:

4.56 to 5.50 mg/L

No. of animals per sex per dose:

3 per sex per dose

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: All animals were observed at the beginning and the end of the working day to ensure the animals were in good health. All animals were observed daily for signs of ill health or overt toxicity. In addition, each animal was given a weekly detailed physical examination as part of the daily dosing observations. The animals were observed pre-exposure and during dosing at hourly intervals, commencing 30 minutes after the start of exposure, until the end of the working day. An observation was performed when the animals were returned to the cage (approximately 10 minutes after the end of exposure), then once daily during the remainder of the study. Individual body weights were recorded for all animals before and after exposure on Day 1 and on Days 2, 3, 4, 8, 14 and 15. As one female had not returned to the pre-exposure body weight, all females were weighed on Day 5.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: No additional observations

Statistics:

No information provided

Results and discussion

Preliminary study:

Not relevant

Effect levels

Sex:

male/female

Dose descriptor:

other:

Effect level:

>= 5.19 mg/L air

Based on:

not specified

Exp. duration:

4 h

Remarks on result:

other: Inhalation exposure to Celloxide 2021P at 5.19 mg/L was well tolerated. No animals died or showed any persistent clinical signs attributable to the test article, and there were no major effects on body weight.

Mortality:

There were no premature decedents during this study. No rats died as a result of exposure to Celloxide 2021P at dose range of 4.56 - 5.50 (mean 5.19 mg/L)

Clinical signs:

other: There were no clinical observations for any animal during the 4-hour exposure or up to 4.5 hours post dose. At the end of the working day (approximately 6 hours post exposure), 2 female animals were lethargic, and the 3rd female was ataxic with tachypnoea

Body weight:

All animals lost body weight during exposure. Males regained their pre-exposure body weights by Day 3 or 4. The females returned to their pre-exposure body weight by Day 4 or 5.

Gross pathology:

There were no findings following macroscopic examination at necropsy.

Other findings:

No additional information

Any other information on results incl. tables

No additional information

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of the study, inhalation exposure to Celloxide 2021P at 5.19 mg/L was well tolerated as there were no mortalities observed and no abnormal clinical signs attributable to the test substance. Based on these results, classification according to Regulation EC No. 1272/2008 or Directive 67/548/EEC was not warranted.

Executive summary:

In a study conducted by Leighton (2010), the test substance Celloxide 2021P, was evaluated for its ability to induce toxicity when tested in male and female Wistar rats via nose only inhalation for a period of 4 hours. The concentration of doses was in the range 4.56 - 5.50mg/L (mean of 5.19mg/L).

Following administration of the test substance, there were no mortalities observed. Some initial weight loss was evident in both males and females post dosing, however, all animals had returned to their pre-exposure body weight by day 5 post-exposure. Approximately 6 hours post exposure), 2 female animals were lethargic, and the 3rd female was ataxic with tachypnoea, exophthalmus and trance like behaviour. On Day 2, all females were unkempt and the 3rd female had exopthalmus. There were no other clinical signs considered to be related to treatment.

Inhalation exposure to Celloxide 2021P at dose range of 4.56 - 5.50 (mean 5.19 mg/L) was well tolerated.

Under the conditions of the study, inhalation exposure to Celloxide 2021P at 5.19 mg/L was well tolerated as there were no mortalities observed and no abnormal clinical signs attributable to the test substance. Based on these results, classification according to Regulation EC No. 1272/2008 or Directive 67/548/EEC was not warranted.