cis-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane-4-ylmethyl benzoate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2006-03-22 to 2006-04-14

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2006

Report date:

2006

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Remarks:

: Testing laboratory indicated that the study procedures met or exceeded the requirements of the guideline.

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

Remarks:

: Testing laboratory indicated that the study procedures met or exceeded the requirements of the guideline.

GLP compliance:

yes (incl. QA statement)

Remarks:

Certificate from the Swiss GLP Monitoring Authorities

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

cis-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane-4-ylmethyl benzoate

EC Number:

262-765-9

EC Name:

cis-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane-4-ylmethyl benzoate

Cas Number:

61397-56-6

Molecular formula:

C18H15BrCl2O4

IUPAC Name:

[(2R,4R)-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl benzoate

Test material form:

solid: particulate/powder

Details on test material:

- Name of test material (as cited in study reports): JNJ-16479671-AAA (T001095)
- Physical state: solid (powder)
- Appearance: White powder

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Janssen Pharmaceutica N.V. 00452023 ZT001095PUA121
- Expiration date of the lot/batch: Unknown
- Purity correction factor: 1

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature, light protected
- Stability under test conditions: Stable under storage conditions

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Does levels are in terms of the test item as supplied by the sponsor.

Test animals

Species:

rat

Strain:

other: HanRcc:WIST (SPF)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd., Laboratory Animal Services, CH-4414 Fullinsdorf / Switzerland
- Age at study initiation: 11 - 12 weeks
- Weight at study initiation: ranged from 185.0 to 203.1 g
- Fasting period before study: approximately 18 hours (access to water was permitted). Food provided again approximately 3 hours after dosing.
- Housing: In groups of three in Makrolon type-4 cages with wire mesh tops and standard softwood bedding ('Lignocel' Schill AG, CH-4132 Muttenz/Switzerland).
- Diet: Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no. 001/06 (Provimi Kliba AG, CH-4303 Kaiseraugst/Switzerland) ad libitum. Results of analyses for contaminants are archived at RCC Ltd.
- Water: Community tap water from Fullinsdorf ad libitum.
- Acclimation period: 2006-03-22 to 2006-03-28 (females, 2000 mg/kg); 2006-03-24 to 2006-03-30 (females, 2000 mg/kg) under laboratory conditions, after health examination


ENVIRONMENTAL CONDITIONS
- Temperature (deg C): 22 +/- 3 deg C
- Humidity (%): 30-70% (values above 70 % during cleaning process were possible)
- Air changes (per hr): air conditioned with 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12/12, music during daytime light period

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 0.2 g/mL
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: PEG 300 was found to be a suitable vehicle. The vehicle was chosen after a non-GLP solubility trial which was performed before the study initiation date.
- Lot/batch no. (if required): 1204719 44705164

MAXIMUM DOSE VOLUME APPLIED:
- 10 mL/kg

DOSAGE PREPARATION (if unusual):
The dose formulations were made shortly before each dosing occasion using a magnetic stirrer and a spatula as homogenizers. The test substance was weighed into a tared glass beaker on a suitable precision balance and the vehicle added (weight:volume). Homogeneity of the test substance in the vehicle was maintained during administration using a magnetic stirrer.

Doses:

two treatment groups both at 2000 mg/kg body weight

No. of animals per sex per dose:

3 females per treatment group

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of mortality / viability observations: 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.
- Frequency of weighing: On test days 1 (prior to administration), 8 and 15.
- Frequency of clinical signs observations: 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.
- Necropsy of survivors performed: yes
- Other examinations performed: macroscopic examinations after necropsy

Statistics:

No statistical analysis was used.

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

No deaths occurred during the study.

Clinical signs:

other: Slightly ruffled fur was noted in five animals at the 30-minute reading and persisted in two animals until the 2- or 3-hour reading, respectively. Hunched posture was also noted in one animal at the 1- and 2-hour readings.

Gross pathology:

No macroscopic findings were recorded at necropsy.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The median lethal dose of the test substance after single oral administration to female rats, observed over a period of 14 days is:
LD50 (female rat): greater than 2000 mg/kg body weight. T001095 is therefore considered not to be classified as acute oral toxicant.