Reaction mass of (E)-3-methylcyclotetradec-5-en-1-one and (Z)-3-methylcyclotetradec-5-en-1-one

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

20 Jan 2004 to 17 Mar 2004

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

conducted under GLP conditions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2004

Report date:

2004

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

2001

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

1996

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

(E)-3-methylcyclotetradec-5-en-1-one

Cas Number:

259854-70-1

Molecular formula:

C15H26O

IUPAC Name:

(E)-3-methylcyclotetradec-5-en-1-one

Constituent 2

Reference substance name:

(Z)-3-methylcyclotetradec-5-en-1-one

Cas Number:

259854-71-2

Molecular formula:

C15H26O

IUPAC Name:

(Z)-3-methylcyclotetradec-5-en-1-one

Test material form:

liquid

Specific details on test material used for the study:

Identification KARMALONE
Description Colourless to pale yellow liquid
Batch number TQT0300497
Purity 90.9%
Expiry date 28-NOV-2004
Stability of test item dilution Unknown in corn oil; is excluded from the statement of compliance.
Storage conditions At room temperature (range of 20 ± 3 °C), light protected.
Safety precautions Routine hygienic procedures were used to ensure the health and safety of the personnel

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

Source: RCC Ltd, Laboratory Animal Services CH-4414 Fullinsdorf / Switzerland
Number of animals per group: 3 females
Total number of animals: 6 females
Age when treated: 11 weeks
Identification: Unique cage number and corresponding color-coded spots on the tail. The animals were marked at acclimatization start.
Randomization: Selected by hand at time of delivery. No computer generated randomization program.
Acclimatization: Under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.
Room no.: 104 / RCC Ltd, Fullinsdorf
Conditions: Standard Laboratory Conditions. Air-conditioned with 10-15
air changes per hour, and continuously monitored environ­ ment with target ranges for room temperature 22 ± 3 °c and
for relative humidity between 30-70 % (values above 70 % during cleaning process possible), automatically controlled light cycle of 12 hours light and 12 hours dark, music during the daytime light period.
Accommodation: 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 raVmouse mainte­ nance diet, batch no. 78/03 (Provimi Kliba AG, CH-4303 KaiseraugsVSwitzerland) ad libitum. Results of analyses for contaminants are archived at RCC Ltd, ltingen.
Water: Community tap water from Fullinsdorf ad libitum. Results of bacteriological, chemical and contaminant analyses are ar­ chived at RCC Ltd, ltingen.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE:
- Concentration in vehicle and amount of vehicle: The test item was di­ luted in vehicle (corn oil) at a concentration of 0.2 g/ml and administered at a volume dosage of 10 mUkg.
- Justification for choice of vehicle: Corn oil 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. This trial formulation is excluded from the GLP statement of compliance.
- Lot/batch no. (if required): 45256603

TREATMENT:
The animals received a single dose of the test item by oral gavage administration at 2000 mg/kg body weight after being fasted for approximately 18 hours (access to water was permitted). Food was provided again 3 hours after dosing.
The application volume was 10 mUkg body weight.
Rationale: Oral administration was considered to be an appropriate application method as it is a possible route of human exposure during manufacture, handling and use of the test item.

Doses:

2000 mg/kg

No. of animals per sex per dose:

2 groups of three females

Control animals:

no

Details on study design:

Observations:
Mortality/ Viability: Daily during the acclimatization period, 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.
Body weights: On test days 1 (prior to administration), 8 and 15.
Clinical signs: Daily during acclimatization 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:
All animals were killed at the end of the observation period by an intraperitoneal injection of Vetanarcol at a dose of at least 2.0 mUkg body weight (equivalent to at least 324 mg sodium pentobarbitone/kg body weight) and discarded after macroscopic examinations were performed. No organs or tissues were retained.

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

Based on:

test mat.

Mortality:

No deaths occurred during the study.

Clinical signs:

other: Slight ataxia was noted in two animals of the first treated group 1 hour after application and in all animals of the same group at the 5-hour reading. Slightly ruffled fur with hunched posture was noted in the same animals from the 2- to the 5-hour read

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 KARMALONE 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

Executive summary:

Two groups, each of three female HanBrl: WIST (SPF) rats, were treated with KARMALONE by oral gavage administration at a dosage of 2000 mg/kg body weight. The test item was di­ luted in vehicle (corn oil) at a concentration of 0.2 g/ml and administered at a volume dosage of 10 mUkg.

The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs at approxi­ mately 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Mortality/viability was recorded 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. Body weights were re­ corded on day 1 (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically.

All animals survived until the end of the study period.

Slight ataxia was noted in two animals of the first treated group 1 hour after application and in all animals of the same group at the 5-hour reading. Slightly ruffled fur with hunched posture was noted in the same animals from the 2- to the 5-hour reading, tremors were also noted at the 5-hourreading.

Slight ataxia was noted in two animals of the second treated group at the 2- and 3-hour reading and in all animals at the 5-hour reading. Tremors were noted in one animal at the 2- and 3-hour reading and in all animals at the 5-hour reading. Slightly ruffled fur with hunched posture was noted in all animals at the 5-hour reading. Slightly ruffled fur was still present in two animals on test day 2 and hunched posture was also still present in one animal.

The body weight of the animals was within the range commonly recorded for this strain and age.

No macroscopic findings were recorded at necropsy.

The median lethal dose of KARMALONE 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