4,8-Cyclododecadien-1-one

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

05-12-2013 to 27-12-2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study performed under GLP. All relevant validity criteria were met.

Justification for type of information:

Information as to the availability of the in vivo study is provided in 'attached justification'.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2014

Report date:

2014

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

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries, Test Data for Registration of Agricultural Chemicals, Acute oral toxicity (2-1-1), 12 Nousan No 8147, Agricultural Production Bureau (2000)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

inspected: November 2012; signature: February 2013

Test type:

acute toxic class method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

(3E,7E)-cyclododeca-3,7-dien-1-one; (4E,8Z)-cyclododeca-4,8-dien-1-one; (4Z,8E)-cyclododeca-4,8-dien-1-one

EC Number:

941-893-5

Cas Number:

15229-79-5

Molecular formula:

C12H18O

IUPAC Name:

(3E,7E)-cyclododeca-3,7-dien-1-one; (4E,8Z)-cyclododeca-4,8-dien-1-one; (4Z,8E)-cyclododeca-4,8-dien-1-one

Test material form:

liquid

Details on test material:

- Physical state: Liquid
- Storage condition of test material: Keep in the dark at 0 - 10 °C, under nitrogen
- Other: Colourless

Test animals

Species:

rat

Strain:

Sprague-Dawley

Remarks:

Crl:CD (SD)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Recognised supplier
- Age at study initiation: 8 - 12 weeks.
- Weight at study initiation: 214 g to 262; The weight variation did not exceed ±20% of the mean weight at the start of treatment.
- Fasting period before study: Overnight before dosing and four hours after dosing.
- Housing: Group housed in groups of up to three in polycarbonate cages with a stainless steel mesh lid with a quantity of autoclaved softwood bark-free fibre bedding.
- Diet (e.g. ad libitum): Certified diet from recognised supplier, provided ad libitum (except for overnight fasting period and four hours post doing).
- Water (e.g. ad libitum): ad libitum (except for fasting period)
- Acclimation period: At least 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 23
- Humidity (%): 40 - 70%
- Air changes (per hr): The room was kept at positive pressure with respect to the outside by its own supply of filtered fresh air, which was passed to atmosphere and not re-circulated. The air changes was monitored periodically.
- Photoperiod: 12 h light / 12 h dark

IN-LIFE DATES: From: To: 2013-12-10 to 2013-27-12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: Formulated at concentration of 200 mg/mL in the vehicle and administered at a volume of 10 mL/kg body weight
- Amount of vehicle (if gavage): Administered at a volume of 10 mL/kg body weight
- Justification for choice of vehicle: Not applicable.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bodyweight

DOSAGE PREPARATION (if unusual): Not applicable.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Assessment of available infornation in accordance with the study guideline.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

6 females per dose (tested sequentially in accordance with the guideline).

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Cages were checked at least twice daily for any mortalities. Observations were made after dosing and at frequent intervals for the remainder of Day 1. On subsequent days, observations were made once in the morning and again at the end of the experimental day (with the exception of Day 15 - morning only). The nature and severity, where appropriate, of the clinical signs and the time were recorded at each observation. Individual body weights were recorded on Day 1 (prior to dosing) and on Days 8 and 15 or at mortality. Individual weekly body weight changes and group mean body weights were calculated.
- Necropsy of survivors performed: yes

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

One female (J4) dosed at 2000 mg/kg was terminated due to poor clinical condition on Day 2.

Clinical signs:

other: 2000 mg/kg bw: Clinical signs prior to humane sacrifice (female J4 on Day 2 ) comprised of unsteady gait, tremors, uncoordinated gait, piloerection, hunched posture, flat posture, shallow breathing and reduced body temperature. These signs were seen from

Gross pathology:

Macroscopic examination of the humanely sacrificed female due to poor condition on day 2 revealed pallor of the lungs, liver and kidneys and yellow fluid content in the small and large intestines. Macroscopic examination at study termination on Day 15 revealed pallor of the kidneys in one female (J1). No abnormalities were revealed in any other surviving females.

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of this study the oral LD50 was established to exceed 2000 mg/kg bw in female Sprague-Dawley Crl:CD (SD) rats. Applicant assessment indicates, under the conditions of this study and according to the OECD TG 423 criteria, the LD50 cut-off value was considered to be greater than 2000 and less than 5000 mg/kg body weight.

Executive summary:

The study was performed according to OECD TG 423 and EU Method B.1 tris, US EPA OPPT 870.1100 and Japan Guidelines for Acute Toxicity Oral Class Method and in accordance with GLP. The objective of the study was to assess the acute oral toxicity of the test material following a single oral administration in the female Sprague-Dawley Crl:CD (SD) strain rat by the acute toxic class method. The test item was formulated in corn oil vehicle at 200 mg/ml and then administered by single oral gavage in an initial group of three females at 2000 mg/kg. As the results of this group indicated the acute lethal oral dose of the test substance to be greater than 2000 mg/kg body weight a further group of three females was dosed at 2000 mg/kg bw in accordance with the guidelines. There was one female humane sacrifice in the second group on day 2. Clinical signs prior to humane sacrifice mortality comprised unsteady gait, tremors, uncoordinated gait, piloerection, hunched posture, flat posture, shallow breathing and reduced body temperature. These signs were seen from approximately 30 minutes after dosing. Macroscopic examination of the female revealed pallor of the lungs, liver and kidneys and yellow fluid content in the small and large intestines. Clinical signs of reaction to treatment for the remaining females receiving 2000 mg/kg comprised of unsteady gait, tremors, uncoordinated gait and piloerection, loose faeces, hunched posture, reduced activity, shallow breathing, elevated gait and urine staining. These signs were first noted approximately 30 minutes after dosing. Recovery of surviving females, as judged by external appearance and behaviour, was complete by Day 4 or 6. Slightly low body weight gain was recorded during the second week of the observation period for the two surviving rats of the second cohort. All other females were considered to have achieved satisfactory body weight gains throughout the study. Macroscopic examination at study termination on Day 15 revealed pallor of the kidneys in one female. No abnormalities were revealed in any other surviving females. Under the conditions of this study the oral LD50 was established to exceed 2000 mg/kg bw in female Sprague-Dawley Crl:CD (SD) rat. Applicant assessment indicates, under the conditions of this study and according to the OECD TG 423 criteria, the LD50 cut-off value was considered to be greater than 2000 and less than 5000 mg/kg body weight.