Cineole

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

Between 27 March and 17 April 1991.

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

To address toxicological endpoints as part of the REACH registration of Cineole (Target Substance) it is proposed to read-across to Clarycet (Source Substance). The use of read-across works within the spirit of REACH and the stated aim of the legislation to reduce animal testing where possible. The Target Substance and Source Substance have been characterised in using the categories and databases present in the OECD (Q)SAR Toolbox. From the profile, it can be seen that the two substances share structural similarities and also "mechanistic action" similarities which are both general and endpoint specific. Therefore read-across is justified.

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

1991

Report date:

1991

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Deviations:

no

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Clarycet

IUPAC Name:

Clarycet

Constituent 2

Reference substance name:

131766-73-9

EC Number:

603-508-6

Cas Number:

131766-73-9

IUPAC Name:

131766-73-9

Constituent 3

Reference substance name:

Tetrahydro-4-methyl-2-propyl-2H-pyran-4-yl acetate

IUPAC Name:

Tetrahydro-4-methyl-2-propyl-2H-pyran-4-yl acetate

Details on test material:

- Name of test material (as cited in study report): Tetrahydro-4-methyl-2-propyl-2H-pyran-4-yl acetate (Clarycet)
- Analytical purity: > 94 %
- Lot/batch No.: 6370
- Storage condition of test material: At room temperature in the dark.
- Physical state: Clear colourless liquid.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River UK Ltd, Margate, Kent, England.
- Age at study initiation: 4 to 6 weeks
- Weight at study initiation: 108 - 152 g
- Fasting period before study: Overnight prior to dosing and approximately 4 h after dosing.
- Housing: In groups of up to five rats by sex in metal cages with wire mesh floors.
- Diet (e.g. ad libitum): standard rodent diet (Biosure LAD 1) ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: Seven days prior to the start.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21- 23 °C
- Humidity (%): mean of 57 %
- Air changes (per hr): Approximately 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light/dark

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

VEHICLE
Not applicable

MAXIMUM DOSE VOLUME APPLIED: 8.16 mL/kg (specific gravity 0.98)

Doses:

Preliminary study: 2.5 g/kg bw
Main study: 3.2, 5.0, 8.0 g/kg

No. of animals per sex per dose:

Preliminary study: 2/sex/dose
Main study: 5/sex/dose

Control animals:

no

Details on study design:

- Duration of observation period following administration:
Preliminary study: 5 days
Main study: 14 days
- Frequency of observations and weighing: Rats were observed soon after dosing and at frequent intervals on Day 1 (day of dosing - minimum period of 5 hours) and twice daily thereafter, once in teh morning and again at the end of the experimental day. Clinical signs were recorded at each observation.

- Necropsy of survivors performed: yes. All surviving animals on the main study were killed on Day 15 and the abdominal and thoracic cavities examined.
- Other examinations performed: Approximate time of death of individual rats, the nature, severity, approximate time of onset and duration of each toxic sign; individual bodywieghts of rats of Days 1 (day of dosing), 8 and 15 or at death.

Statistics:

The acute median lethal oral dose to male and female rats was caluclated using the method of Finney (1871, Probit Analysis). Separate LD50 values for males and females were estimated by undertaking probit analysis on the mortality data from the main study by fittingtwo parallel lines to teh data (males only and females onle) using the technique described by Finney (1978). A chi-square test was carried out to cehcl that the data did not cotnain any evidence on non-parallelism.

Results and discussion

Effect levels

Effect levels 1

Sex:

male/female

Dose descriptor:

LD50

Effect level:

4.5 other: g/kg

Based on:

test mat.

95% CL:

3.3 - 5.8

Remarks on result:

other: The slope of the probit line was 5.6 with a standard error of 1.87 using long transforation of dose.

Effect levels 2

Sex:

male

Dose descriptor:

LD50

Effect level:

4.7 other: g/kg

Based on:

test mat.

95% CL:

3.2

Effect levels 3

Sex:

female

Dose descriptor:

LD50

Effect level:

4.3 other: g/kg

95% CL:

2.8 - 6.1

Mortality:

There were deaths following a single oral dose of the test substance among male and female rats dosed at 3.2 g/lg bw and above. Deaths occurred at intervals from within 5 hours of treatment until Day 4. Among decedencents, slight bodyweight gains were recorded for two males and one female dosed at 8.0 g/kg; bodyweight losses were recorded for remainin rats. Post mortem examination of rats that died during the study revealed no macroscopic abnormalities.

Clinical signs:

other: Pilo-erection and abnormal body carriage (hunched posture) were observed in all rats within 5 minutes of dosing and were accompanied at this time by increased salivation in rats dosed at 5.0 g/kg plus abnormal gait (waddlig) and lethargy in rats treated a

Gross pathology:

Terminal autopsy revealed no macroscopic abnormalities.

Other findings:

Preliminary study: The results of the preliminary study indicated that the acute median lethal oral dose to male and female rats to Clarycet was greater than 2.5 g/kg bodyweight.

The difference between the lines for male and female rats was not statistically significant. Teh chi-square test for parallelism gave no evidence of non-parallelism.

Any other information on results incl. tables

Number of deaths of rats dosed orally with Clarycet

Sex	Dose (g/kg)	No. of deaths per group
Male	3.2	1
	5.0	2
	8.0	5
Female	3.2	2
	5.0	2
	8.0	5

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The test substance was assessed for acute oral toxicity in the rat according to OECD guideline 401. The acute median lethal oral dose and the 95 % confidence limit for males and females combined were 4.5 g/kg body weight (3.3 - 5.8 g/kg confidence limits); for males only it was estimated to be 4.7 g/kg body weight (3.2 - 7.0 g/kg confidence limits) and for females only was 4.3 g/kg body weight (2.8 - 6.1 g/kg confidence limits).

To address toxicological endpoints as part of the REACH registration of Cineole (Target Substance) it is proposed to read-across to Clarycet (Source Substance).

The use of read-across works within the spirit of REACH and the stated aim of the legislation to reduce animal testing where possible.

The Target Substance and Source Substance have been characterised in using the categories and databases present in the OECD (Q)SAR Toolbox. From the profile, it can be seen that the two substances share structural similarities and also "mechanistic action" similarities which are both general and endpoint specific.
Therefore read-across is justified.