Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Acute oral toxicity in rat (pre-guideline study): LD50 = 2790 mg/kg bw (read-across)

Acute inhalation toxicity in mice (non-guideline study): LC50 > 3.2 mg/L (read-across)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
See attached justification
Reason / purpose for cross-reference:
read-across source
Preliminary study:
Not relevant
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 790 mg/kg bw
95% CL:
2 440 - 3 180
Remarks on result:
other: Slope function 1.3 (95% CI 1.2-1.4)
Mortality:
Death time 4-18 hr
Clinical signs:
Ataxia soon after treatment
Body weight:
No data
Gross pathology:
No data
Other findings:
Not relevant

Not relevant

Interpretation of results:
not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The LD50 of Linalool for rats was found to be 2790 mg/kg bodyweight. Based on this LD50 value, the substance is not classified according to Regulation (EC) 1272/2008. This result was used for read-across to ethyllinalyl acetate.
 
Executive summary:

The acute oral toxicity of Linalool to rats was investigated. 10 animals per concentration were used, the substance was administered orally via gavage. The LD50 was found to be 2790 mg/kg body weight. This result was used for read-across to ethyllinalyl acetate.

 

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
no data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Publication with limited details on methods, but study seems to be performed under standardized conditions.
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Osborne-Mendel
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS- Source: no data- Age at study initiation: young adults- Weight at study initiation: no data- Fasting period before study: 18 hours- Water (e.g. ad libitum): animals had access to water at all timesENVIRONMENTAL CONDITIONSNo data
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
No data
Doses:
No data
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: The usual observation period was 2 weeks; in a few cases, where no acute toxic signs were seen, the animals were observed for only one week.- Frequency of observations and weighing: Frequency not known, all animals were maintained under close observation for recording toxic signs and time of death. Such observation was continued until animals appeared normal or showed weight gain.
Statistics:
LD50's were computed by the method of Litchfield & Wilcoxon (1949).
Preliminary study:
Not relevant
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 790 mg/kg bw
95% CL:
2 440 - 3 180
Remarks on result:
other: Slope function 1.3 (95% CI 1.2-1.4)
Mortality:
Death time 4-18 hr
Clinical signs:
Ataxia soon after treatment
Body weight:
No data
Gross pathology:
No data
Other findings:
Not relevant

Not relevant

Interpretation of results:
not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The LD50 of Linalool for rats was found to be 2790 mg/kg bodyweight. Based on this LD50 value, the substance is not classified according to Regulation (EC) 1272/2008.
Executive summary:

The acute oral toxicity of Linalool to rats was investigated. 10 animals per concentration were used, the substance was administered orally via gavage. The LD50 was found to be 2790 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 790 mg/kg bw
Quality of whole database:
The selected study is the key study for this endpoint and performed according to methods similar to an OECD guideline. As such, it is considered appropriate to be used as the basis for the chemical safety assessment.

Acute toxicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study not conducted according to international guideline, but performed under standardized conditions. No data on whether study was conducted under GLP.
Reason / purpose for cross-reference:
reference to same study
Qualifier:
no guideline followed
Principles of method if other than guideline:
Mice were exposed to linalool in air under standardized conditions, and the effects on motility was determined.
GLP compliance:
no
Test type:
other: Inhalation study under standardized conditions
Limit test:
no
Species:
mouse
Strain:
Swiss
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS- Source: no data- Age at study initiation: 6-8 week and 6 months old- Weight at study initiation: 28.5 g- Housing: in groups of 4 on a bedding of wood shavings in polycarbonate cages (Makrolon, type II)- Diet (e.g. ad libitum): standardized pelleted food T 799 (Tagger, Graz, Austria) ad libitum- Water (e.g. ad libitum): ad libitum- Acclimation period: one hour adaptation period was offered to the animals in which no pharmacological treatment occurred.ENVIRONMENTAL CONDITIONS- Temperature (°C): 22 ± 2°C- Humidity (%): 60 ± 10%- Air changes (per hr): 12-15- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Remarks:
the substance was introduced directly into the cage in which the mice were present
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTIONFor the exposure of the animals to the fragrance compounds a small glass tube with a slit measuring 3 mm in width and 5 cm in length was used. The fragrance compounds were injected through a small hole of the cage wall and the rubber plug of the glass tube. Immediately after placing the mice into the cages and the horizontal fixation of the glass tube a transparent plastic seal was fixed at the cage to form an airtight seal. A pumping-evaporating-system as a part of a spirometer system as described by Kovar et al. was used to supply fresh air and to guarantee a steady air flow.One hour adaptation period was offered to the animals in which no pharmacological treatment occurred. The small glass tube was then filled with 1.5 ml of the respective fragrance material which was constantly released by the slit. A steady concentration by constant drug evaporation from glass tubes throughout the experiment was ensured.TEST ATMOSPHERE- Brief description of analytical method used: The mean air concentration of linaloool in the cage was determined by means of capillary GC and GC/MS as follows: The air stream carrying the fragrance compounds was passed through a layer of activated charcoal which afterwards was eluted with carbon disulfide. After evaporation of the solvent the amount of fragrance compounds remaining in the air was determined by measuring the difference between the original amount of fragrance material in the glass tube and the residual amount in the charcoal. VEHICLENot applicable
Analytical verification of test atmosphere concentrations:
yes
Remarks:
To calculate the air concentration of the fragrance compounds in the cage to consider the total drug volume, charcoal tubes were used.
Duration of exposure:
90 min
Concentrations:
27 mg of linalool in approximately 8.4 litres of cage air -> approximately 3.2 mg/l
No. of animals per sex per dose:
4 animals, no data on sex distribution
Control animals:
yes
Details on study design:
- Duration of observation period following administration: no data- Frequency of observations and weighing: no data- Necropsy of survivors performed: no data- Other examinations performed: the motility of the mice was examined.The mice were kept in a light-barrier cage. The light-barrier, 2 cm above the cagefloor, was interrupted due to the motor activity of the animals crossing it and triggered impulses which were evaluated during the experiment.
Statistics:
Statistics were calculated using an Atari 1040 personal computer ("WISTAT" scientific statistic-package program). The significance was determined by Student's "t"-test and F-test, the level of significance chosen for p to reject the null hypothesis was < 0.05.
Preliminary study:
Not relevant
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 3.2 mg/L air
Exp. duration:
90 min
Remarks on result:
other: no deaths after exposure to 27 mg linalool in 8.4 litres of air
Mortality:
No data
Clinical signs:
other: The exposure led to a decrease in motility of the mice. The observed motility compared to the motility of the untreated control animals was 32%/96% after 30 minutes inhalation, 8%/85% after 60 minutes inhalation and 0%/71% after 90 minutes inhalation for
Body weight:
No data
Gross pathology:
No data
Other findings:
No data

The concentration of linalool in the blood samples following inhalation was approximately 1, 2.8 and 3 ng/ml after 30 minutes, 60 minutes and 90 minutes of exposure, respectively.

Interpretation of results:
other: causes a decrease in motility in mice
Conclusions:
Linalool caused a decrease in motility in mice in a 90-minute inhalation study.
Executive summary:

The influence of linalool on the motility in mice was tested in an inhalation study under standardized conditions. After 30 minutes, 60 minutes and 90 minutes, the motility in the exposed mice was decreased to 32%/96%, 8%/85% and 0%/71% (6 -8 week old mice/6 month old mice) of the motility of untreated control animals. No deaths were reported at the concentration tested (approximately 3.2 mg/l), therefore the LC50 was determined to be >3.2 mg/l.

Endpoint:
acute toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
See attached justification
Reason / purpose for cross-reference:
read-across source
Preliminary study:
Not relevant
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 3.2 mg/L air
Exp. duration:
90 min
Remarks on result:
other: no deaths after exposure to 27 mg linalool in 8.4 litres of air
Mortality:
No data
Clinical signs:
other: The exposure led to a decrease in motility of the mice. The observed motility compared to the motility of the untreated control animals was 32%/96% after 30 minutes inhalation, 8%/85% after 60 minutes inhalation and 0%/71% after 90 minutes inhalation for
Body weight:
No data
Gross pathology:
No data
Other findings:
No data

The concentration of linalool in the blood samples following inhalation was approximately 1, 2.8 and 3 ng/ml after 30 minutes, 60 minutes and 90 minutes of exposure, respectively.

Interpretation of results:
other: causes a decrease in motility in mice
Conclusions:
Linalool caused a decrease in motility in mice in a 90-minute inhalation study. This result was used for read-across to ethyllinalyl acetate.
 
Executive summary:

The influence of linalool on the motility in mice was tested in an inhalation study under standardized conditions. After 30 minutes, 60 minutes and 90 minutes, the motility in the exposed mice was decreased to 32%/96%, 8%/85% and 0%/71% (6 -8 week old mice/6 month old mice) of the motility of untreated control animals. No deaths were reported at the concentration tested (approximately 3.2 mg/l), therefore the LC50 was determined to be >3.2 mg/l. This result was used for read-across to ethyllinalyl acetate.

 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
3 200 mg/m³
Quality of whole database:
The study was not conducted according to international guidelines, but performed under standardized conditions and it is considered appropriate to be used as the basis for the chemical safety assessment.

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Acute oral toxicity

The key study was read-across from the substance linalool. An acute toxicity study in rats was performed according to methods similar to OECD 401. Five rats/sex/dose were exposed to linalool by oral gavage. Animals were observed for 14 days. LD50's were computed by the method of Litchfield & Wilcoxon (1949). The LD50 was found to be 2790 mg/kg body weight, which is the most critical LD50 of the four available studies for this endpoint.

In addition, three supporting studies in mice are available of which one was based on read across. The first supporting study was performed with ethyllinalyl acetate and is a pre-guideline study in which 10 CF-1 mice per dose were orally exposed. The animals were observed for 72 hours for mortality. Under the conditions of the test, the LD50 was calculated to be 17974 ± 7568 mg/kg. The second study is a pre-guideline study (Colaianni, 1967) 5 male CFW mice per dose were orally exposed to ethyllinalyl acetate. The animals were observed for 72 hours for mortality. LD50 was calculated by the method of Miller and Tainter and determined to be 8522.0 ± 359 mg/kg bw. The third supporting study was a pre-guideline study performed with Ethyllinalool. 5 male CFW mice per dose were orally exposed to Ethyllinalool. The animals were observed for 72 hours for mortality. LD50 was calculated by the method of Miller and Tainter. Under the conditions of the test, the LD50 was calculated to be 5283 +/- 383 mg/kg bw. This result was read-across to ethyllinalyl acetate.

Acute inhalation toxicity

Two studies are available for this endpoint, both for the read-across substance linalool. The key study is a non-guideline study in which the influence of linalool on the motility in mice was tested after inhalation of vapour under standardized conditions. After 30 minutes, 60 minutes and 90 minutes, the motility in the exposed mice was decreased to 32%/96%, 8%/85% and 0%/71% (6 -8 week old mice/6 month old mice) of the motility of untreated control animals. No deaths were reported at the concentration tested (approximately 3.2 mg/L), therefore the LC50 was determined to be >3.2 mg/L. This result is used for read-across to ethyllinalyl acetate.

The supporting study was a non-guideline study in which the influence of linalool on the motility in mice was tested after inhalation under standardized conditions. After a 1-hour inhalation period, the motility in the exposed mice was decreased by 73% compared to the motility of untreated control animals. No deaths were reported at the dose tested (20-50 mg linalool).

Justification for classification or non-classification

Based on the available information, the test substance does not need to be classified for acute toxicity in accordance with the criteria outlined in Annex I of the CLP Regulation (1272/2008/EC).