Registration Dossier

Administrative data

Description of key information

Acute oral toxicity (similar to OECD TG 401): LD50 > 2000 mg/kg bw

Acute inhalation toxicity (WoE, non-guideline studies): LC50 > 3.2 mg/L (no mortality)

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The study is conducted according to methods similar to OECD guideline 401 and 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:
weight of evidence
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:
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 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:
study cannot be used for classification
Conclusions:
Linalool caused a decrease in motility, but no mortailty in mice in a 90-minute inhalation study with a single concentration of 3.2 mg/L in air. The LC50 is therefore determined to be >3.2 mg/L.
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:
weight of evidence
Justification for type of information:
See attached justification
Reason / purpose:
read-across source
Preliminary study:
Not relevant
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:
study cannot be used for classification
Conclusions:
Linalool caused a decrease in motility, but no mortailty in mice in a 90-minute inhalation study with a single concentration of 3.2 mg/L in air. The LC50 is therefore determined to be >3.2 mg/L. This result was used for read-across to tetrahydrolinalyl 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 tetrahydrolinalyl acetate.

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
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:
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 effect on motility was determined. In addition blood samples were drawn 0m 30, 60 & 90 minutes after inhalation and plasma was analysed by GC-MS, GC-FTIR & GC-FID for the presence of linalool.
GLP compliance:
no
Test type:
other: Inhalation study under standardized conditions
Limit test:
no
Species:
mouse
Strain:
Swiss
Sex:
female
Details on test animals 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 libitumENVIRONMENTAL 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
Type of inhalation exposure:
other: experimental procedure according to Kovar et al. (1987) and technical characteristics according to Buchbauer et al. (1992)
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
No data
Analytical verification of test atmosphere concentrations:
yes
Remarks:
To calculate the air concentration of the fragrance compounds in the cage to determine the total drug volume (20-50 mg per compound), the charcoal tubes (120, NIOSH, Catalogue no. 226-01) supplied by Drager Company, Lübeck, Germany were used.
Duration of exposure:
1 h
Concentrations:
No data
No. of animals per sex per dose:
No data
Control animals:
yes
Details on study design:
- Duration of observation period following administration: minimum 10 minutes- Frequency of observations and weighing: no data- Necropsy of survivors performed: no data- Other examinations performed: the motility of the mice was examined.
Statistics:
Statistics were calculated with an Atari 1040 personal computer (WISTAT scientific statistic package program). Significance was determined by the t test and F-test; the level of significance chosen for p to reject the null hypothesis was <0.05.
Preliminary study:
Not relevant
Sex:
female
Dose descriptor:
LC50
Effect level:
> 20 other: mg
Exp. duration:
1 h
Remarks on result:
other: no deaths after exposure to 20-50 mg linalool
Mortality:
No data
Clinical signs:
other: The exposure led to a decrease in motility of the mice. After a 1-h inhalation period, the motility of mice exposed to linalool was 73% lower than the motility of the untreated control animals.
Body weight:
No data
Gross pathology:
No data
Other findings:
No data

The concentration of linalool in the blood samples following inhalation was 4.22 ng/ml.

Interpretation of results:
study cannot be used for classification
Conclusions:
Linalool caused a decrease in motility, but no mortailty in mice when exposed to 20-50 mg compound in a 1-hour inhalation study.
Executive summary:

The influence of linalool on the motility in mice was tested in an inhalation study 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 concentration tested (20 -50 mg).

Endpoint:
acute toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
See attached justification
Reason / purpose:
read-across source
Preliminary study:
Not relevant
Sex:
female
Dose descriptor:
LC50
Effect level:
> 20 other: mg
Exp. duration:
1 h
Remarks on result:
other: no deaths after exposure to 20-50 mg linalool
Mortality:
No data
Clinical signs:
other: The exposure led to a decrease in motility of the mice. After a 1-h inhalation period, the motility of mice exposed to linalool was 73% lower than the motility of the untreated control animals.
Body weight:
No data
Gross pathology:
No data
Other findings:
No data

The concentration of linalool in the blood samples following inhalation was 4.22 ng/ml.

Interpretation of results:
study cannot be used for classification
Conclusions:
Linalool caused a decrease in motility, but no mortailty in mice when exposed to 20-50 mg compound in a 1-hour inhalation study. This result was used for read-across to tetrahydrolinalyl acetate.
Executive summary:

The influence of linalool on the motility in mice was tested in an inhalation study 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 concentration tested (20 -50 mg). This result was used for read-across to tetrahydrolinalyl acetate.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The studies are not conducted according to international guidelines, but performed under standardized conditions and are therefore 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 an acute oral fixed dose study performed according to OECD TG 420 and in compliance with GLP. Ten Crl: CD (SD) rats (5 male/5 female) were exposed to a single dose of 2000 mg/kg bw test substance by oral gavage. Animals were observed for 14 -days after dosing for clinical signs and body weight gain. After 14 days gross necropsy was performed. No clinical signs of toxicity throughout the observation period were observed and there was no adverse effect on bodyweight gain in animals of either sex. No abnormalities were detected at necropsy. Under the conditions of the test, the LD50 was determined to be > 2000 mg/kg bw. This result is supported by an acute oral toxicity study in rats with read-across substance Linalool, in whic an LD50 of 2790 mg/kg body weight was found.

Acute inhalation toxicity

Two studies were available for read-across substance linalool, which were used in a weight of evidence approach. In the first study, 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) and therefore the LC50 was determined to be >3.2 mg/l. In the other study, the influence of linalool on the motility in mice was also tested in an inhalation study 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 concentration tested (20-50 mg).

Justification for classification or non-classification

Based on the available data, 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).