Linalool

Endpoint summary

Description of key information

Acute toxicity oral:

- Standard acute method (Mouse): LD50 approx. 2200 mg/kg bw (comparable to deleted OECD 401).

- Standard acute method (Rat): LD50 2790 mg/kg bw (similar to deleted OECD 401).

Acute toxicity inhalation:

- Inhalation study under standardized conditions (Mouse): 73% decrease in motility (20-50 mg, 1-hour).

- Inhalation study under standardized conditions (Mouse): LC50 >3.2 mg/L (3200 mg/m³).

Acute toxicity dermal:

- Standard acute method (Rabbit): LD50 5610 mg/kg bw (similar to OECD 402).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

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:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

Publication with limited details on methods, but study seems to be performed under standardized conditions.

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: Animals had access to water at all times

ENVIRONMENTAL CONDITIONS
No 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:

other: Ataxia soon after treatment

Gross pathology:

No data

Other findings:

Not relevant

Not relevant

Interpretation of results:

GHS criteria not met

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.

Reference 2

Endpoint:

acute toxicity: oral

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:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

The current study is not performed according to an international or national guideline. The study can be compared with the deleted OECD 401 for acute oral toxicity (1987); no description of clinical signs, pathology, and housing conditions.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

4 males and 4 females/dose; 10 days observation

Principles of method if other than guideline:

Not relevant

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

mouse

Strain:

CD-1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 19 to 22 g.

ENVIRONMENTAL CONDITIONS: No data

IN-LIFE DATES: No data

Route of administration:

oral: unspecified

Vehicle:

other: a solution in groundnut oil, and an aqueous solution of 10% gum arabic

Details on oral exposure:

VEHICLE: a solution in groundnut oil, and an aqueous solution of 10% gum arabic (SG 10%); no further data.

DOSE VOLUME APPLIED: 25 mL/kg

Doses:

900, 1350, 2000, 3000, and 4000 mg/kg bw.

No. of animals per sex per dose:

4 females and 4 males

Details on study design:

- Duration of observation period following administration: 10 days
Other examinations performed: mortality reported; no other examinations/observations reported.

Statistics:

LD50 calculation according to LITCHFIELD and WILCOXON or DRAGSTEDT and LANG method; Chi-square test.

Preliminary study:

Not applicable

Key result

Sex:

male/female

Dose descriptor:

approximate LD50

Effect level:

ca. 3 500 mg/kg bw

Remarks on result:

other: oral administration in solution in groundnut oil

Key result

Sex:

male/female

Dose descriptor:

approximate LD50

Effect level:

ca. 2 200 mg/kg bw

Remarks on result:

other: oral administration in emulsion in SG 10 %

Mortality:

# Dead/# Dosed
In solution in groundnut oil: at 4500 mg/kg 8 mice/8; at 3000 mg/kg 1 mouse/8; at 2000 mg/kg 2 mice/8; at 1350 and 900 mg/kg 0 mice/8 died.
In emulsion in SG 10 %: at 4500 mg/kg 8 mice/8; at 3000 mg/kg 7 mice/8; at 2000 mg/kg 1 mouse/8; at 1350 and 900 mg/kg 0 mice/8 died.
The animals died within the first 24 hours of observation.

Clinical signs:

other: No data

Gross pathology:

No data

Other findings:

- Other observations: The symptoms of intoxication displayed were hyper-motility with ataxia, followed by sedation or depression according to the dose and dyspnoea before death.

Not relevant

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of the current study a lowest oral LD50 of approx. 2200 mg/kg bw has been established for mice that received 5 oral doses (4500, 3000, 2000, 1350, and 900 mg/kg bw) of Linalool in an aqueous solution of 10% gum arabic. The substance does not have to be classified according to the classification criteria outlined in Regulation (EC) 1272/2008.

Executive summary:

The acute oral toxicity of Linalool in the mouse was assessed. 4 male and 4 female mice per dose, weighing 19 - 22 grams, received 4500, 3000, 2000, 1350, and 900 mg/kg bw, either as a solution in groundnut oil, or an aqueous solution of 10% gum arabic (SG 10%). The animals were observed for 10 days after exposure and mortality was reported. The LD50 was calculated by using the method of Litchfield and Wilcoxon or Dragstedt and Lang.

An oral administration in solution in groundnut oil resulted in an approximate LD50 of 3500 mg/kg bw, and oral administration in emulsion in SG 10 % resulted in an approximate LD50 of 2200 mg/kg bw. The substance does not have to be classified according to the classification criteria outlined in Regulation (EC) 1272/2008.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 200 mg/kg bw

Quality of whole database:

Study well documented, meets generally accepted scientific principles, acceptable for assessment

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

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:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

Study not conducted according to international guideline, but performed under standardized conditions. No data on whether study was conducted under GLP.

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 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: Standardized pelleted food T 799 (Tagger, Graz, Austria) ad libitum
- Water: Ad libitum

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

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

Key result

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:

other: causes a decrease in motility in mice

Remarks:

Criteria used for interpretation of results: other: no criteria used

Conclusions:

Linalool caused a decrease in motility in mice of 73% 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).

Reference 2

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:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

Study not conducted according to international guideline, but performed under standardized conditions. No data on whether study was conducted under GLP.

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: Standardized pelleted food T 799 (Tagger, Graz, Austria) ad libitum
- Water: 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 DESCRIPTION
For 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.

VEHICLE
Not 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

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 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 conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating conc.

Value:

> 3 200 mg/m³ air

Physical form:

inhalation: vapour

Quality of whole database:

Study well documented, meets generally accepted scientific principles, acceptable for assessment

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

No data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Although an old study (1970) and not fully compliant with OECD 402, and non GLP, the report is well documented, and the design is considered scientifically accepted.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

3 animals per dose group of unspecified sex, post exposure (observation) only 7 days, area exposed not specified, animal weight slightly too low, no information on housing conditions.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

other: albino

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: approx. 1500 to 2300 g.

ENVIRONMENTAL CONDITIONS: No data

IN-LIFE DATES: No data

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Type of wrap if used: Saran Wrap

REMOVAL OF TEST SUBSTANCE
- Washing: Gently removed
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amounts applied: 2500, 5000 and 10000 mg/kg/bw
- Concentration: Undiluted

Duration of exposure:

24 hours

Doses:

2500, 5000 and 10000 mg/kg/bw

No. of animals per sex per dose:

3

Control animals:

yes, concurrent no treatment

Details on study design:

- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: observation: daily; weighing: at start and termination (at 7 days) of the study
- Necropsy of survivors performed: Yes
- Other examinations performed: clinical signs, hematology and clinical chemistry were conducted on survivors at five days of the studies.
Hematology: Erythrocyte, leucocyte and differential leucocyte counts; hematocrit; hemoglobin.
Clinical chemistry: Serum glutamic oxaloacetic transaminase (SCOT): glucose; blood urea nitrogen (BUN); serum alkaline phosphatase (SAP); total serum protein; serum albumin; bilirubin; lactic acid dehydrogenase (LDH); cholesterol; serum calcium; serum phosphate; and uric acid, using the SMA-12 methods.

Statistics:

The acute dermal LD50 was calculated by the method of Weil (Biometrics 8, 3, p.249, Sept., 1952).

Preliminary study:

Not applicable

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

5 610 mg/kg bw

95% CL:

>= 3 578 - <= 8 374

Mortality:

At 5000 mg/kg bw one out of three animals died at day 5.
At 10000 mg/kg bw all three rabbits were dead within the first 24 hours of the study.

Clinical signs:

other: - Other observations: Signs of intoxication were depression, coma and death. Signs developed within 24 hours following application of the test material, and survivors were normal after 5 days. On removal of the bandages, the skins of the rabbits at all tr

Gross pathology:

At autopsy no significant gross pathology was noted which could be attributed to the dermal application of the test substance.

Other findings:

- Other observations: All hematology and clinical chemistry values, conducted on survivors at five days of the studies, appeared to be within normal limits and are comparable to control values generated in this laboratory.

Not relevant

Interpretation of results:

GHS criteria not met

Conclusions:

The dermal LD50 of linalool in rabbits is calculated to be 5610 mg/kg, with confidence limits of 8374 - 3578 mg/kg, under the conditions of this study. The substance does not need to be classified for acute dermal toxicity according to the criteria outlined in Regulation (EC) 1272/2008 (CLP/EU-GHS).

Executive summary:

The substance has been tested in an acute dermal toxicity test (similar to OECD 402, test system: Rabbit). Three dose levels, 2500, 5000 and 10000 mg/kg/bw, were applied undiluted for 24 hours. Untreated animals served as control.

On removal of the bandages, the skins of the rabbits at all treatment levels appeared blanched, with moderate erythema and slight edema of the skin surrounding the blanched areas. At 24 hours after removal, the skin of surviving rabbits appeared normal.

At 5000 mg/kg bw one out of three animals died at day 5. At 10000 mg/kg bw all three rabbits were dead within the first 24 hours of the study.

All hematology and clinical chemistry values, conducted on survivors at five days of the studies, appeared to be within normal limits and are comparable to control values generated in this laboratory. At seven days the surviving rabbits showed a normal weight gain for the period (at 2500 and 5000 mg/kg).

At autopsy no significant gross pathology was noted which could be attributed to the dermal application of the test substance.

Signs of intoxication were depression, coma and death. Signs developed within 24 hours following application of the test material, and survivors were normal after 5 days.

The substance does not need to be classified for acute dermal toxicity according to criteria Regulation (EC) 1272/2008/EC), as the LD50 is calculated to be 5610 mg/kg bw, with confidence limits of 8374 - 3578 mg/kg bw, under the conditions of this study.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 610 mg/kg bw

Quality of whole database:

Comparable to guideline study with acceptable restrictions

Additional information

For this endpoint 6 tests, performed comparable or similar to test guidelines were available:

- The acute oral toxicity was assessed in 4 male and 4 female mice per dose, receiving 4500, 3000, 2000, 1350, and 900 mg/kg bw. The animals were observed for 10 days after exposure and mortality was reported. An oral administration in solution in groundnut oil resulted in an approximate LD50 of 3500 mg/kg bw, and oral administration in emulsion in gum arabic 10 % resulted in an approximate LD50 of 2200 mg/kg bw. (Julou, 1974)

 

- The acute oral toxicity was also investigated in rats (10 rats per concentration). The LD50 values were calculated using the method of Lichfield & Wilcoxon. Deaths occurred 4 to 18 hours after dosing. Ataxia was seen soon after treatment. The LD50 was calculated to be 2790 mg/kg bw with 95% confidence limits of 2440-3180 mg/kg bw. (Jenner, 1964)

 

- In addition, one acute oral test on mice is considered a supporting study as it is a short summary in an internal report. The 24-hour and 10-day LD50 was found to be 3120 ± 500 mg/kg bw. (Bächtold, 1977)

 

 

Based on the available data it is obvious from the above described experiments that Linalool is of low acute toxicity when applied via the oral route. Therefore, the overall data suggest that the LD50 is greater than 2000 mg/kg bw.

 

- 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). (Buchbauer et al., 1993)

 

- In another 90-minute inhalation study under standardized conditions Linalool caused a decrease in motility in mice. No deaths were reported at the concentration tested (approx. 3.2 mg/l), therefore the LC50 was determined to be >3.2 mg/l. (Buchbauer et al., 1991)

Although the report of a OECD 403 compliant acute inhalation toxicity study with Linalool as test item is not available, the available data indicate that the LC50 is > 3.2 mg/L.

 

- The acute dermal toxicity test has been tested at three dose levels, 2500, 5000 and 10000 mg/kg/bw. LD50 was calculated to be 5610 mg/kg bw, with confidence limits of 8374 - 3578 mg/kg bw., using the method of Well.

Linalool appears to be of very low acute dermal toxicity as the LD50 value was far above 2000 mg/kg bw. (Fogleman, 1970)

Justification for classification or non-classification

Based on the available information Linalool has been shown to be of low acute toxicity when applied via the oral, dermal, and inhalation route. Therefore, the substance Linalool does not need to be classified for acute toxicity according to the criteria under Regulation (EC) No 1272/2008, as amended for fifteenth time in Regulation (EU) No 2020/1182.