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Link to relevant study record(s)

Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information

Several toxicokinetic studies are available in humans or in rats about the read-across substances lavender oil (which has a composition very close compared to lavandin oil), linalool and linalyl acetate (the major constituents of the registered substance).

 

Absorption:

Oral absorption:

In rats, the majority (55%) of an orally administered 14C-labelled dose of 500 mg/kg linalool was excreted in the urine as the glucuronic acid conjugate, while 23% of the dose was excreted in expired air, and 15% was excreted in the feces within 72 h of dose administration.

Dermal absorption:

An in vitro skin absorption study with linalool in three different vehicles has been conducted using human epidermal membranes from 6 tissue donors. Diffusion cells, under both occluded and unoccluded conditions, were dosed with 4% (w/v) of a 14C-solution of linalool in 70/30 ethanol (EtOH)/water, DEP (diethyl phthalate) or DPG (dipropylene glycol). Permeation of linalool was then measured at 12 time-points over 24 h. The percent of applied dose absorbed at 24 h was 3.57% under unoccluded conditions and 14.1% under occluded conditions with 70/30 EtOH/water as the vehicle; 2.77% for unoccluded and 5.73% for occluded with DEP as the vehicle and 1.8% for unoccluded and 7.49% for occluded with DPG as the vehicle. (RIFM expert panel, 2008)

The in vitro skin absorption and elimination of linalool was studied by applying linalool or linalyl acetate (500 mg/0.65 cm2) to human skin and determine the amount of linalool in the stratum corneum and epidermis and dermis after 1, 2, and 4h. Linalool and linalyl acetate easily penetrated into the skin, however they were not detected in the acceptor fluid. Additionally, 1343 and 130 µg/cm2 linalool and linalyl acetate, respectively, were found in epidermis and dermis. The percentage of applied dose in epidermis and dermis is therefore calculated to be 0.17% and 0.028% for linalool and linalyl acetate, respectively. Considering results of another in vitro penetration study conducted by Green et al (2007), it is likely that most of the applied material is evaporated. For linalool, 60% of the total initial amount was detected in the skin following 1h elimination and this remained unchanged for 4 h. For linalyl acetate, the maximum concentration in stratum corneum was reached after only 2 h. The total amount of linalyl acetate in the skin was unchanged during the elimination phase, but the ratio of the amount in stratum corneum, epidermis and dermis was decreasing, and after 4 h, only 3% of linalyl acetate in total skin was found in stratum corneum. (Cal, 2003)

The percutaneous absorption of lavender oil was studied in vitro by determination of its main components quantities accumulated during the times of exposure. The fastest and progressive penetration into all skin layers was observed for linalool whereas weak diffusion was obtained with linalyl acetate. The amount in skin of all terpenes increased during the first 4 h, then decreased from 4 until 12 h and finally increased again at 24 h. However, no terpenes were detected in the acceptor fluid. (Ben Salah, 2009)

Blood levels of linalool and linalyl acetate were followed for 90 min after the use of a massage oil which contained lavender oil and peanut oil in a 2:98 ratio. The lavender oil contained approximately 25% linalool and approximately 30% linalyl acetate. A 1500 mg sample of the lavender oil was gently massaged for 10 min into a 376 cm2 area on the abdomen of a 60-kg male volunteer. Trace amounts of both linalool and linalyl acetate were detected in the blood 5 min after the massage. Peak plasma concentrations were reached by 19 minutes with a mean plasma concentration of 100 ng/mL for linalool and 121 ng/mL for linalyl acetate. Most of the linalool and linalyl acetate had disappeared from the blood in 90 min with biological half-lives of approximately 14 min for both linalool and linalyl acetate. (Bickers, 2003)

Respiratory absorption:

Groups of 4 mice were exposed to an atmosphere containing 5 mg/L lavender oil (which contained 37.3% linalool and 41.6% linalyl acetate). After lavender oil inhalation, the serum linalool levels were 3 ng/mL and the serum linalyl acetate levels were 11 ng/mL. (Bickers, 2003)

The inhalation of linalool (5 mg/L for 1h) led to significant reduction of the motility of exposed mice (down to 30 - 40%) with respect to the control group. The amounts of linalool and linalyl acetate detected in blood samples were 7-9 ng/mL and 1 -2 ng/mL, respectively, determined by GC/MS with CI and SIM, and GC/FID. (Jirovetz, 1991)

Distribution:

In rats, orally administered 14C-labelled dose of 500 mg/kg linalool, only 3% was detected in tissues after 72 h, with 0.5% in the liver, 0.6% in the gut, 0.8% in the skin and 1.2% in the skeletal muscle. (Bickers, 2003)

Metabolism:

The metabolic fate of linalool has been studied in mammals. Tertiary alcohols such as linalool are metabolized primarily through conjugation with glucuronic acid. Linalool and its P-450 derived metabolites are converted to glucuronide conjugate by rat liver homogenates.

After a single dose of linalool to rats, reduction metabolites such as dihydro- and tetrahydrolinalool have been identified in the urine either free or in the conjugated form.

The in vivo metabolism of linalool in male rats administered a daily oral dose of 800 mg/kg body weight of linalool for 20 days. Metabolites isolated from the urine of rats after administration of Iinalool were identified. The activity of the liver and lung microsomal enzymes was measured after daily oral dose of 600 mg/kg body weight of linalool for 6 days. Metabolites isolated from the urine of rats after administration of Iinalool were 8-hydroxy-linalool and 8-carboxy-linalool. Other minor metabolites present in the acidic fraction could not be separated and identified. A number of liver- and lung-microsomal parameters were studied after one, three and six days of oral administration of linalool to rats. A statistically significant increase (about 50%) in the concentration of cytochrome P-450 in the liver microsomes was noticed after three days of dosing. At the end of six days of treatment, the cytochrome P-450 content in liver had decreased to control values. Glucuronic acid conjugation and excretion is the primary route of metabolism of linalool. Allylic oxidation becomes an important pathway after repeated dosing. (Chadha and Madyastha, 1984) Linalool administered daily by gavage at a dose of 500 mg/kg body weight/day for 64 days to 4-week-old male Wistar rats did not induce cytochrome P-450 until the 30th day of treatment. It has been suggested that the biotransformation of the diol metabolites of geraniol and linalool to the corresponding aldehyde by alcohol dehydrogenase (ADH) is inhibited due to the bulky nature of the neighboring alkyl substituents and the substrate specificity of the enzyme.

 

The non-cyclic terpene alcohols (linalool, citronellol, nerol, and geraniol) were substrates of UDPGTs (UDP-glucuronosyltransferases) and showed typical phenobarbital-inducible behavior in Wistar rats.

Linalool undergoes partial ring closure to yield mainly alpha-terpineol and minor amounts of the terpenoid primary alcohols, geraniol and nerol. In acidic (pH 1.8) artificial gastric juice and in neutral media (pH 7.5), linalool is rapidly rearranged to yield alpha-terpineol and small amounts of geraniol and nerol. Both linalool and alpha-terpineol may then be either conjugated and excreted or oxidized to more polar excretable metabolites. (RIFM expert panel, 2008)

 

Linalool is metabolized in vitro by human skin enzymes CYP2C19 and CYP2D6 to (R/S)-furanoid-linalool oxide, (R/S)-pyranoid-linalool oxide and (cis/trans)-8-hydroxylinalool. A linear relationship was observed between the formation of metabolites and incubation time, enzyme and linalool concentration. (Meesters, 2007)

Treatment of Wistar rats by gavage with (-)-linalool at the dose of 360 mg/kg for 13 days increased the metabolic activity of CYP2A assessed with testosterone as a probe substrate. (-)-Linalool showed weak competitive inhibition of CYP2C6 in rat liver microsomes, with IC50 of 84 μM with use of diclofenac as a probe substrate. (Noskova, 2016)

Lavender Oil Preparation silexan administered daily by oral route for 11 days to human volunteers had no relevant effect on CYP1A2, 2C9, 2D6, and 3A4 activity. Secondary phenotyping metrics confirmed this result. (Doroshyenko, 2013)

To conclude, the major pathways of metabolism are:

- conjugation of the alcohol with glucuronic acid,

- side-chain oxidation yielding polar metabolites, which may be conjugated and excreted,

- hydrogenation of the endocyclic double bond.

 

Excretion:

Tertiary alcohols such as linalool are excreted in the urine and to a lesser extent feces. Biliary excretion of conjugated linalool was determined in male rats that received a single intraperitoneal dose of 20 mg linalool. More than 25% of the dose appeared exclusively in the form of polar conjugates in the bile within 6-11 h, principally in the first 4 h; no free linalool was detected. (Bickers, 2003)