Absorption, Distribution and Excretion
Linalool can penetrate the oral mucosa of pigs (and consequently, humans) at its concentration (14.46% w/w) and in formulations (such as sage oil). Based on rat experiments using a 14C-labeled substance, linalool is rapidly absorbed from the intestines after oral administration…the delay in fecal excretion indicates complete intestinal absorption. Following absorption, linalool is rapidly metabolized, with 14C activity immediately beginning to be excreted in the urine. Several hours after gavage, a significant amount of radioactive material (14CO₂) was detected in exhaled breath, indicating complete intermediate metabolism. The delayed fecal excretion of radioactive material, primarily observed between 36 and 48 hours post-administration, suggests the presence of an entero-hepatic-biliary circulation; this circulation was confirmed in another experiment in which a treated and an untreated rat were connected via a biliary-intestinal cannula for subsequent radiometric analysis. Overall, within 72 hours of administration, approximately 60% of the total excreted dose was detected in urine; approximately 23% of the radioactivity was detected in exhaled breath, and approximately 15% in feces; there was no indication of linalool accumulation in tissues. This study indicates that high-dose oral administration of linalool in rats is primarily metabolized via conjugation reactions and excreted via urine and bile, while a significant portion enters intermediate metabolic pathways, ultimately generating carbon dioxide and being excreted via the lungs. The enterohepatic-biliary circulation may increase the metabolic load on the liver for a certain period. One hour after inhalation of 27 mg linalool in mice, plasma linalool concentrations at 30, 60, and 90 minutes post-exposure were approximately 1, 2.7, and 2.9 ng/mL, respectively. Linalool was not absorbed within two hours after application to the skin of mice. Metabolites/Metabolites… Following oral administration of linalool (VII) to rats, the metabolites isolated from the urine were 8-hydroxylinalool (VIII) and 8-carboxylinalool (IX). After three consecutive days of administration of geraniol or linalool to rats, hepatic microsomal cytochrome P-450 activity increased. During the six-day treatment period, neither NADH nor NADPH cytochrome c reductase activity changed significantly. Oral administration of these two terpenoids had no effect on any of the measured lung microsomal parameters. Based on rat experiments using 14C-labeled material… Linalool is rapidly metabolized after absorption, and 14C activity immediately begins to be excreted in the urine. Several hours after gavage, a large amount of radioactive material (in the form of 14CO₂) was detected in exhaled breath, indicating complete intermediate metabolism. Delayed fecal excretion of the radioactive material, primarily observed between 36 and 48 hours after administration, suggests the presence of entero-hepatic-biliary circulation… Entero-hepatic-biliary circulation may increase the metabolic load on the liver for a period of time. In the induction study, male IISc rats were administered 600 mg/kg body weight of linalool in suspension as a 1% methylcellulose solution via gastric tube once daily for 6 consecutive days. Control rats received only the solvent. To identify the metabolites, 800 mg/kg body weight of linalool was administered once daily for 20 consecutive days… 8-hydroxylinalool and 8-carboxylinalool were detected in urine, indicating selective oxidation of the C8 methyl group of linalool. The 8-hydroxylase present in lung and liver microsomes was confirmed to be mediated by the cytochrome P-450 (CYP450) system. CYP450 activity in liver and lung microsomes increased after 3 days of administration; however, the activities of NADH and NADPH-cytochrome c reductases did not change significantly during the 6-day treatment period. /Purity >99.5%/ …The hydrolysis reaction occurred more rapidly at the low pH of gastric juice. The reaction products were linalool and acetic acid (ester hydrolysis). The results of hydrolysis studies support this conclusion… at pH 4, 7, and 9. Therefore, it is expected that linalool will enter systemic circulation after oral administration of linalyl acetate. Linalool may be converted to geraniol and its metabolites, such as 1,5-dimethylhexadiene-1,6-dicarboxylic acid and 7-carboxy-5-methyloct-6-enoic acid…/Linalyl acetate/
For more complete data on the metabolism/metabolites of linalool (7 metabolites in total), please visit the HSDB record page.

Toxicity Summary
Identification and Uses: Linalool is a colorless liquid with a pungent, herbaceous odor. It is used as a fragrance ingredient in perfumes, cosmetics, soaps, and detergents; and as a flavoring agent in food. It can also be used as a synthetic intermediate. In the United States, linalool is registered as a pesticide, but its approved pesticide uses may change periodically, so it is necessary to consult federal, state, and local authorities for current approved uses. Human Exposure and Toxicity: In maximum dose studies in humans, linalool at concentrations up to 20% consistently did not show sensitization. In human studies, it did not exhibit phototoxicity or photosensitization. Linalool can cause allergic contact dermatitis. In in vitro micronucleus assays, linalool showed no genotoxicity to human peripheral blood lymphocytes. Animal Studies: Linalool is irritating to rabbit skin. A series of Draize tests using fragrance ingredients showed that linalool did not cause sensitization in guinea pigs. Repeated application to sheep skin can cause symptoms similar to acanthosis. Rats were administered linalool 1500 mg/kg/day by gavage for 5 consecutive days. The absolute and relative weights of the liver in the test animals increased, while the microsomal protein content decreased. Psychopharmacological evaluation of linalool in rats showed a significant dose-dependent sedative effect on the central nervous system, including hypnotic, anticonvulsant, and hypothermic effects. This study reported the inhibitory effect of linalool on glutamate binding in the rat cortex. Symptoms of toxicity in cats included excessive salivation, muscle tremors, ataxia, depression, and hypothermia. The sedative effect of linalool was studied in mice. Under standardized experimental conditions, the activity levels of both male and female experimental animals were significantly reduced, and this reduction was closely related to the duration of exposure. Ten male and female rats in each group received oral doses of linalool of 160, 400, or 1000 mg/kg body weight daily for 28 days, respectively. One male and one female rat in the high-dose group died. A 28-day subchronic toxicity study showed that coriander essential oil containing 72.9% linalool and 22.3% other identified terpenoids did not have significant effects on the major reproductive organs (ovaries and uterus) in females and (testes and epididymis) in males across all dose groups (up to 1000 mg/kg body weight/day). These effects were not observed in either anatomical observation or histopathological examination of rats in all high-dose groups (10 males and 10 females). The mutagenicity of linalool was assessed in bacteria and cultured L5718Y tk+/mice. Cellular and cytogenetic studies (including sister chromatid exchange, chromosomal aberration studies, and in vivo micronucleus assays) were performed in Chinese hamster ovary (CHO) cells. Mutagenicity and chromosome breakage data were sufficient to indicate that linalool is not genotoxic. Ecotoxicity studies: Linalool had an LC50 of >28.8 ppm for rainbow trout, 36.8 ppm for bluegill sunfish, and 36.7 ppm for aquatic invertebrates.

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Interactions
Acrylamide (ACR) is a water-soluble monomer widely used in various industries and is also generated during food heating. This monomer is a potent neurotoxin that can damage the central and peripheral nervous systems of humans and animals. Oxidative stress is considered an important pathway of acrylamide (ACR) neurotoxicity; therefore, this study aimed to evaluate the potential role of the naturally occurring enantiomeric monoterpene compound linalool. Linalool has shown antioxidant properties in multiple studies. Male Wistar rats were treated with either ACR (50 mg/kg, intraperitoneal injection) or linalool (12.5, 25, 50, and 100 mg/kg, intraperitoneal injection) for 11 days. Two other groups of rats were treated with linalool (12.5 mg/kg, intraperitoneal injection) for 3 days before and after ACR administration. Behavioral parameters (gait scores) were then measured. Rats were subsequently sacrificed, and the levels of malondialdehyde (MDA, a marker of lipid peroxidation) and glutathione (GSH) in brain tissue were measured. ACR exposure led to severe gait abnormalities, while linalool treatment significantly alleviated these abnormalities. ACR decreased GSH levels and increased MDA levels in the cerebral cortex. Linalool increased GSH levels in rat brain tissue while reducing ACR-induced lipid peroxidation; the optimal approach is to supplement with linalool before or concurrently with ACR administration. We investigated the protective effects of monoterpenes myrcene, eucalyptol, and linalool on tert-butyl hydroperoxide (t-BOOH)-induced reverse mutation assays of Escherichia coli WP2 IC185 strain and its oxyR mutant IC202, as well as on human hepatocellular carcinoma HepG2 cells and human B lymphocytes NC-NC in a comet assay. In bacterial and mammalian cells, the tested concentrations of monoterpenoids ranged from 0.05–1.5 mg/plate and 0.01–1.0 μg/mL, respectively. Inhibition of t-BOOH-induced mutagenesis was detected only in the IC202 strain, and this inhibition was associated with the inhibitory effects of the three monoterpenoids on lipid peroxidation. Linalool and myrcene significantly inhibited t-BOOH-induced mutagenesis. Eucalyptol, in addition to its moderate inhibitory effect on t-BOOH-induced mutagenesis, also inhibited spontaneous mutations. In NC-NC cells, linalool and myrcene at concentrations of 0.01 μg/mL reduced t-BOOH-induced DNA damage by approximately 50%, while eucalyptol showed a weaker inhibitory effect (approximately 50% reduction at a concentration of 1.0 μg/mL). In HepG2 cells, linalool and eucalyptol reduced DNA damage by 30% and 40%, respectively, while myrcene had no effect. Studies in HepG2 cells revealed that monoterpenes had no effect on t-BOOH-induced DNA damage repair. The results indicated that linalool, eucalyptol, and myrcene had significant protective effects against oxidant-induced genotoxicity, primarily attributed to their free radical scavenging activity. This study…reports data evaluating the chemopreventive effects of limonene and five other monoterpenes with different chemical structures using a 7,12-dimethylbenzanthracene (DMBA)-induced rat breast cancer model. The terpenes tested included: oxygen-containing monocyclic ((-)-menthol) and non-oxygen-containing monocyclic (d-limonene), oxygen-containing bicyclic (1,8-eucalyptol), non-oxygen-containing bicyclic ((+/-)-α-pinene), and oxygen-containing acyclic ((+/-)-linalool) and non-oxygen-containing acyclic (β-myrcene). Dietary supplementation with the monocyclic terpenes d-limonene or (-)-menthol significantly inhibited breast cancer development. Furthermore, in a DMBA-induced rat mammary tumor model, menthol exhibited stronger chemopreventive activity than limonene. At the dose levels used in these studies, neither acyclic nor bicyclic terpenes showed significant chemopreventive activity. This study investigated the sedative effects of lavender (Lavandula angustifolia Miller) essential oil and its main components, linalool and linalyl acetate, in mice using a series of experimental procedures. Results showed that under standardized experimental conditions, the activity levels of both female and male animals were significantly reduced, and this reduction was closely related to the duration of drug exposure. However, after injection of caffeine, mice exhibited symptoms of hyperactivity, while inhalation of these aromatic drugs almost restored their activity levels to normal. This study evaluated the chemopreventive effects of limonene and five other monoterpenes with different chemical structures using a 7,12-dimethylbenzanthracene (DMBA)-induced rat mammary tumor model. The terpenoids tested included: oxygenated monocyclic terpenes ((-)-menthol) and non-oxygenated monocyclic terpenes (d-limonene), oxygenated bicyclic terpenes (1,8-cineole) and non-oxygenated bicyclic terpenes ((+/-)-α-pinene), as well as oxygenated acyclic terpenes ((+/-)-linalool) and non-oxygenated acyclic terpenes (β-myrcene). Dietary supplementation with monocyclic terpenes, d-limonene, or (-)-menthol significantly inhibited breast cancer development. Furthermore, menthol exhibited stronger chemopreventive activity than limonene in DMBA-induced mammary tumor development in rats. At the dose levels used in these studies, neither acyclic nor bicyclic terpenes showed significant chemopreventive activity.

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Non-human toxicity values
Oral LD50 in rats: 2790 mg/kg (2440-3180, 95% confidence interval) /from table/
Dermal LD50 in rats: 5610 mg/kg
Intraperitoneal LD50 in rats: 307 mg/kg /from table/
Oral LD50 in mice: 3000 mg/kg /from table/
For more non-human toxicity values (complete data) for linalool (9 compounds in total), please visit the HSDB record page.

[1]. The protective and therapeutic effects of linalool against doxorubicin-induced cardiotoxicity in Wistar albino rats. Hum Exp Toxicol. 2019 Apr 12:960327119842634.

[2]. Linalool is a PPARα ligand that reduces plasma TG levels and rewires the hepatic transcriptome and plasma metabolome. J Lipid Res. 2014 Jun;55(6):1098-110.

[3]. Antitumorigenic potential of linalool is accompanied by modulation of oxidative stress: an in vivo study in sarcoma-180 solid tumor model. Nutr Cancer. 2014;66(5):835-48.

[4]. Anti-cancer mechanisms of linalool and 1,8-cineole in non-small cell lung cancer A549 cells. Heliyon. 2020 Dec 15;6(12):e05639.

[5]. Recent updates on bioactive properties of linalool. Food Funct. 2021 Nov 1;12(21):10370-10389.

Linalool is a monoterpene compound with the structure octyl-1,6-diene, substituted with methyl groups at positions 3 and 7, and a hydroxyl group at position 3. It has been isolated from plants such as basil (Ocimum canum). Linalool is used as a plant metabolite, volatile oil component, antibacterial agent, and fragrance. It is a tertiary alcohol and monoterpene compound. Linalool has been reported in tea (Camellia sinensis), Aristolochia triangularis, and several other organisms with relevant data. 3,7-Dimethyl-1,6-octadien-3-ol is a metabolite found or produced in Saccharomyces cerevisiae. See also: Clary sage oil (partial components); Cinnamon leaf oil (partial components); Cinnamon bark oil (partial)...see more...

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Mechanism of Action
...Therefore, the specific toxic effects of linalool in animals are likely due to its neurotoxic or neuropharmacological mechanisms. Conversely, this might explain the use of linalool-containing natural products (aromatic herbs and spices or their essential oils or extracts) in traditional medicine, particularly for their hypnotic and anticonvulsant effects. Furthermore, it explains the traditional widespread use of linalool-containing herbs to control stored-grain pests, and the use of linalool-containing extracts as flea and tick treatments for pets.

C10H18O

154.25

154.135

78-70-6

Linalool-d3;1216673-02-7

6549

Colorless to light yellow liquid

0.9±0.1 g/cm3

198.5±0.0 °C at 760 mmHg

Freezing point: below -74 °C /OECD Guideline 102 (Melting point / Melting Range)/
< 25 °C

76.1±0.0 °C

0.1±0.8 mmHg at 25°C

1.463

3.28

1

1

4

11

154

0

O([H])C(C([H])=C([H])[H])(C([H])([H])[H])C([H])([H])C([H])([H])/C(/[H])=C(\C([H])([H])[H])/C([H])([H])[H]

CDOSHBSSFJOMGT-UHFFFAOYSA-N

InChI=1S/C10H18O/c1-5-10(4,11)8-6-7-9(2)3/h5,7,11H,1,6,8H2,2-4H3

3,7-dimethylocta-1,6-dien-3-ol

AI3 00942 AI3-00942 Linalool

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~648.30 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (16.21 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (16.21 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (16.21 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)