Absorption, Distribution and Excretion
...The percentage of a dose of l-menthol that is excreted combined with glucuronic acid in the rabbit depends on the magnitude of the dose; the larger the dose, the less is the conjugation. /L-Menthol/
Not all glucuronides are excreted by tubular secretion... conjugates of higher mol wt such as glucuronides of androsterone...are eliminated by glomerular filtration alone, whereas those of menthol...of lower mol wt...by tubules in addition to glomerular filtration... /DL-Menthol/
Many substances with diverse structures are known to be excreted into bile; these incl glucuronides of menthol... /DL-Menthol/
Absorption can occur from topical use. /DL-Menthol/
For more Absorption, Distribution and Excretion (Complete) data for MENTHOL (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
In the United States, cigarette flavorings are banned, with the exception of menthol. The cooling effects of menthol could facilitate the absorption of tobacco toxicants. We examined levels of biomarkers of tobacco exposure among U.S. smokers of menthol and nonmenthol cigarettes. We studied 4,603 White, African-American, and Mexican-American current smokers 20 years of age or older who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 through 2010 and had data on cigarette type and serum cotinine, blood cadmium, and blood lead concentrations. Urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) (NNAL) was studied in 1,607 participants with available measures. A total of 3,210 (74.3%) participants smoked nonmenthol cigarettes compared with 1,393 (25.7%) participants who smoked menthol cigarettes. The geometric mean concentrations comparing smokers of nonmenthol with menthol cigarettes were 163.1 versus 175.9 ng/mL for serum cotinine; 0.95 versus 1.02 ug/L for blood cadmium; 1.87 versus 1.75 ug/dL for blood lead; and 0.27 versus 0.23 ng/mL for urine NNAL. After multivariable adjustment, the ratios [95% confidence interval (CI)] comparing smokers of menthol with nonmenthol cigarettes were 1.03 (0.95-1.11) for cotinine, 1.10 (1.04-1.16) for cadmium, 0.95 (0.90-1.01) for lead, and 0.81 (0.65-1.01) for NNAL. In a representative sample of U.S. adult smokers, current menthol cigarette use was associated with increased concentration of blood cadmium, an established carcinogen and highly toxic metal, but not with other biomarkers. These findings provide information regarding possible differences in exposure to toxic constituents among menthol cigarette smokers compared with nonmenthol cigarette smokers./L-Menthol/
Researchers have recently suggested that nicotine and carcinogen exposure as measured by biomarkers such as cotinine and (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) (NNAL) does not vary with cigarettes smoked per day (CPD) among Black smokers. Researchers have also suggested that nicotine exposure does not differ between menthol and nonmenthol smokers. In this study, we examine NNAL exposure for U.S. smokers by race, CPD, and menthol cigarette use. We analyzed urinary NNAL concentrations for more than 1500 everyday smokers participating in the National Health and Nutrition Examination Survey from 2007-2010. For purposes of comparison, we also analyzed serum cotinine concentrations for these smokers. We used linear regression analysis to estimate mean biomarker concentrations by CPD and race/ethnicity group and to examine the association between biomarker concentrations and menthol cigarette use by race/ethnicity group, controlling for other demographic and smoking characteristics. Biomarker concentrations increased with CPD for White, Black, and Hispanic smokers although NNAL concentrations leveled off for Black smokers at lower CPD levels compared with other smokers. Mean NNAL concentrations were lower among menthol smokers compared with nonmenthol smokers among smokers overall (beta = -0.165, p = .032) and White smokers (beta = -0.207, p = .048). We find evidence in national health survey data that nicotine and carcinogen exposure generally increases with CPD across race/ethnicity groups although the pattern of NNAL exposure differs by race/ethnicity group at high CPD levels. We also find evidence of differences in NNAL exposure for menthol smokers compared with nonmenthol smokers among smokers overall and White smokers /L-Menthol/
Corynebacterium sp. strain RWM1 grew with (-)-menthol, (-)-menthone and other acyclic monoterpenes as sole carbon sources. Growth on menthol was very slow, with a doubling time of more than 24 hr, and was not rapid with (-)-menthone (doubling time 12 hr). Concentrations of either carbon source greater than 0.025% inhibited growth. (-)-Menthone-grown cultures transiently accumulated 3,7-dimethyl-6-hydroxyoctanoate during growth, and (-)-menthol-grown cells oxidized (-)-menthol, (-)-menthone, 3,7-dimethyl-6-octanolide and 3,7-dimethyl-6-hydroxyoctanoate. Although neither a menthol oxidase nor a menthol dehydrogenase could be detected in extracts of (-)-menthol- or (-)-menthone-grown cells, an induced NADPH-linked monooxygenase with activity towards (-)-menthone was readily detected. With crude cell extracts, only 3,7-dimethyl-6-hydroxyoctanoate was detected as the reaction product. When the (-)-menthone monooxygenase was separated from an induced 3,7-dimethyl-6-octanolide hydrolase by chromatography on hydroxyapatite, the lactone 3,7-dimethyl-6-octanolide was shown to be the product of oxygenation. /L-Menthol/
L-Menthol was rapidly but incompletely glucuronidated. The output of l-menthol glucuronide was incr in all but 1 subject pretreated with cimetidine (1 g/day for 1 wk), an inhibitor of oxidative drug metabolism, & in all subjects pretreated with a drug-metabolizing enzyme inducer, phenobarbitone (60 mg nightly for 10 days). /L-Menthol/
For more Metabolism/Metabolites (Complete) data for MENTHOL (16 total), please visit the HSDB record page.
Neomenthol has known human metabolites that include (2S,3S,4S,5R,6R)-3,4,5-Trihydroxy-6-(5-methyl-2-propan-2-ylcyclohexyl)oxyoxane-2-carboxylic acid.

Toxicity Summary
IDENTIFICATION AND USE: Menthol is produced as crystals or granules. DL-Menthol is used as flavoring, disinfectant and cooling compound in confectionery products, liqueurs, chewing gums, toothpastes, cosmetics and common cold ointments and medications for human purposes. L-Menthol is used in large quantities in cigarettes, cosmetics, toothpastes, chewing gum, sweets, and medicines. D-Menthol is used only in research. HUMAN EXPOSURE AND TOXICITY: A maximization test was carried out on 25 volunteers. The material was tested at a concentration of 8% in petrolatum and produced no sensitization reactions. Ingestion of high menthol doses may cause abdominal pain, convulsions, nausea, vomiting, vertigo, ataxia, drowsiness and coma. Menthol may cause allergic reactions (e.g. contact dermatitis, flushing, and headache) in certain individuals. In very few cases, all in children younger than 1 year, menthol applied to the nostrils or near the nose caused reflex apnea. In a representative sample of U.S. adults, menthol cigarette smoking was associated with increased all-cause, cardiovascular and cancer mortality with no differences compared to nonmenthol cigarettes. In the systematic review, menthol cigarette use was associated with inverse risk of cancer compared to nonmenthol cigarette use with some evidence of an increased risk for cardiovascular disease. Epidemiological studies indicate no difference in dependence among U.S. smokers who use menthol compared to non-menthol cigarettes. ANIMAL STUDIES: All studied isomers of menthol are, if applied undiluted, moderately irritating to skin. The menthol isomers are slightly irritating to the eye. In experimental animals, menthol was of low acute toxicity by oral, injection, and dermal routes. Liver and kidney changes have been seen in a number of animals mainly involving oral administration. Inhalation of menthol may produce respiratory tract injury. There was no convincing evidence of carcinogenicity in rats and mice. L-Menthol was not embryo- or fetotoxic and had no teratogenic properties in gavage studies in various species (rat, mouse, rabbit, and hamster) at not maternally toxic doses. The menthol isomers are considered non-genotoxic in bacterial and mammalian test systems in vitro. In vivo, L- and D/L-menthol have demonstrated no mutagenic potential in dominant lethal and cytogenetic tests and in a bone marrow micronucleus test in mice.

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Interactions
The effects of l-menthol ((-)-menthol) combined with ethyl alcohol (ethanol) on the percutaneous absorption of model drugs were studied using 2 equations and a 2-layer in vitro skin model. A nonlinear least-squares method was employed to determine 6 coefficients using the 2 equations and experimentally obtained permeability coefficient through full-thickness skin and full-thickness skin/vehicle concentration ratio. Adding menthol to water and 40% ethyl alcohol increased the diffusion coefficient of drugs in lipid and pore pathways of stratum corneum. Adding ethyl alcohol to water and 5% menthol increased drug solubility in the vehicle, decreased skin polarity, and increased the role of the pore pathway to whole-skin permeation. It was concluded that the effects of l-menthol and ethyl alcohol on percutaneous drug absorption in vitro are synergistic. /L-Menthol/
The permeability of most drugs through the eyes is very limited, so finding safe and effective penetration enhancers is of high importance in current ophthalmology research. In this paper, we use a new approach that integrates Chinese and Western medicine to improve the corneal permeability of baicalin, a water- and fat-insoluble target drug, in vitro. Rabbits were divided into three groups. The first group was dosed with borneol (0.05%, 0.1%). menthol (0.1%, 0.2%), or Labrasol (1%, 2%) individually, the second was dosed with a combination of Labrasol with either borneol or menthol, and the third group received a control treatment. Compared with the control treatment, borneol, menthol, or Labrasol alone clearly improved the permeability of baicalin in vitro. Furthermore, the penetrating effects were significantly increased by combining the application of Labrasol withmenthol or borneol. Among the various combined penetration enhancers, 0.1% borneol with 2% Labrasol achieved the best apparent permeability, approximately 16.35 times that of the control. Additionally, the calculation of corneal hydration level and the Draize test demonstrated the safety of these penetration enhancers to the rabbit corneas in vivo. This study confirms that the combined use of borneol or menthol, compounds both derived from Chinese herbs, with Labrasol can improve the corneal permeability of water- and fat-insoluble drugs. /DL-Menthol/
Inflammation and oxidative stress have been implicated in various pathological processes including skin tumorigenesis. Skin cancer is the most common form of cancer responsible for considerable morbidity and mortality, the treatment progress of which remains slow though. Therefore, chemoprevention and other strategies are being considered. Menthol has shown high anticancer activity against various human cancers, but its effect on skin cancer has never been evaluated. We herein investigated the chemopreventive potential of menthol against 9,10-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation, oxidative stress and skin carcinogenesis in female ICR mice. Pretreatment with menthol at various doses significantly suppressed tumor formation and growth, and markedly reduced tumor incidence and volume. Moreover, menthol inhibited TPA-induced skin hyperplasia and inflammation, and significantly suppressed the expression of cyclooxygenase-2 (COX-2). Furthermore, pretreatment with menthol inhibited the formation of reactive oxygen species and affected the activities of a battery of antioxidant enzymes in the skin. The expressions of NF-kappaB, Erk and p38 were down-regulated by menthol administration. Thus, inflammation and oxidative stress collectively played a crucial role in the chemopreventive efficacy of menthol on the murine skin tumorigenesis./DL-Menthol/
The aim of this research was to investigate the anti-apoptotic, antioxidant and anti-inflammatory properties of menthol against ethanol-induced gastric ulcers in rats. Wistar rats were orally treated with vehicle, carbenoxolone (100 mg/kg) or menthol (50 mg/kg) and then treated with ethanol to induce gastric ulcers. After euthanasia, stomach samples were prepared for histological slides and biochemical analyses. Immunohistochemical analyses of the cytoprotective and anti-apoptotic heat-shock protein-70 (HSP-70) and the apoptotic Bax protein were performed. The neutrophils were manually counted. The activity of the myeloperoxidase (MPO) was measured. To determine the level of antioxidant functions, the levels of glutathione (GSH), glutathione peroxidase (GSH-Px), glutathione reductase (GR) and superoxide dismutase (SOD) were measured using ELISA. The levels of the pro-inflammatory cytokines tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6) and the anti-inflammatory cytokine interleukin-10 (IL-10) were assessed using ELISA kits. The menthol treated group presented 92% gastroprotection compared to the vehicle-treated group. An increased immunolabeled area was observed for HSP-70, and a decreased immunolabeled area was observed for the Bax protein in the menthol treated group. Menthol treatment induced a decrease in the activity of MPO and SOD, and the protein levels of GSH, GSH-Px and GR were increased. There was also a decrease in the levels of TNF-a and IL-6 and an increase in the level of IL-10. In conclusion, oral treatment with menthol displayed a gastroprotective activity through anti-apoptotic, antioxidant and anti-inflammatory mechanisms./DL-Menthol/
For more Interactions (Complete) data for MENTHOL (7 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 2900 mg/kg /DL-Menthol/
LD50 Rat oral 3180 mg/kg /DL-Menthol/
LD50 Rat im 10,000 m g/kg /DL-Menthol/
LD50 Cats oral 1500-1600 mg/kg /DL-Menthol/
For more Non-Human Toxicity Values (Complete) data for MENTHOL (16 total), please visit the HSDB record page.

[1]. Menthol: a natural analgesic compound. Neuroscience Letters. 2002 Apr.

[2]. Menthol decreases oral nicotine aversion in C57BL/6 mice through a TRPM8-dependent mechanism. Tob Control. 2016 Nov;25(Suppl 2):ii50-ii54.

[3]. Menthol attenuates respiratory irritation and elevates blood cotinine in cigarette smoke exposed mice. PLoS One. 2015 Feb 13;10(2):e0117128.

Therapeutic Uses
Antipruritics
EXPL THER Menthol has been tested in humans mainly for its pharmaceutical properties, such as enhancement of lung and airway volume.
Menthol, a natural product of the peppermint plant Mentha x piperita (Lamiaceae), is a monoterpene which is widely used as a natural product in cosmetics, a flavoring agent, and as an intermediate in the production of other compounds. Various extracts from peppermint contain menthol as a major active constituent and have been used for centuries as traditional medicines for a number of ailments including infections, insomnia, and irritable bowel syndrome as well as an insect repellent. /Traditional medicine//
MEDICATION (VET): Its vapors have been used clinically in resp syndromes of horses, swine, & poultry. ... Parenterally, it is used in stimulant expectorant mixture...
For more Therapeutic Uses (Complete) data for MENTHOL (6 total), please visit the HSDB record page.

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Drug Warnings
"Cooling" effect of l-menthol was found...to be superior to that produced by other isomers; odor and taste, too of l-menthol were superior, with some of the isomers producing sharp, irritating and disagreeable perceptions. /L-Menthol/
Glucose-6-phosphate-dehydrogenase-deficiency in newborn babies may result in development of severe jaundice after menthol administration due to the inability of the neonates to conjugate menthol.
Sensitivity reactions associated with the use of mentholated products (including cigarettes) have been reported. Use of mentholated nasal drops in infants has evidently caused isolated cases of spasm of the larynx, and a few cases of nervous or digestive system disturbance have been associated with excessive inhalation or oral exposure to menthol.
Menthol ... may cause allergic reactions (e.g. contact dermatitis, flushing, and headache) in certain individuals. Applying a menthol-containing ointment to the nostrils of infants for the treatment of cold symptoms may cause instant collapse.
Vet: overdosing can cause convulsions &, eventually, death.

C10H20O

156.2652

156.151

1490-04-6

Menthol-d4;1217765-02-0

1254

White to off-white solid powder

0.9±0.1 g/cm3

215.4±8.0 °C at 760 mmHg

34-36 ℃(lit.)

93.3±0.0 °C

0.0±0.9 mmHg at 25°C

1.457

3.2

1

1

1

11

120

0

NOOLISFMXDJSKH-UHFFFAOYSA-N

InChI=1S/C10H20O/c1-7(2)9-5-4-8(3)6-10(9)11/h7-11H,4-6H2,1-3H3

5-methyl-2-propan-2-ylcyclohexan-1-ol

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 : ~250 mg/mL (~1599.80 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (13.31 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 20.8 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: ≥ 2.08 mg/mL (13.31 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 20.8 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: ≥ 2.08 mg/mL (13.31 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 20.8 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.)