(-)-Menthol

log Kow = 3.3

3.40

0.904 at 59 °F (NTP, 1992) - Less dense than water; will float

0.890

0.901 (20 °C); 0.891 (30 °C)

less than 1 mg/mL at 70 °F (NTP, 1992)

Very sol in alcohol, chloroform, ether, petroleum ether; freely sol in glacial acetic acid, liquid petrolatum

VERY SOLUBLE IN ACETONE, BENZENE

In water, 456 mg/l @ 25 °C

0.49 mg/mL at 25 °C

This chemical does not meet GHS hazard criteria for 0.3% (7 of 2060) of reports.

Warning

H315 (97.6%): Causes skin irritation [Warning Skin corrosion/irritation]

P264, P264+P265, P280, P302+P352, P305+P351+P338, P321, P332+P317, P337+P317, and P362+P364 (click each P-code to see the statement)

Aggregated GHS information provided per 2060 reports by companies from 25 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Not Classified

Chemical: Cyclohexanol, 5-methyl-2-(1-methylethyl)-, (1R,2S,5R)-rel-

Chemical: Cyclohexanol, 5-methyl-2-(1-methylethyl)-, [1R-(1.alpha.,2.beta.,5.alpha.)]-

Cyclohexanol, 5-methyl-2-(1-methylethyl)-, (1R,2S,5R)- is listed on the EPA's Chemical Data Reporting (CDR) system. Manufacturers and importers of Cyclohexanol, 5-methyl-2-(1-methylethyl)-, (1R,2S,5R)- are required to report information about their production and use of this chemical to the EPA under the Toxic Substances Control Act (TSCA). (40 eCFR Part 711)

Cyclohexanol, 5-methyl-2-(1-methylethyl)-, (1R,2S,5R)-rel- is listed on the EPA's Chemical Data Reporting (CDR) system. Manufacturers and importers of Cyclohexanol, 5-methyl-2-(1-methylethyl)-, (1R,2S,5R)-rel- are required to report information about their production and use of this chemical to the EPA under the Toxic Substances Control Act (TSCA). (40 eCFR Part 711)

Status: Active Update: 02-11-2022 https://echa.europa.eu/registration-dossier/-/registered-dossier/15383

L-Menthol: Does not have an individual approval but may be used under an appropriate group standard

IMAP assessments - Cyclohexanol, 5-methyl-2-(1-methylethyl)-, [1R-(1.alpha.,2.beta.,5.alpha.)]-: Human health tier I assessment

IMAP assessments - Cyclohexanol, 5-methyl-2-(1-methylethyl)-, (1R,2S,5R)-rel-: Human health tier I assessment

SYMPTOMS: Symptoms of exposure to this compound may include irritation of the skin, eyes, mucous membranes and upper respiratory tract. Exposure may also cause hypersensitivity reactions including contact dermatitis, spasms of the glottis and collapse in young children, urticaria, flushing, headache, insomnia, unsteady gait, thick speech, tremor of the hands, mental confusion, depression, vomiting, cramp in the legs and bradycardia. Exposure to compounds of this class may cause painless blanching or erythema, possible corrosion, profuse sweating, intense thirst, nausea, diarrhea, cyanosis from methemoglobinemia, hyperactivity, stupor, blood pressure fall, hyperpnea, abdominal pain, hemolysis, convulsions, coma and pulmonary edema followed by pneumonia. If death from respiratory failure is not immediate, jaundice and oliguria or anuria may occur. These compounds occasionally cause skin sensitization.

Causes general anesthesia in intraperitoneal lethal-dose studies of rats; [RTECS] Included in list of established contact allergens in humans; [ToxPlanet: EC: Scientific Committee on Consumer Safety: Fragrance allergens in cosmetic products (2011)] An eye and moderate mucous membrane irritant; No skin sensitization observed in maximization test of 24 volunteers at 8% in petrolatum; Reports of sensitivity reactions to mentholated products; [HSDB] Menthol isomers demonstrate moderate skin and mild eye irritation; Low potential for skin sensitization; Low order of toxicity in repeated-dose oral studies (no specific systemic effects); No evidence of toxicity to fertility or development, teratogenicity, or carcinogenicity; [OECD SIDS] An irritant that may cause serious eye injury; [Sigma-Aldrich MSDS] See Menthol.

OPDYKE DL J; MONOGRAPHS ON FRAGRANCE RAW MATERIALS. L-MENTHOL; FOOD COSMET TOXICOL 14 (5): 471 (1976). THE NATURAL OCCURRENCE & ISOLATION, PREPN, COSMETIC & PERFUME USES, LEGAL STATUS OF USE IN FOOD, METABOLISM, & TOXICOLOGY OF L-MENTHOL ARE REVIEWED WITH 25 REFERENCES.

D,L-MENTHOL is incompatible with butyl chloral hydrate, camphor, phenol, chloral hydrate, Exalgine, betanaphthol, resorcinol or thymol in triturations; potassium permanganate, chromium trioxide and pyrogallol. It is also incompatible with strong oxidizers. (NTP, 1992)

Skin Irrit. 2 (97.6%)

Not Classified

Skin corrosion/irritation - Category 2

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

SMALL SPILLS AND LEAKAGE: Should a spill occur while you are handling this chemical, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with 60-70% ethanol and transfer the dampened material to a suitable container. Use absorbent paper dampened with 60-70% ethanol to pick up any remaining material. Seal the absorbent paper, and any of your clothes, which may be contaminated, in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with 60-70% ethanol followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place.

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

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.

Hydroxyurea (HU) is a swiftly acting cytotoxic agent and an inhibitor of DNA synthesis that is teratogenic in all mammals studied. By 2-4 hours after maternal injection, HU causes (1) a rapid episode of embryonic cell death that is observable by light microscopy and (2) profound inhibition of 3H-thymidine incorporation into DNA. Previous work has demonstrated that a variety of antioxidants administered before, after or with HU delay the onset of embryonic cell death and ameliorate the birth defects seen at term but do not block the early inhibition of DNA synthesis. This suggests that the early embryonic cell death is not caused by inhibited DNA synthesis. We have postulated that some HU molecules react within the embryo to produce H2O2 and intermediate free radicals (including the very reactive hydroxyl free radical) that in turn are responsible for the early cell death; antioxidants are believed to block this reaction. To test whether hydroxyl free radicals are the proximate active species, pregnant New Zealand white rabbits were injected sc with a teratogenic dose of HU (650 mg/kg) in the presence or absence of 550 mg/kg of D-mannitol, a specific scavenger of hydroxyl free radicals. The dosage of D-mannitol was equimolar to the doses of antioxidants used in previous work. When the rabbits were allowed to continue pregnancy to term, the teratogenic effects of HU were ameliorated as evidenced by decreased incidences of the expected malformations. When embryos were examined histologically at 4-16 hr after maternal injection, D-mannitol was found to delay the onset of cell death for 6-8 hr. These results are consistent with the hypothesis that hydroxyl free radicals may be the proximate reactive species in HU-induced early embryonic cell death.

Death from respiratory failure can result in cases of severe poisoning. Persons with pre-existing skin disorders or eye problems or impaired respiratory function may be more susceptible to the effects of the substance. Menthol may give rise to hypersensitivity reactions including contact dermatitis. Hyspomia can result from poisoning too. Moreover, jaundice may occur in infants with G6PD deficiency (T36, L1264).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1,500(SRC), determined from a log Kow of 3.3(2) and a regression-derived equation(3), indicates that L-menthol is expected to have low mobility in soil(SRC). Volatilization of L-menthol from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.5X10-5 atm-cu m/mole(SRC), using a fragment constant estimation method(4). L-Menthol is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 0.064 mm Hg(5). A 0% of the theoretical BOD was measured for L-menthol using an activated sludge inoculum over a 4 week incubation period(2).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1,500(SRC), determined from a log Kow of 3.3(2) and a regression-derived equation(3), indicates that L-menthol is expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 1.5X10-5 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Volatilization half-lives for a model river and model lake are 2 and 18 days, respectively(SRC), using an estimation method(3). According to a classification scheme(5), BCF values of 1-15 measured in carp(2) suggest bioconcentration in aquatic organisms is low(SRC). A 0% of the theoretical BOD was measured for L-menthol using an activated sludge inoculum over a 4 week incubation period(2).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), L-menthol, which has a vapor pressure of 0.064 mm Hg at 25 °C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase L-menthol is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 16 hours(SRC) from its estimated rate constant of 2.4X10-11 cu cm/molecule-sec(3).

Vapors or dust can be irritating in large amounts due to the phenolic character of the compound. The normal sensation is that of a pleasant odor. May cause allergic reaction in sensitive individuals. Toxic. Estimated fatal dose, average human, is 2 g. General gastrointestinal upset can occur with pain, vomiting, vertigo, drowsiness and coma. Mild irritant but may cause pain or inflammation on sensitive areas of the skin. Irritant due to its phenolic character. Can cause reddening and tearing (L1264).

The Koc of L-menthol is estimated as approximately 1,500(SRC), using a log Kow of 3.3(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that L-menthol is expected to have low mobility in soil(SRC).

A PALE YELLOW OIL EXTRACTED FROM THE LEAVES OF LANTANA ORANGEMENE CONTAINED 8.2% L-MENTHOL.

L-Menthol is the main component of peppermint oils and cornmint oils obtained from Mentha piperita and Mentha arvenisis(1).

Most l-menthol is obtained ... from Mentha arrensis oil

TESTED AT 8% IN PETROLATUM, /L-MENTHOL/...PRODUCED NO IRRITATION AFTER A 48-HR CLOSED-PATCH TEST IN HUMAN SUBJECTS, ALTHOUGH IT HAS BEEN REPORTED THAT MENTHOL MAY ACT AS A MILD IRRITANT IN MAN. A MAXIMIZATION TEST WAS CARRIED OUT ON 24 VOLUNTEERS. ...CONCN OF 8% IN PETROLATUM...PRODUCED NO SENSITIZATION REACTIONS.

MODERATE IRRITANT TO MUCOUS MEMBRANES ON INHALATION.

THE PSYCHOTROPIC ACTION...IS ALWAYS TRANSIENT & IT IS UNLIKELY THAT IT WOULD HAVE ANY EFFECTS OF THIS KIND IN MAN AT THE CONCENTRATIONS THAT OCCUR IN FOOD OR DRINKS. /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 was reported to be a mild skin irritant in man, but caused more severe damage to the mucous membranes.

Menthol is a covalent organic compound made synthetically or obtained from peppermint or other mint oils. Menthol induces a cooling sensation on the skin upon inhalation, oral ingestion, or topical application by stimulating the cold-sensitive receptors expressed on the skin, without actually causing a drop in the skin temperature.

Menthol primarily activates the cold-sensitive TRPM8 receptors in the skin. Menthol, after topical application, causes a feeling of coolness due to stimulation of 'cold' receptors by inhibiting Ca++ currents of neuronal membranes. It may also yield analgesic properties via kappa-opioid receptor agonism.

L-MENTHOL CONJUGATES READILY IN RABBIT FORMING L-MENTHYL-BETA-D-GLUCURONIDE. ABOUT HALF OF THE L-MENTHOL FED TO RABBITS IS EXCRETED COMBINED WITH GLUCURONIC ACID; THE FATE OF OTHER HALF IS NOT KNOWN, BUT IT IS POSSIBLE THAT RING FISSION OCCURS WITH CONSIDERABLE DEGRADATION OF THE MENTHOL MOLECULE.

IN DOGS, MUCH OXIDATION OF MENTHOL TAKES PLACE AND ONLY ABOUT 5% OF THE DOSE CAN BE RECOVERED IN URINE AS THE GLUCURONIDE. /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).

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 h, and was not rapid with (-)-menthone (doubling time 12 h). 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.

(-)-Menthol has known human metabolites that include p-Menthane-3,-8-diol and (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[(1R,2S,5R)-5-methyl-2-propan-2-ylcyclohexyl]oxyoxane-2-carboxylic acid.

L-Menthol conjugates rapidly, forming L-Methyl-beta-Glucuronide. About half of the menthol absorbed is excreted combined with glucuronic acid (A661).

Found in peppermint oil and other mint oils; Used as a flavor/fragrance in liqueurs, confectionary, perfumes, cigarettes, cough drops, and nasal inhalers; Also used as a topical antipruritic and veterinary local anesthetic, antiseptic, carminative, and gastric sedative; [Merck Index] Used in Canada to control mites and in Europe in paints and lacquers, adhesives, metal care products, cleaning products, shoe and leather care products, disinfectants, solvents, repellents, cosmetics, odor agents, and animal care products; [OECD SIDS]

Painting (Solvents) [Category: Paint]

Medication: topical antipruritic; medication (Vet): has been used as a mild local anesthetic, antiseptic & internally as a carminative & gastric sedative /Menthol/

IN CHEWING GUM; CHEST RUBS /MENTHOL/

AS AN INGREDIENT IN PREPARATIONS FOR THE NOSE & THROAT; IN OINTMENTS TO RELIEVE LOCAL IRRITATIONS OR FOR COUNTERIRRITANT PURPOSES; IN THROAT LOZENGES; ANTIPRURITIC /MENTHOL/

MEDICATION

2023: 10,000,000 - <25,000,000 lb

2023: 1,000,000 - <8,500,000 lb

(1980) 2.63X10+8 g /Menthol/

Fragrance

Fragrance

Flavoring and nutrient

Odor agents

Obtained from peppermint oil or other mint oils, or prepared synthetically by hydrogenation of thymol. /Menthol/

A synthetic process for menthol involves the hydrogenation of thymol or 3-hydroxy-p-cymene which can be obtained from essential oils are produced synthetically from p-cymene (isopropypltoluene) or meta-cresol

GRADES: TECHNICAL; USP; FCC /MENTHOL/

Synthetic menthol is available as the optically active levo-menthol with a purity of 99.9%

/Present in/ cigarettes and pipe tobacco (0.1-0.45%) shaving creams, pre- and aftershave lotions (0.2-0.3%); toothpastes (0.5%); mouthwashes (1-2%); chewing gums (0.5%); cough drops (0.1%); refreshing towels (1%); rubbing alcohol (1-1.2%); and shampoos (2-0.5%) /menthol primary (L)-isomer/

Mentholatum Deep Heating Rub /contains/ 5.9% Menthol; Mentholatum ointment, 1.35%; Mentholatum Deep Heating Lotion, 6%

Cosmetics product ingredient: Menthol (dl-menthol; l-menthol; d-menthol)

Information on 42 consumer products that contain Menthol, L- in the following categories is provided:

Information on 35 consumer products that contain Menthol (Racementhol) in the following categories is provided:

Fragrance Ingredients

Flavoring Agents -> JECFA Flavorings Index

Soap, Cleaning Compound, and Toilet Preparation Manufacturing

Soap, Cleaning Compound, and Toilet Preparation Manufacturing

Cyclohexanol, 5-methyl-2-(1-methylethyl)-, (1R,2S,5R)-rel-: ACTIVE

Cyclohexanol, 5-methyl-2-(1-methylethyl)-, (1R,2S,5R)-: ACTIVE

USP does not distinguish between L-menthol and DL-menthol.

Incompatibilities: butylchloral hydrate, camphor, phenol, chloral hydrate, exalgine, betanaphthol, resorcinol or thymol in triturations; potassium permanganate, chromium trioxide, pyrogallol. /Menthol/