Menthol Toxicology

The Flavoring Extract Manufacturer's Association (FEMA) classifies menthol as GRAS (generally recognized as safe) while the U.S. Food and Drug Administration (FDA) has approved menthol for food use (Opdyke, 1976).

Ingested pure menthol can be poisonous - as little as a teaspoonful (1 gram per kilogram of body weight) can be fatal (http://www.rx.com/reference/natural/Peppermint.jhtml). The estimated acceptable daily intake is up to 200 micrograms per kilogram of body weight (Martindale, The Extra Pharmacopoeia, 1993). Dr. James Duke at the USDA Agricultural Research Center estimates that the LD50 (dose at which half the animals die) for menthol is higher than coffee, oral LD50 in rats of 192 mg/kg (CRC Handbook of Medicinal Herbs, 1987).

Hypersensitivity reactions have been reported in a few instances in adults. These patients have reacted with headache, flush, rash, dizziness and hypertension from contact with menthol in a variety of forms, e.g., toothpaste, cigarette smoke, candies and medications (Larkin and Castellano, 1967). Ingestion of menthol can cause severe abdominal pain, nausea, vomiting, vertigo, ataxia, drowsiness and coma (Martindale, The Extra Pharmacopoeia, 1993). Overdose of menthol, particularly over long periods, e.g., overuse of mentholated cigarettes (see Luke, 1962 below) can result in gastrointestinal distress, ataxia, stupor and convulsions - even blood dyscrasias have been reported (Meyler, 1996).

For information on the treatment of menthol overdosage click on Menthol Overdosage..

Twelve cases of contact sensitivity to menthol and peppermint oil were reported in patients presenting with intra-oral symptoms in association with burning mouth syndrome, recurrent oral ulceration or a lichenoid reaction (interlacing network of white lines - forms a spider web pattern on the mouth cavity mucosa) . Five patients with burning mouth syndrome demonstrated contact sensitivity to menthol and/or peppermint, with one sensitive to both agents, three positive to menthol only and one to peppermint only. Four cases with recurrent intra-oral ulceration were sensitive to both menthol and peppermint. Three patients with an oral lichenoid reaction were positive to menthol on patch testing, with two also sensitive to peppermint. After a mean follow-up of 32.7 months (range 9-48 months), of the nine patients that could be contacted, six patients described clearance or improvement of their symptoms as a consequence of avoidance of menthol/peppermint (Morton, et al., 1995).

A case of contact cheilitis (inflammation of the lip) due to peppermint oil and menthol in toothpaste has been reported. A 70 year old man with a 10 year history of whitish eruption on his lower lip developed erosion and pain on the same area. Results of allergic tests showed positive reactions to cobalt chloride, balsam of Peru, fragrance mix , toothpaste and to captopril. He stopped taking the captopril for four months but the cheilitis did not improve. Further allergic testing with the ingredients of the toothpaste he used revealed that he had a positive reaction to fragrance. Looking at the ingredients of the toothpaste a positive reaction was seen with peppermint oil and menthol (1% pet and 5% pet). After these tests he began to use toothpaste without peppermint oil and menthol and his cheilitis improved within one month (Nishioka et al., 1997) .

Respiratory Distress in Infants Exposed to Menthol

A number of reports have appeared suggesting toxicity to menthol in small infants. Because of respiratory tract infections of unknown severity these patients received home treatments which included menthol containing ointments (Meyler, 1996; Martindale The Extra Pharmacopoeia, 1993; Leung and Foster, 1996, PDR for Herbal Medicne, 2000). The infants reportedly developed severe respiratory distress in most cases and cyanosis in a few. Symptoms persisted for one of more days in many infants and was thought to be due to the inhalation of menthol (Larkin and Castellano, 1967). The contraindications for some menthol-containing products caution against use in infants and young children specifying that menthol containing preparations should not be used on areas of the face, especially the nose (Herbal Medicine, 2000)..

In one case, a six weeks old boy developed a slight cold with a little rhinitis - his condition was good and his temperature was normal. His mother applied the ointment (VapoRub) prior to dressing the child and she noticed he became dyspneic and in a short while stopped breathing, became cyanotic and stiff with very slow movements of the limbs. The grandfather who was present, took the boy, turned him upside down and slapped him slightly on the back. The boy produced a little mucus and started breathing again and recovered uneventfully. The next day the child still had a little rhinitis and the grandfather once again applied VapoRub on the child's chest. Shortly after, while getting him dressed he once again stopped breathing and became cyanotic. The grandmother turned him upside down, slapped him on the back and after coughing up some a little mucus he could breath normally again. Finally after repeating another application of VapoRub with the same result it was realized that the ingredient in the rub that was causing the problem was most likely menthol (K. Wilken-Jensen, 1967).

Federal Register 138: 38762-65, 1998) - The FDA has proposed to amend the final monograph for OTC antitussive drug products to revise the label warning and directions for topical/inhalant products containing the active ingredient camphor and/or menthol. New information indicates that the use of these drug products near an open flame, in hot water or in a microwave oven can cause the product to catch fire and cause serious burns to the user. It was recommended that products for inhalation should be added to cold water in a hot steam vaporizer.

Ataxia, confusion, euphoria, nystagmus and diplopia developed in a 13-year old boy following the inhalation of 5ml of Olbas oil instead of the recommended few drops. {Contains menthol 4.1%, oil of cajuput 18.5%, clove 0.1%, eucalyptus 35.5%, juniper berry 2.7%, peppermint 35.5% and wintergreen oil (methyl salicylate) 3.7%. This oil had been recommended as an inhalant for nasal congestion.} It was thought that the menthol in the preparation was responsible for the symptoms; the amount inhaled was approximately 200mg (it was felt the amount of methyl salicylate was too low to cause salicylate toxicity) (O'Mullane et al., 1982).

A case has been reported where a 63 year old woman with a past history of alcoholism and ongoing nicotine dependence was hospitalized on three occasions in a one-year period secondary to confusional episodes. These episodes (euphoria, confusion, lethargy, agitation, odd behavior and auditory and visual hallucinations) were found to be related to the oral ingestion of Mentholatum (contains: menthol and methyl salicylate). Once in the hospital overall improvement in the patient's status was seen and this was thought a result of a hospital imposed cessation of Mentholatum ingestion. The authors concluded that Mentholatum is no longer available in the United States but point out that several variants of Mentholatum and many topical analgesics with similar ingredients are widely available as OTC products. They wanted to alert clinicians to the possibility of the ingestion of topical analgesics as an etiology of delirium (Huntimer and Bean, 2000) .

A few older studies have reported some possible toxic effects of menthol. A 58 year old woman became addicted to mentholated cigarettes and developed toxic exhaustive psychosis from which she recovered from once she stopped smoking. Excessive smoking of tobacco is often associated with tachycardia and cardiac arrhythmias but in this case pulse was not irregular and bradycardia was pronounced. It was believed that the excessive use and craving for mentholated cigarettes, the bradycardia, ataxia, confusion and mental irritability could be correlated with the inhalation of volatile menthol (Luke, 1962).

A case of non-thrombocytopenic purpura caused by mentholated cigarettes was described by Highstein and Zeligman (1951). Two cases of idiopathic auricular fibrillation were reported both were investigated in the hospital and later admitted to being excessive peppermint addicts (Thomas, 1962).

A study in rats found that exposure to mentholated or non-mentholated tobacco smoke for 13 weeks produced a dose-related epithelial changes throughout the upper respiratory tract. In virtually all rats, there was a significant recovery to normal tissue during the six week period following exposure. It was concluded that as a result of this 13-week inhalation study in rats that the addition of menthol to cigarettes does not significantly alter the pattern, incidence, severity or reversibility of any of the effects attributable to smoke exposure (Gaworski, 1997)..

References

Duke JA, CRC Handbook of Medicinal Herbs, CRC Press, 1987.

Gaworski CL MM Dozier JM Gerhart N Rajendrans LH Brennecke C Aranyi and JD Heck, 13-Week inhalation toxicity study of menthol cigarette smoke, Food and Chem. Toxicol. 35: 683-692, 1997.

Herbal Medicine (expanded Commission E monographs), edited by: Mark Blumenthal, Integration Medicine Communications, 2000.

Huntimer CM and DW Bean, Delirium After Ingestion of Mentholatum, Amer. J. Psychiatry 157(3): 483-484, 2000.

Highstein B and I Zeligman, Nonthrombocytopenic purpura caused by mentholated cigarettes, J. Amer. Med. Assoc. 146(9): 816, 1951.

Kazue N M Murata and T Ishikawa, Contact cheilitis to peppermint oil and menthol in toothpaste, Environ. Dermato. 4: 43-47, 1997.

Larkin P and JC Castellano, Laryngoscopic-findings in acute respiratory infections treated with and without a mentholated rub, pg 108 in Menthol and Menthol - containing External Remedies (Use, Mode of Effect and Tolerance in Children, edited by Dost FH and B Leiber, Georg Thieme Verlag - Stuttgart, 1967.

Leung A and S Foster, Encyclopedia of Common Natural Ingredients Used in Foods, Drugs and Cosmetics, John Wiley & Son, NY, 1996.

Luke E, Addiction to Mentholated Cigarettes, The Lancet I January 13, 1962, pg 110-111.

Martindale The Extra Pharmacopoeia, edited by: James EF Reynolds, The Pharmaceutical Press, 30th edition, 1993.

Meyler's Side Effects of Drugs, edited by: MNG. Dukes, Elsevier - Amsterdam, 13t edition, 1996.

Morton CA J Garioch P Todd PJ Lamey and A Forsyth, Contact sensitivity to menthol and peppermint in patients with intra-oral symptoms, Contact Dermatitis 32(5): 281-284, 1995.

O'Mullane NM P Joyce SV Kamath MK Tham and D Knass, Adverse CNS effects of menthol-containing olbas oil, The Lancet II May 15, 1982 pg 1121.

Opdyke DLJ, Monographs on fragrance raw materials: l-Menthol, Food and Cosmetics Toxicology 14: 471-472, 1976.

PDR for Herbal Medicine, pg 880-881, Medical Economics Co., Montvale, NJ, 2nd edition, 2000.

Thomas JG, Peppermint Fibrillation, The Lancet I January 27, 1962, pg 222.

Wilken-Jensen K, Investigations on children inunctioned with a mentholated ointment from allergologic viewpoint, pg 154, in Menthol and Menthol-containing External Remedies (Use, Mode of Effect and Tolerance in Children, edited by Dost FH and B Leiber, Georg Thieme Verlag - Stuttgart, 1967.