P-menthane-3,8-diol

Other Names

(1R,2R,5R)-2-(2-Hydroxypropan-2-yl)-5-methylcyclohexanol1-(2-Hydroxy-4-methylcyclohexyl)-1-methylethanol1-Hydroxy-2-(1-methyl-1-hydroxyethyl)-5-methylcyclohexane1-Hydroxy-5-methyl-2-(1-methyl-1-hydroxyethyl)cyclohexane2-(1-hydroxy-1-methylethyl)-5-methylcyclohexan-1-ol2-(1-hydroxy-1-methylethyl)-5-methylcyclohexanol2-(2-hydroxypropan-2-yl)-5-methyl-cyclohexan-1-ol2-(2-hydroxypropan-2-yl)-5-methylcyclohexan-1-ol2-(2-Hydroxypropan-2-yl)-5-methylcyclohexanol2-hydroxy-alpha,alpha,4-trimethylcyclohexanemethanol2-Hydroxy-α,α,4-trimethylcyclohexanemethanol3,8 PMD3,8-p-Menthanediol8-HydroxymentholCyclohexanemethanol, 2-hydroxy-α,α,4-trimethyl-Cyclohexanemethanol, 2-hydroxy-α,α,4-trimethyl-, (1-α,2-β,4-β)-Cyclohexanemethanol, 2-hydroxy-α,α,4-trimethyl-, (1R,2R,4E)-geranium cyclohexaneisopulegol hydratementhoglycolp-Menthan-3,8-diolp-Methane-3,8-diolp-methene-diol-3,8para-menthane-3,8-diolPMDQuwenling

Synopsis

p-Menthane-3,8-diol (PMD): A Comprehensive Reference

1. Identity: Names, Chemistry, Botanical Source, and Commercial Forms

Nomenclature and Chemical Classification

p-Menthane-3,8-diol, also known as para-menthane-3,8-diol, PMD, or menthoglycol, is an organic compound classified as a diol and a terpenoid. It is also sold or described under the trade name Citriodiol®. PMD is a naturally occurring monoterpenoid diol with the molecular formula C₁₀H₂₀O₂ and a molecular weight of 172.26 g/mol. It features a cyclohexane ring structure typical of p-menthane derivatives, with hydroxyl groups attached at the C-3 and C-8 positions, and its IUPAC name is 2-(2-hydroxypropan-2-yl)-5-methylcyclohexan-1-ol.

Its name reflects the hydrocarbon backbone, which is that of p-menthane. A total of eight stereoisomers are possible, based on the three stereocenters of the ring; depending on the source, one or more may predominate. Its odor and chemical structure are similar to menthol, and it has a cooling feel. In its pure form at room temperature, para-menthane-3,8-diol is a crystalline material which separates as long needle crystals in standard methods of synthesis.

Botanical Source

PMD is found in small quantities in the essential oil from the leaves of Corymbia citriodora, formerly known as Eucalyptus citriodora. This tree is native to Australia but is now cultivated in many warm places around the world. PMD is also a constituent of the roots of Litsea cubeba (mountain pepper).

C. citriodora oil, when refined to increase its PMD content for use in insect repellents, is known in the United States as oil of lemon eucalyptus (OLE) as well as Citriodiol. Refined OLE contains approximately up to 70% PMD, a mixture of the cis and trans isomers of p-menthane-3,8-diol. Citronellol, limonene, and linalool are also found in the extracts from eucalyptus, together with PMD.

Distinction Between OLE, Synthetic PMD, and Raw Essential Oil

Synthetic PMD is made in a laboratory and is also used as a bug repellent. Although OLE and synthetic PMD have the same active ingredient, the Environmental Protection Agency (EPA) regulates them separately. Commercially available synthetic PMD products have a lower PMD concentration than commercial OLE products; products with synthetic PMD have a PMD concentration of about 10 percent.

The "pure" oil of lemon eucalyptus essential oil — not formulated as a repellent — is not recommended as an insect repellent by the EPA, as there are no studies on its safety and efficacy. The CDC also recommends against using lemon eucalyptus essential oil as a bug repellent, because it has not been tested for safety and effectiveness as thoroughly as OLE and PMD.

Commercial Forms and Dosage Forms

PMD as an active ingredient is used to make products applied to human skin and clothing for the purpose of repelling insects, such as mosquitoes. It can be used in two types of consumer pesticide products: a spray and a lotion. OLE is available in concentrations of 10–40%, and it provides up to 6 hours of protection against mosquitoes. Synthetic PMD is also the active ingredient in some commercially available insect repellent products.

2. Historical and Traditional Use

China: Quwenling

Beginning in China in 1960, many plants were examined to find competent repellents. It was discovered that a waste material from the extraction of lemon eucalyptus oil functioned as an effective mosquito repellent. The main component of this material was p-methene-diol-3,8.

Extracts of the lemon eucalyptus plant Corymbia citriodora have been used in China under the name Quwenling for the purposes of repelling mosquitoes (Li et al., 1974, Studies on the Repellent Quwenling, Malaria Research, p. 6). It has been used in China as an insect repellent, where it is called Quwenling. The main ingredient of Quwenling is PMD, but it also contains a mix of terpenoids (Strickman, 2007). The major active repellent ingredient of these extracts has been demonstrated to be p-menthane-3,8-diol (Trigg and Hill, 1996). A significant milestone occurred in the 1970s when Chinese scientists isolated PMD from eucalyptus sources to develop Quwenling, a widely used repellent formulation that emphasized the compound's practical application in mosquito control.

Early Chemical Identification

An early monograph on the synthesis of p-menthane-3,8-diol was given by P. Barbier and G. Leser (1896), who obtained p-menthane-3,8-diol together with isopulegol on the cyclization of citronellal in dilute sulfuric acid. The reaction probably follows two stages: first the cyclization of citronellal to isopulegol, followed by hydration of the latter material to p-menthane-3,8-diol. No mention is made in these early reports of any potential use for the resultant diol.

Regulatory Milestones

On November 28, 1997, the U.S. EPA received an application from S.C. Johnson & Son, Inc. to register the Manufacturing Use Product, p-Menthane-3,8-diol Technical, containing p-Menthane-3,8-diol, a new biochemical active ingredient used as an insect repellent. The EPA registered the oil of lemon eucalyptus (OLE) or PMD as a biopesticide repellent, under repellents derived from natural materials, in 2000. OLE has been notified under the European Biocidal Products Directive (BPD) 98/8/EC (now BPR Regulation (EU) No. 528/2012) under its generic name "p-Menthane-3,8-diol rich botanic oil." It is also registered with Canada's Pest Management Regulatory Agency under the generic name "p-Menthane-3,8-diol and related oil of lemon eucalyptus compounds."

3. Key Constituents and Chemical Production

Natural Extraction

PMD is an insect repellent that can be synthesized chemically or derived from a steam distillate residue of the leaves of lemon eucalyptus, Corymbia citriodora. Although p-menthane-3,8-diol may be obtained by extraction from the leaves of Corymbia spp., this is economically restricted to the places the plants are growing in sufficient quantity to be commercially viable.

Chemical Synthesis

In a patented method, citronellal is treated with aqueous sulfuric acid to produce p-menthane-3,8-diol. More specifically, the diastereomeric repellents of p-menthane-3,8-diol were produced from citronellal by treatment with 0.25% sulfuric acid at 50°C for 11 hours to give 97.9% conversion and 92.3% selectivity, with citronellal acetal by-products of only 2.7%. Additionally, a biotransformation route has been described in which the monoterpene geraniol was transformed into the cyclic compound p-menthane-3,8-diol (PMD) using Polyporus brumalis, a white rot fungus, as a biocatalyst. Both α-terpineol and PMD are recognized as bioactive monoterpene alcohol compounds.

Isomer Complexity

There are eight possible isomers of p-Menthane-3,8-diol, and the exact composition is rarely specified and is commonly assumed to be a complex mixture. Refined OLE contains approximately 64% p-Menthane-3,8-diol, a mixture of the cis and trans isomers of p-menthane-3,8-diol.

4. Mechanisms of Action

Primary Repellent Mechanism: Olfactory Disruption

The primary mechanism by which p-Menthane-3,8-diol exerts its repellent effect is through the disruption of an insect's ability to locate a host. This is achieved through its interaction with multiple sensory modalities, primarily olfaction (sense of smell) and potentially gustation (sense of taste) and thermosensation. PMD acts as a powerful spatial repellent, creating a vapor barrier that deters insects from a distance, and may also function as a contact repellent upon landing.

The primary mechanism of action for PMD as an insect repellent is through its interaction with the insect's olfactory system. It is believed to work by disrupting the function of olfactory receptors (ORs) located on the antennae and maxillary palps of insects, which are responsible for detecting host cues such as carbon dioxide and skin odors. Research has indicated that PMD, along with other repellents like DEET, can activate specific odorant receptors.

Research suggests that PMD, along with other repellents like DEET, picaridin, and IR3535, activates a specific odorant receptor, OR136, in the Southern house mosquito, Culex quinquefasciatus. This activation disrupts the insect's ability to process olfactory cues.

Stereoelectronic Properties

Stereoelectronic analysis indicates that lower aqueous stabilization (favorable lipophilicity) and larger separation of electrostatic potential energy, together with a large localized negative electrostatic potential region by the oxygen atom, play important roles for repellent activity. The generated pharmacophore model of PMDs showed two aliphatic hydrophobic and a hydrogen-bond donor features for potent activity.

Antiseptic and Other Reported Activities

A European patent (EP-B-1204319) describes the use of PMD as an antiseptic and antifungal agent. In the broader context of eucalyptus extracts, compounds from eucalyptus are recognized for their broad spectrum of action, including antibacterial, antifungal, antiviral, anti-inflammatory, anti-immunomodulatory, antioxidant, and wound healing properties. However, these activities are largely attributed to Eucalyptus essential oils broadly (particularly 1,8-cineole), and specific mechanistic evidence for PMD itself in these roles is limited.

5. Scientific Evidence by Area of Use

5.1 Mosquito Repellency

PMD's most extensively studied and best-supported use is as a topical mosquito repellent. It is one of the few natural products endorsed by the U.S. Centers for Disease Control and Prevention (CDC) for topical application to protect against mosquitoes.

PMD (para-menthane-3,8-diol), the active ingredient in oil of lemon eucalyptus (OLE), has been as effective as DEET against mosquitoes in some studies. More specifically, a 26% PMD formulation provided complete protection for 7–8 hours against Aedes albopictus and Ochlerotatus triseriatus and for 3 hours against Culex nigripalpus, which is comparable to a 7% DEET formulation (Barnard and Xue, 2004).

A key published study (Goodyer et al., 2020, Transactions of the Royal Society of Tropical Medicine and Hygiene) utilized arm-in-cage methodology: a series of arm-in-cage tests against Aedes aegypti mosquitoes were devised using 6 volunteers to estimate complete protection time (CPT) or 10 to estimate the ED95 and half-lives for three repellents: 20% DEET, 30% PMD, and a novel 30% PMD-vanillin formulation. Non-linear regression analysis was used to characterize the relationship between applied dose and CPT. PMD and DEET showed a very similar log dose relationship to CPT.

The quantitative results from that study showed: a 1.5-fold higher CPT for PMD-vanillin compared with 20% DEET when applied at a dose of 1.6 mg/cm², but little difference was observed at lower doses of 0.8–1 mg/cm². The ED95 value for the 30% PMD and PMD-vanillin formulations were 0.25 and 0.24 mg/cm², respectively, these being higher than that for 20% DEET (0.09 mg/cm²). The half-lives for 30% PMD and 20% DEET were similar (2.23 vs. 2.74 h), but longer for the PMD-vanillin formulations (3.8 h).

Several studies have demonstrated the high repellent activity and longevity of PMD against Aedes, Anopheles, and Culex genera, similar to DEET, while having low toxicity — except for eye irritation, which is observed for all non-toxic natural active ingredients — and no adverse effects reported.

Evidence strength: Strong for mosquito repellency at concentrations of 20–40%. Multiple human volunteer arm-in-cage studies support comparable efficacy to DEET. The CDC and EPA both endorse PMD as an effective, registered mosquito repellent, constituting regulatory-level evidence.

5.2 Tick Repellency (Lyme Disease and Other Tick-Borne Illness Prevention)

The Infectious Diseases Society of America (IDSA)/AAN/ACR 2020 guidelines for the prevention of Lyme disease recommend OLE and PMD for the prevention of tick bites (strong recommendation, moderate-quality evidence). In laboratory and field experiments involving human subjects, the use of PMD reduced the number of ticks detected crawling on or attached to subjects compared with controls.

PMD is a highly effective and long-acting mosquito repellent, similar to DEET. Moreover, PMD exhibited better protection against ticks than DEET, by inhibiting attachment and blood-feeding of tick vectors associated with Lyme disease and Rocky Mountain spotted fever.

One study found that, when applied as a daily repellent, para-menthane-3,8-diol significantly reduced attachment of castor bean ticks (Ixodes ricinus) on humans. Another study found that castor bean ticks were significantly repelled by PMD relative to controls.

A 2026 study by Anholeto and colleagues found that lemon eucalyptus oil significantly repelled both blacklegged ticks and American dog ticks, and was an effective repellent when applied to cotton fabric, cotton-poly fabric, or polyester fabric. Para-menthane-3,8-diol performed comparably to DEET in laboratory assays and, when applied to clothing, repelled ticks for several days to a week, depending on tick species and fabric type.

In special cases where environmental exposures to disease-transmitting ticks, biting midges, sandflies, or blackflies are anticipated, topical insect repellents containing oil of lemon eucalyptus (p-menthane-3,8-diol or PMD) would offer better topical protection than topical DEET alone.

Corymbia citriodora (lemon eucalyptus) and its compound PMD have most convincingly been shown to be effective among botanical tick repellents. 2-Undecanone and nootkatone with carvacrol have also shown some promise.

Evidence strength: Moderate to strong. PMD is included in major clinical practice guidelines (IDSA, 2020) for tick-bite prevention with "strong recommendation, moderate-quality evidence." Some comparative data suggest superiority to DEET in certain tick species and fabric-based delivery contexts.

5.3 Repellency Against Other Biting Arthropods

The EPA target pest list for PMD includes repelling specific insects including mosquitoes, biting flies, and gnats. OLE/PMD repels mosquitoes, ticks, flies, gnats, and biting midges.

Evidence strength: Moderate. Regulatory acceptance supports repellency against multiple arthropods, though the depth of controlled clinical evidence is greatest for mosquitoes and Ixodes ticks.

5.4 Antimicrobial, Antifungal, and Antiviral Properties

A U.S. patent application (US 7,872,051) describes an antiviral composition comprising PMD (PCT/GB2005/000803, priority from 2004). A European patent (EP-B-1204319) describes the use of PMD specifically as an antiseptic and antifungal agent.

In the broader eucalyptus literature, given the limited therapeutic management of infectious diseases caused by viruses such as influenza and SARS-CoV-2, the medicinal use of essential oils obtained from eucalyptus trees has emerged as an antiviral alternative. Studies have shown that eucalyptus essential oil and its major monoterpenes have enormous potential for preventing and treating infectious diseases caused by viruses. The main molecular mechanisms involved in antiviral activity include direct inactivation by the direct binding of monoterpenes with free viruses, particularly with viral proteins involved in the entry and penetration of the host cell.

Evidence strength: Very preliminary (patent-stage claims and in vitro data only) for PMD specifically. The broader antimicrobial data for eucalyptus essential oils does not translate directly to PMD in isolation, and no completed human clinical trials exist for these applications.

5.5 West Nile Virus and Vector-Borne Disease Protection

The CDC reported that oil of lemon eucalyptus (with PMD as the active ingredient) is one of only a small number of products recommended to protect against West Nile virus, a serious virus spread by mosquitoes that can cause neurological disease or even death. The EPA lists PMD as effective against mosquitoes, biting flies, and gnats.

Evidence strength: This recommendation reflects the established repellent efficacy against the Culex mosquito vectors of West Nile virus rather than direct clinical trial evidence of disease prevention per se.

6. Dosage Forms and Concentrations Reported in Studies and Regulatory Sources

Oil of Lemon Eucalyptus (OLE) products: Available in concentrations of 10–40%.
Synthetic PMD products: Have a lower PMD concentration than commercial OLE products; products with synthetic PMD have a PMD concentration of about 10 percent.
Arm-in-cage efficacy study (Goodyer et al., 2020): 30% PMD formulation tested; 6–10 human volunteers.
Field repellency study (Barnard & Xue, 2004): A 26% PMD formulation provided complete protection for 7–8 hours against Aedes albopictus and Ochlerotatus triseriatus.
Effective dose (ED95): The ED95 for 30% PMD was 0.25 mg/cm²; for 20% DEET it was 0.09 mg/cm² (Goodyer et al., 2020).
Skin absorption study (Reifenrath et al., 2009): A dose of approximately 80 µg/cm² of PMD in lotion formulation was used on excised pig skin.
Duration of protection: OLE products provide up to 6 hours of protection against mosquitoes.
Consumer product range: PMD concentrations of 10–40% with up to 6 hours of protection against mosquitoes are cited in formulation literature.

7. Body Systems and Health Areas Associated with PMD

Dermatological / Integumentary System (Topical Application)

PMD is applied exclusively to the skin and clothing in its established uses. In a percutaneous absorption study, carbon-14-labeled PMD formulated in lotion and in ethanol solution was applied to excised pig skin in an in vitro flow-through system predictive of human skin absorption. Twenty-four hours after application, the radiolabel recovered from the dermis and receptor fluid was summed to determine percent absorption; at a dose of approximately 80 µg/cm² of PMD in lotion, a value of 3.5 ± 0.8% of applied dose was obtained.

Most of the applied dose of PMD was found to evaporate from pig skin (77 ± 8% for the lotion and 87 ± 1% for ethanol solution), thus limiting percutaneous absorption. These low absorption figures indicate minimal systemic exposure under typical use conditions.

Immune / Infectious Disease Prevention

Through its vector-control function, PMD has relevance to the prevention of mosquito-borne and tick-borne infectious diseases including malaria, dengue fever, West Nile virus, Lyme disease, and Rocky Mountain spotted fever. PMD is a highly effective and long-acting mosquito repellent, similar to DEET. PMD exhibited better protection against ticks than DEET, by inhibiting attachment and blood-feeding of tick vectors associated with Lyme disease and Rocky Mountain spotted fever.

8. Safety: Established Toxicological Data and Regulatory Findings

Acute Toxicity Classification

The technical grade active ingredient, p-Menthane-3,8-diol, is placed into Toxicity Category IV for acute oral toxicity, dermal toxicity and skin irritation — indicating low toxicity in these categories — and into Toxicity Category I for eye irritation (Toxicity Category II for the end-use product). It is not a skin sensitizer.

The EPA has reviewed guideline studies for acute oral toxicity, acute dermal toxicity, and acute dermal irritation and has determined that PMD is of low acute toxicity for these exposures.

Sub-Chronic Dermal Toxicity

The no-observed-adverse-effect level (NOAEL) from a 90-day dermal toxicity study in rats was established at a limit dose of 1,000 mg/kg/day. The NOAEL for immune suppression, as determined in a 28-day dermal study via a primary antibody response assay, was >3,000 mg/kg/day in mice. The NOAEL for maternal and developmental toxicity was established in rabbits at 3,000 mg/kg/day by the dermal route.

Eye Irritation — the Primary Safety Concern

In animal studies evaluated by the EPA during the registration process of PMD, the only adverse effect that PMD showed was eye irritation. One peer-reviewed research study reported that a subject experienced significant skin irritation at the site of application. According to the EPA laboratory exposure of animals to the active ingredient, PMD resulted in no adverse effects except eye irritation. The Product Safety Data Sheets classify PMD as seriously irritating to eyes.

Skin Sensitization

PMD is not a skin sensitizer according to EPA toxicological testing. However, OLE and PMD can cause eye and skin irritation, including allergic skin reactions, particularly in the context of OLE, which contains other constituents. Citronellol and other chemicals in the OLE extract are known allergens.

Age Restrictions: Children Under 3 Years

Because the dangers to children have not been thoroughly explored, products with Oil of Lemon Eucalyptus and PMD have labels that warn, "Do not use on children under the age of 3." The CDC also advises not to use on children under 3 years of age. Users are also advised not to use PMD on the faces or hands of small children. PMD is not to be used on children younger than three years of age because the product has not been adequately tested in this population.

Pregnancy and Breastfeeding

The CDC recommends the use of an EPA-registered repellent with oil of lemon eucalyptus for pregnant mothers in areas with risk of Zika. However, the CDC advises not to use Oil of Lemon Eucalyptus or PMD on very young children, so avoiding it while pregnant is also advised by some authorities. The NOAEL for developmental toxicity was established at 3,000 mg/kg/day dermally in rabbits, suggesting a wide safety margin at typical use levels, though this remains an animal study finding.

Regulatory Safety Completeness

The toxicological database for PMD has been satisfied with guideline studies and information from the public and is considered complete for characterizing hazard and assessing risk from the active ingredient PMD. No additional studies are anticipated to be needed for registration review. All data requirements per 40 CFR 158.2050 have been fulfilled for PMD.

Environmental Safety

Due to its low toxicity and limited use, Eucalyptus citriodora (and by extension PMD) is not considered harmful to the environment. Refined Oil of Lemon Eucalyptus is classified as a biochemical pesticide, which the EPA defines as a naturally occurring ingredient that controls pests by nontoxic mechanisms. Ingredients in this category can qualify for EPA approval with less safety testing than synthetic chemical pesticides.

9. Notable Distinctions and Interactions

PMD vs. DEET interactions: PMD is not as effective as DEET (N,N-diethyl-1,3-toluamide) against all mosquito species. DEET has several undesirable side effects and toxicity concerns. Although PMDs are comparatively safer than DEET, quantitative structure-activity relationship (QSAR) modeling studies have been initiated to develop more effective PMD analogues.
OLE products and skin reactions: OLE products can sometimes cause an allergic skin reaction. Products that contain synthetic PMD may have a lower risk of a skin reaction, since OLE contains additional constituents beyond pure PMD.
Vanillin as an enhancer: The half-life of a PMD-vanillin formulation (3.8 h) was longer than that of 30% PMD alone (2.23 h) or 20% DEET (2.74 h) in arm-in-cage testing.
Sunscreen interactions: Data are not available regarding the use of OLE/PMD in combination with a separate sunscreen; guidance exists only for DEET-based repellents combined with sunscreen.

10. Evidence Summary and Research Gaps

PMD's status as a registered biopesticide — with a complete toxicological dossier accepted by the U.S. EPA and inclusion in CDC and IDSA guidelines — places it among the most rigorously evaluated plant-derived repellents available. PMD (p-menthane-3,8-diol), proven safe to human health, is the only plant-based repellent advocated by the CDC for public use. The evidence base for its repellent efficacy against mosquitoes and several tick species is strong, supported by multiple controlled human volunteer studies.

By contrast, its proposed uses as an antifungal, antiseptic, or antiviral agent remain at the patent and early in vitro stage only. Robust clinical studies validating the specific health benefits of P-menthane-3,8-diol in nutritional or systemic applications are limited. Claims regarding supplemental, oral, or systemic health effects cannot be supported by the current peer-reviewed evidence base.

References

Health Conditions

Health conditions that P-menthane-3,8-diol may help support.

No conditions available.

Body Systems

Body systems that P-menthane-3,8-diol may help support.

No body systems available.