Chemian Technology describes next-generation insect repellent actives, derived from renewable, ethically sourced and sustainable feedstocks, which are offering insect repellent producers a clinically proven COSMOS -certified alternative to established synthetic materials

Consumer demand for natural, plant-based alternatives to synthetic mosquito repellents like DEET (N,N-diethyl-meta-toluamide) has been building for some years. This is driven, in part, by increased consumer awareness of certain negative issues related to the use of DEET and the wider preference for effective, safe-to-use personal care products that are based on raw materials from renewable and sustainable resources.

Ecocert and COSMOS natural certification – long-established and important standards in the cosmetic industry – are now finding increasing relevance in the market for insect repellents and the active ingredients they contain.

Uniquely and unlike materials used in the cosmetic industry, the natural claims made for active ingredients in mosquito repellents remain secondary in importance to their efficacy – for obvious reasons concerning the potential implications for their role in the prevention of dangerous insect vector-borne diseases like malaria, dengue and Zika virus. Natural, plant-based extracts that make notional, unquantified or unsubstantiated claims around repellence are a poor and ineffective substitute for proven and trusted synthetic actives.

A watershed moment

In European markets, the implementation of ECHA’s Biocidal Product Regulation (BPR) represents a watershed for natural offerings due to the Regulation’s compulsory requirement for repellent active manufacturers to provide proof of efficacy according to prescribed, standardised test methodology.

Product claims around efficacy and the quantification of protection, measured in hours, must now be supported by actual data. Prior to this, under the preceding European Biocide Directive (98/8/EC) controlling repellent actives, this had not been the case.

The raising of the technical bar to market entry has narrowed the options available to formulators and para menthane 3,8-diol (PMD)-based actives have emerged as the principle material offering equivalent efficacy to that of established synthetic actives.

First generation PMD-rich botanical oils (PMDRBO) derived from Eucalyptus citriodora (EC) essential oil feedstocks, provided the basis for the first truly Natural, PMD-based repellents and these are now widely available in the market – offered by natural product specialists and available within the portfolio of major consumer goods brand platforms, (repellent) market specialists and retailer brands.

These EC oil-based active ingredients have traditionally been formulated as alcoholic solutions for application by aerosol or pump spray.

Second generation PMDRBO

The growing trend for pleasant, safe-to-use and more cost-effective, water-based formulations has led to the development of a second generation PMDRBO, Citrepel® 75, based on a fractionated Cymbopogon winterianus (Java Citronella) essential oil, which can, uniquely, be formulated with cold process to deliver stable o/w emulsions for lotions, sprays, creams, roll on, wipes and solid stick formulations (warm process), without the need for alcohol or co-solvents (Table 3).

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PMD, as the major constituent and functional molecular component of PMDRBO, is formed by the acid catalysed hydrolysis of a double bond within Citronellal — the main aldehyde component of the fractionated feedstock oil – with simultaneous ring closure (Prins reaction), producing a mixture of isomers — all of which have repellent activity.

Efficacy testing for mosquito repellents

Validated efficacy testing for mosquito repellents is carried out using arm in cage methodology, performed on a pre-qualified sample group (test subjects are selected according detailed fitness criteria and must demonstrate attraction to the mosquito species population used in the test).

The test measures the efficacy of the repellent by recording the number of bites to an exposed area of the treated arm during a 60-second exposure within the mosquito cage, between hourly intervals. The outcomes provide the CPT (Complete Protection Time) and the PE (Protection Efficiency) score.

The CPT score (Table 1) measures the time between product application and the occurrence of the first confirmed probe or bite on the treated arm.

The PE score (Table 2) records the number of mosquitos probing or biting the treated arm compared simultaneously with the untreated (control) arm, during a 60-second exposure, between hourly intervals throughout the test, for up to eight hours or until the product no longer provides 50% protection — at which point the test ends.

Importantly, the repellent effect has been shown to be reproducible across all of the major sub-species of mosquito that are vectors for disease. Supportive data generated by external laboratories confirms the efficacy against Anopheles (malaria), Culex (West Nile virus) and Aedes (dengue, yellow fever, Zika virus, chikungunya). Looking beyond the public health threat posed by mosquitoes, PMD also displays a broad spectrum repellent effect against other biting insects and nuisance species such as ticks, mites, bed bugs, head lice and wasps.

Formulating water-based product from a PMDRBO derived from Eucalyptus citriodora feedstock

The main challenge in formulating a water-based product from a PMDRBO derived from Eucalyptus citriodora feedstock, has been the crystalline nature of the product. At room temperature the product is semi solid – typically a dual phase mixture of a crystalline solid (PMD) and a variable liquid fraction, which can be anything between 30-100% of the total mixture.

The crystalline phase can be easily reconstituted by warming (typically at temperature > 50 C) to give a homogenous liquid that can then (with care) be taken up in the solvating medium (typically ethanol, mixtures of ethanol and water or other polar solvents e.g. dipropylene glycol, isopropyl myristate, benzyl acetate). These PMD solutions can then be delivered through LPG aerosol or pump spray, using suitable solvent resistant packaging media and closures (typically aluminium).

Producing a stable, water-based product without solvents, that can also be cold processed, is less straightforward. Having first homogenised the active, the emulsification step produces a supersaturated PMDRBO (oil) phase that will inevitably begin to recrystalise at ambient temperature and below.

Polar solvents, like those previously mentioned, are the most suitable for preventing that re-crystallisation by keeping the PMD component of the oil solubilised. However, the polarity of these solvents imparts a degree of water miscibility and solvated PMD can be translocated across the weak phase boundary, leading to seeding and crystal ripening within the aqueous phase. The unwanted consequence of this being a blockage of the spray nozzle and non-uniform PMD concentration through the body of the formulation.

This effect can be countered through the modification of the solvating medium with less polar, hydrocarbon solvents, creating a phase boundary with higher surface potential.

For effective long-term storage stability, this boundary has then to be stabilised, typically with higher molecular weight, polymeric materials such as PVOH/PVA copolymer, used in conjunction with the primary emulsifying surfactant and a water soluble thickener.

The emulsion concentrate (EW) so produced comprises a carefully balanced mixture of active, solvents, surfactant(s), emulsion stabiliser(s), thickener and water.

Consequently, the space remaining within the formulation for the active ingredient itself is necessarily reduced – with implications for the overall efficacy of the formulation, given the proportional relationship between active ingredient loading (% PMD content) and CP and PE scores (Figures 2 and 3).

The second generation, Cosmos Certified, PMDRBO based on refined Java Citronella oil (Fractionated Cymbopogon winterianus) presents opportunities for a much simpler, cold process alternative, with lower material cost and no requirement for co-solvents.

Citrepel 75 in its pure form, is itself a homogenous liquid at ambient temperature with low viscosity, very low odour and high PMD content (typically 75 % w/w). The liquid PMDRBO can be premixed, without warming, with emulsifier and water soluble gum and then added directly to water at room temperature under normal agitation, with mixing time between 15 and 20 minutes.

The emulsified oil phase is stable, not prone to crystallisation and a variety of formulation types are possible, with PMD content up to 35 % and above, to give continuous protection in the most extreme conditions.

This 20% Citrepel 75 emulsion has been evaluated in a three-year GLP stability study (for submission within the BPR dossier) and was found to physically and chemically stable throughout the three-year period.

The emulsion is also self-preserving due to the inherent biocidal properties of PMD. Independent challenge test results on high water formulations (5% C75 emulsion) indicate that the emulsion does not require preservatives. Details of challenge test results are available on request.

The homogenous nature of the active material with low propensity for crystallisation of PMD, also lends itself to various encapsulation techniques that are being used to extend the useful protection times of skin applied repellents through the controlled release of PMD and can also be employed in the impregnation of (outdoor) fabrics, e.g. mosquito nets and tents.

The Java citronella oil used as the essential oil feedstock for the Citrepel 75, PMD based active, is extracted from the Java Citronella plant using simple wood-fired steam distillation — often at the farm itself, with minimal capital equipment cost on apparatus built and operated by the farmers themselves (Figure 4).

Waste from the distillation can be used for several purposes — compost, animal feed, plant growth media or fuel for the distillation

The extracted oil is taken from the farms in re-usable containers to centralised, local collection points and transported for further processing at a nearby refining facility. The fractionation of the oil is fuelled by sustainable timber and waste material from timber processing.

The fractionation of Citronella oil produces the refined feedstock oil, enriched to a consistently high, controllable level of Citronellal – the pre-cursor for PMD. Other fractions unsuitable for PMD production are rich in Geraniol and can be used as natural alternatives to synthetic Geraniol in scents for detergents and personal care products. The ashes from the wood fired furnace are then used in fertiliser for the future crops.

Citronella oil is a key product in Indonesia’s essential oil industry and is particularly popular among farmers due to its relatively easy cultivation compared to other essential oil-bearing plants.

The fast-growing perennial Cymbopogon winterianus crop can grow in poor or marginal land up to 700 metres, providing hillside farmers with good income from commercial crops, all year round and flexible land use – something that can be a driver for eco— preservation projects in other developing countries, e.g. the reduction of deforestation.

The Indonesian Essential Oil Council has been actively promoting Circular Economy practices in recent years. This initiative aims to enhance sustainability within the industry — the purpose of this to maximize the use of resources by minimizing waste and reusing or upcycling materials.

Conclusion

In summary, second-generation PMDRBO-based insect repellent actives, derived from renewable, ethically sourced and sustainable feedstocks are offering insect repellent producers a highly consistent, cost effective, COSMOS-certified raw material that is a clinically proven alternative to all of the established synthetic materials available today.

The ease of cold process formulation in water-based, solvent-free systems is adding an additional dimension to natural repellent offerings in terms of safety in use for infants and customers with sensitive skin and the green (sustainable) packaging options available to manufacturers and brand owners.