3. Botanicals

Nature is an old unlimited source of inspiration for people [1, 11, 18, 35] as well as for scientific and technological innovations. Recently, global attention has been paid toward exploring the medicinal benefits of plant extracts [4, 11, 36, 37]. Repellents of natural origin are derived from members of the families as Asteraceae, Cupressaceae, Labiatae, Lamiaceae, Lauraceae, Meliaceae, Myrtaceae, Piperaceae, Poaceae, Rutaceae, Umbelliferae, and Zingiberaceae. They have been evaluated for repellency against various mosquito vectors, but few compounds have been found commercially. Increased curiosity in plant-based arthropod repellents was generated after the United States Environmental Protection Agency (US EPA) added a rule to the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) in 1986 exempting compounds considered to be minimum hazardous pesticides [30]. Increased interest has also been driven by the rapid registration process of plantbased repellents by US EPA, which are often registered in less than a year, while the conventional pesticides are registered in an average of 3 years [30]. The public considers botanicals as safer and suitable alternative repellents; most of them are produced and distributed locally and appear on the market for only a short time. Even though many studies have shown that almost all registered commercial products based on botanical active ingredients offer limited protection and require frequent reapplication than even a low concentration of DEET-based repellents, the growing demand for natural alternative repellents in the community illustrates further need to evaluate new botanical repellents critically for personal protection against mosquitoes and mosquito-borne illnesses [7, 8, 13, 17]. The repellent activity of EOs includes some metabolites, such as the monoterpenes α-pinene, cineole, eugenol, limonene, terpinolene, citronellol, citronellal, camphor, and thymol that are repellents against mosquitoes; the sesquiterpene, β-caryophyllene, is repellent against A. aegypti, and phytol, a linear diterpene alcohol, is repellent against Anopheles gambia. Most of the arthropod-repellent compounds are oxygenated, having the hydroxyl group linked to a primary, secondary, or aromatic carbon. In some metabolites having a hydroxyl group linked to a tertiary carbon, as linalool, α-terpineol, and limonene, the repellent activity is suppressed against A. gambiae, suggesting the likelihood that the type of carbon where the hydroxyl substitution is there modulates repellency. Most insect repellents are volatile terpenoids such as terpinen-4-ol. Other terpenoids can act as attractants. More information is widely discussed [7, 38], and chemical structures of some natural repellent compounds are shown in Figure 2.

### 3.1 PMD and lemon-scented eucalyptus

above all, proved to be tolerant to many repellent products. Ae. albopictus was easier to be repelled than Ae. aegypti. DEET is the most studied insect repellent; at higher concentrations, it presented superior efficacy against Aedes species, providing up to 10 h of protection. Although IR3535 and picaridin showed good repellency against this mosquito genus, their efficacy was on average inferior to that provided by DEET. Fewer studies have been conducted on the mosquito species Anopheles and Culex. The repellency profile against Anopheles species was similar for the four principal repellents of interest: DEET provided on average 5–11 h, IR 3535 4–10 h, picaridin 6–8 h, and Citriodora 1–12 h of protection, depending on study conditions and repellent concentration. Culex mosquitoes are easier to repel, and each repellent provided good protection against this species. DEET showed 5–14 h of protection and IR 3535 2–15 h, depending on product concentration, while the test proving the efficacy of picaridin and commercial products containing PMD was discontinued after 8 h of protection. To go over the main points, DEET remains probably the most efficient insect repellent against mosquitoes, effective against sensitive species as Culex as well as more repellent-tolerant species such as Aedes and Anopheles. Even

though fewer studies have been conducted on these non-DEET compounds,

vectors at the travelers' destination.

3. Botanicals

Malaria

150

picaridin and to some extent IR 3535 represent valid alternatives. Consequently, the choice of repellents could be adjusted somehow according to the profile of biting

Nature is an old unlimited source of inspiration for people [1, 11, 18, 35] as well as for scientific and technological innovations. Recently, global attention has been paid toward exploring the medicinal benefits of plant extracts [4, 11, 36, 37]. Repellents of natural origin are derived from members of the families as Asteraceae, Cupressaceae, Labiatae, Lamiaceae, Lauraceae, Meliaceae, Myrtaceae, Piperaceae, Poaceae, Rutaceae, Umbelliferae, and Zingiberaceae. They have been evaluated for repellency against various mosquito vectors, but few compounds have been found commercially. Increased curiosity in plant-based arthropod repellents was generated after the United States Environmental Protection Agency (US EPA) added a rule to the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) in 1986 exempting compounds considered to be minimum hazardous pesticides [30]. Increased interest has also been driven by the rapid registration process of plantbased repellents by US EPA, which are often registered in less than a year, while the conventional pesticides are registered in an average of 3 years [30]. The public considers botanicals as safer and suitable alternative repellents; most of them are produced and distributed locally and appear on the market for only a short time. Even though many studies have shown that almost all registered commercial products based on botanical active ingredients offer limited protection and require frequent reapplication than even a low concentration of DEET-based repellents, the growing demand for natural alternative repellents in the community illustrates further need to evaluate new botanical repellents critically for personal protection against mosquitoes and mosquito-borne illnesses [7, 8, 13, 17]. The repellent activity of EOs includes some metabolites, such as the monoterpenes α-pinene, cineole, eugenol, limonene, terpinolene, citronellol, citronellal, camphor, and thymol that are repellents against mosquitoes; the sesquiterpene, β-caryophyllene, is repellent against A. aegypti, and phytol, a linear diterpene alcohol, is repellent against Anopheles gambia. Most of the arthropod-repellent compounds are oxygenated, having the hydroxyl group linked to a primary, secondary, or aromatic carbon. In some metabolites having a hydroxyl group linked to a tertiary carbon, as linalool,

Compound p-menthane-3,8-diol (PMD is derived from lemon-scented eucalyptus (Eucalyptus citriodora, Myrtaceae) leaves, and its importance as a repelling agent is increasing due to its good efficacy profile as well as its natural basis. PMD is a potent and commercially available repellent discovered in the 1960s via mass screening of plants for repellent activity, for instance, lemon eucalyptus and Corymbia citriodora (Myrtaceae) formerly known as Eucalyptus maculata citriodora. Lemon eucalyptus EO contains 85% citronellal and is already used in cosmetic industries due to its fresh smell. It was discovered when the waste distillate remaining after hydro-distillation of the EO was far more effective at repelling mosquitoes than the EO itself, and it provides very high protection from a broad range of insect vectors for several hours as well [7, 39]. The EO from C. citriodora also contains active constituents like citronella, citronellol, geraniol, isopulegol, and δ-pinene which play important roles in repelling both mosquitoes and ticks. Such compounds provide short-term repellency against mosquitoes, but PMD has a longer protection time than other plant-derived compounds because it is a monoterpene with low volatility than volatile monoterpenes found in most EOs and does not tend to evaporate rapidly after skin application [7, 8, 14].

There have been attempts to commercialize and market the insecticides/repellent products containing eucalyptus oil as such or based upon them. Crude eucalyptus oil was primarily registered as an insecticide and miticide in the USA in 1948, and 29 of such compounds have been registered in the USA until the year 2007 for use as natural insecticide/insect repellent/germicide. Only four products of them

Figure 2. Chemical structures of some natural repellent compounds found in botanical species.

have been active, whereas 25 have been canceled. These include Citriodiol, Repel essential insect repellent lotion (two variants), Repel essential insect repellent pump spray, and Repel insect repellent 30 by the United Industrial Corp., USA. Some eucalyptus-based products include the following: Quwenling is successfully marketed as an insect repellent in China and provides protection against anopheles mosquitoes parallel to DEET and has exchanged the widely used synthetic repellent dimethylphthalate; Quwenling contains a mixture of PMD, citronellol, and isopulegone. Mosiguard Natural contains 50% eucalyptus oil, Buzz Away is a commercially available product in China based on citronellal, and MyggA1 Natural is based on PMD from lemon eucalyptus and is shown to repel ticks. More details are widely discussed [40].

than DEET. It repels only Cx. quinquefasciatus but does not repel Ae. aegypti, An. gambiae, Phlebotomus flies, and Glossina morsitans, which restricts the application of MJ to C. quinquefasciatus mosquitoes only. On the other hand, MJ has been found to cause aversion in a number of ticks such as nymphal I. ricinis and Hyalomma

EOs are used against insects [20, 42–50] throughout the globe. EOs are distilled from members of the Lamiaceae (mint family), Poaceae (aromatic grasses), and Pinaceae (pine and cedar family). EOs could be used for farm animal protection against nuisance flies and lice [47]. Almost all of the botanical repellents are also used for food flavoring or in the perfume industry, indicating that they are safer than DEET. The most effective oils include thyme, geraniol, peppermint, cedar, patchouli, and clove that have been found to repel malaria, filarial, and yellow fever vectors for a period of 60–180 mins. Most of these EOs are highly volatile, and this contributes to their poor longevity as mosquito repellents. As a result, repellents containing only EOs in the absence of an active ingredient such as DEET should not be recommended as repellents for use in disease-endemic areas, whereas those containing high levels of EOs could cause skin irritation, especially in the presence of sunlight [39]. Although EOs effectively repel mosquitoes as irritants, repellents, antifeedants, or maskants, unfortunately, relatively few have been commercialized, despite being widely used in candles and as topical insect repellents. Botanical, herbal, or natural-based repellents include one or several plant EOs. These oils are considered safe by the EPA at low concentrations but provide a limited duration of protection against mosquitoes (<3 h). Citronella (discussed previously) is the principal and sometimes only active ingredient in many plant-based insect repellents [7]. Eucalyptus oil is used as an antifeedant mainly against biting insects as eucalyptus-based products used on humans as insect repellent can give protection from biting insects up to 8 h depending upon the concentration of the essential oil. Such repellent activity could be extended up to 8 days when eucalyptus EOs are applied on the clothes. Eucalyptus oil (30%) can prevent mosquito bite for 2 h; however, the oil must have at least 70% cineole content [40]. On the other hand, E. citriodora EO alone showed an insufficient protection against the three main

Insect repellents containing DEET are broadly used among populations. DEET

should be used with caution as it may damage spandex, rayon, acetate, and pigmented leather and it could dissolve plastic and vinyl (e.g., eyeglass frames). Moreover, DEET damages synthetic fabrics and painted and varnished surfaces, precluding its use in bed nets and in many urban settings [51]. Being the gold standard of repellents, the safety profile of DEET is largely studied. There is an estimated 15 million people in the UK, 78 million people in the USA, and 200 million people globally that use DEET each year safely when it is applied to the skin at the correct dose indicated at the commercial preparation (in the case of it not being swallowed or rubbed into the mucous membranes). DEET has been used since 1946 with a tiny number of reported adverse effects, many of which had a history of excessive or inappropriate use of repellent. Its toxicology has been more closely

marginatum rufipes Koch, etc. [30].

Commercial Mosquito Repellents and Their Safety Concerns

DOI: http://dx.doi.org/10.5772/intechopen.87436

3.4 Essential oils

mosquito species [14].

4. Safety of repellents

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4.1 Safety of synthetic repellents

#### 3.2 Citronella

The name "Citronella" is derived from the French word "citronelle" around 1858. It was extracted to be used in perfumery and used by the Indian Army to repel mosquitoes at the beginning of the twentieth century and was then registered for commercial use in the USA in 1948. Today, citronella (5–10%) is one of the most widely used natural repellents on the market; such concentrations are lower than most other commercial repellents, whereas higher concentrations can cause skin sensitivity. Among plant-derived substances, products containing Citriodiol showed the most effective repellent profile against mosquitoes. EOs and extracts belonging to plants in the Citronella genus (Poaceae) are commonly used as ingredients of plant-based mosquito repellents, mostly Cymbopogon nardus that is sold in Europe and North America in commercial preparations [39]. Citronella contains citronellal, citronellol, geraniol, citral, α-pinene, and limonene giving an effect similar to that of DEET, but the oils rapidly evaporate causing loss of efficacy and leaving the user unprotected. Among plant-derived substances, products containing Citriodiol showed the most effective repellent profile against mosquitoes. For travelers heading to disease-endemic areas, citronella-based repellents should not be recommended, but if efficacious alternatives are prohibitively expensive or not available, the use of citronella to prevent mosquito bites may provide important protection from disease vectors. Even though citronella-based repellents only give protection from host-seeking mosquitoes for a short time (2 h), formulations could prolong such time (please see the formulation section).

#### 3.3 Neem and methyl jasmonate

The aromatic plants of the Meliaceae family which include neem, Azadirachta indica, Carapa procera, Melia azedarach, Khaya senegalensis, and Trichilia emetica contain substances of the limonoid group and insecticidal and repellent effects on insects [18]. Neem provided a protection of 98.2% for 8 h against An. darlingi. Regardless of being not approved by US EPA for use as a topical insect repellent, neem is widely advertised as a natural alternative to DEET, and it has been tested for repellency against a wide range of arthropods of medical and veterinary importance. MiteStop®, based on a neem seed extract, had a considerable repellent effect on bloodsucking mosquitoes, tabanids, ceratopogonids, simuliids, as well as licking flies [41]. Several field studies from India have shown the very high efficacy of neem-based preparations, contrasting with findings of intermediate repellency by other researchers. However, these contrasting results may be due to differing methodologies and the solvents used to carry the repellents.

Methyl jasmonate (MJ) is derived from the nonvolatile jasmonic acid and has the ultimate vapor pressure for a repellent (0.001 mmHg at 25°C) which is quite higher than DEET. It repels only Cx. quinquefasciatus but does not repel Ae. aegypti, An. gambiae, Phlebotomus flies, and Glossina morsitans, which restricts the application of MJ to C. quinquefasciatus mosquitoes only. On the other hand, MJ has been found to cause aversion in a number of ticks such as nymphal I. ricinis and Hyalomma marginatum rufipes Koch, etc. [30].
