2. Synthetic repellents

care, and spiritual enhancement and in literally all aspects of their daily life [1]. Insect-repellent plants have been applied traditionally for thousands of years through different civilizations [11]. Such plants were used in various forms such as hanged bruised plants in houses, crude fumigants where plants were burnt to drive away mosquitoes, and oil formulations applied to the skin or clothes [12]. Smoke is undoubtedly the most extensively exploited means of repelling mosquitoes, typically by burning plants in rural tropics and by utilizing spiral-shaped incenses like Katori Senk—an archetypal icon of the humid Japanese summers [13].

Mosquitoes have been considered as a major obstacle to the tourism industry and socioeconomic development of developing countries particularly in the tropical and endemic regions [14]. Mosquito problems are ancient as old as the pyramids, and the presence of malaria in Egypt from circa 800 BCE onward has been confirmed using DNA-based methods, and antigens produced by Plasmodium falciparum leading to tertian fever in mummies from all periods were detected, and all mummies were suffering from malaria at the time of their death [1]. Herodotus noted down that the builders of the Egyptian pyramids (circa 2700–1700 BCE) were given large amounts of garlic almost certainly to protect them against malaria [1]. Despite recent considerable efforts to control vector-borne diseases, malaria alone produces 250 million cases per year and 800,000 deaths including 85% of children under 5 years [15]. Global warming has moved the mosquitoes on the way to some temperate and higher altitudes, affecting people who are vulnerable to such diseases [16]. Recently, malaria is a great problem in Africa, but it was well controlled in Egypt [1]. Ahead of the development and commercial success of synthetic insecticides in the mid-1930–1950s, botanical insecticides were the leading weapons for insect control. Synthetic insecticides are distinguished by their efficacy, speed of action, ease of use, and low cost. Therefore, they drove many natural control methods as botanicals, predators, and parasitoids to shadows [8, 17, 18]. Insecticidal treatment of house walls, in particular, could provide a very helpful reduction of mosquito incidence, but such measures need financial and organizational demand, but poor rural areas in endemic regions do not have sufficient resources for such costly protective measures. Because of health and environmental concerns [8, 17], there is an urgent need to identify new nonhazardous vector management strategies that replace harmful chemical insecticides and repellents. There are no vaccines or other specific treatments for arboviruses transmitted by mosquitoes; therefore, avoidance of mosquito bites remains the first line of defense [9, 18]. Hence, the use of the mosquito repellents (MRs) on exposed skin area is highly recommended. Insect repellents usually work by providing a vapor barrier deterring mosquitoes from meeting the skin surface. Insect repellents had been used for thousands of years against biting arthropods. Several species of primates were observed anointing their pelage via rubbing millipedes and plants as Citrus spp., Piper marginatum, and Clematis dioica. Wedge-capped capuchins (Cebus olivaceus) were observed rubbing the millipede Orthoporus dorsovittatus onto their coat during the period of maximum mosquito activity [19]. Such millipede contains benzoquinones and insect-repellent chemicals, and it was hypothesized that the anointing behavior was intended to deter biting insects. Laboratory studies revealed a significant repellent effect of benzoquinones against Aedes (Stegomyia) aegypti (the yellow fever mosquito) and Amblyomma americanum (the lone star tick). Such anointing behavior to deter blood-feeding arthropods is also common among birds, and it could be genetically expressed as an "extended phenotype" as it has an obvious adaptive advantage. Evidence for this lies in the fact that benzoquinones applied to filter paper elicited anointing activity among captive-born capuchins [12]. The World Health Organization (WHO) also recommends repellents for protection against malaria as the resistance of Plasmodium falciparum to anti-malarial drugs

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Malaria

The history of synthetic repellents had been reviewed [12]; before World War II, MRs were primarily plant-based with the oil of citronella being the most widely used compound and the standard against which others were evaluated. At that time, the emergence of synthetic chemical repellents starts. There were only three principal repellents: dimethylphthalate discovered in 1929, Indalone® (butyl-3,3 dihydro-2,2-dimethyl-4-oxo-2H-pyran-6-carboxylate) patented in 1937, and Rutgers 612 (ethyl hexanediol), which became available in 1939. Later on and for military use, 6-2-2 of M-250 (a mixture of six parts DMP and two parts each Indalone® and Rutgers 612) was used [13]. The event of World War II was the primary switch on in the development of new repellent technologies because the Pacific and North African theaters posed significant disease threats to allied military personnel. Over 6000 chemicals had been tested from 1942 to 1947 in a variety of research institutions led to the identification of multiple successful repellent chemistries. Such great aim established several independent research projects that inevitably identified one of the most effective and widely used insect repellents to date, DEET. From then on, several compounds have been synthesized relying on previous research, which identified amide and imide compounds as highly successful contact repellents. Among these are picaridin, a piperidine carboxylate ester, and IR3535, which are currently considered DEET competitors in some repellency bioassays [21]. The chemical structures of some synthetic repellents are shown in Figure 1.

### 2.1 DEET

DEET (N,N-diethyl-3-methylbenzamide) is the standard and most effective broad-spectrum insect-repellent component with a long-lasting effect on mosquitoes, ticks, as well as biting flies, chiggers, and fleas. DEET was discovered as a mosquito repellent by the US Department of Agriculture and patented by the US Army in 1946. It was allowed for public use in 1957, and since then it has been a standard repellent for several insects and arthropods [14]. DEET is the most studied insect repellent and mainly used as a positive control to compare the efficacy of many repellent substances. DEET has a dose-dependent response: the higher the concentration, the longer the protection. DEET, 20–25%, is the conventional concentration used in commercial products. The shorter protection time depended on the mixture as well [14]. In fact, DEET plays a limited role on

#### Malaria

2.4 DEPA

2.5 Insect repellent 3535

2.6 Ethyl anthranilate

ent mosquito species [34].

149

2.7 Comparative efficacy of synthetic repellents

N,N-diethyl-2-phenyl-acetamide (DEPA) is a repellent developed around the same time as DEET and repels a wide range of insects, but DEPA did not get its reputation. The repellency of DEPA has demonstrated almost similar to DEET against mosquito vectors as Ae. aegypti, Ae. albopictus, An. stephensi, and C. quinquefasciatus [13]. It has regained interest recently and could prove to be an important competitor to DEET especially in developing countries due to its low

Learning from nature offered a molecule with an impressive performance in comparison to a natural and pure synthetic repellent solution called insect repellent 3535 (IR3535). Scientists got inspirations from nature for the development of the topical IR 3535 with the intention to create a molecule with optimized protection times and low toxicity. The naturally occurring amino acid β-alanine was used as a basic module, and the selected end groups were chosen to avoid toxicity and increase efficacy. IR 3535 was developed by Merck in 1970 and thus named as Merck IR3535; it has been available in Europe, but it was not available in the USA until 1999 [12]. IR3535 is used for humans and animals, as it is effective against mosquitoes, ticks, flies, fleas, and lice. Its chemical formula is C11H21NO3, and its other names are ethyl-N-acetyl-N-butyl-β-alaninate, ethyl butylacetylaminopropionate (EBAAP), β-alanine, and N-acetyl-N-butyl-ethyl ester. The protection of IR 3535 may be comparable to DEET, but it requires frequent reapplication in every 6–8 h. IR3535 is found in products including Skin So Soft Bug Guard Plus Expedition (Avon, New York, NY) [31]. Although 20% IR 3535 provides complete protection against Aedes and Culex mosquitoes (up to 7–10 h), it offers lesser protection against Anopheles (about 3.8 h), which affects its application in malaria-endemic areas [13]. Several field studies were identified and indicated that IR 3535 is as effective as similarly, DEET in repelling mosquitoes of the Aedes and Culex genera but may be less effective than DEET in repelling anopheline mosquitoes; an uncontrolled field study of a controlled release formulation of IR 3535 reported that these formulations may provide complete protection against mosquito biting for 7.1–10.3 h [32].

Ethyl anthranilate (EA) is a new member in the scope of entomology which drew a significant attention in repellent research in the recent years and is being considered as an improved alternative to DEET [13, 33]. It is a nontoxic, the US FDA approved volatile food additive. EA is novel and repellent against Ae. aegypti, An. stephensi, and Cx. quinquefasciatus as its ED50 values of EA were 0.96, 5.4, and 3.6% w/v, respectively, and CPTs of EA, 10% w/v, throughout the arm-in-cage method were 60, 60, and 30 min, respectively. Moreover, its spatial repellency was found to be extremely effective in repelling all the three tested species of mosquitoes. EA provided comparable results to standard repellent DEPA. As a result, the repellent activity of EA is promising for developing effective, safe, and eco-friendly alternative to the existing harmful repellents for personal protection against differ-

The comparative efficacy of synthetic repellents had been summarized [14] as follows: Aedes species demonstrated an aggressive biting behavior and Ae. Aegypti,

cost, \$25.40 per kg compared to \$48.40 per kg for DEET [30].

Commercial Mosquito Repellents and Their Safety Concerns

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

Figure 1. Chemical structures of some synthetic repellents.

disease control in endemic regions because of its high cost, unpleasant odor, and inconvenience of the continuous application on the exposed skin at high concentrations [22, 23].

#### 2.2 Permethrin

Permethrin is a pyrethroid insecticide derived from the plant Chrysanthemum cinerariifolium. It was registered in the US in 1979 as both repellent and insecticide. Recently, it is the most common insecticide available for use on fabrics such as clothing, bed nets, etc. for its exclusive role as a contact insecticide via neural toxicity and equally as an insect repellent [7, 8, 13, 17]. The protection offered against a broad range of bloodsucking arthropods with negligible safety concerns ranked permethrin-treated clothing an important arthropod protection technique especially when used in combination with other protection strategies as applying topical repellents [13].

#### 2.3 Picaridin

Picaridin (1-piperidinecarboxylic acid 2-(2-hydroxyethyl)-1-methylpropylester) is a colorless, nearly odorless piperidine analog that was developed by Bayer in the 1980s through molecular modeling [12]. It is also known as KBR 3023, icaridin, hydroxyethyl isobutyl piperidine carboxylate, and sec-butyl-2-(2-hydroxyethyl) piperidine-1-carboxylate. Its trade names include Bayrepel and Saltidin, among others. Picaridin was first marketed in Europe in the 1990s and later in the US in 2005 [24, 25]. The efficacy of picaridin is as good as DEET, and notably, 20% picaridin spray was found to protect against three main mosquito vectors, Aedes, Anopheles, and Culex for about 5 h with better efficacy than that of DEET. Therefore, repeated application is required every after 4–6 h [13]. In Australia, a formulation containing 19.2% picaridin provided similar protection as 20% DEET against Verrallina lineata [26]. The same formulation provided >95% protection against Culex annulirostris for 5 h but only 1-hour protection against Anopheles spp. [26]. Picaridin at concentrations of 2–13% v/v in 90% ethanol showed better protection against anophelines in Africa than comparable formulations containing DEET [27]. Field studies against mosquitoes in two locations in Australia indicated that a 9.3% formulation only provided 2-hour protection against V. lineata [26, 28]. It had been concluded that studies showed little significant difference between DEET and picaridin when applied at the same dosage, with a superior persistence for picaridin [29]. To maintain effectiveness than with the higher concentrations (>20%) of picaridin used in the field.

Commercial Mosquito Repellents and Their Safety Concerns DOI: http://dx.doi.org/10.5772/intechopen.87436

### 2.4 DEPA

disease control in endemic regions because of its high cost, unpleasant odor, and inconvenience of the continuous application on the exposed skin at high concen-

Permethrin is a pyrethroid insecticide derived from the plant Chrysanthemum cinerariifolium. It was registered in the US in 1979 as both repellent and insecticide. Recently, it is the most common insecticide available for use on fabrics such as clothing, bed nets, etc. for its exclusive role as a contact insecticide via neural toxicity and equally as an insect repellent [7, 8, 13, 17]. The protection offered against a broad range of bloodsucking arthropods with negligible safety concerns ranked permethrin-treated clothing an important arthropod protection technique especially when used in combination with other protection strategies as applying

Picaridin (1-piperidinecarboxylic acid 2-(2-hydroxyethyl)-1-methylpropylester) is a colorless, nearly odorless piperidine analog that was developed by Bayer in the 1980s through molecular modeling [12]. It is also known as KBR 3023, icaridin, hydroxyethyl isobutyl piperidine carboxylate, and sec-butyl-2-(2-hydroxyethyl) piperidine-1-carboxylate. Its trade names include Bayrepel and Saltidin, among others. Picaridin was first marketed in Europe in the 1990s and later in the US in 2005 [24, 25]. The efficacy of picaridin is as good as DEET, and notably, 20% picaridin spray was found to protect against three main mosquito vectors, Aedes, Anopheles, and Culex for about 5 h with better efficacy than that of DEET. Therefore, repeated application is required every after 4–6 h [13]. In Australia, a formulation containing 19.2% picaridin provided similar protection as 20% DEET against Verrallina lineata [26]. The same formulation provided >95% protection against Culex annulirostris for 5 h but only 1-hour protection against Anopheles spp. [26]. Picaridin at concentrations of 2–13% v/v in 90% ethanol showed better protection against anophelines in Africa than comparable formulations containing DEET [27]. Field studies against mosquitoes in two locations in Australia indicated that a 9.3% formulation only provided 2-hour protection against V. lineata [26, 28]. It had been concluded that studies showed little significant difference between DEET and picaridin when applied at the same dosage, with a superior persistence for picaridin [29]. To maintain effectiveness than with the higher concentrations

trations [22, 23].

Chemical structures of some synthetic repellents.

Figure 1.

Malaria

2.2 Permethrin

topical repellents [13].

(>20%) of picaridin used in the field.

148

2.3 Picaridin

N,N-diethyl-2-phenyl-acetamide (DEPA) is a repellent developed around the same time as DEET and repels a wide range of insects, but DEPA did not get its reputation. The repellency of DEPA has demonstrated almost similar to DEET against mosquito vectors as Ae. aegypti, Ae. albopictus, An. stephensi, and C. quinquefasciatus [13]. It has regained interest recently and could prove to be an important competitor to DEET especially in developing countries due to its low cost, \$25.40 per kg compared to \$48.40 per kg for DEET [30].

#### 2.5 Insect repellent 3535

Learning from nature offered a molecule with an impressive performance in comparison to a natural and pure synthetic repellent solution called insect repellent 3535 (IR3535). Scientists got inspirations from nature for the development of the topical IR 3535 with the intention to create a molecule with optimized protection times and low toxicity. The naturally occurring amino acid β-alanine was used as a basic module, and the selected end groups were chosen to avoid toxicity and increase efficacy. IR 3535 was developed by Merck in 1970 and thus named as Merck IR3535; it has been available in Europe, but it was not available in the USA until 1999 [12]. IR3535 is used for humans and animals, as it is effective against mosquitoes, ticks, flies, fleas, and lice. Its chemical formula is C11H21NO3, and its other names are ethyl-N-acetyl-N-butyl-β-alaninate, ethyl butylacetylaminopropionate (EBAAP), β-alanine, and N-acetyl-N-butyl-ethyl ester. The protection of IR 3535 may be comparable to DEET, but it requires frequent reapplication in every 6–8 h. IR3535 is found in products including Skin So Soft Bug Guard Plus Expedition (Avon, New York, NY) [31]. Although 20% IR 3535 provides complete protection against Aedes and Culex mosquitoes (up to 7–10 h), it offers lesser protection against Anopheles (about 3.8 h), which affects its application in malaria-endemic areas [13]. Several field studies were identified and indicated that IR 3535 is as effective as similarly, DEET in repelling mosquitoes of the Aedes and Culex genera but may be less effective than DEET in repelling anopheline mosquitoes; an uncontrolled field study of a controlled release formulation of IR 3535 reported that these formulations may provide complete protection against mosquito biting for 7.1–10.3 h [32].

#### 2.6 Ethyl anthranilate

Ethyl anthranilate (EA) is a new member in the scope of entomology which drew a significant attention in repellent research in the recent years and is being considered as an improved alternative to DEET [13, 33]. It is a nontoxic, the US FDA approved volatile food additive. EA is novel and repellent against Ae. aegypti, An. stephensi, and Cx. quinquefasciatus as its ED50 values of EA were 0.96, 5.4, and 3.6% w/v, respectively, and CPTs of EA, 10% w/v, throughout the arm-in-cage method were 60, 60, and 30 min, respectively. Moreover, its spatial repellency was found to be extremely effective in repelling all the three tested species of mosquitoes. EA provided comparable results to standard repellent DEPA. As a result, the repellent activity of EA is promising for developing effective, safe, and eco-friendly alternative to the existing harmful repellents for personal protection against different mosquito species [34].

#### 2.7 Comparative efficacy of synthetic repellents

The comparative efficacy of synthetic repellents had been summarized [14] as follows: Aedes species demonstrated an aggressive biting behavior and Ae. Aegypti, 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, 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 vectors at the travelers' destination.

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

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

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

shown in Figure 2.

Figure 2.

151

3.1 PMD and lemon-scented eucalyptus

Commercial Mosquito Repellents and Their Safety Concerns

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

tend to evaporate rapidly after skin application [7, 8, 14].

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