4. Safety of repellents

### 4.1 Safety of synthetic repellents

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

scrutinized than any other repellent, and it has been deemed safe for human use, including its use on children, pregnant women, and lactating women [39]. Even though insect repellents containing DEET are safe, some side effects have been described, mainly after inappropriate use such as dermatitis, allergic reactions, neurologic and cardiovascular side effects, as well as encephalopathy in children. In addition, there are a small number of reports of systemic toxicity in adults following dermal application. The safety profile in the second and third trimester of pregnancy has been well known through inspection of very low placental cord concentrations after maternal application of DEET, but animal models do not indicate any teratogenic effects. DEET also blocks mammalian sodium and potassium ion channels contributing to the numbness of lip following the application of DEET [13]. Approval for use in young children is a controversial issue between countries, with some recommending lower concentrations, whereas others suggesting that higher strengths can be used. However, the causation between the few reported cases of encephalopathy in children and the topical use of DEET cannot be supported by a good evidence base [14, 39].

damage plastics and synthetics. In some studies, picaridin induces no adverse toxic reactions in animal studies but exhibits low toxicity and less dermatologic and olfactory irritant in other studies. Consequently, picaridin's comparable efficacy to DEET and its suitability of application and favorable toxicity profile ranked it as an attractive option and unquestionably an acceptable alternative for protection against mosquitoes and other hematophagous arthropods to control the menace of vector-borne diseases in endemic areas [13]. DEPA does not show cytotoxicity or mutagenicity [59], thereby increasing its suitability in direct skin application. It also exhibits moderate oral toxicity (mouse oral LD50 900 mg/kg) and low to moderate dermal toxicity (rabbit and female mouse LD50 of 3500 and 2200 mg/kg, respectively) [60]. Acute and subacute inhalation toxicity studies of DEPA have also been reported [61] which indicate its applicability as aerosol formulations. Indalone was an early synthetic repellent effective against both mosquitoes and ticks. It was even more effective than DEET; however, its chronic exposure induced kidney and liver damage in rodents which restricted its application [13]. EA is approved by the US FDA, WHO and European Food Safety Authority (EFSA) [62, 63]. Furthermore, EA has been listed in the "generally recognized as safe" [64] list by the Flavour and Extract Manufacturers Association (FEMA) [65]. EA does not damage synthetic fabrics, plastics, and painted and varnished surfaces which further widen the utility of EA in bed nets, cloths, and different surfaces in the endemic settings [14, 66].

Commercial Mosquito Repellents and Their Safety Concerns

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

Because many conventional pesticide products fall into disfavor with the public, botanical-based pesticides should become an increasingly popular choice as repellents. There is a perception that natural products are safer for skin application and for the environment, just because they are natural and used for a long time compared to synthetic non-biodegradable products [14]. In contrast to DEET, some natural repellents are safer than others, and plant-based repellents do not have this strictly tested safety evidence, and many botanical repellents have compounds that need to be used with caution [39]. PMD has no or very little toxicity to the environment and poses no risks to humans and animals. PMD has been developed and registered for use against public health pests and is available as a spray and lotion. Not much is known about the toxicity of eucalyptus oils; however, they have been categorized as GRAS by the US EPA. Further, the oral and acute LD50 of eucalyptus oil and cineole to rat is 4440 mg/kg body weight (BW) and 2480 mg/kg BW, respectively, making it much less toxic than pyrethrins (LD50 values 350– 500 mg/kg BW; US EPA, 1993) and even technical grade pyrethrum (LD50 value 1500 mg/kg BW) [40]. PMD is an important component of commercial repellents in the US and registered by US EPA and Canadian Pest Management Regulatory Agency in 2000 and 2002, respectively [13]. In contrary, lemon eucalyptus EO does not have US EPA registration for use as an insect repellent. PMD is the only plantbased repellent that has been advocated for use in disease-endemic areas by the Centers for Disease Control (CDC), due to its proven clinical efficacy to prevent malaria, and is considered to pose no risk to human health [39]. In 2005, the US Centers for Disease Control and Prevention made use of its influence by endorsing products containing "oil of lemon eucalyptus" (PMD), along with picaridin and DEET as the most effective repellents of mosquito vectors carrying the West Nile virus [67]. PMD provides excellent safety profile with minimal toxicity. In studies using laboratory animals, PMD demonstrated no adverse effects apart from eye irritation. It is safe for both children and adults as the toxicity of PMD is very low. However, the label indicates it should not be used on children under the age of 3 [7].

4.2 Safety of plant-based repellents

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When permethrin is impregnated appropriately in cloths and nets, toxicity fearfulness is minimal [52]. Although synthetic pyrethroids are utilized worldwide as active ingredients in MRs [15] due to their relatively low toxicity to mammals [53], inappropriate application at high doses initiates neurotoxic effects such as tremors, loss of coordination, hyperactivity, paralysis, and an increase in body temperature. Other side effects include skin and eye irritation, reproductive effects, mutagenicity, alterations in the immune system, etc. [13]. Recent studies also showed that some pyrethroids are listed as endocrine disruptors and possible carcinogens [53] and pyrethroids might cause behavioral and developmental neurotoxicity, with special concern revolving around infants and children, due to their potential exposure during a sensitive neurodevelopmental stage [54]. More evidence in the recent years indicates that pyrethroid insecticides can reduce sperm count and motility, cause deformity of the sperm head, increase the count of abnormal sperm, damage sperm DNA, induce its aneuploidy rate, affect sex hormone levels, and produce reproductive toxicity [55]. Moreover, an elevated concentration of transfluthrin in the gaseous phase during the indoor application of an electric vaporizer was detected, but they found inhalation risk of airborne transfluthrin was low. The exposure levels and potential risk of pyrethroids during the applications of other types of commonly used MRs remain unknown [53]. On the other hand, long-term exposure to pyrethroid-based MRs in indoor environments causes chronic neurotoxicity, for example, dysfunction of blood-brain barrier permeability, oxidative damage to the brain, [56] and cholinergic dysfunction which cause learning and memory deficiencies [57]. Even though ventilation through natural air exchange and conditioner dissipate of airborne pollutants, residues persisting in the air and/or on indoor surfaces could potentially cause continuous exposure to the residents.

US EPA-OPP's Biochemical Classification Committee classified IR 3535 as a biochemical in 1997, because it is functionally identical to naturally occurring betaalanine in that both repel insects, the basic molecular structure is identical, the end groups are not likely to contribute to toxicity, and it acts to control the target pest via a nontoxic mode of action [58]. No reported toxicity has been made so far against IR 3535, and it induces less irritation to mucous membranes and exhibits safer oral and dermal toxicity than DEET which makes it an attractive alternative to DEET in disease-inflicted endemic regions [13]. The ester structure of the propionate grants essential advantages because of a short metabolic degradation and quick excretion as a simple water-soluble acid [58]. Picaridin has the advantage of being odorless and non-sticky or greasy. Moreover, unlike DEET, picaridin does not

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

scrutinized than any other repellent, and it has been deemed safe for human use, including its use on children, pregnant women, and lactating women [39]. Even though insect repellents containing DEET are safe, some side effects have been described, mainly after inappropriate use such as dermatitis, allergic reactions, neurologic and cardiovascular side effects, as well as encephalopathy in children. In addition, there are a small number of reports of systemic toxicity in adults following dermal application. The safety profile in the second and third trimester of pregnancy has been well known through inspection of very low placental cord concentrations after maternal application of DEET, but animal models do not indicate any teratogenic effects. DEET also blocks mammalian sodium and potassium ion channels contributing to the numbness of lip following the application of DEET [13]. Approval for use in young children is a controversial issue between countries, with some recommending lower concentrations, whereas others suggesting that higher strengths can be used. However, the causation between the few reported cases of encephalopathy in children and the topical use of DEET cannot be supported by a

When permethrin is impregnated appropriately in cloths and nets, toxicity fearfulness is minimal [52]. Although synthetic pyrethroids are utilized worldwide as active ingredients in MRs [15] due to their relatively low toxicity to mammals [53], inappropriate application at high doses initiates neurotoxic effects such as tremors, loss of coordination, hyperactivity, paralysis, and an increase in body temperature. Other side effects include skin and eye irritation, reproductive effects, mutagenicity, alterations in the immune system, etc. [13]. Recent studies also showed that some pyrethroids are listed as endocrine disruptors and possible carcinogens [53] and pyrethroids might cause behavioral and developmental neurotoxicity, with special concern revolving around infants and children, due to their potential exposure during a sensitive neurodevelopmental stage [54]. More evidence in the recent years indicates that pyrethroid insecticides can reduce sperm count and motility, cause deformity of the sperm head, increase the count of abnormal sperm, damage sperm DNA, induce its aneuploidy rate, affect sex hormone levels, and produce reproductive toxicity [55]. Moreover, an elevated concentration of transfluthrin in the gaseous phase during the indoor application of an

electric vaporizer was detected, but they found inhalation risk of airborne

transfluthrin was low. The exposure levels and potential risk of pyrethroids during the applications of other types of commonly used MRs remain unknown [53]. On the other hand, long-term exposure to pyrethroid-based MRs in indoor environments causes chronic neurotoxicity, for example, dysfunction of blood-brain barrier permeability, oxidative damage to the brain, [56] and cholinergic dysfunction which cause learning and memory deficiencies [57]. Even though ventilation through natural air exchange and conditioner dissipate of airborne pollutants, residues persisting in the air and/or on indoor surfaces could potentially cause

US EPA-OPP's Biochemical Classification Committee classified IR 3535 as a biochemical in 1997, because it is functionally identical to naturally occurring betaalanine in that both repel insects, the basic molecular structure is identical, the end groups are not likely to contribute to toxicity, and it acts to control the target pest via a nontoxic mode of action [58]. No reported toxicity has been made so far against IR 3535, and it induces less irritation to mucous membranes and exhibits safer oral and dermal toxicity than DEET which makes it an attractive alternative to DEET in disease-inflicted endemic regions [13]. The ester structure of the propionate grants essential advantages because of a short metabolic degradation and quick excretion as a simple water-soluble acid [58]. Picaridin has the advantage of being odorless and non-sticky or greasy. Moreover, unlike DEET, picaridin does not

good evidence base [14, 39].

Malaria

continuous exposure to the residents.

154

damage plastics and synthetics. In some studies, picaridin induces no adverse toxic reactions in animal studies but exhibits low toxicity and less dermatologic and olfactory irritant in other studies. Consequently, picaridin's comparable efficacy to DEET and its suitability of application and favorable toxicity profile ranked it as an attractive option and unquestionably an acceptable alternative for protection against mosquitoes and other hematophagous arthropods to control the menace of vector-borne diseases in endemic areas [13]. DEPA does not show cytotoxicity or mutagenicity [59], thereby increasing its suitability in direct skin application. It also exhibits moderate oral toxicity (mouse oral LD50 900 mg/kg) and low to moderate dermal toxicity (rabbit and female mouse LD50 of 3500 and 2200 mg/kg, respectively) [60]. Acute and subacute inhalation toxicity studies of DEPA have also been reported [61] which indicate its applicability as aerosol formulations. Indalone was an early synthetic repellent effective against both mosquitoes and ticks. It was even more effective than DEET; however, its chronic exposure induced kidney and liver damage in rodents which restricted its application [13]. EA is approved by the US FDA, WHO and European Food Safety Authority (EFSA) [62, 63]. Furthermore, EA has been listed in the "generally recognized as safe" [64] list by the Flavour and Extract Manufacturers Association (FEMA) [65]. EA does not damage synthetic fabrics, plastics, and painted and varnished surfaces which further widen the utility of EA in bed nets, cloths, and different surfaces in the endemic settings [14, 66].
