Planta Med 2011; 77(6): 598-617
DOI: 10.1055/s-0030-1270723
Tropical Diseases
Reviews
© Georg Thieme Verlag KG Stuttgart · New York

Patent Literature on Mosquito Repellent Inventions which Contain Plant Essential Oils – A Review

Adrian Martin Pohlit1 , 3 , Norberto Peporine Lopes3 , Renata Antonaci Gama4 , Wanderli Pedro Tadei2 , Valter Ferreira de Andrade Neto4
  • 1Natural Products Department, National Institute for Amazon Research, Manaus, Brazil
  • 2Health Sciences Department, National Institute for Amazon Research, Manaus, Brazil
  • 3Department of Chemistry and Physics, College of Pharmaceutical Sciences, São Paulo University, Ribeirão Preto, Brazil
  • 4Department of Microbiology and Parasitology, Rio Grande do Norte Federal University, Natal, Brazil
Further Information

Prof. Dr. Valter Ferreira de Andrade Neto

Laboratory of Malaria and Toxoplasmosis Biology
Department of Microbiology and Parasitology
Rio Grande do Norte Federal University (UFRN)

Campus Universitário

Lagoa Nova

CEP 59072-970 Natal – RN

Brazil

Phone: + 55 84 32 15 34 37, ext. 225, 226

Fax: + 55 84 32 11 92 10

Email: [email protected]

Publication History

received July 2, 2010 revised Dec. 28, 2010

accepted January 3, 2011

Publication Date:
15 February 2011 (online)

Table of Contents #

Abstract

Bites of mosquitoes belonging to the genera Anopheles Meigen, Aedes Meigen, Culex L. and Haemagogus L. are a general nuisance and are responsible for the transmission of important tropical diseases such as malaria, hemorrhagic dengue and yellow fevers and filariasis (elephantiasis). Plants are traditional sources of mosquito repelling essential oils (EOs), glyceridic oils and repellent and synergistic chemicals. A Chemical Abstracts search on mosquito repellent inventions containing plant-derived EOs revealed 144 active patents mostly from Asia. Chinese, Japanese and Korean language patents and those of India (in English) accounted for roughly 3/4 of all patents. Since 1998 patents on EO-containing mosquito repellent inventions have almost doubled about every 4 years. In general, these patents describe repellent compositions for use in topical agents, cosmetic products, incense, fumigants, indoor and outdoor sprays, fibers, textiles among other applications. 67 EOs and 9 glyceridic oils were individually cited in at least 2 patents. Over 1/2 of all patents named just one EO. Citronella [Cymbopogon nardus (L.) Rendle, C.winterianus Jowitt ex Bor] and eucalyptus (Eucalyptus L'Hér. spp.) EOs were each cited in approximately 1/3 of all patents. Camphor [Cinnamomum camphora (L.) J. Presl], cinnamon (Cinnamomum zeylanicum Blume), clove [Syzygium aromaticum (L.) Merr. & L. M. Perry], geranium (Pelargonium graveolens L'Hér.), lavender (Lavandula angustifolia Mill.), lemon [Citrus × limon (L.) Osbeck], lemongrass [Cymbopogon citratus (DC.) Stapf] and peppermint (Mentha × piperita L.) EOs were each cited in > 10 % of patents. Repellent chemicals present in EO compositions or added as pure “natural” ingredients such as geraniol, limonene, p-menthane-3,8-diol, nepetalactone and vanillin were described in approximately 40 % of all patents. About 25 % of EO-containing inventions included or were made to be used with synthetic insect control agents having mosquito repellent properties such as pyrethroids, N,N-diethyl-m-toluamide (DEET), (±)-p-menthane-3,8-diol (PMD) and dialkyl phthalates. Synergistic effects involving one or more EOs and synthetic and/or natural components were claimed in about 10 % of all patents. Scientific literature sources provide evidence for the mosquito repellency of many of the EOs and individual chemical components found in EOs used in patented repellent inventions.

#

Introduction

#

Mosquito vectors of severe tropical diseases

Severe human tropical diseases such as malaria, dengue and yellow fevers and filariasis are transmitted by the bites of infected hematophagous female mosquitoes belonging to the genera Aedes Meigen, Anopheles Meigen, Culex L. and Haemagogus L. (Diptera: Culicidae). For example, about 3.3 billion people − 1/2 of the world's population – are at risk of contracting malaria. In 2008, there were more than 247 million cases and more than 1 million deaths caused by malaria mainly in African children [1]. Human malaria is caused by infections by unicellular protozoan parasites Plasmodium falciparum Welch, P. vivax Grassi & Feletti, P. malariae Feletti & Grassi and P. ovale Stephens which are transmitted by about 20 Anopheles spp. Another important disease is dengue hemorrhagic fever which is a viral infection caused by several Flavivirus spp. (Flaviviridae) whose most important vector is Aedes (Stegomyia) aegypti L. Dengue and dengue hemorrhagic fevers threaten an estimated 2.5 billion people − 2/5 of the world's population – and an estimated 50 million people contract the disease per year. Around 500 000 dengue patients, most of whom are children, require hospitalization each year and around 2.5 % of those affected die [2]. Another serious tropical disease which threatens about 1 billion people in 80 countries is filariasis or elephantiasis. This disease already affects an estimated 120 million people and severely incapacitates and deforms 40 million people worldwide. Filariasis is caused by infections by several roundworm species of which Wuchereria bancrofti Cobbold (Filariidea: Onchocercidae) is the most important and is transmitted by the bites of the common house mosquito Cx. pipiens L. complex, Cx. quinquefaciatus Say, Aedes and Anopheles spp. [3], [4]. Yellow fever is an arbovirus of the Flavivirus genus (Flaviviridae) which is transmitted from monkeys in the jungle to humans and then from human to human by mosquitoes. The most significant yellow fever mosquito vector is Ae. aegypti. Despite the existence of effective vaccines, there are an estimated 200 000 cases of yellow fever and approximately 30 000 deaths attributed to this disease each year [5]. In public health initiatives which aim to limit or eradicate these and other tropical diseases, mosquito vector control methods such as repellence figure prominently among those which are employed.

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Synthetic mosquito repellents DEET and alkyl phthalates

For more than 50 years, the synthetic compound DEET (N,N-diethyl-m-toluamide), has been the most effective single repellent for mosquito species and is the basis for many commercial repellent products on the market. Despite reports of severe toxic properties which can dramatically affect adults and especially young children including dermatitis, allergic reactions, neurological (seizures, coma) and cardiovascular toxicity, the risk of serious toxic effects from DEET is considered slight. Nevertheless, DEET should always be used at the lowest effective dose possible. Also, dimethyl and di-n-butyl phthalates (DMP and DBP, respectively), which are effective mosquito repellents and were widely used in the last century, are no longer generally recommended for use as mosquito repellents due to their toxicity [6].

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Plants as sources of mosquito control agents

Plants have historically been valuable sources of agents for the control of insects [3], [7]. They are the sources of the natural insecticidal and larvicidal substances nicotine (Nicotiana L. spp.), quassin (Quassia amara L.), rotenone and rotenoids (Derris Lour. spp. and Lonchocarpus Kunth spp. roots), pyrethrins like chrysanthamic acid and its derivatives present in pyrethrum [extracts of Chrysanthemum cinerariifolium (Trevir.) Vis. flowers] and azadirachtin (Azadirachta indica A. Juss. seed kernel). These and other natural insect control agents have served as the basis for the development of the structurally-related synthetic pyrethroid, nicotinoid and rotenoid classes of insecticides and piperonyl butoxide synergist. Also, pyrethroids and piperonyl butoxide synergism are the basis for a number of commercially available mosquito control products in use today [3].

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Botanical repellents

Citronella essential oils (EOs) are obtained mainly from varieties of Cymbopogon nardus (L.) Rendle (Ceylon citronella) and C. winterianus Jowitt ex Bor (Java citronella). They have been used in mosquito repellency for more than a century in much of the world and are the most widely used natural repellents today [3]. Also, EOs of Eucalyptus L'Hér. spp. are widely used to repel insects, including mosquitoes, and contain insecticidal and repellent components p-menthane-3,8-diol (PMD), 1,8-cineole, α-pinene, p-cymene and γ-terpinene among other active compounds [8]. According to a recent review of the scientific literature, the most frequently studied repellent EOs are those obtained from species belonging to the genera Cymbopogon Spreng., Ocimum L. and Eucalyptus L'Hér. spp. and a number of mosquito repellent EOs have been identified in recent years having known active repellent chemical components [7]. Mosquito repellency is believed to be due to the synergistic interactions of the chemical components in EOs. Furthermore, strong synergistic effects between EOs and isolated natural or synthetic substances have been reported [7].

The United States Environmental Protection Agency [9] has registered citronella EO, eucalyptus EO and other plant oils as safe and effective ingredients for use in topical insect repellents. However, caution is recommended in the use of EOs in general due to a number of potential toxic effects [7]. Among the important toxic effects of EOs are mutagenicity and genotoxicity. Another toxic effect is the allergenicity of EO chemical components which are controlled in the European Community and elsewhere. Interestingly, a number of repellent and insecticidal plant EOs and their chemical constituents have been evaluated using a variety of methods and are believed to be non-mutagenic [10].

A number of commercial repellent products have been developed over the past decades which utilize derivatives of plants such as EOs, fractions and their isolated chemical components and synthetic components. Thus, it is important to have a comprehensive knowledge of the commercially significant uses of EOs in mosquito repellent inventions and to the best of our knowledge the patent literature on this topic has not been reviewed. The aim of the present review is to explore and analyze patent literature on mosquito repellent inventions which make use of or are based wholly on plant EOs and/or their chemical components. A secondary aim is to analyze the scientific bases and relevancy of the use of plant EOs and chemical components of these oils in patented mosquito repellent formulations.

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Chemical Abstracts Search Criteria

A Chemical Abstracts search of the patent literature for the period of 1991 through May, 2010 was performed using SciFinder Scholar® [11]. Combinations of the key words “repellent”, “mosquito” and “essential oil” generated an initial set of approximately 160 patents. This set was further refined. Patents describing mosquitocidal/larvicidal inventions, but having no stated claim or use as mosquito repellents were eliminated. Also, patented mosquito repellent inventions which did not make use of at least one commercially-obtained, plant-derived oil [a volatile (essential) oil, a concrete, or a pressed oil] or which did not describe the preparation of an EO by physical means for use within the patent were eliminated. This approach eliminated patents presenting solvent extraction performed on mixtures of several plant materials followed, for example, by distillation and evaporation as a means of obtaining the mosquito repellent invention. Also, by this criterion, incense and other smoke-generating inventions made from mosquito repellent plants but having no (added) EO in the composition were eliminated. Applying the above criteria led to a data set of 144 patents describing plant oil-containing mosquito repellent inventions which was the basis for the analysis presented below.

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Patenting Countries and Patent Families: Trends

The contribution of China, Japan, Korea and India to the overall number of patented EO-containing mosquito repellent inventions is significant. These countries accounted for, respectively, 37, 15, 13 and 8 % (73 %) of all patents ([Fig. 1]). An interesting trend is that all 53 Chinese, 17 of 18 Korean, 20 of 22 Japanese and 9 of 11 Indian patents have only been deposited in their countries of origin and in general have not been followed-up by later patents. Also, all Belgian, Brazilian, German and Polish patents followed the rule of single deposits without follow-up patents. In contrast, industrial, academic and other patents originating in Australia, Canada, the United Kingdom and the United States gave rise to larger patent families, made greater use of the World Patent System and led to deposits of patents on EO-containing repellents in multiple countries as a rule. Finally, more than 75 % of all patented repellent inventions are indexed as agrochemical bioregulators and over 80 % describe chemical compositions (often together with preparation details) ([Fig. 1]).

Zoom Image

Fig. 1 Analysis of EO-containing patented mosquito repellent inventions by patenting country, patent language, patent type and utility.

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EOs Used in Patented Mosquito Repellent Inventions

Plant taxonomic information [12], extraction methods, chemical composition, literature sources [8], [10], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86], [87], [88], [89], [90], [91], [92], [93], [94], [95], [96], [97], [98], [99], [100], [101], [102], [103], [104], [105], [106], [107], [108], [109], [110], [111], [112], [113], [114], [115] and frequency of use for 67 EOs and 9 glyceridic oils which were individually cited in at least 2 (1.4 %) of the total number of patents are presented in [Table 1]. Approximately 60 % of all patents named just one plant EO. One patent claimed to use up to 44 plant oils in formulations. Citronella (34.7 %) and eucalyptus (30.6 %) EOs were each named in about 1/3 of all patented repellent inventions followed by (species, % of patents): lavender (Lavandula angustifolia Mill., 21.5 %), peppermint (Mentha × piperita L., 16.7 %), clove [Syzygium aromaticum (L.) Merr. & L. M. Perry, 15.3 %], lemongrass [Cymbopogon citratus (DC.) Stapf, 14.6 %], cinnamon (Cinnamomum zeylanicum Blume, 12.5 %), geranium (Pelargonium graveolens L'Hér., 11.8 %), camphor [Cinnamomum camphora (L.) J. Presl, 11.1 %] and lemon [Citrus × limon (L.) Osbeck, 11.1 %] EOs.

Table 1 Botanic information, extraction methods, major chemical components, literature sources and frequency (%) of use of plant essential and glyceridic oils in patented mosquito repellent inventions, 1991 – May, 2010.

Oil

Species

Family

Part

Method

Major components

Lit.

% Patents

Essential Oils

Ambrette

Abelmoschus moschatus Medik.

Malvaceae

whole seed

steam distilled

2E,6E-farnesyl acetate, Z-7-hexadecen-16-olide, β-farnesene

[13], [14]

1.4

Angelica

Angelica archangelica L.

Apiaceae

root

steam distilled

ligustilide, α & β -pinene, carvacrol, 3-carene, limonene, β-phellandrene, 15-pentadecanolide

[15], [16]

1.4

Anise

Pimpinella anisum L.

Apiaceae

fruit, seed

steam distilled

trans-anethole

[17]

4.2

Artemisia

Artemisia argyi H. Lév. & Vaniot

Asteraceae

leaf

steam distilled

germacrene D, α-phellandrene, α -myrcene, 1,8-cineole, borneol, terpinol, spathulenol

[18], [19]

4.9

Basil

Ocimum basilicum L.

Lamiaceae

leaf, flower top

steam distilled

estragole, limonene, fenchone, linalool, eugenol E-methyl cinnamate, 1,8-cineole

[20], [21], [22]

4.9

Bay laurel

Laurus nobilis L.

Lauraceae

leaf

steam distilled

1,8-cineole, sabinene, α-terpinyl acetate, linalool

[23], [24]

1.4

Bergamot

Citrus × bergamia Risso

Rutaceae

fresh or dried peel

pressed

limonene, linalyl acetate, β –pinene, γ -terpinene, linalool

[24]

1.4

Camphor

Cinnamomum camphora (L.) J. Presl

Lauraceae

wood, bark, leaf

steam distilled

1,8-cineole, α -terpineol, α -pinene, linalool, camphor, sabinene

[10]

11.1

Cassia

Cinnamomum cassia (L.) C. Presl

Lauraceae

leaf, bark, stalk

steam distilled

bark: E -cinnamaldehyde, methyl o -salicylate; leaf: 3-methoxy-1,2-propanediol, E -cinnamaldehyde, o-methoxycinnamaldehyde

[25], [26]

2.1

Catnip, catmint

Nepeta cataria L.

Lamiaceae

dry leaf, stem

steam distilled

nepetalactone, 1,8-cineole, α-humulene, α-pinene, E -geraniol, β-caryophyllene, citronellol

[20], [27], [28]

4.9

Cedar

Cedrus Trew (Cupressus L., Juniperus L.) spp.

Pinaceae (Cupressaceae)

wood

steam distilled

thujopsene, eudesmol, E-(+)-α-atlantone; α,β & γ-himachalenes; α- & β-cedrenes; limonene, β-phellandrene, α & β -pinene, 3-carene; p-methyl-Δ-3-tetrahydro & p-methyl acetophenones; hinokitiol, carvacrol

[29]

9.7

Chamomile

Chamaemelum nobile (L.) All.
Matricaria recutita L.

Asteraceae

seed, leaf, flower

steam distilled

Roman: isobutyl, isoamyl & 2-methylpentyl angelates, α -pinene
German: E-β-farnesene, E,E-α-farnesene, α -bisabolol, α-bisabolol oxides A & B

[20], [28], [30]

2.1

Chrysanthemum

Chrysanthemum indicum L.

Asteraceae

dry flower

steam distilled

verbenol, 2-(2,4-hexadiynylidene)-1,6-
dioxaspiro[4.4]non-3-ene, 1,8-cineole, α -pinene, camphor, borneol, bornyl acetate

[31], [32]

2.8

Cinnamon

Cinnamomum zeylanicum Blume

Lauraceae

bark, leaf

steam distilled

eugenol, cinnamaldehyde

[25], [33], [34]

12.5

Citronella

Cymbopogon nardus (L.) Rendle, C. winterianus Jowitt ex Bor

Poaceae

leaf

steam distilled

citronellal, geraniol, citronellol, geranyl acetate

[35], [36]

34.7

Citrus

Citrus × limon (L.) Osbeck, C. × sinensis (L.) Osbeck, C. × aurantifolia L.

Rutaceae

peel

pressed, steam distilled

see orange, lemon, lime oil compositions

1.4

Clove

Syzygium aromaticum (L.) Merr. & L. M. Perry

Myrtaceae

flower bud

steam distilled

eugenol, caryophyllene, eugenyl acetate

[37]

15.3

Coriander

Coriandrum sativum L.

Apiaceae

fruit, seed

steam distilled

linalool, geraniol, geranyl acetate, 2-decenal, 3-dodecenal

[20], [38], [39]

2.1

Cypress

Cupressus sempervirens L.

Cupressaceae

needle, twig

steam distilled

sabinene, α -pinene, terpinen-4-ol, limonene

[40], [41]

4.2

Dill

Anethum graveolens L.

Apiaceae

seed, leaf, stem

steam distilled

carvone, limonene, α-phellandrene, α -pinene, cis-dihydrocarvone

[42], [43]

1.4

Eucalyptus

Eucalyptus L'Hér. spp.

Myrtaceae

leaf

steam distilled

1,8-cineole, p -menthane-3,8-diol, α -pinene, p -cymene, γ -terpinene, eucamalol, allo-ocimene, citronellol, α -terpineol

[8]

30.6

Fennel

Foeniculum vulgare Mill.

Apiaceae

fruit

steam distilled

E-anethole, (+)-fenchone, α-phellandrene, (±)-limonene, estragole

[24]

4.9

Garlic

Allium sativum L.

Amaryllidaceae

bulb

steam distilled

diallyl disulfide, diallyl trisulfide, methyl allyl trisulfide

[44], [45]

6.3

Geranium

Pelargonium graveolens L'Hér.

Geraniaceae

leaf, stem

steam distilled

2-phenylethanol, geraniol, citronellol, geranyl acetate

[46]

11.8

Ginger

Zingiber officinale Roscoe

Zingiberaceae

rhizome

steam distilled

geranial, α-zingiberene, E,E-α-farnesene, neral, ar-curcumene, geraniol

[47], [48]

1.4

Grapefruit

Citrus reticulata Blanco

Rutaceae

peel

pressed

limonene, geranial, neral

[49]

2.1

Guaiac wood

Bulnesia sarmientoi Lorentz ex Griseb.

Zygophyllaceae

wood

steam distilled

bulnesol, guaiol, α-bulnesene

[50]

1.4

Hiba

Thujopsis dolabrata (Thunb. ex L. f.) Siebold & Zucc.

Cupressaceae

wood

steam distilled

sabinene, 4-terpineol, thujopsene, hinokitiol, α-thujaplicine, carvacrol

[51], [52], [53]

2.1

Ho leaf

Cinnamomum camphora (L.) J. Presl

Lauraceae

leaf

steam distilled

1,8-cineole, α -terpineol, linalool, camphor, safrole, sabinene, nerolidol

[10], [54], [55]

1.4

Hyssop

Hyssopus officinalis L.

Lamiaceae

leaf, flower

steam distilled

sabinene, pinocamphene, isopinocamphene, isopinocamphone, pinocarvone, cis &  trans-pinocamphones, β -pinene, 1,8-cineole, camphor, linalool

[56], [57], [58]

1.4

Jasmine

Jasminum officinale L.

Oleaceae

flower

solvent extracted

linalool, benzyl acetate, methyl & benzyl benzoates, methyl anthranilate, Z-jasmone, eugenol

[59], [60]

3.5

Juniper

Juniperus communis L.

Cupressaceae

fruit

steam distilled

α -pinene, myrcene, sabinene, germacrene D

[61]

1.4

Lady-of-the-night

Cestrum nocturnum L.

Solanaceae

flower

solvent extracted, steam distilled

phenylethyl alcohol, benzyl alcohol, eugenol

[62]

2.1

Lavender

Lavandula angustifolia Mill.

Lamiaceae

flower

steam distilled

linalool, linalyl acetate, lavandulyl acetate, α -terpineol, geranyl acetate, terpinen-4-ol, 1,8-cineole

[63], [64]

21.5

Lemon

Citrus × limon (L.) Osbeck

Rutaceae

peel

pressed

limonene, β-pinene, γ-terpinene

[65]

11.1

Lemon eucalyptus

Eucalyptus citriodora Hook.

Myrtaceae

leaf, twig

steam distilled

citronellal, citronellol

[8], [66]

8.3

Lemongrass

Cymbopogon citratus (DC.) Stapf

Poaceae

leaf

steam distilled

geranial, neral, myrcene

[41]

14.6

Lemon tea tree

Leptospermum petersonii F. M. Bailey

Myrtaceae

leaf

steam distilled

neral, geranial, γ -terpinene, geraniol, geranyl acetate, α -pinene, citronellal, terpinolene

[67]

1.4

Lime

Citrus × aurantifolia L.

Rutaceae

peel

steam distilled, pressed

D-dihydrocarvone, D -limonene, α -terpineol

[68]

2.1

Manuka

Leptospermum scoparium Forst. & Forst.

Myrtaceae

leaf, stem

steam distilled

leptospermone, trans-calamenene, flavesone, 1,8-cineole, α -pinene

[69], [70]

1.4

Marjoram

Origanum majorana L.

Lamiaceae

leaf, flower

steam distilled

p -cymene, γ -terpinene, terpinen-4-ol, linalool, cis-sabinene hydrate

[71], [72]

2.1

May chang/Litsea

Litsea cubeba (Lour.) Pers.

Lauraceae

fruit

steam distilled

neral, R-(+)-limonene, geranial, citronellal

[46], [73], [74]

4.9

Melaleuca/Tea tree

Melaleuca alternifolia Cheel

Myrtaceae

leaf

steam distilled

terpinen-4-ol, γ -terpinene, α -terpinene, 1,8-cineole

[75]

9.7

Mint, mentha

Mentha L. spp.

Lamiaceae

leaf, flower

steam distilled

menthone, menthol, 1,8-cineole, 4-terpineol

[76]

9.7

Orange

Citrus × sinensis (L.) Osbeck

Rutaceae

peel

pressed

limonene, myrcene

[77]

4.2

Palmarosa

Cymbopogon martini (Roxb.) Will.Watson

Poaceae

dry leaf

steam distilled

geraniol, geranyl acetate, geranial

[78]

4.9

Parsley (Curl leaf)

Petroselinum crispum (Mill.) Fuss

Apiaceae

leaf, stem, seed

steam distilled

β-phellandrene, myristicin, α & β -pinene, myrcene

[79]

1.4

Patchouli

Pogostemon cablin (Blanco) Benth.

Lamiaceae

dry, fermented leaf

steam distilled

(−)-patchoulol, α-guaiene, seychellene, β-caryophyllene, α & β-patchoulenes, selinene, α-bulnesene, norpatchoulenol, pogostol

[80]

4.2

Pepper

Piper nigrum L.

Piperaceae

fruit

steam distilled

E-β-caryophyllene, limonene, β -pinene

[81], [82]

2.1

Peppermint

Mentha × piperita L.

Lamiaceae

aerial part

steam distilled

isomenthol, p -menthone, isomenthyl & menthyl acetates

[83], [84]

16.7

Pine

Pinus sylvestris L.

Pinaceae

twig, bud

steam distilled

3-carene, α & β -pinene, α-cadinol, camphene

[85], [86]

8.3

Rose

Rosa × damascena Mill., R. × centifolia L.

Rosaceae

petal

steam distilled, solvent extracted

2-phenethyl alcohol, citronellol, geraniol, linalool, nonadecane

[30], [87]

6.3

Rosemary

Rosmarinus officinalis L.

Lamiaceae

flower

steam distilled

verbenone, camphor, borneol, bornyl acetate, α -terpineol, terpinen-4-ol

[41], [88]

9.0

Salvia (Sage)

Salvia L. spp.

Lamiaceae

leaf, flower, aerial part

steam distilled

camphor, 1,8-cineole, α -pinene, camphene, limonene, linalool, myrcene, β-caryophyllene, caryophyllene oxide, spathulenol, viridiflorol, 3-carene, α -bisabolol, geraniol, linalyl acetate, γ-muurolene, α -thujone, manool

[89], [90], [91], [92]

1.4

Sandalwood

Santalum L. spp.

Santalaceae

heartwood

steam distilled

α, β & epi-β-santalenes; α, β & epi-β-santalals; α −santalol; spiro, β, E-β & epi-β santalols, trans-α-bergamotene, trans-α-bergamotol

[80], [93]

3.5

Sour (bitter) orange

Citrus × aurantium L.

Rutaceae

peel

pressed

limonene

[94]

3.5

Spearmint

Mentha spicata L.

Lamiaceae

flower

steam distilled

carvone, limonene

[95]

2.8

Star anise

Illicium verum Hook. f.

Schisandraceae

seed

steam distilled

E-anethole, 4-allylanisole

[96], [97]

see anise*

Tagetes

Tagetes minuta L.

Asteraceae

leaf, stalk, flower

steam distilled, solvent extracted

E & Z-β-ocimenes, limonene, α -terpineol, dihydrotagetenone, Z-tagetone, E &  Z-tagetenones

[98]

2.1

Tarragon

Artemisia dracunculus L.

Asteraceae

leaf, flower

steam distilled

sabinene, elemicine, methyl eugenol

[99]

1.4

Thyme

Thymus vulgaris L.

Lamiaceae

flower, leaf

steam distilled

p -cymene, geraniol, cis -thujone, thymol, carvacrol

[41]

7.6

Turmeric

Curcuma longa L.

Zingiberaceae

rhizome

steam distilled, solvent extracted

α-phellandrene, 1,8-cineole, terpinolene, zingiberene, β-sesquiphellandrene, α & β-turmerones

[41]

2.8

Verbena

Lippia triphylla (L'Hér.) Kuntze

Verbenaceae

leaf

steam distilled

geranial, neral, limonene, geraniol

[100]

1.4

Vetiver

Vetiveria zizanioides (L.) Nash

Poaceae

root

steam distilled

khusimol, isonootkatool, β-vetivenene, α & β-vetivones

[101]

2.1

Violet

Viola odorata L.

Violaceae

leaf, flower

solvent extracted

nona-2,6-dienal, cis-hex-3-en-1-ol, hexadec-1-ene, pentadec-3-enal, octadec-1-ene, hexadecanoic & octadeca-9,12-dienoic acids

[102]

1.4

Wintergreen

Gaultheria procumbens L.

Ericaceae

leaf

steam distilled

methyl salicylate

[103]

6.3

Ylang-Ylang

Cananga odorata (Lam.) Hook. f. & Thomson

Annonaceae

flower

steam distilled

linalool, benzyl acetate, benzyl benzoate, benzyl salicylate

[41]

2.8

Glyceridic Oils

Castor

Ricinus communis L.

Euphorbiaceae

seed

pressed

ricinolic, linoleic, oleic acids

[104]

4.9

Evening primrose

Oenothera biennis L.

Onagraceae

seed

pressed

linalool; palmitic, stearic, oleic, linoleic &  γ-linolenic acids

[105], [106]

1.4

Ligusticum/Chuanxiong

Ligusticum chuanxiong Hortorum ex Qiu, et al. in Qiu

Apiaceae

root

CO2 extracted

butylphthalide, 2-propenyl phenoxyacetate, 3-isobutyliden phthalide, palmitic &  octadecenoic acids

[107]

1.4

Mustard

Brassica L. spp.

Brassicaceae

seed

Pressed

erucic, oleic, linoleic, linolenic, palmitic & stearic acids

[108]

2.1

Neem

Azadirachta indica A. Juss.

Meliaceae

seed

pressed

salanin, nimbinin, nimbin, nimbidiol, azadirachtin; palmitic, stearic, oleic, linoleic acids

[104], [109]

8.3

Olive

Olea europaea L.

Oleaceae

fruit

pressed

oleic, palmitic, linoleic & stearic acids

[110]

2.1

Perilla

Perilla frutescens (L.) Britton

Lamiaceae

seed

pressed

oleic, linoleic & linolenic acids, S-limonene, perillaldehyde, elsholzia- ketone, naginataketone, perillaketone, myristicin, dillapiol, elemicin, isoegomaketone, perillene, egomaketone, shisofuran

[111], [112], [113]

1.4

Sesame

Sesamum indicum L.

Pedaliaceae

seed

pressed

linoleic, oleic, palmitic & stearic acids

[114]

3.5

Soybean

Glycine max (L.) Merr.

Fabaceae

seed

solvent extracted

linoleic, oleic, palmitic, α-linolenic & stearic acids

[115]

4.2

Note: chemical components in bold text have proven mosquito repellent and deterrent properties according to literature and patent sources which are summarized in [Table 4]). Tropicos, botanical information system at the Missouri Botanical Garden [12] was used as a general reference on taxonomic information in this table

A number of EOs were cited in only one patented repellent invention (and were not included in [Table 1]). Given the importance of potentially novel sources of mosquito repellent botanicals it is important to mention the following EOs: abies [Abies spectabilis (D. Don) Spach], almond [Prunus dulcis (Mill.) D. A.Webb], Australian yuzu (Citrus junos Siebold ex Tanaka), black pine (Pinus nigra Arnold), Blumea lacera (Burm. f.) DC., calamus (Acorus calamus L.), Canada fleabane [Conyza canadensis (L.) Cronquist], cardamom [Elettaria cardamomum (L.) Maton], cork tree (Phellodendron amurense Rupr.), Elsholtzia hunanensis Hand.-Mazz., flos lonicerae japonicae or jin yin hua (Lonicera japonica Thunb. ex Murray flower), fructus forsythiae [Forsythia suspensa (Thunb.) Vahl], galbanum (Ferula galbaniflua Boiss. & Buhse), herba schizonepetae [Schizonepeta (Benth.) Briq. sp.], hibiscus (Hibiscus L. sp.), larch (Larix Mill. sp.), lemon balm (Melissa officinalis L.), lovage (Levisticum officinale W. D. J. Koch), lilac (Syringa vulgaris L.), Limnanthes alba Hartw. ex Benth. seed, linaloe wood (Bursera delpechiana Poiss. ex Engl.), Michelia × alba DC. leaf, myrtle (Myrtus communis L.), Ocimum canum Sims, onion (Allium cepa L.), oregano (Origanum vulgare L.), peach [Prunus persica (L.) Batsch], pennyroyal (Mentha pulegium L.), pepper (Capsicum annuum L. var. annuum), petitgrain (Citrus aurantium L. var. amara), pimento [Pimenta dioica (L.) Merr.], pine needle (Pinus L. sp.), Rhodomyrtus tomentosa (Aiton) Hassk., rue (Ruta graveolens L.), Stephania sinica Diels, tansy (Tanacetum L. sp.), Torreya grandis Fortune ex Lindl. and valerian (Valeriana L. sp.). Nevertheless, we will not systematically go into details of the composition and repellency of these EOs in this review.

Generally, patent literature on mosquito repellent inventions treats fragrant extracts as EOs whether these extracts are produced using an initial solvent extraction step (such as in the production of concretes), by steam distillation, hydrodistillation, direct distillation or pressing (resulting in proper EOs). Herein, the term EO refers broadly to fragrant extracts obtained using these different extraction techniques. Importantly, fragrant oils and partially volatile balsamic oils which have volatile and non-volatile (glyceridic) chemical components in their compositions ([Table 1]) and mosquito repellent properties, such as evening primrose (Oenothera biennis L.), perilla [Perilla frutescens (L.) Britton], ligusticum (Ligusticum chuanxiong Hortorum ex Qiu, et al. in Qiu) and copaiba (Copaifera L. spp.) oils are used in mosquito repellent patented formulations together with plant EOs.

#

Glyceridic Oils Used in Patented Mosquito Repellent Inventions

Importantly, plant glyceridic oils, several of which are known to possess mosquito repellency, were used in patented formulations as carriers or active ingredients which were associated with prolonged repellent action. The most used glyceridic oils in patented EO-containing repellent inventions were neem/margarosa (Azadirachta indica A. Juss., 8.3 %), castor (Ricinus communis L., 4.9 %), soybean [Glycine max (L.) Merr., 4.2 %] and sesame (Sesamum indicum L., 3.5 %) oils ([Table 1]).

#

Synergist Effects Associated with EO-Containing Compositions

Synergist interactions were claimed to be operating in 8 % of EO-containing patents ([Table 2]) [116], [117], [118], [119], [120], [121], [122], [123]. For example, EO of a species of Lippia L. and any one of a number of EOs formulated into a slowly evaporating hydrocarbon soluble composition was said to modify neuronal activity in invertebrates such as adult mosquitoes and produce repellent activity comparable to commercial pyrethroids [123]. Another example of a synergist formulation involved almost equal amounts of eucalyptus (Eucalyptus spp.) and cassia [Cinnamomum cassia (L.) C. Presl] EOs together with an emulsifying agent and butyl acetate solvent which was meant to be used with pyrethroids in incense formulations [119]. Still another example of a synergist repellent meant for use with pyrethroids (allethrin, dimefluthrin) used EOs of wintergreen (Gaultheria procumbens L.) 30–50 (w/w) and camphor (Cinnamomum camphora (L.) J. Presl) 10–35 (w/w), emulsifier and solvent [117] ([Table 2]).

Table 2 Uses and applications, EOs and other components of patented mosquito repellent inventions which claimed synergist effects.

Use or technology

Plant EO

Plant species

Non-EO component

Source

Applied films

Backhousia citriodora F. Muell.

[116]

Melaleuca ericifolia Sm.

Coatings

Wintergreen

Gaultheria procumbens L.

pyrethroids

[117]

Camphor

Cinnamomum camphora (L.) J. Presl

Floor wash

Eucalyptus

Eucalyptus L'Hér. spp.

[118]

Lemon eucalyptus

Eucalyptus citriodora Hook.

Citronella

Cymbopogon winterianus Jowitt ex Bor

Incense

Eucalyptus

Eucalyptus L'Hér. spp.

pyrethroids

[119]

Cassia

Cinnamomum cassia (L.) C. Presl

Microcapsules for textiles

Eucalyptus

Eucalyptus L'Hér. spp.

DEET, isobornyl derivatives

[120]

Not specified

Rose

Rosa L. sp.

natural pyrethrins

[121]

Jasmine

Jasminum officinale L.

Limonene

synergist natural product

Spray/Fumigation on grass, shrubs, trees

Citronella

Cymbopogon Spreng. sp.

dimethyl phthalate, allyl sulfate

[122]

Neem

Azadirachta indica A. Juss.

Eucalyptus

Eucalyptus L'Hér. spp.

Vaporizer/Fumigant

Lippia

Lippia L. sp.+:

[123]

Geranium

Pelargonium graveolens L'Hér.

Lemon eucalyptus

Eucalyptus citriodora Hook.

Basil etc.

Ocimum basilicum L.

#

Scientific Basis for Mosquito Repellency of EOs in Patented Inventions

The scientific literature on the mosquito repellence of EOs used in patents provides important insights ([Table 3]) [8], [37], [41], [46], [61], [68], [73], [85], [88], [93], [124], [125], [126], [127], [128], [129], [130], [131], [132], [133], [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144], [145], [146], [147], [148], [149], [150], [151], [152], [153], [154], [155], [156], [157], [158], [159], [160], [161], [162], [163], [164], [165], [166], [167], [168], [169], [170], [171], [172], [173], [174], [175], [176], [177]. Firstly, citronella (Cymbopogon nardus, C. winterianus), eucalyptus (Eucalyptus spp.) and lemon eucalyptus (E. citriodora Hook.) EOs which were cited in many patented inventions have been the subject of a number of studies in which repellency against species of Culex, Anopheles and Aedes in some cases comparable to DEET have been reported for these oils alone or in formulations [138], [140], [143], [178]. Furthermore, many EOs used in patented inventions have quite significant repellent properties according to published studies such as: bay laurel (Laurus nobilis L.) [137], camphor (Cinnamomum camphora) [132], cassia (Cinnamomum cassia) [132] EOs against Ae. aegypti; lemon (Citrus × limon) EO [128], [152] against An. stephensi Liston, catnip (Nepeta cataria L.) EO [128], lemongrass (Cymbopogon citratus) [128], may chong/litsea [Litsea cubeba (Lour.) Pers.] [128], [179], tagetes (Tagetes minuta L.) [128], violet (Viola odorata L.) EOs [128] against Ae. aegypti, An. stephensi and Cx. quinquefasciatus; peppermint (Mentha × piperita) EO on human skin against An. annularis van der Wulp, An. culicifacies Giles and Cx. quinquefasciatus [160]; sandalwood (Santalum L. spp.) EO formulations against a Culex sp. [177]; geranium (Pelargonium graveolens) oil formulations [137], [144], [147], [148] against species of Culex, Anopheles and Aedes; thyme (Thymus vulgaris L.) EO against Cx. quinquefasciatus [128], [137], [162]; marjoram (Origanum majorana L.) and juniper (Juniperus communis L.) EOs against Cx. pipiens pallens Coquillet [151]; and wintergreen (Gaultheria procumbens) EO against species of Culex and Aedes [131].

Table 3 Scientific evidence for mosquito repellent and related properties of plant EOs and glyceridic oils used in patented repellent inventions.

Plant oil

Plant species

Mosquito repellent properties

Source

Essential oil

Andiroba

Carapa guianensis Aubl.

patented candles commercialized in Brazil as mosquito fumigant-repellents; repellency in Amazon field test of 1 : 1 : 1 andiroba, copaiba and baby oil mixture

[124], [125]

Anise

Pimpinella anisum L.

good repellent against Cx. pipiens

[126]

Artemisia

Artemisia argyi H. Lév. & Vaniot

repels mosquitoes

[127]

Basil

Ocimum basilicum L.

Ae. aegypti (PP 2 h, R% 81), An. stephensi (PP 3.5 h, R% 67), Cx. quinquefasciatus (PP 8 h, R% 100)*; 5 % hairy basil + 5 % vetiver + 10 % citronella EOs in nanoemulsion repel Ae. aegypti 4.7 h; repels Anopheles sp. in human bait test & Cx. pipiens

[128], [129]

Bay laurel

Laurus nobilis L.

spatial repellence against Ae. aegypti, acceptable smell, definite mosquito repellence

[130]

Bergamot

Citrus × bergamia Risso

repellence against Culex & Aedes spp. is comparable to citronella oil

[131]

Camphor

Cinnamomum camphora (L.) J. Presl

Ae. aegypti (PP 2.5 h, R% 32), An. stephensi (PP 8 h, R% 43), Cx. quinquefasciatus (PP 8 h, R% 57)*; EO (0.1 mg · cm−2 on human skin): repellency and duration against Ae. aegypti comparable to DEET

[128], [132]

Cassia

Cinnamomum cassia (L.) C. Presl

bark extract (0.1 mg · cm−2): repels Ae. aegypti comparably to DEET (on human skin), 5 % EO in cream provided 50 min of protection to humans against female Ae. aegypti

[132]

Catnip, catmint

Nepeta cataria L.

Ae. aegypti (PP 8 h, R% 84), An. stephensi (PP 8 h, R% 100), Cx. quinquefasciatus (PP 8 h, R% 100)*; 1–6 h protection against Ae. albopictus (23 & 468 µg · cm−2); safety pharmacology evaluation: N. cataria oil is safe compared to DEET, p-menthane-3,8-diol, etc. May cause minor skin irritation

[128], [133], [134]

Cedar

Cedrus Trew (Cupressus L., Juniperus L.) spp.

Ae. aegypti (PP 3 h, R% 38), An. stephensi (PP 8 h, R% 38), Cx. quinquefasciatus (PP 8 h, R% 100)*; repels An. stephensi

[127], [128], [135]

Chamomile

Chamaemelum nobile (L.) All.

Ae. aegypti (PP 4 h, R% 65), An. stephensi (PP 8 h, R% 76), Cx. quinquefasciatus (PP 8 h, R% 100)*

[128]

Cinnamon

Cinnamomum zeylanicum Blume

high repellency (RD95 mg · mat−1) against An. stephensi (49.6), Ae. aegypti (53.9), Cx. quinquefasciatus (44.2)

[136]

C. verum J. Presl

Ae. aegypti (PP 5.5 h, R% 70), An. stephensi (PP 8 h, R% 100), Cx. quinquefasciatus (PP 8 h, R% 100)*

[128]

Citronella

Cymbopogon nardus (L.) Rendle, C. winterianus Jowitt ex Bor

repellency by 1 : 1 citronella & lavender EOs in 2 oz. castor oil; Ae. aegypti (PP 2 h, R% 76), An. stephensi (PP 8 h, R% 52), Cx. quinquefasciatus (PP 8 h, R% 100)*; C. winterianus + vanillin repels Ae. aegypti, An. dirus, Cx. quinquefasciatus 8 h; + eucalyptus oil in floor cleaner, 6 h repellency; comparable to DEET & N,N-diethyl mandelic acid amide vs. Aedes spp.; 5 % hairy basil + 5 % vetiver + 10 % citronella EOs in nanoemulsion with 4.7 h protection against Ae. aegypti; C. winterianus LC50 & LC95 = 0.5 & 0.9 % for Cx. quinquefasciatus,1.0 & 2.0 % for Ae. aegypti

[37], [128], [129],  [137], [138], [139], [140], [141]

Clove

Syzygium aromaticum (L.) Merr. & L. M. Perry

Cx. pipiens pallens: isoeugenol & eugenol (from clove oil) > repellency than citronella. Clove bud oil + vanillin (long-term protection) > DEET; repels Ae. aegypti, An. dims, Cx. quinquefasciatus for 2–4 h; knockdown LC50 & LC95=0.5 & 0.9 % for Cx. quinquefasciatus, 1.0 & 2.0 % for Ae. aegypti

[46], [61], [141]

Copaiba

Copaifera L. spp.

1 : 1 : 1 andiroba, copaiba & baby oils repels mosquitoes in Amazon field test

[125]

Dill

Anethum graveolens L.

Ae. aegypti (PP 1.5 h, R% 78), An. stephensi (PP 3.5 h, R% 71), Cx. quinquefasciatus (PP 3 h, R% 57)*

[128]

Eucalyptus

Eucalyptus globulus Labill.

Ae. aegypti (PP 1 h, R% 57), An. stephensi (PP 5.5 h, R% 29), Cx. quinquefasciatus (PP 8 h, R% 100)*

[128]

E. camaldulensis Dehnh.

EO repels Cx. pipiens adult females

[8]

Eucalyptus L'Hér. spp.

+ citronella EO in floor cleaning product, 6 h protection; 15 % oil composition ≥ 3 h protection & 
composition + vanillin ≥ 5 h protection to humans; EO contg 30 % p-menthanediol repels An. darlingi (97 %)

[126], [140], [142], [143]

Eucalyptus, broad-leaved

E. dives Schauer

Ae. aegypti (PP 3.5 h, R% 19), An. stephensi (PP 8 h, R% 38), Cx. quinquefasciatus (PP 8 h, R% 100)*

[128]

Eucalyptus, narrow-leaved

E. radiata Sieber ex DC.

Ae. aegypti (PP 2.5 h, R% 65), An. stephensi (PP 8 h, R% 43), Cx. quinquefasciatus (PP 8 h, R% 100)*

[128]

Fennel

Foeniculum vulgare Mill.

5 % in aerosol or 8 % in cream repels Ae. aegypti comparably to citronella & geranium EOs; cream & EO repel Culex, Anopheles & Aedes spp. comparably to geranium & citronella EOs in field; hexane fraction (0.1 mg · cm−2 repels Ae. aegypti 99 %) of fruit methanol extract contains repellent (+)-fenchone &  E-9-octadecenoic acid

[144], [145]

Galbanum

Ferula galbaniflua Boiss. & Buhse

Ae. aegypti (PP 2.5 h, R% 70), An. stephensi (PP 8 h, R% 100), Cx. quinquefasciatus (PP 8 h, R% 100)*

[128]

Garlic

Allium sativum L.

EO and chemical components have strong repellent properties

[146]

Geranium

Pelargonium graveolens L'Hér.

Ae. aegypti (PP 2.5 h, R% 78), An. stephensi (PP 8 h, R% 62), Cx. quinquefasciatus (PP 8 h, R% 100)*; geranium + lemongrass EOs repel Aedes spp.; geranium + sandalwood EOs + soybean oil in burned stick repellents; geranium (25 % geraniol) EO + lemongrass extract product protect against bites of Ae. atlanticus and Ae. mitchellae for 4 h; geranium + sandalwood EOs + soybean oil product repel Culex sp. & other mosquitoes for 3 h in the field; geranium + citronella EOs (1 : 1) in cream product repels Ae. aegypti and Culex, Anopheles & Aedes spp. in the field; in cold creams with repellency to Cx. fatigans in lab & 
on humans; various forms of EO definite promise as repellents

[46], [128], [137], [144], [147], [148]

Ginko

Ginkgo biloba L.

edulan (isolated from leaf extract) repels Ae. albopictus

[149]

Hibawood

Thujopsis dolabrata (Thunb. ex L. f.) Siebold & Zucc.

hinokitiol isolated from EO, highly repellent hinokitiol-containing non-woven polyester fabric & coated foot band

[150]

Jasmine

Jasminum grandiflorum L.

Ae. aegypti (PP 4.5 h, R% 14), An. stephensi (PP 8 h, R% 100), Cx. quinquefasciatus (PP 8 h, R% 100)*

[128]

Juniper

Juniperus communis L.

Ae. aegypti (PP 3.5 h, R% 43), An. stephensi (PP 8 h, R% 76), Cx. quinquefasciatus (PP 8 h, R% 100)*; good repellency at 5 µg · cm−2 against female Cx. pipiens pallens

[128], [151]

Lavender

Lavandula angustifolia Mill.

Ae. aegypti (PP 3 h, R% 24), An. stephensi (PP 8 h, R% 81), Cx. quinquefasciatus (PP 8 h, R% 86)*; mosquito repellent: citronella 1: lavender 1 & castor oil 2 oz.

[127], [128]

Lemon

Citrus × limon (L.) Osbeck

Ae. aegypti (PP 1.5 h, R% 68), An. stephensi (PP 7 h, R% 10), Cx. quinquefasciatus (PP 8 h, R% 100)*; repellency to An. stephensi ∼ DEET in animal & human tests

[128], [152]

Lemon eucalyptus

Eucalyptus citriodora Hook.

Ae. aegypti (PP 2.5 h, R% 59), An. stephensi (PP 8 h, R% 52), Cx. quinquefasciatus (PP 8 h, R% 100)*; use (p-menthane-3,8-diol, PMD, as active ingredient) recommended by CDC (Center for Disease Control and Prevention, USA) against West Nile vector; adulticide activity against Cx. quinquefasciatus & Ae. aegypti

[8], [46], [128]

Lemongrass

Cymbopogon citratus (DC.) Stapf

Ae. aegypti (PP 3 h, R% 70), An. stephensi (PP 8 h, R% 100), Cx. quinquefasciatus (PP 8 h, R% 100)*; field test of 25 % geraniol oil & lemongrass ext. with 4 h repellency against Ae. atlanticus and Ae. mitchellae; mixture containing lemongrass EO + p-menthanediol (PMD) repels An. darlingi & other spp. 95–98 % for 5–6 h in field (repellency > 15–20 % DEET)

[128], [147], [153]

Lemon tea tree

Leptospermum petersonii F. M. Bailey

limited repellency (< DEET) of Ae. aegypti, Cx. quinquefasciatus, Cx. annulirostris

[154]

Leptospermum

L. liversidgei R. T. Baker & H. G. Sm.

repellent: blocks ability of mosquitoes to perceive CO2 emitted by humans

[155]

Lime

Citrus × aurantifolia L.

+ mustard oil carrier as effective mosquito repellent

[68]

Marjoram

Origanum majorana

5 µg · cm−2 good repellent against female Cx. pipiens pallens

[151]

May chang/Litsea

Litsea cubeba (Lour.) Pers.

Ae. aegypti (PP 8 h, R% 73), An. stephensi (PP 8 h, R% 100), Cx. quinquefasciatus (PP 8 h, R% 100)*; high contact and noncontact repellency to female Ae. aegypti in vitro in cages; formulation to fix on skin with high repellency in human volunteers for up to 8 h & 100 % repellency to An. stephensi, Cx. quinquefasciatus, Ae. aegypti; greater repellence of night-biting mosquitoes An. dirus, Cx. quinquefasciatus and Ae. albopictus than Ae. aegypti

[73], [128], [132], [156]

Melaleuca

Melaleuca alternifolia Cheel

limited repellence of Ae. aegypti, Cx. quinquefasciatus, Cx. annulirostris in lab

[75]

Mint, mentha

Mentha haplocalyx Briq.

d-8-acetoxycarvotanacetone isolated mosquito repellent

[157]

Myrtle

Myrtus communis L.

Ae. aegypti (PP 2.5 h, R% 57), An. stephensi (PP 6.5 h, R% 43), Cx. quinquefasciatus (PP 8 h, R% 86)*

[128]

Palmarosa

Cymbopogon martini (Roxb.) Will.Watson

high geraniol content mosquito repellent

[158]

Patchouli

Pogostemon cablin (Blanco) Benth.

partially repels Ae. aegypti, Cx. quinquefasciatus, An. dims

[159]

Pepper, black

Piper nigrum L.

Ae. aegypti (PP 1.5 h, R% 65), An. stephensi (PP 3 h, R% 62), Cx. quinquefasciatus (PP 8 h, R% 100)*; repels An. dirus, Cx. quinquefasciatus, Ae. albopictus (≥ 4.5 h)

[128], [156]

Peppermint

Mentha × piperita L.

Ae. aegypti (PP 2 h, R% 59), An. stephensi (PP 6.5 h, R% 57), Cx. quinquefasciatus (PP 8 h, R% 100)*; on human skin strongly repels An. annularis (100 %), An. culicifacies (92 %), Cx. quinquefasciatus (85 %); comparable to mylol oil (di-butyl & di-methyl phthalates); repels adult female Cx. pipiens

[126], [128], [160]

Pine

Pinus sylvestris L.

good mosquito repellency

[85]

Rose

Rosa L. sp.

moderate mosquito repellency

[127]

Rosemary

Rosmarinus officinalis L.

Ae. aegypti (PP 5.5 h, R% 43), An. stephensi (PP 8 h, R% 100), Cx. quinquefasciatus (PP 8 h, R% 100)*; repels An. stephensi, Ae. aegypti & Cx. quinquefasciatus; low repellency against Ae. aegypti in lab, acceptable to humans as final fragrance in repellent formulation; repels Ae. aegypti (avg 90 min)

[88], [128], [130], [136]

Sage

Salvia sclarea L.

Ae. aegypti (PP 2 h, R% 46), An. stephensi (PP 5 h, R% 19), Cx. quinquefasciatus (PP 8 h, R% 100)*

[128]

Sandalwood

Santalum album L.

Ae. aegypti (PP 2.5 h, R% 59), An. stephensi (PP 8 h, R% 100), Cx. quinquefasciatus (PP 8 h, R% 100)*

[128]

Santalum L. spp.

repels Cx. pipiens pallens; EO containing cold creams repel Cx. fatigans in the lab & on human skin; area repellency of Culex sp. by commercial sticks (contg 0.5 % EO) (3 h protection); botanical repellent (w/soybean and geranium oil) 100 % effective in field (3-h test period, comparable to DEET)

[93], [148], [151]

Sour (bitter) orange

Citrus × aurantium L.

limited protection (repellency) against mosquitoes

[137]

Spearmint

Mentha spicata L.

repellent; piperitone oxide from M. spicata (var. viridis) EO repels An. stephensi

[161]

Tagetes

Tagetes minuta L.

Ae. aegypti (PP 1 h, R% 84), An. stephensi (PP 8 h, R% 100), Cx. quinquefasciatus (PP 8 h, R% 100)*; repels Ae. aegypti (avg 90 min)

[88], [128]

Thyme

Thymus serpyllum L.

Ae. aegypti (PP 2.5 h, R% 57), An. stephensi (PP 7.5 h, R% 33), Cx. quinquefasciatus (PP 8 h, R% 100)*

[128]

Thymus vulgaris L.

repels lab-reared adult female Ae. albopictus for 2 h; 0.01 % totally repels Cx. quinquefasciatus

[134], [162]

Turmeric

Curcuma longa L.

+ 5 % vanillin repels Ae. aegypti, An. dirus and Cx. quinquefasciatus in cage & large room for 8 h; turmeric, citronella & hairy basil EOs + vanillin provide substitute for DEET; repels DEET & IR3535-resistant Ae. aegypti for 4.5 h

[138], [156]

Verbena

Lippia triphylla (L'Hér.) Kuntze

Ae. aegypti (PP 2.5 h, R% 70), An. stephensi (PP 5.5 h, R% 38), Cx. quinquefasciatus (PP 8 h, R% 100)*

[128]

Vetiver

Vetiveria zizanioides (L.) Nash

stable nanoemulsion of 5 % hairy basil, 5 % vetiver & 10 % citronella EO: repels Ae. aegypti for 4.7 h

[41]

Violet

Viola odorata L.

Ae. aegypti (PP 6 h, R% 68), An. stephensi (PP 8 h, R% 100), Cx. quinquefasciatus (PP 8 h, R% 86)*

[128]

Wild verbena (Lippie)

Lippia sidoides, L. javanica, Lippia spp.

sources of perillaldehyde (repels An. gambiae) & perillic acid (repels An. arabiensis & Ae. aegypti)

[163], [164]

Wintergreen

Gaultheria procumbens L.

strongly repels Culex and Aedes spp. in different tests

[131]

Wormwood

Artemisia annua L.

mosquito repellent properties

[165]

Zanthoxylum

Z. piperitum DC.,

repel mosquitoes

[159]

Z. armatum DC.,

Z. bungei Planch. & Linden ex Hance

Glyceridic oils

Castor

Ricinus communis L.

best carrier for pyrethrum extracts (long-lasting)

[137]

Mustard

Brassica L. spp.

longer protection (up to 5 h with Zanthoxylum limonella or lime oils) than coconut (Cocus nocifera) oil against Ae. albopictus

[166]

Neem/Margosa

Azadirachta indica A. Juss.

knockdown repellency against Ae. aegypti, Ae. albopictus, An. quadrimaculatus Say; repels female An. stephensi (ED50 0.191–0.156 mg · cm−2) in lab; low repellency against Ae. albopictus & Cx. nigripalpus; 2 % in coconut (Cocus nocifera) oil on exposed body parts of human volunteers provided complete protection for 12 h from all Anopheles spp.; protection from Anopheles spp. (96–100 %), Aedes (85 %), Culex sp. (61–94 %); significant protection by neem cream against adult Ae. aegypti; 1 % in kerosene lamps in preclinical & clinical safety evaluation is safe to humans; 1 % in kerosene burned in lamps effective in 2 field tests. Repellence: Anopheles > Culex; 1–4 % in coconut oil on exposed body parts of humans: 81–91 % protection for 12 h

[167], [168], [169], [170], [171], [172], [173], [174], [175]

Olive

Olea europaea L.

Ae. aegypti (PP 3.5 h, R% 68), An. stephensi (PP 8 h, R% 71), Cx. quinquefasciatus (PP 8 h, R% 71)*; 1 : 1 w/pyrethrum repels mosquitoes for 4 h

[128], [137]

Soybean

Glycine max (L.) Merr.

Ae. aegypti (PP 3 h, R% 54), An. stephensi (PP 8 h, R% 76), Cx. quinquefasciatus (PP 8 h, R% 100)*; oil-based product provided 1.5 h (low) repellency, 24 % DEET provided 5 h protection; good repellency in product w/sandalwood + geranium in burned sticks vs. DEET; commercial product containing 2 % oil repels Ae. albopictus, Cx. nigripalpus, Ae. triseriatus for 5, 8.5 & ≥ 7.3 h, respectively

[128], [169], [176], [177]

Soybean, wild (carotin)

Glycine soja Siebold & Zucc.

Ae. aegypti (PP 3 h, R% 16), An. stephensi (PP 8 h, R% 10), Cx. quinquefasciatus (PP 8 h, R% 100)*

[128]

* PP = protection period (h), R% = percent repellency; 0.1 mL of a 20 % EO solution (in 20 % Genapol, 10 % PEG, 20 % ethanol, 50 % water) applied to 30 cm2 of human forearm; for 20 % DEET solution (in same as above) these values were: Ae. aegypti (PP 6 h, R% 46), An. stephensi (PP 8 h, R% 100), Cx. quinquefasciatus (PP 8 h, R% 100) [24]

A broad-scale screening of plant oils against Ae. aegypti, An. stephensi and Cx. quinquefasciatus evaluated protection periods and percent of repellence on human skin as compared to 20 % DEET [128]. In general, Ae. aegypti was the most difficult species to repel, followed by An. stephensi and finally Cx. quinquefasciatus for both oils and controls. The control (DEET) exhibited a protection period (PP) of 6 h and percent repellency (R%) of 46 % against Ae. aegypti, whereas against An. stephensi and Cx. quinquefasciatus protection was for 8 h at 100 % repellency [128] ([Table 3]). While the most active EOs against all three mosquito species were cited above, the following oils were active against An. stephensi and Cx. quinquefasciatus, but not significantly active against Ae. aegypti: chamomile (Chamaemelum nobile), cinnamon (Cinnamomum verum), galbanum (Ferula galbaniflua), jasmine (Jasminum grandiflorum), lavender (Lavandula angustifolia), pepper (Piper nigrum), rosemary (Rosmarinus officinalis), sandalwood (Santalum album) and soybean (Glycine max) [128]. Another group of oils in this study actively repelled only Cx. quinquefasciatus: cedar (Cedrus, Cupressus and Juniperus spp.), citronella (Cymbopogon nardus, C. winterianus), eucalyptus (Eucalyptus globulus), broad and narrow-leaved eucalyptus (E. dives and E. radiata, respectively), geranium (Pelargonium graveolens), juniper (Juniperus communis), lemon (Citrus × limon), lemon eucalyptus (Eucalyptus citriodora), myrtle (Myrtus communis), peppermint (Mentha × piperita), sage (Salvia sclarea), thyme (Thymus serpyllum) verbena (Lippia triphylla) and wild soybean (Glycine soja) [128]. Differences in the species specificity of the repellence profiles of these and other EOs may explain their use in repellent mosquito products. This may have to do with differences in the local and regional profiles of mosquito species populations and explain the use of mixtures of these EOs to generate broad spectrum formulations for simultaneous repellency of multiple mosquito species.

While Ae. aegypti and other adults may in general be difficult to repel using plant-based products or synthetic repellents, a number of plant EOs have been identified which are effective against this species ([Table 3]). The following repellency effects of EOs against adult Ae. aegypti have been observed: hairy basil (Ocimum basilicum) in stable nanoemulsions with vetiver (Vetiveria zizanioides) and citronella (Cymbopogon nardus and C.winterianus) EOs are a good repellent [129], bay laurel (Laurus nobilis) EO is an acceptable smelling, good spatial repellent [130], camphor (Cinnamomum camphora) EO and cassia (C. cassia) bark extract on human skin are repellents comparable to DEET [137], catmint (Nepeta cataria) EO exhibited 8 h of protection on human skin, cinnamon (Cinnamomum zeylanicum, C. verum) EOs exhibit moderate to good repellency [128], citronella (C. winterianus) EO exhibits knockdown repellency at 1–2 % [141] and C. winterianus EO + vanillin exhibits 8 h of repellency [138], fennel (Foeniculum vulgare) fruit extract/fractions offer complete repellency [145] and EO as an aerosol or cream has comparable repellency to other EO repellents [144], geranium (Pelargonium graveolens) + citronella EO in a cream product exhibited good repellency in the field [46], lemon eucalyptus (E. citriodora) has knockdown repellency/adulticide activity [46], may chang/litsea (Litsea cubeba) EO exhibits contact and noncontact repellency and is a good/excellent repellent in formulations on the human forearm providing protection over 8 h [73], [128], turmeric (Curcuma longa) EO + 5 % vanillin exhibits 8 h of repellency and in formulations with other EOs + 5 % vanillin offers protection from DEET and IR3535-resistant strains of Ae. aegypti over 4.5 h [138], [156] and violet (Viola odorata) EO on human skin exhibited 8 h protection at a good level of repellency [128] ([Table 3]).

Several EOs from Zanthoxylum L. spp. (Z. piperitum DC., Z. armatum DC., Z. bungei Planch. & Linden ex Hance) were cited in patented mosquito repellent inventions. According to recent literature, Zanthoxylum L. spp. EOs have mosquito repellent activity [159], [180]. Also, besides A. argyi H. Lév. & Vaniot (artemisia) EO, which is known to repel mosquitoes [127], the EOs of several other Artemisia L. spp. were used in patented formulations such as A. annua L. (wormwood), A. vulgaris L. and A. apiacea Hance. This is interesting given that A. annua EO has proven insect repellent properties [165].

The Amazon region is a source of plant-derived mosquito repellent oils. For example, Carapa guianensis Aubl. (andiroba) pressed fruit oils or extracts are formulated preferentially into candles during manufacturing as fumigant mosquito repellents [124], burned in kerosene lamps or used in topical repellent formulations which are commercially available in Brazil. Copaifera L. spp. (copaiba) balsam oils or extracts are used in mosquito repellency in Brazil especially in the Amazon region ([Table 3]). Furthermore, a formulation of andiroba, copaiba and baby oils exhibited repellency to mosquitoes in an Amazon field study [125].

#

Scientific Basis for Mosquito Repellency of Glyceridic Oils

Neem or margarosa oil is obtained by pressing the fruit of the neem tree (Azadirachta indica). Neem oil is burned in 1 % compositions in kerosene lamps as indoor mosquito emitters of chemical repellent-fumigant deterrents which have been evaluated and are considered to be safe [173], [174]. Also, neem oil in mixtures with coconut (Cocos nucifera L.) oil provides good protection for very long periods against Anopheles and Aedes spp. [170], [171], [175]. Castor (Ricinus communis L.), mustard (Brassica spp.), olive (Olea europaea) and other glyceridic oils have important roles in several patented repellent compositions containing pyrethrum extracts and EOs where they act as carriers and can extend the duration of repellent effects for several hours perhaps by slowing the release or evaporation of EOs from surfaces.

There are mixed scientific reports on the effective mosquito repellency of several glyceridic oils. Thus, for soybean (Glycine max) oil low repellency was observed as compared to 24 % DEET formulations [176] and good repellency was observed for the smoke generated from burned sticks which contained soybean oil. Especially interesting is a report from a United States Department of Agriculture laboratory where 4 well-known synthetic mosquito repellents based on 10 % KBR3023 [1-piperidinecarboxylic acid 2-(2-hydroxyethyl)-1-methylpropyl ester], 7.5 % IR3535 [3-(N-butyl-N-acetyl)-aminopropionic acid ethyl ester], 15 % and 7 % DEET and 8 natural product-based repellents based on 2 % soybean oil, 10 % citronella (Cymbopogon spp.) EO, neem oil (Azadirachta indica) and others were tested in the lab against Ae. albopictus Skuse, Cx. nigripalpus Theobald and Ae. triseriatus Say [169]. The 2 % soybean oil formulation exhibited mosquito repellency comparable to both 10 % KBR3023 and 15 % DEET based products each of which provided estimated mean protection time (eMPT) responses averaged over all three mosquito species of ≥ 7.2 h [169]. This study is evidence for the potential of soybean oil as a stand-alone repellent and as a component oil of repellent formulations.

#

Mosquito Repellent Chemical Components of EOs and Added Isolated Compounds

Approximately 20 % of all EO-containing patents mentioned a non-EO plant derivative and 40 % mentioned a specific EO repellent component or added isolated natural chemical ingredient. Chrysanthamic acid and its derivatives which are components of pyrethrum (Chrysanthemum L. spp. flower extracts) were cited in 12 % of all patented formulations involving EOs. Also, patents cited many “natural” chemical constituents which were either added to formulations or were important chemical components of EOs comprising the formulations. The most widely cited chemicals of plant origin were (% of patents): camphor (8.3), geraniol (7.6), linalool (7.6), menthol (7.6), geranial (7.0), citronellal (6.9), limonene (4.9), citronellol (4.9), borneol (4.2), 1,8-cineole (4.2), p-menthane-3,8-diol (4.2), camphene (3.5) and nepetalactone and derivatives (3.5). Many of these and other chemical components of EOs are potent mosquito repellents ([Table 4]) [131], [137], [143], [145], [151], [163], [169], [181], [182], [183], [184], [185], [186], [187], [188], [189], [190], [191], [192], [193] and are discussed below.

Table 4 Mosquito repellency or deterrency effects of individual major chemical components of EOs used in patented inventions.

EO component

No. EOs

Repellency

Mosquito

Source

α-Bisabolol

2

d84 % spatial repellency for 180 min, avoidance freq. (contact repellency) = DEET

female Ae. aegypti

[181]

Borneol

3

b1.4 mg (−)-borneol · cm−2 = 70 % repellency

female Ae. aegypti

[182]

b,cRD50 = 1.7 × 10−3 mg · cm−2

female An. gambiae

[163]

Bornyl acetate

2

b1.4 mg · cm−2 = 15 % repellency

female Ae. aegypti

[182]

Camphene

2

b,cRD50 = 2.2 × 10−3 mg · cm−2

female An. gambiae

[163]

Camphor

6

b,cRD50 = 1.4 × 10−3 mg · cm−2

female An. gambiae

[163]

b1.4 mg · cm−2 (±)-camphor, (+)-camphor, (−)-camphor = 36, 35 & 47 % repellencies, resp.

female Ae. aegypti

[182]

3-Carene

4

b,cRC50 = 8.6 × 10−4 mg · cm−2

female An. gambiae

[183]

1 h, 1.92 µg · cm−2 = 68, 65 % repellency

Ae. aegypti, Ae. albopictus

[163]

Carvacrol

4

b,cRC50 = 2.4 × 10−4 mg · cm−2

female An. gambiae

[183]

Carvone

2

b,cRD50 = 1.3 × 10−3 mg · cm−2

female An. gambiae

[163]

d-carvone & l-carvone: feeding deterrents/repellents, good spatial repellents/inhibitors, contact repellents/deterrents

[184]

Cinnamaldehyde

2

definite mosquito repellent potential

[137]

E-cinnamaldehyde (0.051 mg · cm−2) & DEET (0.025 mg · cm−2) provided 87 & 95 % protection, resp., after 30 min

female Aedes aegypti

[184]

1,8-Cineole

15

bcineole 1.4 mg · cm−2 = 21 % repellency

female Ae. aegypti

[182]

b3 % in vaseline or olive oil = 73 or 120 min protection

1 : 1 male : female Cx. pipiens molestus

[185]

b,cRD50 = 1.2 × 10−3 mg · cm−2

female An. gambiae

[163]

Citronellal

4

b,cRD50 = 2.2 × 10−4 mg · cm−2

female An. gambiae

[163]

feeding deterrent/repellent, spatial repellent/inhibitor, contact repellent/deterrent

[186]

Citronellol

6

repellent component

[145]

feeding deterrent/repellent, spatial repellent/inhibitor

[186]

p-Cymene

3

b,cRD50 = 1.0 × 10−5 mg · cm−2

female An. gambiae

[163]

Eugenol

5

high repellency

female Cx. pipiens pallens

[151]

b,cRD50 = 1.3 × 10−3 mg · cm−2

female An. gambiae

[163]

Fenchone

2

b,cRD50 = 1.9 × 10−3 mg · cm−2

female An. gambiae

[163]

0.4 mg (+)-fenchone · cm−2 = 51 % repellency after 1 hb,f

female Ae. aegypti

[145]

Geranial

7

at 0.2 mg · cm−2, blood-sucking by mosquitoes reduced by 10, 15, and 18 % after 1, 2 and 3 h, respectively

Cx. pipiens pallens, Cx. pipiens quinquefasciatus

[187]

Geraniol

11

b,cRD50 = 1.1 × 10−4 mg · cm−2

female An. gambiae

[163]

spatial repellent: 0.25 µg · cm−2 ca. 100 % (reversible) inhibition of host-seeking after 48 h exposure

female Ae. albopictus

[188]

Geranyl acetate

6

effective feeding deterrent/repellent, effective spatial repellent/inhibitor, contact repellent/deterrent

Mosquitoes

[186]

Limonene

19

b3 % in vaseline/olive oil = 61/78 min protection

1 : 1 male : female Cx. pipiens molestus

[185]

1 h, 1.92 µg · cm−2 = 70, 70 % repellency

Ae. aegypti, Ae. albopictus

[189]

b,cRD50 = 1.8 × 10−3 mg · cm−2

female An. gambiae

[163]

Linalool

14*

b1.4 mg (±)-linalool · cm−2 = 67 % repellency

female Ae. aegypti

[182]

b3 % in vaseline/olive oil = 52/65 min protection

1 : 1 male : female Cx. pipiens molestus

[185]

b,cRD50 = 1.5 × 10−3 mg · cm−2

female An. gambiae

[163]

p-Menthane-3,8-diol

1

26 % formula more repellent than 4 synthetic & 7 natural product repellents

Ae. albopictus, Cx. nigripalpus, Ochlerotatus triseriatus

[169]

15 % formula with lemongrass EO (Cymbopogon citratus) = 99 % protection for 5 h in the field; h16 % formula with lemongrass EO = 95 % protection for 6 h in the field

An. darling, Ae. ochlerotatus taeniorhynchus

[143]

Menthone

2

b3 % in olive oil = 35 min protection

1 : 1 male : female Cx. pipiens molestus

[185]

Methyl salicylate

2

most repellent (screening)

[131]

Myrcene

6

b,cRC50 = 8.4 × 10−4 mg · cm−2

female An. gambiae

[183]

b1.4 mg · cm−2 = 20 % repellency

Ae. aegypti

[182]

Nepetalactone

1

mosquito repellent ingredient in formulations

[190]

E-Nerolidol

1

d67 % spatial repellency for 180 min, avoidance freq. (contact repellency) < DEET

female Ae. aegypti

[181]

Oleic acid

8**

0.4 mg · cm−2 = 52 % repellency after 1 hb,f

female Ae. aegypti

[145]

Perillaldehyde

1

b,cRD50 = 3.2 × 10−4 mg · cm−2

female An. gambiae

[163]

α-Pinene

15

d-α-pinene, 2 h protection

Mosquito

[191], [192]

b3 % in vaseline/olive oil = 27/56 min protection

1 : 1 male : female Cx. pipiens molestus

[185]

β-Pinene

8

b3 % in vaseline/olive oil = 22/39 min protection

1 : 1 male : female Cx. pipiens molestus

[185]

b,cRD50 = 1.6 × 10−3 mg · cm−2

female An. gambiae

[163]

α-Santalol

1

d87 % spatial repellency for 180 min, avoidance freq. (contact repellency) = DEET

female Ae. aegypti

[181]

Spathulenol

2

eproportion not biting = 0.73, 0.75, respectively

Ae. aegypti, An. stephensi

[193]

α-Terpinene

1

1 h, 1.92 µg cm2 = 68, 55 % repellency

Ae. aegypti, Ae. albopictus

[189]

b1.4 mg · cm−2 = 15 % repellency

female Ae. aegypti

[182]

b,cRD50 = 2.4 × 10−3 mg · cm−2

female An. gambiae

[163]

γ-Terpinene

6

1 h, 1.92 µg · cm−2 = 60, 72 % repellency

Ae. aegypti, Ae. albopictus

[189]

b3 % in vaseline/olive oil = 35/48 min protection

1 : 1 male : female Cx. pipiens molestus

[185]

b,cRD50 = 2.7 × 10−3 mg · cm−2

female An. gambiae

[163]

Terpinen-4-ol

5

1 h, 1.92 µg · cm−2 = 92, 85 % repellency

Ae. aegypti, Ae. albopictus

[189]

b1.4 mg · cm−2 = 83 % repellency

Ae. aegypti

[182]

b,cRD50 = 1.5 × 10−3 mg · cm−2

female An. gambiae

[163]

spatial repellent/inhibitor

[186]

α-Terpineol

7

b3 % in vaseline/olive oil = 78/99 min protection

1 : 1 male : female Cx. pipiens molestus

[185]

feeding deterrent/repellent, spatial repellents/inhibitor, contact repellent/deterrent

[186]

b,cRD50 = 1.3 × 10−3 mg · cm−2

female An. gambiae

[163]

Terpinolene

2

1 h, 1.92 µg · cm−2 = 55, 70 % repellency

Ae. aegypti, Ae. albopictus

[189]

b,cRD50 = 2.6 × 10−3 mg · cm−2

female An. gambiae

[163]

(α + β)-Thujone

2

b1.4 mg · cm−2 = 20 % repellency

Ae. aegypti

[182]

b,cRD50 = 1.5 × 10−3 mg · cm−2

female An. gambiae

[163]

Thymol

1

b,cRC50 = 1.9 × 10−3 mg · cm−2

female An. gambiae

[183]

b3 % in vaseline/olive oil = 52/65 min protection

1 : 1 male : female Cx. pipiens molestus

[186]

cis-Verbenol

1

b,cRD50 = 7.5 × 10−5 mg · cm−2

female An. gambiae

[163]

Verbenone

1

b,cRD50 = 1.6 × 10−3 mg · cm−2

female An. gambiae

[163]

– = Information not found. Number of oils in [Table 1] which contain this as their major component. *In evening primrose (Oenothera biennia) glyceridic oil. ** Mosquito repellent component of glyceridic oils. DEET = 50 % repellency. DEET = 60 % repellency. a Used as additive in one patent. b Human-bait assay. c Positive control DEET exhibited RC50 = 3.3 ×  10−4 mg · cm− 2. d Applied concentration 78.6 µg · cm−2. Repellency is statistically different from negative control. DEET and turmerone had 83 and 89 % repellencies, respectively. Contact repellency is defined as 100 % of individuals off treated surface. Avoidance frequency of DEET and turmerone = 0.8. e Substance was applied at 25 nmol · cm−2 cloth. Positive control was (1S,2′S)-2-methylpiperidinyl-3-cyclohexen-1-carboxamide (SS-220) at 25 nmol · cm−2 cloth (provided 0.80 and 0.78 non-biting mosquitoes, respectively, for Ae. aegypti and An. stephensi). f 0.2 mg · cm−2 DEET (positive control) provided 97 % repellency after 1 h. g Positive control 15 % DEET (in EtOH) = 92 % protection (average over trial period). h Positive control 20 % DEET (in EtOH) = 64 % protection (average over trial period)

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Vanillin in EO containing mosquito repellent inventions

Vanillin was cited as an additive in 4 % of EO-containing patents. According to several scientific publications, it increases the duration and magnitude of the repellent effect of synthetic repellents such as DEET as well as plant EOs. For example, 5 % vanillin in formulations of EOs of turmeric (Curcuma longa L.), citronella (C. winterianus) or hairy basil (Ocimum americanum L.) provided up to 8 h of protection against Ae. aegypti, An. dirus and Cx. quinquefasciatus under cage conditions. Interestingly, 5 % vanillin in formulations with DEET increased the protection time as compared to DEET alone against these three mosquito species (≥ 8 h protection). In another example, 15 % eucalyptus (Eucalyptus spp.) EO and 5 % vanillin provided 5 h of repellency against Ae. albopictus [18] and in other work involving human volunteers, clove (Syzygium aromaticum) bud EO and vanillin mixtures provided long acting repellency against adult female Cx. pipiens pallens [151]. Thus, combinations of vanillin with plant EOs can lead to formulations which are substitutes for DEET [138], [142], [151].

In patents, vanillin is cited as an ingredient in mosquito repellent formulations with: Zanthoxylum armatum DC. and/or Z. piperitum DC. EOs [194], clove bud and leaf (Syzygium aromaticum), juniper berry (Juniperus communis) and/or marjoram (Origanum majorana) EOs [195], lemongrass (Cymbopogon citratus) EO/p-menthane-3,8-diol formulations [196], combinations of citronella, clove, geranium (Pelargonium graveolens), lavender (Lavandula angustifolia), patchouli [Pogostemon cablin (Blanco) Benth.] and peppermint (Mentha × piperita) EOs [197] among others.

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Synthetic additives in EO-containing inventions

About 25 % of all EO-containing patented repellents had at least one synthetic repellent component. Thus, DEET (N,N-diethyl m-toluamide), the gold-standard synthetic mosquito repellent [11], was used in 10 % and dimethyl (dialkyl) phthalates were cited in 5 % of EO-containing patented inventions. Also, one or more synthetic pyrethroids (allethrin, cyhalothrin, deltamethrin, dimefluthrin, esbiothrin, metofluthrin, permethrin, tetramethrin and vaporthrin) were used in 10 % of EO-containing mosquito repellents. It must be stressed that pyrethroids can be strong mosquitocides (toxicity), spatial mosquito repellents and mosquito irritants as was shown, for example, for permethrin in field studies [6] and α-cypermethrin, deltamethrin, permethrin in a very recent publication [198]. Only about 3 % of patents made use of the synthetic synergist piperonyl butoxide.

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Chemical Composition of EOs Used in Patented Inventions

Information on the major chemical components of plant EOs used in mosquito repellent inventions is presented in [Table 1]. Among these are EOs which are concentrated sources of proven mosquito repellent monoterpenes and phenylpropanoids such as the EOs of angelica (Angelica archangelica), artemisia (Artemisia argyi), basil (Ocimum basilicum), bergamot (Citrus × bergamia), camphor (Cinnamomum camphora), cassia (Cinnamomum cassia), catnip (Nepeta cataria), chrysanthemum (Chrysanthemum indicum), cinnamon (Cinnamomum zeylanicum), citronella (Cymbopogon nardus, C. winterianus), coriander (Coriandrum sativum), cypress (Cupressus sempervirens), dill (Anethum graveolens), eucalyptus (Eucalyptus spp.), geranium (Pelargonium graveolens), grapefruit (Citrus reticulata), ho leaf (Cinnamomum camphora), hyssop (Hyssopus officinalis), juniper (Juniperus communis), lavender (Lavandula angustifolia), lemon (Citrus × limon), lemon eucalyptus (Eucalyptus citriodora), lemongrass (Cymbopogon citratus), lemon tea tree (Leptospermum petersonii), lime (Citrus × aurantifolia), marjoram (Origanum majorana), may chang/litsea (Litsea cubeba), melaleuca/tea tree (Melaleuca alternifolia), mint/mentha (Mentha), orange (Citrus × sinensis), palmarosa (Cymbopogon martini), curl leaf parsley (Petroselinum crispum), pepper (Piper nigrum), pine (Pinus sylvestris), rose (Rosa × damascena, R. × centifolia), rosemary (Rosmarinus officinalis), salvia/sage (Salvia spp.), sour (bitter) orange (Citrus × aurantium), spearmint (Mentha spicata), thyme (Thymus vulgaris), verbena (Lippia triphylla) and wintergreen (Gaultheria procumbens). In these EOs, proven mosquito repellent volatile components camphor, 1,8-cineole, citronellol, eugenol, geranial, geraniol, limonene, linalool, myrcene, α and β-pinenes, γ-terpinene, terpinen-4-ol and α-terpineol are well represented among the major components ([Table 4]).

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Chemical composition of glyceridic oils used in patented EO-containing inventions

Glyceridic plant oils are important components of EO-containing mosquito repellent formulations not only for their carrier properties, but because they contain trace or larger amounts of free, long-chain mono- and polyunsaturated fatty acids and derivatives of these. It has been known for some time that insect antennae are highly sensitive to gas-phase long-chain fatty acids. For example, Hwang et al. [199] showed that gravid Cx. quinquefasciatus Say in an olfactometer in contact with room temperature vapors of C14-C24 mono-, di- and polyunsaturated fatty acids were significantly repelled. These authors also demonstrated that fatty acids having at least one Z-configuration olefin bond (analogous saturated and E-configuration fatty acids were less repellent or inactive) were especially effective repellents. One of the most repellent fatty acids was oleic acid (9Z-olefin) which is a common free fatty acid in vegetable oils whose 18 carbon chain was considered to be optimal within the group of fatty acids studied [199]. Independently, female Ae. aegypti were found to be moderately repelled by oleic acid as compared to DEET in a human-bait assay [145]. Thus, free, long-chain, unsaturated fatty acids which are present in glyceridic oils are sufficiently volatile to be mosquito repellent substances in formulations containing plant EOs. This is especially relevant given claims in several patents of the mosquito repellent effects of olive (Olea europaea L.), sesame (Sesamum indicum L.), mustard (Brassica L. spp.), soybean [Glycine max (L.) Merr.] and other oils (for examples, see [200] or [201]).

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Mosquito repellent major chemical components of EOs

Among the more widely distributed mosquito repellent major chemical components of EOs used in patented inventions are the cyclic and noncyclic monoterpenes limonene, α-pinene, 1,8-cineole and linalool ([Table 4]). These are major components of, respectively, 28, 22 [including limonene-containing perilla (Perilla frutescens) oil], 22 and 21 % [including linalool-containing evening primrose (Oenothera biennis) oil] of the EOs most used in patented repellent inventions ([Table 1]).

EOs in patented mosquito repellent inventions are composed of a number of chemical components which individually exhibit important mosquito repellency, deterrency and inhibitory effects ([Table 1] and [Table 4]). For example, α-bisabolol and α-santalol provided 3 h of high spatial repellency and contact repellency equivalent to DEET against female Ae. aegypti while E-nerolidol exhibited good spatial repellency for 3 h and less contact repellency than DEET [181]. Also, the following substances singly exhibited good repellency against the mosquito species indicated: carvacrol (RC50 = 2.4 × 10−4 mg · cm−2, female An. gambiae) [183], cinnamaldehyde (0.051 mg · cm−2 against female Aedes aegypti, repellency comparable to DEET) [184], citronellal (RD50 = 2.2 × 10−4 mg · cm−2), p-cymene (RD50 = 1.0 × 10−5 mg · cm−2) and cis-verbenol (RD50 = 7.5 × 10−5 mg · cm−2) against female An. gambiae [163], geranial (0.2 mg · cm−2, reduces blood-sucking by Cx. pipiens pallens and Cx. pipiens quinquefasciatus over 3 h). The following EO components provided reasonable repellency at ca. 2 µg · cm−2 against adult Ae. aegypti and Ae. albopictus: 3-carene, limonene, α-terpinene, γ-terpinene, terpinen-4-ol and terpinolene [189].

Several interesting isolated repellent substances are described in patented EO-containing products ([Table 3]). For example, hinokitiol-containing polyester non-woven fabric and hinokitiol-coated polyester foot band are said to provide 100 % repellency against mosquitoes and hinokitiol from hibawood (Thujopsis dolabrata) EO (and other sources) is an important natural repellent [150]. Another example is the isolation of edulan from ginkgo (Ginkgo biloba) EO and the repellent activity of this compound and derivatives against Ae. albopictus are described in a patent in which it is also claimed that these compounds are safe to humans [149]. The mosquito repellent natural substance d-8-acetoxycarvotanacetone was isolated from Mentha haplocalyx Briq. [157]. Also, several Lippia spp. EOs were cited in patents [e.g., L. sidoides and L. javanica (wild verbena or lippie oil)] and are important sources of the mosquito repellent compounds perrilic acid and perillaldehyde [163], [164] ([Table 3]). The latter compound is a component of perilla (Perilla frutescens) oil and exhibited good repellency (RD50 = 3.2 × 10−4 mg · cm−2) against female An. gambiae [163] ([Table 4]). In another patented invention, garlic (Allium sativum) EO and isolated component chemicals of garlic EO were tested for repellency against mosquitoes. More than a dozen allyl sulfide, allyl disulfide and allyl polysulfide components of garlic EO applied to human skin were found to deter Ae. aegypti, An. gambiae and Cx. quinquefasciatus landing and blood feeding [202].

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Geraniol

Geraniol is a major component of 16 % of the more used EOs in patented inventions ([Table 1]) and its mosquito repellency has been studied. As an isolated chemical, it exhibited good repellency on human skin in the lab [163] and reversible spatial repellency/protection from bites [188]. A 25 % formulation of this substance was the basis for a commercial product which exhibited effective repellency in the lab [93], [167], [169] but was less effective as compared to other products at repelling mosquitoes according to an early field study [143]. In a recent field study, a 25 % geraniol and lemongrass (Cymbopogon citratus) composition offered superior protection against the bites of Ae. atlanticus and Ae. mitchellae (4 h) than repellent formulations based on 12 % EOs (1 h) and EOs, benzophenone-3, octinoxate and octisalate mixture (1.5 h) [147].

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p-Menthane-3,8-diol

The mosquito repellency of the component of Eucalyptus spp. EOs, p-menthane-3,8-diol (PMD), is firmly established [8], [143], [178]. As a repellent additive in formulations, 15–16 % PMD/lemongrass formulations provided 5–6 h of excellent repellency (95–99 %) against Anopheles and Aedes spp. [153]. Indeed, in a U. S. Dept. of Agriculture study, 26 % PMD-containing product was more repellent in the lab to Ae. albopictus, Cx. nigripalpus and Ae.triseriatus than synthetic products based on 10 % KBR3023, 7.5 % IR3535, 15 % and 7 % DEET, and 7 natural product-based repellents based on 2 % soybean oil, 10 % citronella EO, neem oil, 25 % geraniol, etc. [169].

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Mosquito repellent minor components of EOs

Some minor or lower concentration components of EOs are worth mentioning because they exhibit significant mosquito repellency. For example, citral (geranial + neral) and fenchyl alcohol are minor components of citronella (Cymbopogon nardus, C. winterianus) and rose (Rosa damascena) EOs, respectively, and exhibit moderate repellency to female An. gambiae (RD50 = 1.3 × 10−3 and 1.4 × 10−3 mg · cm−2, respectively) [163]. Also, linalool oxide, a minor component of lemon eucalyptus (E. citriodora) EO was found to be repellent (RC50 = 6.5 × 10−4 mg · cm−2) to female An. gambiae [183] and Tripathi et al. [161] found that the peppermint (Mentha × piperita) EO component piperitone oxide was highly repellent to adult An. stephensi. In other works, farnesol [a component of chamomile, jasmine and rose (Rosa damascena) EOs], elemol (a component of catnip, citronella and hyssop EOs) and hedycaryol (a component of black pepper EO) exhibited 69, 89 and 95 % spatial repellency over 180 min to adult female Ae. aegypti and avoidance frequency (contact repellency) greater than or equal to that of DEET [181]. Cinnamyl alcohol, a minor constituent of cassia (Cinnamomum cassia) EO, exhibits less repellency to female Ae. aegypti than the major component, cinnamaldehyde, but still this repellency is significant (at 0.051 mg · cm−2, 86 % protection after 30 min) and worth mentioning here [184]. Also, a minor component of EO of catmint (Nepeta L. spp.) EOs [28], dihydronepetalactone, exhibits important repellency against arthropods, including mosquitoes [203]. Citronellyl acetate is a minor component of eucalyptus (Eucalyptus spp.) [165], lemon eucalyptus (E. citriodora) [66], rose (Rosa damascena) [87] and tarragon (Artemisia dracunculus) [99] EOs and is a feeding deterrent/repellent and mosquito spatial repellent/inhibitor. Also, the minor component of salvia/sage EO [92], hydroxy-p-cymene, is both a feeding deterrent/repellent and mosquito contact repellent/deterrent [186]. Lastly, isoeugenol (a component of clove EO) was found to be highly repellent to female Cx. pipiens pallens [151].

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Synthetic EOs: Additive Effects/Synergism versus Suppression/Dilution

In some cases, patented formulations in effect improve upon the natural repellency of an essential oil by mimicking or synthesizing an oil which ideally contains components which together contribute to the repellent effect and eliminates those which counteract (attract mosquitoes), make no contribution or suppress the repellency of other components. Work done by Odalo et al. [183] nicely illustrates this process. An initial observation was that major components of 6 EOs when tested singly were less repellent than the natural EOs in which these components are found. Synthetic EOs were prepared by mixing pure major components in the same proportion in which they occur in the natural EOs. Repellencies of synthetic EOs ranged from comparable to up to three times the activity of the corresponding natural EOs against An. gambiae in the human-bait test based on RC75 values [183]. The activity of synthetic EOs substantiates the additive and/or synergistic nature of the interaction of blended EO components (and also suppressive or diluting/repellency diminishing effects of nonactive components). The same principles of addition/synergism and suppression/dilution are operational in the process of formulating EOs and isolated components into patented repellent inventions.

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Enantiomeric Composition of EOs

Scientific (and patent) literature on the composition of EOs is often based on non-chiral column gas chromatography-mass spectrometry (GC‐MS) and compound retention time/index analysis. Thus, information is not systematically available on the enantiomeric purity of the EO components in [Table 1]. Enantiospecificity in mosquito repellency is an important issue. For example, Gu et al. [189] found that commercial R-(−)-terpinen-4-ol exhibited > 90 % repellency against Ae. aegypti and Ae. albopictus adults at a concentration of 1.92 µg · cm−2 in a test lasting 1 h. S-(+)-terpinen-4-ol of high enantiomeric purity is found in lavender (Lavandula angustifolia) EOs [204]. No mosquito repellency data were found in the literature for S-(+)-terpinen-4-ol. In principle, enantiomers may not be equally repellent to mosquitoes and their organoleptic and other properties (toxic, allergic, etc.) are not equally desirable for use as repellents. More research is needed on the comparative mosquito repellency of enantiomerically pure EO components such as S-(+)-terpinen-4-ol and R-(−)-terpinen-4-ol against different mosquito species.

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Allergenicity of EO Chemical Components

Limonene, benzyl alcohol, linalool, citronellol, geraniol, citral, anisyl alcohol, cinnamaldehyde, eugenol, isoeugenol, coumarin, farnesol, benzyl benzoate, benzyl salicylate among other volatile components are known allergens. As described above, these components are major or minor components of EOs used in repellent inventions ([Table 1] and references cited therein). These and other volatile allergens are easily detected by GC‐MS and are controlled in the European Union and elsewhere.

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Conclusion

Patents on plant EO and volatile component-containing mosquito repellent inventions make use of scientifically substantiated claims to repellency to mosquitoes based on lab and field experiences. Our experience is that mosquito repellents and other insect control products, must be evaluated in the environments and settings in which they are to be used. Repellents must be developed based on plant oils and isolated chemical components by targeting Aedes, Anopheles, Culex and other mosquito species which are found locally and regionally. Repellency approaches should be multipronged and make use of sprays, fumigants, paints and varnishes, incense, candles, etc. in domestic settings, fumigation and spraying in outdoor settings and topical repellents, clothes made of repellent fabrics, repellent wristbands among other available products for individual protection.

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Acknowledgements

The authors are grateful to Joanne Bero and Joëlle Quetin-Leclercq for the invitation for this review. Our thanks also go to the anonymous referee for many invaluable corrections and suggestions. The authors are thankful for grants and/or scholarships received from Brazilian agencies MCT/INPA, CNPq 561559/2008-2 and 555.669/2009-2 (Brazilian Malaria Network), CNPq Bionorte Network grant 2009, FAPERN.

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References

Prof. Dr. Valter Ferreira de Andrade Neto

Laboratory of Malaria and Toxoplasmosis Biology
Department of Microbiology and Parasitology
Rio Grande do Norte Federal University (UFRN)

Campus Universitário

Lagoa Nova

CEP 59072-970 Natal – RN

Brazil

Phone: + 55 84 32 15 34 37, ext. 225, 226

Fax: + 55 84 32 11 92 10

Email: [email protected]

#

References

Prof. Dr. Valter Ferreira de Andrade Neto

Laboratory of Malaria and Toxoplasmosis Biology
Department of Microbiology and Parasitology
Rio Grande do Norte Federal University (UFRN)

Campus Universitário

Lagoa Nova

CEP 59072-970 Natal – RN

Brazil

Phone: + 55 84 32 15 34 37, ext. 225, 226

Fax: + 55 84 32 11 92 10

Email: [email protected]

Zoom Image

Fig. 1 Analysis of EO-containing patented mosquito repellent inventions by patenting country, patent language, patent type and utility.