Insect repellents - Past, present and future

Abstract

Chris Peterson and Joel Coats from the Department of Entomology at Iowa State University, USA, review the history of insect repellents from the 1920s down to recent work on plant-derived repellents.

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154 Pesticide Outlook – August 2001 DOI: 10.1039/b106296b
This journal is © The Royal Society of Chemistry 2001
Introduction
Insect repellents are an alternative to the use of insecticides.
They may be applied to the skin to protect an individual
from the bites of mosquitoes, mites, ticks and lice or, less
commonly, may be used to exclude insects from an area,
such as in packaging to prevent infestation of stored
products. In our opinion, these latter uses are under-
exploited at the current time. With increasing problems of
insecticide resistance and increasing public concerns
regarding pesticide safety, new, safer active ingredients are
becoming necessary to replace existing compounds on the
market. Furthermore, the use of repellents in an integrated
pest management program has been ignored to a large
extent. This article comprises a review of insect repellents,
followed by some new research conducted in our laboratory
on plant-derived insect repellents. Much of the current work
is condensed from Peterson (2001).
History of insect repellents
The use of insect repellent compounds dates back to
antiquity, when various plant oils, smokes, tars, etc. were
used to displace or kill insects. Before the Second World
War, there were only four principal repellents: oil of
citronella, sometimes used as a hair dressing for head lice,
dimethyl phthalate, discovered in 1929, Indalone
®
, which
was patented in 1937 and Rutgers 612, which became
available in 1939. At the outbreak of World War II, the
latter three components were combined into a formulation
for use by the military known as 6-2-2; six parts dimethyl
phthalate, two parts Indalone and two parts Rutgers 612.
Other military repellent formulae for use on clothing were
developed during the war, but they all failed to provide
desired protection of military personnel deployed around
the world. As a result, by 1956 the United States
government had screened over 20,000 potential mosquito
repellent compounds. In 1953, the insect repellent properties
of N,N-diethyl-m-toluamide (DEET, Figure 1) were
discovered and the first DEET product was introduced in
1956. DEET is still the most widely used mosquito repellent.
It has generally been regarded as safe, but toxic effects have
been recorded, including encephalopathy in children,
urticaria syndrome, anaphylaxis, hypotension and decreased
heart rate.
Several other compounds have been evaluated for
repellent activity, but none have had the commercial success
of DEET. For example, N,N-diethylphenyl acetamide
(DEPA) is licensed for use as a cockroach repellent in India
(Prakash et al., 1990) and Colgate-Palmolive has released in
Europe a cockroach repellent floor cleaner, Ajax Expel
®
, the
active ingredient of which is N-methyl neodecanamide. This
product has been shown to cause cockroaches to leave their
harborages and cockroaches are less likely to re-infest
previously occupied areas after treatment with the cleaner
(Brenner et al., 1998). Bayer AG plans to market a mosquito
repellent with the name BayRepel
®
, the active ingredient of
which is 1-piperidinecarboxylic acid, 2-(2-hydroxyethyl)-1-
methylpropylester (KBR 3023) (Yap et al., 2000). Active
ingredients for some insect repellents are shown in Figure 1.
Insect repellents of natural origin
Natural ingredients are included in some formulations of
insect repellents. Of 65 formulations of non-US-produced
insect repellents, 33 contained DEET and the remainder
contained natural oils (Schreck and Leonhardt, 1991). Of
901 substances (872 synthetics and 29 botanical oils) tested
INSECT REPELLENTS – PAST, PRESENT AND FUTURE
1
Chris Peterson and Joel Coats from the Department of Entomology at Iowa State University, USA, review the
history of insect repellents from the 1920s down to recent work on plant-derived repellents
INSECT REPELLENTS
1
This is journal paper J-19451 of the Iowa Agriculture and Home
Economics Experimental Station, Iowa State University, Ames, Iowa
50011, USA.
Figure 1. Structures of several insect repellents.

for repellency to four species of domiciliary cockroaches by
the US Department of Agriculture (USDA) between 1953
and 1974, 127 repelled 94% or more of the German
cockroaches, 61 repelled 100% and 13 repelled 100% of all
four species tested. None of those 13 was a botanical
extract, but many were analogs of natural products. 1,4-
Naphthoquinone has many substituted forms that occur in
nature (such as vitamin K). Klun et al. (2000) found that
Anopheles mosquitoes were differentially repelled by
isomers of some piperidines.
In the United States, citronella is a popular botanical
ingredient in insect repellent formulations. Candles and
incense containing oil of citronella are sold as insect
repellents. The insecticidal properties of this oil were
discovered in 1901, and it was used for a time as a hair
dressing for the control of fleas and lice. Few studies have
been undertaken to evaluate the efficacy of such products.
Despite popular conception, Lindsay et al. (1996) reported
that citronella candles or incense were ineffective for
reducing the biting pressure of mosquitoes. It was found
that burning an unscented candle had the same effects on
reducing the biting rate of mosquitoes in the field as a
citronella candle.
Three commercial products were recently evaluated for
repellency in a laboratory olfactometer against Aedes
aegypti. Buzz Away
®
(containing citronella, cedarwood,
eucalyptus and lemongrass oils), Green Ban
®
(containing
citronella, cajuput, lavender, safrole-free sassafras,
peppermint and bergaptene-free bergamot oils) and Skin-So-
Soft (containing various “oils and stearates”) failed to cause
any repellency in the olfactometer, though DEET formula-
tions were effective (Chou et al., 1997).
Neem oil, from Azadirachta indica, when formulated as
2% in coconut oil, provided complete protection (i.e. no
confirmed bites) for 12 hours from Anopheles mosquitoes
(Sharma et al., 1993). A neem extract proprietary product,
AG1000, has been shown to be repellent to the biting midge
Culicoides imicola, which can spread cattle diseases
(Braverman et al., 1999).
Quwenling, a popular Eucalyptus-based repellent
product, contains a mixture of p-menthane-3,8-diol (PMD),
isopulegone and citronellol. Quwenling has largely replaced
dimethyl phthalate as the insect repellent of choice in China
(Trigg, 1996). Eucalyptus oil itself, the principal ingredient
of which is PMD, provided protection comparable to DEET
in repelling Anopheles mosquitoes in field studies (Trigg,
1996). Although repellent to Culicoides impunctatus,
Eucalyptus oil was attractive to C. imicola (Braverman et
al., 1999).
A common practice is to place red cedar blocks or sachets
in closets to repel clothing moths. This is probably why
many hope chests are made of red cedar for protection of
heirloom clothing. Milled red cedar flake boards were found
to be repellent to the German cockroach, but not to
American or brown-banded cockroaches (Appel and Mack,
1989).
Insect repellent mode of action
In many cases, it has been found that behavior that can be
labelled as repellency may be the result of any number of
physiological or biochemical events. Mosquito repellency
caused by DEET is thought to be due to the blocking of
lactic acid receptors, abolishing upwind flight, resulting in
the insect “losing” the host (Davis and Sokolove, 1976).
Oleic and linoleic acids have been indicated in death
recognition and death aversion (repellency) in cockroaches,
and the term “necromone” has been proposed to describe a
compound responsible for this type of behavior (Rollo et al.,
1995).
Lactic acid is present in warm-blooded animal body odor
and sweat, and is attractive to female mosquitoes. In
behavioral studies lactic acid is essential to attraction of
Aedes aegypti, but lactic acid by itself is only mildly
attractive, indicating synergism with other unidentified
human odor components (Geier et al., 1996). Further
evidence for the role of lactic acid in host seeking comes
from studies examining mosquito physiology following a
blood meal. Host-seeking behavior in Aedes aegypti stops
after taking a blood meal. It has been found that following a
blood meal, the sensitivity of lactic acid sensitive neurons
drops, and this drop is co-incident with the cessation of
host-seeking behavior. Lactic acid sensitivity returns to
normal after oviposition (Davis, 1984). This serves to
support the hypothesis that host seeking behavior may be
modified by affecting the lactic acid receptor mechanisms of
a mosquito.
It is unclear if repellents work by common mechanisms in
different arthropods, and conflicting evidence exists in the
literature. On the one hand, DEET is effective against many
other Diptera of medical importance, as well as
hematophagous Hemiptera, Siphonaptera, Hymenoptera,
Acarina and Gnathobdellidae (an annelid family), suggesting
that DEET operates on a fundamental physiological basis
common to members of the arthropod-annelid evolutionary
line (Rutledge et al., 1978, and references therein). Ticks
detect repellents on the tarsi of the first pair of legs (Haller’s
organ) and insects detect the same substances on the
antennae. These structures are thought to be serially
homologous between the two classes. Furthermore, the
differences in sensitivity to repellents between different
classes, orders and families are differences of degree only; no
fundamental differences in the type of response are observed
(Rutledge et al., 1997). On the other hand, virtually no
sequence homology was found between genes coding for the
olfactory receptors of Drosophila and Caenorhabiditis
elegans (Vosshall et al., 1999). Furthermore, there is not yet
any comparison of olfactory gene sequence among the
various arthropods, and there is no record of the response of
C. elegans to DEET or other arthropod repellents.
Different insects differ in their sensitivity to insect
repellents. Differences are loosely related to the taxonomic
distance between the groups compared. Among mosquitoes,
observed ED
50
values for DEET differed by as much as 1.75
times between different strains of Aedes aegypti, as much as
3.45 times among species of the same genus (observed in
Anopheles) and as much as 7 times between different
genera. The most sensitive species of Culex, Cx. pipiens, is
6.9 times more sensitive than the most tolerant species of
Anopheles, An. albimanus; An. quadrimaculatus, however,
Pesticide Outlook – August 2001 155
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is not significantly more tolerant than Cx. tarsalis.
Differences in sensitivity were stable over several
generations, indicating a genetic, heritable basis of tolerance
(Rutledge et al., 1978). DEET tolerance was found to be
incompletely dominant (Rutledge et al., 1994).
Structure-activity relationships of repellents are unclear,
and little definitive work has been done. Visual examination
of Figure 1 shows that when an insect repellent incorporates
a ring structure, there is often a carbonyl group immediately
removed from the ring. Davis (1985) mentions other sources
that report that an oxygen functional group is necessary for
activity. In one study, patterns of sensitivity were similar
among some chemicals of unrelated structure, but some
differences existed between the sensitivity to compounds of
similar structure. Observed non-correlation of structure
with activity suggests that repellent tolerances may be non-
adaptive; i.e. evolved by random drift of selectively neutral
mutations (Rutledge et al., 1997). Although effective topical
mosquito repellents fall in a range of molecular weights of
150–250 (Taylor et al., 1996), vapor pressure is the only
parameter significantly related to mosquito repellent activity
(Davis, 1985). Partition coefficient, molecular weight,
infrared absorption, viscosity, surface tension, molecular
polarizability, and Hammett substituent constants have all
failed to be correlated to repellent activity (Davis, 1985).
Current research in insect repellents
Over the past several years, our laboratory has conducted
research investigating insect repellents of natural origin.
Insect repellents for protection of humans from biting
arthropods, principally mosquitoes, make up the lion’s share
of insect repellents sold in the United States. As mentioned
earlier, we believe that many applications of insect repellent
technology are under-utilized at this time. The use of
repellent barrier strips to prevent entry of insects into
sensitive areas is a largely untried approach. Pyrethroid
insecticides are sometimes used in this manner, but the acute
toxicity of these compounds to the insects is the principal
mode of action of these compounds. Also, impregnation of
repellents into packaging to prevent insect infestation of
stored or shipped products is also not commonly used. Our
work addresses some of the methods and materials that may
be employed in screening potential new active repellents in
novel applications.
Our work has focussed on insect repellents derived from
two plant species, the Osage orange (hedgeapple) (Maclura
pomifera) and catnip (Nepeta cataria).
Osage orange
The fruit of the osage orange has been utilized as an insect
repellent for many years. Pioneers in the American West
placed the ripe fruit of this tree in cupboards to repel
cockroaches and other insects (Sand, 1991). The scientific
validity of this well-popularized practice has been little
studied. Karr and Coats (1991) found that fragments of
Osage orange fruit, as well as its hexane and methanol
extracts, were significantly repellent to the German
cockroach Blattella germanica. Later research in our
laboratory demonstrated that the dichloromethane extracts
of Osage orange fruit were also repellent to the maize weevil
Sitophilus zeamais. We examined the extracts and found
that they contained two isoflavones, osajin and pomiferin
(Figure 2) (Peterson et al., 2000).
The previous study made no attempt to determine volatile
components of the Osage orange extracts. Volatility is
viewed by many as being essential to repellent activity,
although a compound irritating to the feet of an insect will
cause that insect to spend less time in a treated area. Our
next study employed gas chromatography and mass spectro-
scopy (GC-MS) to identify volatile components of Osage
orange essential oil and test the oil and its constituents in
repellency trials. Numerous sesquiterpenoids were deter-
mined to be present in the oil, and many of them were
repellent to the German cockroach (Figure 3) (Peterson et
al., accepted). To our knowledge, this was the first
examination of volatile components of Osage orange oil.
Because all of the compounds identified are well-known and
some are available from other sources, and because there is
only a small quantity of essential oil in an Osage orange, it
may be more economical to extract active compounds from
other sources. Whether these compounds are synergistically
enhanced in mixture or if the compounds would be effective
singly is currently under investigation.
Catnip
Catnip has been noted for many years for its intoxicating
effect on cats. Nepetalactone has been isolated as the active
component of catnip, with two isomers being present in the
plant’s essential oil: Z,E (cis, trans) and E,Z (trans, cis), with
Z,E-nepetalactone predominating (Figure 4). Modern
nomenclature denotes the cis, trans isomer as Z,E and the
trans-cis isomer as E,Z. Catnip has folk uses as an insect
repellent, some of which have been confirmed scientifically.
Hot water extracts of catnip deterred flea beetles in one
study, and fresh catnip repelled black ants (Riotte, 1975),
and it was found to be repellent to members of 13 families
of insects (Eisner, 1964).
Nepetalactone is also an important component of the
defensive secretions of the coconut stick insect (Smith et al.,
1979) and the lubber grasshopper (Snook et al., 1993). We
isolated and purified the individual isomers of nepatalactone
and compared their activities to DEET. It was found that the
E,Z- isomer was more active than the Z,E- isomer and
DEET at both concentrations tested (Figure 5) (Peterson et
156 Pesticide Outlook – August 2001
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Figure 2. Chemical structures of osajin (R = H) and pomiferin
(R = OH).

al., submitted). The structures of the nepetalactone isomers
(Figure 4) differ only in the orientation of a single chemical
bond. Why this difference results in higher repellency is
unknown. Obviously the E,Z- isomer has greater action
than the Z,E- isomer at some receptor. Very little is known,
however, about the receptors responsible for the repellent
response in cockroaches; it is not known if receptors specific
for repellents even exist. In all likelihood, the receptors
involved are specific for other compounds, and the action of
repellents at these receptors is secondary (such as the
proposed mode of action of DEET mentioned in this article).
Future outlook
Much more work needs to be done before it can confidently
be stated if insect repellents work in integrated pest
management systems. The safety of many of these
compounds still needs to be evaluated and field efficacy
trials are also required. It is hoped that repellent compounds
may be applied at levels lower than those compounds that
are acutely toxic, thereby lowering the pesticide load on the
urban environment, but this hope is purely conjectural at
this point.
The use of repellents by travellers (civilian and military)
may reduce the occurrence of local disease incidences in
temperate areas. In countries such as Kenya, where tourism
is a major source of national income, the use of repellents
can increase the pleasure and comfort of tourists. In military
operations, they may reduce the incidence of illness and
reduce annoyance to personnel, who can then complete their
operations more efficiently. Repellents can therefore be
viewed as a tool with a specific role in protecting people
from insect-borne illnesses. More traditional pest
management operations (larval control treatments for
mosquitoes, poisoned baits for cockroaches etc.) need to be
used in conjunction with repellent technology. Repellents
may have an increasingly important role in eliminating
insects from certain environments (such as schools, hospitals
and food preparation areas), and we believe that natural
products, such as essential oils, could play a major role in
new repellent technology.
Pesticide Outlook – August 2001 157
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Figure 3. Repellency of Osage orange constitutents to the
German cockroach.
Figure 4. Structures of nepetalactone isomers from catnip.
Figure 5. Repellency of Z,E- and E,Z-nepetalactone isomers
compared to DEET.
Osage orange (hedgeapple) (left) and catnip (right), two plant species from which insect repellents have been extracted.

References
Appel, A. G.; Mack, T. P. (1989) Repellency of milled aromatic
eastern red cedar to domiciliary cockroaches (Dictypotera: Blat-
tellidae and Blattidae). Journal of Economic Entomology, 82(1),
152–155.
Braverman, Y.; Chizov-Ginzburg, A.; Mullens, B. A. (1999)
Mosquito repellent attracts Culicoides imicola (Diptera: Cerato-
pogonidae). Journal of Medical Entomology, 36(1), 113–115.
Brenner, R. J.; Milne, D. E.; Kinscherf, K. M.; Connors, T. F.
(1998) Measuring spatial displacement of Blattella germanica
(Blattaria: Blattellidae) populations pressured by repellent-
treated harborages. Environmental Entomology, 27(1), 10–21.
Chou, J. T.; Rossignol, P. A.; Ayres, J. W. (1997) Evaluation of
commercial insect repellents on human skin against Aedes
aegypti (Diptera: Culicidae). Journal of Medical Entomology,
34(6), 624–630.
Davis, E. E. (1984) Regulation of sensitivity in the peripheral
chemoreceptor systems for host-seeking behavior by a
haemolymph-borne factor in Aedes aegypti. Journal of Insect
Physiology, 30(2), 179–183.
Davis, E. E. (1985) Insect repellents: Concepts of their mode of
action relative to potential sensory mechanisms in mosquitoes
(Diptera: Culicidae). Journal of Medical Entomology,22(3),
237–243.
Davis, E. E.; Sokolove, P. G. (1976) Lactic acid-sensitive receptors
on the antennae of the mosquito, Aedes aegypti. Journal of
Comparative Physiology, 105, 43–54.
Eisner, T. (1964) Catnip: its raison d’etre. Science 146, 1318.
Geier, M.; Sass, H.; Boeckh, J. (1996) A search for components in
human body odour that attract females of Aedes aegypti. In:
Olfaction in Mosquito-Host Interactions. Ciba Foundation
Symposium 200, Wiley, Chichester, UK. pp. 132–148.
Karr, L. L.; Coats, J. R. (1991) Repellency of dried bay leaves
(Laurus nobilis), Wrigley’s
©
spearmint gum, raw Osage orange
fruit (Maclura pomifera), and extracts of Osage orange fruit to
the German cockroach. Insecticide and Acaricide Tests 17, 393.
Klun, J. A.; Ma, D.; Gupta, R. (2000) Optically active arthropod
repellents for use against disease vectors. Journal of Medical
Entomology,37(1), 182–187.
Lindsay, L. R.; Surgeoner, G. A.; Heal, J. D.; Gallivan, G. J. (1996)
Evaluation of the efficacy of 3% citronella candles and 5%
citronella incense for protection against field populations of
Aedes mosquitoes. Journal of the American Mosquito Control
Association, 12, 293–294.
Peterson, C. J.; Zhu, J-W.; Coats, J. R. (in press) Identification of
components of Osage orange fruit (Maclura pomifera) and their
repellency to German cockroaches. Journal of Essential Oil
Research.
Peterson, C. J.; Nemetz, L. T.; Jones, L. M.; Coats, J. R. Behavioral
activity of catnip, Nepeta cataria (Lamiaceae), essential oil
components to the German cockroach, Blattella germanica
(Blattodea: Blattellidae). Journal Economic Entomology,
(submitted 2001)
Peterson, C. J.; Fristad, A.; Tsao, R.; Coats, J. R. (2000)
Examination of osage orange fruits and two isoflavones, osajin
and pomiferin, for repellency to the maize weevil, Sitophilus
zeamais (Coleoptera: Curculionidae). Environmental
Entomology, 29, 1133–1137.
Peterson, C. J. (2001) Insect repellents of natural origin: Catnip
and osage orange. Ph.D. Dissertation, Iowa State University,
Ames, IA.
Prakash, S.; Srivastava, C. P.; Kumar, S.; Pandey, K. S.; Kaushik,
M. P.; Rao, K. M. (1990) N,N-Diethylphenylacetamide – A new
repellent for Periplaneta americana (Dictyoptera: Blattidae),
Blattella germanica, and Supella longipalpa (Ditcyoptera: Blat-
tellidae). Journal of Medical Entomology, 27(6), 962–967.
Riotte, L. (1975) In Carrots Love Tomatoes: Secrets of Companion
Planting for Successful Gardening. Garden Way Publ.
Charlotte, VT.
Rollo, C. D.; Borden, J. H.; Casey, I. B. (1995) Endogenously
produced repellent from American cockroach (Blattaria:
Blattidae): function in death recognition. Environmental
Entomology, 24(1), 116–124.
Rutledge, L. C.; Gupta, R. K.; Mehr, Z. A. (1997) Evolution of
repellent tolerances in representative arthropods. Journal of the
American Mosquito Control Association,13(4), 329–334.
Rutledge, L. C.; Gupta, R. K.; Piper, G. N.; Lowe, C. A. (1994)
Studies on the inheritance of repellent tolerances in Aedes
aegypti. Journal of the American Mosquito Control
Association, 10(1), 93–100.
Rutledge, L. C.; Moussa, M. A.; Lowe, C. A.; Sofield, R. K. (1978)
Comparative sensitivity of mosquito species and strains to the
repellent diethyl toluamide. Journal of Medical Entomology,
14(5), 536–541.
Sand, S. (1991) A tree of history, the Osage orange. American
Horticulturalist, 70, 37.
Schreck, C. E.; Leonhardt, B. A. (1991) Efficacy assessment of
quwenling, a mosquito repellent from China. Journal of the
American Mosquito Control Association, 7(3), 433–436.
Sharma, V. P.; Ansari, M. A.; Razdan, R. K. (1993) Mosquito
repellent action of neem (Azadirachta indica) oil. Journal of the
American Mosquito Control Association, 9(3), 359–360.
Smith, R. M.; Brophy, J.; Joseph, C.; Davies, N. (1979) Iridodials
and nepetalactone in the defensive secretions of the coconut
stick insects Graeffea crouani. Journal of Chemical Ecology, 5,
727–735.
Snook, M. E.; Blum, M. S.; Whitman, D. W.; Arrendale, R. F.;
Costello, C. E.; Harwood, J. S. (1993) Caffeoyltartronic acid
from catnip (Nepeta cataria): a precursor for catechol in lubber
grasshopper (Romalea guttata) defensive secretions. Journal of
Chemical Ecology, 19, 1957–1966.
Taylor, W. G.; Hall, T. W.; Schreck, C. E. (1996) Synthesis and
mosquito repellent properties of 2,2-dialkyl- and 2-alkyl-4,4-
dimethyl-N-acetyloxazolidines. Pesticide Science, 46, 307–314.
Trigg, J. K. (1996) Evaluation of a eucalyptus-based repellent
against Anopheles spp. in Tanzania. Journal of the American
Mosquito Control Association, 12(2), 243–246.
Vosshall, L. B.; Amrein, H.; Morozov, P. S.; Rzhetsky, A.; Axel, R.
(1999) A spatial map of olfactory receptor expression in the
Drosophila antenna. Cell, 96, 725–736.
Yap, H. H.; Jahangir, K.; Zairi, J. (2000) Field efficacy of four
insect repellent products against vector mosquitoes in a tropical
environment. Journal of the American Mosquito Control
Association,16(3), 241–244.
158 Pesticide Outlook – August 2001
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