Transcript Insect repellents

Repellents
Scientific and statutory evaluation
Déborah LAIDIÉ, Pauline RABOURDIN, Clio VASSILIADIS
January 2009 Faculty of Pharmacy of Lille 2 University
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Definition: Insect repellents (répulsifs)
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Products that people use on skin, clothing. To repel
or keep away insects without killing them.

To repel insects = to prevent them from attacking
men and animals.
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Work on several arthropods like mosquitoes, flies,
ticks, fleas, acarids …
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Remain ineffective on the bee and the wasp.
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Should not pass in systemic ideally.
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Various contact repellents
Repellents of natural origin
Essential oils
citronella
geranium
?
Synthetic repellents
DEET =
Diéthyltoluamide
Éthylhexanediol
peppermint
Diméthylphtalate
eucalyptus
lemongrass
soybean
Picaridin
Ethyl Butylacetylaminopropionate: IR3535
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A crucial role for vector-borne diseases.
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Endemic zones:
■ Malaria
■ Dengue
■ Yellow fever
■ Lyme disease
■ West Nile Virus
■ Chikungunya
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Repellents History
1901
1957
1946
Citronella oil
discovery
1980
Reassessment
by US
Environmental
Protection
Agency
First
registration for
public use in
the US
Development of
DEET by US
Department of
Agriculture and
US Army
1998
2002
Reassessment by
Santé Canada
Registration
Standard
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DEET Compound

Chemical family :
N,N dialkylamide.

Solubility :
Insoluble in water and glycerin
but miscible with several organic
solvents.

Physical properties :
Relatively stable, highly
hygroscopic and sensitive to light.
Chemical name :
N,N-diéthyl-3-méthylbenzamide
or
N,N diéthyl-m-toluamide
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How mosquitoes smell humans?
Physical factors
 Visual factors
 Human emanations or secretions are attractive:

 Human breath :
CO2
 1-octen-3-ol
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 Human sweat :
Lactic acid
 Ammonia
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Mechanism of action
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Pharmacological action ( in mosquito)
DEET binds to specific ORNs (olfactory receptor neuron)
situated on the antennae and maxillary palps of the mosquitoes
 inhibition of the electrophysiological responses to attractive
odors.

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« Fixative » effect ( on human skin )

DEET suppresses the release of physiologically relevant
compounds that are attractant for the mosquitoes
Spikes/s
Mosquitoes smell DEET and avoid it
Excitatory responses from an ORN
Source dose (µg)
upon stimulation with increasing doses of DEET.
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13598-13603 / PNAS September 9, 2008 / vol.105
Measure of efficacy
Control
DEET
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USDA-ARS-CMAVE Mosquito and Fly research Unit
DEET efficacy
Duration of
action
60%
8,2h
50%
8h
30%
6h
20%
7%
4h
2h
9
8
7
6
duration of action (h)
Concentration in
ethanol
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Série1
4
3
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The protection provided by DEET is
proportional to the concentration of the
applied solution.
Higher concentrations of DEET provide
longer-lasting protection.
The duration of action tends to a plateau at a
concentration of about 50%.
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1
0
0,00%
10,00%
20,00%
30,00%
40,00%
50,00%
60,00%
70,00%
80,00%
concentration (%)
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DEET efficiency

In practice, the following factors reduce the duration of action of the
repellents :
Sweating
 Water contact (swimming, washing-off from rain…)
 Friction (physical activities, abrasion from clothing…)
 Ambient temperature
 Ambient humidity
 Windy environment


No guidelines are available to help consumers decide what
concentration of DEET is appropriate for their specific need.

 « Insect Repellent Factor »?
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Systemic exposure of DEET
Pharmacokinetics in human

Absorption
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Systemic absorption begins within 2h of topical application and continues over 8
hours.
Between 3% and 56% of dermal applied DEET is absorbed through the skin.
17% of the absorbed dose enters the bloodstream.
Distribution

DEET distributes into :
-
skin
fatty tissues
but does not accumulate in the
superficial layers of the skin.
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Centre de toxicologie du Quebec Bulletin d’information toxicologique, Avril 1998-Vol.14 Num
Pharmacokinetics
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Metabolism by liver
 Oxidation
1A2.
by cytochromes P450 2B6 and
 Dealkylation
and 3A4.
by cytochromes P450 2C19
 Residual
metabolites may persist for up
to 3 months in adipose tissues, muscles
and other tissues adjacent to the site of
application.
Pathway of DEET Metabolism
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Centre de toxicologie du Quebec Bulletin d’information toxicologique, Avril 1998-Vol.14 Num 2
Pharmacokinetics

Elimination via the kidneys
 10 to 15% of the parent compound
is
excreted unchanged.
 There is a relationship
between DEET
urine concentrations and use.
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Centre de toxicologie du Quebec Bulletin d’information toxicologique, Avril 1998-Vol.14 Num 2
DEET : reported side effects (last 50 years)
Caused by prolonged use or ingestion.
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Cardiovascular : One case (systemic effects)
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Central nervous system : 25 cases, especially children (accumulation in fatty tissues)
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Bradycardia
Hypotension
Lethargy, confusions, acute manic psychosis
Headaches, disorientation, ataxia
Convulsions, coma
Behavioral changes, confusions, tremors, encephalopathy, seizures
Cutaneous or allergic reaction : 17 cases
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Anaphylaxis
Wheals
Irritation, redness, rash, and swelling
Haemorrhagic bulla and erosion.
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Am. J. Trop. Med. Hyg., 59(2), 1998, pp. 323–324
Children / Adults

Compared with adults, children may absorb more DEET because their
skin surface area is proportionally larger relative to their weight.
20 years, 177cm, 66kg
SC = 1,80m²
SC/weight = 280cm²/kg
8 years, 128cm, 25kg
SC = 0,95m²
SC/weight = 380cm²/kg
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DEET and children

Topical application of high-concentration products might be problematic in
children because of their high surface area to body mass ratios.
Children age
Under 6 months
Products with
10% of
DEET
Do not use
Products with
11-30% of DEET
From 6 months
to 2 years
From 2 years to
12 years
Only one
3 applications per
application per day day to the maximum
Do not use for children under 12 years
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Pest Management Regulatory Agency, Health Canada, Septembre 2004
Actual exposure of Children
to DEET
Active ingredients and concentrations
( in an American camp during summer 2002)
Deet 95%
Deet 31-40%
Deet 21-30%
Deet 11-20%
Deet < 10%
0
5
10
15
20
25
30
35
40
45
Percent of subjects applying products to children (n=301)
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AMERICAN JOURNAL OF INDUSTRIAL MEDICINE 47:91–97 (2005)
Other recommended precautions
for DEET uses on children
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Not allowing young children to apply repellents themselves
Not treating faces directly
Avoiding application to palms of the hands
Avoiding application to non-exposed skin
Avoiding application to irritated or abraded sites
Wash the repellent off before going to bed
 It would be prudent to increase efforts to educate parents about
recommended procedures for use of repellents on children.
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AMERICAN JOURNAL OF INDUSTRIAL MEDICINE 47:91–97 (2005)
Profit / Risk
Endemic zones:
Malaria
Dengue
Yellow fever
Lyme disease
West Nile Virus
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Dengue
The risk of DEET-related adverse effects
pales in comparison with the risk of
acquiring vector-borne infection.
Lyme disease
West Nile Virus
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http://www.centres-antipoison.net/lyon/vigitox14/index.html
A
DEET
and
sunscreens
A case of drug-drug interaction?
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Association with sunscreen

Can I use an insect repellent containing DEET and sunscreen at
the same time?
VS
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DEET and Sunscreens

Questions to address :
 Application order (sequence)
 Multiple formulations: lotions, gels, sprays…
 Age
 Skin type and anatomical site
 Time between both applications
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Phased out of sunscreen-DEET
combination products

Incompatible label instructions regarding methods
of application of each component :
Insect repellents should be applied sparingly.
▪ Sunscreens should be applied liberally and frequently.
▪
 Phased out of December 31, 2003.
252004
HealthCanada, Tips on using personal insect repellents, September
What about applying an insect repellent
and a sunscreen successively ?
Influence of formulation and application order
Study design
1
2
4
5
Repellent (g)
1,0 (A)
1,0 (B)
0,5 (A)
0,5 (A)
Sunscreen (g)
0
0
0,5 (C)
0,5 (C)
A : top
C : bottom
No mixing
A : bottom
C : top
No mixing
Application
method
Direct
Direct
application application
A: OFF® Spray (DEET)
B: OFF® Lotion (DEET)
C: Coppertone® Sunblock Lotion (SPF 30)
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J Pharm Pharmaceutical Sciences17-25, 2007
Permeation of oxybenzone is also
modified by DEET
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J Pharm Pharmaceutical Sciences 17-25, 2007
Time between applications
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Effect of insect repellent on protection provided by sunscreen
Sunscreen alone after 15min
Sunscreen with insect repellent
after 15min
Sunscreen with insect repellent
after 45min
Sunscreen with insect repellent
after 75min
Sunscreen with insect repellent
after 105min
Sunscreen alone after 105min
Insect repellent alone after 15min
SPF value (Sun Protection Factor)
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The Lancet , Insect Repellents and the efficacy of sunscreens, Vol. 349 . June 7, 1997
Systemic exposure
Profit / Risk
Pharmacokinetics
Regulatory status of DEET?
Side effects
Interactions
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DEET: Is it a cosmetic? A drug?
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How does the law define a cosmetic?
Articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or
otherwise applied to the human body...for cleansing, beautifying, promoting
attractiveness, or altering the appearance.

Cosmeceuticals
Cosmetic products that are claimed, primarily by those within the cosmetic industry,
to have drug-like benefits, example : antiaging cream.

How does the law define a drug?
Substance intended for use in the diagnosis, cure, relief, treatment, or prevention
of disease or intended to affect the structure or function of the body.
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FDA, July 8 2002 .
Drug definition
A drug is defined by U.S. law as any substance
(other than a food or device) intended for use in the
diagnosis, cure, relief, treatment, or prevention of
disease or intended to affect the structure or
function of the body.
 A simpler but workable definition of a drug is any
chemical substance that affects the body and its
processes.

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Last full review May 2007 by Eva M. Vivian, PharmD
Regulatory
12 Décembre 2002 : Health Canada
Re-evaluation of personal insect repellents containing DEET
New view : The usage of products containing DEET (with concentrations of
30 percent and below; 10 percent and below for children) provides
protection against insects including mosquitoes and black flies and can be
used safely when used according to label directions.
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Pest Management Regulatory Agency-Health Canada
Survey about labelling
Dosage
Duration of action
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Pest Management Regulatory Agency-Health Canada
Labelling Requirements
DEET …… XX,XX %
DIRECTIONS FOR USE
TELEPHONE NUMBER
INSECT REPELLENT
PRECAUTIONS
FIRST AID
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Pest Management Regulatory Agency-Health Canada
A particular status

Regulatory Status : Biocides.
Group 3 : anti-parasitical products.
PHARMACOVIGILANCE

COSMETOVIGILANCE
Repellents will be subjected to a re-evaluation
procedure with a view to obtain an Marketing
Authorization in 2009-2010.
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Ministère de la Santé, de la Jeunesse et des Sports, 24 Juillet 2008
New generation of repellents

To be economically viable, any competitor not only
must repel insects better than DEET, but also
overcomes its disadvantages :
More efficacious
 Safer
 Effective for a longer duration

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Promising compounds :
Acylpiperidines
 Carboxamides
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Piperidines: a pharmaceutical
approach
O
O
N
CH3
N
HN
CH3
CH3
CH3
DEET
Piperidine
1-(3-methylbenzoyl)piperidine
Development of models for repellents based on pharmacophores
using a quantitative structure–activity relationship (QSAR) approach.
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Carboxamides : a pharmaceutical
approach
O
N
CH3
CH3
CH3
DEET
SS220
(1S, 2'S)-2-methylpiperidinyl-3-cyclohexene-1carboxamide
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Product subjected to EPA chronic toxicity studies.
More efficient than DEET : a 20% SS220 solution is as good as 33% DEET.
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New test for evaluation
2008 : Development of quantitative studies more scientific.
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Science, 28 March 2008 , Vol.319
Summary of Product Characteristics
of DEET
1 - Name of the medicinal product
2 - Qualitative et quantitative composition
3 - Pharmaceutical form
4 - Therapeutic indications
5 - Posology and method of administration
6 - Contraindications
7 - Special warnings and precautions
for use
8 - Interaction with other medicinal
products and other forms of interactions
9 - Undesirable effects
10 - Pharmacodynamic properties
11 - Pharmacokinetic properties
12 - Overdose
13 - Marketing autorisation holder
14 - Marketing autorisation number
DEET = DRUG
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Thank you for your attention!
Déborah LAIDIÉ, Pauline RABOURDIN, Clio VASSILIADIS
January 2009 Faculty of Pharmacy of Lille 2 University
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References
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Pest Management Regulatory Agency, Health Canada « Décision de réevaluation insectifuges
corporels contenant du DEET » (2002)
The Lancet, « Insect Repellents and the efficacy of sunscreens » Vol. 349, June 7, 1997.
New England Journal of Medicine, « Comparative Efficacy of Insect Repellents against Mosquito
Bite » 347:13-18, July 4, 2002.
HealthCanada, « Tips on using personal insect repellents » September, 2004.
Proceedings of the National Academy of Sciences, « Mosquitoes smell and avoid the insect
repellent DEET » June 12, 2008.
University of Florida-Department of Chemistry, « Discovery of Novel Biting Fly Repellent and
Insecticides from Structure Activity Studies » March 2-6, 2008.
Centre de toxicologie du Quebec, « Innocuité de l’insectifuge DEET »Vol.14 num.2, Avril 1998.
American Journal of Industrial Medicine, « Exposure of children to deet and other topically
applied insect repellents » Vol.47 Issue 1, December 13, 2004.
Science, « Insect Odorant Receptors Are Molecular Targets of the Insect Repellent DEET » Vol.319,
March 28, 2008.
Environmental Protection Agency « Reregistration Eligibility Decision DEET » September, 1998.
Mark S. Fradin « Mosquitoes and Mosquito Repellents: A Clinician's Guide » Vol.128 issue 11,
June 1, 1998.
Food and Drug Administration, « Is it a cosmetic,drug or both? » July 8, 2002.
Ministère de la Santé, de la Jeunesse et des Sports, « Comment se protéger des piqûres
d’insectes et autres arthropodes » 24 Juillet 2008.
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References
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Reregistration Eligibility Decision DEET ,EPA738-R-98-010 September 1998
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La revue Prescrire 1994; 14 (141) : 347-356
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La revue Prescrire 2008; 28 (296): 436-445
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CIRCULAIRE N°DGS/DUS/RI1/2008/138 du 17 avril 2008
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Qiu, Y.T. “Sensory and behavioral responses of the malaria mosquito Anopheles gambiae
to human odors” , 2005
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The American Society for Pharmacology and Experimental Therapeutics,
DMD 32:783–785, 2004
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Synthesis and bioassay of improved mosquito repellents predicted from chemical
structure, Proc Natl Acad Sci U S A. 2008 May 27; 105(21): 7359–7364.