IR3535: Several Applications

Denis Martins Joo Marketing Development October, 2011

Content
Section 1: Section 2: Insect Repellents Repellent Products

Section 3:
Section 4: Section 5:

Repellent Market
Marketing Information IR3535 Insect Repellent Regulations

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Section 1:
Definition Mode of Action

Insect Repellents

Competitive Repellent Actives

Competitive Repellent Actives and Uses

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Insect Repellents
Definition: Substance or formulation that causes insects to make oriented movements away from its source. IR3535 is: a personal repellent. Intended use: human and animal use on skin, hair or clothes a topical repellent. Application: to chosen parts of the skin and clothes. a synthetic repellent.
Synthetic repellents are developed for long lasting protection in comparison to natural repellents However, IR3535 is close to nature (similar structure like -alanin)
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Competitive Repellent Actives

First repellents were derived from nature. This repellents show high evaporation. Therefore the long time protection on skin was not possible. Examples are: Citronella Lemon Eucalyptus derived actives (PMD) Geraniol Modern synthetic repellents are optimized for long lasting protection on skin. Examples are:

DEET
IR3535 Icaridin
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Competitive Repellent Actives and Uses

Protection against: Mosquitoes (human use) IR3535 DEET Icaridin Protection against: Ticks (human use) Protection against: Flies (human use) Protection against: Lice (human use) Animal prod.

x
x x

x
x x

x
x x

x
x x

Citronella
Eucalyptus (PMD)

x
x

x
x

x
x

x
x

x
x

Geraniol
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Section 2:

Repellent Products

Application Forms on the Market Product Examples with IR3535

Mosquitoes, ticks, flies protection

Lice prevention Animal products Other Repellent Uses

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Application Forms on the Market

Intended use Human use on skin Target Organism Mosquitoes, flies, ticks, wasps, bees lice Formulation Aerosol, pump sprays, gel, cream, lotion, wipe, roll-on, mousse Pump spray

Human use on hair

Animal use

Flies, ticks, mosquitoes

Pump spray, gels, wipe

Innovations are possible. In any case leave-on products are needed. The repellent have to be available on skin or hair to be effective. Therefore, shampoos and shower gels are not suitable for the application of repellents.
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Product Examples with IR3535

Mosquitoes, ticks and flies protection

France

Asia and South America

Scandinavia

USA

in EU and Asia

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Product Examples with IR3535

Lice prevention

Europe

Belgium

Spain

Mexico

France

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Product Examples with IR3535

Animal products
Intended use: horse, against skin irritation Intended use: cat and dog, flea infestation Intended use: horse, insect repellent Intended use: horse, insect repellent Intended use: human&dog, tick protection

UK

UK

Germany

Germany

Germany

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Section 3:
Example USA Segments

Repellent Market

Claims
Example Europe Segments IR3535 Children Product Market IR3535 Animal Product Market

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Example US Insect Repellent Market

Segments (Target Groups) Family Nature & Sport

Family
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Active Expedition

Deep Woods

Example US Insect Repellent Market

Segments (special products) Soft Formulations Max-Products

Xtreme soft, gentle

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Maxi

claim example: maximum strength up to 10 hours protection

Claims
Efficacy Claims: long lasting protection repels mosquitoes that may carry West Nile Virus maximum strength up to 10 hours protection (high concentration products) Target Organism, for example: protection from ticks, mosquitoes and biting flies Formulation Claims: odorless non-greasy / not oily resists perspiration unscented Secondary Cosmetic Claims, for example: with Aloe Vera
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European Insect Repellent Market

Segments (Target Groups) Every Day european use Holiday tropical use

European Lotion

Europe

Tropic 35% IR3535

Jungle Formula

claim example: extra strong formula up to 8 hours protection

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European Insect Repellent Market

IR3535 Children Product Market Children
infents not specified

12% 22% 28% 37%

adults and infents

adults

22% of products are specific for infants 59% of products are claimed for infants

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European Insect Repellent Market

IR3535 Animal Products Market Animal
The horse market dominates

cat and dog market

fleas horse fly, ticks, flies, mosquitoes

horse (dog) market

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Section 4: IR3535
PROS of IR3535

Marketing Information

Broad Spectrum of Efficacy

Long Lasting Protection

Close to Nature Excellent Toxicological Profile Gentle to the Environment IR3535 in Children Products

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PROS of IR3535
Marketed since more than 30 years in Europe Broad spectrum of efficacy (1)

US-CDA recommendation for long lasting protection (2)

Close to nature: structural similarity with natural occurring -alanine (3) Excellent toxicological profile (classification as Bio-Pesticide in USA) (4) No danger symbols required for product labeling of IR3535 Gentle to the environment (biodegradable) (5) Excellent cosmetic properties: odourless liquid, highly stable excellent skin feeling

For all this reasons preferred active for especially children products (6)

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Broad Spectrum of Efficacy (1)

Claims with IR3535:
Mosquitoes Ticks Lice Stable flies Black flies Sand flies Deer flies Biting midges House flies Wasps Bees

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Efficacy IR3535
Repelling effect of is proven for:

Mosquitoes (Aedes spec., Culex spec. and Anopheles spec.) Ticks (Ixodes scapularis and Ixodes ricinus) Lice (Pediculus humanus corporis and capitis) Stable flies (Stomoxys calcitrans) Black flies (Simuliidae) Deer flies (Tabanidae) House flies (Musca domestica)

Wasps (Pollistes galliens)

Bees (Apis melifera)

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Broad Spectrum of Efficacy (1)

Year
1975 1981

Author / Institute
Kuhlow, F. Bernhard Nocht-Institut, Hamburg Liebisch A. Tierrztlichen Hochschule, Hannover

Type
Field test Lab test

Target organism
Mosquito An. funestus/gambiae Black Fly Simulium Mosquito Aedes aegypti

1982
1989/ 1990 1992 1993

Buescher M.D. et al.

Research Laboratory of Dainihon Ichugiku Co., Tokyo, Japan Coosemans N. Institute of Tropical Medicine, Belgium Combescot C. Faculty of Medicine,Tours, France

Lab test
Field test Lab test in-vitro test

Sand fly Lutzomyia longipalpis

Mosquito Aedes albopictus Mosquito Aedes aegypti Louse Pediculus humanus

1993
1995 1995

Combescot C. Faculty of Medicine,Tours, France

Burgess I. Medical Entomology Centre, Cambridge, UK Roubier C. BIO-TOX S.A.R.L. Vallauris, France

in-vivo test
in-vitro Test in-vitro Field test

Louse Pediculus humanus

Fly Musca domestica Wasp Polistes galliens, Bee Apis melifera

1996

Buczek A. Silesian Medical Academy, Katowice, Poland

in-vivo lab test

Tick Ixodes ricinus

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Broad Spectrum of Efficacy (1)

Year
1996 1996

Author / Institute
Benzon G.L. Benzon Research, Carlisle, PA, USA Broce A.B. Department of Entomology, KS, USA Cilek J.E. Mulrennan Research Laboratory A&M, FL, USA Hunter F. Department of Biologicsal Sciences, St. Catharines Shashina N.I. Russion Acedemy of Medical Sciences, Moscow Yap H.H. Vector Control Research Unit, Malaysia Yap H.H. Vector Control Research Unit, Malaysia Mulitinovic et al. EKOSAN Co. Faculty of Pharmacy, Yugoslavia Usavadee et al. National Institute of Health, Nonthaburi, Thailand

Type
in-vitro lab test in-vitro lab test Lab test in-vitro lab test Lab test Lab test Field test In-vivo lab test Lab test Field test

Target organism
Tick (Nymphs) Ixodes scapularis Stable fly Stomoxys calcitrans Fly Musca autumnalis Cat flea Ctenocephalides felis Ticks Ixodes scapularis Stable fly Stomoxys calcitrans Black fly Simulium venustum Deer fly Chrysops ssp Stable fly Stomoxys calcitrans Mosquito Aedes aegypti, Culex pipiens Mosquito Aedes albopictus, Anopheles maculatus Mosquito Aedes albopictus, Culex quinquefasciatus Mosquito Aedes aegypti Mosquito Aedes aegypti, Culex quinquefasciatus, Culex Tritaeniorhynchus, Anopheles dirus

1996 1996

1998 1998 1998 2000 2000

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Broad Spectrum of Efficacy (1)

Year
2002

Author / Institute
Peter B.A. et al Department of Health Sciences, Sydney, Australia Cilek J.E. Mulrennan Research Laboratory A&M, FL, USA Naucke T.J. et al Institute for Medical Parasitology, Bonn, Germany Scott Carroll Carroll-Loye Biological Reserch, Davis, CA, USA

Type
Field test

Target organism
Mosquito Verrallinia funerus, Ochlerotatus vigilix, Aedes aegypt Bitting midge Culicoides ornatus Mosquito Aedes aegypti, Culex quinquefasciatos Sand flies Phlebotomus mascittii, Phlebotomus duboscqi Mosquito Anopheles freeborni, Aedes melanimon, Aedes vexans, Aedes nigromaculus, Culex tarsalis, Culex erythrothorax, Culiseta incidens

2004 2005 2006

Lab test Lab test Field test

2006
2007

Scott Carroll Carroll-Loye Biological Reserch, Davis, CA, USA

Hill N., (Krpke R. et al.) London School of Hygiene and Tropical Medicine, London, UK Combescot Catherine Faculty of Medicine,Tours, France

Lab test
Field test

Ticks Ixodes scapularis

Mosquito Anopheles darlingi, Anopheles albitarsus, Aedes aegypti, Culex pedroi Louse Pediculus humanus

2009

in-vitro test

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IR3535: Cage Test with Sand Fly

Naucke (2006) Laboratory testing of the insect repellents IR3535 and Deet against Phlebotomus mascittii and P. duboscqi (Diptera: Psychodidae)

Comparable and better protection with IR3535 in comparison with Deet

Study Type
Deet 10% IR3535 10%

Cage Test (Germany) 2 Volunteers (male and female), each 5 repetitions, 1g test substance, EPA Guideline OPPTS 810.3700
Phlebotomus mascittii Phlebotomus duboscqi, (sand fly)

Conditions

P. mascittii

Species
P. duboscqi

0,00

2,00

4,00

6,00

8,00

10,00

12,00

Tested material

Protection time on hours (h)

IR3535 / Deet 10 % solution in ethanol

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Presentation title in footer | 00 Month 0000

Product examples from Europe 1

Product name: Anti-Phebotome - spray and collar Company: Tafarm (veterenay products, Greece) Active Substance: DEET (spray) http://www.tafarm.gr/main.html

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Presentation title in footer | 00 Month 0000

Efficacy IR3535: Mosquito

Aedes albopictus: CDC Public Health Image Library The efficacy of IR3535 is approved by cage and field studies with e.g.: Aedes albopictus and aegypti Anopheles dirus and darlingi Culex quinquefaciatus and tritaeniorhyncus

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Long Lasting Protection (2)

In May 2008, the

US-CDC recommended the use of IR3535:

products containing these active ingredients typically provide reasonably long-lasting protection.
CDC, Centers for Disease Control

www.cdc.gov/ncidod/dvbid/westnile/repellentupdates.htm.
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Close to Nature (3)

Chemically, the structure of IR3535 can be regarded as derivative of the natural occurring amino acid beta-alanine.
O N O O OC2 H 5

H2 N

OH
-alanine

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Excellent Toxicological Profile (4)

EPA registration as Biopesticide US-EPA classification:

IR3535 is practically non-toxic to mammals including infants and children

Please compare with Section 6, Regulations in USA

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Gentle to the Environment (5)

Biodegradation

IR3535 Closed bottle test (OECD 301D):

Biodegradation of 11% after 28 days

Sewage treatment simulation assay (OECD 303A):

Biodegradation at 99% and showed complete mineralization

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IR3535 in Children Products (6)

Documents about safety of IR3535 in children products: MERCK KGaA, INSTITUTE OF TOXICOLOGY Calculation of MOS (Margin of Safety): 20% formulation does not represent a risk to the general population including children However, as a precautionary measure we recommend not to use IR3535 in children <12 months, as several physiological functions (excretion metabolism) are not fully developed in newborn and maturate within the first twelve months.
please contact: Dr. AM Bohlmann, anja-martina.bohlmann@merck.de

RUSSIAN MINISTRY FOR HEALTH PROTECTION CONCLUSION on the results of the investigation of repellent (active substance) IR3535: IR3535 can be used as a component of various preparation forms on human skin directly, and prepared according to specific formulations on the skin of children of various age groups (from one year of age and older)
please contact: Dr. AM Bohlmann, anja-martina.bohlmann@merck.de

EPA web-page: see section E - Human Health Effects, Acute and Chronic Dietary Risks for Sensitive
Subpopulations, Particularly Infants and Children:

IR3535 is practically non-toxic to mammals including infants and children

http://www.epa.gov/pesticides/biopesticides/ingredients/tech_docs/tech_113509.htm

Remark: before age recommendations will be claimed on a product label, national recommendations should be checked (example France: general recommendation > 30 month).
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Section 5:

Insect Repellent Regulations

Global Insect Repellent Regulations Regulations in Asia/Pacific

Regulation in European Union (EU)

Regulations in South America Regulations in USA

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Global Overview
Country/Region Registration Comments

Asia/Pacific

Different types of registration

Registered and marketed in some countries

Australia
European Union

NRA registration

Approved 2000

Biocidal Products Directive

Dossier submitted, review ongoing

South America
USA WHO

Different types of registration

Registered and marketed in most countries

EPA registration

Approved 1999

WHOPES evaluation and recommendation

Approved 2001

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European Union
Insect Repellents will be regulated under Biocidal Product Directive (BPD) in the EU Existing active substances are currently under review (like IR3535). Active substances which pass the review will be listed in a positive list in Annex I of the BPD (time line for IR3535: listing in Annex I in about end of 2013 or beginning of 2014). The date of the listing of an active substance in Annex I is the deadline for submission of dossiers for existing products. Overall Goals of BPD:

Harmonization of biocides legislations in the EU

Authorization / registration of biocidal products before marketing Until listing of the active substance in Annex I national legislations are still valid in any EU country (transitional periode)

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European Union (transitional periode)

country Austria Belgium Bulgaria Cyprus Czech Rep. Denmark Estonia Finland France Germany Greece Hungary Iceland Ireland
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n.i.a. = no information available

legislation
Biocide notification Biocide registration Biocide notification Registration Registration Biocide registration Biocide registration Biocide registration Biocide declaration Biocide notification Registration Depends on use n.i.a. Biocide notification

marketed yes yes n.i.a. yes yes no n.i.a. yes yes yes yes yes n.i.a. yes

countery Italy Latvia Lithuania Luxembourg Poland Portugal Romania Slovac Rep. Slovenia Spain Sweden Netherlands UK

legislation
Medical Device Agency for Env. Biocide registration Depends on use Biocide registration Registration Biocide registration Registration Biocide notification Registration Biocide registration Biocide registration Depends on use

marketed yes n.i.a. yes n.i.a. yes yes n.i.a. yes yes yes yes no yes

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South America
Country
Argentina Brazil Chile

AI = active ingredient FP = finished product

IR3535 status
registered
not needed not needed

Type of registration
Cosmetic (ANMAT) Cosmetic (ANVISA)

Registration for
FP (human use) FP (class 2)

marketed
yes yes yes

Columbia
Ecuador Mexico Peru Cosmetic (COFEPRIS) Cosmetic

IA, FP
IA, FP

yes
yes

yes
yes yes yes

Venezuela

IA?, FP

yes

Harmonization process in South America: Cosmetic regulations were discussed in Mercosul (Argentina, Brazil, Paraguay and Uruguay), such as good manufacturing practices and demands of registration of cosmetics. The harmonized text have to be nationalized in each country.

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USA
Country USA Type of registration Bio-Pesticide

AI = active ingredient FP = finished product

IR3535 status
registered yes marketed yes

Registration for AI, FP

In 1997, EPA-OPP's Biochemical Classification Committee classified IR3535 as a biochemical, based on facts that it is functionally identical to naturally occurring beta alanine in that both repel insects, the basic molecular structure is identical, the end groups are not likely to contribute to toxicity and it acts to control the target pest via a non-toxic mode of action (1). Therefore, the insect is not affected by IR3535.

(1) http://www.epa.gov/pesticides/biopesticides/ingredients/tech_docs/tech_113509.htm
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IR3535 Ordering and Product Information

Ordering information
Item NO 111887 Name Insect Repellent IR3535 Pack size 1 kg, 25kg, 200kg

For SDS and Specification

http://www.merck4cosmetics.com/

For more Detail Information and Technological Support

please contact: Dr. AM Bohlmann, anja-martina.bohlmann@merck.de

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