Compendium of the most significant studies with reference to properties, intake, effects.

Mapossa AB, Sitoe A, Focke WW, Izadi H, du Toit EL, Androsch R, Sungkapreecha C, van der Merwe EM. Mosquito repellent thermal stability, permeability and air volatility. Pest Manag Sci. 2020 Mar;76(3):1112-1120. doi: 10.1002/ps.5623. 

Abstract. The effectiveness of mosquito repellents, whether applied topically on the skin or released from a wearable device, is determined by the evaporation rate. This is because a repellent has to be present in the form of a vapour in the vicinity of the exposed skin that needs protection. Therefore, gravimetric techniques were used to investigate the direct evaporation of selected liquid repellents, their permeation through polymer films, and their release from a microporous polyethylene matrix....

Tavares M, da Silva MRM, de Oliveira de Siqueira LB, Rodrigues RAS, Bodjolle-d'Almeida L, Dos Santos EP, Ricci-Júnior E. Trends in insect repellent formulations: A review. Int J Pharm. 2018 Mar 25;539(1-2):190-209. doi: 10.1016/j.ijpharm.2018.01.046

Abstract. The use of natural and synthetic repellents, marketed in different pharmaceutical forms, is growing in the world due to the emerging vector-borne viral diseases as Dengue, Zika, Chikungunya, Yellow Fever and Malaria. The choice of the ideal formulation will depend on a series of factors to be analyzed: type of repellent active (natural or synthetic), pharmaceutical forms (spray, lotion, cream, gel), action time duration (short or long), environment of exposure and the user (adult, pregnant women, children, newborn)....

Pinto IC, Cerqueira-Coutinho CS, Santos EP, Carmo FA, Ricci-Junior E. Development and characterization of repellent formulations based on nanostructured hydrogels. Drug Dev Ind Pharm. 2017 Jan;43(1):67-73. doi: 10.1080/03639045.2016.1220564. 

Abstract. ... Ethyl butylacetylaminopropionate (EB) is a synthetic mosquito repellent, which could be used in products for adults and children due to its low-allergenic potential. The aim of this study was to develop and characterize EB and Poloxamer 407 nanoemulsions regarding their droplets mean size, pH, rheological properties, cytotoxicity and in vitro permeation profile. ...

N'Guessan R, Rowland M, Moumouni TL, Kesse NB, Carnevale P. Evaluation of synthetic repellents on mosquito nets in experimental huts against insecticide-resistant Anopheles gambiae and Culex quinquefasciatus mosquitoes. Trans R Soc Trop Med Hyg. 2006 Dec;100(12):1091-7. doi: 10.1016/j.trstmh.2006.04.005.

Abstract. Owing to the development of pyrethroid resistance in Anopheles gambiae, there is a need to develop chemical alternatives for use on mosquito nets. Synthetic insect repellents are widely used for personal protection as skin or clothing applications. The efficacy of repellent-treated nets (RTN) was evaluated in experimental huts in Côte d'Ivoire against pyrethroid-resistant populations of An. gambiae and Culex quinquefasciatus. The repellents tested were DEET (N,N-diethyl-3-methylbenzamide) at 7.9 g/m2 and two formulations of ethyl butylacetylaminopropionate (IR3535) at 7.6 g/m2 and 7.3 g/m2. Over 45 nights there was a 74-82% reduction in the number of An. gambiae entering the huts containing RTNs but no significant reduction in entry of C. quinquefasciatus. There was a 63-64% reduction in the proportion of An. gambiae blood feeding but no reduction in the proportion of C. quinquefasciatus blood feeding in huts with RTNs. An unexpected result was the 69-76% mortality of An. gambiae and 51-61% mortality of C. quinquefasciatus in huts containing RTNs. Treated filter paper bioassays in WHO test kits confirmed that confined contact with DEET induces mortality. The DEET-based product provided better and longer protection; tunnel test bioassays confirmed that residual activity lasted for up to 6 weeks. Application of repellents to nets warrants further investigation and development.

Izadi H, Focke WW, Asaadi E, Maharaj R, Pretorius J, Loots MT. A promising azeotrope-like mosquito repellent blend. Sci Rep. 2017 Aug 31;7(1):10273. doi: 10.1038/s41598-017-10548-y. 

Abstract. Topical repellents play a key role in reducing the outdoor transmission of mosquito-borne diseases by reducing human-vector contact. Excellent repellents are available, but there is always room for improvement. This article reports on a particularly effective binary repellent blend of ethyl butylacetylaminopropionate and nonanoic acid. A composition containing 25 mol% of the acid exhibits negative pseudo-azeotrope behaviour at 50 °C, meaning that the liquid vapour pressure is lower than that of the parent compounds and evaporation occurs without a change in the liquid composition. In tests performed using the South African Medical Research Council's cup-on-arm procedure, this mixture provided better protection for a longer time than the "gold standard of mosquito repellents", namely N,N-diethyl-m-toluamide, commonly known as DEET.

Frances SP, MacKenzie DO, Rowcliffe KL, Corcoran SK. Comparative field evaluation of repellent formulations containing deet and IR3535 against mosquitoes in Queensland, Australia. J Am Mosq Control Assoc. 2009 Dec;25(4):511-3. doi: 10.2987/Moco-09-5938.1. 

Abstract. Field trials comparing repellent formulations containing IR3535 (ethyl butylacetylaminopropionate) and deet (N,N-diethyl-3-methylbenzamide) against mosquitoes in Queensland, Australia, were conducted. Two repellents were compared: Avon Bug Guard, containing 7.5% IR3535; and Australian Defense Force (ADF) deet, containing 35% deet in a gel. Two tests were conducted, one in February-March 2006, and the second in February 2007. In the 1st test, the predominant mosquito species collected were Mansonia uniformis (58.9% of collection) and Culex annulirostris (33.4%), and in the 2nd test, the predominant species was Aedes vigilax (85.7% of collection). In the 1st test, Avon Bug Guard provided >95% protection against all mosquitoes for only 1 h, and ADF deet provided the same level of protection for 5 h. In the 2nd field test, Avon Bug Guard provided only 85% protection against all mosquitoes 1 h after repellent application, while ADF deet provided 5 h of protection. The study showed that ADF deet provided significantly better protection against mosquitoes than Avon Bug Guard (IR3535).

Fradin MS, Day JF. Comparative efficacy of insect repellents against mosquito bites. N Engl J Med. 2002 Jul 4;347(1):13-8. doi: 10.1056/NEJMoa011699.

Abstract. We conducted studies involving 15 volunteers to test the relative efficacy of seven botanical insect repellents; four products containing N,N-diethyl-m-toluamide, now called N,N-diethyl-3-methylbenzamide (DEET); a repellent containing IR3535 (ethyl butylacetylaminopropionate); three repellent-impregnated wristbands; and a moisturizer that is commonly claimed to have repellent effects. These products were tested in a controlled laboratory environment in which the species of the mosquitoes, their age, their degree of hunger, the humidity, the temperature, and the light-dark cycle were all kept constant....Conclusions: Currently available non-DEET repellents do not provide protection for durations similar to those of DEET-based repellents and cannot be relied on to provide prolonged protection in environments where mosquito-borne diseases are a substantial threat.

Ethyl butylacetylaminopropionate is a natural product derived from Averrhoa bilimbi, a fruit tree belonging to the Oxalidaceae family, is an ethyl ester, a member of the acetamides and a tertiary carboxamide. It is also commonly identified as IR3535.

Ethyl Butylacetylaminopropionate is a synthetic compound primarily used as an insect repellent in cosmetic and personal care products. It is a safe and non-toxic ingredient that provides effective protection against mosquitoes, flies, and other insects. Known for being gentle on the skin, it has a lower risk of irritation compared to other insect repellents like DEET.

Chemical Composition and Structure

Ethyl Butylacetylaminopropionate is an ester derived from butylacetylaminopropionic acid and ethanol. Its chemical structure is specifically designed to interfere with the olfactory receptors of insects, repelling them without harmful effects on humans. This makes it a safe and effective option for use in insect repellent products for both children and adults.

Physical Properties

It appears as a colorless or slightly yellowish liquid with a mild characteristic odor. It is soluble in organic solvents and partially soluble in water. Ethyl Butylacetylaminopropionate has good stability across a range of temperatures and pH levels, making it suitable for use in a wide variety of cosmetic and insect repellent formulations.

Production Process

Ethyl Butylacetylaminopropionate is synthetically produced through an esterification reaction between butylacetylaminopropionic acid and ethanol. The synthesis process is carefully controlled to ensure the purity and effectiveness of the ingredient in insect repellent products.

The name defines the structure of the molecule:

• Ethyl. It refers to an ethyl group (C₂H₅), which is a functional group derived from ethane (C₂H₆). It consists of two carbon atoms and five hydrogen atoms.
• Butyl. Refers to the butyl group (C₄H₉), which is a functional group derived from butane (C₄H₁₀). It consists of four carbon atoms and nine hydrogen atoms.
• Acetyl. Refers to an acetyl group (CH₃CO-), which is a functional group derived from acetic acid (CH₃COOH). It consists of a methyl group (CH₃-) bonded to a carbonyl group (C=O).
• Amino. Refers to an amine group (-NH2), which is a functional group containing a nitrogen atom linked by single bonds to hydrogen atoms.
• Propionate. Refers to a propionate group (C₂H₅COO-), which is a functional group derived from propionic acid (C₂H₅COOH). It consists of a two-carbon propyl group attached to a carboxyl group (-COOH).

The synthesis process takes place in two steps:

• Butylacetylaminopropionic acid production. The process begins with the production of butylacetylaminopropionic acid . This can be synthesised through a series of reactions involving the condensation of butyraldehyde with aminopropanoic acid, followed by acetylation of the resulting compound.
• Esterification. Butylacetylaminopropionic acid is reacted with ethanol in a process called esterification. In this process, the carboxylic group (COOH) of butylacetylaminopropionic acid reacts with the hydroxyl group (OH) of ethanol to form an ester, releasing water as a by-product. The resulting compound is ethyl butylacetylaminopropionate.

It appears as a colourless to yellowish liquid.

What it is used for and where

Insecticides

Ethyl butylacetylaminopropionate, like all repellents in commercial use, tends to have, as a liquid form, low volatility, but has proven to be an effective and safe mosquito repellent (1).

Antiviral test results revealed that IR3535 showed antiviral effects against Poliovirus and Adenovirus and is therefore a promising agent for new therapeutic areas (2).

Due to its low allergenic potential, Ethyl butylacetylaminopropionate can also be used in products for children (3).

It is an ingredient that can be included in commercial mosquito and insect repellent products in the form of an emulsion, gel, solution, coating agent, microcapsule, aerosol, etc. (3).

Alternative a Ethyl butylacetylaminopropionate

Nepeta cataria also known as catnip, has shown some effectiveness as a spatial repellent but less effective than DEET as a contact repellent (4).

VUAA1, a chemical compound that functions as a co-receptor ion channel agonist of the insect odour receptor (5).

Icaridina, newly developed repellent and its recommended use starts at a concentration of 5% and goes up to a maximum of 10%. It is the least toxic compound although toxicity in these repellents is rather relative.

Repellents of natural and plant origin cinnamon oil have shown almost equal repellency to DEET while margosa extract (Azadirachta indica (A.Juss., Sapindales: Meliaceae) has slightly lower efficacy (6). Other repellents: lemon eucalyptus oil, citronella oil, catnip oil, 2-undecanone, para-menthane-3,8-diol (distilled from Eucalyptus citriodora), geraniol.

Health and Safety Considerations

Safety in Use
Ethyl Butylacetylaminopropionate is generally considered safe for use in cosmetic and personal care products. It is well tolerated by the skin and has a low risk of irritation, making it suitable for use on children and individuals with sensitive skin.

Allergic Reactions
Allergic reactions to this compound are rare, but as with any cosmetic ingredient, it is advisable to perform a patch test before using products on sensitive skin.

Toxicity and Carcinogenicity
There is no evidence to suggest that Ethyl Butylacetylaminopropionate is toxic or carcinogenic. It is considered safe for topical use and poses no known health risks when used at recommended concentrations.

Environmental and Safety Considerations
As a synthetic compound, Ethyl Butylacetylaminopropionate is relatively safe for the environment when used properly. It is not known to have a significant environmental impact, but it is always important to follow safe disposal guidelines for products containing repellents.

Regulatory Status
Ethyl Butylacetylaminopropionate is approved for use in insect repellents in many regions, including the European Union and the United States. It is subject to regulations that ensure its safety in products intended for human use.

For more information:   Ethyl butylacetylaminopropionate studies

Typical commercial product characteristics BAAPE/Ethyl butylacetylaminopropionate 

Appearance	Light yellow or colorless clear liquid
pH	4.0-6.0
Boiling Point	314.8±25.0 °C at 760 mmHg
Purity	99%
Melting Point	<-20°C
Density	1.0±0.1 g/cm3
Vapor Pressure	0.0±0.7 mmHg at 25°C
Refraction Index	11.450
PSA	46.61000
LogP	1.65
Sulfated ash	≤0.1%
Water	≤0.5%
Free acid	≤1%
Shelf life	2 years
Safety

• Molecular Formula    C₁₁H₂₁NO₃
• PMolecular Weight     215.29
• Exact Mass    215.152145
• CAS  52304-36-6
• UNII    65GQA237EH
• EC Number   257-835-0
• DSSTox Substance ID  DTXSID9035753
• IUPAC  ethyl 3-[acetyl(butyl)amino]propanoate
• InChI=1S/C11H21NO3/c1-4-6-8-12(10(3)13)9-7-11(14)15-5-2/h4-9H2,1-3H3  
• InChl Key      VZRKEAFHFMSHCD-UHFFFAOYSA-N
• SMILES   CCCCN(CCC(=O)OCC)C(=O)C
• MDL number  MFCD00214076
• PubChem Substance ID    
• ChEBI  81991
• NCI    
• ICSC    
• NSC   
• RTECS   
• UN    

Synonyms

• Ethyl N-acetyl-N-butyl-β-alaninate
• IR3535
• Baape
• Ebaap
• Cleaneraddtion
• β-Alanine, N-acetyl-N-butyl-, ethyl ester
• N-Acetyl-N-butyl-β-alanine, ethyl ester

References________________________________________________________________

(1) WHO. Ethyl butylacetylaminopropionate (World Health Organisation, Geneva, 2006).

(2) Iyigundogdu Z, Kalayci S, Asutay AB, Sahin F. Determination of antimicrobial and antiviral properties of IR3535. Mol Biol Rep. 2019 Apr;46(2):1819-1824. doi: 10.1007/s11033-019-04632-x. 

Abstract. Insect repellent is a substance directly applied to skin or clothing in order to repel flies, mosquitoes, ticks etc. IR3535 or Ethyl butylacetylaminopropionate (EBAAP) is a relatively new repellent which is classified as a biopesticide due to exceptional skin tolerance and overall safety. The repellency against various insect and ticks, and the low toxicity of IR3535 are well acknowledged. However, there has been no attempt to investigate the effects on microorganisms or viruses up to now. In the present study, antimicrobial activity was investigated based on disc diffusion and micro-well dilution assays. Disc diffusion assays revealed IR3535 displayed remarkable antimicrobial activity on the microorganisms tested. MIC results showed that the antifungal efficiency of IR3535 is higher with respect to its antibacterial and anticandidal efficiency. Moreover, antiviral test results revealed that IR3535 showed antiviral effects against Poliovirus and Adenovirus. This is the first study that reveals IR3535's antimicrobial and antiviral properties against a broad range of microorganisms and viruses. In consideration of the antimicrobial and antiviral properties, IR3535 is a promising agent that could be used to develop novel therapeutic approaches, new application areas and formulations in the future.

(3) Pinto IC, Cerqueira-Coutinho CS, Santos EP, Carmo FA, Ricci-Junior E. Development and characterization of repellent formulations based on nanostructured hydrogels. Drug Dev Ind Pharm. 2017 Jan;43(1):67-73. doi: 10.1080/03639045.2016.1220564.

Abstract. Diseases caused by insects could lead to epidemic scenarios in urban areas and insect repellents are a shield against a wide range of insects, but they need to be safe without compromising efficacy. Ethyl butylacetylaminopropionate (EB) is a synthetic mosquito repellent, which could be used in products for adults and children due to its low-allergenic potential. The aim of this study was to develop and characterize EB and Poloxamer 407 nanoemulsions regarding their droplets mean size, pH, rheological properties, cytotoxicity and in vitro permeation profile. The developed formulations (F1 with 12.5% of EB and F2 with 25% of EB) were compared with a commercial formulation containing 12.5% of EB. Droplets mean size was determined by DLS, and for both nanoemulsions they were around 200 nm; however, the commercial formulation presented a droplets mean size of 10 nm, which could contribute to its high permeation. F1 and F2 presented a gel-like behavior, however F2 presented lower viscosity due to the presence of more EB between the polymer chains preventing them to interact with each other. Also, F2 was less retained by the epidermis when compared to F1 probably due to its lower viscosity. For the cytotoxicity assay only F2, which presented the highest concentration of EB was tested, and it was not toxic to the cells. This result could be also extended to F1 which presented half the EB concentration. The present study demonstrated that EB and Poloxamer 407 nanoemulsions are promising as new insect-repellent formulations.

(4) Bernier UR, Furman KD, Kline DL, Allan SA, Barnard DR. Comparison of contact and spatial repellency of catnip oil and N,N-diethyl-3-methylbenzamide (deet) against mosquitoes. J Med Entomol. 2005 May;42(3):306-11. doi: 10.1603/0022-2585(2005)042[0306:cocasr]2.0.co;2.

Abstract. Nepetalactone, the primary component of catnip oil, was compared with the repellent N,N-diethyl-3-methylbenzamide (deet) for its ability to affect the host-seeking ability of Aedes aegypti (L.). A triple cage olfactometer was used to bioassay each substance and to assess its attraction inhibition (spatial repellent) attributes when combined with the following attractants: carbon dioxide, acetone, a blend of L-lactic acid and acetone, and human odors. Repellent tests were conducted with each substance against female Ae. aegypti, Anopheles albimanus Weidemann, and Anopheles quadrimaculatus Say. Catnip oil and deet were both weakly attractive to Ae. aegypti, catnip oil was the better spatial repellent, whereas deet was a more effective contact repellent in tests with all three species of mosquitoes.

(5) Bernier UR, Furman KD, Kline DL, Allan SA, Barnard DR. Comparison of contact and spatial repellency of catnip oil and N,N-diethyl-3-methylbenzamide (deet) against mosquitoes. J Med Entomol. 2005 May;42(3):306-11. doi: 10.1603/0022-2585(2005)042[0306:cocasr]2.0.co;2.

(6)  Krüger A, Schmolz E, Vander Pan A. Methods for Testing Repellents Against Bed Bugs (Hemiptera: Cimicidae). J Econ Entomol. 2021 Feb 9;114(1):265-273. doi: 10.1093/jee/toaa304.