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The aim of the investigation is the toxicological characterization and analysis of the danger criteria of the insecticide metofluthrin with an assessment of the carcinogenic risk to health caused by chronic inhalation exposure to the substance at the level of the maximum possible concentrations in the air environment of human life. The analysis of scientific reports of the US Environmental Protection Agency (US EPA) and the European Chemicals Agency (ECHA) on the toxicological properties of metofluthrin was carried out. The assessment of the risk of the development of carcinogenic effects due to chronic inhalation exposure to metofluthrin was carried out taking into account the average daily dose of the substance that can enter the human body during the natural life span (LADD) and the carcinogenic potential factor (SF) in accordance with domestic guidelines. Classification of levels of carcinogenic risk was carried out using domestic and international approaches. It was established that the limiting criteria for the danger of metofluthrin are the average lethal concentration in air (LC50 =1080 mg/m³) and the size of the zone of chronic action (Zch=7.46), which characterizes the danger of occurrence of chronic intoxication due to long-term inhalation exposure. According to these indicators, metofluthrin is classified as a dangerous substance (hazard class 2). The key effects of the toxic action of metofluthrin are determined – neurotoxicity, hepatotoxicity and nephrotoxicity. The threshold non-genotoxic oncogenic potential of metofluthrin according to the phenobarbital type was established. Individual carcinogenic risk under different scenarios of chronic inhalation exposure to metofluthrin was calculated. The substance concentration of 3.54 mg/m³ leads to a high level of risk (1.5×10-3), which is considered unacceptable for production conditions and the population. At concentrations of 0.28 mg/m³ and 1.0 mg/m³, the risk is estimated as average and acceptable for production conditions (1.1-4.1×10-4). The risk of exposure to a concentration of 0.14 mg/m³ is classified as low and acceptable for the population (5.7×10-5). Thus, the results obtained in the study indicate that such concentrations of metofluthrin in the air as 0.14 – 0.28 – 1.0 mg/m³ are safe for human health, subject to compliance with medical and sanitary regulations at the stage of production and application of insecticides based on metofluthrin as prescribed.

Outdoor spatial mosquito repellents, such as mosquito coils or heating devices, release pyrethroid insecticides into the air to provide protection from mosquitoes within a defined area. This broadcast discharge of pyrethroids into the environment raises concern about the effect on non-target organisms. A previous study found that prallethrin discharged from a heating device did not affect honey bee (Apis mellifera L.) [Hymenoptera: Apidae] foraging or recruitment. In this second study, there was no significant difference in foraging frequency (our primary outcome), waggle dance propensity, or persistency in honey bees collecting sucrose solution between those exposed to metofluthrin from a different heating device and bees exposed to a non-metofluthrin control. One measure, waggle dance frequency, was higher in the metofluthrin treatment than the control but this outcome was likely a spurious result due to the small sample size. The small particle size of the emissions, averaging 4.43 µm, from the heated spatial repellent products, which remain airborne with little settling, may play an important role in the lack of effect found on honey bee foraging. [ABSTRACT FROM AUTHOR]

The aim of the investigation is the toxicological characterization and analysis of the danger criteria of the insecticide metofluthrin with an assessment of the carcinogenic risk to health caused by chronic inhalation exposure to the substance at the level of the maximum possible concentrations in the air environment of human life. The analysis of scientific reports of the US Environmental Protection Agency (US EPA) and the European Chemicals Agency (ECHA) on the toxicological properties of metofluthrin was carried out. The assessment of the risk of the development of carcinogenic effects due to chronic inhalation exposure to metofluthrin was carried out taking into account the average daily dose of the substance that can enter the human body during the natural life span (LADD) and the carcinogenic potential factor (SF) in accordance with domestic guidelines. Classification of levels of carcinogenic risk was carried out using domestic and international approaches. It was established that the limiting criteria for the danger of metofluthrin are the average lethal concentration in air (LC50 =1080 mg/m³) and the size of the zone of chronic action (Zch=7.46), which characterizes the danger of occurrence of chronic intoxication due to long-term inhalation exposure. According to these indicators, metofluthrin is classified as a dangerous substance (hazard class 2). The key effects of the toxic action of metofluthrin are determined – neurotoxicity, hepatotoxicity and nephrotoxicity. The threshold non-genotoxic oncogenic potential of metofluthrin according to the phenobarbital type was established. Individual carcinogenic risk under different scenarios of chronic inhalation exposure to metofluthrin was calculated. The substance concentration of 3.54 mg/m³ leads to a high level of risk (1.5×10-3), which is considered unacceptable for production conditions and the population. At concentrations of 0.28 mg/m³ and 1.0 mg/m³, the risk is estimated as average and acceptable for production conditions (1.1-4.1×10-4). The risk of exposure to a concentration of 0.14 mg/m³ is classified as low and acceptable for the population (5.7×10-5). Thus, the results obtained in the study indicate that such concentrations of metofluthrin in the air as 0.14 – 0.28 – 1.0 mg/m³ are safe for human health, subject to compliance with medical and sanitary regulations at the stage of production and application of insecticides based on metofluthrin as prescribed. [ABSTRACT FROM AUTHOR]

Abstract Background Spatial repellents (SR) may complement current vector control tools and provide additional coverage when people are not under their bednets or are outdoors. Here we assessed the efficacy of a metofluthrin-based SR in reducing exposure to pyrethroid-resistant Anopheles funestus in Siaya County, western Kenya. Methods Metofluthrin was vaporized using an emanator configured to a liquid petroleum gas (LPG) canister, placed inside experimental huts (phase 1) or outdoors (phase 2), and evaluated for reductions in human landing rate, density, knockdown and mortality rates of An. funestus, which are present in high density in the area. To demonstrate the mosquito recruiting effect of LPG, a hut with only an LPG cooker but no metofluthrin was added as a comparator and compared with an LPG cooker burning alongside the emanator and a third hut with no LPG cooker as control. Phase 2 evaluated the protective range of the SR product while emanating from the centre of a team of mosquito collectors sitting outdoors in north, south, east and west directions at 5, 10 and 20 feet from the emanating device. Results Combustion of LPG with a cook stove increased the density of An. funestus indoors by 51% over controls with no cook stove. In contrast, huts with metofluthrin vaporized with LPG combustion had lower indoor density of An. funestus (99.3% less than controls), with knockdown and mortality rates of 95.5 and 87.7%, respectively, in the mosquitoes collected in the treated huts. In the outdoor study (phase 2), the outdoor landing rate was significantly lower at 5 and 10 feet than at 20 feet from the emanator. Conclusions Vaporized metofluthrin almost completely prevented An. funestus landing indoors and led to 10 times lower landing rates within 10 feet of the emanator outdoors, the first product to demonstrate such potential. Cooking with LPG inside the house could increase exposure to Anopheles mosquito bites, but the use of the metofluthrin canister eliminates this risk. Graphical abstract

Simple Summary: Aedes aegypti (L.) is a major vector of dengue fever in tropical regions. To prevent their contact with human hosts, spatial repellents (SRs) like transfluthrin (TFT) and metofluthrin (MFT) have shown promise in delaying pesticide resistance and addressing gaps in outdoor transmission not covered by other interventions such as indoor residual spray or long-lasting insecticide-treated nets. In this study, we successfully identified optimal discriminating concentrations of TFT and MFT, using a high-throughput screening system toxicity bioassay (HITSS-TOX). These concentrations were effective against both susceptible and resistant Ae. aegypti mosquitoes. However, it was observed that TFT required a 4.7-fold higher concentration compared to MFT. Additionally, after 60 min of exposure, TFT caused a stronger knockdown (KD60) of mosquitoes but did not significantly increase the 24 h mortality rate compared to MFT. This means that more mosquitoes exposed to TFT were able to recover from KD60, unlike those exposed to MFT. To better understand the behavioral response of mosquitoes to these repellents, further research is required using the HITSS contact irritancy and spatial repellency assays. Such investigations could provide valuable insights into improving vector control strategies and combating the transmission of dengue fever and other mosquito-borne diseases. Aedes aegypti is a major vector of dengue fever in tropical regions. Spatial repellents (SRs) have shown promise in delaying pesticide resistance. Methods for discriminating concentrations (DCs) are well established using various bioassay tools, while data for high-throughput screening system (HITSS) toxicity bioassay (TOX) are absent. In this study, we compared and optimized lethal (LCs) and sub-lethal concentrations (SLCs) of transfluthrin (TFT) and metofluthrin (MFT) on pyrethroid-susceptible (USDA) and pyrethroid-resistant (Pu-Teuy) Ae. aegypti (L.) strains, using the HITSS-TOX. Mean mortality (MT) was 100% at LC99 and DC, compared to LC50 (45.0 ± 3.7%) and LC75 (65.8 ± 7.0%) for the USDA strain. However, the resistant strain (Pu-Teuy) showed reduced susceptibility against TFT and a significantly lower MT at LC50 (12.5 ± 4.4%; t = 5.665, df = 10, p < 0.001), LC75 (9.2 ± 3.5%; t = 4.844, df = 10, p = 0.001), LC99 (55.0 ± 9.9%; t = 4.538, df = 5, p = 0.006), and DC (75.0 ± 5.2%; U = 3.0, p = 0.007). The DC of TFT (0.15222%) was 4.7-fold higher than for MFT (0.03242%) in USDA strain. The baseline DCs established are useful to better understand susceptibility and the efficacy of various repellents against field populations of Ae. aegypti. [ABSTRACT FROM AUTHOR]

Aedes aegypti is a major vector of dengue fever in tropical regions. Spatial repellents (SRs) have shown promise in delaying pesticide resistance. Methods for discriminating concentrations (DCs) are well established using various bioassay tools, while data for high-throughput screening system (HITSS) toxicity bioassay (TOX) are absent. In this study, we compared and optimized lethal (LCs) and sub-lethal concentrations (SLCs) of transfluthrin (TFT) and metofluthrin (MFT) on pyrethroid-susceptible (USDA) and pyrethroid-resistant (Pu-Teuy) Ae. aegypti (L.) strains, using the HITSS-TOX. Mean mortality (MT) was 100% at LC99 and DC, compared to LC50 (45.0 ± 3.7%) and LC75 (65.8 ± 7.0%) for the USDA strain. However, the resistant strain (Pu-Teuy) showed reduced susceptibility against TFT and a significantly lower MT at LC50 (12.5 ± 4.4%; t = 5.665, df = 10, p < 0.001), LC75 (9.2 ± 3.5%; t = 4.844, df = 10, p = 0.001), LC99 (55.0 ± 9.9%; t = 4.538, df = 5, p = 0.006), and DC (75.0 ± 5.2%; U = 3.0, p = 0.007). The DC of TFT (0.15222%) was 4.7-fold higher than for MFT (0.03242%) in USDA strain. The baseline DCs established are useful to better understand susceptibility and the efficacy of various repellents against field populations of Ae. aegypti.

U.S. military troops are exposed to mosquito-borne pathogens when deployed to endemic regions. Personal protective measures such as permethrin-treated uniforms and dermal repellents are the cornerstones of mosquito-borne disease prevention for the U.S. military. These measures have limitations and additional personal protection tools, such as spatial repellent devices to decrease the risk of vector-borne pathogen transmission, are required. Novel spatial repellent controlled-release devices formulated with metofluthrin were evaluated in an outdoor setting in the northern Amazon of Peru to evaluate performance under field conditions. The metofluthrin emitting devices lowered the number of mosquitoes captured in protected human landing collections (HLC) compared to blank devices, although there were effect differences between Anopheles spp. and species in other mosquito genera. A computational-experimental model was developed to correlate HLC and active ingredient (AI) concentrations as a function of time and space. Results show a strong correlation between the released AI and the decrease in HLC. This model represents the first effort to obtain a predictive analytical tool on device performance using HLC as the entomological endpoint.

Abstract Background Large-scale use of insecticide-treated nets and indoor residual spraying have contributed to a significant decrease in malaria transmission worldwide. Further reduction and progress towards elimination, however, require complementary control measures which can address the remaining gaps in protection from mosquito bites. Following the development of novel pyrethroids with high knockdown effects on malaria vectors, programmatic use of spatial repellents has been suggested as one potential strategy to fill the gaps. This report explores social and contextual factors that may influence the relevance, uptake and sustainable use of a spatial repellent in two remote villages in Mondulkiri province, Cambodia, with endemic malaria transmission. The repellent consisted of polyethylene emanators, held in an open plastic frame and impregnated with 10% metofluthrin. Results In a baseline survey, 90.9% of households in Ou Chra (n = 30/33) and 96.6% in Pu Cha (n = 57/59) were interviewed. Behavioural data were collected for all household occupants (n = 448). In both villages, there were times and places in which people remained exposed to mosquito bites. Prior to the installation of the repellent, 50.6 and 59.5% of respondents noted that bites occurred “very often” inside the house and in the outdoor area surrounding the house, respectively. Indoor biting was reported to occur more frequently in the evening, followed by at night, while outdoor biting occurred more frequently in the early morning. In a follow-up survey, spatial repellents were well received in both villages, although 63.2% of respondents would not replace bed nets with repellents. Most participants (96.6%) were willing to use the product again; the mean willingness to pay was US$ 0.3 per unit. A preference for local procurement methods emerged. Conclusion Widespread use of spatial repellents would not fill all protective gaps, but, if their entomological efficacy can be ascertained, outdoor application has the potential to enhance vector control strategies in Cambodia. Successful implementation would require subsidisation and integration with the existing national malaria control strategy. It is hoped that this study, while contributing to a better understanding of the social contexts of residual malaria transmission, will generate further interest in the evaluation of spatial repellents for malaria control.

Abstract Background Metofluthrin is highly effective at reducing biting activity in Aedes aegypti. Its efficacy lies in the rapid onset of confusion, knockdown, and subsequent kill of a mosquito. In the field, there are a variety of scenarios that might result in sublethal exposure to metofluthrin, including mosquitoes that are active at the margins of the chemical’s lethal range, brief exposure as mosquitoes fly in and out of treated spaces or decreasing efficacy of the emanators with time. Sublethal effects are key elements of insecticide exposure and selection. Methods The metofluthrin dose for each treatment group of male and female Ae. aegypti was controlled using exposure time intervals to a 10% active ingredient (AI) metofluthrin emanator. Room size and distance from the emanator for all groups was maintained at 3 m. In bioassay cages, male Ae. aegypti were exposed at 0, 5, 10, 20, 30 and 40-min intervals. Females were exposed in bioassay cages at 0, 10, 20, 30, 40 and 60-min intervals. Mortality rates and fecundity were observed between the exposure time groups for both sexes. Results Female Ae. aegypti exposed for 60 min had a significantly higher mortality rate (50%), after a 24-h recovery period, than other exposure times, 10, 20, 30 and 40 min (P 0.05). Conclusion Regardless of sex, if a mosquito survived exposure, it would be as biologically successful as its unexposed counterpart. Portability of the metofluthrin emanator and delayed knockdown effects create opportunities for sublethal exposure and potential pyrethroid resistance development in Ae. aegypti, and should be taken into consideration in recommendations for field application of this product, including minimum exposure periods and a prescribed number of emanators per room based on volume.

Abstract Background Metofluthrin reduces biting activity in Aedes aegypti through the confusion, knockdown, and subsequent kill of a mosquito. A geographical spread in dengue, chikungunya, and Zika viruses, increases intervention demands. Response to a Zika outbreak may require a different strategy than dengue, as high-risk individuals, specifically pregnant women, need to be targeted. Methods In semi-field conditions within a residential property in Cairns, Queensland, the impacts of metofluthrin on biting behaviour of free-flying Wolbachia-infected Ae. aegypti were evaluated. Results Mortality in Ae. aegypti exposed to metofluthrin over a 22 h period was 100% compared to 2.7% in an untreated room. No biting activity was observed in mosquitoes up to 5 m from the emanator after 10 min of metofluthrin exposure. Use of metofluthrin reduced biting activity up to 8 m, regardless of the host’s proximity (near or far) to a dark harbourage area (HA) (P

Three mosquito coil formulations, each containing either metofluthrin 0.025% w /w, d-allethrin 0.225% w/w, or esbiothrin 0.10% w/w were evaluated for knockdown and killing properties against laboratory populations of female Aedes aegypti (L.) and Culex quinquefasciatus Say under different nutritional-energy sources of blood, sucrose, and water. The tests were conducted in a 70 cm × 70 cm × 70 cm glass chamber. Mosquito responses were measured by knockdown times during the 20-min exposure period and mortality at 24 h post-exposure. The results showed the metofluthrin coil provided the most rapid knockdown for both test species and regardless of nutritional condition compared with the other two coils. Metofluthrin and d-allethrin were highly effective in killing Ae. aegypti (95–100% mortality), whereas esbiothrin produced 100% mortality to water-fed mosquitoes and 78.3 and 80% mortality for blood- and sucrose-fed specimens, respectively. >85% mortality was observed in sucrose- and water-fed Cx. quinquefasciatus against metofluthrin, while 78.3% blood-fed females survived exposure. This species showed very low mortality with d-allethrin (3.3% to 28.3%), with the highest mortality recorded (71.7%) for water-fed with esbiothrin. Overall, Ae. aegypti was more sensitive to all three coil products than Cx. quinquefasciatus. The mortality between species and nutritional conditions showed significant differences for all comparisons except for sucrose-fed mosquitoes exposed to metofluthrin. Unlabelled Image • Knockdown and mortality effects of mosquito coils were studied in a glass chamber. • Three mosquito coils were compared between Ae. aegypti and Cx. quinquefasciatus. • Metofluthrin coil provided the fastest knockdown of the two mosquito species tested. • Metofluthrin and d-allethrin were more effective in killing Ae. aegypti than esbiothrin. • Aedes aegypti was more sensitive to all three coils than Cx. quinquefasciatus. [ABSTRACT FROM AUTHOR]

A field study to compare a formulation containing 40% deet (N,N-diethyl-3-methyl benzamide) in ethanol (Bushman™) and a battery-powered fan emanator with a chemical strip containing 31.2% metofluthrin (OFF!® Clip-On™) was conducted at Redcliffe, Queensland, Australia, in February 2016. The 40% deet provided 100% protection against mosquitoes for 5 h until tests ceased, while the OFF! Clip-On device provided only 42.2–60.8% protection against Aedes vigilax during the same period. [ABSTRACT FROM AUTHOR]

Abstract The recent advancement in new generation fluorinated pyrethroids (e.g., transfluthrin, metofluthrin etc.), the use of semi-volatile vapour phase insecticides for control of mosquitoes and other domestic pests rises. Enabling the examination of the vapour toxicity profiles of these molecules and many other similar new generation molecules will provide new avenues for researchers for understanding the bio-potency in the spatial killing of pests. Hence, it is critical to establish a well-controlled portable vapour-phase bioassay method that can provide the desired precision, accuracy, linearity and robustness. In this respect, we have designed a vapour-toxicity apparatus comprising glass assemblies and developed a novel bioassay method. We found that KT 50 and percentage knockdown at 60 min reflect the concentration dependency. This validates and confirms that the method is sensitive enough to distinguish between concentrations and suitable for concentration-response experiments. We found that KT 50 and percentage knockdown at 60 min at a given concentration does not differ significantly between experiments. Hence, the method has repeatability and precision. Percentage mortality and total KT 50 against Culex quinquefasciatus shows that percentage mortality increases and KT 50 decreases linearly with the increasing concentration. This method provides an easy to operate tool to test the vapour toxicity profiles of any vapour phase insecticide molecules against mosquitoes and flying insects. Graphical abstract Unlabelled Image Highlights • Portable non-contact bioassay method for evaluation of vapour phase insecticides • Enable evaluation of the vapour toxicity profiles of all semi-volatile insecticides • Enable evaluation of spatial killing ability of household insecticide actives • Method can be used to screen potential new vapour phase insecticide molecules. [ABSTRACT FROM AUTHOR]

Aedes aegypti (L.) (Diptera: Culicidae) is the primary vector of several arthropod-borne viral infectious diseases globally. Relentless vector control efforts are performed to curtail disease transmissions, insecticides remain as the first line of defense in Indonesia. With a dearth of publication on the efficacy of mosquito coil in Indonesia, this is the first report related to mosquito coil despite its common use in households. Ae. aegypti mosquitoes were sampled from nine regencies in Indonesia and tested using the glass-chamber method against three commercially available local pyrethroid-based mosquito coils containing d-allethrin, transfluthrin, and metofluthrin. The 50% knockdown time of female Ae. aegypti tested with d-allethrin, transfluthrin, and metofluthrin containing coils ranged from 0.65 to 14.32; 0.8 to 16.4; and 0.78 to 20.57 min, respectively. Mortality rates in accordance with WHO resistance indicators showed that strains from Denpasar, Mataram, Kuningan, Padang, Samarinda, and Sumba Timur were resistant (<80% mortality rate), whereas strains from Manggarai Barat, Dompu, and Pontianak were susceptible (>98% mortality rate) to the active ingredients assayed. Moreover, the knockdown rates between d-allethrin and transfluthrin, d-allethrin and metofluthrin, as well as transfluthrin and metofluthrin displayed significant associations, portraying the presence of cross-resistance within pyrethroid insecticides. The minimal insecticidal effect of mosquito coils against some Indonesian Ae. aegypti also pointed out the development of pyrethroid resistance, prompting a revamping of the vector control system. [ABSTRACT FROM AUTHOR]

1.14 C-Labelled E/Z isomers of a synthetic pyrethroid metofluthrin ((E/Z)-(1 R,3 R)-2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl 2,2-dimethyl-3-(1-propenyl)-cyclopropanecarboxylate, abbreviated as RTE/RTZ, respectively) were used for rat metabolism studies. 14 C-RTE or RTZ labelled at the carbonyl-carbon [acid-14C] or the methoxymethylbenzyl-α-carbon [alcohol-14 C] was administered orally to rats at 1 and 20 mg/kg. 2.Dosed compounds were mostly absorbed, metabolised, and rapidly excreted. Dose-related increase in blood AUC suggested no saturation of absorption at the high dose. Blood 14 C was maximal at 3-8 h and decreased with a half-life of 52-163 h. Radioactivity in tissues, blood and plasma decreased basically at the same rate and the sum fell below 0.2% of the dose at 168 h. 3.Although the major metabolic pathways of the isomers, that is, ester cleavage, O-demethylation and ω-oxidation, were similar, there was a notable difference. The RTZ double bond commonly undergoes epoxidation while RTE double bond mainly undergoes glutathione conjugation, which causes faster elimination from plasma and greater excretion into faeces on RTE. Faster urinary excretion and elimination from blood were observed for the alcohol moiety than the acid moiety. 4.In conclusion, this study described the overall metabolic profiles of metofluthrin and identified the differences in metabolic breakdown between the isomers. No marked sex-/dose-related differences were observed. [ABSTRACT FROM AUTHOR]

Methods for investigating the Mode of Action (MoA) for rodent liver tumors via constitutive androstane receptor (CAR) activation are outlined here, based on current scientific knowledge about CAR and feedback from regulatory agencies globally. The key events (i.e., CAR activation, altered gene expression, cell proliferation, altered foci and increased adenomas/carcinomas) can be demonstrated by measuring a combination of key events and associative events that are markers for the key events. For crop protection products, a primary dataset typically should include a short-term study in the species/strain that showed the tumor response at dose levels that bracket the tumorigenic and non-tumorigenic dose levels. The dataset may vary depending on the species and the test compound. As examples, Case Studies with nitrapyrin (in mice) and metofluthrin (in rats) are described. Based on qualitative differences between the species, the key events leading to tumors in mice or rats by this MoA are not operative in humans. In the future, newer approaches such as a CAR biomarker signature approach and/or in vitro CAR3 reporter assays for mouse, rat and human CAR may eventually be used to demonstrate a CAR MoA is operative, without the need for extensive additional studies in laboratory animals. [ABSTRACT FROM AUTHOR]

Intensive exposure to insecticides has resulted in the evolution of insecticide resistance in the mosquitoes. We tested the bio-efficacy of two Culex quinquefasciatus Say (Diptera: Culicidae) laboratory strains differentially bio-responsive to pyrethroids to understand the comparative efficacy of different polyfluorobenzyle and conventional pyrethroid molecules and the role of piperonyl butoxide (PBO) in synergizing these molecules in increased tolerance of mosquitoes to these molecules. We have taken deltamethrin (α-cyano pyrethroid with phenoxybenzyl moiety); permethrin (phenoxybenzyl pyrethroid without an α-cyano group); transfluthrin, dimefluthrin, metofluthrin, and meperfluthrin (polyfluorinated benzyl compounds); and prallethrin (modified cyclopentadienone compound) for this study. We found higher bio-efficacy in dimefluthrin, metofluthrin, and meperfluthrin compared with transfluthrin against tested mosquito strains. We found that transfluthrin exhibited synergism with PBO, which supports the hypothesis that P450 enzymes could play a role in the detoxification process of transfluthrin, which was earlier not believed. However, other polyfluorobenzyl pyrethroids with a 4-(methoxymethyl) phenyl capping in the tetrafluorobenzyl ring (dimefluthrin, metofluthrin, and meperfluthrin) exhibit greater synergism with PBO compared with transfluthrin. Further study is required to understand the mechanism for higher synergistic ratios in polyfluorobenzyl pyrethroids with 4-(methoxymethyl) phenyl moiety and ascertain the possible involvement of novel mechanisms that may involve in developing resistance. This is the first report of comparative bio-efficacy of multiple polyfluorobenzyl pyrethroids and PBO synergism against mosquitoes. [ABSTRACT FROM AUTHOR]

1. Metofluthrin (2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (Z/E)-(1R)-trans-2,2-dimethyl-3-(1-propenyl)-cyclopropanecarboxylate) is a novel pyrethroid insecticide, which hasE/Zisomers at prop-1-enyl group. 2. Rats were orally dosed with each [14C]-labelledE/Zisomer, and the excreta were collected for isolation and identification of metabolites. Analysis of the excreta by LC/MS and NMR revealed formation of 33 and 23 (total 42) metabolites from rats dosed withZ-isomer andE-isomer, respectively. 3. Major metabolic reactions were cleavage of ester linkage,O-demethylation, hydroxylation, epoxidation or reduction of double bond, glutathione conjugation and its further metabolism, hydroxylation of epoxide and formation of lactone ring. Notably, the acid side, 2,2-dimethyl-3-(1-propenyl)-cyclopropanecarboxylic acid, was much more variously metabolised compared to chrysanthemic acid, the acid side of the known pyrethroids. 4. Major metabolites forZ-isomer mostly retained ester linkage with 1,2-dihydroxypropyl group and/or 2-methylalcohol of cyclopropane ring, while most of those forE-isomer received hydrolysis of the ester linkage without oxidation at the 1-propenyl group or thegem-methyl groups, suggesting epoxidation and hydroxylation could occur more easily onZ-isomer. 5. As the novel metabolic pathways for pyrethroids, isomerisation of ω-carboxylic acid moiety, reduction or hydration of double bond and cleavage of cyclopropane ring via epoxidation were suggested. [ABSTRACT FROM PUBLISHER]

Three repellent products, OFF! Mosquito Lamp, Insecticandel, and Rescue DecoShield, were comparatively evaluated against Aedes aegypti in 130-m2 enclosed areas with a 317-m3 air volume. The results showed that the OFF! Mosquito Lamp with metofluthrin had a greater effect than the Insecticandel with transfluthrin, which had greater effect than the DecoShield with lemongrass oil and several other plant oils against Ae. aegypti. The OFF! Mosquito Lamp was the only product to exceed 50% mortality. An outdoor semi-field evaluation was conducted to determine the effect by distance of the product. Mosquitoes were stationed in cages at 3, 6, 9, 12, and 15 m away from the treatment in a downwind linear array and exposed for 10 min. They were recorded for knockdown after treatment and at 24 h for mortality. The OFF! Mosquito Lamp produced 100% mortality indoors and >80% knockdown and 90% mortality within 6 m while outdoors against Ae. aegypti. [ABSTRACT FROM AUTHOR]

Background: Large-scale use of insecticide-treated nets and indoor residual spraying have contributed to a significant decrease in malaria transmission worldwide. Further reduction and progress towards elimination, however, require complementary control measures which can address the remaining gaps in protection from mosquito bites. Following the development of novel pyrethroids with high knockdown effects on malaria vectors, programmatic use of spatial repellents has been suggested as one potential strategy to fill the gaps. This report explores social and contextual factors that may influence the relevance, uptake and sustainable use of a spatial repellent in two remote villages in Mondulkiri province, Cambodia, with endemic malaria transmission. The repellent consisted of polyethylene emanators, held in an open plastic frame and impregnated with 10% metofluthrin. Results: In a baseline survey, 90.9% of households in Ou Chra (n = 30/33) and 96.6% in Pu Cha (n = 57/59) were interviewed. Behavioural data were collected for all household occupants (n = 448). In both villages, there were times and places in which people remained exposed to mosquito bites. Prior to the installation of the repellent, 50.6 and 59.5% of respondents noted that bites occurred "very often" inside the house and in the outdoor area surrounding the house, respectively. Indoor biting was reported to occur more frequently in the evening, followed by at night, while outdoor biting occurred more frequently in the early morning. In a follow-up survey, spatial repellents were well received in both villages, although 63.2% of respondents would not replace bed nets with repellents. Most participants (96.6%) were willing to use the product again; the mean willingness to pay was US$ 0.3 per unit. A preference for local procurement methods emerged. Conclusion: Widespread use of spatial repellents would not fill all protective gaps, but, if their entomological efficacy can be ascertained, outdoor application has the potential to enhance vector control strategies in Cambodia. Successful implementation would require subsidisation and integration with the existing national malaria control strategy. It is hoped that this study, while contributing to a better understanding of the social contexts of residual malaria transmission, will generate further interest in the evaluation of spatial repellents for malaria control. [ABSTRACT FROM AUTHOR]

This study was conducted using the glass chamber method to determine the susceptibility status of the dengue vector, Aedes aegypti (L.) from 11 states in Malaysia to commercial mosquito coils containing four different active ingredients, namely metofluthrin, d-allethrin, d-trans allethrin, and prallethrin. Aedes aegypti exhibited various knockdown rates, ranging from 14.44% to 100.00%, 0.00% to 61.67%, 0.00% to 90.00%, and 0.00% to 13.33% for metofluthrin, d-allethrin, d-trans allethrin, and prallethrin, respectively. Overall, mortality rates ranging from 0.00% to 78.33% were also observed among all populations. Additionally, significant associations were detected between the knockdown rates of metofluthrin and d-allethrin, and between metofluthrin and d-trans allethrin, suggesting the occurrence of cross-resistance within pyrethroid insecticides. Overall, this study revealed low insecticidal activity of mosquito coils against Ae. aegypti populations in Malaysia, and consequently may provide minimal personal protection against mosquito bites. [ABSTRACT FROM AUTHOR]

Background: Metofluthrin is highly effective at reducing biting activity in Aedes aegypti. Its efficacy lies in the rapid onset of confusion, knockdown, and subsequent kill of a mosquito. In the field, there are a variety of scenarios that might result in sublethal exposure to metofluthrin, including mosquitoes that are active at the margins of the chemical's lethal range, brief exposure as mosquitoes fly in and out of treated spaces or decreasing efficacy of the emanators with time. Sublethal effects are key elements of insecticide exposure and selection. Methods: The metofluthrin dose for each treatment group of male and female Ae. aegypti was controlled using exposure time intervals to a 10% active ingredient (AI) metofluthrin emanator. Room size and distance from the emanator for all groups was maintained at 3 m. In bioassay cages, male Ae. aegypti were exposed at 0, 5, 10, 20, 30 and 40-min intervals. Females were exposed in bioassay cages at 0, 10, 20, 30, 40 and 60-min intervals. Mortality rates and fecundity were observed between the exposure time groups for both sexes. Results: Female Ae. aegypti exposed for 60 min had a significantly higher mortality rate (50%), after a 24-h recovery period, than other exposure times, 10, 20, 30 and 40 min (P < 0.001). An overall difference in fecundity was not observed in females between treatments. A significant effect on male mortality was only observed at 40 min exposure times, three meters from the 10% AI emanator (X= 98%, P < 0:001). Males that survived metofluthrin exposure were as likely to produce viable eggs with an unexposed female as males that had not been exposed (P > 0.05). Conclusion: Regardless of sex, if a mosquito survived exposure, it would be as biologically successful as its unexposed counterpart. Portability of the metofluthrin emanator and delayed knockdown effects create opportunities for sublethal exposure and potential pyrethroid resistance development in Ae. aegypti, and should be taken into consideration in recommendations for field application of this product, including minimum exposure periods and a prescribed number of emanators per room based on volume. [ABSTRACT FROM AUTHOR]

Background: Metofluthrin reduces biting activity in Aedes aegypti through the confusion, knockdown, and subsequent kill of a mosquito. A geographical spread in dengue, chikungunya, and Zika viruses, increases intervention demands. Response to a Zika outbreak may require a different strategy than dengue, as high-risk individuals, specifically pregnant women, need to be targeted. Methods: In semi-field conditions within a residential property in Cairns, Queensland, the impacts of metofluthrin on biting behaviour of free-flying Wolbachia-infected Ae. aegypti were evaluated. Results: Mortality in Ae. aegypti exposed to metofluthrin over a 22 h period was 100% compared to 2.7% in an untreated room. No biting activity was observed in mosquitoes up to 5 m from the emanator after 10 min of metofluthrin exposure. Use of metofluthrin reduced biting activity up to 8 m, regardless of the host's proximity (near or far) to a dark harbourage area (HA) (P < 0.0001 and P = 0.006), respectively. In the presence or absence of the metofluthrin emanator, the host was most likely bitten when located immediately next to a HA (within 1 m) versus 8 m away from the HA (P = 0.006). The addition of a ceiling fan (0.8 m/s airflow) prevented all biting activity after 10 min of metofluthrin exposure. Previously unexposed Ae. aegypti were less likely to reach the host in a metofluthrin-treated room ̄X = 31%) compared to an untreated room (̄X = 100%) (P < 0.0001). In a treated room, if the mosquito had not reached the host within 30 s, they never would. Upon activation, the time required for metofluthrin to infiltrate protected locations within a room causing knockdown in caged mosquitoes, required more time than exposed locations (P < 0.003); however exposed and protected locations do eventually reach equilibrium, affecting mosquitoes equally throughout the room. Conclusion: Metofluthrin is effective in interrupting indoor host-seeking in Ae. aegypti. Metofluthrin's efficacy is increased by centrally locating the emanator in the room, and by using a fan to increase airflow. Newly treated rooms may require a period of 2-4 h for sufficient distribution of the metofluthrin into protected locations where mosquitoes may be resting. [ABSTRACT FROM AUTHOR]

Background: Indoor residual spraying is key to dengue control in Cairns and other parts of northern Queensland, Australia, where Aedes aegypti is prevalent, but the strategy faces challenges with regards to slow application time and, therefore, community coverage. A faster potential improvement might be the use of polyethylene netting impregnated with the volatile pyrethroid metofluthrin (SumiOne™). This formulation was assessed in rooms in three houses in Cairns, Australia. One emanator was placed in each room and cages of 10 female Aedes aegypti were exposed at distances of 1 and 3 m. Knockdown and landings on a human hand were counted before metofluthrin exposure and at 10, 30, 60, 90 and 120 min during exposure. In addition, two trials continued over 48 h of exposure to assess the long-term sublethal effects of metofluthrin on caged mosquitoes. Results: Percentage landing rates fell to 0-2.5% in the first 10 min of exposure. Knockdown was most evident between 10 and 30 min (54% at 1 m and 33% at 3 m). Distance from the emanator strongly affected the results: mosquitoes at 3 m exhibited less knockdown and more landings than those at 1 m. As room volume increased, knockdown decreased and the number of landing increased. There is a cumulative mortality and landing inhibition and, for mosquitoes exposed to metofluthrin for > 48 h, mortality was 100% at 1 m and 90% at 3 m. Of those still alive, a small number continued to land and bite. After being removed from metofluthrin-treated rooms, exposed insect cages were found to reducing landing rates for up to 2 h. Conclusions: Despite only moderate levels of knockdown during the initial hours of exposure, metofluthrin emanators were effective in reducing mosquito landing rates, especially within 1 m, even when exposed on an open veranda. The evaluation methods and results described in this paper will help inform the optimal conditions of deployment of metofluthrin emanators. These devices have the potential to reduce contact between humans and urban disease vectors faster than indoor residual spraying so supplement our current arsenal of dengue control tools. [ABSTRACT FROM AUTHOR]

The emergence of artemisinin-resistant malaria in Southeast Asia is a major problem. The fact that many people become infected with malaria when they are outside has prompted the development of 'spatial' rather than topical repellents. The respective effects of one or four slow-release emanators of metofluthrin, a pyrethroid, were tested in Pailin, Pursat and Koh Kong, Cambodia. Numbers of mosquitoes counted in outdoor landing catches when one or four emanators were suspended close to the collector were compared with control collections. In Pailin, the effects of emanators on catches in Furvela tent traps and Centers for Disease Control ( CDC) light traps suspended underneath houses were also investigated. Rate ratios were used to determine differences. A total of 29 255 mosquitoes were collected over 2934 h of landing collections, 87 nights of tent trapping and 81 nights of light trap capture. In Pailin, landing rates were reduced by 48% by a single emanator and by 67% by four emanators ( P < 0.001). Similar reductions were observed in the number of mosquitoes collected in tent traps and the number of anophelines only collected in light traps. Results were similar in Pursat, but, for unknown reasons, those in Koh Kong showed no difference between control and metofluthrin collections ( P > 0.05). These findings suggest that although the product can produce a significant effect, it requires further improvement. [ABSTRACT FROM AUTHOR]

The efficacy of a metofluthrin-impregnated net (MIN) known as the 'Mushikonazu' on the house entry behavior of female Aedes aegypti and Anopheles dirus mosquitoes was evaluated using a semi-field 50-m tunnel setup. While the MIN is labeled for the control of chironomids and moth flies, this study determined the feasibility of using the device, given its current construction and metofluthrin formulation, as a spatial repellent against mosquitoes. Sentinel and cone bioassays were used to determine the insecticidal effect of the MIN. A spatial activity index (SAI) was calculated to evaluate responses of the mosquitoes. For the spatial repellent evaluation against Ae. aegypti, the overall mean of SAI was slightly less than 0 at wk 1 after the MIN application and then decreased for the last 4 wk showing a preference to treatment tent. For An. dirus, the mean SAI at wk 1 was positive, indicating a presumed repellent effect of the MIN against An. dirus. For the subsequent 4 wk, the SAI was negative, indicating a preference for the MIN. Results suggested that the MIN may not be a promising approach to repel Ae. aegypti and An. dirus under field conditions in Thailand. However, it remains probable that the MIN may be effective as a spatial repellent if modifications are made to the metofluthrin concentration or formulation and/or the construction of the device. [ABSTRACT FROM AUTHOR]

U.S. military troops are exposed to mosquito-borne pathogens when deployed to endemic regions. Personal protective measures such as permethrin-treated uniforms and dermal repellents are the cornerstones of mosquito-borne disease prevention for the U.S. military. These measures have limitations and additional personal protection tools, such as spatial repellent devices to decrease the risk of vector-borne pathogen transmission, are required. Novel spatial repellent controlled-release devices formulated with metofluthrin were evaluated in an outdoor setting in the northern Amazon of Peru to evaluate performance under field conditions. The metofluthrin emitting devices lowered the number of mosquitoes captured in protected human landing collections (HLC) compared to blank devices, although there were effect differences between Anopheles spp. and species in other mosquito genera. A computational-experimental model was developed to correlate HLC and active ingredient (AI) concentrations as a function of time and space. Results show a strong correlation between the released AI and the decrease in HLC. This model represents the first effort to obtain a predictive analytical tool on device performance using HLC as the entomological endpoint.