Benzoylphenyl Urea Research Articles

A new generation of biocides for control of crustacea in fish farms

Farming of salmon has become a significant industry in many countries over the past two decades. A major challenge facing this sector is infestation of the salmon by sea lice. The main way of treating salmon for such infestations is the use of medicines such as organophosphates, pyrethrins, hydrogen peroxide or benzoylphenyl ureas. The use of these medicines in fish farms is, however, highly regulated due to concerns about contamination of the wider marine environment. In this paper we report the use of photochemically active biocides for the treatment of a marine copepod, which is a model of parasitic sea lice. Photochemical activation and subsequent photodegradation of PDAs may represent a controllable and environmentally benign option for control of these parasites or other pest organisms in aquaculture.

Resistance to benzoylphenyl urea insecticides in Australian populations of the sheep body louse

A laboratory bioassay based on the failure of eggs laid by diflubenzuron-treated sheep body lice Bovicola ovis (Schrank) (Phthiraptera; Trichodectidae) to produce nymphs is described. The test is capable of detecting benzoylphenyl urea-resistant populations. A susceptible discriminating dose (topical treatment of female lice with 0.10 microg diflubenzuron) suitable for screening suspect resistant populations is suggested but testing of further populations that are naïve to these insect growth regulator insecticides is warranted.

Resistance to insect growth regulator insecticides in populations of sheep lice as assessed by a moulting disruption assay

Low-volume, backline applications with the benzoylphenyl urea insecticides triflumuron and diflubenzuron represent in excess of 70% of treatments for the control of sheep lice, Bovicola ovis (Schrank) (Phthiraptera: Trichodectidae), in Australia. Reports of reduced effectiveness from 2003 and subsequent controlled treatment trials suggested the emergence of resistance to these compounds in B. ovis populations. A laboratory assay based on the measurement of moulting success in nymphs was developed and used to assess susceptibility to diflubenzuron and triflumuron in louse populations collected from sheep where a control failure had occurred. These tests confirmed the development of resistance to triflumuron and diflubenzuron in at least two instances, with estimated resistance ratios of 67-94X at LC(50).

Influence of biotic-abiotic factors on the degradation of novaluron in tropical soil

In this study, the degradation of novaluron (benzoylphenyl urea insect growth regulator) was investigated under controlled laboratory conditions in clay loam alluvial and coastal saline soils of West Bengal, India. The application rates were field rate (FR); 2FR and 10FR. The incubation study was carried out at 30 °C and 60% of maximum water holding capacity of both the soils. Degradation of novaluron in both the soils followed first order reaction kinetics at all application rates under non-sterile and sterile conditions. The half-lives of novaluron in non-sterilized soils ranged from 17.0–17.8 days (alluvial soil) and 11.4–12.7 days (coastal saline soil), while the values in case of the sterilized soils were 53.7–59.0 days (alluvial soil) and 28.9–29.8 days (coastal saline soil) respectively. The novaluron degradation patterns were found to be highly influenced by soil types, application rates, and biotic abiotic factors. Abiotic factors strongly influenced novaluron degradation in both the soils. Biotic degradation was higher in alluvial soil compared to the coastal saline soil.

Diflubenzuron effects on reproduction and hemolymph ecdysteroid levels in female locusts Schistocerca gregaria (Forskål, 1775) (Orthoptera, Acrididae)

The insecticide diflubenzuron (DFB), a benzoylphenyl urea, decreases fecundity in insects by a still unknown mechanism. The objective of this study was firstly to see the effects of DFB on female reproduction, after its ingestion by Schistocerca gregaria females five days following imaginal molt. DFB significantly delayed the timing of the first and of the second laying when compared to control females. DFB-treated females laid eggs only twice, while control females had, as typical, up to five ovipositions. DFB action on ovarian development and hemolymphatic ecdysteroid levels were also evaluated in females. Ecdysteroid titres in control females fluctuated according to the ovarian cycle, reaching a peak of around 170 pmol/mL hemolymph during the vitellogenic phase. In DFB-treated females, hemolymph ecdysteroid titres remained very low and oocyte growth was reduced. The treatment caused early oocyte resorption and any eggs deposited never hatched.

Insecticidal properties of bistrifluron against sycamore lace bug, Corythucha ciliata (Hemiptera: Tingidae)

Bistrifluron, a member of the benzoylphenylurea (BPU) class, was developed in the Republic of Korea as an inhibitor of chitin synthesis. This study examined the effect of bistrifluron on insecticidal activity, adult longevity, fecundity and ovarian development in the sycamore lace bug, Corythucha ciliata. The results showed that bistrifluron had no direct effect on the egg, but produced 100% mortality in larvae hatched within 24 hr with a similar effect regardless of the instars of the larvae (LC50=0.01–0.06 ppm). When the final instar was treated with bistrifluron, the emergence rate, adult longevity and reproduction decreased with increasing concentration (up to 100 ppm). With the passage of time after the final larvae had emerged, chemical treatment delayed the preoviposition period of the adults at high concentrations, and decreased adult longevity, fecundity and the hatching rate. Ovarian development of the adult was also inhibited.

Synergistic effect of a fungicide containing polyoxin B with insect growth regulators (IGRs) in the killing of common cutworm, Spodoptera litura (Lepidoptera: Noctuidae)

Polyoxin AL water-soluble powder (Polyoxin AL), a fungicide that inhibits chitin synthase, showed a synergistic effect with benzoylphenyl urea insect growth regulators (BPU-IGRs) in killing Spodoptera litura larvae. First, eight different commercially available insecticides were examined for a synergistic effect with Polyoxin AL in killing S. litura. Only Cascade, one of the BPU-IGRs, showed a synergistic effect. Next, eight BPU chemicals (six BPU-IGRs including Cascade and two reagents) were used. All eight chemicals showed a synergistic effect except for Dimilin. Finally, six fungicides, including Polyoxin AL, were examined for a synergistic effect with Cascade. Only Polyoxin AL showed a synergistic effect. These results suggest that the synergistic effect was specific for the combination of BPU chemicals and Polyoxin AL.

Development and application of a method for analysis of lufenuron in wheat flour by gas chromatography–mass spectrometry and confirmation of bio-efficacy against Tribolium castaneum (Herbst) (Coleoptera: Tenebrionidae)

A new analytical method using gas chromatography with mass spectrometry (GC–MS) for the quantitative determination of lufenuron, a benzoylphenylurea (BPU) class of insecticide, from wheat flour has been developed and applied for time-dependant residue monitoring in treated wheat flour. The analyte was extracted from wheat flour by a single step solid–liquid extraction by using ethyl acetate and subsequently cleaned up using the Primary Secondary Amine as a sorbent prior to GC–MS analysis. The present method provides sufficient sensitivity as reflected by the values of limit of detection (LOD) and limit of quantification (LOQ), 5 ng/mL (S/N ∼3) and 50 ng/mL (the lowest validation point on the calibration curve), respectively. The calibration curve showed an excellent linearity in the concentration range of 50–1000 ng/mL ( r 2 = 0.998). The average recovery for spiked samples at three concentrations (150, 300, and 450 ng/g) was 98.23 ± 2.52% R.S.D. The method was applied for the determination of lufenuron residues in treated wheat flour samples. Simultaneous determination of bio-efficacy of lufenuron residues was also carried out against the red flour beetle, Tribolium castaneum to correlate the actual residual effect of lufenuron as detected by the analytical method, over a period of 3 months. The findings revealed that the residual concentration of lufenuron were neither uniform nor in descending order over a period of 3 months in wheat flour, possibly because of an uneven dispersal in the treated wheat which was subsequently milled into flour, as confirmed by GC–MS analysis. However, the residues of lufenuron were sufficient to produce 100% mortality of T. castaneum larvae up to 3 months . The results have been discussed in view of the potential of lufenuron as a candidate molecule for the control of stored product pests.

Reduced viability of Colorado potato beetle, Leptinotarsa decemlineata, eggs exposed to novaluron

Novaluron is a benzoylphenyl urea chitin synthesis inhibitor that combines good activity against larval stages of the Colorado potato beetle, Leptinotarsa decemlineata (Say) (Coleoptera: Chrysomelidae), with low mammalian toxicity. Previous studies suggest that it has deleterious sublethal effects on adults. Continuous exposure of adult Colorado potato beetles to novaluron-treated foliage as both ovipositional and feeding substrate did not affect their survivorship or the number of eggs produced, but viable larvae hatched only from the eggs that were laid on the first day of the experiment. Viability was restored after adult beetles spent 48-96 hours on untreated leaves. In a separate experiment, direct exposure to novaluron of eggs laid by unexposed beetles also reduced the number of larvae hatching. Results confirm a negative effect of novaluron on the number of progeny produced by the Colorado potato beetle. Direct toxicity did not explain all of the reduction in egg hatch observed, suggesting that novaluron probably acted on reproductive adults as well as on eggs after they were deposited.

Biology and Control of the Raspberry Crown Borer (Lepidoptera: Sesiidae)

This study explored the biology of raspberry crown borer, Pennisetia marginata (Harris) (Lepidoptera: Sesiidae), in Arkansas and the optimum timing for insecticide and nematode applications. The duration of P. marginata's life cycle was observed to be 1 yr in Arkansas. Insecticide trials revealed that bifenthrin, chlorpyrifos, imidacloprid, metaflumizone, and metofluthrin efficacy were comparable with that of azinphosmethyl, the only labeled insecticide for P. marginata in brambles until 2005. Applications on 23 October 2003 for plots treated with bifenthrin, chlorpyrifos, and azinphosmethyl resulted in >88% reduction in larvae per crown. Applications on 3 November 2004 of metaflumizone, metofluthrin, and bifenthrin resulted in >89% reduction in larvae per crown. Applications on 7 April 2005 for metofluthrin, imidacloprid, bifenthrin, metaflumizone, and benzoylphenyl urea resulted in >64% reduction in the number of larvae per crown. Applications on 6 May 2004 did not reduce larval numbers. The optimum timing for treatments was found to be between October and early April, before the larvae tunneled into the crowns of plants. Applying bifenthrin with as little as 468 liters water/ha (50 gal/acre) was found to be as effective against larvae as higher volumes of spray. Nematode applications were less successful than insecticides. Nematode applications of Steinernemafeltiae, Steinernema carpocapsae, and Heterorhabditis bacteriophora reduced larvae counts per plant by 46, 53, and 33%, respectively.

Biology and Control of the Raspberry Crown Borer (Lepidoptera: Sesiidae)

This study explored the biology of raspberry crown borer, Pennisetia marginata (Harris) (Lepidoptera: Sesiidae), in Arkansas and the optimum timing for insecticide and nematode applications. The duration of P. marginata’s life cycle was observed to be 1 yr in Arkansas. Insecticide trials revealed that bifenthrin, chlorpyrifos, imidacloprid, metaflumizone, and metofluthrin efficacy were comparable with that of azinphosmethyl, the only labeled insecticide for P. marginata in brambles until 2005. Applications on 23 October 2003 for plots treated with bifenthrin, chlorpyrifos, and azinphosmethyl resulted in >88% reduction in larvae per crown. Applications on 3 November 2004 of metaflumizone, metofluthrin, and bifenthrin resulted in >89% reduction in larvae per crown. Applications on 7 April 2005 for metofluthrin, imidacloprid, bifenthrin, metaflumizone, and benzoylphenyl urea resulted in >64% reduction in the number of larvae per crown. Applications on 6 May 2004 did not reduce larval numbers. The optimum timing for treatments was found to be between October and early April, before the larvae tunneled into the crowns of plants. Applying bifenthrin with as little as 468 liters water/ha (50 gal/acre) was found to be as effective against larvae as higher volumes of spray. Nematode applications were less successful than insecticides. Nematode applications of Steinernema feltiae, Steinernema carpocapsae, and Heterorhabditis bacteriophora reduced larvae counts per plant by 46, 53, and 33%, respectively.

Phase I study of continuous weekly dosing of dimethylamino benzoylphenylurea (BPU) in patients with solid tumours

A phase I study of dimethylamino benzoylphenylurea (BPU), a tubulin inhibitor, was performed using a weekly continuous schedule. Patients with refractory solid tumours received oral BPU once weekly without interruption at doses ranging from 5 to 320 mg using an accelerated titration design. Nineteen subjects received 54 cycles of BPU. Early pharmacokinetic findings of decreased clearance with increasing dose and plasma accumulation led to the expansion of the 320 mg dose level. Two subjects then developed late haematologic dose-limiting toxicities (DLTs) that were associated with the highest plasma exposure to BPU and metabolites. Study enrollment resumed at dose 150 mg with real-time pharmacokinetic monitoring. Seven additional subjects (6 evaluable) were treated for a median of 2 cycles (range 1.5–4) without further myelotoxicity. A long half-life and accumulation of BPU and active metabolites were observed, recommending against a continuous administration. Weekly oral BPU therapy should be further tested using an interrupted schedule.

Effects of cattle treatment with a fluazuron pour-on on survival and reproduction of the dung beetle species Onthophagus gazella (Fabricius)

While resistance against many other classes of acaricides has been described, products containing benzoylphenyl urea are currently still successfully used against the pesticide-resistant blue tick ( Boophilus decoloratus) in South Africa. In order to assess any adverse impact of these tickicides on the important dung beetle (Coleoptera: Scarabaeidae) fauna, a bioassay was undertaken on the ecotoxicological effects of a fluazuron (benzoylphenyl urea) pour-on formulation (Acatak ®) on the survival and reproduction of the African dung beetles species Onthophagus gazella (Fabricius). The experiment yielded no significant differences in adult or larval survival, egg production, fecundity and fertility between the control and treatment group following three beetle generations over. These results suggested that treatment of cattle with the fluazuron pour-on formulation Acatak ® was not detrimental to the selected dung beetle species in any notable way.

Field efficacy of novaluron for control of Colorado potato beetle (Coleoptera: Chrysomelidae) on potato

Field trials were conducted in 2003 and 2004 to assess the effectiveness of novaluron (Rimon 10EC), a benzoylphenyl urea chitin synthesis inhibitor, for Colorado potato beetle, Leptinotarsa decemlineata (Say), management on potato. Foliar applications of novaluron did not significantly reduce numbers of L. decemlineata adults, egg masses, or first instar larvae, but second–fourth instars were greatly suppressed. Although an application rate of 12.5 g AI ha −1 provided unsatisfactory protection, rates of 25 and 50 g AI ha −1 proved effective when applied 2 days after second instars were first observed on plants. These rates were much less effective when applied 2 days after observance of egg masses. At 50 g AI ha −1, novaluron provided excellent, prolonged protection, whether applied twice a season, or once in alternation with imidacloprid. Defoliation was minimized, resulting in yields 3.8–5.2 times greater than those harvested from control plots. The results suggest that novaluron could be a valuable tool in future L. decemlineata management programs.

In vitro and In vivo Clinical Pharmacology of Dimethyl Benzoylphenylurea, a Novel Oral Tubulin-Interactive Agent

Dimethyl benzoylphenylurea (BPU) is a novel tubulin-interactive agent with poor and highly variable oral bioavailability. In a phase I clinical trial of BPU, higher plasma exposure to BPU and metabolites was observed in patients who experienced dose-limiting toxicity. The elucidation of the clinical pharmacology of BPU was sought. BPU, monomethylBPU, and aminoBPU were metabolized by human liver microsomes. Studies with cDNA-expressed human cytochrome P450 enzymes revealed that BPU was metabolized predominantly by CYP3A4 and CYP1A1 but was also a substrate for CYP2C8, CYP2D6, CYP3A5, and CYP3A7. BPU was not a substrate for the efflux transporter ABCG2. Using simultaneous high-performance liquid chromatography/diode array and tandem mass spectrometry detection, we identified six metabolites in human liver microsomes, plasma, or urine: monomethylBPU, aminoBPU, G280, G308, G322, and G373. In patient urine, aminoBPU, G280, G308, and G322 collectively represented <2% of the given BPU dose. G280, G308, G322, and G373 showed minimal cytotoxicity. When BPU was given p.o. to mice in the presence and absence of the CYP3A and ABCG2 inhibitor, ritonavir, there was an increase in BPU plasma exposure and decrease in metabolite exposure but no overall change in cumulative exposure to BPU and the cytotoxic metabolites. Thus, we conclude that (a) CYP3A4 and CYP1A1 are the predominant cytochrome P450 enzymes that catalyze BPU metabolism, (b) BPU is metabolized to two cytotoxic and four noncytotoxic metabolites, and (c) ritonavir inhibits BPU metabolism to improve the systemic exposure to BPU without altering cumulative exposure to BPU and the cytotoxic metabolites.

Validation and implementation of a liquid chromatography/tandem mass spectrometry assay to quantitate dimethyl benzoylphenylurea (BPU) and its five metabolites in human plasma and urine for clinical pharmacology studies

A method has been developed for the quantitation of N-[4-(5-bromo-2-pyrimidinyloxy)-3-methylphenyl]-N'-(2-dimethylamino-benzoyl)urea (BPU) and its metabolites in human plasma and urine. BPU and metabolites were separated on a C18 column with acetonitrile-water mobile phase containing 0.1% formic acid using isocratic flow for 5 min. The analytes were monitored by tandem mass spectrometry. Calibration curves were generated over the range of 2.5-500 ng/mL for BPU, mmBPU, and aminoBPU in plasma; and 0.1-20, 0.1-20, 0.5-100, 10-2000, 1-200, and 3-600 ng/mL for BPU, mmBPU, aminoBPU, G280, G308, and G322 in urine, respectively. The method has been successfully applied to study the pharmacokinetics of BPU.

Residual Activity and Population Effects of Noviflumuron for German Cockroach (Dictyoptera: Blattellidae) Control

A benzoylphenyl urea insect growth regulator with the common name noviflumuron was evaluated for efficacy and residual activity on the German cockroach, Blattella germanica (L.). In laboratory studies evaluating residual activity, 0.05% noviflumuron suspension concentrate produced 100% nymphal mortality 120 d after application to steel and masonite substrates. Residual activity of noviflumuron was more variable on painted plywood substrates compared with stainless steel and masonite. In bioassay arenas, population reductions caused by noviflumuron were significantly greater than Archer and the untreated populations. After 16 wk, populations exposed to 0.05, 0.1, and 0.2% noviflumuron were reduced by 51.9 +/- 19.8, 62.2 +/- 6.5, and 62.6 +/- 18.4%, respectively. Control cockroach populations and populations exposed to 1.3% pyriproxyfen at labeled rate (Archer, 0.61 g/m2) increased by 1286.3 +/- 125.1 and 937.2 +/- 137.1%, respectively, at the end of 16 wk. A field study in multifamily housing complexes showed noviflumuron (0.2 and 0.5%) to provide 73.3 +/- 8.0 and 90.6 +/- 3.6% trap catch reduction at 4 wk posttreatment, respectively. There were no significant differences in the performance of noviflumuron, Maxforce FC Roach Bait Stations (0.05% [AI] fipronil), and Avert dust bait (0.05% [AI] abamectin B1). Noviflumuron shows excellent potential for use in cockroach management programs.

Novel insecticides: Modes of action and resistance mechanism

AbstractEfforts have been made during the past three decades to develop insecticides with selective properties that act specifically on biochemical sites present in particular insect groups, but whose properties differ from other insecticides. This approach has led to the discovery of compounds that affect the hormonal regulation of molting and developmental processes in insects, e.g., ecdysone agonists (tebufenozide and methoxyfenozide), juvenile hormone mimics (pyriproxyfen and fenoxycarb), and chitin synthesis inhibitors (benzoylphenyl ureas and buprofezin). In addition, compounds that selectively interact with the insect nicotinic acetylcholine receptor such as imidacloprid, acetamiprid, and thiamethoxam have been introduced for the control of aphids, whiteflies, and other insect species.In this issue, we report on some new insecticides that fit the current approach of pest management programs, such as the new non‐steroidal ecdysone agonist THQ [1‐aroyl‐4‐(arylamino)1,2,3,4‐tetrahydroquinoline], which acts preferentially against mosquitoes with no appreciable effect on other insect groups or mammals. The mode of action of this compound, along with its selectivity, is discussed in detail in the report of Palli et al. Another novel compound reported in this issue is pyradalyl (S‐1812), which was found to act selectively on lepidopterans and thrips. In laboratory assays, pyradalyl was found to act on insect cell lines with no appreciable effect on mammal cell lines. The potential use of this compound in agricultural systems is discussed by Isayama et al.Three reports in this issue deal with resistance mechanisms and resistance management of novel insecticides. Nauen et al. present an up‐to‐date review on insect resistance mechanisms to neonicotinoids and ways to optimize their use in pest management programs. Horowitz et al. report on Bemisia tabaci biotypes B and Q and their resistance to neonicotinoids and pyriproxyfen. One of the most striking findings in their report is that the Q biotype develops resistance to pyriproxyfen and neoicotinopid faster than biotype B, while the latter exhibits better fitness. The practical implications of these findings are discussed. In another report, Ishaaya et al. present a study detailing the toxicity and cross‐resistance of selected biorational insecticides. Their findings indicate that no appreciable cross‐resistance was observed between the benzoylphenyl urea, novaluron, the juvenile hormone mimic, pyriproxyfen, and the neonicotinoids, acetamiprid and imidacloprid. Hence, these compounds could be used, in alternation, as components in insecticide resistance management programs.

Biorational insecticides: Mechanism and cross‐resistance

Potency and cross-resistance of various biorational insecticides, exemplified by the whitefly Bemisia tabaci, have been studied. Bemisia tabaci were exposed to the juvenile hormone mimic pyriproxyfen for the past 12 years resulting in an over 2,000-fold resistance, but there was no appreciable cross-resistance with the benzoylphenyl urea novaluron. Similarly, no cross-resistance was found between pyriproxyfen and the two neonicotinoids, acetamiprid and imidacloprid. On the other hand, a slight cross-resistance of 5-13-fold was observed with another neonicotinoid thiamethoxam. Among the neonicotinoids, a resistant strain of B. tabaci to thiamethoxam (approximately 100-fold) showed no appreciable cross-resistance to either acetamiprid or imidacloprid, while another strain 500-fold resistant to thiamethoxam resulted in a mild of 4-6-fold resistance to acetamiprid and imidacloprid. In other assays, B. tabaci strain resistant to thiamethoxam (approximately 100-fold) had no cross-resistance to pyriproxyfen. Our findings indicate that no appreciable cross-resistance was observed between the benzoylphenyl urea novaluron, the juvenile hormone mimic pyriproxyfen, and the neonicotinoids acetamiprid and imidacloprid. Hence, these compounds could be used as components in insecticide resistance management programs.

FC‐1 Comparative efficacy of lufenuron and itraconazole in a guinea pig model of cutaneous Microsporum canis

During the last few years, reports have appeared claiming that lufenuron diminished or even cured dermatophyte infections in cats and dogs. As these observations have a rather anecdotal character leading to some ambiguity in the literature, it was decided to test lufenuron in a generally accepted animal model for dermatomycotic infection. The test was carried out in guinea pigs artificially infected with Microsporum canis on scarified dorsal skin and orally treated with lufenuron (Program™). The efficacy of up to five doses of 80 mg/kg was assessed 7 and 14 days after the start of treatment. All animals failed to show any improvement in skin lesions as compared to the vehicle‐only treated animals. Clinical symptoms taken into account were scaling, crust formation, erythema, and exudation. Neither the number of treatments (one or five) nor the dose range (40 or 80 mg/kg) made any difference. Itraconazole, tested earlier under identical circumstances, resulted in a clear and consistent improvement at day 7 of the infection at a dose of 15 mg/kg, given either in one dose or spread over several days. The absence of antimycotic activity of lufenuron in this established animal model constitutes a significant element in the discussion on the antifungal potency of lufenuron and supports the fact that there is, as yet, no evidence that benzoylphenyl urea derivative compounds have an effect on chitin synthesis in fungi. Funding: J&amp;J Pharmaceutical Research and Development, Janssen Animal Health.