Safeners Research Articles

A MOF-based pH-responsive dual controlled-release system for herbicide pretilachlor and safener AD-67 delivery that enhances the herbicidal efficacy and reduces side effects

The herbicide-safener dual controlled release system AD-67@Pre@ZIF-67 was successfully prepared for the high efficiency and low toxicity of herbicide.

From screening to the hectogram scale: sustainable electrochemical synthesis of mefenpyr-diethyl

A solvent-controlled electrochemical method for the preparation of commercial herbicide safener mefenpyr-diethyl is established, demonstrating its application potential from screening to hectogram scale.

Evaluation of rice tolerance and weed control with acetochlor and fenclorim

AbstractMany problematic weeds have evolved resistance to herbicides in mid-southern U.S. rice fields. With the lack of new effective herbicides, rice producers seek alternatives that are currently not labeled for rice production. Inhibitors of very-long chain fatty acid elongase (VLCFA) are currently not labeled for use with U.S. rice crops but are labeled for use in other U.S. row cropping systems and rice production in Asia. Previous research has demonstrated the utility of VLCFA inhibitors for weed control in rice; however, these herbicides induce variable amounts of injury to the crop when applied early in the growing season. Experiments were initiated in 2020 and 2021 at the Rice Research and Extension Center near Stuttgart, AR, to evaluate rice tolerance and weed control with acetochlor and seed treatment with a herbicide safener, fenclorim. Three rates of a microencapsulated formulation of acetochlor (630, 1,260, and 1,890 g ai ha−1), four application timings (preemergence, PRE; delayed-preemergence, DPRE; spiking; and 1-leaf), and without or with the fenclorim seed treatment (2.5 g kg−1 of seed) were used to evaluate rice tolerance, weedy rice control, and barnyardgrass control. Acetochlor applied DPRE at 1,260 g ai ha−1 provided better weedy rice and barnyardgrass control than applications at the 1-leaf stage at the same rate. Acetochlor rates of 1,260 and 1,890 g ai ha−1 reduced barnyardgrass and weedy rice densities by more greater than the 630 g ai ha−1 rate. The fenclorim seed treatment did not influence weedy rice or barnyardgrass control but did reduce injury for DPRE acetochlor applications. Based on these results, acetochlor can be safely applied to rice DPRE (≤19% injury) at 1,260 g ai ha−1 when the seed is treated with fenclorim, leading to ≥88% barnyardgrass and ≥45% weedy rice control 28 d after treatment.

Fenclorim Increasing Butachlor Selectivity between Wheat and Roegneria kamoji by Seed Soaking

Roegneria kamoji Ohwi (Poaceae), a wild relative plant of wheat which is widely distributed across China, has become a dominant and problematic weed in wheat fields in some regions. We have previously confirmed that R. kamoji is highly tolerant to foliar-applied acetyl-CoA carboxylase (ACCase) and acetolactate synthase (ALS) inhibitors in wheat (Triticum aestivum L.). The sensitivity of R. kamoji to pre-emergence (PRE) herbicides and the basis of fenclorim increase selectivity to butachlor between wheat and R. kamoji were evaluated in this study. Screenhouse bioassay showed that R. kamoji exhibited similar sensitivity to wheat to PRE herbicides at their recommended field doses (RFD); it also showed that buatchlor provides the highest relative control for R. kamoji (53.4% emergence and 81.5% fresh weight reduction, respectively), while it had no impact on seedling emergence of wheat among the six PRE herbicides. When butachlor was applied at four-fold RFD, no R. kamoji seedlings emerged; however, it significantly reduced the above-ground biomass of wheat compared with the non-treated control. Pre-treatment with herbicide safener fenclorim by seed soaking increased the ED10 value of butachlor to wheat from 221.8 to 1600.1 g a.i. ha−1, thus increasing the selectivity index from 9.6 to 68.9 between wheat and R. kamoji. The activities of α-amylase activity and protein content during germination, and glutathione-S-transferase (GST) and β-ketoacyl-CoA synthase (KCS) in the seedlings, could be induced by butachlor in both wheat seeds with or without fenclorim pre-soaking. These results suggested that butachlor provides the highest control for R. kamoji and did not affect germination and emergence in wheat. The basis of fenclorim-increased selectivity to butachlor was associated with the induced GST and KCS-mediated enhanced herbicide metabolism in wheat.

Current Advances in the Action Mechanisms of Safeners

Herbicide safeners are a series of agrochemicals that can selectively protect crop plants from herbicide injury without affecting herbicidal efficacy. Understanding mechanisms by which safeners act is significant for discovery of novel types. Safeners primarily alleviate herbicide phytotoxicity to crop plants via several actions: (i) enhancing metabolism of herbicides in crops; (ii) affecting absorption and transportation of herbicides in crops; (iii) competitively binding to herbicide target sites; and (iv) affecting activity of target enzymes. This review describes recent advances in the action mechanisms of safeners, analyzes existing problems, anticipates the future direction of studies of modes of action of safeners, and prospects potential strategies to design safeners related to their reported mechanisms. The aim of this paper is to provide insight into mechanisms of safeners and give tips for development of new safeners.

Sorption behaviour and toxicity of an herbicide safener “cyprosulfamide”

Cyprosulfamide is a herbicide safener that works against the injurious effects of herbicides such as isoxaflutole, dicamba, nicosulfuron, tembotrione, thiencarbazone-methyl. However, its sorption behaviour in soils and toxicity to aquatic organisms are yet to be thoroughly examined. This study determined the octanol-water partition coefficient, sorption properties, acute and chronic toxic effects, and potency of cyprosulfamide to the cladoceran water flea (Daphnia magna). The influence of soil properties such as organic carbon content, cation exchange capacity, pH, and field capacity on adsorption and desorption properties were also examined. The Log Kow (0.55) of cyprosulfamide was less than that of some other safeners, such as benoxacor or furilazole, found in aquatic environments. The sorption of cyprosulfamide to the soil was driven by pH, so sorption decreased with an increase in pH. Other characteristics, such as cation exchange capacity (CEC), organic carbon content, and field capacity, do not directly correlate with the distribution coefficient. Cyprosulfamide generally has a low affinity for soil and is thus mobile and prone to transport to surrounding surface waters. No lethality was observed at the highest concentration (120 mg/L) tested for acute toxicity to D. magna; hence the LC50 will be >120 mg/L. During chronic exposures, cyprosulfamide caused adverse effects at a concentration of 120 mg/L on the number of neonates and brood size. The death rate for the chronic study was a function of concentration and increased with days of exposure. Cyprosulfamide is unlikely to cause lethality to D. magna at relevant environmental concentrations.

The dichloroacetamide safener benoxacor is enantioselectively metabolized by monkey liver microsomes and cytosol

The metabolism and toxicity of current-use herbicide safeners remain understudied. We investigated the enantioselective metabolism of the safener benoxacor in Rhesus monkey subcellular fractions. Benoxacor was incubated with liver microsomes and cytosol from female and male monkeys (≤30 min). Benoxacor levels and enantiomeric fractions were determined with gas chromatography. Benoxacor was metabolized by microsomal cytochrome P450 enzymes (CYPs), cytosolic glutathione-S-transferases (GSTs), and microsomal and cytosolic carboxylesterase (CESs). CES-mediated microsomal metabolism followed the order males > females, whereas the CYP-mediated clearance followed the order females > males. CYP-mediated metabolism initially resulted in an enrichment of the second eluting benoxacor enantiomer (E2-benoxacor), whereas the first eluting benoxacor enantiomer (E1-benoxacor) was enriched after 10 or 30 min in female or male microsomal incubations. Benoxacor metabolism by GSTs was enantiospecific, with a total depletion of E1-benoxacor after approximately 20 min. Thus, the enantioselective metabolism of benoxacor by GSTs and CYPs may affect its toxicity.

Diazabicyclo derivatives as safeners protect cotton from injury caused by flumioxazin

Flumioxazin, a protoporphyrinogen oxidase (PPO; EC 1.3.3.4) inhibitor, has been used in soybean, cotton, grapes, and many other crops to control broad leaf weeds. Unfortunately, it can cause damage to cotton. To ameliorate phytotoxicity of flumioxazin to cotton, this work assessed the protective effects of diazabicyclo derivatives as potential safeners in cotton. A bioactivity assay proved that the phytotoxicity of flumioxazin on cotton was alleviated by some of the compounds. In particular, the activity of glutathione S-transferases (GSTs) was significantly enhanced by Compound 32, which showed good safening activity against flumioxazin injury. The physicochemical properties and absorption, distribution, metabolism, excretion and toxicity (ADMET) predictions proved that the pharmacokinetic properties of Compound 32 are similar to those of the commercial safener BAS 145138. The present work demonstrated that diazabicyclo derivatives are potentially efficacious as herbicide safeners, meriting further investigation.

Spatially Resolved Investigation of Herbicide-Safener Interaction in Maize (Zea mays L.) by MALDI-Imaging Mass Spectrometry.

Monitoring agrochemical distribution within plant tissues delivers significant insights into the adsorption, distribution, metabolism, and elimination of agrochemicals. Detection and imaging of the safener cyprosulfamide (CSA) and the herbicide thiencarbazone-methyl (TCM) after micro-droplet application on the surface of maize leaves (Zea mays L.) have been achieved using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI). The agrochemicals were deposited onto the adaxial surface of maize leaves on growing plants, and their uptake, distribution, and metabolism were investigated at four timepoints (3 h, 24 h, 4 days, and 7 days) to assess the influence of CSA treatment on TCM metabolism. MALDI MSI visualized significant changes for the metabolism of TCM after 24 h. Although TCM metabolism was detected neither in the control without the safener nor in the approach with CSA on the second leaf, the co-application on the same leaf showed significant metabolism of the herbicide by detecting the metabolite N-demethylated TCM. These findings suggest that safener protection against herbicide injury is a rapid process in which CSA and TCM need to be present in the same tissues. This study showcases the use of MALDI MSI to visualize and analyze indirect interactions of two substances in planta.

Comparative Toxicity of Herbicide Active Ingredients, Safener Additives, and Commercial Formulations to the Nontarget Alga Raphidocelis Subcapitata.

Chloroacetanilide herbicides are used worldwide to control weeds that affect crops such as corn, soybeans, and cotton. These herbicides are frequently paired with a "safener," which prevents herbicidal damage to the crop without diminishing weed control. Formulated herbicide products that include safeners and other ingredients are infrequently assessed for toxicity. Our goal was to understand the potential toxicity of safeners and herbicide + safener formulations relative to the toxicity of associated active ingredients. We quantified the concentration of safeners in commercially available formulations and tested effects on nontarget algae, Raphidocelis subcapitata, when exposed to individual herbicide active ingredients, safeners, and commercial formulations. The median effective concentrations (EC50s) causing 50% reduction in population growth for the herbicide active ingredients S-metolachlor and acetochlor were 0.046 and 0.003 ppm, respectively. The safeners benoxacor, AD-67, furilazole, and dichlormid were all substantially less toxic than the herbicides and were not toxic at environmentally relevant concentrations. The commercial formulations Dual II Magnum®, Me-Too-Lachlor II®, Harness®, and Surpass EC® all resulted in EC50 values that fell within the 95% confidence interval of the associated active ingredient herbicide. Interestingly, a significant increase in cell size was observed when algae were exposed to all the formulations, herbicides (acetochlor and S-metolachlor), and safener (dichlormid). The safener furilazole caused a significant decrease in cell size, whereas benoxacor and AD-67 had no observed effect on algae cell size. Significant algae cell size effects all occurred at or above the EC50 concentrations for each chemical, suggesting that other morphological effects may be occurring. Importantly, safeners in commercial formulations appeared not to impact toxicity to R. subcapitata compared with the active ingredient alone.Environ Toxicol Chem 2022;41:1466-1476. © 2022 SETAC.

Research Progress in the Design and Synthesis of Herbicide Safeners: A Review

Detoxification plays an important role in herbicide action. Herbicide safeners selectively protect crops from herbicide injury without reducing the herbicidal efficiency against the target weeds. With the large-scale use of herbicides, herbicide safeners have been widely used in sorghum, wheat, rice, corn, and other crops. In recent years, an increasing number of unexpected new herbicide safeners have been designed. The varieties, structural characteristics, uses, and synthetic routes of commercial herbicide safeners are reviewed in this paper. The design ideas and structural characteristics of novel herbicide safeners are summarized, which provide a basis for the design of bioactive molecules as new herbicide safeners in the future.

Significance of application timing, formulation, and cytochrome P450 genotypic class on sweet corn response to dicamba

AbstractSweet corn (Zea mays L.) tolerance to dicamba and several other herbicides is due to cytochrome P450 (CYP)-mediated metabolism and is conferred by a single gene (Nsf1). Tolerance varies by CYP genotypic class, with hybrids homozygous for functional CYP (Nsf1Nsf1) being the most tolerant and hybrids homozygous for mutant CYP alleles (nsf1nsf1) being the least tolerant. The herbicide safener cyprosulfamide (CSA) increases tolerance to dicamba by stimulating the expression of several CYPs. However, the extent to which CSA improves the tolerance of different sweet corn CYP genotypic classes to dicamba is poorly understood. Additionally, the effect of growth stage on sweet corn sensitivity to dicamba is inadequately described. The objective of this work was to quantify the significance of application timing, formulation, and CYP genotypic class on sweet corn response to dicamba. Hybrids representing each of the three CYP genotypes (Nsf1Nsf1, Nsf1nsf1, nsf1nsf1), were treated with dicamba or dicamba + CSA at one of three growth stages: V3, V6, or V9. Across all timings, the nsf1nsf1 hybrid was the least tolerant to dicamba, displaying 16% higher crop injury levels 2 wk after treatment and 2,130 kg ha−1 lower ear mass yields compared with the Nsf1Nsf1 hybrid. The V9 growth stage was the most susceptible time for dicamba injury regardless of genotypic class, with 1.89 and 1,750 kg ha−1 lower ear mass yields compared with the V3 and V6 application timings, respectively. The addition of CSA to dicamba V9 applications reduced the injury from dicamba for all three genotypic classes; however, it did not eliminate the injury. The use of Nsf1Nsf1 or Nsf1nsf1 sweet corn hybrids along with herbicide safeners will reduce the frequency and severity of injury from dicamba and other CYP-metabolized herbicides.

Transcriptomic Analysis of Maize Uncovers Putative Genes Involved in Metabolic Detoxification Under the Treatment of Four Herbicide Safeners

Transcriptomic Analysis of Maize Uncovers Putative Genes Involved in Metabolic Detoxification Under the Treatment of Four Herbicide Safeners

A Retrospective Study on Agrocultural Poisoning: Causes and Effects

A rise in the usage of pesticides in agriculture has coincided with an increase in the number of people who have been poisoned by them. Herbicides greater part are incessant agrochemical poisons, trailed by organophosphates. Numerous horticultural toxins, such as ethyl parathion and defoliant, have been banned in recent years. To discourage illicit use, they are combined with a coloring agent such as indigo carmine. Additionally, parquet has a "stanching" ingredient. Organochlorines work through a completely different process. Whereas Organophosphates are anti-cholinesterase, while organochlorines are anti-cholinesterase. Meddling with the transmission of driving forces through nerve cells. Organochlorines give out a kerosene-like odor when people die. The presence of organochloride in the gut contents or offal is used to make the diagnosis. Organochlorines are resistant to putrefaction and can be identified long after a person has died. Suicidal, accidental, and homicidal poisonings have all been linked to paraquat. This poisoning is moderately caustic, and ulcers around the lips and mouth is frequent. The severe alterations in the lungs, especially after the sufferer has lived a few days, are the hallmark of paraquat poisoning. Algicides, aphicides, herbicide safeners, fertilisers, and other agrochemicals are less often seen. Most governments have enacted regulations to avoid unintentional poisonings from these substances. The Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) was passed by the US government in 1962, while the Indian sovereignty proceeded The Insecticides Act in 1968. These laws, in addition via other things compel pesticide producers to include signal phrases on their labels to alert the public to their toxicity and associated dangers.

Acid- and Base-Mediated Hydrolysis of Dichloroacetamide Herbicide Safeners.

Safeners are used extensively in commercial herbicide formulations. Although safeners are regulated as inert ingredients, some of their transformation products have enhanced biological activity. Here, to fill gaps in our understanding of safener environmental fate, we determined rate constants and transformation products associated with the acid- and base-mediated hydrolysis of dichloroacetamide safeners AD-67, benoxacor, dichlormid, and furilazole. Second-order rate constants for acid- (HCl) and base-mediated (NaOH) dichloroacetamide hydrolysis (2.8 × 10–3 to 0.46 and 0.3–500 M–1 h–1, respectively) were, in many cases (5 of 8), greater than those reported for their chloroacetamide herbicide co-formulants. In particular, the rate constant for base-mediated hydrolysis of benoxacor was 2 orders of magnitude greater than that of its active ingredient co-formulant, S-metolachlor. At circumneutral pH, only benoxacor underwent appreciable hydrolysis (5.3 × 10–4 h–1), and under high-pH conditions representative of lime-soda softening, benoxacor’s half-life was 13 h—a timescale consistent with partial transformation during water treatment. Based on Orbitrap LC–MS/MS analysis of dichloroacetamide hydrolysis product mixtures, we propose structures for major products and three distinct mechanistic pathways that depend on the system pH and compound structure. These include base-mediated amide cleavage, acid-mediated amide cleavage, and acid-mediated oxazolidine ring opening. Collectively, this work will help to identify systems in which hydrolysis contributes to the transformation of dichloroacetamides, while also highlighting important differences in the reactivity of dichloroacetamides and their active chloroacetamide co-formulants.

Quinoxaline derivatives as herbicide safeners by improving Zea mays tolerance

Isoxaflutole (IXF), a 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor, causes injury to crops leading to reductions in grain yield. In order to solve the phytotoxicity caused by IXF, the present work evaluated the protective response of the substituted quinoxaline derivatives as potential safeners on Zea mays. The bioassay results showed that all of the test compounds displayed protection against IXF. In particular, safener I-6 exhibited excellent safener activity against IXF injury via enhancing glutathione (GSH) content, glutathione S transferases (GSTs) and cytochrome P450 monooxygenases (CYP450) activity. The tested compounds induced the activity of CYP450 and GSTs in Z. mays. The physicochemical properties and ADMET properties of safener I-6, benoxacor and diketonitrile (DKN, IXF metabolite) were compared to predict pharmaceutical behavior. The present work demonstrates that the safener I-6 could be considered as a potential candidate for developing novel safeners in the future.

Fragmenlt Recombination Design, Synthesis, and Safener Activity of Novel Ester-Substituted Pyrazole Derivatives.

Fenoxaprop-p-ethyl (FE), a type of acetyl-CoA carboxylase (ACCase) inhibitor, has been extensively applied to a variety of crop plants. It can cause damage to wheat (Triticum aestivum) even resulting in the death of the crop. On the prerequisite of not reducing herbicidal efficiency on target weed species, herbicide safeners selectively protect crops from herbicide injury. Based on fragment splicing, a series of novel substituted pyrazole derivatives was designed to ultimately address the phytotoxicity to wheat caused by FE. The title compounds were synthesized in a one-pot way and characterized via infrared spectroscopy, 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, and high-resolution mass spectrometry. The bioactivity assay proved that the FE phytotoxicity to wheat could be reduced by most of the title compounds. The molecular docking model indicated that compound IV-21 prevented fenoxaprop acid (FA) from reaching or acting with ACCase. The absorption, distribution, metabolism, excretion, and toxicity predictions demonstrated that compound IV-21 exhibited superior pharmacokinetic properties to the commercialized safener mefenpyr-diethyl. The current work revealed that a series of newly substituted pyrazole derivatives presented strong herbicide safener activity in wheat. This may serve as a potential candidate structure to contribute to the further protection of wheat from herbicide injury.

Cyprosulfamide: Analysis of the Herbicide Safener and Two of Its Degradates in Surface Water and Groundwater from the Midwestern United States

Herbicide safeners are commonly included in herbicide formulations to selectively protect crops from herbicide toxicity but are poorly understood in terms of their environmental occurrence and fate. This study established an analytical method for a newer safener, cyprosulfamide, and two of its degradates, cyprosulfamide desmethyl and N-cyclopropyl-4-sulfamoylbenzamide, in water via solid-phase extraction and liquid chromatography with tandem mass spectroscopy. To evaluate the potential for off-field transport and transformation of cyprosulfamide, the method was used to analyze groundwater and surface water samples collected near cornfields in the midwestern United States where cyprosulfamide had been applied. All three compounds were detected in surface water samples (N = 34); N-cyclopropyl-4-sulfamoylbenzamide was most frequently detected (56%), followed by cyprosulfamide (25%) and cyprosulfamide desmethyl (19%). Maximum concentrations ranged from 22.0 to 5185.9 ng/L, with the highest concentrations and detection rates during the growing season. None of our target analytes were detected in groundwater.

Herbicide safener increases weed-management tools for control of annual grasses in wheat – ERRATUM

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Tribenuron-methyl treatment affects glutathione metabolization and other physiological processes in bread wheat

To maximize crop yield, farmers use a wide array of herbicides. These chemicals have different mechanisms of action such as inhibition of photosynthesis and synthesis of aminoacids, lipids, and carotenoids in plant organs. The action of herbicides is often accompanied by the release of ROS (reactive oxygen species) in cells, and under their effect, modification of physiological processes occur in non-target plant organs, leading to the reduction of crop yields. To overcome stress conditions, plants react through the production of specific metabolites in their cell organelles, synthesizing detoxifying metabolites, among which glutathione (γ-glutamylcisteinylglycine, GSH) and its derivates are the most important. The detoxifying ability of crops varies between species and even between cultivars. Glutathione plays a major role in the detoxification pathways, and its quantity indicates the plant’s capability to metabolize herbicide. In wheat cultivation, the tribenuron-methyl herbicide is widely used. A study on short-term effect of tribenuron-methyl different concentrations (0.5 M, 1 M, 1.5 M) in three wheat cultivars (Pobjeda, Adelajde, and Dajti) and two ancestors Aegilops (accessions Ardenica and Borshi), by evaluating the GSH and pigment content was conducted in 2018 in Albania. A difference in both component content between the control and treated plants was observed. Among the cultivars assessed, Dajti showed the best ability to tolerate herbicide-induced stress. Knowledge on the plants’ reaction under herbicide treatments contributes to the identification of tolerance trait, selection of the right treatment formulation, and development of more effective herbicide safeners.