Acid- and Base-Mediated Hydrolysis of Dichloroacetamide Herbicide Safeners

Abstract

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.

Microbial Biotransformation Products and Pathways of Dichloroacetamide Herbicide Safeners

“…In contrast, over the same time period, only 40.6 ± 0.8% of benoxacor transformed in aqueous systems where benoxacor was the sole carbon source and 48 ± 3% in systems containing humic acid, a more recalcitrant carbon source unlikely to facilitate cometabolism . Only 39.0 ± 1.3% of the total benoxacor concentration was transformed in abiotic controls, likely due to hydrolysis; the decay followed first-order kinetics at a rate consistent with our prior studies . Batch tests for the other safeners studied were conducted as described in the presence of acetate.…”

“…Dichloroacetamide safeners are coapplied with chloroacetamide herbicides to selectively protect crops from unintended herbicide toxicity. − Due to their extensive use (>8 × 10 6 kg/year globally) and hydrophilic nature, the four most common dichloroacetamides (AD-67, benoxacor, dichlormid, and furilazole) have been detected in surface waters throughout the midwestern U.S., yet their environmental fates remain largely underinvestigated. ,− Existing research, including studies by our groups, indicates that safeners can transform in the environment to yield products with increased biological activity and, in some cases, increased toxicity. ,, For example, dichloroacetamides in iron-rich anaerobic environments can undergo reductive dechlorination to yield more toxic products, including formation of CDAA (known as allidochlor or 2-chloro-N,N-bis­(prop-2-enyl)­acetamide; an herbicide banned in the United States due in part to human health concerns) from dichlormid, as well as monochloro-benoxacor (toxic toward insect larvae; LOEC = 0.1 mg kg –1 ) from benoxacor. ,, Recently, we probed dichloroacetamides' environmental fate, focusing on photolysis and hydrolysis. , Only benoxacor transformed by direct photolysis, and hydrolysis rates were slow and only environmentally relevant under basic (pH 10–11) conditions. , Thus, there are potentially significant environmental fate processes relevant to dichloroacetamide safeners, notably microbial biotransformation, that remain uncharacterized and may yield transformation products of concern.…”

“…photolysis, and hydrolysis rates were slow and only environmentally relevant under basic (pH 10−11) conditions 13,14. Thus, there are potentially significant environmental fate processes relevant to dichloroacetamide safeners, notably microbial biotransformation, that remain uncharacterized and may yield transformation products of concern.Microbial biotransformation is likely relevant because dichloroacetamide safeners are biologically active, and their structurally related chloroacetamide herbicide coformulants undergo microbial biotransformation.3,15−18 Dichloroacetamide safeners are designed to activate crop defense genes to promote conjugation of herbicides to glutathione (GSH), yielding conjugates of lessened phytotoxicity 1,2,4,19.…”

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

“…Importantly, dichloroacetamide safeners can undergo photolysis (Kral et al, 2019;Su et al, 2019), hydrolysis (McFadden et al, 2022), abiotic reductive dechlorination (Ricko et al, 2020;Sivey & Roberts, 2012;Xu et al, 2020Xu et al, , 2022, and *Indicates significant difference compared with controls (shown as 0 for each figure). AD, AD-67.…”

“…Importantly, dichloroacetamide safeners can undergo photolysis (Kral et al, 2019; Su et al, 2019), hydrolysis (McFadden et al, 2022), abiotic reductive dechlorination (Ricko et al, 2020; Sivey & Roberts, 2012; Xu et al, 2020, 2022), and biotransformation (Abu‐Qare & Duncan, 2002) in the environment. These processes can result in the safener changing into structures like those of herbicides, which could be more toxic than the parent (Abu‐Qare & Duncan, 2002; Sivey & Roberts, 2012).…”