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

Monica E Mcfadden,Keith P Reber,David M Cwiertny,Gregory H Lefevre,John D Sivey,Ian W Gilbert,Eric V Patterson

doi:10.1021/acs.est.1c05958

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.

Highlights

The dichloroacetamide safeners AD-67, benoxacor, dichlormid, and furilazole are commonly included in chloroacetamide herbicide formulations to selectively protect crops against herbicide toxicity.[1,2]
Dichloroacetamides (Figure 1) are modestly hydrophilic and mobile in aqueous environments, which has led to their detection in Midwestern drinking water sources at concentrations of up to 190 ng/L.2−6 Given their widespread use and occurrence in the environment, there is a growing body of research regarding the environmental fate and effects of dichloroacetamides.[2,4−10] Recent studies have demonstrated moderate acute toxicity of dichloroacetamides toward model freshwater fish species (LC50 values of 1.4−4.6 mg/L),[11,12] and toxicity screening data available from the U.S Environmental Protection Agency (EPA) indicate the potential for benoxacor to interact with multiple human nuclear receptors.[13]
Considering the structural and behavioral similarity of dichloroacetamide safeners and their chloroacetamide herbicide co-formulants, it is possible that dichloroacetamides could yield analogous products with similar environmental and health effects

Summary

INTRODUCTION

The dichloroacetamide safeners AD-67, benoxacor, dichlormid, and furilazole are commonly included in chloroacetamide herbicide formulations to selectively protect crops against herbicide toxicity.[1,2] Dichloroacetamides (Figure 1) are modestly hydrophilic (log Kow 1.84−3.19) and mobile in aqueous environments, which has led to their detection in Midwestern drinking water sources at concentrations of up to 190 ng/L.2−6 Given their widespread use (estimated >8 × 106 kg/year globally) and occurrence in the environment, there is a growing body of research regarding the environmental fate and effects of dichloroacetamides.[2,4−10] Recent studies have demonstrated moderate acute toxicity of dichloroacetamides toward model freshwater fish species (LC50 values of 1.4−4.6 mg/L),[11,12] and toxicity screening data available from the U.S Environmental Protection Agency (EPA) indicate the potential for benoxacor to interact with multiple human nuclear receptors.[13]. Some dichloroacetamide safeners, including dichlormid and benoxacor, can transform under environmentally relevant conditions to yield products with increased biological activity that may pose even greater risks to the environment and human health. 2-chloro2′,6′-diethylacetanilide, the N-dealkylation product of acidand base-mediated hydrolysis of alachlor and butachlor, is mutagenic and may bind to DNA.[17,31,35−37] Products of both acetochlor (2,6-diethylaniline) and 2-chloro-N-methylacetanilide (N-methylaniline) are teratogenic; 2,6-diethylaniline demonstrates increased teratogenicity toward frog embryos compared to its parent compound and is a promutagen.[32,33,38,39] Considering the structural and behavioral similarity of dichloroacetamide safeners and their chloroacetamide herbicide co-formulants, it is possible that dichloroacetamides could yield analogous products with similar environmental and health effects. Findings from this study will better aid environmental fate and risk assessment of this widely used yet overlooked chemical class in agroecosystems

MATERIALS AND METHODS

RESULTS AND DISCUSSION

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