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# Toxicity and environmental fate of the less toxic chiral neonicotinoid pesticides: a review

Zenglong Chen, Lilin Zhao, Shanshan Kang, Rock Keey Liew, Eric Lichtfouse

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Zenglong Chen, Lilin Zhao, Shanshan Kang, Rock Keey Liew, Eric Lichtfouse. Toxicity and environmental fate of the less toxic chiral neonicotinoid pesticides: a review. Environmental Chemistry Letters, 2025, 23, pp.733-750. 10.1007/s10311-024-01808-1. hal-04862697

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Submitted on 3 Jan 2025

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# Toxicity and environmental fate of the less toxic chiral neonicotinoid pesticides: a review

Zenglong Chen<fnref n="1" /> ID · Lilin Zhao<fnref n="1" /> · Shanshan Kang<fnref n="1" /> · Rock Keey Liew<fnref n="2" /> · Eric Lichtfouse<fnref n="3" /> ID

## Abstract

Neonicotinoids represent 25% of the insecticidal market and are essential for crop production, yet traditional neonicotinoids are toxic to most pollinators, which are also essential for food production. This issue may be addressed by the use of some chiral neonicotinoid isomers, which are much less toxic. Here, we review the chiral neonicotinoids dinotefuran, sulfoxaflor, cycloaxprid, and paichongding, with focus on their chiral characteristics, configuration stability, biological activity, ecological toxicology, and environmental fate. Isomeric separation of chiral neonicotinoids can be achieved by chromatography. The dinotefuran *R* isomer is less toxic than the *S* isomer to honeybees and earthworms by a factor of 2.7–145.9, with similar control efficiency of common agricultural pests. The insecticidal activity of (*5R*,*7S*)-paichongding are up to 20.1 times higher than that of other isomers, and it is absorbed fastest by crop roots and tends to be preferentially degraded and mineralized in soils. Therefore, formulations containing *R*-dinotefuran or (*5R*,*7S*)-paichongding could decrease ecological damage without compromising food production. On the other hand, it has not been possible to synthesize chiral isomers of sulfoxaflor and cycloaxprid, owing to the instability of their monomers in polar solvents.

**Keywords** Chiral neonicotinoid · Configuration stability · Biological activity · Ecological toxicology · Stereoselective characteristic · Mechanism of action

## Introduction

Neuroactive neonicotinoids are commonly used to control piercing-sucking pests and have been registered for use in hundreds of crops worldwide (Fig. 1). They have gained approximately one-fifth of the total insecticide market and possess a significant market share [1, 2]. Neonicotinoids, derived from a natural compound of nicotine and acting on

nicotinic acetylcholine receptors, have until a fourth generation [3, 4] (Fig. 2). However, increasing evidence has highlighted their severe effects on global ecosystems, particularly on pollinators that visit 75% of the top 115 global crops [5–14]. The chronic and sublethal effects of neonicotinoids on pollinators are considerably serious, reducing their lifetime foraging flights, reproductive success and social immunity, increasing homing failure in foraging, and queenlessness [10, 14–16], which further contribute to the colony collapse disorder worldwide [10, 17]. The cascading impact of neonicotinoids has also been observed in ecosystems by altering the food web structure and dynamics, thereby affecting higher-level consumers [9, 18]. For instance, the decline in invertebrate densities induced by higher than 20.00 ng L⁻<fnref n="1" /> imidacloprid in surface water caused insectivorous birds to decrease by 3.5% annually on average because of food deprivation [9].

These concerns have led many countries, such as the European Union, the USA, and France, to accelerate their prohibition or restrictions and recommend the use of alternative systemic insecticides [19, 20]. Neonicotinoid molecules belonging to the third generation exhibit chiral

<footnote>✉ Zenglong Chen
chenzenglong@ioz.ac.cn</footnote>

<footnote>Eric Lichtfouse
eric.lichtfouse@icloud.com</footnote>

<footnote n="1">¹ State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, People's Republic of China</footnote>

<footnote n="2">² Center for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India</footnote>

<footnote n="3">³ State Key Laboratory of Multiphase Flow in Power Engineering, Xi'an Jiaotong University, 28 Xianning West Rd, Xi'an 710049, Shaanxi, People's Republic of China</footnote>
<figure><img src="image_2.png" /><figcaption>**Fig. 1** Neonicotinoids represent 25% of the insecticidal market and are essential for crop production, yet traditional neonicotinoids are toxic to most pollinators, which are also essential for food production. This issue may be addressed by the use of some chiral neonicotinoid isomers, which are much less toxic</figcaption></figure>

characteristics, with one of the stereoisomers being much less toxic [21–23]. However, chiral neonicotinoids are still marketed as racemates—mixtures of the two stereoisomers—and are thus in the same ecological dilemma as first- and second-generation neonicotinoids, whose residue levels in crop cultivation systems vary in matrices, with the highest being found in lettuce leaf vegetables at up to 4.66 mg/kg [23–26]. Growing evidence suggests that the fate characteristics, insecticidal potencies, and adverse effects of neonicotinoids differ significantly among stereoisomers by selectively interacting with biological systems in agroecosystems [12, 22, 27, 28]. Can chirality be a potential approach to decrease the impact of neonicotinoids on ecosystems while preserving their efficacy in crop cultivation systems?

Here, we review the enantiomeric analysis of chiral neonicotinoids with favorable insecticidal potency, such as dinotefuran, sulfoxaflor, cycloaprid, and paichongding, in multiple aspects, including configuration stability, biological activity, ecological toxicity, environmental fate, action mechanism, and analysis methods. Future prospects for potential chiral products are proposed to reduce the ecological risk of neonicotinoids from a chiral perspective. A review of each enantiomer of chiral neonicotinoids in different environmental compartments and their possible mechanisms are important complements to traditional research and

provide a potential approach for the sustainable development of modern agriculture.

## Chiral characteristics of neonicotinoids

To date, four chiral neonicotinoid pesticides—dinotefuran, sulfoxaflor, cycloaprid, and paichongding—have been developed and promoted worldwide. Chromatographic techniques with chiral columns dominate the separation of the stereoisomers of dinotefuran and sulfoxaflor. These techniques are implemented in either the normal- or reverse-phase modes, depending on their polarity [29–32]. Cycloaprid and paichongding are identified as cis-neonicotinoids independently created by China. The chiral determination of these compounds relies mainly on radioisotope tracing techniques in environmental samples [28, 33, 34].

The first chiral neonicotinoid of dinotefuran was expressed as an enantiomer pair with an asymmetrically substituted carbon atom. Its enantiomer stereoconfiguration was identified through optical rotation, and its relationship with the absolute configuration was established in a previous study during the early synthesis stage. The enantiomers were labeled S-(+)-dinotefuran and R-(-)-dinotefuran [22, 35] (Fig. 1). Dinotefuran has been marketed and used worldwide as a racemate, and has gained a global market of greater than 105 million dollars annually based on its exceptional control effect on insects of various orders, including Hemiptera, Lepidoptera, and Coleoptera, as well as on medical vectors, particularly mosquitoes [36–38].

Subsequently, a novel sulfoximine insecticide, sulfoxaflor, was developed for resistance management and is considered a four-generation neonicotinoid possessing two tetrahedral atoms and manifesting as two pairs of enantiomers [3]. Sulfoxaflor stereoisomers have been confirmed by combining single-crystal X-ray diffraction and polarimetry, and include 2S,3S-(+)-sulfoxaflor, 2R,3R-(-)-sulfoxaflor, 2R,3S-(+)-sulfoxaflor, and 2S,3R-(-)-sulfoxaflor [21, 30, 39] (Fig. 1). The trade volume of sulfoxaflor racemate has reached 190 million dollars worldwide because of the lack of cross-resistance in pest strains that have developed resistance to first- and second-generation neonicotinoids owing to its unique interaction with nicotinic acetylcholine receptors [40, 41].

Cycloaprid, as the only antagonist of nicotinic acetylcholine receptors, has two chiral carbon atoms but contains a pair of enantiomers stemming from the formation of an oxygen bridge between two chiral carbons [42]. Paichongding has two chiral centers, resulting in four diastereoisomers as two pairs of enantiomers [28, 43]. The absolute configuration of the cis-neonicotinoids has been identified using single-crystal X-ray diffraction. They were designated as (5R,8S)-cycloaprid, (5S,8R)-cycloaprid, (5R,7R)-paichongding,
<figure><img src="image_3.png" /><figcaption>**Fig. 2** Chemical structures of chiral neonicotinoid pesticides, with the third generation including dinotefuran, the fourth generation comprising sulfoxaflor, and cis-neonicotinoids including cyclokaprid and paichongding</figcaption></figure>

(5S,7S)-paichongding, (5R,7S)-paichongding, and (5S,7R)-
paichongding [23] (Fig. 2).

**Stability of chiral neonicotinoids**

The stability of chiral neonicotinoids is directly relevant to
whether they can develop isomer-enriched products with
high activity and low risk [44], particularly their potential
isomerization in water and organic solvents. This is impor-
tant to avoid pointless application in agricultural practice
and analytical biases in the chiral selective investigation of
target pure products [22, 45]. Isomer stability is inextricably
linked to the exposed chemical systems.

Dinotefuran has an enantiomeric configuration that is sta-
ble in typical organic solvents, including methanol, ethanol,
isopropanol, ethyl acetate, acetonitrile, and dichloromethane,
as well as in ultrapure water and β-cyclodextrin solution
under a xenon lamp, natural light, and in the dark at room
temperature [46]. There is no isomerization of paichongding
stereoisomers found in water characterized by pH 5.8 and
8.2, methanol, ethanol, acetonitrile, ethyl acetate, dichlo-
romethane, acetone, tetrahydrofuran, n-hexane, and calcium
chloride aqueous solutions [23]. However, the four stereoi-
somers of sulfoxaflor are prone to diastereoisomerization in
proton solvents, such as water and methanol, mainly depend-
ing on the acidity of these solutions. They are relatively
stable in non-proton solvents, including dichloromethane,
n-hexane, trichloromethane, ethyl acetate, and acetonitrile [21]. Additionally, irreversible racemization occurs when individual pure stereoisomers of sulfoxaflor are stored at room temperature, which may be attributed to the S=O and S=N groups directly or indirectly attached to the chiral center. Surprisingly, the conversion rates of the (2S,3S)-/(2R,3S)-isomers are reported to be 2.5 times higher than those of the (2R,3R)-/(2S,3R)-isomers, which is speculated to be related to differences in their spatial steric [39]. In addition, significant racemization of cycloxacrid enantiomers has been found in methanol, ethanol, and water, in which water occupies the first place and cycloxacrid individual isomers tend to be transformed into their antipodes until equilibrium, with half-lives ranging from 2.3 to 5.1 h. Li obtained similar results in methanol and ethanol, with half-lives of 6.8–7.1 h in methanol being shorter than those of 15.6 h in ethanol [23]. However, they were relatively stable in acetonitrile, ethyl acetate, dichloromethane, acetone, tetrahydrofuran, and n-hexane, with less than 4% transformation after 7 days [23].

From these results, we can conclude the configurational stability of dinotefuran and paichongding isomers in water and typical organic solvents. However,

significant isomerization occurs when the pure sulfoxaflor cycloxacrid monomer is incubated in water or small-molecule alcohols. The relationship between the configurational stability of chiral neonicotinoids and their structures was further explored by Li and co-workers using a proton exchange process [44]. The proton acidity at the chiral center determines the occurrence and degree of conversion and is significantly affected by anion stability, which is determined by the ability of the substituent groups to stabilize the negative charge and hybridization of the chiral atom [47]. The stability of dinotefuran and paichongding can be ascribed to the absence of an α-carbon chiral center with carbanion-stabilizing groups in their absolute configurations. In addition, an α-carbon chiral center with a carbanion-stabilizing group is found at position 2 of the sulfoxaflor molecule, which may be responsible for diastereoisomerization in proton solvents. The protons on the chiral carbon are acidic and tend to exchange with protons in the solvents (Fig. 3A). Furthermore, the mechanism for cycloxacrid racemization in proton solvents may result from the instability of the oxygen bridge [48, 49] as shown in Fig. 3B, which showed significant acid-decelerating and high-temperature facilitation during racemization [23].

<figure><img src="image_4.png" /><figcaption>**Fig. 3** Proposed isomerization of chiral neonicotinoids. **A** refers to the diastereoisomerization of sulfoxaflor isomers in proton solvents, and **B** refers to the racemization of cycloxacrid isomers in proton solvents by the fracture of the oxygen bridge</figcaption></figure>
## Biological activity

Creating new pesticides to enhance application efficiency is accompanied by huge capital and time costs [50]. The development of chiral pesticides may be a potentially complementary approach, such as the two successful cases of S-metolachlor and *R*-metalaxyl [51, 52]. Hence, identifying the highly active isomers of chiral neonicotinoids is necessary to improve their control efficiency.

As shown in Fig. 4, dinotefuran exhibits favorable control effects on both agricultural and health pests, *S*-dinotefuran being 2.2–54.5 times more active than *R*-dinotefuran. The enantioselective intensity of healthy pests is stronger than that of agricultural pests [22, 53, 54], which may arise from the difference in stereochemical sensitivity among the nico- tinic acetylcholine receptor subtypes of pests of different

<figure><img src="image_5.png" /><figcaption>**Fig. 4** Stereoselective preference of dinotefuran (A), cycloaxprid (B) and paichongding C in terms of bioactivity. lg(S/R) refers to the logarithm of the S/R ratio based on 10; lg(S/R) greater than 0 indicates that *S*-dinotefuran shows greater bioactivity whereas lg(S/R) less than 0 indicates that *R*-dinotefuran shows greater bioactivity. The same goes for cycloaxprid and paichongding. *Represents statistical significance at *P* less than 0.05 with a 95% confidence interval, **Represents statistical significance at *P* less than 0.01 with a 99% confidence interval for both Tukey's honestly significant difference test and Student's t test, and *ns* represents statistical insignificance</figcaption></figure>

orders [55]. The insecticidal activities of dinotefuran enantiomers have been assayed in agricultural pests of the cotton aphid (*Aphis gossypii*) and mirid bug (*Apolygus lucorum*) by contact and oral modes, indicating that the *S* isomer was more active than the *R* isomer by a factor of 2.7–3.4 (*P* less than 0.05) [53]. However, the knockdown and insecticidal activities of *S*-dinotefuran have been reported to be up to 50-fold higher than those of *R*-dinotefuran against the health pests of the German cockroach (*Blattella germanica*). An in vivo assay further identified a higher affinity of the *S* isomer for the nicotine acetylcholine receptors of a cockroach than its antipode [54]. For housefly (*Musca domestica*), the 50% effective concentration decreased by 16.2 times from *S*-dinotefuran to *R*-dinotefuran, which they further validated by an in vivo experiment showing the potency of *S*-dinotefuran in inhibiting the binding of [³Hydrogen] imidacloprid was 12.4 times higher than that of *R*-dinotefuran [22]. The selective activities of dinotefuran isomers have been also found to be linked to the assay mode, such as the potency of *S*-dinotefuran against cotton aphid and mirid bug agricultural pests under physical contact mode is 0.8–1.0 times than that under oral ingestion mode, which may be attributed to the chiral specificity of the biological barriers under different exposure modes [53].

The enantioselective activities of cycloaxprid and paichongding have only been reported for alfalfa aphids (*Aphis medicaginis*), as shown in Fig. 4. In a study by Li, (5S,8R)-cycloaxprid was found to be 1.6 times more active than (5R,8S)-cycloaxprid [23]. The order of the bioactivity for paichongding stereoisomers was (5R,7S) > (5S,7S) ≈ (5S,7R) > (5R,7R), with (5R,7S)-paichongding being the most effective, showing a 20-fold higher activity than (5R,7R)-paichongding. The difference between (5S,7S) and (5S,7R) is almost negligible [23]. Knowledge of the stereoselective bioactivity exposed to chiral neonicotinoids has indicated *S*-dinotefuran, (5S,8R)-cycloaxprid and (5R,7S)-paichongding showed greater activities towards target pests as compared with their isomers.

## Ecological toxicity

Contaminating ecosystems with chiral neonicotinoids is of great environmental concern because of their extensive use in various crops, which poses a potential threat to bios-security, particularly for pollinators [2, 14]. Therefore, it is necessary to clarify the toxicological effects of neonicotinoids at the enantiomeric level. Opposite enantioselectivity profiles of dinotefuran have been reported in invertebrates of Italian honeybees (*Apis mellifera*), Chinese honeybees (*Apis cerana*), earthworms (*Eisenia fetida*), *Daphnia magna*, and vertebrates of zebrafish (*Danio rerio*). To be specific, *S*-dinotefuran has been found to be 22.9–145.9 times more
toxic than *R*-dinotefuran in *Apis mellifera* and *Apis cerana*, and *S*-dinotefuran has also been found to cause greater inhibition of sucrose responsiveness in *Apis mellifera* than *R*-dinotefuran [56–59]. Artificial soil and contact filter paper tests have indicated the acute toxicity of dinotefuran enantiomers in *Eisenia fetida*, and *S*-dinotefuran is reported to be 2.7 to 71.5 times more toxic than *R*-dinotefuran, whose great variability may be closely related to the difference in assay mode, earthworm populations, experimental operation and assay period [60–62]. At sublethal dosages, *S*-dinotefuran has been shown to have greater adverse effects on the growth and reproduction of *Eisenia fetida* [62]. *S*-dinotefuran also causes greater damage to aquatic invertebrates in *Daphnia magna* than *R*-dinotefuran with respect to reproduction and feeding behaviors [43]. However, lethal and nonlethal exposure to *S*-dinotefuran causes less hazardous effects on aquatic vertebrates of *Danio rerio* than exposure to *R*-dinotefuran [63, 64]. The differences between invertebrates and

vertebrates may be attributable to the chiral specificity of their nicotinic acetylcholine receptors, which have diverse subunit combinations and target sites [4, 64].

However, in the case of sulfoxaflor, cycloxaprid, and paichongding, information related to their enantioselective toxicity remains poorly understood. Deng et al. evaluated the stereoselective bioaccumulation of four sulfoxaflor isomers in *Danio rerio* and observed selectivity in both diastereomers and between enantiomers, as shown in Fig. 5 [21]. They further observed that (2S,3S)-sulfoxaflor and (2R,3S)-sulfoxaflor preferentially accumulated in *Danio rerio* compared with their antipode, whereas (2R,3R)-sulfoxaflor and (2R,3S)-sulfoxaflor showed similar accumulation levels [21]. For cycloxaprid, the detected concentrations of its (5S,8R) isomer in the blood samples of rats have been reported to be 0.6 times lower than those of the (5R,8S) isomer. Similar results were also observed in a study by Wu et al [65] on the tissue distribution of the two enantiomers, in which

<figure><img src="image_6.png" /><figcaption>**Fig. 5** Stereoselective preference of dinotefuran (A), sulfoxaflor (B), cycloxaprid (C) and paichongding D in terms of ecotoxicity. lg(S/R) refers to the logarithm of the S/R ratio based on 10; lg(S/R) greater than 0 indicates that S-dinotefuran shows greater ecotoxicity, whereas lg(S/R) less than 0 indicates that R-dinotefuran shows greater ecotoxicity. The same goes for sulfoxaflor, cycloxaprid and paichongding. *Represents statistical significance at *P* less than 0.05 with a 95% confidence interval, **Represents statistical significance at *P* less than 0.01 with a 99% confidence interval for both Tukey's honestly significant difference test and Student's t test, and ns represents statistical insignificance</figcaption></figure>
the (5S,8R) isomer showed less accumulation in eight
organs than its antipode. A greater proportion of (5S,8R)-
cycloxacaprid (74.5%) was excreted than (5R,8S)-cycloxacaprid
(59.7%) as shown in Fig. 5 [65]. However, as shown in
Fig. 5, no significant difference has been observed in the
accumulation behavior of cycloxacaprid enantiomers as soil-
bound residues in *Metaphire guillelmi* [66]. In addition, the
metabolic potential of the paichongding stereoisomers has
been found to be in the following order: (5R,7S) > (5S,7S) > (
5R,7R) > > (5S,7R) by human cytochrome P450 3A4 [67]. A
conclusion can be drawn that *R*-dinotefuran, (2S,3R)-sulfox-
aflor, (5S,8R)-cycloxacaprid, (5R,7S)-paichongding displayed
lower toxic effects towards non-target organisms based on
reported studies, whose application potentially contributed
to the sustainable development of ecological environment.

Ecotoxicological mechanisms

The enantioselective activity and toxicity of chiral neonicotinoids could result from their affinity for nicotinic acetylcholine receptors, fate characteristics within living beings, affinity for biofilms, oxidative stress and so on. First, the affinity diversity of neonicotinoid isomers with the agonist/antagonist action of nicotinic acetylcholine receptors caused by different configurations is the primary factor that contributes to their chiral selectivity [22, 54, 68]. S-dinotefuran binds more tightly than its antipode to the α8 subunit of nicotinic acetylcholine receptors of *Apis mellifera* by one order of magnitude based on an extensive hydrogen bond network, further leading to greater toxic effects [57]. Quantitative analysis of the insecticidal activity of dinotefuran enantiomers to *Musca domestica*, with the binding potency measured with [³Hydrogen] imidacloprid, indicates that the higher the binding activity, the higher the insecticidal activity [22].

The second aspect responsible for the isomeric effects of
chiral neonicotinoids appears to be the difference in enani-
tiomers in fate characteristics within living beings, such
as bio-selective uptake, accumulation, degradation, and
metabolic processes [69]. The effects of enantiomers on
organisms may be inconsistent because of enantioselective
absorption across the membrane and selectivity variations
within the accumulation process. For example, S-dinotefuran
preferentially accumulates in *Eisenia fetida* compared with
*R*-dinotefuran [62]. Similarly, the (2S, 3S) and (2R, 3S) iso-
mers of sulfoxaflor show a higher risk of bioaccumulation in
*Danio rerio* than their antipodes [21]. In addition, the effects
of neonicotinoid isomers may correlate with their degrada-
tion and metabolism in organisms. One enantiomer is pref-
erentially degraded and metabolized [70]. The binding of
paichongding stereoisomers with human cytochrome P450
3A4 shows chiral specificity, predominantly determining

their differences in metabolite composition and further caus-
ing statistical gaps in their potential mutagenicity to humans
[67].

Third, it also results from the high specificity of biomac-
romolecules and the different bio-affinities of enantiom-
ers to their surfaces [71, 72]. The stronger interactions of
S-dinotefuran with biomacromolecules of *Eisenia fetida*,
such as enzymes, proteins, and nucleic acids, and greater
damage to the rough and smooth endoplasmic reticulum
than R-dinotefuran contribute to its greater toxicity [73]. The
interference of S-dinotefuran on gene expression in *Daph-
nia magna* has also been found to be significantly higher
than that of R-dinotefuran [74]. S-dinotefuran has a greater
influence on the metabolic pathway and energy metabolism
of *Apis cerana*, which is mediated by biological enzyme
systems, further reducing the degradation rates in its detoxi-
fication systems [59].

Fourth, oxidative stress is linked to the stereoselective
effects of chiral neonicotinoids. The higher toxicity of
S-dinotefuran toward *Eisenia fetida* has been ascribed to its
preferential induction of excess generation of reactive oxy-
gen species [60, 62, 75]. S-dinotefuran causes more signifi-
cant oxidative stress in *Daphnia magna* than R-dinotefuran
[74]. Finally, enantioselective variations within the food web
and selective accumulation in different tissues and organs
may contribute to the stereoselective effects of chiral neoni-
cotinoids within organisms [65, 76].

Environmental fate

Absorption of neonicotinoids

Neonicotinoids are quickly absorbed by crops and cause
delayed mortality in sucking and chewing pests, and the
resulting amount of permeation plays an important role in
their control effects [77]. Recent studies have shown sig-
nificant stereoselectivity in the absorption characteristics of
chiral neonicotinoids, which vary with uptake pathways. As
shown in Table 1, Enantioselective absorption of dinotefuran
has been observed within the collard (Brassica oleracea var.
acephala DC) after root treatment, and S-dinotefuran was
more utilizable than R-dinotefuran, with a faster absorption
rate [60]. As shown in Table 1, (5R,8S)-cycloxacaprid show a
3.8-fold higher absorption rate than its antipode by water-
logged Youdonger (Brassica campestris subsp. Chinensis)
after root immersion, whereas no significant chiral specific-
ity was observed between the (5R,8S) and (5S,8R) isomers
after foliar treatment, with absorption rates of 3.1% and
4.0%, respectively [43]. Similar results have been observed
for the absorption behavior of Chinese cabbage (Bras-
sica chinensis L.) leaves toward cycloxacaprid enantiomers,
in which the distinction between (5R,8S)-cycloxacaprid and
<table><caption>**Table 1** Isomeric absorption of chiral neonicotinoids</caption><thead><tr><th rowspan="2">Assay plant</th><th rowspan="2">Application method</th><th rowspan="2">Assay period (h)</th><th colspan="2">The absorption proportion of applied amount (%)</th><th rowspan="2">Selective ratio S/R<sup>a</sup></th></tr><tr><th>S-dinotefuran</th><th>R-dinotefuran</th></tr></thead><tbody><tr><td>Collard (Brassica oleracea var. acephala DC.)</td><td>Root uptake</td><td>120</td><td>β<br>(5R,8S)-cyclokaprid</td><td>/<br>(5S,8R)-cyclokaprid</td><td>> 1<br>SR/RS</td></tr><tr><td>Youdonger (Brassica campestris subsp. Chinensis)</td><td>Root uptake<br>Foliar spray</td><td>192<br>96</td><td>12.39 ± 0.48<sup>b</sup><br>3.11 ± 0.41<sup>a</sup></td><td>3.31 ± 0.29<sup>a</sup><br>4.03 ± 0.55<sup>a</sup></td><td>0.3<br>1.0<sup>γ</sup></td></tr><tr><td>Chinese cabbage (Brassica chinensis L.)</td><td>Foliar spray</td><td>192</td><td>/<br>(5R,7R)-paichongding</td><td>/<br>(5S,7R)-paichongding</td><td>1.0<br>(RS, SR)/(RR, SS)</td></tr><tr><td>Chinese pak choi (Brassica campestris ssp. chinensis)</td><td>Root uptake<br>Foliar spray</td><td>144<br>96</td><td>16.49<sup>a</sup><br>35.40<sup>a</sup></td><td>19.85<sup>a</sup><br>36.66<sup>a</sup></td><td>24.57<sup>b</sup><br>38.20<sup>a</sup></td><td>28.82<sup>b</sup><br>36.80<sup>a</sup></td><td>1.5 ± 0.2<br>1.0</td></tr></tbody></table>

<sup>a</sup>The difference in absorption proportion between dinotefuran enantiomers S/R ratio > 1.0 indicates that S-dinotefuran is preferentially absorbed by plants, S/R ratio < 1.0 indicates that R-dinotefuran is preferentially absorbed by plants, and S/R ratio = 1.0 indicates that there is no significant difference between dinotefuran enantiomers, SR/RS for cyclokaprid enantiomers and (RS, SR)/(RR, SS) for paichongding diastereoisomers are similar to S/R; β No reference data; γ No significant difference

Data in table are represented as mean or mean ± standard deviation of the mean (SD), and the different superscript lowercase letters in the same row differ significantly (p < 0.05)

(5S,8R)-cyclokaprid can be ignored [78]. The diastereoselective root uptake of four paichongding diastereoisomers was documented in Chinese pak choi (Brassica campestris ssp. chinensis) by Wang, and they found that (5R,7S)-/(5S,7R)-paichongding was more readily taken up by the roots than (5R,7R)-/(5S,7S)-paichongding by a factor of 1.5 [28]. However, paichongding was absorbed by Chinese pak choi non-stereoselectively, with absorption rates of 35.4%–38.2% under foliage treatment [28].

In summary, S-dinotefuran, (5R,8S)-cyclokaprid, and (5R,7S)-/(5S,7R)-paichongding are preferentially absorbed by crops than their enantiomer or diastereoisomer by the root uptake pathway, with a difference of up to 3.8 times, whereas there is no significant stereoselectivity in the foliage uptake pathway. This difference potentially depends on the diverse routes by which chiral neonicotinoids penetrate crops under foliage and root treatments [28, 43, 79, 80]. As shown in Fig. 6, they enter the xylem through the apoplast, symplast, or both routes after root treatment, and are bound to undergo selective action either by selective biofilms of epidermal cells or endothelial cells [80]. There are two pathways for chiral neonicotinoid entry after foliar treatment including absorption through the stomata and waxy cuticles, which mainly rely on their polarity [79, 81, 82]. The highly hydrophilic characteristics of dinotefuran, with an octanol-water partition coefficient of -0.55, may induce its tendency to enter leaves through stomata non-stereoselectively [83]. The lipophilic characteristics of cyclokaprid with an octanol-water partition coefficient of 1.12 and

paichongding with an octanol-water partition coefficient of 2.86, calculated using ChemDraw 3D, may contribute to their absorption into the blade through the waxy cuticle and then undergo transmembrane transport, and the loss of isomeric absorption due to the absence of stereoselective diffusion on the biomembrane after passing through the waxy cuticle [28, 65, 84].

## Isomeric distribution

In addition to the ability to penetrate crops, neonicotinoid potency also depends on whether they can migrate to the target site and the migration amount; therefore, their chiral profiles of distribution in crops are crucial for increasing efficacy. Little information is available, and only the stereoselective distribution of cyclokaprid and paichongding has been reported in typical leafy vegetables under foliage and root treatment. These two compounds were conducted upwards and were mainly concentrated on edible leaves under root treatment. However, they remained in leaves under foliage treatment and occupied 67.3%–94.9% of the absorbed amounts. [28, 43, 78, 85].

As shown in Table 2, 57.8% of the absorbed amount of (5S,8R)-cyclokaprid is translocated to the shoots of waterlogged Youdonger (Brassica campestris subsp. Chinensis) under the root uptake pathway, compared with 52.9% for its antipode [43]. For foliar treatment, slightly higher or equal proportions of (5S,8R)-cyclokaprid have been reported to be distributed in the treated leaves of waterlogged Youdonger,
<figure><img src="image_7.png" /><figcaption>**Fig. 6** Absorption pathways of chiral neonicotinoids in foliage (A) and roots (B). Chiral neonicotinoids are absorbed by crop leaves by stomata or waxy cuticles and by crop roots via the apoplast and sym-</figcaption></figure>

plast routes, potentially undergoing selective action by the biofilms of epidermal cells in crop leaves and roots or endodermis cells in crop roots

Chinese cabbage (*Brassica chinensis* L.), and oilseed rape (*Brassica napus* L.) compared with (5R,8S)-cyclo赵prid. The stereoselectivity in the upper and lower parts of the treated leaves has been shown to vary significantly with crop species and parts, although the fractions were relatively limited, ranging from 6.3% to 16.0% [43, 78, 85]. Unlike cyclo赵prid, the distribution of paichongding epimers shows significant diastereoselectivity via both the foliage and root uptake pathways, as shown in Table 2. The (5R,7S)-/(5S,7R)-enantiomers accumulate more readily than the (5R,7R)-/(5S,7S)-enantiomers in the edible leaves of Chinese pak choi (*Brassica campestris* ssp. *chinensis*) by a factor of 1.4 after root treatment. In the foliage uptake pathway, the proportion of (5R,7S)-/(5S,7R)-paichongding (90.3%–94.9%) is much higher than that of (5R,7R)-/(5S,7S)-paichongding (67.3%–72.6%) in treated leaves, whereas reverse diastereomeric distribution occur in the leaves above the treated leaf and below the treated leaf, stalk, and root [28].

The stereoselective distribution of chiral neonicotinoids shows considerable variability with SR/RS selective ratios of 0.4–1.7 for cyclo赵prid and (RS, SR)/(RR, SS) selective ratios of 0.2–1.4 for paichongding, which are influenced by

the uptake pathways, crop species, and crop parts. It is presumed that cyclo赵prid and paichongding stereoisomers are transported across various membranes and stereoselectively interact with chiral macromolecules on the cell membrane via different uptake pathways, leading to a distinct stereoselective distribution. Additionally, biofilm specificity among different crop species or plant parts may be another factor in their selective distribution [86, 87].

## Degradation and metabolism

Several studies have revealed that chiral neonicotinoids undergo stereoselective degradation and metabolism during crop cultivation and special attention should be paid to the balanced and sustainable development of agroecosystems [31, 36, 88, 89]. The main challenge in identifying preferentially degraded monomers is related to their contrasting selectivity in different environmental compartments.

As shown in Fig. 7, significant enantioselective dissipation and metabolism of dinotefuran are observed during agricultural practices, and their variations differ between crops and soil matrices. R-dinotefuran tends to be degraded
<table><caption>**Table 2** Isomeric distribution of chiral neonicotinoids</caption><thead><tr><th rowspan="2">Assay plant</th><th rowspan="2">Application method</th><th rowspan="2">Assay period (h)</th><th rowspan="2">Assay part</th><th colspan="2">The distribution proportion of absorbed amount (%)</th><th rowspan="2">Selective ratio SR/RS<sup>a</sup></th></tr><tr><th>(5R,8S)-cycloxacrid</th><th>(5S,8R)-cycloxacrid</th></tr></thead><tbody><tr><td rowspan="4">Youdonger (Brassica campestris subsp. Chinensis)</td><td>Root uptake</td><td>192</td><td>Shoot<sup>b</sup></td><td>52.90<sup>b</sup></td><td>57.80<sup>ba</sup></td><td>1.1</td></tr><tr><td rowspan="3">Foliar spray</td><td rowspan="3">96</td><td>TL</td><td>83.56 ± 6.91<sup>bb</sup></td><td>93.68 ± 1.82<sup>ba</sup></td><td>1.1</td></tr><tr><td>LATL</td><td>5.12 ± 3.11<sup>bb</sup></td><td>2.12 ± 0.63<sup>ba</sup></td><td>0.4</td></tr><tr><td>LBTL</td><td>11.32 ± 6.20<sup>ba</sup></td><td>4.20 ± 1.29<sup>ba</sup></td><td>1.0<sup>e</sup></td></tr><tr><td rowspan="3">Chinese cabbage (Brassica chinensis L.)</td><td rowspan="3">Foliar spray</td><td rowspan="3">192</td><td>TL</td><td>93.40<sup>a</sup></td><td>93.70<sup>a</sup></td><td>1.0</td></tr><tr><td>LATL</td><td>3.39<sup>a</sup></td><td>2.36<sup>a</sup></td><td>1.0</td></tr><tr><td>LBTL</td><td>1.52<sup>a</sup></td><td>1.51<sup>a</sup></td><td>1.0</td></tr><tr><td rowspan="5">Oilseed rape (Brassica napus L.)</td><td rowspan="5">Foliar spray</td><td rowspan="5">87</td><td>TL</td><td>84.0<sup>a</sup></td><td>84.8<sup>a</sup></td><td>1.0</td></tr><tr><td>LATL+LBTL</td><td>1.80<sup>b</sup></td><td>3.10<sup>a</sup></td><td>1.7</td></tr><tr><td>Root</td><td>0.09<sup>b</sup></td><td>0.05<sup>a</sup></td><td>0.5</td></tr><tr><td>Anther</td><td>0.03<sup>a</sup></td><td>0.03<sup>a</sup></td><td>1.0</td></tr><tr><td>The rest of the flower except the anther</td><td>0.31<sup>b</sup></td><td>0.35<sup>a</sup></td><td>1.1</td></tr><tr><td rowspan="7">Chinese pak choi (Brassica campestris ssp. chinensis)</td><td>Root uptake</td><td>144</td><td>Shoot</td><td>54.51</td><td>66.67</td><td>86.90</td><td>84.85</td><td>1.4 ± 0.2<sup>b</sup></td></tr><tr><td rowspan="6">Foliar spray</td><td rowspan="6">96</td><td>TL</td><td>72.60 ± 1.69<sup>ya</sup></td><td>67.28 ± 8.05<sup>ya</sup></td><td>94.92 ± 2.24<sup>yb</sup></td><td>90.25 ± 1.13<sup>yb</sup></td><td>1.3 ± 0.07<sup>b</sup></td></tr><tr><td>LATL</td><td>7.47 ± 0.54<sup>ya</sup></td><td>8.19 ± 4.33<sup>yb</sup></td><td>2.00 ± 0.73<sup>yb</sup></td><td>1.79 ± 0.51<sup>yb</sup></td><td>0.2 ± 0.02<sup>b</sup></td></tr><tr><td>LBTL</td><td>12.17 ± 1.62<sup>ya</sup></td><td>20.96 ± 0.06<sup>yb</sup></td><td>2.69 ± 0.46<sup>yc</sup></td><td>4.27 ± 0.19<sup>rd</sup></td><td>0.2 ± 0.1<sup>b</sup></td></tr><tr><td>Stalk</td><td>5.98 ± 1.39<sup>ya</sup></td><td>3.32 ± 1.37<sup>yb</sup></td><td>1.61 ± 0.07<sup>yc</sup></td><td>1.32 ± 0.54<sup>yc</sup></td><td>0.3 ± 0.1<sup>b</sup></td></tr><tr><td>Root</td><td>2.68 ± 0.58<sup>ya</sup></td><td>0.64 ± 0.17<sup>yb</sup></td><td>0.40 ± 0.21<sup>yb</sup></td><td>0.30 ± 0.22<sup>yb</sup></td><td>0.3 ± 0.2<sup>b</sup></td></tr></tbody></table>

HAT hour after treatment; TL treated leaf; LATL leaf above the treated leaf; LBTL leaf below the treated leaf

aThe difference in distribution proportion between cycloxacrid enantiomers, SR/RS ratio greater than 1.0 indicates that (5S,8R)-cycloxacrid preferentially accumulates in plants, SR/RS ratio less than 1.0 indicates that (5R,8S)-cycloxacrid preferentially accumulates in plants, and SR/RS ratio equal to 1.0 indicates that there is no significant difference between cycloxacrid enantiomers, (RS,SR)/(RR,SS) are similar to SR/RS; bData are represented as mean ± standard deviation of the mean (SD); γData are represented as mean ± standard error of the mean (SEM); δAll leaves and cotyledons; εNo significant difference

The different superscript lowercase letters in the same row differ significantly (p < 0.05)

preferentially, resulting in the relative enrichment of S-dinotefuran in greenhouse vegetables, such as cucumber and tomato under both foliage and root treatments [35, 36]. However, the chiral profiles regarding the dissipation of dinotefuran enantiomers differ across natural soils characterized by specific properties, with S/R selective ratios ranging from 0.7 to 1.5, and the redox conditions of incubation soils do not influence the specific directions of enantioselective dissipation [60]. For the metabolism of dinotefuran enantiomers, 1-methyl-3-(tetrahydro-3-furylmethyl) urea enantiomers appear during the degradation of S-dinotefuran and R-dinotefuran in tomato, with variations depending on the application mode, in which the (−) isomer is generated at a faster rate and is more persistent in the foliage uptake

pathway, whereas the enantiomers are only observed at 7 days by the root uptake pathway [36]. Interestingly, the (+) and (−)-isomers of 1-methyl-3-(tetrahydro-3-furylmethyl) urea are selectively generated by S-dinotefuran and R-dinotefuran in soils, without any alteration in optical rotation [60].

Sulfoxaflor undergoes non-enantioselective degradation in greenhouse vegetables, such as cucumber and tomato or soil matrices, as shown in Fig. 7 [30, 31]. However, environmental studies have historically neglected to confirm the differences in the degradation of sulfoxaflor diastereoisomers as well as their stereoselective metabolism. The dissipation of cycloxacrid also does not exhibit a clear enantioselective preference in a crop of oilseed rape (Brassica napus L.) as
<figure><img src="image_8.png" /><figcaption>**Fig. 7** Stereoselective preference of dinotefuran (A), sulfoxaflor (B), cycloaxprid (C) and paichongding (D) in terms of degradation. lg(S/R) refers to the logarithm of the S/R ratio based on 10; lg(S/R) greater than 0 indicates that S-dinotefuran is preferentially degraded, whereas lg(S/R) less than 0 indicates that R-dinotefuran is preferentially degraded. The same goes for sulfoxaflor, cycloaxprid and paichongding. ns represents statistical insignificance</figcaption></figure>

well as various soil matrices (Fig. 7), due to its rapid trans-
formation into achiral metabolites [60, 85, 89]. Interestingly,
cycloaxprid metabolites in crop oilseed rape show significant
enantioselectivity, although obtaining the same metabolites
and transformation pathways [85]. However, cycloaxprid
enantiomers are non-stereoselectively converted to achiral
metabolites in soils, although their metabolic dynamics vary
depending on redox conditions and soil characteristics [60,
89].

Significant diastereoselective preferences appear during
the dissipation of paichongding in multiple natural soils,
and (5R,7R)-/(5S,7S)-paichongding are more persistent than
(5R,7S)-/(5S,7R)-paichongding by a factor of 1.2–17.2, as
shown in Fig. 7 [12, 33, 88, 90]. Paichongding also shows
significant diastereoselective metabolism in multiple soil,
and the chiral-specific metabolic dynamics have obvious soil
preferences and vary depending on redox conditions [12,
88]. Nevertheless, until recently, information related to the
isomeric degradation and metabolism of paichongding in
crop matrices was still poorly understood.

In summary, significant enantioselective dissipation of
dinotefuran has been observed during agricultural practices,

such as the priority degradation of *R*-dinotefuran in plants.
Sulfoxaflor undergoes non-enantioselective degradation.
The dissipation of cycloaxprid does not exhibit a clear
enantioselective preference, and the compound is rapidly
transformed into achiral metabolites. Diastereoselectivity
dominates the dissipation and metabolism of paichongding
stereoisomers. Soil microorganisms, exposure concentra-
tions, chemical structures, and physicochemical properties
of the target compounds are thought to contribute to shap-
ing the stereoselective dissipation and metabolism of chiral
neonicotinoids. (1) There is evidence highlighting the roles
of microorganisms in contributing to the enantioselective
dissipation of dinotefuran in soils, in which the half-life of
61.3 days for *R*-dinotefuran is significantly lower than that of
74.5 days for *S*-dinotefuran in the unsterilized soil, whereas
no obvious enantioselectivity is found after sterilization
[62]. (2) The greater original accumulation of *S*-dinotefuran
in tomato crops by transpiration compared with *R*-dinote-
furan further results in its higher persistence [36]. (3) The
racemization of sulfoxaflor stereoisomers at room tempera-
ture, as well as the instability of the oxabridged ring in the
cycloaxprid configuration, is probably responsible for their
non-stereoselective dissipation in crop and soil matrices [30, 31, 39, 60, 85, 91]. In addition, greater degradation rates of (5R,7S)-/(5S,7R)-paichongding over (5R,7R)-/(5S,7S)-paichongding are observed in sterilized soils, unsterilized soils, and soils containing bacteria capable of degrading paichongding [90]. This implies that selective degradation between paichongding epimers might involve abiotic processes, and diastereomers may differ in physiochemical properties, further resulting in distinct degradation dynamics [12, 90]. In addition, enzymes or other chiral macromolecules may play an important role in the isomeric degradation and metabolism of neonicotinoid insecticides [88].

## Isomeric mineralization of neonicotinoids

Chiral neonicotinoids undergo mineralization in soils and inevitably exhibit isomer specificity due to the selective effects of microorganisms. Therefore, identifying individual monomers with a higher potential for mineralization is crucial for reducing their ecological risks [49]. However, substantial knowledge gaps remain regarding the stereoselective mineralization of chiral neonicotinoids, and only cycloaxprid and paichongding have received some consideration.

Several studies have highlighted the non-stereoselective mineralization of cycloaxprid enantiomers in various soils, with mineralization rates ranging from less than 1.0% to 20.1% as the soil characteristics and incubation conditions change [48, 49] (Table 3). As shown in Table 3, diastereoselective behaviors have been found in the mineralization of paichongding stereoisomers across multiple soils under aerobic and anaerobic incubations. The (5R,7S)-/(5S,7R)-paichongding exhibited a higher mineralization rate than (5R,7R)-/(5S,7S)-paichongding by a factor of 2.2–5.5 [23, 92].

The preferential mineralization of (5R,7S)-/(5S,7R)-paichongding and the non-stereoselective mineralization of cycloaxprid in soils can be summarized. Soil microorganisms are inextricably associated with the isomeric mineralization of cycloaxprid and paichongding in soil [93, 94]. Moreover, the oxygen bridge in the cycloaxprid configuration, which can be easily cleaved leading to the formation of non-chiral metabolites, may explain the loss of stereoselectivity during mineralization [48, 49].

## Residues of neonicotinoids in plant and soils

Chiral neonicotinoids are widely used in agricultural production to prevent or control pests to reduce or eliminate crop yield losses, and the magnitude of their exposure concentrations affects the safety of agricultural products and ecological balance [53, 95]. Identification of monomers with minor residue levels is associated with a reduction in the risk of chiral neonicotinoids. Pesticide residues are classified into

extractable and bound residues, according to whether they persist in the matrix in the form of the parent substance or its metabolites after extraction. Extractable residues are the major objects of pesticide residue analysis [96].

Previous studies have mainly focused on identifying the stereoselectivity of extractable residual levels artificially exposed to chiral neonicotinoids, which are found to vary depending on the specific compound types and environmental matrices. As shown in Fig. 8, S-dinotefuran shows a greater magnitude than R-dinotefuran by a factor of 1.2–1.5 in greenhouse vegetables such as cucumber and tomato through foliage spraying and root douching [36, 46]. The enantioselectivity of dinotefuran exposure shows a significant soil preference, with the *S* isomer/*R* isomer ratio ranging from 0.6–2.1, with the chiral-specific directions not changing under aerobic and anaerobic conditions [60]. 1-methyl-3-(tetrahydro-3-furylmethyl) urea is the only metabolite detected after exposure to dinotefuran enantiomers in greenhouse tomato and various soils, where the terminal concentrations of its (+) isomer are 0.8–1.6 times higher than those of its (−) isomer. Researchers have observed THE selective metabolism of (+)- and (−)-isomers from *S*-dinotefuran and *R*-dinotefuran in soils. However, this observation could not be made in tomato, as dinotefuran was treated as a racemate [36, 60].

No significant difference has been found between the final concentrations of sulfoxaflor enantiomers in either crop or soil matrices [30, 31] (Fig. 8). In addition, no enantiomer-specific trends for cycloaxprid were observed in the residual levels in either crop or soil matrices because of its rapid and complete conversion into achiral metabolites [60, 85, 89] (Fig. 8). However, contrasting chiral profiles regarding the levels of cycloaxprid metabolites were evident between crop and soil matrices, showing a clear chiral preference in the crop of oilseed rape (*Brassica napus* L.), whereas no such preference was observed in the soil matrices [60, 85, 89].

The stereoselective shifts of paichongding residues have been extensively documented in various soils; however, the lack of data on crops restricts their applicability to general conclusions in agricultural systems. As shown in Fig. 8, significant diastereoselectivity occurred in the terminal concentrations of paichongding isomers, indicating that more *RR/-SS*-enantiomers remained in the tested soils than *RS/-SR*-enantiomers [12, 88, 90]. Multiple transformation products of paichongding have been identified in soils, the concentrations of which also show significant selection among different epimers under both aerobic and anaerobic conditions [12, 88].

In addition to the well-known extractable residues, attention should also be paid to the formation of bound residues [97]. These residues represent compounds that persist in the matrix in the form of the parent substance or its metabolites after extraction, because their release causes delayed
<table><caption>**Table 3** Mineralization of chiral neonicotinoids</caption><thead><tr><th rowspan="2">Assay soil</th><th rowspan="2">Incubation condition</th><th rowspan="2">Assay period (d)</th><th colspan="3">The mineralization proportion of applied amount (%)</th><th rowspan="2">Selective ratio SR/RS<sup>a</sup></th></tr><tr><th>(5R,8S)-cycloxacrid</th><th>(5S,8R)-cycloxacrid</th><th>rac-cycloxacrid</th></tr></thead><tbody><tr><td>Fluvio-marine yellow loam soil</td><td rowspan="3">Aerobic</td><td rowspan="3">100</td><td>6.90 ± 0.60<sup>βa</sup></td><td>6.70 ± 0.40<sup>βa</sup></td><td>7.30 ± 1.00<sup>βa</sup></td><td>1.0<sup>β</sup></td></tr><tr><td>Coastal saline soil</td><td>14.80 ± 3.00<sup>βa</sup></td><td>20.10 ± 0.90<sup>βa</sup></td><td>16.50 ± 1.30<sup>βa</sup></td><td>1.0</td></tr><tr><td>Red clay soil</td><td>0.23 ± 0.07<sup>βa</sup></td><td>0.22 ± 0.07<sup>βa</sup></td><td>0.11 ± 0.02<sup>βa</sup></td><td>1.0</td></tr><tr><td>Fluvio-marine yellow loam soil</td><td rowspan="3">Anaerobic</td><td rowspan="3">100</td><td>0.39 ± 0.04<sup>γa</sup></td><td>0.37 ± 0.30<sup>γa</sup></td><td>0.33 ± 0.03<sup>γa</sup></td><td>1.0</td></tr><tr><td>Coastal saline soil</td><td>0.13 ± 0.01<sup>γa</sup></td><td>0.10 ± 0.02<sup>γa</sup></td><td>0.08 ± 0.01<sup>γa</sup></td><td>1.0</td></tr><tr><td>Red clay soil</td><td>&lt; 0.01<sup>a</sup><br>(5R,7R)-paichongding</td><td>&lt; 0.01<sup>a</sup><br>(5R,7S)-paichongding</td><td>&lt; 0.01<sup>a</sup><br>(5S,7R)-paichongding</td><td>&lt; 0.01<sup>a</sup><br>rac-paichongding</td><td>1.0<br>(RS, SR)/(RR, SS)</td></tr><tr><td>Fluvio-marine yellow loam soil</td><td rowspan="3">Aerobic</td><td rowspan="3">100</td><td>2.55<sup>a</sup></td><td>2.60<sup>a</sup></td><td>6.97<sup>b</sup></td><td>/<sup>f</sup></td><td>2.8 ± 0.1<sup>γ</sup></td></tr><tr><td>Coastal saline soil</td><td>3.75<sup>a</sup></td><td>2.50<sup>a</sup></td><td>6.00<sup>b</sup></td><td>/</td><td>2.2 ± 0.5<sup>γ</sup></td></tr><tr><td>Red clay soil</td><td>&lt; 0.60<sup>a</sup></td><td>&lt; 0.60<sup>a</sup></td><td>&lt; 0.60<sup>a</sup></td><td>/</td><td>1.0</td></tr><tr><td>Fluvio-marine yellow loam soil</td><td rowspan="3">Anaerobic</td><td rowspan="3">100</td><td>1.08<sup>a</sup></td><td>0.90<sup>a</sup></td><td>3.90<sup>b</sup></td><td>/</td><td>4.0 ± 0.4<sup>γ</sup></td></tr><tr><td>Coastal saline soil</td><td>0.40<sup>a</sup></td><td>0.40<sup>a</sup></td><td>2.40<sup>b</sup></td><td>/</td><td>5.5 ± 0.6<sup>γ</sup></td></tr><tr><td>Red clay soil</td><td>&lt; 0.50<sup>a</sup></td><td>&lt; 0.50<sup>a</sup></td><td>&lt; 0.50<sup>a</sup></td><td>/</td><td>1.0</td></tr></tbody></table>

harm through biotic or abiotic processes [98]. Knowledge of the stereoselective formation of bound residues exposed to cycloxacrid and paichongding has been reported previously. No stereoselective behavior appeared in the bound residues of racemic cycloxacrid and its enantiomers in three soils under both aerobic and anaerobic conditions [48, 49]. In the formation of paichongding bound residues in soils, (5R,7S)-/(5S,7R)-paichongding were preferentially bound to soils than (5R,7R)-/(5S,7S)-paichongding [23, 92]. It can be concluded that S-dinotefuran exhibits a higher exposure magnitude than R-dinotefuran in plants, and the terminal

concentrations of (5R,7R)-/(5S,7S)-paichongding are higher than those of (5R,7S)-/(5S,7R)-paichongding in soils. There was no apparent enantioselectivity for the final levels of sulfoxaflor and cycloxacrid in plant and soil matrices.

## Conclusion

The chiral neonicotinoids dinotefuran and sulfoxaflor, two cis-neonicotinoids of cycloxacrid and paichongding, demonstrate high insecticidal potency against sucking pest strains.

<footnote><sup>a</sup>The difference in the mineralization rate between cycloxacrid enantiomers, SR/RS greater than 1.0 indicates that (5S,8R)-cycloxacrid is preferentially mineralized, SR/RS</footnote>

<footnote><1.0 indicates that (5R,8S)-cycloxacrid is preferentially mineralized, and SR/RS equal to 1.0 indicates that there is no significant difference between cycloxacrid enantiomers, (RS, SR)/(RR,SS) for paichongding diastereoisomers are similar to SR/RS; <sup>b</sup>Data are represented as mean ± standard error of the mean (SEM); <sup>c</sup>Data are represented as mean ± standard deviation of the mean (SD); <sup>d</sup>No significant difference; <sup>e</sup>No reference data; The different superscript lowercase letters in the same row differ significantly (p < 0.05)</footnote>
<figure><img src="image_9.png" /><figcaption>**Fig. 8** Stereoselective preference of dinotefuran (A), sulfoxaflor (B), cycloxaclid (C) and paichongding (D) in terms of residual levels. lg(S/R) refers to the logarithm of the S/R ratio based on 10; lg(S/R) greater than 0 indicates that S-dinotefuran shows greater residual levels, whereas lg(S/R) less than 0 indicates that R-dinotefuran shows greater residual levels. The same goes for sulfoxaflor, cycloxaclid and paichongding. ns represents statistical insignificance</figcaption></figure>

However, these promising agrochemicals have encountered
ecological dilemmas, particularly for pollinators. Chirality
in neonicotinoids complements the possibility of decreasing
hazard magnitude. New chiral pesticide products with a high
proportion of pure *R*-dinotefuran or (*5R*,*7S*)-paichongding
enantiomers are potential development targets favorable in
biosecurity and agricultural environments from the perspec-
tive of enantiomers. Based on this review, three aspects of
improvement or concerns should attract more attention in
the future. (1) It is inaccurate and incomplete to determine
the highly active or toxic isomers of chiral neonicotinoids
through a single assay indicator, while acute, chronic, and
bioaccumulation toxicities should be comprehensively con-
sidered. (2) The stereoselectivity of neonicotinoids varies
among crops and soils with different properties, and the
selection of isomer formulations can be determined based on
specific cultivation systems or application scenarios. (3) The
extent of mineralization and bound residues of neonicotinoid
isomers potentially exceeds the threshold approved by the
European Union for authorized application, which may also
hinder the development of neonicotinoid chiral products.

**Author contributions** All authors contributed to the study concep-
tion and design. Manuscript writing and supervision were performed
by Zenglong Chen, Lilin Zhao and Shanshan Kang, and manuscript
reviewing was conducted by Rock Keey Liew and Eric Lichtfouse. All
authors read and approved the final manuscript.

**Funding** This research was financially supported by the National Natural Science Foundation of China (China, No. 32472594), and Initiative Scientific Research Program, Institute of Zoology, Chinese Academy of Sciences (China, No. 2023IOZ010). The authors would like to thank Saveetha Institute of Medical and Technical Sciences for the support provided.

**Availability of data and material** Not applicable.

**Code availability** Not applicable.

**Declarations**

**Conflicts of interest** On behalf of all authors, the corresponding author
states that there is no conflict of interest.

**Ethics approval** Not applicable.

**Consent to participate** Not applicable.

**Consent for publication** Not applicable.
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