Comparative cytotoxicity of plant protection products and their active ingredients

Adler-Flindt, Sarah; Martin, Sabine

doi:10.1016/j.tiv.2018.10.020

Cited by 9 publications

(8 citation statements)

References 24 publications

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“…Co-formulants perform specific functions in the formulation, such as solvents, surfactants, diluents, thickeners, dispersing agents, binding agents, stabilizing agents, wetting agents, antifoaming agents, preservatives or antifreeze agents. [8][9][10] In the context of PPP toxicity, Regulation (EU) 284/2013 11 mainly evaluates acute effects through tests for acute toxicity, irritation and skin sensitization. However, as generally active substances assumed to dominate toxicity, they are analyzed thoroughly for acute, chronic and subchronic effects in short-and long-term in vivo studies.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the composition of plant protection products in different formulation types employing suspect screening and unknown approaches

2022

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BACKGROUND Plant protection products (PPPs) are used extensively in agriculture to control crops. These PPPs, which may be found in different types of formulations, are composed of a designated pesticide (active principle) and other inactive ingredients as co‐formulants. They perform specific functions in the formulation, as solvents, preservatives or antifreeze agents, among others. RESULTS A research technique based on ultra‐high‐performance liquid chromatography (UHPLC) coupled to a Quadrupole‐Orbitrap mass analyzer was successfully applied to characterize the composition of six different PPPs in terms of the presence of co‐formulants and types of formulations: emulsifiable concentrate (EC), emulsion in water (EW), suspension concentrate and water‐dispersible granule. These PPPs (FLINT MAX, MASSOCUR 12.5 EC, IMPACT EVO, TOPAS, LATINO and IMPALA STAR) had antifungal activity, containing one triazole compound as active principle (tebuconazole, penconazole, myclobutanil, flutriafol or fenbuconazole, respectively). Non‐targeted approaches, applying suspect and unknown analysis, were carried out and ten compounds were identified as potential co‐formulants. Six (glyceryl monostearate, 1‐monopalmitin, dimethyl sulfoxide, N,N‐dimethyldecanamide, hexaethylene glycol and 1,2‐benzisothiazol‐3(2H)‐one) were confirmed by injecting analytical standards. Finally, these compounds were quantified in the PPPs. CONCLUSION The current study allowed for detecting co‐formulants in a wide range of concentrations, between 0.04 (dimethyl sulfoxide) and 19.00 g L−1 (glyceryl monostearate), highlighting the feasibility of the proposed analytical methodology. Moreover, notable differences among the types of formulations of PPPs were achieved, revealing that EC and EW were the formulations that contained the largest number of co‐formulants (four out of six detected compounds). © 2022 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

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Section: Introductionmentioning

confidence: 99%

Characterization of the composition of plant protection products in different formulation types employing suspect screening and unknown approaches

2022

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“…However, this method produces a high number of falsenegative predictions compared with in vivo derived classification for PPPs although intended to provide worst-case estimation. 5,[59][60][61][62] For example, Kurth et al assessed all authorised PPPs on the German market that were classified for the specific endpoints. 61 They concluded that false-negative predictions using the CLP calculation method were especially high at ∼ 40% for acute oral and inhalation toxicity.…”

Section: The Clp Calculation Methodsmentioning

confidence: 99%

“…For this purpose, we propose to investigate the applicability of liver cell cytotoxicity testing and the zebrafish early-life stage test. 5,6,32 The test systems were selected based on regulatory acceptance, the relevance of target sites, and sensitivity. On the one hand, they allow for the investigation of the kinetic influence of co-formulants on AS bioavailability.…”

Section: Tiered Toxicity Testingmentioning

confidence: 99%

“…[2][3][4] Nevertheless, non-active co-formulants may affect the toxicity of PPPs via toxicodynamic and toxicokinetic interaction, as demonstrated in studies comparing AS and PPPs. [5][6][7] Even though co-formulants need not be toxic themselves, their properties can influence the toxicity of the PPP. This influence is not likely to be limited to the generally tested acute endpoints.…”

Section: Introductionmentioning

confidence: 99%

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Towards a tiered test strategy for plant protection products to address mixture toxicity by alternative approaches in human health assessment

Bloch

Marx‐Stoelting

Martin

2020

Pest Management Science

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Plant protection products (PPPs) consist of pesticide active substances and co‐formulants. Generally, active substance effects are assumed to dominate in PPP toxicity. Nevertheless, co‐formulants may well affect the toxicity of PPPs via toxicodynamic and toxicokinetic interaction. To account for potential mixture effects and improve PPP data requirements for application in risk assessment, a tiered test strategy is proposed. The strategy is based on a comparison of PPP and active substance toxicity, which enables the prioritisation of PPPs for further testing, adaptation of the toxicological threshold value or removal of toxic co‐formulants from the PPP. Moreover, it focuses on the integrative assessment of existing information and newly generated data using alternative test methods. The proposed strategy will improve PPP toxicological assessment by accounting for mixture toxicity, providing a set of regulatory options for risk assessment and the necessary data for hazard assessment. The predictivity of alternative methods for PPPs will improve by evaluation of their reliability and uncertainty. © 2020 The Authors. Pest Management Science published by JohnWiley & Sons Ltd on behalf of Society of Chemical Industry.

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“…Although co-formulants are by definition non-active, they contribute to toxicodynamic or toxicokinetic mixture effects, potentially resulting in the altered toxicity of the PPP. In recent years several articles were published comparing active substances and PPPs, showing that the products may exhibit increased toxic effects (Adler-Flindt and Martin 2019;Hernandez et al 2013;Zahn et al 2018). Furthermore, Regulation (EU) 1107/2009 requires that "interaction between the active substance, safeners, synergists and coformulants shall be taken into account" in the evaluation and authorisation of PPPs (EC 2009).…”

Section: Introductionmentioning

confidence: 99%

Effects of co-formulants on the absorption and secretion of active substances in plant protection products in vitro

et al. 2021

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Currently, the authorisation process for plant protection products (PPPs) relies on the testing of acute and topological toxicity only. Contrastingly, the evaluation of active substances includes a more comprehensive set of toxicity studies. Nevertheless, mixture effects of active ingredients and co-formulants may result in increased toxicity. Therefore, we investigated effects of surface active co-formulants on the toxicity of two PPPs focussing on qualitative and quantitative toxicokinetic effects on absorption and secretion. The respective products are based on the active substances abamectin and fluroxypyr-meptyl and were tested for cytotoxicity in the presence or absence of the corresponding surfactants and co-formulants using Caco-2 cells. In addition, the effect of co-formulants on increased cellular permeation was quantified using LC–MS/MS, while potential kinetic mixture effects were addressed by fluorescence anisotropy measurements and ATPase assays. The results show that surface active co-formulants significantly increase the cytotoxicity of the investigated PPPs, leading to more than additive mixture effects. Moreover, analytical investigations show higher efflux ratios of both active substances and the metabolite fluroxypyr upon combination with certain concentrations of the surfactants. The results further point to a significant and concentration-dependent inhibition of Pgp transporters by most of the surfactants as well as to increased membrane fluidity. Altogether, these findings strongly support the hypothesis that surfactants contribute to increased cytotoxicity of PPPs and do so by increasing the bioavailability of the respective active substances.

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Comparative cytotoxicity of plant protection products and their active ingredients

Cited by 9 publications

References 24 publications

Characterization of the composition of plant protection products in different formulation types employing suspect screening and unknown approaches

Characterization of the composition of plant protection products in different formulation types employing suspect screening and unknown approaches

Towards a tiered test strategy for plant protection products to address mixture toxicity by alternative approaches in human health assessment

Effects of co-formulants on the absorption and secretion of active substances in plant protection products in vitro

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