A proposed NAM-based tiered phototoxicity testing and human risk assessment framework for agrochemicals.

Phototoxicity testing is required by European regulations for agrochemicals with UV/visible molar extinction/absorption coefficient (MEC) higher than 10 L x mol-1 x cm-1 in the 290-700 nm wavelength range. Furthermore, regulations identify a need of considering human exposure in case of positive results. While in vitro OECD test guidelines are available for hazard characterisation, there is no guidance on how to utilise positive results in human exposure risk assessments. Our goal was to take a first step towards developing a NAM based tiered testing approach and a framework for non-dietary acute human dermal risk assessment for phototoxicity to agrochemicals. The proposed framework can be divided into a few steps: 1) use the OECD updated MEC values of 1000 L x mol-1 x cm-1 as trigger for phototoxicity testing; 2) establish a reference concentration (RfC) from in vitro phototoxicity studies using BMC approach, 3) estimate potential exposure to skin, target organ for phototoxicity, using EFSA exposure models, product specific labels and skin penetration values, and 4) phototoxicity risk assessment; 5) refinement to RfC and/or exposure estimates can be considered. Finally, case studies of a nematicide and an herbicide active substance are provided to illustrate the proposed framework.

In-silico prediction of dislodgeable foliar residues and regulatory implications for plant protection products.

BACKGROUND: When experimentally determined dislodgeable foliar residue (DFR) values are not available, regulatory agencies use conservative default DFR values as a first-tier approach to assess post-application dermal exposures to plant protection products (PPPs). These default values are based on a limited set of field studies, are very conservative, and potentially overestimate exposures from DFRs. OBJECTIVE: Use Random Forest to develop classification and regression-type ensemble models to predict DFR values after last application (DFR0) by considering experimentally-based variability due to differences in physical and chemical properties of PPPs, agronomic practices, crop type, and climatic conditions. METHODS: Random Forest algorithm was used to develop in-silico ensemble DFR0 prediction models using more than 100 DFR studies from Corteva AgriscienceTM. Several variables related to the active ingredient (a.i.) that was applied, crop, and climate conditions at the time of last application were considered as model parameters. RESULTS: The proposed ensemble models demonstrated 98% prediction accuracy that if a DFR0 is predicted to be less than the European Food Safety Authority (EFSA) default DFR0 value of 3 µg/cm2/kg a.i./ha, it is highly indicative that the measured DFR value will be less than the default if the study is conducted. If a value is predicted to be larger than or equal to the EFSA default, the model has an 83% prediction accuracy. IMPACT STATEMENT: This manuscript is expected to have significant impact globally as it provides: A framework for incorporating in silico DFR data into worker exposure assessment, A roadmap for a tiered approach for conducting re-entry exposure assessment, and A proof of concept for using existing DFR data to provide a read-across framework that can easily be harmonized across all regulatory agencies to provide more robust assessments for PPP exposures.

S-oxygenation of thiocarbamides. 3. Nonlinear kinetics in the oxidation of trimethylthiourea by acidic bromate.

The oxidation of trimethylthiourea (TMTU) by acidic bromate has been studied. The reaction mimics the dynamics observed in the oxidation of unsubstituted thiourea by bromate with an induction period before formation of bromine. The stoichiometry of the reaction was determined to be 4:3, thus 4BrO(3)- + 3R(1)R(2)C=S+ 3H(2)O --> 4Br- + 3R(1)R(2)C=O + 3SO(4)(2-) + 6H+. This substituted thiourea is oxidized at a much faster rate than the unsubstituted thiourea. The oxidation mechanism of TMTU involves initial oxidations through sulfenic and sulfinic acids. At the sulfinic acid stage, the major oxidation pathway is through the cleavage of the C-S bond to form a reducing sulfur leaving group, which is easily oxidized to sulfate. The minor pathway through the sulfonic acid produces a very stable intermediate that is oxidized only very slowly to urea and sulfate. The direct reaction of aqueous bromine with TMTU was faster than reactions that form bromine, with a bimolecular rate constant of (1.50 +/- 0.04) x 10(2) M(-1) s(-1). This rapid reaction ensured that no oligooscillatory bromine formation was observed. The oxidation of TMTU was modeled by a simple reaction scheme containing 20 reactions.

S-oxygenation of thiocarbamides I: Oxidation of phenylthiourea by chlorite in acidic media.

The oxidation of 1-phenyl-2-thiourea (PTU) by chlorite was studied in aqueous acidic media. The reaction is extremely complex with reaction dynamics strongly influenced by the pH of reaction medium. In excess chlorite concentrations the reaction stoichiometry involves the complete desulfurization of PTU to yield a urea residue and sulfate: 2ClO2- + PhN(H)CSNH2 + H2O --> SO4(2-) + PhN(H)CONH2 + 2Cl- + 2H+. In excess PTU, mixtures of sulfinic and sulfonic acids are formed. The reaction was followed spectrophotometrically by observing the formation of chlorine dioxide which is formed from the reaction of the reactive intermediate HOCl and chlorite: 2ClO2- + HOCl + H+ --> 2ClO2(aq) + Cl- + H2O. The complexity of the ClO2- - PTU reaction arises from the fact that the reaction of ClO2 with PTU is slow enough to allow the accumulation of ClO2 in the presence of PTU. Hence the formation of ClO2 was observed to be oligooscillatory with transient formation of ClO2 even in conditions of excess oxidant. The reaction showed complex acid dependence with acid catalysis in pH conditions higher than pKa of HClO2 and acid retardation in pH conditions of less than 2.0. The rate of oxidation of PTU was given by -d[PTU]/dt = k1[ClO2-][PTU] + k2[HClO2][PTU] with the rate law: -d[PTU]/dt = [Cl(III)](T)[PTU]0/K(a1) + [H+] [k1K(a1) + k2[H+]]; where [Cl(III)]T is the sum of chlorite and chlorous acid and K(a1) is the acid dissociation constant for chlorous acid. The following bimolecular rate constants were evaluated; k1 = 31.5+/-2.3 M(-1) s(-1) and k2 = 114+/-7 M(-1) s(-1). The direct reaction of ClO2 with PTU was autocatalytic in low acid concentrations with a stoichiometric ratio of 8:5; 8ClO2 + 5PhN(H)CSNH2 + 9H2O --> 5SO4(2-) + 5PhN(H)CONH2 + 8Cl- + 18H+. The proposed mechanism implicates HOCl as a major intermediate whose autocatalytic production determined the observed global dynamics of the reaction. A comprehensive 29-reaction scheme is evoked to describe the complex reaction dynamics.