William P. Eckel, Ph.D. Office of Pesticide Programs (OPP) US EPA QSAR and Calculators for Freundlich Adsorption Coefficient (Kf) Based on 18 Agricultural Soils American Chemical Society 254th National Meeting, August 24, 2017 Washington, DC William P. Eckel, Ph.D. Office of Pesticide Programs (OPP) US EPA

Question: Is data in OPP’s Possession useful for new Quantitative Structure-Activity Relationships? OPP has hundreds of guideline studies for mobility and metabolism of pesticide active ingredients Could new QSARs complement methods already available to OPPT? EPISuite methods based on logKow and Molecular Connectivity Index Soil mobility (batch equilibrium guideline) as a pilot

Batch Equilibrium Study (835.1230 or 163-1) Soil - water partitioning at several concentrations Several agricultural soils required per chemical FIFRA requirement for all conventional pesticides Regression of results yields Freundlich coefficient (Kf) and exponent (1/n) for each soil

Question: Is Kf a Function of the Soil Used? Same soils are used repeatedly in submitted studies Is there a relationship between a property of the chemical, and its Kf on a particular soil? Regressed Kf versus “sub-cooled liquid” solubility Sub-cooled liquid solubility (S_scl) calculated by “fugacity ratio” method; requires melting point and solubility of solid

Fugacity Ratio for Subcooled Liquid solubility ln(Fugacity ratio) = (ΔHfus/R)*((mp/298)– 1) Melting point of solid in Kelvins ΔHfus/R (or Sfus) estimated as -56.5 J/mol-K Subcooled liquid solubility (S-scl) = Solubility(solid)/fugacity ratio Interpreted as Solubility if substance were a liquid at 25°C

Data Mining of Data Evaluation Records (DERs) 18 soils in recent OPP electronic files had at least 3 chemicals with Batch Equilibrium study DERs 41 chemicals total over the 18 soils (US and European) Soils were identified by name (e.g., Don Uglem clay loam) Soil identity verified by sand/silt/clay content and %organic carbon Ranged from Sand (0.38 %OC) to Humic (19% OC) Log-log plot (Kf vs. solubility) and power function regression

Summary of Soils and Chemical Data Used

Data for Speyer 2.2 Loamy Sand with Kf estimates vs. Measured Kf

Log-Log Plot of Kf vs. S_scl (r2 = 0.75)

Example of Subcooled Liquid Solubility Calculator: Atrazine. Avg Example of Subcooled Liquid Solubility Calculator: Atrazine. Avg. Kfoc = 174; range = 70 - 429

Test of Subcooled Liquid Calculator 333 pesticide active ingredients of all classes from Footprint (EU) database Each had reported Kfoc range/average, melting point and solubility Calculated S_scl for all 333, then calculated average Kf and Kfoc Compared Average Predicted to Average Reported Prediction within 2x, 3x, 10x ?

Results of Footprint Database Analysis Predicted/Reported Kfoc: Ratio 0.1 – 10: 278 (83%) Ratio 0.33 – 3: 217 (65%) Ratio 0.5 – 2: 142 (43%)

Effect of Ionized Chemicals (pKa reported)

Correlation of 1/n to mp (Laacherhof Axxa soil)

Initial Analysis of 1/n versus melting point

Prediction on Molar solubility basis

Individual classes: Carbamates

Individual classes: Conazoles

Individual Classes: Strobilurins

Individual Classes: Urea herbicides

Conclusions Yes, OPP’s Batch Equilibrium data holdings are useful for constructing QSARs Sub-cooled liquid Solubility is a useful independent variable to predict Kf for both neutral and ionized chemicals Most predictions of Kfoc are within 10x; almost half within 2x Class-specific regressions might improve predictions of Kf May be possible to estimate exponent, 1/n