# 26-27 Jan 2005 Page 1 FOCUS Kinetics training workshop Chapter 7 Recommended Procedures to Derive Endpoints for Parent Compounds Practical Exercise - Answers.

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26-27 Jan 2005 Page 1 FOCUS Kinetics training workshop Chapter 7 Recommended Procedures to Derive Endpoints for Parent Compounds Practical Exercise - Answers Ralph L. Warren, Ph.D. DuPont Crop Protection Delaware, USA

26-27 Jan 2005 Page 2 FOCUS Kinetics training workshop Goal of the exercise The goal of this exercise is to calculate the 2 error and to conduct a visual assessment for kinetic model fits to measured levels of parent compound in soil. Based on this information, the most appropriate kinetic model and endpoints for comparison with regulatory triggers and for use in regulatory exposure modelling should be identified. You will need ModelMaker 4 results from this morning for Example 1 and Example 2. Try Example 3 if time allows (you will need to first do the optimization using MM4). Excel file Parent degradation kinetic training unprotected.xls Excel file t_test.xls Excel file DFOP_DT50.xls

26-27 Jan 2005 Page 3 FOCUS Kinetics training workshop General instructions for the exercise Follow the parent only flow chart for triggers, then the flow chart for modelling to determine which fits are needed. Generate optimized results from ModelMaker (record necessary information!) Create plots for observed versus fitted values and for residuals using Excel (record necessary information!) Calculate the 2 error percentages using Excel (record!). Decide which kinetic model and endpoints to use for triggers and for modelling. Record your conclusions and be prepared to report them to the class. In the interest of time, we will not iteratively modify the fitting routines (e.g. excluding outliers, constraining M O, weighting). Also assume that there are no experimental artifacts (e.g. microbial die off).

Page 4 Triggers flowchart FOCUS Kinetics training workshop 26-27 Jan 2005

Page 5 Modelling flowchart FOCUS Kinetics training workshop

Page 6 Time (days) Obs. (% AR) Calc. (% AR) 0 0 2 2 7 7 14 14 21 21 29 29 45 45 64 64 89 89 119 119 96.7 105.0 83.3 97.5 81.9 87.2 46.3 43.1 35.2 36.5 24.5 19.7 9.8 9.3 4.1 3.0 1.1 1.6 0.3 0.2 103.365 93.3763 72.4271 50.7491 35.5594 23.6809 10.4985 3.99416 1.11992 0.2435 EXAMPLE 1 – SFO ParameterOptimized value Standard error Different than 0 by t-test? M0 k 103.365 0.0507544 2.90251 0.00329378 Not required Yes EndpointValue (days) DT 50 DT 90 13.6 45.4 Fitting statisticValue (%) 2 error (%) 9.2

Page 7 EXAMPLE 1 - SFO Draw the fitted line to the observed data points. Does the fitted line adequately describe the data?Yes Are there obvious over or under predictions?No Does the line cross the y-axis near the Day 0 data?Yes Other comments? Draw in the residual points (approximate). Do the residuals have a distinct pattern?No Are most of the residual points above or below 0?No Are the residual magnitudes large?Only at early time points. Other comments?Points randomly scattered about the 0 line.

Page 8 Time (days) Obs. (% AR) Calc. (% AR) 0 0 2 2 7 7 14 14 21 21 29 29 45 45 64 64 89 89 119 119 96.7 105.0 83.3 97.5 81.9 87.2 46.3 43.1 35.2 36.5 24.5 19.7 9.8 9.3 4.1 3.0 1.1 1.6 0.3 0.2 103.367 93.3726 72.4165 50.7378 35.5318 23.6784 10.506 4.00194 1.12497 0.245697 EXAMPLE 1 - FOMC ParameterOptimized value Standard error Different than 0 by t-test? M0 alpha beta 103.367 1504.36 29623.2 2.99666 7182.86 141191 Not required Not required Not required EndpointValue (days) DT 50 DT 90 13.6 45.4 Fitting statisticValue (%) 2 error (%) 9.6

Page 9 EXAMPLE 1 - FOMC Draw the fitted line to the observed data points. Does the fitted line adequately describe the data?Yes Are there obvious over or under predictions?No Does the line cross the y-axis near the Day 0 data?Yes Other comments? Draw in the residual points (approximate). Do the residuals have a distinct pattern?No Are most of the residual points above or below 0?No Are the residual magnitudes large?Only at early time points. Other comments?Points randomly scattered about the 0 line.

26-27 Jan 2005 Page 10 FOCUS Kinetics training workshop Conclusions – Example 1 Triggers flowchart Most appropriate kinetic model (SFO, FOMC, other): SFO Most appropriate endpoint values (days): DT 50 = 13.6 DT 90 = 45.4 Modelling flowchart Most appropriate kinetic model (SFO, FOMC, other): SFO Most appropriate endpoint values (days): DT 50 = 13.6

Page 11 Time (days) Obs. (% AR) Calc. (% AR) 0 0 1 1 3 3 7 7 14 14 28 28 42 42 61 61 91 91 118 118 96.7 102.5 71.2 78.6 51.0 69.4 42.7 41.5 28.5 22.4 18.6 14.3 10.3 8.4 6.3 5.6 6.0 2.8 2.9 3.0 88.6733 80.7067 66.8566 45.8789 23.7369 6.35307 1.69978 0.283231 0.0167182 0.0013095 9 EXAMPLE 2 - SFO ParameterOptimized value Standard error Different than 0 by t-test? M0 k 88.6733 0.0939487 4.03138 0.0122743 Not required Yes EndpointValue (days) DT 50 DT 90 7.38 24.5 Fitting statisticValue (%) 2 error (%) 15.5

Page 12 EXAMPLE 2- SFO Draw the fitted line to the observed data points. Does the fitted line adequately describe the data?No Are there obvious over or under predictions?Yes Does the line cross the y-axis near the Day 0 data?No, low Other comments?Fitted line under predicts much of the data points, especially after Day 20. Draw in the residual points (approximate). Do the residuals have a distinct pattern?Yes Are most of the residual points above or below 0?Yes, below Are the residual magnitudes large?Yes, most >5% Other comments?

Page 13 Time (days) Obs. (% AR) Calc. (% AR) 0 0 1 1 3 3 7 7 14 14 28 28 42 42 61 61 91 91 118 118 96.7 102.5 71.2 78.6 51.0 69.4 42.7 41.5 28.5 22.4 18.6 14.3 10.3 8.4 6.3 5.6 6.0 2.8 2.9 3.0 96.9914 79.8848 59.3269 39.5089 25.216 14.8529 10.6187 7.70828 5.42071 4.29718 EXAMPLE 2 - FOMC ParameterOptimized value Standard error Different than 0 by t-test? M0 alpha beta 96.9914 0.930673 4.32709 2.9586 0.17099 1.4789 Not required Not required Not required EndpointValue (days) DT 50 DT 90 4.8 47.0 Fitting statisticValue (%) 2 error (%) 5.5

Page 14 EXAMPLE 2- FOMC Draw the fitted line to the observed data points. Does the fitted line adequately describe the data?Yes Are there obvious over or under predictions?No Does the line cross the y-axis near the Day 0 data?Yes Other comments? Draw in the residual points (approximate). Do the residuals have a distinct pattern?No Are most of the residual points above or below 0?Trend > 0 Are the residual magnitudes large?Only at early time points. Other comments?

Page 15 Time (days) Obs. (% AR) Calc. (% AR) 0 0 1 1 3 3 7 7 14 14 28 28 42 42 61 61 91 91 118 118 96.7 102.5 71.2 78.6 51.0 69.4 42.7 41.5 28.5 22.4 18.6 14.3 10.3 8.4 6.3 5.6 6.0 2.8 2.9 3.0 97.4133 79.4295 57.7849 39.7511 28.4258 16.8358 10.0414 4.97992 1.64559 0.607452 EXAMPLE 2 - DFOP ParameterOptimized value Standard error Different than 0 by t-test? M0 g k1 k2 97.4133 0.513067 0.39253 0.0368533 3.19895 0.0827071 0.117258 0.00783263 Not required Not required Yes Yes EndpointValue (days) DT 50 DT 90 DT 50 fast phase DT 50 slow phase 4.5 43.0 1.8 18.8 Fitting statisticValue (%) 2 error (%) 6.4

Page 16 EXAMPLE 2- DFOP Draw the fitted line to the observed data points. Does the fitted line adequately describe the data?Yes Are there obvious over or under predictions?Slight Does the line cross the y-axis near the Day 0 data?Yes Other comments?Slight under prediction at the last two time points, which are below 10% of the initial measured value. Draw in the residual points (approximate). Do the residuals have a distinct pattern?No Are most of the residual points above or below 0?No Are the residual magnitudes large?Only at early time points. Other comments?Slight trend for residuals to be negative after Day 60. However, the associated magnitude of the residuals is small (5% or less).

26-27 Jan 2005 Page 17 FOCUS Kinetics training workshop Conclusions – Example 2 Triggers flowchart Most appropriate kinetic model (SFO, FOMC, other): FOMC Most appropriate endpoint values (days): DT 50 = 4.8 DT 90 = 47.0 Modelling flowchart Most appropriate kinetic model (SFO, FOMC, other): FOMC Most appropriate endpoint values (days): DT 50 = 47.0/3.32 = 14.2

Page 18 Time (days) Obs. (% AR) Calc. (% AR) 0 7 14 28 56 84 112 292 380 91.5 64.1 53.6 68.8 25.6 14.0 18.6 1.2 0.04 82.7476 73.348 65.0162 51.0842 31.5368 19.4693 12.0193 0.54112 0.118841 EXAMPLE 3 - SFO ParameterOptimized value Standard error Different than 0 by t-test? M0 k 82.7476 0.0172133 7.17998 0.00383787 Not required Yes EndpointValue (days) DT 50 DT 90 40.3 134 Fitting statisticValue (%) 2 error (%) 19.0

Page 19 EXAMPLE 3 - SFO Draw the fitted line to the observed data points. Does the fitted line adequately describe the data?Yes Are there obvious over or under predictions?Day 0? Does the line cross the y-axis near the Day 0 data?Yes Other comments?Day 0 could be under predicted. Check Day 0 recoveries from the study (e.g. application monitor data) to rationalize. If ~85% confirmed then okay. If ~100% supported then consider constraining M0 in the fitting. Draw in the residual points (approximate). Do the residuals have a distinct pattern?No Are most of the residual points above or below 0?No Are the residual magnitudes large?Several, up to Day 125. Other comments?Keep in mind that this is a field study, which typically have more variable data than lab studies. This variability is reflected in the residual magnitude. The residual pattern is okay.

Page 20 Time (days) Obs. (% AR) Calc. (%AR) 0 7 14 28 56 84 112 292 380 91.5 64.1 53.6 68.8 25.6 14.0 18.6 1.2 0.04 83.8357 73.3257 64.3321 49.9532 31.0844 20.0656 13.3661 1.66168 0.750887 EXAMPLE 3 - FOMC ParameterOptimized value Standard error Different than 0 by t-test? M0 alpha beta 83.8357 5.6639 292.783 9.04697 25.615 1476.18 Not required Not required Not required EndpointValue (days) DT 50 DT 90 38.1 147 Fitting statisticValue (%) 2 error (%) 20.0

Page 21 EXAMPLE 3 - FOMC Draw the fitted line to the observed data points. Does the fitted line adequately describe the data?Yes Are there obvious over or under predictions?Day 0? Does the line cross the y-axis near the Day 0 data?Yes Other comments?Day 0 could be under predicted. Check Day 0 recoveries from the study (e.g. application monitor data) to rationalize. If ~85% confirmed then okay. If ~100% supported then consider constraining M0 in the fitting. Draw in the residual points (approximate). Do the residuals have a distinct pattern?No Are most of the residual points above or below 0?No Are the residual magnitudes large?Several, up to Day 125. Other comments?Keep in mind that this is a field study, which typically produce more variable data than lab studies. This variability is reflected in the residual magnitude. The residual pattern is okay.

26-27 Jan 2005 Page 22 FOCUS Kinetics training workshop Conclusions – Example 3 Triggers flowchart Most appropriate kinetic model (SFO, FOMC, other):SFO Most appropriate endpoint values (days): DT 50 = 40.3 DT 90 = 134 Modelling flowchart Most appropriate kinetic model (SFO, FOMC, other): SFO Most appropriate endpoint values (days): DT 50 = 40.3

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