# Evaluation of NAFTA Kinetics Guidance

Russell L Jones 1



### , Jane Tang 1



### , Michael Huang 2



### , Wenlin Chen 3 

### , Richard Allen 4 

### , Sue Hayes 3



### , Robin Sur 1

1 Bayer CropScience

2 DuPont

3 Syngenta

4 Valent
**Exposure Modeling Public Meeting March 24, 2014** 

# Introduction

• The rates at which parent and metabolites degrade are important input parameters to exp o sure models used in regulatory risk assessments

• For many assessments (for example, potential movement to ground water) the predicted concentrations are sensitive to the choice of degradation rates.

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# Introduction

• Most regulatory models use first order kinetics

 However, degradation of parent and metabolites is often not adequately described by first order kinetics

 Therefore an appropriate first

- order degradation rate must be derived from non

- first order data



## • Therefore, to obtain consistency in performing risk assessments, consistency is needed in determining degradation rates from kinetic analyses

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# Introduction

• Two kinetics analysis approaches are currently used by regulatory agencies

 EU guidance document (2006) developed by FOCUS

 NAFTA Guidance Document, (2012) developed by NAFTA Technical Working Group on Pesticides



## • Kinetic analysis tools were also developed to implement the respective guidance

 EU

- KinGUI (other models also acceptable)

 NAFTA

- PESTDF

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# Introduction

• CropLife America established a work group to evaluate the NAFTA kinetics guidance and the associated tool PESTDF

 Evaluate appropriateness of the approach and assumptions

 Compare results obtained by PESTDF and the FOCUS guidance

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# Definitions

• DT50

 Time between application and when 50% of the originally applied material has degraded



## • DT90

 Time between application and when 90 % of the originally applied material has degraded



## • Half

- life

 Time required for half the material to degrade

 The half

- life is constant as a function of time only when degradation follows first order kinetics

 The half

- life is equal to the DT50 only when degradation follows first order kinetics

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# Kinetic Models

7 

### Model Mathematical Equations Guidance

SFO (Single First

- Order) EU

- FOCUS NAFTA

FOMC (First

- Order Multiple

Compartment) EU

- FOCUS

DFOP (Double First

- Order in Parallel) EU

- FOCUS NAFTA

HS (Hockey

- Stick) EU

- FOCUS

IORE (Indeterminate Order Rate Equation/n th order rate equation) NAFTA Equivalent to FOMC n

# Note on the DFOP Kinetic Model

• Use of DFOP kinetics in exposure models

 While exp o sure models require SFO, kinetics, DFOP kinetics can be simulated in most models by using two compounds
 One compound is assigned the fast phase degradation rate and the other the slow phase degradation rate  Slight inconsistency when the Freundlich isotherm is used to model sorption

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# NAFTA Guidance

9 Source: http ://www.epa.gov/oppefed1/ecorisk_ders/degradation _kinetics/NAFTA_Degradation_Kinetics.htm H alf

- life of a SFO model that passes through a hypothetical DT90 of the IORE fit 

## * * Acceptability criteria

• t est if n =1 of IORE by
F

- test at 50% level

# Differences in NAFTA and FOCUS

• Acceptability criteria for first order kinetics

 Difference of most practical significance

 The NAFTA acceptance criteria are more strict



## • Procedures when DT90 not reached

 While procedures are different the end result is often the same



## • Use of IORE rather than FOMC

 Mathematically equivalent expressions but this difference influences the acceptability criteria

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# Comparison Simulations

• Twenty data sets were used for the evaluations

 All the data sets were taken from EU approved registration documents, indicating that the kinetic endpoints derived were accepted by the EU



## • Based on the FOCUS approach:

 11 data sets fit SFO

 6 data sets fit DFOP

 3 data sets fit FOMC

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# Endpoint Comparison for SFO Fits by FOCUS

12 Data Set FOCUS NAFTA

Half

- life Model Half

- life Model

#1 60 SFO 94 DFOP (slow phase)

#2 39 SFO 53 IORE t R #3 55 SFO 102 IORE t R #4 211 SFO 282 DFOP (slow phase)

#5 232 SFO 1,070 DFOP (slow phase)

#6 62 SFO 97 IORE t R #7 66 SFO 94 DFOP (slow phase)

#8 41 SFO 74 IORE t R #9 43 SFO 87 IORE t R #10 2.9 SFO 2.5 IORE t R #11 2.2 SFO 2.2 SFO

# Endpoint Comparison for SFO Fits by FOCUS

• In 10 out of 11 cases, PESTDF chose IORE or DFOP kinetics when FOCUS guidance indicated SFO kinetics provided an adequate fit of the data

 In 9 of these 10 cases, the representative half

- life chosen by PESTDF was significantly longer than obtained with FOCUS kinetics

 Up to a factor of four



###  Especially problematic for laboratory studies where microbes can slow with time due to removal from their natural environment

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# Example

- PESTDF

14 

## Data set #11

 SFO is the best fit based on both guidance, therefore, the half

- life is the same

# Example

- PESTDF

15 

### Data set #3

SFO is not a best fit statistically, but appears to adequately describe the main portion of the degradation

# Example

- PESTDF

16



### Data set #5

 SFO and IORE/DFOP kinetics describe the observed degradation quite similarly  However, the half

- life from IORE is 4 times higher than SFO
 The parameters describing DFOP have wide confidence intervals

# Endpoint Comparison from Different Tools

17 Tools SFO DFOP IORE

t 1/2 (d) Overall
DT 90 (d) Slow

- phase (k 2 )
t 1/2 (d) Overall
DT 90 (d) t R , IORE (d)

KinGUII 228 779 238

- -

Model Maker

- 778 238 2,503 754

NAFTA 228 2,931 1,070 5,397 1,620 

### Data set #5

 Half

- lives for SFO fits are comparable
 Endpoints for DFOP fits derived from KinGUII and ModelMaker are comparable, and are 4 times shorter than those from NAFTA  Endpoints for IORE fits derived from ModelMaker were significant different than those from NAFTA

# Endpoint Comparison for FOMC Fits by FOCUS

18 Data Set FOCUS NAFTA
Endpoint Model Endpoint Model

#12 57 FOMC 46 DFOP (slow phase)

#13 30 FOMC 30 IORE t R #14 65 FOMC 58 DFOP (slow phase)


##  Data sets described by FOCUS guidance with FOMC kinetics are described with DFOP or IORE kinetics based on the NAFTA guidance

 The derived half

- lives are comparable when IORE t R , IORE 

## was used, and slightly shorter when the slow phase of DFOP is selected based on the NAFTA guidance

# Endpoint Comparison for DFOP Fits by FOCUS

19 Data Set FOCUS NAFTA FOCUS/NAFTA Model

#15 158 160 DFOP (slow phase)

#16 169 170 DFOP (slow phase)

#17 210 210 DFOP (slow phase)

#18 142 143 DFOP (slow phase)

#19 90 91 DFOP (slow phase)

#20 434 434 DFOP (slow phase)



##  Data sets are described by DFOP using both FOCUS and NAFTA guidance ; therefore the derived half

- lives are comparable

# Conclusions

• The most significant difference between FOCUS and NAFTA kinetic guidance is the criteria for acceptability of SFO fits

 The NAFTA criteria for acceptability of SFO fits is more strict, resulting in longer half

- lives when the data is described by IORE and DFOP kinetics

 These longer half

- lives are made even longer when NAFTA specifies the degradation rate to be the upper bound of the 90 th percentile confidence interval compared to the mean value specified in the FOCUS guidance

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# Conclusions

• For data sets described by DFOP or FOMC according to FOCUS guidance, similar half

lives are obtained with FOCUS and NAFTA guidance

• In one of the test cases, PESTDF did not reach an optimum solution

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# Recommendations

• When SFO kinetics provides an adequate fit of the data, its use should be considered, even if an improved fit is obtained with other types of kinetics

 In laboratory experiments, degradation rates often slow down near the end due to decreased bio

availability and slow down of microbial activity, which would not be representative of behavior under field conditions



## • Perform model/parameter significance test to reject/accept non

- first order, and avoid endpoints determined from a model fit with broad confidence intervals

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# Recommendations

• Options to include non

- first order degradation patterns should be considered in NAFTA refined exposure assessments

 Modeling non

- first order degradation using DFOP
 Modeling fast and slow degradation rates as two different compounds each with SFO kinetics



###  Non

- first order degradation resulting from time

dependent sorption

 When data is available for individual metabolites, non

first order degradation patterns in TTR (total toxic residue) simulations can often be more appropriately addressed by using a formation

- decline approach

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