OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

RE : Teleconference between Dow AgroScience s (DAS) and EPA to Discuss EPA’s Feedback on the Oxon Portion of the March 19, 2013 PBPK Meeting

List of Documents

1. Meeting Summary Page 1 2. Meeting Attendees Page 1 3. DAS Talking Points for the Meeting Page 2

1. Meeting Summary

On Thursday, May 2 , 201 3 , EPA’s Office of Pesticide Programs met with Dow AgroSciences (DAS) via teleconference to discuss the feedback EPA had given DAS concerning the oxon portion of the March 19, 2013 meetin g that EPA and DAS had

.

2. Meeting Attendees

DAS attendees Darin Lickfeldt, Dow Mike Bartells, Dow Daland Juberg , Dow Ian vanWesenbeeck, Dow Sue Marty , Dow Jon Hotch k iss , Dow

EPA attendees Jeff Dawson, HED Wade Britton, HED Rochelle Bohaty, EFED Charle s (Chuck) Peck, EFED Tom Myers, PRD Joel Wolf, PRD

# PBPK MODEL DISCUSSION

Michael Bartels May 2, 2013| 2 

## • With regards to the PBPK modeling

• Using the model, what doses of both the oxon and chlorpyrifos would be predicted to produce 10% inhibition in brain? In RBC? In diaphragm?

• The model (Timchalk et al 2002) does include diaphragm as a separate compartment with ChE inhibition, does Dow’s current model
still include that?

• Concerning model outputs, it seems like a table of predictions for differing levels of ChE inhibition, from both chlorpyrifos and oxon, in brain, RBC, and diaphragm would be very helpful? 

# EPA Questions of May 2, 2013| 3 

## • With regards to the PBPK modeling

• Using the model, what doses of both the oxon and chlorpyrifos would be predicted to produce 10% inhibition in brain? In RBC? In diaphragm?

- Values have been calculated for chlorpyrifos. Also for for oxon, up to maximum predicted levels in drinking water. Oxon doses predicted to cause 10% inhibition can be calculated within 2
weeks.

• The model (Timchalk et al 2002) does include diaphragm as a separate compartment with ChE inhibition, does Dow’s current model
still include that?

• Concerning model outputs, it seems like a table of predictions for differing levels of ChE inhibition, from both chlorpyrifos and oxon, in brain, RBC, and diaphragm would be very helpful? 

# Questions| 4 

## CPF

CPO 

# RBC Brain • Predictions of blood metabolites from a single oral dose of CPF

(3.5 ng /g)

(3.5 pg/g)

DAS Presentation at April 2012 SAP| 5 

## • With regards to the PBPK modeling

• Using the model, what doses of both the oxon and chlorpyrifos would be predicted to produce 10% inhibition in brain? In RBC? In diaphragm?

• The model (Timchalk et al 2002) does include diaphragm as a separate compartment with ChE inhibition, does Dow’s current model
still include that?

- Yes

• Concerning model outputs, it seems like a table of predictions for differing levels of ChE inhibition, from both chlorpyrifos and oxon, in brain, RBC, and diaphragm would be very helpful? 

# Questions| 6 Poet 2013 (MRID 49074901) 

# • Current PBPK/PD model design| 7 

## • With regards to the PBPK modeling

• Using the model, what doses of both the oxon and chlorpyrifos would be predicted to produce 10% inhibition in brain? In RBC? In diaphragm?

• The model (Timchalk et al 2002) does include diaphragm as a separate compartment with ChE inhibition, does Dow’s current model
still include that?

• Concerning model outputs, it seems like a table of predictions for differing levels of ChE inhibition, from both chlorpyrifos and oxon, in brain, RBC, and diaphragm would be very helpful? 

# Questions| 8 

## • With regards to the PBPK modeling

• Using the model, what doses of both the oxon and chlorpyrifos would be predicted to produce 10% inhibition in brain? In RBC? In diaphragm?

• The model (Timchalk et al 2002) does include diaphragm as a separate compartment with ChE inhibition, does Dow’s current model
still include that?

• Concerning model outputs, it seems like a table of predictions for differing levels of ChE inhibition, from both chlorpyrifos and oxon, in brain, RBC, and diaphragm would be very helpful?

- DAS agrees. Predictions of ChE inhibition in RBC and brain, from both chlorpyrifos and oxon in drinking water have been included in the recent Oxon PBPK model report (MRID 49047701). 

# Questions| 9 Poet 2013 (MRID 49047701) 

# • Predictions of ChE inhibition, as percent of control values, in human RBC and Brain tissue following repeated oral exposures to Oxon or Chlorpyrifos for 21 days. Doses are administered 3x/day.| 10 Lessire

, ToxApplPharm 138: 201

- 210, 1996 

## • Relationship between the guinea pig lung cholinesterase activity measured after 18 min of perfusion with paraoxon (A), parathion (B), parathion plus piperonyl butoxide . Data are expressed as percentage of the initial cholinesterase activity measured at zero time.



# Paraoxon

Parathion

Parathion + CYP inhibitor Data show comparable response in lung tissue from Parent OP and Oxon metabolite| 11 Hotchkiss 2013 (MRID pending) 

## • Summary of blood levels of chlorpyrifos and oxon and maximum % ChE inhibition (relative to the individual time

- matched point control levels) in RBC, plasma, lung and brain tissues of rats nose

- only exposed 6 hours to a near saturated chlorpyrifos vapors (0.254 mg/m 3 

## ) or to solid particulate aerosolized chlorpyrifos aerosols (3.7, 12.9, 22.1, or 53.5 mg/m 3 

## ).