UNITED STATES ENVIRONMENT AL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

Aaron Colangelo, Esq. 

Senior Attorney 

Natural Resources Defense Council 

1152 15th Street NW, Suite 300 

Washington, D.C. 20005 

Margaret Reeves, Ph.D. 

MAR 2 6 2015 

Senior Scientist/Program Coordinator (Environmental Health and Worker:s' Rights) 

Pesticide Action Network North America 

49 Powell Street, Suite 500 

San Francisco, CA 94102 

Re: Chlorpyrifos Petition Dated September 12, 2007; March 2015 Provisional Response 

Dear Mr. Colangelo and Dr. Reeves: 

This letter constitutes the U.S. Environmental Protection Agency's (EPA) provisional 

response to the Natural Resources Defense Council (NRDC) and Pesticide Action Network 

North America's (PANNA) jointly submitted September 12, 20071 petition. The petition 

specifically requested that EPA revoke all tolerances and cancel all registrations for the 

insecticide chlorpyrifos. This response incorporates EPA's two partial responses of July 16, 

20122

, and July 15, 20143

, and describes EPA's provisional approach for addressing the three 

remaining claims in the petition. It also outlines the activities EPA expects to undertake to 

address the concerns identified in the Revised Human Health Risk Assessment (RHHRA)4 . 

As you are aware, while EPA has addressed seven of the ten claims raised in your 

petition through our July 16, 2012 and July 15, 2014 partial petition responses, we determined 

that additional analyses were necessary to complete our response to your three interrelated 

claims 'regarding chlorpyrifos toxicology and that it would be appropriate to address those claims 

in the same time frame as the RHHRA for registration review. Specifically, the three remaining 

claims you raised in your petition were: ( 1) EPA failed to incorporate into its risk assessment, in 

a quantitative manner, data indicating that long-lasting effects in children result from early life 

1 Available at http://www.regulations.gov/#!documentDetail;D=EPA-HO-OPP-2007-I 005-0005. 2 Available at http;//www.regulations.gov/#!documentDetail;D=EPA-HQ-QPP-2007-I 005-0095. 3 Available at http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2007- I 005-0098. 4 Available at http://www.regulations.gov/# !documentDetail;D=EPA-HQ-OPP-2008-0850-0195. 

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exposure to chlorpyrifos; (2) EPA disregarded data demonstrating that there is no evidence of a 

safe level of exposure during pre-birth and early life stages; and (3) EPA failed to cite or 

quantitatively incorporate studies and clinical reports suggesting potential adverse effects below 

10% cholinesterase inhibition. 

On December 31, 2014, EPA made the RHHRA available for public review and on 

January 14, 2015, EPA issued a Federal Register Notice5 opening the public comment period for 

the RHHRA. In sum, the RHHRA shows some risks to workers who mix, load, and apply 

chlorpyrifos pesticide products. The assessment also shows potential risks of concern in limited 

geographic areas from drinking water in smaJJ watersheds. There were no additional risks of 

concern from pesticide exposures in food or exposures to bystanders and workers from airborne 

chlorpyrifos. This RHHRA is also among the first ·assessments informed by a physiologically 

based pharmacokinetic and pharmacodynamic (PBPK/PD) model. EPA is now taking comment 

on the assessment and will consider the comments received and determine whether additional 

refinements are necessary in light of those comments. Because we are taking comment on the 

RHHRA, this document constitutes our provisional response to your petition. We intend to 

finalize our response later this year following review and analysis of comments received on the 

RHHRA. 

The Three Remaining Petition Claims 

The RHHRA addresses the issues embodied in the three remaining petition claims as 

interrelated questions regarding the potential for neurodevelopmental effects to occur at levels 

lower than EPA's current regulatory point of departure - 10% acetyl cholinesterase (AChE) 

inhibition. Below summarizes our position as presented in the RHHRA, but please refer to the 

RHHRA 6 for the entire discussion. In short though, we do not believe that the claims raised in 

your petition establish a basis to revoke all chlorpyrifos tolerances and cancel all chlorpyrifos 

registrations. 

In the RHHRA we conducted a weight-of-evidence (WOE) analysis integrating recent 

epidemiology studies that involved chlorpyrifos exposures with chlorpyrifos experimental 

toxicology studies to evaluate the potential for adverse neurodevelopmental outcomes. The WOE 

was also informed by EPA' s use of a physiologically-based pharmacokinetic-pharmacodynamic 

(PBPK-PD) model recently completed by Dow AgroSciences, one of the chlorpyrifos registrants. 

Following EPA's quality assurance evaluation, we used the robust PBPK-PD model7 to estimate 

human equivalent doses/concentrations which were used as the toxicological points of departure 

(PoDs) and also to define inter- and intra-species factors for chlorpyrifos and/or its oxon 

specifically tailored to all applicable exposure pathways for chlorpyrifos (e.g. food, water, 

occupational, residential). 

5 Available at http: www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2008-0850-0200. 6 Available at http: www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2008-0850-0195. 

7 U.S. EPA 2011. FIFRA Science Advisory Panel Meeting Minutes - Chlorpyrifos Physiologically-Based 

Pharmacokinetic/Pharmacodynamic (PBPK/PD) Modeling linked to the Cumulative and Aggregate Risk Evaluation 

System (CARES). Available at http://www.epa.gov/scipoly/sap/meetings/2011 /021511 meeting.html. 

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The key issues considered in the WOE were whether chlorpyrifos causes long-term 

effects from prenatal and/or early lifestage exposure and whether these adverse effects can be 

attributed to doses lower than those which elicit 10% inhibition ofRBC AChE. When taken 

together, the evidence from (1) the experimental toxicology studies evaluating outcomes such as 

behavior and cognitive function; (2) mechanistic data on possible modes of action/ adverse 

outcome pathways (MOA/ AOP); and (3) epidemiologic and biomonitoring studies, indicate that 

chlorpyrifos likely played a role in the neurodevelopmental outcomes reported by the Columbia 

University epi<lemiologic study investigators. Uncertainties such as the lack of an established 

MOA/ AOP for neurodevelopmental effects, and the fact that the epidemiologic study cohorts 

were potentially exposed to multiple AChE-inhibiting pesticides precludes definitive causal 

inference and precludes the use of the epidemiologic studies in a quantitative risk assessment. 

However, as detailed in the RHHRA, EPA believes there is sufficient uncertainty in the human 

dose-response relationship for neurodevelopmental effects to preclude us from reducing or 

removing the statutory l OX Food Quality Protection Act (FQPA) safety factor. 

In addition, EPA believes the evidence is insufficient to suggest altering the use of 10% 

AChE inhibition as the point of departure. In 20088 and 20129 the Federal Insecticide, Fungicide, 

and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) recommended that AChE data 

provide the most appropriate endpoint and dose-response data for deriving PoDs for purposes of 

risk assessment. EPA agrees with the SAP's recommendation. While EPA believes that the 

epidemiologic data give rise to a measure of uncertainty regarding the relationship between 

AChE inhibition and certain adverse neurodevelopmental outcomes, many of the same factors 

that make these studies inappropriate for use in quantitative risk assessment also counsel against 

their use as a basis for departing from 10% AChE inhibition as a regulatory point of departure. 

Although EPA's dose reconstruction exercise certainly suggests that it is possible that the cohort 

members in the Columbia study did not experience cholinesterase inhibition, with no established 

MOA/ AOP for the observed neurodevelopmental effects, limited cohort exposure data, and 

possible additive effects from co-exposures to other AChE inhibiting compounds, there are 

simply too many uncertainties surrounding the neurodevelopmental data for EPA to conclude 

that our use of 10% AChE inhibition is no longer appropriate. Accordingly, as provided in the 

RHHRA, EPA has retained AChE inhibition as the regulatory point of departure. 

Provisional EPA Response 

For the reasons explained above, and as outlined in our two partial responses, EPA does 

not believe the claims raised in your petition establish a basis to revoke all chlorpyrifos 

tolerances and cancel all chlorpyrifos registrations. 

As set forth in the RHHRA, however, EPA has risk concerns stemming from routes of 

human exposure not addressed in your petition, specifically from estimated drinking water 

exposure and risks to workers (i.e., mixers, loaders, and applicators). We are currently taking 

public comment on the RHHRA. Assuming that we do not receive any comments that persuade 

8 U.S. EPA 2008. FlFRA Science Advisory Panel Meeting Minutes -The Agency's Evaluation of the Toxicity 

Profile of Chlorpyrifos. Available at http: www.epa.gov/scipoly1sap/meetings'2008/september/sap0908reoort.pdf. 

9 U.S. EPA 2012. FIFRA Science Advisory Panel Meeting Minutes - Scientific Issues Concerning Health Effects of 

Chlorpyrifos. Available at http://www.epa.gov/scipoly/sap/meetings/20 I 2/april/0410 I 2minutes.pdf. 

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us that exposures are acceptable, we intend to seek any necessary labeling changes to currentlyregistered chlorpyrifos products to ensure that the continued use of chlorpyrifos is consistent 

with FIFRA and FFDCA standards. Indeed, EPA has already begun discussions with the 

chlorpyrifos registrants regarding mitigation of worker risk. 

In addition, over the coming months EPA will be working to refine the drinking water 

assessment (DW A). The DWA component of the RHHRA contained a national level screen, as 

well as a regional screen for two areas, the Pacific Northwest and the South Atlantic-Gulf. The 

regional level methodology, which involves using a drinking water intake watershed approach 

that accounts for geospatial differences and regional percent cropped area (PCA), will be 

expanded to encompass the remaining regions of the country. The refined DWA will also be 

informed by any mitigation addressing worker risks. 

While we agree with petitioners that some action should be taken to mitigate the risks of 

chlorpyrifos, we do not believe that either revoking all tolerances or canceling all chlorpyrifos 

products, the remedies sought in your petition, will ultimately be necessary to appropriately 

mitigate these risks concerns. We believe these risks likely can be mitigated by appropriate 

changes to the FIFRA label. Accordingly, should our position on the risks from chlorpyrifos 

exposure and any necessary mitigation remain unchanged following our review of comments on 

the RHHRA, we intend to formally deny your petition to revoke all tolerances and cancel all 

registrations. However, should we be unable to work successfully with the chlorpyrifos 

registrants to achieve necessary label mitigation, we will take appropriate action under the 

FFDCA and/or FIFRA to ensure that exposures to chlorpyrifos are consistent with the 

requirements of those statutes. 

While EPA intends to work expeditiously to review the comments and complete any 

necessary revisions to its regulatory position, EPA cannot at this point provide assurance that we 

will complete the final response by the summer of this year as previously estimated, but we are 

continuing to work with that goal in mind and will be happy to provide you with updates on our 

progress. 

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