Vol. 80 Friday, 

No. 215 November 6, 2015 

Part IV 

Environmental Protection Agency 

40 CFR Part 180 

Chlorpyrifos; Tolerance Revocations; Proposed Rule 

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ENVIRONMENTAL PROTECTION 

AGENCY 

40 CFR Part 180 

[EPA–HQ–OPP–2015–0653; FRL–9935–92] 

Chlorpyrifos; Tolerance Revocations 

AGENCY: Environmental Protection 

Agency (EPA). 

ACTION: Proposed rule. 

SUMMARY: On August 10, 2015, the U.S. 

Court of Appeals for the Ninth Circuit 

ordered EPA to respond to an 

administrative Petition to revoke all 

tolerances for the insecticide 

chlorpyrifos by October 31, 2015, by 

either denying the Petition or issuing a 

proposed or final tolerance revocation. 

At this time, the agency is unable to 

conclude that the risk from aggregate 

exposure from the use of chlorpyrifos 

meets the safety standard of section 

408(b)(2) of the Federal Food, Drug, and 

Cosmetic Act (FFDCA). Accordingly, 

EPA is proposing to revoke all 

tolerances for chlorpyrifos. EPA is 

specifically soliciting comment on 

whether there is an interest in retaining 

any individual tolerances, or group of 

tolerances, and whether information 

exists to demonstrate that such 

tolerance(s) meet(s) the FFDCA section 

408(b) safety standard. EPA encourages 

interested parties to comment on the 

tolerance revocations proposed in this 

document and on the proposed time 

frame for tolerance revocation. Issues 

not raised during the comment period 

may not be raised as objections to the 

final rule, or in any other challenge to 

the final rule. 

DATES: Comments must be received on 

or before January 5, 2016. 

ADDRESSES: Submit your comments, 

identified by docket identification (ID) 

number EPA–HQ–OPP–2015–0653 by 

one of the following methods: 

• Federal eRulemaking Portal: http:// 

www.regulations.gov. Follow the online 

instructions for submitting comments. 

Do not submit electronically any 

information you consider to be 

Confidential Business Information (CBI) 

or other information whose disclosure is 

restricted by statute. 

• Mail: OPP Docket, Environmental 

Protection Agency Docket Center (EPA/ 

DC), (28221T), 1200 Pennsylvania Ave. 

NW., Washington, DC 20460–0001. 

• Hand Delivery: To make special 

arrangements for hand delivery or 

delivery of boxed information, please 

follow the instructions at http://www.

epa.gov/dockets/contacts.html. 

Additional instructions on 

commenting or visiting the docket, 

along with more information about 

dockets generally, is available at http:// 

www.epa.gov/dockets. 

FOR FURTHER INFORMATION CONTACT: 

Dana Friedman, Pesticide Re-Evaluation 

Division (7508P), Office of Pesticide 

Programs, Environmental Protection 

Agency, 1200 Pennsylvania Ave NW., 

Washington, DC 20460–0001; telephone 

number: (703) 347–8827; email address: 

friedman.dana@epa.gov. 

SUPPLEMENTARY INFORMATION: 

I. General Information 

A. Does this action apply to me? 

You may be potentially affected by 

this action if you are an agricultural 

producer, food manufacturer, or 

pesticide manufacturer. The following 

list of North American Industrial 

Classification System (NAICS) codes is 

not intended to be exhaustive, but rather 

provides a guide to help readers 

determine whether this document 

applies to them. Potentially affected 

entities may include: 

• Crop production (NAICS code 111). 

• Animal production (NAICS code 

112). 

• Food manufacturing (NAICS code 

311). 

• Pesticide manufacturing (NAICS 

code 32532). 

B. What should I consider as I prepare 

my comments for EPA? 

1. Submitting CBI. Do not submit this 

information to EPA through 

regulations.gov or email. Clearly mark 

the part or all of the information that 

you claim to be CBI. For CBI 

information in a disk or CD–ROM that 

you mail to EPA, mark the outside of the 

disk or CD–ROM as CBI and then 

identify electronically within the disk or 

CD–ROM the specific information that 

is claimed as CBI. In addition to one 

complete version of the comment that 

includes information claimed as CBI, a 

copy of the comment that does not 

contain the information claimed as CBI 

must be submitted for inclusion in the 

public docket. Information so marked 

will not be disclosed except in 

accordance with procedures set forth in 

40 CFR part 2. 

2. Tips for preparing your comments. 

When preparing and submitting your 

comments, see the commenting tips at 

http://www.epa.gov/dockets/

comments.html. 

C. What can I do if I wish the Agency 

to maintain a tolerance that the Agency 

proposes to revoke? 

This proposed rule provides a 

comment period of 60 days for any 

interested person to submit comments 

on the agency’s proposal. EPA will issue 

a final rule after considering the 

comments that are submitted. 

Comments should be limited only to the 

pesticide and tolerances subject to this 

proposal. 

EPA’s finding that it cannot determine 

if aggregate exposure from all existing 

uses of chlorpyrifos are safe, does not 

necessarily mean that no individual 

tolerance or group of tolerances could 

meet the FFDCA 408(b)(2) safety 

standard and be maintained. EPA’s risk 

assessment supporting this proposed 

rule indicates that the primary source of 

risk comes from chlorpyrifos and 

chlorpyrifos oxon in drinking water in 

highly vulnerable watersheds (generally 

small watersheds where the land is 

agricultural and could be treated with 

chlorpyrifos (i.e., heavily cropped 

areas)). However, as explained in this 

proposed rule, some uses of chlorpyrifos 

do not by themselves present risks of 

concern from either food or drinking 

water and are only a concern when 

aggregated with all exposures to 

chlorpyrifos. EPA therefore invites 

comments that address whether some 

tolerances or groups of tolerances can be 

retained. In that regard, in addition to 

information related to the safety of such 

tolerances, use site specific information 

pertaining to the pests targeted by 

chlorpyrifos, and the alternatives to 

chlorpyrifos for these pests, may help to 

inform the agency’s final decision if 

EPA is able to conclude that some 

tolerances may be retained under the 

FFDCA safety standard. In addition, if 

EPA receives information that would 

allow it to better refine the location of 

at risk watersheds and protect such 

watersheds through appropriate product 

labeling restrictions, it is possible EPA 

could conclude that such mitigation 

would eliminate the need for some or all 

of the proposed tolerance revocations. It 

is important to stress, however, that 

because the FFDCA is a safety standard, 

EPA can only retain chlorpyrifos 

tolerances if it is able to conclude that 

such tolerances are safe. 

After consideration of comments, EPA 

will issue a final regulation determining 

whether revocation of some or all of the 

tolerances is appropriate under section 

408(b)(2). Such regulation will be 

subject to objections pursuant to section 

408(g) (21 U.S.C. 346a(g)) and 40 CFR 

part 178. 

In addition to submitting comments 

in response to this proposal, you may 

also submit an objection at the time of 

the final rule. If you anticipate that you 

may wish to file objections to the final 

rule, you must raise those issues in your 

comments on this proposal. EPA 

received numerous comments on its 

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December 2014 Revised Human Health 

Risk Assessment (RHHRA) (Ref. 1) 

related to the scientific bases underlying 

this proposed rule. In light of the U.S 

Court of Appeals for the Ninth Circuit’s 

August 10, 2015 order in Pesticide 

Action Network North America 

(PANNA) v. EPA, No. 14–72794 

(PANNA), compelling EPA to take this 

action by October 31, 2015, EPA has not 

addressed these prior comments in this 

proposed rule. Persons wishing to have 

EPA consider previously submitted 

comments on the RHHRA in connection 

with this proposal should submit a 

comment indicating that intention and 

identifying their earlier comments on 

the RHHRA. EPA will treat as waived 

any issue not raised or referenced in 

comments submitted on this proposal. 

Similarly, if you fail to file an objection 

to the final rule within the time period 

specified, you will have waived the 

right to raise any issues resolved in the 

final rule. After the specified time, 

issues resolved in the final rule cannot 

be raised again in any subsequent 

proceedings on this rule making. 

II. Background 

A. What action is the Agency taking? 

EPA is proposing to revoke all 

tolerances for residues of the insecticide 

chlorpyrifos as contained in 40 CFR 

180.342. This includes tolerances for 

residues of chlorpyrifos on specific food 

commodities (180.342(a)(1)); on all food 

commodities treated in food handling 

and food service establishments in 

accordance with prescribed conditions 

(180.342(a)(2) and(a)(3)); and on specific 

commodities when used under regional 

registrations (180.342(c)). 

The agency is proposing to revoke all 

of these tolerances because EPA cannot, 

at this time, determine that aggregate 

exposure to residues of chlorpyrifos, 

including all anticipated dietary 

exposures and all other nonoccupational exposures for which there 

is reliable information, are safe. 

EPA’s full risk conclusions supporting 

this proposal are set forth in the 2014 

RHHRA for chlorpyrifos that EPA issued 

for public comment. That document, 

supporting materials, and the public 

comments on those documents are 

available in the chlorpyrifos registration 

review docket, EPA–HQ–OPP–2008– 

0850. While EPA’s assessment indicates 

that contributions to dietary exposures 

to chlorpyrifos from food and 

residential exposures are safe, when 

those exposures are combined with 

estimated exposures from drinking 

water, as required by the FFDCA, EPA 

has determined that safe levels of 

chlorpyrifos in the diet may be 

exceeded for people whose drinking 

water is derived from certain vulnerable 

watersheds throughout the United 

States. This primarily includes those 

populations consuming drinking water 

from small water systems in heavily 

cropped areas where chlorpyrifos may 

be used widely. 

B. What is the Agency's authority for 

taking this action? 

EPA is taking this action, pursuant to 

the authority in FFDCA sections 

408(b)(1)(A), 408(b)(2)(A), and 

408(d)(4)(A)(ii). 21 U.S.C. 346a(b)(1)(A), 

(b)(2)(A), (d)(4)(A)(ii). 

III. Statutory and Regulatory 

Background 

A ‘‘tolerance’’ represents the 

maximum level for residues of pesticide 

chemicals legally allowed in or on raw 

agricultural commodities and processed 

foods. Section 408 of FFDCA, 21 U.S.C. 

346a, authorizes the establishment of 

tolerances, exemptions from tolerance 

requirements, modifications of 

tolerances, and revocation of tolerances 

for residues of pesticide chemicals in or 

on raw agricultural commodities and 

processed foods. Without a tolerance or 

exemption, food containing pesticide 

residues is considered to be unsafe and 

therefore ‘‘adulterated’’ under FFDCA 

section 402(a), 21 U.S.C. 342(a). Such 

food may not be distributed in interstate 

commerce, 21 U.S.C. 331(a). For a fooduse pesticide to be sold and distributed, 

the pesticide must not only have 

appropriate tolerances under the 

FFDCA, but also must be registered 

under FIFRA, 7 U.S.C. 136a(a); 40 CFR 

152.112(g). Food-use pesticides not 

registered in the United States must 

have tolerances in order for 

commodities treated with those 

pesticides to be imported into the 

United States. 

Section 408(d) of the FFDCA, 21 

U.S.C. 346a(d), authorizes EPA to 

revoke tolerances in response to 

administrative petitions submitted by 

any person. Because EPA is unable to 

determine at this time that aggregate 

exposures to chlorpyrifos are safe, EPA 

is proposing to revoke these tolerances 

in response to a Petition from PANNA 

and the Natural Resources Defense 

Council (NRDC) to revoke all 

chlorpyrifos tolerances (Ref. 2). The 

timing of this proposal is the result of 

the August 10, 2015 order in the 

PANNA decision to respond to that 

petition by October 31, 2015. This 

proposal also implements the agency 

findings made during the registration 

review process required by section 3(g) 

of FIFRA (7 U.S.C. 136(a)(g)) which EPA 

is conducting in parallel with its 

petition response. That process requires 

EPA to re-evaluate existing pesticides 

every 15 years to determine whether 

such pesticides meet the FIFRA 

registration standard set forth in FIFRA 

section 3(c)(5), 7 U.S.C. 136a(c)(5). In 

part, that standard requires EPA to 

ensure that dietary risks from the 

pesticide meet the FFDCA section 408 

safety standard. Section 408 directs that 

EPA may establish or leave in effect a 

tolerance for pesticide only if it finds 

that the tolerance is safe, and EPA must 

revoke or modify tolerances determined 

to be unsafe. FFDCA 408(b)(2)(A)(i) (21 

U.S.C. 346a(b)(2)(A)(i)). Section 

408(b)(2)(A)(ii) defines ‘‘safe’’ to mean 

that ‘‘there is a reasonable certainty that 

no harm will result from aggregate 

exposure to the pesticide chemical 

residue, including all anticipated 

dietary exposures and all other 

exposures for which there is reliable 

information.’’ This includes exposure 

through drinking water and all nonoccupational exposures (e.g. in 

residential settings), but does not 

include occupational exposures to 

workers (i.e., occupational). 

Risks to infants and children are given 

special consideration. Specifically, 

pursuant to section 408(b)(2)(C), EPA 

must assess the risk of the pesticide 

chemical based on available information 

concerning the special susceptibility of 

infants and children to the pesticide 

chemical residues, including 

neurological differences between infants 

and children and adults, and effects of 

in utero exposure to pesticide 

chemicals; and available information 

concerning the cumulative effects on 

infants and children of such residues 

and other substances that have a 

common mechanism of toxicity. 

(21 U.S.C. 346a(b)(2)(C)(i)(II) and 

(III)). 

This provision further directs that ‘‘in 

the case of threshold effects, . . . an 

additional tenfold margin of safety for 

the pesticide chemical residue and other 

sources of exposure shall be applied for 

infants and children to take into account 

potential pre- and post-natal toxicity 

and completeness of the data with 

respect to exposure and toxicity to 

infants and children.’’ (21 U.S.C. 

346a(b)(2)(C)). EPA is permitted to ‘‘use 

a different margin of safety for the 

pesticide chemical residue only if, on 

the basis of reliable data, such margin 

will be safe for infants and children.’’ 

(21 U.S.C. 346a(b)(2)(C)). Due to 

Congress’s focus on both pre- and postnatal toxicity, EPA has interpreted this 

additional safety factor as pertaining to 

risks to infants and children that arise 

due to pre-natal exposure as well as to 

exposure during childhood years. For 

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convenience sake, the legal 

requirements regarding the additional 

safety margin for infants and children in 

section 408(b)(2)(C) are referred to 

throughout this proposed rule as the 

‘‘FQPA safety factor for the protection of 

infants and children’’ or simply the 

‘‘FQPA safety factor.’’ 

IV. Chlorpyrifos Background, 

Regulatory History, and Litigation 

Chlorpyrifos (0,0-diethyl-0-3,5,6- 

trichloro-2-pyridyl phosphorothioate) is 

a broad-spectrum, chlorinated 

organophosphate (OP) insecticide that 

has been registered for use in the United 

States since 1965. Currently registered 

use sites include a large variety of food 

crops (including fruit and nut trees, 

many types of fruits and vegetables, and 

grain crops), and non-food use settings 

(e.g., golf course turf, industrial sites, 

greenhouse and nursery production, sod 

farms, and wood products). Public 

health uses include aerial and groundbased fogger mosquito adulticide 

treatments, roach bait products and 

individual fire ant mound treatments. In 

2000, the chlorpyrifos registrants 

reached an agreement with EPA to 

voluntarily cancel all residential use 

products except those registered for ant 

and roach baits in child-resistant 

packaging and fire ant mound 

treatments. 

In 2006, EPA completed FIFRA 

section 4 reregistration and FFDCA 

tolerance reassessment for chlorpyrifos 

and the OP class of pesticides. Given 

ongoing scientific developments in the 

study of the OPs generally, EPA chose 

to prioritize the FIFRA section 3(g) 

registration review (the next round of reevaluation following reregistration) of 

chlorpyrifos and the OP class. The 

registration review of chlorpyrifos and 

the OPs has presented EPA with 

numerous novel scientific issues that 

have been the subject of multiple FIFRA 

Scientific Advisory Panel (SAP) 

meetings since the completion of 

reregistration that have resulted in 

significant developments in the conduct 

of EPA’s risk assessments generally, 

and, more specifically, in the study of 

chlorpyrifos’s effects. These SAP 

meetings included review of new 

worker and non-occupational exposure 

methods, experimental toxicology and 

epidemiology, risk assessment 

approaches for semi-volatile pesticides 

and the evaluation of a chlorpyrifosspecific pharmacokineticpharmacodynamic (PBPK–PD) model. 

A. Registration Review 

In 2011, in connection with FIFRA 

registration review, EPA issued its 

Preliminary Human Health Risk 

Assessment (PHHRA) (Ref. 3) for 

chlorpyrifos that evaluated exposures 

from food, drinking water, other nonoccupational sources, and occupational 

risk (such as risks to farmworkers 

applying chlorpyrifos and working in 

treated fields). At the time of the 

PHHRA, EPA had not yet performed an 

integrated weight of evidence analysis 

on the lines of evidence related to the 

potential for neurodevelopmental 

effects. The PHHRA indicated that for 

food alone, the acute and chronic 

dietary risk estimates for all populations 

assessed were below the level of 

concern. The residue of concern in 

treated drinking water is the 

chlorpyrifos oxon because chlorpyrifos 

transforms to the more toxic 

chlorpyrifos oxon in treated drinking 

water (e.g. chlorination). For drinking 

water alone, EPA had a concern for 

infant exposures to the chlorpyrifos 

oxon. 

In December 2014, EPA completed the 

RHHRA for registration review (Ref. 1). 

The RHHRA represents a highly 

sophisticated assessment of hazard and 

exposure to chlorpyrifos and its oxon. 

The dietary risk assessment in the 

RHHRA provides the scientific support 

for this proposed rule. The approach 

EPA used for the chlorpyrifos dietary 

assessment and for this proposed rule 

can be described as follows: EPA 

conducted dietary exposure modeling 

using the Dietary Exposure Evaluation 

Model (DEEM) and the Calendex models 

(Ref. 4) to develop a probabilistic 

evaluation of human dietary 

consumption. Most of the pesticide food 

residue values used in those models 

were based upon U.S. Department of 

Agriculture’s (USDA) Pesticide Data 

Program (PDP) monitoring data. Percent 

crop treated and empirical food 

processing factors were used where 

available. EPA then utilized a PBPK–PD 

model to calculate both acute (24 hour) 

and steady state (21 days (i.e., the 

approximate time to reach steady state 

for most OPs)) points of departure (PoD) 

dose levels that represent the minimum 

amount of chlorpyrifos that presents a 

risk concern. (OPs exhibit a 

phenomenon known as steady state 

AChE inhibition. After repeated dosing 

at the same dose level, the degree of 

inhibition comes into equilibrium with 

the production of new, uninhibited 

enzyme. OP AChE studies of 2–3 weeks 

generally show the same degree of 

inhibition as those of longer duration 

(i.e., up to 2 years of exposure). 

Therefore, a steady state assessment 

based on 21 days of exposure may be 

conducted in place of the traditional 

chronic assessment). 

For chlorpyrifos, the risk of concern is 

10% acetylcholinesterase inhibition 

(AChE) in red blood cells (RBC)—a 

precursor for adverse neurological 

symptoms—for both acute and steady 

state exposure durations. The PBPK–PD 

PoD predictions for each human 

lifestage exposure route and pathway 

were modeled separately (e.g., for 

residential exposure i.e. dermal, 

inhalation and incidental oral 

calculations). PoDs are divided by the 

total uncertainty factors (which are used 

to account for potential differences in 

sensitivities within populations or 

extrapolations from test results in 

animals to effects on humans) to derive 

a population adjusted dose (PAD). There 

are potential risks of concern when the 

estimated dietary exposures exceed 

100% of the PAD. For the food intake 

portion of the dietary assessment, the 

only potential residue of concern is 

chlorpyrifos (the oxon metabolite is not 

an expected residue on foods). EPA 

incorporated total uncertainty factors of 

100X for adult females (a 10X FQPA 

safety factor and another 10X intraspecies extrapolation factor since the 

PBPK–PD model does not include a 

component that specifically models 

pregnant women) and 40X for the other 

relevant populations (a 10X FQPA 

safety factor and another 4X intraspecies data derived extrapolation 

factor) using the PBPK–PD model to 

account for potential metabolic and 

physiological differences between 

populations. The chlorpyrifos exposure 

values resulting from dietary modeling 

are then compared to the PAD to 

determine the portion of the ‘‘risk cup’’ 

that is taken up by exposures from food. 

In the case of chlorpyrifos, the RHHRA 

concluded that food and nonoccupational exposures by themselves 

take up only a small portion of the risk 

cup and are therefore not a risk concern 

when considered in isolation. 

For the drinking water portion of the 

dietary assessment, the chlorpyrifos 

oxon, which is more toxic than 

chlorpyrifos, is the residue of concern 

assumed to occur in drinking water. 

Based on available information 

regarding the potential effects of certain 

water treatments (e.g., chlorination 

appears to hasten transformation of 

chlorpyrifos to chlorpyrifos oxon), EPA 

believes it is appropriate to assume that 

all chlorpyrifos in water is converted to 

chlorpyrifos oxon upon treatment. The 

chlorpyrifos oxon total uncertainty 

factors are 100X for adult females (10X 

FQPA safety factor and 10X intraspecies extrapolation factor to account 

for potential differences between 

populations) and 50X for the other 

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relevant populations (10X FQPA safety 

factor and 5X intra-species data derived 

extrapolation factor) using the PBPK–PD 

model to account for potential metabolic 

and physiological differences between 

populations. See Unit VI.5 for how the 

intra-species factors for chlorpyrifos and 

chlorpyrifos oxon were derived. After 

considering food and residential 

contributions to the risk cup, EPA 

determined that drinking water 

concentrations to chlorpyrifos oxon 

greater than 3.9 ppb for a 21-day average 

would exceed EPA’s Drinking Water 

Level of Comparison (DWLOC) and 

present a risk of concern. EPA’s water 

exposure assessment indicated that 

multiple labeled use scenarios for 

chlorpyrifos exceed the DWLOC and 

therefore present a risk concern. On 

January 14 2015, EPA published a 

Federal Register Notice seeking public 

comment on the RHHRA. 

EPA’s drinking water analysis in the 

RHHRA also showed that the DWLOC 

exceedances are not expected to be 

uniformly distributed across the 

country. As a result, EPA began to 

conduct further analysis to look at the 

spatial distribution of Estimated 

Drinking Water Concentrations (EDWCs) 

at more refined geographic levels. This 

exercise demonstrated that chlorpyrifos 

applications will result in variable 

drinking water exposures that are highly 

localized and that the highest exposures 

generally occur in small watersheds 

where there is a high percent cropped 

area on which chlorpyrifos use could 

occur. Accordingly, following the 

development of the RHHRA in 

December 2014, EPA has continued 

working to develop a more refined 

assessment to examine EDWCs on a 

regional and/or watershed scale to 

pinpoint community drinking water 

systems where exposure to chlorpyrifos 

oxon as a result of chlorpyrifos 

applications may pose an exposure 

concern. At this time this more refined 

drinking water assessment that will 

allow EPA to better identify where atrisk watersheds are located throughout 

the country is not completed. Thus, we 

are not currently able to determine with 

any great specificity which uses in 

which areas of the country do or do not 

present a risk concern. EPA intends to 

update this action, as warranted, with 

any significant refinements to its 

drinking water assessment, and intends, 

to the extent practicable, to provide the 

public an opportunity to comment on 

the refined drinking water assessment 

prior to a final rule. 

B. PANNA±NRDC Petition and 

Associated Litigation 

In September 2007, PANNA and 

NRDC submitted to EPA a Petition 

seeking revocation of all chlorpyrifos 

tolerances and cancellation of all FIFRA 

registrations of products containing 

chlorpyrifos. In connection with both 

EPA’s response to the Petition and the 

FIFRA registration review of 

chlorpyrifos, EPA has taken most of the 

complex and novel science questions 

raised in the Petition to the SAP for 

review and EPA has developed 

numerous new methodologies 

(including approaches to address 

pesticide drift, volatility, and the 

integration of experimental toxicology 

and epidemiology) to consider these 

issues. 

While EPA agreed that these new 

methodologies were necessary to 

properly evaluate PANNA and NRDC’s 

(Petitioners’) claims, Petitioners have 

been dissatisfied with the pace of EPA’s 

response efforts and have sued EPA in 

federal court on three separate occasions 

to compel a prompt response to the 

Petition. Although EPA has to date 

addressed 7 of the 10 claims asserted in 

the Petition by either issuing a 

preliminary denial or approving label 

mitigation to address the claim, on June 

10, 2015, in the PANNA decision, the 

U.S. Court of Appeals for the Ninth 

Circuit signaled its intent to order EPA 

to complete its response to the Petition 

and directed EPA to inform the court 

how—and by when—EPA intended to 

respond. On June 30, 2015, EPA 

informed the court that, based on the 

results of its drinking water assessment, 

EPA intended to propose by April 15, 

2016, the revocation of all chlorpyrifos 

tolerances in the absence of pesticide 

label mitigation that ensures that 

drinking water exposures will be safe. 

EPA proposed this time frame in part to 

accommodate the completion of a 

refined drinking water assessment that 

might allow EPA to identify high risk 

areas of the country where additional 

label mitigation could be put in place to 

address drinking water concerns. On 

August 10, 2015, the court rejected 

EPA’s time line and issued a mandamus 

order directing EPA to ‘‘issue either a 

proposed or final revocation rule or a 

full and final response to the 

administrative Petition by October 31, 

2015.’’ As a result of this order, EPA is 

issuing this proposed rule in advance of 

completing its refined drinking water 

assessment. In addition, EPA has had 

insufficient time to address comments 

received on the RHHRA. As a result, 

EPA may update this action with new 

or modified analyses as EPA completes 

additional work after this proposal. For 

any significant new or modified 

analyses, to the extent practicable, EPA 

intends to provide the public an 

opportunity to comment on that work 

prior to issuing a final rule. 

V. EPA’s Approach to Dietary Risk 

Assessment 

EPA performs a number of analyses to 

determine the risks from aggregate 

exposure to pesticide residues. A short 

summary is provided below to aid the 

reader. For further discussion of the 

regulatory requirements of section 408 

of the FFDCA and a complete 

description of the risk assessment 

process, refer to References 5 and 6 

respectively. To assess the risk of a 

pesticide tolerance, EPA combines 

information on pesticide toxicity with 

information regarding the route, 

magnitude, and duration of exposure to 

the pesticide. The risk assessment 

process involves four distinct steps: (1) 

Identification of the toxicological 

hazards posed by a pesticide; (2) 

determination of the exposure ‘‘level of 

concern’’ for humans; (3) estimation of 

human exposure; and (4) 

characterization of human risk based on 

comparison of human exposure to the 

level of concern. 

A. Hazard Identification and Selection 

of Toxicological Endpoint 

Any risk assessment begins with an 

evaluation of a chemical’s inherent 

properties, and whether those properties 

have the potential to cause adverse 

effects (i.e., a hazard identification). 

EPA then evaluates the hazards to 

determine the most sensitive and 

appropriate adverse effect of concern, 

based on factors such as the effect’s 

relevance to humans and the likely 

routes of exposure. 

Once a pesticide’s potential hazards 

are identified, EPA determines a 

toxicological level of concern for 

evaluating the risk posed by human 

exposure to the pesticide. In this step of 

the risk assessment process, EPA 

essentially evaluates the levels of 

exposure to the pesticide at which 

effects might occur. An important aspect 

of this determination is assessing the 

relationship between exposure (dose) 

and response (often referred to as the 

dose-response analysis). In evaluating a 

chemical’s dietary risks, EPA uses a 

reference dose (RfD) approach, which 

first involves establishing a PoD—or the 

value from a dose-response curve that is 

at the low end of the observable data 

and that is the toxic dose that serves as 

the starting point in extrapolating a risk 

to the human population. In typical risk 

assessments, PoDs are derived directly 

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from laboratory animal studies, and 

then EPA extrapolates to potential 

effects on humans and human 

populations by applying both inter and 

intra-species uncertainty factors. 

Traditionally, EPA has used a 10X factor 

to address each of these uncertainties. In 

the case of chlorpyrifos and its oxon, 

however, EPA has used PBPK–PD 

modeling to estimate PoDs for all age 

groups using Data-Derived Extrapolation 

Factors (DDEF) rather than default 

uncertainty factors to address 

intraspecies extrapolation for some 

groups (Ref. 1). The PBPK–PD model 

accounts for PK (pharmacokinetic) and 

PD (pharmacodynamic) characteristics 

to derive age, duration, and route 

specific PoDs. Specifically, the 

following characteristics have been 

evaluated: exposure (acute, 21-day 

(steady state); routes of exposure 

(dermal, oral, inhalation); body weights 

which vary by lifestage; exposure 

duration (hours per day, days per week); 

and exposure frequency (e.g., eating and 

drinking events per day). While the 

current PBPK–PD model accounts for 

age-related growth from infancy to 

adulthood by using polynomial 

equations to describe tissue volumes 

and blood flows as a function of age, the 

model does not include any 

descriptions on physiological, 

anatomical, and biochemical changes 

associated with pregnancy. Due to the 

uncertainty in extrapolating the current 

model predictions among women who 

may be pregnant, the agency is applying 

the standard 10X intra-species 

extrapolation factor for women of 

childbearing age. 

Although the PBPK–PD model’s use 

of data-derived extrapolation factors 

renders unnecessary the use of 

traditional inter- and intra- species 

uncertainty factors for evaluating most 

populations, as required by FFDCA 

section 408(b)(2)(C), EPA must also 

address the need for an additional safety 

factor to protect infants and children. 

That provision requires EPA to retain an 

additional 10-fold margin of safety 

unless EPA concludes, based on reliable 

data, that a different safety factor will be 

safe for infants and children. The PoDs 

calculated by the PBPK–PD model are 

then divided by the uncertainty factors 

to derive a PAD. There are potential 

risks of concern when the estimated 

dietary exposure exceeds 100% of the 

PAD. 

B. Estimating Human Exposure Levels 

Pursuant to section 408(b) of the 

FFDCA, EPA evaluated dietary risks for 

chlorpyrifos based on ‘‘aggregate 

exposure’’ to chlorpyrifos. By ‘‘aggregate 

exposure,’’ EPA is referring to exposure 

to chlorpyrifos residues by multiple 

pathways of exposure. EPA uses 

available data, together with 

assumptions designed to be protective 

of public health, and standard analytical 

methods to produce separate estimates 

of exposure for a highly exposed 

subgroup of the general population, for 

each potential pathway and route of 

exposure. For both acute and steady 

state risks, EPA then calculates potential 

aggregate exposure and risk by using 

probabilistic techniques to combine 

distributions of potential exposures in 

the population for each route or 

pathway. (Probabilistic analysis is used 

to predict the frequency with which 

variations of a given event will occur. 

By taking into account the actual 

distribution of possible consumption 

and pesticide residue values, 

probabilistic analysis for pesticide 

exposure assessments ‘‘provides more 

accurate information on the range and 

probability of possible exposure and 

their associated risk values.’’ (Ref. 7). In 

capsule, a probabilistic pesticide 

exposure analysis constructs a 

distribution of potential exposures 

based on data on consumption patterns 

and residue levels and provides a 

ranking of the probability that each 

potential exposure will occur. People 

consume differing amounts of the same 

foods, including none at all, and a food 

will contain differing amounts of a 

pesticide residue, including none at all). 

For dietary analyses, the relevant 

sources of potential exposure to 

chlorpyrifos are from the ingestion of 

residues in food and drinking water. 

EPA uses a combination of monitoring 

data and predictive models to evaluate 

environmental exposure of humans to 

chlorpyrifos. 

1. Exposure from food. Acute and 

steady state dietary (food only) exposure 

analyses for chlorpyrifos were 

conducted using the Dietary Exposure 

Evaluation Model (DEEM) and Calendex 

software with the Food Commodity 

Intake Database (FCID). The DEEM– 

FCID model uses 2003–2008 food 

consumption data from the USDA 

National Health and Nutrition 

Examination Survey, What We Eat in 

America (NHANES/WWEIA). These 

current analyses reflect the latest 

available consumption data as well as 

more recent food monitoring and 

percent crop treated data. Both the acute 

and steady state dietary exposure 

analyses are highly refined. The large 

majority of food residues used were 

based upon USDA’s PDP monitoring 

data except in a few instances where no 

appropriate PDP data were available. In 

those cases, field trial data or tolerance 

level residues were assumed. 

DEEM–FCID also compares exposure 

estimates to appropriate RfD or PAD 

values to estimate risk. EPA uses these 

models to estimate exposure for the 

general U.S. population as well as 

subpopulations based on age, sex, 

ethnicity, and region. For its 

chlorpyrifos assessment, EPA used 

DEEM–FCID to calculate risk estimates 

based on a probabilistic distribution that 

combines the full range of residue 

values for each food with the full range 

of data on individual consumption 

amounts to create a distribution of 

exposure and risk levels. More 

specifically, DEEM–FCID creates this 

distribution by calculating an exposure 

value for each reported day of 

consumption per person (‘‘person/day’’) 

in the food survey, assuming that all 

foods potentially bearing the pesticide 

residue contain such residue at the 

chosen value. The exposure amounts for 

the thousands of person/days in the 

food survey are then collected in a 

frequency distribution. 

The probabilistic technique that 

DEEM–FCID uses to combine differing 

levels of consumption and residues 

involves the following steps: 

(1) identification of any food(s) that 

could possibly bear the residue in 

question for each person/day in the 

USDA food survey; 

(2) calculation of an exposure level for 

each of the thousands of person/days in 

the USDA food survey database, based 

on the foods identified in Step #1 by 

randomly selecting residue values for 

the foods from the residue database; 

(3) repetition of Step #2 one thousand 

times for each person/day; and 

(4) collection of all of the hundreds of 

thousands of potential exposures 

estimated in Steps # 2 and 3 in a 

frequency distribution. 

The resulting probabilistic assessment 

presents a range of exposure/risk 

estimates that can be compared to 

appropriate PADs to determine the 

safety of food exposures. 

2. Exposure from water. EPA may use 

field monitoring data and/or simulation 

water exposure models to generate 

pesticide exposure estimates in drinking 

water. Monitoring and modeling are 

both important tools for estimating 

pesticide concentrations in water and 

can provide different types of 

information. Monitoring data can 

provide estimates of pesticide 

concentrations in water that are 

representative of the specific 

agricultural or residential pesticide 

practices in specific locations, under the 

environmental conditions associated 

with a sampling design (i.e., the 

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locations of sampling, the times of the 

year samples were taken, and the 

frequency by which samples were 

collected). Further, monitoring data can 

reflect the actual use of a pesticide 

rather than the label rates. Although 

monitoring data can provide a direct 

measure of the concentration of a 

pesticide in water, it generally does not 

provide a reliable basis for estimating 

spatial and temporal variability in 

exposures because sampling may not 

occur in areas with the highest pesticide 

use, and/or when the pesticides are 

being used and/or at an appropriate 

sampling frequency to detect high 

concentrations of a pesticide that occur 

over the period of a day to several days. 

Because of the limitations in most 

monitoring studies, EPA’s standard 

approach is to use water exposure 

models as the primary means to 

estimate pesticide exposure levels in 

drinking water. EPA’s computer models 

use detailed information on soil 

properties, crop characteristics, and 

weather patterns to estimate exposure in 

vulnerable locations where the pesticide 

could be used according to its label. 

(Ref. 8). These models calculate 

estimated water concentrations of 

pesticides using laboratory data that 

describe how fast the pesticide breaks 

down to other chemicals and how it 

moves in the environment at these 

vulnerable locations. The modeling 

provides an estimate of pesticide 

concentrations in ground and surface 

water. Depending on the modeling 

algorithm (e.g., surface water modeling 

scenarios), daily concentrations can be 

estimated continuously over long 

periods of time, and for places that are 

of most interest for any particular 

pesticide. 

As discussed in Unit VI.B. in greater 

detail, EPA relied on models developed 

for estimating exposure in both surface 

water and ground water. A detailed 

description of the models routinely used 

for exposure assessment is available 

from the EPA Office of Pesticide 

Programs (OPP) Water Models Web site: 

http://www.epa.gov/oppefed1/models/

water/. The Surface Water 

Concentration Calculator provides a 

means for EPA to estimate daily 

pesticide concentrations in surface 

water sources of drinking water (a 

reservoir) using local soil, site, 

hydrology, and weather characteristics 

along with pesticide applications and 

agricultural management practices, and 

pesticide environmental fate and 

transport properties. EPA also considers 

percent cropped area (PCA) factors 

which take into account the potential 

extent of cropped areas that could be 

treated with pesticides in a particular 

area. 

In modeling potential surface water 

concentrations, EPA attempts to model 

areas of the country that are highly 

vulnerable to surface water 

contamination rather than simply model 

‘‘typical’’ concentrations occurring 

across the nation. Consequently, EPA 

models exposures occurring in small 

watersheds in different growing areas 

throughout the country over a 30-year 

period. The scenarios are designed to 

capture residue levels in vulnerable 

drinking water sources and are adjusted 

by PCA factors. The PCA is calculated 

from satellite derived land cover data to 

account for the area of watershed that is 

cropped. 

EPA believes these assessments are 

likely reflective of a subset of the 

watersheds across the country that are 

used for drinking water supply, 

representing a drinking water source 

generally considered to be more 

vulnerable to frequent high 

concentrations of pesticides than most 

locations. For this reason, in its 

evaluation of chlorpyrifos, EPA has also 

begun to refine its assessment to 

evaluate drinking water risk at a 

regional and drinking water intake 

scale. While it is currently challenging 

to assess exposure on a local scale due 

to the unavailability of data and wide 

range of characteristics (i.e., 

environmental factors such as soil, 

weather, etc. or others (e.g., drinking 

water treatment process)) that affect the 

vulnerability of a given community 

drinking water system to chlorpyrifos 

oxon contamination, EPA developed a 

method to examine the potential 

geospatial concentration differences 

using specific examples for two 

Hydrological Unit Code (HUC) 2 

Regions—HUC 2 Region 17: Pacific 

Northwest and HUC 2 Region 3: South 

Atlantic-Gulf, in order to identify use 

patterns in those regions that may result 

in EDWCs that exceed the DWLOC on 

a regional basis. There are 21 HUC 2 

regions with 18 in the conterminous 

United States. These areas contain 

either the drainage area of a major river, 

or a combined drainage of a series of 

rivers. The average size is 177,560 

square miles. Additional information 

can be found at https://water.usgs.gov/

GIS/huc.html. The analysis used a 

number of modeling scenarios to 

represent all potential chlorpyrifos 

agricultural use sites. This analysis 

showed an overlap of potential 

chlorpyrifos use sites that may result in 

an exceedance of the DWLOC with 

watersheds that supply source water for 

community drinking water systems. In 

addition, this analysis shows that 

exposure is not uniform within a HUC 

2 Region and that some watersheds 

present risk concerns while others do 

not. In general, the refined analysis 

confirms that smaller watersheds with 

high percent cropped areas are much 

more vulnerable than large watersheds. 

When this assessment is complete (i.e., 

when EPA has completed this analysis 

for the rest of the country), it may 

provide EPA with a basis for tailoring its 

drinking water risk mitigation efforts 

through pesticide product labeling 

rather than revoking tolerances 

nationwide. Because of the PANNA 

decision on August 10, 2015 compelling 

EPA to respond to the PANNA–NRDC 

Petition by October 31, 2015, EPA has 

not been able to complete its refined 

drinking water assessment for 

chlorpyrifos in advance of this proposed 

rule. As a result, this proposal relies 

only on the results of the national 

screen that do not provide a basis for 

more tailored risk mitigation. EPA is 

continuing to conduct its regional and 

water-intake level assessment and 

intends to update this action if 

warranted with the results of that 

assessment when it is completed. For 

any significant new or modified 

drinking water analyses, to the extent 

practicable, EPA intends to provide the 

public an opportunity to comment on 

the work prior to issuing a final rule. 

3. Residential and Other NonOccupational Exposures. EPA’s 

‘‘residential’’ assessments actually 

examine exposure to pesticides in both 

residential and other non-occupational 

settings (e.g., homes, parks, schools, 

athletic fields or any other areas 

frequented by the general public). All 

residential uses of chlorpyrifos except 

ant and roach baits (in child resistant 

packaging) and fire ant mound 

treatments were voluntary cancelled by 

registrants in 2000. As such, the use of 

the term ‘‘residential’’ throughout this 

document does not connote there are 

residential uses, rather it is used 

interchangeable with ‘‘nonoccupational’’ exposures. Exposures to 

pesticides may occur to persons who 

apply pesticides or to persons who enter 

areas previously treated with pesticides. 

Such exposures may occur through oral, 

inhalation, or dermal routes. For 

chlorpyrifos, the uses that could result 

in non-occupational exposures are the 

public health uses as an aerial and 

ground-based ultra-low volume (ULV) 

fogger for adult mosquito control, the 

fire ant mound treatments, the use in 

ant and roach bait stations, and foliar 

use on golf course turfgrass. 

Non-occupational assessments are 

conducted through examination of 

significant exposure scenarios (e.g., 

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children playing on treated lawns or 

homeowners spraying their gardens) 

using a combination of generic and 

pesticide-specific data. To regularize 

this process, OPP has prepared Standard 

Operating Procedures (SOPs) for 

conducting ‘‘residential’’ assessments 

on a wide array of scenarios that are 

intended to address all major possible 

means by which individuals could be 

exposed to pesticides in a nonoccupational environment (e.g. homes, 

schools, parks, athletic fields, or other 

publicly accessible locations). The SOPs 

identify relevant generic data and 

construct algorithms for calculating 

exposure amounts using these generic 

data in combination with pesticidespecific information. The generic data 

generally involve survey data on 

behavior patterns (e.g., activities 

conducted on turf and time spent on 

these activities), unit exposure, and 

transfer coefficient data to evaluate the 

transfer of pesticide to humans from a 

treated surface. 

Typically, non-occupational risks are 

quantified by comparison of estimates of 

exposure to toxicological PoDs for each 

route of exposure as selected from 

laboratory animal studies. In the case of 

chlorpyrifos, the PBPK–PD model was 

used to derive age-, duration-, and 

route-specific human equivalent doses. 

Separate PoDs were calculated for 

residential exposures by varying inputs 

on types of exposures and populations 

exposed. Residential risk estimates, or 

margins of exposure (MOEs) were 

calculated with use of the scenario- and 

lifestage-specific PoDs by comparison to 

exposure estimates (doses) quantified 

with use of standard occupational and 

residential exposure assessment 

methodologies. 

C. Selection of Acute and Steady State 

Dietary Exposure Level of Concern 

Because probabilistic assessments 

generally present a realistic range of 

residue values to which the population 

may be exposed, EPA’s starting point for 

estimating exposure and risk for its 

aggregate risk assessments is the 99.9th 

percentile of the population under 

evaluation. When using a probabilistic 

method of estimating acute and steady 

state dietary exposure, EPA typically 

assumes that, when the 99.9th 

percentile of exposure is equal to or less 

than the PAD, the level of concern has 

not been exceeded and dietary 

exposures are safe. 

D. Aggregating Exposures and Deriving 

a Risk Estimate 

In an aggregate risk assessment, 

pesticide exposures from relevant 

sources (i.e., food, drinking water and 

non-occupational uses) are added 

together and compared to quantitative 

estimates of hazard (e.g., PAD), or the 

risks themselves can be aggregated. 

When aggregating exposures and risks 

from various sources, both the route and 

duration of exposures are considered. 

For chlorpyrifos, EPA has considered 

aggregate exposures and risks from 

combined food, drinking water, and 

non-occupational exposures. Residues 

in food consist of parent compound 

chlorpyrifos only, while concentrations 

in water are assumed to consist of 

chlorpyrifos oxon only. The acute 

aggregate assessment includes only food 

and drinking water while the steady 

state aggregate assessment includes 

exposures from food, drinking water, 

and non-occupational scenarios. 

Typically, in aggregate assessments, 

total dietary exposure (food and 

drinking water combined) are derived 

by incorporating both food residues and 

EDWCs in the dietary exposure model. 

In the chlorpyrifos RHHRA, only food 

exposures were derived from the dietary 

model. For drinking water exposure and 

risk, a DWLOC approach was used to 

calculate the amount of exposure which 

could occur without exceeding the risk 

level of concern (i.e., the available space 

in the total aggregate risk cup for 

exposures to chlorpyrifos oxon in 

drinking water after accounting for 

exposures to parent chlorpyrifos from 

food and non-occupational scenarios). 

The calculated DWLOCs were then 

compared to the EDWCs of oxon 

modeled under a variety of conditions. 

When the EDWC is less than the 

DWLOC, there are no risk concerns for 

exposures to the pesticide in drinking 

water which also indicates aggregate 

exposures are not of concern. 

Conversely, when the EDWC is greater 

than the DWLOC, then potential risks of 

concern are identified. 

VI. Aggregate Risk Assessment and 

Conclusions Regarding Safety 

Consistent with section 408(b)(2)(D) 

of FFDCA, EPA has reviewed the 

available scientific data and other 

relevant information in support of this 

action. EPA’s assessment of exposures 

and risks associated with chlorpyrifos 

use follows. 

A. Hazard Identification and Endpoint 

Selection 

This unit summarizes EPA’s review of 

relevant data for extrapolating risk and 

its integrative analysis using multiple 

lines of evidence from experimental 

toxicology and epidemiology with 

respect to AChE/ChE inhibition 

(acetylcholinesterase/cholinesterase) 

and neurodevelopmental outcomes. 

This section also describes EPA’s use of 

a robust PBPK–PD model for deriving 

PoDs and refined intra-species factors. 

Finally, this unit provides the 

quantitative results of the end-point 

selection process, including EPA’s 

evaluation and application of the FQPA 

safety factor. 

1. Background. Mode of action (MOA) 

and adverse outcome pathways (AOPs) 

provide important concepts and 

organizing tools for risk assessment. 

MOAs/AOPs describe a set of 

measureable key events that make up 

the biological processes leading to an 

adverse outcome and the causal linkages 

between such events. An AOP further 

defines the initial step in the process as 

the molecular initiating event. 

Fundamentally, MOA and AOP are 

different terms for basically the same 

concept. 

It is well established that AChE 

inhibition is the mode of action/adverse 

outcome pathway (MOA/AOP) for the 

cholinergic toxicity of OP pesticides, 

including chlorpyrifos. AChE breaks 

down acetylcholine (ACh), a compound 

that assists in transmitting signals 

through the nervous system. When 

AChE is inhibited at nerve endings by 

chlorpyrifos or another AChE inhibiting 

pesticide, the inhibition prevents the 

ACh from being degraded and results in 

prolonged stimulation of nerves and 

muscles. If a person has enough 

exposure to chlorpyrifos for poisoning 

to occur the physical signs and 

symptoms include headache, nausea, 

dizziness, blurred vision, slurred 

speech, excessive perspiration, 

salivation, vomiting, diarrhea, and 

muscle twitching. Severe exposure to 

chlorpyrifos can lead to convulsions, 

loss of bladder and bowel control, coma, 

difficulty breathing, pulmonary edema, 

muscle paralysis, and death from 

respiratory failure. Because AChE 

inhibition is the initiating event for this 

MOA/AOP, using AChE inhibition as a 

regulatory endpoint is protective of 

downstream cholinergic effects. 

Moreover, given the sensitivity of AChE 

inhibition data for OPs, using AChE 

inhibition to establish a regulatory point 

of departure has historically been 

considered to be protective of other 

potential toxicities. EPA uses a value of 

10% AChE inhibition as a point of 

departure in its regulation of AChE 

inhibiting pesticides, including 

chlorpyrifos. EPA’s analyses have 

demonstrated that 10% is a level that 

can be reliably measured in the majority 

of animal toxicity studies; is generally at 

or near the limit of sensitivity for 

discerning a statistically significant 

decrease in AChE activity across the 

brain compartment; and is a response 

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level close to the background AChE 

level. 

Newer lines of research on 

chlorpyrifos, notably epidemiological 

studies, have raised some uncertainty 

about EPA’s historical risk assessment 

approach for chlorpyrifos with regard to 

the potential for neurodevelopmental 

effects that may arise from prenatal 

exposure to chlorpyrifos. This research 

is summarized in Unit VI.A.6.iii. 

2. Summary of data evaluated for 

deriving PoDs. Chlorpyrifos and its oxon 

are widely studied and thus have an 

extensive database of scientific studies. 

Included in the database are: Studies 

developed by registrants pursuant to 

EPA guidelines, special studies 

conducted by the registrants, and 

studies in the public literature. These 

studies reflect different levels of 

biological organization (e.g., 

metabolism, MOA/AOP, in vitro and in 

vivo experimental toxicology, 

biomonitoring, and epidemiology), 

various species (mouse, rabbit, dog, 

non-rodent, and human) and address 

multiple lifestages (fetal, postnatal, 

pregnant, and non-pregnant adult). The 

metabolism and pharmacokinetic (PK) 

profile of chlorpyrifos and its oxon have 

been extensively studied in in vitro 

systems, in vivo laboratory animals, as 

well as humans. Chlorpyrifos is 

bioactivated to the more toxic and 

potent AChE inhibitor, the oxon form. 

3,5,6-trichloro-2-pyridinol (TCPy) is the 

major excreted metabolite and is used as 

the biomarker in PK, biomonitoring, and 

epidemiology studies. Diethylphosphate 

(DEP) is another metabolite often used 

in biomonitoring studies, but since it is 

produced by a number of OPs, DEP is 

not a specific marker for chlorpyrifos. 

Summarized below are key findings 

from experimental toxicology studies on 

AChE inhibition as presented in detail 

in the June 2011 PHHRA and the 

December 2014 RHHRA. Readers should 

refer to those documents (Refs. 3 and 1) 

and their appendices in the public 

docket for this proposed rule for a 

complete summary of EPA’s data 

review. Chlorpyrifos has also been 

evaluated for other adverse outcomes 

such as reproductive toxicity, 

developmental toxicity, cancer, 

genotoxicity, dermal toxicity, inhalation 

toxicity, and immunotoxicity. These 

adverse outcomes are less sensitive (i.e., 

are likely to occur at higher doses) than 

AChE inhibition and 

neurodevelopmental effects, which form 

the scientific foundation of this 

proposed rule, and are thus not 

discussed in detail here. Concerns for 

neurodevelopmental effects provide the 

basis for retention of the FQPA safety 

factor and are summarized in Unit 

VI.A.6. 

AChE inhibition remains the most 

robust quantitative dose response data 

for chlorpyrifos and thus continues to 

be the critical effect for the quantitative 

risk assessment. This approach is 

consistent with the advice EPA received 

from the FIFRA SAP in both 2008 and 

2012 (Refs. 9 and 10) when EPA sought 

input specifically on the agency’s 

approach to evaluating the toxicity of 

chlorpyrifos. EPA has conducted 

benchmark dose (BMD) analysis of 

numerous studies using empirical 

approaches previously endorsed by the 

FIFRA SAP (Ref. 11) and consistent 

with the 2006 OP cumulative risk 

assessment (Ref. 12) and other single 

chemical OP risk assessments. Details 

on AChE studies and related analyses 

can be found in Appendix 1 of the 

PHHRA (Ref. 3). 

There are many chlorpyrifos studies 

evaluating AChE inhibition in red blood 

cell (RBC) or brain in multiple lifestages 

(gestational, fetal, post-natal, and nonpregnant adult), multiple species (rat, 

mouse, rabbit, dog, human), methods of 

oral administration (oral gavage with 

corn oil, dietary, gavage via milk), and 

routes of exposure (oral, dermal, 

inhalation via vapor, and via aerosol). In 

addition, chlorpyrifos is unique in the 

availability of ChE data from peripheral 

tissues in some studies (e.g., heart, lung, 

liver). There are also literature studies 

comparing the in vitro ChE response to 

a variety of tissues (Ref. 13) which show 

similar sensitivity and intrinsic activity. 

Across the database, brain AChE tends 

to be less sensitive than RBC AChE or 

peripheral ChE. In oral studies, RBC 

AChE inhibition is generally similar in 

response to peripheral tissues (e.g., 

liver, heart, and lung). Thus, the in vitro 

data and oral studies combined support 

the continued use of RBC AChE 

inhibition as the critical effect for 

quantitative dose-response assessment. 

As with many OPs, female rats tend 

to be more sensitive than males to these 

AChE effects. For chlorpyrifos, there are 

data from multiple studies which 

provide robust RBC AChE data in 

pregnant, lactating, and non-pregnant 

female rats from oral exposure (e.g., 

DNT, reproductive, and subchronic 

rats), respectively. The BMD10/BMDL10

values from these studies range from 

0.05/0.04 to 0.15/0.09 mg/kg/day. 

(BMD10 is the estimated dose to yield 

10% inhibition in RBC AChE inhibition 

compared to controls or background 

levels. The BMDL10 is the lower 95% 

confidence limit on the BMD10). Studies 

are available in juvenile pups which 

show age-dependent differences, 

particularly following acute exposures, 

in sensitivity to chlorpyrifos and its 

oxon. As discussed above, this 

sensitivity is not derived from 

differences in the AChE enzyme itself 

but instead is derived largely from the 

immature metabolic clearance capacity 

in the juveniles. 

Multiple route-specific laboratory 

animal studies for the dermal and 

inhalation routes are available. Dermal 

AChE data are available from a 21-day 

study and 4-day probe study (Ref. 14) in 

rats which together establish a No 

Observed Adverse Effect Level (NOAEL) 

of 5 mg/kg/day and a Lowest Observed 

Adverse Effect Level (LOAEL) of 10 mg/ 

kg/day. Two subchronic inhalation 

toxicity studies (Refs. 15, 16, and 17) in 

the rat are available using vapor phase 

chlorpyrifos which show no ChE effects 

up to a concentration of 20.6 ppb (287 

mg/m3 or 0.082 mg/kg/day). Multiple 

acute inhalation studies are also 

available. In a special acute inhalation 

study, female rats were exposed by nose 

only (mass median aerodynamic 

diameter/geometric standard deviation 

was 1.9/1.51, respectively) to 

atmospheric concentrations of up to 

53.9 mg/m3 of particulate chlorpyrifos 

for six hours and allowed an additional 

72 hours to recover (Refs. 18 and 19). 

Consistent and significant lung ChE 

inhibition were noted at the lowest 

concentration tested of 3.7 mg/m3, 

which is a LOAEL. RBC and brain ChE 

inhibition were noted at ≥ 12.9 mg/m3

and 53.9 mg/m3, respectively, indicating 

they are less sensitive than lung and 

plasma ChE inhibition following acute 

inhalation exposures. 

Since the 2011 PHHRA, two acute 

inhalation studies on the saturated 

vapor have been performed on the 

parent chlorpyrifos and chlorpyrifos 

oxon (Refs. 20 and 21). In these studies, 

female rats were exposed by nose only 

to a saturated vapor of chlorpyrifos or 

its oxon for 6 hours to a time-weighted 

concentration of 17.7 ppb (0.254 mg/m3) 

(Ref. 20) or 2.58 ppb (35.3 mg/m3) (Ref. 

21), respectively. There were no 

statistically-significant decreases in ChE 

activity in the RBC, lung, brain, or 

plasma tissues. These acute studies 

along with the subchronic inhalation 

studies with vapor phase chlorpyrifos 

support a conclusion that acute 

exposure to the saturated vapor of 

chlorpyrifos or its oxon do not result in 

hazard due to AChE inhibition. 

3. Durations of Exposure, Critical 

Windows of Exposure, & Temporality of 

Effects Relevant for AChE Inhibition. In 

risk assessment, exposure is evaluated 

in conjunction with the toxicology 

profile. More specifically, a variety of 

pharmacokinetic and pharmacodynamic 

factors are considered. In the case of 

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chlorpyrifos, exposure can occur from a 

single exposure (e.g., eating a meal) or 

from repeated days of exposure (e.g., 

worker, residential). 

With respect to AChE inhibition, 

these effects can occur from a single 

exposure or from repeated exposures. 

Generally, for OPs, repeated exposures 

result in more AChE inhibition at a 

given administered dose compared to 

acute studies. Moreover, AChE 

inhibition in repeated dosing guideline 

toxicology studies with OPs show a 

consistent pattern of inhibition reaching 

steady state at or around 2–3 weeks of 

exposure in adult laboratory animals 

(Ref. 22). This pattern is observed with 

repeated dosing and is a result of an 

equilibrium between the amount of 

AChE inhibition and the production of 

new enzyme. As such, AChE studies of 

2–3 weeks generally show the same 

degree of inhibition with those of longer 

duration (i.e., up to 2 years of exposure). 

Thus, for most of the single chemical 

human health risk assessments for the 

OPs, EPA is focusing on the critical 

duration range from a single day up to 

21 days (i.e., the approximate time to 

reach steady state for most OPs). As 

described below, PoDs for various 

lifestages, routes, and scenarios have 

been derived at the acute and steady 

state durations. For this proposed rule, 

PoDs for various lifestages, routes, and 

scenarios have been derived at the acute 

and steady state durations. 

4. Use of the Chlorpyrifos PBPK±PD 

Model to Establish PoDs. As described 

in detail in EPA’s 2006 document 

entitled, ‘‘Approaches for the 

Application of Physiologically Based 

Pharmacokinetic (PBPK) Models and 

Supporting Data in Risk Assessment,’’ 

(Ref. 23) PBPK modelling is a 

scientifically sound and robust 

approach to estimating the internal dose 

of a chemical at a target site and as a 

means to evaluate and describe the 

uncertainty in risk assessments. PBPK 

models consist of a series of 

mathematical representations of 

biological tissues and physiological 

processes in the body that simulate the 

absorption, distribution, metabolism, 

and excretion (ADME) of chemicals that 

enter the body. Examples of PBPK 

model applications in risk assessments 

include interspecies extrapolation, 

intra-species extrapolation, route-toroute extrapolation, estimation of 

response from varying exposure 

conditions, and high-to-low dose 

extrapolation. PBPK models can be used 

in conjunction with an exposure 

assessment to improve the quantitative 

characterization of the dose-response 

relationship and the overall risk 

assessment. These models can also be 

used to evaluate the relationship 

between an applied dose and 

biomonitoring data. 

For a full discussion of the 

development and evaluation of the 

chlorpyrifos PBPK–PD model, please 

refer to the December 2014 RHHRA (Ref. 

1) in the public docket for this rule. 

As discussed above, in typical risk 

assessments, PoDs are derived directly 

from laboratory animal studies and 

inter- and intra-species extrapolation is 

accomplished by use of ‘‘default’’10X 

factors. In the case of chlorpyrifos and 

its oxon, EPA is using a PBPK–PD 

model as a data-derived approach to 

estimate PoDs. This model was 

originally developed by Timchalk and 

coworkers in 2002 (Refs. 24 and 25), 

partially funded by EPA Star Grants, 

and most recently supported by Dow 

AgroSciences. The PBPK–PD model for 

chlorpyrifos has been heavily peer 

reviewed through numerous scientific 

publications and a review by the FIFRA 

SAP (Ref. 26). All model code for the 

PBPK–PD model are provided in the 

public docket for the chlorpyrifos risk 

assessment. Developers of the 

chlorpyrifos PBPK–PD model sponsored 

a third-party quality assurance 

assessment to verify model parameter 

values and their respective sources. EPA 

has also done a quality assurance 

assessment of the model for human 

health risk assessment applications. 

(Ref. 27). 

The chlorpyrifos PBPK–PD model 

includes the description of a molecular 

initiating event in the cholinergic 

toxicity MOA/AOP: AChE inhibition. 

Thus, the PBPK–PD model can be used 

to predict the dose metrics associated 

with cholinergic toxicity following 

chlorpyrifos exposure, i.e., RBC and 

brain AChE inhibition. The model also 

predicts levels of chlorpyrifos, its oxon, 

and TCPy in various tissues, such as 

plasma and urine. Age-specific 

parameters are incorporated allowing 

for lifestage-specific evaluations from 

infant through adulthood. The model 

can be run in two modes: deterministic 

and variation. In the deterministic 

mode, the output accounts for human 

specific metabolism and physiology, 

thus obviating the need for the interspecies extrapolation factor for all age 

groups. In variation mode, distributions 

for 16 parameters, which are critical for 

determining human variations in RBC 

AChE inhibition, are incorporated and 

thus the output accounts for intraspecies extrapolation for infants, 

toddler, youths, and non-pregnant 

adults. The approach to intra-species 

extrapolation is described in Unit 

VI.A.5. 

With respect to AChE inhibition, as 

noted, EPA typically uses a 10% 

response level in its human health risk 

assessments. This response level is 

consistent with EPA’s 2006 OP 

cumulative risk assessment (Ref. 12) and 

other single chemical OP risk 

assessments. As such, EPA has used the 

PBPK–PD model to estimate exposure 

levels resulting in 10% RBC AChE 

inhibition following single day (acute; 

24 hours) and 21-day exposures for a 

variety of exposure scenarios. The 

model accounts for PK and PD 

characteristics to derive age, duration, 

and route specific PoDs (see Table 1 

below). Separate PoDs have been 

calculated for dietary (food, drinking 

water) and residential exposures by 

varying inputs on types of exposures 

and populations exposed. Specifically, 

the following characteristics have been 

evaluated: Duration (acute, 21-day 

(steady state)); route (dermal, oral, 

inhalation); body weights which vary by 

lifestage; exposure duration (hours per 

day, days per week); and exposure 

frequency (events per day (eating, 

drinking)). 

For each exposure scenario, the 

appropriate body weight for each age 

group or sex was modeled as identified 

from the Exposure Factors Handbook 

(Ref. 28) for residential exposures and 

from the NHANES/WWEIA Survey (Ref. 

29) for dietary exposures. 

EPA evaluated the following 

scenarios: dietary exposure to the oxon 

exposures via drinking water (24-hour 

and 21-day exposures for infants, 

children, youths, and female adults); 

exposure to chlorpyrifos exposures via 

food (24-hour and 21-day exposures for 

infants, children, youths, and female 

adults); 21-day residential exposures to 

chlorpyrifos via skin for children, 

youths, and female adults; 21-day 

residential exposures to chlorpyrifos via 

hand-to-mouth ingestion for children 1– 

2 years old; and 21-day residential 

exposures to chlorpyrifos via inhalation 

for children 1–2 years old and female 

adults. 

For all residential dermal exposures 

to chlorpyrifos, EPA set the fraction of 

skin in contact with chlorpyrifos to 50% 

and assumed a daily shower (i.e., 

washing off the chlorpyrifos) following 

chlorpyrifos exposure. All residential 

exposures were set to be continuous for 

21 days. For residential exposures via 

golfing on treated turf, the daily 

exposure time is assumed to be 4 hours/ 

day; for residential exposures via 

contact with turf following public 

health mosquitocide application, the 

daily exposure duration is assumed to 

be 1.5 hours. For residential inhalation 

exposures following public health 

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mosquitocide application, the exposure 

duration was set to 1 hour per day for 

21 days. The exposure times selected 

are based on those recommended in the 

2012 Standard Operating Procedures for 

Residential Pesticide Exposure 

Assessment (2012 Residential SOPs). 

(Ref. 30). 

Summarized in Table 1 are the PBPK– 

PD model results used to estimate 

exposure levels resulting in 10% RBC 

AChE inhibition for each evaluated 

population. 

TABLE 1—CHLORPYRIFOS PBPK MODELED DOSES (PODS) CORRESPONDING TO 10% RBC ACHE INHIBITION 1

RA Type 

Exposure pathway 

(all chlorpyrifos 

unless noted) 

Infants 

( < 1 yr old) 

Young Children 

(1–2 years old) 

Children 

(Residential: 6–11 

years old; Dietary: 

6–12 years old) 

Youths 

(Residential: 11–16 

years old; Dietary: 

13–19 years old) 

Females 

(13–49 years old) 

Acute 

Steady 

state 

(21 day) 

Acute 

Steady 

state 

(21 day) Acute 

Steady 

state 

(21 day) 

Acute 

Steady 

state 

(21 day) 

Acute 

Steady 

state 

(21 day) 

Dietary ................... Drinking Water 

(oxon conc, ppb).

1,183 217 3,004 548 7,700 1,358 4,988 878 5,285 932 

Food (ug/kg/day) ... 600 103 581 99 530 90 475 80 467 78 

Residential 

(Golfers).

Dermal (ug/kg/day) ................ ................ ................ ................ ................ 25,150 ................ 16,370 ................ 14,250 

Residential 

(Mosquitocide 

Application).

Dermal (ug/kg/day) ................ ................ ................ 187,000 ................ ................ ................ ................ ................ 38,650 

Oral (ug/kg/day) .... ................ ................ ................ 101 ................ ................ ................ ................ ................ ................

Inhalation (concn. 

in air mg/m3).

................ ................ ................ 2.37 ................ ................ ................ ................ ................ 6.15 

1Empty cells are not populated because these exposure scenarios are either not relevant for the age group (e.g., infants or 1–2 year olds golfing), or do not represent the most health protective life stage for assessment of a particular exposure scenario as recommended in the 2012 SOPs (e.g., for mosquitocide exposure assessment, children 1 to < 2 years old result in a more protective assessment than infants). 

5. Use of the Chlorpyrifos PBPK±PD 

Model to Extrapolate from Animals to 

Humans (Inter-species) and Among the 

Human Population (Intra-species). Once 

EPA determines the appropriate 

toxicological PoDs (Table 1), it then 

applies appropriate uncertainty factors 

or DDEFs to account for inter-species 

and intra-species variation, and to 

address the requirements of section 

408(b)(2)(C) regarding the need for an 

additional margin of safety for infants 

and children. Specifically, the modeled 

doses (PoDs) in this table are divided by 

appropriate factors to establish PADs 

that are used for regulatory purposes. 

The PADs are presented in Unit VI.B.2.ii 

and iii, Tables 2 and 3. 

In a typical risk assessment, the 

agency uses PoDs derived from 

laboratory animal studies. For these 

typical assessments, the agency must 

then extrapolate from animals to 

humans which is generally performed 

with a 10X inter-species factor. As noted 

above in Unit V.A., the output of the 

chlorpyrifos PBPK–PD model accounts 

for human specific metabolism and 

physiology, thus obviating the need for 

the inter-species extrapolation factor for 

all age groups. 

EPA has, however, calculated a DDEF 

to address intra-species variation not 

accounted for in the output of the 

PBPK–PD model. Consistent with EPA’s 

‘‘Guidance for Applying Quantitative 

Data to Develop Data-Derived 

Extrapolation Factors for Interspecies 

and Intraspecies Extrapolation’’ (Ref. 

31), when calculating a DDEF, EPA 

compares the administered doses 

leading to the response level of interest 

(10% change in RBC AChE inhibition) 

between a measure of average response 

and response at the tail of the 

distribution representing sensitive 

individuals. Dow AgroSciences has 

conducted an analysis to derive the oral 

doses that cause 10% RBC AChE 

inhibition in both adults and 6-month 

old infants. (Ref. 1 at 69–70). The ratio 

of the adult ED10 (effective dose) to the 

infant ED10 was then used to derive 

intraspecies extrapolation factors. In the 

subsequent Monte Carlo simulations, 

the target age group is six month old 

individuals. Based on the 1st percentile 

of the distributions being used to 

extrapolate human health, the DDEF for 

intraspecies extrapolation is 4X for 

chlorpyrifos and 5X for the oxon (Ref. 

32) for all groups except women who 

are pregnant or may become pregnant. 

While the current PBPK–PD model 

accounts for age-related growth from 

infancy to adulthood by using 

polynomial equations to describe tissue 

volumes and blood flows as a function 

of age, the model does not include any 

descriptions on physiological, 

anatomical and biochemical changes 

associated with pregnancy. Due to the 

uncertainty in extrapolating the current 

model predictions among women who 

may be pregnant, EPA is applying the 

standard 10X intra-species extrapolation 

factor for women of child bearing age. 

6. Retention of the statutory 10X 

FQPA Safety Factor for purposes of this 

proposed rule for infants, children, 

youths, and women of childbearing age 

for all exposure scenarios. Section 408 

of FFDCA provides that EPA shall apply 

an additional tenfold margin of safety 

for infants and children in the case of 

threshold effects to account for prenatal 

and postnatal toxicity and the 

completeness of the data base on 

toxicity and exposure unless EPA 

determines that a different margin of 

safety will be safe for infants and 

children. Margins of safety are 

incorporated into EPA assessments 

either directly through use of a margin 

of exposure analysis or through using 

uncertainty (safety) factors in 

calculating a dose level that poses 

acceptable risk to humans. 

In applying the FQPA safety factor 

provision, EPA has interpreted the 

statutory language as imposing a 

presumption in favor of applying an 

additional 10X safety factor (Ref. 33). 

Thus, EPA generally refers to the 

additional 10X factor as a presumptive 

or default 10X factor. EPA has also 

made clear, however, that the 

presumption can be overcome if reliable 

data demonstrate that a different factor 

is safe for infants and children. (Ref. 33). 

In determining whether a different 

factor is safe for infants and children, 

EPA focuses on the three factors listed 

in section 408(b)(2)(C)—the 

completeness of the toxicity database, 

the completeness of the exposure 

database, and potential pre- and postnatal toxicity. 

In examining these factors, EPA 

strives to make sure that its choice of a 

safety factor, based on its weight-ofevidence evaluation, does not 

understate the risk to infants and 

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children. New lines of research on 

chlorpyrifos, notably epidemiological 

studies, have raised some uncertainty 

about EPA’s risk assessment approach 

for chlorpyrifos with regard to the 

potential for neurodevelopmental effects 

that may arise from prenatal exposure to 

chlorpyrifos. Over the last several years, 

the agency has taken a stepwise, 

objective and transparent approach to 

evaluate, interpret, and characterize the 

strengths and uncertainties associated 

with all the lines of scientific 

information related to the potential for 

adverse neurodevelopmental effects in 

infants and children as a result of 

prenatal exposure to chlorpyrifos. The 

agency has evaluated multiple lines of 

evidence with regard to the potential for 

neurodevelopmental outcomes 

associated with exposure to 

chlorpyrifos. These are summarized 

below; full details of this analysis can be 

found in the RHHRA. Given the degree 

of uncertainty EPA has in the human 

dose-response relationship for 

neurodevelopmental effects, EPA is 

retaining the statutory 10X FQPA Safety 

Factor for purposes of this proposed 

rule for infants, children (including 

youths), and women of childbearing age 

(to address prenatal exposure to the 

fetus) for all exposure scenarios. 

i. Neurodevelopmental outcomes in 

laboratory animals. There is a 

considerable and still-growing body of 

literature on the effects of chlorpyrifos 

on the developing brain of laboratory 

animals (rats and mice) indicating that 

gestational and/or postnatal exposure 

may cause persistent behavioral effects 

into adulthood. These data provide 

support for the susceptibility of the 

developing mammalian brain to 

chlorpyrifos exposure. Literature 

searches have been conducted and 

periodically updated by EPA to review 

papers addressing long-term outcomes 

from developmental exposure. This 

review has focused on studies in which 

chlorpyrifos was administered during 

gestation and/or the pre-weaning period 

and the offspring are examined at some 

time after weaning, and on studies using 

relatively low doses (e.g., 1 mg/kg/day) 

that would not be expected to produce 

considerable brain AChE inhibition and 

resultant cholinergic toxicity. 

There are substantial differences in 

the studies, including critical features of 

experimental design such as 

developmental period of exposure, 

dosing scenarios, testing methods, age at 

testing, and statistical analyses. Despite 

these differences, behavioral changes of 

some sort were reported in most studies. 

Given the wide array of testing that has 

been conducted, some variability is not 

unexpected and in fact, the consistency 

of finding neurological effects is 

striking. After presentation of these 

reviews, FIFRA SAP Panels (Refs. 9 and 

10) have agreed that exposure to doses 

of 1 mg/kg/d and greater, during some 

developmental period, produce 

significant and long-term effects on 

animal behavior. 

Many of these studies using various 

cognitive tests report perturbations of 

learning and/or memory, even though in 

a few cases these may be manifested as 

improved function. Several findings 

using specific test methods have been 

replicated across studies and 

laboratories, increasing confidence in 

the outcomes. Likewise, alterations in 

some domains, such as those describing 

anxiety and social interactions, are not 

fully consistent, but are still suggestive 

of long-term impacts on these behaviors. 

Motor activity measures, on the other 

hand, produce results as varied as the 

different measures of assessment. Taken 

together, these data provide evidence for 

more global alterations in 

neurobehavioral function rather than a 

specific profile of effects. 

In these papers, testing was 

conducted at various times after 

weaning (adolescents to adults), and 

there is a presumption that the effects 

are permanent; however, no study has 

directly addressed this issue. Doseresponse is not always evident, since 

many studies only use one dose, and of 

those using two or more doses, there is 

not always a monotonic response. There 

are differences in route of 

administration (oral, subcutaneous) and 

vehicle (corn oil, DMSO), but the 

outcomes do not provide obvious 

differences due to these factors. 

Likewise, the experimental literature 

has not consistently shown that any 

specific developmental period is critical 

overall to the long-term outcomes. For 

example, using one specific test 

cognitive changes were observed 

following gestational and early 

postnatal, but not late postnatal, 

exposures (Refs. 34, 35, 36, and 37). On 

the other hand, deficits have been 

reported using a different cognitive test 

following both gestational and late 

postnatal exposures (Refs. 38, 39, and 

40). Similarly, some changes in anxiety 

and social behaviors were reported at 

both gestational and postnatal exposure 

periods. Unfortunately, no laboratory 

has provided systematic comparisons 

across exposure period, dosing regimen, 

and age of testing; such studies would 

improve understanding of the impact of 

these critical factors. 

These studies have almost exclusively 

focused on doses that could produce 

some degree, however minimal, of 

AChE inhibition. For example, a 

number of papers use a dose of 1 mg/ 

kg/d administered 1–4 days after birth, 

and this dose inhibits 5–10% of brain 

AChE in the pups when measured 2 

hours after the last dose (e.g., Refs. 34, 

37, and 41). In another study of 

chlorpyrifos administered in feed to 

pregnant rats, the lowest intake of 0.36 

mg/kg/d produced about 20–25% RBC 

ChE inhibition in the dams (Ref. 42). 

Currently there are no animal studies 

that support or dispute the potential for 

adverse neurodevelopmental outcomes 

at lower doses that do not inhibit AChE 

at any time, since this has not been 

adequately studied. 

Overall, across the literature on 

neurodevelopmental outcomes and 

including most recent publications, 

there continue to be reports of effects on 

cognitive, anxiety/social behaviors, and 

motor activity. There are, however, 

inconsistencies in these effects with 

regards to dosing paradigms and genderspecificity. Studies report effects at 

doses that inhibit fetal/pup brain AChE 

activity to some degree, but there are 

also studies with no effects at the same 

doses. The broad profile of neurological 

effects that has been reported do not aid 

in the development of a specific AOP 

(AChE inhibition or other mechanisms), 

and existing experimental studies have 

not been designed to examine and track 

possible mechanisms from early 

initiating events to the final 

neurological outcome. 

ii. Modes of action/adverse outcome 

pathways (MOA/AOP). Mode of action 

(MOA) and adverse outcome pathways 

(AOPs) describe a set of measureable 

key events that make up the biological 

processes leading to an adverse outcome 

and the causal linkages between such 

events. A review of the scientific 

literature on potential MOA/AOP 

leading to effects on the developing 

brain was conducted for the 2012 FIFRA 

SAP meeting (Ref. 10) and updated for 

the December 2014 chlorpyrifos RHHRA 

(Ref. 1). In short, multiple biologically 

plausible hypotheses and pathways are 

being pursued by researchers including: 

AChE as a morphogen; cholinergic 

system; endocannabinoid system; 

reactive oxygen species; serotonergic 

system; tubulin, microtubule associated 

proteins, and axonal transport. 

However, no one pathway has sufficient 

data to be considered more plausible 

than the others. Among the available 

studies, there are effects which are 

either as or more sensitive than AChE 

inhibition. The fact that there are, 

however, sparse data to support the in 

vitro to in vivo extrapolation, or the 

extrapolation from biological 

perturbation to adverse consequence 

significantly limits their quantitative 

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use in risk assessment. The SAP 

concurred with the agency in 2008 and 

2012 about the lack of definable key 

events in a MOA/AOP leading to 

developmental neurobehavioral effects. 

The lack of an established MOA/AOP 

makes quantitative use of the 

epidemiology study in risk assessment 

challenging, particularly with respect to 

dose-response, critical duration of 

exposure, and window(s) of 

susceptibility. The agency will continue 

to monitor the scientific literature for 

studies on the MOA/AOP for 

neurodevelopmental effects. 

iii. Epidemiology studies in mothers 

and children. In the chlorpyrifos 

RHHRA, EPA included epidemiologic 

research results from three prospective 

birth cohort studies. These include: (1) 

The Mothers and Newborn Study of 

North Manhattan and South Bronx 

performed by the Columbia Children’s 

Center for Environmental Health 

(CCCEH) at Columbia University; (2) the 

Mt. Sinai Inner-City Toxicants, Child 

Growth and Development Study or the 

‘‘Mt. Sinai Child Growth and 

Development Study’’ (Mt. Sinai); and (3) 

the Center for Health Assessment of 

Mothers and Children of Salinas Valley 

(CHAMACOS) conducted by researchers 

at University of California Berkeley. In 

these epidemiology studies, motherinfant pairs were recruited for the 

purpose of studying the potential health 

effects of environmental exposures 

during pregnancy on subsequent child 

development. Importantly, each of these 

cohorts evaluated the association 

between prenatal chlorpyrifos or OP 

exposure with adverse 

neurodevelopmental outcomes in 

children through age 7 years. 

These studies reflect different types of 

exposed groups in the total population 

which strengthens the weight of the 

evidence considerations regarding this 

stream of information. The CCCEH 

Mother’s and Newborn study and the 

Mt. Sinai Child Growth and 

Development study participants were 

likely exposed to OPs through the diet 

and through residential use of the 

pesticide for indoor pest control. In the 

residential setting, study populations 

were most likely exposed through 

indoor residential use of the pesticide 

during the study time period and 

additionally exposed to OPs via the oral 

route through ingesting residues in the 

diet and from hand-to-mouth contact 

with in-home surfaces, as well as 

possible dermal or inhalation exposure 

through contact with treated areas in the 

home environment (Refs. 43, 44, 45, and 

46). In contrast, CHAMACOS cohort 

participants were employed as farm 

laborers or were residing in homes with 

farm laborers. The CHAMACOS study 

participants likely experienced 

exposure to OPs through the diet and 

from occupational exposure (primarily 

inhalation and dermal routes), as well as 

probable indirect take-home exposures 

(the ‘‘tracking in’’ of pesticide residues 

through shoes and clothing, augmented 

by poor hygiene practices) (Ref. 47). In 

each of the three U.S. children’s health 

cohorts, EPA has considered the 

strengths and limitations of these 

studies, and believes that random or 

systematic errors in the design, conduct 

or analysis of these studies were 

unlikely to fully explain observed 

positive associations between in utero 

OP exposure and adverse 

neurodevelopmental effects observed at 

birth and through childhood (age 7 

years). EPA believes these are strong 

studies which support a conclusion that 

OPs likely played a role in these 

outcomes. 

These cohort studies each enrolled 

pregnant women during roughly the 

same time period, measured both 

environmental exposure to the pesticide 

during pregnancy and also measured 

biomarkers representing internal dose 

during pregnancy and at delivery, and 

prospectively assessed associations in 

their newborns and young children 

through age 7 years. Each study 

includes several hundred 

(approximately 100–400) mother-infant 

pairs; these sample sizes are sufficient 

to perform statistically valid analyses. 

Investigators from each study cohort 

utilized a similarly strong study design 

(prospective birth cohort); measured 

pesticide exposure using several 

different methods including 

environmental indicators as well as 

specific and non-specific biomarkers of 

OPs; ascertained developmental 

outcomes using validated assessment 

tools well-established in both clinical 

and research settings; and, measured, 

analyzed, selected and statistically 

adjusted for potentially confounding 

variables including socio-economic 

status and other environmental 

exposures using reasonable and 

appropriate methods. Limitations exist 

as well. These studies utilized a onetime measure (or the average of two 

measures) of chlorpyrifos or OP 

exposure to assess prenatal pesticide 

exposure throughout the gestational 

period, were unable to assess the 

influence of mixtures (co-occurring 

exposures in the relevant biological time 

window), and reflect a small sample 

size to fully evaluate the effect of more 

than one simultaneous exposure on 

neurodevelopment, i.e., evidence of 

effect modification. 

As noted, two major uncertainties in 

environmental epidemiology studies are 

the accurate and reliable measurement 

of exposure and potential confounding 

variables such as the influence of 

mixtures. The researchers with each of 

the three cohorts have provided 

supplemental methodological research 

to address these areas to the extent 

possible. Across the three children’s 

health cohorts, study authors measured 

biomarkers of OP exposure. There is 

uncertainty as to the extent 

measurement of non-specific 

metabolites of OP or chlorpyrifos 

accurately reflects OP exposure; CCCEH 

and Mt. Sinai studies do not estimate 

post-natal exposure to chlorpyrifos 

among child participants, therefore the 

influence of early life and childhood OP 

exposure is unaccounted for in these 

analyses. The CHAMACOS cohort 

measured urinary levels of dialkyl 

phosphates (DAPs) in young children 

and did not observe negative significant 

associations in relation to 

neurodevelopment from post-natal 

exposure (Ref. 48). The CHAMACOS 

cohort investigators also measured 

AChE and butyl ChE as supplemental 

indicators of OP exposure. 

Potential confounding bias is another 

major uncertainty within environmental 

epidemiology studies. Confounding 

variables, exposures that could be 

related to OP exposure and 

neurodevelopmental outcomes such as 

blood lead, may result in an incorrect 

epidemiological risk estimate. Across 

these cohort studies, investigators 

collected relevant information 

concerning demographic characteristics 

and other environmental exposures, and 

were, to the extent possible with the 

existing information, able to effectively 

hold constant the influence of these 

other variables when estimating the 

association between prenatal 

chlorpyrifos and adverse 

neurodevelopmental outcomes. Control 

of these variables is important to reduce 

the chances of a false positive study 

result. Overall, statistical analyses were 

judged to be appropriate and reasonable 

(not overly large number of statistical 

model variables) to the research 

question by EPA and expert Panel 

reviews (Refs. 9 and 10). 

Researchers with both the Mt. Sinai 

and CHAMACOS cohorts evaluated 

neonatal neurological functioning in 

association with prenatal OP exposure; 

CCCEH did not conduct these 

measurements. To measure indices of 

abnormal neonatal behavior and/or 

neurological integrity, the Mt. Sinai and 

CHAMACOS authors used outcome 

measures derived from the Brazelton 

Neonatal Behavioral Assessment Scale 

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(BNBAS), a neurological assessment of 

28 behavioral items and 18 primitive 

reflexes. This tool was administered to 

infants 2–5 days post-partum by trained 

neonatologists in the hospital setting 

using similar environmental conditions. 

The authors with both study groups 

observed an increased number of 

abnormal reflexes in relation to 

increasing measures of OP exposure 

(Refs. 49 and 50). Among the other 27 

measures in the BNBAS, neither study 

group reported evidence of any other 

positive associations. The authors also 

observed evidence of potential effect 

modification by PON1 activity level in 

the relation between DAPs and neonatal 

neurodevelopment in which infants of 

mothers who are slower metabolizers 

have greater risk of abnormal reflexes 

(Refs. 49 and 50). However, EPA notes 

these studies are likely under-powered 

to make a statistically robust estimate of 

this statistical interaction. 

Researchers across the three 

children’s health cohorts utilized the 

Bayley Scales of Infant Development II 

(BSID–II) to generate a Mental 

Development Index (MDI) and a 

Psychomotor Development Index (PDI) 

to assess neurodevelopment in early 

childhood. In the CCCEH Mothers and 

Newborn study, Rauh et al. (Ref. 51) 

investigated MDI and PDI at 12, 24, and 

36 months of age. Children were 

categorized as having either high (>6.17 

pg/g) or low (≤6.17 pg/g) prenatal 

chlorpyrifos exposure, using categories 

informed by results of the previous 

study on birth characteristics (Ref. 52). 

Authors reported that the difference in 

MDI scores was ‘‘marginally significant’’ 

(p = 0.06) between the ‘‘high’’ and 

‘‘low’’ exposed groups; the high exposed 

group scoring an average of 3.3 points 

lower than the low exposed (Ref. 51). 

Regarding the PDI score (motor skills), 

none of the 12 or 24 month PDI scores 

showed significant effects, but the 36 

month score was significantly related to 

chlorpyrifos exposure. Researchers 

noted that the effects were most 

pronounced at the 36 month testing 

period. Within the 36 month testing 

period, the likelihood of highly exposed 

children developing mental delays were 

significantly greater (MDI: 2.4 times 

greater (95% CI: 1.12–5.08, p = 0.02) 

and PDI: 4.9 times greater (95% CI: 

1.78–13.72; p = 0.002)) than those with 

lower prenatal exposure (Id.). Within 

the Mt. Sinai study, authors 

administered the BSID–II to 

participating children at 12 and 24 

months and observed that prenatal total 

DAP metabolite level was associated 

with a decrement in mental 

development at 12 months among 

blacks and Hispanic children; however, 

these associations either attenuated or 

were non-existent at the 24-month visit 

(Ref. 52). In the CHAMACOS cohort, 

Eskenazi et al. (Ref. 53) observed that 

prenatal DAP levels were adversely 

associated with MDI, and at 24 months 

of age these associations reached 

statistical significance. In this study, 

neither prenatal DAPs nor maternal 

TCPy were associated with PDI (motor 

skills), nor did authors observe evidence 

of different risk by PON1 status. (Ref. 

54). 

With respect to the findings related to 

the autism spectrum, from CCCEH, 

Rauh et al. (Ref. 51) reported a 

statistically significant odds ratio for 

pervasive developmental disorder (PDD) 

(OR = 5.39; 95% CI: 1.21–24.11) when 

comparing high to low chlorpyrifos 

exposure groups. As described above, 

among 7–9 years old children in the Mt. 

Sinai Cohort (Ref. 55), there was no 

overall statistically significant 

association between maternal third 

trimester urinary DAP metabolite levels 

and reciprocal social responsiveness. 

However, some evidence of 

modification of the association between 

prenatal OP pesticide exposure and 

impaired social responsiveness in early 

childhood was observed by both race/

ethnicity and child sex, with an 

association between diethyl 

alkylphosphate (DEAP) and poorer 

social responsiveness observed among 

black participants and boys. No 

association was observed among whites 

or Hispanics, among girls, or for DAP or 

dimethyl alkylphosphate (DMAP) 

biomarker levels. In the CHAMACOS 

cohort, Eskenazi et al. (Ref. 54) reported 

non-significant, but suggestive, 

increased odds of PDD of 2.0 (0.8 to 5.1; 

p = 0.14), whereas Eskenazi et al. (Ref. 

53) reported a statistically significant 

association between total DAP exposure 

and increased odds of PDD. 

With respect to attention problems, 

Rauh et al. (Ref. 50) also investigated 36- 

month child behavior checklist (CBCL) 

(behavioral) scores. Significant 

differences were observed between the 

high and low chlorpyrifos exposure 

groups in the general category of 

attention-problems (p = 0.010), and in 

the more specific DSM–IV (Diagnostic 

and Statistical Manual of Mental 

Disorders version IV) scale for ADHD 

problems (p = 0.018). The CHAMACOS 

cohort also investigated attention 

problems in early childhood using three 

different assessment tools: maternal 

report of child behavior at 3.5 and 5 

years of age; direct assessment of the 

child at 3.5 and 5 years; and by a 

psychometrician’s report of the behavior 

of the child during testing at 5 years. In 

this study population, higher 

concentrations of OP metabolites in the 

urine of pregnant women were 

associated with increased odds of 

attention problems and poorer attention 

scores in their children at age 5 years. 

(Ref. 53). 

To measure intelligence among school 

aged children, authors from each of the 

three children’s health cohorts used the 

Wechsler Intelligence Scale for 

Children, 4th edition (WISC–IV). The 

instrument measures four areas of 

mental functioning: The Verbal 

Comprehension Index, the Perceptual 

Reasoning Index, the Working Memory 

Index, and the Processing Speed Index. 

A Full-Scale IQ score combines the four 

composite indices. WISC–IV scores are 

standardized against U.S. populationbased norms for English and Spanishspeaking children. In the CCCEH 

Mothers and Newborn Study, Rauh et 

al. (Ref. 56) evaluated the relationship 

between prenatal chlorpyrifos exposure 

and neurodevelopment among 265 of 

the cohort participants who had reached 

the age of 7 years and had a complete 

set of data including prenatal maternal 

interview data, prenatal chlorpyrifos 

marker levels from maternal and/or cord 

blood samples at delivery, postnatal 

covariates, and neurodevelopmental 

outcome data (Ref. 56). While models 

were developed using continuous 

measures of both prenatal chlorpyrifos 

exposure and Wechsler scores, for ease 

of interpretation, investigators reported 

that for each standard deviation increase 

in exposure (4.61 pg/g) there is a 1.4% 

reduction in Full-Scale IQ and a 2.8% 

reduction in Working Memory. In the 

Mt. Sinai study, prenatal maternal DEP 

urinary metabolite concentrations were 

associated with slight decrements in 

Full Scale Intelligence Quotient (FSIQ), 

Perceptual Reasoning, and Working 

Memory between the ages of 6 and 9 

years, and difference in intelligence 

measures by putative PON1 status were 

also noted. (Ref. 52). Similarly, in the 

CHAMACOS cohort, Bouchard et al. 

(Ref. 57) observed evidence of an 

association between prenatal exposures 

to OPs as measured by urinary DAP 

(total DAP, DEP, and DMP) metabolites 

in women during pregnancy, and 

decreased cognitive functioning in 

children at age 7. In this study, children 

in the highest quintile of maternal DAP 

concentrations had a statistically 

significant 7 point difference in IQ 

points compared with those in the 

lowest quintile. 

To ascertain whether observed 

differences in neurodevelopment after 

prenatal chlorpyrifos exposure may be 

explained by differences in brain 

morphology between exposed groups, 

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the CCCEH study investigators 

compared MRI brain images between 

high and low chlorpyrifos exposed child 

study participants. (Ref. 58). Authors 

determined there were distinct 

morphological differences in brain areas 

associated with these 

neurodevelopmental outcomes. The 

pilot study included 40 child 

participants due to strict inclusion and 

exclusion criteria, and the high cost of 

performing the imaging studies on each 

child. EPA convened a Federal Panel of 

experts to perform a written peer-review 

of this study. (Ref. 59). The Federal 

Panel concurred with the authors’ 

conclusions in general; however the 

Federal Panel also noted that 

significantly greater and more 

sophisticated MRI imaging studies 

would be needed to link the 

morphological changes indicated in this 

study with specific functional outcomes 

noted in the CCCEH IQ study. 

Therefore, while generally supportive of 

the epidemiologic findings, additional 

study is needed to make specific links 

with areas of brain development change. 

In sum, across these three children’s 

environmental health studies, authors 

consistently identified associations with 

neurodevelopmental outcomes in 

relation to OP exposure. There is 

evidence of delays in mental 

development in infants (24–36 months), 

attention problems and autism spectrum 

disorder in early childhood, and 

intelligence decrements in school age 

children who were exposed to 

chlorpyrifos or OPs during gestation. 

Investigators reported strong measures 

of statistical association across several 

of these evaluations (odds ratios 2–4 

fold increased in some instances), and 

observed evidence of exposuresresponse trends in some instances, e.g., 

intelligence measures. 

7. Weight-of-Evidence Analysis Across 

Multiple Lines of Evidence. The 

discussion above summarized key 

scientific information on two different 

adverse health outcomes: AChE 

inhibition and potential 

neurodevelopmental effects. The agency 

has conducted a weight-of-evidence 

(WOE) analysis utilizing the draft 

‘‘Framework for Incorporating Human 

Epidemiologic & Incident Data in Health 

Risk Assessment’’ in an effort to 

integrate this information in the 

development of an appropriate PoD for 

chlorpyrifos. That assessment focuses 

on two key scientific questions: (1) The 

degree to which scientific data suggest 

that chlorpyrifos causes long-term 

neurodevelopmental effects from fetal or 

early life exposure and (2) the degree to 

which adverse effects can be attributed 

to doses lower than those which elicit 

10% inhibition of AChE, i.e., the dose 

levels previously used for regulatory 

decision making. 

i. Dose-response relationships and 

temporal concordance. Since the 

MOA(s)/AOP(s) is/are not established 

for neurodevelopmental outcomes, it is 

not possible to describe the concordance 

in key events or biological steps leading 

to neurodevelopmental outcomes. As 

such, the quantitative linkages between 

molecular initiating events, 

intermediate steps, and ultimately the 

adverse outcome (i.e., 

neurodevelopmental effects) cannot be 

determined. Experimental toxicology 

studies in rodents suggest that long-term 

effects from chlorpyrifos exposure may 

occur. Due to the dose selections in 

most of these in vivo studies evaluating 

effects such as behavior and cognition, 

it is not known whether such adverse 

effects would be shown at doses lower 

than those which elicit 10% RBC AChE 

inhibition. It is notable, however, that 

comparing the lowest NOAEL observed 

in the in vivo animal studies (0.2 mg/kg/ 

day; Ref. 60) for the 

neurodevelopmental outcomes to the 

repeated dosing reliable BMDL10

ranging from 0.05–0.17 mg/kg/day for 

RBC AChE inhibition suggests that 

neurodevelopmental outcomes may 

occur in the same range as AChE 

inhibition in rat. 

Within the epidemiology studies, the 

relationship in time between prenatal 

chlorpyrifos exposure and adverse 

neurodevelopmental outcomes is 

concordant. Specifically, with regard to 

the children’s environmental health 

epidemiology studies, each of the three 

study cohorts utilized a prospective 

birth cohort study design in which 

mothers were recruited into study prior 

to the birth of the infants and 

development and identification of 

adverse effects; therefore, it is known 

with certainty that exposure preceded 

effect. In addition, because the time 

period under study within these 

cohorts, and specifically the CCCEH 

study, spanned the point in time in 

which pesticide manufacturers 

voluntarily cancelled the use of 

chlorpyrifos in the home environment, 

researchers were able to show the 

change in exposure before (high use 

period) and after (low/no use period) 

the period of removal of chlorpyrifos 

products from the residential 

marketplace. Moreover, prior to the 

voluntary cancellation there were >80% 

detectable levels of chlorpyrifos in cord 

blood but in the time period after the 

cancellation only 16% of the measured 

values were greater than the LOD; there 

was only one child born in the time 

period subsequent to the voluntary 

cancellation of chlorpyrifos in the 

residential marketplace for whom the 

cord blood chlorpyrifos level was in the 

upper-tertile of pre-cancellation 

exposure levels. The significantly 

reduced proportion of measured values 

greater than the limit of detection as 

well as the observation of an absence of 

an association between prenatal 

chlorpyrifos exposure and 

neurodevelopmental outcomes among 

infants born after the voluntary 

cancellation of chlorpyrifos support the 

hypothesis that chlorpyrifos is related to 

these outcomes. However, as noted by 

study authors, EPA, and the FIFRA SAP 

(Ref. 10), this could also be due to an 

inadequate sample size to detect a small 

to modest effect among the group of 

infants born after the voluntary 

cancellation. 

With respect to the timing of 

exposure, the cord blood and other 

(meconium) measures from the CCCEH 

study provide evidence that exposure 

did occur to the fetus during gestation 

but the actual level of such exposure 

during the critical window(s) of 

susceptibility is not known. While 

significant uncertainties remain about 

the actual exposure levels experienced 

by mothers and infant participants in 

the three children’s health cohorts, 

particularly during the time period prior 

to the voluntary cancellation of indoor 

residential uses of chlorpyrifos, 

exposures measured in the range 

reported in the epidemiology studies 

(pg/g plasma) are likely low enough that 

they were unlikely to have resulted in 

AChE inhibition. The FIFRA SAP (Ref. 

10) concurred with the conclusion that 

measured levels of chlorpyrifos among 

epidemiology study participants were 

unlikely to have resulted in AChE 

inhibition. The urinary TCPy 

concentrations among mothers were 

comparable to the general population 

levels measured in NHANES. 

Comparing cord blood concentrations 

with the concentrations in which AChE 

inhibition was observed in adult 

volunteers indicates AChE inhibition 

would likely not have occurred at levels 

observed in the epidemiology studies 

(6.17 pg/g). Therefore, while uncertainty 

exists as to actual chlorpyrifos exposure 

at (unknown) critical windows of 

exposure, EPA believes it is unlikely 

mothers enrolled in the birth cohort 

studies experienced RBC AChE 

inhibition (greater than 10%). 

The biomarker data from the CCCEH 

studies are supported by EPA’s dose 

reconstruction analysis using the PBPK– 

PD model, which support a conclusion 

that indoor application of chlorpyrifos, 

when used as allowed prior to 

cancellation from the residential 

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marketplace in 2000, likely would not 

have resulted in RBC AChE inhibition 

greater than 10% in pregnant women or 

young children. 

ii. Strength, consistency, and 

specificity. As stated in the EPA 

neurotoxicity guidelines (Ref. 61), direct 

extrapolation of developmental 

neurotoxicity results from laboratory 

animals to humans is limited by the lack 

of knowledge about underlying 

toxicological mechanisms and the 

relevance of these results to humans. 

EPA notes consistencies across these 

two databases, although challenges of 

making a direct comparison between 

neurodevelopmental domain interspecies remain. It can be assumed that 

developmental neurotoxicity effects in 

animal studies indicate the potential for 

altered neurobehavioral development in 

humans, although the specific types of 

developmental effects seen in 

experimental animal studies may not be 

the same as those that may be produced 

in humans. However, considering the 

toxicological and epidemiological data 

in the context of three major 

neurodevelopmental domains 

(specifically, cognition, motor control, 

and social behavior), insights can be 

gained. For example, chlorpyrifos 

studies in rats and/or mice have 

reported impaired cognition (spatial 

learning and working memory; e.g., 

Refs. 35 and 38); changes in locomotor 

activity levels (exploration, rearing; e.g., 

Refs. 36 and 62); altered social 

interaction (aggression, maternal 

behavior; Refs. 63 and 64); and effects 

on brain morphometrics (Refs. 65 and 

66). Similarly, epidemiologic 

investigations have reported effects on 

cognition (Bayley scale indices; Refs. 50 

and 53), abnormal motor development 

in neonates (reflexes, Brazelton score; 

Refs. 49 and 48), altered social 

development (e.g., ADHD; Refs. 50 and 

67), and MRI brain scans (Ref. 68). It is 

notable that the laboratory animal 

studies vary in experimental designs 

such as species, strain, gender, dosing 

regimens (age, routes, vehicle), and test 

parameters (age, protocol). Likewise, 

observational epidemiology studies vary 

by population characteristics (race/

ethnicity, socio-economic status (SES), 

and pesticide use/exposure profile), coexposures (mix of chemicals, windows 

of exposure), and method of exposure 

and outcome assessment. Given the 

differences across laboratory animal and 

epidemiology studies, the qualitative 

similarity in research findings is 

striking. 

In contrast, quantitatively, there are 

notable differences between animals 

and humans. Specifically, in animals, 

the doses most often used in the 

behavior studies (1 and 5 mg/kg/day) 

are sufficient to elicit approximately 

≥10% brain AChE inhibition and ≥30% 

in RBC AChE inhibition, depending on 

the study design, age of the animal, and 

sampling time. In the epidemiology 

studies, based on the comparisons with 

biomonitoring data and the results of 

the dose-reconstruction analysis, it is 

unlikely that RBC AChE would have 

been inhibited by any meaningful or 

measurable amount, if any at all, and 

most likely none in the brain. This key 

difference in dose response between the 

experimental toxicology and 

epidemiology studies poses challenges 

in interpreting such data. There are a 

number of possible hypotheses such as: 

(1) Limitations of experimental 

laboratory studies which have limited 

statistical power due to relatively small 

sample sizes; (2) humans display a 

broader array of behaviors and cognitive 

abilities than rats, thus limiting the 

sensitivity of the rat studies; and (3) in 

the epidemiology studies, the timing of 

chlorpyrifos application and blood 

collections are not coupled—thus higher 

levels of blood chlorpyrifos were likely 

missed (albeit the results of the dose 

reconstruction analysis reduce the 

likelihood of this hypothesis). 

In making a weight-of-the-evidence 

analysis, it is important to consider the 

strength of the statistical measures of 

association between prenatal 

chlorpyrifos exposure and adverse 

neurodevelopmental outcomes through 

childhood (epidemiology) and possibly 

into adulthood (animal studies). It is 

also important to consider the strength 

of the integrated qualitative and 

quantitative evidence, the consistency 

of the observed associations across 

epidemiology studies and considering 

both animal and human data support 

the conclusion that chlorpyrifos plays a 

role in adverse neurodevelopmental 

outcomes. While it cannot be stated that 

chlorpyrifos alone is the sole 

contributor to the observed outcomes 

(specificity), since other environmental, 

demographic or psychosocial exposures 

may also play a part in these outcomes, 

this does not obviate the contribution of 

prenatal chlorpyrifos exposure in the 

development of adverse 

neurodevelopmental outcomes as 

echoed by the FIFRA SAP (Ref. 10). 

The CCCEH study, which measures 

chlorpyrifos specifically, provides a 

number of notable associations. 

Regarding infant and toddler 

neurodevelopment, the CCCEH authors 

also reported statistically significant 

deficits of 6.5 points on the Bayley 

Psychomotor Development Index (PDI) 

at 3 years of age when comparing high 

to low exposure groups (Ref. 50). 

Notably these decrements in PDI persist 

even after adjustment for group and 

individual level socioeconomic 

variables (Ref. 69). These investigators 

also observed increased odds of mental 

delay (OR = 2.4; 95% CI: 1.1–5.1) and 

psychomotor delay (OR = 4.9; 95% CI: 

1.8–13.7) at age three when comparing 

high to low exposure groups. (Ref. 50). 

Rauh et al. (Ref. 50) also reported large 

odds ratios for attention disorders (OR 

= 11.26; 95% CI: 1.79–70.99), ADHD 

(OR = 6.50; 95% CI: 1.09–38.69), and 

PDD (OR = 5.39; 95% CI: 1.21–24.11) 

when comparing high to low 

chlorpyrifos exposure groups. (Ref. 50). 

EPA notes that the magnitude of these 

results are so large that they are unlikely 

to be affected by residual confounding 

although limited sample sizes resulted 

in imprecise estimates. 

Decrements in intelligence measures 

were identified in relation to increasing 

levels of prenatal chlorpyrifos exposure. 

The CCCEH study reported statistically 

significant decreases of 1.4% in full 

scale IQ and 2.8% in working memory 

among seven-year olds for each standard 

deviation increase in chlorpyrifos 

exposure. (Ref. 56). These results persist 

even when performing sensitivity 

analyses including only those with 

detectable chlorpyrifos levels. 

iii. Biological plausibility and 

coherence. Although MOA(s)/AOP(s) 

has/have not been established for 

neurodevelopmental outcomes, the 

growing body of literature does 

demonstrate that chlorpyrifos and/or its 

oxon are biologically active on a number 

of processes that affect the developing 

brain. Moreover, there is a large body of 

in vivo laboratory studies which show 

long-term behavioral effects from early 

life exposure. EPA considers the results 

of the toxicological studies relevant to 

the human population, as qualitatively 

supported by the results of 

epidemiology studies. The lack of 

established MOA/AOP does not 

undermine or reduce the confidence in 

the findings of the epidemiology 

studies. The CCCEH study data are not 

considered in isolation, but rather are 

strengthened when considered in 

concert with the results from the other 

two cohort studies, as noted by the 

FIFRA SAP. (Ref. 10). As noted above, 

the CHAMACOS and Mt. Sinai cohorts 

that measured neurological effects at 

birth (the Brazelton index), observed a 

putative association with chlorpyrifos. 

(Ref. 48 and 49). Similarly, while not 

consistent by age at time of testing 

(ranging from 6 months to 36 months 

across the three cohorts), each cohort 

reported evidence of impaired mental 

and psychomotor development. 

Attentional problems and ADHD were 

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reported by both Columbia and 

CHAMACOS investigators. Finally, each 

of the three cohort study authors 

observed an inverse relation between 

the respective prenatal measures of OP 

and intelligence measures at age 7 years. 

iv. Weight of evidence conclusions. 

Key issues being considered by the 

Agency in its weight-of-evidence 

evaluation of chlorpyrifos toxicity are 

(1) whether chlorpyrifos causes longterm effects from fetal or early life 

exposure and (2) whether adverse 

effects can be attributed to doses lower 

than those which elicit 10% inhibition 

of AChE—EPA’s current regulatory 

point of departure for chlorpyrifos and 

other OPs. When taken together the 

evidence from (1) the experimental 

toxicology studies evaluating outcomes 

such as behavior and cognitive function; 

(2) mechanistic data on possible adverse 

outcome pathways/modes of action; and 

(3) epidemiologic and biomonitoring 

studies leads the agency to the following 

conclusions: 

• Qualitatively, these lines of 

evidence together support a conclusion 

that exposure to chlorpyrifos results in 

adverse neurodevelopmental outcomes 

in humans, at least under some 

conditions. 

• Quantitatively, the dose-response 

relationship of AChE inhibition across 

different life stages is established, but 

MOAs/AOPs for neurodevelopmental 

outcomes are not established. 

• The database of in vivo animal 

toxicology neurodevelopmental studies 

on adverse outcomes includes only a 

small number of studies at doses lower 

than 1 mg/kg/day. Despite this, the 

agency noted that the BMD values in 

adult (pregnant and nonpregnant) 

female rats (0.05–0.15 mg/kg/day) are 

generally 10-fold or more lower than the 

doses where effects on 

neurodevelopmental outcomes in 

laboratory rats are observed. 

• With respect to the mechanistic 

data, there are sparse data to support the 

in vitro to in vivo extrapolation, or the 

extrapolation from biological 

perturbation to adverse consequence, 

which significantly limits their 

quantitative use in risk assessment. 

• As noted above, the lack of an 

established MOA/AOP makes 

quantitative use of the epidemiology 

study in risk assessment challenging, 

particularly with respect to doseresponse, critical duration of exposure, 

and window(s) of susceptibility. Despite 

this uncertainty, the cord blood and 

other measures (meconium) provide 

evidence of exposure to the fetus during 

gestation. Moreover, exposure levels in 

the range measured in the epidemiology 

studies (pg/g) are likely low enough that 

they are unlikely to result in AChE 

inhibition, as supported by the dose 

reconstruction analysis of residential 

use prior to 2000 (although the agency 

has not investigated the degree to which 

exposure to multiple AChE-inhibiting 

pesticides indoors simultaneously could 

impact this conclusion). 

• Given the totality of the evidence, 

the agency concludes that chlorpyrifos 

likely played a role in the 

neurodevelopmental outcomes reported 

in the CCEH study but uncertainties 

such as the lack of an established MOA/ 

AOP for neurodevelopmental effects 

and the exposure to multiple AChEinhibiting pesticides precludes 

definitive causal inference. 

• In light of the uncertainties 

regarding the relationship of observed 

neurodevelopmental outcomes to AChE 

inhibition, EPA is retaining the 10X 

FQPA safety factor. 

Following publication of the 

December 2014 RHHRA, EPA received 

public comments suggesting that the 

uncertainty surrounding the doseresponse relationship for 

neurodevelopmental effects warranted 

the application of a larger safety factor 

than the statutory default 10X factor. 

The commenters suggested that EPA’s 

assessment had failed to establish that, 

even with the retained 10X FQPA safety 

factor, exposures to chlorpyrifos will 

not result in adverse 

neurodevelopmental outcomes. Some of 

the commenters suggested that EPA 

evaluate available biomonitoring from 

the epidemiologic data to help assess 

whether these outcomes could in fact be 

occurring at levels below EPA’s PAD 

that it is using for purposes of this 

proposed rule. EPA is currently in the 

process of evaluating the available 

biomonitoring; however, in light of the 

August 10, 2015 PANNA decision that 

orders EPA to respond to the PANNA– 

NRDC Petition not later than October 

31, 2015, EPA has not been able to 

complete that evaluation in advance of 

this proposal. EPA is continuing its 

evaluation of the available 

biomonitoring and will update this 

action to reflect the results of that 

review, if warranted. 

Further, EPA is aware that some 

commenters on EPA’s RHHRA believe 

the PBPK–PD model used to derive 

PoDs is inappropriate for the evaluation 

of neurodevelopmental effects, given 

that there is no established association 

between AChE inhibition and long term 

adverse neurodevelopmental outcomes 

observed in recent epidemiology 

studies. While EPA’s evaluation of 

biomonitoring from available human 

epidemiology studies will not help to 

further determine the MOA/AOP for 

these adverse neurodevelopmental 

outcomes, as noted, it will help EPA 

better assess whether the doses (PADs) 

EPA is proposing to use for regulatory 

purposes in this proposed rule are 

protective for potential adverse 

neurodevelopmental effects. While, as 

noted, that assessment is still not 

complete, because EPA is proposing to 

revoke all tolerances in this proposed 

rule based on its concern regarding 

AChE inhibition, it is unnecessary for 

EPA to determine at this time whether 

its current PADs bound the chlorpyrifos 

exposures measured in the 

epidemiology studies. In any case, as 

EPA completes its further evaluation it 

will update this action, as warranted. 

B. Dietary Exposure and Risk 

Assessment. 

The general approach for the 

chlorpyrifos dietary exposure and risk 

assessment is as follows: The PBPK–PD 

model was used to predict acute (24 

hour) and steady state (21-day) PoDs 

which correspond to 10% RBC AChE 

inhibition for the lifestages relevant to 

chlorpyrifos risk assessment. The PoDs 

are then divided by the total uncertainty 

factor to determine the PAD. 

For the dietary risk assessment for 

food only, the exposure values resulting 

from Dietary Exposure Evaluation 

Model (DEEM) and the Calendex model 

are compared to the PBPK–PD-based 

acute PAD and steady state PAD, 

respectively. When estimated dietary 

risk estimates exceeds 100% of the PAD 

there is generally a risk concern. 

For the dietary assessment for water, 

a drinking water level of comparison 

(DWLOC) approach to aggregate risk 

was used to calculate the amount of 

exposure available in the total ‘risk cup’ 

for chlorpyrifos oxon in drinking water 

after accounting for any chloropyrifos 

exposures from food and/or residential 

use. 

1. Residues of concern. The 

qualitative nature of the residue in 

plants and livestock is adequately 

understood based on acceptable 

metabolism studies with cereal grain 

(corn), root and tuber vegetable (sugar 

beets), and poultry and ruminants. The 

residue of concern, for tolerance 

expression and risk assessment, in 

plants (food and feed) and livestock 

commodities is the parent compound 

chlorpyrifos. 

Based on evidence (various crop field 

trials and metabolism studies) 

indicating that the metabolite 

chlorpyrifos oxon would be not be 

present in edible portions of the crops 

(particularly at periods longer than the 

currently registered PHIs), it is not a 

residue of concern in food or feed at this 

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time. Also, the chlorpyrifos oxon is not 

found on samples in the USDA PDP 

monitoring program. In fact, from 2007 

to 2012, out of several thousand samples 

of various commodities, only one 

sample of potato showed presence of the 

oxon at trace levels, 0.003 ppm where 

the LOD was 0.002 ppm, even though 

there are no registered uses of 

chlorpyrifos on potato in the U.S. 

The oxon metabolite was not found in 

milk or livestock tissues in cattle and 

dairy cow feeding studies, at all feeding 

levels tested, and is not a residue of 

concern in livestock commodities. 

Oxidation of chlorpyrifos to 

chlorpyrifos oxon can occur through 

photolysis, aerobic metabolism, and 

chlorination as well as other oxidative 

processes. Because of the toxicity of the 

oxon and data indicating that 

chlorpyrifos rapidly converts to the 

oxon during typical drinking water 

treatment (chlorination), the drinking 

water risk assessment considers the 

oxon as the residue of concern in treated 

drinking water and assumes 100% 

conversion of chlorpyrifos to 

chlorpyrifos oxon. (Ref. 70). This 

approach of assuming 100% conversion 

of chlorpyrifos to the more toxic 

chlorpyrifos oxon, is a conservative 

approach and thus protective of other 

likely exposure scenarios of chlorpyrifos 

only and chlorpyrifos and chlorpyrifos 

oxon. 

The chlorpyrifos degradate TCPy is 

not considered a residue of concern for 

this assessment as it does not inhibit 

cholinesterase (a separate human health 

risk assessment has been performed for 

TCPy, which has its own toxicity 

database). TCPy (derived from triclopyr, 

chlorpyrifos, and chlorpyrifos-methyl) 

was previously assessed on June 6, 

2002. (Ref. 71). 

2. Dietary (food only) risk assessment. 

The general approach for the 

chlorpyrifos (food only) exposure and 

risk assessment can be described as 

follows: The PBPK–PD model was used 

to predict acute (24 hour) and steady 

state (21-day) PoDs which correspond to 

10% RBC AChE inhibition for the index 

lifestages relevant to chlorpyrifos risk 

assessment (children of various ages 

which differ due to exposure pattern, 

and adult females of childbearing age). 

The PoDs are then divided by the total 

uncertainty factor to determine the PAD. 

For food, the residue of concern is 

chlorpyrifos (the oxon metabolite is not 

an expected residue on foods). The 

chlorpyrifos total uncertainty factors are 

100X for adult females (10X FQPA SF 

and 10X intra-species extrapolation 

factor) and 40X for the other 

populations (10X FQPA SF and 4X 

intra-species extrapolation factor). For 

the dietary risk assessment for food 

only, the exposure values resulting from 

Dietary Exposure Evaluation Model 

(DEEM) and the Calendex model are 

compared to the PBPK–PD-based acute 

PAD and steady state PAD, respectively. 

The chlorpyrifos exposure values 

resulting from dietary modeling are 

compared to the PAD. Dietary exposures 

greater than 100% of the PAD are 

generally cause for concern and would 

be considered ‘‘unsafe’’ within the 

meaning of FFDCA section 408(b)(2)(B). 

i. Description of residue data used in 

dietary (food only) assessment. Acute 

and steady state dietary (food only) 

exposure analyses for chlorpyrifos were 

conducted using the Dietary Exposure 

Evaluation Model (DEEM) and Calendex 

software with the Food Commodity 

Intake Database (FCID) (Ref. 90). This 

software uses 2003–2008 food 

consumption data from NHANES/

WWEIA. The most recent previous 

dietary assessment was conducted in 

support of the 2011 PHHRA and the 

ongoing chlorpyrifos registration 

review. (Ref. 72). This current analysis 

reflect the latest consumption data as 

well as more recent food monitoring and 

percent crop treated data. These 

analyses were performed for the 

purpose of obtaining food exposure 

values for comparison to the 

chlorpyrifos doses predicted by the 

PBPK–PD model to cause RBC ChEI. 

The acute and steady state exposure 

analyses do not include drinking water 

which is assessed separately as 

discussed in Unit VI.2.B. 

Both the acute and steady state 

dietary exposure analyses are highly 

refined. The large majority of food 

residues used were based upon U.S. 

Department of Agriculture’s PDP 

monitoring data except in a few 

instances where no appropriate PDP 

data were available. In those cases, field 

trial data were used or tolerance level 

residues were assumed. The same data 

were used for both the acute and steady 

state analyses. EPA also considered 

percent crop treated information. Food 

processing factors from submitted 

studies were used as appropriate. 

The acute and steady state dietary 

exposure assessment used percent crop 

treated information from EPA’s 

Screening Level Usage Analysis (Ref. 

73) to estimate chlorpyrifos exposures 

from the consumption of food. Reported 

percent crop treated ranged from <2.5% 

to 70%. 100% crop treated was assumed 

for many crops for which no usage data 

were available. 

ii. Acute dietary (food only) risk 

assessment. Chlorpyrifos acute (food 

only) dietary exposure assessments were 

conducted using the Dietary Exposure 

Evaluation Model software with the 

Food Commodity Intake Database 

DEEM–FCIDTM, Version 3.16, which 

incorporates consumption data from 

NHANES/WWEIA. This dietary survey 

was conducted from 2003 to 2008. 

Acute dietary risk estimates are 

presented below for the sentinel 

population subgroups for acute risk 

assessment: infants (<1 year old), 

children (1–2 years old), youths (6–12 

years old) and adults (females 13–49 

years old). The assessment of these 

index lifestages will be protective for 

the other population subgroups. 

As Table 2 indicates, EPA believes 

that acute dietary risk from food only 

does not present a significant risk, as 

estimates are all far below 100% of the 

acute PAD for food (aPADfood) at the 

99.9th percentile of exposure. The 

subgroup with the highest risk estimate 

was females (13–49 years old) at 3.2% 

aPADfood. 

TABLE 2—ACUTE DIETARY (FOOD ONLY) EXPOSURE AND RISK ESTIMATES FOR CHLORPYRIFOS

Population subgroup aPoDfood 1

(ug/kg/day) 

aPADfood 2

(ug/kg/day) 

Food 

exposure 3

(ug/kg/day) 

Percent of 

aPADfood

Infants (<1 yr) .................................................................................................. 600 15 0.273 1.8 

Children (1–2 yrs) ............................................................................................ 581 14 0.423 3.0 

Youths (6–12 yrs) ............................................................................................ 530 13 0.189 1.4 

Adults (Females 13–49 yrs) ............................................................................ 469 4.7 0.150 3.2 

1Acute point of departure; daily dose predicted by PBPK–PD model to cause RBC ChEI of 10% for acute dietary (food) exposures. 

2 aPAD = acute PAD = PoD (Dose predicted by PBPK–PD model to cause 10% RBC ChEI) ÷ total UF; Total uncertainty factor = 100X for females 13–49 years (10X intraspecies factor and 10X FQPA safety factor) and 40X for other populations (4X intraspecies factor and 10X FQPA 

safety factor). 3Acute food only exposure estimates from DEEM (at 99.9th percentile). Refined with monitoring data and %CT. 

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iii. Steady state detary (food only) risk 

assessment. A chlorpyrifos steady state 

dietary (food only) exposure analysis 

was conducted using Calendex-FCIDTM. 

EPA’s steady state assessment considers 

the potential risk from a 21-day 

exposure duration using a 3-week 

rolling average (sliding by day) across 

the year. For this assessment, the same 

food residue values used in the acute 

assessment were used for the 21-day 

duration. In the Calendex software, one 

diary for each individual in the WWEIA 

is selected to be paired with a randomly 

selected set of residue values for each 

food consumed. The steady state 

analysis calculated exposures for the 

sentinel populations for infant, child, 

youths, and adult (infants <1 year, 

children 1–2 years, youths 6–12 years, 

females 13–49 years). 

Calendex reported dietary exposures 

for each population subgroup at several 

percentiles of exposure ranging from 

10th percentile to 99.9th percentile. 

Similar to acute risks, the dietary (food 

only) exposures for chlorpyrifos were all 

well below 100% ssPADfood (all 

populations, at all percentiles of 

exposure). Only the 99.9th percentile of 

exposure is presented in Table 3. For 

the steady state dietary (food only) 

exposure analyses, children (1–2 years 

old) was the population subgroup with 

the highest risk estimate at 9.7% of the 

ssPADfood at the 99.9th percentile of 

exposure. 

TABLE 3—STEADY STATE DIETARY (FOOD ONLY) EXPOSURE AND RISK ESTIMATES FOR CHLORPYRIFOS

Population subgroup SS PoDfood 1

(ug/kg/day) 

ssPADfood 2

(ug/kg/day) 

Food 

exposure 3

(ug/kg/day) 

Percent of 

ssPADfood

Infants (<1 yr) .................................................................................................. 103 2.6 0.186 7.2 

Children (1–2 yrs) ............................................................................................ 99 2.5 0.242 9.7 

Youths (6–12 yrs) ............................................................................................ 90 2.2 0.128 5.8 

Adults (Females 13–49 yrs) ............................................................................ 78 0.78 0.075 9.6 

1Steady state point of departure; daily dose predicted by PBPK–PD model to cause RBC ChEI of 10% for steady state (21-day) dietary (food) 

exposures. 2 ssPAD = Steady state PAD = PoD (Dose predicted by PBPK–PD model to cause 10% RBC ChEI) ÷ total UF; Total uncertainty factor = 100X 

for females 13–49 years (10X intraspecies factor and 10X FQPA safety factor) and 40X for other populations (4X intraspecies factor and 10X 

FQPA safety factor). 3Steady state (21-day) food only exposure estimates from Calendex (at 99.9th percentile). Refined with monitoring data and %CT. 

As Tables 2 and 3 make clear, EPA 

does not believe that food exposures to 

chlorpyrifos by themselves present a 

significant risk of AChE inhibition. 

Based on the analysis above, EPA would 

therefore not be proposing the 

revocation of chlorpyrifos if dietary 

exposures were confined to food. As 

outlined below, however, EPA believes 

that for some portions of the country, 

food exposures, when aggregated with 

residential exposures and potentially 

more significant drinking water 

exposures, do present a significant risk 

concern and support revocation of all 

chlorpyrifos tolerances. 

iv. Residential (non-occupational) 

exposure/risk characterization. As 

explained above in Unit V.B.3., in 

assessing dietary risk under the FFDCA, 

EPA must consider not only direct 

dietary exposure from food and drinking 

water, but also non-occupational 

exposures to the pesticide, such as 

residential exposure and bystander 

exposure from the use of agricultural 

pesticides. For simplicity, EPA refers to 

its assessment of all such exposures as 

its ‘‘residential exposure assessment.’’ 

For chlorpyrifos, the vast majority of 

residential use products were cancelled 

as of 2001. Current chlorpyrifos 

residential uses now include a granular 

fire ant mound use (commercial 

applicator only) and ant and roach bait 

in child-resistant packaging 

(homeowner applicator). Additionally, 

chlorpyrifos is labeled for public health 

aerial and ground-based fogger ULV 

mosquito adulticide applications and 

for golf course turf applications. For the 

purpose of residential exposure 

assessment, the parent compound 

chlorpyrifos is the residue of concern. 

With respect to bystander exposure, 

EPA’s worker protection standard 

prohibits using any pesticide in a way 

that will contact either workers or 

bystanders through spray drift. Further, 

in connection with EPA’s 2012 spray 

drift evaluation, EPA imposed 

additional no-spray buffers to limit 

deposition of chlorpyrifos through drift 

in areas adjacent to agricultural fields 

where bystanders may be present 

following application. With respect to 

bystander exposure to volatilized (vapor 

form) chlorpyrifos following 

application, as noted in Unit VI.A., 

recently submitted rat acute toxicity 

studies of vapor phase chlorpyrifos 

along with available subchronic vapor 

phase inhalation studies support a 

conclusion that acute exposure to the 

saturated vapor of chlorpyrifos or its 

oxon do not result in hazard due to 

AChE inhibition. Accordingly, EPA 

concludes that with the additional no 

spray buffer restrictions, risk concerns 

to bystanders from spray drift have been 

eliminated and therefore bystander 

exposures are not included as part of 

EPA’s aggregate risk assessment. 

Residential Handler Exposure. EPA 

uses the term ‘‘handlers’’ to describe 

those individuals who are involved in 

the pesticide application process. EPA 

believes that there are distinct tasks 

related to applications and that 

exposures can vary depending on the 

specifics of each task. Residential (nonoccupational) handlers are addressed 

somewhat differently by EPA as 

homeowners are assumed to complete 

all elements of an application without 

use of any protective equipment. 

Based upon review of all chlorpyrifos 

registered uses, only the ant and roach 

bait products can be applied by a 

homeowner in a residential setting. 

Because the ant and roach bait products 

are designed such that the active 

ingredient is contained within a bait 

station, the potential for contact with 

the chlorpyrifos-containing bait material 

has been eliminated and therefore these 

products do not pose a risk concern. 

Residential Post-Application 

Exposure. There is the potential for 

post-application exposures as a result of 

being in an environment that has been 

previously treated with chlorpyrifos. 

Chlorpyrifos can be used in areas 

frequented by the general population 

including golf courses and as an aerial 

and ground-based ULV mosquito 

adulticide applications made directly in 

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residential areas. Post-application 

exposure from residential fire ant 

mound treatment is not quantitatively 

assessed here as exposures are 

considered to be negligible and do not 

pose a risk concern; these products can 

only be applied professionally and EPA 

therefore does not anticipate direct nonoccupational exposure with treated ant 

mounds. 

In the RHHRA which supports this 

rule, EPA has updated the postapplication exposure assessment to 

reflect: (1) Use of the PBPK–PD model 

for determining toxicological PoDs; (2) 

use of the 2012 Residential SOPs (Ref. 

28); (3) use of the AgDISP model for 

estimation of airborne concentrations 

and residue dissipation following 

chlorpyrifos mosquito adulticide 

applications; (4) updated methodology 

for determining the airborne 

concentration of active ingredient 

following ground-based mosquito 

adulticide applications; and (5) use of 

updated body weights for all residential 

populations assessed. 

In addition, EPA utilized only steady 

state durations of exposure in the 

updated residential assessment. The 

steady state endpoint selection for 

chlorpyrifos overlaps EPA’s traditional 

short-term exposure duration endpoint 

selection and is considered health 

protective for both short- and 

intermediate-term exposures. 

The quantitative exposure/risk 

assessment for residential postapplication exposures is based on the 

following scenarios: 

Golf Course Use (Emusifiable 

Concentrate (EC) and Granular (G) 

Formulations) 

• Children 6 to <11 years old, youths 

11 to <16 years old, and adult postapplication dermal exposure from 

contact with treated turf while golfing. 

Public Health Mosquito Adulticide Use 

(Aerial and Ground Applications) 

• Children 1 to <2 years old and adult 

post-application dermal exposure from 

contact with turf following the 

deposition of chlorpyrifos residues from 

public health mosquito adulticide 

application. 

• Children 1 to <2 years old and adult 

post-application inhalation exposure 

from airborne chlorpyrifos following 

public health mosquito adulticide 

application. 

• Children 1 to <2 years old postapplication incidental oral (hand-tomouth) exposure from contact with turf 

following the deposition of chlorpyrifos 

residues from public health mosquito 

adulticide application. 

• Children 1 to <2 years old postapplication incidental oral (object-tomouth) exposure from contact with toys 

containing residues from turf following 

the deposition of chlorpyrifos residues 

from public health mosquito adulticide 

application. 

The following assumptions and 

exposure factors served as the basis for 

completing the residential postapplication risk assessment. These 

assumptions and factors are described 

in detail in the updated occupational 

and residential exposure and risk 

assessment. (Ref. 74). 

Exposure Duration: Residential postapplication exposures to chlorpyrifos 

are assumed to be steady state (i.e., 21 

days or longer). 

The application of mosquitocide in 

residential areas may result in the 

potential for post-application inhalation 

exposures. The aerosolized particulate 

remaining following application is 

assumed to persist for no longer than 

one hour in proximity of the application 

source and, accordingly, would be most 

appropriately defined as acute in 

duration. However, this assessment 

assumes that post-application inhalation 

exposures are steady state which is a 

highly conservative approach given how 

infrequently mosquitocides are 

repeatedly applied to the same locations 

and how rapidly aerosols dissipate after 

these types of applications. The 

parameters used to define this exposure 

scenario in the PBPK–PD model 

conservatively reflect daily, one hour 

exposures for 21 days. 

Application Rates: In order to seek 

clarification of chlorpyrifos usage, the 

agency compiled a master use summary 

document reflective of the use profile of 

all active product labels. The document, 

among other information, presents all 

registered uses of chlorpyrifos and 

corresponding maximum single 

application rates, equipment types, 

restricted entry intervals (REIs), etc. 

This assessment assumes that the 

detailed information on application 

rates and use patterns presented in 

Appendix 9 (Master Use Summary 

Document) in support of the 2014 

RHHRA will be implemented on all 

chlorpyrifos labels and is the basis of 

the occupational and residential risk 

assessment. If, for any reason, the final 

chlorpyrifos labels contain higher 

application rates, the actual risks posed 

by those products may exceed the risks 

estimated in this assessment. 

Body Weights: The body weights 

assumed for this assessment differ from 

those used in 2011 residential exposure 

assessment and are based on the 

recommendations of the 2012 

Residential SOPs. These body weights 

are the same as selected for derivation 

of PBPK–PD PoDs for use in assessment 

of residential exposures. 

The standard body weights are as 

follows: Youths 11 to <16 years old, 57 

kg; children 6 to <11 years old, 32 kg; 

and children 1 to <2 years old, 11 kg. 

For adults when an endpoint is not sexspecific (i.e., the endpoints are not 

based on developmental or fetal effects) 

a body weight of 80 kg is typically used 

in risk assessment. However, in this 

case, a female-specific body weight of 

69 kg was used. While the endpoint of 

concern, RBC AChE inhibition, is not 

sex-specific, the female body weight 

was used due to concerns for 

neurodevelopmental effects related to 

early life exposure to chlorpyrifos. 

Post-application exposures from 

golfing have been assessed using the 

2012 Residential SOPs and with use of 

exposure data from a chemical-specific 

turf transferable residue (TTR) study. 

The study was conducted with an 

emulsifiable concentrate, a granular, 

and a wettable powder formulation. 

Only the emulsifiable concentrate and 

granular data were used because there 

are no currently registered wettable 

powder formulations. The study was 

conducted in 3 states, California, 

Indiana and Mississippi, with use of the 

emulsifiable concentrate and wettable 

powder formulations. Exposure was 

estimated by normalizing Day 0 TTR 

measures from study application rates to 

the current maximum application rate 

allowable by the label. Chlorpyrifos 

oxon residues were not analyzed. 

The post-application exposure 

potential from public health mosquito 

adulticide applications has been 

considered for both ground based truck 

foggers and aerial applications. For 

assessment of the mosquito adulticide 

use, the algorithms and inputs 

presented in the 2012 Residential SOP 

Lawns/Turf section were used coupled 

with the available TTR data described 

above. The deposition of chlorpyrifos 

from these applications are not based on 

the application rate alone, but also using 

the AgDISP (v8.2.6) model (aerial 

applications, the currently 

recommended model for assessment of 

mosquito adulticide applications) or 

empirical data (ground applications) to 

determine how much pesticide is 

deposited on residential lawns as a 

result of mosquito adulticide treatments 

at the maximum application rates for 

each. The TTR data are then used to 

determine the fraction of the total 

residue deposited following the 

mosquitocide application which can 

result in exposures to impacted 

individuals. Inhalation exposures are 

also estimated using AgDrift for aerial 

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application and a recently developed 

well-mixed box (WMB) model approach 

for outdoor foggers. 

EPA used the AgDISP (v8.2.6) model 

to estimate the deposition of 

chlorpyrifos from aerial applications 

and the airborne concentration of 

chlorpyrifos following public health 

mosquitocide application. AgDISP 

predicts the motion of spray material 

released from aircraft, and determines 

the amount of application volume that 

remained aloft and the amount of the 

resulting droplets deposited on the 

surfaces in the treatment area, as well as 

downwind from the treatment area. The 

model also allows for the estimation of 

air concentrations in the breathing 

zones of adults and children for use in 

calculating the post-application 

inhalation risks to individuals residing 

in areas being treated by aerial 

application of chlorpyrifos. The aerial 

fraction of the mosquito adulticide 

application rate applied (0.010 lb ai/A) 

is 0.35 (i.e., 35 percent of application 

rate is deposited on turf); and the 

airborne concentration at the breathing 

height of adults and children of 

chlorpyrifos 1 hour following aerial 

mosquito adulticide application is 

0.00060 mg/m3. 

EPA used empirical data to derive the 

ground-based deposition of chlorpyrifos 

following public health mosquitocide 

application. These data, conducted by 

Moore et al. (Ref. 75) and Tietze et al. 

(Ref. 76), measured the deposition of 

malathion via ULV ground equipment 

as applied for mosquito control. Based 

on these data, EPA used an off-target 

deposition rate of 5 percent of the 

application rate to evaluate groundbased ULV applications (i.e., 5 percent 

of the target application rate deposits on 

turf). A value slightly higher than the 

mean values for both studies was 

selected because of the variability in the 

data and the limited number of data 

points. The adjusted application rate 

was then used to define TTR levels by 

scaling the available TTR data as 

appropriate. 

In order to calculate airborne 

concentrations from ULV truck fogger 

applications, EPA used the 2012 

Residential SOPs for Outdoor Fogging/ 

Misting Systems, with minimal 

modification to the well-mixed box 

(WMB) model. The WMB model allows 

for the estimation of air concentrations 

in the breathing zones of adults and 

children for use in calculating the postapplication inhalation exposure to 

individuals residing in areas being 

treated by ground application of 

chlorpyrifos. This methodology is a 

modification of the previous method 

used in the 2011 occupational and 

residential exposure assessment to 

evaluate post-application inhalation 

exposure resulting from truck mounted 

mosquito fogger. The revised 

methodology more accurately accounts 

for dilution. 

Combining Residential Exposure and 

Risk Estimates. Since dermal, incidental 

oral, and inhalation exposure routes 

share a common toxicological endpoint, 

RBC AChE inhibition risk estimates 

have been combined for those routes. 

The incidental oral scenarios (i.e., handto-mouth, object-to-mouth, and soil 

ingestion) should be considered interrelated, as it is likely that these 

exposures are interspersed over time 

and are not each occurring 

simultaneously. Combining all three of 

these scenarios with the dermal and 

inhalation exposure scenarios would be 

unrealistic because of the conservative 

nature of each individual assessment. 

Therefore, the post-application exposure 

scenarios that were combined for 

children 1 <2 years old are the dermal, 

inhalation, and hand-to-mouth 

scenarios (the highest incidental oral 

exposure expected). This combination 

should be considered a protective 

estimate of children’s exposure to 

pesticides. 

Summary of Residential Postapplication Non-Cancer Exposure and 

Risk Estimates. The assessment of 

steady state golfer post-application 

exposures (dermal only) to chlorpyrifos 

treated turf for the lifestages adults, 

children 6 to <11 years old, and youths 

11 to <16 years old, results in no risks 

of concern (i.e., children 6 to <11 and 

youths 11 to <16 years old, MOEs are 

≥40; adults, MOEs are ≥100). For the 

assessment of post-application 

exposures from public health 

mosquitocide applications, no 

combined risks of concern were 

identified for adults (dermal and 

inhalation) and children 1 to <2 years 

old (dermal, incidental oral, and 

inhalation). A summary of risk estimates 

is presented in Table 4. 

TABLE 4—RESIDENTIAL POST-APPLICATION NON-CANCER EXPOSURE AND RISK ESTIMATES FOR CHLORPYRIFOS

Lifestage 

Post-application exposure scenario 

Application rate 1 State 

(TTR data) 

Dose 

(mg/kg/day) 3 MOEs 4 Combined routes 5

Combined 

MOEs 6

Use site Route of exposure 

Adult (Females) .....

Youths 11 to <16 

yrs old.

Golf Course Turf ..

...............................

Dermal ..................

...............................

1.0 (Emulsifiable 

Concentrate).

...............................

CA ..............

IN ................

MS ..............

Mean ..........

CA ..............

0.010 ....................

0.0069 ..................

0.012 ....................

0.0095 ..................

0.010 ....................

1,400 

2,100 

1,200 

1,500 

1,600 

NA 

..................

..................

..................

..................

NA 

..................

..................

..................

..................

IN ................ 0.0069 .................. 2,300 .................. ..................

MS .............. 0.012 .................... 1,400 .................. ..................

Mean .......... 0.0096 .................. 1,700 .................. ..................

Children 6 to <11 

years old.

............................... ............................... ............................... CA .............. 0.012 .................... 2,100 .................. ..................

IN ................ 0.0082 .................. 3,100 .................. ..................

MS .............. 0.014 .................... 1,800 .................. ..................

Mean .......... 0.011 .................... 2,200 .................. ..................

Adult (Females) ..... ............................... ............................... 1.0 (Granular) ....... CA .............. 0.0088 .................. 1,600 .................. ..................

Youths 11 to <16 

yrs old.

............................... ............................... ............................... .................... 0.0088 .................. 1,900 .................. ..................

Children 6 to <11 

years old.

............................... ............................... ............................... .................... 0.010 .................... 2,400 .................. ..................

Adult (Females) ..... Aerial and Ground 

Based ULV 

Mosquitocide 

Applications.

Dermal ..................

Inhalation ..............

0.010 (Aerial) ........ MS ..............

NA ..............

0.00052 ................

0.00060 (mg/m3) ..

75,000 

10,300 

X 

X 

9,100 

Children 1 to <2 yrs 

old.

Mosquitocide Applications.Dermal ..................

Inhalation ..............

............................... MS ..............

NA2 ............

0.00088 ................

0.00060 (mg/m3) ..

210,000 

4,000 

X 

X 

2,300 

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TABLE 4—RESIDENTIAL POST-APPLICATION NON-CANCER EXPOSURE AND RISK ESTIMATES FOR CHLORPYRIFOS— 

Continued 

Lifestage 

Post-application exposure scenario 

Application rate 1 State 

(TTR data) 

Dose 

(mg/kg/day) 3 MOEs 4 Combined 

routes 5

Combined 

MOEs 6

Use site Route of exposure 

Hand-to-Mouth ..... ............................... MS .............. 0.000018 .............. 5,600 X 

Object-to-Mouth .... ............................... MS .............. 5.5 × 10¥7 ............ 180,000 NA NA 

Soil Ingestion ........ ............................... NA2 ............ 1.2 × 10¥7 ............ 4,900,000 NA NA 

Adult (Females) ..... ............................... Dermal .................. 0.010 (Ground) ..... MS .............. 0.000074 .............. 520,000 X 1,200 

Inhalation .............. ............................... NA .............. 0.0051 (mg/m3) .... 1,200 X 

Children 1 to <2 yrs ............................... Dermal .................. ............................... MS .............. 0.00013 ................ 1,500,000 X 460 

old. ............................... Inhalation .............. ............................... NA .............. 0.0051 (mg/m3) .... 460 X ..................

Hand-to-Mouth ..... ............................... MS .............. 2.6 × 10¥6 ............ 39,000 X 

Object-to-Mouth .... ............................... MS .............. 7.9 × 10¥8 ............ 1,300,000 NA NA 

Soil Ingestion ........ ............................... NA2 ............ 1.7 × 10¥8 ............ 34,000,000 NA NA 

1Based on the maximum application rates registered for golf course turf and ULV mosquito adulticide uses. 

2The airborne concentrations of chlorpyrifos following ULV mosquito adulticide applications was determined with use of the AgDISP (v8.2.6) model. 

3 Dose (mg/kg/day) equations for golfing and mosquitocide applications are provided in Appendices B and C (Ref. 1) of the updated occupational and residential exposures assessment. For calculation of doses (i.e., dermal, hand-to-mouth, and object-to-mouth) from exposure to ULV mosquito adulticide, TTR data was used. The 

MS TTR data was selected for use because it is the worst case and, as a result, most protective of human health. Additionally, the fraction of chlorpyrifos residue deposited following mosquitocide application, 35% (0.35), was determined with use of the AgDISP (v8.2.6) model and used for dose calculation. The fraction of 

chlorpyrifos deposited following ground ULV application, 5% (0.050), is based on surrogate exposure data (malathion). For dose estimation from exposures to golfing 

on treated turf, on the TTR data was used. Doses have been presented for all State sites, including the mean of all State sites. 4 MOE = PoD (mg/kg/day) ÷ Dose (mg/kg/day). 5X indicates the exposure scenario is included in the combined MOE; NA = Not applicable. 

6 Combined MOE = 1 ÷ (1/dermal MOE) + (1/inhalation MOE) + (1/incidental oral MOE), where applicable. 

v. Aggregating exposures and 

developing the drinking water level of 

concern. Consistent with FFDCA section 

408(b)(2)(D)(vi), EPA considers and 

aggregates (adds) pesticide exposures 

and risks from three major sources: 

Food, drinking water, and residential 

exposures. In an aggregate assessment, 

exposures from relevant sources are 

added together and compared to 

quantitative estimates of hazard, or the 

risks themselves can be aggregated. The 

durations of exposure identified for 

chlorpyrifos uses are acute and steady 

state. The acute aggregate assessment 

includes high end exposure values for 

food and drinking water but does not 

include residential exposure estimates. 

The steady state aggregate assessment 

includes food, drinking water, and 

residential exposures and for 

chlorpyrifos it is protective of the acute 

aggregate risks because examination 

indicates it results in higher risk 

estimates for all situations—so in effect 

acute residential exposures have also 

been considered in the aggregate risk 

assessment process. 

For purposes of this proposed rule, 

EPA is using a DWLOC approach to 

aggregate risk. Under this approach, 

EPA calculates the amount of exposure 

available in the total ‘risk cup’ for 

chlorpyrifos oxon in drinking water 

after accounting for any chlorpyrifos 

exposures from food and/or residential 

use. 

The DWLOC approach for this 

proposed rule uses a reciprocal MOE 

calculation method for adults (females 

of childbearing age) since the target 

MOEs are the same for all relevant 

sources of exposure, i.e., 100X for 

residential dermal and for dietary food 

and water. This entails calculating the 

MOE for water (MOEwater) by 

deducting the contributions from food 

(MOEfood) and residential dermal 

exposure (MOEdermal) from the 

aggregate MOE (MOEagg) of 100. The 

aggregate MOE value is the same as 

target MOE (level of concern). The 

DWLOC is then calculated by dividing 

the PoDwater by the MOEwater. The 

general reciprocal MOE formula is as 

follows: 

MOEagg = 1/((1/MOEwater) + (1/

MOEfood) + (1/MOEdermal)) 

MOEwater = 1/((1/MOEagg)¥((1/

MOEfood) + (1/MOEdermal))) 

DWLOC= PoDwater/MOEwater 

When target MOEs (levels of concern) 

are not the same across the relevant 

sources of exposure, the reciprocal MOE 

approach for calculating DWLOCs is not 

appropriate; instead an aggregate risk 

index (ARI) method is used. For 

purposes of this proposed rule, EPA 

therefore employed the ARI method for 

infants, children, and youths because 

the target MOEs for the relevant sources 

of exposure are not the same i.e., the 

target MOE for dietary food and for 

residential dermal exposures is 40X 

while the target MOE for drinking water 

exposure is 50X. In this approach, the 

aggregate, or ‘total’, ARI value is 

assigned as 1 (EPA is generally 

concerned when any calculated ARIs 

are less than 1). Similar to the reciprocal 

MOE approach, the ARIs for food and 

dermal are deducted from the aggregate 

ARI to determine the ARI for water. The 

water ARI is multiplied by the target 

MOE for water to determine the 

calculated water MOE (MOEwater). The 

DWLOC is then calculated by dividing 

the PoDwater by the MOEwater. The 

general ARI method formula is as 

follows: 

ARIs for food or dermal are calculated 

as ARIfood or dermal = (MOEfood or 

dermal)/(MOEtarget for food or 

dermal)). 

ARIagg = 1/((1/ARIwater) + (1/ARIfood) 

+ (1/ARIdermal)) 

ARIwater = 1/((1/ARIagg)¥((1/ARIfood) 

+ (1/ARIdermal))); Where ARIagg = 

1 

MOEwater = ARIwater × MOEtarget. 

DWLOC = PoDwater/MOEwater 

Determination of Acute DWLOC. The 

acute aggregate assessment includes 

only food and drinking water. The acute 

DWLOCs were calculated for infants, 

children, youths, and adults and are 

presented in Table 5. The lowest acute 

DWLOC calculated was for infants (<1 

year old) at 24 ppb. Acute exposures 

greater than 24 ppb are generally 

considered a risk concern and unsafe for 

purposes of FFDCA section 408(b). 

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TABLE 5—ACUTE AGGREGATE (FOOD AND DRINKING WATER) CALCULATION OF DWLOCS 1 2

Population 

Food exposure 

(chlorpyrifos) 3

Drinking water exposure 

(chlorpyrifos) 4 Acute DWLOC 5

(ppb chlorpyrifos oxon) 

MOE ARI MOE ARI 

Infants 1 (<1 yr) .................................................... 2200 55 50 1.0 24 

Children 1 (1–2 yrs) .............................................. 1400 35 50 1.0 60 

Youths 1 (6–12 yrs) .............................................. 2800 70 50 1.0 150 

Adults 2 (Females 13–49 yrs) ............................... 3100 NA 100 NA 53 

1 DWLOCs for infants, children and youths are calculated using the ARI (Aggregate Risk Index) approach since target MOEs are different for 

drinking water (chlorpyrifos oxon target MOE = 50) and for food and residential (chlorpyrifos target MOE = 40) exposure. 2 DWLOCs for adults (females 13–49 years) are calculated using the reciprocal MOE approach since the target MOEs are the same for drinking water (chlorpyrifos oxon target MOE = 100) and for food and residential (chlorpyrifos target MOE = 100) exposure. 3FOOD: MOEfood = PoDfood (ug/kg/day) (from Table 4.8.4)/Food Exposure (ug/kg/day) (from Table 5.4.3). ARIfood = ((MOEfood)/

(MOEtarget)). 4WATER (ARI approach): ARIwater = 1/((1/ARIagg)¥((1/ARIfood) + (1/ARIdermal))); Where ARIagg = 1 (Note: EPA is generally concerned 

when calculated ARIs are less than 1). MOEwater = ARIwater × MOEtarget. WATER (Reciprocal MOE approach): MOEwater = 1/((1/

MOEagg)¥((1/MOEfood) + (1/MOEdermal))); Where MOEagg =Target MOE. 5 DWLOC: DWLOC ppb = PoDwater (ppb; from Table 4.8.4)/MOEwater. 

Determination of Steady State 

DWLOC. The steady state aggregate 

assessment includes dietary exposures 

from food and drinking water and 

dermal exposures from residential uses 

(dermal exposures represent the highest 

residential exposures). The steady state 

DWLOCs were calculated for infants, 

children, youths, and adults and are 

presented in Table 6. The lowest steady 

state DWLOC calculated was for infants 

(<1 year old) at 3.9 ppb. Exposures to 

chlorpyrifos oxon in drinking water at 

levels that exceed the steady state 

DWLOC of 3.9 ppb are therefore a risk 

concern and are considered unsafe for 

purposes of FFDCA section 408(b). 

TABLE 6—STEADY STATE AGGREGATE (FOOD, DRINKING WATER, RESIDENTIAL) CALCULATION OF DWLOCS 1 2

Population 

Food exposure 

(chlorpyrifos) 3

Dermal exposure 

(chlorpyrifos) 4

Drinking water exposure 

(chlorpyrifos oxon) 5

Steady state 

DWLOC 6

(ppb 

chlorpyrifos 

oxon) MOE ARI MOE ARI MOE ARI 

Infants 1 (<1 yr) ............ 550 14 NA NA 55 1.1 3.9 

Children 1 (1–2 yrs) ...... 410 10 NA NA 55 1.1 10 

Youths 1 (6–12 yrs) ...... 700 18 1800 45 55 1.1 16 

Adults 2 (Females 13– 

49 yrs) ...................... 1000 NA 1200 NA 120 NA 7.8 

1 DWLOCs for infants, children and youths are calculated using the ARI (Aggregate Risk Index) approach since target MOEs are different for 

drinking water (chlorpyrifos oxon target MOE = 50) and for food and residential (chlorpyrifos target MOE = 40) exposure. 2 DWLOCs for adults (females 13–49 years) are calculated using the reciprocal MOE approach since the target MOEs are the same for drinking water (chlorpyrifos oxon target MOE = 100) and for food and residential (chlorpyrifos target MOE = 100) exposure. 3FOOD: MOEfood = PoDfood (ug/kg/day) (from Table 4.8.4)/Food Exposure (ug/kg/day) (from Table 5.4.4). ARIfood = ((MOEfood)/

(MOEtarget)). 4 DERMAL: MOEdermal = PoDdermal (ug/kg/day) (from Table 4.8.4)/Dermal Exposure (ug/kg/day) (from Table 6.2). ARIdermal = ((MOE dermal)/(MOEtarget)). 5WATER (ARI approach): ARIwater = 1/((1/ARIagg)¥((1/ARIfood) + (1/ARIdermal))); Where ARIagg = 1 (Note: EPA is generally concerned 

when calculated ARIs are less than 1). MOEwater = ARIwater × MOEtarget. WATER (Reciprocal MOE approach): MOEwater = 1/((1/

MOEagg)¥((1/MOEfood) + (1/MOEdermal))); Where MOEagg = Target MOE. 6 DWLOC: DWLOC ppb = PoDwater (ppb; from Table 4.8.4)/MOEwater. 

vi. Estimating aggregate riskÐ 

comparing DWLOCs to estimated 

drinking water concentrations. In a 

DWLOC aggregate risk assessment, the 

calculated DWLOC is compared to the 

EDWC. When the EDWC is less than the 

DWLOC, there are no risk concerns for 

exposures to the pesticide in drinking 

water. Conversely, when the EDWC is 

greater than the DWLOC, there may be 

a risk concern. For chlorpyrifos, 

DWLOCs were calculated for both the 

acute and steady state aggregate 

assessments for infants, children, youths 

and adult females. However, for the 

national screening level drinking water 

assessment, only the steady state 

DWLOCs were compared to the 

modeled EDWCs (based on a national 

screen). The calculated steady state 

DWLOCs are much lower than those for 

the acute. For example, for infants, the 

lowest acute DWLOC is 24 ppb while 

the lowest steady state DWLOC is 3.9 

ppb (Tables 5 and 6). Since the lowest 

DWLOC calculated for any duration or 

population was the 3.9 ppb steady state 

exposure value (infants), it is the 

concentration used for comparison to 

EPA’s modeled EDWCs. Drinking water 

concentrations of chlorpyrifos oxon 

above 3.9 ppb may therefore be unsafe. 

Were EPA to conduct further analyses 

that compared all acute exposures to 

EDWC, it is possible that for some 

limited numbers of use scenarios, the 

EDWC could result in an exceedance of 

the acute DWLOC, but not the steady 

state DWLOC. However, because EPA is 

proposing to revoke all tolerances based 

on the steady state DWLOC, it is 

unnecessary to address that issue at this 

time. 

EDWCs in Groundwater and Surface 

Water. EPA conducted a national 

screening level drinking water 

assessment for both groundwater and 

surface water, with focus on the 

agricultural uses. For both assessments, 

EPA calculated EDWCs for chlorpyrifos 

and chlorpyrifos oxon. Chlorpyrifos 

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EDWCs were multiplied by 0.9541 

(molecular weight correction factor) and 

100% (maximum conversion during 

water purification) to generate 

chlorpyrifos oxon EDWCs. EPA used a 

100% conversion factor for the 

oxidation of chlorpyrifos to chlorpyrifos 

oxon as an approximation based on 

empirical bench scale laboratory data 

that indicate chlorpyrifos rapidly 

oxidizes to form chlorpyrifos oxon 

almost completely during typical water 

treatment (chlorination). (Ref. 77). There 

are limited data available on the 

removal efficiency of chlorpyrifos prior 

to oxidation or the removal efficiency of 

chlorpyrifos oxon during the drinking 

water treatment process. Based on 

community water systems survey 

showing that more than 75 percent of 

community water systems use 

chlorination to disinfect drinking water 

in the United States (Ref. 78), the 

assumption of exposure to chlorpyrifos 

oxon equivalent to 100% conversion of 

chlorpyrifos is not considered overly 

conservative. It is possible that some 

drinking water treatment procedures, 

such as granular activated carbon 

filtration and water softening (increased 

rate of chlorpyrifos oxon hydrolysis at 

pH > 9) could reduce the amount of 

chlorpyrifos oxon in finished drinking 

water; however, these treatment 

methods are not typical practices across 

the country for surface water. 

While there is the potential to have 

both chlorpyrifos and chlorpyrifos oxon 

present in finished drinking water, no 

information is available to readily 

quantify how much of each form 

remains in the finished water. In the 

absence of available information, EPA 

conservatively assumes that 100% of 

chlorpyrifos that enters a drinking water 

treatment facility exists after treatment 

and that during treatment 100% of it 

converts to chlorpyrifos oxon. 

Although chlorpyrifos oxon has a 

hydrolysis half-life of 5 days, the 

drinking water treatment simulation 

half-life for chlorpyrifos oxon is 

approximately 12 days. (Refs. 79, 80, 

and 81). Hydrolysis of chlorpyrifos oxon 

under simulated drinking water 

treatment processes is slower when 

compared to hydrolysis of chlorpyrifos 

oxon in water only; thus, the use of a 

half-life of 12 days under simulation. 

Therefore, once chlorpyrifos oxon forms 

during treatment, little transformation is 

expected to occur before consumption 

(during drinking water distribution). 

There are a wide range of treatment 

processes and sequences of treatment 

processes employed at community 

water systems across the country and 

there are limited data available on a 

community-water-system-specific basis 

to assess the removal or transformation 

of chlorpyrifos during treatment. These 

processes are not specifically designed 

to remove pesticides and pesticide 

transformation products including 

chlorpyrifos and chlorpyrifos oxon. In 

general, drinking water treatment 

processes, with the exception of 

activated carbon (Ref. 82), have been 

shown to have little impact on removal 

of conventional pesticides. 

To illustrate the range of EDWC, two 

maximum label rate application 

scenarios were selected to represent 

high and low end exposures, i.e., tart 

cherries at 5 applications totaling 14.5 

pounds per acre per year, and bulb 

onions at a single application of one 

pound per acre per year, respectively. 

To estimate groundwater EDWCs for 

chlorpyrifos and chlorpyrifos oxon, EPA 

conducted a conservative Tier I 

assessment using SCI–GROW (Screening 

Concentration in Groundwater, version 

2.3, August 8, 2003) and PRZMGroundwater (PRZM–GW version 1.0, 

December 11, 2012), using the GW–GUI 

(Graphical User Interface, version 1.0, 

December 11, 2012). (Ref. 83). For this 

assessment, EPA used the results from 

the model (either SCI–GROW or PRZM– 

GW) that provided the highest EDWCs. 

Despite the conservative assumptions 

used in the Tier I models, as presented 

below in Table 7 estimated groundwater 

EDWCs are well below the DWLOCs and 

therefore do not represent a risk 

concern. 

To calculate the national screening 

level surface water EDWCs for 

chlorpyrifos and chlorpyrifos oxon, EPA 

used the Tier II Surface Water 

Concentration Calculator (SWCC) 

version 1.106. The SWCC uses PRZM 

version 5.0+ (PRZM5) and the Variable 

Volume Water Body Model (VVWM). 

PRZM is used to simulate pesticide 

transport as a result of runoff and 

erosion from an agricultural field. 

VVWM estimates environmental fate 

and transport of pesticides in surface 

water. For the national screen, upper 

and lower bound exposure scenarios for 

surface water were modeled using the 

highest application rate (tart cherries), 

and the lowest application rate (bulb 

onions). This analysis showed that even 

with only one application, several 

chlorpyrifos uses may exceed the 

DWLOC at rates lower than maximum 

labeled rates (both single as well as 

yearly), including an application rate of 

one pound per acre per year. The 

analysis also showed that the DWLOC 

exceedances are not expected to be 

uniformly distributed across the 

country. The application of chlorpyrifos 

to tart cherries in Michigan resulted in 

concentrations that exceeded the 

drinking water level of concern 

(DWLOC); whereas, chlorpyrifos 

applications to bulb onions in Georgia 

resulted in concentrations below the 

DWLOC. To investigate with more 

specificity whether other chlorpyrifos 

application scenarios may result in 

concentrations that exceed the DWLOC, 

a screen (A risk assessment screen is a 

procedure designed to quickly separate 

out pesticides uses patterns that meet 

the safety standard from those that may 

not meet the safety standard) of all 

available surface water modeling 

scenarios was completed considering 

three different application dates and a 

single application at several different 

application rates that ranged from one to 

six pounds. 

EPA also conducted a refined, but 

limited analysis of the spatial 

distribution of EDWCs at a regional 

level and at the drinking water intake 

level. This exercise demonstrated that 

chlorpyrifos applications will result in 

variable drinking water exposures that 

are highly localized, with 

concentrations of concern generally 

occurring in small watersheds where 

there is a high percent cropped area 

where chlorpyrifos use is expected. 

Finally, EDWCs were also compared 

to monitoring data. This analysis 

showed that when modeling scenarios 

are parameterized to reflect reported use 

and EDWCs are adjusted to reflect 

percent cropped area, the EDWCs are 

within a range of 10x of the measured 

concentrations reported in the 

monitoring data. In addition, evaluation 

of the monitoring data further illustrates 

that exposures are highly localized. EPA 

is currently conducting a broader 

refined assessment that examines 

EDWCs on a regional and/or watershed 

scale to pin-point community drinking 

water systems where exposure to 

chlorpyrifos oxon as a result of 

chlorpyrifos applications may pose an 

exposure concern. As a result of the 

PANNA decision ordering EPA to 

respond to the PANNA–NRDC Petition 

by October 31, 2015, EPA has not been 

able to complete that assessment in 

advance of this proposed rule. EPA is 

continuing that assessment and will 

update this action with the results of 

that assessment, as warranted. 

Estimated Aggregate RiskÐNational 

Drinking Water Screen Results. To 

determine whether the EDWC exceeds 

the steady state DWLOC of 3.9 ppb, as 

noted above, EPA initially conducted a 

bounding estimate of exposure using a 

screening level national assessment 

approach. The results of that exercise 

are reported in Table 7 for Tier I 

groundwater and Tier II surface water 

model simulations. 

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TABLE 7—ESTIMATED DRINKING WATER CONCENTRATIONS RESULTING FROM THE USE OF CHLORPYRIFOS

Residue 

Surface water Groundwater 

1-in-10 Year peak 

concentration ppb 

21-Day average 

concentration ppb 

1-in-10 Year 

annual average 

concentration ppb 

30 Year annual 

average 

concentration ppb 

SCI–GROW Tier I 

concentration ppb 

Michigan Tart Cherries 

Chlorpyrifos .......................................... 129 83.8 39.2 29.7 0.16 

Chlorpyrifos-oxon ................................. 123 80.0 37.4 28.3 0.15 

Georgia Onion 

Chlorpyrifos .......................................... 6 .2 3.1 1.2 0.8 0.01 

Chlorpyrifos-oxon ................................. 5 .9 3.0 1.1 0.8 0.01 

SCI–GROW resulted in higher EDWCs than PRZM–GW simulations. 

As Table 7 makes clear, the surface 

water EDWCs for the high application 

rate Michigan tart cherry scenario 

significantly exceed the steady state 

DWLOC of 3.9 ppb for chlorpyrifos 

oxon, while the low application rate 

Georgia bulb onion scenario results in 

EDWC below the DWLOC. Given that 

the results of the initial bounding 

estimate showed these mixed results, 

EPA conducted a further evaluation of 

additional use scenarios to determine 

which chlorpyrifos uses do and do not 

exceed the DWLOC, based on a single 

application of chlorpyrifos per year at 1 

and 4 pounds (where permitted by 

labeling) of chlorpyrifos per acre. The 

results for 1 and 4 pounds per acre are 

reported here as a representation of 

what EPA believes to be the range of 

likely chlorpyrifos applications, bearing 

in mind that chlorpyrifos can be applied 

at lower and higher single rates (e.g., an 

application rate of 6 pounds per acre on 

citrus). This analysis showed that the 

current maximum application rate 

scenarios, as well as maximum single 

application rates for a wide range of 

chlorpyrifos use scenarios, may result in 

a 21-day average concentration that 

exceeds the DWLOC. Table 8 represents 

the use scenarios that resulted in 

exceedances of the DWLOC from a 

single application to the crop and it 

shows the estimated percentage of 21- 

day intervals over a 30-year period for 

which the average concentration is 

expected to exceed the DWLOC. 

TABLE 8—NATIONAL SCREENING RESULTS USING DWLOC APPROACH—SCENARIO REPRESENTATION AND LABELED RATE

COMPARISON FOR EXAMPLE USES THAT EXCEED THE DWLOC 

Scenario 

Highest 21-day average 

concentration ppb 

(application date) 

21-Day 

exceedance 

count Represented use site examples 

(maximum single application rate) 

Percent a

1 lb a.i./A 

MScornSTD .............................

TXcornOP ................................

16.5 at 1.0 lb a.i./A .................

13.9 at 1.0 lb a.i./A 

21 

13 

Corn [2 lb a.i./A (aerial and ground)]. 

Soybean [1 lb a.i./A (aerial); 2.2 (ground)]. 

ILcornSTD ............................... 14.6 at 1.0 lb a.i./A ................. 16 

MScotton .................................

NCcotton ..................................

19.8 at 1.0 lb a.i./Ae ...............

14.4 at 1.0 lb a.i./A .................

16 

25 

Cotton [1 lb a.i./A (foliar aerial and ground); seed treatment 

permitted at 2.2 lb a.i./A]. 

TXcotton .................................. 15.1 at 1.0 lb a.i./A ................. 8 

NYgrape .................................. 15.7 at 1.0 lb a.i./A ................. 27 Grape [2.25 lab a.i./A (ground)]. 

TXsorghumOP ......................... 25.8 at 1.0 lb a.i./A ................. 12 Wheat [1 lb a.i./A (aerial and ground)]. 

Sunflower [2 lb a.i./A (aerial and ground)]. 

TXwheatOP ............................. 21.0 at 1.0 lb a.i./A ................. 6 Other Grains: 

Sorghum [3.3 lb a.i./A (granular) b]. 

Alfalfa [1 lb a.i./A (aerial and ground)]. 

PAVegetableNMC ................... 21.1 at 1.0 lb a.i./A ................. 18 Vegetables and Ground Fruit: 

Strawberry [2 lb a.i./A (aerial and ground)]. 

Radish [3 lb a.i./A (ground) d]. 

Pepper [1 lb a.i./A (ground)] Onion [1 lb a.i./A (ground)]. 

CAlettuce ................................. 12.8 at 1.0 lb a.i./A ................. 8 

MEpotato .................................

NCsweetpotatoSTD .................

10.7 at 1.0 lb a.i./A .................

13.5at 1.0 lb a.i./A ..................

17 

9 

Other Row Crops: 

Tobacco [2 lb a.i./A (aerial and ground)]. 

Sugarbeets [2 lb a.i./A (granular) b]. 

Peanuts [4 lb a.i./A (granular) c] Sweet Potato [2 lb a.i./A 

(aerial and ground)]. 

2 lb a.i./A 

MIcherriesSTD .........................

GApecansSTD .........................

19.6 at 2.0 lb a.i./A .................

20.7 at 2.0 lb a.i./A .................

42 

12 

Orchards and Vineyards (Tree fruit and Nuts): 

Fruit and Nuts [4 lb a.i./A (ground)]. 

Pecans [2 lb a.i./A (air); 4.3 (ground)]. 

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TABLE 8—NATIONAL SCREENING RESULTS USING DWLOC APPROACH—SCENARIO REPRESENTATION AND LABELED RATE

COMPARISON FOR EXAMPLE USES THAT EXCEED THE DWLOC—Continued 

Scenario 

Highest 21-day average 

concentration ppb 

(application date) 

21-Day 

exceedance 

count Represented use site examples 

(maximum single application rate) 

Percent a

PAapples ................................. 29.1 at 2.0 lb a.i./A ................. 11 Apple [2 lb a.i./A (air and ground)]. 

Peach [2 lb a.i./A (air); 3 (ground)]. 

NCPeanutSTD ......................... 21.0 at 2.0 lb a.i./A ................. 21 Peanut: 

2.0 lb a.i./A (aerial and ground) 

4 lb a.i./A (granular ground). 

FLCitrusSTD ............................ 10.1 at 2.0 lb a.i./A ................. 6 Citrus: 

6.0 lb a.i./A [ground including airblast]. 

2.3 lb a.i./A (aerial). 

aThe highest percent of 21-day time periods where the average concentration exceeds the DWLOC. There are approximately 10,000 21-day 

time periods per 30 year simulation; however, it should be noted that not all scenarios contain exactly 30 years of weather data. b (1.0 (air and ground)). 

c (2.0 (air and ground)). 

d Incorporated or in furrow otherwise (1.0 (air and ground)). 

eA preplant seed treatment is permitted at 2.2 lb a.i./A and assumes 100% of the applied material washes off the seed coat in the field and is 

available for transport. 

In summary, EPA’s analysis shows 

that the current maximum single 

application rates for a wide range of 

chlorpyrifos use scenarios result in a 21- 

day average concentration that exceeds 

the DWLOC. And the analysis makes 

clear that exceedances may occur with 

considerable frequency. 

Regional Screen. Although Table 8 

makes clear that numerous labeled 

chlorpyrifos uses result in exceedances 

of the DWLOC on a national basis, EPA 

analysis indicates that exposure is likely 

to be highly localized. While it is 

currently challenging to assess exposure 

on a local scale due to the unavailability 

of data and wide range of characteristics 

(e.g., environmental characteristics such 

as soil, weather, etc. or other variables 

such as drinking water treatment 

processes) that affect the vulnerability of 

a given community drinking water 

system to chlorpyrifos oxon 

contamination, EPA developed a 

method to examine the potential 

geospatial concentration differences for 

two Hydrological Unit Code (HUC) 2 

Regions—HUC 2 Region 17: Pacific 

Northwest and HUC 2 Region 3: South 

Atlantic-Gulf, in order to identify use 

patterns that may result in EDWCs that 

exceed the DWLOC on a regional basis. 

(Ref. 84). This analysis considered all 

potential chlorpyrifos use sites within 

the HUC 2 regions based on the National 

Agricultural Statistics Service cropland 

data layers and survey data. For HUC 2 

Region 17, only four chlorpyrifos use 

patterns were identified as a potential 

concern based on maximum single 

application rates of 1 and 4 pounds per 

acre. However, for HUC 2 Region 3, 

several chlorpyrifos use scenarios were 

identified that could exceed the 

DWLOC, based on the use of available 

scenarios. 

Watershed Screen. The uses that 

exceeded the DWLOC from the regional 

screening exercise for HUC 2 Region 3 

were further explored by utilizing the 

DWI watershed database. This analysis 

shows an overlap of potential 

chlorpyrifos use sites that may result in 

an exceedance of the DWLOC with 

watersheds that supply source water for 

community drinking water systems. In 

addition, this analysis shows that 

exposure is not uniform within a HUC 

2 Region and that some watersheds are 

more vulnerable than others. Watershed 

vulnerability is expected to be greatest 

for smaller watersheds with high 

percent cropped areas. Smaller 

community water systems are generally 

more vulnerable due to short 

distribution times and the reliance of 

chlorination to treat source surface 

water as well as limited access to other 

treatment methods such as granular 

activated carbon. 

As noted above, on August 10, 2015, 

the PANNA decision ordered EPA to 

issue either a proposed or final 

revocation rule or a full and final 

response to PANNA–NRDC 

administrative Petition by October 31, 

2015. As a result of that order, EPA is 

issuing this proposed revocation in 

advance of completing its refined 

drinking water assessment. As a result, 

EPA may update this action with a new 

or modified drinking water analyses as 

EPA completes additional work after 

this proposal. 

Monitoring Data Analysis. In EPA’s 

PHHRA in 2011, the agency evaluated 

water monitoring data from the USGS 

National Water Quality Assessment 

Program (NAWQA), USEPA/USGS Pilot 

Reservoir Monitoring Program, USDA 

PDP, and California Department of 

Pesticide Regulation (CDPR). The 

monitoring data showed chlorpyrifos 

detections at low concentrations, 

generally not exceeding 0.5 mg/L. For 

example, USGS NAWQA, which 

contains an extensive monitoring 

dataset for chlorpyrifos and chlorpyrifos 

oxon, reports a peak chlorpyrifos 

detection of 0.57 mg/L in surface water 

with a detection frequency of 

approximately 15%. CDPR has detected 

chlorpyrifos concentrations greater than 

1 mg/L in surface water on several 

occasions, with an observed peak 

chlorpyrifos concentration of 3.96 mg/L. 

Sampling frequencies in these 

monitoring programs were sporadic, 

however, and generally range from only 

once per year to twice per month. 

Since the preliminary assessment, 

EPA has evaluated additional water 

monitoring data from Washington State 

Department of Ecology and Agriculture 

(WSDE/WSDA) Cooperative Surface 

Water Monitoring Program (Refs. 85 and 

86), Dow AgroSciences (Ref. 87), and 

Oregon Department of Environmental 

Quality. The previously referenced data 

have also been re-examined to consider 

short-term exposure (i.e., 21-day average 

concentrations) considering the 

importance of the single day exposure 

and the temporal relationship of 

exposure. A summary of all surface 

water monitoring data examined to date 

for chlorpyrifos are presented in Table 

9. Some of the monitoring programs 

analyzed for chlorpyrifos oxon; 

however, the number of detections as 

well as the concentrations were 

generally much lower. Since the 

majority of the conversion of 

chlorpyrifos to chlorpyrifos oxon is 

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assumed to occur during drinking water 

treatment, and not in the environment, 

the monitoring data presented in Table 

9 are limited to chlorpyrifos and not its 

oxon. 

TABLE 9—SURFACE WATER MONITORING DATA SUMMARY FOR CHLORPYRIFOS

Monitoring data Scale Years of sampling 

(number of samples) 

Detection frequency 

(%) 

Maximum 

concentration 

(μg/L) 

USGS NAWQA .......................... National ..................................... 1991–2012 (30,542) ................. 15 0 .57 

California Department of Pesticide Regulation.State ......................................... 1991–2012 (13,121) ................. 20 3 .96 

Washington State Department 

of Ecology and Agriculture 

Cooperative Surface Water 

Monitoring Program.

State ......................................... 2003–2013 (4,091) ................... 8 .4 0 .4 

USDA Pesticide Data Program National ..................................... 2004–2009 (raw water; 1,178)

2001–2009 (finished water; 

2,918).

0 na 

USGS–EPA Pilot Drinking 

Water Reservoir.

National ..................................... 1999–2000 (323) ...................... 5 .3 0 .034 

Oregon Department of Environmental Quality.Watershed ................................

(Clackamas) ..............................

2005–2011 (363) ...................... 13 2 .4 

MRID 44711601 (Ref. 87) ......... Watershed ................................

(Orestimba Creek) ....................

1996–1997 (1,089) ................... 61 2 .22 

In general, the monitoring data 

include sampling sites that represent a 

wide range of aquatic environments 

including small and large water bodies, 

rivers, reservoirs, and urban and 

agricultural locations, but are limited for 

some areas of the United States where 

chlorpyrifos use occurs. Also, the 

sampling sites, as well as the number of 

samples, vary by year. In addition, the 

vulnerability of the sampling site to 

chlorpyrifos contamination varies 

substantially due to use, soil 

characteristics, weather and agronomic 

practices. While almost all samples in 

the monitoring results are below EPA’s 

lowest DWLOC (infant steady state 

exposures) of 3.9 ppb, none of the 

monitoring programs examined to date 

were specifically designed to target 

chlorpyrifos use (except the Registrant 

Monitoring Program Ref. 87); therefore, 

peak concentrations (and likely 21-day 

average concentrations) of chlorpyrifos 

and chlorpyrifos oxon likely went 

undetected in these programs. See Table 

9 for a summary of the chlorpyrifos 

surface water monitoring data. 

As a general matter, sampling 

frequency needs to be approximately 

equal to the duration of exposure 

concern. (Ref. 88). The chlorpyrifos 

monitoring data evaluated thus far also 

show that as sample frequency 

increases, so does the detection 

frequency. This is evident in the 

registrant-submitted monitoring data, as 

well as examination of individual 

sampling sites within the various 

datasets. The highest detection 

frequency noted for chlorpyrifos is for 

Marion Drain (a sample site in 

Washington), where 103 samples were 

collected between 2006 and 2008, with 

53 chlorpyrifos detections (51%). 

Therefore, while there is a large 

number of individual samples collected 

and analyzed for chlorpyrifos (or 

chlorpyrifos oxon) across the United 

States, it would not be appropriate to 

combine these data sources to generate 

exposure estimates or to use these 

datasets to represent exposure on a 

national or even regional basis. Thus, 

comparing the monitoring data results 

to the DWLOC would not be a 

reasonable approach for the reasons 

given above, including limited sample 

frequency, limited use information, and 

sampling site variability, on a national 

or even a regional basis. EPA believes 

that model estimated concentrations 

provide more suitable upper bound 

concentrations for chlorpyrifos and 

chlorpyrifos oxon. 

Additionally, model simulations were 

completed to represent two different 

water monitoring datasets—WSDE/

WSDA Cooperative Surface Water 

Monitoring Program (Refs. 85 and 86) 

and Dow AgroSciences (Ref. 87) 

Orestimba Creek. For both of these 

water monitoring programs, enough 

information was available, including 

chlorpyrifos use information as well as 

the PCA, to parameterize the model. In 

these simulations, the modeled EDWCs 

were similar to the measured 

concentrations. This suggests that the 

modeling results are not overly 

conservative and supports the use of the 

model to estimate chlorpyrifos oxon 

concentrations in drinking water. 

As noted above, EPA is continuing to 

work to refine its drinking water 

assessment with the goal of pinpointing 

regions or watersheds where EDWCs 

may exceed the DWLOC. This effort 

would include completing the regional 

assessment presented here for all HUC 

2 Regions and crop uses, as well as 

considering multiple applications per 

year. Because of the PANNA decision 

ordering EPA to respond to the 

PANNA–NRDC Petition by October 31, 

2015, EPA has not been able to complete 

this more refined drinking water 

assessment for chlorpyrifos in advance 

of this proposed rule. As a result, this 

proposal does not provide a basis for 

supporting a more tailored approach to 

risk mitigation. EPA is continuing to 

conduct its regional and water-intake 

level assessment and may update this 

action with the results of that 

assessment when it is completed. 

Summary. EPA’s examination of 

chlorpyrifos agricultural use across the 

country indicates that there are multiple 

uses of chlorpyrifos that may result in 

exposure to chlorpyrifos oxon in 

finished drinking water at levels that 

exceed the 21-day steady state DWLOC 

of 3.9 ppb for infants and children. EPA 

therefore believes that infants and 

children in some portions of the country 

are at some risk from cholinesterase 

inhibition. While there are uncertainties 

associated with the model input 

parameters for which conservative 

assumptions were made (e.g., one 

aerobic aquatic metabolism half-life 

value multiplied by the uncertainty 

factor of three, stable to hydrolysis, 

100% of the cropped watershed is 

treated, and use of the Index Reservoir 

as the receiving waterbody), the 

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modeling is sufficiently representative 

of some vulnerable water bodies that we 

cannot make a safety finding based on 

drinking water exposure. Comparison of 

model estimated concentrations with 

measured concentrations suggests that 

model estimates are consistent with 

measured concentrations when actual 

application rates and representative 

SWCC scenarios are considered and a 

PCA adjustment factor is applied to the 

model estimates. This modeling/

monitoring comparison suggests that 

when growers use maximum 

application rates, or even rates much 

lower than maximum, chlorpyrifos oxon 

concentrations in drinking water could 

pose an exposure concern for a wide 

range of chlorpyrifos uses. However, 

these exposures are not expected to be 

uniformly distributed across the 

country. As noted, additional analyses 

are still being conducted in an effort to 

determine the community water systems 

where concentrations may be of 

concern. While that evaluation may 

ultimately lead to a more tailored 

approach to risk mitigation, at this point 

in time, based on the information before 

EPA, EPA cannot determine that current 

dietary exposures to chlorpyrifos are 

safe within the meaning of FFDCA 

section 408(b)(2)(A). Additionally, 

although EPA’s current assessment 

indicates that the tolerances for food 

service and food handling 

establishments by themselves would not 

present an unsafe risk (since they do not 

result in drinking water exposure), 

because EPA must aggregate all dietary 

and non-occupational exposures to 

chlorpyrifos in making a safety finding 

under the FFDCA, EPA cannot find that 

any current tolerances are safe and is 

therefore proposing to revoke all 

chlorpyrifos tolerances. As noted, 

however, EPA is soliciting comment on 

whether it may be possible to retain 

some group of tolerances. 

vii. Cumulative exposure/risk 

characterization. Section 408(b)(2)(D)(v) 

of the FFDCA provides that when 

determining the safety of a pesticide 

chemical, EPA shall base its assessment 

of the risk posed by the chemical on, 

among other things, available 

information concerning the cumulative 

effects to human health that may result 

from the pesticide’s residues when 

considered together with other 

substances that have a common 

mechanism of toxicity. Chlorpyrifos is a 

member of the OP class of pesticides, 

which share AChE inhibition as a 

common mechanism of toxicity. The 

agency completed a cumulative risk 

assessment for OPs in connection with 

FIFRA reregistration and FFDCA 

tolerance reassessment (Ref. 10) which 

can be found on EPA’s Web site http:// 

www.epa.gov/pesticides/cumulative/

rraop/. To the extent that chlorpyrifos 

tolerances and uses remain following 

this action, prior to the completion of 

the FIFRA registration review for 

chlorpyrifos and the OP class, OPP will 

update the OP cumulative assessment to 

ensure that cumulative dietary 

exposures to the OPs are safe. 

C. When do these actions become 

effective? 

EPA is proposing that the revocation 

of the chlorpyrifos tolerances for all 

commodities become effective 180 days 

after a final rule is published. The 

agency believes this revocation date will 

allow users to exhaust stocks and allow 

sufficient time for passage of treated 

commodities through the channels of 

trade. However, if EPA is presented 

with information that unused stocks 

would still be available and that 

information is verified, the agency will 

consider extending the expiration date 

of associated tolerances. If you have 

comments regarding stocks of remaining 

chlorpyrifos products and whether the 

effective date allows sufficient time for 

treated commodities to clear the 

channels of trade, please submit 

comments as described under 

SUPPLEMENTARY INFORMATION. 

Any commodities listed in this 

proposal treated with the pesticides 

subject to this proposal, and in the 

channels of trade following the 

tolerance revocations, shall be subject to 

FFDCA section 408(1)(5), as established 

by FQPA. That section provides that, 

any residues of the subject pesticide in 

or on such food shall not render the 

food adulterated so long as it is shown 

to the satisfaction of the Food and Drug 

Administration that: 

1. The residue is present as the result 

of an application or use of the pesticide 

at a time and in a manner that was 

lawful under FIFRA, and 

2. The residue does not exceed the 

level that was authorized at the time of 

the application or use to be present on 

the food under a tolerance or exemption 

from tolerance. Evidence to show that 

food was lawfully treated may include 

records that verify the dates when the 

pesticide was applied to such food. 

VII. International Residue Limits and 

Trade Considerations 

The tolerance revocations in this 

proposal are not discriminatory and are 

designed to ensure that both 

domestically-produced and imported 

foods meet the food safety standard 

established by the FFDCA. The same 

food safety standards apply to 

domestically produced and imported 

foods. 

In making its tolerance decisions, EPA 

seeks to harmonize U.S. tolerances with 

international standards whenever 

possible, consistent with U.S. food 

safety standards and agricultural 

practices. EPA considers the 

international maximum residue limits 

(MRLs) established by the Codex 

Alimentarius Commission (Codex), as 

required by FFDCA section 408(b)(4). 

The Codex Alimentarius is a joint 

United Nations Food and Agriculture 

Organization/World Health 

Organization food standards program, 

and it is recognized as an international 

food safety standards-setting 

organization in trade agreements to 

which the United States is a party. 

EPA also ensures that its tolerance 

decisions are in keeping with the World 

Trade Organization’s Sanitary and 

Phytosanitary Measures Agreement. 

Consistent with that agreement, the 

effective date EPA is proposing for the 

revocation of chlorpyrifos tolerances in 

this proposed rule ensures that the 

tolerances will remain in effect for a 

period sufficient to allow a reasonable 

interval for producers in the exporting 

countries to adapt to the requirements of 

these modified tolerances. 

VIII. Statutory and Executive Order 

Reviews 

In this proposed rule, EPA is 

proposing to revoke specific tolerances 

established under FFDCA section 408. 

The Office of Management and Budget 

(OMB) has exempted this type of action 

(e.g., tolerance revocation for which 

extraordinary circumstances do not 

exist) from review under Executive 

Order 12866, entitled ‘‘Regulatory 

Planning and Review’’ (58 FR 51735, 

October 4, 1993). Because this proposed 

rule has been exempted from review 

under Executive Order 12866, this 

proposed rule is not subject to Executive 

Order 13211, entitled ‘‘Actions 

Concerning Regulations That 

Significantly Affect Energy Supply, 

Distribution, or Use’’ (66 FR 28355, May 

22, 2001). 

This proposed rule does not contain 

any information collections subject to 

OMB approval under the Paperwork 

Reduction Act (PRA) (44 U.S.C. 3501 et 

seq.), or impose any enforceable duty or 

contain any unfunded mandate as 

described under Title II of the Unfunded 

Mandates Reform Act (UMRA) (2 U.S.C. 

1501 et seq.). Nor does it require any 

special considerations as required by 

Executive Order 12898, entitled 

‘‘Federal Actions to Address 

Environmental Justice in Minority 

Populations and Low-Income 

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Federal Register / Vol. 80, No. 215 / Friday, November 6, 2015 / Proposed Rules 69107 

Populations’’ (59 FR 7629, February 16, 

1994); or OMB review or any other 

Agency action under Executive Order 

13045, entitled ‘‘Protection of Children 

from Environmental Health Risks and 

Safety Risks’’ (62 FR 19885, April 23, 

1997). However, EPA considered the 

best available science in order to protect 

children against environmental health 

risks and this proposed rule is 

consistent with EPA’s 1995 Policy on 

Evaluating Health Risks to Children 

(http://www2.epa.gov/sites/production/

files/201405/documents/1995_

childrens_health_policy_statement.pdf), 

reaffirmed in 2013 (http://

www2.epa.gov/sites/production/files/

201405/documents/reaffirmation_

memorandum.pdf). 

This proposed rule does not involve 

any technical standards that would 

require Agency consideration of 

voluntary consensus standards pursuant 

to section 12(d) of the National 

Technology Transfer and Advancement 

Act (NTTAA) (15 U.S.C. 272 note). In 

addition, the Agency has determined 

that this proposed rule will not have a 

substantial direct effect on States, on the 

relationship between the national 

government and the States, or on the 

distribution of power and 

responsibilities among the various 

levels of government, as specified in 

Executive Order 13132, entitled 

‘‘Federalism’’ (64 FR 43255, August 10, 

1999). This proposed rule directly 

regulates growers, food processors, food 

handlers, and food retailers, not States. 

This proposed rule does not alter the 

relationships or distribution of power 

and responsibilities established by 

Congress in the preemption provisions 

of FFDCA section 408(n)(4). For these 

same reasons, the Agency has 

determined that this proposed rule does 

not have any ‘‘tribal implications’’ as 

described in Executive Order 13175, 

entitled ‘‘Consultation and Coordination 

with Indian Tribal Governments’’ (65 FR 

67249, November 9, 2000). 

I certify that this action will not have 

a significant economic impact on a 

substantial number of small entities 

under the Regulatory Flexibility Act 

(RFA), 5 U.S.C. 601 et seq. The small 

entities subject to this proposed action, 

which directly regulates growers, food 

processors, food handlers, and food 

retailers, include small businesses but 

not small government jurisdiction or 

small not-for-profit organizations as 

defined by the RFA. 

For purposes of assessing the impacts 

of this proposed revocation on small 

businesses, a small business is defined 

either by the number of employees or by 

the annual dollar amount of sales/

revenues. The level at which an entity 

is considered small is determined for 

each NAICS code by the Small Business 

Administration (SBA). Farms are 

classified under NAICS code 111, Crop 

Production, and the SBA defines small 

entities as farms with total annual sales 

of $750,000 or less. 

Based upon the screening analysis 

completed (Ref. 89), EPA has 

determined that less than 39,000 of the 

1.2 million small farms nationwide, or 

approximately 3% of all small farms, 

may be impacted by this proposed 

revocation. Of these, 38,000 have 

potential impacts of less than 1% of 

gross farm revenue. The analysis 

indicates that fewer than 1,000 small 

farms, or 0.1% percent of all small 

farms, may experience impacts greater 

than 1%, depending on the availability 

and cost of alternatives. Based on this 

analysis, EPA concludes that revoking 

all tolerances for chlorpyrifos will not 

have a significant economic impact on 

a substantial number of small entities. 

Details of this analysis are presented in 

EPA’s analyses which can be found in 

the docket (Ref. 89). 

IX. References 

EPA has established an official record 

for this rulemaking. The official record 

includes all information considered by 

EPA in developing this proposed rule 

including documents specifically 

referenced in this action and listed 

below, any public comments received 

during an applicable comment period, 

and any other information related to this 

action, including any information 

claimed as CBI. This official record 

includes all information physically 

located in docket ID number EPA–HQ– 

OPP–2015–0653, any documents 

identified in this proposal, and 

documents referenced in documents in 

the docket. The public version of the 

official record does not include any 

information claimed as CBI. 

1. U.S. EPA (2014). Chlorpyrifos: Revised 

Human Health Risk Assessment for 

Registration Review. Available in docket 

number EPA–HQ–OPP–2008–0850, 

http://www.regulations gov/

#!documentDetail;D=EPA-HQ-OPP-2008- 

0850-0195. 

2. The Petition from NRDC and PANNA and 

EPA’s various responses to it are 

available in docket number EPA–HQ– 

OPP–2007–1005 available at 

www.regulations.gov. 

3. U.S. EPA (2011). Chlorpyrifos: Preliminary 

Human Health Risk Assessment for 

Registration Review. Available in docket 

number EPA–HQ–OPP–2008–0850, 

http://www.regulations.gov/

#!documentDetail;D=EPA-HQ-OPP-2008- 

0850-0025. 

4. Information and software related to Dietary 

Exposure Evaluation Model and the 

Calendex models is available at http://

www.epa.gov/pesticides/science/deem/. 

5. For information related to Section 408 of 

FFDCA see http://www2.epa.gov/lawsregulations/summary-federal-food-drugand-cosmetic-act. 

6. For information on the EPA’s Office of 

Pesticide Programs risk assessment 

process see http://www.epa.gov/

pesticides/about/overview_risk_

assess.htm. 

7. U.S. EPA (2000). Choosing a Percentile of 

Acute Dietary Exposure as a Threshold 

of Regulatory Concern. Available at 

http://www.epa.gov/oppfead1/trac/

science/trac2b054.pdf. 

8. Information on the water exposure models 

used by EPA’s Office of Pesticide 

Programs is available at http://

www.epa.gov/oppefed1/models/water/

models4.htm. 

9. FIFRA Scientific Advisory Panel (2008). 

‘‘The Agency’s Evaluation of the Toxicity 

Profile of Chlorpyrifos.’’ Report from the 

FIFRA Scientific Advisory Panel Meeting 

of September 16–19, 2008. Available: 

http://www2.epa.gov/sap/fifra-scientificadvisory-panel-meetings. 

10. FIFRA Scientific Advisory Panel (2012). 

‘‘Scientific Issues Associated with 

Chlorpyrifos’’. Available at: http://

www2.epa.gov/sap/meeting-materialsapril-10-12-2012-scientific-advisorypanel. 

11. FIFRA Scientific Advisory Panel (2002). 

‘‘Organophosphate Pesticides: 

Preliminary OP Cumulative Risk 

Assessment.’’ Information on how to 

obtain the meeting report is available at 

http://www2.epa.gov/sap/fifra-scientificadvisory-panel-meetings. 

12. U.S. EPA (2006). Revised 

Organophosphorous Pesticide 

Cumulative Risk Assessment. Available 

at http://www.epa.gov/pesticides/

cumulative/2006-op/index.htm. 

13. Chambers, J.E. (2013). In vitro Sensitivity 

of Cholinesterase to Inhibition by 

Chlorpyrifos-oxon in Several Tissues of 

the Rat. College of Veterinary Medicine, 

Mississippi State University. 

14. Calhoun LL, Johnson KA. (1988) 

Chlorpyrifos: 4-Day Dermal Probe and 

21-Day Dermal Toxicity Studies in 

Fischer 344 Rats. MRID 40972801. 

15. Corley, R.; Landry, T.; Calhoun, L.; et al. 

(1986) Chlorpyrifos: 13-Week Nose-only 

Vapor Inhalation Exposure Study in 

Fischer 344 Rats. MRID 40013901. 

16. Corley, R.; Landry, T.; Calhoun, L.; et al. 

(1986) Chlorpyrifos: 13-Week Nose-only 

Vapor Inhalation Exposure Study in 

Fischer 344 Rats: Supplemental Data: 

Lab. MRID 40166501. 

17. Newton, P. (1988) AThirteen Week NoseOnly Inhalation Toxicity Study of 

Chlorpyrifos Technical (Pyrinex) in the 

Rat. MRID 40908401. 

18. Hotchkiss, J.; Krieger, S.; Brzak, K.; et al. 

(2010) Acute Inhalation Exposure of 

Adult Crl: CD (SD) Rats to Particulate 

Chlorpyrifos Aerosols: Kinetics of 

Concentration-Dependent Cholinesterase 

(ChE) Inhibition in Red Blood Cells, 

Plasma, Brain, and Lung. MRID 

48139303. 

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19. U.S. EPA (2011) Chlorpyrifos: Review of 

the Comparative Cholinesterase 

(including chlorpyrifos oxon), special 

acute inhalation study and 

immunotoxicity studies (MRIDs 

48139301, 48139303, 48139304). TXR 

No. 0055409. 

20. Hotchkiss, J.; Krieger, S.; Mahoney, K.; et 

al. (2013) Nose-only Inhalation of 

Chlorpyrifos Vapor: Limited 

Toxicokinetics and Determination of 

Time-dependent Effects on Plasma, Red 

Blood Cell, Brain and Lung 

Cholinesterase Activity in Femal CD(SD): 

Crl Rats. MRID 49119501. 

21. Hotchkiss, J.; Krieger, S.; Mahoney, K.; et 

al. (2013) Nose-Only Inhalation of 

Chlorpyrifos-Oxon Vapor: Limited 

Toxicokinetics and Determination of 

Time-Dependent Effects on Plasma, Red 

Blood Cell, Brain and Lung 

Cholinesterase Activity in Female 

CD(SD): Crl Rats. MRID 49210101. 

22. U.S. EPA (2002). Revised 

Organophosphorous Pesticide 

Cumulative Risk Assessment. Available 

at http://www.epa.gov/pesticides/

cumulative/rra-op/. 

23. U.S. EPA (2006). Approaches for the 

Application of Physiologically Based 

Pharmacokinetic (PBPK) Models and 

Supporting Data in Risk Assessment. 

Available at http://cfpub.epa.gov/ncea/

cfm/recordisplay.cfm?deid=157668. 

24. Timchalk, C., et al., 2002a. Monte Carlo 

analysis of the human chlorpyrifosoxonase (PON1) polymorphism using a 

physiologically based pharmacokinetic 

and pharmacodynamic (PBPK/PD) 

model. Toxicology Letters. 135, 51. 

25. Timchalk, C., et al., 2002b. A 

Physiologically based pharmacokinetic 

and pharmacodynamic (PBPK/PD) model 

for the organophosphate insecticide 

chlorpyrifos in rats and humans. 

Toxicological Sciences. 66, 34–53. 

26. U.S EPA FIFRA Scientific Advisory 

Panel. (2011). ‘‘Chlorpyrifos 

Physiologically Based Pharmacokinetic 

and Pharmacodynamic (PBPK–PD) 

Modeling linked to Cumulative and 

Aggregate Risk Evaluation System 

(CARES).’’ Report from the FIFRA 

Scientific Advisory Panel Meeting of 

February 15–18, 2011. Available at 

http://www2.epa.gov/sap/fifra-scientificadvisory-panel-meetings. 

27. U.S. EPA 2014. Chlorpyrifos: Quality 

Assurance Assessment of the 

Chlorpyrifos Physiologically Based 

Pharmacokinetic/Pharmacodynamic 

Model for Human Health Risk 

Assessment Applications. TXR No. 

0056896. Available at http://

www.regulations.gov/

#!documentDetail;D=EPA-HQ-OPP-2008- 

0850-0843. 

28. U.S. EPA. Exposure Factors Handbook 

2011 Edition (Final). U.S. Environmental 

Protection Agency, Washington, DC, 

EPA/600/R–09/052F, 2011. Available at 

http://cfpub.epa.gov/ncea/risk/

recordisplay.cfm?deid=236252. 

29. NHANES/WWEIA survey and supporting 

documentation is available at http://

www.ars.usda.gov/Services/

docs.htm?docid=13793. 

30. US EPA (2012). Standard Operating 

Procedures for Residential Pesticide 

Exposure Assessment available at http:// 

www.epa.gov/pesticides/science/USEPAOPP-HED_Residential%20SOPs_

Oct2012.pdf. 

31. Guidance for Applying Quantitative Data 

to Develop Data-Derived Extrapolation 

Factors for Interspecies and Intraspecies 

Extrapolation Available at http://

www2.epa.gov/osa/guidance-applyingquantitative-data-develop-data-derivedextrapolation-factors-interspecies-and. 

32. Dow AgroSciences (2014), P. Price. 

Development of Chemical Specific 

Adjustment Factors for Chlorpyrifos and 

Chlorpyrifos Oxon Using Target Red 

Blood Cell Acetyl Cholinesterase 

Inhibition Levels of 10%, 5%, and 1%. 

Available at http://www.regulations.gov/ 

#!documentDetail;D=EPA-HQ-OPP-2008- 

0850-0218. 

33. U.S. EPA (2002). Determination of the 

Appropriate FQPA Safety Factor(s) in 

Tolerance Assessment. Available at 

http://www.epa.gov/oppfead1/trac/

science/determ.pdf). 

34. Aldridge, J. E., Levin, E. D., Seidler, F. J., 

& Slotkin, T. A. (2005). Developmental 

exposure of rats to chlorpyrifos leads to 

behavioral alterations in adulthood, 

involving serotonergic mechanisms and 

resembling animal models of depression. 

Environ Health Perspect, 113(5), 527– 

531. 

35. Icenogle, L. M., Christopher, N. C., 

Blackwelder, W. P., Caldwell, D. P., 

Qiao, D., Seidler, F. J., et al. (2004). 

Behavioral alterations in adolescent and 

adult rats caused by a brief subtoxic 

exposure to chlorpyrifos during 

neurulation. Neurotoxicol Teratol, 26(1), 

95–101. 

36. Levin, E. D., Addy, N., Baruah, A., Elias, 

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water/. 

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69110 Federal Register / Vol. 80, No. 215 / Friday, November 6, 2015 / Proposed Rules 

Report, February 2013 (Washington State 

Department of Ecology and Washington 

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11Report.pdf. 

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Business Impacts of Revoking 

Chlorpyrifos Food Tolerances. Available 

at www.regulations.gov in docket 

number EPA–HQ–OPP–2015–0653. 

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Steady State Dietary (Food Only) 

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List of Subjects in 40 CFR Part 180 

Environmental protection, 

Administrative practice and procedure, 

Agricultural commodities, Pesticides 

and pests, Reporting and recordkeeping 

requirements. 

Dated: October 28, 2015. 

Jack E. Housenger, 

Director, Office of Pesticide Programs. 

Therefore, it is proposed that 40 CFR 

chapter I be amended as follows: 

PART 180—[AMENDED] 

■ 1. The authority citation for part 180 

continues to read as follows: 

Authority: 21 U.S.C. 321(q), 346a and 371. 

§ 180.342 [Removed] 

■ 2. Remove § 180.342. 

[FR Doc. 2015–28083 Filed 11–5–15; 8:45 am] 

BILLING CODE 6560–50–P 

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