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[Federal Register Volume 80, Number 215 (Friday, November 6, 2015)]
[Proposed Rules]
[Pages 69079-69110]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-28083]

[[Page 69079]]

Vol. 80

Friday,

No. 215

November 6, 2015

Part IV

Environmental Protection Agency

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40 CFR Part 180

Chlorpyrifos; Tolerance Revocations; Proposed Rule

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

[[Page 69080]]

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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.

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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

[[Page 69081]]

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 non-occupational 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 
food-use 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 non-occupational 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 post-natal 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

[[Page 69082]]

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 
ground-based 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 re-evaluation 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 chlorpyrifos-specific 
pharmacokinetic-pharmacodynamic (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 
non-occupational 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 intra-species 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 intra-species 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 non-occupational 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 intra-species 
extrapolation factor to account for potential differences between 
populations) and 50X for the other

[[Page 69083]]

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 at-risk 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

[[Page 69084]]

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

[[Page 69085]]

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 Non-Occupational 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 ``non-occupational'' 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.,

[[Page 69086]]

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 non-occupational 
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 pesticide-specific 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

[[Page 69087]]

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 non-pregnant 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 [micro]g/m\3\ 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/
m\3\ 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/m\3\, which is a LOAEL. RBC and brain ChE inhibition 
were noted at >= 12.9 mg/m\3\ and 53.9 mg/m\3\, 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/m\3\) (Ref. 20) 
or 2.58 ppb (35.3 [mu]g/m\3\) (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

[[Page 69088]]

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-
to-route 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 inter-species 
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 intra-species 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

[[Page 69089]]

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\
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                      Infants ( 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
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Empty 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 10 (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 post-natal toxicity.
    In examining these factors, EPA strives to make sure that its 
choice of a safety factor, based on its weight-of-evidence evaluation, 
does not understate the risk to infants and

[[Page 69090]]

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. Dose-response 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 gender-specificity. 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

[[Page 69091]]

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, mother-infant 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 one-time 
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

[[Page 69092]]

(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 (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. 
population-based norms for English and Spanish-speaking 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,

[[Page 69093]]

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 
exposures-response 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

[[Page 69094]]

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 inter-species 
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), co-exposures (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

[[Page 69095]]

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 long-term 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 dose-response, 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 AChE-inhibiting 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 dose-
response 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

[[Page 69096]]

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 TM, 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 (kg/     Percent of
                                                    (ug/kg/day)     (ug/kg/day)        day)          aPADfood
----------------------------------------------------------------------------------------------------------------
Infants ( 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).
\3\ Acute food only exposure estimates from DEEM (at 99.9th percentile). Refined with monitoring data and %CT.

[[Page 69097]]

    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 kg/     Percent of
                                                    (ug/kg/day)     (ug/kg/day)        day)          ssPADfood
----------------------------------------------------------------------------------------------------------------
Infants ( 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).
\3\ Steady 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 (non-occupational) 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

[[Page 69098]]

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 non-occupational exposure with treated ant mounds.
    In the RHHRA which supports this rule, EPA has updated the post-
application 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 post-
application exposures is based on the following scenarios:
Golf Course Use (Emusifiable Concentrate (EC) and Granular (G) 
Formulations)
     Children 6 to  Children 1 to  Children 1 to  Children 1 to  Children 1 to 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

[[Page 69099]]

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 
ground-based 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 
post-application 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., hand-
to-mouth, object-to-mouth, and soil ingestion) should be considered 
inter-related, 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 =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 kg/day) \3\       MOEs \4\       Combined    Combined
                                           Use site          Route of exposure                                                                                            routes \5\   MOEs \6\
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Adult (Females)...................  Golf Course Turf.....  Dermal...............  1.0 (Emulsifiable      CA.................  0.010....................           1,400          NA           NA
                                    .....................  .....................   Concentrate).         IN.................  0.0069...................           2,100  ...........  ..........
                                    .....................  .....................  .....................  MS.................  0.012....................           1,200  ...........  ..........
                                    .....................  .....................  .....................  Mean...............  0.0095...................           1,500  ...........  ..........
Youths 11 to m\3\)........          10,300           X
                                     Mosquitocide
                                     Applications.
Children 1 to m\3\)........           4,000           X

[[Page 69100]]

 
                                                           Hand-to-Mouth........  .....................  MS.................  0.000018.................           5,600           X
                                                           Object-to-Mouth......  .....................  MS.................  5.5 x 10-7...............         180,000          NA           NA
                                                           Soil Ingestion.......  .....................  NA \2\.............  1.2 x 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/m\3\).........           1,200           X
Children 1 to m\3\).........             460           X   ..........
                                                           Hand-to-Mouth........  .....................  MS.................  2.6 x 10-6...............          39,000           X
                                                           Object-to-Mouth......  .....................  MS.................  7.9 x 10-8...............       1,300,000          NA           NA
                                                           Soil Ingestion.......  .....................  NA \2\.............  1.7 x 10-8...............      34,000,000          NA           NA
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Based on the maximum application rates registered for golf course turf and ULV mosquito adulticide uses.
\2\ The 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).
\5\ X 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 x 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 (kg/day) (from Table 4.8.4)/Food Exposure (ug/kg/day) (from Table 5.4.3). ARIfood = ((MOEfood)/(MOEtarget)).
\4\ WATER (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 x 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 (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)).
\5\ WATER (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 x 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 risk--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

[[Page 69102]]

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 PRZM-Groundwater (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 Risk--National 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.

[[Page 69103]]

                                 Table 7--Estimated Drinking Water Concentrations Resulting From the Use of Chlorpyrifos
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                         Surface water                                    Groundwater
                                                         -----------------------------------------------------------------------------------------------
                         Residue                                                                    1-in-10 Year      30 Year annual
                                                           1-in-10 Year peak    21-Day average     annual average        average        SCI-GROW Tier I
                                                           concentration ppb  concentration ppb  concentration ppb  concentration ppb  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
----------------------------------------------------------------------------------------------------------------
                                                                       21-Day
                                          Highest 21-day average     exceedance    Represented use site examples
               Scenario                     concentration ppb           count        (maximum single application
                                            (application date)    ----------------             rate)
                                                                     Percent \a\
----------------------------------------------------------------------------------------------------------------
                                                   1 lb a.i./A
----------------------------------------------------------------------------------------------------------------
MScornSTD.............................  16.5 at 1.0 lb a.i./A....              21  Corn [2 lb a.i./A (aerial and
TXcornOP..............................  13.9 at 1.0 lb a.i./A....              13   ground)].
                                                                                   Soybean [1 lb a.i./A
                                                                                    (aerial); 2.2 (ground)].
ILcornSTD.............................  14.6 at 1.0 lb a.i./A....              16
MScotton..............................  19.8 at 1.0 lb a.i./A \e\              16  Cotton [1 lb a.i./A (foliar
NCcotton..............................  14.4 at 1.0 lb a.i./A....              25   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..............................  10.7 at 1.0 lb a.i./A....              17  Other Row Crops:
NCsweetpotatoSTD......................  13.5at 1.0 lb a.i./A.....               9  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.........................  19.6 at 2.0 lb a.i./A....              42  Orchards and Vineyards (Tree
GApecansSTD...........................  20.7 at 2.0 lb a.i./A....              12   fruit and Nuts):
                                                                                   Fruit and Nuts [4 lb a.i./A
                                                                                    (ground)].
                                                                                   Pecans [2 lb a.i./A (air);
                                                                                    4.3 (ground)].

[[Page 69104]]

 
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).
----------------------------------------------------------------------------------------------------------------
\a\ The 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)).
\e\ A 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 [micro]g/L. For example, 
USGS NAWQA, which contains an extensive monitoring dataset for 
chlorpyrifos and chlorpyrifos oxon, reports a peak chlorpyrifos 
detection of 0.57 [micro]g/L in surface water with a detection 
frequency of approximately 15%. CDPR has detected chlorpyrifos 
concentrations greater than 1 [micro]g/L in surface water on several 
occasions, with an observed peak chlorpyrifos concentration of 3.96 
[micro]g/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

[[Page 69105]]

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
----------------------------------------------------------------------------------------------------------------
                                                       Years of sampling                            Maximum
         Monitoring data                 Scale            (number of           Detection         concentration
                                                           samples)          frequency (%)       ([micro]g/L)
----------------------------------------------------------------------------------------------------------------
USGS NAWQA......................  National..........  1991-2012 (30,542)                15                 0.57
California Department of          State.............  1991-2012 (13,121)                20                 3.96
 Pesticide Regulation.
Washington State Department of    State.............  2003-2013 (4,091).                 8.4               0.4
 Ecology and Agriculture
 Cooperative Surface Water
 Monitoring Program.
USDA Pesticide Data Program.....  National..........  2004-2009 (raw                     0                na
                                                       water; 1,178).
                                                      2001-2009
                                                       (finished water;
                                                       2,918).
USGS-EPA Pilot Drinking Water     National..........  1999-2000 (323)...                 5.3               0.034
 Reservoir.
Oregon Department of              Watershed.........  2005-2011 (363)...                13                 2.4
 Environmental Quality.           (Clackamas).......
MRID 44711601 (Ref. 87).........  Watershed.........  1996-1997 (1,089).                61                 2.22
                                  (Orestimba Creek).
----------------------------------------------------------------------------------------------------------------

    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

[[Page 69106]]

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

[[Page 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/2014 05/documents/
1995_childrens_health_policy_statement.pdf), reaffirmed in 2013 (http:/
/www2.epa.gov/sites/production/files/2014 05/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/laws-regulations/summary-federal-food-drug-and-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-scientific-advisory-panel-meetings.
10. FIFRA Scientific Advisory Panel (2012). ``Scientific Issues 
Associated with Chlorpyrifos''. Available at: http://www2.epa.gov/sap/meeting-materials-april-10-12-2012-scientific-advisory-panel.
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-scientific-advisory-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 Nose-Only 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.

[[Page 69108]]

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 
chlorpyrifos-oxonase (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-scientific-advisory-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/USEPA-OPP-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-applying-quantitative-data-develop-data-derived-extrapolation-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.
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0850.

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]

0
1. The authority citation for part 180 continues to read as follows:

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

Sec.  180.342  [Removed]

0
2. Remove Sec.  180.342.

[FR Doc. 2015-28083 Filed 11-5-15; 8:45 am]
 BILLING CODE 6560-50-P
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