[Federal Register Volume 80, Number 215 (Friday, November 6, 2015)]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-28083]
November 6, 2015
Environmental Protection Agency
40 CFR Part 180
Chlorpyrifos; Tolerance Revocations; Proposed Rule
Federal Register / Vol. 80 , No. 215 / Friday, November 6, 2015 /
ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
Chlorpyrifos; Tolerance Revocations
AGENCY: Environmental Protection Agency (EPA).
ACTION: Proposed rule.
SUMMARY: On August 10, 2015, the U.S. Court of Appeals for the Ninth
Circuit ordered EPA to respond to an administrative Petition to revoke
all tolerances for the insecticide chlorpyrifos by October 31, 2015, by
either denying the Petition or issuing a proposed or final tolerance
revocation. At this time, the agency is unable to conclude that the
risk from aggregate exposure from the use of chlorpyrifos meets the
safety standard of section 408(b)(2) of the Federal Food, Drug, and
Cosmetic Act (FFDCA). Accordingly, EPA is proposing to revoke all
tolerances for chlorpyrifos. EPA is specifically soliciting comment on
whether there is an interest in retaining any individual tolerances, or
group of tolerances, and whether information exists to demonstrate that
such tolerance(s) meet(s) the FFDCA section 408(b) safety standard. EPA
encourages interested parties to comment on the tolerance revocations
proposed in this document and on the proposed time frame for tolerance
revocation. Issues not raised during the comment period may not be
raised as objections to the final rule, or in any other challenge to
the final rule.
DATES: Comments must be received on or before January 5, 2016.
ADDRESSES: Submit your comments, identified by docket identification
(ID) number EPA-HQ-OPP-2015-0653 by one of the following methods:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the online instructions for submitting comments. Do not submit
electronically any information you consider to be Confidential Business
Information (CBI) or other information whose disclosure is restricted
Mail: OPP Docket, Environmental Protection Agency Docket
Center (EPA/DC), (28221T), 1200 Pennsylvania Ave. NW., Washington, DC
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:
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
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
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
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.
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
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
IV. Chlorpyrifos Background, Regulatory History, and Litigation
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
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
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
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
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
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
(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;
(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
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
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.,
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
C. Selection of Acute and Steady State Dietary Exposure Level of
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
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
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
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
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
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
Table 1--Chlorpyrifos PBPK Modeled Doses (PoDs) Corresponding to 10% RBC AChE Inhibition \1\
Infants ( < 1 yr Young Children (1-2 Children Youths (Residential: Females (13-49 years
old) years old) (Residential: 6-11 11-16 years old; old)
-------------------------------------------- years old; Dietary: Dietary: 13-19 years ---------------------
Exposure pathway (all 6-12 years old) old)
RA Type chlorpyrifos unless noted) Steady Steady -------------------------------------------- Steady
Acute state (21 Acute state (21 Steady Steady Acute state (21
day) day) Acute state (21 Acute state (21 day)
Dietary........................................ Drinking Water (oxon conc, ppb).. 1,183 217 3,004 548 7,700 1,358 4,988 878 5,285 932
Food (ug/kg/day)................. 600 103 581 99 530 90 475 80 467 78
Residential (Golfers).......................... Dermal (ug/kg/day)............... ......... ......... ......... ......... ......... 25,150 ......... 16,370 ......... 14,250
Residential (Mosquitocide Application)......... Dermal (ug/kg/day)............... ......... ......... ......... 187,000 ......... ......... ......... ......... ......... 38,650
Oral (ug/kg/day)................. ......... ......... ......... 101 ......... ......... ......... ......... ......... .........
Inhalation (concn. in air mg/m3). ......... ......... ......... 2.37 ......... ......... ......... ......... ......... 6.15
\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 < 2 years old result in a
more protective assessment than infants).
5. Use of the Chlorpyrifos PBPK-PD Model to Extrapolate from
Animals to Humans (Inter-species) and Among the Human Population
(Intra-species). Once EPA determines the appropriate toxicological PoDs
(Table 1), it then applies appropriate uncertainty factors or DDEFs to
account for inter-species and intra-species variation, and to address
the requirements of section 408(b)(2)(C) regarding the need for an
additional margin of safety for infants and children. Specifically, the
modeled doses (PoDs) in this table are divided by appropriate factors
to establish PADs that are used for regulatory purposes. The PADs are
presented in Unit VI.B.2.ii and iii, Tables 2 and 3.
In a typical risk assessment, the agency uses PoDs derived from
laboratory animal studies. For these typical assessments, the agency
must then extrapolate from animals to humans which is generally
performed with a 10X inter-species factor. As noted above in Unit V.A.,
the output of the chlorpyrifos PBPK-PD model accounts for human
specific metabolism and physiology, thus obviating the need for the
inter-species extrapolation factor for all age groups.
EPA has, however, calculated a DDEF to address intra-species
variation not accounted for in the output of the PBPK-PD model.
Consistent with EPA's ``Guidance for Applying Quantitative Data to
Develop Data-Derived Extrapolation Factors for Interspecies and
Intraspecies Extrapolation'' (Ref. 31), when calculating a DDEF, EPA
compares the administered doses leading to the response level of
interest (10% change in RBC AChE inhibition) between a measure of
average response and response at the tail of the distribution
representing sensitive individuals. Dow AgroSciences has conducted an
analysis to derive the oral doses that cause 10% RBC AChE inhibition in
both adults and 6-month old infants. (Ref. 1 at 69-70). The ratio of
the adult ED10 (effective dose) to the infant
ED10 was then used to derive intraspecies extrapolation
factors. In the subsequent Monte Carlo simulations, the target age
group is six month old individuals. Based on the 1st percentile of the
distributions being used to extrapolate human health, the DDEF for
intraspecies extrapolation is 4X for chlorpyrifos and 5X for the oxon
(Ref. 32) for all groups except women who are pregnant or may become
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
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
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
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
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
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
(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
Researchers across the three children's health cohorts utilized the
Bayley Scales of Infant Development II (BSID-II) to generate a Mental
Development Index (MDI) and a Psychomotor Development Index (PDI) to
assess neurodevelopment in early childhood. In the CCCEH Mothers and
Newborn study, Rauh et al. (Ref. 51) investigated MDI and PDI at 12,
24, and 36 months of age. Children were categorized as having either
high (>6.17 pg/g) or low (<=6.17 pg/g) prenatal chlorpyrifos exposure,
using categories informed by results of the previous study on birth
characteristics (Ref. 52). Authors reported that the difference in MDI
scores was ``marginally significant'' (p = 0.06) between the ``high''
and ``low'' exposed groups; the high exposed group scoring an average
of 3.3 points lower than the low exposed (Ref. 51). Regarding the PDI
score (motor skills), none of the 12 or 24 month PDI scores showed
significant effects, but the 36 month score was significantly related
to chlorpyrifos exposure. Researchers noted that the effects were most
pronounced at the 36 month testing period. Within the 36 month testing
period, the likelihood of highly exposed children developing mental
delays were significantly greater (MDI: 2.4 times greater (95% CI:
1.12-5.08, p = 0.02) and PDI: 4.9 times greater (95% CI: 1.78-13.72; p
= 0.002)) than those with lower prenatal exposure (Id.). Within the Mt.
Sinai study, authors administered the BSID-II to participating children
at 12 and 24 months and observed that prenatal total DAP metabolite
level was associated with a decrement in mental development at 12
months among blacks and Hispanic children; however, these associations
either attenuated or were non-existent at the 24-month visit (Ref. 52).
In the CHAMACOS cohort, Eskenazi et al. (Ref. 53) observed that
prenatal DAP levels were adversely associated with MDI, and at 24
months of age these associations reached statistical significance. In
this study, neither prenatal DAPs nor maternal TCPy were associated
with PDI (motor skills), nor did authors observe evidence of different
risk by PON1 status. (Ref. 54).
With respect to the findings related to the autism spectrum, from
CCCEH, Rauh et al. (Ref. 51) reported a statistically significant odds
ratio for pervasive developmental disorder (PDD) (OR = 5.39; 95% CI:
1.21-24.11) when comparing high to low chlorpyrifos exposure groups. As
described above, among 7-9 years old children in the Mt. Sinai Cohort
(Ref. 55), there was no overall statistically significant association
between maternal third trimester urinary DAP metabolite levels and
reciprocal social responsiveness. However, some evidence of
modification of the association between prenatal OP pesticide exposure
and impaired social responsiveness in early childhood was observed by
both race/ethnicity and child sex, with an association between diethyl
alkylphosphate (DEAP) and poorer social responsiveness observed among
black participants and boys. No association was observed among whites
or Hispanics, among girls, or for DAP or dimethyl alkylphosphate (DMAP)
biomarker levels. In the CHAMACOS cohort, Eskenazi et al. (Ref. 54)
reported non-significant, but suggestive, increased odds of PDD of 2.0
(0.8 to 5.1; p = 0.14), whereas Eskenazi et al. (Ref. 53) reported a
statistically significant association between total DAP exposure and
increased odds of PDD.
With respect to attention problems, Rauh et al. (Ref. 50) also
investigated 36-month child behavior checklist (CBCL) (behavioral)
scores. Significant differences were observed between the high and low
chlorpyrifos exposure groups in the general category of attention-
problems (p = 0.010), and in the more specific DSM-IV (Diagnostic and
Statistical Manual of Mental Disorders version IV) scale for ADHD
problems (p = 0.018). The CHAMACOS cohort also investigated attention
problems in early childhood using three different assessment tools:
maternal report of child behavior at 3.5 and 5 years of age; direct
assessment of the child at 3.5 and 5 years; and by a psychometrician's
report of the behavior of the child during testing at 5 years. In this
study population, higher concentrations of OP metabolites in the urine
of pregnant women were associated with increased odds of attention
problems and poorer attention scores in their children at age 5 years.
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
To ascertain whether observed differences in neurodevelopment after
prenatal chlorpyrifos exposure may be explained by differences in brain
morphology between exposed groups,
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
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
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
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
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
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
time. Also, the chlorpyrifos oxon is not found on samples in the USDA
PDP monitoring program. In fact, from 2007 to 2012, out of several
thousand samples of various commodities, only one sample of potato
showed presence of the oxon at trace levels, 0.003 ppm where the LOD
was 0.002 ppm, even though there are no registered uses of chlorpyrifos
on potato in the U.S.
The oxon metabolite was not found in milk or livestock tissues in
cattle and dairy cow feeding studies, at all feeding levels tested, and
is not a residue of concern in livestock commodities.
Oxidation of chlorpyrifos to chlorpyrifos oxon can occur through
photolysis, aerobic metabolism, and chlorination as well as other
oxidative processes. Because of the toxicity of the oxon and data
indicating that chlorpyrifos rapidly converts to the oxon during
typical drinking water treatment (chlorination), the drinking water
risk assessment considers the oxon as the residue of concern in treated
drinking water and assumes 100% conversion of chlorpyrifos to
chlorpyrifos oxon. (Ref. 70). This approach of assuming 100% conversion
of chlorpyrifos to the more toxic chlorpyrifos oxon, is a conservative
approach and thus protective of other likely exposure scenarios of
chlorpyrifos only and chlorpyrifos and chlorpyrifos oxon.
The chlorpyrifos degradate TCPy is not considered a residue of
concern for this assessment as it does not inhibit cholinesterase (a
separate human health risk assessment has been performed for TCPy,
which has its own toxicity database). TCPy (derived from triclopyr,
chlorpyrifos, and chlorpyrifos-methyl) was previously assessed on June
6, 2002. (Ref. 71).
2. Dietary (food only) risk assessment. The general approach for
the chlorpyrifos (food only) exposure and risk assessment can be
described as follows: The PBPK-PD model was used to predict acute (24
hour) and steady state (21-day) PoDs which correspond to 10% RBC AChE
inhibition for the index lifestages relevant to chlorpyrifos risk
assessment (children of various ages which differ due to exposure
pattern, and adult females of childbearing age). The PoDs are then
divided by the total uncertainty factor to determine the PAD. For food,
the residue of concern is chlorpyrifos (the oxon metabolite is not an
expected residue on foods). The chlorpyrifos total uncertainty factors
are 100X for adult females (10X FQPA SF and 10X intra-species
extrapolation factor) and 40X for the other populations (10X FQPA SF
and 4X intra-species extrapolation factor). For the dietary risk
assessment for food only, the exposure values resulting from Dietary
Exposure Evaluation Model (DEEM) and the Calendex model are compared to
the PBPK-PD-based acute PAD and steady state PAD, respectively. The
chlorpyrifos exposure values resulting from dietary modeling are
compared to the PAD. Dietary exposures greater than 100% of the PAD are
generally cause for concern and would be considered ``unsafe'' within
the meaning of FFDCA section 408(b)(2)(B).
i. Description of residue data used in dietary (food only)
assessment. Acute and steady state dietary (food only) exposure
analyses for chlorpyrifos were conducted using the Dietary Exposure
Evaluation Model (DEEM) and Calendex software with the Food Commodity
Intake Database (FCID) (Ref. 90). This software uses 2003-2008 food
consumption data from NHANES/WWEIA. The most recent previous dietary
assessment was conducted in support of the 2011 PHHRA and the ongoing
chlorpyrifos registration review. (Ref. 72). This current analysis
reflect the latest consumption data as well as more recent food
monitoring and percent crop treated data. These analyses were performed
for the purpose of obtaining food exposure values for comparison to the
chlorpyrifos doses predicted by the PBPK-PD model to cause RBC ChEI.
The acute and steady state exposure analyses do not include drinking
water which is assessed separately as discussed in Unit VI.2.B.
Both the acute and steady state dietary exposure analyses are
highly refined. The large majority of food residues used were based
upon U.S. Department of Agriculture's PDP monitoring data except in a
few instances where no appropriate PDP data were available. In those
cases, field trial data were used or tolerance level residues were
assumed. The same data were used for both the acute and steady state
analyses. EPA also considered percent crop treated information. Food
processing factors from submitted studies were used as appropriate.
The acute and steady state dietary exposure assessment used percent
crop treated information from EPA's Screening Level Usage Analysis
(Ref. 73) to estimate chlorpyrifos exposures from the consumption of
food. Reported percent crop treated ranged from <2.5% to 70%. 100% crop
treated was assumed for many crops for which no usage data were
ii. Acute dietary (food only) risk assessment. Chlorpyrifos acute
(food only) dietary exposure assessments were conducted using the
Dietary Exposure Evaluation Model software with the Food Commodity
Intake Database DEEM-FCIDTM, Version 3.16, which
incorporates consumption data from NHANES/WWEIA. This dietary survey
was conducted from 2003 to 2008. Acute dietary risk estimates are
presented below for the sentinel population subgroups for acute risk
assessment: infants (<1 year old), children (1-2 years old), youths (6-
12 years old) and adults (females 13-49 years old). The assessment of
these index lifestages will be protective for the other population
As Table 2 indicates, EPA believes that acute dietary risk from
food only does not present a significant risk, as estimates are all far
below 100% of the acute PAD for food (aPADfood) at the 99.9th
percentile of exposure. The subgroup with the highest risk estimate was
females (13-49 years old) at 3.2% aPADfood.
Table 2--Acute Dietary (Food Only) Exposure and Risk Estimates for Chlorpyrifos
Population subgroup aPoDfood \1\ aPADfood \2\ \3\ (ug/kg/ Percent of
(ug/kg/day) (ug/kg/day) day) aPADfood
Infants (<1 yr)................................. 600 15 0.273 1.8
Children (1-2 yrs).............................. 581 14 0.423 3.0
Youths (6-12 yrs)............................... 530 13 0.189 1.4
Adults (Females 13-49 yrs)...................... 469 4.7 0.150 3.2
\1\ Acute point of departure; daily dose predicted by PBPK-PD model to cause RBC ChEI of 10% for acute dietary
\2\ aPAD = acute PAD = PoD (Dose predicted by PBPK-PD model to cause 10% RBC ChEI) / total UF; Total uncertainty
factor = 100X for females 13-49 years (10X intraspecies factor and 10X FQPA safety factor) and 40X for other
populations (4X intraspecies factor and 10X FQPA safety factor).
\3\ Acute food only exposure estimates from DEEM (at 99.9th percentile). Refined with monitoring data and %CT.
iii. Steady state detary (food only) risk assessment. A
chlorpyrifos steady state dietary (food only) exposure analysis was
conducted using Calendex-FCIDTM. EPA's steady state
assessment considers the potential risk from a 21-day exposure duration
using a 3-week rolling average (sliding by day) across the year. For
this assessment, the same food residue values used in the acute
assessment were used for the 21-day duration. In the Calendex software,
one diary for each individual in the WWEIA is selected to be paired
with a randomly selected set of residue values for each food consumed.
The steady state analysis calculated exposures for the sentinel
populations for infant, child, youths, and adult (infants <1 year,
children 1-2 years, youths 6-12 years, females 13-49 years).
Calendex reported dietary exposures for each population subgroup at
several percentiles of exposure ranging from 10th percentile to 99.9th
percentile. Similar to acute risks, the dietary (food only) exposures
for chlorpyrifos were all well below 100% ssPADfood (all populations,
at all percentiles of exposure). Only the 99.9th percentile of exposure
is presented in Table 3. For the steady state dietary (food only)
exposure analyses, children (1-2 years old) was the population subgroup
with the highest risk estimate at 9.7% of the ssPADfood at the 99.9th
percentile of exposure.
Table 3--Steady State Dietary (Food Only) Exposure and Risk Estimates for Chlorpyrifos
Population subgroup SS PoDfood \1\ ssPADfood \2\ \3\ (ug/kg/ Percent of
(ug/kg/day) (ug/kg/day) day) ssPADfood
Infants (<1 yr)................................. 103 2.6 0.186 7.2
Children (1-2 yrs).............................. 99 2.5 0.242 9.7
Youths (6-12 yrs)............................... 90 2.2 0.128 5.8
Adults (Females 13-49 yrs)...................... 78 0.78 0.075 9.6
\1\ Steady state point of departure; daily dose predicted by PBPK-PD model to cause RBC ChEI of 10% for steady
state (21-day) dietary (food) exposures.
\2\ ssPAD = Steady state PAD = PoD (Dose predicted by PBPK-PD model to cause 10% RBC ChEI) / total UF; Total
uncertainty factor = 100X for females 13-49 years (10X intraspecies factor and 10X FQPA safety factor) and 40X
for other populations (4X intraspecies factor and 10X FQPA safety factor).
\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
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)
Children 6 to <11 years old, youths 11 to <16 years old,
and adult post-application dermal exposure from contact with treated
turf while golfing.
Public Health Mosquito Adulticide Use (Aerial and Ground Applications)
Children 1 to <2 years old and adult post-application
dermal exposure from contact with turf following the deposition of
chlorpyrifos residues from public health mosquito adulticide
Children 1 to <2 years old and adult post-application
inhalation exposure from airborne chlorpyrifos following public health
mosquito adulticide application.
Children 1 to <2 years old post-application incidental
oral (hand-to-mouth) exposure from contact with turf following the
deposition of chlorpyrifos residues from public health mosquito
Children 1 to <2 years old post-application incidental
oral (object-to-mouth) exposure from contact with toys containing
residues from turf following the deposition of chlorpyrifos residues
from public health mosquito adulticide application.
The following assumptions and exposure factors served as the basis
for completing the residential post-application risk assessment. These
assumptions and factors are described in detail in the updated
occupational and residential exposure and risk assessment. (Ref. 74).
Exposure Duration: Residential post-application exposures to
chlorpyrifos are assumed to be steady state (i.e., 21 days or longer).
The application of mosquitocide in residential areas may result in
the potential for post-application inhalation exposures. The
aerosolized particulate remaining following application is assumed to
persist for no longer than one hour in proximity of the application
source and, accordingly, would be most appropriately defined as acute
in duration. However, this assessment assumes that post-application
inhalation exposures are steady state which is a highly conservative
approach given how infrequently mosquitocides are repeatedly applied to
the same locations and how rapidly aerosols dissipate after these types
of applications. The parameters used to define this exposure scenario
in the PBPK-PD model conservatively reflect daily, one hour exposures
for 21 days.
Application Rates: In order to seek clarification of chlorpyrifos
usage, the agency compiled a master use summary document reflective of
the use profile of all active product labels. The document, among other
information, presents all registered uses of chlorpyrifos and
corresponding maximum single application rates, equipment types,
restricted entry intervals (REIs), etc. This assessment assumes that
the detailed information on application rates and use patterns
presented in Appendix 9 (Master Use Summary Document) in support of the
2014 RHHRA will be implemented on all chlorpyrifos labels and is the
basis of the occupational and residential risk assessment. If, for any
reason, the final chlorpyrifos labels contain higher application rates,
the actual risks posed by those products may exceed the risks estimated
in this assessment.
Body Weights: The body weights assumed for this assessment differ
from those used in 2011 residential exposure assessment and are based
on the recommendations of the 2012 Residential SOPs. These body weights
are the same as selected for derivation of PBPK-PD PoDs for use in
assessment of residential exposures.
The standard body weights are as follows: Youths 11 to <16 years
old, 57 kg; children 6 to <11 years old, 32 kg; and children 1 to <2
years old, 11 kg. For adults when an endpoint is not sex-specific
(i.e., the endpoints are not based on developmental or fetal effects) a
body weight of 80 kg is typically used in risk assessment. However, in
this case, a female-specific body weight of 69 kg was used. While the
endpoint of concern, RBC AChE inhibition, is not sex-specific, the
female body weight was used due to concerns for neurodevelopmental
effects related to early life exposure to chlorpyrifos.
Post-application exposures from golfing have been assessed using
the 2012 Residential SOPs and with use of exposure data from a
chemical-specific turf transferable residue (TTR) study. The study was
conducted with an emulsifiable concentrate, a granular, and a wettable
powder formulation. Only the emulsifiable concentrate and granular data
were used because there are no currently registered wettable powder
formulations. The study was conducted in 3 states, California, Indiana
and Mississippi, with use of the emulsifiable concentrate and wettable
powder formulations. Exposure was estimated by normalizing Day 0 TTR
measures from study application rates to the current maximum
application rate allowable by the label. Chlorpyrifos oxon residues
were not analyzed.
The post-application exposure potential from public health mosquito
adulticide applications has been considered for both ground based truck
foggers and aerial applications. For assessment of the mosquito
adulticide use, the algorithms and inputs presented in the 2012
Residential SOP Lawns/Turf section were used coupled with the available
TTR data described above. The deposition of chlorpyrifos from these
applications are not based on the application rate alone, but also
using the AgDISP (v8.2.6) model (aerial applications, the currently
recommended model for assessment of mosquito adulticide applications)
or empirical data (ground applications) to determine how much pesticide
is deposited on residential lawns as a result of mosquito adulticide
treatments at the maximum application rates for each. The TTR data are
then used to determine the fraction of the total residue deposited
following the mosquitocide application which can result in exposures to
impacted individuals. Inhalation exposures are also estimated using
AgDrift for aerial
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 <2 years old are the
dermal, inhalation, and hand-to-mouth scenarios (the highest incidental
oral exposure expected). This combination should be considered a
protective estimate of children's exposure to pesticides.
Summary of Residential Post-application Non-Cancer Exposure and
Risk Estimates. The assessment of steady state golfer post-application
exposures (dermal only) to chlorpyrifos treated turf for the lifestages
adults, children 6 to <11 years old, and youths 11 to <16 years old,
results in no risks of concern (i.e., children 6 to <11 and youths 11
to <16 years old, MOEs are >=40; adults, MOEs are >=100). For the
assessment of post-application exposures from public health
mosquitocide applications, no combined risks of concern were identified
for adults (dermal and inhalation) and children 1 to <2 years old
(dermal, incidental oral, and inhalation). A summary of risk estimates
is presented in Table 4.
Table 4--Residential Post-Application Non-Cancer Exposure and Risk Estimates for Chlorpyrifos
Post-application exposure scenario
Lifestage ---------------------------------------------- Application rate \1\ State (TTR data) Dose (mg/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 <16 yrs old.......... ..................... ..................... ..................... CA................. 0.010.................... 1,600 ........... ..........
IN................. 0.0069................... 2,300 ........... ..........
MS................. 0.012.................... 1,400 ........... ..........
Mean............... 0.0096................... 1,700 ........... ..........
Children 6 to <11 years old....... ..................... ..................... ..................... CA................. 0.012.................... 2,100 ........... ..........
IN................. 0.0082................... 3,100 ........... ..........
MS................. 0.014.................... 1,800 ........... ..........
Mean............... 0.011.................... 2,200 ........... ..........
Adult (Females)................... ..................... ..................... 1.0 (Granular)....... CA................. 0.0088................... 1,600 ........... ..........
Youths 11 to <16 yrs old.......... ..................... ..................... ..................... ................... 0.0088................... 1,900 ........... ..........
Children 6 to <11 years old....... ..................... ..................... ..................... ................... 0.010.................... 2,400 ........... ..........
Adult (Females)................... Aerial and Ground Dermal............... 0.010 (Aerial)....... MS................. 0.00052.................. 75,000 X 9,100
Based ULV Inhalation........... NA................. 0.00060 (mg/m\3\)........ 10,300 X
Children 1 to <2 yrs old.......... Mosquitocide Dermal............... ..................... MS................. 0.00088.................. 210,000 X 2,300
Applications. Inhalation........... NA \2\............. 0.00060 (mg/m\3\)........ 4,000 X
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 <2 yrs ..................... Dermal............... ..................... MS................. 0.00013.................. 1,500,000 X 460
old. ..................... Inhalation........... ..................... NA................. 0.0051 (mg/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
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)))
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 =
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 (<1 year old) at 24
ppb. Acute exposures greater than 24 ppb are generally considered a
risk concern and unsafe for purposes of FFDCA section 408(b).
Table 5--Acute Aggregate (Food and Drinking Water) Calculation of DWLOCs \1\ \2\
Food exposure (chlorpyrifos) Drinking water exposure
\3\ (chlorpyrifos) \4\ Acute DWLOC \5\ (ppb
Population ---------------------------------------------------------------- chlorpyrifos oxon)
MOE ARI MOE ARI
Infants \1\ (<1 yr)............................................ 2200 55 50 1.0 24
Children \1\ (1-2 yrs)......................................... 1400 35 50 1.0 60
Youths \1\ (6-12 yrs).......................................... 2800 70 50 1.0 150
Adults \2\ (Females 13-49 yrs)................................. 3100 NA 100 NA 53
\1\ DWLOCs for infants, children and youths are calculated using the ARI (Aggregate Risk Index) approach since target MOEs are different for drinking
water (chlorpyrifos oxon target MOE = 50) and for food and residential (chlorpyrifos target MOE = 40) exposure.
\2\ DWLOCs for adults (females 13-49 years) are calculated using the reciprocal MOE approach since the target MOEs are the same for drinking water
(chlorpyrifos oxon target MOE = 100) and for food and residential (chlorpyrifos target MOE = 100) exposure.
\3\ FOOD: MOEfood = PoDfood (ug/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 (<1 year old)
at 3.9 ppb. Exposures to chlorpyrifos oxon in drinking water at levels
that exceed the steady state DWLOC of 3.9 ppb are therefore a risk
concern and are considered unsafe for purposes of FFDCA section 408(b).
Table 6--Steady State Aggregate (Food, Drinking Water, Residential) Calculation of DWLOCs \1\ \2\
Food exposure (chlorpyrifos) Dermal exposure (chlorpyrifos) Drinking water exposure Steady state
\3\ \4\ (chlorpyrifos oxon) \5\ DWLOC \6\ (ppb
Population ------------------------------------------------------------------------------------------------ chlorpyrifos
MOE ARI MOE ARI MOE ARI oxon)
Infants \1\ (<1 yr)..................... 550 14 NA NA 55 1.1 3.9
Children \1\ (1-2 yrs).................. 410 10 NA NA 55 1.1 10
Youths \1\ (6-12 yrs)................... 700 18 1800 45 55 1.1 16
Adults \2\ (Females 13-49 yrs).......... 1000 NA 1200 NA 120 NA 7.8
\1\ DWLOCs for infants, children and youths are calculated using the ARI (Aggregate Risk Index) approach since target MOEs are different for drinking
water (chlorpyrifos oxon target MOE = 50) and for food and residential (chlorpyrifos target MOE = 40) exposure.
\2\ DWLOCs for adults (females 13-49 years) are calculated using the reciprocal MOE approach since the target MOEs are the same for drinking water
(chlorpyrifos oxon target MOE = 100) and for food and residential (chlorpyrifos target MOE = 100) exposure.
\3\ FOOD: MOEfood = PoDfood (ug/kg/day) (from Table 4.8.4)/Food Exposure (ug/kg/day) (from Table 5.4.4). ARIfood = ((MOEfood)/(MOEtarget)).
\4\ DERMAL: MOEdermal = PoDdermal (ug/kg/day) (from Table 4.8.4)/Dermal Exposure (ug/kg/day) (from Table 6.2). ARIdermal = ((MOE dermal)/(MOEtarget)).
\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
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
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.
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
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
Highest 21-day average exceedance Represented use site examples
Scenario concentration ppb count (maximum single application
(application date) ---------------- rate)
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
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
TXsorghumOP........................... 25.8 at 1.0 lb a.i./A.... 12 Wheat [1 lb a.i./A (aerial
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
Alfalfa [1 lb a.i./A (aerial
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)
Pepper [1 lb a.i./A (ground)]
Onion [1 lb a.i./A
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
Sugarbeets [2 lb a.i./A
Peanuts [4 lb a.i./A
(granular) \c\] Sweet Potato
[2 lb a.i./A (aerial and
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
Pecans [2 lb a.i./A (air);
PAapples.............................. 29.1 at 2.0 lb a.i./A.... 11 Apple [2 lb a.i./A (air and
Peach [2 lb a.i./A (air); 3
NCPeanutSTD........................... 21.0 at 2.0 lb a.i./A.... 21 Peanut:
2.0 lb a.i./A (aerial and
4 lb a.i./A (granular
FLCitrusSTD........................... 10.1 at 2.0 lb a.i./A.... 6 Citrus:
6.0 lb a.i./A [ground
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
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
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
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
Washington State Department of State............. 2003-2013 (4,091). 8.4 0.4
Ecology and Agriculture
Cooperative Surface Water
USDA Pesticide Data Program..... National.......... 2004-2009 (raw 0 na
USGS-EPA Pilot Drinking Water National.......... 1999-2000 (323)... 5.3 0.034
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
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
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
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
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,
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
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
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
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/
1995_childrens_health_policy_statement.pdf), reaffirmed in 2013 (http:/
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).
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-
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
3. U.S. EPA (2011). Chlorpyrifos: Preliminary Human Health Risk
Assessment for Registration Review. Available in docket number EPA-
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.
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
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.
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.
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.
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/
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
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
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List of Subjects in 40 CFR Part 180
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
Dated: October 28, 2015.
Jack E. Housenger,
Director, Office of Pesticide Programs.
Therefore, it is proposed that 40 CFR chapter I be amended as
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]
2. Remove Sec. 180.342.
[FR Doc. 2015-28083 Filed 11-5-15; 8:45 am]
BILLING CODE 6560-50-P