[Federal Register Volume 86, Number 165 (Monday, August 30, 2021)]
[Rules and Regulations]
[Pages 48315-48336]
[FR Doc No: 2021-18091]

-----------------------------------------------------------------------

ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[EPA-HQ-OPP-2021-0523; FRL-5993-04-OCSPP]

Chlorpyrifos; Tolerance Revocations

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

-----------------------------------------------------------------------

SUMMARY: On April 29, 2021, the United States Court of Appeals for the
Ninth Circuit ordered EPA to issue a final rule concerning the
chlorpyrifos tolerances by August 20, 2021. Based on the currently
available data and taking into consideration the currently registered
uses for chlorpyrifos, EPA is unable to conclude that the risk from
aggregate exposure from the use of chlorpyrifos meets the safety
standard of the Federal Food, Drug, and Cosmetic Act (FFDCA).
Accordingly, EPA is revoking all tolerances for chlorpyrifos.

DATES: This final rule is effective October 29, 2021. The tolerances
for all commodities expire on February 28, 2022.
    Written objections, requests for hearings, or requests for a stay
identified by the docket identification (ID) number EPA-HQ-OPP-2021-
0523 must be received on or before October 29, 2021, and must be filed
in accordance with the instructions provided in 40 CFR part 178 (see
also Unit I.C. of the SUPPLEMENTARY INFORMATION unit in this document).

ADDRESSES: The docket for this action, identified by docket
identification (ID) number EPA-HQ-OPP-2021-0523, is available at http://www.regulations.gov or at the Office of Pesticide Programs Regulatory
Public Docket (OPP Docket) in the Environmental Protection Agency
Docket Center (EPA/DC), West William Jefferson Clinton Bldg., Rm. 3334,
1301 Constitution Ave. NW, Washington, DC 20460-0001.
    Due to public health concerns related to COVID-19, the EPA/DC and
Reading Room are closed to visitors with limited exceptions. The staff
continues to provide remote customer service via email, phone, and
webform. For the latest status information on EPA/DC services and
docket access, visit http://www.epa.gov/dockets.

FOR FURTHER INFORMATION CONTACT: Elissa Reaves, Pesticide Re-Evaluation
Division (7508P), Office of Pesticide Programs, Environmental
Protection Agency, 1200 Pennsylvania Ave. NW, Washington, DC 20460-
0001; telephone number:<PHONE_NUMBER>; email address:
<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this action apply to me?

    You may be potentially affected by this action if you are an
agricultural producer, food manufacturer, or pesticide manufacturer.
The following list of North American Industrial Classification System
(NAICS) codes is not intended to be exhaustive, but rather provides a
guide to help readers determine whether this document applies to them.
Potentially affected entities may include:
     Crop production (NAICS code 111).
     Animal production (NAICS code 112).
     Food manufacturing (NAICS code 311).
     Pesticide manufacturing (NAICS code 32532).
    Other types of entities not listed in this unit could also be
affected. The NAICS codes have been provided to assist you and others
in determining whether this action might apply to certain entities. To
determine whether you or your business may be affected by this action,
you should carefully examine the applicability provisions in Unit II.
If you have any questions regarding the applicability of this action to
a particular entity, consult the contact listed under FOR FURTHER
INFORMATION CONTACT.

B. How can I get electronic access to other related information?

    You may access a frequently updated electronic version of 40 CFR
part 180 through the Government Printing Office's e-CFR site at http://www.ecfr.gov/cgi-bin/text-idx?&c=ecfr&tpl=/ecfrbrowse/Title40/40tab_02.tpl.

C. How can I file an objection or hearing request?

    Under FFDCA section 408(g), 21 U.S.C. 346a, any person may file an
objection to any aspect of this regulation and may also request a
hearing on those objections. You must file your objection or request a
hearing on this regulation in accordance with the instructions provided
in 40 CFR part 178. To ensure proper receipt by EPA, you must identify
docket ID number EPA-HQ-OPP-2021-0523 in the subject line on the first
page of your submission. All objections and requests for a hearing must
be in writing and must be received by the Hearing Clerk on or before
October 29, 2021. Addresses for mail and hand delivery of objections
and hearing requests are provided in 40 CFR 178.25(b), although at this
time, EPA strongly encourages those interested in submitting objections
or a hearing request, to submit objections and hearing requests
electronically. See Order Urging Electronic Service and Filing (April
10, 2020), https://www.epa.gov/sites/production/files/2020-05/documents/2020-04-10_-_order_urging_electronic_service_and_filing.pdf.
At this time, because of the COVID-19 pandemic, the judges and staff of
the Office of Administrative Law Judges (OALJ) are working remotely and
not able to accept filings or correspondence by courier, personal
deliver, or commercial delivery, and the ability to receive filings or
correspondence by U.S. Mail is similarly limited. When submitting
documents to the U.S. EPA OALJ, a person should utilize the OALJ e-
filing system, at https://yosemite.epa.gov/OA/EAB/EAB-ALJ_upload.nsf.
    Although EPA's regulations require submission via U.S. Mail or hand
delivery, EPA intends to treat submissions filed via electronic means
as properly filed submissions during this time that the Agency
continues to maximize telework due to the pandemic; therefore, EPA
believes the preference for submission via electronic means will not be
prejudicial. If it is

impossible for a person to submit documents electronically or receive
service electronically, e.g., the person does not have any access to a
computer, the person shall so advise OALJ by contacting the Hearing
Clerk at<PHONE_NUMBER>. If a person is without access to a computer
and must file documents by U.S. Mail, the person shall notify the
Hearing Clerk every time it files a document in such a manner. The
address for mailing documents is U.S. Environmental Protection Agency,
Office of Administrative Law Judges, Mail Code 1900R, 1200 Pennsylvania
Ave. NW, Washington, DC 20460.
    In addition to filing an objection or hearing request with the
Hearing Clerk as described in 40 CFR part 178 and above, please submit
a copy of the filing (excluding any Confidential Business Information
(CBI)) for inclusion in the public docket. Information not marked
confidential pursuant to 40 CFR part 2 may be disclosed publicly by EPA
without prior notice. Submit the non-CBI copy of your objection or
hearing request, identified by docket ID number EPA-HQ-OPP-2021-0523,
using the Federal eRulemaking Portal at http://www.regulations.gov.
Follow the online instructions for submitting comments. Do not submit
electronically any information you consider to be CBI or other
information whose disclosure is restricted by statute.
    If you would like to submit CBI with your hearing request, please
first contact the Pesticide Re-Evaluation Division by telephone, 703-
347-0206, or by email address<EMAIL_ADDRESS>Do not
submit CBI to EPA through the Federal eRulemaking Portal or email.

D. What can I do if I want the Agency to maintain a tolerance that the
Agency has revoked?

    Any affected party has 60 days from the date of publication of this
order to file objections to any aspect of this order with EPA and to
request an evidentiary hearing on those objections (21 U.S.C.
346a(g)(2)). A person may raise objections without requesting a
hearing.
    The objections submitted must specify the provisions of the
regulation deemed objectionable and the grounds for the objection (40
CFR 178.25). While 40 CFR 180.33(i) indicates a fee is due with each
objection, EPA currently cannot collect such fees per 21 U.S.C.
346a(m)(3). If a hearing is requested, the objections must include a
statement of the factual issue(s) on which a hearing is requested, the
requestor's contentions on such issues, and a summary of any evidence
relied upon by the objector (40 CFR 178.27).
    Although any person may file an objection, EPA will not consider
any legal or factual issue presented in objections, if that issue could
reasonably have been raised earlier in the Agency's review of
chlorpyrifos relative to this petition. Similarly, if you fail to file
an objection to an issue resolved in the final rule within the time
period specified, you will have waived the right to challenge the final
rule's resolution of that issue (40 CFR 178.30(a)). After the specified
time, issues resolved in the final rule cannot be raised again in any
subsequent proceedings on this rule. See Nader v EPA, 859 F.2d 747 (9th
Cir. 1988), cert denied 490 U.S. 1931 (1989).
    EPA will review any objections and hearing requests in accordance
with 40 CFR 178.30, and will publish its determination with respect to
each in the Federal Register. A request for a hearing will be granted
only to resolve factual disputes; objections of a purely policy or
legal nature will be resolved in the Agency's final order, and will
only be subject to judicial review pursuant to 21 U.S.C. 346a(h)(1),
(40 CFR 178.20(c) and 178.32(b)(1)). A hearing will only be held if the
Administrator determines that the material submitted shows the
following: (1) There is a genuine and substantial issue of fact; (2)
There is a reasonable probability that available evidence identified by
the requestor would, if established, resolve one or more of such issues
in favor of the requestor, taking into account uncontested claims to
the contrary; and (3) Resolution of the issue(s) in the manner sought
by the requestor would be adequate to justify the action requested (40
CFR 178.30).
    You must file your objection or request a hearing on this
regulation in accordance with the instructions provided in 40 CFR part
178. To ensure proper receipt by EPA, you must identify docket ID
number EPA-HQ-OPP-2021-0523 in the subject line on the first page of
your submission. All requests must be in writing and must be received
by the Hearing Clerk as required by 40 CFR part 178 on or before
October 29, 2021.

II. Background

A. What action is the Agency taking?

    EPA is revoking all tolerances for residues of chlorpyrifos. In
2007, the Pesticide Action Network North America (PANNA) and the
Natural Resources Defense Council (NRDC) filed a petition with EPA
under section 408(d) of the Federal Food, Drug, and Cosmetic Act
(FFDCA), 21 U.S.C. 346a(d), requesting that EPA revoke all chlorpyrifos
tolerances. (Ref. 1). In an April 29, 2021 decision concerning the
Agency's orders denying that 2007 Petition and the subsequent
objections to that denial, the Ninth Circuit ordered EPA to ``(1) grant
the 2007 Petition; (2) issue a final regulation within 60 days
following issuance of the mandate that either (a) revokes all
chlorpyrifos tolerances or (b) modifies chlorpyrifos tolerances and
simultaneously certifies that, with the tolerances so modified, the EPA
`has determined 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,' including for `infants and
children'; and (3) modify or cancel related FIFRA registrations for
food use in a timely fashion consistent with the requirements of 21
U.S.C. 346a(a)(1).'' League of United Latin Am. Citizens v. Regan, 996
F.3d 673 (9th Cir. 2021) (the LULAC decision).
    In today's action, EPA is granting the 2007 Petition, which
requested revocation of the tolerances. While EPA previously responded
to and denied the individual claims in the original petition, the Court
found EPA's denial, at least with regard to the issues raised in the
litigation, to be unsupported by the record before the Court and
ordered EPA to grant the 2007 Petition and issue a final rule revoking
or modifying tolerances. EPA is granting the petition by granting the
relief sought by the petition, i.e., the revocation of the chlorpyrifos
tolerances, for the reasons stated in this rulemaking. Moreover, the
Court expressly ordered EPA to respond to the petition by issuing a
final rule under FFDCA section 408(d)(4)(A)(i). 996 F.3d at 702. That
provision of the statute involves the issuance of a final rule
``without further notice and without further period for public
comment.'' 21 U.S.C. 346a(d)(4)(A)(i). While the FFDCA provides an
option for EPA to respond to a petition with the issuance of a proposed
rule under FFDCA section 408(d)(4)(A)(ii) and thereafter to finalize
the proposal, the Court did not direct EPA to exercise its authority to
finalize its 2015 proposal to revoke tolerances pursuant to
subparagraph (d)(4)(A)(ii). Nothing in the Ninth Circuit's opinion
reflects an expectation that, in complying with the Court's order, EPA
would or should finalize the 2015 proposed rule. As such, EPA is
viewing this action as independent from the 2015 proposal, and this
final rule is based on the Agency's current assessment of the available
scientific information, rather

than a continuation of and finalization of the Agency's proposal in
2015 to revoke chlorpyrifos tolerances.
    In this final rule, EPA is revoking all tolerances for residues of
chlorpyrifos contained in 40 CFR 180.342. This includes tolerances for
residues of chlorpyrifos on specific food and feed 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)).
    EPA finds that, taking into consideration the currently available
information and the currently registered uses of chlorpyrifos, EPA
cannot make a safety finding to support leaving the current tolerances
for residues of chlorpyrifos in place, as required under the FFDCA
section 408(b)(2). 21 U.S.C. 346a(b)(2). As described in greater detail
below, the Agency's analysis indicates that aggregate exposures (i.e.,
exposures from food, drinking water, and residential exposures), which
stem from currently registered uses, exceed safe levels, when relying
on the well-established 10% red blood cell acetylcholinesterase (RBC
AChE) inhibition as an endpoint for risk assessment and including the
statutory tenfold (10X) margin of safety to account for uncertainties
related to the potential for neurodevelopmental effects to infants,
children, and pregnant women. Accordingly, the Agency is therefore
revoking all tolerances because given the currently registered uses of
chlorpyrifos, EPA cannot determine that there is a reasonable certainty
that no harm will result from aggregate exposure to residues, including
all anticipated dietary (food and drinking water) exposures and all
other exposures for which there is reliable information.

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)(i). 21 U.S.C.
346a(b)(1)(A), (b)(2)(A), (d)(4)(A)(i).

C. Overview of Final Rule

    When assessing pesticides, EPA performs a number of analyses to
determine the risks from aggregate exposure to pesticide residues. For
further discussion of the regulatory requirements of section 408 of the
FFDCA, see https://www.epa.gov/laws-regulations/summary-federal-food-drug-and-cosmetic-act, and for a complete description of the risk
assessment process, see https://www.epa.gov/pesticide-science-and-assessing-pesticide-risks/overview-risk-assessment-pesticide-program
and https://www.epa.gov/pesticide-science-and-assessing-pesticide-risks/epas-risk-assessment-process-tolerance-reassessment.
    In general, 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, which
includes choosing a point of departure (PoD) that reflects the adverse
health endpoint that is most sensitive to the pesticide, as well as
uncertainty factors; (3) Estimation of human exposure to the pesticide
through all applicable routes; and (4) Characterization of human risk
based on comparison of the estimated human exposure to the level of
concern. For tolerances, if aggregate exposure to humans is greater
than the Agency's determined level of concern, the Agency's
determination is the tolerances are not safe.
    The following provides a brief roadmap of the Units in this rule.
     Unit III. contains an overview of the statutory
background, including the safety standard in FFDCA, and the
registration standard under FIFRA. FFDCA provides the statutory basis
for evaluating tolerances and directs the Agency to revoke tolerances
that are not safe.
     Unit IV. provides an overview of the FFDCA petition that
requested that EPA revoke chlorpyrifos tolerances on the grounds that
those tolerances were not safe under the FFDCA. While that petition
raised numerous issues, the primary scientific challenge to the
chlorpyrifos tolerances that was before the Ninth Circuit related to
whether EPA had selected the correct PoD for assessing risk. While
EPA's PoD was based on inhibition of the enzyme acetylcholinesterase
(AChE), petitioners asserted that the most sensitive health endpoint
was neurodevelopmental outcomes from exposure to chlorpyrifos. A
summary of that petition, EPA's response to that petition, and the
subsequent litigation and Ninth Circuit's order directing EPA to revoke
or modify the chlorpyrifos tolerances is included in this section.
     Unit V. provides an overview of the regulatory background
for chlorpyrifos, including the numerous human health risk assessments
EPA has conducted and FIFRA Scientific Advisory Panels (SAPs) that were
convened to discuss the complex scientific issues associated with
chlorpyrifos.
     Units VI. through VIII. summarizes EPA's risk assessment,
which reflect the four-step process described above.
     Unit VI, which focuses on the hazard assessment of
chlorpyrifos, combines the first two steps to provide a full picture of
how EPA conducts its hazard assessment. After describing the process
generally, this unit discusses EPA's analysis of the hazards posed by
chlorpyrifos, including a discussion of the available data on AChE
inhibition and the potential for neurodevelopmental outcomes in the
young. Unit VI. also discusses the Agency's process for determining the
endpoint on which to regulate chlorpyrifos exposure and the rationale
for basing the PoD analysis on 10% AChE inhibition. Finally, this Unit
includes a discussion of the FQPA safety factor and the Agency's
reasons for retaining the default 10X value.
     Unit VII. describes EPA's exposure assessment for
chlorpyrifos. The unit includes a description of the general approach
for estimating exposures to pesticide residues in or on food and in
drinking water, as well as exposures that come from non-occupational
and non-dietary sources, also referred to as residential exposures. The
unit walks through how EPA conducted those exposure assessments for
chlorpyrifos, including a detailed discussion of the recent refinements
to the drinking water analysis conducted by EPA for chlorpyrifos.
     Unit VIII. describes the Agency's process for assessing
aggregate risk based on the hazard discussed in Unit VI. and the
exposure discussed in Unit VII. and provides the Agency's rationale and
conclusions concerning the overall risks posed by chlorpyrifos based on
the currently registered uses. Unit VIII. concludes that the aggregate
risks exceed the level of concern and therefore the chlorpyrifos
tolerances must be revoked.
    Units IX. and X. address procedural matters, international
obligations, statutory and executive order review requirements, and the
specific revisions that will be made to the Code of Federal Regulations
with this final rule.

III. Statutory Background

A. Federal Food, Drug, and Cosmetic Act (FFDCA) Tolerances

    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, pesticide residues
in or on food is considered unsafe, 21 U.S.C. 346a(a)(1), and such
food, which is then rendered ``adulterated'' under FFDCA section
402(a), 21 U.S.C. 342(a), may not be distributed in interstate
commerce, 21 U.S.C. 331(a).
    Section 408(b)(2) of the FFDCA directs that EPA may establish or
leave in effect a tolerance for a 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 food, 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 postnatal
toxicity and completeness of the data with respect to exposure and
toxicity to infants and children.'' (21 U.S.C. 346a(b)(2)(C)). EPA is
permitted to ``use a different margin of safety for the pesticide
chemical residue only if, on the basis of reliable data, such margin
will be safe for infants and children.'' (21 U.S.C. 346a(b)(2)(C)). Due
to Congress's focus on both pre- and postnatal toxicity, EPA has
interpreted this additional safety factor as pertaining to risks to
infants and children that arise due to prenatal exposure as well as to
exposure during childhood years. This section providing for the special
consideration of infants and children in section 408(b)(2)(C) was added
to the FFDCA through the Food Quality Protection Act (FQPA) (Pub. L.
104-170, 110 Stat. 1489 (1996)); therefore, this additional margin of
safety is often referred to as the ``FQPA safety factor (SF)''.
    Section 408(d) of the FFDCA, 21 U.S.C. 346a(d), authorizes EPA to
revoke tolerances in response to an administrative petition submitted
by any person. As explained in more detail in Unit IV, PANNA and NRDC
submitted a petition in 2007 requesting revocation of all chlorpyrifos
tolerances. The Ninth Circuit has directed EPA to grant that petition
and issue a rule revoking or modifying those tolerances. EPA is issuing
this rule in response to that petition and revoking all chlorpyrifos
tolerances because EPA is unable to determine, based on data available
at this time, that aggregate exposures to chlorpyrifos are safe.

B. Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA)
Registration Review

    Under FIFRA, a pesticide may not be sold or distributed in the
United States unless it is registered. (7.U.S.C. 136a(a)). EPA must
determine that a pesticide ``will not generally cause unreasonable
adverse effects on the environment in order to register a pesticide.''
7 U.S.C. 136a(c)(5). The term ``unreasonable adverse effects on the
environment'' is defined to include ``a human dietary risk from
residues that result from a use of a pesticide in or on any food
inconsistent with the standard under section 346a of Title 21.'' 7
U.S.C. 136(bb). Thus, the FIFRA registration standard incorporates the
FFDCA safety standard and requires consideration of safety at the time
of registration and during the registration review process.
    Under section 3(g) of FIFRA (7 U.S.C. 136(a)(g)), EPA is required
to re-evaluate existing registered pesticides every 15 years in a
process called ``registration review.'' The purpose of registration
review is ``to ensure that each pesticide registration continues to
satisfy the FIFRA standard for registration,'' 40 CFR 155.40(a)(1),
taking into account changes that have occurred since the last
registration decision, including any new relevant scientific
information and any changes to risk-assessment procedures, methods, and
data requirements. 40 CFR 55.53(a). To ensure that a pesticide
continues to meet the standard for registration, EPA must determine,
based on the available data, including any additional information that
has become available since the pesticide was originally registered or
re-evaluated, that the pesticide does not cause ``unreasonable adverse
effects on the environment.'' 7 U.S.C. 136a(c)(1), (5); see also 40 CFR
152.50.
    Chlorpyrifos is currently undergoing registration review, which
must be completed by October 1, 2022. 7 U.S.C. 136a(g)(1)(A)(iv). For
information about the ongoing registration review process for
chlorpyrifos, see https://www.regulations.gov/docket/EPA-HQ-OPP-2008-0850.

IV. FFDCA Petition and Related Litigation

A. 2007 FFDCA Petition

    In 2006, EPA issued the Registration Eligibility Decision (RED) for
chlorpyrifos, which concluded that chlorpyrifos was eligible for
reregistration as it continued to meet the FIFRA standard for
registration. In September 2007, PANNA and NRDC submitted to EPA a
petition (the Petition) seeking revocation of all chlorpyrifos
tolerances under FFDCA section 408 and cancellation of all chlorpyrifos
pesticide product registrations under FIFRA. (Ref. 1). That petition
raised several claims regarding EPA's 2006 FIFRA reregistration
decision for chlorpyrifos and the active registrations in support of
the request for tolerance revocations and product cancellations. Those
claims are described in detail in EPA's earlier order denying the
petition (82 FR 16581, April 5, 2017) (FRL-9960-77).

B. Agency Responses and 2017 Order Denying Petition

    On March 29, 2017, EPA denied the Petition in full (82 FR 16581,
April 5, 2017) (FRL-9960-77). Prior to issuing that order, EPA provided
the Petitioners with two interim responses on July 16, 2012 and July
15, 2014, which denied six of the Petition's claims. EPA made clear in
both the 2012 and 2014 responses that, absent a request from
Petitioners, EPA's denial of those six claims would not be made final
until EPA finalized its response to the entire Petition. Petitioners
made no such request, and EPA therefore finalized its response to those
claims in the March 29, 2017 Denial Order.
    As background, three of the Petition's claims all related to the
same issue: Whether the potential exists for chlorpyrifos to cause
neurodevelopmental effects in children

at exposure levels below EPA's existing regulatory standard (10% RBC
AChE inhibition). Because the claims relating to the potential for
neurodevelopmental effects in children raised novel, highly complex
scientific issues, EPA originally decided it would be appropriate to
address these issues in connection with the registration review of
chlorpyrifos under FIFRA section 3(g) and decided to expedite that
review, intending to finalize it in 2015, well in advance of the
October 1, 2022 registration review deadline (Ref. 2). EPA decided as a
policy matter that it would address the Petition claims raising these
matters on a similar timeframe. Id. at 16583.
    The complexity of these scientific issues precluded EPA from
finishing its review according to EPA's original timeline, and the
Petitioners brought legal action in the Ninth Circuit Court of Appeals
to compel EPA to either issue an order denying the Petition or to grant
the Petition by initiating the tolerance revocation process. The result
of that litigation was that on August 10, 2015, the Court ordered EPA
to ``issue either a proposed or final revocation rule or a full and
final response to the administrative [P]etition by October 31, 2015.''
In re Pesticide Action Network N. Am., 798 F.3d 809, 815 (9th Cir.
2015).
    In response to that 2015 order, EPA issued a proposed rule to
revoke all tolerances for chlorpyrifos on October 28, 2015 (published
in the Federal Register on November 6, 2015 (80 FR 69080)), based on
its unfinished registration review risk assessment. EPA acknowledged
that it had had insufficient time to complete its drinking water
assessment and its review of data addressing the potential for
neurodevelopmental effects. Although EPA noted that further evaluation
might enable more tailored risk mitigation, EPA was unable to conclude,
based on the information before EPA at the time, that the tolerances
were safe, since the aggregate exposure to chlorpyrifos exceeded safe
levels.
    On December 10, 2015, the Ninth Circuit issued a further order
requiring EPA to take final action on its proposed revocation rule and
issue its final response to the Petition by December 30, 2016. In re
Pesticide Action Network N. Am., 808 F.3d 402 (9th Cir. 2015). In
response to EPA's request for an extension of the deadline in order to
be able to fully consider the July 2016 FIFRA Scientific Advisory Panel
(SAP) report regarding chlorpyrifos toxicology, the Ninth Circuit
ordered EPA to complete its final action by March 31, 2017. In re
Pesticide Action Network of North America v. EPA, 840 F.3d 1014 (9th
Cir. 2016). Following that order, EPA published a Notice of Data
Availability (NODA), seeking comment on EPA's revised risk assessment
and water assessment and reopening the comment period on the proposal
to revoke tolerances. (81 FR 81049, November 17, 2016) (FRL-9954-65).
    On March 29, 2017, and as published in the Federal Register on
April 5, 2017, the EPA issued an order denying the Petition (the Denial
Order) (82 FR 16581). The specific responses are described in full in
that Denial Order and summarized again in the Agency's denial of
objections (84 FR 35555, July 24, 2019) (FRL-9997-06). EPA's Denial
Order did not issue a determination concerning the safety of
chlorpyrifos. Rather, EPA concluded that, despite several years of
study, the science addressing neurodevelopmental effects remained
unresolved and that further evaluation of the science on this issue
during the remaining time for completion of registration review was
warranted. EPA therefore denied the remaining Petition claims,
concluding that it was not required to complete--and would not
complete--the human health portion of the registration review or any
associated tolerance revocation of chlorpyrifos without resolution of
those issues during the ongoing FIFRA registration review of
chlorpyrifos.

C. Objections and EPA's Denial of Objections

    In June 2017, several public interest groups and states filed
objections to the Denial Order pursuant to the procedures in FFDCA
section 408(g)(2). Specifically, Earthjustice submitted objections on
behalf of the following 12 public interest groups: Petitioners PANNA
and NRDC, United Farm Workers, California Rural Legal Assistance
Foundation, Farmworker Association of Florida, Farmworker Justice,
GreenLatinos, Labor Council for Latin American Advancement, League of
United Latin American Citizens, Learning Disabilities Association of
America, National Hispanic Medical Association and Pineros y Campesinos
Unidos del Noroeste. Another public interest group, the North Coast
River Alliance, submitted separate objections. With respect to the
states, New York, Washington, California, Massachusetts, Maine,
Maryland, and Vermont submitted a joint set of objections (Ref. 1). The
objections focused on three main topics: (1) The Objectors asserted
that the FFDCA requires that EPA apply the FFDCA safety standard in
reviewing any petition to revoke tolerances and that EPA's decision to
deny the Petition without making a safety finding failed to apply that
standard; (2) The Objectors contended that the risk assessments EPA
conducted in support of the 2015 proposed rule and the 2016 Revised
Human Health Risk Assessment (HHRA) demonstrated that chlorpyrifos
results in unsafe drinking water exposures and adverse
neurodevelopmental effects and that EPA therefore was required to issue
a final rule revoking all chlorpyrifos tolerances; and (3) The
Objectors claimed that EPA committed procedural error in failing to
respond to comments, and they specifically pointed to comments related
to neurodevelopmental effects, inhalation risk, and Dow AgroSciences'
(now doing business as Corteva AgriScience) physiologically based
pharmacokinetic model (PBPK model) used in EPA's 2014 and 2015 human
health risk assessments, which are discussed further in Unit V.
    On July 18, 2019, EPA issued a final order denying all objections
to the Denial Order and thereby completing EPA's administrative denial
of the Petition (the Final Order) (84 FR 35555). Again, the Final Order
did not issue a determination concerning the safety of chlorpyrifos.
Rather, EPA denied the objections in part on the grounds that the data
concerning neurodevelopmental toxicity were not sufficiently valid,
complete, and reliable to meet the petitioners' burden.

D. Judicial Challenge to Objections Denial and 2021 Ninth Circuit Order

    On August 7, 2019, the Objectors (LULAC Petitioners) and States
petitioned the Ninth Circuit for review of the Denial Order and the
Final Order. The LULAC Petitioners and States argued that EPA was
compelled to grant the 2007 Petition and revoke chlorpyrifos tolerances
because (1) EPA lacked authority to maintain chlorpyrifos tolerances
without an affirmative finding that chlorpyrifos is safe, (2) EPA's
findings that chlorpyrifos is unsafe in the Agency's risk assessments
from 2014 and 2016, compel it to revoke chlorpyrifos tolerances, and
(3) The 2007 Petition provided a sufficient basis for EPA to reconsider
the question of chlorpyrifos's safety and was not required to prove
that a pesticide is unsafe.
    On April 29, 2021, the Ninth Circuit issued its decision, finding
that when EPA denied the 2007 Petition to revoke chlorpyrifos
tolerances, it was essentially leaving those chlorpyrifos tolerances in
effect, which, the Court noted, the FFDCA only permits if EPA has made
a determination that such tolerances were safe. League of United

Latin Am. Citizens v. Regan, 996 F.3d. 673 (9th Cir. 2021). Although
EPA argued that it was not compelled to reconsider its safety
determination because the 2007 Petition had failed to meet the
threshold requirement of providing reliable evidence that the
tolerances were unsafe, the Court found that the Petition provided the
necessary ``reasonable grounds,'' which triggered EPA's duty to ensure
the tolerances were safe. Id. at 695. Since EPA's Denial Order and
Final Order failed to make any safety determinations for chlorpyrifos,
the Court concluded that EPA violated the FFDCA by leaving those
tolerances in place without the requisite safety findings. Id. at 695-
96. Moreover, in light of the record before the Court, including the
2016 HHRA indicating that the current chlorpyrifos tolerances are not
safe, the Court found EPA's denial of the 2007 Petition to be arbitrary
and capricious. Id. at 697. Based on the available record, the Court
concluded that EPA must grant the Petition and issue a final rule
modifying or revoking the tolerances under FFDCA section
408(d)(4)(A)(i). Id. at 701.
    The Court recognized that EPA had been continuing to evaluate
chlorpyrifos in registration review and had issued additional
regulatory documents concerning chlorpyrifos after the record closed in
the litigation, e.g., the 2020 Proposed Interim Registration Review
Decision and 2020 SAP, both of which are discussed in more detail in
Unit V. below, and noted that such information could be relevant to a
safety determination. Id. at 703. The Court allowed that if the new
information could support a safety determination, EPA might issue a
final rule modifying chlorpyrifos tolerances rather than revoking them,
although the Court directed EPA to act ``immediately'' and not engage
in ``further factfinding.'' Id. at 703. As a result, the Court ordered
EPA to: (1) Grant the 2007 Petition; (2) Issue a final rule within 60
days of the issuance of the mandate that either revokes all
chlorpyrifos tolerances or modifies chlorpyrifos tolerances, provided
that such modification is supported by a safety finding, and (3) Modify
or cancel related FIFRA registrations for food use in a timely fashion.
Id. at 703-04. Since the mandate was issued on June 21, 2021, the
deadline for issuing this final rule is August 20, 2021.

V. Chlorpyrifos Background and Regulatory History

    Chlorpyrifos (0,0-diethyl-0-3,5,6-trichloro-2-pyridyl
phosphorothioate) is a broad-spectrum, chlorinated organophosphate (OP)
insecticide. Given the complex scientific nature of the issues
reflected in this rule, EPA is alerting the reader that many of the
technical terms used in this unit will be described more fully in a
subsequent unit.
    Chlorpyrifos, like other OP pesticides, affects the nervous system
by inhibiting acetylcholinesterase (AChE), an enzyme necessary for the
proper functioning of the nervous system. This can ultimately lead to
signs of neurotoxicity. As discussed in more detail below, while there
are data that indicate an association between chlorpyrifos and
neurodevelopmental outcomes, there remains uncertainty in the dose-
response relationship and the levels at which these outcomes occur. In
an effort to resolve this scientific uncertainty, evaluation of
toxicology and epidemiology studies of chlorpyrifos, specific to
determining the appropriate regulatory endpoint, has been the focus of
EPA's work on chlorpyrifos for over a decade.
    Chlorpyrifos 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.
See, e.g., 65 FR 76233, December 6, 2000) (FRL-6758-2); 66 FR 47481,
September 12, 2001) (FRL-6799-7).
    In 2006, EPA completed FIFRA section 4 reregistration and FFDCA
tolerance reassessment for chlorpyrifos and the OP class of pesticides,
concluding that the existing tolerances were safe and that chlorpyrifos
continued to meet the FIFRA standard for registration. In that effort,
EPA relied on RBC AChE inhibition as the endpoint for examining risk.
    Subsequently, given ongoing scientific developments in the study of
the OPs generally, EPA chose to prioritize the FIFRA section 3(g)
registration review (the subsequent 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 which the Agency has taken to multiple
independent FIFRA SAP reviews. (Note: The SAP is a federal advisory
committee created by FIFRA section 25(d), 7 U.S.C. 136w(d), and serves
as EPA's primary source of peer review for significant regulatory and
policy matters involving pesticides.)
    These SAPs, which have included the review of new worker and non-
occupational exposure methods, experimental toxicology and
epidemiology, and the evaluation of a chlorpyrifos-specific
physiologically-based pharmacokinetic-pharmacodynamic (PBPK-PD, see
Unit VII. for definitions) model. These FIFRA SAP reviews have resulted
in significant developments in EPA's risk assessments generally, and,
more specifically, in the study of chlorpyrifos's effects. In
particular, and partly in response to the issues raised in the 2007
Petition, EPA has conducted extensive reviews of available data to
evaluate the possible connection between chlorpyrifos and adverse
neurodevelopmental effects, and to assess whether the
neurodevelopmental effects could be used to determine points of
departure (PoDs) for assessing chlorpyrifos. On this particular topic,
EPA has convened three FIFRA SAP reviews. EPA has taken FIFRA SAP
recommendations into consideration as it has developed risk assessments
and regulatory documents for chlorpyrifos. The remainder of this Unit
provides a brief regulatory overview for chlorpyrifos by presenting a
summary of the chronology of the FIFRA SAPs and Agency assessments of
chlorpyrifos.
    The 2008 FIFRA SAP evaluated the Agency's preliminary review of
available literature and research on epidemiology in mothers and
children following exposures to chlorpyrifos and other OPs, laboratory
studies on animal behavior and cognition, AChE inhibition, and
mechanisms of action. (Ref. 3) The 2008 FIFRA SAP recommended that AChE
inhibition remain as the source of data for the points of departure
(PoDs, see Unit VII. for definitions), but noted that despite some
uncertainties, the Columbia Center for Children's Environmental Health
(CCCEH) epidemiologic studies ``is epidemiologically sound'' and
``provided extremely valuable information'' for evaluating the
potential neurodevelopmental effects of chlorpyrifos (Ref. 3). See Unit
VI.A.2. for neurodevelopmental toxicity.
    The 2010 FIFRA SAP favorably reviewed EPA's 2010 draft epidemiology
framework. (Ref. 4, 5) This draft framework, titled ``Framework for
Incorporating Human

Epidemiologic & Incident Data in Risk Assessments in Pesticides,''
described the use of the Bradford Hill Criteria as modified in the Mode
of Action Framework to integrate epidemiology information with other
lines of evidence. As suggested by the 2010 FIFRA SAP, EPA did not
immediately finalize the draft framework but instead used it in several
pesticide evaluations prior to making revisions and finalizing it.
EPA's Office of Pesticide Program's (OPP) finalized this epidemiology
framework in December 2016 (Ref. 5).
    In 2011, EPA released its preliminary human health risk assessment
(2011 HHRA) for the registration review of chlorpyrifos. The 2011 HHRA
used 10% RBC AChE inhibition from laboratory rats as the critical
effect (or PoD) for extrapolating risk. It also used the default 10X
uncertainty factors for inter- and intra-species extrapolation. The 10X
FQPA SF was removed with a note to the public that a weight of evidence
(WOE) evaluation would be forthcoming, as described in the 2010 draft
``Framework for Incorporating Human Epidemiologic & Incident Data in
Health Risk Assessment.''
    In 2011, EPA convened a meeting of the FIFRA SAP to review the
PBPK-PD model for chlorpyrifos. The panel made numerous recommendations
for the improvement of the model for use in regulatory risk assessment,
including the inclusion of dermal and inhalation routes. From 2011-
2014, Dow AgroSciences, in consultation with EPA, refined the PBPK-PD
model, and those refinements were sufficient to allow for use of the
PBPK-PD model in the next HHRA.
    In 2012, the Agency convened another meeting of the FIFRA SAP to
review the latest experimental data related to RBC AChE inhibition,
cholinergic and non-cholinergic adverse outcomes, including
neurodevelopmental studies on behavior and cognition effects. The
Agency also performed an in-depth analysis of the available
chlorpyrifos biomonitoring data and of the available epidemiologic
studies from three major children's health cohort studies in the United
States, including those from the CCCEH, Mount Sinai, and University of
California, Berkeley. The Agency explored plausible hypotheses on mode
of actions/adverse outcome pathways (MOAs/AOPs) leading to
neurodevelopmental outcomes seen in the biomonitoring and epidemiology
studies.
    The 2012 FIFRA SAP described the Agency's epidemiology review as
``very clearly written, accurate'' and ``very thorough review''. (Ref.
6 at 50-52, 53) It went further to note that it ``believes that the
[Agency's] epidemiology review appropriately concludes that the studies
show some consistent associations relating exposure measures to
abnormal reflexes in the newborn, pervasive development disorder at 24
or 36 months, mental development at 7-9 years, and attention and
behavior problems at 3 and 5 years of age. . . . .'' The 2012 FIFRA SAP
concluded that the RBC AChE inhibition remained the most robust dose-
response data, though expressed significant concerns about the degree
to which 10% RBC AChE inhibition is protective for neurodevelopmental
effects, pointing to evidence from epidemiology, in vivo animal
studies, and in vitro mechanistic studies, and urged the EPA to find
ways to use the CCCEH data.
    In 2014, EPA released a revised human health risk assessment (2014
HHRA. (Ref. 7). The revised assessment used the chlorpyrifos PBPK-PD
model for deriving human PoDs for RBC AChE inhibition, thus obviating
the need for the inter-species extrapolation factor (as explained later
in this Unit) and providing highly refined PoDs which accounted for
gender, age, duration and route specific exposure considerations. The
PBPK-PD model was also used to develop data derived intra-species
factors for some lifestages. The 10X FQPA SF was retained based on the
outcome of the 2012 FIFRA SAP and development of a WOE analysis on
potential for neurodevelopmental outcomes according to EPA's
``Framework for Incorporating Human Epidemiologic & Incident Data in
Risk Assessments for Pesticides.'' The 2014 HHRA, taken together with
the Agency's drinking water assessment, identified estimated aggregate
risks exceeding the level of concern for chlorpyrifos.
    On November 6, 2015, EPA issued a proposed rule to revoke all
tolerances of chlorpyrifos, based on the aggregate risks exceeding the
level of concern (80 FR 69079) (FRL-9935-92). In this proposed
rulemaking, EPA specified that it was unable to conclude that aggregate
exposures from use of chlorpyrifos met the FFDCA's ``reasonable
certainty of no harm'' standard due to risks identified from the
drinking watering using a national-scale assessment (i.e., using
default values and conservative assumptions). At that time, the EPA had
not completed a refined drinking water assessment (i.e., a higher-tier
and more resource-intensive assessment relying on more targeted inputs)
or an additional analysis of the hazard of chlorpyrifos that was
suggested by several commenters to the 2014 HHRA. Those commenters
raised the concern that the use of 10% RBC AChE inhibition for deriving
PoDs for chlorpyrifos may not provide a sufficiently health protective
human health risk assessment given the potential for neurodevelopmental
outcomes.
    In 2015, EPA conducted additional hazard analyses using data on
chlorpyrifos levels in fetal cord blood reported by the CCCEH study
investigators. The Agency convened another meeting of the FIFRA SAP in
April 2016 to evaluate a proposal of using cord blood data from the
CCCEH epidemiology studies as the source of data for the PoDs. The 2016
SAP did not support the ``direct use'' of the cord blood and working
memory data for deriving the regulatory endpoint, due in part to
insufficient information about timing and magnitude of chlorpyrifos
applications in relation to cord blood concentrations at the time of
birth, uncertainties about the prenatal window(s) of exposure linked to
reported effects, lack of a second laboratory to reproduce the
analytical blood concentrations, and lack of raw data from the
epidemiology study. (Ref. 8)
    Despite its critiques of uncertainties in the CCCEH studies, the
2016 FIFRA SAP expressed concern that 10% RBC AChE inhibition is not
sufficiently protective of human health. Specifically, the FIFRA SAP
stated that it ``agrees that both epidemiology and toxicology studies
suggest there is evidence for adverse health outcomes associated with
chlorpyrifos exposures below levels that result in 10% RBC AChE
inhibition (i.e., toxicity at lower doses).'' (Id. at 18). (Ref. 8)
    Taking into consideration the conclusions of the 2016 SAP, EPA
issued another HHRA using a dose reconstruction approach to derive the
PoD based on the neurodevelopmental effects observed in the CCCEH
study. In 2016, EPA also issued a revised drinking water assessment
(2016 DWA). EPA issued a Notice of Data Availability seeking public
comment on the 2016 HHRA and 2016 DWA. (81 FR 81049, November 17, 2016)
(FRL-9954-65).
    In 2017, in response to a Ninth Circuit order, EPA denied the 2007
Petition on the grounds that ``further evaluation of the science during
the remaining time for completion of registration review is warranted
to achieve greater certainty as to whether the potential exists for
adverse neurodevelopmental effects to occur from current human
exposures to chlorpyrifos.'' (82 FR at 16583). As part of this
commitment to further evaluate the science, EPA evaluated the new
laboratory animal studies with results

suggesting effects on the developing brain occur at doses lower than
doses that cause AChE inhibition, and concluded that they are not
sufficient for setting a PoD. While EPA sought to verify the
conclusions of the epidemiology studies conducted by Columbia
University it has been unable to confirm the findings of the CCCEH
papers or conduct alternative statistical analyses to evaluate the
findings. In summary, while EPA sought to address the potential
neurodevelopmental effects associated with chlorpyrifos exposure over
the past decade, these efforts ultimately concluded with the lack of a
suitable regulatory endpoint based on these potential effects. However,
these efforts do not alleviate the Agency's concerns regarding
potential neurodevelopmental effects.
    In October 2020, EPA released its latest human health risk
assessment (2020 HHRA) and drinking water assessment (2020 DWA). (Ref.
9 and 10) Due to the shortcomings of the data upon which the 2016 HHRA
was based and the uncertainty surrounding the levels around which
neurodevelopmental effects may occur, the 2020 HHRA uses the same
endpoint and PoDs as those used in the 2014 HHRA (i.e., the PBPK-PD
model has been used to estimate exposure levels resulting in 10% RBC
AChE inhibition following acute (single day, 24 hours) and steady state
(21-day) exposures for a variety of exposure scenarios for chlorpyrifos
and/or chlorpyrifos oxon). The 2020 HHRA retained the default 10X FQPA
SF, but also presented risk estimates at a reduced 1X FQPA SF, though
it did not adopt or attempt to justify use of this approach.
    Then, in December 2020, as part of its FIFRA registration review,
EPA issued its Proposed Interim Registration Review Decision (2020 PID)
for chlorpyrifos (85 FR 78849, December 7, 2020) (FRL-10017-13). The
2020 PID was based on comparing estimates in the 2020 HHRA with the
values from the 2020 DWA, and retaining the 10X FQPA safety factor, the
PID proposed to limit applications of chlorpyrifos in this country
would be reduced to certain uses in certain regions of the United
States. The PID proposed to conclude that the Agency could make a
safety finding for the approach in this path forward, as risk would be
based on limited uses in limited geographic areas, as specified. This
proposed path forward was intended to offer to stakeholders a way to
mitigate the aggregate risk from chlorpyrifos, which the Agency had
determined would exceed risk levels of concern without the proposed use
restrictions.
    In December 2020, EPA requested public comment on the 2020 PID,
2020 HHRA, and 2020 DWA. EPA extended the 60-day comment period by 30
days and it closed on March 7, 2021.

VI. EPA's Hazard Assessment for Chlorpyrifos

A. General Approach to Hazard Identification, Dose-Response Assessment,
and Extrapolation

    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). In evaluating
toxicity or hazard, EPA reviews toxicity data, typically from studies
with laboratory animals, to identify any adverse effects on the test
subjects. Where available and appropriate, EPA will also take into
account studies involving humans, including human epidemiological
studies. The animal toxicity database for a conventional, food use
pesticide usually consists of studies investigating a broad range of
endpoints including potential for carcinogenicity, mutagenicity,
developmental and reproductive toxicity, and neurotoxicity. These
studies include gross and microscopic effects on organs and tissues,
functional effects on bodily organs and systems, effects on blood
parameters (such as red blood cell count, hemoglobin concentration,
hematocrit, and a measure of clotting potential), effects on the
concentrations of normal blood chemicals (including glucose, total
cholesterol, urea nitrogen, creatinine, total protein, total bilirubin,
albumin, hormones, and enzymes such as alkaline phosphatase, alanine
aminotransferase and cholinesterases), and behavioral or other gross
effects identified through clinical observation and measurement. EPA
examines whether adverse effects are caused by different durations of
exposure ranging from short-term (acute) to long-term (chronic)
pesticide exposure and different routes of exposure (oral, dermal,
inhalation). Further, EPA evaluates potential adverse effects in
different age groups (adults as well as fetuses and juveniles). (Ref.
11 at 8-10).
    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
typically involves a number of considerations including:
     A ``point of departure'' (PoD): Typically, the PoD is the
value from a dose-response curve that is at the low end of the
observable data in laboratory animals and that is the toxic dose that
serves as the `starting point' in extrapolating a risk to the human
population, although a PoD can also be derived from human data as well.
PoDs are selected to be protective of the most sensitive adverse toxic
effect for each exposure scenario, and are chosen from toxicity studies
that show clearly defined No Observed Adverse Effect Levels (NOAELs) or
Lowest Observed Adverse Effect Levels (LOAELs), dose-response
relationships, and relationships between the chemical exposure and
effect. EPA will select separate PoDs, as needed, for each expected
exposure duration (e.g., acute, chronic, short-term, intermediate-term)
and route of exposure (e.g., oral, dermal, inhalation). For
chlorpyrifos, as discussed later in this Unit, EPA derived PoDs based
on 10% RBC AChE inhibition.
     Interspecies extrapolation: Because most PoDs are derived
from toxicology studies in laboratory animals, there is a need to
extrapolate from animals to humans. In typical risk assessments, a
default tenfold (10X) uncertainty factor is used to address the
potential for a difference in toxic response between humans and animals
used in toxicity tests. For chlorpyrifos, as described further below,
EPA used a sophisticated model called a physiologically based
pharmacokinetic-pharmacodynamic (PBPK-PD) model that accounts for
differences in laboratory animals and humans, thereby obviating the
need for the default interspecies factor.
     Intraspecies extrapolation: To address the potential for
differences in sensitivity in the toxic response across the human
population, EPA conducts intraspecies extrapolation. In typical risk
assessments, a 10X default uncertainty factor is used. For
chlorpyrifos, the PBPK-PD model used to derive PoDs also accounts for
differences in metabolism and toxicity response across the human
population for some age groups and some subpopulations, which allows
the default factor of 10X to be refined in accordance with EPA's 2014
Guidance for Applying Quantitative Data to Develop Data-Derived
Extrapolation Factors for Interspecies and Intraspecies Extrapolation.

     Food Quality Protection Act safety factor (FQPA SF)): The
FFDCA section 408(b)(2)(C) instructs EPA, in making its ``reasonable
certainty of no harm'' finding, 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 data with respect to exposure and toxicity
to infants and children.'' Section 408(b)(2)(C) further states that
``the Administrator may 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.'' For chlorpyrifos, as
discussed later in this Unit, EPA is retaining the default 10X FQPA SF.
    In the human health risk assessment process, as indicated above,
EPA uses the selected PoD to calculate a RfD for extrapolating risk.
The RfD is calculated by dividing the selected PoD by any applicable
interspecies and intraspecies factors and other relevant uncertainty
factors such as LOAEL to NOAEL factor or database uncertainty factor.\
    After calculating the RfD, as indicated above, EPA retains an
additional safety factor of 10X to protect infants and children (the
FQPA safety factor), unless reliable data support selection of a
different factor, as required under the FFDCA. As described in EPA's
policy for determining the appropriate FQPA safety factor, this
additional safety factor often overlaps with other traditional
uncertainty factors (e.g., LOAEL to NOAEL factor or database
uncertainty factor), but it might also account for residual concerns
related to pre- and postnatal toxicity or exposure. (Ref. 35 at 13-16)
In implementing FFDCA section 408, EPA calculates a variant of the RfD
referred to as a Population Adjusted Dose (PAD), by dividing the RfD by
the FQPA SF. Risk estimates less than 100% of the PAD are safe.

B. Toxicological Effects of Chlorpyrifos

    Consistent with FFDCA section 408(b)(2)(D), EPA has reviewed the
available scientific data and other relevant information for
chlorpyrifos in support of this action. For over a decade, EPA has
evaluated the scientific evidence surrounding the different health
effects associated with chlorpyrifos. The Agency has conducted
extensive reviews of the scientific literature on health outcomes
associated with chlorpyrifos and presented approaches for evaluating
and using that information to the FIFRA SAP on several occasions, as
discussed above in Unit V. Chlorpyrifos has been tested in
toxicological studies for the potential to cause numerous different
adverse outcomes (e.g., reproductive toxicity, developmental toxicity,
cancer, genotoxicity, dermal toxicity, endocrine toxicity, inhalation
toxicity, and immunotoxicity). The inhibition of AChE leading to
cholinergic neurotoxicity and the potential for effects on the
developing brain (i.e., neurodevelopmental effects) are the most
sensitive effects seen in the available data. (2020 HHRA p. 6). The SAP
reports have rendered numerous recommendations for additional study and
sometimes conflicting advice for how EPA should consider (or not
consider) the data in conducting EPA's registration review human health
risk assessment for chlorpyrifos.
    Unit VI. discusses the Agency's assessment of the science relating
to AChE inhibition and the potential for neurodevelopmental effects.
Other adverse outcomes besides AChE inhibition and neurodevelopment are
less sensitive and are thus not discussed in detail here. Further
information concerning those effects can be found in the 2000 human
health risk assessment which supported the RED and the 2011 preliminary
human health risk assessment. (Ref. 12 and 13).
1. Acetylcholinesterase (AChE) Inhibition
    Chlorpyrifos, like other OP pesticides, affects the nervous system
by inhibiting AChE, an enzyme necessary for the proper functioning of
the nervous system and ultimately leading to signs of neurotoxicity.
This mode of action, in which AChE inhibition leads to neurotoxicity,
is well-established, and thus has been used as basis for the PoD for OP
human health risk assessments, including chlorpyrifos. This science
policy is based on decades of work, which shows that AChE inhibition is
the initial event in the pathway to acute cholinergic neurotoxicity.
    The Agency has conducted a comprehensive review of the available
data and public literature regarding this adverse effect from
chlorpyrifos. (Ref. 8 at 24-25, Ref. 13 at 25-27) There are many
chlorpyrifos studies evaluating RBC AChE inhibition or the 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 AChE data from peripheral tissues in some studies (e.g., heart,
lung, liver). There are also literature studies comparing the in vitro
AChE response to a variety of tissues which show similar sensitivity
and intrinsic activity. Across the database, brain AChE tends to be
less sensitive than RBC AChE or peripheral AChE. In oral studies, RBC
AChE inhibition is generally similar in response to peripheral tissues.
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.
    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., developmental neurotoxicity
(DNT), reproductive, and subchronic data).
    In addition, 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 are derived largely from the immature metabolic clearance
capacity in the juveniles.
2. Neurodevelopmental Toxicity
    In addition to information on the effects of chlorpyrifos on AChE,
there is an extensive body of information (in the form of laboratory
animal studies, epidemiological studies, and mechanistic studies)
studying the potential effects on neurodevelopment in infants and
children following exposure to OPs, including chlorpyrifos.
    There are numerous laboratory animal studies on chlorpyrifos in the
literature that have evaluated the impact of chlorpyrifos exposure in
pre- and post-natal dosing on the developing brain. These studies vary
substantially in their study design, but all involve gestational and/or
early postnatal dosing with behavioral evaluation from adolescence to
adulthood. The data provide qualitative support for chlorpyrifos to
potentially impact the developing mammalian brain with adverse outcomes
in several neurological domains including cognitive, anxiety and
emotion, social interactions, and neuromotor function. It is, however,
important to note that there is little consistency in patterns of
effects across studies. In addition, most of these studies use doses
that far exceed EPA's 10% benchmark response level for RBC AChE
inhibition. There are only a few studies with doses at or near the 10%
brain or RBC AChE inhibition levels;

among these only studies from Carr laboratory at Mississippi State
University are considered by EPA to be high quality. EPA has concluded
that the laboratory animal studies on neurodevelopmental outcomes are
not sufficient for quantitatively establishing a PoD. Moreover, EPA has
further concluded that the laboratory animal studies do not support a
conclusion that adverse neurodevelopmental outcomes are more sensitive
than 10% RBC AChE inhibition. (Ref. 8 at 25-31, Ref. 9 at 88-89).
    EPA evaluated numerous epidemiological studies on chlorpyrifos and
other OP pesticides in accordance with the ``Framework for
Incorporating Human Epidemiologic & Incident Data in Health Risk
Assessment.'' (Ref. 8, 14, and 15) The most robust epidemiologic
research comes 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 Mount Sinai Inner-City
Toxicants, Child Growth and Development Study or the ``Mt. Sinai Child
Growth and Development Study;'' and (3) the Center for Health
Assessment of Mothers and Children of Salinas Valley (CHAMACOS)
conducted by researchers at University of California Berkeley. (Ref. 8
at 32-43).
    In the case of the CCCEH study, which specifically evaluated the
possible connections between chlorpyrifos levels in cord blood and
neurodevelopmental outcomes on a specific cohort, there are a number of
notable associations. (Ref. 8 at 36-38). Regarding infant and toddler
neurodevelopment, the CCCEH authors reported statistically significant
deficits of 6.5 points on the Psychomotor Development Index at three
years of age when comparing high to low exposure groups. Notably, these
decrements persist even after adjustment for group and individual level
socioeconomic variables. These investigators also observed increased
odds of mental delay and psychomotor delay at age three when comparing
high to low exposure groups. The CCCEH authors also report strong,
consistent evidence of a positive association for attention disorders,
attention deficit hyperactivity disorder (ADHD), and pervasive
development disorder (PDD) when comparing high to low chlorpyrifos
exposure groups. Moreover, it was reported that for children in the
CCCEH cohort at age seven for each standard deviation increase in
chlorpyrifos cord blood exposure, there is a 1.4% reduction in Full-
Scale IQ and a 2.8% reduction in Working Memory. In addition, the CCCEH
authors evaluated the relationship between prenatal chlorpyrifos
exposure and motor development/movement and reported elevated risks of
arm tremor in children around 11 years of age in the CCCEH cohort.
    Notwithstanding the observed associations, EPA and the 2012 and
2016 FIFRA SAPs identified multiple uncertainties in the CCCEH
epidemiology studies (Ref. 6 and 8). Some of these include the
relatively modest sample sizes, which limited the statistical power;
exposure at one point in prenatal time with no additional information
regarding postnatal exposures; representativeness of a single point
exposure where time-varying exposures or the ability to define
cumulative exposures would be preferable; lack of specificity of a
critical window of effect and the potential for misclassification of
individual exposure measures; and lack of availability of the raw data
from the studies that would allow verification of study conclusions.
    One of the notable uncertainties in the CCCEH epidemiology studies
identified by EPA and the 2016 FIFRA SAP is the lack of specific
exposure information on the timing, frequency, and magnitude of
chlorpyrifos application(s) in the apartments of the women in the
study. Despite extensive effort by EPA to obtain or infer this exposure
information from various sources, the lack of specific exposure data
remains a critical uncertainty. EPA made efforts in 2014 and 2016 to
develop dose reconstruction of the exposures to these women. These dose
reconstruction activities represent the best available information and
tools but are highly uncertain. In addition, the pregnant women and
children in the CCCEH studies were exposed to multiple chemicals,
including multiple potent AChE inhibiting OPs and N-methyl carbamates.
Moreover, using EPA's dose reconstruction methods from 2014 suggest
that the pregnant women likely did not exhibit RBC AChE inhibition
above 10%. The 2012 and 2016 FIFRA SAP reports expressed concern that
it is likely that the CCCEH findings occurred at exposure levels below
those that result in 10% RBC AChE inhibition (Ref. 6 and 8). However,
given the available CCCEH exposure information and the exposures to
multiple potent AChE inhibiting pesticides, EPA cannot definitively
conclude the level of AChE inhibition. EPA remains unable to make a
causal linkage between chlorpyrifos exposure and the outcomes reported
by CCCEH investigators. (Ref. 8) Moreover, given the uncertainties,
particularly in the exposure information available from CCCEH (single
timepoints, lack of time varying exposure, lack of knowledge about
application timing), uncertainties remain about the dose-response
relationships from the epidemiology studies.
    Finally, there are several lines of evidence for actions of
chlorpyrifos distinct from the classical mode of action of AChE
inhibition. This information has been generated from model systems
representing different levels of biological organization and provide
support for molecular initiating events (binding to the morphogenic
site of AChE, muscarinic receptors, or tubulin), cellular responses
(alterations in neuronal proliferation, differentiation, neurite
growth, or intracellular signaling), and responses at the level of the
intact nervous system (serotonergic tone, axonal transport). Among the
many in vitro studies on endpoints relevant to the developing brain
available for chlorpyrifos, only three have identified outcomes in
picomole concentrations, including concentrations lower than those that
elicit AChE inhibition in vitro. However, as is the case for many other
developmental neurotoxicants, most of these studies have not been
designed with the specific goal of construction or testing an adverse
outcome pathway. Thus, there are not sufficient data available to test
rigorously the causal relationship between effects of chlorpyrifos at
the different levels of biological organization in the nervous system.
(Ref. 8 at 27-31)
    Due to the complexity of nervous system development involving the
interplay of many different cell types and developmental timelines, it
is generally accepted that no single in vitro screening assay can
recapitulate all the critical processes of neurodevelopment. As a
result, there has been an international effort to develop a battery of
new approach methodologies (NAMs) to inform the DNT potential for
individual chemicals. This DNT NAM battery is comprised of in vitro
assays that assess critical processes of neurodevelopment, including
neural network formation and function, cell proliferation, apoptosis,
neurite outgrowth, synaptogenesis, migration, and differentiation. In
combination the assays in this battery provide a mechanistic
understanding of the underlying biological processes that may be
vulnerable to chemically-induced disruption. It is noteworthy, however,
that to date the quantitative relationship between alterations in these

neurodevelopmental processes and adverse health outcomes has not been
fully elucidated. Moreover, additional assays evaluating other critical
neurodevelopmental processes such as myelination are still being
developed (Ref. 15).
    In September 2020, EPA convened a FIFRA SAP on developing and
implementing NAMs using methods such as in vitro techniques and
computational approaches. Included in that consideration was use of the
DNT NAM battery to evaluate OP compounds as a case study. These methods
presented to the 2020 FIFRA SAP provide a more systematic approach to
evaluating pharmacodynamic effects on the developing brain compared to
the existing literature studies. Initial data from the NAM battery were
presented to the SAP for 27 OP compounds, including chlorpyrifos and
its metabolite, chlorpyrifos oxon, and, when possible, compared to in
vivo results (by using in vitro to in vivo extrapolation). On December
21, 2020, the SAP released its final report and recommendations on
EPA's proposed use of the NAMs data. (Ref. 16). The advice of the SAP
is currently being taken into consideration as EPA develops a path
forward on NAMs, but analysis and implementation of NAMs for risk
assessment of chlorpyrifos is in progress and was unable to be
completed in time for use in this rulemaking. The Agency is continuing
to explore the use of NAMs for the OPs, including chlorpyrifos, and
intends to make its findings available as soon as it completes this
work.

C. Hazard Identification: Using AChE as the Toxicological Endpoint for
Deriving PADs

    The RED for chlorpyrifos was completed in 2006 and relied on RBC
AChE inhibition results from laboratory animals to derive PoDs and
retained the FQPA 10X safety factor due to concerns over age-related
sensitivity and uncertainty associated with potential
neurodevelopmental effects observed in laboratory animals. Based on a
review of all the studies (guideline data required, peer reviewed
literature, mechanistic), AChE inhibition remains the most robust
quantitative dose-response data and thus continues to be the critical
effect for the quantitative risk assessment. This approach is
consistent with the advice of the SAP from 2008 and 2012. The Agency
typically uses a 10% response level for AChE inhibition in human health
risk assessments. This response level is consistent with the 2006 OP
cumulative risk assessment and other single chemical OP risk
assessments. (Ref. 17 and 18).
    In response to the 2015 proposed rule to revoke chlorpyrifos
tolerances, as noted above, the Agency received some comments raising a
concern that the use of the 10% AChE inhibition may not be sufficiently
health protective. Taking those comments into consideration, EPA
conducted an additional hazard analysis and convened the 2016 FIFRA SAP
to evaluate a proposal of using cord blood data from the CCCEH
epidemiology studies as the source of data for PoDs. The 2016 FIFRA SAP
did not support the ``direct use'' of the cord blood and working memory
data for deriving the regulatory endpoint, due to insufficient
information about timing and magnitude of chlorpyrifos applications in
relation to cord blood concentrations at the time of birth,
uncertainties about the prenatal window(s) of exposure linked to
reported effects, and lack of a second laboratory to reproduce the
analytical blood concentrations. (Ref. 8) Despite their critiques
regarding uncertainties in the CCCEH studies, the 2016 SAP expressed
concern that 10% RBC AChE inhibition is not sufficiently protective of
human health.
    The 2016 FIFRA SAP, however, did present an alternative approach
for EPA to consider. First, it is important to note that this SAP was
supportive of the EPA's use of the PBPK-PD model as a tool for
assessing internal dosimetry from typical OPP exposure scenarios. Use
of the PBPK-PD model coupled with typical exposure scenarios provides
the strongest scientific foundation for chlorpyrifos human health risk
assessment. Given that the window(s) of susceptibility are currently
not known for the observed neurodevelopmental effects, and the
uncertainties associated with quantitatively interpreting the CCCEH
cord blood data, this SAP recommended that the Agency use a time
weighted average (TWA) blood concentration of chlorpyrifos for the
CCCEH study cohort as the PoD for risk assessment. Thus, in 2016 EPA
attempted, using the PBPK-PD model, to determine the TWA blood level
expected from post-application exposures from the chlorpyrifos indoor
crack-and-crevice use scenario. Despite that effort, EPA's position is
that the shortcomings of the data with regard to the dose-response
relationship and lack of exposure information discussed above, continue
to raise issues that make quantitative use of the CCCEH data in risk
assessment not scientifically sound.
    Thus, taking into consideration the robustness of the available
data at this time, EPA has determined that the most appropriate
toxicological endpoint for deriving points of departure for assessing
risks of chlorpyrifos is 10% RBC AChE inhibition. The Agency is not
ignoring or dismissing the extensive data concerning the potential for
adverse neurodevelopmental outcomes, however. As discussed later in
this Unit, the Agency is addressing the uncertainties surrounding the
potential for adverse neurodevelopmental outcomes by retaining the
default 10X FQPA safety factor.
1. Durations of Exposure
    As noted in Unit VI.A., EPA establishes PoDs for each expected
exposure duration likely to result from pesticide exposure. For
chlorpyrifos, exposure can occur from a single event or on a single day
(e.g., eating a meal) or from repeated days of exposure (e.g.,
residential). With respect to AChE inhibition, effects can occur from a
single exposure or from repeated exposures. For OPs, repeated exposures
generally result in more AChE inhibition at a given administered dose
compared to acute exposures. Moreover, AChE inhibition in repeated
dosing guideline toxicology studies with most OPs show a consistent
pattern of inhibition reaching a ``steady state'' of inhibition at or
around 2-3 weeks of exposure in adult laboratory animals (Ref. 19).
This pattern observed with repeated dosing is a result of the amount of
inhibition coming to equilibrium with 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 human health risk assessments for the
OPs, the Agency is focusing on the critical durations ranging from a
single day up to 21 days (i.e., the approximate time to reach steady
state for most OPs). As such, EPA has calculated PoDs for the acute and
steady-state durations. As described below, these PoDs have been
derived for various lifestages, routes, and exposure scenarios.
2. Deriving PODs, Inter- and Intra-Species Extrapolation: Use of the
PBPK Model
    The process for developing RfDs and PADs typically involves first
deriving PoDs directly from laboratory animal studies, followed by
dividing the PoD by the default uncertainty factors of 10X for
interspecies extrapolation and intraspecies extrapolation, and the FQPA
safety factor. For chlorpyrifos, as discussed previously in Unit V,
there is a sophisticated PBPK-PD model available for chlorpyrifos.
Numerous

Federal Advisory Committees and external review panels have encouraged
the use of such a modeling approach to reduce inherent uncertainty in
the risk assessment and facilitate more scientifically sound
extrapolations across studies, species, routes, and dose levels. The
PBPK-PD model for chlorpyrifos has undergone extensive peer review by
various individual or groups, including the FIFRA SAPs. Significant
improvements have been made to the model over the years in response to
recommendations from the 2008, 2011, and 2012 FIFRA SAPs and comments
from both internal and external peer reviewers. (Ref. 9 at 20). As a
result, EPA has concluded that the current PBPK-PD model is
sufficiently robust and is using it for deriving PoDs for chlorpyrifos.
a. Derivation of PoDs
    As noted above, the PoDs for chlorpyrifos are based on the levels
at which 10% RBC AChE inhibition is observed. The PBPK-PD model
accounts for pharmacokinetic and pharmacodynamic characteristics to
derive age-, duration-, and route-specific PoDs. 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 [24-hour (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. 21) for
residential exposures and from the U.S. Department of Agriculture's
(USDA) National Health and Nutrition Examination Survey (NHANES)/What
We Eat in America (WWEIA) Survey for dietary exposures.
    Within the PBPK-PD model, the Agency evaluated the following
exposure scenarios: Oxon (chlorpyrifos metabolite) exposures via
drinking water (acute and steady-state exposures for infants, children,
youths, and female adults); chlorpyrifos exposures via food (acute and
steady-state exposures for infants, children, youths, and female
adults); steady-state residential exposures to chlorpyrifos via skin
for children, youths, and female adults; steady-state residential
exposures to chlorpyrifos via hand-to-mouth ingestion for children 1-2
years old; steady-state residential exposures to chlorpyrifos via
inhalation for children 1-2 years old and female adults. (Ref. 9 at 22-
25).
    Steady-state dietary exposure was estimated daily for 21 days. For
drinking water exposure, infants and young childrens (infants <1 year
old, children between 1-2 years old, and children between 6-12 years
old) were assumed to consume water 6 times per day, with a total
consumption volume of 0.69 L/day. For youths and female adults, they
were assumed to consume water 4 times per day, with a total consumption
volume of 1.71 L/day.
    For all residential dermal exposures to chlorpyrifos the dermal
PoDs were estimated assuming 50% of the skin's surface was exposed.
Exposure times for dermal exposure assessment were consistent with
those recommended in the 2012 Residential Standard Operating Procedures
(SOPs) (Ref. 18). For residential inhalation exposures following public
health mosquitocide application, the exposure duration was set to 1
hour per day for 21 days. The incidental oral PoDs for children 1 to <2
years old for other turf activities were estimated assuming that there
were six events, 15 minutes apart, per day.
    The PBPK-modeled PoDs derived for the various lifestages, routes,
and exposure scenarios discussed above, can be found in Table <IP_ADDRESS>.2
of the 2020 HHRA (Ref 8).
b. Inter-Species Extrapolation
    As indicated above, the PBPK-PD model directly predicts human PoDs
based on human physiology and biochemistry, and thus there is no need
for an inter-species uncertainty factor to extrapolate from animal
PoDs.
c. Intra-Species Extrapolation
    The PBPK-PD model can account for variability of critical
physiological, pharmacokinetic, and pharmacodynamic parameters in a
population to estimate, using the Monte Carlo analysis, the
distribution of doses that result in 10% RBC AChE inhibition.
Therefore, Data-Derived Extrapolation Factors (DDEF) for intra-species
extrapolation have been estimated to replace the default intra-species
uncertainty factor for some groups (Ref. 22).
    According to EPA's DDEF guidance (Ref. 22), when calculating a DDEF
intra-species extrapolation factor, administered doses leading to the
response level of interest (in the case of chlorpyrifos, the 10% change
in RBC AChE inhibition) are compared between a measure of average
response and response at the tail of the distribution representing
sensitive individuals. The tail of the distribution may be selected at
the 95th, 97.5th, and 99th percentile.
    As to chlorpyrifos, the 99th percentile was used in risk assessment
to provide the most conservative measure (Ref. 7). In addition to
estimating DDEF using the above approach for specific age groups,
intra-species DDEF was also calculated by comparing between average
responses between adults and 6-month old infants. For the 2020 HHRA,
the largest calculated DDEFs, 4X for chlorpyrifos and 5X for the oxon
metabolite, were used for intraspecies extrapolation for all groups
except women of childbearing age. There was a slightly higher
variability between adults and infants when considering the
distributions for the oxon metabolite, thus, the slightly higher intra-
species factor. For women of childbearing age, the Agency is applying
the standard 10X intra-species extrapolation factor due to limitations
in the PBPK-PD model to account for physiological, anatomical, and
biochemical changes associated with pregnancy. (Ref. 9 at 21-22).
d. Summarizing the PoDs, Inter- and Intra-Species Extrapolation Factors
    In summary, for assessing the risks from exposure to chlorpyrifos,
the human PBPK-PD model has been used to derive PoDs based on 10% RBC
AChE inhibition for various populations, durations, and routes. The
model, which calculates a human PoD directly, obviates the need for an
interspecies extrapolation factor since animal data are not used. To
account for variations in sensitivities, the Agency has determined that
an intra-species factor of 4X for chlorpyrifos and 5X for the oxon is
appropriate for all groups except women of childbearing age. For women
of childbearing age, the typical 10X intra-species factor is being
applied, due the lack of appropriate information and algorithms to
characterize physiological changes during pregnancy.
3. FQPA Safety Factor
    As noted above, the FFDCA requires EPA, in making its ``reasonable
certainty of no harm'' finding, 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 postnatal
toxicity and completeness of data with respect to exposure and toxicity
to infants and children.'' 21 U.S.C. 346A(b)(2)(C). Section
408(b)(2)(C) further states that ``the Administrator may 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.''
    In applying the FQPA safety factor provision, EPA has interpreted
it as imposing a presumption in favor of retaining it as an additional
10X safety factor. (Ref. 5 at 4, 11). Thus, EPA generally refers to the
10X factor as a presumptive or default 10X factor. EPA has also made
clear, however, that this presumption or default in favor of the 10X is
only a presumption. The presumption can be overcome if reliable data
demonstrate that a different factor is safe for children. (Id.). In
determining whether a different factor is safe for children, EPA
focuses on the three factors listed in FFDCA 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 a weight-of-the-evidence evaluation, does not
understate the risk to children. (Id. at 24-25, 35).
    EPA's 2020 HHRA assessed the potential risks from exposures to
chlorpyrifos in two ways--with one scenario being the retention of the
default 10X FQPA SF, and the other scenario being the reduction of the
FQPA SF to 1X. The purpose of using both values was to provide an
indication of what the potential risk estimates would be under either
scenario. The 2020 document, however, retained the 10X and did not
adopt or offer support for reducing to 1X. To reduce the FQPA safety
factor to 1X, the FFDCA requires that EPA determine that reliable data
demonstrate that the 1X would be safe for infants and children. The
2020 document did not make that determination. For chlorpyrifos, of the
three factors mentioned in the previous paragraph, the primary factor
that undercuts a determination that a different safety factor would be
safe for children is the uncertainty around the potential for pre- and
post-natal toxicity for infants and children in the area of
neurodevelopmental outcomes.
    Based on the weight of the evidence concerning the potential for
neurodevelopmental outcomes as discussed in Unit VI.B.2. above, there
is ample qualitative evidence of a potential effect on the developing
brain; however, there remains uncertainty around the levels at which
these potential neurodevelopmental outcomes occur. Although the
laboratory animal studies do not support a conclusion that
neurodevelopmental outcomes are more sensitive than AChE inhibition,
the mechanistic data are, at this time, incomplete in their
characterization of dose-response. This conclusion may be further
evaluated upon EPA's completion of the review of the 2020 FIFRA SAP
report concerning NAMs; however, due to the time constraints of this
rule, EPA has not been able to include that information in the current
assessment of chlorpyrifos. Finally, while the epidemiology data
indicates an association between chlorpyrifos and adverse
neurodevelopmental outcomes, there remains some uncertainty in the
dose-response relationship. As such, because the data available at this
time indicate remaining uncertainties concerning pre- and post-natal
toxicity due to insufficient clarity on the levels at which these
outcomes occur, the Agency is unable to conclude, at this time, that a
different safety factor would be safe for infants and children; thus,
the Agency is retaining the default 10X FQPA safety factor.
4. Total Uncertainty Factors and PADs
    In conclusion, the Agency used a total uncertainty factor of 100X
for determining the food and drinking water PADs for females of
childbearing age (1X interspecies factor, 10X intra-species factor, and
10X FQPA safety factor); 40X for determining the food PADs for
remaining populations (1X interspecies factor, 4X intra-species factor,
and 10X FQPA safety factor); and 50X for determining the PADs for
drinking water for remaining populations (1X interspecies factor, 5X
intra-species factor, and 10X FQPA safety factor).
    Taking into consideration the PoDs, intra-species extrapolation
factors, and FQPA safety factor, the Agency calculated acute PADs
(aPADs) and steady state PADs (ssPADs) for infants (less than 1 year
old), children (1 to 2 years old), children (6 to 12 years old), youths
(13 to 19 years old), and females (13-49 years old); these
subpopulations will be protective of other subpopulations. (Ref. 9 at
30-32.) Values may be found in table 5.0.1 in the 2020 HHRA.

VII. EPA's Exposure Assessment for Chlorpyrifos

    Risk is a function of both hazard and exposure. Thus, equally
important to the risk assessment process as determining the hazards
posed by a pesticide and the toxicological endpoints for those hazards
is estimating human exposure. Under FFDCA section 408, EPA must
evaluate the aggregate exposure to a pesticide chemical residue. This
means that EPA is concerned not only with exposure to pesticide
residues in food but also exposure resulting from pesticide
contamination of drinking water supplies and from use of pesticides in
the home or other non-occupational settings. (See 21 U.S.C.
346a(b)(2)(D)(vi)).
    Pursuant to FFDCA section 408(b), EPA has evaluated chlorpyrifos's
risks based on ``aggregate exposure'' to chlorpyrifos. By ``aggregate
exposure,'' EPA is referring to exposure to chlorpyrifos by multiple
pathways of exposure, i.e., food, drinking water, and residential. EPA
uses available data and standard analytical methods, together with
assumptions designed to be protective of public health, to produce
separate estimates of exposure for a highly exposed subgroup of the
general population, for each potential pathway and route of exposure.
    The following reflect a summary of the Agency's exposure assessment
from the 2020 HHRA unless otherwise specified. (Ref. 10).

A. Exposure From Food

1. General Approach for Estimating Food Exposures
    There are two critical variables in estimating exposure in food:
(1) The types and amount of food that is consumed; and (2) The residue
level in that food. Consumption is estimated by EPA based on scientific
surveys of individuals' food consumption in the United States conducted
by the U.S. Department of Agriculture (USDA), (Ref. 11 at 12).
Information on residue values can come from a range of sources
including crop field trials; data on pesticide reduction (or
concentration) due to processing, cooking, and other practices;
information on the extent of usage of the pesticide; and monitoring of
the food supply. (Id. at 17).
    Data on the residues of chlorpyrifos in foods are available from
both field trial data and monitoring data, primarily the USDA's
Pesticide Data Program (PDP) monitoring data. Monitoring data generally
provide a characterization of pesticide residues in or on foods
consumed by the U.S. population that closely approximates real world
exposures because they are sampled closer to the point of consumption
in the chain of commerce than field trial data, which are generated to
establish the maximum level of legal residues that could result from
maximum permissible use of the pesticide immediately after harvest.
    EPA uses a computer program known as the Dietary Exposure
Evaluation Model and Calendex software with the Food Commodity Intake
Database

(DEEM-FCID version 3.16/Calendex) to estimate exposure by combining
data on human consumption amounts with residue values in food
commodities. The model incorporates 2003-2008 consumption data from
USDA's NHANES/WWEIA. The data are based on the reported consumption of
more than 20,000 individuals over two non-consecutive survey days.
Foods ``as consumed'' (e.g., apple pie) are linked to EPA-defined food
commodities (e.g., apples, peeled fruit--cooked; fresh or N/S (Not
Specified); baked; or wheat flour--cooked; fresh or N/S, baked) using
publicly available recipe translation files developed jointly by USDA
Agricultural Research Service (ARS) and EPA. For chronic exposure
assessment (or in the case of chlorpyrifos, for steady-state exposure
assessment), consumption data are averaged for the entire U.S.
population and within population subgroups; however, for acute exposure
assessment, consumption data are retained as individual consumption
events. Using this consumption information and residue data, the
exposure estimates are calculated for the general U.S. population and
specific subgroups based on age, sex, ethnicity, and region.
    For chlorpyrifos, EPA determined that acute and steady-state
exposure durations were relevant for assessing risk from food
consumption. EPA calculates potential risk by using probabilistic
techniques to combine distributions of potential exposures in sentinel
populations. The resulting probabilistic assessments present a range of
dietary exposure/risk estimates.
    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 such assessments is
the 99.9th percentile of the population under evaluation. When using a
probabilistic method of estimating acute dietary exposure, EPA
typically assumes that, when the 99.9th percentile of acute exposure is
equal to or less than the aPAD, the level of concern for acute risk has
not been exceeded. By contrast, where the analysis indicates that
estimated exposure at the 99.9th percentile exceeds the aPAD, EPA would
generally conduct one or more sensitivity analyses to determine the
extent to which the estimated exposures at the high-end percentiles may
be affected by unusually high food consumption or residue values. (The
same assumptions apply to estimates for steady state dietary exposure
and the ssPAD.) To the extent that one or a few values seem to
``drive'' the exposure estimates at the high-end of exposure, EPA would
consider whether these values are reasonable and should be used as the
primary basis for regulatory decision making (Ref. 20).
2. Estimating Chlorpyrifos Exposures in Food
    The residue of concern, for tolerance expression and risk
assessment, in plants (food and feed) and livestock commodities is the
parent compound chlorpyrifos. EPA has determined that the metabolite
chlorpyrifos oxon is not a residue of concern in food or feed, based on
available field trial data and metabolism studies that indicate that
the oxon is not present in the edible portions of the crops. In
addition, the chlorpyrifos oxon is not found on samples in the USDA PDP
monitoring data. Furthermore, the oxon metabolite was not found in milk
or livestock tissues (Ref. 9 at 33).
    Acute and steady-state dietary (food only) exposure analyses for
chlorpyrifos were conducted using the DEEM-FCID version 3.16/Calendex
software (Ref. 23). 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 AChE Inhibition. The acute
and steady-state dietary (food only) exposure analyses do not include
drinking water exposures, which were assessed separately, see Unit
VII.B.2.
    Both the acute and steady state dietary exposure analyses are
highly refined. The large majority of food residues used were based
upon 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. EPA also used food processing factors from
submitted studies as appropriate. In addition, EPA's acute and steady
state dietary exposure assessments used percent crop treated (PCT)
information. (Ref. 23)
    The chlorpyrifos acute dietary exposure analysis was conducted
using the DEEM-FCID, version 3.16, which incorporates 2003-2008 survey
consumption data from USDA's NHANES/WWEIA. The acute risk estimates
were presented for the sentinel populations for infants (less than 1 yr
old); children (1-2 years old); youths (6-12 years old); and adults
(females 13-49 years old). The assessment of these index lifestages is
protective of other population subgroups.
    The chlorpyrifos steady-state dietary exposure analysis was
conducted using the Calendex component of DEEM-FCID (with 2003-2008
survey consumption data from USDA's NHANES/WWEIA). Calendex provides a
focus detailed profile of potential exposures to individuals across a
calendar year. A calendar-based approach provides the ability to
estimate daily exposures from multiple sources over time to an
individual and is in keeping with two key tenets of aggregate risk
assessment: (1) That exposures when aggregated are internally
consistent and realistic; and (2) that appropriate temporal and
geographic linkages or correlations/associations between exposure
scenarios are maintained.
    The chlorpyrifos 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 infants (less
than 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 is protective of other population subgroups.

B. Exposure From Drinking Water

1. General Approach for Assessing Exposure From Drinking Water
a. Modeling and Monitoring Data
    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). Although
monitoring data can provide a direct measure of the concentration of a
pesticide in water, it does not always 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. Modeling is a
useful tool for characterizing vulnerable sites and can be used to
estimate upper-end pesticide water concentrations from infrequent,
large rain events. EPA's computer models use detailed information on
soil properties, crop characteristics, and weather patterns to estimate
water concentrations in vulnerable locations where the pesticide could
be used according to its label (Ref. 24 at 27-28). EPA's 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 water and surface water. Depending on the
modeling algorithm (e.g., surface water modeling scenarios), daily
concentrations can be estimated continuously over long periods of time,
and for places that are of most interest for any particular pesticide.
    EPA relies on models it has developed for estimating pesticide
concentrations in both surface water and groundwater. The most common
model used to conduct drinking water assessments is the Pesticide in
Water Calculator (PWC). PWC couples the Pesticide Root Zone Model
(PRZM) and Variable Volume Water Model (VVWM) models together to
simulate pesticide fate and transport from the field of application to
an adjacent reservoir. (Ref. 24 at 27-28). The PWC estimates pesticide
concentrations for an index reservoir that is modeled for site-specific
scenarios (i.e., weather and soil data) in different areas of the
country. A detailed description of the models routinely used for
exposure assessment is available from the EPA OPP Aquatic Models
website: https://www.epa.gov/pesticide-science-and-assessing-pesticide-risks/models-pesticide-risk-assessment#aquatic.
    In modeling potential surface water concentrations, EPA attempts to
model areas of the country that are vulnerable to surface water
contamination rather than simply model ``typical'' concentrations
occurring across the nation. Consequently, EPA models exposures
occurring in small highly agricultural watersheds in different growing
areas throughout the country, over a 30-year period. The scenarios are
designed to capture residue levels in drinking water from reservoirs
with small watersheds with a large percentage of land use in
agricultural production. EPA believes these assessments are likely
reflective of a small subset of the watersheds across the country that
maintain drinking water reservoirs, representing a drinking water
source generally considered to be more vulnerable to frequent high
concentrations of pesticides than most locations that could be used for
crop production.
    When monitoring data meet certain data quantity criteria, EPA has
tools available to quantify the uncertainty in available monitoring
data such that it can be used quantitively to estimate pesticide
concentrations in drinking water. (Ref. 25) Furthermore, monitoring
data can be used in a weight of evidence approach with model estimated
concentrations to increase confidence in the conclusions of a drinking
water assessment.
b. Drinking Water Level of Comparison (DWLOC)
    The drinking water level of comparison (DWLOC) is a benchmark that
can be used to guide refinements of the drinking water assessment
(DWA). This value relates to the concept of the ``risk cup,'' which EPA
developed to facilitate risk refinement when considering aggregate
human health risk to a pesticide. (Ref. 26). The risk cup is the total
exposure allowed for a pesticide considering its toxicity and required
safety factors. The risk cup is equal to the maximum safe exposure for
the duration and population being considered. Exposures exceeding the
risk cup are of potential concern. There are risk cups for each
pertinent duration of exposure (e.g., acute, short-term, chronic). The
exposure durations most commonly of interest for acute or short-term
pesticide exposure risk assessments are 1-day, 4-day, and 21-day
averages. For example, the relevant exposure duration for AChE
reversible inhibition from exposure to carbamate insecticides is 1-day,
while AChE irreversible inhibition resulting from exposure to OP
insecticides is usually 21-days based on steady-state kinetics. (Ref.
19)
    In practice, EPA calculates the total exposure from food
consumption and residential (or other non-occupational) exposures and
subtracts this value from the maximum safe exposure level. The
resulting value is the allowable remaining exposure without the
potential for adverse health effect. Knowing this allowable remaining
exposure and the water consumption for each population subgroup (e.g.,
infants), the Agency can calculate the DWLOC, which is the estimate of
safe concentrations of pesticides in drinking water. Using this process
of DWLOC calculation allows EPA to determine a target maximum safe
drinking water concentration, thereby identifying instances where
drinking water estimates require refinement. (Ref. 24 at 19-20).
c. Scale of Drinking Water Assessment
    Although food is distributed nationally, and residue values are
therefore not expected to vary substantially throughout the country,
drinking water is locally derived and concentrations of pesticides in
source water fluctuate over time and location for a variety of reasons.
Pesticide residues in water fluctuate daily, seasonally, and yearly
because of the timing of the pesticide application, the vulnerability
of the water supply to pesticide loading through runoff, spray drift
and/or leaching, and changes in the weather. Concentrations are also
affected by the method of application, the location, and
characteristics of the sites where a pesticide is used, the climate,
and the type and degree of pest pressure, which influences the
application timing, rate used, and number of treatments in a crop
production cycle.
    EPA may conduct a drinking water assessment (DWA) for a national
scale depending on the pesticide use under evaluation. A national scale
DWA may use a single upper-end pesticide concentration as a starting
point for assessing whether additional refinements are needed or
estimated pesticide concentrations for certain site-specific scenarios
that are associated with locations in the United States vulnerable to
pesticide contamination based on pesticide use patterns. (Ref. 24 at
22.)
    EPA may also conduct a regional scale DWA to focus on areas where
pesticide concentrations may be higher than the DWLOC. Under this
assessment, EPA estimates pesticide concentrations across different
regions in the United States that are subdivided into different areas
called hydrologic units (HUCs). There are 21 HUC 2 regions with 18 in
the contiguous United States. These areas contain either the drainage
area of a major river or a combined drainage of a series of rivers.
This information can eb found at: https://water.usgs.gov/GIS/huc.html.
Estimated pesticide concentrations under this approach would be
associated with a vulnerable pesticide use area somewhere within the
evaluated region. (Ref. 24 at 23).

d. Drinking Water Refinements
    EPA has defined four assessment tiers for drinking water
assessments. Lower tiered assessments are more conservative based on
the defaults or upper bound assumptions and may compound conservatisms,
while higher tiers integrate more available data and provide more
realistic estimates of environmental pesticide concentrations.
    These four tiers are generally based on the level of effort, the
amount of data considered, the spatial scale, and the certainty in the
estimated pesticide concentration. Tier 1 requires the least amount of
effort and the least amount of data, whereas Tier 4 is resource
intensive, considers a wide range of sources and types of data, and is
spatially explicit, resulting in high confidence in the reported
pesticide concentration. Each successive tier integrates more focused
pesticide, spatial, temporal, agronomic, and crop-specific information.
The order in which refinements are considered (i.e., the order in which
the assessment is refined) is pesticide-specific and depends on the
nature and quality of the available data used to support the
refinement. Additional information on the conduct of drinking water
assessments can be found in the ``Framework for Conducting Pesticide
Drinking Water Assessment for Surface Water'' (USEPA, 2020).
    As discussed in the Framework document, EPA can incorporate several
refinements in higher tiered modeling. Two such refinements are the
percent cropped area (PCA) and the percent crop treated (PCT). These
are described in the recently completed document titled ``Integrating a
Distributional Approach to Using Percent Crop Area (PCA) and Percent
Crop Treated (PCT) into Drinking Water Assessment'' (Ref. 27) The PCA
refers to the amount of area in a particular community water system
that is planted with the crop of interest (e.g., the default assumption
is that the entire watershed is planted with a crop of interest). The
PCT refers to the amount of the cropped area that is treated with the
pesticide of interest (e.g., the default is that the entire cropped
area is treated with the pesticide of interest). With additional use
and usage data, EPA can refine assumptions about the application rate
and PCT for use in modeling to generate estimated drinking water
concentrations (EDWCs) that are appropriate for human health risk
assessment and more accurately account for the contribution from
individual use patterns in the estimation of drinking water
concentrations.
2. Drinking Water Assessment for Chlorpyrifos.
    For the chlorpyrifos drinking water assessment, the metabolite
chlorpyrifos oxon, which forms because of drinking water treatment and
is more toxic than chlorpyrifos, was chosen as the residue of concern.
(Ref. 28 and 29) The range of conversion from parent to oxon depends
upon the type of water treatment and other conditions. 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 assumed that all chlorpyrifos
in source water is converted to chlorpyrifos oxon upon treatment.
    The Agency used a DWLOC approach for assessing aggregate risk from
chlorpyrifos. As such, EPA calculated DWLOCs for different age groups
for both the acute aggregate assessment and the steady-state aggregate
assessment, taking into consideration the food and residential
contributions to the risk cup. These numbers were provided as a
benchmark for evaluating drinking water contributions from uses of
chlorpyrifos across the United States, and whether such concentrations
would result in aggregate exposures to chlorpyrifos that exceeded the
Agency's levels of concern. The lowest acute DWLOC calculated was for
exposure to chlorpyrifos oxon to infants (<1 year old) at 23 ppb; the
lowest steady state DWLOC calculated was also for exposure to
chlorpyrifos oxon to infants (<1 year old) at 4.0 ppb. (Ref. 9 at 45-
45). In other words, EDWCs of chlorpyrifos oxon greater than 4.0 ppb
for a 21-day average would exceed EPA's DWLOC and present a risk that
exceeds the Agency's level of concern.
    In its 2014 drinking water assessment, EPA concluded that there
were multiple uses of chlorpyrifos that could lead to exposures to
chlorpyrifos oxon in drinking water that exceed the DWLOC identified at
that time. (Ref. 29). This assessment provided the basis for the
Agency's proposal to revoke tolerances in 2015. (Ref. 30). In 2016, EPA
conducted a refined drinking water assessment that estimated drinking
water concentrations based on modeling of all registered uses, as well
as all available surface water monitoring data. That assessment
considered several refinement strategies in a two-step process to
derive exposure estimates for chlorpyrifos and chlorpyrifos oxon across
the country. The first step was an assessment of potential exposure
based on the current maximum label rates at a national level. This
indicated that the EDWCs could be above the DWLOC.
    Because estimated concentrations at the national level exceeded the
DWLOC, the Agency conducted a more refined assessment of uses on a
regional level. (Ref. 28 at 73-86). This more refined analysis derived
EDWCs using the PWC modeling for maximum labeled rates and 1 pound per
acre by region for each use. The analysis indicated that approved uses
of chlorpyrifos in certain vulnerable watersheds in every region of the
country would result in EDWCs that exceed the DWLOC. For example, Table
25 of EPA's 2016 DWA, which provides the range of estimated
concentrations of chlorpyrifos in drinking water from uses on golf
courses and agricultural or production crops, shows EDWCs that exceed
the DWLOC in vulnerable watersheds in every region in the country.
While the lower end of some of the ranges provided in that table are
below the DWLOC, those lower numbers reflect a single use (i.e., single
crop) and do not reflect potential exposure from other uses where
applications occur at higher rates, more frequently, or in more
locations made more vulnerable due to soil type, weather, or agronomic
practices. The relevant estimated concentration for risk assessment
purposes is the highest concentration across all uses because it
reflects concentrations that may occur in vulnerable sources of
drinking water (Ref. 28 at 73-74).
    In addition, a robust quantitative analysis of the monitoring data
was conducted resulting in concentrations consistent with model-
estimated concentrations above the DWLOC. (Ref. 28 at 90-121).
Considering both monitoring data and modeling estimates together
supports the conclusion that drinking water concentrations in regions
across the country will exceed the DWLOC. (Ref. 28 at 121-123).
    After the EPA's 2016 DWA showed that the DWLOC exceedances are
possible from several uses, EPA developed refinement strategies to
examine those estimated regional/watershed drinking water
concentrations to pinpoint community drinking water systems where
exposure to chlorpyrifos oxon as a result of chlorpyrifos applications
may pose an exposure concern. At that time, EPA was anticipating that a
more refined drinking water assessment might allow EPA to better
identify where at-risk watersheds are located throughout the country to
support more targeted risk mitigation through the registration review
process. The refinements better account for variability in the use area
treated within a watershed that may

contribute to a drinking water intake (referred to as PCA or percent
use area when considering non-agricultural uses) and incorporate data
on the amount of a pesticide that is actually applied within a
watershed for agricultural and non-agricultural uses (referred to as
PCT). These refinement approaches underwent external peer review and
were issued for public comment in January 2020: https://www.epa.gov/pesticide-science-and-assessing-pesticide-risks/about-water-exposure-models-used-pesticide. In addition, EPA used average application rates,
average numbers of annual applications for specific crops, and
estimated typical application timing at the state-level based on
pesticide usage data derived from a statistically reliable private
market survey database, publicly available survey data collected by the
USDA, and state-specific scientific literature from crop extension
experts.
    The recently developed refinements were integrated in the Updated
Chlorpyrifos Refined Drinking Water Assessment for Registration Review,
which was issued in September 2020. (2020 DWA) (Ref. 10) The updated
assessment applied the new methods for considering the entire
distribution of community water systems PCA adjustment factors,
integrated state level PCT data, incorporated refined usage and
application data, and included quantitative use of surface water
monitoring data in addition to considering state level usage rate and
data information. In addition, given the 2016 DWA calculation of
estimated drinking water concentrations exceeding the DWLOC of 4.0 ppb,
the Agency decided to focus its refinements for the 2020 updated
drinking water assessment on a subset of uses in specific regions of
the United States. The purpose of the focus on this subset of uses was
to determine, if these were the only uses permitted on the label,
whether or not the resulting estimated drinking water concentrations
would be below the DWLOC. The subset of uses assessed were selected
because they were identified as critical uses by the registrant and/or
high-benefit uses to growers. That subset of currently registered uses
included alfalfa, apple, asparagus, cherry, citrus, cotton, peach,
soybean, sugar beet, strawberry, and wheat in specific areas of the
country. The results of this analysis indicated that the EDWCs from
this subset of uses limited to certain regions are below the DWLOC.
(Ref. 10 at 16-17). However, the 2020 DWA refined estimates did not
include chlorpyrifos exposures from uses beyond that subset. In the
2020 DWA, EPA stated that if additional uses were added or additional
geographic areas included, a new separate assessment would need to be
prepared in order to evaluate whether concentrations would remain below
the DWLOC. In addition to the modeling of the EDWCs for the specific
subset of uses, the 2020 DWA conducted a quantitative surface water
monitoring data analysis. That analysis indicated that monitored
chlorpyrifos concentrations, which reflect existing uses, are above the
DWLOC. (Ref. 10 at 62, 75). These data would need to be considered in
the context of any additional uses beyond the subset evaluated.

C. Residential Exposure to Pesticides

1. General Approach to Assessing Non-Occupational Exposures
    Residential assessments examine exposure to pesticides in non-
occupational or residential settings (e.g., homes, parks, schools,
athletic fields or any other areas frequented by the general public),
based on registered uses of the pesticide. Exposures to pesticides may
occur to persons who apply pesticides (which is referred to as
residential handler exposure) or to persons who enter areas previously
treated with pesticides (which is referred to as post-application
exposure). Such exposures may occur through oral, inhalation, or dermal
routes and may occur over different exposure durations (e.g., short-
term, intermediate-term, long-term), depending on the type of pesticide
and particular use pattern.
    Residential 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, EPA has
prepared 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). (Ref. 18) 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) and transfer coefficient data. Transfer coefficient data
measure the amount of pesticide that transfers from the environment to
humans from a defined activity (e.g., hand contact with a treated
surface or plant). Specific information on pesticides can include
information on residue levels as well as information on environmental
fate such as degradation data.
    Once EPA assesses all the potential exposures from all applicable
exposure scenarios, EPA selects the highest exposure scenario for each
exposed population to calculate representative risk estimates for use
in the aggregate exposure assessment. Those specific exposure values
are then combined with the life stage appropriate exposure values
provided for food and drinking water to determine whether a safety
finding can be made.
2. Residential Exposure Assessment for Chlorpyrifos
    Most chlorpyrifos products registered for residential treatment
were voluntarily cancelled or phased out by the registrants between
1997 and 2001; however, some uses of chlorpyrifos remain that may
result in non-occupational, non-dietary (i.e., residential) exposures.
Based on the remaining registered uses, the Agency has determined that
residential handler exposures are unlikely. Chlorpyrifos products
currently registered for residential use are limited to roach bait
products or ant mound treatments. Exposures from the application of
roach bait products are expected to be negligible. The roach bait
product is designed such that the active ingredient is contained within
a bait station, which eliminates the potential for contact with the
chlorpyrifos containing bait material. Since the ant mound treatments
can only be applied professionally, residential handler exposure is
also not anticipated. (Ref. 9 at 36-44).
    There is a potential for residential post-application exposures.
Chlorpyrifos is registered for use on golf courses and as an aerial and
ground-based ultra-low volume (ULV) mosquito adulticide applications
made directly in residential areas. Based on the anticipated use
patterns reviewed under the SOP, EPA assessed these exposures as
steady-state residential post-application exposures, which would be
protective of shorter durations of exposure. There is a potential for
dermal post-application exposures from the golf course uses for adults
(females 13-49 years old); youths (11 to less than 16 years old); and
children (6 to less than 11 years old). There is also a potential for
dermal, incidental oral, and inhalation post-application exposures

for children (1 to less than 2 years old) and dermal and inhalation
post-application exposures for adults from exposure to mosquitocide
uses. The Agency combined post-application exposures for children (1 to
less than 2 years old) for dermal, inhalation, and incidental oral
exposure routes because these routes all share a common toxicological
endpoint. EPA used the post-application exposures and risk estimates
resulting from the golfing scenarios in its aggregate exposure and risk
assessment.

VIII. Aggregate Risk Assessment and Conclusions Regarding Safety for
Chlorpyrifos

    The final step in the risk assessment is the aggregate exposure
assessment and risk characterization. In this step, EPA combines
information from the first three steps (hazard identification, level of
concern (LOC)/dose-response analysis, and human exposure assessment) to
quantitatively estimate the risks posed by a pesticide. The aggregated
exposure assessment process considers exposure through multiple
pathways or routes of exposure (e.g., food, water, and residential) for
different sub-populations (e.g., infants, children ages 1-6) and
exposure duration or types of effects (e.g., acute noncancer effects
(single dose), chronic noncancer effects, and cancer). The aggregated
exposure assessments can be deterministic (levels of exposure for each
pathway are point estimates), probabilistic (levels of exposure are a
distribution for a given population), or a combination of the two and
are dependent on the level of refinement or assessment tier.
    As noted above, EPA evaluates aggregate exposure by comparing
combined exposure from all relevant sources to the safe level. Where