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Federal Register / Vol. 86, No. 165 / Monday, August 30, 2021 / Rules and Regulations 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 EPAs 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.

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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
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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 windows 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 EPAs use of the PBPKPD model as a tool for assessing internal dosimetry from typical OPP exposure scenarios.
Use of the PBPKPD model coupled with typical exposure scenarios provides the strongest scientific foundation for chlorpyrifos human health risk assessment. Given that the windows 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, EPAs 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
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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 23 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 23 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, Interand IntraSpecies 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 PBPKPD model available for chlorpyrifos. Numerous
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