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Federal Register / Vol. 86, No. 165 / Monday, August 30, 2021 / Rules and Regulations
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Food Quality Protection Act safety factor FQPA SF: The FFDCA section 408b2C 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 preand postnatal toxicity and completeness of data with respect to exposure and toxicity to infants and children. Section 408b2C 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 EPAs 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 preand postnatal toxicity or exposure. Ref. 35
at 1316 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 408b2D, 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
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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 EPAs registration review human health risk assessment for chlorpyrifos.
Unit VI. discusses the Agencys 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 2425, Ref. 13 at 2527 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
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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 agedependent 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 preand postnatal 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 EPAs 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;

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