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Federal Register / Vol. 86, No. 114 / Wednesday, June 16, 2021 / Rules and Regulations
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assumed that tolfenpyrad has a common mechanism of toxicity with other substances. For information regarding EPAs efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see EPAs website at https
www.epa.gov/pesticide-science-andassessing-pesticide-risks/pesticidecumulative-risk-assessment-framework.
D. Safety Factor for Infants and Children 1. In general. Section 408b2C of FFDCA provides that EPA shall apply an additional tenfold 10X margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the database on toxicity and exposure unless EPA determines based on reliable data that a different margin of safety will be safe for infants and children. This additional margin of safety is commonly referred to as the FQPA Safety Factor SF. In applying this provision, EPA either retains the default value of 10X, or uses a different additional safety factor when reliable data available to EPA support the choice of a different factor.
2. Prenatal and postnatal sensitivity.
There is no evidence of increased quantitative or qualitative susceptibility in the guideline rabbit developmental studies, the rat two-generation reproduction study, or the developmental immunotoxicity DIT
study. Quantitative susceptibility was observed in the developmental rat study and the range-finding one-generation reproduction study. In the developmental rat study, decreased fetal weights and number of ossified metacarpals were observed in the absence of adverse maternal toxicity only a 9% decrease in bodyweight. In the one-generation reproduction study, decreased pup weights were observed at a dose lower than the dose at which parental bodyweight decreases reached biological significance. All of the reviewed studies developmental toxicity studies in the rat and rabbit and the oneand two-generation reproductive toxicity studies in the rat include decreased bodyweight in the maternal LOAEL statement, as well as mortality in both of the developmental rabbit studies and the two-generation rat reproduction study. Reproductive toxicity was seen in rats as increased total litter loss in the two-generation study and decreased pup viability in the oneand two-generation study.
Decreased pup weight was observed in all six studies, and additional offspring effects include: An increase in skeletal
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variation in both developmental toxicity studies; blackish abdominal cavity, dark green intestinal contents, and decreased survival of offspring in the developmental immunotoxicity study;
decreased pup viability in both reproduction studies, with the addition of a delay in developmental landmarks in the two-generation reproductive toxicity study. Since most of these effects occurred in the presence of comparable or more severe maternal toxicity, or were partially attributable to the maternal animal behavior, they were not considered evidence of qualitative susceptibility.
3. Conclusion. EPA has determined that reliable data show the safety of infants and children would be adequately protected if the FQPA SF
were reduced to 1X. That decision is based on the following findings:
i. The toxicity database for tolfenpyrad is complete and includes acceptable developmental and reproductive toxicity studies.
ii. Based on the available toxicity database, there is no indication that tolfenpyrad is a neurotoxic chemical, and there is no need for a developmental neurotoxicity study or additional uncertainty factors to account for neurotoxicity.
iii. While there was evidence of quantitative susceptibility in two studies, the Agencys degree of concern for the susceptibility is low because the offspring effects consistently occurred at or near doses which caused maternal toxicity bodyweight decrease, and because endpoints and doses selected for risk assessment are protective of the observed susceptibility.
iv. There are no residual uncertainties identified in the exposure databases.
The dietary exposure assessment is partially refined but does not underestimate potential dietary exposure to tolfenpyrad. EPA made conservative protective assumptions in the ground and surface water modeling used to assess exposure to tolfenpyrad in drinking water. These assessments will not underestimate the exposure and risks posed by tolfenpyrad.
E. Aggregate Risks and Determination of Safety EPA determines whether acute and chronic dietary pesticide exposures are safe by comparing aggregate exposure estimates to the acute PAD aPAD and chronic PAD cPAD. For linear cancer risks, EPA calculates the lifetime probability of acquiring cancer given the estimated aggregate exposure. Short-, intermediate-, and chronic-term risks are evaluated by comparing the estimated aggregate food, water, and
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residential exposure to the appropriate PODs to ensure that an adequate MOE
exists.
1. Acute risk. Using the exposure assumptions discussed in this unit for acute exposure, the acute dietary exposure from food and water to tolfenpyrad will occupy 69% of the aPAD for children 1 to 2 years of age, the population group receiving the greatest exposure.
2. Chronic risk. Using the exposure assumptions described in this unit for chronic exposure, EPA has concluded that chronic exposure to tolfenpyrad from food and water will utilize 59% of the cPAD for all infants less than 1-year old, the population group receiving the greatest exposure. There are no residential uses for tolfenpyrad.
3. Short-term and Intermediate-term risks. Short-term and intermediate-term aggregate exposures take into account short-term and intermediate-term residential exposures plus chronic exposures to food and water considered to be a background exposure level.
Short-term and intermediate-term adverse effects were identified;
however, tolfenpyrad is not registered for any use patterns that would result in short-term or intermediate-term residential exposures. Short-term and intermediate-term risks are assessed based on short-term and intermediateterm residential exposures plus chronic dietary exposure. Because there are no short-term or intermediate-term residential exposures and chronic dietary exposures have already been assessed under the appropriately protective cPAD which is at least as protective as the POD used to assess short-term and intermediate-term risk, no further assessments of short-term and intermediate-term risks are necessary, and EPA relies on the chronic dietary risk assessment for evaluating shortterm and intermediate-term risks for tolfenpyrad.
4. Aggregate cancer risk for U.S.
population. Based on the lack of evidence of carcinogenicity in two adequate rodent carcinogenicity studies, tolfenpyrad is not expected to pose a cancer risk to humans.
5. Determination of safety. Based on these risk assessments, EPA concludes that there is a reasonable certainty that no harm will result to the general population, or to infants and children from aggregate exposure to tolfenpyrad residues.
IV. Other Considerations A. Analytical Enforcement Methodology An acceptable high-performance liquid chromatography method with
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