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Federal Register / Vol. 86, No. 147 / Wednesday, August 4, 2021 / Rules and Regulations
II. Summary of Petitioned-For Tolerance In the Federal Register of April 15, 2020 85 FR 20910 FRL1000654, EPA issued a document pursuant to FFDCA section 408d3, 21 U.S.C.
346ad3, announcing the filing of a pesticide petition PP 9E8790 by IR4, Rutgers, The State University of New Jersey, 500 College Road East, Suite 201W, Princeton, NJ 08540. The petition requested EPA to establish tolerances in 40 CFR part 180 for residues of zetacypermethrin S-cyano3phenoxyphenyl methyl cis-trans 32,2-dichloroethenyl-2,2
dimethylcyclopropanecarboxylate, including its metabolites and degradates, measuring only total cypermethrin, cyano3phenoxyphenylmethyl 3-2,2dichloroethenyl-2,2dimethylcyclopropane carboxylate, in or on 116 separate commodities and to remove 52 established commodities upon establishment of the new commodities. Due to the length of the list of commodities, please refer to the Notice of Filing referenced above for a complete list of commodities to be established and removed. That document referenced a summary of the petition prepared by FMC, the registrant, which is available in the docket, http www.regulations.gov. A
comment was received on the notice of filing. EPAs response to this comment is discussed in Unit IV.C.
Based upon review of the data supporting the petition, EPA is establishing some tolerances at different levels than were petitioned for and is also modifying some of the commodity definitions to be consistent with Agency nomenclature. The reason for these changes is explained in Unit IV.D.

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III. Aggregate Risk Assessment and Determination of Safety Section 408b2Ai of FFDCA
allows EPA to establish a tolerance the legal limit for a pesticide chemical residue in or on a food only if EPA
determines that the tolerance is safe.
Section 408b2Aii of FFDCA
defines safe to mean that there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information. This includes exposure through drinking water and in residential settings but does not include occupational exposure. Section 408b2C of FFDCA requires EPA to give special consideration to exposure of infants and children to the pesticide
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chemical residue in establishing a tolerance and to ensure that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to the pesticide chemical residue . . . .
Consistent with FFDCA section 408b2D, and the factors specified in FFDCA section 408b2D, EPA has reviewed the available scientific data and other relevant information in support of this action. EPA has sufficient data to assess the hazards of and to make a determination on aggregate exposure for zetacypermethrin including exposure resulting from the tolerances established by this action. EPAs assessment of exposures and risks associated with zeta-cypermethrin follows.
A. Toxicological Profile EPA has evaluated the available toxicity data and considered its validity, completeness, and reliability as well as the relationship of the results of the studies to human risk. EPA has also considered available information concerning the variability of the sensitivities of major identifiable subgroups of consumers, including infants and children.
Type II pyrethroids, such as the cypermethrins cypermethrin, zetacypermethrin, and alpha-cypermethrin, contain an alpha-cyano moiety, and in rats produce a syndrome that includes pawing, burrowing, salivation, hypothermia, and coarse tremors leading to choreoathetosis. The adverse outcome pathway AOP shared by pyrethroids involves the ability to interact with voltage-gated sodium channels VGSCs in the central and peripheral nervous system, leading to changes in neuron firing and, ultimately, neurotoxicity.
The toxicology database for the cypermethrins is considered complete with respect to guideline toxicity studies. While each active ingredient does not have its own complete database, studies have been bridged across the three chemicals and together are considered adequate for human health risk assessment. When evaluated together, the toxicity database for the cypermethrins can be used to characterize the overall suite of effects associated with cypermethrin exposure, including potential developmental and reproductive toxicity, immunotoxicity, and neurotoxicity.
The cypermethrins affect the nervous system, and neurotoxicity is the most sensitive effect observed throughout the toxicology database. Effects clinical signs of neurotoxicity were seen for all three compounds across species, sexes,
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and routes of administration. The endpoints and points of departure PODs selected for risk assessment are based on neurotoxicity and are protective of all toxic effects observed in the database.
There was no evidence of increased quantitative or qualitative susceptibility in the available rat and rabbit developmental toxicity studies and rat two-generation reproductive studies with the cypermethrins. A
developmental neurotoxicity DNT
study with zeta-cypermethrin indicated increased sensitivity in the offspring, based on body weight changes in pups in the absence of treatment-related effects in maternal animals at the highest dose tested. However, there is a clear NOAEL for effects seen in pups, and the doses and endpoints selected for risk assessment are protective of the susceptibility.
For pyrethroid chemicals, the pharmacokinetics indicate that the onset of neurotoxicity is rapid, with the time to peak effect for neurobehavioral effects occurring within hours. This is followed by rapid metabolism and elimination that does not result in accumulation.
For the cypermethrins, the points of departure PODs for clinical signs after single or repeated exposure are comparable across durations of exposure. Thus, consistent with this class of compounds, neurotoxicity is not considered to progress with repeated exposure. Therefore, repeated dosing is essentially a series of acute exposures.
As there is no apparent increase in hazard from repeated/chronic exposures to cypermethrins, the acute exposure assessment is protective of chronic exposures. The totality of the information suggests that only single day risk assessments need to be conducted for the cypermethrins.
Cypermethrin is classified as a Group C Possible human carcinogen, based on an increased incidence of benign lung adenomas and adenomas plus carcinomas combined in females in a mouse carcinogenicity study. No tumors were seen in cypermethrin cancer studies in rats or in a cancer study in mice with alpha-cypermethrin. The Agency has determined that quantification of cancer risk using a non-linear approach i.e., RfD will adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to the cypermethrins. While the Agency would typically use a chronic population adjusted dose cPAD to protect for cancer concerns, use of the acute population adjusted dose aPAD is considered protective because increasing toxicity with increasing
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