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Federal Register / Vol. 86, No. 35 / Wednesday, February 24, 2021 / Rules and Regulations 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 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 tetraniliprole including exposure resulting from the tolerances established by this action.
EPAs assessment of exposures and risks associated with tetraniliprole follows.

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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.
The submitted animal toxicity studies on tetraniliprole demonstrate low toxicity, which is expected based on two factors. Tetraniliprole is an anthranilimide insecticide that targets the activation of insect ryanodine receptors, which leads to insect paralysis and death. In contrast, mammalian ryanodine receptors are substantially less sensitive i.e., 350 to >2,500 times less sensitive to the effects of anthranilic diamides than insect ryanodine receptors. Moreover, available data indicate that tetraniliprole has limited absorption at the higher dose levels >20 mg/kg,
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which may contribute to the low toxicity seen in the animal testing.
In subchronic toxicity studies 28-day and 90-day in rats and mice, no adverse effects were seen at dose levels ranging from approximately 600 to 1,228 mg/kg/
day. In the subchronic studies 28-day and 90-day in dogs, an increase in the incidence and frequency of salivation was found, but this finding did not show a dose related-response, was a common occurrence in dogs, and was not considered to be adverse.
No systemic or dermal toxicity was seen in a 28-day dermal toxicity study at 1,000 mg/kg/day; this finding was consistent with rather low dermal absorption as the DAF for humans was estimated to be approximately 9%
upper limit.
No adverse maternal or developmental effects were found at the limit dose 1,000 mg/kg/day in the developmental toxicity studies in rats and rabbits. In the reproduction study, the offspring effect, slight decrease in pup weight near and above the limit dose, was found in the absence of any adverse parental effect. Because the potential increase in susceptibility occurred at the limit dose and on postnatal days PND 14 to 21 at which time the pups were exposed to the test material through both milk and food resulting in a higher compound intake, the Agencys concern for the potential risk to infants and children is low.
Tetraniliprole did not cause any effects on reproductive parameters.
The combined chronic/
carcinogenicity study in rats showed a decrease in body weights, increased incidence of squamous cell hyperplasia in the cervix and vagina, and corpora lutea depletion in the ovary at the limit dose. In addition, a slight increase in the incidence of uterine tumor was observed at a dose slightly above the limit dose. No genotoxic potential was detected in the battery of genotoxicity studies. There were no treatment-related tumors seen in mice and no adverse effects were observed in male rats. The only adverse effects observed in female rats occurred at the limit dose, which was the only dose where pre-neoplastic or neoplastic lesions were observed.
Furthermore, there is no concern for mutagenicity and none of the identified structurally-related compounds induced tumors in rats or mice. Based on the available data that indicates that the increased incidence of uterine tumor was seen in only one species rat, one sex female, and is only slightly outside of the historical control range, EPA has classified tetraniliprole as having suggestive evidence of carcinogenic potential.

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Typically, for chemicals so classified, EPA recommends that a non-linear or RfD approach be used because the RfD
would be protective for all toxicity, including carcinogenicity. However, in the case of tetraniliprole, EPA
determined that the existing data do not support establishing toxicity endpoints and that a qualitative assessment is more appropriate for assessing tetraniliprole. This analysis is discussed more fully in Unit III.B. below.
Similarly, because of the suggestive nature of the carcinogenicity effects and the fact that the only tumor effects are seen at doses above the limit dose, EPA
has determined that a qualitative risk assessment would be appropriate in this case to account for all toxicity including carcinogenicity.
No acute and subchronic neurotoxicity studies were submitted for tetraniliprole because this requirement was waived. However, no evidence of neurotoxicity was seen in any of the other studies in the tetraniliprole database.
Specific information on the studies received and the nature of the adverse effects caused by tetraniliprole as well as the no-observed-adverse-effect-level NOAEL and the lowest-observedadverse-effect-level LOAEL from the toxicity studies can be found at http
www.regulations.gov in the document titled Tetraniliprole: New Active Ingredient, First Food Use. Human Health Risk Assessment for the Establishment of Permanent Tolerances on Brassica Head and Stem Vegetables, Corn Field, Pop and Sweet, Citrus Fruit, Fruiting Vegetables, Leafy Vegetables, Pome Fruit, Small Fruit Vine Growing except Fuzzy Kiwifruit including Grape, Soybean, Stone Fruit, Tree Nuts, and Tuberous and Corm Vegetables, Plus Registration for Seed Treatment Uses on Corn Field, Pop and Sweet, Use on Tobacco, and Use on Golf Course Turf, Sport Fields, and Sod Farms on pages 3369 in docket ID
number EPAHQOPP20170233.
B. Toxicological Points of Departure/
Levels of Concern Once a pesticides toxicological profile is determined, EPA identifies toxicological points of departure POD
and levels of concern to use in evaluating the risk posed by human exposure to the pesticide. For hazards that have a threshold below which there is no appreciable risk, the toxicological POD is used as the basis for derivation of reference values for risk assessment.
PODs are developed based on a careful analysis of the doses in each toxicological study to determine the dose at which no adverse effects are
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