Excerpts from: Registration Decision for the New Active Ingredient Sulfoxaflor
Federal Register, Final Rule May 17, 2013
• A fluoridated pesticide made by Dow AgroSciences, CAS No. 946578-00-3
• Approved in May 2013, revoked September 10, 2015, by the 9th Circuit Court of Appeals

The database of guideline toxicity studies indicates that the nervous system and liver are the target organ systems, resulting in developmental toxicity, hepatotoxicity, and other apical effects.

Developmental/offspring toxicity, manifested as skeletal abnormalities and neonatal deaths, was observed in rats only. The skeletal abnormalities, including forelimb flexure, bent clavicles, and hindlimb rotation, likely resulted from skeletal muscle contraction due to activation of the skeletal muscle nAChR in utero. Contraction of the diaphragm, also related to skeletal muscle nAChR activation, prevented normal breathing in neonates and resulted in increased mortality in the reproduction studies. Furthermore, targeted studies indicate that offspring effects are dependent upon in utero exposure to sulfoxaflor. The skeletal abnormalities were observed at high doses in the developmental and reproduction studies while decreased neonatal survival was observed at slightly lower levels (e.g., mid- and high-dose animals)…

For sulfoxaflor, hepatoxicity occurred at lower doses in long-term studies compared to short-term studies.

In addition to the developmental and hepatic effects, treatment with sulfoxaflor resulted in decreased food consumption and body weight as well as changes in the male reproductive system…

Effects in the male reproductive organs were observed in the chronic/carcinogenicity study in rats that included increased testicular and epididymal weights, atrophy of seminiferous tubules, and decreased secretory material in the coagulating glands, prostate, and seminal vesicles. Additionally, there was an increased incidence of interstitial cell (Leydig cell) tumors. The Leydig cell tumors observed after exposure to sulfoxaflor are not considered treatment related due to the lack of dose response, the lack of statistical significance for the combined tumors (unilateral and bilateral), and the high background rates for this tumor type in F344 rats. The primary effects on male reproductive organs are considered secondary to the loss of normal testicular function due to the size of the interstitial cell (Leydig Cell) adenomas. Consequently, the secondary effects to the male reproductive organs are also not considered treatment related.

Clinical indications of neurotoxicity were only observed at high doses in the acute neurotoxicity study in rats. At the highest dose tested, muscle tremors and twitches, convulsions, hindlimb splaying, increased lacrimation and salivation, decreased pupil size and response to touch, gait abnormalities and decreased rectal temperature were observed. Decreased motor activity was also observed in the mid- and high-dose groups. Since the neurotoxicity was observed only at a very high dose and many of the effects are not consistent with the perturbation of the nicotinic receptor system (e.g., salivation, lacrimation, and pupil response), it is unlikely that these effects are due to activation of the nAChR.

Finally, tumors were observed in chronic rat and mouse studies. In rats, significant increases in the incidence of hepatocellular adenomas and combined adenomas and/or carcinomas in the high-dose males were observed when compared to controls. In mice, there were significant increases in hepatocellular adenomas, carcinomas, and combined adenomas and/or carcinomas in high dose males when compared to controls. In female mice, there was an increase in the incidences of carcinomas at the high dose. Although this increase did not reach statistical significance, the incidences exceeded the historical control range for this tumor type was corroborated with the presence of non-neoplastic lesions at this dose. EPA determined that the liver tumors in mice were treatment-related. Using data from several mechanistic studies, EPA also determined that the liver effects in mice and rats are non-linear (threshold) in their mode of action (MoA) and the MoA for the liver tumors is consistent with a constitutive androstane receptor (CAR) mediated, mitogenic mode-of-action. Leydig cell tumors were also observed in the high-dose group of male rates, but it was determined that the tumors were not related to treatment. There was also a significant increase in the incidence of preputial gland tumors in male rats in the high-dose group. Marginal increases were also observed in the low- and mid-dose groups; however, the incident values for these groups were within the range of historical control values. Given that the liver tumors are produced by a non-linear mechanism, the Leydig cell tumors were not treatment-related, and the preputial gland tumors only occurred at the high dose in one sex of one species, EPA concluded that the evidence of potential carcinogenicity was weak and that that quantification of risk using a non-linear approach (i.e., reference dose (RfD) will adequately account for all chronic toxicity, including any potential carcinogenic effects, that could result from exposure to sulfoxaflor. The current NOAEL of 5.13 mg/kg/day used for chronic dietary risk assessment is significantly (4x) lower than the dose where tumors were observed ? 21.3 mg/kg/day.

In addition, EPA determined there was sufficient evidence to support a developmental mode-of-action (i.e., activation of the nAChR) accounting for the skeletal abnormalities and increased mortality observed in the rat. Furthermore, there was sufficient evidence to support that rats are uniquely sensitive to these developmental effects, informing interspecies uncertainty. Although the database indicates that the developmental effects are unlikely to be relevant to humans, the effects will be considered as relevant to humans unless additional information to the contrary is provided. Data are sufficient to support reducing the interspecies uncertainty factor to 3X for the developmental effects.

Approved tolerances for the following commodities:

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