|September 28, 2007
Bayer CropScience. Pesticide Tolerance. FINAL RULE. This regulation establishes tolerances for combined residues of tembotrione and its metabolite (M5); 2-[2-chloro-4-(methylsulfonyl)-3-[(2,2,2- trifluoroethoxy)methyl]benzoyl]-4,6-dihydroxy-1,3-cyclohexanedione in or on corn (field, sweet and pop) and livestock commodities.
||Corn, sweet, forage
|Corn, field, forage
||Corn, sweet, stover
|Corn, field, grain
|Corn, field, stover
|Corn, pop, grain
|Corn, pop, stover
|Corn, sweet, kernel plus cob with husks removed
||Goat, meat byproducts, except liver
Cattle, meat byproducts, except liver
||Horse, meat byproducts, except liver
|Sheep, meat byproducts, except liver
• Tembotrione. Human-Health Risk Assessment for Proposed Uses on Field Corn, Sweet Corn and Popcorn. This report is "a shared joint review" by the USEPA Health Effects Division of the Office of Pestides and the Pest Management Regulatory Agency (PMRA) in Canada. September 7, 2007. (105 pages)
-- decreased absolute brain weight (pp 7, 16, 20, 56, 68, 88)
-- In the DNT study, brain morphometric changes and decreased acoustic startle response were observed in offspring at the lowest dose tested (0.8 mg/kg/day). These effects were observed at a dose lower than that which caused maternal toxicity (16.3 mg/kg/day, corneal opacity). (p 16)
-- The endpoint chosen, decreased acoustic startle response and brain morphometric changes were presumed to occur following a single exposure. (p 22)
-- Relative brain weight was significantly (p<0.01) increased in both males and females by 11 and 12% respectively, at 7000 ppm. Absolute brain weight decreased significantly (p<0.001) by 6% in 7000 ppm males only and was comparable to controls in females. (p 56)
-- absolute brain weights were dose-dependently decreased (p≤0.05) in both sexes in both generations. In F1 male and female pups, absolute brain weights significantly decreased 3-10% in all treatment groups. In the F2 generation, absolute brain weights significantly decreased 5-9% in males and females at ≥ 200 ppm. Relative brain weights were significantly increased (p≤0.05) in only F1 males and females by 8-9% at ≥200 ppm. (p 68)
-- In an acute neurotoxicity study (MRID 46695723), groups of non- fasted, young-adult Wistar rats (12/sex/dose) were given a single oral (gavage; 10 mL/kg) dose of AE 0172747 at doses of 0, 200, 500 or 2000 mg/kg (limit dose) and observed for 14 days. The brain and peripheral nervous system tissues collected from the perfused animals in the control and 2000 mg/kg groups were subjected to histopathological evaluation. Positive control data were not provided; however, data previously reviewed by the Agency have been included in this DER. (p 85)
• Classification: ``Suggestive Evidence of Carcinogenic Potential'' based on the observance of squamous cell carcinomas of the cornea in male rats in a rat carcinogenicity study. EPA's Cancer Assessment Review Committee (CARC ) recommended that a separate quantification of cancer risks is not required, while noting that the progression of non- neoplastic related lesions in rats was biologically plausible by non-genotoxic modes of action for the corneal tumors."
• Developmental Neurotoxicity Study: Offspring NOAEL was not established. Offspring LOAEL = 0.8 mg/kg/day based on decreased acoustic startle response on PND 60 (males), and brain morphometric changes on PND 75 (males and females).
• Chronic/Carcinogenicity Study: LOAEL = 0.79 mg/kg/day based on neovascularization and edema of the cornea and snow flake-like corneal opacity, unilateral or bilateral keratitis of the eye, decreased mean body weight and mean body-weight gain, increased total cholesterol, higher ketone levels and lower pH values, higher protein levels, increased kidney weight, kidney to body weight and kidney to
brain weight ratios, chronic nephropathy and atrophy of the sciatic nerve.
• Prenatal and postnatal sensitivity. There is evidence of increased susceptibility in rabbit and rat fetuses to in utero exposure to tembotrione compared to the doses for the effects found in maternal animals.
-- In a developmental toxicity study in rabbits, the NOAEL of 1 milligram per kilogram of body weight per day (mg/kg bw/day) was based on decreased growth and/or delayed development of the skeleton and increased incidences of skeletal variations and anomalies in fetuses seen at a LOAEL of 10 mg/kg/day. This LOAEL is ten-fold lower than the dose resulting in maternal toxicity (100 mg/kg/day, few or no feces, late abortion, decreased body weight and food consumption).
In a rat developmental toxicity study, increased skeletal variations (e.g., delayed ossifications) and other fetal effects (decreased fetal body weights and an increased number of runts) occurred at a dose of 25 mg/kg/day (the lowest dose tested), which is lower than the 125 mg/kg bw dose that caused marginal maternal toxicity (decreased body-weight gains and food consumption).
-- In a rat developmental neurotoxicity study (DNT), decreased post-weaning body weight (males), decreased acoustic startle response and brain morphometric* changes were seen in rat fetuses at a dose of 0.8 mg/kg/day (the lowest dose tested) which was lower than the dose of 16.3 mg/kg/day at which maternal toxicity occurred (cornel opacity during lactation). Other effects indicative of neurotoxicity (altered brain morphometrics, decrease in auditory startle response) were seen in the rat developmental neurotoxicity study at the lowest dose tested. The response for brain morphometrics seen at termination is considered to be marginal or equivocal since the changes were small and no clear dose response was observed. The decreased acoustic startle response was not found in young pups (post-natal day 22) but only observed in adult rats (post-natal day 60) and was statistically significant at the mid and high dose but not at the lowest dose tested.
* definition of morphometric:
-- (1) Measurement of the form of organisms or of their parts.
-- (2) external measurement: the measurement of the outside of something
-- (3) (Science: technique) method that involves measurement of shape.
• ENDOCRINE DISRUPTOR: Certain changes in multiple organs seen in the subchronic, chronic, dermal, and reproduction studies (e.g., microscopic changes in the thyroid gland, adrenal gland, and pancreas; increased number of corpora lutea in the ovary, and delayed preputial separation) may be due to various mechanisms including possible liver-pituitary-thyroid homeostatic disruption or inhibition of steroid synthesis. (p 6 health risk assessment) ... Compared to controls, the time until preputial separation was dose-dependently delayed in all treated groups in the F1 and F2 offspring. This effect was considered treatment related. Also, the time to vaginal opening was longer in the 1500 ppm F1 offspring. (p 68 health risk assessment). When additional appropriate screening and/or testing protocols being considered under the Agency’s EDSP (Endocrine Disruptor Screening Program) have been developed, tembotrione may be subjected to further screening and/or testing to better characterize effects related to endocrine disruption.
Tembotrione, belongs to a class of herbicides (including pyrasulfotole, isoxaflutole (both fluoridated), mesotrione and topramezone) that inhibit the liver enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD). As discussed above, EPA has concluded that the ocular effects caused by these herbicides has limited relevance to humans. Nonetheless, as a worst case scenario, EPA has assessed aggregate exposure to tembotrione based on ocular effects in rats.
• Safety factor. EPA has determined that reliable data show that it would be safe for infants and children to reduce the FQPA safety factor to 1X for assessing chronic risk. That decision is based on the following findings:
-- Despite evidence of sensitivity in pre- and post-natal studies, as detailed in Unit III.D.2., the chronic RfD based on an adult animal study (chronic rat study) is considered to be protective of the chronic offspring toxicity found in the rat DNT and 2-generation reproduction studies. The 2-generation reproduction study did not identify a NOAEL or the chronic effects seen on brain weight and preputial separation but a NOAEL can be characterized from the DNT, as discussed above, at 0.8 mg/kg/day. The NOAEL used to set the chronic RfD is 20-fold lower than this 0.8 mg/kg/day dose and is not based on an effect as to which the data have raised sensitivity concerns. Similarly, the chronic rat study and the NOAEL from that study are protective of the chronic effects seen in the DNT study and the other chronic effects found in the 2-generation reproduction study. The endpoints of concern for the chronic RfD are based on ocular toxicity, body weight decreases, kidney toxicity, and changes in the clinical chemistry parameters. Target organ toxicity such as ocular toxicity, kidney toxicity, body weight changes and nervous system effects were assessed in the young through pre- and post-natal exposure to tembotrione in the 2-generation reproduction study and the DNT study. In those studies, these effects were observed at higher doses in the young than in the adults in the chronic rat study. Therefore, the chronic RfD is considered to be protective of effects in the young. As noted, the NOAEL (0.04 mg/kg/ day) selected for the chronic RfD is 20-fold lower than the dose at which developmental and neurological effects were observed in any study; it is also 20-fold lower than the NOAEL for other chronic effects seen in the young.