# i

**EPA REGISTRATION DIVISION -**  **COMPANY NOTICE OF FILING FOR PESTICIDE PETITION**  **EPA Registration Division contact: Sidney Jackson, (703) 305 -**  **7610 Docket I.D. Number: EPA**  **- HQ**  **- OPP**  **- 2014**  **- 0879**  **Interregional Research Project Number 4 (I R** **- 4)**  **Pesticide Petition Number: PP# 4E8330** EPA has received a pesticide petition (PP# 4E8330) from Interregional Research Project No. 4 (IR - 4), 500 College Road East, Suite 201 W, Princeton, NJ 08540 request ing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance for residues of the herbicide, penoxsulam (2 - (2,2 - difluoroethoxy) - N - (5,8 - dimethoxy [1,2,4] triazolo[1,5 - c]py rimidin - 2 - yl ) - 6 - (trifluoromethyl)benz enesulfonamide) in/on the following raw agricultural commodities: Fruit, Pome, group 11 - 10 at 0.01 parts per million (ppm) , Fruit, Stone, group 12 - 12 at 0.01 ppm, Fruit, Small, Vine Climbing, s ubgroup 13 - 07F, except Fuzzy Kiwifruit at 0.01 ppm, Nut, Tree, group 14 - 12 at 0.01 ppm, Olive at 0.01 ppm, and Pomegranate at 0.01 ppm . Inaddition, the petitioner proposes based upon the establishment of the new tolerances above, removal of existing tolerance s at 40 CFR 180.605 for Grape at 0.01 ppm , Nut, tree, grou p 14 at 0.01 ppm and Pistachio at 0.01 ppm . EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data support granting of the petition. Additional data may be needed before EPA rules on the petition. A. Residue Chemistry 1. Plant metabolism. Based on results of the metabolism studies in plants that are summarized below, it i s concluded that the residue definition in plants is the parent compound alone, penoxsulam. A nature of residue study (NOR) was conducted in grapes using a soil application of p enoxsulam. Penoxsulam, 14 C - labeled either in the 2 - position on the triazolo py rimidine ring (TP) or uniforml y labeled in the phen yl - ring (Ph), was applied as a broadcast spray onto soil around established grape vines at a single application rate of approximately 20 g a.i./ha. The soil in this study was a sand y clay

loam. Application was made when grapes vines were at growth stage BBCH 55 (earl y flowering). After application, the plots were irrigated with 1 cm of water daily for 7 day s. Grapes and leaves were harvested at 118 day s after application.2

Mature grapes contained res idues below the limit of quantification (0.0008 μg/g penoxsulam equivalents). The PH - label and TP - label leaves collected at maturity contained 0.016 μg/g and 0.013 μg/g penoxsulam equivalents, respectivel y. In the mature leaves, approximately 65% of the leaf TRR was extractable with neutral solvent, of which approximately

half partitioned into organic solvent. The majority of the organic phase was identified as numerous low - level metabolites, while the aqueous phase consisted of primaril y polar, solvent - front residues. The residue was characterized as low - level degradates, tentatively including the 5 - hydroxy - penoxsulam and the dihydroxy penoxsulam metabolites. In summary , very

low levels of soil - applied penoxsulam and degradates are taken up by the vine . No penoxsulam was detected in the leaves, and due to the low TRR levels in the grapes, no penoxsulam is predicted there either. The residue was characterized as low - level degradates, tentatively including the 5 - hydroxy - penoxsulam and the dihydroxy peno xsulam metabolites. Metabolism studies in livestock animals with 14 C - labeled penoxsulam (2 - position on the triazolopy

rimidine ring or uniformly labeled in the phenyl ring) at a concentration equivalent to about 10 ppm in the diet indicated that approximat ely 99% of the administered dose was eliminated in the excreta. The low levels of residues (0.002 - 0.07 ppm) in fat and edible tissues, milk or eggs demonstrate that residues due to penoxsulam would not accumulate in the animals. Additionally , the dose le vels in these studies are about 200 to 1000 times higher than the theoretical maximum exposure in the animal diet of rice commodities treated with penoxsulam, therefore, livestock feeding studies are not considered necessary . 2. Analytical method. [ Inth e Magnitude of Residue (MOR) studies conducted in Pome Fruit and Stone Fruit to support tolerances proposed in this petition, residues of penoxsulam were determined using the anal yt ical method GRM 04.09. Residues of penoxsulam were extracted from the crop samples by homogenizing and shaking with an acetonitrile/water solution (80:20 v/v). An aliquot was diluted with 0.1N HCl and purified using a 96 - well poly meric - reverse phase extraction (SPE) plate. The SPE plate was washed with a 40/60 methanol/water s olution and eluted with acetonitrile into a 96 - well plate containing an acetonitrile/methanol/water mobile phase (15:15:70 containing 0.1% acetic acid) and a stable isotope internal standard. The final solution was anal yz ed by liquid chromatography

with p ositive - ion electrospray tandem mass spectrometry (L C/MS/MS). The limit of detection (LOD) and limit of quantitation (L OQ) are 0.003 μg/g and 0.010 μg/g, respectivel y. 3. Magnitude of residues. The proposed tolerances (Section F) are supported by MOR studies in grapes, almonds and pecans conducted in the U.S. Trials were conducted in almonds and pecans to support a tolerance for the nut tree crop group (Nuts, tree, group 14) including pistachios, and almond hulls. Additionally , trials were conducted in grapes to support a tolerance for grapes. B. Toxicological Profile3 1. Acute toxicity. The acute toxicity of penoxsulam is considered low. The acute oral and dermal lethal dose ( LD ) 50 s were greater than 5000 milligram per kilogram ( mg/kg ) , while the a cute inhalation lethal concentration ( LC ) 50 was greater than the highest attainable aerosol concentration (3.50 mg/L). Only very slight, transient dermal irritation was seen, and mild ey e irritation was noted. Penoxsulam was negative for skin sensitizatio n in a Magnussen and Kligman maximization test involving intradermal injection of penoxsulam with an adjuvant. 2. Genotoxicty. Penoxsulam was negative for genotoxicity when tested in in vitro and in vivo sy stems . 3. Reproductive and developmental toxic ity. Penoxsulam did not have an y effect on reproductive parameters at dose levels that induced treatment - related effects in parental rats. At the highest dosage tested (300 mg/kg/day), bod y weights and weight gains in both males and females were depressed , liver and/or kidney weights were increased, and histologic changes were noted in the liver (males) and kidneys (females). At 100 mg/kg/day , increased liver weights were recorded in males, with no histologic correlate, and histologic changes noted in the kidney s of females. Transient decreases in pup body weights were seen at the highest dosage tested, but dietary concentrations were targeted for adults and consumption of treated diets by the pups resulted in dose levels to the pups approximately

3 - fold higher than in adults. A teratogenic potential was not demonstrated for penoxsulam in either rats or rabbits. 4. Subchronic toxicity. Dietary exposure to penoxsulam identified the liver and/or urinary tract (kidney s and bladder) as target organs in rats , mice and dogs following 4 - week and 13 - week administration. Effects on the liver were reflected in increased liver weights and hepatocellular h ypertroph y, but these effects were not associated with increases in mixed function oxidase (MFO) enz yme activity. Effects noted in the kidneys included cry stal deposition, most likely from precipitation of penoxsulam from the urine, with resultant irritation, inflammation and hy perplasia of renal pelvic transitional epithelium. Other than the cry stal deposition i n the kidney s, all effects following subchronic exposure to rats appeared to be reversible. Very high doses were associated with significant decreases in body weight and weight gain, and feed consumption. 5. Chronic toxicity. Chronic exposure in the dog indicated that the renal effects were not exacerbated with long - term exposure. Following long - term exposure in rats, the kidney s and urinary

bladder were the primary target organs. Histologic changes seen at the end of 2 - ye ars of exposure consisted of i nflammation and hy perplasia of the renal pelvic transitional epithelium, cry stal deposition in the kidney s and urinary bladder, and hy perplasia of the mucosa of the urinary bladder. In the mouse, the liver was the primary target organ, and histologic chan ges consisted of hepatocellular h yp ertrophy . There were no treatment - related increases in tumors in either rats or mice. The incidence of mononuclear cell leukemia (Fischer rat leukemia) was increased in all groups of treated male rats compared to the co ncurrent controls. However, the incidences in the treated groups were identical across a 50 - fold increase in dosage, and well within the range of control values reported in the literature. Penoxsulam was classified as having “Suggestive Evidence of Carcin ogenicity , but Not Sufficient to Assess Human Carcinogenic4

Potential”. E PA ha s concluded that cancer risk associated with penoxsulam is negligible . 6. Animal metabolism. Orally administered penoxsulam is rapidly absorbed, excreted and extensivel y metabol ized in both male and female rats, thus, indicating that penoxsulam is not expected to accumulate in biological sy stems. The majority of the residue was associated with the parent, penoxsulam. Several metabolites were also observed but the vast majority were <1% of the administered dose. The major route of metabolism involves O - demethylation, producing the OH - Penoxsulam metabolite followed b y conjugation. 7. Metabolite toxicology . A metabolism study with penoxsulam in rice revealed the presence of the parent, a desmethylation metabolite (5 - OH - Penoxsulam), and two other polar metabolites, which may represent conjugates of the desmeth yl ated metabolite. The 5 - OH - Penoxsulam metabolite and its glucuronide and glutathione conjugates have also been identifi ed in the plasma and liver of rats, therefore, plant metabolites are considered of little toxicological concern. 8. Endocrine disruption . Penoxsulam did not have any effects on endocrine organs or tissues in mice, rats or dogs in an y of the studies condu cted. There were no indications of effects on fetal development in either rats or rabbits, or on reproductive performance in rats. Based on the lack of an y effects on the endocrine system, penoxsulam is not considered an endocrine disrupter. C. Aggregate Exposure 1. Dietary exposure. Tier 1 dietary risk assessments were performed using Dietary Exposure Evaluation Model software with the Food Commodity Intake Database ( DEEM - FCIDTM ) software (version 3.14) to determine consumption of Fruits, Pome group 11 - 10, and Fruits, Stone group 12 - 12, Fruit, Small, Vine Climbing, Subgroup 13 - 07F, except Kiwifruit, olive and pomegranate containing penoxsulam residues and to determine dietary

exposure resulti ng from consumption of Fruits, Pome group 11 - 10, and Fruits, S tone group 12 - 12, Fruit, Small, Vine Climbing, Subgroup 13 - 07F, except Kiwifruit, Olive and Pomegranate treated with penoxsulam. i. Food. Penoxsulam is registered for use as an herbicide on rice. Therefore, consumption of rice that has been treated with penoxsulam could result in dietary exposures. On September 24, 2004, EPA finalized tolerances for penoxsulam in rice, grain (0.02 ppm) and rice, straw (0.5 ppm) (69 FR 57188 - 57197). In establishing the tolerances for rice, grain and rice, straw, EPA con cluded that chronic dietary exposures were <1% of the chronic population adjusted dose ( cPAD ) , but exposure estimates were not provided. On July

25, 2007, EPA finalized tolerances for penoxsulam in fish, and shellfish. On April 24, 2009 EPA finalized tole rances for penoxsulam in or on almond hulls; grape; nut, tree, group 14; and pistachio. For the purposes of this aggregate assessment, it is necessary to estimate dietary exposures of penoxsulam resulting from tolerance level residues on rice, fish and she llfish , almond hulls; grape; nut, tree, group 14; and pistachio in addition to the proposed new uses. Secondary residues in meat, milk and poultry

were not included because the transferability of penoxsulam to edible tissues5

is quite low and tolerances ar e not required. A chronic dietary exposure and risk assessment for tolerance - level residues in existing and proposed uses was performed using the DEEM - FCIDTM software (version 3 .14). An acute dietary assessment was not performed because no toxicity endpoi nt has been identified to evaluate acute dietary exposures to penoxsulam (EPA, 2004). To produce a conservative Tier 1 dietary risk assessment, tolerance - level residues were assumed for all commodities, and 100 percent crop treated was assumed for all commodities. Dietary penoxsulam exposures are low, accounting for less than 6% of the cRfD (0.147 mg/kg/d) for all subpopulations. ii. Drinking water. The estimated drinking water concentrations (EDWCs) for the herbicide penoxsulam in groundwater and surfac e water resulting from ground spray applications in Tree crops have been calculated according to EPA guidance. For groundwater, EDWCs were derived using the Screening Concentration in Ground Water (SCI - GROW) and Pesticide Root Zone Model - Ground Water ( PRZ M - GW ) models. For surface water, the PRZM - Exposure Analy sis Modeling S ys tem ( EXAMS ) model was used. The values generated were lower than the conservative values generated for aquatic weed control. For the purpose of these assessments, 150 ppb was used fo r the chronic exposure estimate for water, and this value was incorporated as a single point estimate for both “water, direct, all sources” and “water, indirect, all sources” within DEEM - FCID TM food categories exposure modeling. Based on the conservative assumptions used and using a cPAD of 0.147 mg/kg/day , the chronic dietary exposure to penoxsulam from all registered and proposed uses and drinking water, to all population subgroups is approximately

<6% of the cPAD. All Infants have been identified as th e most highly exposed population subgroup y et utilizing only <6% of the cPAD. 2. Non - dietary exposure . The residential exposure portion of the risk assessment has been updated using current EPA practices. The proposed changes do not impact the previous human health assessment conclusion for penoxsulam in which it was determined that the percentages of chronic population adjusted dose for all population subgroups were less than 100% and therefore do not exceed the Agency ’s level of concern. The change in the dietary

contribution and the estimated residential exposures also do not change the conclusions of the previous assessment regarding Short - Term and Intermediate - Term exposures; aggregate margin of exposures ( MOEs ) remain acceptable. Thus, anticipated aggregate exposures estimated with conservative assumptions regarding use patterns of the full range of registered and proposed penoxsulam products are not of concern. D. Cumulative Effects Currently no common mechanism of toxicity has been found betwee n penoxsulam and an y other substances EPA and penoxsulam does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, it is not assumed that penoxsulam has a common mechanism of toxicity with other substances. E. Safety Determination6 1. U.S. population. Using the conservative exposure assumptions described above, and based on the completeness and reliability of the toxicity

data, the aggregate exposure to penoxsulam, as determined under the guidan ce of the FQPA, will utilize less than 6% of the RfD from the dietary exposure for all subgroups of the U.S. population. Generally and under the FQPA, the U.S. EPA has no concern for exposures below 100% of the RfD because the RfD represents the level at or below which daily dietary exposure over a lifetime will not pose appreciable risks to human health. Additionally , the chronic dietary exposure to penoxsulam from all registered and proposed uses and drinking water, to all population subgroups is approx imately 6% of the cPAD. Therefore, there is a reasonable certaint y that no harm will result to the general U.S. population from aggregate exposure to penoxsulam residues from the proposed use. 2. Infants and children . In assessing the potential for addi tional sensitivity of infants and children to residues of penoxsulam, data from developmental toxicity studies in rats and rabbits and a multi - generation reproduction study in the rat are considered. The developmental toxicity studies are designed to eval uate adverse effects on the developing organism resulting from pesticide exposure during prenatal development. Reproduction studies provide information relating to effects from exposure of both parents to the pesticide on the reproductive capability and p otential s ys temic toxicity of mating animals and on various parameters associated with the well being of offspring. FFDCA section 408 provides that the U.S. EPA may appl y an additional safety factor for infants and children in the case of threshold effect s to account for pre - and post - natal toxicity and the completeness of the database. Based on the current toxicological data requirements, the database for penoxsulam relative to pre - and post - natal effects for children is complete. Overall, penoxsulam ha d no effect on reproduction or embryo - fetal development at an y dosage tested. No quantitative or qualitative susceptibility was seen following pre - and post - natal exposures. In a rabbit developmental toxicity study , effects on in - utero survival were obse rved onl y at a dose level where clear maternal toxicity was seen. In a 2 - generation reproductive toxicity study in rats, no effects on reproductive performance were observed and effects on neonatal growth were seen onl y at a dose level where parental toxi city

was seen. In addition, the no - observed adverse effect level (NOAEL ) in the chronic dog study (14.7 mg/kg/day), used to calculate the chronic reference dose ( RfD ) (0.147 mg/kg/day), is already lower than the NOAEL from the rabbit developmental study ( 25 mg/kg/day). Therefore, an additional FQPA uncertaint y factor is not needed and the RfD at 0.147 mg/kg/day is appropriate for assessing risk to infants and children. Using the conservative exposure assumptions previously described, the percent RfD util ized by the potential exposure to residues of penoxsulam is less than 6% for the population subgroup predicted to be potentially the most highly

exposed. Based on the aggregate exposure to penoxsulam, Dow AgroSciences concludes with reasonable certainty

that no harm will result to infants and children, females 13+ y ears old and the prenatal development of infants. F. International Tolerances A review of Maximum Residue L imits (MRLs) established globall y indicates that7

MRL s of 0.01 have been established in Japan for penoxsulam in or on Pome Fruit, Stone Fruit, grapes, Almond, and Pecan.