EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE

PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division contact: Andrew Ertman, (703) 308-9367

Interregional Research Project Number 4 (IR-4)

PP #1E7855

EPA has received a pesticide petition (PP #1E7855) from Interregional Research Project Number 4 (IR-4), 500 College Road East, Suite 201W, Princeton, NJ 08540 proposing, pursuant to section 408 (d) of the Federal Food, Drug, and Co smetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.434 by establishing tolerance for residue of propiconazole, 1-[[2-(2,4-dichloro phenyl)-4-propyl-1,3-dioxolan-2-yl] methyl]-1H-1,2,4-triazole and its metabolites de termined as 2,4,-dichlorobenzoic acid and expressed as parent compound in or on the raw agricultural commodity Bean, snap at 0.8 parts per million (ppm); bean, succulent shelled at 0.15 ppm; bean, dry seed at 0.3 ppm; legume, foliage at 25 pp m; tomato at 2.5 ppm; fruit, citrus, group 10-10 at 8.0 ppm; fruit, stone, group 12, except plum, at 7.0 ppm; plum at 1.0 ppm and by removing the established

tolerance on fruit, stone, group 12 at 1.0 ppm.

EPA has determined that the petition contains da ta or information regarding the elements set forth in section 408 (d)(2) of the FDDCA; however , EPA has not fully evaluated the sufficiency

of the submitted data at this time or whether th e data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry.

1. Plant metabolism. The metabolism of propiconazole as we ll as the nature of the residues is adequately understood for purposes of the tolerances. Plant me tabolism has been evaluated in five diverse crops, wheat, grapes , celery, peanuts and carrots wh ich should serve to define the similar metabolism of propiconazole in a wide range of crops. The plant metabolism pathway for propiconazole is well understood. Pa rent metabolite CGA-64250 is the major compound found in crops. Comparison of the metabolism of propiconazole in different plant species shows that the differences between the respectiv e metabolic pathways to be quantitative in

nature.

2. Analytical method. The metabolism data in plants and anim als suggest that analytical methods to detect either the phenyl or the triazole ring would be appropriate for the measurement of residues. However, because of the natural o ccurrence of compounds that interfere with the measurement of triazoles, methods designed to de tect this moiety have been proven unreliable and unacceptable. Conversely, conversion of phenyl moiety to 2,4-dichlorobenzoic acid (DCBA) has proven to be satisfactory for all agricu ltural products analyzed to date. Analytical methods AG-626 and AG-454A were developed for the determination of residues of propiconazole and its metabolites containing th e DCBA moiety. Analytical method AG-626 has been accepted and published by EPA as th e tolerance enforcement method for crops. Thelimit of quantitation (LOQ) for the method is 0.05 ppm.

3. Magnitude of residues.

. IR-4 conducted magnitude of resi due trials on several crops under OPPTS 860.1500 to support the reques ted uses of propiconazole . Th ese residue trials satisfy the proposed tolerances for these crops.

B. Toxicological Profile

1. Acute toxicity. Propiconazole exhibits low toxicity. Data indicated the following: a rat acute oral LD50 of 1,517 milligrams/kilograms (mg/kg) ; a rabbit acute dermal LD50 >6,000 mg/kg; a rat inhalation LC50 >5.8 mg /liter air; minimal skin and slight eye irritation; and nonsensitization.

2. Genotoxicty. Propiconazole exhibits low toxicity. Data indicated the following: a rat acute oral LD50 of 1,517 milligrams/kilograms (mg/kg) ; a rabbit acute dermal LD50 >6,000 mg/kg; a rat inhalation LC50 >5.8 mg /liter air; minimal skin and slight eye irritation; and nonsensitization.

3. Reproductive and developmental toxicity. In an oral teratology study in the rabbit, a maternal no observed adverse effect level (NOAEL) of 30 mg/kg was based on reduced food intake but without any fetotoxicity even at the top dose of 180 mg/kg. In an oral teratology study in the rabbit, a maternal NOAEL of 100 mg/kg was base d on reductions in body weight gain and food consumption and a fetal NOAEL of 250 mg/kg was based on increased skeletal variations at 400 mg/kg. In an oral teratology study in the ra t, a maternal and fetal NOAEL of 100 mg/kg was based on decreased survival, body weight gain, a nd food consumption in the dams and delayed ossification in the fetuses at 300 mg/kg. In a se cond teratology study in th e rat, a maternal and fetal NOAEL of 30 mg/kg was based on reductions in body weight gain and food consumption in the dams and delayed development in the fetuses at 90 and 360/300 mg/kg. A supplemental teratology study in the rat involving eight times as many animals per group as usually required showed no teratogenic potential for the compoun d. A 2-generation reproduction study in the rat showed excessive toxicity at 5,000 ppm without any teratogeni c effects. A 2-generation reproduction study in the rat showed no effects on reproductive or fetal parameters at any dose level. Postnatal growth and survival were a ffected at the top dose of 2,500 ppm, and parental toxicity was also eviden t. The NOAEL for development toxicity is 500 ppm.

4. Subchronic toxicity. In a 21-day dermal study in the ra bbit, a NOAEL of 200 mg/kg was based on clinical signs of systemic toxicity. In a 28- day oral toxicity study in the rat, a NOAEL of 50 mg/kg was based on increased liver weight. In a subchronic feeding study in the mouse, a NOAEL of 20 ppm (3 mg/kg) was based on liver pa thologic changes. In a 13 week feeding study in the male mouse, a NOAEL of 20 ppm (3 mg/kg) was based on liver pathologic changes. In a 90 day feeding study in rats, the NOAEL was 24 0 ppm (24 mg/kg) based on a reduction in body weight gain. In a 90 day feeding study in dogs, the NOAEL was 250 ppm (6.25 mg/kg) based on reduced food intake and stomach histologic changes.

5. Chronic toxicity. In a 12-month feeding study in th e dog, a NOAEL of 50 ppm (1.25 mg/kg) was based on stomach histologic changes. In a 24 month oncogenicity feeding study in the mouse, the NOAEL was 100 ppm (15 mg/kg). The MTD was exceeded at 2,500 ppm in males

based on decreased survival and body weight. Increased incidence of liver tumor was seen inthese males but no evidence of carcinogenicity wa s seen at the next lower dose of 500 ppm in either sex. In a 24 month chronic feeding/onc ogenicity study in the rat, a NOAEL of 100 ppm (5 mg/kg) was based on body weight and bl ood chemistry. The MTD was 2,500 ppm based on reduction in body weight gain and no eviden ce of oncogenicity was seen. Based on the available chronic toxicity data, Syngenta believes the Reference dose (RfD) for propiconazole is 0.0125 mg/kg/day. This RfD is based on a 1 year feeding study in dogs with a NOAEL of 1.25 mg/kg/day (50 ppm) and an uncertainly factor of 100. No additional modifying factor for the nature of effects was judged to be necessa ry as stomach mucous hyperemia was the most

sensitive indicator of to xicity in that study.

Using the Guidelines for Carcinogenic Risk Assessment published on September 24, 1986 (51 FR 33992), the USEPA has classified propiconazole in group C for carcinogenicity (evidence of possible carcinogenicity for humans). The comp ound was tested in 24 month studies with both rats and mice. The only evidence of carcinogenicity was an increase in liver tumor incidence in male mice at a dose level that exceeded the maximum tolerated dose (MTD). Dosage levels in the rat study were appropriate for identifying a cancer risk. The Cancer Peer Review Committee recommended the RfD approach for quant itation of human risk. Therefore, the RfD is deemed protective of all chronic hu man health effects, including cancer.

6. Animal metabolism. Metabolism in animals is similar to plant metabolism. In animals both the rat and the goat rapidly metabolize and excr ete propiconazole. Neither animal retains significant amounts of propiconazole or its metabolites in tissu es. Significant quantities of parent or metabolites do not appear in goat’s milk. Similar metabolites are produced by both species, and unconjugated (phase I) metabolite s are similar in plants and animals. The metabolism profile supports the use of an an alytical enforcement method that accounts for combined residues of propiconazole and its metabolites that contai n the 2,4-dichlo robenzoic acid (DCBA) moiety.

7. Metabolite toxicology

. There are no metabolites of c oncerned based on a differential metabolism between plants and animals.

8. Endocrine disruption

. Developmental toxicity studies in rats and rabbits and reproduction studies in rats gave no indicat ion that propiconazole might have any effects on endocrine function related to development and reproduction. The subchronic and chronic studies also showed no evidence of a long–term effect related to the endocrine system. Further, due to the moderate rate of degradation of the product, th ere is no risk that propiconazole may accumulate in the environment. In animals, propiconazo le is quickly excreted and has no tendency for accumulation in the body. Based on these results, it is very likely that propiconazole has no potential to interfere specifical ly with the endocrine system.

C. Aggregate Exposure

1. Dietary exposure. Tier I acute, short-term, and chronic aggregate exposure assessments were performed for propiconazole using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-F CIDTM, version 2.16) from Exponent. Propiconazole is currently regist ered for use on alfalfa (indirect), avocado (Section 18), bananas,barley, berries (Crop Groups 13-07A, 13-07B, and 13-07G), carrots, cilantro, corn (field, sweet, and popcorn), cranberries (regional) , garden beets, grasses, leaf petioles (Crop Subgroup 4B), mushrooms, nectarines and peaches (Section 18, expires 31-Dec-2013), oa ts, onions (bulb and green), parsley, peanuts, peppermint, pineapples (seed piece treatment), pistachios, rice, rye, sorghum, soybeans, spearmint, stone fruits (Cr op Group 12), strawberries, sugar beets, tree nuts (Crop Group 14), wheat, wild rice (regional), and tu rf and ornamental uses. A revised use on mint (7-day PHI) and revised use patterns for Propi-ShieldTM brand pain t and stain additive products are pending. Proposed new IR-4 uses include succulent and dried legumes (Crop Group 6) and post-harvest applic ations to citrus fruit (Cr op Group 10-10), stone fruit (Crop Group 12), and tomatoes (Crop subgroup 8–10A). Existing (40CFR180.434) or estimated tolerances were used for all commodities. No adjustments were made for “percent crop treated,” i.e., 100%CT was assumed. DEEMTM (v ersion 7.87) default processing factors were used for all processed commodities except citrus oil (185X), orange juice (0.011X), pineapple juice (0.11X), and pineapple proces s residue (1.49X). Anticipated residues in milk (0.12 ppm) were calculated by constructing a theoretical “maximum reasonably balanced diet” (MRBD) livestock diet using the J une 2008 revisions to the OPPT S 860.1000 Table 1 feedstuffs;

established tolerances were used for meat, liver, fat, and kidney. Drinking water estimates were selected using the higher of the estimated dri nking water concentrations (EDWCs) for surface and ground water. All consumption data for th ese assessments were ta ken from the USDA’s Continuing Survey of Food Intake by indi viduals (CSFII) with the 1994-1996 consumption database and the Supplemental CSFII children’s survey (1998) consumption database.

i. Food

. The acute dietary (food only) risk asse ssment was performed for all population subgroups with an acute reference dose of 0.3 mg/kg-bw/day based on an acute no observable adverse effect level (NOAEL) of 30 mg/kg-bw/day from an acute neurotoxicity study in rats and an uncertainly factor of 100X. The 100X safety factor includ ed intra- and inter-species variations. No additional FQPA safety factor was applied. For the purpose of the aggregate risk assessment, the exposure value was expresse d in terms of margin of exposure (MOE), which was calculated by dividing the NOAEL by the exposure for each population subgroup. In addition, exposure was expressed as a percent of the acute refere nce dose (%aRfD). At the 95th percentile, acute exposure to the U.S. population re sulted in a MOE of 654 or 15.3% of the aRfD (Benchmark = 100; aRfD = 0.3 mg/kg-bw/day). Acute exposure to the most sensitive subpopulation (children 1-2 years old) resulte d in a MOE of 271 or 36.8% of the aRfD (Benchmark = 100; aRfD = 0.3 mg/kg-bw/day). Since the Benchmark MOE for this assessment is 100 and since EPA generally has no concern for exposures above the benchmark or below 100% of the reference dose, Syngenta believes that there is a reasonable certainty that no harm will result from acute dietary (food) exposure to residues arising from all current, pending, and proposed uses for propiconazole.

Chronic Food Risk: The chronic dietary (food only) ri sk assessment was performed for all population subgroups with a chronic reference do se of 0.1 mg/kg-bw/day based on a 24-month oncogenicity study in mice with a NOAEL of 10 mg /kg-bw/day and an uncertainly factor of 100X. The 100X safety factor included intra- an d interspecies variations. No additional FQPA safety factor was applied. For the purpose of th e aggregate risk assessment, the exposure values were expressed in terms of margin of expos ure (MOE), which was calculated by dividing the NOAEL by the exposure for each population subgroup. In addition, exposure was expressed asa percent of the chronic reference dose (%cRf D). Chronic exposure to the U.S. population

resulted in a MOE of 699 or 14.3% of the cRfD (Benchmark = 100; cRfD = 0.1 mg/kg-bw/day). Chronic exposure to the most exposed sub-populati on (children 1-2 years old) resulted in a MOE of 261 or 38.3% of the cRfD (Benchmark = 100; cRfD = 0.1 mg/kg-bw/day). Since the

Benchmark MOE for this assessment is 100 a nd since EPA generally has no concern for exposures above the benchmark or below 100% of the reference dose, Syngenta believes that there is a reasonable certainty that no harm w ill result from chronic dietary (food) exposure to residues arising from all current, pending, and proposed uses for propiconazole.

Cancer Risk: A quantitative risk assessment using a cancer endpoint was not performed. The chronic risk assessment is adequately protective fo r cancer risk as well as other chronic effects.

ii. Drinking Water

. The Estimated Drinking Water Concen trations (EDWCs) of propiconazole were determined using Tier l SCI-GROW (versi on 2.3) which estimates pesticide concentration in ground water and Tier II PRZM/EXAMS (PE version 5.0) which estimates pesticide

concentration in surface water. This drinki ng water assessment was conducted to assess all currently registered uses, the pe nding change to the us e pattern for mint, and the proposed use on legume vegetables (succulent and dried) as well as proposed post-harvest uses on citrus, stone fruit, and tomatoes. The post-harvest uses have no impact on drinking water because post-harvest treatment is an indoor use pos ing negligible impact to drinking water concentrations. For groundwater, the currently registered use on turf provided the highest EDWC of 0.725 ppb (acute and chronic). For surf ace water, the currently registered use on turf provided an acute EDWC of 101.826 ppb and a chronic EDWC of 52.438 ppb. No Percent Cropped Area (PCA) adjustments were made for surface water EDWCs. Since the surface water EDWCs exceed the ground water EDWC, the surface water values were used for risk assessment purposes and will be considered protect ive for any ground water exposure concerns.

Acute Exposure from Drinking Water

. The acute surface water EDWC of 101.826 ppb was input directly into the DEEM-FCIDTM software as “water, direct and i ndirect, all sources” to model the acute drinking water e xposures. Exposure contributions at the 95%-ile of exposures were determined by taking the difference be tween the aggregate (food + drinking water) exposures and the food (alone) exposures fo r each population subgroup. Acute drinking water exposure U.S. population resulted in a MOE of 3,654 (0.8% of the aRfD of 0.30 mg/kg-bw/day). The most exposed sub-population was all infants (<1 year old) with a MOE of 2,363 (1.3% of the aRfD of 0.30 mg/kg/day). Since the benchm ark MOE for this assessment was 100 and since EPA generally has no concern for exposures be low 100% of the aRfD, Syngenta believes that there is a reasonable certainty that no harm w ill result from acute drinking water exposure to residues arising from all current, pendi ng, and proposed uses for propiconazole.

Chronic Exposure from Drinking Water

. The chronic surface water EDWC of 52.438 ppb was input directly into the DEEM-FCIDTM software as “water, direct and indi rect, all sources” to model the chronic drinking water exposures. Chronic drinking water exposure to the U.S. population resulted in a MOE of 9,048 (1.1% of the cRfD of 0.10 mg/kg-bw/day). Chronic drinking water exposure to the most exposed sub- population (infants, <1 y ear old) resulted in a MOE of 2,760 (3.6% of the cRfD of 0.10 mg/kg-bw/day). Sinc e the Benchmark MOE for this assessment was 100 and since EPA generally has no concern for exposures below 100% of thecRfD, Syngenta believes that there is a reasonable certainty that no harm will result from chronic drinking water exposure to resi dues arising from all current, pending, and proposed uses for propiconazole.

2. Non-dietary exposure

. Short-term exposure assessments were conducted to assess exposures resulting from non-dietary uses of propiconazole arising from registered turf and ornamental uses and from Propi-ShieldTM bra nd paint and stain additive produc ts containing propiconazole.

Adult turf and ornamental handl er scenarios assessed included lo w-pressure hand wand sprayer, garden hose-end sprayer, granular push spreader , hand held belly grinder spreader, and spreading granular formulation by hand. Adult and youth post-application exposure scenarios included high contact activities (lawns) and golf. For child ren, re-entry to treated turfgrass areas resulted in dermal and non-dietary oral exposures via hand-to-mouth, object-to-m outh, and ingestion of treated soil. A dermal absorption value of 40% was used to calculate exposure for turf and ornamental uses. For Propi-ShieldTM brand pain t additive products, adult applicator scenarios assessed included paintbrush and ro ller applications of in-can treated paint and stain, airless sprayer application of in-can treated paint and stain, and lo w-pressure hand wand sprayer application of wood preservati ve stains. Dermal absorption values of 1.0% and 26.6% for consumers applying paint or stai n, respectively, were taken from a recent EPA assessment (DP# D364956, Nov. 2009). For all turf and ornamental scenarios assessed, the worst-case combined short-term MOE was 181 (Benchmark = 100) for ch ildren 1-6 years old for combined dermal and non-dietary oral exposures resulting from post-application exposures to propiconazole treated turfgrass. Post-applic ation exposure to ornamental plants is negligible; and was, therefore, not assessed. For all paint and st ain scenarios assessed, the worst-case combined short-term MOE was 160 (Benchmark = 100) for all adults 20+ years old a pplying in-can treated stain with an airless sprayer. Exposure risks were also asse ssed for children’s accidental ingestion of lawn granules (MOE = 331) and paint chips (MOE = 4,500) containing propiconazole and were found to be acceptable (B enchmark MOE = 100); the ingestion of lawn granules and paint chips by children is considered to be episodic in nature and is not aggregated with dietary or other residentia l exposures. Since the Benchmark MOE for this assessment was 100 and since the EPA generally has no concern for exposures above the benchmark, Syngenta

believes that there is a reasonabl e certainty that no harm will re sult from short-term non-dietary exposures arising from all current, pendi ng, and proposed uses for propiconazole.

D. Cumulative Effects

Cumulative Exposure to Substances with a Common Mechanism of Toxicity. Section 408(b)(2)(D)(v) requires that, when considering whether to esta blish, modify, or revoke a tolerance, the Agency consider “available info rmation” concerning the cumulative effects of a particular pesticide’s residues and “other s ubstances that have a common mechanism of toxicity”. Propiconazole is a member of the triazole-containing class of pesticides. Although conazoles act similarly in plan ts (fungi) by inhibiting ergostero l biosynthesis, there is not necessarily a relationship between this pesticidal activity and th eir mechanism of toxicity in

mammals. Structural similarities do not constitu te a common mechanism of toxicity. There is currently no evidence to indicate that conazoles share common m echanisms of toxicity and the EPA is not following a cumulative risk approach based on a common mechanism of toxicity for

the conazoles.E. Safety Determination

1. U.S. population. Using the conservative a ssumptions described above, and based on the completeness and reliability of the toxicity data , the acute aggregate (food plus water) exposure calculation for all current, pe nding, and proposed uses of propi conazole provided a MOE of 621 for the U.S. population. For short-term exposur es, chronic dietary (food and water) exposures were aggregated with residential exposures, resu lting in a worst-case short-term aggregate MOE of 148 for the U.S. population. The chronic a ggregate exposure analysis (food and water) showed that exposures from all current, pending, and proposed propi conazole uses resulted in a MOE of 649 for the U.S. population. Since th e worst case aggregate MOE of 148 (short-term risk) exceeds the Benchmark MOE of 100, Syngenta believes that there is a reasonable certainty that no harm will occur to the U.S. population from aggregate exposures arising from all current, pending, and proposed uses for propiconazole.

2. Infants and children

. Using the conservative assumptions described above, and based on the completeness and reliability of the toxicity data , the acute aggregate (food plus water) exposure calculation for all current, pe nding, and proposed uses of propi conazole provided a MOE of 265 for children 1-2 years old. For short-term exposures, chronic dietary (food and water) exposures were aggregated with residential expo sures resulting in a short-term aggregate MOE of 149 for children 1-6 years old. The chroni c aggregate exposure analysis (food and water) showed that exposures from all current, pending, and proposed propi conazole uses resulted in a MOE of 250 for children 1-2 years old. Since th e worst case aggregate MOE of 149 (short-term risk) exceeds the Benchmark MOE of 100, Syngenta believes that there is a reasonable certainty

that no harm will occur to infants and children fro m aggregate exposures arising from all current, pending, and proposed uses for propiconazole.

F. International Tolerances

The Codex Alimentarius Commission has estab lished several maximum residue limits (MRLs) for propiconazole in or on various raw agri cultural commodities. The Codex MRLs are expressed in terms of propiconazole per se . In addition, both Canada and Mexico have

established MRLs/tolerances on several commodities which also have U.S. tolerances. The U.S. tolerance expression includes all metabolite s determined as 2,4-dichloro-benzoic acid. In conjunction with the reregistrati on process EPA intends to revise the tolerance expression to propiconazole per se . To the extent possible, for the pr esent petitions, U.S. tolerances have been numerically harmonized with Codex, Cana dian and Mexican MRLs; however, differences in use patterns and the supporti ng residue data have preclude d reducing many tolerances. A summary of Codex MRLs, Canadian MRLs and Me xican tolerances and the corresponding U.S. tolerances for propiconazole is disc usses at www.regulations.gov Docket No. EPA-HQ-OPP-2006-0347-0004; pages 53-54