Metcon azole Tolerance Petition, September 20 , 2013

Page 1 of 9 Interregional Research Project Number 4 (IR - 4) Valent U.S.A. Corporation Pesticide Petition, PP# 4E8244 EPA has received a pesticide petition , 4E8244 , from Interregional Research Project Number 4 (IR- 4), IR- 4 Project Headquarters, Rutgers, The State University o f New Jersey, 500 College Road East, Suite 201 W, Princeton, NJ 0 8450 , proposing, pursuant to section 408(d) of the Federal F ood, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.617 by establishing tolerances for residues of metconazole, 5 - [(4 - chlorophenyl) - methyl] - 2, 2 - dimethyl - 1 - (1H - 1,2,4 - triazol - 1 - ylmethyl) cyclopentanol, measured as the sum of cis - and trans - isomers in or on the following raw agricultural commodities: Fruit, stone, group 12 - 12 at 0.2 parts per million (ppm) ; Nut, tree, group 14 - 12 at 0.04 ppm ; Pea and bean, dried shelled, except soy bean, subgroup 6C at 0.15 ppm; Rapeseed subgroup 20A at 0.0 8 ppm ; and Sunflower subgroup 20B at 0.9 ppm . Upon establishment of the above tolerances, the petition additionally requests to amend 40 CFR part 180.617 by deleting the tolerances for residues tolerances of metconazole, 5 - [(4 - chlorophenyl ) - methyl ] - 2,2 - dimethyl - 1 - (1H - 1,2,4 - triazol - 1 - ylmethyl)cyclopentanol, measured as the sum of cis - and trans - isomers in or on the commodities : C anola seed at 0.04 ppm; Fruit, s tone, group 12 at 0.2 ppm; Pistachio at 0.04 ppm; and Nut , Tree, Group 14 at 0.04 ppm. These previousl y established tolerances will be superseded by

inclusion in crop group or subgroup tolerances established by this action. EPA has determined that the petitions contain data or information regarding the elements set forth in section 408(d)(2) of the FFDCA; however, EPA has not fully evaluated the sufficiency

of the submitted data at this time or whether the data supports granting of the petitions. Additional data may be needed before EPA rules on the petitions. A. Residue Chemistry 1. Plant metabolism . The metabolism of Metconazole is adequately understood for the purpose of granting the proposed tolerances. N ature of the residue studies (OPPTS Harmonized Guideline 860.1300) were conducted in wheat, canola, banana, peas, and mandarin oranges as representative crops in order to characterize the fate of metconazole in all crop matrices. Two radiocarbon labeling positions were studied in each crop. In all crops triazole ring labeling was used, and the other label was positioned either in the p - chlorophenyl or the cyclopentylrings. In all five crops the metconazole, Residue of Concern was identified as parent metconazole. 2. Analytical method. Independentl y validated anal ytical methods have been submitted for analyzing parent metconazole residues with appropriate sensitivity f orMetcon azole Tolerance Petition, September 20 , 2013

Page 2 of 9 crops and processed commodities for which a tolerance is being requested. 3. Magnitude of residues . Field trials were carried out with dry bean, dry pea and sunflower to determine the magnitude of the residue. A total of 13 trials representing NAFTA growing regions were conducted for dry bean. A total of 6 trials representing NAFTA growing regions were conducted for dry pea. A total of 11 trials representing NAFTA growing regions were conducted for sunflower. N o additional residue data is needed to support the updated crop groupings of stone fruit group (12 - 12) , tree nut group (14 - 12) and the expansion of canola to rapeseed subgroup 20A since the proposed tolerance levels remain the same as the established tol erances for stone fruits (CG12), tree nuts (CG14) and canola.Metcon azole Tolerance Petition, September 20 , 2013

Page 3 of 9 B. 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. 1. Acute Toxicity . Metconazole technical is considered to be slightly t oxic (Toxicity Category I II) to the rat by

the oral route of exposure. In an acute oral study in rats, the LD50 value of metconazole technical was 727 milligrams per kilogram of body w eight (mg/kg b.w.) for males and 595 mg/kg b.w. for females. The oral LD50 for combined sexes was 660 mg/kg b.w. Metconazole technical demonstrates no acute toxicity via the dermal route of exposure [LD50 value >2000 mg/kg (highest dose t ested)] (Toxicity Category I II) or inhalation route of exposure [L C50 >5.6 mg/L] (Toxicity C ategory IV). The material is mildly

irritating to the eye (Toxicity C ategory I II) and is not irritating to the skin (Toxicity

Category IV), nor is it a skin sensiti zer. 2. Genotoxicity . Both metconazole technical and WL 136184 technical (greater than 95% cis isomer) have been tested in an extensive battery o f in vitro and in vivo genotoxicity assays measuring several different endpoints of potential genotoxicity . C ollective results from these studies indicate that metconazole does not pose a genotoxic risk, and therefore, is not likely

to be a genotoxic carcinogen. 3. Reproductive and developmental toxicity . Several developmental toxicity s tudies in rats conducted with metconazole technical and WL1 36184 showed no evidence of teratogenic effects in fetuses, and no evidence of developmental toxicity in the absence of maternal toxicity . Thus, metconazole is neither a selective developmental toxicant nor a teratogen in the rat. Two rat developmental toxicity s tudies have been conducted with metconazole technical. Inthe first study, the no - observable - adverse - effect- level (NOAEL) for maternal toxicity was 12 mg/kg b.w./ day, based on decreased body weight gain at 30 mg/kg b.w./day, the next highest dose tested, and the NOAEL for developmental toxicity

was also 12 mg/kg b.w./day, based on decreased fetal body weights and an increased incidence of skeletal ossification variations at 30 mg/kg b.w./day . In the second study, the maternal and fetal NOAEL was 16 mg/kg/day based on findings similar to the first study at the next higher dose level of 65 mg/kg/day . In the rat developmental toxicity

s tudy c onducted with WL 136184 technical, the NOAEL for maternal toxicity

w as 24 mg/kg b.w./day b ased on decreased body weight gain at 60 mg/kg b.w./day, the highest dose tested, and the NOAEL for developmental toxicity w as also 24 mg/kg b.w./day, based on an increase in the total number of resorptions, reductions in fetal body weights and an increased incidence of skeletal ossification variations at 60 mg/kg b.w./day . Results from a developmental toxicity s tudy in rabbit’s metconazole technical also indicated no evidence of teratogenicity or developmental toxicity in the absence of mater nal toxicity . Thus, metconazole technical is neither a selective developmental toxicant nor a teratogen in the rabbit. Inthis rabbit developmental study, the NOAEL for maternal toxicity

was 20 mg/kg b.w./day

based on decreased food consumption and bodyMetcon azole Tolerance Petition, September 20 , 2013

Page 4 of 9 we ight gain, reductions in hemoglobin, hematocrit and corpuscular volume, increases in platelet counts and alkaline phosphatase activity, and increased absolute and relative liver weights at 40 mg/kg b.w./day (the highest dose tested). The NOAEL for developmental toxicity was also 20 mg/ kg b.w./day, based on an increase in the total number and mean number of resorptions and decreased fetal body weight at 40 mg/kg b.w./day. Two multi - generation reproduction studies were conducted with Metconazole Technical -

- one with the >95% cis form and one with the 85/15 cis/trans form. D ose levels and results in both studies were similar, although the 95% cis study diet was adjusted to maintain a constant dose. D ose levels in the >95% cis study were 0, 2, 8, 32 and 48 mg/kg/day

and in the 85/15 cis study were 0, 30, 150 and 750 ppm (approximately 0, 2.1, 10.6 and 52.8 mg/kg/day f or pre - mating growth period). F or the >95% cis study, the results support a NOAEL for parental toxicity of 8 mg/kg/day

based on increased ovarian weight and increased gestation length at the next highest dose tested (32 mg/kg/day). The NOAEL for growth and development of the offspring is also 8 mg/kg/day, based on reductions in live litter size for F2 litters at 32 mg/kg/day . The NOAEL for reproductive performance and fertility w as 48 mg/kg/day

(the highest dose tested). In the 85/15 cis/trans study, the NOAELi dentified for parental toxicity, offspring growth and development and reproductive toxicity was 10.8 mg/kg/day

( 150 ppm) based on eff ects observed at the highest dose tested of 52.8 mg/kg/day (750 ppm). Results of reproduction and developmental toxicity s tudies conducted with metconazole technical show no increased sensitivity to developing offspring as compared to parental animals. 4 . Subchronic toxicity . Subchronic (90 - day) dietary s tudies in rats were conducted with metconazole technical. In the study the NOAEL was 100 ppm (approximately 6.8 mg/kg b.w./day) based on hepatic fatty vacuolation in males at 300 ppm, the next highest c oncentration tested. In a 90 - day

dietary study in mice conducted with metconazole technical, the NOAEL was 30 ppm (approximately

5 .5 mg/kg b.w./day), based on increased aspartate and alanine aminotransferase activities in males, increased absolute and rel ative weights of the liver and spleen of females, and increased incidences of hepatocellular vacuolation and hy pertrophy for males and females at 300 ppm, the next highest concentration tested. Ina9 0 - day

dietary s tudy in beagle dogs with metconazole te chnical the NOAEL was 60 ppm (approximately

2 .5 mg/kg b.w./day) based on decreased body w eight gain and food consumption for females, and a slight increase in reticulocy te count for males at 600 ppm, the next highest concentration tested. 5. Chronic toxicity . F indings similar to those observed in the short- term and subchronic studies were apparent in the long - term dietary toxicity studies conducted in rats, dogs and mice. In a chronic toxicity

s tudy, long - term (104 - weeks) administration of metconazole technical to rats supported a NOAEL for systemic toxicity o f 100 ppm (approximatelyMetcon azole Tolerance Petition, September 20 , 2013

Page 5 of 9 4.8 mg/kg b.w./day), based on increased adjusted liver weight, clinical chemistry changes, and increased incidences of hepatocellular lipid vacuolation and centrilobular hy pertrophy at interim sacrifice for males at 300 ppm, the next highest concentration tested. Ina 1 04 - week carcinogenicity s tudy in rats fed diets containing 0, 100, 300 or 1000 ppm metconazole technical, the NOAEL for carcinogenicity was 1000 ppm (50 mg/kg/day) the highest dose tested. The NOAELf or chronic systemic toxicity was 100 ppm (5.6 mg/kg/day) based on increased incidences of centrilobular hy pertrophy and pigment disposition in the liver and increased incidences of cortical vacuolation in the adrenal at 300 ppm. In a one - ye ar dietary

s tudy in beagle dogs, the NOAEL was 300 ppm (approximately 11.1 mg/ kg b.w./day), based on decreased body weight gain for males during weeks 1 to 13 and increased alkaline phosphatase activity f or males and females at 1,000 ppm, the next highest concentration tested. A 91 -week carcinogenicity s tudy in mice with metconazole technical supports a NOAEL for non -neoplastic effects of 30 ppm (approximately 4 .8 mg/kg b.w./ day), based on increased white blood cell count f or males, increased aspartate and alanine aminotransferase activities and increased absolute and adjusted liver weight for females, and microscopic changes in the liver, spleen and adrenal gland for males and females at 300 ppm (the next highest concentration tested). The NOAEL for carcinogenicity w as 300 ppm (approximately 4 8.3 mg/kg b.w./day) based on increased incidences of hepatocellular adenomas in males and females and hepatocellular carcinomas in females at 1,000 ppm, the highest concentration tested . The increased incidences of hepatic adenomas and carcinomas at the highest concentration tested are considered to occur through promotional and non - genotoxic secondary mechanisms following toxicity and induction of mixed function oxidase in mice. Consequently, metconazole is not likely to be oncogenic in humans at the low levels of exposure that will result from its use as a fungicide. 6. Animal metabolism . The rat metabolism studies show that the qualitative nature of the fate of metconazole in animals is adequatel y understood. In studies conducted with radiolabeled metconazole (85:15 isomer mixture) or radiolabeled WL1 36184 radioactivity

w as rapidly eliminated in urine and feces within 48 hours of dosing. Biliary excretion was shown to be a prominent route of elimination. At both high and low doses of metconazole, male rats generally excreted lower amounts of radioactivity in the urine, and greater amounts of radioactivity in the feces as compared to females. The pattern of metabolites detected in males and females was similar at high and low doses, and little or no parent compound was found in either feces or urine. Five days following oral dosing of metconazole at the highest dose, low levels of radioactivity were detected in the majority o f tissues anal yzed; however higher concentrations of radioactivity were found in the adrenal gl ands, gastro - intestinal tract and liver. A comparison of radioactivity levels in the adrenal glands following oral administration of low and high doses indicates that uptake in the adrenal may b e saturable. No differences in tissue levels were noted between males and females.Metcon azole Tolerance Petition, September 20 , 2013

Page 6 of 9 7. Metabolite toxicology . The metabolism of metconazole is similar in plants and mammals with extensive hydroxylation being the predominate reactions. Due to the similar structural nature of most metabolites, the toxicity o f the plant metabolites is adequatel y estimated from the results of studies performed with the technical in various animals. EPA concern for unique plant metabolites common to most tri azole fungicides has been addressed with research conducted b y the U.S. Triazole Task Force. 8. Endocrine disruption The toxicology database for metconazole technical is current and complete. This includes a thorough evaluation of the potential effects o n reproduction and development, and the pathology o f the endocrine organs following short- term and long - term exposures. The battery o f tests included as part of this petition fully characterizes potential endocrine -related in vivo effects, clearly defines NOAEL/L OAEL values, and indicates no increased sensitivity to developing offspring. C. Aggregate Exposure 1. Dietary exposure and risk Food : Dietary

e xposure estimates were based on established tolerance values, default processing factors with the exception of a determined process factor for sugar beet molasses, and 100% of all crops treated. The consumption data was from the USDA Continuing Survey

of Food Intake by

Individuals (CSFII 1994 - 1996, 1998). Residues (proposed tolerances) from use of Metconazole on Dried Shelled Pea and Bean (Except Soy

bean), Subgroup 6C and Sunflower Subgroup 20B were not included in the assessment because the contribution to the overall aggregate exposure is considered negligible. These minor crop residues will be included in the aggregate exposure assessment at a later date. The additional exposure resulting from the crop expansion of stone fruit group (CG 12 - 12), tree nut group (CG 14 - 12) and rapeseed subgroup 20A is anticipated to be negligible as well. Drinking water: The Agency used screening level water exposure models in the dietary exposure anal ys is and risk assessment for metconazole in drinking water. These simulation models take into account data on the physical, chemical, and fate/transport characteristics of metconazole. Based on the Pesticide Root Zone Model/Exposure Analysis Modeling S ys tem (PRZM/EXAMS) and Screening Concentration in Ground Water (SCI- GROW) models, the estimated environmental concentrations (EECs) of metconazo le for acute exposures are estimated to be 45 .48 parts per billion (ppb) for surface water and 0.38 ppb for ground water. The EECs for chronic exposures for non cancer assessments are estimated to be 38.16 ppb for surface water and 0.38 ppb for ground water. Exposure assessments have been conducted to evaluate the potential risk due to acute and chronic dietary

exposure of the U.S. population and various subgroups to residue of metconazole. The latest assessment included all the existing tolerance values for canola, soy bean, sugar beet, barley, wheat, oats, rye, triticale, cotton, corn (field, pop, sweet)Metcon azole Tolerance Petition, September 20 , 2013

Page 7 of 9 stone fruit (crop group 12), tree nuts (crop group 14), tuberous and corm v egetables ( subgroup 1C ), bushberries subgroup (13 - 07B ), sugarcane, peanuts, bananas, milk, meat, and eggs. a. Acute Dietary Exposure The acute dietary

exposure from food and water to the residues of metconazole, including its metabolites and degradates, occupies 3.8 % of the aPAD for the population group (females 13 - 49 years old) receiving the greatest exposure. The estimated exposure is well below the Agency's level of concern

b. Chronic Dietary Exposure The chronic dietary

exposure to the residues of metconazole, including its metabolites and degradates, from food and water will utilize 12 .6 % of the cPAD for the most highly exposed population group (children 1 - 2 years old). The estimated exposure is well below the Agency's level of concern. 2. Non - dietary exposure and risk. Metconazole use is registered on residential and recreational turf. The following post- application exposure scenarios were evaluated: 1) adults and toddler (< 1 year old) post- application dermal exposure; 2) toddlers’ incidental ingestion of pesticide residues on lawns from hand- to - mouth transfer; 3) toddlers’ objectto - mouth transfer from mouthing pesticide - treated turf grass; and 4) toddlers’ incidental ingestion of soil from pesticide - treated residential areas. The post- application exposure assessment was based on generic assumpti ons specified in the Recommended Revisions to the Residential Standard Operating Procedures and recommended approaches by an EPA science advisory

c ouncil. A dermal absorption value of 3 % was used in the assessment of metconazole. The amount of metconazole available for transfer following the application of metconazole at the rate of 0.6 lb ai/A was determined from turf transferable residue studies conducted by V alent U.S.A Corporation (MRID No. 468051 - 07, 468051 - 08). The regression equations provided in the reports were used to determine the turf dislodgeable foliar residue, 0.044 μg/cm2 , present immediately after the spray treatment has dried (Time 0). The exposure and risk estimates for the residential exposure scenarios are assessed for the day o f appli cation because adults and toddlers could contact treated turf immediately after application. All short-/intermediate - term MOE were greater than 100 which indicates that exposure from all residential scenarios result in exposures well below a level of concern. 3. Short- term risk. Short- term risk takes into account residential exposure plus chronic exposure to food and water (considered to be a back ground exposure level). Metconazole is currentl y registered for uses that could result in short- term residential exposure and the Agency has determined that it is appropriate to aggregate chronic food, water, and short-Metcon azole Tolerance Petition, September 20 , 2013

Page 8 of 9 term exposures for the residues of metconazole, including its metabolites and degradates. EPA has concluded that short- term aggregate MOE from dietary exposure (food + drinking water) and non- occupational/ residential handler exposure (inhalation) for adults is 1700 . The short- term aggregate MOE from dietary exposure (food + drinking water) and non- occupational/residential exposure (incidental oral) for children 1 - 2 years old is 420 . These MOEs are not of concern to the Agency since they

are greater than the LOC of 100.

. 4. Intermediate- term risk. Intermediate - term risk takes into account residential exposure plus chronic exposure to food and water (considered to be a background exposure level). Metconazole is currently

registered for uses that could result in intermediate - term residential exposure and the Agency has determined that it is appropriate to aggregate chronic food, water, and intermedi ate - term exposures for the residues of metconazole, including its metabolites and degradates. EPA has concluded that intermediate - term aggregate MOEs from dietary exposure (food + drinking water) and non occupational/residential handler exposure (inhalation) for adults is 1700 . . The intermediate - term aggregate MOE from dietary exposure (food + drinking water) and non - occupational/residential exposure (incidental oral) for children 1 - 2 years old is 460 . These MOEs are not of concern to the Agency since the y are greater than the LOC of 100. 5. Aggregate cancer risk for U.S. population . Metconazole is classified as ``not likel y to be carcinogenic to humans'' at levels that do not cause mitogenesis. The cPAD is protective of mitogenesis and because the chronic risk assessment for metconazole shows exposure to be below the cPAD, there is no cancer concern. D. Cumulative Effects Metconazole is a member of the triazole - containing class of pesticides. In Oct 2008, the HED issued an updated dietary exposure and risk anal ys is for the common triazole metabolites 1,2,4 - triazole (T), triazolylalanine (TA), triazolylacetic acid (TAA), and triazolylpy

ruvic acid (TP). The assessment covers the new uses of the triazole - derivative fungicides metconazole (canola, corn, cotton, and sugarcane; PP#s 7F7221, 7F7292, 08FL03), propiconazole (beets, parsley, and pineapple; PP# 7F7300), prothioconazole (wheat, barley ; PP# 7F7279), and tetraconazole (grapes; PP# 7E7273). Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model DEEM - FCIDTM, Version 2.03 which use food consumption data from the U.S. Department of Agriculture’s Continuing Surveys of Food Intakes by

Individuals (CSFII) from 1994 - 1996 and 1998. Four assessments were conducted: acute and chronic durations for T, and acute and chronic durations for combined residues of TA, TAA, and TP. Residue chemistry databases for most of the subject- listed parent compounds do not include re sidue measurements for the triazole metabolites; therefore, metabolite residues have been estimated based on metabolism studies and parent compound tolerances. As with the previous triazole metabolite assessments, this assessment includes exposure estimate s resulting from direct consumption of T, TA, TAA, and/or TP as well as indirect exposure resulting fromMetcon azole Tolerance Petition, September 20 , 2013

Page 9 of 9 consumption of parent fungicides followed b y in vivo conversion to the metabolites. For each food form in the acute assessment, the residue used is the maximum estimate from the various food/triazole fungicide combinations combined with the average indirect residue estimate. For the chronic assessments, the residue estimates are the average residue from the food- specific food/triazole combinations combined with the average indirect residue estimates. All four assessments assume 100% crop treated and include conservative estimates for residues of the metabolites in drinking water. The resulting exposure and risk estimates are based on health-protective assumptions and should be characterized as conservative. For all four analys es, risk estimates are below HED’s level of concern for all population subgroups. E. Safety Determination Based on the above risk assessment, IR - 4 concludes that there is a reasonable certainty that no harm will result to the general population or to infants and children from the aggregate exposure to metconazole from the proposed use s on dried shelled pea and b ean (except soy

bean), subgroup 6C , sunflower subgroup 20B and the updated crop groupings of stone fruit group (12 - 12) and tree nut group (14 - 12) and rapeseed subgroup 20A F. International Tolerances There are no CODEX maximum residue levels established or proposed for residues of metconazole.