FILE NAME: company.wpt (1/1/2005) (xml)

Template Number P25 Sugarcane Section 3

- metaconazole 

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COMPANY FEDERAL REGISTER DO CUMENT SUBMISSION TEMPLATE (1/1/2005) EPA Registration Division contact: [insert name and telephone number with area code]

INSTRUCTIONS: Please utilize this outline in preparing tolerance petition documents. In cases where the outline element does not apply please insert “NA-Remove” and maintain the outline. The comment notes that appear on the left margin represent hidden typesetting codes designed to expedite the processing of the Federal Register document. Please do not remove or alter these co mment notes or change the margins, font, or format in your document. Simply replace the instructions that appear in italics and brackets, i.e., “[insert company name],” with the information specific to your action. TEMPLATE: [BASF Corporation] [Insert petition number]

EPA has received a pesticide petition [insert petition number] from [BASF Corporation] , [26 Davis Drive, P.O. Box 13528, Research Triangle Park, NC 27709-3528] proposing, 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 [ 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 raw agricultural commodities [ Sugarcane, cane at 0.06 parts per million (ppm), Sugarcane, molasses at 0.08 ppm] .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

. [Nature 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 cyclopentyl rings. In all five crops the metconazole Residues of Concern (ROC) were characterized as parent metconazole. A confined rotational crop study also determined that parent metconazole was the residue of concern in the representative crops of wheat, radish, and lettuce/spinach . ]

2. Analytical method

. [Independently validated analytical methods have been submitted for analyzing parent metconazole residues with appropriate sensitivity in the raw crop and processed commodities for sugarcane for which tolerances are being requested. ] 3. Magnitude of residues . [Field trials were carried out to determine the magnitude of the residue in/on sugarcane. The number and locations of field trials are in accordance with OPPTS Guideline 860.1500. Field trials were carried out using the maximum label rates, the maximum number of applications, and the minimum pre-harvest intervals (PHI) for the crop. Detected residues of metconazole in all the sugarcane crop commodities support the proposed tolerances. ] B. Toxicological Profile [A complete, valid and reliable database of mammalian and genetic toxicology studies supports the proposed tolerance for metconazole on sugarcane. Two geometric isomers of metconazole exist, with the fungicidal activity being associated primarily with the cis isomer. The technical material is a mixture of cis- and trans- isomers in an 85 to 15 ratio (85:15). T oxicology studies submitted in support of this petition were conducted on the metconazole technical material composed of either the 85:15 isomer mixture (AC 900768) or a more purified (greater than 95%) sample of the cis-isomer (WL 136184). ] 1. Acute Toxicity

. [AC 900768 technical is considered to be slightly toxic (Toxicity Category III) to the rat by the oral route of exposure. In an acute oral study in rats, the LD50 value of AC 900768 technical was 727 milligrams per kilogram of body weight (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. An oral LD50 study in rats conducted with WL 136184 technical also supports the classification of metconazole as slightly toxic by the oral route of exposure. The oral LD50 values of WL 136184 technical were 1,626 mg/kg b.w. for males and 1,312 mg/kg b.w. for females, with an LD 50 value for combined sexes of 1,459 mg/kg b.w.The 85:15 isomer mixture demonstrates no acute toxicity via the dermal route of exposure

[LD50 value >2000 mg/kg (highest dose tested)] (Toxicity Category III) or inhalation route of exposure [LC50 >5.6 mg/L] (Toxicity Category IV). The material is mildly irritating to the eye (Toxicity Category III) and is not irritating to the skin (Toxicity Category IV), nor is it a skin sensitizer.] 2. Genotoxicity

. [AC 900768 technical (the 85:15 isomer mixture) and WL 136184 technical (greater than 95% cis isomer) were tested in an extensive battery of in vitro and in vivo genotoxicity assays measuring several different endpoints of potential genotoxicity. Collective 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

. [Developmental toxicity studies in rats conducted with AC 900768 technical and WL 136184 technical 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 studies have been conducted with AC 900768 technical. In the first study, the no-obs ervable- 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 decreas ed 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 study conducted with WL 136184 technical, the NOAEL for maternal toxicity was 24 mg/kg b.w./day based on decreased body weight gain at 60 mg/kg b.w./day, the highest dose tested, and the NOAEL for developmental toxicity was 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 study in rabbits with the 85:15 isomer mixture also indicated no evidence of teratogenicity or developmental toxicity in the absence of maternal toxicity. Thus, metconazole technical is neither a selective developmental toxicant nor a teratogen in the rabbit. In this rabbit developmental study, the NOAEL for maternal toxicity was 20 mg/kg b.w./day based on decreased food consumption and body weight gain, reductions in hemoglobin, hematocrit and corpuscular volume, increases in platelet counts and alkaline phosph atase 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 resultsin 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 for pre-mating growth period). For 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 was 48 mg/kg/day (the highest dose tested). In the 85/15 cis/trans study, the NOAEL identified for parental toxicity, offspring growth and development and reproductive toxicity was 10.8 mg/kg/day (150 ppm) based on effects observed at the highest dose tested of 52.8 mg/kg/day (750 ppm).

Results of the pilot and definitive reproduction studies and developmental toxicity studies conducted with AC 900768 technical and/or WL 136184 technical show no increased sensitivity to developing offspring as compared to parental animals, as comparable NOAELs were obtained for parental toxicity and growth and development of offspring.] 4. Subchronic toxicity

. [Short-term (28-day) dietary toxicity studies in rats were conducted with AC 900768 and WL 136184 technical materials. In the 28-day study with AC 900768, the NOAEL was 100 ppm (approximately 9.6 mg/kg b.w./day), based on reductions in body weight, body weight gain, food consumption, and hemoglobin concentration for males, as well as increased absolute and relative liver weights, and increased incidences of hepatic fatty vacuolation and parenchymal hypertrophy for males and females at 1,000 ppm (the next highest concentration tested). Similar results were observed in the study conducted with WL 136184 technical. Based on these results, the NOAEL for WL 136184 is 300 ppm (approximately 28.5 mg/kg b.w./day), supported by decreased body weights and body weight gains and increased incidences of hepatic fatty vacuolation for males and females, increased absolute and adjusted liver weights for females, and decreased food consumption for males at 1,000 ppm(the next highest concentration tested). In a 28-day dietary study in dogs conducted with AC 900768 technical (85:15 isomer mixture), the NOAEL was a dietary concentration of 1,000 ppm (approximately 38.6 mg/kg b.w./day), based on decreased food consumption, body weight losses, increased alkaline phosphatase activity, increased spleen and liver weights, and urinalysis changes for males and females, and increased absolute and relative thyroid gland weights for females at 7,000 ppm, the highest concentration tested. Subchronic (90-day) dietary studies in rats were conducted with AC 900768 technical and WL 136184 technical. In the study conducted with AC 900768, 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 concentration tested. The NOAEL from the study conducted with WL 136184 technical was 450 ppm (approximately 30.9 mg/kg b.w./day) based on decreased food consumption, body weights, and body weight gains, clinical chemistrychanges, increased absolute and adjusted liver weights, and histopathological changes in

the liver and/or stomach for males and females, and decreased red blood cell parameters for females at 1,350 ppm, the highest concentration tested. In a 90-day dietary study in mice conducted with AC 900768, 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 relative weights of the liver and spleen of females, and increased incidences of hepatocellular vacuolation and hypertrophy for males and females at 300 ppm, the next highest concentration tested. A 90-day dietary study in beagle dogs with AC 900768 technical supports a NOAEL of 60 ppm (approximately 2. 5 mg/kg b.w./day) based on decreased body weight gain and food consumption for females, and a slight increase in reticulocyte count for males at 600 ppm, the next highest concentration tested. ] 5. Chronic toxicity

. [Findings similar to those observed in the short-term subchronic studies were also apparent in the long-term dietary toxicity studies conducted in rats, dogs and mice. In a chronic toxicity study, long-term (104 -weeks) administration of metconazole technical to rats supported a NOAEL for systemic toxicity of 100 ppm (approximately 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 hypertrophy at interim sacrifice for males at 300 ppm, the next highest concentration tested. In a 104-week carcinogenicity study 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 NOAEL for chronic systemic toxicity was 100 ppm (5.6 mg/kg/day) based on increased incidences of centrilobular hypertrophy and pigment disposition in the liver and increased incidences of cortical vacuolation in the adrenal at 300 ppm. In a one-year dietary study 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 for males and females at 1,000 ppm, the next highest concentration tested. A 91 -week carcinogenicity study in mice with AC 900768 supports a NOAEL for nonneoplastic effects of 30 ppm (approximately 4.8 mg/kg b.w./ day), based on increased white blood cell count for 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 was 300 ppm (approximately 48.3 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 concentrationtested. 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 insignificant levels of exposure resulting from its use as a fungicide. ] 6. Animal metabolism

. [The rat metabolism studies indicate that the qualitative nature of the residues of metconazole in animals is adequately understood. In studies conducted with radiolabeled AC 900768 (85:15 isomer mixture) or radiolabeled WL 136184 (greater than 95% cis isomer) radioactivity was 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 AC 900768, male rats generally excreted statistically significantly lower amounts of radioactivity in the urine, and greater amounts of radioactivity in the feces, compared to females. The pattern of metabolites detected was similar at high and low doses, and little or no parent compound was found in the feces or urine. Five days following oral dosing of AC 900768 at the higher level, low levels of radioactivity were detected in the majority of tissues analyzed; however higher concentrations of radioactivity were found in the adrenal glands, 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 be saturable. No differences in tissue levels were noted between males and females. ] 7. Metabolite toxicology

. [The metabolism of metconazole technical is similar in plants and mammals with extensive hydroxylation being the predominate reaction. Du e to the similar structural nature of most metabolites, the toxicity of the plant metabolites is adequately estimated from the results of studies performed in animals. EPA concern for several unique plant metabolites common to most triazole fungicides is being addressed with research conducted by the US Triazole Task Fo rce. On the basis of this research, an interim human health risk assessment for aggregate exposure to 1, 2, 4-triazole was published in the Federal Register (40 CFR Part 180, Vol. 69 No. 14 9 Page 47005, 8/4/04) and will be refined once the research is complete.] 8. Endocrine disruption

. [The toxicology database for metconazole technical is current and complete. This includes a thorough evaluation of the potential effects on reproduction and development, and the pathology of the endocrine organs following short-term and longterm exposure. The battery of tests included as part of this petition fully characterizes potential endocrine-related in vivo effects, clearly defines NOAEL/LOAEL valu es, and indicates no increased sensitivity to developing offspring.] C. Aggregate Exposure

1. Dietary exposure . [Exposure assessments were conducted to evaluate the potential risk due to acute and chronic dietary exposure to residues of metconazole. This fungicide considering both the cis and trans isomers, in or on raw agriculturalcommodities, was expressed as the parent compound. The analysis included all current

tolerances for metconzole (180.617) plus new proposed tolerances for sugarcane. ]

i. Food

. [Acute Dietary Exposure Assessment Acute dietary exposure estimates were based on current and proposed tolerance values, default process factors, and 100% of all crops treated. The consumption data was from the USDA Continuing Survey of Food Intake by Individuals (CSFII 1994 - 1996, 1998) and the EPA Food Commodity Ingredient Database (FCID) using Exponent's Dietary Exposure Evaluation Module (DEEM-FCID) software. The result exposure estimates were compared against the metconazole acute Population Adjusted Dose (aPAD) of 0. 12 mg/kg b.w./day for females 13 -49 years of age. This endpoint is based on the NOAEL of 1 2 mg/kg/day with an FQPA safety factor of 1 which was proposed by EPA in the most recent review of metconazole (“Metconazole. FQPA Human Health Risk Assessment for Proposed New Section 3 Uses on Corn and Cotton and Section 18 Use on Sugarcane” August 15, 2008). An acute dietary exposure assessment is not required for any other sub-population. The exposure assessment included residues f rom food commodities and drinking water. Metconazole acute dietary exposure from food and drinking water is 3.7 % aPAD for females 13 -49 years of age. The results of the acute dietary assessment are presented in Table 1.

Table 1. Results for Metconazole Acute Dietary Exposure Analysis Considering all

Current and Proposed Food Tolerances and Exposure from Drinking Water using DEEM-FCID at the 95 th Percentile Population Exposure Estimate %aPAD Subgroups (mg/kg b.w./day)* Females (13-49 years old) 0.00446 3.7 The results of the analysis show that for females 13 -49 years of age, the estimated exposure is well below the Agency's level of concern (< 100% aPAD). Additional refinements in the dietary risk assessment (i.e. utilizing anticipated residue values, percent crop treated values) would further reduce the estimated exposure values. Acute Aggregate Exposure and Risk (food and water) The aggregate acute risk includes residues of metconazole from food and drinking water (Table 1). Exposures from residential uses are not included in the acute aggregate assessment. The results demonstrate that there are no safety concerns for any subpopulation based on the proposed uses and the results clearly meet the FQPA standard of reasonable certainty of no harm.Chronic Dietary Exposure Assessment

Chronic dietary exposure estimates were based on current and proposed tolerance values, default process factors, and 100% crop treated values for all commodities. The consumption data was from the USDA Continuing Survey of Food Intake by Individuals (CSFII 1994 - 1996, 1998) and the EPA Food Commodity Ingredient Database (FCID) using Exponent's Dietary Exposure Evaluation Module (DEEM-FCID) software. The chronic Population Adjusted D ose (cPAD) used for U.S. population and all subpopulations is 0.043 mg/kg bw/day. This endpoint is based on the NOAEL value of 4.3 mg/kg/day with an FQPA safety factor of 1 which was proposed by EPA in the most recent review of metconazole (“Metconazole. FQPA Human Health Risk Assessment for Proposed New Section 3 Uses on Corn and Cotton and Section 18 Use on Sugarcane” August 15, 2008). The exposure assessment included residues from food commodities and drinking water. The most highly exposure population sub group was children 1 -2 years of age at 10.96% cPAD. The results of the chronic dietary assessment are presented in Table 2. Table 2. Results for Metconazole Chronic Dietary Exposure Analysis Considering all

Current and Proposed Food Tolerances and Drinking Water Exposure using DEEM-FCID Population Exposure Estimate %cPAD Subgroups (mg/kg b.w./day) U.S. Population 0.002227 5.2 All Infants (< 1 year old) 0.004257 9.9 Children (1 -2 years old) 0.004678 10.9 Children (3-5 years old) 0.004475 10.4 Children (6- 12 years old) 0 .003066 7.1 Youth (13- 19 years old) 0.0018 4.2 Females (13-49 years old) 0.001972 4.6 Adults (20-49 years old) 0.001672 3.9 Adults (50+ years old) 0.00169 3.9 The results of the analysis show that for all sub-populations, the exposures are below a level of concern (< 100% cPAD). Additional refinements in the chronic dietary risk assessment (i.e. utilizing anticipated residue values and percent crop treated values) would further reduce the estimated exposure values. Chronic Aggregate Exposure and Risk (food and water) The aggregate chronic risk includes residues of metconazole from food and drinking water (Table 2). Exposures from residential uses are not included in the chronic aggregate assessment. The results demonstrate there are no safety concerns for any subpopulationbased on the proposed uses and the results clearly meet the FQPA standard of reasonable

certainty of no harm. ]

ii. Drinking water. [The drinking water concentrations used in the assessment are from the most recent analysis by EPA. T he EPA acute drinking water value is 45.48 ug/L and the EPA chronic drinking water value is 31.25 ug/L. These water concentration were included in the dietary assessment conducted for metconazole (Tables 1 and 2). ]

2. Non

-dietary exposure . [HERE Metconazole is currently registered for use on residential and recreational turf. The US EPA has determined that the quantification of dermal exposure and risk is not required due to lack of systemic or dermal toxicity observed at the limit dose in the 21 -day dermal toxicity study in rat and the lack of target organ toxicity, neurotoxicity, developmental or reproductive toxicity (“Metconazole. FQPA Human Health Risk Assessment for Proposed New Section 3 Uses on Corn and Cotton and Section 18 Use on Sugarcane” August 15, 2008). The US EPA also stated in their recent assessment that post-application inhalation exposure is insignificant and does not need to be assessed. The only exposure which needs to be assessed is toddler post-application incidential oral exposure. The results shown in Table 3 are from the US EPA’s evaluation of toddler post-application incidental oral exposure. The exposure values in Table 3 are for the total incidental oral exposure including, hand-to-mouth, object-to-mouth, and soil ingestion. Table 3. Toddler Incidental Oral Post-Application Exposure and MOE values.

Population Total Exposure (mg/kg bw-day) MOE 1 Subgroup Short term Int. Term Short term Int. Term Children 1 -6 years old 0.0112 0.0064 810 995 1 Short Term NOAEL = 9.1 mg/kg bw-day, Intermediate Term NOAEL = 6.4 mg/kg bwday. MOE = NOAEL / total exposure. The MOE level of concern is 100. The MOE values for toddler incidental post-application oral exposure exceed the level of concern which indicates th at the total exposure is below the level of concern. Short-Term and Intermediate Term Aggregate Exposure. Short-term and intermediate term aggregate exposure includes exposure from food, drinking water, and residential exposure. The most highly dietary exposure children subgroup was children 1 -2 years old, therefore, this group was used in the aggregate assessment. The aggregate exposures for children 1 -2 years old are shown in Table 4. Table 4. S hort-Term and Intermediate-Term Aggregate Exposure for Children 1 -2 Years Old.Population Exposure Term Aggregate Exposure

(mg/kg bw-day Aggregate Exposure (mg/kgbwday) Aggregate

MOE 1 Food+ Drinking water Incidental

Oral Children 1

– 2 years old Short

– Term 0.004678 0.0112 0.01588 572

Int. - Term 0.004678 0.0064 0.01108 576 1 Short Term NOAEL = 9.1 mg/kg bw-day, Intermediate Term NOAEL = 6.4 mg/kg bwday. MOE = NOAEL / total exposure. The MOE level of concern is 100. The MOE values for aggregate exposure for children 1 -2 years old exceed the level of concern which indicates that the total exposure is below the level of concern. ] D. Cumulative Effects [Metconazole is a triazole fungicide. There are several triazole fungicides registered for use within the United States. Although metconazole and other triazole fungicides may have similar modes of action, no data are available to determine if these compounds have common mechanisms of mammalian toxicity or information on how to include metconazole in a cumulative risk assessment. Therefore, for the purposes of this tolerance petition no assumption has been made with regard to cumulative exposure with other compounds having a common mode of action. Further, triazole fungicides, including metconazole, have a common primary metabolite, 1,2,4-triazole, with secondary metabolites triazolylalanine and triazolacetic acid. EPA’s concern with these common metabolistes is being addressed with research conducted by the US Triazole Task Force. On the basis of this research, an interim human health risk assessment for aggregate exposure to 1, 2, 4-triazole was published in the Federal Register (40 CFR Part 180, Vol. 69 No. 149 Page 47005, 8/4/04) and will be refined once the research is complete.] E. Safety Determination

1. U.S. population

. [Based on this risk assessment, BASF concludes that there is a reasonable certainty that no harm will result to the general population from the aggregate exposure to metconazole from the pending and proposed uses.]

2. Infants and children

. [Based on this risk as sessment, BASF concludes that there is a reasonable certainty that no harm will result to infants or childeren from the aggregate exposure to metconazole from the pending and proposed uses.] F. International Tolerances [There are no CODEX maximum residue levels established or proposed for residues of metconazole in sugarcane. ]