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EPA REGISTRATION DIVISION CO MPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Divisi on contact: Susan Lewis

Monsanto Company

4F8339

EPA has received a pesticide petition (4F8339) from [Monsanto Company], [1300 I Street NW, Suite 450 East, Washington, D.C. 20005] requesting, pursuant to section 408(d) of the Federal Food, Drug, and Cosme tic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tole rance for residues of [tioxazafen (MON 102100): (3-phenyl-5-(2-thienyl )-1,2,4-oxadiazole) and its metabolite, benzamidine (benzenecarboximidamide)] in or on the following raw agricultural and processed commodities [Corn, field, forage] at [0.01] parts per million (ppm), [Corn, field, grain] at [0.01] ppm, [Corn, field, stover] at [0.02] ppm, [Cotton, gi n byproducts] at [0.02] ppm, [Cotton, undelinted seed] at [0.01] ppm, [Soyb ean, forage] at [0.15] ppm, [Soybean, hay] at [0.3] ppm, [Soybean, meal] at [0.05] ppm, [Soybean, seed] at [0.04] ppm; and in or on the following food commodities [Cattle, fat] at [0.01] ppm, [Cattle , meat] at [0.01] ppm, [Cattle, meat byproducts] at [0.01] ppm, [Goat, fa t] at [0.01] ppm, [Goat, meat] at [0.01] ppm, [Goat, meat byproducts] at [0.01] ppm, [Horse, fat] at [0.01] ppm, [Horse, meat] at [0.01] ppm, [Horse, meat byproduc ts] at [0.01] ppm, [Milk] at [ 0.01] ppm, [Sheep, fat] at [0.01] ppm, [Sheep, meat] at [0.01] ppm, and [Sheep, meat byproducts] 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 tim e or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. [Nature of the residue stud ies were conducted with tioxazafen applied as a seed treatment in corn, cotton, and soybean. Two radiolabeled forms of the parent molecule, [phenyl-U- 14 C] tioxazafen and [thiophene-2- 14 C] tioxazafen, were studied in each crop. Parent tioxazafen was a significant residue only in soybean forage and hay. Benzamidine was found in all three crops, and was the only identified metabolite found at or above appr oximately 10% of the TRR (total radioactive residues), and greater than or equal to 0.01 ppm, in any of the crop matrices. In a confined rotational crop study c onducted as a seed treatment on corn as a primary crop, residues were low in rotational crop commodities of lettuce, radish and wheat with no single metabolite residue exceeding 0.01 ppm. Small amounts of MON 102100 and benzamidine were observed in rotational crop matrices.2

Based on the results of these metabolism studies, the crop tolerance expression is proposed to be:

“The sum of tioxazafen (3-phenyl-5-(2-th ienyl)-1,2,4-oxadiazole) and its metabolite benzamidine (benzenecarboximidamide), expressed as tioxazafen.”]

2. Analytical method. [An independently validated analytical method has been submitted for the residue analysis of parent tioxazafen and its metabolite, benzamidine, in crop and processed commodities for corn, cotton, and soybean. Additionally, an independently validated method has been used in cattle and hen feeding studies for the analysis of residues in the food commodities animal meat, fat, liver, kidney, cream, and milk, and poultry meat, fat, liver and eggs, a nd is proposed for enforcement of requested tolerances in animal food commodities.]

3. Magnitude of residues. [Field trials were conducted to determine the magnitude of the residue in or on corn, cotton, and soybea n. The number and locatio ns of field trials

were in accordance with OPPTS Guideline 860.1500, with minor adjustments in location

distribution for cotton to better reflect current planted acreage. Seed was treated using the maximum label rates, planted in the fi eld, and commodities grown from the treated seed were harvested per OPPTS Residue Guidelines.

The magnitude of the residues (tioxazafen plus benzamidine) in field corn forage and grain was <0.01 ppm. Residues in field corn stover ranged from <0.01 to 0.01 ppm, with a median value of <0.01 ppm. In the processing study, there were no quantifiable residues in corn grain or in any processed fraction.

The magnitude of the residues (tioxazafen pl us benzamidine) in undelinted cotton seed was <0.01 ppm. Residues in cotton gin bypr oducts ranged from <0.01 to 0.01 ppm, with a median value of <0.01 ppm.

The magnitude of the residues (tioxazafen plus benzamidine) in soybean forage samples ranged from <0.01 ppm to 0.11 ppm, with a median value of 0.03 ppm. Residues in soybean hay ranged from 0.02 to 0.24 ppm, with a median value of 0.07 ppm. Residues in soybean seed ranged from <0.01 to 0.04 ppm, with a median value of <0.01 ppm. In the processing study, benzamidine residues in so ybean seed concentrated in the meal and toasted meal, with concentration factors of about 1.5. Benzamidine levels were reduced in hulls (average concentrati on factor of 0.41) and significantl y reduced in a ll the oil and lecithin fractions (concen tration factor <0.1).

In a limited field rotation crop study, conduc ted as a seed treatment on soybean as a primary crop, residues (tioxazafen plus ben zamidine) were <0.01 ppm in rotational crop commodities of lettuce, radish and grain sorghum at a 30-day plant-back interval, and were <0.01 ppm in lettuce, radish, and wh eat commodities at a 120-day plant-back interval.]

B. Toxicological Profile3

1. Acute toxicity. [Tioxazafen displayed low acute toxicity via the oral, dermal and inhalation routes of exposur e. It was mildly irritating to the eye, non-irritating to the skin, and is not a dermal sensitizer. The acu te toxicity studies pl ace technical tioxazafen in toxicity Category IV for acute oral, de rmal, inhalation, and eye and skin irritation. Tioxazafen is not a dermal sensitizer.]

2. Genotoxicty. [Tioxazafen was not genotoxic in a battery of assays. It was negative for inducing mutations in bacteria l and mammalian cell assays. No clastogenic

effect was observed in vitro human lymphocytes or in vivo mouse bone marrow micronucleus.]

3. Reproductive and developmental toxicity. [The reproductive and developmental toxicity of tioxazafen was investigated in a two-generation rat reproduction study and in rat and rabbit developmental toxicity studies . In the reproduction study, the reproductive and developmental no-observed-adverse-eff ect level (NOAEL) was the highest dose tested (HDT), 60 mg/kg bw/day, based on no effects on reproduction or pup growth and development. The parental systemic NOAE L was 60 mg/kg bw/day (HDT) for females and 20 mg/kg bw/day for males, based on lo wer body weight gains, body weights, food consumption, or food efficiency in the 60 mg/kg bw/day males. !!

In the rat developmental toxicity stu dy, the maternal NOAEL was 10 mg/kg bw/day, based on lower food consumption that resulted in mean body weight losses or reduced body weight gains at 50 and 200 mg/kg bw/day. No evidence of developmental toxicity was observed in the rat up to the HDT of 200 mg/kg bw/day.

In the rabbit teratology study, the maternal NOAEL was 5 mg/kg bw/day, based on lower mean body weight gains, food consumption, a nd food efficiency with the corresponding clinical finding of decreased defecation at dose levels greate r than, or equal to, 20 mg/kg bw/day. The developmental NOAEL was 100 mg/kg bw/day (HDT), based on the absence of effects on intrauterine gr owth, survival, and fetal morphology.]

4. Subchronic toxicity. [The adrenal gland and bone were the primary target organs in subchronic toxicity studies in rats, whereas the liver was the primary target organ in mice. No target organs were iden tified in dogs, where t oxicity was manifested primarily through clinical signs and decrea sed body weight. Th e lowest NOAEL in 90- day subchronic oral toxicity studies was approximately 16 mg/kg bw/day in the rat.

In the 28-day repeat dose dermal toxi city study, the NOAEL was 100 mg/kg bw/day, based on lower mean cumulative body weight gains in the 300 and 1000 mg/kg bw/day males and females, and adrenal cortic al cytoplasmic vacuolation in the ≥ 300 mg/kg bw/day males.

In a 13-week rat inhalation toxicity st udy, the lowest no-observed-adverse-effect concentration (NOAEC) of MON 102100 was 15 mg/m 3 , based on adrenal cortical vacuolation, with or without adre nal cortical atrophy, in the 50 mg/m 3 and 275 mg/m 3

males.4

No evidence of a direct or specific eff ect on the nervous system was observed in the

acute and subchronic neurotoxic ity studies conducted in th e rat. Although a NOAEL was not determined in the acute neurotoxicity study, a decrease in motor act ivity at the time of peak effect was noted at ≥ 250 mg/kg/day. The NOAEL for the subchronic study was the HDT, 1000 ppm (equivalent to 67 mg/kg bw/d ay and 75 mg/kg bw/day for males and females, respectively).]

5. Chronic toxicity. [In the two-year oral toxicity and carcinoge nicity study in the rat, no clinical findings resulted from e xposure to tioxazafen. Additionally, no test substance-related effects on survival, inci dence of palpable masses, hematology and coagulation parameters, ophthalmic findings , macroscopic findings, microscopically noted tumors, or organ weights were noted. The NOAEL was 75 ppm (3.9 mg/kg bw/day) in males and 250 ppm (16.0 mg/kg bw/day) in females, based on mean cumulative body weight gain differences of 10% or more in the 250 and 750 ppm males and 750 ppm females during the early phases of the study. No onc ogenic findings were observed at any dose level in the rat.

In the 18-month oral toxicity and carcinogeni city study in the mouse, there were no test substance-related effects on body weights, f ood consumption, food efficiency, incidence of palpable masses, or macroscopic findi ngs. There was a statistically significant decreased trend in survival of females, indi cating a possible test su bstance-related effect on survival in the high dose. Based on clin ical signs and hepatocellular damage, the lowest-observed-adverse-effect levels (L OAELs) were 750 ppm (120 mg/kg bw/day) and 250 ppm (50 mg/kg bw/day), for males and fe males, respectively, and the NOAEL were 250 ppm (41 mg/kg bw/day) a nd 50 ppm (10 mg/kg bw/day), for males and females, respectively.

Chronic administration of tioxazafen at cytot oxic doses is associated with a marginal increase in hepatocellular carcinomas in male mice and hepatocellular adenomas in female mice at the highest doses tested. Additional data demonstrated that the mouse liver tumors were caused by a non-genotoxic, cytotoxic mode of action at doses above the maximum tolerated dose. Therefore, no onocogenic effects that are relevant to humans were observed in the mouse.]

6. Animal metabolism. [Metabolism studies were conduc ted in rats, lactating goats and laying hens to determine metabolism pathways and the nature of tioxazafen residues

in animals. The metabolism of two radi olabeled forms of the parent molecule, [phenyl-U- 14 C] tioxazafen and [thiophene-2- 14 C] tioxazafen, was investigated in each species. In rats, tioxazafen is rapidly and almost completely absorbed (>88% in a bile cannulation experiment) following administ ration by oral gavage. Tioxazafen is extensively metabolized and the metabolites ar e readily eliminated, pr imarily in the feces via biliary excretion, with little retention in tissues. No unc hanged parent is observed in excreta. Tioxazafen is also extensively meta bolized in goats and hens to metabolites that are readily excreted with very little or no unchanged parent observed in excreta and minimal accumulation in edible tissues, milk or eggs. The primary pathways of

metabolism of tioxazafen were consistent acro ss the three species. Major pathways were 1) reductive opening (N-O bond reduction) and hydrolytic cleavage of the oxadiazole5

ring affording benzamidine and 2-thiophenecarboxylic acid, and 2) hydroxylation of the thiophene ring and conjugation as the glucur onide or sulfate. Benzamidine was a principal residue in livestock edible tissues, milk and eggs. The glycine conjugate of 2- thiophenecarboxylic acid, 2-thenoylglycine, wa s a significant residue in goat milk and kidney. Sulfate and glucur onic acid conjugates of hydr oxylated tioxazafen were significant residues only in milk. Only in fat, however at lo w levels, was unchanged

tioxazafen observed as a significant residue.]

7. Metabolite toxicology . [Metabolism of tioxazafen in plants and animals proceeds through a number of competing pa thways. The primary pathways of metabolism (oxadiazole ring cleavage and th iophene ring hydroxyla tion and conjugation) are observed in crops, livestock and the rat. The most significant metabolites identified in crops and livestock are also observed as metabolites in the rat. Benzamidine is consistently observed in crop and poultry matrices, and is a major metabolite in ruminants. In the rat metabolism study, ben zamidine was the major excreted metabolite and was present in both urine and feces. In rat urine, benzamidine constituted up to 13% of the administered dose. The glucuronic acid conjugate of h ydroxylated tioxazafen, analogous to the glucuronic acid and sulfat e conjugates in goat milk, was the major metabolite excreted in rat bile (up to 27% of the administered dose) and also was present in rat urine (up to 5% of administered dose). The goat milk and kidney metabolite, 2-thenoylglycine was a significant rat meta bolite and was excreted in the urine in amounts up to 6% of the administered dose. Thus, systemic exposure to the principal crop and livestock metabolites, benzamidine, 2-thenoylglycine and the conjugates of hydroxylated tioxazafen was signifi cant in the rodent toxicol ogy studies of tioxazafen.]

8. Endocrine disruption . [Tioxazafen does not belong to a class of chemicals known for having adverse effects on the endocri ne system. There were no significant findings in other relevant toxicity studie s (subchronic, chronic, reproductive or developmental toxicity studies) that w ould suggest that tioxazafen produces any endocrine disruption.]

C. Aggregate Exposure

1. Dietary exposure. [Based on the results of crop field trials, animal transfer studies, and exposure analysis, Monsanto is proposing a tolerance expression of parent tioxazafen plus its metabolite, benzamidin e (expressed as tioxazafen equivalents).]

i. Food. [Acute Dietary Exposure Assessment

Acute dietary exposure estimates are well within acceptable limits for all population subgroups. Exposure estimates from the proposed uses of tioxazafen as a seed treatment on corn, soybean, and cotton seed were ba sed on the proposed tolerances for the combined residues of tioxazafen plus its meta bolite, benzamidine. The acute module of the Dietary Exposure Evaluation Model soft ware with the Food Commodity Intake Database (DEEM-FCIDTM, version 3.16, 03-08-d) was used to conduct the assessment with the acute Population Adjusted Dose (a PAD) of 0.05 mg/kg bw/day for females 13- 49 in age and the aPAD of 0.8 mg/kg/day fo r all other population groups. This model6

incorporates nation-wide food consumption data as reported by re spondents in the US Department of Agriculture (USDA) 2003-2008 two-day National Heal th and Nutrition Examination Survey (NHANES). Food tran slations (i.e., between surveyed “as

consumed” foods and EPA-defined food commodities) are based on the EPA/USDA FCID recipe set as of Februa ry 2012. Food residues associat ed with the proposed uses of tioxazafen on corn, cotton, and soybean were set at tolerance leve ls adjusted with processing factors where applicable. The per centage of crop treated was assumed to be 100% for all crops. Acute dietary modeling results for the general population and for the most highly exposed subpopulations are summarized in Table 1.

Table 1. Acute Dietary Analysis of Tioxazafen + Benzamidine (Food Only)

Population Subgroup Acute Dietary

Food Only (95 percentile)

Exposure

(mg/kg/day) % of aPAD

General population 0.000333 0.04

Non-nursing infants 0.000761 0.10

Children 1-2 years 0.001087 0.14

Females 13-49 0.000167 0.33

Chronic Dietary Exposure Assessment

Chronic dietary exposure estimates are well within acceptable limits for all population subgroups. Exposure estimates from the proposed uses of tioxazafen as a seed treatment on corn, soybean, and cotton seed were ba sed on the proposed tolerances for the combined residues of tioxazafen plus its me tabolite, benzamidine. The chronic module of the Dietary Exposure Evaluation Model so ftware with the Food Commodity Intake Database (DEEM-FCID version 3.16, 03-08-d) was used to conduct the assessment with the chronic Population Adjusted Dose (cP AD) of 0.04 mg/kg bw/day for all population groups. This model incorporates nationwid e food consumption data as reported by respondents in the U.S. Department of Agriculture (USDA) 2003-2008 two-day National Health and Nutrition Examination Survey (NHANES). Food translat ions (i.e., between surveyed “as consumed” foods and EPA-de fined food commodities) are based on the EPA/USDA FCID recipe set as of February 2012. Food residues associated with the proposed uses of tioxazafen on corn, cotton, a nd soybean were set at tolerance levels adjusted with processing factors where appl icable. The percentage of crop treated was assumed to be 100% for all crops. Chronic dietary modeling results for the general population and for the most highly exposed s ubpopulations are summarized in Table 2.

Table 2. Chronic Dietary Analysis of Tioxazafen + Benzamidine (Food Only)7

Population Subgroup Chronic Dietary

Food Only

Exposure

(mg/kg/day) % of cPAD

General population 0.000101 0.3

Non-nursing infants 0.000226 0.6

Children 1-2 years 0.000516 1.3

Females 13-49 0.000065 0.2

]

ii. Drinking water.

[All proposed uses of tioxazafen were evalua ted at maximum application rates using the SWCC v.1.106, PRZM-GW v.1.07, and SCI-GROW v.2.3 to estimate surface water and groundwater concentrations of tioxazafen. The highest acute Estimated Drinking Water Concentration (EDWC) was 0.283 ppb, and th e highest chronic EDWC was 0.013 ppb. These EDWCs do not contribute significantl y to the total dietary exposure estimates (food and water) presented below.

Acute Aggregate Exposure A ssessment: Food and Water

Acute aggregate (food and water) dietary e xposure was evaluated using the DEEM-FCID as described above (tolerance-level food resi dues, processing factors, and 100% of crop treated) and with the incl usion of the acute EDWC of 0.283 ppb. The acute dietary exposure of the US population to tioxazafen and benzamidine from cotton, corn, and soybean application utilizes <1% of th e aPAD for the overall U.S. population. No population subgroup had an exposure that utilized more than 1% of the aPAD. Based on these results, there is reasonable certainty th at no acute effects would result from dietary exposure to tioxazafen. Acute dietary modeling results for the ge neral population and for the most highly exposed subpopulations are summarized in Table 3.8

Table 3. Acute Dietary An alysis of Tioxazafen and Benzamidine (Food and Water)

Population Subgroup Acute Dietary

Food and Water (95 percentile)

Exposure

(mg/kg/day) % of aPAD

General population 0.000340 0.04

Non-nursing infants 0.000768 0.10

Children 1-2 years 0.001094 0.14

Females 13-49 0.000175 0.35

Chronic Aggregate Exposure Assessment: Food and Water

Chronic aggregate (food and water) dietary exposure was evaluated using the DEEMFCID as described above (tol erance-level food residues, proc essing factors, and 100% of crop treated) and with the inclusion of th e chronic EDWC of 0.013 ppb. The chronic dietary exposure of the US population to tio xazafen and benzamidine from cotton, corn, and soybean application util izes <1% of the cPAD for the overall U.S. population. No population subgroup had an exposure that utilized more than 2% of the cPAD. Based on these results, there is reasonable certainty that no chronic effects would result from dietary exposure to tioxazafen a nd benzamidine. Chronic dietary modeling results for the general population and for the most highly exposed subpopulations are summarized in

Table 4.

Table 4. Chronic Dietary Risk (D EEMTM) Analyses of Tioxazafen

Population Subgroup Chronic Dietary

Food and Water

Exposure

(mg/kg/day) % of cPAD

General population 0.000101 0.3

Non-nursing infants 0.000227 0.6

Children 1-2 years 0.000516 1.3

Females 13-49 0.000066 0.2

]

2. Non-dietary exposure . [There are no current or pr oposed residential uses for9

tioxazafen. Therefore, a residential exposur e and risk evaluation was not conducted.]

D. Cumulative Effects

["Section 408(b){2){D){v) of the Federal Food, Drug, and Cosmetic Act (FFDCA) requires that, when considering whether to establish, modify, or revoke a tolerance, th e Agency consider "available information" concerning the cumulative effects of a part icular pesticide's residues and "other

substances that have a common mechanism of toxicity." Unlike other pesticides for

which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechan ism of toxicity finding for tioxazafen. For the purposes of this tolerance action, therefor e, Monsanto has not assumed that tioxazafen

has a common mechanism of toxici ty with other substances.]

E. Safety Determination

1. U.S. population. [Based on this risk assessment, Monsanto concludes that there is a reasonable certainty that no harm will result to th e general population from the aggregate exposure to tioxazafen from the proposed uses.]

2. Infants and children . [Based on this risk assessment, Monsanto concludes that there is a reasonable certainty that no harm will result to infants or children from the aggregate exposure to tioxazafen from the proposed uses.]

F. International Tolerances

[No CODEX or European Union (EU) Maximum Residue Levels (MRL) have been established for tioxazafen in any agricultural commodity. Tioxazafen is submitted for registration as a joint re view between Canada PMRA and US EPA, and thus any

MRL based on tioxazafen should coincide between the two countries.]