Page 3 of 23

Introduction

HED has evaluated the existing human health risk assessments for kresoxim

- methyl to determine whether sufficient data are available and whether a new human health risk assessment is needed to support Registration Review. HED has considered the most recent risk assessments for kresoxim

- methyl, updates to its toxicity, exposure and usage databases, and current Agency science policies and risk assessment methods. The most recent risk assessment for kresoxim

methyl was conducted in 2006 (D313836, S. Levy, 07/ 26/2006).

Hazard Identification/ Toxicology

Kresoxim

- methyl, a strobilurin fungicide, blocks fungal growth by disrupting mitochondrial respiration through inhibiting Complex III electron transfer at the Cytochrome bc1 (ubiquinol oxidase) Q 0 site. There are no mammalian molecular data to specifically show this mode of action in the test animals; however, effects such as decrease body weight, food consumption, and food efficiency are frequently found in test animals treated with compounds whic h disrupt mitochondria respiration with the subsequent disruption of energy production, and similar effects are also demonstrated in kresoxim

- methyl treated animals at higher dose levels relative to other strobilurins.

In subchronic toxicity studies, the target organ was the liver ( elevated serum gamma

- glutamyl transferase or SGGT levels ) in rats. Decreased body weights and body

- weight gains were observed above the Limit Dose, also in rats. Significant toxicity was not observed in m ice or dogs.

In chronic studies, the target organ in rats and mice was the liver. SGGT levels were elevated accompanied by liver weight changes and liver histopathological changes in rats

. Liver amyloidosis was seen in mice. C hanges in body weights and body

- weight gains were observed in rats, mice and dogs.

The Mutagenicity battery of studies was negative; however kresoxim

- methyl has been classified as “likely to be carcinogenic to humans” based on liver and biliary carcinomas observed in rats

, with a Q 1 * of 0.0029 (mg/kg/day) - 1 (3/4 scaling factor ) ( TXR 0 013685 S. Diwan 08/19/1999 )

. Special studies were subsequently voluntarily submitted in summary form on a possible mechanism of hepatic turmorigenesis observed in the rat. HED requested the detailed data on these special studies to aid the cancer assessment process. Since the requested details of the special studies have not been submitted to date , the existing CARC classification stands

. The developmental toxicity studies in the rat and rabbit prod uced no toxicity in mothers and offspring at the limit dose level (1000 mg/kg/day). The reproductive toxicity study indicated systemic and postnatal developmental toxicity in the form of reduced body weight and body weight gain in F 0 and F 1 parental animals, and delayed growth and maturation in F 1 and F 2 pups , in the presence of parental toxicity (decreased body weights and body weight gains)

. As such, there are no concerns for quantitative or qualitative susceptibility in offspring.Page 4 of 23

No neurotoxicity was seen in an acute neurotoxicity study up to 2000 mg/kg or the subchronic neurotoxicity study at up to 1267 mg/kg/day. Both these dose levels are at or above the Limit Dose level for the respective studies. As such, kresoxim

- methyl is con sidered to be negative for neurotoxicity in the neurotoxicity battery.

Upon examination of the toxicity database, the FQPA safety factor was reduced to 1X because: a) there were no qualitative or quantitative susceptibility concerns based on the developme ntal and reproductive toxicity data and there are no residual concerns regarding prenatal or postnatal exposure; b) there is no evidence of neurotoxicity in the neurotoxicity battery ; c) there is no evidence of immunotoxicity, as indicated by hematology, lymphoid organ weights and histopathology in the available subchronic and chronic studies ; d) there are no residual uncertainties in the exposure database.

Kresoxim

- methyl is classified in toxicity category I V for acute oral and acute inhalation toxicitie s, and III for acute dermal toxicity . It is a mild eye irritant (III) and is not a skin irritant

or sensitizer.

In accordance with the revised 40 CFR Part 158 data requirements, studies that is now required but missing from the kresoxim

- methyl toxicity data base is an immunotoxicity study (OPPTS Guideline §870.7800 )

. The conditional requirement for a subchronic inhalation study (OPPTS Guideline §870.3465) has been waived (TXR 0056513, K. Rury, 11/27/2012)

. OPP is conducting an independent retrospective analysis of more than 120 immunotoxicity studies submitted to the Agency. Preliminary findings of OPP’s retrospective analysis suggest that immunotoxicity studies have not yet provided lower PoDs than are sel ected from other guideline experimental toxicology studies and thus, so far, immunotoxicity studies would not have impacted the Agency’s risk assessments. The OPP retrospective analysis is anticipated to be completed in 2012. In the interim, HED recommend s that an immunotoxicity study continue to be required for registration and registration review chemicals.

Toxicity endpoints, points of departure, and safety factors for kresoxim

- methyl risk assessment were selected by HED in 2006 (Appendix 3)

. Quant ification of dermal risk is not required as n o dermal or systemic toxicity was seen following repeated dermal applications at the Limit Dose

. T here are no concerns for neuro

- , developmental, or reproductive toxicity. Inhalation endpoints

are not identif

ied because of the Toxicity Category IV for acute inhalation, and because the particle was considered non

- respirable

. In addition, the conditional requirement for an inhalation toxicity study has been waived ( TXR 0056513, K. Rury, 11/27/2012 ) The toxicit y endpoints are presented in Attachment 3.

The European Food Safety Authority published a Peer Review risk assessment of kresoxim

methyl (EFSA Journal 2010. 8(11): 1891)

. This document corroborates EPA’s 1999 and 2006 risk assessments and presents no new toxicity data. No new toxicity data have been identif ied from the available lite rature.

Conclusions : No new toxicity data beyond the immunotoxicity and subchronic inha lation toxicity stud ies are required to support the registration review of kresoxim

- methyl . Once all dataPage 5 of 23

have been received and reviewed, the kresoxim

- methyl Registration Review Team recommends that the toxicological endpoints, points of departure and sa fety factors used for risk assessment purposes for kresoxim

- methyl be re

- examined.

Dietary Exposure

An acute dietary assessment was not performed, as a toxicological endpoint attributable to a single dose has not been identified for kresoxim

- methyl.

A chronic aggregate dietary (food and drinking water) exposure and risk assessment was conducted for kresoxim

- methyl using the Dietary Exposure Evaluation Model, DEEM

- FCIDTM, Version 2.03, which uses food consumption data from the U.S. Department of Agricul ture’s Continuing Surveys of Food Intakes by Individuals (CSFII). The surveys were taken from 1994

- 1996 and included a supplemental children’s survey taken in 1998.

The chronic/cancer dietary exposure analysis incorporated combined average field trial residues of kresoxim

- methyl and its metabolites of concern for pome fruits, grapes, pecans, and cucurbit vegetables. The average apple field trial residue was used to compute an anticipated cattle dietary burden, which was used to calculate an anticipated residue in meat byproducts.

Anticipated residues for apples, grapes, pears and pecans were further refined based on screening level percent crop treated (%CT) data provided by the Biological and Economic Analysis Division (BEAD) (2006). 100 % of cucurb its were assumed to be treated. Drinking water was incorporated directly into the dietary assessment using the estimated drinking water concentration (EDWC) for surface water generated using Pesticide Root Zone Model/Exposure Analysis Modeling System (PRZ M/EXAMS) models. The 1

- in

- 10

- year annual mean concentration value ( 14.91 ppb chronic (non

- cancer) and 7.88 ppb for cancer) was used to estimate drinking water exposure.

BEAD has provided updated % CT information using available proprietary data for th e most recent years (2003

- 2010) on apples, cantaloupes, grapes, pears, pecans, pumpkins, squash, and watermelons (April 30, 2012). Based on the available data, BEAD determined that the usage of kresoxim

- methyl is slightly higher than the previous assessme nt; except for pears which had the same estimate. These marginally higher %CT estimates will have minimal impact on the dietary exposure/risk. %CT data was provided for cantaloupes, pumpkins, and squash (<1 to < 2.5%), which will reduce the dietary expos ure since 100%CT was used in the previous dietary
assessment.

Based on the submitted apple and grape processing studies, concentration factors for grape juice, raisins and apple juice/cider were reduced to 0.7, 1.4 and 0.2, respectively. Default concentration factors were used for all other commodities.

Results o f Chronic Dietary Exposure Analysis

C hronic dietary (food + drinking water) exposure estimates are below HED’s level of concern (LOC) for the U.S. population and each of the population subgroups. Dietary exposure wasPage 6 of 23

estimated at 0.000382 mg/kg/day for t he U.S. population (<1.0% of the cPAD) and 0.001139 mg/kg/day (<1.0% of the cPAD) for the most highly exposed population subgroup (all infants, < 1 year old).

Results of Cancer Dietary Exposure Analysis

The estimated exposure of the general U.S. population to kresoxim

- methyl is 0.000234 mg/kg/day. Applying the Q1* of 0.0029 (mg/kg/day) - 1 to the exposure value results in a lifetime cancer risk estimate of 6.80 x 10 - 7 which is below HED’s LOC.

Drinking Water Data

The drinking water residues used in the dietary risk assessment were provided by the Environmental Fate and Effects Division (R. Kashuba, 07/17/2006, DP#330783). Water residues were incorporated directly into the DEEM

- FCID assessment under the food catego ries “water, direct, all sources” and “water, indirect, all sources.”

There are no drinking water monitoring data available for kresoxim

- methyl or its metabolite. Estimated ground water and surface water concentrations were generated using the Screenin g Concentration in Ground Water (SCI

- GROW) and PRZM/EXAMS models, respectively. Estimated Drinking Water Concentrations (EDWCs) were provided for both kresoxim

- methyl and BF 490

- 1 ( ( E )

- 2

- [2

- (2

- methylphenoxy)methyl]

- phenyl

- 2

- (methoxyimido)acetic acid) . Th e PRZM

- EXAMS surface water modeling estimates were based on a Florida cucurbits crop scenario.

Surface water EDWCs were used in the dietary assessments since these values are higher than the ground water EDWC (6.27 ppb). In accordance with HED policy, the 1

- in

- 10 year mean of 14.91 ppb was used for the chronic (non

- cancer) analysis, and the 30

- year mean of 7.88 ppb was used for the cancer analysis.

The residue chemistry database is sufficient to support current registrations. The nature of the residue s in plants is adequately understood based on acceptable metabolism studies conducted on pome fruits, grapes, and wheat. The submitted plant metabolism studies are sufficient for registration of kresoxim

- methyl for use on pome fruits, cucurbits, grapes

, p ecans , and related crops (fruit or fruiting vegetables). The nature of the residue in plants and livestock has been defined. The residue of concern in plant commodities for risk assessment and tolerance setting
purposes include kresoxim methyl, BF 490

- 1, BF 490

- 2 (free and glucose conjugated) and BF 490

- 9 (free and glucose conjugated) (For chemical names and structures refer to Attachment I, Table 1b). T he metabolite BF 490

- 1 is included in the tolerance expression because the analytical methods do not d istinguish between kresoxim

- methyl and BF 490

- 1. The only residue of concern in ruminant tissues for tolerance and risk assessment purposes is the metabolite, BF 490

- 1.

The nature of the residues in rotational crops is adequate. T olerances for rotatio nal crop commodities are not required provided the label specifies a plantback interval ( PBI) of 14 days.Page 7 of 23

Adequate storage stability data are available to support storage durations for kresoxim

- methyl.

There is adequate analytical methodology for toler ance enforcement of regulated residues in/on plant commodities. BASF Methods 350/3

- US and D9611A are high

- performance liquid chromatography (HPLC)/column

- switching methods with ultraviolet (UV) detection (270 nm) which have been determined to meet Agency guidelines for the enforcement of kresoxim

- methyl tolerances on plant commodities. The data requirement for multi

- residue methods is fulfilled; however, the methods are not suitable for enforcement of tolerances.

Conclusions: Provided that EFED drinking water estimates do not need revision, a new dietary assessment for kresoxim

- methyl may not be required for the purpose of registration review. Furthermore, although a new version of DEEM (Version 3. 16 ) will be released, a new dietary risk assessment may not be needed since it is anticipated that the changes in the model will not affect the risk conclusion.

Residential Exposure

Residential handler exposures are not expected because kresoxim

- methyl is only registered for use in agricultural and nonresidential settings. However, post

- application exposures are possible due to registered uses of kresoxim

- methyl in retail nurseries.

Residential Post

- Application

- Noncancer A dermal endpoint was not selected due to lack of observed toxic effects; th erefore, residential post

- application exposure and risk assessments were not conducted. A new residential post

application risk assessment may be needed if the endpoints are re

- evaluated and dermal endpoints are selected.

Residential Post

- Application

- C ancer Cancer risks were not previously conducted for residential post

- application exposures. A residential post

- application cancer risk assessment is needed to assess for possible residential exposure from ornamentals treated at retail nurseries and broug ht into residential settings , while accounting for changes in risk assessment policies, i.e. transfer coefficients, body weights, and expected lifespan.

Residential Bystander Post

- Application Inhalation Exposure Based on the Agency's current practices, a quantitative residential bystander post

- application inhalation exposure assessment has not been performed for kresoxim

- methyl at this time

. However, volatilization of pesticides may be a potential source of post

- application inhalation exposure to individu als nearby to pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate post

- application inhalation
expo sure into the Agency's risk assessments. If new policies or procedures are put into place, thePage 8 of 23

Agency may revisit the need for a quantitative post

- application inhalation exposure assessment for kresoxim

- methyl

. Spray Drift Spray drift is always a potent ial source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for kresoxim

- methyl

. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices, and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more inf ormation at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT ® computer model to its risk assessments for pesticides applied by air, orchard airblast, and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target drift with specific products with significant risks associate d with drift.

Conclusions: Because kresoxim

- methyl is not registered for use in residential settings, residential exposure to handlers is not anticipated. However, post

- application residential exposures are expected from kresoxim

- methyl use on ornamenta ls grown in retail nurseries. If exposure data and methodologies for estimating exposure have changed for issues such as volatilization and spray drift, then a new noncancer exposure assessment may be required. For

cancer , an up

- to

- date residential post

- application risk assessment is needed to account for changes in residential exposure and risk assessment policies.

Aggregate Risk Assessment

Aggregate assessments consider exposures from food, drinking water, and residential uses. In the most recent human health risk assessment (D313836, S. Levy, 07/26/2006), aggregate exposure risk assessments were assessed by incorporating the drinking water estimates directly into the dietary exposure assessment for the following scenarios: chronic and cancer aggregate exposure (food + drinking water). A short

- term aggregate risk assessment may be required if the endpoints are re

- evaluated and dermal endpo ints are selected , because post

- application exposures are possible due to registered uses of kresoxim

- methyl in retail nurseries

. An acute aggregate

risk assessment was not performed because no appropriate endpoint was available to determine the acute Ref

er e nce Dose for the general population or any population subgroup. Therefore, the chronic and cancer exposure estimates provided in the Dietary Exposure section represent aggregate exposure.

Occupational Exposure

In addition to the agricultural uses li sted on the Sovran® label (cucurbit vegetables, grapes, pecans, and pome fruits), kresoxim

- methyl is intended for use on ornamentals in greenhouses,Page 9 of 23

lath

- and shade

- houses, outdoor nurseries, retail nurseries, and other nonresidential landscape areas (Cygn us® label). Both labels indicate REIs of 12 hours with required personal protective equipment (PPE) of the following: coveralls, chemical

- resistant gloves made of any waterproof material, and shoes plus socks.

There is a potential for short

- term (1

- 30 days) and intermediate

- term (1

- 6 months) exposure to kresoxim

- methyl during handling activities (mixing, loading, and applying); long

- term exposures are not anticipated. Since there are no applicable dermal or inhalation toxicological endpoints,

noncancer exposure and risk assessments were not conducted for any registered uses. However, since kresoxim

- methyl is classified as “likely to be a carcinogen,” a cancer assessment for occupational handlers has been completed for use on cucurbit vegetables.

Occu pational Handlers

- Noncancer Dermal and inhalation end points were not selected due to lack of observed toxic effects; therefore, noncancer occupational handler exposure and risk assessments were not conducted. A new occupational handler risk assessment may be needed if the endpoints are re

- evaluated and dermal and inhalation endpoints are selected.

Occupational Handlers

- Cancer Previously conducted cancer risk estimates (with baseline PPE) for use on cucurbits ranged from 1.03 × 10 - 7 to 4.87 × 10 - 7 . A new occupational handler cancer risk assessment may be needed to include all of the registered crops, while accounting for changes in occupational cancer assessment policies, i.e. unit exposures, body weights, and expected lifespan.

Occupational Post

- App lication

- Noncancer A dermal endpoint was not selected due to lack of observed toxic effects; therefore, occupational post

- application exposure and risk assessments were not conducted. A new occupational post

application risk assessment may be needed if the endpoints are re

- evaluated and dermal endpoints are selected.

Occupational Post

- Application

- Cancer Previously conducted post

- application cancer risk estimates for use on cucurbits ranged from 4.87 × 10 - 7 to 2.42 × 10 - 6 on Day 0 of the application. A new occupational post

- application cancer risk assessment is needed to include all of the registered crops, while accounting for changes in occupational cancer assessment policies, i.e. transfer coefficients, body weights, and expected lifespan.

Conclusi ons: There is sufficient information available to assess occupational handler and post

application exposures for both noncancer and cancer. If exposure data and methodologies for estimating exposure have changed for issues such as volatilization, then new exposure and risk assessments may be required for noncancer. For cancer
, up

- to

- date occupational risk assessments (for both handler and post

- application exposures) are needed to include all of the registered crops, while accounting for changes in occupat ional exposure and risk assessment policies.

Public Health and Pesticide Epidemiology DataPage 10 of 23

The evaluation of the OPP Incident Data System (IDS) indicated a low frequency and severity of incident cases reported for kresoxim

- methyl ( D405758 , S. Recore, 10/09 /12). In Aggregate IDS, from January 1, 2007 to June 13, 2012, there were 2 reported incidents involving kresoxim

methyl . For the Main IDS, from January 1, 2007 to June 13, 2012, there were no incidents reported for kresoxim

- methyl in the database. Kresoxim

- methyl is not included in the Agricultural Health Study, and therefore this study does not provide information for this report. Based on the low frequency and severity of incident cases reported for kresoxim

- methyl, there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the risk assessment.

Tolerance Assessment and Internation al Harmonization

Tolerances are established under 40 CFR §180.554(a) for the combined residues of kresoxim

methyl and its metabolites in or on apple pomace (1.0 ppm), pome fruit (0.5 ppm), grape (1.0 ppm), raisin (1.5 ppm), pecans (0.15 ppm), and cucurbit vegetables (0.40 ppm). Based on the review of additional field trial data for grape to fulfill geographic representation , HED recommended that the grape tolerance be rais ed to 1.2 ppm ( D260302, T. Bloem

. 10/21/99); however, to date, the tolerance has not been raised.

Tolerances are established under 40 CFR §180.554(b) for residues of the metabolite, BF 490

- 1, in or on ruminant meat by

- products of cattle, goats and sheep a t 0.01 ppm.

Codex and Canada have established maximum residue limits (MRLs) for kresoxim

- methyl on various crop commodities. The U.S. and Codex tolerances/MRLs are not compatible with regard to tolerance expression. The U.S. tolerances on pome fruit, gr ape, grape raisin, and pecan are in harmony with Canadian MRLs. The additional field trial data on grapes submitted to resolve the deficiency regarding geographic representation necessitate increasing the U.S. tolerance on grapes to 1.2 which will cause a disharmony. MRLs are established in Canada on apple juice and pear juice. Based on apple processing data, residues did not concentrate in apple juice; therefore, the U.S. did not establish a tolerance on apple juice. There are no Canadian MRLs for cucurbi t vegetables

. The U.S. tolerances for meat byproducts of cattle, goat, and sheep are not in harmony with Canada. Canada has established MRLs in meat byproducts of hogs and horses; meat of cattle, goats, hogs, horses, and sheep; and milk while the U.S. do es not. The U.S. has not proposed a tolerance for these commodities based on the maximum reasonably balanced diet ( MRBD) calculations.

The U.S. and Codex tolerances/MRLs are not compatible with regard to tolerance expression and MRLs. The Codex residu e definition for kresoxim

- methyl in plant commodities are in terms of the parent. The residue definition in the U.S. included the metabolites. The U.S. tolerances for pome fruits (0.5 ppm) and cucurbit vegetables (0.40 ppm) cannot be harmonized with the Codex MRL’s of 0.2 ppm and 0.05 ppm, respectively, because the Codex MRLs are lower than the U

. S. tolerances.Page 11 of 23

The U.S. tolerances (0.01 ppm) for meat byproducts of cattle, goat, and sheep are not in harmony with Codex (0.05 ppm). Codex has established MR Ls in fat, meat, and meat byproducts of mammals at 0.05 ppm and milk at 0.01 ppm, while U.S. does not.

The reasons for differences in established U.S. tolerances and Codex MRLs for kresoxim

- methyl are summarized as follows:

Pome Fruits: The Codex MRL for pome fruits (0.2 mg/kg) is based on field trials conducted in different countries (JMPR Report 1998). The MRL was estimated using combined results of apples and pears. The field trials were conducted with lower application rates (total) than the U.S. trials (0.5 lb/A vs 0.8 lb/A). The highest residue was 0.11 ppm. The U.S. MRL (0.5 ppm) was based on field trial data on apples and pears; the highest residue was 0.4 ppm.

Grapes: The Codex MRL for grapes (1.0 mg/kg) is based on field t rials conducted in Austria and South Africa (JMPR Report 1998). The MRL was estimated using combined results; t he highest residue was 0.73 ppm. The U.S. tolerance (1.0 ppm) was based on field trial data that received about the same application rate as Codex (0.8 lb/A vs 0.7 lb/A) and similar PHI; the highest residue was 0.79 ppm. The U.S. tolerance on grapes needs to be increased to 1.2 ppm due to submission of additional residue data, which will cause a disharmony. Codex has an established MRL on dri ed grapes (currants, raisins, and sultanas) at 2 ppm and the U.S. has an established tolerance on grape raisin at 1.5 ppm.

Cucurbit Vegetables: The Codex MRL for cucumber (0.05 mg/kg) is based on indoor cucumber field trials conducted in Spain (JMPR Rep ort 1998). Residues were <0.05 ppm at 0

- day and 3

- day PHIs. The U.S. tolerance on cucurbit vegetables (0.40 ppm) was based on field trial data conducted on cucumber, cantaloupe, and summer squash that received a maximum application rate (0.8 lb/A); the h ighest residue was 0.34 ppm. Tolerance was estimated using the NAFTA calculator. An

a djuvant was added in the U.S. trials.

U.S. tolerances and international MRLs are summarized in Attachment 2.

Environmental Justice

Potential areas of environmental justice concerns, to the extent p ossible, were considered in the human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," http://www.eh.doe.gov/nepa/tools/guidance/Volume1/2

- 6

- EO_12898envjustice.pdf ) . The Office of Pesticide Programs (OPP) typically considers the highest potential exposures from the legal use of a pesticide when conducting human health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diets within the U.S., and people who may be exposed when h arvesting crops. Should these highestPage 12 of 23

exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure that the risk estimates are based on the best available information.

Cumulative

Unlike other pesticides for which E PA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as
to kresoxim

- methyl and any other substances

, and kresoxim

- methyl does not appear to produce a toxic metabolite pr oduced by other substances. For the purposes of this action, therefore, EPA has not assumed that kresoxim

- methyl has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

Human Studies

The previous risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies, which comprise the PHED, the Outdoor Residential Exposure Task Force (ORETF), and the Agricultural Reentry Task Force (ARTF) have been determined to require a review of their eth ical conduct, and have received that review.

Data Requirements

Toxicology

870.3465 Subchronic Subchronic Inhalation Toxicity

Under the data requirements as presented in 40 CFR Part 158, a subchronic inhalation toxicity study is required.

870.7800 Immunotoxicity

Under the data requirements as presented in 40 CFR Part 158, an immunotoxicity study is required.

Residue Chemistry 860. 1340 Residue Analytical Method

The petitioner should submit a revised Method 354/2 which incorporates the revisions suggested by Analytical Chemistry Laboratory (ACL) and submit a radiovalidation study of Method 354/2. (D259287. T. Bloem, 10/18/99).Page 13 of 23Page 14 of 23

References

Memoranda Relevant t o Registration Review of Kresoxim

- methyl Author Barcode

(DP#) Date Title

G. Kramer D328725 05/26/2006 Kresoxim

- Methyl . Petition for the Establishment of a Crop Group Tolerance on Cucurbit Vegetables. Summary of Analytical Chemistry and Residue Data. PP#3E6594 T. Bloem D259287 10/18/1999 PP#7F04880. Kresoxim

- Methyl in/on Pome Fruits, Grapes and Pecans. Amendment to Evaluation of Residue Data and Analytical Methods

. Memorandum of 12

- April

- 1999 T. Bloem D255097 04/12/1999 PP#7F04880. Kresoxim

- Methyl in/on Pome Fruits, Grapes and Pecans. Evaluation of Residue Data and Analytical Methods. S. Levy D313836 07/26/2006 Kresoxim

- Methyl on Cucurbit Vegetables (PP#3E6594). Health Effects Division (HED) Human

- Health Risk Assessme nt

. S. Diwan TXRs**

0 013383

, 0 013685 0 8 / 19 /1999 Evaluation of the Carcinogenic Potential of Kresoxim

- methyl. Final Report.

S. Recore D405758 10/09 /2012 Kresoxim

- methyl: Review of Human Incidents N/A N/A 03/31/2010 Conclusion on the peer review of the pesticide risk assessment of the active substance kresoxim

- methyl. EFSA Journal 2010. 8(11): 1891 ** HED Document No.

Attachments 1. Chemical Identity and Structure Table 2. Tolerance Summary Table 3. Endpoint Selection Table 4. Toxicity TablesPage 15 of 23

Attachment 1

Table 1a Chemical Identity of Kresoxim

- Methyl (BAS 490F)
Compound

Common name Kresoxim

- methyl Company experimental name BAS 490 F
IUPAC name m ethyl ( E )

- 2

- methoxyimino

- 2

- [2

- ( o

- tolyloxymethyl)phenyl]acetate
CAS name methyl (α E )

- α

- (methoxyimino)

- 2

- [(2

- methylphenoxy)methyl]benzeneacetate CAS registry number 143390

- 89

- 0
End

- use product (EP) Sovran ® Fungicide ( EPA Reg. No. 7969

- 154)

Table 1b. Chemical Name and Structures of Regulated Metabolites of Kresoxim

- methyl Common Name and Company Code Structure

Z

- isomer of kresoxim

- methyl (BF 490

- Z)

methyl (E)

- 2

- [2

- (2

- methylphenoxy)

- methyl]phenyl

2

- (methyoxyimido)acetate

BF 490

- 1 (acid)

(E)

- 2

- [2

- (2

- methylphenoxy)methyl]

- phenyl

- 2

- (methoxyimido)acetic acidPage 16 of 23

Table 1b. Chemical Name and Structures of Regulated Metabolites of Kresoxim

- methyl Common Name and Company Code Structure

BF 490

- 2 (hydroxymethyl metabolite)

(E)

- 2

- [2

- (2

- hydroxymethylphenoxy)methyl]

- phenyl

2

- (methoxyimido)acetic acid

BF 490

- 9 (para hydroxy metabolite)

(E)

- 2

- [2

- (4

- hydroxy

- 2

- methylphenoxy)

- methyl]phenyl

- 2

- (methoxyimido)acetic acidPage 17 of 23

Attachment 2

Table 2. Summary of U.S. and International Tolerances and Maximum Residue Limits Residue Definition : U.S. Canada Mexico 1 Codex 2

40 CFR 180.554:

Plant: a) General. (1) combined residues of the fungicide kresoxim

methyl (methyl ( E )

- 2

- [2

- (2

- methylphenoxy)

- methyl]phenyl

- 2

- (methoxyimido)acetate) and its metabolites as follows: ( E )

- 2

- [2

- (2

- methylphenoxy)methyl]

- phenyl

- 2

- (methoxyimido)acetic acid; ( E )

- 2

- [2

- (2

- hydroxymethylphenoxy)methyl]

- phenyl

- 2

- (methoxyimido)acetic acid (free and glucose conjugated); and ( E )

- 2

- [2

- (4

- hydroxy

- 2

- methylphenoxy)

- methyl]phenyl

- 2

- (methoxyimido)acetic acid (free and glucose conjugated) methyl (α E )

- α

- (methoxyimino)

- 2

- [(2

- methylphenoxy) methyl]benzeneacetate, including the metabolites ( E )

- 2

- [2

- (2

- methylph enoxymethyl)phenyl]

- 2

- methoxyiminoacetic acid, 2

- [2

- (2

- hydroxymethylphenoxymethyl) phenyl]

- 2

- methoxyiminoacetic acid and 2

- [2

- (4

- hydroxy

- 2

- methylphenoxymethyl)phenyl]

- 2

- methoxyiminoacetic acid Plant :kresoxim

methyl Animal commodities: alpha

- (p

hydroxy

- o

tolyloxy)

- o

tolyl(methoxyimi no)acetic acid, expressed as kresoxim

- methyl.

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) U.S. Canada Mexico 1 Codex 2 Apple, dry pomace 1.0 Apple, wet pomace 1.0 Fruit, pome 0.5 0.5 apples, asian pears, crabapples, loquats, mayhaws, pears, quinces

0.15 apple juice, pear juice 0.2

Grape 1.0 1.0 1 Grape, raisin 1.5 1.5 raisins 2 dr ied grapes ( =currants, raisins and sultanas) Pecan 0.15 0.15 Vegetable, cucurbit, group 9 0.40 0.05 (*) cucumber U.S. [40 CFR §180.554(a)(2)] Canada Mexico 1 Codex 2
Livestock: metabolite ( E )

- 2

- [2

- (2

- methylphenoxy)methyl]

- phenyl

- 2

- (methoxyimido)acetic acid Same as above Same as above

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) U.S. Canada Mexico 1 Codex 2 Cattle, meat byproducts 0.01 0.03 meat byproducts of cattle 0.05 (*) edible offal mammalian Goat, meat byproducts 0.01 0.03 meat byproducts of goats Sheep, meat byproducts 0.01 0.03 meat byproducts of sheep MRLs with no U.S. Equivalent Barley 0.1 Grapefruit 0.5 Mammalian fats (except milk fats) 0.05 (*)Page 18 of 23

Table 2. Summary of U.S. and International Tolerances and Maximum Residue Limits Residue Definition : U.S. Canada Mexico 1 Codex 2 Meat (from mammals other than marine mammals) 0.05 (*)

Milks 0.01 (*) Olives oil, virgin 0.7 Olives 0.2 Oranges, Sweet, sour (including Orange

- like hybrids): several cultivars 0.5

Poultry meat 0.05 (*) Rye 0.05 (*) Straw and fodder (dry) of cereal grains 5

Wheat 0.05 (*) Meat byproducts of hogs, horses, and sheep 0.03

Meat of cattle, goats, hogs, horses, and sheep 0.03

Milk 0.004 Completed: M. Negussie; 07/20/2012 1 Mexico adopts U.S. tolerances and/or Codex MRLs for its export purposes.
2 * = absen t at the limit of quantitation.Page 19 of 23

Attachment 3

Table 3

. Summary of T oxicological D ose and E ndpoints for K resoxim

- methyl for U se in H uman R isk A ssessment 1

.

Exposure Scenario Point of

Departure Uncertainty/

FQPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects

Acute Dietary (general population including infants and children) NA NA NA Not applicable. An endpoint attributable to a single exposure was not identified for the U.S. population or any population subgroup.

Chronic Dietary all populations NOAEL=

36 mg/kg/day UF = 100

FQPA SF = 1X cRfD = 0.36

mg/kg/day

cPAD = cRfD FQPA SF= 0.36 mg/kg/day Combined Oral Chronic

Toxicity/Carcinogenicity Study

– Rat. LOAEL = 375/497 mg/kg/day in males/females, based on decreased body weights and body weight gains a nd increased gross and microscopic liver and biliary lesions, and (in females) increased incidences of liver

masses

. Incidental Oral

-- short

term, (1 to 30 days)

-- intermediat

e

- term (1

– 6 months) NA NA NA Risk assessment not required. Residential exposure not anticipated.

Dermal

-- short

term, (1 to 30 days)

-- intermediat

e

- term (1

– 6 months) NA NA NA Risk assessment not required. Dermal or systemic toxicity was not seen at the limit dose of 1000 mg/kg/day in the 21

- day dermal study

Inhalation (all durations) NA NA NA Inhalation risk assessments are not required based on low inhalation toxicity, and a particle size which is not in the respirable range. Cancer (oral, dermal, inhalation) Kresoxim

- methyl has been classified as “likely to be carcinogenic to humans” by the HED CARC

( Meeting, 17

- Mar

- 1999). The Q 1 * for kresoxim

- methyl is 0.0029 (mg/kg/day) - 1 (3/4 scaling factor; Memo, L. Brunsman, 20

- MAY

- 1999 ; HED Doc. No. 013383 )

.

1 UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no

- observed

- adverse

- effect

- level, LOAEL = lowest

- observed

- adverse

- effect

- level, PAD = population

- adjusted dose (a = acute, c = chronic) RfD = reference dose, MOE = margin of exposure, LOC = le vel of concernPage 20 of 23

Attachment 4

Table 4a Acute Toxicity of Kresoxim

- methyl technical

Guideline No. Study Type MRID # Results Toxicity Category

81

- 1 Acute Oral

- Rats 43864232 LD 50 >5000 mg/kg IV

81

- 2 Acute Dermal

- Rats 43864233 LD 50 > 2000 mg/kg III

81

- 3 Acute Inhalation

- Rats 43864234 LC 50 >5.6 mg/L IV

81

- 4 Primary Eye Irritation

- Rabbits 43864235 Mild eye irritant III

81

- 5 Primary Skin Irritation

- Rabbits 43864236 Non

- irritant IV

81

- 6 Dermal Sensitization

- Guinea pigs 43864237 Not a skin sensitizer N/A

Table 4b. Subchronic and Chronic Toxicity Profile

Guideline No./ Study Type MRID (year) Doses / Classification Results

870.3100 Subchronic feeding

– rat 43864245 ()

0, 500, 2000, 8000, or 16,000 ppm 0, 36, 146, 577, 1170 mg/kg/day (M) 0, 43, 172, 672, 1374 mg/kg/day (F) females

Acceptable Guideline NOAEL = 146 / 1374 mg/kg/day (M/F) LOAEL = 577mg/kg/day (M) based on elevated serum GGT (consistent with results s een in other studies) Not established in (F)

870.3150 Subchronic feeding

– mouse 43864244 ()

0, 250, 1000, 4000, or 8000 ppm 0, 57, 230, 909, 1937 mg/kg/day (M) 0, 80, 326, 1326, 2583 mg/kg/day (F) Acceptable Guideline NOAEL = 1937 / 2583 mg/kg/day (M/F) > Limit Dose LOAEL = Not established

870.3200 Repeated dose dermal

– rat 43883603 ()

0 or 1000 mg/kg/day Acceptable Guideline NOAEL = 1000 mg/kg/day (limit dose) LOAEL = not established

870.6200a Acute neurotoxicity

-- rat 44341010

Acceptable Guideline NOAEL = 2000 mg/kg (Limit Dose) LOAEL > not established

870.6200b Subchronic neurotoxicity

– rat 44341011

Acceptable Guideline NOAEL = 314 mg/kg/day LOAEL = 1267 mg/kg/day based on decreased body wt, body wt gain and food consumptionPage 21 of 23

Guideline No./ Study Type MRID (year) Doses / Classification Results

870.4300 Chronic feeding

– rat 43864247

0, 200, 800, 8000, or 16,000 ppm 0, 9, 36, 370, 746 mg/kg/day (M) 0, 12, 48, 503, 985 mg/kg/day (F)

Acceptable Guideline NOAEL = 36 / 48 mg/kg/day (M/F) LOAEL = 370 / 503 mg/kg/day (M/F) based increased SGGT levels, liver weight and histopathological changes (M), and roughly 10% lowered body weights and weight gains throughout much of the study (F)

Evidence of carcinogenicity in male & female rats (liver tumors)

870.4100b Chronic feeding

– dog 43864248

0, 1000, 5000, or 25,000 ppm 0, 27, 138, 714 mg/kg/day (M) 0, 30, 146, 761 mg/kg/day (F) Acceptable Guideline NOAEL = 138 / 761 mg/kg/day (M/F) LOAEL = 714 mg/kg/day (M) not established in (F)

870.4300 Carcinogenicity

– rat 4386249 ()

0, 200, 800, 8000, or 16,000 ppm 0, 9, 36, 375, and 770 mg/kg/day (M) 0, 12, 47, 497, and 1046 mg/kg/day (F)

Acceptable Guideline NOAEL = 36 / 47 mg/kg/day (M/F) LOAEL = 375 / 497mg/kg/day (M/F) based on decreased body weight gain and increased gross and microscopic liver (and biliary) lesions (M) and decreased body weight gains and increased incidence of liver masses (F).

Evidence of carcinogenicity (liver tumors) in male & female rats

870.4200 Carcinogenicity

– Mouse 43864250

0, 400, 2000, a nd 8000 ppm 0, 60, 304, 1305 mg/kg/day (M) 0, 81, 400, 1662 mg/kg/day (F) Acceptable Guideline NOAEL = 81 / 304 mg/kg/day (M/F) LOAEL = 1305 / 400 mg/kg/day (M/F) based on decreased weight gain, and liver amyloidosis (M), and decreased weight gain (F)

No evidence of carcinogenicity

870.3700a Developmental Toxicity

– Rat 43864251

0, 100, 400, or 1000 mg/kg/day Acceptable Guideline Maternal NOAEL = 1000 mg/kg/day (Limit Dose) LOAEL = not established Developmental NOAEL =1000 mg/kg/day

LOAEL = not established

870.3700b Developmental Toxicity

– Rabbit 43864252

0, 100, 400, or 1000 mg/kg/day Acceptable Guideline Maternal NOAEL = 1000 mg/kg/day (Limit Dose) LOAEL = not established Developmental NOAEL =1000 mg/kg/da

LOAEL = not established

870.3800 Two

- generation reproduction

– rat 43864253

Parental: 0, 50, 1000, 4000, or 16,000 ppm F 0 premating: 0, 5.1, 103, 411, 1623 mg/kg/day (M) 0, 5.6, 108.7, 437 1741 mg/kg/day (F) F 1 premating: 0, 4.4, 88.3, 363, 1482 mg/kg/day (M) 0, 5.0, 101, 417, 1653 mg/kg/day (F) Acceptable Guideline Parental/Systemic NOAEL = 108.7 mg/kg/day LOAEL = 411.0 mg/kg/day based on decreased body wt and body wt gain.

Offspring NOAEL =108.7 mg/kg/day

LOAEL = 411.0 mg/kg/day based on delayed development and decreased body wt gain.Page 22 of 23

Guideline No./ Study Type MRID (year) Doses / Classification Results

870.5500 Gene Mutation

– Salmonella 43864254, 43864258

0, 20, 100, 500, 2500, 5000 μg/plate in the presence and absence of mammalian metabolic activation (S9

- mix) Acceptable Guideline Non mutagenic + activation

870.5300 Gene Mutation

– CHO Cells 43864255

Experiment 1: 0.1, 0.5, 1, 5, 10, and 100 μg/Ml in the presence and absence of mammalian metabolic activation (S9

- mix) Experiment 2: 1, 2.15, 4.64, 10, 21.5, 46.4, and 100 μg/mL in the presence and absence of S9

- mix Acceptable Guideline Non mutagenic + activation

870.5375 Chromosomal Aberrations 43864256

10, 20 and 40 μ g/mL with and without metabolic activation (S9

- mix) Acceptable Guideline Non mutagenic + activation

870.5395 Micronucleus Assay

– mouse 43864257

500, 1000, and 2000 mg/kg Acceptable Guideline Non mutagenic + activation

870.5500 Unscheduled DNA Synthesis

– Rat 43864259

0.33, 1, 3.33, 10, 33.3 and 100 μ g/mL Acceptable Guideline Non mutagenic

870.5500 Unscheduled DNA Synthesis

– Rat 43864260

200 or 16,000 ppm Acceptable Guideline Non mutagenic

870.5500 Unscheduled DNA Synthesis

– Rat 43864261

20, 200 and 1000 mg/kg

Acceptable Guideline Non mutagenicPage 23 of 23

Guideline No./ Study Type MRID (year) Doses / Classification Results

Metabolism

– Rat 43864262, 43864263, 43864264, 43883604, 43883605 ()

Acceptable Guideline Male and female rats given kresoxim

- methyl technical at single gavage doses of 50 or 500 mg/kg or repeated doses of 50 mg/kg/day, indicated that about 63% of the given radioactivity was absorbed 48 hours after a single 50 mg/kg oral dose in both sexes. At 500 mg/kg, however, rats excreted only about 8

- 13% of the given dose in the urine and 14

- 15% in the bile (total of about 23

- 27% of dose) after 48 hours. This was due to absorption saturation; there was no evi dence for an increased tissue burden. There were some sex, dose, route, and label

- dependent differences in the metabolite profiles. M9 or M1 (also called BF 490

- 9 and BF 490

- 1) were the most abundant metabolites in the urine and feces of all groups.