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 kresoximmethyl 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) Q0 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 which 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 mice 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. Changes 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 Q1* of 0.0029 (mg/kg/day)-1(3/4 scaling factor) (TXR 0013685 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 produced 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 F0 and F1 parental animals, and delayed growth and maturation in F1 and F2 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 considered 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 developmental 

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 IV for acute oral and acute inhalation 

toxicities, 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 selected 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 recommends 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). Quantification of dermal risk is not required as no 

dermal or systemic toxicity was seen following repeated dermal applications at the Limit Dose. 

There are no concerns for neuro-, developmental, or reproductive toxicity. Inhalation endpoints 

are not identified 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 toxicity endpoints are 

presented in Attachment 3.

The European Food Safety Authority published a Peer Review risk assessment of kresoximmethyl (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 identified 

from the available literature.

Conclusions: No new toxicity data beyond the immunotoxicity and subchronic inhalation 

toxicity studies are required to support the registration review of kresoxim-methyl. Once all data 
Page 5 of 23

have been received and reviewed, the kresoxim-methyl Registration Review Team recommends 

that the toxicological endpoints, points of departure and safety 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 Agriculture’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 cucurbits 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 (PRZM/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 the 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 assessment; 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 exposure 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 of Chronic Dietary Exposure Analysis

Chronic 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 was 
Page 6 of 23

estimated at 0.000382 mg/kg/day for the 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)-1to 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 categories 

“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 Screening 

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). The 

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 

residues 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, pecans, 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). The metabolite BF 490-1 is included in the tolerance expression because the 

analytical methods do not distinguish 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. Tolerances for rotational 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 tolerance 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; therefore, residential 

post-application exposure and risk assessments were not conducted. A new residential postapplication risk assessment may be needed if the endpoints are re-evaluated and dermal 

endpoints are selected.

Residential Post-Application - Cancer

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 brought 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 individuals 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 

exposure into the Agency's risk assessments. If new policies or procedures are put into place, the 
Page 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 potential 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 information 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 

associated 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 ornamentals 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 endpoints are selected, because post-application exposures 

are possible due to registered uses of kresoxim-methyl in retail nurseries. An acute aggregaterisk assessment was not performed because no appropriate endpoint was available to determine 

the acute Reference 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 listed 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 (Cygnus® 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.

Occupational 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 × 10-7to 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-Application - 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 postapplication 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 × 10-7to 2.42 × 10-6on 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.

Conclusions: There is sufficient information available to assess occupational handler and postapplication 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 occupational exposure and risk assessment 

policies.

Public Health and Pesticide Epidemiology Data
Page 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 kresoximmethyl. 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 International Harmonization

Tolerances are established under 40 CFR §180.554(a) for the combined residues of kresoximmethyl 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 raised 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 at 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, grape, 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 cucurbit 

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. does 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 residue 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 MRLs 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 trials conducted in Austria and South 

Africa (JMPR Report 1998). The MRL was estimated using combined results; the 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 dried 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 Report 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 highest residue was 0.34 ppm. Tolerance was estimated using the NAFTA calculator. An 

adjuvant 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 possible, 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 harvesting crops. Should these highest 
Page 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 EPA 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 produced 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 ethical 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 23
Page 14 of 23

References

Memoranda Relevant to 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 Assessment. 

S. Diwan TXRs**

0013383, 

0013685

08/19/1999 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 Tables
Page 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 methyl (E)-2-methoxyimino-2-[2-(o-tolyloxymethyl)phenyl]acetate

CAS name methyl (αE)-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]phenyl2-(methyoxyimido)acetate

O

N

O

O

H3C

CH3

O

CH3

BF 490-1 (acid)

(E)-2-[2-(2-methylphenoxy)methyl]-phenyl-2-

(methoxyimido)acetic acid

O

N

O

CH3

O

HO

CH3

O

CH3

N

O

CH3

O

O

H3C
Page 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]-phenyl2-(methoxyimido)acetic acid

O

N

O

CH3

O

HO

OH

BF 490-9 (para hydroxy metabolite)

(E)-2-[2-(4-hydroxy-2-methylphenoxy)-

methyl]phenyl-2-(methoxyimido)acetic acid

O

N

O

CH3

O

HO

CH3

HO
Page 17 of 23

Attachment 2

Table 2. Summary of U.S. and International Tolerances and Maximum Residue 

Limits 

Residue Definition:

U.S. Canada Mexico1 Codex2

40 CFR 180.554:

Plant: a) General. (1) combined 

residues of the fungicide kresoximmethyl (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 (αE)-α-

(methoxyimino)-2-[(2-

methylphenoxy)

methyl]benzeneacetate, 

including the metabolites (E)-

2-[2-(2-

methylphenoxymethyl)phenyl]-

2-methoxyiminoacetic acid, 2-

[2-(2-

hydroxymethylphenoxymethyl)

phenyl]-2-methoxyiminoacetic 

acid and 2-[2-(4-hydroxy-2-

methylphenoxymethyl)phenyl]-

2-methoxyiminoacetic acid

Plant :kresoximmethyl 

Animal 

commodities: 

alpha-(phydroxy-otolyloxy)-otolyl(methoxyimi

no)acetic acid, 

expressed as 

kresoxim-methyl.

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

U.S. Canada Mexico1 Codex2

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 dried 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 Mexico1 Codex2

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 Mexico1 Codex2

Cattle, meat byproducts 0.01 0.03 meat byproducts of cattle 0.05 (*) edible 

Goat, meat byproducts 0.01 0.03 meat byproducts of goats offal mammalian

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 Mexico1 Codex2

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

* = absent at the limit of quantitation.
Page 19 of 23

Attachment 3

Table 3. Summary of Toxicological Dose and Endpoints for Kresoxim-methyl for Use in Human Risk 

Assessment1.

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 and increased 

gross and microscopic liver and biliary lesions, 

and (in females) increased incidences of liver 

masses.

Incidental 

Oral

--shortterm, (1 to 

30 days)

--

intermediat

e-term (1 –

6 months)

NA NA NA Risk assessment not required. Residential 

exposure not anticipated.

Dermal

--shortterm, (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 Q1* 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 = level of concern
Page 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 LD50 >5000 mg/kg IV

81-2 Acute Dermal- Rats 43864233 LD50 >2000 mg/kg III

81-3 Acute Inhalation- Rats 43864234 LC50 >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 seen 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 consumption
Page 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, and 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

F0 premating: 

0, 5.1, 103, 411, 1623 mg/kg/day (M) 

0, 5.6, 108.7, 437 1741 mg/kg/day (F)

F1 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 μg/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 μg/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 mutagenic
Page 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 evidence 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.