### Cymoxanil Registration Review Scoping Document DP395155

Page 2 of 27 Executive Summary

The Health Effects Division (HED) has evaluated the database and the most recent human health

risk assessments for the fungicide cymoxanil. HED performed this evaluation in order to determine the scope of work necessary to support the established tolerances and existing registrations. The primary source of information for this evaluation was the most recent human

health risk assessment ― Cymoxanil; Human Health Risk Assessment for Pro posed Uses on Bulb Vegetables (Crop Group 3

- 07), Leafy Greens (Subgroup 4A), and Leaf Petioles (Subgroup 4B )” ( R. Mitkus et al. , D347653, 0 9

, July 2008 )

.

Cymoxanil

- [ 2

- cyano

- N

- [(ethylamino)carbonyl]

- 2

- (methoxyimino) acetamide] is a fungicide that

has been registered in the United States (U.S.) for potato seed piece treatment, c aneberry, h op s
, head l ettuce, l ychee, p otato, cucurbit vegetable group, fruiting vegetable group, g rape, b ulb vegetables, s ubgroup 3

- 07 A, b ulb vegetables, s ubgroup 3

- 07 B, l eaf vegetables, s ubgroup 4A,

l eafy Petioles, and c ilantro l eaves. Cymoxanil also ha s been registered in Europe and Latin America for the control of select plant diseases in crops such as tomatoes, grapes, and potatoes. Cymoxanil is used to control downy m ildew, and early and late blights. There are also Special Local Need (SLN) registrations for use on the following crops: spinach, cabbage, Swiss chard

, and table beets when they are grown for seed. In addition, there is a n SLN registration for use for

comm ercial seed treatment for peas intended for export. There are currently no registered or proposed residential uses of cymoxanil

.

Tolerances are established for residues of cymoxanil on crops listed in 40CFR section 180.503. Additionally, tolerances with regional registrations are established for the s tates of Idaho, Washington and Utah. Codex has not established maximum residue limits (MRLs) but MRLs are

established in Canada for several commodities. US and Canadian tolerances are harmonized for caneberry, subgroup 13A

- 07 and potato.

Cymoxanil is formulated as dry flowable and dust. Cymoxanil has one technical (manufacturing use) product containing 98.7% active ingredient ; o ne end

- use product, Curzate® 60 DF, is use d

as a tank

- mix with a protectant fungicide, such as a copper product. Another cymoxanil containing product is Tanos®, which includes 25% cymoxanil and 25% femoxadone. The third registered product is Evolve®, which is a potato seed

- piece treatment containi ng 1 % cymoxanil, 2.5% thiophanate

- methyl, and 6% mancozeb. Cymoxanil may be applied as a seed treatment to potato seed pieces and also to peas (export only). Seed treatments may be made using slurry or mist seed treatment equipment. Foliar applications ma y be made using ground, aerial, and chemigation equipment. Cymoxanil has a complete toxicology database, including studies relating to subchronic and developmental neurotoxicity, developmental and reproductive toxicity, and immunotoxicity. The Agency has granted a waiver for a 28

- day inhalation toxicity study.

Cymoxanil has low acute toxicity via oral, dermal, inhalation, and ocular routes of exposure. It is a mild skin irritant and not a skin sensitizer. Systemic toxicity, as evidenced by decreased

b ody weights, body weight gains, and food consumption, was observed in subchronic, chronic, developmental, reproductive and neurotoxicity studies across species. The dog appears to be the most sensitive species for cymoxanil

- induced toxicity with the thymu s gland identified as a

### Cymoxanil Registration Review Scoping Document DP395155

Page 3 of 27 target organ in this species during subchronic and chronic exposures. No evidence of immunotoxicity was observed

. Cymoxanil was not carcinogenic in rats and mice and is classified

as ―not likely to be carcinogenic to humans‖

.

Ba sed on toxicological considerations by the Hazard Identification Assessment Review

Committee

, 

### HIARC (HED Doc. Date 02 , Jan 2003 ) and updated toxicology review by RAB1 toxicologists, recently reviewed studies, conservative residue assumptions used in the dietary risk assessment, and the completeness of the toxicology, residue chemistry and environmental fate databases, the Food Qua lity Protection Act ( FQPA ) Safety Factor (SF) was reduced from 10X to 1X for acute exposure, dermal exposure (short

- and intermediate

- term), and inhalation exposure (short

- and intermediate

- term) scenarios. The 10X FQPA SF is being retained, however, for chronic and long

- term exposure scenarios in the form of a n Uncertainty Factor LOAEL ( UF L 

### ) , due to the use of a LOAEL to extrapolate a NOAEL for the point of departure.

In the developmental and postnatal studies for which there is increased susceptibili ty, the effects are well characterized and NOAELs were established for developmental and offspring effects. In addition, the doses selected for risk assessment are based on the lowest NOAELs from the developmental and reproductive toxicity studies, where appropriate, and are protective of any potential pre

- and post

- natal effects. Therefore, there are low levels of concern and no residual uncertainties for pre

- and post

- natal toxicity.

Unlike other pesticides for which the Agency has followed a cumulative risk approach based on a common mechanism of toxicity, the agency has not made a common mechanism of toxicity finding for cymoxanil and any other substances. Cymoxanil does not appear t o produce a toxic metabolite produced by other substances. For the purposes of this scoping action, therefore, the agency has assumed that cymoxanil does not have a common mechanism of toxicity with other

substances.

In the most recent human health risk a ssessment ( R. Mitkus et al. , D347653, 09 July 2008 ) n o chemical

- specific data were available to assess potential exposure to occupational handlers. Therefore, occupational handler assessments were based primarily on surrogate unit exposures

from the Pesti cide Handler's Exposure Database (PHED) as presented in the PHED Surrogate Exposure Guide

. Occupational handler risk estimates for the registered uses of cymoxanil did

not exceed below HED’s level of concern for all activities (i.e. MOEs >100)

. However, f or some scenarios, mitigation measures were required the use of Personal Protective Equipment (PPE)

. The PPE requirement is included in all active labels (i.e

. , coveralls, gloves, respirator s )

. Risk estimates for dermal postapplication exposure were not of concern. Based on the Agency’s current practices, and the low likelihood of exposure, quantitative postapplication inhalation exposure assessments were not performed for cymoxanil

. The handler dermal and inhalation

, and dermal post application risk cal culations were based on maximum application rates and assuming maximum area treated per day. For the purpose of cymoxanil registration review the Agency anticipates that if the new Occupational Pesticide Handlers Exposure Database (OPHED) or the

revised A gricultural Re

- entry Task Force (ARTF) data base were incorporated in to the

assessment, MOEs are likely to be lower ( higher risk concern) than those presented in the last

risk assessment.

### Cymoxanil Registration Review Scoping Document DP395155

Page 4 of 27 Although there are currently no uses for cymoxanil that would result in direct residential exposure, residential bystander exposures might occur as a result of cymoxanil aerial applications , volatilization, and/or transport from treated areas. HED will evaluate the need for a bystander assessment under re gistration review.

The existing residue chemistry database for cymoxanil is adequate for risk assessment purposes. The qualitative nature of the residue is understood. The residue of concern for tolerance

enforcement and risk assessment i ncludes only pa rent cymoxanil [ 2

- cyano

- N

- [(ethylamino) carbonyl]

- 2

- (methoxyimino) acetamide]

.

T he dietary exposure database is adequate to support registration review of cymoxanil. The most recent dietary risk estimates for cymoxanil are based on unrefined residue assumptions ( 01, July

2008 and 100% crop treated). The acute and chronic dietary (food and drinking water) risk estimates are not of concern for the existing uses of cymoxanil. Currently, there are no uses for cymoxanil tha t would result in residential exposures; therefore, aggregate risk estimates are equivalent to the dietary (food and water) risk estimates. A new risk assessment would be required for registration review only if there are any revisions to the toxicologica l points of departure

, uncertainty factors , or revised drinking water estimates which would potentially lead to higher estimated risks

.

Introduction

The Health Effects Division (HED) has evaluated the database and the most recent human health

risk assessments for the fungicide cymoxanil. HED performed this evaluation in order to determine the scope of work necessary to support the established tolerances and existing registrations. The primary source of information for this evaluation was the most recent human

health risk assessment ( R. Mitkus et al. , D347653, 09, July 2008 )

.

T he structure of cymoxanil

, as well as its chemical names and other identifiers can be found in the chemical identity table attached to this document (Attachment 1)

.

Cymoxanil

- [ 2

- cyano

- N

- [(ethylamino)carbonyl]

- 2

- (methoxyimino) acetamide] is a fungicide that has been registered in the United States (U.S.) for potato seed piece treatment, c aneberry, hop s
, head lettuce, lychee, potato, cucurbit vegetable group, fruiting vegetable group, grape, bulb vegetables, subgroup 3

- 07 A, bulb vegetables, subgroup 3

- 07 B, leaf vegetables, subgroup 4A, leafy Petioles, and cilantro leaves. Cymoxanil also ha s been registered in Europe and Latin America for the control of select plant dis eases in crops such as tomatoes, grapes, and potatoes. Cymoxanil is used to control downy mildew, early and late blights. It has been formulated and sold alone or in combination with other fungicides. There are also Special Local Need (SLN) registrations f

or use on the following crops: spinach, cabbage, Swiss chard

, and table beets when they are grown for seed. In addition, there is a SLN registration for use for commercial seed treatment for peas intended for export. There are currently no registered or pr oposed residential uses of cymoxanil

.

A report of the current registrations (OPPIN, 0 4

, September 201 1 ) indicates that four Section 3 registrations that have been granted

. T here have been a number of Section 18 Emergency

### Cymoxanil Registration Review Scoping Document DP395155

Page 5 of 27 Exemptions and Section 24 Special Local Needs for cymoxanil , with the last being issued in

200 3

.

Hazard Identification/ Toxicology

The following hazard profile was obtained from and updates the 4 th 

### Hazard Identification Assessment Review Committee (HIARC) report for cymoxanil (TXR# 0051440, 02 , Jan 2003). Several studies have been added to the hazard database since that report and the last risk assessment for cymoxanil (DP Num: 340367, D. Rate, et. al. , 17 M ay 2007 )

. All submitted

studies are summarized in t ables 2.1 and 2.2 in Attachment 2

.

Cymoxanil has low acute toxicity (categories III and IV) via oral, dermal, inhalation, and ocular routes of exposure. It is a mild skin irritant and not a skin sensitizer. Systemic toxicity, as evidenced by decreased body w eights, body weight gains, and food consumption, was observed in subchronic, chronic, developmental, reproductive and neurotoxicity studies across species. The dog appears to be the most sensitive species for cymoxanil

- induced toxicity with the thymus gla nd identified as a target organ in this species during subchronic and chronic exposures. While the thymic effect in dog is suggestive of potential immunotoxicity, n o evidence of immunotoxicity was observed following subchronic exposure of rats or mice up to 108/ 117 (M/F) or 218/552 (M/F) mg/kg/day, respectively

. In addition, c ymoxanil was not immunotoxic to either mice or rats when administered in the diet for 28 days in studies designed specifically to assess immunotoxicity. Also, the endpoints selected for risk assessment are protective of potential thymic effects.

In a 21

- day dermal toxicity study in rats, no systemic toxicity was observed up to the limit dose. In a subchronic neurotoxicity study in rats, systemic toxicity (decreased body weight an d decreased food efficiency in males and females, and increased incidences of testicular and epididymal histological effects in males) was observed at 102/137 mg/kg/day (M/F); however, no neurotoxicity and/or neuropathology were observed up to 224/333 mg/k g/day (M/F; highest dose tested). In addition, no evidence of neurotoxicity was observed in the developmental toxicity studies in rats or rabbits, the 2

- generation reproduction study in rats, the subchronic or chronic dog studies, or the 18

- month mouse ca rcinogenicity study. However, in the combined chronic toxicity/carcinogenicity study in rats, clinical signs of hyperactivity and aggressiveness in males (≥30.3 mg/kg/day), as well as retinal atrophy in both sexes (≥30.3 mg/kg/day) were

observed.

Increas ed susceptibility of rats and rabbits was observed following in utero exposure to cymoxanil. In acceptable developmental toxicity studies in both of these species, developmental effects were seen at doses below those that caused maternal toxicity. In the rat developmental toxicity studies, skeletal anomalies, delays in skeletal ossification, and/or increases in overall malformations were observed at lower doses than those at which maternal toxicity was observed. In a rabbit developmental study, increased skeletal malformations were observed at 8 mg/kg/day (LOAEL), which was also below the maternal NOAEL of 32 mg/kg/day. Cleft palate was also observed in fetuses at 32 mg/kg/day. In the first 2

- generation reproduction toxicity study (1993), decreased pup viability (PND 0

- 4) was observed at maternally toxic doses. In a second 2

- generation reproduction toxicity study (2001), decreased body weight was observed during

lactation in both F 1 

### and F 2 

### offspring at a dose that was lower than that at which parental toxicity

### Cymoxanil Registration Review Scoping Document DP395155

Page 6 of 27 was observed. The increased susceptibility of offspring observed in this study was concordant with the results obtained in the developmental toxicity studies.

In a developmental neurotoxicity study, offspring toxicity

– adverse effects includ ed decreased pup survival, decreased pup weight and body weight gain during early lactation, increases in morphometric measurements (anterior/posterior cerebrum for males, cerebellar height for females) at PND 79

- 83, and decreased retention in the water ma ze task for adult females

– was observed at the same dose as maternal toxicity (slight decreases in body weight, body weight gain during gestation, and food consumption). The LOAEL for both maternal animals and offspring was 100 mg/kg/day. No residual un certainties exist in the database for pre

- /post

- natal toxicity, and the endpoints selected (increased skeletal anomalies, delays in skeletal ossification,

and/or increases in overall malformations ) for risk assessment are considered protective of

effects o bserved in offspring in developmental and reproduction toxicity studies.

The Agency has granted a waiver for a 28

- day inhalation toxicity study. Based on a comparison of inhalation and oral points of departure for a series of 89 pesticides, and on the ma ximum inhalation exposure expected from occupational and residentia l uses of cymoxanil, HED concludes that a new inhalation toxicity study on cymoxanil is unlikely to result in a point of departure indicating risks of concern.

Cymoxanil was not carcinogenic in rats and mice and is classified as ―not likely to be carcinogenic to humans‖ . The available studies indicate that c ymoxanil is not mutagenic in

bacteria or cultured mammalian cells. There is, however, evidence of clastogenic acti vity and

induction of unscheduled DNA synthesis in vitro . In contrast, c ymoxanil was neither clastogenic nor aneugenic in vivo in mouse bone marrow cells and did not induce a genotoxic response in rat somatic or germinal cells. T he negative results from the in vivo mouse bone marrow micronucleus assay support the lack of a carcinogenic effect in long

- term rat and mouse feeding

studies.

FQPA Considerations

Adequacy of the Toxicity Database

The toxicology database for cymoxanil is adequate for assessing pre

- and/or post

- natal susceptibility. The following studies are available:

· Subchronic neurotoxicity study in rat (acceptable)

· Developmental toxicity studies in rat and rabbits (acceptable)

· 2

- Generation r eproduction toxicity study in rat (acceptable)

· Developmental neurotoxicity study in rat (acceptable)

Pre

- and/or Postnatal Toxicity

T here is an indication of increased susceptibility of rats and rabbits to in utero exposure to cymoxanil. In several developmental toxicity studies in the rat and rabbit, developmental toxicity was observed at doses that were lower than those that caused maternal toxicity. In the

### Cymoxanil Registration Review Scoping Document DP395155

Page 7 of 27 rat developmental toxicity studies, skeletal anoma lies, delays in skeletal ossification, and/or

increases in overall malformations were observed at lower doses than those at which maternal toxicity was observed. However, in the developmental neurotoxicity study in rat, offspring toxicity was observed at the same dose as maternal to xicity

, indicating increased qualitative susceptibility in the offspring. Other studies indicated an increase in quantitative susceptibility in the offspring. In on e rabbit developmental study, increased skeletal anomalies were observed at 8 mg/kg/day (LOAEL), which was below the maternal NOAEL of 32 mg/kg/day. In a second rabbit developmental toxicity study, an increased incidence of visceral and skeletal anomalies was observed at 25 mg/kg bw/day; a maternal LOAEL was not observed in this study. In the 2

- generation reproduction toxicity study, decreased pup body weight was observed at a lower dose than that which caused toxicity in adults.

Degree of Concern Analys is and Residual Uncertainties for Pre

- and/or Postnatal Susceptibility

In the developmental and postnatal studies for which there is increased susceptibility, the effects

are well chara cterized and conservative NOAELs were established for developmental and offspring effects. In addition, the doses selected for risk assessment are based on the lowest NOAELs from the developmental and reproductive toxicity studies, where appropriate, and are protective of any potential pre

- and post

- natal effects. Therefore, there are low levels of concern and no residual uncertainties for pre

- and post

- natal toxicity.

FQPA Safety Factor for Infants and Children

Based on toxicological considerations by the Hazard Identification Assessment Review

Committee

, 

### HIARC (HED Doc. Date 02 , Jan 2003) and updated toxicology review by RAB1 toxicologists, recently reviewed studies, conservative residue assumptions used in the dietary risk assessment (currently no residential exposures), and the completeness of the toxicology, residue chemistry and e nvironmental fate databases (evaluated by the risk assessment team), the FQPA Safety Factor (SF) was reduced from 10X to 1X for acute exposure, incidental oral exposure (short

- and intermediate

- term), dermal exposure (short

- and intermediate

- term), and

inh alation exposure (short

- and intermediate

- term) scenarios. The 10X FQPA SF is being retained, however, for chronic and long

- term exposure scenarios in the form of a UF L 

### , due to the use of a LOAEL to extrapolate a NOAEL for the point of departure.

Toxicit y Endpoint Selection

Acute Reference Dose (aRfD)

- Females age 13

- 49

The acceptable developmental toxicity study in the rabbit was used to select the endpoint for establishing the acute RfD (aRfD) for females 13

- 49 years old. The aRfD is based on increased

skeletal anomalies of the cervical and thoracic vertebrae and ribs observed in fetuses at the developmental LOAEL of 8 mg/kg/day. Because a cl ear NOAEL of 4 mg/kg/day was observed in the study and there are no residual uncertainties for pre

- /post

- natal toxicity, the FQPA safety factor (SF) is 1X.

### Cymoxanil Registration Review Scoping Document DP395155

Page 8 of 27 Acute Reference Dose (aRfD)

- General Population

An endpoint of concern (effect) attributable to a single dose was not identified in the database for acute risk to the general population, including infants and children. Therefore, quantification of acute risk to these populations i s not required.

Chronic Reference Dose (cRfD)

The chronic toxicity study in the dog (2003) was used to select the endpoint for establishing the chronic RfD (cRfD). The cRfD is based on decreased absolute and relative thymus weights and histopathology of the thymus (thymic atrophy/involution) in males and decreased thymus weights in females seen at the LOAEL of 1.3/0.8 mg/kg/day (M/F). This LOAEL was the lowest

in the database. A NOAEL was not observed in th is study; therefore, the FQPA SF (10X) was retained for the use of a LOAEL to extrapolate a NOAEL. Although the thymic effects in dogs suggest potential immunotoxicity, no immunotoxicity was observed in 2 specialized well

designed immunotoxicity studies i n the rodents, and the cRfD is protective of any potential thymic effects.

Incidental Oral Exposure (Short

- and Intermediate

- Term)

Short

- Term: A short

- term incidental oral endpoi nt was selected from the second two

- generation reproduction toxicity study in rats (2001). The endpoint was decreased body weight observed during lactation in both F 1 

### and F 2 

### offspring at the offspring LOAEL of 31.6/42.8 mg/kg/day (M/F). Because a clear o ffspring NOAEL of 10.5 mg/kg/day was observed in the study and there are no residual uncertainties for pre

- /post

- natal toxicity, the FQPA SF is 1X.

Intermediate

- Term: An intermediate

- term incidental oral endpoint was selected from the first

two

- generation reproductive toxicity study in rats (1993). The endpoint was based on reduced

pre

- mating body weight, body weight gain, and food consumption observed in P

- generation males and decreased gestation and lactation body weight in F1 dams at the parental LOAEL of 32.1/40.6 mg/kg/day (M/F). Because a clear parental NOAEL of 6.5 mg/kg/day was observed in the study and there are no residual uncertainties for pre

- /post

- natal toxicity, the FQPA SF is 1X.

Dermal Absorption

An upper

- bound estimate of dermal absorption was calculated by comparing the maternal LOAEL from the oral developmental toxicity study (rat) with the NOAEL from the dermal toxicity study (rat): [(75 mg/kg/day ÷ 1000 mg/kg/day) x 100%] = 7.5%. The H IARC report of Jan. 2, 2003 incorrectly calculated this to be 2.5%.

Dermal Exposure (Short

- , Intermediate

- and Long

- Term)

Short

- and intermediate

- term dermal endpoints were selected from an acceptable developmental toxicity study in rabbits. Increased skeletal anomalies of the cervical and thoracic vertebrae and ribs were reported at the LOAEL of 8 mg/kg/day. The adverse eff ects observed in this study were considered appropriate for this exposure scenario, since they are pertinent to a portion of

### Cymoxanil Registration Review Scoping Document DP395155

Page 9 of 27 the exposed worker population, but were not measured in the 21

- day dermal study in rats. Because a clear developmental NOAEL of 4 mg/kg/day was observed in the study and there are no residual uncertainties for pre

- /post

- natal toxicity, the FQPA SF is 1X. Since endpoints from an oral study were selected for this exposure scenario, a 7.5% dermal absorption factor was used

for route

- to

- route extrapolation.

The chronic toxicity study in the dog (2003) was used to select the endpoint for the long

- term dermal exposure scenario. D ecreased absolute and relative thymus weights and histopathology of the thymus (thymic atrophy/involution) in males and decreased thymus weights in females were observed at the LOAEL of 1.3/0.8 mg/kg/day (M/F). A NOAEL was not observed in this study; therefore, the FQPA SF (10X) was retained for the use of a LOAEL to extrapolate a NOAEL. Since an oral endpoint w as selected for this exposure scenario, a 7.5% dermal absorption factor was used for route

- to

- route extrapolation.

Inhalation Exposure (Short

- , Intermediate

- and Long

- Term)

Short

- and intermediate

- term inhalation endpoints were selected from an acceptable developmental toxicity study in rabbits. Increased skeletal anomalies of the cervical and thoracic vertebrae and ribs were reported at the LOAEL of 8 mg/kg/day. Because a clear d evelopmental NOAEL of 4 mg/kg/day was observed in the study and there are no residual uncertainties for

pre

- /post

- natal toxicity in the database, the FQPA SF is 1X. The adverse effects observed in the oral developmental toxicity study in rabbits were cons idered appropriate for this exposure

scenario in the absence of route

- specific data. Oral and inhalation toxicity were assumed to be equivalent.

The chronic toxicity study in the dog (2003) was used to select the endpoint for the long

- term inhalation exp osure scenario. D ecreased absolute and relative thymus weights and histopathology of the thymus (thymic atrophy/involution) in males and decreased thymus weights in females were observed at the LOAEL of 1.3/0.8 mg/kg/day (M/F). A NOAEL was

not observed i n this study; therefore, the FQPA SF (10X) was retained for the use of a LOAEL to extrapolate a NOAEL. Since an oral endpoint was selected in the absence of route

- specific data, oral and inhalation toxicity were assumed to be equivalent

.

The Agency has g ranted a waiver for a 28

- day inhalation study. Based on a comparison of inhalation and oral points of departure for a series of 89 pesticides, and on the maximum inhalation exposure expected from occupational and residentia l uses of cymoxanil, HED

conclud es that a new inhalation toxicity study on cymoxanil is unlikely to result in a point of departure indicating risks of concern.

### Cymoxanil Registration Review Scoping Document DP395155

Page 10 of 27 Level of Concern for Margin of Exposure

The target MOEs for occupational and non

- dietary residential exposure risk assessments are as

follows:

Summary of Levels of Concern for Risk Assessment.

Route Duration

Short

- Term (1

- 30 days) Intermediate

- Term (1

- 6 Months) Long

- Term (> 6 Months)

Occupational (Worker) Exposure

Dermal 100 100 1000

Inhalation 100 100 1000
Residential (Non

- Dietary) Exposure

Oral 100 100 N/A

Dermal 100 100 1000

Inhalation 100 100 1000



### Recommendation for Aggregate Exposure Risk Assessments

An aggregated exposure risk assessment is not required since there are no residential uses for cymoxanil at this time.

Classification of Carcinogenic Potential

On December 2, 1997, the HIARC, in accordance with the Draft Proposed Guidelines for Carcinogen Risk Assessment (April 10, 1996) classified c ymoxanil as ―not likely to be carcinogenic to humans‖ based on the lack of evidence of carc inogenicity in mice and rats at doses that were judged to be adequate to assess the carcinogenic potential.

For a summary of toxicological doses and endpoints for use in human risk assessments see table

3.1

, Attachment 3

.

Endocrine D isruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments o f carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, est rus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in di fferent taxonomic groups. As part of c ymoxanil ’s most recent registration decision , EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), c ymoxanil is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

### Cymoxanil Registration Review Scoping Document DP395155

Page 11 of 27 EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an eff ect in humans or wildlife similar to an effect produced by a ―naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.‖ The EDSP employs a two

- tiered approach to making the statutorily required

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the poten tial to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and

establish a dose

- response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issu ed test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. C ymoxanil is not among the group of 58 pesticide active ingredients on the initial list to be screened under the

EDSP. Accordingly, as part of registration review, EPA will issue future EDSP orders/data call

ins, requiring the submission of EDSP screening assays for c ymoxanil

. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.

Conclusions Regarding Hazard Identification/Toxicology

Cymoxanil has a complete database, including studies relating to subchronic and developmental neurotoxicity, developmental and reproductive toxicity, and immunotoxicity. The Agency has granted a waiver for a 28

- day inhalation toxicity study. Based on a compariso n of inhalation and oral points of departure for a series of 89 pesticides, and on the maximum inhalation exposure expected from occupational and residentia l uses of cymoxanil, HED concludes that a new inhalation toxicity study on cymoxanil is unlikely to result in a point of departure indicating risks

of concern.

Public Health and Pesticide Epidemiology Data

The OPP Incident Data System ( IDS ) records incidents resulting in high er severity outcom es in more detail, in a module called the Main IDS module . This system stores incident data for death, major and moderate incidents, and it includes more details about the location, date and nature of

the incident. Main IDS incidents involving only one pesticide are considered to provide more certain information about the potential effects of exposure from the pesticide. The less severe

human incidents (minor, unknown, or no effects outcomes) are reported by registrants as counts
called aggregate summar ies and are recorded in a separate module called Aggregate IDS

.

In A ggregate IDS , from 0 1, January 200 6 to 05, May 2011 there is one incident involving cymoxanil

. For the M ain IDS, (for the period) there were no cases that involve the active ingredient cymoxanil ( 18, October 2011, DP 395156).

### Cymoxanil Registration Review Scoping Document DP395155

Page 12 of 27 Conclusions for Public Health and Pesticide Epidemiology Data

Based on the low frequency and low severity of incident cases, 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 cymoxanil risk assessment.

Dietary Exposure

Tolerances are currently established for residues of the fungicide cymoxanil in/on various plant commodities, at levels ranging from 0. 05 to 4.0 ppm (as listed in 40CFR §180. 503 [a]). R esidue data from field trials conducted to support the existing registrations show that, generally,

residues of cymoxanil are relatively low

. The requirements for residue analytical methods are fulfilled for the purpose of registration review. Adequate me thods are available for enforcement and data collection purposes for both plant and animal commodities. The registration review requirements for magnitude of the residue in/on plants and milk and livestock tissues as well as in eggs and poultry are fulfill ed. Cymoxanil is currently registered for use on potato seed piece

treatment, c aneberry , h ops, head l ettuce, l ychee, p otato, cucurbit vegetable group, fruiting vegetable group, g rape, b ulb vegetables, s ubgroup 3

- 07 A, b ulb vegetables, s ubgroup 3

- 07 B, l eaf vegetables, s ubgroup 4A, l eafy p etioles, and c ilantro l eaves.

The most recent dietary exposure assessment for cymoxanil ( D

. Rate , D 349396

, 01 July 2008) evaluated acute and chronic dietary (food + drinking water) exposure using the Dietary Exposure Evaluation Model (DEEM

- FCID, Version 2.03), which uses food consumption data from the USDA’s Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994

- 1996 and 1998. The acute analysis dated 01, July 2008 assumed 100% crop treated for all commod ities

, and

DEEM 7.81 default processing factors were used for all commodities except grapes. For grape, tolerance level residues and 100% CT were assumed and the processing factors for grape juice (1.4x) and raisins (1x) derived from the grape processing study were used (DP Num: 218035 and 219844, G. Kramer, 25 , Apr 1996 ). The EDWC for cymoxanil in surface water and groundwater were calculated using the screening model FIRST (FQPA Index Reservoir Screening Tool; v.1.1.0; dated 8/1/2001) and the regression model SCI

- GROW ( Screening Concentration in

Ground Water , v.2.3; dated 7/29/2003), respectively

. Estimated drinking water concentrations (EDWCs) were incorporated directly into the dietary assessment using the acute concentration of 9.3 ppb for surface wat er generated by FIRST model

. This assessment indicates that the acute dietary exposure estimate ( 95 th 

### percentile) is below the Agency’s level of concern [<100% acute Population Adjusted Dose (aPAD)] for females 13

- 49 years old , utilizing 89 % of the aPAD.

The chronic analysis was performed for the general U.S. population and various population subgroups using tolerance level residues or anticipated residues and percent crop treated from BEAD ( 02, Nov 2006 , J Carter) for potatoes, head lettuce, peppers, to matoes, watermelon, cucumber, pumpkin, and summer and winter squash

. DEEM 7.81 default processing factors were used for all commodities except grapes. Processing factors for grape juice (1.4x) and raisins (1x) were derived from grape processing data (DP Num: 218035 and 219844, G. Kramer, 25, Apr 1996 )

. The EDWC for cymoxanil in surface water and groundwater were calculated using the screening model FIRST (FQPA Index Reservoir Screening Tool; v.1.1.0; dated

### Cymoxanil Registration Review Scoping Document DP395155

Page 13 of 27 8/1/2001) and the regression model SCI

- GROW ( Scre ening Concentration in Ground Water

, v.2.3; dated 7/29/2003), respectively

. EDWCs were incorporated directly into the dietary assessment using the chronic concentration for surface water generated by FIRST model at 0.05 ppb. This assessment indicate d tha t the chronic dietary exposure estimates are below the Agency’s level of concern [<100% chronic Population Adjusted Dose (cPAD)] for the general U.S. population ( 48 % of the cPAD) and all population subgroups. The most highly exposed population subgroup wa s children 1

- 2 years old utilizing 74 % of the cPAD.

Since cymoxanil is classified as ―not likely to be carcinogenic to humans,‖ a cancer risk

assessment is not needed.

Summary of Dietary Exposure and Risk for Cymoxanil . The population subgroup with the maximum estimated exposure is bolded. Population Subgroup Acute Dietary (95th Percentile) Chronic Dietary Cancer Exposure mg/kg/day) % aPAD Exposure (mg/kg/day) % cPAD Exposure (mg/kg/day)
General U.S. Pop. NA 0.000383 48 Not Applicable

All Infants (< 1 year) 0.000404 51 Children (1

- 2 years) 0.000588 74 Children (3

- 5 years) 0.000521 65 Children (6

- 12 years) 0.000348 44 Youth (13

- 19 years) 0.000267 33 Adults (20

- 49 years) 0.000401 50 Adults (50+ years) 0.000357 45 Females (13

- 49 years) 0.035388 89.0 0.000333 42



### Conclusions for Dietary Exposure

At this time, dietary risk estimates are below HED’s level of concern ( i.e. , less than 100% of the PAD). If the points of departure

, safety factors , or water concentrations for cymoxanil are revised, a new dietary assessment will be required during registration review and may need

additional refinement

.

Residential Exposure

Although there are currently no uses for cymoxanil that would result in direct residential

exposure
, residential bystander exposures m ight occur as a result of cymoxanil aerial applications and/or transport from treated areas. Spray drift is always a potential source of exposure to residents nearby to spr aying 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 cymoxanil . The Agency has been working with the Spray

Drift Tas k 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/spray drift.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. Other potential sources of residential

exposure include volatilization of pestici des and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel ( SAP) in December 2009, and received the SAP’s final report on 02, Mar 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposu re

### Cymoxanil Registration Review Scoping Document DP395155

Page 14 of 27 data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate residential

post

- application inhalation exposure into the Agency's risk as sessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative residential post

application inhalation exposure assessment for cymoxanil

.

Aggregate Exposure and Risk Assessment

Currently, there are no uses for cymoxanil that would result in residential exposures; therefore, aggregate risk estimates are equivalent to the dietary (food and water) risk estimates. During registration review, updated aggregate assessments may be condu cted to include changes in toxicological endpoints, dietary exposure estimates, and any exposure estimates resulting from drinking water and residential uses, if applicable.

Occupational E xpos ure

Occupational exposure to cymoxanil is anticipated for adu lts who apply cymoxanil

- containing products and from post

- application exposure, or re

- entry into previously treated areas. A list of currently registered products containing cymoxanil as an active ingredient is included in t ables

4.1 and 4.2 in Attachment 4

.

Occupational Handlers

Based upon the current use patterns, potential occupational exposure scenarios include:

1. Potato seed treatment workers (loader/applicators, sewers, baggers)

. 2. Mixer/loader using open

- pour loading of dust and dry flowable formulations for ground chemigation, and aerial application operations.

3. Applicator using open

- cab airblast sprayers.

4. Aerial applicators (enclosed cockpit)

. 5. A pplicator using open

- cab groun dboom spray equipment

. 6. Flaggers supporting aerial application operations

.

Occupational handler risk estimates for the registered uses of cymoxanil were below HED’s

level of concern for all activities (i.e. MOEs >100)

. However, f or some scenarios, mitigation

measures were required entail ing the use of Personal Prote ctive Equipment (PPE) control for mixing and loading of various formulation s. The PPE requirement is included in all active labels (i.e, coveralls, gloves, respirators). Risk estimates for dermal postapplication exposure were not

of concern. As for the se ed treatment use (potato seed piece treatment), the maximum amount of seed treated per day might have to be revisited since HED is currently in the process of revising ExpoSAC Policy 15: Amount of Seed Treated or Planted per Day ( 02, Mar , 2004) in efforts to update the daily amount of seed treated in commercial seed treatment facilities.

Furthermore, recommended unit exposures for occupational handler assessments have generally been derived only from PHED. However, recently HED, the Outdoor Residential Exposure Task Force (ORETF) and Agricultural Handler Exposure Task Force (AHETF) have produced Occupational Pesticide Handlers Exposure Database (OPHED) that the Agency is using in place

### Cymoxanil Registration Review Scoping Document DP395155

Page 15 of 27 of PHED ( http://www.epa.gov/pesticides/scienc e/handler

- exposure

- data.html ). For the purpose

of cymoxanil registration review the Agency anticipates that if the new Occupational Pesticide Handlers Exposure Database (OPHED) were incorporated in to the assessment, MOEs are likely

to be lower than those p resented in the last risk assessment (risk estimates will be higher )

. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued reliance on these studies.

Occupational Post

- Application

It is possible for agricultural workers to have post

- application exposure to pesticide residues during the course of typical agricultural activities. HED in conjunction with the Agricultural Re

entry Task Force (ARTF) has identified a number of post

- appli cation agricultural activities that may occur and which may result in post

- application exposures to pesticide residues. HED has

revised t he ARTF database (SOP # 3.1) and is intending to use this data base in future

assessments

. For the purpose of cymoxan il registration review the Agency anticipates that if the

revised Agricultural Re

- entry Task Force (ARTF) data base were incorporated in to the

assessment, for some scenarios risk estimates are likely to be higher than those presented in the

last risk asses sment.

Cymoxanil is classified in Acute Toxicity Category III for acute dermal toxicity and IV for eye irritation. It is classified in Acute Toxicity Category IV for acute inhalation toxicity and for

dermal irritation. It is not a dermal sensitizer. Ba sed on these acute toxicity categories, t he restricted entry interval (REI) of 12 hours is determined to be adequate for all crops considering Worker Protection Standard (WPS) requirements.

Based on the Agency's current practices, a quantitative post

- app lication inhalation exposure assessment was not performed for cymoxanil. However, there are multiple potential sources of

post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potent ial sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, an d Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on 02, Mar , 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational

post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational

post

- applica tion inhalation exposure assessment for cymoxanil

.

Conclusions for Occupational Exposure

An updated occupational handler and post

- application assessment may be required for any cymoxanil use site if new data are identified which impact exposure estimates , new points of

### Cymoxanil Registration Review Scoping Document DP395155

Page 16 of 27 departure, revised uncertainty factors , or revisions to exposure policies and procedures are made.

An updated occupational post

- application assessment may be required to account for recent

revisions to the exposure policies and procedure s of the Science Advisory Council for Exposure (ExpoSAC) Policy 3 , released on June 2011.

Tolerance Assessment and International Harmonization

U.S. permanent tolerances (listed in 40 CFR 180.5 0 3), and Canadian MRLs are summarized

in t able 6.1 of the attachment 6. Codex has not established MRLs in/on any commodity, and
Mexico generally adopts US tolerances and/or Codex MRLs for export purposes

. The
tolerance expression for cymoxanil will be reviewed during registration review to ensure that
it appropriately covers the metabolites and degradates of cymoxanil and that it specifies the
residues to be measured for each commodity.

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, will be considered in

future human health risk assessments for cymoxanil , in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minorit y Populations and Low

Income Populations," http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf . The Office of Pesticide Programs (OPP) typically con siders 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 th e U.S., and people who may be exposed when harvesting crops. Should these highest 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.

Cumula tive Risk Assessment

The Food Quality Protection Act (FQPA) requires the Agency to consider the cumulative risks of chemicals sharing a common mechanism of toxicity. T he Agency determined that there was insufficient evidence to suggest cymoxanil shares a common mechanism of toxicity with other

chemical substances. For the purposes of this scoping action, therefore, t he A gency has assumed that cymoxanil does not have a common mechanism of toxicity with other substances.

Human Studies

Past cymoxa nil risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as the Pesticide Ha ndlers Exposure Database (PHED) and the Agricultural Reentry Task Force (ARTF) Database

. EPA has reviewed all the studies supporting these multi

- pesticide generic exposure databases, and has fou nd no clear and

### Cymoxanil Registration Review Scoping Document DP395155

Page 17 of 27 convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevailing at the time the research was

conducted. A ll applicable requirements of EPA’s Rul e for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied , and t here is no regulatory barrier to continued

reliance on these studies

Data Requirements

Under current guidelines, t here are no data deficiencies for cymoxanil.

R eferences

Barcode Date Title

D349397 05, Mar 2008 CYMOXANIL

- Nondietary Human Exposure/Risk Assessment fot the Use of Cymoxanil Leafy Greens Crop Subgroup 4A, Bulb Vegetables Crop Group3, Cilantro Leaves, Caneberries (Crop Subgroup 13A), and Leaf Petiole Vegetables, Crop Subgroup 4B

D 324318 07, Feb2006 CYMOXANIL

- Exposure/Risk Assessment for the Proposed Use of Cymoxanil on Grapes and Hops, February 7, 2006

D 286768 14

, June 001 CYMOXANIL

- Exposure/Risk Assessment fromthe Proposed New Uses of Cymoxanil on Cucurbit Vegetables (Cucumber, Melon, Squash), Fruiting Vegetable (Tomato, Bell/Non Bell Pepper) and Head Lettuce

D347653 09, Jul 2008 CYMOXANIL; Human Health Risk Assessment f or Proposed Uses on Bulb Vegetables (Crop Group 3

- 07), Leafy Greens (Subgroup 4A), and Leaf Petioles (Subgroup 4B)

D349396 01, Jul 2008 Cymoxanil Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment[s] for the Section (3) Registration Action July,

1st 2008

. NA 05

, May 2011 Agricultural Transfer Coefficients ( Policy 3.2 )

, Science Advisory Council for Exposure (ExpoSAC)

D 395156 18, Oct 2011 CYMOXANIL

- Review of Human Incidents



### Attachment s :

Attachment 1 Chemical Identity Table Attachment 2 Cymoxanil Toxicology Study Status

Attachment 3 Cymoxanil Endpoint Selection Table

Attachment 4 Cymoxanil Products and Use Sites

Attachment 4 Cymoxanil Toxicology Study Status Attachment 5 Cymoxanil Toxicology Study Status

Attachment 6 International Residue Limit Status

### Cymoxanil Registration Review Scoping Document DP395155

Page 18 of 27 Attachment 1 Chemical Identity Table
Chemical Identity Table

Compound

Common name Cymoxanil

Company experimental name DPX

- T3217

IUPAC name 1

- [(EZ)

- 2

- cyano

- 2

- methoxyiminoacetyl]

- 3

- ethylurea

CAS name 2

- cyano

- N

- [(ethylamino)carbonyl]

- 2

- (methoxyimino) acetamide

CAS registry number 57966

- 95

- 7

### Cymoxanil Registration Review Scoping Document DP395155

Page 19 of 27 A ttachment 2 Cymoxanil Toxicology Study Status

Table 2.1 Acute Toxicity of Cymoxanil Technical Grade Active Ingredient (TGAI).

Guidelin

e No. Study Type MRID NO. Results Toxicity Category

81

- 1 Acute Oral 43616512 LD 50 = 960 mg/kg III

81

- 2 Acute Dermal 43616513 LD 50 > 2000 mg/kg III

81

- 3 Acute Inhalation 42706303 LC 50 = >5.06 mg/L IV

81

- 4 Primary Eye Irritation 43616514 Non

- irritant IV

81

- 5 Primary Skin Irritation 43616515 Mild or slight irritant IV

81

- 6 Dermal sensitization 43640501 Non sensitizer N/A

NA = Not applicable

Table 2.2 Toxicity Profile of Cymoxanil

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

870.3100

90

- Day oral Toxicity rodents (rat) 43616516 (1993)

Acceptable/Guideline 0, 100, 750, 1500, or 3000 ppm, M: 0, 6.54, 47.6, 102, or 224 mg/kg/day

F: 0, 8, 59.9, 137, or 333 mg/kg/day Systemic Toxicity NOAEL = 47.6 mg/kg/day in males and 59.9 mg/kg/day in females Systemic Toxicity LOAEL = 102 mg/kg/day in males and 137 mg/kg/day in females, based on decreases in body weights, body weight gains and food efficiency in the females, and body weight decreases and testicular and epidid y al changes in males.

870.3100

90

- Day oral Toxicity rodents (mouse) 43616517 (1992)

Acceptable/Guideline 0, 50, 5 00, 1750, 3500, or 7000 ppm M: 0, 8.25, 82.4, 294, 566, or 1306 mg/kg/day F: 0, 11.3, 121, 433, 846, or 1130 mg/kg/day Systemic Toxicity NOAEL = 8.25 mg/kg/day in males and 121 mg/kg/day in females Systemic Toxicity LOAEL = 82.4 mg/kg/day in males

and 433 mg/kg/day in females, based on statistically significant dose

- related decreased body weights in males and increased absolute liver weights in females.

870.3150

90

- Day oral toxicity in non

rodents (dog) 43640502 (1992)

Acceptable/Guideline 0, 100, 200 ppm (0, 3, 5 mg/kg/day) for 13 weeks, or 250 ppm (5 mg/kg/day) for 2 weeks followed by 500 ppm (11 mg/kg/day) for 11 weeks. Systemic Toxicity NOAEL not established Systemic Toxicity LOAEL= 3 mg/kg/day , based on decreased body weights (13%) and food consump tion in

females.

870.3200

21/28

- Day dermal toxicity (rat) 44180705 (1996)

Acceptable/Guideline 0, 50, 500 or 1000 mg/kg/day Systemic and Dermal Toxicity NOAEL = 1000 mg/kg/day (HDT) Systemic and Dermal Toxicity LOAEL was not
established.

870.3700a

Prenatal developmental (rat) 43616524 (1993)

Acceptable/Guideline 0, 10, 25, 75, or 150 mg/kg/day Maternal NOAEL = 25 mg/kg/day Maternal LOAEL= 75 mg/kg/day, based upon reduced body weight, body weight change and food consumption Developmental NOAEL = 10 mg/kg/day Developmental LOAEL = 25 mg/kg/day, based upon significant increase in overall malformations, and generalized dose

- related delay in skeletal ossification; at 75 and 150 mg/kg/day significant decrease in fetal body weights; at 150 mg/kg/day increa sed early resorptions resulting in reduced litter size.

870.3700b

Prenatal developmental (rabbit) 43640503 & 43616523 (1982)

Acceptable/Guideline 0, 1, 4, 8, or 32 mg/kg/day Maternal NOAEL 32 mg/kg/day

Maternal LOAEL was not established Developmental NOAEL = 4 mg/kg/day Developmental LOAEL = 8 mg/kg/day , based upon an

increase in skeletal anomalies of the cervical and thoracic vertebrae and ribs; at 32 mg/kg/day, cleft palate was also

observed.

870.3700b 43616522 (1981) Maternal NOAEL = 16 mg/kg/day

### Cymoxanil Registration Review Scoping Document DP395155

Page 20 of 27 Table 2.2 Toxicity Profile of Cymoxanil

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

Prenatal developmental (rabbit) Unacceptable/Guideline, however, in conjunction

with MRIDs 43616521, 43616523 & 43640503 provides valuable information in selecting the maternal and developmental end

- points. 0, 8, 16, or 32 mg/kg/day Maternal LOAEL = 32 mg/k g/day, based upon increased incidence of clinical signs and body weight loss during first 4 days of treatment. Developmental NOAEL 8 mg/kg/day (not established) Developmental LOAEL = 8 mg/kg/day, based upon an

increase in skeletal anomalies of the cervical and thoracic

vertebrae and ribs.

870.3700b

Prenatal developmental (rabbit) 4361652 1 (198 0 )

Unacceptable/Guideline, however, in conjunction

with MRIDs 4361652 2 , 43616523 & 43640503 provides valuable information in selecting the maternal and developmental end

- points. 0, 4

, 8 , or 16 mg/kg/day Maternal NOAEL = 16 mg/kg/day (HDT)

Maternal LOAEL = not determined. Developmental NOAEL ≥16 mg/kg/day (HDT)) Developmental LOAEL = not determined.

870.3800

2

- Generation Reproduction and Fertility Effects (rat; dietary) 43616520 (1993)

Acceptable/Non

- guideline

0, 1 0 0, 50 0, or 150 0 ppm [equal to 0/0, 6.5 / 7.9,

32.1 / 40.6 , or 9 7.9 / 130 mg/kg bw/day (M/F)] Parental NOAEL = 6.5 / 7.9 (M/F) mg/kg/day

Parental LOAEL = 32.1 /

40.6 (M/F) mg/kg/day based on reduced premating body weight, body weight gain, and food consumption for P males; decreased gestation and lactation body weight for F1 females.

Offspring NOAEL = 6 .5/ 7 .9 (M/F) mg/kg/day

Offspring LOAEL = 32.1 / 40.6 (M/F) mg/kg/day based on

decreased F1 pup viability on postnatal days 0

- 4 and on significant reduction in F2b pup weight.

870.3800

2

- Generation Reproduction and Fertility Effects (rat; dietary) 46749810 (2001)

Acceptable/Non

- guideline

0, 150, 450, or 350 ppm [equal to 0/0, 10.5/14.9, 31.6/42.8, or 94/116.3 mg/kg bw/day (M/F)] Parental NOAEL = 31.6/42.8 (M/F) mg/kg/day

Parental LOAEL = 94/116.3 (M/F) mg/kg/day based on decreases in body weight, body weight gain, and food consumption in F0 and F1 generat ions

Reproductive NOAEL = 94/42.8 (M/F) mg/kg/day

Reproductive LOAEL = 116.3 (F) mg/kg/day based on decreased mean number of corpora lutea and mean number of implantations and increased post

- implantation loss in F1 females (LOAEL not observed in males)

Offspring NOAEL = 10.5/14.9 (M/F) mg/kg/day

Offspring LOAEL = 31.6/42.8 (M/F) mg/kg/day based on decreased body weight during lactation in both F1 and F2 generations

870.4100

Chronic Toxicity (dog; dietary) 46749811 (2003)

Acceptable/Guideline

0/0, 50/ 25, 100/50, or 250/100 ppm (equal to 0/0, 1.3/0.8, 2.8/1.4, or 5.6/2.9 mg/kg bw/day) (M/F) NOAEL not observed.

LOAEL = 1.3/0.8 (M/F) mg/kg/day based on decreased absolute and relative thymus weights and histopathology of the thymus (thymic atrophy/involu tion) (M) and decreased thymus weights (F)

870.4 2 00

C arcinogenicity rodents ( mouse) 436165 19 (1994)

Acceptable/Guideline 0, 30

, 3 00, 15 00, or 3 000 ppm M: 0, 4.19

, 42.0

, 216 , or 446 mg/kg/day F: 0, 5.83

, 58.1

, 298 , or 582 mg/kg/day Systemic toxicity NOAEL = 4. 19 mg/kg/day for males

and 5. 83 mg/kg/day for females Systemic toxicity LOAEL = 42 mg/kg/day for males and

58.1 mg/kg/day for females (HDT)

, based upon increased frequency of sperm cyst/cystic dilation, tubular dilation and lymphoid aggregates in male s and hyperplastic gastropathy

in females. No evidence of carcinogenicity.

870.4300

Combined chronic toxicity/carcinogeni city rodents (rat) 43616525 (1994)

Acceptable/Guideline 0, 50, 100, 700, or 2000 ppm M: 0, 1.98, 4.08, 30.3, or 90.1 mg/kg/day

F: 0, 2.71, 5.36, 38.4, or 126 mg/kg/day Systemic toxicity NOAEL = 4.08 mg/kg/day for males and 5.36 mg/kg/day for females Systemic toxicity LOAEL = 30.3 mg/kg/day for males and 38.4 mg/kg/day for females, based upon decreased body weight, body weight gain, and food efficiency, increased incidence of elongate spermatid degeneration and increased aggressiveness and/or hyperactivity in males and

increased incidence of non

- neoplastic lesions of the lungs,

live r, sciatic nerve and retinal atrophy in females. No evidence of carcinogenicity.

### Cymoxanil Registration Review Scoping Document DP395155

Page 21 of 27 Table 2.2 Toxicity Profile of Cymoxanil

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

870.5100 Bacterial gene mutation assay 43616526 (1992)

Acceptable/Guideline Salmonella typhimurium strains TA1535, TA97, TA98 and TA100 were exposed to Cymoxanil Technical (96.5

- 97.8%) at concentrations of 10

- 2500 μg/plate with or without S9 activation (both trials). Cytotoxicity in all strains was seen at 750 μg/plate

- S9 and 1000 μg/plate +S9. The positive controls induced the expected mutagenic responses in the appropriate tester

strain. There was, however, no evidence that the test material induced a mutagenic effect under any test

condition.

870.5300

In vitro mammalian cell gene mutation assay (CHO) 43616527 (1993)

Acceptable/Guideline Chinese hamster ovary (CHO) cells were exposed to Cymoxanil Technical (96.5

- 97.8%) in dose ranges of

5

- 750 μg/mL

- S9 (both trials) and S9

- activated doses

of 10

- 1500 μg/mL (Trials 1 and 2) or 250

- 1500 μg/mL (Trial 3). Severe cytotoxicity was seen at 750 μg/ mL

- S9 and 1000 μg/mL +S9. The positive controls induced the expected mutagenic responses. There was, however, no evidence that the test material was mutagenic at the HGPRT locus at any dose under any assay condition.

870.5375

In vitro mammalian

chro mosomal

aberration test 42706302 (1993)

Acceptable/Guideline Human lymphocytes were exposed to Cymoxanil Technical (96.5

- 97.8%) in dose ranges of 100

- 1500 μg/mL ± S9 activation. Significant and dose

- related clastogenic effects were seen at 1250 and 1500 μg/mL

- S9 activation and at 850, 1250 and 1500 μg/mL +S9 activation. Cymoxanil is clastogenic both in the presence and absence of S9 activation.

870.5395

Mammalian erythrocyte

micronucleus test 43616528 (1993)

Accep table/Guideline Groups of six male and six female CR1:CD®

- 1(ICR)BR mice received single oral gavage administrations of 450 or 350 mg/kg Cymoxanil Technical (96.5

- 97.8%), respectively; lower doses (125 or 225 mg/kg) were administered to groups of

five male and five female mice. High

- dose group were sacrificed at 24, 48 and 72 hours post

administration; mice in the low

- and mid

- dose groups were sacrificed 24 hours post

- dosing. Death occurred in 6/18 high

- dose (350 mg/kg) females. Other signs of compound tox icity noted in the high

- dose males and females included abnormal gait, lethargy and tremors. Suggestive evidence of bone marrow cytotoxicity was seen in the high

- dose females at the 48

- hour cell harvest and in the high

- dose males at the 24

- hour harvest. The positive control induced the expected high yield of MPEs in

males and females. There was, however, no evidence that the test material induced a clastogenic or aneugenic effect in either sex at any dose or sacrifice time.

870.5550

Unscheduled DNA synthesis in

mammalian cells in

culture 42706301 (1993)

Acceptable/Guideline Primary rat hepatocytes were exposed to Cymoxanil Technical (96.5

- 97.8%) at dose levels of 5 to 500 μg/mL Cytotoxicity was observed at levels 500 μg/mL. Cymoxanil tested positiv e over 5 to 500 μg/mL range.

870.5550

Unscheduled DNA synthesis in

mammalian cells in

culture 43616529(1994)

Acceptable/Guideline Groups of five male CR1:CD®BR rats were administered single oral gavage doses of 500 or 1000 mg/kg Cymoxanil Technical (96.5

- 97.8%) in 0.5% methyl cellulose. At 2 and 16 hours post

- treatment hepatocytes and spermatocytes were scored for UDS. Clinical signs of toxicity noted in both treatment groups included death (3 of 10 rats at 1000 mg/kg; 1 of 10 rats at

50 0 mg/kg), lethargy, prostrate posture, labored or rapid respiration, tremors, diarrhea and abnormal gait (both study groups). Cytotoxicity was not observed in either target tissue. Positive controls responded appropriately. There was, however, no evidenc e that the test material induced a genotoxic response in either tissue at any dose or

sacrifice time.

870.6200 Neurotoxicity screening/Subchron ic neurotoxicity 43616516 (1993)

Acceptable/Guideline 0, 100, 750, 1500, or 3000 ppm, M: 0, 6.54, 47.6, 102, or 224 mg/kg/day F: 0, 8, 59.9, 137, or 333 mg/kg/day No effects on the functional observation battery, or motor activity were observed. No treatment

- related gross or microscopic findings in the nervous system or skeletal

muscles of the male and female ra ts were observed.

Subchronic systemic toxicity consisted of decreases in body weight/body weight gains and food efficiency in females, and body weight decreases and testicular and epididymal changes in males.

The Subchronic systemic LOAEL = 102/137 mg/kg/day (M/F). The systemic NOAEL = 47.6/59.9 mg/kg/day (M/F).

The Neurotoxicity NOAEL 3000 ppm (224 mg/kg/day in males and 333 mg/kg/day in females; HDT). Neurotoxicity LOAEL was not established.

### Cymoxanil Registration Review Scoping Document DP395155

Page 22 of 27 Table 2.2 Toxicity Profile of Cymoxanil

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

870.6300 Developmental

neu rotoxicity (rat) 45377901 (2001)

Acceptable/Non

- guideline 0, 5, 50 or 100 mg/kg/day Maternal Toxicity NOAEL = 50 mg/kg/day Maternal Toxicity LOAEL = 100 mg/kg/day , based on slight decrease body weight, body weight gains (17%) and food consumption. Offspring NOAEL = 50 mg/kg/day Offspring LOAEL = 100 mg/kg/day , based on decreased pup survival, decreased pup weight and body weight gain during early lactation (less than 6%), increases in morphometric measurements (anterior/posterior cerebrum for males, cerebellar height for females) at PND 79

- 83, and

decreased retention in the water maze task for adult females (latency 158% of control levels) seen at the LOAEL of 100 mg/kg/day. 870.7485

Metabolism and pharmacokinetics (rat) 43616530 & 43616531 (1994)

A cceptable/Guideline

[2

- 14 C]cymoxanil (98% a.i.) was administered to male and female Crl:CD/BR rats (3

- 5 animals/sex/dose) by gavage as a single dose at levels of 2.5 or 120 mg/kg, or as a single dose (2.5 mg/kg) following a 14

- da y pretreatment with unlabeled cymoxanil (2.5 mg/kg/day). Cymoxanil was readily absorbed and 86 to 94% of the administered dose was excreted in 96 hours. The majority of the administered dose was recovered in the urine (64

- 57%) with smaller amounts excre ted in the feces (16

- 24%) and carcass (< 1%). There were no sex

- related differences in the absorption, distribution and metabolism of cymoxanil.

In urine about 37

- 55% of the dose was free and/or conjugated [ 14 C]glycine and 2 cyano

- 2

- methoxyiminoaceti c acid (IN

- W3595; about 7 to 33% of the dose). Intact cymoxanil was not isolated in urine. In feces intact [ 14 C]cymoxanil (< 1%) and IN W3595 was detected, but the majority of radioactivity was [ 14 C]glycine (about 9

- 13%). Based on the data, the metab olic pathway involves hydrolysis of cymoxanil to IN W3595, which is then degraded to glycine, which in turn is incorporated into

natural const ituents or further metabolized.

870.7800 Immunotoxicity (rat; dietary) 44944601 (1999)

Acceptable/Guideline 0, 200, 400, 800, or 1600 ppm [equivalent to 0/0, 14/16, 27/31, 54/59, or 108/117 mg/kg bw/day (M/F)] NOAEL = 108/117 (M/F) mg/kg/day

LOAEL not observed.

870.7800 Immunotoxicity (mouse; dietary) 44944602 (1999)

Acceptable/Guideline 0/0, 30/30, 300/300, 600/1200, or 1200/2400 ppm (equivalent to 0/0, 5/7, 56/71, 108/269, or 218/552 mg/kg bw/day) (M/F) NOAEL = 218/552 (M/F) mg/kg/day

LOAEL not observed.

### Cymoxanil Registration Review Scoping Document DP395155

Page 23 of 27 Attachment 3 Cymoxanil Endpoint Selection Table

Table3.1 Summary of Toxicological Doses and Endpoints for Cymoxanil for Use in Human Health Risk Assessments 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) N/A N/A N/A An endpoint of concern (effect) attributable to a single dose was not identified in the database. Quantification of acute risk to general population, including infants and children, is not required.

Acute Dietary (Females

13

- 49 years of age) NOAEL = 4 mg/kg/day UF A = 10X

UF H = 10X

FQPA SF = 1X aRfD = aPAD = 0.04 mg/kg/day Developmental toxicity (rabbit)

Offspring LOAEL = 8 mg/kg/day based

on increased skeletal malformations of

the cervical and thoracic vertebrae and

ribs

Chronic Dietary (All populations) NOAEL < 0.8 mg/kg/day UF A = 10X

UF H = 10X

FQPA SF 1 = 10X (includes UF L = 10X) cRfD = cPAD = 0.0008 mg/kg/day Chronic toxicity (dog; 2003) LOAEL =

1.3/0.8 mg/kg/day (M/F), based on decreased absolute and relative thymus weights and histopathology of the thymus (thymic atrophy/involution) in males and decreased thymus weights in

females

Incid ental Oral

Short

- Term (1

- 30 days) NOAEL = 10.5 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Residential LOC

for MOE = 100 2

- generation reproduction (rat; 2001)

Offspring LOAEL = 31.6/42.8 mg/kg/day (M/F) based on decreased body weight during lactation in both F 1 and F 2 generations

Incidental Oral

Intermediate

- Term (1

- 6 months) NOAEL = 6.5 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Residential LOC

for MOE = 100 2

- generation reproduction (rat; 1993)

Parental LOAEL = 32.1 mg/kg/day (M/F) based on reduced premating body weight, body weight gain, and food consumption for P males; and decreased gestation and lactation body weights for

F1 females

Dermal

Short

- Term (1

- 30 days) NOAEL = 4 mg/kg/day

(Dermal absorption = 7.5%) 2 UF A = 10X

UF H = 10X FQPA SF = 1X Residential/ Occupational LOC

for MOE = 100 Developmental toxicity (rabbit)

Offspring LOAEL = 8 mg/kg/day based

on increased skeletal malformations of

the cervical and thoracic vertebrae and

ribs

Dermal

Intermediate

- Term (1

- 6 months) NOAEL = 4 mg/kg/day

(Dermal absorption = 7.5%) 2 UF A = 10X

UF H = 10X FQPA SF = 1X Residential/ Occupational LOC

for MOE = 100 Developmental toxicity (rabbit)

Offspring LOAEL = 8 mg/kg/day based

on increased skeletal malformations of

the cervical and thoracic vertebrae and

ribs

Dermal Long

- Term (> 6 months) NOAEL < 0.8 mg/kg/day

(Dermal absorption = 7.5%) 2 UF A = 10X

UF H = 10X FQPA SF 1 = 10X (includes UF L = 10X) Residential/ Occupational LOC

for MOE = 1000 Chronic toxicity (dog; 2003) LOAEL =

1.3/0.8 mg/kg/day (M/F), based on decreased absolute and relative thymus weights and histopathology of the thymus (thymic atrophy/involution) in

males and decreased t hymus weights in

females

Inhalation

Short

- Term (1

- 30 days) NOAEL = 4 mg/kg/day

(100% inhalation absorption assumed) UF A = 10X

UF H = 10X FQPA SF = 1X Residential/ Occupational LOC

for MOE = 100 Developmental toxicity (rabbit)

Offspring LOAEL = 8 mg/kg/day based

on increased skeletal malformations of

the cervical and thoracic vertebrae and

ribs

Inhalation

Intermediate

- Term (1

- 6 months) NOAEL = 4 mg/kg/day

(100% inhalation absorption assumed) UF A = 10X

UF H = 10X FQPA SF = 1X Residential/ Occupational LOC

for MOE = 100 Developmental toxicity (rabbit)

Offspring LOAEL = 8 mg/kg/day based

on increased skeletal malformations of

the cervical and thoracic vertebrae and

ribs

Inhalation NOAEL < 0.8 UF A = 10X Residential/ Chronic toxicity (dog; 2003) LOAEL =

### Cymoxanil Registration Review Scoping Document DP395155

Page 24 of 27 Long

- Term (>6 months) mg/kg/day

( 100% inhalation absorption assumed) UF H = 10X

FQPA SF 1 = 10X (includes UF L = 10X) Occupational LOC

for MOE = 1000 1.3/0.8 mg/kg/day (M/F), based on

decreased absolute and relative thymus weights and histopathology of the thymus (thymic atrophy/involution) in males and decreased thymus weights in

females

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning

of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human ( interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = to account for the absence of key date (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposur e. LOC = level of concern. N/A = not appli cable.

The 10X FQPA SF has been retained in the form of a UF L to account for the use of a LOAEL to extrapolate a NOAEL

2 An upper

- bound estimate calculated as follows by comparing the maternal LOAEL from the oral developmental toxicity study (rat) with th e NOAEL from the dermal toxicity study (rat): [(75 mg/kg/day ÷ 1000 mg/kg/day) x 100%] = 7.5%; the last HIARC report of Jan. 2, 2003 incorrectly calculated this to be 2.5%

### Cymoxanil Registration Review Scoping Document DP395155

Page 25 of 27 Attachment 4 . Cymoxanil Products and Use Sites

The currently registered products containing cymoxanil as an active ingredient and t he use

directions of end

- products containing cymoxanil are listed in the tables below.

Table 4.1 List of Products Containing Cymoxanil.

EPA Reg. No. Active Ingredient (%) Product's Name Use Site Formulation Type

264

- 973 1 Evolve TM Potato Seed Piece Treatment Dust

352

- 591 98.7 Dupont TM Cymoxamil

Technical Manufacture of fungicides_ Dry Flowable

352

- 592 60 Dupont TM Curzate ® Potatoes, Potato Seed Piece Treatment

, Curcurbits, Lettuce, Spinach, Hops and

Tomatoes Dry Flowable

352

- 604 25 Dupont TM Tanos ® 1 Bulb Vegetables (subgroup 3

- 07A) Green onion (subgroup 3

- 07B) Caneberries (subgroup13

- 07 A)

Curcurbit Vegetables Grapes (East of Rocky Mountains) Hops Leafy vegetables (except Brassica) Leafy greens ((subgroup 4A) Leaf petioles (subgroup 4B) Peppers

Potatoes

Tomatoes Dry Flowable

1 Not intended for use in home plantings

Table4.2 Use Directions of End

- use Product Formulations Containing Cymoxanil.
EPA Reg. No.

Appl ication Application Rate Appl. Equipment Timing of Applications REI

264

- 973 Potato seed piece treatment 0.75 lb ai /100 lb

of seed Seed T reater Plant seed

– pieces as soon as possible after cutting and treating. 48

hours

352

- 592 Applications may be repeated at 14

day intervals. There is a 7 day preharvest interval (PHI). 0.15 lb ai/A Ground, Air and Chemigation Seed Treatment (except CA) Crop rotation restrictions 12

hours

352

- 604 Make preventive applications on a

5

- to 7

- day schedule. Tanos ® Fungicide must be tank

- mixed with a contact fungicide which has a

different mode of action. Do not

alternate or tank mix with other Group 11 fungicides or with fungicides to which resistance has developed. In a cropping season, no

more than 50% of the total applications should contain Tanos® Fungicide or other Group 11 fungicides. PHI varies per crop (0 days for caneberries up to 30 days for grapes. 0.16 lb ai/A

0.16 lb ai /100 lb

of seed Foliar spray

Ground (20 GPA), Aerial (min 5 GPA), or Chemigati on Crop rotation restrictions for some crops 12

hours

### Cymoxanil Registration Review Scoping Document DP395155

Page 26 of 27 Attachment 5 Cymoxanil Toxicology Study Status

Table 5.1. Toxicology Data Requirements

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ...................... 870.1200 Acute Dermal Toxicity

................................ ................. 870.1300 Acute Inhalation Toxicity

................................ ............. 870.2400 Primary Eye Irritation

................................ ................... 870.2500 Primary Dermal Irritation

................................ ............. 870.2600 Dermal Sensitization

................................ .................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

................................ .............. 870.3150 Oral Subchronic (nonrodent)

................................ ........ 870.3200 21/28

- Day Dermal

................................ ........................ 870.3250 90

- Day Dermal

................................ ............................. 870.3465 90

- Day Inhalation

................................ ......................... yes

yes

yes

no

yes yes

yes

yes

no

yes

870.3700a Developmental Toxicity (rodent)

................................ . 870.3700b Developmental Toxicity (nonrodent)

........................... 870.3800 Reproduction

................................ ................................ yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

................................ ............. 870.4100b Chronic Toxicity (nonrodent)

................................ ....... 870.4200a Oncogenicity (rat)

................................ ......................... 870.4200b Oncogenicity (mouse)

................................ .................. 870.4300 Chronic/Oncogenicity

................................ .................. yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

.................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

............... 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

.. 870.5395 Mutagenicity

— Other Genotoxic Effects

...................... yes

yes

yes

yes yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen)

................................ .... 870.6100b 90

- Day Neurotoxicity (hen)

................................ ......... 870.6200a Acute Neurotox. Screening Battery (rat)

...................... 870.6200b 90 Day Neurotox. Screening Battery (rat)

.................... 870.6300 Develop. Neuro

................................ ............................ no

no

yes

yes

yes no

no

yes

yes

yes

870.7485 General Metabolism

................................ ..................... 870.7600 Dermal Penetration

................................ ....................... 870.7800 Immunotoxicity in Rats..................................... yes

no

yes yes

no

yes

### Cymoxanil Registration Review Scoping Document DP395155

Page 27 of 27 Attachement 6 : International Residue Limits

Table 6.1 Summary of US and International Tolerances and Maximum Residue Limits for Cymoxanil

Residue Definition :
US Canada Mexico 2 Codex 3

40 CFR 180.503: Plant: Cymoxanil

- [ 2

- cyano

- N

- [(ethylamino)carbonyl]

- 2

- (methoxyimino) acetamide]

Livestock: N/A 2

- cyano

- N

- [(ethylamino)carbonyl]

- 2

- (methoxyimino)

acetamide None

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

US Canada Mexico 2 Codex 3

Caneberry, subgroup 13A

- 07 4.0 4.0 Blackberries, loganberries, raspberries, wild raspberries
Cilantro, leaves 19 Hop, dried cones 7.0 Leafy greens, subgroup 4A 19 Leaf petioles, subgroup 4B 6.0 Lychee 1 1.0 Onion, bulb, subgroup 3

- 07A 0.05 Onion, green, subgroup 3

- 07B 1.1

Potato 0.05 0.05 Vegetable, cucurbit, group 9 0.05 Vegetable, fruiting, group 8 0.2 MRLs with No US Equivalent

Fat of cattle 0.05 Fat of goats 0.05 Fat of hogs 0.05 Fat of sheep 0.05 Meat by products of cattle 0.05 Grape 0.1 Meat by products of goats 0.05 Meat by products of hogs 0.05 Meat by products of sheep 0.05

Meat of cattle 0.05 Meat of goats 0.05 Meat of hogs 0.05 Meat of sheep 0.05

Milk 0.05 Completed: M. Negussie; 05/09/2011

1 There is no U.S. registration for lychee.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation ; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.