Mandipropamid Risk Assessment Document DP Number: 374096 PC Code: 036602

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Page 1 of 15 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION MEMORANDUM

Date: 27-April-2010

SUBJECT: Mandipropamid; Human Health Risk Assessment for the Section 18 Use on Basil.

PC Code: 036602 DP Number: 374096 Decision No.: 421080 Registration No.: 100-1254 Petition No.: 09IL01 Regulatory Action: Section 18 Risk Assessment Type: Single Chemical, Aggregate Case No.: NA

T XR No.: Not Applicable CAS No .: 374726-62-2 MRID No.: None 40 CFR: § 180.637

FROM: Roger Chesser, Biologist ARIA/RIMUERB/RD (7505P)

THROUGH: Breann Hanson, Biologist ARIA/RIMUERB/RD (7505P)

Michael A. Doherty, Ph.D., Chemist Registration Action Branch 2 (RAB2) Health Effects Division (HED; 7509P)

TO: Barbara Madden ARIA/RIMUERB/RD (7505P)Mandipropamid Risk Assessment Document DP Num: 374096

Page 2 of 15 Table of Contents 1.0 Executive Summary .......................................................................................................... 3 2.0 Ingredient Profile .............................................................................................................. 4 2.1 Structure and Nomenclature ............................................................................... 4 2.2 Physical and Chemical Properties ....................................................................... 5 2.3 Summary of Proposed Uses .................................................................................. 5 3.0 Hazard Characterization/Assessment ............................................................................. 6 3.1 Endocrine Disruption ........................................................................................... 7 4.0 Public Health and Pesticide Epidemiology Data ............................................................ 8 5.0 Dietary Exposure/Risk Characterization ....................................................................... 8 5.1 Pesticide Residue Profile ...................................................................................... 8 5.2 Dietary Exposure and Risk ................................................................................ 10 6.0 Residential and Other Expo sures (Spray Drift, etc.) ................................................... 11 7.0 Aggregate Risk Assessments and Risk Characterization ............................................ 12 8.0 Cumulative Risk Characterization/Assessment ........................................................... 12 9.0 Occupational Exposure/Risk Pathway .......................................................................... 12 9.1 Short-/Intermediate-Term Occupational Handler Risk .................................. 13 9.2 Short-/Intermediate-Term Occupa tional Post-application Risk .................... 13 10.0 References: ....................................................................................................................... 14 Appendix A: Tolerance Setting ................................................................................................. 15 Appendix B: Review of Human Research ................................................................................ 15Mandipropamid Risk Assessment Document DP Num: 374096

Page 3 of 15 1.0 Executive Summary

The Illinois Department of Agriculture has decl ared a crisis Section 18 exemption allowing the use of mandipropamid (as RevusTM Fungicide , EPA Reg. No. 100-1254) on basil to control downy mildew. Basil is harvested many times during the season, and the use of RevusTM Fungicide will extend the growing season until th e first frost, approximately six additional weeks. The previous risk assessment c onducted for mandipropamid was completed in conjunction with its registration for use on t obacco (DP Num; 365919, D. Rate, 8/JUL/2009).

Mandipropamid is a fungicide in the mandelamide class developed by Syngenta Crop Protection, Inc. for the control of foliar oomycete pathogens in a range of crops including Plasmopara viticola in grapes, Phytophthora infestans in potatoes and tomatoes, and Pseudoperonospora cubensis in cucurbits.

The product requested for emergency use is RevusTM Fungicide (EPA Reg. No. 100-1254). The use pattern summary is taken from draft Sect ion 18 labeling and the RevusTM product label. Revus is a liquid formulation which contains 2.08 lb ai (23.3%) mandipropamid per gallon. The product is proposed for multiple foliar applic ations using ground, chemigation, or aerial equipment at a maximum seasonal rate of 32 fluid oz formulation/A/season or 4 applications/A/season at the maximum rate of a pplication. The proposed preharvest interval (PHI) is 7 days.

For the purposes of this Section 18, the toxicolo gy data base is adequate. Mandipropamid has low or minimal acute toxicity vi a the oral (Category IV), dermal (Category IV), and inhalation routes of exposure (Category IV). It is minimally irritating to the eye (Category IV), nonirritating to the skin (Category IV) and is negative for skin sens itization. Liver toxicity was the primary effect and was observed in rats, mi ce and dogs. There was no evidence of increased neonatal sensitivity in the developmental and repr oduction toxicity studies, and no evidence of developmental effects, neurotoxicity, mutage nicity or carcinogenici ty after exposure to mandipropamid. The FQPA Safety Fact or (SF) has been reduced to 1X.

Based on the available data, there are no eff ects attributable to a 1-day exposure to mandipropamid which are appropriate for assessing acu te risks. Similarly, there are no effects attributable to dermal exposure. Therefore, only inhalation and chr onic dietary points of departure have been selected.

No data depicting residues of mandipropamid in /on basil are available at this time. ARIA translated residue data from vegetables, leafy (C rop Group 4) to derive an appropriate tolerance level for basil, fresh, and used maximum theoretical concentration factors (12X) for recommending a conservative to lerance for basil, dried.

A screening-level dietary assessment (food + dri nking water), based on tolerance-level residues and 100% of crops treated, indicate s that chronic dietary risks ar e below OPP’s level of concern for all population subgroups. There are no us es of mandipropamid that would result in residential exposure that OPP can assess; theref ore, there are no aggregate risks of concernMandipropamid Risk Assessment Document DP Num: 374096

Page 4 of 15 either. Occupational risk estimates associated with this emergency exemption are also below OPP’s level of concern.

No risks of concern have been identified fo r the emergency exemption use of mandipropamid on basil; therefore, ARIA recommends for gran ting the exemption and establishing time-limited tolerances for residues of mandipropamid in/on ba sil, fresh at 20 ppm a nd basil, dried at 240

ppm.

Environmental Justice

Potential areas of environmental ju stice concern, to the extent possi ble, were considered in this human-health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions to Address Environmental Just ice in Minority Populations an d Low-Income Populations," ( http://homer.ornl.gov/nuclearsafety/n sea/oepa/guidance/justice/eo12898.pdf ).

As a part of every pesticide risk assessment , OPP considers a large variety of consumer subgroups according to well-establis hed procedures. In line with O PP policy (as it relates to an imported crop), ARIA estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food consum ption. Extensive data on food consumption patterns are compiled by the USDA under the Conti nuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all proposed/registered food uses/tolerances of a pesticide. These data ar e analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specia lized subgroups and exposure assessments are performed when conditions or ci rcumstances warrant. Further c onsiderations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure fr om traditional dietary patterns among specific subgroups.

Human Data

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies (listed in Appendix B) have been determined to require a re view of their ethical conduct, and have received that review.

2.0 Ingredient Profile

The chemical structure and nomenclature of ma ndipropamid are presented in Table 2.1. The physicochemical properties of th e technical grade mandipropami d are presented in Table 2.2. Mandipropamid is a fungicide in the mandelamide class developed by Syngenta Crop Protection, Inc. for the control of foliar oomycete pathoge ns in a range of crops . A summary of the proposed uses is presented in Table 2.3.

2.1 Structure and NomenclatureMandipropamid Risk Assessment Document DP Num: 374096

Page 5 of 15 Table 2.1. Test Compound Nomenclature. Compound

Common name Mandipropamid

Cl O CH

O N H O CH 3

O CH

Company experimental name NOA 446510

IUPAC name ( RS )-2-(4-chloro-phenyl)- N -[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2- prop-2-ynyloxy-acetamide

CAS name 4-chloro- N -[2-[3-methoxy-4-(2-propynyloxy)phenyl]ethyl]- α -(2-propynyloxy)- benzeneacetamide CAS registry number 374726-62-2 End-use product (EP) RevusTM (2.08 lb/gal; EPA Reg. No. 100-1254), (Alternate Brand Name: Mandy Flowable Fungicide)

2.2 Physical and Chemical Properties Table 2.2. Physical and chemical Properties of the Technical Grade of Mandipropamid.

Parameter Value Reference Melting point/range 96.4-97.3oC Molecular formula/weight C 23 H 22 ClNO 4 / 411.9 pH 6-8 at 25oC (1% aqueous dispersion) Density 1.24 x 10 3 kg/m 3 at 22oC Water solubility (25°C) 4.2 mg/L Solvent solubility (25°C) n-hexane 42 mg/L n-octanol 4.8 g/L toluene 29 g/L methanol 66 g/L ethyl acetate 120 g/L acetone 300 g/L dichloromethane 400 g/L Vapor pressure <9.4 x 10 -7 Pa at 25°C or <7.0 x 10 -9 mmHg Dissociation constant, pK a No dissociation constant in the pH range of 1 to 12 Octanol/water partition coefficient, Log(P OW ) 3.3 at 25oC MRID 46800006 (100-REIR.doc, S. Mathur, 22/MAY/2007)

2.3 Summary of Proposed Uses

Table 2.3. Details of Proposed Uses of 2.08 lb ai/gal FlC (Revus TM ) on Basil.

Application Timing, Type, and Equipment Maximum Single Application Rate (lb ai/A) Maximum Number of Applications per Season Maximum Seasonal Application Rate (lb ai/A) PHI (days)Mandipropamid Risk Assessment Document DP Num: 374096

Page 6 of 15 Table 2.3. Details of Proposed Uses of 2.08 lb ai/gal FlC (Revus TM ) on Basil.

Application Timing, Type, and Equipment Maximum Single Application Rate (lb ai/A) Maximum Number of Applications per Season Maximum Seasonal Application Rate (lb ai/A) PHI (days)

Basil

0.13 4 0.52 7

Postemergence Foliar spray Ground, aerial, or Chemigation Use Directions and Restrictions: Begin applications prior to disease development and continue throughout the season on a 7-10 day interval. Make no more than 2 consecutive applications before switching to an effec tive non-Group 40 fungicide. May be tank mixed with another fungicide labeled for downy mildew that has a different mode of action. The addition of a spreading/penetrating type adjuvant such as a non-ionic based surfactant or blend may improve activity.

The supplemental label for Revus TM is adequate to allow evaluation of the residue data relative to the proposed uses on basil.

3.0 Hazard Characterization/Assessment

No changes have been made in the ingredient profile of mandipropamid si nce the previous risk assessment. Please refer to the previous risk assessment for detailed hazard characterization for mandipropamid (DP Num; 365919, D. Rate, 8/JUL/2009).

HED previously recommended that the FQPA Safety Factor (SF) be reduce d to 1X because there is no evidence of increased susceptibility, there are no/low concerns and no residual uncertainties regarding pre- and/or postnatal to xicity, there is no evidence of ne urotoxicity in the database and a DNT study is not required. Although the data base is missing the immunotoxicity study as per the revised 40 CFR§158 (FR/Vol. 72, No. 207), the t oxicological database is adequate for risk assessment and based on available toxicity data, there is no need for an additional uncertainty factor while the immunotoxicity st udy is completed. The overall weight of evidence in terms of hematology, clinical chemistry, organ wei ghts, and/or histopathology suggests that mandipropamid does not directly target the imm une system. Therefore ARIA does not believe that conducting a functional immunotoxicity stud y will result in a lower point of departure (POD) than currently selected for overall risk as sessment, and therefore, a database uncertainty factor (UF DB ) is not needed to account for the lack of this study. Furthermore, the exposure assessments are based on reliable data and reasonable worst-case assumptions and will not likely underestimate risks.

Table 3.1a Toxicological Doses and Endpoints for Ma ndipropamid for Use in Dietary and Non-Occupational 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 No appropriate endpoint was identified, and a risk assessment was not conducted.Mandipropamid Risk Assessment Document DP Num: 374096

Page 7 of 15 Table 3.1a Toxicological Doses and Endpoints for Ma ndipropamid for Use in Dietary and Non-Occupational 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 (Females 13-49 years of age) N/A N/A N/A No appropriate endpoint was identified, and a risk assessment was not conducted

. Chronic Dietary (All Populations) NOAEL = 5 mg/kg/day UF A = 10X UF H = 10X FQPA SF = 1X Chronic RfD = 0.05 mg/kg/day

cPAD = 0.05 mg/kg/day Chronic toxicity – dogs LOAEL = 40 mg/kg/day, based on evidence of liver toxicity (increased incidence and severity of microscopic pigment in the liver and increased alkaline phosphatase activity in both sexes as well as increased alanine aminotransferase activity in males). Cancer (oral, dermal, inhalation) “Not Likely to be Carcinogenic to Humans.” No treatment-related tumors observed in carcinogenicity studies in rats and mice. A cancer risk assessmen t was not conducted, the chronic risk assessment would be protec tive of any cancer effects.

NOAEL = no observed adverse effect level. LOAEL = lowest obser ved 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). FQPA SF = FQPA Safety Factor. PAD = population ad justed dose (c = chronic). RfD = reference dose. N/A = not applicable.

Table 3.1b Summary of Toxicological Doses and Endpoints for Mandipropamid for Use in Occupational Human Health Risk Assessments Exposure/ Scenario Point of Departure Uncertainty Factors Level of Concern for Risk Assessment Study and Toxicological Effects

Dermal (1-30 days) andIntermediateterm (1-6 months) N/A N/A N/A No appropriate endpoint was identified, and a risk assessment was not conducted. 28-day dermal toxicity study – rat, no systemic or dermal effect up to the limit dose of 1000 mg/kg/day; there were no neurotoxicity or developmental concerns. Inhalation Short-(1-30 days) andIntermediateterm (1-6 months) NOAEL = 41 mg/kg/day

IAF=100% UF A = 10X UF H = 10X Residential LOC for MOE = 100 90-day oral toxicity – rats LOAEL = 260 mg/kg/day, based on decreased body weights, body weight gains and food utilization in males and slight hepatotoxicity in both

sexes. Cancer (oral, dermal, inhalation) “Not Likely to be Carcinogenic to Humans.” No treatment-related tumors observed in carcinogenicity studies in rats and mice. A cancer risk assessment was not conducted, the chronic risk assessment would be protective of any cancer effects.

NOAEL = no observed adverse effect level. LOAEL = lowest obser ved 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 (intra-species). MOE = margin of exposure. LOC = level of concern. N/A = not applicable. IAF=inha lation absorption factor.

3.1 Endocrine Disruption

As required under FFDCA section 408(p), EP A has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (inc luding pesticide active and other ingredients) may have an effect in humans or wildlife si milar to an effect produced byMandipropamid Risk Assessment Document DP Num: 374096

Page 8 of 15 a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two-tiered ap proach 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 estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine related eff ects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticid e active ingredients and 9 inert ingredients. This list of chemicals was selected based on th e potential for human exposure through pathways such as food and water, residen tial activity, and certain post-applic ation agricultural scenarios. This list should not be construed as a lis t of known or likely endocrine disruptors.

Mandipropamid is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingly, EPA anticipates issuin g future EDSP test orders/data call-ins for all pesticide active ingredients.

For further information on the status of the ED SP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, pleas e visit our website: http://www.epa.gov/endo/

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4.0 Public Health and Pesticide Epidemiology Data

Based on the recent registration of this chemical, usage patterns and the la ck of residential use sites, no incident reports are expected at this time. A dditionally, no public health or epidemiology data were found for this chemical when searched in the National Library of Medicine TOXNET databases.

5.0 Dietary Exposure/Risk Characterization

5.1 Pesticide Residue Profile

The nature of the residue for mandipropamid is adequately understood fo r purposes of tolerance enforcement and risk assessment, and the residue s of concern are summarized in Table 5.1.1. A tolerance-enforcement method, based on the German Multi-residue Method DFG S-19, is available and has been validated for a number of plant commodities. The method is expected to be suitable for analysis of basil.

Table 5.1.1. Summary of Metabolites and Degradates to be Included in the Risk Assessment and Tolerance Expression.Mandipropamid Risk Assessment Document DP Num: 374096

Page 9 of 15 Matrix Residues included in Risk Assessment Residues included in Tolerance Expression

Primary Crop Parent mandipropamid

(Parent + SYN 500003 for root and tuber vegetables ) Parent mandipropamid Plants

Rotational Crop Not applicable Parent mandipropamid*

Ruminant Not applicable Not applicable Livestock

Poultry Not applicable Not applicable

Drinking Water Parent, SYN 504851 and SYN 500003* Not Applicable

*Although the parent compound is a residue of concern in rotational crops, tolerances are not needed for the present uses, based on the absence of residues in the field rotational crops study following the label’s 30 day plantback interval.

There are no data available depi cting residues of mandipropamid in fresh or dried basil. As a surrogate, ARIA had translated data from vegeta bles, leafy (Crop Group 4) (Table 5.1.2). These data support the recommended tolerance of 20 ppm in/on fresh basil. A conservative tolerance of 240 ppm in/on basil, drie d is recommended to accommodate a maximum theoretical concentration factor of 12X.

Table 5.1.2. Summary of Resi due Chemistry Considerations

Parameter Proposed Use on Basil Translated Residue Data from Leafy Vegetables

Chemical Mandipropamid Mandipropamid

Formulation RevusTM RevusTM Crop Basil Leafy vegetable Type of Application Ground, Aerial, Ch emigation Ground, Aerial, Chemigation Number of Applications 4 4 Timing/Retreatment Interval Post emergent foliar spray Post emergent foliar spray Individual Application Rate 0.13 lb ai/A 0.13 lb ai/A Seasonal Application Rate 0.52 lb ai/A 0.52 lb ai/A

Pre-harvest Interval 7 day 1 day

Maximum Residue --- 12.8 ppm

Restrictions Non-ionic surfactant may be used. Non-ionic surfactant may be used.

Residue Data Source Section 18 09IL01 DP#328534, D. McNeilly, 08/28/2007 Performing Laboratory Not Applicable Field Trial Studies

There are no specific Codex, Canadian, or Mexican maximum residue limits (MRLs) for mandipropamid.

The maximum seasonal application proposed for the Section 18 use on basil is less than or equal to currently registered use rates. As such, a previously modeled Tier I drinking water assessmentMandipropamid Risk Assessment Document DP Num: 374096

Page 10 of 15 conducted by EFED for the established mandi propamid uses(DP Num: 339258, I. Abdel-Saheb, 23/APR/2007) was used in this assessment. The assessment included mandipropamid and its major aquatic degradates (SYN 500003 and SYN 5044851) in drinking water. The estimated drinking water concentrations (EDWCs) are ba sed on the highest labeled use pattern of 4 applications of 0.13 lbs ai/A for a total rate of 0.52 lbs ai/A/Season. The modeled EDWCs are shown in the Table 5.1.3. The EDWC used in the dietary analysis is 36.5 ppb, the sum of the surface water numbers for Mandi propamid, SYN500003, and SYN504851.

Table 5.1.3. Estimated Drinking Water Concentrations for Mandipro pamid and Metabolites for Chronic Dietary Analysis Mandipropamid (ppb) SYN500003 (ppb) SYN504851 (ppb) Surface Water 25.2 2.32 8.99

Ground Water 5.22E-02 5.85E-01 1.73 Four applications at 0.13 lb ai/A with 7 days between applications Note: The chronic drinking water values were incorporat ed directly into the dietary assessments under the DEEMFCID food categories “wat er, all sources” and “water, indirect, all sources.”

5.2 Dietary Exposure and Risk

A chronic dietary risk assessment was conducte d using the Dietary E xposure Evaluation Model (DEEM-FCIDTM, Version 2.03) which uses food c onsumption data from the USDA’s Continuing Surveys of Food Intakes by Indi viduals (CSFII) from 1994-1996 and 1998.

No acute dietary endpoint could be identified based on th e toxicology data currently available for mandipropamid and mandipropamid is classified as not likely to be a human carcinogen. Therefore, acute and cancer risks are not of concern.

A tolerance level (unrefined) chronic exposure assessment that assumes 100% crop treated was conducted for the registered and proposed Section18 uses of mandipropamid. The DEEM analysis incorporates estimates of drinking wate r concentrations from EF ED directly into the analysis. The chronic dietary exposure analysis for mandipropa mid results in dietary risk estimates for food and water that are below the Agency’s level of concern for chronic dietary exposure. For mandipropamid, the DEEM chroni c dietary exposure esti mate was 26% of the cPAD for the U.S. population and was 44% of the cPAD for the highest exposed population subgroup, children 1-2 years of age.

Table 5.2. Results of Chronic Dietary Exposure Analysis Using DEEM FCID. 1 Chronic Dietary Cancer
Population Subgroup Dietary Exposure (mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) Risk

General U.S. Population 0.012927 26 All Infants (< 1 year old) 0.009489 19 Children 1-2 years old 0.022136 44 1 Children 3-5 years old 0.019329 39 Children 6-12 years old 0.013175 26 Youth 13-19 years old 0.010474 21 N/A N/AMandipropamid Risk Assessment Document DP Num: 374096

Page 11 of 15 Table 5.2. Results of Chronic Dietary Exposure Analysis Using DEEM FCID. 1 Chronic Dietary Cancer
Population Subgroup Dietary Exposure (mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) Risk

Adults 20-49 years old 0.012470 25 Adults 50+ years old 0.012470 25 Females 13-49 years old 0.012212 24

1 The population subgroup with the highest estimated chronic dietary (food + drinking water) exposure and risk is indicated by bold text. Note: % cPAD reported to 2 significant figures.

6.0 Residential and Other Expo sures (Spray Drift, etc.)

Residential exposures were not assessed b ecause the registered and proposed uses of mandipropamid do not involve applications by ho meowners or by commercial applicators in residential settings.

Based on the available toxicity database and the Agency's current practices, a quantitative postapplication inhalation exposure assessmen t was not performed for mandipropamid at this time primarily because it has a low vapor pressure (<7.0 x 10 -9 mmHg) and it is applied at a relatively low rate. However, volatilization of pesticides may be a potential source of postapplication inhalation exposure to individuals nearby to pestic ide applications. The Agency sought expert advice and input on is sues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rode nticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SA P/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, th e way to incorporate pos tapplication inhalation exposure into the Agency's risk assessments. If ne w policies or procedures are put into place, the Agency may revisit the need fo r a quantitative post application inhalation exposure assessment for mandipropamid.

Spray drift is always a potential source of exposur e to residents near spraying operations. This is particularly the case with aerial application, but, to a lesser exte nt, could also be a potential source of exposure from the ground applica tion method employed for mandipropamid. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and ot her parties to develop the best spray drift management practices. On a chem ical 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 regi strants, 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, orch ard airblast and ground hydraulic me thods. 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 ri sks associated with drift.Mandipropamid Risk Assessment Document DP Num: 374096

Page 12 of 15 7.0 Aggregate Risk Assessment s and Risk Characterization

In accordance with the FQPA, ARIA must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or th e risks themselves can be aggregated. When aggregating exposures and risk s from various sources, ARIA considers both the route and duration of exposure.

There are no residential uses proposed or regist ered for mandipropamid, and therefore aggregate risk is equal to that from consumption of food and water. Chronic aggregate risk estimates associated with exposure to mandipropamid residues in food and water do not exceed ARIA’s level of concern. See section 5.2 for additional de tails. Acute and cancer aggregate risks are not of concern due to the absence of an acute di etary endpoint and because mandipropamid is not likely to be carcinogenic.

8.0 Cumulative Risk Characterization/Assessment

Section 408(b)(2)(D)(v) of the FFDCA requires that, when cons idering whether to establish, modify, or revoke a tolerance, the Agency consider "available information concerning the cumulative effects” of a particular pesticide's re sidues and "other substances that have a common mechanism of toxicity.”

Unlike other pesticides for which EPA has fo llowed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to mandipropamid and any other substances, a nd mandipropamid does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that mandipropa mid has a common mechanis m of toxicity with other substances. For information regarding EPA’ s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate th e cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and proc edures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pest icides/cumulative/

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9.0 Occupational Exposure/Risk Pathway

Exposure to pesticide handlers is likely duri ng the use of mandipropamid in a variety of occupational environments. The product may be applied using groundboom equipment, aerial equipment, chemigation, and airblast equipment (grapes only).

The quantitative exposure/risk assessment developed for occupati onal handlers is based on the following scenarios: (1) mixing/lo ading liquids for aerial applica tions; (2) mixing/loading liquids for chemigation applications; (3) mixing/lo ading liquids for groundboom applications; (4) mixing/loading liquids for airbla st applications; (5) applying sprays with aerial equipment; (6) applying sprays with groundboom equipment; (7) applying sprays with airblast equipment; and (8) flagging for aerial spray applications. Occupa tional exposures are expect ed to be short- andMandipropamid Risk Assessment Document DP Num: 374096

Page 13 of 15 intermediate-term. ARIA does not expect l ong-term exposure due to the limited number of applications.

9.1 Short-/Intermediate-Term Occupational Handler Risk

Short- and intermediate-term dermal exposures and risks were not assessed for mandipropamid, since no short- or intermediate-term dermal endpoint was identified. Short-term and intermediate-term inhalation risk assessments were completed based on the inhalation toxicity endpoint that was identified. Long-term handler exposures are not expected to occur based on the uses of mandipropamid.

Daily Exposure: Daily inhalation handler exposures are es timated for each applicable handler task with the application rate, the area trea ted in a day, and the applicable inhalation unit exposure. The daily inhalation dose is calcula ted by normalizing the daily inhalation exposure by body weight and adjusting with an appr opriate inhalation absorption factor.

Daily Dose: The daily inhalation dose is calculated by normalizing the daily inhalation exposure by body weight and adjusting with an appr opriate inhalation absorption factor.

Margins of Exposure: Non-cancer inhalation risks for each applicable handler scenario are calculated using a Margin of Exposure (MOE), whic h is a ratio of the dail y dose to the relevant toxicological points of departure.

All short- and intermediate-term inhalation risk estimates meet or exceed the MOE of 100 at the baseline level of mitigation. This indicates that occupational inhalation risks are not of concern. A summary of the short- and intermediate-term inhalation risk estimates for each exposure scenario is presented below in Table 9.1.

Table 9.1. Summary of Exposure & Risk to Occupational Handlers From Mandipropamid. Unit Exposure 1 mg ai/lb handled Applic. Rate 2
lb ai/unit Units Treated 3 Avg. Daily Exposure 4 mg ai/kg bw/day MOE 5

Mixer/Loader - Liquid - Open Pour Inhalation 0.0012 0.13 lb ai/A 350 A/day Inhalation 0.00078 53,000 Applicator - Air-blast - Open Cab Inhalation 0.0045 0.13 lb ai/A 40 A/day Inhalation 0.00033 124,000 Aerial Applicator (Pilots not required to wear gloves) Inhalation 0.000068 0.13 lb ai/A 350 A/day Inhal. 0.000044 932,000 1. Unit Exposures are taken from “PHED SURROGATE EXPO SURE GUIDE”, Estimates of Worker Exposure from The Pesticide Handler Exposure Database Version 1.1, August 1998. Dermal = Single Layer Work Clothing No Gloves ; Single Layer Work Clothing With Gloves ; Inhal. = Inhalation. Units = mg a.i./pound of active ingredient handled. Data Confidence: LC = Low Confidence, MC = Medium Confidence, HC = High Confidence. 2. Applic. Rate. = Taken fro m draft supplemental label. 3. Units Treated are taken from “Standard Values for Daily Acres Trea ted in Agriculture”; ExpoSAC SOP No. 9.1. Revised 5 July 2000. 4. Average Daily Dose = Unit Expos ure * Applic. Rate * Units Treated ÷ 70 kg Body Weight. 5. MOE = Margin of Exposure = NOAEL ÷ ADD. NOAEL for short- and intermedia te-term duration inhalation exposure = 41 mg ai/kg bw/day.

9.2 Short-/Intermediate-Term Occupa tional Post-application RiskMandipropamid Risk Assessment Document DP Num: 374096

Page 14 of 15 Occupational post-application expo sures/risks were not quantified because no appropriate dermal endpoints were identified. The 4- hr Restricted Entry Interval (REI) appearing on the product label for Revus TM Fungicide adequately supports the Wo rker Protection Standard (WPS).

Based on the Agency's current practices, a quant itative post-application inhalation exposure assessment was not performed for mandipropamid at this time primarily because it has a very low vapor pressure ( <7.0 x 10 -9 mmHg ) and is applied at a very low rate. However, volatilization of pesticides may be a potential source of post-app lication inhalation exposure to individuals nearby to pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticid es from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (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 ev aluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for a nd, subsequently, the wa y to incorporate postapplication inhalation exposure in to the Agency's risk assessments. If new policies or procedures are put into place, the Agency may re visit the need for a qua ntitative post-application inhalation exposure assessment for mandipropamid.

10.0 References:

MANDIPROPAMID – Human Occupational Exposure/ Risk Assessment for the Illinois Section 18 Use of Mandipropamid on Basil, DP Num: 371728, M. Dow, 29/DEC/2009.

MANDIPROPAMID – Exposure/Risk Assessment fo r the Proposed Uses of Mandipropamid on Brassica Vegetables, Bulb Vegetables, Cucurbits, Fr uiting Vegetables, Leafy Green Vegetables, Grapes, Tomatoes, and Tuberous and Corm Vegetables, DP Num: 357873, M. Dow, 28/OCT/2008.

Mandipropamid. Section 3 Regist ration Request to Re gister New Uses on Hops and Tobacco. Summary of Analytical Ch emistry and Residue Data. DP Num: 348229 and 352322, Debra Rate, 11/DEC/2008.

Mandipropamid. Request to Register Ne w Food/Feed Uses on Head and Stem Brassica , Leafy Brassica Greens, Cucurbit Vegetables, Fruiting Vege tables, Leafy Vegetables, Tuberous and Corm Vegetables, Grapes, and Onions (Dry Bulb and Green). Summary of Analytical Chemistry and Residue Data. Petition Numbers 6F7057 and 7F7184. DP Num: 340784, Dennis McNeilly, 28/AUG/2007.

Mandipropamid: Chronic Dietary (Food and Dri nking Water) Exposure and Risk Assessment for Section 18 use of Mandipropamid to Basil. PC Code: 036602. DP Num: 371321. R. Chesser. 12/JAN/2010.

Mandipropamid: AMENDED Chronic Dietary (Food and Drinking Water) Exposure and Risk Assessment for Section 18 use of Mandipropami d to Basil. PC Code: 036602. DP Num: 376967. R. Chesser. 27/APR/2010.Mandipropamid Risk Assessment Document DP Num: 374096

Page 15 of 15 Appendix A: Tolerance Setting

Table A.1. Tolerance Summary for Mandipropamid. Commodity Proposed Tolerance (ppm) Recommended Tolerance (ppm) Comments; Correct Commodity Definition

Proposed Time-limited Tolerances Basil, fresh --- 20 Recommended tolerance translated from vegetables, leafy (Crop Group 4). Basil, dried --- 240 Recommended tolerance for basil, fresh, multiplied by a maximum theoretical concentration factor of 12X.

Appendix B: Review of Human Research

The PHED Task Force, 1995. The Pesticide Hand lers Exposure Database, Version 1.1. Task Force members Health Canada, U.S. Envir onmental Protection Agency, and the National Agricultural Chemicals Associat ion, released February, 1995.