Mandipropamid Human Health Risk Assessment D 4 14944

Page 1 of 41 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA**  **L SA FETY**  **AND POLLUTION PREVENTION**  **MEMORANDUM** Date : Aug 2 7 , 2013 **SUBJECT: Mandipropamid**  : Revised Human Health Risk Assessment F or New Use s O n Basil, G inseng and Snap Beans, as Well as Crop Group Expansions for Fruiting V egetable ; Small F ruit, V ine C limbing , Except Fuzzy Kiwifruit ; and Bulb O nion and Green O nion Subgroups . PC Code: 036602 DP Number: D 4 14944 Decision No.: 472747 Registration No. : 100 - 1254 Petition No.: 2E8126 Regulatory Action: Section 3 Risk Assessment Type: Single Chemical Aggregate Case No.: 7058 TXR No.: NA CAS No.: 3 7 4726 - 62 - 2 MRID No.: None 40 CFR: **§** 180. 637 **FROM:** Dennis McNeill y, Chemist and Risk Assessor

Jaime D’Agostino, Toxicologist William T. Drew, Chemist Zaida Figueroa, Industrial Hygienist Risk Assessment Branch II Health Effects Division (7509P) **THROUGH:** Michael A. Doherty, Ph.D., Chemist

Christina Swartz, Chief Risk Assessment Branch II Health Effects Division (7509P) **TO:** Laura Nollen/Barbara Madden, RM 05

Risk Integration, Minor Use, Emergency Response Branch Registration Division (7505P) This document is the same as D409103 , except it was r evised to i nclude the T oxicity Profile Tables in Appendix B2 .Mandipropamid Human Health Risk Assessment D 4 14944

Page 2 of 41 **Table of Contents**  1.0 Executive Summary ................................ ................................ ................................ ................ 4 2.0 HED Recommendations ................................ ................................ ................................ .......... 5 2.1 Data Deficiencies ................................ ................................ ................................ ................ 6 2.2 Tolerance Considerations ................................ ................................ ................................ .... 6 2.2.1 Enforcement Anal ytical Method ................................ ................................ .................. 7 2.2.2 Recommended Tolerances ................................ ................................ ........................... 7 2.2.3 Revisions to Petitioned - For Tolerances ................................ ................................ ....... 7 2.2.4 International Harmonization ................................ ................................ ........................ 8 2.3 Label Recommendations ................................ ................................ ................................ ..... 8 3.0 Introduction ................................ ................................ ................................ ............................. 9 3.1 Chemical Identity ................................ ................................ ................................ ................ 9 3.2 Pesticide Use Pattern ................................ ................................ ................................ ........... 9 3.3 Anticipated Exposure Pathway s ................................ ................................ ........................ 10 3.4 Consideration of Environmental Justice ................................ ................................ ........... 11 4.0 Hazard Characterization and Dose - Response Assessment ................................ ................... 11 4.1 Summary

of Toxicological Effects ................................ ................................ ................... 12 4.2 Safety

Factor for Infants and Children (FQPA Safety Factor) ................................ .......... 13 4.2.1 Completeness of the Toxicology Database ................................ ................................ 13 4.2.2 Evidence of Neurotoxicity ................................ ................................ ......................... 13 4.2.3 Evidence of Sensitivity /Susceptibility

in the Developing or Young Animal ............ 14 4.2.4 Residual Uncertainty in the Exposure Database ................................ ........................ 14 4.3 Toxicity

Endpoint and Point of Departure Selections ................................ ....................... 14 5.0 Dietary

Exposure and Risk Assessment ................................ ................................ ............... 16 5.1 Residues of Concern Summary and Rationale ................................ ................................ .. 16 5.2 Food Residue Profile ................................ ................................ ................................ ......... 17 5.2.1 Crop Field Trials (860.1500) ................................ ................................ ..................... 18 5.2.2 Field Rotational Crops (860.1900) ................................ ................................ ............ 19 5.2.3 Processed Food and Feed (860.1520) ................................ ................................ ........ 20 5.3 Water Residue Profile ................................ ................................ ................................ ....... 20 5.4 Dietary

Risk Assessment ................................ ................................ ................................ ... 21 5.4.1 Description of Residue Data Used in Dietary Assessment ................................ ........ 21 5.4.2 Percent Crop Treated Used in Dietary Assessment ................................ ................... 22 5.4.3 Acute Dietary

Risk Assessment ................................ ................................ ................. 22 5.4.4 Chronic Dietary

Risk Assessment ................................ ................................ ............. 22 5.4.5 Cancer Dietary

Risk Assessment ................................ ................................ ............... 22 5.4.6 Summary

Table ................................ ................................ ................................ .......... 22 6.0 Residential (Non - Occupational) Exposure/Risk Characterization ................................ ....... 23 6.1 Residential By stander Post - application Inhalation Exposure ................................ ........... 23 6.2 Spray

Drift ................................ ................................ ................................ ......................... 23 7.0 Aggregat e Exposure/Risk Characterization ................................ ................................ .......... 24 7.1 Acute & Chronic Aggregate Risk ................................ ................................ ..................... 24 7.2 Short - and Intermediate - Term Aggregate Risk ................................ ................................ . 24 8.0 Cumulative Exposure/Risk Characterization ................................ ................................ ........ 24 9.0 Occupational Exposure/Risk Characterization ................................ ................................ ..... 25 10.0 References ................................ ................................ ................................ ............................. 30Mandipropamid Human Health Risk Assessment D 4 14944

Page 3 of 41 Appendix A. International Residue Limits ................................ ................................ ..................... 31 Appendix B. Toxicology Profile ................................ ................................ ................................ ..... 32 B.1 Toxicology

Data Requirements ................................ ................................ ......................... 32 B.2 Toxicity

Profiles ................................ ................................ ................................ ................ 33 B.2.3 Immunotoxicity ................................ ................................ ................................ .......... 38 Appendix C. Physical/Chemical Properties ................................ ................................ .................... 40 Appendix D. Review of Human Research ................................ ................................ ...................... 41Mandipropamid Human Health Risk Assessment D 4 14944

Page 4 of 41 **1.0 Executive Summary**  Mandipropamid is a fungicide in the mandelamide class developed b y S yn genta Crop Protection, In c. 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. IR - 4 has requested new Section 3 uses for mandipropamid and tolerance s for residues of mandipropamid in/on f

resh b asil , dried basil, g inseng , cowpea forage, s ucculent bean s, and for greenhouse tomatoes . Inaddition, there is a proposal to expand the current use on grapes to the new crop subgroup 13 - 07F for small fruit vine , e xcept f uzzy kiwifruit ; to expand the use on onion, dry bulb to bulb onion (subgroup 3 - 07A) ; to expand the use on green onions to green onion (subgroup 3 - 07B) ; and finally to expand the use on fruiting vegetables ( crop group 8 ) to the updated fruiting vegetables crop group ( 8 - 10) . Revus (EPA Reg. No. 100 - 1254) is a suspension concentrate (S C ) formulation containing 2 3 . 3 % ai by weight, equivalent to 2 .08 lb ai/gal (250 grams/liter) . The toxicology

database is adequate . Mandipropamid has low acute toxicity via oral, dermal, and inhalation routes; and no dermal or eye irritation (Toxicity Category IV). It is not a skin sensitizer. Liver toxicity

was the primary

effect and was observed in rats, mice and dogs. There was no evidence of increased neonatal or postnatal sensitivity in the developmental and reproduction to xicity studies, and no evidence of developmental effects, neurotoxicity , mutagenicity or carcinogenicity

after exposure to mandipropamid. The FQPA Safety Factor (SF) has been reduced to 1X. Based on the available data, there are no effects attributable t o a single exposure to mandipropamid which are appropriate for assessing acute risks , including acute dietary exposure . Similarly , there are no effects associated with dermal exposure. O nly inhalation and chronic dietary endpoints and points of departure have been selected for risk assessment . Adequate field trials were conducted on basil , ginseng, and snap beans ; in addition , adequate greenhouse trials were submitted for tomatoes . Further, metabolism data, storage stability and anal ytical methods are considered adequate to support the recommended tolerances for both new uses and crop group expansions. HED notes however that the submitted data for snap bean s do not support the proposed tolerance s for succulent bean and cowpea forage . In addition a tol erance cannot be established for cowpea forage , a livestock feed item, due to the lack of a validated livestock anal ytical enforcement method. A screening - level dietary assessment (food + drinking water), based on tolerance - level residues and 100% of crop treated for all included commodities , and conservative assumptions with respect to mandipropamid residues in drinking water sources, indicates that chronic dietary risk s are below HED ’s level of concern for all population subgroups. There are no uses of mandipropamid that would result in residential exposure; therefore, chronic dietary is the onl y aggregate scenario, and there are no aggregate risks of concern.Mandipropamid Human Health Risk Assessment D 4 14944

Page 5 of 41 Occupational risk estimates associated with th e new uses are also below HED ’s level of concern . No chemical - specific handler exposure data were submitted in support of this registration; therefore, HED relied on surrogate data in accordance with standard policies. Default assumptions established by

the HED Science Advisory Council for Exposure (E xpoSAC) were used for parameters such as body weight and amount handled. Occupational assessments for mandipropamid are based on inhalation exposures only . All occupational handler scenarios for the proposed uses resulted in MOEs greater than 100 at baseline (i.e., baseline attire with no respirator; engineering control for aerial applications (enclosed cockpits)) and, therefore , are not of concern , and no additional personal protective equipment (PPE) will be needed on the proposed label . Although a point of departure from an oral study was used to assess handler inhalation risk, the calculated MOEs are all ≥ 65,000 , thus providing an ample margin to account for any uncertainties in the route - to - route extrapolation. Furthermore, since there is no difference between the occupational scenarios and the agrono mics/practices previously assessed, the exposure resulting from mandipropamid use on the additional crops in the expanded crop groups are already covered b y an existing risk assessment ( D 357873 , M. Dow, 10/28/2008 ) . Therefore, a new occupational assessment for the registered uses was not needed to support the tolerances for crop group expansion. Occupational post - application risk estimates for agricultural workers following treatments to agricultural crops were not assessed, since no dermal endpoint of concern was identified. In addition, m andipropamid is categorized as a reduced risk chemical. Therefore, the restricted entry interval ( REI ) o f 4 hours is considered appropriate . Based on the Agency's current practices, a quantitative non - cancer occupational post - application inhalation exposure assessment was not performed at this time. I f new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inhalation exposure assessment for mandipropamid. 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 D , have been determined to require a review of their ethical conduct. So me of these studies are also subject to review b y the Human Studies Review Board. All of the studies used have received the appropriate review. Potential areas of environmental justice concerns, to the extent possible, were considered in this human heal th risk assessment, in accordance with U.S. Executive Order 12898, “ Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations, ” http://www.eh. doe.gov/oepa/guidance/justice/eo12898.pdf . **2.0 HED**  **Recommendations** HED recommend s in favor o f establishing tolerance s for residues of mandipropamid as specified in Section 2.2 . 2.Mandipropamid Human Health Risk Assessment D 4 14944

Page 6 of 41 **2.1 Data Deficiencies**  No additional data are required to support HED’s currentl y recommended tolerances, however additional data would be need to support all of the proposed tolerances associated with the petition. The submitted snap bean data do not support the proposed tolerances in succulent beans and cowpea forage (ChemSAC meeting; 17 July 2013). Additional field trial data on a succulent shelled bean cultivar (such as lima beans) would be necessary in order to establish a tolerance in succulent beans. Because of the poss ibility of detectable residues occurring in dairy cattle commodities (fat, milk and liver) arising from the feeding of treated cowpea forage, the concurrent establishment of mandipropamid tolerances at the limit of quantitation (LOQ) in those commodities w ould be necessary . However, with no validated anal ytical method for enforcing tolerances in livestock commodities, it is not possible to establish such tolerances. Therefore, the proposed tolerance in cowpea forage cannot be established until a validated method for determining mandipropamid residues in livestock (cattle) commodities is available. Any such method submitted would need an independent laboratory validation (ILV) . (If tolerances for additional livestock feed items other than cowpea forage are proposed , a livestock feeding study should be submitted.) Since the last risk assessment, an immunotoxicity study was received which fulfills a previously identified data gap . In this study , no evidence of immunotoxicity was observed up to the highest d ose tested (649 mg/kg/day). In addition, HED’s Hazard and Science Policy Council ( HASPOC ) determined that a subchronic inhalation study in the rat is not required for mandipropamid ( TXR # 0056 610, J. Alstine, 3/ 14 /2013 ). **2.2 Tolerance Considerations**  HED has examined the toxicology and residue chemistry

database for mandipropamid. There are no issues that would preclude establishing tolerance s for mandipropamid for the commodities listed in Table 2.2.2. The submitted snap bean data do not support the proposed tolerance in succulent bean, and a cowpea forage tolerance cannot be established due to the lack of a livestock anal ytical enforcement method. **Note s**  **to RD:** a) When the crop subgroup 13 - 07F tolerance is established , then the grape tolerance should be deleted. b) When the crop subgroup 3 - 07A tolerance is established , then the tolerance for onion, dry

bulb, should be deleted. c) When the crop subgroup 3 - 07B tolerance is established , then the tolerance for o nion, green should be deleted. d) According to HED’s Interim Guidance on Tolerance Expressions (S. Knizner; 27 May 2009), the tolerance expression for mandipropamid cited in 40CFR §180.6 37 [a] should be revised to state: Tolerances are established for residues of mandipropamid, including i ts metabolites and degradates, in or on the commodities listed in the table below. Compliance with the tolerance levels specified below is to be determined b y measuring only mandipropamid ( 4 - chloro -N - [2 - [3 - methoxy- 4 - (2 - prop ynylox y) phenyl]ethyl] - α - (2 - propy nyloxy)benzeneacetamide ) in or on the commodity .Mandipropamid Human Health Risk Assessment D 4 14944

Page 7 of 41 **2.2.1 Enforcement Analytical Method**  There is an adequate enforcement method available for the quantitation of mandipropamid in plant commodities. M ethod RAM 415/01 , using h igh performance l iquid chromato graph y with tandem mass spectrometric detection (L C/MS/MS) , has been adequatel y validated by an independent laboratory . It has a validated limit of quantitation (LOQ) of 0.01 ppm. An acceptable confirmatory

method is also available. The FDA Multiresid

ue methods are not adequate for determining residues of mandipropamid. **2.2. 2**  **Recommended Tolerances** HED has examined the residue chemistry database for mandipropamid . Pending submission of a revised Section F (to propose tolerance levels in accord ance with those recommended by HED , and to correct some of the commodity definitions) , there are no residue chemistry issues that would preclude establishing tolerance s in the requested commodities , except for those in cowpea forage and succulent beans . The recommended tolerances are listed in Table 2.2.2, below. **Table 2.2.2**  **. Tolerance Summary for**  **Mandipropamid .**  **Comm odity as Proposed by**  **Registrant Proposed**  **Tolerance (ppm) Recommended** 

**Tolerance (ppm) Comments;**  **Correct Commodity Definition**  Basil, fresh 30 30 Basil, fresh leaves Basil, dried 200 200 Basil, dried leaves Bean, succulent 0.90 None Field trial data on a succulent shelled bean cultivar is needed. Bean, snap None 0.90 The snap bean field trials support the establishment of this tolerance. Ginseng 0.3 0.30 Cow pea, forage 15 None A validated method (i.e. with an ILV) for residues in cattle commodities is needed . Vegetable, fruiting, group 8 - 10 1.0 1.0 Fruit, small, vine climbing, subgroup 13 - 07F, except fuzzy kiwifruit 2.0 2.0 Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13
- 07F . See footnote a below. Onion, bulb, subgroup 3 - 07A 0.1 0.10 See foot note b below. Onion, green, subgroup 3 - 07B 7.0 7.0 See foot note c below. * Notes: a) When the crop subgroup 13 - 07F tolerance is established, then the grape tolerance should be deleted. b) When the crop subgroup 3 - 07A tolerance is established, then the tolerance for onion, dry bulb should be deleted. c) When the crop subgroup 3 - 07B tolerance is established, then the tolerance for Onion, green should be deleted. **2.2. 3**  **Revisions to Petitioned -**  **For Tolerances** Instead of the proposed tolerance in ginseng (0.3 ppm), HED recommends establishing the tolerance at 0.30 ppm, in order to avoid the situation where a field sample containing residues significantl y above the tolerance (0.34 ppm, for example) would be consi dered non - violative. ForMandipropamid Human Health Risk Assessment D 4 14944

Page 8 of 41 the same reason, HED recommends that the proposed tolerance of 0.1 ppm in bulb onions ( subgroup 3 - 07A) be revised to 0. 1 0 ppm . The submitted snap bean data do not support the proposed tolerance in succulent bean s . A cowpea forag e tolerance cannot be established due to the lack of a livestock anal ytical enforcement method , and a supporting livestock anal ytical method ILV ( See Section 2.1 ). Therefore, HED is not recommending in favor of the proposed tolerances in succulent bean s and cowpea forage . **2.2. 4**  **International Harmonization** Neither Codex nor PMRA have established MRLs for mandipropamid in any of the commodities associated with the proposed new uses. As such, there is no harmonization issue associated with Codex for the proposed new uses in the current action. PMRA and EPA are jointly reviewing the basil, ginseng and snap bean data in the current action, and EPA and PMRA are harmonized for fresh basil, dried basil, and ginseng. PMRA is establishing an MRL in edible - podded beans at 0.9 ppm, while HED is recommending for a tolerance in snap beans at 0.90 ppm. Although the tolerance/MRL level is harmonized, HED cannot harmonize with PMRA on the commodity definition, as the submitted snap bean data do not support use on all succulent beans, since no data were submitted for a succulent shelled bean, and/or do not meet the requirements of subgroup 6A, since no data were submitted for an edible - podded pea. Both the current tolerance in crop group 8 (1.0 ppm) and the proposed tolerance in crop group 8 - 10 (1.0 ppm) are harmonized with the Codex (bell and non - bell peppers) and PMRA ’s (tomato es , okra s and pepper s ) MRLs. For the other crop group expansions, EPA is harmoniz ing with Codex, even tho ugh this will result in discrepancies between US tolerances and Canadian MRLs. The proposed tolerance of 2.0 ppm in subgroup 13 - 07F, translated from grape data, w ill be harmonized with the Codex MRLin grapes, but w ill no longer be harmonized with PMRA’s MRLof 1.4 mg/kg in grapes. The proposed tolerance of 0.1 ppm in subgroup 3 - 07A, translated from dry bulb onion data, w ill be harmonized with the Codex MRLin bulb onions, but w ill no longer be harmonized with PMRA’s MRLof 0.05 ppm in various bulb onions . The proposed tolerance of 7.0 ppm in subgroup 3 - 07B, translated from green onion data, w ill be harmonized with the Codex MRLin spring onions, but w ill no longer be harmonized with PMRA’s MRLof 4. 0 ppm in various green onions. **2.3 Label Recommendation**  **s** Because the submitted snap bean data do not support the proposed use on all succulent beans, t he section containing directions for use on succulent beans ( “ Bean, succulent ”) should instead refer to snap beans (“Bean, sn ap ”) , and the listing of succulent bean commodities should be deleted . The requested use on greenhouse tomatoes listed in the proposed label is supported by the submitted greenhouse trial data. A cowpea forage tolerance cannot be established due to the lack of a livestock anal ytical enfo rcement method, and supporting li vestock analy tical method ILV. Use on cowpea forage must not be added to the label at this time .Mandipropamid Human Health Risk Assessment D 4 14944

Page 9 of 41 **3.0 In**  **troduction 3.1**  **Chemical Identity** The chemical structure and nomenclature of mandipropamid are presented in Table 3 .1. The phy sicochemical properties of the technical grade mandipropamid are presented in Appendix C . Mandipropamid is a fungicide in the mandelamide class developed b y S yn genta Crop Protection, In c. for the control of foliar oomycete pathogens in a range of crops. **T able**  **3 .1. Test Com** **pound Nom enclature.**  Com pound Common name Mandipropamid

Com pany 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) Revus ® (2.08 lb ai/gal; EPA Reg. No. 100 - 1254), (Alternate Brand Name: Mandy Flowable Fungicide) **3. 2**  **Pesticide Use Pattern** IR - 4 has requested that new Section 3 uses of the fungicide mandipropamid be added to the label for Revus 2.08SC (EPA Reg . No. 100 - 1254 ). The proposed new uses would be on basil, cowpea forage, ginseng, succulent beans, and greenhou se tomatoes . The proposed use directions are summarized in Table 3. 2 . **Table 3.**  **2 .**  **Summ ary of Directions for Use of**  **Mandipropam id**  **. Application Type;**  **Equipment 1**  **Use**

**Rate (lb ai/A)**  **Max. Uses**

**Per Season Max. Seasonal** 

**Use Rate (lb ai/A)**  **PHI 2** 

**(Days) Use Directions,**  **Application Timing,**

**and Limitations 3**  **Basil** Foliar; any ground or aerial equipment . 0.09 -

0.13 4 0.52 1 RTI **4** of 7 - 10 days. **Ginseng** Foliar; any ground or aerial equipment. 0.09 -

0.13 4 0.52 2 RTI of 7 - 10 days.

**Succulent B eans**  **(Cowpea Forage)** Cl O

C H

O N

H O C H 3 O C HMandipropamid Human Health Risk Assessment D 4 14944

Page 10 of 41 **Table 3.**  **2 .**  **Summ ary of Directions for Use of**  **Mandipropam id**  **. Application Type;**  **Equipment 1**  **Use**

**Rate (lb ai/A)**  **Max. Uses**

**Per Season Max. Seasonal** 

**Use Rate (lb ai/A)**  **PHI 2** 

**(Days) Use Directions,**  **Application Timing,**

**and Limitations 3**  Foliar; any ground or aerial equipment. 0.09 -

0.13 4 0.52 1 RTI of 7 - 10 days.

**G reenhouse**  **T om**  **atoes** Foliar; any ground or aerial equipment. 0.09 -

0.13 4 0.52 1 RTI of 7 - 10 days. May be applied via chemigation . 1. For ground application, apply in a minimum of 10 gallons of water per acre (GPA) , unless specified otherwise on the label. Do not apply through any ultra - low volume (ULV) spray system. For a erial application, u se only on crops w here aerial applications are indicate d. Apply in a minimum of 5 GPA, unless specified otherwise on this label. Do not apply through any ULV spray system. For c hemigation, u se only on crops where chemigation is specified on the label. Apply no more than 2 sequential applications unless oth erwise stated in the crop - specific section. Do not use in transplant production. 2. PHI = Pre - Harvest Interval. 3. Begin applications prior to disease development. Use the shorter interval and/or higher rates under high pressure, or when conditions are conducive to disease. The addition of a spreading/penetrating type adjuvant such as a non - ionic based surfactant (NI S) or crop oil concentrate (COC) or blend is recommended. 4. RTI = Re - Treatment Interval. The Personal Protective Equipment (PPE) statement on the proposed label requires applicators, flaggers and other handlers to wear: long - sleeved shirt and long pants, shoes plus socks. PPE recommended on the proposed label for earl y entry to treated areas include: coveralls, chemical resistant gloves made of any waterproof material, shoes plus socks. Conclusions : The use directions are adequate to allow for evaluation of the residue data. However, as the submitted snap bean data do not support the proposed use on succulent beans, the label section containing directions for use on succulent beans ( “ Bean, succulent ”) should instead refer to snap beans (“Bean, sn ap ”) , and the listing of all other succulent bean commodities should be deleted . A cowpea forage tolerance cannot be established due to the lack of a livestock anal ytical enforcement method, and supporting livestock anal ytical method ILV. **3. 3**  **Anticipated Exposure Pathways**  The Registration Division has requested an assessment of human health risk to support the proposed tolerance s for mandipropamid on basil, ginseng, succulent beans (including s nap beans ) , and greenhouse tomatoes , as well as addition of th e use on basil, ginseng, s ucculent beans , and greenhouse tomatoes to the Revus ® label . Humans may be exposed to mandipropamid in food and drinking water, since it may be applied directly

to growing crops and application may

result in mandipropamid reachin g surface and ground water sources of drinking water. There are no residential uses of mandipropamid , so there is not likely to be exposure in residential or non - occupational settings. In an occupational setting, handlers may be exposed while handling the pesticide prior to application, as well as during application. There is a potential for post - application exposure for workers re - entering treated fields. Risk assessments have been previousl y conducted for mandipropamid ; t oxicity data submitted prior to the last risk assessment but not incorporated into HED’s review have been evaluated in the current a ssessment , but did not affect HED’s conclusions with respect to hazardMandipropamid Human Health Risk Assessment D 4 14944

Page 11 of 41 characterization and endpoint selection . A detailed description of the toxicity data and metabolism information may be found in the risk assessment dated 6 / 1 2/2008 ( D. Dotson , D34 43 5 1 ) . Th e current risk assessment considers all of the aforementioned exposure pathway s based on the existing uses of mandipropamid , and also considers the potential for increased dietary (food + water) exposure associated with the new uses . There have been no changes to any of the previously selected endpoints, points of departure, or the cancer classification for mandipropamid from the previous risk assessment (D365919, D. Rate, 7/8/2009). **3. 4**  **Consideration of Environmental Justice** Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 1 2898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well - established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled from the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey , What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized b y 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, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non - dietary

exposures base d on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post application are evaluated. Further considerations are currentl y in development as OPP has committ ed resources and expertise to the development of specialized software and models that consider exposure to b ys tanders and farm workers as well as lifestyl e and traditional dietary patterns among specific subgroups. **4.0 Hazard Characterization and Dose**  **- Resp**  **onse Assessment** A comprehensive human health risk assessment for mandipropamid was conducted in 200 9 ( D. Rate, 8 July

2009, D 365919 ) . Since the last risk assessment, an immunotoxicity study ( MRID 4 8771701 ) was received which fulfills a previously identif ied data gap . In this study, no evidence of immunotoxicity

was observed up to the highest dose tested (649 mg/kg/day). In addition, HED’s Hazard and Science Policy Council ( HASPOC ) determined that a subchronic inhalation study in the rat is not required for mandipropamid (Alstine, J. 14 March 2013, TXR # 0056 610). Therefore, the toxicology database for mandipropamid is considered to be complete. No other changes have been made to the hazard characterization of mandipropamid since the 2009 risk assessment.Mandipropamid Human Health Risk Assessment D 4 14944

Page 12 of 41 **4.1 Summary of Toxicological Effects**  Subchronic and chronic studies indicate that the liver is the primary target organ for mandipropamid. Li ver effects were identified in subchronic studies with rats, mice, and dogs. Liver effects included : periportal hy pertrophy (rats), increased eosinophilia(rats and mice), increased plasma albumin, total protein, cholesterol, and gamma - glutam yltransferase (rats), increased liver weights (rats, mice and dogs), increased liver enz ym es (dogs), increased pi gment in hepatocy tes and Kupffer cells (dogs), and centrilobular hepatocy te vacuolation (dogs). In the chronic dog study, increases in microscopic pigment in the liver and increased liver enzymes were observed. No liver effects were observed in chronic rat and mouse studies up to the highest doses tested. Instead, nephrotoxicity was observed in the chronic rat study and only decreased body weight and food utilization was observed in the chronic mouse study . The findings of liver toxicity and nephrotoxic ity

are consistent with the results from metabolism studies where the tissues with the highest levels of radioactivity were the liver followed b y the kidney . No evidence of neurotoxicity was observed in the acute or subchronic neurotoxicity screening battery . No s ys temic or dermal toxicity was observed following dermal exposure for 28 day s up to the limit dose. No evidence of increased quantitative or qualitative susceptibility was seen in developmental toxicity studies in rats and rabbits or in a reproduction study in rats . The only

effects observed in fetuses or pups were in the two - generation reproduction study , where decreased pup body weight was observe d in the presence of maternal toxicity (decreased body weight, body weight gain, and food utilization). Inaddition, there was a delay in preputial separation in F1 males which was considered to be the result of lower body weights. There was no evidence of tumors in the carcinogenicity study in mice or in the chronic/carcinogenicity s tudy in rats and there was no evidence that mandipropamid was mutagenic or clastogeni c. Therefore, mandipropamid is classified as “not likely to be carcinogenic to humans.” In metabolism studies, absorption of [ 14 C] - mandipropamid was 67 - 74% at 3 mg/kg and 30 - 45% at 300 mg/kg after 48 hours. The rate of absorption was higher in females resulting in a blood T max at 3 mg/kg of 8.5 hours for males and 4.5 hours for females; at 300 mg/kg T max was 24 hours for males and 10 hours for females. Most of the radioactivity was eliminated in the feces except for the 3 mg/kg females where elimination in urine and feces were similar. In bile cannulated rats, elimination in the bile was high at 3 mg/kg (55 - 73% of the dose) but was lower at 300 mg/kg (22 - 28% of the dose, with a corresponding increase of residues in feces in males and urine in females). The highest level of radioactivity in tissues was in th e liver followed b y the kidney . Bioaccumulation was not observed in any tissue and the dose remaining in the body after 168 hours was less than 1.1%. The parent and the following metabolites were detected at ≥ 5% of the applied dose at 3 and/or 300 mg/kg: NOA 458422, NOA 458422 glucuronide, SYN 534133 and CGA 380778. The amount of NOA 458422 glucuronide in females was almost 3 - fold more than in males, which coincided with a lesser amount of parent and NOA 458422 in females. Parent wa sMandipropamid Human Health Risk Assessment D 4 14944

Page 13 of 41 the major residue detected in feces of animals of both sexes regardless of bile duct cannulation status, while SYN 534133 was the major metabolite in the urine of male rats that didn’t undergo bile duct cannulation and NOA 458422 glucuronide was the majo r metabolite in the urine and bile of male rats that did undergo bile cannulation. NOA 458422 glucuronide was also the major metabolite in urine and bile of female rats regardless of bile duct cannulation status. The major metabolic transformations involved loss of one or both propargyl groups followed by glucuronidation and O - demethylation. A dermal penetration study in rats was conducted for mandipropamid. In the study , <0.17 - 3.44% of the applied dose was absorbed. Mandipropamid has low acute toxicity via oral, dermal, and inhalation routes (Toxicity Category IV ) ; and no dermal or eye irritation (Toxicity Category IV). It is not a skin sensitizer. **4. 2**  **Safety F**  **actor for Infants and Children (FQPA Safety Factor)** HED has determined that the required 1 0X F ood Q uality P rotection A ct (FQPA) Safety Factor should be reduced to 1X in assessing the risk posed by mandipropamid. This recommendation was based on the following considerations:

• The toxicity

database is complete with no data gaps for the assessment of the effects of mandipropamid following in utero and/or postnatal exposure . • There is no evidence of neurotoxicity following exposure to mandipropamid. • There is no indication of quantitative or qualitative susceptibil ity of rats or rabbits to in utero and/or postnatal exposure to mandipropamid . • The risk assessment does not underestimate exposure, since the dietary assessment is based on conservative assumptions such as tolerance - level residues in foods, 100% crop treat ed, and upper - bound modeled estimates of residues in drinking water. In addition, there are no registered residential uses for mandipropamid. **4.2.1 Completeness**  **o f**  **the Toxicology Database**  The toxicology

database is considered complete and is adequate fo r the purpose of assessing pre and postnatal susceptibility . Acceptable/guideline developmental toxicity studies in rats and rabbits and a reproduction study in rats, as well as acute and subchronic neurotoxicity studies in rats were available for FQPA a ssessment . There is no concern for increased susceptibility in the developing young , and no evidence of neurotoxicity in the database. Therefore, a developmental neurotoxicity

study is not required . **4.2.2 Evidence of N**  **eurotoxicity** There was no evidence of neurotoxicity observed in any

of the studies in the toxicology database. In the acute neurotoxicity study , the rats were dosed up to the limit dose (2000 mg/kg). In the 90 - day neurotoxicity

study in rats, the only

effects appeare d to be decreased body weight, body weight gain and food utilization in males up to the highest dose tested (192.5 mg/kg/day for males and 206.7 mg/kg/day

for females).Mandipropamid Human Health Risk Assessment D 4 14944

Page 14 of 41 **4.2.3 Evidence**  **o f Sensitivity/Su**  **sceptibility in the Developing o r Young Animal**  There were no treatment - related effects observed in dams or fetuses in the developmental toxicity studies in rats or rabbits up to the limit dose of 1000 mg/kg/day . In the rat reproductive study, decreased pup weight occurred onl y in the presence of comparable maternal toxicity (decreased body weight . Therefore, HED conclude s that there is no increased quantitative or qualitative susceptibility

to rat or rabbit offspring exposed in utero and/or postnatally to mandipropamid, and there are no residual uncertainties with respect to pre - or postnatal exposure . **4.2.4 Residual**  **Uncertainty in the Exposure Datab ase**  There is no residual uncertainty in the exposure database . There are no exposure data gaps and the current dietary

exposure assessment is based on high - end assumptions such as tolerance - level residue values , 100% crop treated, and modeled estimates of drinking water residues . There are currentl y no registered or proposed residential uses for mandipropamid , so exposure is limited to dietary expos ure. Therefore, the assessment is conservative and does not underestimate exposure. **4. 3**  **Toxicity Endpoint and Point of D**  **eparture Selections** The toxicological endpoints and points of departure selected for dietary and occupational exposure and risk asses sment are summarized in Tables 4.3.1 and 4.3.2 . There have been no changes to any of the previousl y selected endpoints, points of departure, or the cancer classification for mandipropamid from the previous risk assessment (D365919, D. Rate, 7/8/2009).Mandipropamid Human Health Risk Assessment D 4 14944

Page 15 of 41 **Table 4.3.1 .**  **Summary of Toxicological Doses and Endpoints for Mandipropamid**  **Use in Dietary and Non**  

** Occupational Hum** **an Health Risk Assessments .**  **Exposure Scenario**  **Point of Departure Uncertainty/**  **FQPA Safety**  **Factors RfD, PAD, Level of** 

**Concern for Risk Assessment**  **Study and Toxicological Effects**  Ac ute Dietary (General population, including Infants and Children and females 13 - 49 ) N/A N/A N/A No appropriate endpoint wa s identified in the TOX databases . Chronic Dietary (all populations) NOAEL = 5

mg/kg/day UF A=10X

UF H=10X FQPA SF = 1X Chronic RfD = 0.0 5

mg/kg/day cPAD = 0.0 5 mg/kg/day Chronic Toxicity Study in

Dogs LOAEL = 40 mg/kg/day, based on 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) No Evidence of Carcinogenicity. Classified as “Not Likely to be Carcinogenic to Humans.” 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). FQPA SF = FQPA Safety Factor . PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. N/A = not applicable. **Table 4.3.2 .**  **Summary of Toxicological Doses and Endpoints for Mandipropamid**  **Use in Occupational**

**Hum an Health Risk Assessments**  **. Exposure**  **Scenario Point of Departure**  **Uncertainty Factors**  **Level of Concern**

**for Risk Assessment**  **Study and Toxicological Effects**  Dermal Short - Term

(1 - 30 days) and Intermediate Term (1 - 6 mo nths) 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.Mandipropamid Human Health Risk Assessment D 4 14944

Page 16 of 41 **Table 4.3.2 .**  **Summary of Toxicological Doses and Endpoints for Mandipropamid**  **Use in Occupational**

**Hum an Health Risk Assessments**  **. Exposure**  **Scenario Point of Departure**  **Uncertainty Factors**  **Level of Concern**

**for Risk Assessment**  **Study and Toxicological Effects**  Inhalation Short - Term (1 - 30 days) and Intermediate Term (1 - 6 mo nths) NOAEL = 41 mg/kg

/day UF A=10X

UF H=10X LOC =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) No Evidence of Carcinogenicity. Classified as “Not Likely to be Carcinogenic to Humans.” 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). MOE = margin of exposure. LOC = level of concern. **5.0 Dietary Exposure and Risk Assessment**  **5.1 Residues of Concern Summary a**  **nd Rationale** The nature of the residue in plants, rotational crops, and ruminants is adequately understood. For the purposes of tolerance enforcement and risk assessment, the residue of concern in primary crops, rotational crops, and ruminants is the parent mandipropamid , with the exception of root and tuber vegetables , where the metabolite SYN 500003 is included for risk assessment. The metabolism data indicate that there is no reasonable expectation of finite residues in milk, meat, and/or meat by

products (40 CFR §180.6, Category 3) as a result of the proposed uses , except for the use on cowpea forage which is a feed item for dairy cow s . There are no poultry feed items associated with the proposed uses. Drinking Water D409108 ; R. Shamblen ; 7/9/2013 . The assessment included mandipropamid and its major aquatic degradates, SYN 500003 and SYN 504851 , in drinking water. Two significant degradates were observed in the aerobic aquatic metabolism study SYN 504851 (maximum 29% of applied material; very mobile) and SYN 500003 (maximum 9.4%; mobile). Based on the European Union monograph, SYN 500003 has a short residence time in soil (DT50 = 2 day s), but is considerabl y more stable under aerobic aquatic conditions (DT50 = 30 day s). Five degradates were found in the aerobic soil metabolism study, but the maximum level of any of these was 4.25% of applied material. An acute oral and Ames - test were performed for the metabolite SYN 500003. This metabolite was not detected in rat metabolism studies. SYN 500003 was administered once b y oral gavage to female rats at doses of 550 or 2000 mg/kg. The oral LD50 was calculated to be 1049 mg/kg ,Mandipropamid Human Health Risk Assessment D 4 14944

Page 17 of 41 in dicating it’s more acutely toxic via the oral route than the parent compound (however, it is only 0.005 - 0.006 ppm o r 10.5 - 12.7% of the TRR in root and tuber crops) . The study is acceptable/guideline , with the SYN 500003 degradate classified as Toxicity Category III for oral toxicity . In addition, a bacterial reverse gene mutation assay (Ames Test) with SYN 500003 was conducted. No evidence of induced mutant colonies over background was detected in that study . HED notes that SYN 500003 still possesses a propargyl side chain like those found in the parent. Loss of this side chain could produce the reactive compound propiolaldehyde. The latter is believed to be the source of the liver toxicity of propargyl alcohol, for which the petitioner has submitted a 14 - day

repeat exposure study

with rats showing similar hepatotoxicity as seen with mandipropamid. Therefore, HED concludes that metabolites and degradates still having a propargyl side should be considered comparabl y as toxic as the parent fungicide. No toxicity

data were submitted for the metabolite SYN 504851. While SYN 504851 does not have the propargyl side ch ain, it could generate a reactive aldehyde (e.g., acrolein) similar to propiolaldehyde with a vinyl group instead of the alky ne function. Therefore, in the absence of repeated dose studies, HED concludes this degradate should also be considered toxicologi call y equivalent to the parent. **Table 5.1. Summary of Metabolites and Degradates to be Included in the Risk Assessment and**

**Tolerance Expression.** Matrix Residues I ncluded in Risk Assessment Residues I ncluded in Tolerance Expression Plants Primary Crop M andipropamid (Parent + SYN 500003 for root and tuber vegetables ) M andipropamid Rotational Crop Not applicable M andipropamid* Livestock Ruminant Not applicable Not applicable

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 existi ng or proposed , uses based on the absence of residues in the field rotational crops study following the label’s 30 - day plantback interval. **5 .2**  **Food Residue**  **Profile** The nature of the residue in plants, rotational crops, and ruminants is adequately understood. For the purpo ses of tolerance enforcement and risk assessment, the terminal residue of concern in primary crops, rotational crops, and ruminants is the parent mandipropamid , with the exception of root and tuber vegetables , where the metabolite SYN 500003 is included fo r risk assessment. The only significant livestock feed item associated with the proposed new uses is cowpea forage,Mandipropamid Human Health Risk Assessment D 4 14944

Page 18 of 41 which is not fed to beef cattle, swine or poultry . It is fed to dairy cattle at up to 20% of the diet in select locations, or as seasonally available. At the proposed tolerance level of 15 ppm, the calculated dietary

burden to dairy

cattle is 10 ppm (the contribution to dietary burden from the only current feed items, potato culls and processed waste, is negligible at 0.025 ppm). No li vestock feeding studies were submitted with this petition. An acceptable ruminant metabolism study

is available. Goats were dosed with radiolabeled mandipropamid at 30 - 36 ppm (3 - 3.6X the dietary

burden to dairy

cattle) in the feed for 7 consecutive day s. The parent compound was identified only in fat (0.013 - 0.019 ppm), milk (0.013 ppm), and liver (0.004 - 0.007 ppm). Based on the highest detected residue of 0.019 ppm in goat fat, anticipated residues from feeding cowpea forage containing mandipropamid at the recommended tolerance level of 15 ppm would be roughl y 0.006 ppm. HED’s ChemSAC recommended against establish ing a tolerance in cowpea forage, due to the potential for finite residues in cattle commodities (fat, milk and liver). Establishing a tolerance in cowpea forage would necessitate the concurrent establishment of tolerances at the LOQ in cattle fat, milk and liver, which would require a suitable method for the enforcement of tolerances in these commodities. However, with no validated method for enforcing tolerances in cattle commodities, it is not possible to establish tolerances in them (m inutes from ChemSAC meeting of 17 July 2013). The proposed tolerance in cowpea forage cannot be established until a validated method for determining mandipropamid residues in livestock (cattle) commodities is available. **5.2.1 Crop Field Trials (860.1500)**  D409363 ; W . Drew ; Aug 27, 2013. Adequate field trial data were provided to support the proposed tolerances for residues in basil and dried basil. The residue data in snap beans are adequate to support tolerances in snap beans, but not in all succulent beans (ChemSAC meeting; 17 July 201 3) ; if tolerances in succulent beans are desired, then additional field trial data on a succulent shelled bean cultivar (such as lima beans) w i l l be necessary . Adequate field trial data were submitted to support the use on ginseng, as well as on greenhous e tomatoes. The additional data for tomatoes grown in a greenhouse do not indicate the need for any change to the existing tolerances. In all cases, the studies were considered to have been conducted in geographically representative locations (except gre enhouse tomatoes for which no location is specified), with application rates, re - treatment intervals and pre harvest intervals (PHIs) reflecting the proposed label directions for use . In all cases, the tolerances are based on detectable residues in the crops/commodities. A table reflecting the results of the submitted field trial data is provided below .Mandipropamid Human Health Risk Assessment D 4 14944

Page 19 of 41 **TABLE 5.2.1**  **Summary of Residue Data from Crop**  **Field and Greenhouse Trials with Mandipropamid.**  **Comm odity**  **Total**

**Use Rate (lb ai/A)**  **PHI**

**(Days) Resid**  **ue Levels (ppm)**

**n Min.**  **Max. LAFT** * **HAFT*** **Median Me**  **an Std. Dev.**  **Basil (f**  **ield and g**  **reenhouse )**  Fresh stems and leaves 0.520 -

0.528 1 12 **1** 3.5 19 - - 9.0 9.3 4.8

6 **2**

- - 3.6 19 8.8 9.4 5.0 Dried stems and leaves 0.520 -

0.528 1 6 **1, 2** 36 91 - - 63 63 20 **Ginseng (**  **f**

**ield only** **)** Mandipropamid Roots 0.521 -

0.547 2 8 **1** 0.0222 0.167 - - 0.0586 0.07 17 0.0 551

4 **2**

- - 0.0271 0.119 0.0705 0.0718 0.0 47 5 Metabolite SYN500003 Roots 0.521 -

0.547 2 8 **1** <0.005 <0.005 - - <0.005 <0.005 -

4 **2**

- - <0.005 <0.005 <0.005 < 0.005 - **Snap b**  **ean (f** 

**ield only)**  Pods with seed 0.490 -

0.540 1 20 **1** 0.0858 0.761 - - 0.210 0.256 0. 175

10 **2**

- - 0.10 0.58 0.220 0.256 0. 164 Plants with pods 0.490 -

0.540 1 20 **1** 1.24 9.84 - - 4.15 4.14 2 .34

10 **2**

- - 1.27 9.27 4.35 4.14 2 .36 **Tom ato**  **(g reenhouse**  **only)** F ruit 0.480 -

0.651 1 8 **1** 0.045 0.339 - - 0.147 0.168 0.101

4 **2**

- - 0.059 0.289 0.115 0.168 0.105 * LAFT = Lowest Average Field Trial; HAFT = Highest Average Field Trial. 1. n = total number of samples. 2. n = total number of field trials. For the crop group expansions, the requested tolerances are supported b y existing data. These include Vegetable, fruiting, crop group 8 - 10 ; Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13 - 07F ; Onion, bulb, subgroup 3 - 07A ; and Oni on, green subgroup 3 - 07B . Concomitant with the establishment of the new crop subgroup tolerances, the grape, dry bulb onion and green onion tolerances should be deleted. **5.2.2 Field Rotational Crops (860.1900)**  D328534, D337543; D. McNeilly; 28 August 200 7 An adequate limited field rotational crop study was reviewed in P etition s # 6F7057 and # 7F7184. Mandipropamid residues were below the LOQ (<0.01 ppm) in all samples of rotated radish roots, radish tops, spinach leaves, fall wheat forage, spring wheat fo rage, wheat hay , wheat grain, and wheat straw planted at the 28/31 - day and 61 - day PBI s. HED has determined that the rotational crop restriction on the label which states “ d o not plant any crop which is not registered for use with mandipropamid for a perio d of 30 days after the last application” is appropriate . Given the label restriction , tolerances in rotational crop s are not needed.Mandipropamid Human Health Risk Assessment D 4 14944

Page 20 of 41 **5.2 .3**  **Processed Food and Feed (860.1520)** Because there are no processed commodities for ginseng or succulent beans , processing studies are not required for these RACs. The processed commodity for basil is dried basil, for which adequate data were pro vided in support of the petition . A processing study is not need ed for tomatoes, as this requirement was addressed in a previous document ( D328534 ; D. McNeilly ; August 28, 2007 ). **5.3 Water Residue Profile**  D 409108 ; R. Shamblen ; Jul 9 , 20 13 . The estimated drinking water concentrations (EDWCs) used in the dietary risk assessments were provided b y the Environmental Fate and Effects Division (EFED ) , ( D409108, R. Shamblen, 7/9/2013). The EDWCs were incorporated directly into these dietary

assessments in the food categories “water, direct, all sources” and “water, indirect, all sources.” The EDWCs for mandipropamid were generated using the FQPA In dex Reservoir Screening Tool (FIRST) Version 1.1.1 model for surface water , and both the Pesticide Root Zone Model for Ground Water (PRZM GW v. 1.01) and Screening Concentration in Ground Water ( SCI - GROW version 2.3) models for groundwater. Modeled surface water and groundwater EDWCs are based on the maximum label application rate to tomato and basil (chronic value). A Total Residue (TR) modeling approach was used to estimate aerobic aquatic half - lives, and estimate drinking water concentrations in surface waters. Previous drinking water assessments calculated separate half

- lives for the parent compound and two degradates of concern , for which exposure was estimated with separate model runs . Simple addition of the exposure estimates for mandipropamid and it’s degradates of concern was used to generate estimated drinking water concentrations. Previous authors acknowledge this approach is conservative because the exposure estimates may

not be temporally coincident. The TR method, however, tallies the parent compound and its degradates of concern prior to calculating a Total Residue half - life. The Environmental Fate and Effects Division (EFED ) conducted a Tier 1 drinking water exposure assessment for the fungicide mandipropamid. Tier 1 exposure model ing results are summarized in Table 5.3. PRZM - GW resulting in the highest estimate of the potential for mandipropamid residues in ground water sources of drinking water . Maximum estimated drinking water concentrations (EDWC) in ground water are 87 and 79 μg/L for acute and chronic exposures, respectivel y. These values are as much as 480 times higher than SCI - GROW model results. Maximum acute and chronic EDWCs in surface waters are 79 and 9.0 μg/L, respectivel y.Mandipropamid Human Health Risk Assessment D 4 14944

Page 21 of 41 **Table 5.3. Tier 1 Estimated Drinking Water Concentrations (EDWC) for Maxim um** **Mandipropamid Use Patterns.** **Drinking Water Source**

**(M odel, Version)**  **PCA (%)**  **Crop Use Pattern**

**(M aximum Annual Rate)**  **Acute (μg/L)**  **Chronic**

**(μg/L)** Surface Water (FIRST, 1.1.1) 91 Tomato & Basil (2.08 lbs a.i./A) 79 9.0 Ground Water (PRZM - GW, 1.01) N/A Tomato & Basil (2.08 lbs a.i./A) **87 79**  Ground Water (SCI - GROW, 2.3) N/A Tomato & Basil (2.08 lbs a.i./A) 0.18 **Abbreviations:** A= acre; a.i. = active ingredient; ha = hectare; kg = kilograms ; μg = micrograms; lbs = pounds (US); N/A = not applicable Two previous Tier 1 drinking water assessments of mandipropamid produced nearl y identical exposure estimates (USEPA, 2007; and, 2011). Results of multiple FIRST (v.1.1.0) model scenarios indicat ed EDWCs in surface waters rang ing from 7 to 36 μg/Lfor chronic and acute exposures. Ground water exposure estimates in both assessments were about 2.4 μg/Lwhen calculated b y SCI - GROW (v. 2.3). PRZM - GW (v. 1.01) was not used in the 2007 and 2011 assessments . Differences between the previous two and current drinking water exposure assessment s reveal that ground water exposure concentrations decreased by more than a factor of 13 (as determined us ing the SCI - GROW model) , whereas a cute surface water exposure concentrations nearl y doubled . These differences are likely attributed to a variety of recent changes incorporated into the drinking water assessment (see D409108, R. Shamblen, 7/9/2013). Note that although EFED provided HED with estimates of acute surface and ground water estimates, these have not been incorporated into the dietary model due to the lack of an acute endpoint for mandipropamid. The drinking water models and description s are available at the EPA internet site: http://www.epa.gov/oppefed/models/water/ . **5.4 Dietary Risk Assessment**  **5.4.1 Description of Residue Data Used in Dietary Assessment**  D412238 ; D. McNeill y ; Aug 27, 2013. A c hronic dietary exposure assessment w as performed for mandipropamid. The assumptions underlying this unrefined assessment were 100% crop treated (CT), HED - recommended tolerance levels or tolerance - level residues (with the exception of vegetable, tuberous and corm, crop subgroup 1C), and default DEEM - FCID  (ver. 7.81) processing factors (with the exception of chemical - specific processing factors for grape wine and sherry). The mean (i.e., relevant toMandipropamid Human Health Risk Assessment D 4 14944

Page 22 of 41 chronic exposure) drinking water e stimate of 79 ppb was provided b y the Environmental Fate and Effects Division ( EFED ) and directl y incorporated into the chroni c assessment. **5.4.2 Percent Crop Treated Used in Dietary Assessment**  The chronic dietary assessment is based on 100% crop treated assumptions for all commodities. **5.4.3 Acute Dietary Risk Assessment**  No acute dietary

toxicity endpoint could be identified based on the toxicology data currentl y available for mandipropamid. **5.4.4 Chronic Dietary Risk Assess**  **ment** All populations were evaluated for chronic dietary risk. No risks of concern were identified in the chronic dietary

exposure anal ys is. The most highly exposed population subgroup is children 1 - 2 ye ars old which utilizes 46 % of the cPAD (Table 5. 4 .6 ). The general U.S. population utilizes 2 7 % of the cPAD. Since highly conservative assumptions were used in the assessment, actual dietary exposures for all population subgroups is expected to be much lower than those shown in Table 5.4.6. **5.4.5 Cancer**  **Dietary Risk Assessment** The Cancer Assessment Review Committee (CARC) classified mandipro pamid as “Not likely to be a human c arcinogen ;” therefore a cancer assessment was not performed. **5.4.6 Summary Table**  D412238 ; D.McNeill y ; Aug 27, 2013. The results of the dietary exposure and risk anal ys i s for chronic dietary exposures are summarized below in Table 5.4.6.Mandipropamid Human Health Risk Assessment D 4 14944

Page 23 of 41 **Table 5.4.6. Summary of Dietary Exposure and Risk for Mandipropamid (Food and Drinking Water).** Population Subgroup Ac ute Dietary Chronic Dietary Cancer Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) Risk General U.S. Population
N/A N/A 0.013475 27
N/A N/A All Infants (< 1 year old) 0.011653 23 **Children 1 -**  **2 years old 0.022893**  **46** Children 3 - 5 years old 0.020342 41 Children 6 - 12 years old 0.012364 25 Youth 13 - 19 years old 0.009617 19 Adults 20 - 49 years old 0.013459 27 Adults 50 - 99 years old 0.013425 27 Females 13 - 49 years old 0.013293 27 N/A = Not applicable. **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  There are no registered or proposed residential uses for mandipropamid . Therefore, a residential exposure assessment is not required. **6. 1**  **Residential Bystander Post**  **- application**  **Inhalation Exposure** Based on the Agency's current practices, a quantitative post - application inhalation exposure assessment was not performed for mandipropamid at this time primarily because of the low acute inhalation toxicity

(Toxicity Category

IV), low vapor pressure (<7.0 x 10 - 9 mm Hg at 25oC) , and the low proposed use rate ( 0.13 lb ai/A). However, volatilization of pesticides may be a source of post - application inhalation exposure to individuals nearb y pesticide applications. The Ag ency 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 March 2, 2010 1 . 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, subsequentl y, the way to incorporate post - application inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative post - application inhalation exposure assessment for mandipropamid. **6. 2**  **Spray Drift** Spray drift is alway s a potential source of exposure to residents nearby to sp raying operations. This is particularly

the case with aerial application s allowed on mandipropamid labels , but, to a lesser extent, could also be a potential source of exposure from ground application method s employed for mandipropamid . The Agency has be en working with the Spray Drift Task Force, EPA Regional Offices and State L ead Agencies for pesticide regulation and other parties to develop the best spray

drift management practices (see the Agency ’s Spray Drift website for 1 Available at: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlMandipropamid Human Health Risk Assessment D 4 14944

Page 24 of 41 more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by- chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted b y the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriatel y apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied b y air, orchard airblast and ground h ydraulic methods. After the policy is in place, the Agency

may impose further refinements in spray

drift management practices to reduce off - target drift with spe cific products with significant risks associated with drift. Although a quantitative residential post - application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation e xposure assessment was performed for flaggers. This exposure scenario is representative of a wors t - case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post - application inhalation exposure scenarios . **7.0 Aggregate Exposure/Risk Characterization**  In accordance with the FQPA, HED 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 the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. **7.1 Acute & Chronic Aggregate Risk**  Acute and chronic (both cancer and non - cancer) aggregate exposures include food plus drinking water exposures. No acute dietary toxicity endpoint could be identified based on the toxicology d ata currentl y available for mandipropamid. As demonstrated under Section 5. 4, chronic aggregate risk is not of concern. **7.2 Short**  **- and Intermediate**  **- Term Aggregate Risk**  Short - and intermediate - term aggregate exposure s take into account residential exposure plus average exposure levels to food and water (considered to be a background exposure level). For mandipropamid , there are no residential uses , and therefore short - and/or intermediate - term aggregate risk s are not of concern . **8.0 Cumulative Exposure** **/Risk Characterization** FQPA (1996) stipulates that when determining the safety of a pesticide chemical, EPA shall base its assessment of the risk posed by the chemical on, among other things, available informationMandipropamid Human Health Risk Assessment D 4 14944

Page 25 of 41 concerning the cumulative effects to human health that may result from dietary , residential, or other non - occupational exposure to other substances that have a common mechanism of toxicity . The reason for consideration of other substances is due to the possibility that low - level exposures to multiple chemical substances that cause a common toxic effect by a common mechanism could lead to the same adverse health effect as would a higher level of exposure to any of the other substances individually . A person exposed to a pesticide at a level that is considered safe may in fact experience harm if that person is also exposed to other substances that cause a common toxic effect b y a mechanism common with that of the subject pesticide, even if the individual exposure levels to the other substances are also considered safe. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to mandipropamid and any other substances, and mandipropamid does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that mandipropamid has a common mechanism of toxicity with other substances. For information re garding EPA’s efforts to determine which chemicals have a common mechanism of toxicity

and to evaluate the cumulative effects of such chemicals, see the policy statements released b y EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. **9.0 Occupational Exposure/Risk**  **Characterization** D412239; Z. Figueroa; Aug 27, 2013 Based on the anticipated use patterns and current labeling, typ es of equipment and techniques that can potentiall y be used, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios: Mixer/L oaders 1. Mixing/loading liquid concentrates to support aerial applications , 2. Mixing/loading liquid concentrates to support chemigation application s, 3. Mixing/loading liquid concentrates to support groundboom applications , Applicators 4. Applying spray s with aircraft (enclosed cockpit) , 5. Applying spray s with groundboom equipment , Flaggers 6. Flagging to support aerial spray applications , and Mixer/L oader/Applicators 7. Mixing/loading/appl yi ng liquid concentrates to support mechanically- pressurized handgun applications.Mandipropamid Human Health Risk Assessment D 4 14944

Page 26 of 41 The maximum single application rates for the proposed uses range d from 0.09 - 0.13 lb ai/ acre . The inputs for area treated were based on information in ExpoSAC Policy 9.1 . Based on the proposed use pattern , directions (e.g., 2 - 4 applications per season with a minimum 7 - 10 day spray interval) and resistance management practices (e.g., no more than 2 consecutive applications ) , short - and intermediate - term exposures are expected for occupational handlers. Since the same endpoint and point of departure were selected for short - and intermediate - term durations, short - term exposure and risk estimates are considered to be protective of intermediate term exposure and risk. Long - term exposures are not expected; therefore, a long - term assessment was not conducted. Results of inhalation exposure are presented for “baseline” level of PPE, defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator . The mandipropamid product labels direct mixers, loaders, applicators and other handlers to wear long - sleeved shirt and long pants, shoes plus socks. PPE re commende d on the proposed label for early

entry to treated areas include: coveralls, chemical - resistant gloves made of any waterproof material, shoes plus socks. The maximum application rate for each exposure scenario is presented as the worst - case , and standard assumptions were used with respect to the area treated for each crop/application method, along with the assumption of 80 kg body weight . Since no short - or intermediate - term dermal endpoints of concern were identified, there is no dermal risk associated with exposure to mandipropamid. Only

inhalation risk estimates have been assessed. Summaries of the risks for occupational handlers are included in Table 9 .1 . All occupational handler scenarios resulted in inhalation MOEs greater than the level of concern (MOEs > 100 for inhalation) at some level of risk mitigation (i.e., baseline attire with no respirator; engineering control for aerial applications (enclosed cockpits) ) . No additional PPE recommendations are needed o n the proposed label. The Agency

matches quantitative occupational exposure assessment with appropriate characterization of exposure potential. While HED presents quantitative risk estimates for human flaggers where appropriate, agricultural aviation has changed dramatically over the past two decades. According the 2012 National Agricultural Aviation Association (NAAA) survey of their membership, the use of GPS for swath guidance in agricultural aviation has grown steadil y from the mid 1990’s. Over the same time period, the use of human flaggers for aerial pesticide applications has decreased steadily from ~15% in the late 1990’s to onl y 1% in the most recent (2012) NAAA survey . The Agency will continue to monitor all available information sources to be st assess and characterize the exposure potential for human flaggers in agricultural aerial applications. HED has no data to assess exposures to pilots using open cockpits. The only data available reflect exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the engineering control (enclosed cockpits) and baseline attire (lon g - sleeve shirt, long pants, shoes, and socks); per the Agency ’s Worker Protection Standard stipulations for engineering controls,Mandipropamid Human Health Risk Assessment D 4 14944

Page 27 of 41 pilots are not required to wear protective gloves duration the application. With this level of protection, there are no risk estimates of concern for applicators.Mandipropamid Human Health Risk Assessment D 4 14944

Page 28 of 41 **Table 9**  **.1. Occupational Handler Non**  **- Cancer Exposure and Risk Estimates for**  **Man dipropamid.**  **Exposure Scenario Crop or Target**  **Inhalation Unit Exposure ( μ**  **g/lb ai) 1**  **Ma xim**  **um Application Rate**  **2 Am**  **ount or Area** 

**Treated 3**  **Inhalation Mitigation Level**  **Dose (mg/kg/day) 4**  **MOE 5**  Mixer/Loader M/L Liquids for Aerial Applications [AHETF/PHED] Basil, Snap bean, Ginseng 0.219

(Baseline; No Respirator) 0.13 350 A 0.000125 330,000 M/L Liquids for Chemigation [AHETF/PHED] Basil, Snap bean, Ginseng 0.219

(Baseline; No Respirator) 0.13 350 A 0.000125 330,000 M/L Liquids for Groundboom Applications [AHETF/PHED] Basil, Snap bean, Ginseng 0.219

(Baseline; No Respirator) 0.13 80 A 0.0000285 1,400,000 Applicator Sprays for Aerial Applications [PHED] Basil, Snap bean,

Ginseng 0.0049

E ngineering control (enclosed

cockpits) 0.13 350 A 0.0000028 15,000,000 Sprays for Groundboom Applications [AHETF/PHED] Basil, Snap bean, Ginseng 0.34

(Baseline; No Respirator) 0.13 80 A 0.000044 930,000 Flagger Sprays for Aerial Applications [PHED] Basil, Snap bean,

Ginseng 0.35

(Baseline; No Respirator) 0.13 350 A 0.000199 210,000

Mixer/Loader/Applicator M/L/A Liquids for Mechanically- pressurized Handgun Applications [PHED] Basil, Snap bean,

Ginseng 3.9

(Baseline; No Respirator) 0.013 1,000 gals 0.000634 65,000 1. Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March, 2013) ; Level of mitigation: Baseline; Eng . control for aerial applications (enclosed cockpits) . 2. Based on registered or proposed label ( EPA Reg. No. 100 - 1254 ). 3. Exposure Science Advisory Council Policy #9.1. 4. Inhalation Dose = Inhalation Unit Exposure ( μg/lb ai) × Conversion Factor (0.001 mg/ μg) × Application Rate (lb ai/A) × Ar ea Treated (A/day) ÷ BW ( 80 kg). 5. Inhalation MOE = I

nhalation NOAEL ( 41 mg/kg/day) ÷ I nhalation Dose (mg/kg/day). LOC=100.Mandipropamid Human Health Risk Assessment D 4 14944

Page 29 of 41 Occupational Post - Application Assessments Dermal Although there is potential for dermal post - application exposure, no dermal endpoint was selected because the rat 28 - day dermal toxicity

study demonstrated no toxicity up to the limit dose (1,000 mg/kg/day). Therefore, a quantitative dermal post - applicati on exposure assessment was not conducted. The restricted entry

interval (REI) listed on the master label is based on the acute toxicity of the technical material. Mandipropamid has low acute dermal toxicity (Toxicity Category IV), and is not an ocular or dermal irritant , nor a dermal sensitizer. Mandipropamid is not classified as a carcinogen or a neurotoxicant. In addition, it is not associated with known reproductive or developmental effects. Based on this information, mandipropamid is categorized as a reduced risk chemical. Therefore, the REIof 4 hours is adequate to protect agricultural workers from post - application exposures to mandipropamid. Inhalation Based on the Agency's current practices, a quantitative post - application inhalation exposure assessment was not performed for mandipropamid at this time primarily because of the low acute inhalation toxicity

(Toxicity Category IV), low vapor pressure (<7.0 x 10 - 9 mm Hg at 25oC) , and the low proposed use rate (0.13 lb ai/A). However, there are multiple potential sources of post application inhalation exposure to individuals performing post - application activities in previously

treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulat es 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 f

inal report on March 2, 2010 2 . The Agency is in the process of evaluating the SAP report as well as available post - application inhalation exposure data generated b y the ARTF 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 - application inhalation exposure assessment for mandipropamid. Although a quantitative occupational post - application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler e xposure resulting from application of pesticides outdoors is likely to result in higher exposure than post - application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post - appli cation inhalation exposure scenarios.

2 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlMandipropamid Human Health Risk Assessment D 4 14944

Page 30 of 41 **10.0 References**  Mandipropamid: Chronic Aggregate Dietary (Food and Drinking W ater) Exposure and Risk Assessment for the Section 3 Registration Action on Fresh Basil, Dried Basil, Ginseng, Fruiting Vegetable (Crop Group 8 - 10); Small Fruit, Vine Climbing (Crop Subgroup 13
- 07F), except Fuzzy Kiwifruit; Snap Bean, Bulb Onion (Crop Subgroup 3
- 07A), and Green Onion (Crop Subgroup 3
- 07B). D412238, D.McNeilly; Aug 27, 2013. Mandipropamid. Occupational and Residential Exp osure Assessment for the Proposed Uses on Basil, Snap Bean, and Ginseng, and the Request to Update Several Existing Crop Groups with Revised Crop Group Definitions. D 412239, Zaida Figueroa ; Aug 27, 2013. Mandipropamid. Petition to Establish Permanent Tolerances (and Section 3 Registration) for Residues Resulting from Use of the Fungicide on Basil, Succulent Beans, Cowpea Forage, Ginseng and Greenhouse Tomatoes; to Update Fruiting Vegetables Group 8 to Group 8
- 10; to Extend the Tolerance in Grapes to S ubgroup 13
- 07F, the Tolerance in Dry Bulb Onions to Subgroup 3
- 07A, and the Tolerance in Green Onions to Subgroup 3
- 07B. Summary of Analytical Chemistry and Residue Data. D409363, W. Drew; Aug 27, 2013. Drinking W

ater Exposure Assess ment for Proposed Section 3 New Uses on: Basil, Ginseng and Succulent Beans; and Expanded Uses on Bulb Vegetables, Cucurbits, Grapes, and Fruiting Vegetables including Tomatoes., D409108, R. Shamblen, 7/9/2013

. Mandipropamid. Section 3 Registration Reque st to Register New Uses on Hops and Tobacco and Confirmatory Residue Analytical Method for Determination of Residues in Crop Matrices. Summary of Analytical Chemistry and Residue Data. ; D 348229, D352322 , D. Rate; 11 December 2008. Mandipropamid. Request to Register New Food/Feed Uses on Head and Stem Brassica, Leafy Brassica Greens, Cucurbit Vegetables, Fruiting Vegetables, Leafy Vegetables (except Brassica), Tuberous and Corm Vegetables, Grapes, and Onions (Dry Bulb and Green). Summary of Analytical Chemistry and Residue Data. Petition Numbers 6F7057 and 7F7184. ; D328534, D337543; D. McNeill y; 28 August 2007. Ecological Risk Assessment for the Mandipropamid Section 3 New Use on Outdoor/Non
- food Ornamentals and Listed Vegetables Grown for Tran splant and Retail Sale to Consumers ; D382369; C. Wendel; 26 July 2011 .Mandipropamid Human Health Risk Assessment D 4 14944

Page 31 of 41 **Appendix A. International Residue Limits Mandipropamid (PC Code**  **036602 )**  **Summary of US Tolerances and International Maxim um Residue Limits.**  **Residue Definitions US (40CFR**  **§180.637) Canada**  **Codex Plants:**  Mandipropamid (4 - chloro -N - [2 - [3 - methoxy - 4 - (2 - propynyloxy)phenyl] ethyl] - α - (2 - propynyloxy) - benzeneacetamide). Mandipropamid (4 - chloro -N - [2 - [3 - methoxy - 4 - (2 -propynyloxy) phenyl]ethyl] - α - (2 -propynyloxy) - benzeneacetamide). Mandipropamid.
**Comm odity**  **2 Tolerance** 

**(ppm) 3**  **Comm odity**  **MRL (m**  **g/kg) Comm**  **odity MRL**  **4 (m**  **g/kg)** Basil, fresh leaves 30 Basil, dried leaves 200 Bean, succulent Bean, snap NA 0.9 Ginseng 0.30 Cow pea, forage NA Vegetable, fruiting, group 8 - 10 1.0 Bell peppers, eggplants, ground cherries, non -bell peppers, okras, pepinos, pepper hybrids, tomatillos, tomatoes 1 Bell peppers, non -bell peppers 1 Dried chili peppers 10 Tomatoes 0.3 Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13 - 07F 2.0 Grapes 1.4 Grapes 2 Onion, bulb, subgroup 3 - 07A 0.10 Chinese onions, daylilies, dry bulb onions, fritillaria, bulbs, garlic, great - headed garlic, lilies, pearl onions, potato onions, serpent garlic, shallot bulbs 0.05 Bulb onions 0.1 Onion, green, subgroup 3 - 07B 7.0 Beltsville bunching onions, elegans hosta, fresh Chinese chive leaves, fresh chive leaves), fresh onions, fritillaria leaves, green onions, kurrats, lady's leek, leeks, macrostem onions, shallot leaves, tree oni on tops, Welsh onion tops, wild leeks 4 Spring onions 7

**Completed:** M. Negussie, 27 June 2013. 1. Mexico adopts US tolerances, and/or Codex MRLs, for its export purposes. 2. Includes only commodities of interest for this action. 3. Tolerance values are those recommended by HED, not those proposed by the petitioner. 4. * = absent at the LOQ . Po = post - harvest treatment, such as treatment of stored grains. PoP = processed post harvest treated commodity , such as a process ed commodity of post - harvest treated stored wheat . (Fat) = to be measured in the fat portion of the sample. MRLs indicated as “proposed ” have not been finalized by the CCPR and the CAC.Mandipropamid Human Health Risk Assessment D 4 14944

Page 32 of 41 **A ppendix B.**  **Toxicology Profile B**  **.1 Toxicology Data Requirement**  **s** The requirements (40 CFR 158.340) for food uses of mandipropamid are in Table B 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. The acute and chronic toxicity profiles are shown in Tables B.2.1 and B .2.2, respectively . **Study Technical**  **Required Satisfied**  870.1100 Acute Oral Toxicity ................................ ....................... 870.1200 Acute Dermal Toxicity ................................ .................. 870.1300 Acute Inhalation Toxicity ................................ .............. 870.2400 Acute Eye Irritation ................................ ....................... 870.2500 Acute Dermal Irritation ................................ ................. 870.2600 Skin Sensitization ................................ .......................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 90 - Day

Oral Toxicity in Rodents ................................ .. 870.3150 90 - Day

Oral Toxicity in Nonrodents ............................. 870.3200 21 /28 - Day Dermal Toxicity ................................ ........... 870.3250 90 - Day

Dermal Toxicity ................................ ................ 870.3465 28/ 90 - Day Inhalation Toxicity ................................ ...... yes yes yes no no yes

yes yes

-

- 870.3700a Prenatal Developmental Toxicity (rodent) ..................... 870.3700b Prenatal Developmental Toxicity (nonrodent) ............... 870.3800 Reproduction and Fertility Effects ................................ . yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent) ................................ .............. 870.4100b Chronic Toxicity (nonrodent) ................................ ........ 870.4200a Carcino genicity (rat) ................................ ...................... 870.4200b Car c in ogenicity (mouse) ................................ ................ 870.4300 Combined Chronic Toxicity / Carcinogenicity ................ yes yes yes yes yes yes

yes yes yes yes 870.5100 Mutagenicity

—Bacterial Reverse Mutation Test .......... 870.5300 Mutagenicity

—Mammalian Cell Gene Mutation Test .. 870.5385 Mutagenicity

— Structural Chromosomal Aberrations ... 870.5550 Mutagenicity

—Other Genotoxic Effects ....................... yes yes yes yes yes

yes yes yes 870.6200a Acute Neurotox icity Screening Battery (rat) ................. 870.6200b 90 - Day

Neuro toxicity Screening Battery (rat) ............... 870.6300 Develop me ntal Neuro toxicity ................................ ........ no no no -

-

- 870.7485 Metabolism and Pharmacokinetics ................................ 870.7600 Dermal Penetration ................................ ........................ 870.7800 Immunotoxicity ................................ ............................. yes yes yes yes

yes yesMandipropamid Human Health Risk Assessment D 4 14944

Page 33 of 41 **B .2**  **Toxicity Profile s**  **Table B.2.1 Acute Toxicity Profile**  **- Man**  **dipropamid Guideline No.**  **Study Type MRID(s)**  **Results Toxicity Category**  870.1100 Acute oral rat 46800201 LD 50 > 5000 mg/kg IV 870.1200 Acute dermal rat 46800202 LD 50 > 5050 mg/kg IV 870.1300 Acute inhalation rat 46800204 LC 50 > 5.19 ± 0.55 mg/L IV 870.2400 Acute eye irritation rabbit 46800206 Iritis and positive signs of conjunctivitis clearing within 24 hours. IV

870.2500 Acute dermal irritation rabbit 46800208 PDI = 0.33 IV 870.2600 Skin sensitization guinea pig 46800210 Replaced by 47259001. N/A 870.2600 Skin sensitization mouse 47259001 Test substance is not a dermal sensitizer. NegativeMandipropamid Human Health Risk Assessment D 4 14944

Page 34 of 41 **Table B.2.2 Subchronic, Chronic and Other Toxicity Profile**  **for Mandipropamid Guideline**  **No. Study Type**  **MRID No. (year)/**  **Classification Dose levels**  **Results** 870.3100 90 - Day

oral toxicity (rat) 46800216

(2005) Acceptable/ Guideline ppm= 0, 100, 500,

3000, 5000 mg/kg/day= M: 0, 8, 41, 260, 435 F: 0, 9, 45, 260, 444 NOAEL = 41/45 mg/kg/day M/F

LOAEL = 260 mg/kg/day both sexes, based on decreased body weights, weight gains and food utilization in males and slight hepatotoxicity in both sexes 830.3100 28 - Day

oral toxicity (rat) 46800214

(2005) Acceptable/ Guideline ppm

= 0, 1000, 3000, 10,000, 16,000 [10,000 & 16,000 died < day 4] mg/kg/day = M: 0, 135, 418, 624, 604 F: 0, 121, 381, 784, 1410 NOAEL = not established

LOAEL = M=135, F=121 mg/kg/day, based on decreased food consumption in both sexes and decreased body weights and weight gains in males (liver changes at 418/381 mg/kg/day M/F).
870.3100 90 - Day

oral toxicity (mouse) 46800213

46800217 (2005) Acceptable/ Guideline ppm= 0, 300, 800,

2000, 5000 mg/kg/day= M: 0, 37, 98, 248, 624 F: 0, 47, 129, 316, 800 NOAEL = M/F = 248/316 mg/kg/day

LOAEL = M/F = 624/800 mg/kg/day, based on decreased body weight gain in males and females (as well as the suggestion of effects on the liver: increased weights in both sexes and microscopic pathology). 870.3150 90 - Day oral

toxicity (dog) 46800218

46800219 46800220 (2005) Acceptable/ Guideline mg/kg/day=

0, 5, 25, 100, 400 (capsule) NOAEL = 100 mg/kg/day

LOAEL = 400 mg/kg/day, based on liver toxicity (increased cholesterol, alkaline phosphatase activity, ALT activity, liver weights and microscopic pigment in hepatocytes and Kupffer cells in both sexes and centrilobular hepatocyte vacuolation in females). 870.3200 21/28 - Day dermal

toxicity (rat) 46800222

46800221 ( 2005) Acceptable/ Guideline mg/kg/day=

0, 250, 500, 1000 (limit dose) Sy stemic/Dermal NOAEL = 1000

mg/kg/day LOAEL = not determined 870.3700a Prenatal

developmental (rat) 46800224

46800223 (2005) 46800228 (2001) Acceptable/ Guideline mg/kg/day=

0, 50, 200, 1000 **Maternal** NOAEL = 1000 mg/kg/day

LOAEL = not determined **Developm ental**  NOAEL = 1000 mg/kg/day LOAEL = not determined 870.3700b Prenatal

developmental (rabbit) 46800227

46800225 46800226 46800229 (2005) Acceptable/ Guideline mg/kg/day=

0, 50, 250, 1000 **Materna** l NOAEL = 1000 mg/kg/day

LOAEL = not determined **Developm enta**  l NOAEL = 1000 mg/kg/day LOAEL = not determinedMandipropamid Human Health Risk Assessment D 4 14944

Page 35 of 4 1 **Table B.2.2 Subchronic, Chronic and Other Toxicity Profile**  **for Mandipropamid Guideline**  **No. Study Type**  **MRID No. (year)/**  **Classification Dose levels**  **Results** 870.3800 Reproduction and

fertility effects (rat) 46800230

46800231 (2005) Acceptable/ Guideline ppm=(males/

females) 0, 50, 250, 1500 mg/kg/day= (mean of premating both sets of parents) = 0/0, 4.6/5.0, 22.9/24.5, 146.3/148.2 **Parental/System ic**  NOAEL = M/F =

22.9/24.5 mg/kg/day LOAEL = M/F = 146.3/148.2 mg/kg/day, based on decreased body weights, weight gains, food consumption and food utilization in males **Reproductive** NOAEL = M = 146.3/148.2 mg/kg/day LOAEL = not determined **Offspring** NOAEL = M/F = 22.9/24.5 mg/kg/day LOAEL = M/F = 146.3/148.2 mg/kg/day, based on decreased pup body weights in both sexes. 870.4100 Chronic toxicity

(dog) 46800232

(2005) Acceptable/ Guideline mg/kg/day=

0, 5, 40, 400 (capsule) NOAEL = 5 mg/kg/day

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). 870.4300 Com

bined chronic toxicity/ carcinogenicity (rat) 46800234

(2005) Acceptable/ Guideline ppm

= 0, 50, 250, 1000 mg/kg/day= M/F = 0/0, 3.0/3.5, 15.2/17.6, 61.3/69.7 NOAEL = M/F = 15.2/17.6

LOAEL = 61.3/69.7mg/kg/day, based on decreased body weight gain and food utilization and increased nephrotoxicity in males. **There was no evidence of carcinogenicity in rats.**  870.4200 Carcinogenicity

(mouse) 46800233

(2005) Acceptable/ Guideline ppm

= 0, 100, 500, 2000 mg/kg/day= M/F = 0/0, 10.6/13.2, 55.2/67.8, 222.7/284.6 NOAEL = M/F = 55/68 mg/kg/day

LOAEL = 223/285 mg/kg/day, based on decreased body weight gain in both sexes and decreased food utilization in males. **There was no evidence of carcinogenicity in m** **ice.** 870.5100 Bacterial Reverse

Mutation Assay 46800235

(2005) Acceptable/ Guideline Tested up to limit

dose of 5000 μg/plate Negative
870. 5300 In Vitro

Mammalian Cell Gene Mutation Test

– Mouse Lymphoma 46800236

(2005) Acceptable/ Guideline Tested up to limit

dose (4119 μg/mL) NegativeMandipropamid Human Health Risk Assessment D 4 14944

Page 36 of 41 **Table B.2.2 Subchronic, Chronic and Other Toxicity Profile**  **for Mandipropamid Guideline**  **No. Study Type**  **MRID No. (year)/**  **Classification Dose levels**  **Results** 870. 5375 In Vitro

Chromosome Aberration test

– Human Peripheral Blood Lymphocytes 46800237

(2002) Acceptable/ Guideline Up to cytotoxic

concentrations Negative

870.5395 Micronucleus

Assay in Rats 46800238

(2005) Acceptable/ Guideline Limit dose of 2000

mg/kg Negative
870.5550 In Vivo/In Vitro

Unscheduled DNA Synthesis Assay in Primary Rat Hepatocytes 46800239

Acceptable/ Guideline mg/kg = 0 or 2000 Negative

870.6200a Ac ute

neurotoxicity (rats) 46800242

(2005) 46800241 (2003) Acceptable/ Guideline mg/kg = 0, 200,

600, 2000 (limit dose) NOAEL = M/F = 2000 mg/kg

LOAEL = M/F = not observed

870.6200b Subchronic

neurotoxicity (rats) 46800240

(2005) Acceptable/ Guideline ppm

= 0, 100, 500, 2500 mg/kg/day = M/F = 0/0, 7.4/8.4, 37.3/41.0, 192.5/206.7 NOAEL = M/F = 37/41 mg/kg/day

LOAEL = M/F = 192/207 mg/kg/day, based on slightly decreased body weight, weight gain and food utilization in males.Mandipropamid Human Health Risk Assessment D 4 14944

Page 37 of 41 **Table B.2.2 Subchronic, Chronic and Other Toxicity Profile**  **for Mandipropamid Guideline**  **No. Study Type**  **MRID No. (year)/**  **Classification Dose levels**  **Results** 870.7485 Metabolism and

pharmacokinetics (rat) 46800243 -

46800246 (2005) Acceptable/ Guideline mg/kg/day =

single oral 3 or 300 methoxy label repeated 3 methoxy label single oral 3 or 300 methoxy/chloro labels After 48 hours, absorption was 67 - 74%

at 3 mg/kg and 30 - 45% at 300 mg/kg. Blood T max at 3 mg/kg was 8.5 hours for M and 4.5 hours for F; at 300 mg/kg was 24 hours for M and 10 hours for F (rate of resorption greater in F; extent and rate greater in low dose). Recoveries at 168 hours 88 - 99% (most eliminated by 48 hours). Excluding 3 mg/kg F, most excreted in feces; at 3 mg/kg F, feces and urine similar. Elimination after 48 hours in bile was high at 3 mg/kg (55 - 73%), but wa s 22 - 28% at 300 mg/kg. Liver had highest concentration at all measurements. More radioactivity in plasma than whol e blood. Identified compounds 66 - 94% of administered dose in each group (168 hours). Parent and following metabolites at ≥5% at 3 and/or 300 mg/kg: NOA 458422, NOA 458422 glucuronide, SYN 534133 and CGA 380778. Differences in metabolic profile due to se x, dose and radiolabel position. Each unknown compound < 5%. Major metabolic transformations involved loss of one or both propargyl groups followed by glucuronidation and O - demethylation. 870.7600 Dermal

Penetration (rat) 46800248

(2005) Acceptable/ Guideline Nominal doses:

mg/cm2 skin = 0.00152, 0.0076, 2.54. Spray strength dilutions of 1/333 and 1/1667 v/v. Recovery was 96 - 112%. Minimal

absorption (<0.17 to 3.44% of applied dose). 91 - 105% recovered from 6 hour skin wash. Greatest absorption in 1/ 1667 aqueous dilution 114 hours after 6 hours of exposure (3.44% absorbed). 870.7800 Immunotoxicity

(mouse) 48771701

(2011) Acceptable/Gu ideline 0, 56,187 and 649

mg/kg/day NOAEL = 649 mg/kg/day

LOAEL = not established Non Guideline Methods

Development and Validation for Dietary Form ulation Analyses 46800215

(2002) Acceptable/ Non - Guideline N/A Validation of analytical method for determining concentrations, stability and homogeneity of test article in dietary formulations. Non Guideline In Vitro Dermal

Penetration Study, Rat epidermis 46800247

(2003) Acceptable/ Non - Guideline μg/cm2 skin = 2570

or 2510 Absorption rate greatest during first 30

minutes of exposure, 0.715 - 0.746 μg/cm2/hour. Absorption rates over 24 hours were 0.077 - 0.091 μg/cm2/hour.Mandipropamid Human Health Risk Assessment D 4 14944

Page 38 of 41 **Table B.2.2 Subchronic, Chronic and Other Toxicity Profile**  **for Mandipropamid Guideline**  **No. Study Type**  **MRID No. (year)/**  **Classification Dose levels**  **Results** Non Guideline In Vitro Dermal

Penetration Study, Rat epidermis 46800251

(2005) Acceptable/ Non - Guideline μg/cm2 skin = 1.35,

6.69, 2538 Absorption was poor (recovery of

applied radioactivity 99 - 105%). Absorption rates over 24 hours were <0.04 μg/cm

2 /hour in concentrate formulation and 0.01 μg/cm2/hour in aqueous spray dilutions. Non Guideline In Vitro Dermal

Penetration Study, Pig epidermis 46800249

(2003) Acceptable/ Non - Guideline μg/cm2 skin =

neat: 38,600 in acetone: 39.9 Absorption was poor (<0.01%).

Absorption rate for neat was greatest during first 4 hours (0.03 μg/cm2/hour) and was 0.02 μg/cm2/hour over 24 hours. Absorption rate for acetone was 3.58% (first hour = 0.56, 24 hours = 0.05 μg/cm2 /hour). Absorption enhanced by acetone. Non Guideline In Vitro Dermal

Penetration Study, Human epidermis 46800250

(2005) Acceptable/ Non - Guideline μg/cm2 skin = 1.35,

6.69, 2538 Recovery of radioactivity was 95 -

102%. Absorption was minimal. Over 24 hours, absorption was <0.04 μg/cm2/hour in the concentrate formulation and ≤0.001 μg/cm2/hour in the aqueous spray dilutions. **B.2.3 Immunotoxicity**  Immunotoxicity

study in mice. In an immunotoxicity

study (MRID 48771701), M andipropamid (96.5% a.i., Lo t No. SEZ2BP007) was administered to female CD - 1 mice (10 /dose ) in the diet at con centrations of 0, 300, 1000, or 3000 ppm (equivalent to 0, 56, 187, and 649 mg/kg bw/day , respectivel y) for 28 consecutive day s. A con current (positive control) group of 10 female mice received cyclophos phamide m onohydrate (CPH) 10 mg/kg bw/day by gavage for the duration of the study . On Day 25, all mice were immun ized with sheep red blood cells (SRBC), a single intravenous (IV) injection 0.25 mL ( dose volume of 2 × 10 8 /mL). During the study , clinical conditi on, body weight, food and water consumption were evaluated. At sacrifice, blood was collected for the determination of anti - S RBC specific IgM, and the liver, thymus, and spleen were removed and weighed. The anti - SRBC IgM concentration was measured with Enzyme Linked Immunosorbent Assay

(ELISA). The positive control group treated with cyclophosphamide (CPH) had one death on Day 3 but the cause was unable to determine. There were no treatment related clinical signs of toxicity or effects on body

weight, f ood intake, or organ weights. The positive control group had statistically

significant decreased (p< 0.05) body weight throughout the study , and the terminal body weight gain was ~50% of the concurrent control. The average absolute spleen weight of CP H - treated mice was decreased b y 16% at study termination , but there was no difference in relative spleen weight when compared to the controls .Mandipropamid Human Health Risk Assessment D 4 14944

Page 39 of 41 The sy stemic NOAEL was 3000 ppm (equivalent to 649 mg/kg bw/day), the highest dose tested. A sy stemic LOAEL was not established. There were no stati stically significant decreased in anti - SRBC specific IgM levels in the in treated groups when compare to the vehicle control group. High inter - individual variability was noted in all the treatment groups as well as in the control group. Evaluation of the individual animal data of this study

did not show any

trend or distribution that would demonstrate significant suppression of anti - S RBC antibody response. Positive control group had 91% decreased in the IgM response . This confirmed the ability of the test sy stem to detect immuno suppressive effects and confirmed the validity of the study

design. The Natural Killer (NK) cells activity was not evaluated in this study . The toxicology database for mandipropamid does not reveal any evidence of immunotoxicity . The overall weight of evidence suggests that the chemical does not directly target the immune s ys tem. Under HED guidance a NK cel l activity assay is not required at this time. The immunotoxicity

NOAELwas 3000 ppm (equivalent to 649 mg/kg bw/day), the highest dose tested. Immunotoxicity

L OAEL was not established. This immunotoxicity

study is classified Acceptable/Guideline and satisfies the guidelineMandipropamid Human Health Risk Assessment D 4 14944

Page 40 of 41 **Appendix C**  **. Physical/Chemical Properties**  **Table A.C. Physical and chemical Properties of the Technical Grade of Mandipropam id.**  Parameter Value Reference Melting point/range 96.4 - 97.3oC MRID 46800006 (100 - REIR.doc, S. Mathur, 22/MAY/2007) 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, pKa No dissociation constant in the pH range of 1 to 12 Octanol/water partition coefficient, Log(P OW) 3.3 at 25oCMandipropamid Human Health Risk Assessment D 4 14944

Page 41 of 41 **Appendix D**  **. Review of Human Research**  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 s tudies, lis ted below , have been reviewed for ethical conduct. The studies were considered appropriate for use in risk assessments. **The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task Force members Health Canada, U.S.**  **Environmental Protection Agency, and the National Agricultural Chemicals Association, released February, 1995.**  **The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler Unit Exposure Surrogate Reference Table. U.S.**  **Environmental Protection Agency. Released June 21, 2011.**