### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 1 of 43 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA**  **L SA FETY**  **AND POLLUTION PREVENTION**  

### MEMORANDUM **D ATE**  **:** June 28 , 2012 **SUBJECT: Cyazofamid**  **.** Human Health Risk Assessment for Proposed New Use s on Leafy

Greens ( Crop Subgroup 4A), Succulent - Podded and Succulent - Shelled Beans, Basil, Tuberous and Corm Vegetables (Subgroup 1C), and Fruiting Vegetables (Crop Group 8 - 10 ) with Updated Residential Risk Estimates of All Existing Residential Uses. **PC Code:** 085651 **DP Barcode:** 397213 **Decision No.:** 456373 **Re gistration**  **No s**  **. :**  71512 - 3 **Petition No .**  **:** 1E7929 **Regulatory Action:** Section 3 Registration **Case No.:**  NA **Risk A**  **ss essment Type**  **:** Single Chemical/Aggregate **T XR No.:**  NA **CAS No.:** 120116 - 88 - 3 **MRID No .**  **:** NA **40 CFR:** § 180.60 1 **FROM:** Nancy

Tsaur, Chemist, Risk Assessor Nancy Dodd , Chemist Kristin Rury , Biologist Whang Phang, PhD, Senior Toxicologist Risk Assessment Branch 3 Health Effects Division (7509P) **THROUGH:** Paula Deschamp, Branch Chief

Risk Assessment Branch 3 He alth Effects Division (7509P) **TO:** Barbara Madden/Laura Nollen , Risk Manager Team 05

Risk Integration, Minor Use, and Emergency Response Branch (RIMUERB) Registration Division (7505P) RD requested that HED provide an evaluation of proposed new use s and tolerance s for cyazofami d in/on leafy

greens (crop subgroup 4A), succulent - podded and succulent - shelled beans, basil, tuberous and corm vegetables (subgroup 1C), and f ruiting vegetables (crop group 8 - 10 ) . A summary

of the findings and an assessment of human health risk resulting from the proposed and registered uses of cyazofamid are provided in this document and its attachments. This assessment has incorporated the updated 2012 Residential Standard Operating Procedures (SOPs) .

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 2 of 43 The residue chemistry

data review and the dietary exposure assessment were completed b y Nancy Dodd. The occupational and residential exposure updates were completed by Kristin Rury , and the aggregate human health risk assessment was conducted b y Nancy Tsaur. The drinking water assessment was conducted b y Jos é Meléndez of the Environmental Fate and Effects Division (EFED) . **Table of Contents 1.0**  **Executive Summary ................................**  **................................ ................................**  **............. 4**  **2.0 HED Recommendations**  **................................ ................................**  **................................ ......**  **6 2.1**  **Data Deficiencies** ................................ ................................ ................................ ............ 6 **2.2 Tolerance Considerations**  ................................ ................................ .............................. 7 **2.2.1 Enforcement Analytical Method**  ................................ ................................ ............... 7 **2.2.2 International Harmonization**  ................................ ................................ ..................... 7 **2.2.3 Recommended Tolerances**  ................................ ................................ ......................... 8 **2.2.4 Revisions to Petitioned**  **- For Tolerances**  ................................ ................................ .... 8 **2.3 Label Recommendations**  ......... **Error! Bookmark not defined. Error! Bookmark not**  **defined. 3.0**  **Introduction ................................**  **................................ ................................**  **.......................... 8**  **3.1 Chemical Identity**  ................................ ................................ ................................ ........... 9 **3.2 Physical** **/Chemical Characteristics** ................................ ................................ ............... 9 **3.3 Pesticide Use Pattern**  ................................ ................................ ................................ ...... 9 **3.4 Anticipated Exposure Pathways**  ................................ ................................ ................. 12 **3.5 Consideration of Environmental Justice**  ................................ ................................ .... 12 **4.0 Hazard Characterization and Dose**  **- Response Assessment**  **................................ ............**  **12 4.1**  **Summary of Toxicological Effects** ................................ ................................ .............. 13 **4.2 Safety Factor for Infants and Children (FQPA Safety Factor)**  ............................... 14 **4.2.1 Completeness of the Toxicology Database**  ................................ .............................. 14 **4.2.2 Evidence of Neurotoxicity**  ................................ ................................ ........................ 14 **4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal**  ........ 14 **4.2.4 Residual Uncertainty in the Exposure Database**  ................................ ................... 15 **4.3 Toxicity Endpoint and Point of Departure Selections**  ................................ .............. 15 **5.0 Dietary Exposure and Risk Assessment**  **................................ ................................**  **........... 17**  **5.1 Residues of Concern Summary and Rationale**  ................................ .......................... 17 **5.2 Food Residue Profile**  ................................ ................................ ................................ .... 17 **5.3 Water Residue Profile**  ................................ ................................ ................................ .. 19 **5.4 Di**  **etary Risk Assessment** ................................ ................................ .............................. 20 **5.4.1 Description of Residue Data Used in Dietary Assessment**  ................................ .... 20 **5.4.2 Acute Dietary Risk Assessment**  ................................ ................................ ............... 20 **5.4.3 Chronic Dietary Risk Assessment**  ................................ ................................ ........... 20 **5.4.4 Cancer Dietary Risk Assessment**  ................................ ................................ ............. 20 **5.4.5 Summary Table**  ................................ ................................ ................................ ......... 20 **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  **............................... 21**  **6.1 Residential Handler Exposure**  ................................ ................................ .................... 21 **6.2 Post**  **- Application Exposure**  ................................ ................................ .......................... 24 **6. 3**  **Combined Exposure** ................................ ................................ ................................ ..... 24

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 3 of 43 **6.4 Residential Bystander Post**  **- Application Inhalation Exposure**  ................................ 25 **6.5 Spray Drift**  ................................ ................................ ................................ .................... 25 **7.0 Aggregate Exposure/Risk Characterization**  **................................ ................................**  **.... 26**  **7.1 Acute Aggregate Risk**  ................................ ................................ ................................ ... 26 **7.2 Short**  **- Term Aggregate Risk**  ................................ ................................ ........................ 26 **7. 3**  **Intermediate -**  **Term Aggregate Risk** ................................ ................................ ........... 27 **7.4 Chronic Aggregate Risk**  ................................ ................................ .............................. 27 **7.5 Cancer Aggregate Risk**  ................................ ................................ ................................ 27 **8.0 Cumulative Exposure/Risk Characterization**  **................................ ................................**  **. 27**  **9.0 Occupational Exposure/Risk Characterization**  **................................ ..............................**  **27 9.1**  **Short -**  **and Intermediate -**  **Term Handler Risk** ................................ ........................... 27 **9.2.1 Dermal Post**  **- Application Risk**  ................................ ................................ ................. 28 **9.2.2 Inhalation Post**  **- Application Risk**  ................................ ................................ ............ 29 **Appendix A. Toxicology Profile and Executive Summaries**  **................................ ................**  **31 A.1**  **Toxicology Data Requirements** ................................ ................................ ................... 31 **A.2 Toxicity Profiles**  ................................ ................................ ................................ ............ 32 **Appendix B .**  **Physical/Chemical Properties and Metabolic Profile ................................**  **.... 37**  **Appendix C. Review of Human Research**  **................................ ................................**  **............. 38**  **Appendix D. Occupational Exposure and Risk Estimates Summary Table**  **...................... 39**  **Appendix E. International Residue Limit Summary**  **................................ ...........................**  **43**

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 4 of 43 **1.0 Executive Summary**  In PP# 1E7929 , the Interregional Research Project No. 4 (IR - 4) of Rutgers, New Jersey , has petitioned for the establishment of new tolerance s for combined residues of the fungicide cyazofamid, 4 - chloro - 2 - cyano -N , N - dimethyl - 5 - (4 - methylphen yl ) - 1 H - imidazole - 1 - sulfonamide, and its metabolite, 4 - chloro - 5 - (4 - methylphenyl) - 1 H - imidazole - 2 - carbonitrile, calculated as the stoichiometric equivalent of cyazofamid, in/on the following raw agricultural commodit ies (RAC s ): Bean, succulent ................................ ........................ 0.4 ppm

Bean, succulent, shelled ................................ ......... 0.07 ppm Leafy gre ens subgroup 4A ................................ ...... 9.0 ppm Basil, fresh leaves ................................ ..................... 30 ppm Basil, dried leaves ................................ ..................... 8 0 ppm Vegetable, tuberous and corm, subgroup 1C ......... 0.02 ppm Vegetable, fruiting, group 8 - 10 .............................. 0.40 ppm Pending submission of a revised Section B label with resolutions identified in Section 2.1 , there are no toxicology

or residue chemistry

issues that would preclude granting unconditional registration for the requested uses of cyazofamid or for the establishment of permanent tolerances for the combined residues of cyazofamid. The most recent human health risk assessment, conducted for use on Brassica (cole) leafy vegetables, turnip greens, spinach, and hops , reported the hazard characterization and toxicity en dpoints for risk assessment (D 370671 , N. Tsaur, 0 4 / 07 /201 0 ). Since the last risk assessment, the registrant has agreed to submi t immunotoxicity and subchronic neurotoxicity studies by the end of July

2012. Aside from the two out standing studies, the hazard characterization and toxicity endpoints for risk assessment remain unchanged. Furthermore, HED has waived the data requirement for inhalation toxicity sinc e the last risk assessment (TXR 0056341). The detailed rationale for toxicity endpoint selection will not be repeated in this risk assessment. A brief hazard charact erization along with the salient features for the Food Quality Protection Act (FQPA) safety factor will be summarized. Proposed Use Profile Broadcast application of cyazofamid may be applied at the maximum single application rate of 0.078 lb ai/A (3.0 fl oz/A) to field - grown basil and basil grown in greenhouses; and at 0.072 lb ai/A (2.75 fl oz/A) to leafy greens (subgroup 4A), succulent - podded and shelled beans, tuberous and corm vegetables (subgroup 1C), and fruiting vegetables (crop group 8 - 10). At - planting applications to tuberous and corm vegetables (subgroup 1C) may be made at the maximum single rate of 0.16 lb ai/A (6.1 fl oz/A), and soil drench applications (based on 60 gallons of water per acre) may

be made to fruiting vegetables (crop group 8 - 10) at the maximum single application rate of 0.047 lb ai/A (1.8 fl oz/A). Cyazofamid may also be applied to greenhouse transplant tomatoes with a soil drench application at a maximum application rate of 1 pint of solution per square foot (0.0085 lb ai/A).

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 5 of 43 Occupational handlers may appl y Ranman ® 400SC using ground, aerial, and chemigation equipment for broadcast application. For soil drench applications, cyazofamid may be applied using chemigation and h andheld equipment. Exposure Profile Exposures to cyazofamid are expected to o ccur for short - , intermediate - , and long - term (chronic) durations . The proposed agricultural use s result in new exposures in both food and drinking water. There are also existi ng residential uses that result in non - occupational exposure from handler and post - application activities . In occupational settings, exposure is also expected during handler and post - application activities . Toxicity/Hazard Cyazofamid has low acute toxicity via the oral, dermal, and inhalation routes of exposure. It produces minimal but reversible eye irritation, is a slight dermal irritant, and is a weak dermal sensitizer. The propensity of cyazofamid to be a slight dermal irritant and a weak sens itizer might be due to the sulfonamide moiety in the compound. Following repeated administration in more than one species, cyazofamid seems to have mild or low toxicity . The kidney appear ed to be affected the most . Skin lesions were observed in male mic e only , likel y due to systemic allergy . In dogs, there were no major toxicity findings. In the acute neurotoxicity

study, there were no indications of treatment - related adverse neurotoxicity . The pre - and post - natal toxicology database for cyazofamid in cludes rat and rabbit developmental toxicity

studies and a two - generation reproduction toxicity study in rats. There was some evidence of increased susceptibility following in utero exposure to rats in the prenatal developmental toxicity

study ; the increa sed incidence of bent ribs in the high - dose fetuses was considered adverse and was used for setting th e developmental NOAEL/LOAEL (no observed adverse effect level/lowe st observed adverse effect level). HED considers this approach conservative and highly protective because bent ribs are a reversible developmental anomaly rather than a malformation. Cyazofamid is classified as “not likely to be carcinogenic to humans” based on the lack of evidence of carcinogenicity in both the rat and the mouse studies. Additionally , cyazofamid does not appear to be mutagenic , based on several negative in vivo and in vitro studies. Dietary Exposure (Food and W ater) and Risk Estimates The residue chemistry

data and environmental fate data are adequate to assess human expo sure. Conservative dietary

exposure anal ys es using DEEM - FCIDTM indicate that acute and chronic dietary exposures to cyazofamid from food and drinking water are well below the Agency ’s level of concern (LOC) . Both acute and chronic dietary (food + drinking water) assessments were conservative, assuming that residues in all crops were at tolerance levels and that 100% of the crops were treated. An acute dietary (food + drinking water) exposure assessment was onl y performed for females 13 - 49 years old since an acute endpoint of concern was not identified for the general population. The acute dietary risk estimate for females 13 - 49 years old at the 95 th 

### percentile of exposure was 2.5% of the aPAD . The chronic dietary (food and drinking water) exposure assessment f

or the general U.S. population resulted in <1% of the cPAD. The chronic

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 6 of 43 dietary risk estimate for the highest reported exposed population subgroup , children (1 - 2 years old), was 1.5% of the cPAD. Cyazofam id is classified as “not likel y to be carcinogenic to humans;” therefore, no cancer risk is expected. Residential Exposure and Risk Estimates All existing residential exposures have been reassessed to reflect updates to HED’s 2012 Residential SOPs along with policy changes for body

weight assumptions. There are no registered products that would lead to any residential handler or post - applicatio n risk estimates of concern. Short - term residential handler (margins of exposure) MOEs range from 2,400 to 59,000. Short - term post - application MOEs for adults and children range from 660 to 570,000. Residential Aggregate Exposure Risk Estimates There is potential for short - term aggregate exposure to cyazofamid via the dietary (which is considered background exposure) and residential (which is considered primary) pathway s. All MOEs are greater than 100, which indicates that exposure and risk do n ot exceed HED’s LOC . The adult and children short - term aggregate (dietary and residential ) MOEs are 390 and 2,200 , respectivel y. Acute aggregate risk for females 13 - 49 is expected to be equivalent to the acute exposure via the dietary

pathway . Intermedi ate - term and chronic aggregate risk are expected to be equivalent to chronic exposure via the dietary pathway . Occupational Exposure and Risk Estimates There is potential for short - and intermediate - term occupational exposure to cyazofamid during handling activities (e.g. mixing, loading, application). There are no risk estimates of concern at the baseline level of personal protective equipment (PPE); all short - term combined (dermal and inhalation) handler risk estimates resulted in MOEs ranging from 200 to 140,000. There is potential for short - and intermediate - term occupational exposure during post - application activities. There are no risk estimates of concern on day 0 (12 hours after application); all scenarios resulted in MOEs greate r than the LOC of 100 (ranging from 9,500 to 1,200,000 ) on day 0 (12 hours after application). Based on a quantitative post - application assessment , the 12 - hour restricted entry

interval ( REI ) on the proposed label is appropriate. P ost - application inhalat ion exposures and risk estimates were not quantitatively assessed. **2.0 HED**  **Recommendations** Pendin g submission of a revised Section B label with resolutions identified in Section 2.1 , there are no toxic ology or residue chemistry issues that would preclude granting unconditional registration for the requested use s of cyazofamid or establishment of the tolerances for the combined residues of cyazofamid listed in Section 2.2.3. **2.1 Requirements Prior to Registrati**  **on** The following changes are required prior to establishing a tolerance or allowing a registration: 860.1200 Directions for Use

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 7 of 43  The Ranman ® 400 SC label should be amended to prohibit applications to cowpea grown for livestock feeds because no residue dat a are available for cowpea forage and hay . The statement “Do not appl y to cowpea used for livestock feed” should be added to the label. Cowp ea is a succulent shelled bean.”  The label indicates that Ranman ® 400SC should be tank mixed with an organosilicon e surfactant, non - ionic surfactant, or a blend of an organosilicone and non - ionic surfactant. The label should be revised to specify that an organosilicone surfactant can be used on basil, snap beans, lima beans, pepper, potato, spinach and tomato, and ei ther a nonionic surfactant or an organosilicone surfactant can be used on head and leaf lettuce. 860.1480 Meat, Milk, Poultry, and Eggs  Tolerances for residues of cyazofamid in poultry and swine commodities are not required provided that application to cowpea used for livestock feed is prohibited on the label. 870.7800 Immunotoxicity  The registrant has informed the Agency of their inte nt to submit an immunotoxicity study by the end of July

2012 . 870.6100b Subchronic Neurotoxicity  The registrant has informed the Agency of their intent to submit a subchronic neurotoxicity study by

the end of July

2012 . **2.2 Tolerance Considerations**  **2.2.1 Enforcement Analytical Method**  Adequate enforcement methods are available to determine residues of cyazofamid and its metabolite CCIM in lettuce, basil, snap bean, lima bean, pepper, potato, spinach, and tomato. An enforcement method for non - fatty c ommodities is FDA’s Multiresidue Protocol D (without cleanup), which completely recovers (>80% recovery) cyazofamid and metabolite CCIM. In addition, the HPL C/UV method is acceptable for use as a single analy te enforcement method provided a confirmatory

m ethod such as the LC/MS/MS data collection method (a modified version of the method in MRID 45409020) is used. **2.2.2 International Harmonization**  There are no Codex or Mexican maximum residue limits (MRL s) on the proposed c rops. Canada has a tolerance of 0.02 ppm on potatoes, which is the same level as the U . S . tolerance for vegetable, tuberous and corm, subgroup 1C which includes potatoes . Canada also has a tolerance of 0.2 ppm on tomatoes, which is less than the recommended U . S . tolerance of 0.9 ppm fo r vegetable, fruiting, group 8 - 10 which includes tomatoes . This variation is because Canada has set a single commodity tolerance on tomatoes while the U.S. tolerance is based on the highest value for the representative crops of the entire fruiting vegetable crop group.

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 8 of 43 The tolerance definition for the U.S. and Canada are the same. Both the U.S. and Canada include parent and the metabolite, 4 - chloro - 5 - (4 - methylphen yl ) - 1 H - imidazole - 2 - carbonitrile, in the tolerance expression. The International Residue L imit Status is attached in Appendix E . **2.2.3 Recommended Tolerances**  Table 2.2 .3 summarizes the HED recommendations for establishing tolerances . **Table 2.2. 3.**  **Tolerance Summary for Cyazofam** **id** Commodity Tolerance (ppm) Comments Correct Commodity Definition Established Proposed Recommended a

40 CFR §180.609(a)(1) Bean, succulent --- 0.4 0.5

none Bean, succulent, shelled --- 0.07 0.08 Leafy greens subgroup 4A --- 9.0 10 Basil, fresh leaves 30 30 Basil, dried leaves --- 80 90 Vegetable, tuberous and corm, subgroup 1C --- 0.02 0.02 Vegetable, fruiting, group

8 - 10 --- 0.40 0.9 a See Section 2.2.4 “Revisions to Petitioned - For Tolerance . ” 

### When the above tolerances are established, the existing tolerances on spinach, potato, fruiting vegetable group 8 , and okra can be removed as requested by the petitioner. **2.2.4 Revisions to Petitioned**  **- For Tolerances**  The revisions to petitioned - for tolerances for the following commodities are due to the Organization for Economic Coo peration and Development (OECD) tolerance calculation procedures: b ean, succulent ( 0.4 ppm to 0.5 ppm ); b ean, succulent, shelled ( 0.07 ppm to 0.08 ppm ); l eafy greens subgroup 4A ( 9 ppm to 10 ppm ); and b asil, dried leaves (8 0 ppm to 90 ppm ). The v egetable, fruiting, group 8 - 10 tolerance must be revised from 0 .40 to 0.9 ppm . The OECD calculation procedures us ing average field trials of existing data result in value s of 0.2 ppm for tomato , 0.4 ppm for bell pepper , and 0.9 ppm for nonbell pepper. Thus, the highest value of 0.9 ppm is recommended as the crop group tolerance . **3.0 In**  **troduction** Cyazofamid is a broad - spectrum fungicide active against oomycete fungi (such as Phytophthora, Plasmopara, Pseudoperonospora, and Pythium ) and Plasmodiophoromycetes ( Plasmodiospora brassicae ). It inhibits all stages of fungal development in the life cycle, specificall y interfering with the cy

tochrome bc 1 

### complex in the mitochondrial respiratory chain of oomycetes fungi. In PP# 1E7929 , IR - 4 has petitioned for new toler ance s for combined residues of the fungicide cyazofamid on the RACs listed in Table 2.2.3. Concomitantly , IR - 4 is proposing that the new

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 9 of 43 u ses be added to the currently registered label for Ranman® 400SC ( EPA Reg. No. 71512 - 3) , consisting of 34.5 % ai at 3. 33 lb ai/gal . **3.1 Chemical Identity**  Table 3.1 summarizes the residue profile for the parent cyazofamid and its major metabolite, CCIM. Structures of other metabolites and degradates are shown in Appendix B, Table B - 2. **Table 3.1 .**  **Cyazofam id**  **Nomenclature** Parent Chemical Structure Em pirical Formula C 1 3 H 1 3 ClN 4 O 2 S Common N ame cyazofamid Com pany Experimental N ame NA IUPAC Name 4 - chloro - 2 - cyano -N, N - dimethyl - 5 -

p - tolylimidazole - 1 - sulfonamide CAS Name 4 - chloro - 2 - cyano -N,N - dimethyl - 5 - (4 - methylphenyl) - 1 H - imidazole - 1 - sulfonamide CAS Registry Number 120116 - 88 - 3 Chemical Class imidazole, sulfonamide Known Impurities of Concern None Metabolite Chemical Structure Common name CCIM IUPAC name 4 - chloro - 5 - p - tolylimidazole - 2 - carbonitrile CAS name 4 - chloro - 5 - (4 - me thylphenyl) - 1 H - imidazole - 2 - carbonitrile 

### 3.2 **Physical/Chemical Characteristics** Cyazofamid has a low vapor pressure ( 1 . 3 3 × 10 - 5 

### Pa at 2 5 °C or 9.98 × 10 - 8 

### mm Hg at 25°C ); therefore, inhalation via chemical vaporization is unlikely . Cyazofamid has a log octanol/water partition coefficient (log P ow

### ) of 3.2 and is considered relatively insoluble in water. Additionall y, cyazofamid has a molecular weight of 327.79 amu ; therefore, the potential to cross biological barriers, such as the skin, is somewhat limited. More detailed phy sicochemical properties of cyazofamid are summarized in Appendix B , Table B - 1. **3.3 Pesticide Use Pattern**  Cyazofamid is currently

registered for us e on a variety of field crops including the following : Brassica leafy

vegetables, carrots, hops, potatoes, spinach, turnip greens, cucurbits, and fruiting vegetables . The proposed use s of Ranman® 400SC are presented in Table 3.3. **Table 3.3. Summ ary**  **of Proposed Directions**  **for Use of Ranm**  **an® 400SC (EPA Reg. No. 71512 -**  **3)** N N C H3 Cl CN S O 2 N ( C H3 ) 2

N H N C H3 Cl CN

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 10 of 43 Applic. Timing, Ty pe, and Equip. Applic.

Rate Max.

No. Applic. per Season Max.

Seasonal Applic. Rate PHI Use Directions and Limitations a lb ai/A lb ai/A days **Basil** Post - emergence. Foliar broadcast sprays using ground, aerial, or sprinkler irrigation equipment. Can be grown in a greenhouse. 0.072 -

0.078 9 0.7 0 Normal water volume is 50 - 75 gals water per acre. For downy mildew on basil, make applications on a 7 to 10 day schedule. **Beans, Succulent Podded and Succulent Shell ed**  Cicer arietinum (chickpea, garbanzo bean); Lupinus spp. (including sweet lupine, white sweet lupine, white lupine, and grain lupine); Phaseolus spp. (including kidney bean, lima bean, mung bean, navy bean, pinto bean, snap bean, and waxbean); Vicia faba (broad bean, fava bean); Vigna spp. (including asparagus bean, blackeyed pea and cow

pea) Post - emergence. Foliar broadcast sprays using ground, aerial, or sprinkler irrigation equipment. 0.072 6 0.43 0 Normal water volumes are 20 - 60 gals water per acre. For downy mildew on lima beans: Make applications on a 7 to 10 day schedule. For cottony leak control: Make the initial application at full bloom (1 st pods) and repeat on a 7 - 14 - day schedule. For P hytophthora blight control: Make the 1 st application at 100% bloom- pin pod development and a 2 nd application at late pin - small pod development and repeat every seven days. **Fruiting Vegetables (Crop Group 8 -**  **10)** African eggplant; bush tomato; bell pepper; cocona; currant tomato; eggplant; garden huckleberry; goji berry; groundcherry; martynia; naranjilla; okra; pea eggplant; pepino; nonbell pepper; roselle; scarlet eggplant; sunberry;

tomatillo; tomato; tree tomato; cultivars, varieties, and/or hybrids of these Post - emergence. Broadcast foliar or soil drench to the base of the plants at transplanting or in transplant water. Ground, aerial, or sprinkler irrigation equipment. Tomatoes for transplant can be grown in the greenhouse. A soil drench can be appli ed to tomatoes in the greenhouse. 0.054 -

0.072 Soil drench: 0.078 lb ai/100 gals water 6 0.43 0 Normal water volumes are 30 - 60 gals water per acre. For late blight control, make applications on a 7 to 10 day schedule. For Phytophthora blight control, apply to the base of the plants at the time of transplanting. Alternatively, apply in transplant water at the time of transplanting. Apply 0.072 lb ai/A in transplant water in a water volume of at least 50 gals/A for the initial application. Apply on a 7 to 10 day schedule. Tomato Greenhouse Transplant Production: For control of Pythium spp., make a single fungicide application to the seeding tray at the time of planting or at any time thereafter up until 1 week before transplanting. Apply the fungici de solution as a drench to thoroughly wet the growing medium (1 pt of solution per square foot if the growing medium is 4 inches deep). Do not use a

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 11 of 43 **Table 3.3. Summ ary**  **of Proposed Directions**  **for Use of Ranm**  **an® 400SC (EPA Reg. No. 71512 -**  **3)** Applic. Timing, Ty pe, and Equip. Applic.

Rate Max.

No. Applic. per Season Max.

Seasonal Applic. Rate PHI Use Directions and Limitations a lb ai/A lb ai/A days surfactant with this drench application.

**Leafy Greens, Crop Subgroup 4A** Amaranth (leafy amaranth, Chinese spinach, tampala); arugula (Roquette); chervil; edible - leaved chrysanthemum; garland chrysanthemum; corn salad; garden cress; upland cress (yellow rocket, winter cress); dandelion; dock (sorrel); endive (escarole); lettuce (head and leaf); orach; parsley; garden purslane; winter purslane; radicchio (red

chicory); spinach; Ne w Zealand spinach; vine spinach (Malabar spinach, Indian spinach). Post - transplant; Post - seeding; Post emergence. Foliar broadcast or soil drench band spray using ground, aerial, or sprinkler irrigation equipment. 0.072 b 6 0.43 0 Downy mildew: Apply at 7 - 14 - day intervals. Py thium: Make first application as a band to the soil as a directed, post - transplant or post - seeding application; alternatively, apply in transplant water at the time of transplant as a soil drench in at least 50 gals water per acre. Apply at 7 to 10 day intervals. Normal water volumes are 20 - 60 gals water per acre. **Tuberous and Corm Vegetables, Crop Subgroup 1C** Arracacha; arrow

root; Chinese artichoke; Jerusalem artichoke; edible canna; bitter cassava; sweet cassava; chayote (root); chufa; dasheen (taro); ginger; leren; potato; sweet potato; tanier; turmeric; yam bean; true yam

Post - emergence foliar sprays using ground, aerial, or sprinkler irrigation e quipment. Can also be at planting, in - furrow at planting, or lay by/ hilling Foliar:

0.036 - 0.072 b At planting: 0.42 fl oz per 1000 linear feet (0.16 lb ai/A based on a 36” row spacing) Lay - by/ Hilling: 0.072 10 0.72 b 7 Normal water volumes are 20 - 50 gals water per acre. For foliar blight, make applications on a 7 to10 day schedule. For tuber and corm rot control, make the last 2 to 3 applications prior to harvest at the rate of 0.072 lb ai/A applied weekly. For pink rot, Phythium root and crown rot control at planting, apply 0.42 fl oz product per 1000 linear foot of row

in - furrow at planting using a minimum of 5 gals water per acre. Apply in a 6 - 8 inch band directly over the seed pieces prior to furrow closure. Mefenoxam can be added as a tank mi x. For additional control of Pythium root and crown rot, in combination with an at - planting, in - furrow application, apply as a broadcast spray at 0.072 lb ai/A in a minimum of 20 gals of finished spray solution per acre at hilling. a Use directions and limitations: The plantback interval is 0 days for crops on the label and 30 days for other crops. Spray volumes will usually range from 20 - 100 gals per acre for dilute sprays and 5 - 10 gals/A for concentrate sprays and aerial sprays. A erial sprays should be made in a minimum of 5 gals of water per acre.

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 12 of 43 Alternate sprays of Ranman ® 400SC with a fungicide with a different mode of action ; d o not make more than three consecutive applications of Ranman ® 400SC followed by at least three applications of fungicides having different modes of action before ap plying additional Ranman® 400SC. Ranman ® 400SC should be t ank mix ed with an organosilicone surfactant, non - ionic surfactant, or a blend of an organosil icone and a non - ionic surfactant. b 2.75 fl oz product /A = 0.0715 lb ai/A and 27.5 fl oz product /A= 0.715 lb ai/A. HED rounds up to 0.072 and 0.72, respectively, as per HED’s Hot Sheet #10. 

### 3.4 **Anticipated Exposure Pathways** Humans may

be exposed to cyazofamid in food and drinking water, since cyazofamid may be applied directl y to growing crops and application may result in cyazofamid reaching surface and ground water sources of drinking water. There are also residential uses of cyazofamid ; thus, the re is likely

to be exposure in residential or n on - occupational settings. In both residential and occupational setting s , applicators may be exposed while handling the pesticide prior to application, as well as during application. There is also a potential for post - application exposure for residents and occupational workers re - entering treated area s. Several risk assessments have been previousl y prepared for the existing uses of cyazofamid . This risk assessment considers all of the aforementioned exposure pathways based on the proposed new uses of cy azofamid , but also considers the existing uses as well, particularl y for the dietary

exposure assessment. **3.5 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 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 . 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 by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are an al yz ed and categorized by subgroups based on age, season of the ye ar, 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 based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lifestyle and traditional dietary patt erns among specific subgroups. **4.0 Hazard Characterization and Dose**  **- Response Assessment** 

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 13 of 43 The cyazofamid hazard characterization is detailed in a previous risk assessment ( D 342612 , K . O’Rourke , 03/ 19/2008 ). New toxicity data have not been submitted since the last risk assessment ( D 370671 , N . Tsaur , 04 / 07 /20 10 ) . HED has waived the data requirement for inhalation toxicity

since the last risk assessment (TXR#0056307). All available toxicity studies are listed in Appendix A. **4.1 Summary of Toxicological Eff**  **ects** Cyazofamid belongs to a chemical class based on the cyanoimidazole and sulf o n amide moiet ies . Cyazofamid is a broad spectrum fungicide active against oom ycet e fungi and Plasmodiophoromycetes. It specificall y interferes with the cy tochrome bc 1 

### complex (ubiquinol cy tochrome c oxidoreductase) in the mitochondrial respiratory chain of oomycetes fungi. The mechanism of toxicity

in mammal s is not clear. The available toxicity

studies show that f

ollowing repeated administration in more than one spe cies, cyazofamid seems to have mild or low toxicity . The kidney seemed to be affected the most following 13 weeks of dietary feeding in male rats which had increased microscopic kidney lesions characterized as an “increased number of basophilic tubules, graded as slight” with associated mild increases in urinary output, protein, and pH. Female rats of the same study were less sensitive, with the only change being a marginal increase in urine volume and pH . However, there were no adverse kidney effects or any

other toxicity

findings following lifetime dietary feeding at concentrations up to 171.1 mg/kg/day and 856.0 mg/kg/day in male and female rats, respectivel y. Skin lesions (likely

due to sy stemic allergy) were observed in males in the mouse carcinogen icity study . The skin lesions occurred at a relative ly high dose (985 mg/kg/day) and were characterized b y hair loss, body sores, dermatitis, ulceration and acanthosis (hyperplasia). The sulfonamide moiety

in the cyanoimidazole ring might have rendered c yazofamid a weak allergen . Cyazofamid’s allergenic properties are supported by the fact that cyazofamid is a slight dermal irritant (Toxicity

Category III) in the primary

rabbit skin test and is a positive weak sensitizer in the guinea pig skin maximizati on test. In addition, sulfonamide antimicrobial drugs (e.g., sulfamethoxazole) have been known to cause idiosy ncratic drug reactions including delayed type skin reactions (benign rash and potentially lethal toxidermias ) . The dog is not the most sensitive species. With the exception of increased parathy roid cy sts in male dogs at the high est dose (1000 mg/kg/day) in the chronic ( one - ye ar) study , there were no major toxicity

findings in the 13 - week and one - ye ar dog studies up to a dose of 1 , 000 mg/kg/day . Cyazofamid is classified as “not likely to be carcinogenic to humans” based on the lack of evidence of carcinogenicity in both the rat and the mouse studies. Additionally , cyazofamid did not show mutagenicity potential, based on several negative in vivo and in vitro studies. Cyazofamid has a low order of acute toxicity via the oral, dermal, and inhalation routes of exposure. It produces minimal but reversible eye irritation, is a slight dermal irritant, and is a weak dermal sensitizer. The propensity of c yazofamid to be a sl ight dermal irritant and a weak sensitizer might be due to the sulfonamide moiety in the compound.

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 14 of 43 **4. 2**  **Safety F actor for Infants and Children (FQPA Safety Factor)**  The FQPA safety factor is reduced to 1X; consideration of the toxicology database leads to no additional concerns for infants and children . **4. 2**  **.1 Completeness**  **o f**  **the Toxicology Database**  The toxicological database for cyazofamid is complete except for the immunotoxicity and subchronic neurotoxicity

studies . The registrant has agreed to submit both studies by the end of July 2012. Furthermore, HED has waived the data requirement for inhalation toxicity since the last risk assessment (TXR#0056307). The submitted toxicology studies are of good quality . They are sufficient to select endpo ints for risk assessment and to determine whether cyazofamid poses a human health hazard. To address the issue of the immunotoxicity data gap and the associated database uncertainty factor, RAB3 has examined the entire database of cyazofamid and concluded that the toxicology database does not show any evidence of biologically

relevant structural effects on the immune sy stem. The overall weight of evid ence suggests that cyazofamid does not directly target the immune sy stem . HED does not believe that condu cting a functional immunotoxicity study will result in a lower no observed adverse effect level (NOAEL ) than the regulatory doses for risk assessment, and an additional factor for database uncertainty (UF DB 

### ) is not needed to account for lack of this study . B ased on the available data, conducting a subchronic neurotoxicity study is unlikely

to result in a lower NOAE L than the available relevant toxicity results because the acute neurotoxicity study , which tested dose levels as high as 2 , 000 mg/kg, shows no neurotoxic effects with gavage dosing. Neurotoxicity

is also not seen in subchronic, chronic, reproduction, or developmental toxicity studies. At this time, the lack of a subchronic neurotoxicity study does not present an y uncertainty for evaluating the toxicity of cyazofamid. Therefore, a database uncertainty factor (UF DB 

### ) for lack of a subchronic neurotoxicity is not needed. **4. 2**  **.2 Evidence of N**  **eurotoxicity** The available toxicity

database for cyazofamid do es not show an y evidence of neurotoxicity . In the acute neurotoxicity

study , there were no indications of treatment - related adverse neurotoxicity

findings including clinical signs, qualitative or quantitative neurobehavioral effects, brain weight, or gross/microscopic pathology . **4. 2**  **.3 Evidence**  **o f Sensitivity/Su**  **sceptibility in the Developing o r Young Animal**  The available studies used to evaluate pre - and post - natal exposure susceptibility do not indicate increased susceptibility

of developing rats or rabbits to cyazofamid . The pre - and post - natal toxicology

database for cyazofamid includes rat and rabbit developmental toxicity studies and a two - generation reproduction toxicity study in rats . Inthe prenatal developmental toxicity study in rabbits, there were no maternal or developmental effects at an y dose up to the limit dose of

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 15 of 43 1,000 mg/kg/day . In the two - generation reproduction study , the highest dose tested (>1,000 mg/kg/day) did not cause maternal s ys temic toxicity nor did it elicit reproductive or offspring toxicity . **4. 2**  **.4 Residual**  **Uncer tainty in the Exposure Datab**  **ase** The exposure databases are complete or are estimated based on data that reasonably account for potential exposures. New 2012 Residential SOPs we re used to assess post - application exposure to children including incide ntal oral exposure. The residential post - application assessment assumes maximum application rates and conservative day zero hand - to - mouth activities. All of the exposure estimates are based on conservative high - end assumptions and are not likel y to underestimate risk. The dietary

exposure assessments (food and drinking w ater) which assumed tolerance - level resides, 100% crop treated, and high - end estimates of water concentrations (EDWCs), are conservative , high - end assessments . They do not underestimate the potential dietary exposures. The calculated residential risks represent conservative estimates of exposure because maximum application rates are used to define residue levels. Exp osures are unlikely to be underestimated because the assessment is a screening - level assessment. **4. 3**  **Toxicity Endpoint and Point of D**  **eparture Selections** There are no changes to the previous dose - response assessment. A summary of the toxicological endpoints for cyazofamid for use in dietary and occupation al human health risk assessments is presented in Table 4.3. **Table 4.3. Summ**  **ary of Toxicological Doses and Endpoints for Cyazofam** **id for Use in Dietary**  **, Non**   ** Occupational,** **and Occupational Hum an Health Risk Assessments**  a 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 None: There is no indication of an adverse effect attributable to a single dose. An aRfD was not

established. Ac ute Dietary ( Females 13 - 49 years of age ) NOAEL =

100 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Ac ute RfD =

1.0 mg/kg/day aPAD = 1.0 mg/kg/day Rat Prenatal Develo pm ental Toxicity

LOAEL = 1,000 mg/kg/day based on developmental toxicity findings of increased incidence of bent ribs.

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 16 of 43 **Table 4.3. Summ**  **ary of Toxicological Doses and Endpoints for Cyazofam** **id for Use in Dietary**  **, Non**   ** Occupational,** **and Occupational Hum an Health Risk Assessments**  a Exposure/ Scenario Point of

Departure Uncertainty/

FQPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects

Chronic Dietary (All Populations) NOAEL=

94.8 mg/kg/day UF A = 10X

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

= 0.948 mg/kg/day cPAD = 0.948 mg/kg/day 18 - Month Mouse Oral Carcinogenicity

(MRID 45408932) LOAEL = 985 mg/kg/day based on increased skin lesions. Incidental Oral Short - Term (1 - 30 days) and Intermediate Term (1 - 6 mo nths) NOAEL=

30 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Residential

LOC for MOE = 100 90 - Day

oral toxicity study in rats. LOAEL= 295 mg/kg based on i ncreased number of basophilic tubules of the kidneys, increased urinary volume, pH, & protein. This toxicity endpoint is also supported by th e results of a 28 - day oral dose range - finding study

in rats. In this study, at 370 mg/kg/day or above increased incidence of basophilic tubules in the kidneys was found.

Dermal Short Term (1 - 30 days) and Intermediate Term (1 - 6 mo nths) **For CHILDREN:**

No toxicity was found at 1000 mg/kg in a 28 - day dermal toxicity study ; therefore, in the absence of hazard identified for this population, a risk assessment is not necessary. **For ADULTS:**  NOAEL = 100 mg/kg/day dermal absorption factor = 37% UF A = 10X

UF H = 10X FQPA SF = 1X Residential

LOC for MOE = 100 Occupational LOC for MOE = 100 Rat Prenatal Developmental Toxicity (MRID

45408933) LOAEL = 1,000 mg/kg/day based on developmental toxicity findings of increased incidence of bent ribs. Inhalation Short - Term (1 - 30 days) and Intermediate Term (1 - 6 mo nths) NOAEL=

100 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Residential

LOC for MOE = 100 Occupational LOC for MOE = 100 Rat Prenatal Developmental Toxicity (MRID

45408933) LOAEL = 1,000 mg/kg based on developmental toxicity findings of increased incidence of bent ribs. Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant

tumor increases in two adequate rodent carcinogenicity studies. a 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 observe d 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. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 17 of 43 Based on the available toxicity database and the Agency's current practice s, the inhalation risk for cyazofamid was assessed using an oral toxicity study . The Agency

sought expert advice and input on issues related to this route to route extrapolation approach (i.e. the use of oral toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory

Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency

is in the process of evaluating the SAP report and may , as appropriate, reexamine and develop new policies and procedures for conducting inhalation risk assessments, including route to route extrapolation of toxicity data. If any new polici es or procedures are developed, the Agency may revisit the need for an inhalation toxicity study for cyazofamid and/or a reexamination of the inhalation toxicity risk assessment. **5.0 Dietary Exposure and Risk Assessment**  **5.1 Residues of Concern Summary a**  **nd Rationale** The residues of concern for dietary risk assessment and the tolerance expression are summarized in Table 5.1. Although potato and carrot commodities may be significant feed item s for cattle, currentl y registered and newly proposed uses fall under 40 CFR § 180.6(a)(3) (i.e. there is no reasonable expectation of finite residues in livestock commodities). Based on the available ruminant metabolism studies in goats, HED recommends that the following metabolites should be anal yz ed for future catt le feeding studies: cyazofamid, CCIM, CCBA, CCBA - cy steine conjugate. In addition, there are no poultry or swine feed items. (These conclusions assume that the recommended restriction against use on cowpea used for livestock feed is added to the label . ) **Table 5.1. Summ ary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance**  **Expression** a Matrix Residues I ncluded in Risk Assessment Residues Included in Tolerance Expression Plants Parent and CCIM Parent and CCIM Livestock No decision (For future cattle feeding studies, the MARC

recommended that the petitioner analyze parent, CCIM, CCBA, and CCBA - cysteine conjugate.) No decision Rotational crops Parent only Parent only Water Parent, CCIM, CCIM - AM, and CTCA N/A a Currently registered and proposed uses fall under 40 CFR § 180.6(a)(3) (i.e. there is no reasonable expectation of finite residues in livestock commodities). In addition, there are no poultry or swine feed items. (These conclusions assume that the recommended restriction against use on cow pea used for livestock feed is added to the label.) 

### 5 **.2 Food**  **Residue Profile**  To support the newl y proposed uses, IR - 4 has submitted field trials of cyazofamid on basil, lima beans, snap beans, head lettuce, and leaf lettuce . There are adequate data for risk assessment and tolerance assess ment. Inthe residue decline studies, combined residues of cyazofamid and its metabolite, CCIM, were quantifiable, generall y declining with increasing sampling interval. The results from these studies are summarized in Table 5.2.

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 18 of 43 Crop Field Trials Provided the requested revisions are made to the Ranman ® 400 SC label, the field trials are adequate to establish tolerances on all the proposed commodities at levels recommended in Table 2.2.3 . Detectable residues may occur in food. Field trial decline studies show that residues in agricultural commodities decline with increasing preharvest intervals. **Table 5.2. Summ**  **ary of Residue Data from** **Field Trials with Cyazofam id**  a , b Crop Matrix Analyte Applic. Rate (lb ai/acre) PHI

(days) n Residues (ppm)

Min. Max. LAFT HAFT Median Mean SD **BASIL P roposed Use = 0.7 lb ai/acre total application rate, 0**  **- day PHI**  Basil, fresh (leaves and stems) c Cyazofamid

+ CCIM 0.693 -

0.721 0 6 2.4 15 2.6 14 8.5 8.4 5.1 Basil, dried (leaves and stems) c Cyazofamid

+ CCIM 0.693 -

0.721 0 4 11 46 11 43 30 28 13 **BEAN, LIMA Proposed Use = 0.43 lb ai/acre total application rate, 0**  **- day PHI**  Bean, lima (succulent seeds) Cyazofamid

+ CCIM 0.427 -

0.523 0 - 1 6 <0.02 <0.057 <0.02 <0.050 0.020 0.025 0.012 **BEAN, SNAP Proposed Use = 0.43 lb ai/acre total application rate,**  **0 -**  **day PHI** Bean, snap (pods with seeds) Cyazofamid

+ CCIM 0.426 -

0.507 0 8 <0.022 <0.23 <0.029 <0.21 0.12 0.12 0.072 **LETTUCE, HEAD Proposed Use = 0.43 lb ai/acre total application rate, 0**  **- day PHI**  Lettuce, head (head with wrapper leaves) Cyazofamid

+ CCIM 0.419 -

0.506 0 11 <0.06 2.0 <0.080 1.8 0.65 0.83 0.61 **LETTUCE, LEAF Proposed Use = 0.43 lb ai/acre total application rate, 0**  **- day PHI**  Lettuce, leaf (leaves) Cyazofamid

+ CCIM 0.427 -

0.587 0 11 <0.49 4.6 <0.54 4.5 1.8 2.1 1.3 a Except for sample min/max, values reflect per trial averages; n = no. of field trials. b LAFT = Lowest Average Field Trial; HAFT = Highest Average Field Trial; SD = Standard Deviation. For computation of the LAFT, HAFT, median, mean, and standard deviation, values < LOQ ar e assumed to be at the LOQ. c Data for fresh basil include field trials and greenhouse trials. Data for dried basil reflect field trials. 

### Processing Studies A dditional processing studies are not required. The previousl y submitted tomato and potato proce ssing studies are adequate to show that residues in tomato and potato processed commodities will not concentrate above the tolerance levels for the raw agricultural commodities; therefore, separate tolerances on the processed commodities of tomato and pota to are not required. Storage Stability The available storage stability data are adequate to support the storage durations and conditions of the field trial s amples . Except for residues of the metabolite CCIM in fresh basil, the data are adequate to conclude that residues of cyazofamid and CCIM in the field trial samples were stable

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 19 of 43 during frozen storage. Residues of CCIM in fresh basil declined b y 46% after 284 days (9.3 months) of freezer storage ; therefore, residues in fresh basil in the field trials were corrected for loss of CCIM in storage . Meat, Milk, Poultry, and Eggs The results of the goat metabolism study indicate that tolerances for residues of cyazof amid in ruminant commodities are not required for the purpose of this petition since there is no reasonable expectation that finite residues will occur in ruminant commodities [40 CFR §180.6(a)(3)]. Tolerances for residues of cyazofamid in poultry and sw ine commodities are not required provided that application to cowpea used for livestock feed is prohibited on the label. With that label prohibition, there are no poultry or swine feed items associated with the proposed or registered uses, and the propose d and registered uses fall under 40 CFR §180.6(a)(3) for poultry commodities. Rotational Crops Since the results of the confined rotational crop study showed that cyazofamid and structurally related metabolites are each expected to be present at a level l ess than 0.01 ppm at a plantback interval of 30 day s , no field rotational crop studies are required. The rotational crop plantback interval of 0 day s for crops which are on the label and 30 day s for other crops is appropriate. **5.3 Water Residue Profile**  Available environmental fate studies suggest cyazofamid is not very mobile and quickl y degrades into a number of degradation products under different environmental conditions. HED concluded that cyazofamid and the metabolites designated as CCIM, CCIM - AM ( 4 - chloro - 5 - p tolylimidazole - 2 - carboxamide ), and CTCA ( 4 - chloro - 5 - p - tol yl imidazole - 2 - carbox yl ic acid) are considered to be the major residues in water and should be included in the drinking water risk assessment. Among the three major degradates for cyazofamid (CCIM, CCIM - AM and CTCA), the two terminal ones are CCIM and CTCA. CCIM is expected to be the major terminal degradate in water bodies with low biological activity because it forms as a result of abiotic hydrol ys is of the parent. In contrast, CTCA is expected to be the major terminal degradate in biologicall y active soils and water/sediment s ys tems. Both CCIM and CTCA are stable to abiotic hydrol ys is and susceptible to leaching, but only CCIM is highl y su sceptible to biodegradation. Given these fate characteristics, cyazofamid and/or its degradates could potentially

reach surface water via spray drift or runoff under certain environmental conditions, but the potential for it to reach ground water is very low. CCIM and/or CTCA could potentially be the terminal degradates in surface water bodies affected b y spray drift and/or runoff depending on the level of biological activity . However, onl y CTCA has a high potential to contaminate ground water due to its high persistence and mobility . Table 5.3 summarizes the EDWCs . T he acute value of 136.2 ppb and the non - cancer chronic value of 133.5 ppb were directly entered into the exposure model to assess the contributions from drinking water. EDWCs in surface water were modeled using Tier 2 PRZM/EXAMS (Pesticide Root Zone Model/Exposure Anal ys is Modeling Sy stem ) for residues from use on turf and

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 20 of 43 ornamentals, which had the highest seasonal rates among the proposed and registered uses. EDWCs in ground water as mod eled b y Tier 1 SCI - GROW (Screening Concentration in Ground Water) were lower. The models and their descriptions are available online at : http://www.epa.gov/oppefed1/models/water/ . **Table 5.3 . Surfac**  **e/Ground Water EDWCs for Cyazofamid and its Major Degradates.** Scenario Chemical Surface W ater EDWCs (ppb) Ground W ater EDWC (ppb) Ac ute (1 - in - 10 y

r. peak) Chronic

(1 - in - 10 y

r. mean) 1 st Scenario Parent 14.362 0.377 0.01180 2 nd Scenario CCIM 17.106 12.094 0.00061

CCIM - AM 6.699 6.312 0.00270 3 rd Scenario CTCA **136.242 133.458**  2.18000 

### 5.4 **Dietary Risk Assessment** Conservative dietary

exposure anal ys es using DEEM - FCIDTM indicate that acute and chronic dietary risk estimates for cyazofamid exposure from food and drinking water are well below HED’s LOC (i.e. <100% of the population adjusted dose ). **5.4.1 Description of Residue Data Used in Dietary Assessment**  Both acute and chronic dietary (food + drinking water) assessments were conservative, assuming that residues in all crops were at tolerance levels and that 100% of the crops were treated. **5.4. 2**  **Acute Dietary Risk Assessment** An acute dietary

(food + drinking water) exposure assessment was onl y performed for females 13 - 49 years old since an acute endpoint of concern was not identified for the general population. The acute dietary

risk estimate for females 13 - 49 years old at the 95 th 

### percentile of exposure was 2.5% of the aPAD . The results of the acute dietary exposure anal ys is are reported in Table 5.4.5. **5.4.3 Chronic Dietary Risk Assessment**  The chronic dietary (food and drinking water) exposure assessment f or the general U.S. population resulted in a risk estimate of <1% of the cPAD. The chronic dietary risk estimate for the highest reported exposed population subgroup , children (1 - 2 years old), was 1.5% of the cPAD. The results of the chronic dietary exposure anal ys is are reported in Table 5.4.5 . **5.4.4 Cancer Dietary**  **Risk Assessment** Cyazofamid is classified as “not likely to be carcinogenic to humans;” therefore, no cancer risk is expected. **5.4. 5**  **Summary Table of Dietary Risk Assessments** 

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 21 of 43 **Table 5.4.6. Summary of Dietary Exposure and Risk for Cyazofam** **id** a Population Subgroup Ac ute Dietary 95 th Percentile (Food and Drinking Water) Chronic Dietary Exposure Estimates (Food and Drinking Water) mg/kg/day % cPAD General U.S. Population NA b 0.008157 <1% All Infants (< 1 year old) 0.012989 1.4 **Children 1 -**  **2 years old**  **0.014334 1.5**  Children 3 - 5 years old 0.012279 1.3 Children 6 - 12 years old 0.008139 <1% Youth 13 - 19 years old 0.006274 <1% Adults 20 - 49 years old 0.007733 <1% Adults 50+ years old 0.007855 <1% Females 13 - 49 years old 0.024799 2.5 0.007725 <1% a aPAD (acute population adjusted dose) = 1.0 mg/kg/day. cPAD (chronic population adjusted dose) = 0.95 mg/kg/day. The population subgroup with the greatest exposure is in bold . b NA = Not applicable. 

### 6.0 **Residential (Non -**  **Occupational) Exposure/Risk Characterization**  There are no proposed residential uses at this time; however, cyazofamid is registered for use on several residential and non - agricultural use sites. C yazofamid 400SC Turf and Ornamentals Fungicide (EPA Reg. No. 71512 - 13) may be used on turf areas associated with golf courses, sod farms, seed farms, college and professional sports fields, residential and commercial lawns, and on ornamental plants in landscapes and those grown in commercial greenhouses and nurseries. Whil e the label say s “application by homeowners to residential turf is prohibited,” the label does not identify

this product as a restricted use; therefore, a residential handler exposure assessment was performed to be protective of potential residential handler exposure. Residential exposure and risks from use on gardens, trees, and turf have been reassessed to reflect updates to the 2012 HED Residential SOPs along with policy changes for body

weight assumptions . All residential handler risk estimates range from 2,400 to 59,000 and all residential post - application risk estimates ranged from 660 to 570,000; and therefore, are not of concern to HED. Th is revision of residential exposures impacts the human health aggregate risk assessment for cyazofamid. Based o n the Agency's current practices, a quantitative residential post - application inhalation exposure assessment was also not performed for cyazofamid at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV ) and low vapor pres sure of cyazofamid ( 9.98 x 10 - 8 

### mm Hg at 25 oC ) . If new policies or procedures are developed, the Agency may revisit the need for a quantitative post - application inhalation exposure assessment for cyazofamid . **6.1 Residential Handler Exposure**  Residential h andler exposure is expected to be short - term . Intermediate - term exposures are not likely because of the intermittent nature of applications by homeowners . Additionally , h omeowners are assumed to complete all elements of an application without use of an y protective equipment .

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 22 of 43 The quantitative exposure/risk assessment developed for residential handlers is based on the following exposure scenarios: 1. Mixing/L oading/Applying for Spray s Using Manually- Pressurized Handwand , 2. Mixing/L oading/Applying for Sprays with Back - Pack Sprayer , 3. Mixing/L oading/Applying for Spray s with H ose - end Sprayer, and 4. Mixing/L oading/Applying for Application with a Sprinkler Can. The maximum application rate for each exposure scenario is present ed as the worst case scenario. All re sidential risk estimates are not of concern to HED (MOEs ranged from 2,400 to 59,000 ). A s ummary of the short - term risk estimate s ( dermal and inhalation) for residential handlers are included in Table 6.1 .

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 23 of 43 **Table 6**  **.1 .**  **Short -**  **Term Residential Handler Exposure and Risk Estimates for Cyazofamid** Exposure Scenario Target MOE Dermal

Unit Exposure Inhalation

Unit Exposure Maximum

Application Rate a Area Treated or

Amount Handled Daily b Dermal Inhalation Total

Dose c MOE d Dose c MOE d MOE e μg/lb ai mg/kg/day mg/kg/day

Mixer/Loader/Applicator Manually Pressurized Hand wand to Gardens and Trees 100 63 0.018 0.0016 lb ai/gal 5 gallons 0.0027 37,000 0.0000021 48,000,000 37,000 Manually Pressurized Hand wand to Gardens and Trees 100 63 0.018 0.000036 lb ai/ sq ft 1200 sq ft 0.015 6,900 0.000011 8,900,000 6,900 Hose - End Sprayer to Gardens

and Trees 100 58 0.0014 0.000036 lb ai/ sq ft 1200 sq ft 0.013 7,500 0.00000087 110,000,000 7,500 Hose - End Sprayer to Gardens

and Trees 100 58 0.0014 0.0016 lb ai/gal 11 gallons 0.0055 18,000 0.00000036 280,000,000 18,000 Hose - End Sprayer to Turf 100 13.4 0.022 1.02 lb ai/A 0.5 acres 0.037 2,700 0.00016 620,000 2,700 Manually Pressurized Handwand to Turf 100 63 0.018 0.012 lb ai/gal 5 gallons 0.020 5,100 0.000015 6,500,000 5,100 Backpack Sprayer to Gardens

and Trees 100 130 0.14 0.000036 lb ai/ sq ft 1200 sq ft 0.030 3,300 0.000087 1,100,000 3,300 Backpack Sprayer to Gardens

and Trees 100 130 0.14 0.0016 lb ai/gal 5 gal 0.0056 18,000 0.000016 6,2000,000 18,000 Sprinkler Can to Gardens and

Trees 100 58 0.0014 0.000036 lb ai/ sq ft 1200 sq ft 0.013 7,500 0.00000087 110,000,000 7,500 Sprinkler Can to Gardens and

Trees 100 58 0.0014 0.0016 lb ai/gal 5 gal 0.0025 40,000 0.00000016 620,000,000 40,000 Sprinkler Can to Lawns and

Turf 100 13.4 0.022 0.000023 lb ai/ sq ft 1000 sq ft 0.0017 59,000 0.0000075 13,000,000 59,000 Backpack Sprayer to Lawns and

Turf 100 130 0.14 0.012 lb ai/gal 5 gal 0.041 2,500 0.00012 840,000 2,400 a Application Rates based on proposed uses for cyazofamid ( Cyazofamid 400SC Turf and Ornamentals Fungicide , EPA Reg. No. 71512 - 1 3) . b Amount Treated or Amount Handled Daily taken from Exposure Science Advisory Council (ExpoSAC) 2012 Residential SOPs . c Dose = Dermal/Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gallons/day) x AF (37% for dermal) / BW (69 kg). d Dermal or Inhalation MOE = NOAEL (100 mg/kg/day) / Dose (mg/kg/day). e Total MOE = NOAEL (mg/kg/day) / (Dermal Dose + Inhalation Dose) OR Total MOE = 1/ [(1/Dermal MOE) + (1/Inhalation MOE)] .

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 24 of 43 **6.2 Post**  **- Application Exposure**  Adults and children performing ph ys ical post - application activities on turf (e.g. golfing, mowing) may receive dermal exposure to cyazofamid residues. Young children 1 to <2 years old may also receive incidental oral post - application exposure to cyazofamid from treated turf. Table 6.2 presents the residential post - application dermal and incidental oral MOE values calculated for the appropriate lifestages after application of cyazofamid to gardens, trees, and residential turf. A dermal risk estimate for children was not conducted becaus e there is no dermal toxicity

for children up to the limit dose of 1000 mg/kg/day in a 28 - day

dermal toxicity study . Post - application risk estimates were not of concern to HED for any of the scenarios assessed (MOEs range from 66 0 to 57 0,000) . **Table 6.2. Short**  **- Term** **Residential Post -**  **A pplication Exposure and Risk Estimates for Cyazofam** **id.** Lifestage Post - Application Exposure Scenario Dose a MOEs b mg/kg/day Adult Gardens/Trees

Liquid Formulation 1.56 lb ai/A Dermal Contact with gardens 0.15 660 Contact with trees 0.017 6,000 Adult Turf

Liquid Formulation 1.02 lb ai/A Physical Activities on Turf 0.095 1,100 Mowing 0.0019 52,000 Golfing 0.0074 13,000 Child 1 - 2 years old Oral Incidental Oral Hand to Mouth 0.0089 3,400 Incidental Oral Object to Mouth 0.00042 72,000 Incidental Oral Soil Ingestion 0.000053 570,000 a Dermal Dose = TTR/DFR (μg/cm2 ) × CF1 (0.001 mg/μg) × TC (cm2 /hr) × Exposure Time (hrs) ÷ body weight (kg) . TC for p hysical activities on turf: 180,00 0 cm2 /hr for adults and 49,000 cm2 /hr for children 1 - 2 years old. TCs for mowing: 5,500 cm2 /hr for adults and 4,500 cm2 /hr for children 11 to < 16 years old. TCs for g olfing: 300 cm2 /hr for adults, 4,400 cm2 /hr for children 11 to < 16 years old, and 2,900 cm2 /hr for children 6 to < 11 years old. Exposure times for physical activities on turf: 1.5 hrs for adults and children. Exposure time for mowing: 1 hr. Exposure time for golfing: 4 hr s. Body weight for adult: 69 kg. Body weight for children 11 to < 16 years old: 57 kg. Body weight for children 6 to < 11 years old: 32 kg. Body weight for children 1 to < 2: 11 kg. Hand - to -Mouth Dose = hand residue loading (mg/cm 2 ) × fraction of hand mouthed (0.127) × surface area of 1 hand (150 cm2 ) × exposure time (1.5 hrs/d ay) × # of replenishment intervals/hr (4 int/hr) × (1 - ((1 - saliva extraction factor (0.5))^(Number of hand - to - mouth events per hour (13.9 events/hr) ÷ # of replenishment intervals/hr)) ÷ body weight (11 kg). Object- to -Mouth Dose = object residue loading (μ g/cm2 ) × unit conversion factor (0.001 mg/μg) × object surface area mouthed / event (10 cm2 /event) × exposure time (1.5 hrs/day) × # replenishment intervals/hr (4 int/hr) × (1 - ((1 - saliva extraction factor (0.50))^(# Object - to - Mouth Events/hr (8.8 events/hr) ÷ # replenishment intervals/hr)) ÷ body weight (11 kg). Soil Ingestion = soil residue (μg/g) × ingestion rate (50 mg/day) × conversion factor (0.000001 g/μg) ÷ body weight (11 kg). b MOE = NOAEL (mg/kg/day) ÷ Daily Dose (mg/kg/day). ST Dermal NOAEL= 100 mg/kg/day . ST Oral NO AEL = 30 mg/kg/day. 

### 6.3 **Combined Exposure** B ased on the residential use profile and the 2012 Revised Residential SOPs, exposure duration is expected to be short - term only . HED combines risk values resulting from separate post application exposure scenarios when it is likely they can occur simultaneously based on the use pattern and the behavior associated with the exposed population. Since exposure to treated gardens and turf could occur within the same day , the handler and post - application exposures from dermal contact with treated gardens and turf were combined for adults. For children, the most conservative post - application exposure estimate is hand - to - mouth incidental oral exposure from treated turf. All residential handler and post - application exposure estimates resulted in

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 25 of 43 MOEs greater than 100, and were not of concern. Table 6.3 presents a summary of the worst case residential exposure estimates for adults and children. **Table 6.3. Short**  **- Term** **Residential Exposur es for the**  **Cyazofam id**  **Residential Risk Calculations** Population Handler Exposure a Residential Handler Total Exposure b MOE Post - Application Exposure b Residential Post Application Total Exposure c MOE Dermal Inhalation Dermal Inhalation Oral

mg/kg/day mg/kg/day Adult 0.041 0.00012 0.041 2,400 0.15 0.095 NA 0.25 400 Child NA NA 0.0089 0.0069 3,400 a Handler exposure represents high end handler exposure of existing registered uses (see Table 6.2) . b Post - application exposure represents high end incidental oral exposure for existing registered uses (see Table 6.2) . c MOE = NOAEL (mg/kg/day) ÷ Daily Dose (mg/kg/day). ST Dermal NOAEL = 100 mg/kg/day. ST Oral NOAEL = 30 mg/kg/day . 

### 6.4 **Residential Bystander Post -**  **A pplication Inhalation Exposure**  Based on the Agency's current practices, a quantitative post - application inhalation exposure assessment was not performed for cyazofamid at this time primarily because of the low acute inhalation toxicity

(Toxicity Category IV), low vapor pressure ( 9.98 x 10 - 8 

### mm Hg at 25 oC ), and the low proposed use rate (0.16 lb ai/A). However, volatilization of pesticides may be a source of post - application inhalation exposure to individuals nearb y pesticide applications. The Agency sought expert advice and input on i ssues 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 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may , as appropriate, develop policies and procedures to identify the need for and, 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 cyazofam id. **6. 5**  **Spray Drift** Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. This is particularly

the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for the previousl yregistered uses of cyazofamid . The Agency has been 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 sp ray

drift management practices. 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 data base submitted by 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 hydraulic methods. Aft er the policy is in place, the Agency

may impose further refinements in spray drift management practices to reduce

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 26 of 43 off - target drift and risk estimates associated with aerial as well as other application ty pes where appropriate . Although a quantitative res idential post - application inhalation exposure assessment was not performed to address pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers. This exposure scenario is representative of a worst - 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. For cyazofamid , potential exposures from food, drinking water, and residential scenarios were aggregated. **7.1 Acute Aggregate Risk**  Acute exposures were only considered for females 13 - 49 years old because an adverse effect attributable to a single dose was not identified for the general population . However, acute exposure is not expe cted for the adult residential exposure pathway . Therefore, the acute aggregate risk estimate for females 13 - 49 years old would be equivalent to the acute dietary exposure e stimate. Refer to Section 5.4.2 . **7.2 Short**  **- Term Aggregate Risk**  There is potential short - term exposure to cyazofamid via the dietary (which is considered background exposure) and residential (which is considered primary) pathway s. For adults, these pathway s lead to exposure via the oral (background), and dermal and inhalati on (primary) routes. For children, these pathway s lead to exposure via the oral (background), and incidental oral and dermal (primary) routes. All aggregate risk estimates ( MOEs ) are greater than 100, which indicates that exposure and risk do not exceed HED’s LOC . The adult and children short - term aggregate dietary

and residential MOEs are 390 and 2 , 2 0 0, respectivel y. **Table 7.2 Short -**  **Term Aggregate Risk Calculations**  Population Short - Term Scenario LOC for Aggregate Risk a Dietary

MOE b MOE Oral

Residential Exposure c Com

bined MOE (Dermal and Inhalation) Residential Exposure d Aggregate MOE

(food, water, and residential) e Adult 100 11,600 NA 400 390 Children 1 - 2 years old 100 6,600 3,400 NA 2,200 a LOC = 100 (based on inter - and intra - species uncertainty factors totaling 100X). b MOE dietary = short - term oral NOAEL ÷ chronic dietary exposure . NOAEL = 94.8 mg/kg/day .

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 27 of 43 c MOE oral = short - term oral NOAEL ÷ hand - to - mo uth residential exposure. NOAEL = 30 mg/kg/day . Residential exposure for childre n 1 - 2 years old = incidental oral only for children (See Table 6.3) . d MOE dermal = short - term dermal NOAEL ÷ high end dermal residential exposure. NOAEL = 100 mg/kg/day. Residential exposure for adults = post - application combined dermal and inhalation (Se e Table 6.3) . e MOE Aggregate Adult = 1 ÷ [(1/MOE dietary) + (1/MOE combined dermal and i nhalation) ]. MOE Aggregate Children 1 - 2 years old = 1 ÷ [ (1/MOE dietary) + (1/incidental oral) ] . 

### 7.3 **Intermediate -**  **Term Aggregate Risk** Intermediate - term exposure is not expe cted for the adult residential exposure pathway . Therefore, the intermediate - term aggregate risk estimate would be equivalent to the chronic dietary exposure estimate. Refer to Section 5.4. 3 . **7.4 Chronic Aggregate Risk**  Chronic exposure is not expe cted for the adult residential exposure pathway. Therefore, the chronic aggregate risk estimate would be equivalent to the chronic dietary exposure estimate . Refer to Section 5.4. 3 . **7.5 Cancer**  **Aggregate Risk** Cyazofamid is classified as “not likely to be carcinogenic to humans;” therefore, an aggregate cancer assessment was not conducted. **8.0 Cumulative Exposure/Risk Characterization**  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 cyazofamid and an y other substances and cyazofamid does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, there fore, EPA has no t assumed that cyazofamid has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the p olicy statements released by

EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. **9 .0**  **Occupational Exposure/Risk Characterization 9.1**  **Short -**  **and Intermediate -**  **Term Handler Risk**  Ranman® 400SC may

be applied as a foliar spray via groundboom, aircraft, and chemigation . The proposed use pattern is summarized in Table 3.3 . Handler expos ure is expected to be short or intermediate - term based on information provided on the proposed label. The personal protective equipment (PPE) label requirements include: long - sleeved shirt, long pants, shoes plus socks, and chemical - resistant gloves made of an y waterproof material, such as nitrile, butyl, neoprene and/or barrier laminate.

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 28 of 43 The quantitative exposure/risk assessment developed for occupational handlers is based on the following exposure scenarios: Mixer/L oaders 1. Mixing/ L oading liquids to su pport groundboom applications, 2. Mixing/L oading liquids to support aerial and chemigation applications , Flaggers 3. Flagging to support aerial application, Applicators 4. Applying spray s with groundboom equipment , and 5. Applying spray s with aerial equipment . No handler exposures are expected from appl yi ng spray s via chemigation sy stems. Ranman® 400SC is not expected to be applied using handheld equipment to field - grown tuberous and corm vegetables, fruiting vegetables, or succulent shelled and succulent podded b eans. Furthermore, because a minimum of 60 gallons of solution is recommended to treat basil in greenhouses , cyazofamid is also not expected to be applied using handheld equipment . As a conservative estimate of exposure, and to be protective of smaller- scale t omato transplant operations, a mixer/loader/applicator assessment has been conducted for greenhouse tomato transplants for the following exposure scenarios : 1. Mixing/L oading/Applying with a manually- pressurized handwand; 2. Mixing/L oading/Applying with a backpack sprayer; and 3. Mixing/L oading/Applying with a mechanically- pressurized handgun. Summaries of the risk estimate s for occupational handlers are included in Appendix D , Table D 1 . At baseline, without any required PPE, all combined (dermal and inhalation) handler risk estimates are not of concern (greater than the LOC of 100); all short - and intermediate - term handler risk estimates resulted in MOEs ranging from 200 to 140,000. **9.2 Short**  **- and Intermediate**  **- Term**  **Post -**  **Application Risk**  Agricultural workers performing typical post - application activities (e.g. scouting, hand weeding) may receive exposure to cyazofamid residues. **9.2.1 Dermal Post**  **- A** **pplication Risk** The post - application exposure estimates are partially based on surrogate data. Default transfer coefficients ( TCs ) are considered to be central tendency . Maximum application rates were used in this assessment. Overall, the post - application risk estimates are characterized as being central to high - end estimates. The registrant previously submitted chemical - specific dislodgeable foliar residue ( DFR) studies on tomatoes, grape s , and squash. These data have been reviewed and the results were used for risk assessment purposes. The predicted DFR values have been used in this assessment to e stimate dermal exposure to treated vegetables in accordance with current HED exposure assessment policy .

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 29 of 43 Based on the proposed use pattern, the squash DFR study was used to assess post - application exposure risks from contact with treated leafy greens, b asil, and tuberous and corm vegetables. These crops are low - growing, with mostly broad leaves. The tomato DFR study was used to assess post - application exposure risks from contact with treated fruiting vegetables. The grape DFR study

was used to assess post - application exposure risks from contact with treated beans, as both commodities can grow on vines, and have small leaves. A ll scenarios resulted in MOEs greater than the LOC of 100 (ranging from 9 , 5 00 to 1,200 ,000 ) on day 0 (12 hours after application) and , therefore , are not of concern to HED. The post application exposure scenarios associated with the proposed uses are summarized in Appendix D , Table D - 2 . Even though post - application exposure to potatoes while hand harvesting was not ass essed, the resulting MOE for foliar contact to treated tomatoes was 45,000. Even if soil residues were 10X higher than the estimated foliar residues, hand harvesting would not result in risks of concern, even using the at - planting application rate. There fore, HED believes th e occupational post application assessment for foliar contact to tuberous and corm vegetables would be protective of hand harvesting potatoes due to the conservative nature of the application rate (0.16 lb ai/A vs. 0.072 lb ai/A) , the conservative TC (1900 cm 2 

### /hr) , and environmental fate properties. Restricted Entry Interval Ty pically , under the Worker Protection Standard for Agricultural Pesticides, active ingredients classified as acute toxicity categories III or IV for these routes are assigned a 12 - hour REI. Based on the quantitative post - application assessment , the 12 - hour REI that appears on the proposed label is adequate to protect agricultural workers from post - application exposures to cyazofamid. **9.2.2 Inhalation Post**  **- A** **pplication Risk** Based on the Agency's current practices, a quantitative post - application inhalation exposure a ssessment was not performed for cyazofamid at this time primarily because of the low acute inhalation toxicity

(Toxicity Category IV), low vapor pressure (9.98 x 10 - 8 

### mm Hg at 25 oC) and the low proposed use rate s (<0. 1 6 lb ai/A, at - planting ). However, th ere 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 particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as avai lable post - application inhalation exposure data generated b y the Agricultural Reentry Task Force and may , as appropriate, develop policies and procedures to identify the need for and, subsequently , the way to incorporate occupational post - application inhal ation exposure into the Agency's risk assessments. If new policies or

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 30 of 43 procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inhalation exposure assessment for cyazofamid. Although a quantitative o ccupational post - application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure 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 - application inhalation exposure scenarios. The Worker Protection Standard for Agricultural Pesticides contains requirements for protecting workers from inhalation exposures during and after greenhouse applications through the use of ventilation requirements [40 CFR 170.110, (3) (Restrictions associated with pesticide applications)]. **10. 0**  **References** Dodd, Nancy . 04/25/2012. DP Barcode 396051. “Cyazofamid. Petition for the Establishment of Permanent Tolerances and Registration for Use on Basil, Succulent Beans, the Fruiting Vegetable Group 8 - 10, the Leafy Greens Subgroup 4A, and the Tuberous and Corm Vegetable Subgroup 1C. Summary of Anal yt ical Chemistry

and Residue Data. ” Dodd, Nancy . 04/30/2012. DP Barcode 397214. “ Cyazofamid Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Action on Basil, Succulent Beans, the Fruiting Vegetable Group 8 - 10, the Leafy Greens Subgroup 4A, and the Tuberous and Corm Vegetable Subgroup 1C. ” Meléndez, José. 02/10/2012. DP Barcode 396052. “Estimat ed Drinking Water Concentrations of Cyazofamid and its Degredates of Concern CCIM, CCIM - AM and CTCA, for Use in Human Health Risk Assessment: IR - 4 Petition for the Use on Succulent Beans, Chelled Beans, Leafy Greens Subgroup 4A, Basil (Fresh and Dried Leav es), Tuberous and Corm Vegetables Subgroup 1C, and Fruiting Vegetables Group 8 - 10.” O’Rourke, Kelly . 03/ 19/2008. DP Barcode 342612 . “ Human Health Risk Assessment to Support the Registration of C yaz ofamid for Use on Carrot .” Rury , Kristin. 06/18/2012. DP Barcode 397215. “ Cyazofamid. Occupational Exposure Assessment for Proposed Uses on Leafy Greens, Subgroup 4A; Succulent - Podded and Succulent - Shelled Beans; Basil; Vegetable, Tuberous and Corm, Subgroup 1C; and Vegetables, Fruiting, Crop Group 8 - 10 with An Updated Residential Exposure Assessment of All Existing Residential Uses.” Tsaur, Nancy . 04/07/2010 . DP Barcode 37 0671 . “ Cyazofamid. Human Health Risk Assessment for Proposed Uses on Brassica (Cole) Leafy Vegetables Crop Group 5, Turnip Greens, Spinach, and Hops . ”

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 31 of 43 **A ppendix**  **A .**  **Toxicology Profile and Executive Summaries A.1**  **Toxicology Data Requirements** The requirements (40 CFR § 158. 500 ) for food use for cyazofamid are in Table A.1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. **Table A.1. Satisfication of Cyazofam** **id Toxicology Data Requirements**  **Study Technical**  **Required Satisfied**  870.1100 Acute Oral Toxicity ................................ ......................... 870.1200 Acute Dermal Toxicity ................................ .................... 870.1300 Acute Inhalation Toxicity ................................ ................ 870.2400 Primary Eye Irritation ................................ ...................... 870.2500 Primary Dermal Irritation ................................ ................ 870.2600 Dermal Sensitization ................................ ........................ yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent) ................................ ................. 870.3150 Oral Subchronic (nonrodent) ................................ ........... 870.3200 21 - Day

Dermal ................................ ................................ 870.3250 90 - Day

Dermal ................................ ................................ 870.3465 90 - Day

Inhalation ................................ ............................ yes yes yes CR 1 CR2 yes

yes yes

-

- 870.3700a Developmental Toxicity (rodent) ................................ ..... 870.3700b Developmental Toxicity (nonrodent) ............................... 870.3800 Reproduction ................................ ................................ ... yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent) ................................ ................ 870.4100b Chronic Toxicity (nonrodent) ................................ .......... 870.4200a Oncogenicity (rat) ................................ ............................ 870.4200b Oncogenicity (mouse) ................................ ...................... 870.4300 Chronic/Oncogenicity ................................ ...................... yes yes yes yes yes yes

yes yes yes yes 870.5100 Mutagenicity

—Gene Mutation - bacterial ....................... 870.5300 Mutagenicity

—Gene Mutation - mammalian .................. 870.5 375 Mutagenicity

— Structural Chromosomal Aberrations ..... 870.5 395 Mutagenicity

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

yes yes yes 870.6100a Acute Delayed Neurotoxicity (hen) ................................ . 870.6100b 90 - Day

Neurotoxicity (hen) ................................ ............. 870.6200a Acute Neurotoxicity Screening Battery (rat) ................... 870.6200b 90 - Day

Neurotoxicity Screening Battery (rat) ................. 870.6300 Develop. Neurotoxicity ................................ ................... yes no yes yes no yes

- yes no

- 870.7485 General Metabolism ................................ ........................ 870.7600 Dermal Penetration ................................ .......................... 870.7800 Immunotoxicity ................................ ............................... yes CR 1 yes yes

- no Special Studies for Ocular Effects

Ac ute Oral (rat) ................................ ............................. Subchronic Oral (rat) ................................ .................... Six - mo nth Oral (dog) ................................ .................... CR 1 = Conditionally required; CR 2 = The Agency is in the process of evaluating the SAP report and may, as appropriate, reexamine and develop new policies and procedures for conducting inhalation risk assessments, including route to route extrapolation of toxi city data; * = needs to be upgraded.

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 32 of 43 **A.2 Toxicity Profiles**  **Table A.2 -**  **1. Cyazofam** **id Acute Toxicity Profile**  **Guideline No.**  **Study Type MRID**  **Results Toxicity**  **Categor y**  870.1100 Ac ute Oral

– Rat 45408910 LD 50 > 5000 mg/kg [M/F] IV 870.1200 Ac ute Dermal

– Rat 45408911 LD 50 > 2000 mg/kg [M/F] III 870.1300 Ac ute Inhalation

– Rat 45408912 LC 50 > 5.5 mg/L [M/F] IV 870.2400 Primary Eye Irritation

– Rabbit 45408913 Grade 2 conjunctival redness and discharge that resolved by 24 hours IV 870.2500 Primary Skin Irritation

– Rabbit 45408914 Very slight to well defined erythema that cleared by 7 days III 870.2600 Dermal Sensitization

(Guinea Pig Maximization T est) 45408915 Positive (weak sensitizer) - **Table A.2 -**  **2. Toxicity Profile of Cyazofam id [IKF**  **- 916]**  **Technical Guideline No./**  **Study Type MRID No. (year)/** 

**Classification /Doses Results** 

870.3100 90 - Day oral toxicity in rats 45408928 (1999)

Acceptable/guideline Males: 0, 10, 50, 500, or 5,000 ppm 0, 0.6, 2.9, 29.5, or 294.5 mg/kg/day Females: 0, 50, 500, 5,000, or 20,000 ppm 0, 3.3, 33.3, 337.6, or 1,359.0 mg/kg/day NOAEL = 29.5 [M] mg/kg/day LOAEL = 295 [M] mg/kg/day based on increased number of “basophilic kidney tubules,” and increa sed urinary volume, pH, and protein.

870.3100 90 - Day oral toxicity in mice Study not available. Study not available. 870.3150 90 - Day oral toxicity in dogs 45408929 (2001)

Acceptable/guideline 0, 40, 200, or 1,000 mg/kg/day NOAEL = 1,000 [M/F] mg/kg/day LOAEL = not observed. 870.3200 28 - Day dermal toxicity in rats 45408930 (1997)

Acceptable/guideline 0, 250, 500, or 1,000 mg/kg/day NOAEL = 1,000 [M/F] mg/kg/day LOAEL = not observed. 870.3250 90 - Day dermal toxicity Study not available. 870.3465 90 - Day inhalation toxicity Study not available.

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 33 of 43 **Table A.2 -**  **2. Toxicity Profile of Cyazofam id [IKF**  **- 916]**  **Technical Guideline No./**  **Study Type MRID No. (year)/** 

**Classification /Doses Results**  870.3700a Prenatal developmental in rats 45430404 (1999)

Acceptable/guideline 0, 30, 100, or 1,000 mg/kg/day **Maternal** NOAEL = 1,000 mg/kg/day LOAEL = not observed **Developm ental**  NOAEL = 100 mg/kg/day LOAEL = 1,000 mg/kg/day based on increased incidence of bent ribs. 870.3700b Prenatal developmental in rabbits 45408934 (1999)

Acceptable/guideline 0, 30, 100, or 1,000 mg/kg/day **Maternal** NOAEL = 1,000 mg/kg/day LOAEL = not observed **Developm ental**  NOAEL = 1,000 mg/kg/day LOAEL = not observed

870.3800 Reproduction and fertility effects in rats 45408935 (1998)

Acceptable/guideline 0, 200, 2,000, or 20,000 ppm F 0 M: 11 - 22, 108 - 213, and 1114 - 2185 mg/kg/day F 0 F: 14 - 21, 137 - 219, and 1416 - 2179 mg/kg/day F 1 M: 11 - 27, 107 - 267, and 1117 - 2714 mg/kg/day F 1 F: 14 - 27, 135 - 267, and 1451 - 2678 mg/kg/day **Parental/System ic**  NOAEL = 1114/ 1416 [M/F] mg/kg/day LOAEL = not observed **Reproductive** NOAEL = 1114/ 1416 [M/F] mg/kg/day LOAEL = not observed **Offspring** NOAEL = 1114/ 1416 [M/F] mg/kg/day LOAEL = not observed

870.4100a Chronic toxicity in rats 45408936 (1999)

Acceptable/guideline Males: 0, 10, 50, 500, or 5,000 ppm 0, 0.35, 1.7, 17.1, or 171.1 mg/kg/day Females: 0, 50, 500, 5,000, or 20,000 ppm 0, 2.0, 20.2, 207.8, or 856.0 mg/kg/day NOAEL = 171/ 856 [M/F] mg/kg/day LOAEL = not observed.

870.4100b Chronic toxicity in dogs 45408931 (2001)

Acceptable/guideline 0, 40, 200, 1,000 mg/kg/day NOAEL = 200 [M/F] mg/kg/day LOAEL = 1,000 [M/F] mg/kg/day based on i ncreased cy sts in parathyroids in males. 870.4200 Carcinogenicity rats 45408936 (1999)

Acceptable/guideline NOAEL = 171/ 856 [M/F] mg/kg/day LOAEL = not observed. **No evidence of carcinogenicity** 870.4300 Carcinogenicity mice 45408932 (1999)

Acceptable/guideline NOAEL = 94.8 [M] mg/kg/day LOAEL = 985 [M] mg/kg/day based on increased incidence of skin lesions including hair loss, body sores, dermatitis, ulceration, and acanthosis. **No evidence of carcinogenicity** Gene Mutation 870.5100 Bacterial reverse mutation assay 45408937 (1998)

Acceptable/ guideline (ai) **Negative** ± S9 up to 5,000 μ g/plate by standard plate and tube preincubation (not cytotoxic but there was precipitation at ≥1,500 μg/plate.

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 34 of 43 **Table A.2 -**  **2. Toxicity Profile of Cyazofam id [IKF**  **- 916]**  **Technical Guideline No./**  **Study Type MRID No. (year)/** 

**Classification /Doses Results**  Gene Mutation 870.5300 Mammalian cell c ulture 45409002 (1998)

Acceptable/ guideline (ai) **Negative** ± S9 up to cytotoxic and precipitating concentration of 100 μ g/mL Cy togenetics 870.5375 Chromosomal aberrations 45409003 (1996)

Acceptable/ guideline (ai) **Negative** ± S9 for clastogenic/aneugenic activity up to cy totoxic and precipitating 200 μ g/mL Cy togenetics 870.5395 Micronucleus test on mouse 45409004 (1996)

Acceptable/ guideline (ai) **Negative** up to the highest dose tested (limit dose) 2,000 mg/kg Other Effects 870.5500 Bacterial DNA repair test (Rec assay) 45409005 (1998)

Acceptable/ guideline (ai) **Negative** ± S9 up to limit of solubility at 8,000 μ g/disc

870.6200a Ac ute neurotoxicity screening battery 45434601 (2000)

Acceptable/guideline 0, 80, 400, or 2000 mg/kg NOAEL = 2000 [M/F] mg/kg/day LOAEL = not observed. T he slight increase ( ∼ 45%) in motor activity at day 14 among the mid - and high - dose males is marginal and should not be considered an adverse finding. 870.6200b Subchronic neurotoxicity screening battery Study not available. 870.6300 Developmental neurotoxicity Study not available.

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 35 of 43 **Table A.2 -**  **2. Toxicity Profile of Cyazofam id [IKF**  **- 916]**  **Technical Guideline No./**  **Study Type MRID No. (year)/** 

**Classification /Doses Results** 

870.7485 Metabolism and pharmacokinetics in rats 45409006 - 45409009 and

45434602 (1998 - 1999) Acceptable/guideline Dose: 0.5, 1,000, or 14 day 0.5 mg/kg repeat non - labeled followed by 0.5 mg/kg [phenyl U 14 C] - or [ 14 C - Imidazole] IKF - 916. Biliary excretion study: 0.5 or 1,000 mg/kg [phenyl - U 14 C] - or [ 14 C - Imidazole] IKF - 916. There was rapid absorption (irrespective of dose t cmax = 0.25 - 0.5 hrs) and rapid elimination at the low dose (t 1/2 4.4 - 5.8 hrs) w

hile there was saturated absorption with prolonged elimination (t 1/2 of 7.6 - 11.6 hrs) at the high dose. The extent of absorption (as per cent of administered dose) was highly dose - dependent being nearly 75% at the low dose and only about 5% at the high dose. Both the urine and feces were major routes of excretion at the low dose with most of the urinary radioactivity being a metabolite named CCBA (4 - (4 - chloro - 2 - cyanoimidazol - 5 - yl)benzoic acid). The biliary elimination was highly variable at the low dose ( ∼ 12 - 39% of the administered low dose) and negligible (<2%) in the high - dose groups. Urinary or biliary excretion in the high - dose groups was low (each ∼ 2%) with most of the radioactivity being CCBA. Irrespective of the dosing regimen, most of the recovered fecal radioactivity was unchanged parent compound; the major fecal metabolites were CCBA and 4 - chloro - 5 - p tolylimidazole - 2 - carbonitrile (CCIM) each of which being less than 5% of the administered dose. Tissue burdens at t 1/2 , tmax , and at 168 hours post dose indicated rapid clearance and low

tissue burdens suggesting little or no bioaccumulation or sequestration. 870.7600 Dermal penetration Study not available. Special study: In Vitro Metabolism of IKF - 916 and CCIM in Blood and Stomach Contents MRID 45409010 (1999)

Acceptable/non - guideline The in vitro biodegradation of [ 14 C - Bz]IKF - 916 or [ 14 C Bz)CCIM by rat blood or rat stomach contents was examined. The results indicated that, during the 60 - minute incubation period, IKF - 916 underwent degradation to CCIM ( ∼ 30%) in blood but was stable in stomach contents while CCIM was unaffected in either medium. The results also suggest that CCIM could be produced in rats following IKF - 916 entering the blood compartment but not necessarily in the stomach compartment. Special study: In Vitro Metabolism of CCIM in S9 Fraction MRID 45409011 (1999)

Acceptable/non - guideline The in vitro metabolism of 14 C - CCIM was followed up to five minutes in the presence of rat liver S9. The results suggested that CCIM was rapidly and completely metabolized within 5 minutes to at least three metabolites with the major one being CHCN (4 - chloro 5(4 - hydroxymethyl - phenyl) - imidazole - 2 - carbonitrile) which accounted for 77 - 94% of the radioa ctivity. Lo wer concentrations were found of CCBA (3 - 13%) and one or more unknown metabolites. It was concluded that CCIM produced in the intestines or blood would be rapidly and completely metabolized by the liver.

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 36 of 43 **Table A.2 -**  **2. Toxicity Profile of Cyazofam id [IKF**  **- 916]**  **Technical Guideline No./**  **Study Type MRID No. (year)/** 

**Classification /Doses Results**  Special study: In Vitro Study to Identify Metabolites Absorbed Through the Intestinal Mucosa After Incubation with IKF - 916 and CCIM MRID 45409012 (1999)

Acceptable/non - guideline Using in vitro isolated rat intestinal segments containing [ 14 C]IKF - 916 or [ 14 C]CCIM, 2.6% of IKF - 916 and 10.4% of CCIM was transferred from the lumen (m ucosal side) to the exterior (serosal side) of the gut segment. Of the IKF - 916 that was absorbed and transferred to the buffer solution, approximately 60% had undergone biotransformation/degradation to C CIM, CCBA and three additional products. Also, CCIM appeared to be degraded to two metabolites not observed for intestine preparations containing IKF - 916. Based on the findings of this study, cyazofamid seems to be poorly absorbed from the intestinal lum en although its conversion to CCIM or other metabolites may increase overall transfer across the gut wall. Special study: Com parative metabolism of [ 14 C]IKF - 916 or [ 14 C]CCIM in rats MRID 45409013 (1999)

Acceptable/non - guideline Rats were given a single gavage dose of 0.46 mg/kg of [ 14 C - Bz]IKF - 916 or 0.33 mg/kg of [ 14 C - Bz]CCIM and, after 30 minutes, blood, liver, stomach (plus contents), and duodenum (plus contents) were collected and analyzed for radioactivity and metabolites. Following a single gavage do se of CCIM, the metabolites CCBA and CHCN, in addition to unchanged CCIM, were detected in the plasma and liver. The same metabolites, as well as CCIM, were also detected in plasma and liver following administration of IKF - 916. Therefore, orally administe red IKF - 916 is converted to CCIM and subsequently to CCBA and CHCN.

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 37 of 43 **A ppendix B.**  **Physical/Chemical Properties and Metabolic Profile**  **Table B -**  **1. Physico**  **c hem** **ical Properties of the Technical Grade Cyazofam** **id** Parameter Value Reference Melting point (°C) 152.7 PMRA Regulatory Note REG2006 - 05 on Cyazofamid, 12/6/06 pH 4.9 e - Pesticide Manual, 13 th Edition Density at 20 °C (g/mL) 1.446 Water solubility (at 20 °C) pH Solubility (mg/L) REG2006 - 05 5 7 9 0.121

0.107 0.109 Solvent solubility (at 21.2°C) Solvent Solubility (g/L) Acetone Ethyl acetate Methanol Dichloromethane Toluene Hexane n - Octanol Acetonitrile 2 - Propanol 43.1

16.19 1.74 94.82 6.0 0.03 0.04 29.446 0.43 Vapor pressure at 25°C <1.33 x 10 - 5 Pa Dissociation constant (pKa) Does not dissociate in water. No pKa in the pH range of 2 - 12. Octanol/water partition coefficient Log KOW = 3.2 KOW = 1.585 x 10 3 UV/visible absorption spectrum pH Λ max (nm) 2 7 10 285

279 287 **Table B -**  **2. Identification of Compounds from the Cyazofam** **id Metabolism**  **Studies** Common Name/ C ode/M atrix Chemical N ame Chemical S tructure Cyazofamid/ IKF - 916 4 - chloro - 2 - cyano -N,N - dimethyl - 5 - (4 - methylphenyl) - 1 H

- imidazole - 1 - sulfonamide

CCIM 4 - chloro - 5 - p - tolylimidazole - 2 - carbonitrile N N C H 3 Cl C N S O 2 N ( C H 3 ) 2



### N H N C H 3 

### Cl CN

### CYAZOFAM ID Human Health Risk Assessment DP No. D3 97213

Page 38 of 43 **Table B -**  **2. Identification of Compounds from the Cyazofam** **id Metabolism**  **Studies** Common Name/ C ode/M atrix Chemical N ame Chemical S tructure CCBA 4 - (4 - chloro - 2 - cyanoimidazol - 5 - yl)benzoic acid

CCIM - AM 4 - chloro - 5 - p - tolylimidazole - 2 - carboxamide

CTCA 4 - chloro - 5 - p - tolylimidazole - 2 - carboxylic acid



### Appendix C. **Review of Human Research Studies reviewed for ethical conduct:**  MRID 44972201

– ORETF data PHED Surrogate Exposure Guide 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, which comprise the Pesticide Handler Exposure Database (PHED) and the Outdoor Residential Exposure Task Force (ORETF), have been determined to require a review of their ethical conduct and have rece ived that review. In this assessment, ORETF data were used to assess loading/applying with a push ty pe spreader (data from MRID 44972201 ) and PHED data were used to assess loading/appl yi ng with a belly

grinder. **Studies reviewed by the Human Studies Review Board:**  None. N H N Cl C N O H O

N H N C H 3 

### Cl O N H 2

### CYAZOFAM ID Human Health Risk Assessment DP No. D397213

Page 39 of 43 **Appendix D .**  **Occupa tional Exposure and**  **Risk Estimates**  **Summary Table Table**  **D -**  **1 .**  **Short -**  **and Intermediate -**  **Term Agricultural Handler Exposure and Risk Estim ates for Cyazofam** **id** Exposure Scenario Crop or Target App Rate 1 Amount

Treated Daily Unit Exposure 3 Combined Dose 5 MOE 6 lb ai/A or lb ai/gal Baseline Dermal PPE - G

Dermal Baseline

Inhalation Baseline

Dermal + Baseline Inhalation PPE - G

Dermal + Baseline Inhalation Combined

Baseline Dermal + Inhalation Combined

PPE - G + Baseline Inhalation μg/lb ai mg/kg/day **Mi xer/Loader**  M/L to Support Aerial Application Leafy Greens, Succulent - Podded and

Succulent - Shelled Beans, Tuberous and Corm Vegetables, and Fruiting

Vegetables 0.072 350 acres 220 37.6 0.219 0.030 0.0052 3,400 19,000 Basil 0.078 350 acres 220 37.6 0.219 0.032 0.0056 3,100 18,000

M/L to Support Chemigation Leafy Greens, Succulent - Podded and

Succulent - Shelled Beans, Tuberous and Corm Vegetables, and Fruiting

Vegetables 0.072 350 acres 220 37.6 0.219 0.030 0.0052 3,400 19,000 Basil 0.078 350 acres 220 37.6 0.219 0.033 0.0056 3,100 18,000 Tuberous and Corm Vegetables At

Pla nting 0.16 350 acres 220 37.6 0.219 0.066 0.015 1,500 8,700 Fruiting Vegetables Soil Drench 0.047 350 acres 220 37.6 0.219 0.019 0.0034 5,100 30,000

M/L to Support Groundboom Application Leafy Greens, Succulent - Podded and

Succulent - Shelled Beans, Tuberous and Corm Vegetables, and Fruiting

Vegetables 0.072 80 acres 220 37.6 0.219 0.0068 0.0012 15,000 85,000 Basil 0.078 80 acres 220 37.6 0.219 0.0074 0.0013 14,000 78,000 Tuberous and Corm Vegetables At

Pla nting 0.16 80 acres 220 37.6 0.219 0.015 0.0026 6,600 38,000 Fruiting Vegetables Soil Drench 0.047 80 acres 220 37.6 0.219 0.0044 0.00077 22,000 130,000 **Applicator**

### CYAZOFAM ID Human Health Risk Assessment DP No. D397213

Page 40 of 43 **Table D**  **- 1**  **. Short**  **- and Intermediate**  **- Term Agricultural Handler Exposure and Risk Estim**  **ates for Cyazofam id**  Exposure Scenario Crop or Target App Rate 1 Amount

Treated Daily Unit Exposure 3 Combined Dose 5 MOE 6 lb ai/A or lb ai/gal Baseline Dermal PPE - G

Dermal Baseline

Inhalation Baseline

Dermal + Baseline Inhalation PPE - G

Dermal + Baseline Inhalation Combined

Baseline Dermal + Inhalation Combined

PPE - G + Baseline Inhalation μg/lb ai mg/kg/day Applying Sprays via Aerial Equipment Leafy Greens, Succulent - Podded and

Succulent - Shelled Beans, Tuberous and Corm Vegetables, and Fruiting

Vegetables 0.072 350 acres 5 N/A 0.068 0.00070 N/A 140,000 N/A Basil 0.078 350 acres 5 N/A 0.068 0.00076 N/A 130,000 N/A

Applying Sprays via Groundboom Equipment Leafy Greens, Succulent - Podded and

Succulent - Shelled Beans, Tuberous and Corm Vegetables, and Fruiting

Vegetables 0.072 80 acres 78.6 16.1 0.34 0.0025 0.00053 41,000 190,000 Basil 0.078 80 acres 78.6 16.1 0.34 0.0027 0.00057 38,000 180,000 Leafy Greens, Succulent - Podded and Succulent - Shelled Beans, Tuberous and Corm Vegetables, and Fruiting

Vegetables 0.16 80 acres 78.6 16.1 0.34 0.0055 0.0012 18,000 86,000 Fruiting Vegetables Soil Drench 0.047 80 acres 78.6 16.1 0.34 0.0016 0.00034 62,000 290,000 **Flagger** Flagging for Aerial Sprays Leafy Greens, Succulent - Podded and

Succulent - Shelled Beans, Tuberous and Corm Vegetables, and Fruiting

Vegetables 0.072 350 acres 11 12 0.35 0.0016 0.0018 62,000 57,000 Basil 0.078 350 acres 11 12 0.35 0.0018 0.0019 57,000 53,000 **Mi xer/Loader/Applicator**  Manually Pressurized Handwand To mato Greenhouse Transplant Soil Drench 0.0085 40 gallons 100,000 430 30 0.21 0.0011 480 93,000 Backpack Sprayer To mato Greenhouse Transplant Soil Drench 0.0085 40 gallons 8,260 8,260 2.58 0.017 0.017 5,800 5,800

### CYAZOFAM ID Human Health Risk Assessment DP No. D397213

Page 41 of 43 **Table D**  **- 1**  **. Short**  **- and Intermediate**  **- Term Agricultural Handler Exposure and Risk Estim**  **ates for Cyazofam id**  Exposure Scenario Crop or Target App Rate 1 Amount

Treated Daily Unit Exposure 3 Combined Dose 5 MOE 6 lb ai/A or lb ai/gal Baseline Dermal PPE - G

Dermal Baseline

Inhalation Baseline

Dermal + Baseline Inhalation PPE - G

Dermal + Baseline Inhalation Combined

Baseline Dermal + Inhalation Combined

PPE - G + Baseline Inhalation μg/lb ai mg/kg/day Mechanically Pressurized Handgun To mato Greenhouse Transplant Soil Drench 0.0085 625 gallons 4,310 4,310 3,931 0.49 0.49 200 200 a Application Rates based on proposed uses for cyazofamid ( Ranman® 400SC, EP A Reg. No. 71512 - 3). b Amount Treated Daily taken from Exposure Science Advisory Council (ExpoSAC) Policy No. 9.1. c UEs = Unit Exposures based on PHED Version 1.1. L evel of mitigation = Baseline (no gloves, no respirator) or PPE (gloves , no respirator). d Dose (mg/kg/day) = daily unit exposure (μg/lb ai) × application rate (lb ai/acre or gal) × area treated or amount handled/day (acres/day or gal/day) x conversion factor (1 mg/1,000 μg) × absorption factor (%) ÷ body weight (69 kg). Dermal absorption factor = 37%. No inhalation absorption factor . e Combined Dose = Dermal Dose (mg/kg/day) + Inhalation Dose (mg/kg/day). f Combined MOE = NOAEL ÷ Combined Dose (mg/kg/day). ST/IT Dermal/Inhalation NOAEL = 100 mg/kg/day. ST/IT level of concern = 100. **Table D**  **- 2**  **. Post**  **- A**  **pplication Exposure and Risk E stimates for Cyazofam** **id on Day of Application (Day 0)**

Crop Proposed

Application Rate Activity Transfer Coefficient a Chemical S pecific DFR Data b Normalized

DFR c Daily

Dermal Dose d Short - and

Intermediate Term MOE e lb ai/A cm 2 /hr μg/cm 2 mg/kg/day Leafy Greens 0.072 Irrigation (hand set) 1900 Squash DFR 0.061 0.0049 20,000 Irrigation (non - hand set), Mechanical Weeding 0 0.061 N/A N/A

Scouting 210 0.061 0.00055 180,000 Hand Harvesting 1100 0.061 0.0029 35,000 Thinning plants, Hand W eeding 70 0.061 0.000018 550,000 Transplanting 230 0.061 0.00060 170,000 Succulent - P odded and Succulent - S helled B eans Beans, S nap and Pea, Green 0.072 Irrigation (hand set) 1900 Grape DFR 0.129 0.0105 9,500 Irrigation (non - hand set), Mechanical Harvesting, Mechanical Weeding, Fertilizing 0 0.129 N/A N/A

Scouting 210 0.129 0.0012 86,000 Hand weeding 70 0.129 0.00039 260,000 Hand Harvesting 1100 0.129 0.0061 16,000 Tuberous and Corm Vegetables Potato 0.16 Irrigation (hand set) 1900 Squash DFR 0.027 0.0022 45,000

### CYAZOFAM ID Human Health Risk Assessment DP No. D397213

Page 42 of 43 **Table D**  **- 2**  **. Post**  **- A**  **pplication Exposure and Risk E stimates for Cyazofam** **id on Day of Application (Day 0)**

Crop Proposed

Application Rate Activity Transfer Coefficient a Chemical S pecific DFR Data b Normalized

DFR c Daily

Dermal Dose d Short - and

Intermediate Term MOE e lb ai/A cm 2 /hr μg/cm 2 mg/kg/day Irrigation (non - hand set), Mechanical Weeding,

Mechanical Harvesting 0 0.027 N/A N/A Scouting 210 0.027 0.00025 400,000 Hand Weeding 70 0.027 0.000082 1,200,000 Hand Harvesting Alternate Guidance f 0.027 See Footn ote f Fruiting Vegetables Eggplant 0.072 Hand Harvesting 550

To mato DFR 0.069 0.0016 61,000 Tying/Training 550 0.069 0.0016 61,000 Scouting, Hand Weeding, Hand Pruning, Fruit

Thinning 90 0.069 0.00027 380,000 Eggplant, Okra, Bell Pepper, Chili Pepper, Tomato 0.072 Irrigation, Hand Set 1900 0.069 0.0056 18,000 Irrigation (Non Hand Set), Mechanical Weeding,

Mechanical Harvesting 0 0.069 N/A N/A Eggplant, Okra, Tomato Transplanting 230 0.069 0.00068 150,000 Okra, Bell Pepper, Chili Pepper, Tomato Hand Harvesting and/or Tying/Training 1100 0.069 0.0033 31,000 Scouting 210 0.069 0.00062 160,000 Hand Weeding 70 0.069 0.00021 480,000 Chili Pepper, Tomato Hand Pruning 70 0.069 0.00021 480,000 Basil (Mint as surrogate) Basil (Mint as surrogate) 0.078 Irrigation (hand set) 1900 Squash DFR 0.056 0.0046 22,000 Irrigation (non - hand set), Mechanical Harvesting, Transplating 0 0.056 N/A N/A Scouting 1100 0.056 0.0027 38,000 Weeding, Hand 70 0.056 0.00017 590,000 a Transfer Coefficient taken from Exposure Science Advisory Council (ExpoSAC) Policy No. 3.2: Agricultural Transfer Coefficients (March, 2012). b Chemical - Specific DFR Values calculated from original DFR studies on tomatoes (MRID 45409118), squash (MRID 45409119), and grapes (MRID 45409118) . c Normalized DFR = Study DFR ( μ g/cm2 × Application Rate DFR (lb ai/A) ÷ Proposed Application Rate (lb ai/A). d Daily Dermal Dose (mg/kg/day) = Normalized DFR (μg/cm2 ) × TC (cm2 /hr) × exposure time (8 hrs) × dermal abs factor ( 37%) × CF (1000 μg/mg) ÷ body weight (69 kg). e MOE = NOAEL (mg/kg/day) ÷ Daily Dermal Dose (mg/kg/day). ST/IT Dermal NOAEL = 100 mg/kg/day. LOC = 100. f Exposure to cyazofamid while hand harvesting potatoes is likely to be from treated soil. However, TCs are only available for exposure following foliar application. HED believes the foliar post - application assessment would be protective of hand harvesting following cyazofamid application to potatoes due to the conservative nature of the application rat e (0.16 lb ai/A vs. a 0.072 lb ai/A) and the TC (1900 cm2 /hr).

### CYAZOFAM ID Human Health Risk Assessment DP No. D397213

Page 43 of 43 **Appendix E. International Residue Limit Summary**  **Table E. Summary of**  **U.S. and International Tolerances and Maxim**  **um Residue Limits**  Residue Definition U.S. Canada Mexico b Codex 40 CFR 180.601: sum of 4 - chloro - 2 - cyano -N ,N - dimethyl - 5 - (4 - methylphenyl) - 1 H

- imidazole - 1 - sulfonamide and its metabolite, 4 - chloro - 5 - (4 - methylphenyl) - 1 Himidazole - 2 - carbonitrile, calculated as the stoichiometric equivalent of cyazofamid 4 - chloro - 2 - cyano -N ,N - dimethyl 5 - (4 - me thylphenyl) - 1 H

imidazole - 1 - sulfonamide, including the metabolite 4 - chloro - 5 - (4 - me thylphenyl) - 1 Himidazole - 2 - carbonitrile None Tolerance or Maximum Residue Limit Commodity a U.S. Canada Mexico b Codex ppm mg/kg Bean, succulent 0.5 Bean, succulent, shelled 0.08 Leafy greens subgroup 4A 10 Basil, fresh leaves 30 Basil, dried leaves 90 Vegetable, tuberous and corm , subgroup 1C 0.02 0.02 potatoes Vegetable, fruiting, group 8 - 10 0.9 0.2 tomatoes Com pleted: M. Negussie , 02/02/2012 . a Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant. b Mexico adopts U.S. tolerances and/or Codex MRLs for its export purposes.