                                       
                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
\* MERGEFORMAT
                                                           POLLUTION PREVENTION
MEMORANDUM

DATE:	June 28, 2012

SUBJECT:	Cyazofamid.  Human Health Risk Assessment for Proposed New Uses 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
Registration Nos.:  71512-3
Petition No.:  1E7929
Regulatory Action:  Section 3 Registration
Case No.:  NA
Risk Assessment Type:  Single Chemical/Aggregate
TXR No.:  NA
CAS No.:  120116-88-3
MRID No.:  NA
40 CFR:  §180.601

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
	Health 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 uses and tolerances for cyazofamid in/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).  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).

The residue chemistry data review and the dietary exposure assessment were completed by Nancy Dodd.  The occupational and residential exposure updates were completed by Kristin Rury, and the aggregate human health risk assessment was conducted by Nancy Tsaur.  The drinking water assessment was conducted by José 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.
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	Dietary 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
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

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 tolerances for combined residues of the fungicide cyazofamid, 4-chloro-2-cyano-N, N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonamide, and its metabolite, 4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile, calculated as the stoichiometric equivalent of cyazofamid, in/on the following raw agricultural commodities (RACs):
            Bean, succulent	0.4 ppm
            Bean, succulent, shelled	0.07 ppm
            Leafy greens subgroup 4A 	9.0 ppm
            Basil, fresh leaves	30 ppm
            Basil, dried leaves	80 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 endpoints for risk assessment (D370671, N. Tsaur, 04/07/2010).  Since the last risk assessment, the registrant has agreed to submit immunotoxicity and subchronic neurotoxicity studies by the end of July 2012.  Aside from the two outstanding studies, the hazard characterization and toxicity endpoints for risk assessment remain unchanged.  Furthermore, HED has waived the data requirement for inhalation toxicity since the last risk assessment (TXR0056341).  The detailed rationale for toxicity endpoint selection will not be repeated in this risk assessment.  A brief hazard characterization 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).  

Occupational handlers may apply Ranman(R) 400SC using ground, aerial, and chemigation equipment for broadcast application.  For soil drench applications, cyazofamid may be applied using chemigation and handheld equipment.

Exposure Profile
Exposures to cyazofamid are expected to occur for short-, intermediate-, and long-term (chronic) durations.  The proposed agricultural uses result in new exposures in both food and drinking water.  There are also existing 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 sensitizer 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 appeared to be affected the most.  Skin lesions were observed in male mice only, likely 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 includes 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 increased incidence of bent ribs in the high-dose fetuses was considered adverse and was used for setting the developmental NOAEL/LOAEL (no observed adverse effect level/lowest 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 Water) and Risk Estimates
The residue chemistry data and environmental fate data are adequate to assess human exposure.  Conservative dietary exposure analyses using DEEM-FCID(TM) 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 only 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 for the general U.S. population resulted in <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.  Cyazofamid is classified as "not likely 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-application 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) pathways.  All 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 2,200, respectively.  Acute aggregate risk for females 13-49 is expected to be equivalent to the acute exposure via the dietary pathway.  Intermediate-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 greater 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.  Post-application inhalation exposures and risk estimates were not quantitatively assessed.

2.0	HED Recommendations

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 establishment of the tolerances for the combined residues of cyazofamid listed in Section 2.2.3.

2.1	Requirements Prior to Registration

The following changes are required prior to establishing a tolerance or allowing a registration:

860.1200  Directions for Use
   * The Ranman(R) 400SC label should be amended to prohibit applications to cowpea grown for livestock feeds because no residue data are available for cowpea forage and hay.  The statement "Do not apply to cowpea used for livestock feed" should be added to the label.  Cowpea is a succulent shelled bean."
   * The label indicates that Ranman(R) 400SC should be tank mixed with an organosilicone 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 either 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 intent 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 commodities is FDA's Multiresidue Protocol D (without cleanup), which completely recovers (>80% recovery) cyazofamid and metabolite CCIM.  In addition, the HPLC/UV method is acceptable for use as a single analyte enforcement method provided a confirmatory method 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 (MRLs) on the proposed crops.  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 for 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.

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-methylphenyl)-1H-imidazole-2-carbonitrile, in the tolerance expression.  The International Residue Limit 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 Cyazofamid
                                   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 Cooperation and Development (OECD) tolerance calculation procedures: bean, succulent (0.4 ppm to 0.5 ppm); bean, succulent, shelled (0.07 ppm to 0.08 ppm); leafy greens subgroup 4A (9 ppm to 10 ppm); and basil, dried leaves (80 ppm to 90 ppm).

The vegetable, fruiting, group 8-10 tolerance must be revised from 0.40 to 0.9 ppm.   The OECD calculation procedures using average field trials of existing data result in values 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	Introduction

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, specifically interfering with the cytochrome bc1 complex in the mitochondrial respiratory chain of oomycetes fungi.

In PP#1E7929, IR-4 has petitioned for new tolerances for combined residues of the fungicide cyazofamid on the RACs listed in Table 2.2.3.  Concomitantly, IR-4 is proposing that the new uses be added to the currently registered label for Ranman(R) 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.  Cyazofamid Nomenclature
Parent Chemical Structure

Empirical Formula
C13H13ClN4 O2S
Common Name
cyazofamid
Company Experimental Name
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)-1H-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-methylphenyl)-1H-imidazole-2-carbonitrile

3.2	Physical/Chemical Characteristics

Cyazofamid has a low vapor pressure (1.33 x 10[-][5] Pa at 25°C or 9.98 x 10[-8] mm Hg at 25°C); therefore, inhalation via chemical vaporization is unlikely.  Cyazofamid has a log octanol/water partition coefficient (log Pow) of 3.2 and is considered relatively insoluble in water.  Additionally, 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 physicochemical properties of cyazofamid are summarized in Appendix B, Table B-1.

3.3	Pesticide Use Pattern

Cyazofamid is currently registered for use on a variety of field crops including the following: Brassica leafy vegetables, carrots, hops, potatoes, spinach, turnip greens, cucurbits, and fruiting vegetables.  The proposed uses of Ranman(R) 400SC are presented in Table 3.3.

Table 3.3.  Summary of Proposed Directions for Use of Ranman(R) 400SC (EPA Reg. No. 71512-3)
                       Applic. Timing, Type, 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 Shelled
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 cowpea)
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 Phytophthora 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 applied 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 fungicide 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 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; New 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.

Pythium:  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; arrowroot; 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 equipment.

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 mix.

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.  Aerial sprays should be made in a minimum of 5 gals of water per acre.
  Alternate sprays of Ranman(R) 400SC with a fungicide with a different mode of action; do not make more than three consecutive applications of Ranman(R) 400SC followed by at least three applications of fungicides having different modes of action before applying additional Ranman(R) 400SC.  
  Ranman(R) 400SC should be tank mixed with an organosilicone surfactant, non-ionic surfactant, or a blend of an organosilicone 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 directly 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, there is likely to be exposure in residential or non-occupational settings.  In both residential and occupational settings, 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 areas.  

Several risk assessments have been previously prepared for the existing uses of cyazofamid.  This risk assessment considers all of the aforementioned exposure pathways based on the proposed new uses of cyazofamid, but also considers the existing uses as well, particularly 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 Low-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 analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, 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 bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0	Hazard Characterization and Dose-Response Assessment

The cyazofamid hazard characterization is detailed in a previous risk assessment (D342612, K. O'Rourke, 03/19/2008).  New toxicity data have not been submitted since the last risk assessment (D370671, N. Tsaur, 04/07/2010).  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 Effects

Cyazofamid belongs to a chemical class based on the cyanoimidazole and sulfonamide moieties.  Cyazofamid is a broad spectrum fungicide active against oomycete fungi and Plasmodiophoromycetes.  It specifically interferes with the cytochrome bc1 complex (ubiquinol cytochrome c oxidoreductase) in the mitochondrial respiratory chain of oomycetes fungi.  The mechanism of toxicity in mammals is not clear.

The available toxicity studies show that following repeated administration in more than one species, 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, respectively.

Skin lesions (likely due to systemic allergy) were observed in males in the mouse carcinogenicity study.  The skin lesions occurred at a relatively high dose (985 mg/kg/day) and were characterized by hair loss, body sores, dermatitis, ulceration and acanthosis (hyperplasia).  The sulfonamide moiety in the cyanoimidazole ring might have rendered cyazofamid 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 maximization test.  In addition, sulfonamide antimicrobial drugs (e.g., sulfamethoxazole) have been known to cause idiosyncratic 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 parathyroid cysts in male dogs at the highest dose (1000 mg/kg/day) in the chronic (one-year) study, there were no major toxicity findings in the 13-week and one-year 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 cyazofamid to be a slight dermal irritant and a weak sensitizer might be due to the sulfonamide moiety in the compound. 

4.2	Safety Factor 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 of 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 endpoints 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 system.  The overall weight of evidence suggests that cyazofamid does not directly target the immune system.  HED does not believe that conducting 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 (UFDB) is not needed to account for lack of this study.

Based on the available data, conducting a subchronic neurotoxicity study is unlikely to result in a lower NOAEL 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 any uncertainty for evaluating the toxicity of cyazofamid.  Therefore, a database uncertainty factor (UFDB) for lack of a subchronic neurotoxicity is not needed.  

4.2.2	Evidence of Neurotoxicity

The available toxicity database for cyazofamid does not show any 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 of Sensitivity/Susceptibility in the Developing or 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.  In the prenatal developmental toxicity study in rabbits, there were no maternal or developmental effects at any dose up to the limit dose of 1,000 mg/kg/day.  In the two-generation reproduction study, the highest dose tested (>1,000 mg/kg/day) did not cause maternal systemic toxicity nor did it elicit reproductive or offspring toxicity. 

4.2.4	Residual Uncertainty in the Exposure Database

The exposure databases are complete or are estimated based on data that reasonably account for potential exposures.  New 2012 Residential SOPs were used to assess post-application exposure to children including incidental 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 likely to underestimate risk.

The dietary exposure assessments (food and drinking water) 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.  Exposures are unlikely to be underestimated because the assessment is a screening-level assessment.

4.3	Toxicity Endpoint and Point of Departure Selections

There are no changes to the previous dose-response assessment.  A summary of the toxicological endpoints for cyazofamid for use in dietary and occupational human health risk assessments is presented in Table 4.3.

Table 4.3.  Summary of Toxicological Doses and Endpoints for Cyazofamid for Use in Dietary, Non-Occupational, and Occupational Human 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
Acute 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.
Acute Dietary (Females 13-49 years of age)
NOAEL = 100 mg/kg/day
                                   UFA = 10X
                                   UFH = 10X
                                 FQPA SF = 1X
                           Acute RfD = 1.0 mg/kg/day
                                       
                             aPAD = 1.0 mg/kg/day
Rat Prenatal Developmental Toxicity
LOAEL = 1,000 mg/kg/day based on developmental toxicity findings of increased incidence of bent ribs.
Chronic Dietary (All Populations)
NOAEL= 94.8 mg/kg/day
UFA = 10X
UFH = 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 months)
NOAEL= 30 mg/kg/day 
UFA = 10X
UFH = 10X
FQPA SF = 1X
                         Residential LOC for MOE = 100
 90-Day oral toxicity study in rats. LOAEL= 295 mg/kg based on 
increased number of basophilic tubules of the kidneys, increased urinary volume, pH, & protein.  This toxicity endpoint is also supported by the 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 months)
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%
                                   UFA = 10X
                                   UFH = 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 months)
                             NOAEL= 100 mg/kg/day
                                       
                                   UFA = 10X
                                   UFH = 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 observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = 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.

Based on the available toxicity database and the Agency's current practices, 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 policies 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 and 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 items for cattle, currently 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 analyzed for future cattle feeding studies: cyazofamid, CCIM, CCBA, CCBA-cysteine 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.  Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression [a]
                                    Matrix
                     Residues Included 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 cowpea used for livestock feed is added to the label.)

5.2	Food Residue Profile

To support the newly 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 assessment.   In the residue decline studies, combined residues of cyazofamid and its metabolite, CCIM, were quantifiable, generally declining with increasing sampling interval.   The results from these studies are summarized in Table 5.2.

Crop Field Trials
Provided the requested revisions are made to the Ranman(R) 400SC 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.  Summary of Residue Data from Field Trials with Cyazofamid [a][,][b]
                                 Crop Matrix 
                                    Analyte
                                 Applic. Rate
                                 (lb ai/acre)
                                  PHI (days)
                                       n
                                Residues (ppm)
                                       
                                       
                                       
                                       
                                       
                                     Min.
Max.
                                     LAFT
                                     HAFT 
                                    Median
                                     Mean
                                      SD
     BASIL  Proposed 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 are 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
Additional processing studies are not required.  The previously submitted tomato and potato processing 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 potato are not required. 

Storage Stability
The available storage stability data are adequate to support the storage durations and conditions of the field trial samples.  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 during frozen storage.  Residues of CCIM in fresh basil declined by 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 cyazofamid 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 swine 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 proposed 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 less than 0.01 ppm at a plantback interval of 30 days, no field rotational crop studies are required.  The rotational crop plantback interval of 0 days for crops which are on the label and 30 days for other crops is appropriate.

5.3	Water Residue Profile

Available environmental fate studies suggest cyazofamid is not very mobile and quickly 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-tolylimidazole-2-carboxylic 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 hydrolysis of the parent.  In contrast, CTCA is expected to be the major terminal degradate in biologically active soils and water/sediment systems.  Both CCIM and CTCA are stable to abiotic hydrolysis and susceptible to leaching, but only CCIM is highly susceptible 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 by spray drift and/or runoff depending on the level of biological activity. However, only CTCA has a high potential to contaminate ground water due to its high persistence and mobility. 

Table 5.3 summarizes the EDWCs.  The 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 Analysis Modeling System) for residues from use on turf and ornamentals, which had the highest seasonal rates among the proposed and registered uses.  EDWCs in ground water as modeled by 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.  Surface/Ground Water EDWCs for Cyazofamid and its Major Degradates.
                                   Scenario
                                   Chemical
                           Surface Water EDWCs (ppb)
                            Ground Water EDWC (ppb)


                                     Acute
                              (1-in-10 yr. peak)
                                    Chronic
                              (1-in-10 yr. 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 analyses using DEEM-FCID(TM) 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 only 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 analysis are reported in Table 5.4.5.  

5.4.3	Chronic Dietary Risk Assessment

The chronic dietary (food and drinking water) exposure assessment for 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 analysis 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

 Table 5.4.6.  Summary of Dietary Exposure and Risk for Cyazofamid [a]
                              Population Subgroup
                        Acute 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.  Cyazofamid 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.  While the label says "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.  This revision of residential exposures impacts the human health aggregate risk assessment for cyazofamid.

Based on 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 pressure 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 handler exposure is expected to be short-term.  Intermediate-term exposures are not likely because of the intermittent nature of applications by homeowners.  Additionally, homeowners are assumed to complete all elements of an application without use of any protective equipment.

The quantitative exposure/risk assessment developed for residential handlers is based on the following exposure scenarios: 
   1. Mixing/Loading/Applying for Sprays Using Manually-Pressurized Handwand, 
   2. Mixing/Loading/Applying for Sprays with Back-Pack Sprayer,
   3. Mixing/Loading/Applying for Sprays with Hose-end Sprayer, and
   4. Mixing/Loading/Applying for Application with a Sprinkler Can.

The maximum application rate for each exposure scenario is presented as the worst case scenario.  All residential risk estimates are not of concern to HED (MOEs ranged from 2,400 to 59,000).  A summary of the short-term risk estimates (dermal and inhalation) for residential handlers are included in Table 6.1.

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. 71512-13).
b	Amount Treated or Amount Handled Daily taken from Exposure Science Advisory Council (ExpoSAC) 2012 Residential SOPs.
c	Dose = Dermal/Inhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) 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)].
6.2	Post-Application Exposure

Adults and children performing physical 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 because 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 660 to 570,000).

Table 6.2.  Short-Term Residential Post-Application Exposure and Risk Estimates for Cyazofamid.
                                   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 (ug/cm[2]) x CF1 (0.001 mg/ug) x TC (cm[2]/hr) x Exposure Time (hrs) /  body weight (kg). TC for physical activities on turf: 180,000 cm[2]/hr for adults and 49,000 cm[2]/hr for children 1-2 years old. TCs for mowing: 5,500 cm[2]/hr for adults and 4,500 cm[2]/hr for children 11 to < 16 years old. TCs for golfing: 300 cm[2]/hr for adults, 4,400 cm[2]/hr for children 11 to < 16 years old, and 2,900 cm[2]/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 hrs. 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]) x fraction of hand mouthed (0.127) x surface area of 1 hand (150 cm[2]) x exposure time (1.5 hrs/day) x # of replenishment intervals/hr (4 int/hr) x (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 (ug/cm[2]) x unit conversion factor (0.001 mg/ug) x object surface area mouthed / event (10 cm[2]/event) x exposure time (1.5 hrs/day) x # replenishment intervals/hr (4 int/hr) x (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 (ug/g) x ingestion rate (50 mg/day) x conversion factor (0.000001 g/ug) / body weight (11 kg).
b	MOE = NOAEL (mg/kg/day) / Daily Dose (mg/kg/day). ST Dermal NOAEL= 100 mg/kg/day. ST Oral NOAEL = 30 mg/kg/day.

6.3	Combined Exposure

Based 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 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 Exposures for the Cyazofamid 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-Application 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 nearby pesticide applications.  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 and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are developed, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for cyazofamid.

6.5	Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations.  This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for the previously-registered uses of cyazofamid.  The Agency has been working with the Spray Drift Task Force, EPA Regional Offices, and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices.  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 appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast, and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift and risk estimates associated with aerial as well as other application types where appropriate.

Although a quantitative residential 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 expected 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 estimate.  Refer to Section 5.4.2.

.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) pathways.  For adults, these pathways lead to exposure via the oral (background), and dermal and inhalation (primary) routes.  For children, these pathways 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 2,200, respectively.

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]
         Combined 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.  
c	MOE oral = short-term oral NOAEL / hand-to-mouth residential exposure. NOAEL = 30 mg/kg/day. Residential exposure for children 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 (See Table 6.3).
e	MOE Aggregate Adult = 1 / [(1/MOE dietary) + (1/MOE combined dermal and inhalation)].
	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 expected 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 expected 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 any other substances and cyazofamid does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that 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 policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.

9.0	Occupational Exposure/Risk Characterization

9.1	Short- and Intermediate-Term Handler Risk

Ranman(R) 400SC may be applied as a foliar spray via groundboom, aircraft, and chemigation.  The proposed use pattern is summarized in Table 3.3.  Handler exposure 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 any waterproof material, such as nitrile, butyl, neoprene and/or barrier laminate. 

The quantitative exposure/risk assessment developed for occupational handlers is based on the following exposure scenarios: 
   Mixer/Loaders
   1.          Mixing/Loading liquids to support groundboom applications, 
   2.          Mixing/Loading liquids to support aerial and chemigation applications,
   Flaggers
   3.          Flagging to support aerial application,
   Applicators
   4.          Applying sprays with groundboom equipment, and
   5.          Applying sprays with aerial equipment.
No handler exposures are expected from applying sprays via chemigation systems.

Ranman(R) 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 beans.   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 tomato transplant operations, a mixer/loader/applicator assessment has been conducted for greenhouse tomato transplants for the following exposure scenarios:
   1. Mixing/Loading/Applying with a manually-pressurized handwand;
   2. Mixing/Loading/Applying with a backpack sprayer; and
   3. Mixing/Loading/Applying with a mechanically-pressurized handgun. 

Summaries of the risk estimates 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-Application 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, grapes, 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 estimate dermal exposure to treated vegetables in accordance with current HED exposure assessment policy.  

Based on the proposed use pattern, the squash DFR study was used to assess post-application exposure risks from contact with treated leafy greens, basil, 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. 

All scenarios resulted in MOEs greater than the LOC of 100 (ranging from 9,500 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 assessed, 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.  Therefore, HED believes the 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
Typically, 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-Application Risk

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 rates (<0.16 lb ai/A, at-planting).  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields.  These potential sources include volatilization of pesticides and resuspension of dusts and/or 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 available post-application inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for cyazofamid.

Although a quantitative occupational 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 Analytical 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. "Estimated 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 Leaves), 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 Cyazofamid 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 370671. "Cyazofamid. Human Health Risk Assessment for Proposed Uses on Brassica (Cole) Leafy Vegetables Crop Group 5, Turnip Greens, Spinach, and Hops."

Appendix 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 Cyazofamid 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]
                                     CR[2]
                                      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	
870.5375    Mutagenicity -- Structural Chromosomal Aberrations	
870.5395    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
         Acute Oral (rat)	
         Subchronic Oral (rat)	
         Six-month 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 toxicity data; * = needs to be upgraded.
A.2	Toxicity Profiles

Table A.2-1.  Cyazofamid Acute Toxicity Profile
                                 Guideline No.
                                  Study Type
                                     MRID
                                    Results
                               Toxicity Category
                                   870.1100
                              Acute Oral  -  Rat
                                   45408910
                           LD50> 5000 mg/kg [M/F]
                                      IV
                                   870.1200
                             Acute Dermal  -  Rat
                                   45408911
                          LD50 > 2000 mg/kg [M/F]
                                      III
                                   870.1300
                           Acute Inhalation  -  Rat
                                   45408912
                           LC50 > 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 Test)
                                   45408915
                          Positive (weak sensitizer)
                                       -

Table A.2-2.  Toxicity Profile of Cyazofamid [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 increased 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.

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
Developmental 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
Developmental 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
F0 M: 11-22, 108-213, and 1114-2185 mg/kg/day
F0 F: 14-21, 137-219, and 1416-2179 mg/kg/day
F1 M: 11-27, 107-267, and 1117-2714 mg/kg/day
F1 F: 14-27, 135-267, and 1451-2678  mg/kg/day
Parental/Systemic 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 increased cysts 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 ug/plate by standard plate and tube preincubation (not cytotoxic but there was precipitation at >=1,500 μg/plate.
Gene Mutation
870.5300
Mammalian cell culture
45409002 (1998)
Acceptable/ guideline
(ai)
Negative  +- S9 up to cytotoxic and precipitating concentration of 100 ug/mL
Cytogenetics
870.5375 Chromosomal aberrations
45409003 (1996)
Acceptable/ guideline
(ai)
Negative +- S9 for clastogenic/aneugenic activity up to cytotoxic and precipitating 200 ug/mL
Cytogenetics
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 ug/disc
870.6200a
Acute neurotoxicity screening battery
45434601 (2000)
Acceptable/guideline
0, 80, 400, or 2000 mg/kg
NOAEL = 2000 [M/F] mg/kg/day
LOAEL = not observed.
The 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.

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 tcmax = 0.25-0.5 hrs) and rapid elimination at the low dose (t1/2 4.4-5.8 hrs) while there was saturated absorption with prolonged elimination (t1/2 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 t1/2, 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 radioactivity.  Lower 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.
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 (mucosal 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 CCIM, 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 lumen although its conversion to CCIM or other metabolites may increase overall transfer across the gut wall.
Special study:
Comparative 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 dose 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 administered IKF-916 is converted to CCIM and subsequently to CCBA and CHCN.

Appendix B.	Physical/Chemical Properties and Metabolic Profile

Table B-1.  Physicochemical Properties of the Technical Grade Cyazofamid
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
                                  Λmax (nm)
                                       

                                       2
                                       7
                                      10
                                      285
                                      279
                                      287
                                       

Table B-2.  Identification of Compounds from the Cyazofamid Metabolism Studies
Common Name/ Code/Matrix
Chemical Name
	Chemical Structure
Cyazofamid/
IKF-916


4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonamide

CCIM


4-chloro-5-p-tolylimidazole-2-carbonitrile

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 received that review.  In this assessment, ORETF data were used to assess loading/applying with a push type spreader (data from MRID 44972201) and PHED data were used to assess loading/applying with a belly grinder.
  
Studies reviewed by the Human Studies Review Board:
None.
Appendix D.	Occupational Exposure and Risk Estimates Summary Table

Table D-1.	Short- and Intermediate-Term Agricultural Handler Exposure and Risk Estimates for Cyazofamid
                               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


                                       

                                   ug/lb ai
                                       
                                       
                                       
                                       


                                       

                                       
                                   mg/kg/day
                                       
                                       
                                 Mixer/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 Planting
                                     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 Planting
                                     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
                     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
                            Mixer/Loader/Applicator
                         Manually Pressurized Handwand
                   Tomato Greenhouse Transplant Soil Drench
                                    0.0085
                                      40
                                    gallons
                                    100,000
                                      430
                                      30
                                     0.21
                                    0.0011
                                      480
                                    93,000
                               Backpack Sprayer
                   Tomato Greenhouse Transplant Soil Drench
                                    0.0085
                                      40
                                    gallons
                                     8,260
                                     8,260
                                     2.58
                                     0.017
                                     0.017
                                     5,800
                                     5,800
                       Mechanically Pressurized Handgun
                   Tomato 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(R) 400SC, EPA 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.  Level of mitigation = Baseline (no gloves, no respirator) or PPE (gloves, no respirator).
d	Dose (mg/kg/day) = daily unit exposure (μg/lb ai) x application rate (lb ai/acre or gal) x area treated or amount handled/day (acres/day or gal/day) x conversion factor (1 mg/1,000 μg) x 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-Application Exposure and Risk Estimates for Cyazofamid on Day of Application (Day 0)
                                     Crop 
                           Proposed Application Rate
                                   Activity
                            Transfer Coefficient a
                         Chemical-Specific 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 Weeding
                                      70

                                     0.061
                                   0.000018
                                    550,000


                                 Transplanting
                                      230

                                     0.061
                                    0.00060
                                    170,000
                 Succulent-Podded and Succulent-Shelled Beans
                          Beans, Snap 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


     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 Footnote f 
                              Fruiting Vegetables
                                   Eggplant 
                                     0.072
                                Hand Harvesting
                                      550
                                  Tomato 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 (ug/cm[2] x Application Rate DFR (lb ai/A) / Proposed Application Rate (lb ai/A).
d	Daily Dermal Dose (mg/kg/day) = Normalized DFR (ug/cm[2]) x TC (cm[2]/hr) x exposure time (8 hrs) x dermal abs factor (37%) x CF (1000 ug/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 rate (0.16 lb ai/A vs. a 0.072 lb ai/A) and the TC (1900 cm[2]/hr).     

Appendix E.	International Residue Limit Summary

Table E.  Summary of U.S. and International Tolerances and Maximum 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)-1H-imidazole-1-sulfonamide and its metabolite, 4- chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile, calculated as the stoichiometric equivalent of cyazofamid
4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonamide, including the metabolite
4-chloro-5-(4-methylphenyl)-1H-imidazole-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
                                       
                                       
Completed:  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.
