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


MEMORANDUM

Date:		July 3, 2013

SUBJECT:	Pyraclostrobin  -  Human Health Risk Assessment for a Section 3 Registration of New Uses on Sugarcane, Globe Artichoke, Belgium Endive, Persimmon, Greenhouse Grown Tomato Transplants for Home Consumer Market, and Residential Ornamentals, Landscape Gardens, Fruit Trees, and Nut Trees; Plus Crop Group Expansions/Revisions for Bulb Vegetable Group 3-07, Fruiting Vegetable Group 8-10, Citrus Fruit Group 10-10, Pome Fruit Group 11-10, Berry Subgroups 13-07A, B, F, and G, and Oilseed Group 20.

PC Code:  099100
DP Barcode:  D403462, D398877, D405065, D406472, D406652
Decision Nos.:  465126, 468304, 459294, 470110, 467106
Registration Nos.:  7969-185, 7969-186, 7969-247, 7969-258, 7969-289, 7969-291, 7969-199, 7969-251, 7969-GLG, 4-UII
Petition No.:  2F8038, 2F8069
Regulatory Action:  Section 3 Registration
Risk Assessment Type:  Single Chemical/Aggregate
Case No.:  NA
TXR No.:  NA
CAS No.:  175013-18-0
MRID No.:  NA
40 CFR:  180.582

FROM:	Barry O'Keefe, Senior Biologist
		Vincent Chen, Toxicologist
		Steve Funk, Senior Chemist
		Cassi Walls, Senior Biologist
		Risk Assessment Branch III (RAB III)
		Health Effects Division (7509P)

THROUGH:	Christine Olinger, Branch Chief 
		Risk Assessment Branch III (RAB III) 
		Health Effects Division (7509P)

TO:		Heather Garvie, Risk Manager
		Dominic Schuler, Risk Manager
      Robert Westin, Risk Manager
		Fungicide Branch
		Registration Division (7505P)
			and
      Andrew Ertman, Risk Manager
		Risk Integration, Minor Use and Emergency Response Branch
		Registration Division (7505P)

This document and attachments provide an assessment of the human health risk resulting from the proposed and registered uses of pyraclostrobin.  The toxicology reevaluation was performed by Vincent Chen, the drinking water assessment was conducted by Faruque Khan (EPA Environmental Fate and Effects Division (EFED)), the review of the residue chemistry data and the dietary exposure assessment were conducted by Steve Funk, the occupational and residential exposure assessment was conducted by Cassi Walls, and human health risk assessment was conducted by Barry O'Keefe.  




1.0	Executive Summary	5
2.0	HED Recommendations	7
2.1	Data Deficiencies	8
2.2.1	Enforcement Analytical Method	8
2.2.2	Recommended Tolerances	8
2.2.3	Revisions to Petitioned-For Tolerances	11
2.2.4	International Harmonization	12
3.0	Introduction	13
3.1	Chemical Identity	14
3.2	Physical/Chemical Characteristics	14
3.3	Pesticide Use Pattern	14
3.4	Anticipated Exposure Pathways	17
3.5	Consideration of Environmental Justice	18
4.0	Hazard Characterization and Dose-Response Assessment	18
4.1	Toxicology Studies Available for Analysis	18
4.2	Absorption, Distribution, Metabolism and Excretion (ADME)	19
4.2.1	Dermal Absorption	19
4.3	Summary of Toxicological Effects	19
4.4	Safety Factor for Infants and Children (FQPA Safety Factor)	20
4.4.1	Completeness of the Toxicology Database	20
4.4.2	Evidence of Neurotoxicity	20
4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal	20
4.4.4	Residual Uncertainty in the Exposure Database	21
4.5.1	Dose-Response Assessment	21
4.5.2	Recommendation for Combining Routes of Exposure for Risk Assessment	22
4.5.3	Cancer Classification and Risk Assessment Recommendation	23
4.5.4	Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment	23
5.0	Dietary Exposure and Risk Assessment	25
5.1	Residues of Concern Summary and Rationale	25
5.2	Food Residue Profile	25
5.3	Water Residue Profile	27
5.4	Dietary Risk Assessment	28
5.4.1	Description of Residue Data Used in Dietary Assessment	28
5.4.2	Percent Crop Treated Used in Dietary Assessment	29
5.4.3	Acute Dietary Risk Assessment	29
5.4.4	Chronic Dietary Risk Assessments	30
5.4.5	Summary Table	30
6.0	Residential (Non-Occupational) Exposure/Risk Characterization	30
6.1	Residential Handler Exposure	31
6.2	Post-Application Exposure	33
6.3	Combined Residential Risk Estimates (Multiple Exposure Scenarios)	35
6.4	Residential Risk Estimates for Use in Aggregate Assessment	35
6.5	Residential Bystander Post-application Inhalation Exposure	36
6.6	Spray Drift	36
7.0	Aggregate Exposure/Risk Characterization	37
7.1	Acute Aggregate Risk	37
7.2	Short-Term Aggregate Risk	37
7.3	Intermediate-Term Aggregate Risk	38
7.4	Chronic Aggregate Risk	38
8.0	Cumulative Exposure/Risk Characterization	38
9.0	Occupational Exposure/Risk Characterization	39
9.1	Short-/Intermediate-Term Handler Risk	39
9.2	Short-and Intermediate-Term Post-Application Risk	40
9.2.1	Dermal Post-Application Risk	40
9.2.2	Inhalation Post-Application Risk	41
10.0	References	42
Appendix A.  Toxicology Profile and Executive Summaries	43
A.1	Toxicology Data Requirements	43
A.2	Toxicity Profiles	43
Appendix B.  Physicochemical Properties of Pyraclostrobin.	50
Appendix C.  Review of Human Research	50
Appendix D.  Summaries of Field Residue Data	51
Appendix E.  Summaries of Occupational Handler and Post-application Exposure and Risk Estimates	53
Appendix F.  Summary of Pyraclostrobin DFR Study Results	57
Appendix G.  International Residue Limits Status Sheet	58

1.0	Executive Summary

Introduction
Pyraclostrobin [carbamic acid, [2-[[[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy]methyl] phenyl]methoxy-, methyl ester] belongs to the strobilurin class of fungicides (β-methoxyacrylate class of compounds).  Strobilurins are synthetic analogs of a natural antifungal substance which inhibit spore germination, mycelial growth, and sporulation of the fungus on the leaf surface.  Pyraclostrobin is currently registered on numerous agricultural crops and on residential and golf course turf.

Use Profile
The proposed actions of pyraclostrobin are as follows: 1) BASF Corporation (BASF) is proposing a new agricultural use (PP# 2F8038) on sugarcane; 2) The Interregional Research Project No. 4 (IR-4) is proposing new agricultural uses (PP# 2F8069) on artichoke, Belgium endive, and persimmon; 3) BASF is proposing a new greenhouse tomato use for commercial production and for tomato transplants grown for the home consumer market; 4) Bonide Products is proposing a new use on residential fruit and nut trees; and 5) BASF is proposing new uses on residential ornamentals and landscape gardens.  Additionally, crop group expansions/revisions were requested for the bulb vegetable group 3-07, fruiting vegetable 8-10, citrus fruit group 10-10, pome fruit group 11-10, berry subgroups 13-07A, B, F, and G, and oilseed group 20.

The proposed agricultural labels require occupational handlers to wear the following personal protective equipment (PPE): long-sleeved shirts, long pants, chemical resistant gloves, and coveralls in a few cases.  The 12 hour restricted entry interval (REI) listed on the labels is appropriate.  

Exposure Profile
The proposed residential uses result in short-term handler dermal and inhalation exposures for adults, short-term post-application dermal exposures for adults, youths (11 to 16 years old), and children 6 to 11 years old, and short-term post-application dermal and incidental oral exposures for children (1 to <2 years old).  Exposure pathways include dietary (food and drinking water), and residential exposure sources.  Dietary exposures are also expected for acute and chronic durations.  Occupational exposures are expected via dermal and inhalation routes for short- and intermediate-term durations.

Hazard Assessment 
Pyraclostrobin has moderate to low acute toxicity via the oral, dermal, and inhalation routes of exposure.  Pyraclostrobin is not a dermal sensitizer, but was determined to produce a low acute dermal effect and eye irritation.  The primary target tissues appear to be mucosal membranes, with pathology or secondary effects (e.g. diarrhea) observed in different species.  The primary effects were decreased body weight, body weight gain, and food consumption, and diarrhea. Pyraclostrobin was classified as "Not likely to be Carcinogenic to Humans."  There are no concerns for reproductive susceptibility, neurotoxicity, mutagenicity, genotoxicity, or immunotoxicity.  Based on the available data, toxicity endpoints and points of departure (PODs) have been selected for acute and chronic dietary, short-term incidental oral, and short- and intermediate-term dermal and inhalation exposure scenarios.  Dermal absorption is 14%.  Inhalation toxicity is assumed to be equivalent to oral toxicity for non-cancer risk assessments.  The Food Quality Protection Act (FQPA) Safety Factor has been reduced to 1X because the toxicity database is complete, there is no concern for susceptibility in infants and young children, there are no neurotoxicity concerns, and there are no residual uncertainties regarding exposure.

Dietary Exposure
The residue chemistry data and environmental fate data are adequate to assess human dietary exposure.  The assessments are based on reliable data and will not underestimate exposure or risk.  Estimated drinking water concentrations (EDWCs) were incorporated directly into the dietary exposure assessments; i.e., for acute dietary 35.6 ug/L from surface water (from turf use) and for chronic dietary 2.3 ug/L from surface water (from turf use).

The results of the acute dietary (food and drinking water) analysis using tolerance level residues or highest field trial residues indicate that acute dietary risks do not exceed the Agency's level of concern (LOC <100% of the acute Population Adjusted Dose (aPAD)) for the U.S. population and all subgroups.  Combined dietary exposure from food and drinking water at the 95[th] percentile of exposure for the U.S. population is equivalent to 1.5% of the aPAD.  The population subgroup with the highest estimated acute dietary exposure to pyraclostrobin is females 13-49 years, with an estimated exposure at the 95[th] percentile of 87% of the aPAD.

The results of the refined chronic dietary (food and drinking water) analysis using tolerance level residues or highest field trial residues and percent crop treated values are below the Agency's LOC for all population subgroups.  The dietary exposure for food and drinking water for the general U.S. population is 8.0% of the chronic Population Adjusted Dose (cPAD) and 27% of the cPAD for children 1-2 years old, the population subgroup with the highest estimated chronic dietary exposure to pyraclostrobin.

Residential Exposure
New residential uses were requested in this action.  However, pyraclostrobin is currently registered for use on residential and golf course turf.  Existing residential exposures and risks from use on turf were reassessed using the updated 2012 HED Residential Standard Operating Procedures (SOPs).  All residential handler dermal and inhalation exposure risk estimates were not of concern to HED, with margins of exposure (MOEs) ranging from 590 to 3,900,000.  All residential post-application exposure risk estimates were also not of concern to HED, with MOEs ranging from 150 to 340,000.  

Aggregate Exposure 
The adult aggregate MOE is 230, which includes post-application exposure to treated turf and background dietary exposure and is not of concern to HED.  The aggregate MOE for children 1-2 years old, including incidental oral exposures from treated turf, is 120, which is not of concern to HED.

Occupational Exposure
Based on the proposed use pattern of pyraclostrobin, there is potential for short- and intermediate-term occupational exposure during mixing, loading, and other handling tasks; and during post-application activities.  The proposed labels require occupational handlers to wear the following personal protective equipment (PPE): long-sleeved shirts, long pants, and chemical resistant gloves.  All of the dermal MOEs are not of concern with labeled PPE (gloves).

The handler inhalation MOEs range from 33 to 8,500 at baseline PPE (no respirator).  The two inhalation scenarios with MOEs below 100 at baseline PPE [mixing/loading of WDG formulation to support aerial and chemigation applications to artichoke and persimmon (MOE=33); and mixing/loading/applying (M/L/A) of WDG formulation using a mechanically pressurized handgun to treat greenhouse tomatoes (MOE=85)] were no longer a concern to HED when assessed with a PF5 respirator (MOEs >100).  A PF5 respirator needs to be proposed on the affected Pristine Fungicide [EPA Reg. No.7969-199] and Pagent(R) Fungicide [EPA Reg. No.7969-251] labels.

The short- and intermediate-term post-application dermal exposure risk estimates for workers for all scenarios were not of concern on day 0 (12 hours after application), with MOEs ranging from 120 to 12,000.

Based on the Agency's current practices, a quantitative occupational post-application inhalation exposure assessment was not performed for pyraclostrobin at this time.  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 pyraclostrobin.  The 12 hour restricted entry interval (REI) listed on the labels is appropriate.  

Review of Human Research
This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These data, which include studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler Exposure Task Force (AHETF) database, the Residential SOPs (lawns and turf), and MRID 45773201 are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements.  For certain studies that review may have included review by the Human Studies Review Board.  Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html and http://www.epa.gov/pesticides/science/post-app-exposure-data.html. 

Environmental Justice Considerations
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.  

2.0	HED Recommendations

HED has examined the toxicology and residue chemistry databases for pyraclostrobin.  Pending submission of revised Sections B and F, there are no toxicology or residue chemistry issues that would preclude granting Section 3 registration for the requested uses of pyraclostrobin, or establishment of tolerances for residues of pyraclostrobin.  Additional data are needed, as outlined below in Section 2.1.  The specific tolerance recommendations are discussed in Section 2.2, and label modifications are discussed in Section 2.3.

2.1	Data Deficiencies

None

2.2	Tolerance Considerations

2.2.1	Enforcement Analytical Method

There are adequate residue analytical methods for tolerance enforcement.  Two adequate methods are available for enforcement purposes for residues of pyraclostrobin and the metabolite BF 500-3 in/on plant commodities: an LC/MS/MS method (BASF Method D9908) and an HPLC/UV method (Method D9904).  The validated method LOQ for both pyraclostrobin and BF 500-3 is 0.02 ppm in all tested plant matrices, for a combined LOQ of 0.04 ppm.  Adequate independent method validation and radiovalidation data were submitted for both methods.

Pyraclostrobin was successfully evaluated through several of the FDA protocols, while recovery of BF 500-3 was unsuccessful in all protocols.  The results of the multiresidue testing for pyraclostrobin were forwarded to FDA on 1/4/02 for the purpose of updating the Pesticide Analytical Manual, Volume I (PAM I).

2.2.2	Recommended Tolerances

HED has examined the residue chemistry database for pyraclostrobin and evaluated the adequacy of submissions associated with the current actions.  For the proposed use on sugarcane, a tolerance is required.  A time-limited Section 18 tolerance of 0.02 ppm exists (40 CFR §180.582(b).  Based on evaluation of the sugarcane field trial data with the Organization for Economic Cooperation and Development (OECD) tolerance calculation procedure, a permanent tolerance of 0.2 ppm is appropriate for sugarcane, cane.  Pyraclostrobin residues did not concentrate in sugarcane molasses and sugarcane refined sugar.  Therefore, these commodities are covered by the tolerance for the raw agricultural commodity, sugarcane, cane.

The proposed updating of certain existing crop groups and the removal of certain oilseed tolerances and certain previous crop group/subgroup tolerances are acceptable.  However, an additional oilseed tolerance will need to be removed, and IR-4 should request the following removal: cotton, undelinted seed (0.3 ppm).  

The Section 18 tolerance for Belgium endive should be removed concurrent with the establishment of the Section 3 tolerance for Belgium endive.

The recommended tolerances for pyraclostrobin commodities or commodity groups are presented in Table 2.2.2.1.  Compliance with the tolerance levels is to be determined by measuring only the sum of pyraclostrobin (carbamic acid, [2-[[[1-(4-chlorophenyl)-1H- pyrazol-3-yl]oxy]methyl]phenyl]methoxy-, methyl ester) and its desmethoxy metabolite (methyl N-[[[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy]methyl]phenyl carbamate), calculated as the stoichiometric equivalent of pyraclostrobin.  

Table 2.2.2.1.  Tolerance Summary for Pyraclostrobin.
Commodity
                       Proposed/Existing Tolerance (ppm)
                    Recommended/ Harmonized Tolerance (ppm)
Comments; Correct Commodity Definition
                               40CFR§180.582(a)
Artichoke, globe
                                      3.0
                                      3.0

Endive, belgium
                                      3.0
                                      4.0
OECD statistical calculation estimates  4.0 ppm.
Persimmon
                                      3.0
                                      3.0

Sugarcane, cane 
                                      0.2
                                     0.20

Vegetable, bulb, group 3-07
                                      0.9
                                      0.9
Crop group update
Vegetable, bulb, group 3
                                      0.9
                                    Remove
Crop group update
Vegetable, fruiting, group 8-10
                                      1.4
                                      1.4
Crop group update
Vegetable, fruiting, group 8
                                      1.4
                                    Remove
Crop group update
Fruit, citrus, group 10-10
                                      2.0
                                      2.0
Crop group update
Fruit, citrus, group 10
                                      2.0
                                    Remove
Crop group update
Fruit, pome, group 11-10
                                      1.5
                                      1.5
Crop group update
Fruit, pome, group 11
                                      1.5
                                    Remove
Crop group update
Oilseed group 20
                                     0.45
                                     0.45
Crop group creation.
Cotton, undelinted seed
                                      0.3
                                    Remove
To be replaced by oilseed group 20.  IR-4 needs to request this removal.
Borage, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Castor oil plant, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Chinese tallowtree, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Crambe, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Cuphea, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Echium, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Euphorbia, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Evening primrose, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Flax, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Gold of pleasure, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Hare's ear mustard, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Jojoba, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Lesquerella, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Lunaria, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Meadowfoam, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Milkweed, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Mustard, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Niger seed, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Oil radish, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Poppy, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Rapeseed, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Rose hip, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Safflower, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Stokes aster, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Sunflower, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Sweet rocket, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Tallowwood, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Tea oil plant, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Vernonia, seed
                                     0.45
                                    Remove
To be replaced by oilseed group 20.  
Caneberry subgroup 13-07A
                                      4.0
                                      4.0
Group update
Bushberry subgroup 13-07B
                                      4.0
                                      4.0
Group update
Small fruit, vine climbing subgroup (except fuzzy kiwi) 13-07F
                                      2.0
                                      2.0
Fruit, small vine climbing, except fuzzy kiwifruit, subgroup 13-07F
Group update
Low growing berry subgroup 13-07G except cranberry
                                      1.2
                                      1.2
Berry, low growing, subgroup 13-07G, except cranberry
Group update
Berry, group 13
                                      4.0
                                    Remove
Group update.  Replaced with subgroups 13-07A and 13-07B
Grape
                                      2.0
                                    Remove
Group update.  Replaced with subgroup 13-07F
Strawberry
                                      1.2
                                    Remove
Group update.  Replaced with subgroup 13-07G
               40CFR§180.582(b) Section 18 emergency exemptions
Endive, belgium
                                     11.0
                                    Remove
Replaced with Section 3 tolerance for endive, belgium
Sugarcane, cane
                                     0.02
                                    Revoke
Replaced with new tolerance in (a)
Sugarcane, molasses
                                     0.40
                                    Revoke
Replaced with new tolerance in (a) for sugarcane, cane

No new tolerances are proposed for pyraclostrobin based on the proposed greenhouse use on fruiting vegetables.  The existing tolerance for fruiting vegetables will cover the requested new uses of the Pageant[TM] fungicide (EPA Reg. No. 7969-251) formulation.

No new tolerances are proposed for pyraclostrobin based on the proposed residential use on pome fruit, stone fruit, and tree nuts using the proposed label for the Bonide Products, Inc FT09 (EPA File Symbol 4-UII).  The existing tolerances based on the BASF Pristine[(R)] label cover these residential uses on pome fruit, stone fruit, and tree nuts.  The Bonide Products, Inc FT09 label compares favorably with the BASF Pristine[(R)] label.  Therefore, the existing tolerances for pome fruit, stone fruit, and tree nuts will also cover the proposed new residential uses.

2.2.3	Revisions to Petitioned-For Tolerances

The available data for Belgium endive will not support a tolerance level of 3.0 ppm.  A revised Section F should be submitted with a tolerance for endive, Belgium at 4.0 ppm.  

Several crop group conversions were requested.  Most were crop group updates. One request was to replace individual oilseed tolerances with an oilseed crop group 20 tolerance.  This was accompanied by a request to remove numerous individual commodity oilseed tolerances.  These changes have been made to the proposed labels.  In addition to the requested removals, the existing tolerance for cotton undelinted seed will be replaced by oilseed group 20, and IR-4 needs to make this request.  The tolerance covering undelinted cotton seed is raised from 0.3 ppm to 0.45 ppm.  This is acceptable as cottonseed is one of the three representative commodities for the oilseed group (cottonseed, rapeseed, sunflower), and the highest estimate from the three commodities is adopted for the group.  The changes are acceptable, as detailed in Table 2.2.2.1.


860.1550 Proposed Tolerances
   * The available data for Belgium endive will not support a tolerance level of 3.0 ppm.  A revised Section F should be submitted with a tolerance for endive, Belgium at 4.0 ppm.
   * The existing tolerance for undelinted cottonseed seed should be removed as it is replaced by the proposed and recommended tolerance for oilseed group 20.  A revised Section F should be submitted.

2.2.4	International Harmonization

Codex and Canada have not established maximum residue limits (MRLs) for pyraclostrobin on sugarcane, Belgium endive and persimmon.  Therefore, there is no issue of harmonization at this time (see Appendix G). 

A Codex MRL has been established for pyraclostrobin in/on globe artichoke at 2.0 ppm.  The recommended US tolerance is 3.0 ppm.  Residue definitions are different in the US and in Codex, and the US tolerance is based on application of the OECD tolerance calculation procedure to the validated field trial data.  The tolerance cannot be lowered to the Codex level as this could result in apparent violations for crops treated in accordance with the label.  Canada does not have pyraclostrobin tolerances for globe artichoke, Belgium endive, or persimmon.  Therefore, there is no issue of harmonization with Canada at this time (see Appendix G).

The crop group/subgroup conversions were considered for possible harmonization with Codex.  The Codex has established an MRL for one or more commodities in the bulb vegetable group 3-07, in the fruiting vegetables group 8-10, in the pome fruit group 11-10, in the caneberry subgroup 13-07A, in the bushberry subgroup 13-07B, in the small fruit vine climbing subgroup 13-07F, and in the low growing berry subgroup 13-07G.  The Codex has established an MRL for the Codex equivalent of the US citrus fruit group 10-10 and for the oilseed group 20.  Harmonization with these groups or subgroups is not possible because the residue definitions used by the US and Codex are different.  Therefore, the resulting numerical values refer to different residues.

The US and Canadian residue definitions are harmonized.  For the crop group conversions, the US is harmonized with Canada for bulb vegetables group 3-07, citrus fruit group 10-10, pome fruit group 11-10, oilseed group 20, caneberry subgroup 13-07A, bushberry subgroup 13-07B, small fruit, vine climbing subgroup 13-07F, and low growing berry subgroup 13-07G.  The US is not harmonized with Canada for fruiting vegetables group 8-10, where the US group tolerances is 1.4 ppm and Canada has 1.0 ppm for tomato and pepper.  The US is not harmonized with Canada for caneberry subgroup 13.07A and for bushberry subgroup 13-07B.  The US tolerances for caneberry subgroup 13.07A and for bushberry subgroup 13-07B are 4.0 and 4.0 ppm, respectively, whereas the Canadian tolerances are 3.5 and 3.5 ppm, respectively.  


2.3	Label Recommendations

860.1200 Directions for Use
   * A revised label is required for EPA Reg. No. 7969-247 (12.0% EC, Multiva(R)).  The proposed label has a maximum seasonal rate of 0.52 lb ai/acre for sugarcane.  However, the directions state that no more than 80 ounces of Multiva(TM) should be applied per season, which is equivalent to 0.68 lb ai.  The 80 ounces is incorrect and must be changed to 62 ounces of product.
   * The proposed labels for EPA Reg. No. 7969-199 (Pristine(R) Fungicide), and EPA Reg. No. 7969-187(Cabrio(R) EG Fungicide) provide directions for use on the low growing berry subgroup.  Cranberry must be removed from the list of crops.  The title "low growing berry subgroup" should be changed to "low growing berry subgroup except cranberry."
   * Revised labels are required for EPA Reg. No.7969-199 (Pristine Fungicide) and EPA Reg. No.7969-251 (Pagent(R) Fungicide).  A PF5 respirator needs to be proposed on these labels.

3.0	Introduction

Pyraclostrobin belongs to the strobilurin class of fungicides (β-methoxyacrylate class of compounds).  Strobilurins are synthetic analogs of a natural antifungal substance which inhibit spore germination, mycelial growth, and sporulation of the fungus on the leaf surface.

Pyraclostrobin is currently registered on barley, berries, Brassica vegetables, bulb vegetables, citrus, corn (field, pop and sweet), cotton, cucurbit vegetables, fruiting vegetables, grapes, grass grown for seed, hops, leafy vegetables, legumes (dried peas and beans, succulent shelled peas and beans), mint, oats, oilseed group (canola & flax), peanuts, pistachios, pome fruits, potatoes, root vegetables, rye, soybean, strawberries, stone fruits, sugar beets, sunflower, tropical fruits (avocado, black sapote, canistel, mamey sapote, mango; papaya, sapodilla, & star apple), tuberous and corm vegetables, tree nuts, and wheat, as well as seed treatment on oats, canola, and flax, and residential and golf course turf.  

The proposed actions of pyraclostrobin are as follows: 1) BASF Corporation (BASF) is proposing a new agricultural use (PP# 2F8038) on sugarcane; 2) The Interregional Research Project No. 4 (IR-4) is proposing new agricultural uses (PP# 2F8069) on artichoke, Belgium endive, and persimmon; 3) BASF is proposing a new greenhouse tomato use for commercial production and for tomato transplants grown for the home consumer market; 4) Bonide Products is proposing a new use on residential fruit and nut trees; and 5) BASF is proposing new uses on residential ornamentals and landscape gardens.  Additionally, crop group expansions/revisions were requested for the bulb vegetable group 3-07, fruiting vegetable 8-10, citrus fruit group 10-10, pome fruit group 11-10, berry subgroups 13-07A, B, F, and G, and oilseed group 20.


3.1	Chemical Identity

TABLE 3.1.	Pyraclostrobin Nomenclature.
Chemical Structure
                                       
Common name
Pyraclostrobin
Company experimental name
BAS 500 F
IUPAC name
methyl 2-[1-(4-chlorophenyl)pyrazol-3-yloxymethyl]-N-methoxycarbanilate
CAS name
methyl N-[2-[[[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy]methyl]phenyl]-N-methoxycarbamate
CAS registry number
175013-18-0
End-use product (EP)
Headline(R) EC Fungicide, EPA Reg. No. 7969-186.
Cabrio(R) EG fungicide, EPA Reg. No. 7969-187.
Pristine(R) fungicide, EPA Reg. No. 7969-199.
Headline(R) SC fungicide, EPA Reg. No. 7969-289.

3.2	Physical/Chemical Characteristics

Pyraclostrobin has a log octanol/water partition coefficient (log Kow) of 3.99.  Pyraclostrobin has a molecular weight of 387.82 g/mol; therefore, the potential to cross biological barriers is somewhat limited.  If released to air, a low vapor pressure of 1.9x10[-][8] mm Hg at 20 ºC limiting the potential for volatilization.  The physiochemical properties of pyraclostrobin are summarized in Appendix B.  

3.3	Pesticide Use Pattern

Sugarcane
BASF is proposing the use of Headline(R) Fungicide, Headline(R) SC Fungicide, Multiva(TM) Fungicide, and BAS 556 SC Fungicide on sugarcane at a maximum single application rate ranging from 0.13 to 0.20 lb ai/A using ground, aerial, or chemigation equipment.  Each product may be applied 4 times per year at a maximum yearly application rate of 0.52 to 0.78 lb ai/A/yr and a 14-day retreatment interval.

Headline(R) Fungicide (EPA Reg. No. 7969-186) and Headline(R) SC Fungicide (EPA Reg. No.7969-289) are suspension concentrate (SC) fungicides containing 23.6% pyraclostrobin.  Multiva(TM) Fungicide (EPA Reg. No.7969-247) and BAS 556 SC Fungicide (EPA Reg. No.7696-291) are multiple active ingredient (MAI) SC fungicides containing 12% pyraclostrobin and 7.4% metconazole, and 13.64% pyraclostrobin and 5.14% metconazole, respectively.

Globe artichoke, Belgium endive, and persimmon
IR-4 is proposing the use of Pristine Fungicide on globe artichokes, Belgium endive, and persimmons.  Pristine Fungicide (EPA Reg. No.7969-199) is a multiple active ingredient (MAI) water dispersible granular (WDG) fungicide containing 12.8% pyraclostrobin and 25.2% boscalid.  Belgium endive may be treated at a maximum rate of 0.013 lb ai/1000 lb roots prior to cold storage and 0.014 lb ai/70 ft[2] prior to forcing, each at one application per season.  The maximum single application rate for artichoke and persimmon is 0.18 lb ai/A using aerial, ground, or chemigation equipment.  Pristine may be applied to artichoke and persimmon 3 times per crop cycle at a maximum crop-cycle application rate of 0.55 lb ai/A/yr.  

Greenhouse tomato use for commercial production and for tomato transplants grown for the home consumer market
BASF is proposing the use of Pagent(R) Fungicide on greenhouse grown tomatoes.  Pagent(R) Fungicide label (EPA Reg. No.7969-251) is a MAI WDG fungicide containing 12.8% pyraclostrobin and 25.2% boscalid.  Pagent may be applied at a maximum single application rate of 0.18 lb ai/A (or 0.0018 lb ai/gal).  Pagent may be applied 3 times per crop cycle at a maximum crop-cycle application rate of 0.55 lb ai/A (or 0.0055 lb ai/gal).  Handlers may apply Pagent using handheld equipment.  

Residential fruit and nut trees
Bonide Products is proposing a new product, Bonide(R) Fruit Tree Spray Concentrate (FT09), for use on home orchard fruit and nut trees.  Bonide(R) Fruit Tree Spray Concentrate (EPA Reg. No. 4-UII) is a MAI SC fungicide containing 0.500% lambda-cyhalothrin, 3.06% pyraclostrobin, and 5.622% boscalid.  The maximum single application rate is 0.12 lb ai/A with no more than 4 or 5 applications per year, depending on the tree type.  The retreatment interval ranges from 7 to 10 days.  Residential handlers may apply FT09 using handheld spray equipment.

Residential ornamentals and landscape gardens
BASF is proposing a new product, Homeowner Garden Spray Fungicide, for use on residential ornamentals and landscape gardens via a residential applicator.  Homeowner Garden Spray Fungicide (EPA Reg. No. 7969-GLG) is a MAI SC fungicide containing 9.0% pyraclostrobin and 18.0% boscalid.  The maximum single application rate for this product is 0.0016 lb ai/gal via residential handheld spray equipment or hose-end sprayers.

The proposed agricultural labels require occupational handlers to wear the following personal protective equipment (PPE): long-sleeved shirts, long pants, chemical resistant gloves, and coveralls in a few cases.  The 12 hour restricted entry interval (REI) listed on the labels is appropriate.  

The proposed uses of pyraclostrobin are summarized in Table 3.3.


Table 3.3. Use Profile for Proposed Pyraclostrobin Uses
                                   Proposed
                                      Use
                              Product Formulation
                                [EPA Reg. No.]
                             Application Equipment
                          Max. Single 
Applic. Rate 
                                   (lb ai/A)
                          Max. No. Applic. Per Season
                          Max. Seasonal Applic. Rate 
                                 (lb ai/A/yr)
                                     PHI 
                                    (days)
                        Use Directions and Limitations
Sugarcane
                                       
                             Headline(R) Fungicide 
                            [EPA Reg. No. 7969-186]
                            SC 23.6% pyraclostrobin
                                       
                 Headline(R) SC Fungicide [EPA Reg No.7969-289]
                            SC 23.3% pyraclostrobin
                        Ground, Aerial, or Chemigation
                                     0.20
                                       4
                                     0.78
                                      14
Do not make more than two sequential applications.  Continue treatment on a 14 to 28 day interval.

                             Multiva(TM) Fungicide 
                            [EPA Reg. No.7969-247]
                                       
                             SC 12% pyraclostrobin
                                       
                                     0.13
                                       4
                                     0.52
                                      14
Do not make more than two sequential applications.  Continue treatment on a 14 to 28 day interval.

                             BAS 556 SC Fungicide 
                            [EPA Reg. No.7696-291]
                                       
                           SC 13.64% pyraclostrobin
                                       
                                     0.19
                                       4
                                     0.76
                                      14
Do not make more than two sequential applications.  Continue treatment on a 14 to 28 day interval.
Globe Artichoke

Persimmon
                              Pristine Fungicide 
                            [EPA Reg. No.7969-199]
                                       
                           WDG 12.8% pyraclostrobin
                        Ground, Aerial, or Chemigation
                                     0.18
                                       3
                                     0.55
                                       0
Continue treatment on a 7 to 14 day interval.
Belgium endive
                                       
Make one app as a spray to roots when brought into cold storage prior to forcing.  Apply again at the beginning of forcing after the roots have been packed in forcing trays
                                       
                            Prior to cold storage:
0.013 lb ai/1000 lb roots
                                       1
                                       
                                      19
Prior to Cold Storage: make one app as a spray to the roots as they move along a conveyor belt used to bring the roots from field transportation into cold storage bins.

                                       
                                       
                              Prior to forcing: 
                       0.014 lb ai/70ft2 of forcing tray
                                       1
                                       
                                       
Prior to Forcing: make one app as a spray to roots at the beginning of forcing, after they have been packed into forcing trays.
Greenhouse tomatoes
                              Pagent(R) Fungicide
                             [EPA Reg. No.7969-251]
                                       
                           WDG 12.8% pyraclostrobin
                                       
                            Chemigation, Ground, or
                           Handheld spray equipment
                                 0.18 lb ai/A
                                      or
                               0.0018 lb ai/gal  
                                       3
                                     0.55 
                                        
                                       0
For commercial production :

Apply as a foliar spray in a minimum of 100 gal/A water volume.  

Allow at least 7 days between applications.

Do not make more than one application before alternations to a fungicide with a different mode of action for at least on application

                                       
                                       
                                 0.14 lb ai/A
                                      or
                               0.0014 lb ai/gal  
                                       
                                     0.42
                                        
                                      NA
For tomato transplants grown for the home consumer market:

Do not exceed 100 gal/A spray volume.

Allow at least 7 days between applications.

Do not use in transplant production for commercial field-grown tomatoes.

Do not apply more than 2 consecutive applications in any crop production cycle.
Residential fruit and nut trees

                 Bonide(R) Fruit Tree Spray Concentrate (FT09)
                              [EPA Reg. No.4-UII]
                                       
                                       
                            SC 3.06% pyraclostrobin
                           Handheld spray equipment
                               0.0041 lb ai/gal
                                       
                             0.0000028 lb ai/ft[2]
                                       
                                 0.12 lb ai/A
Pome and Tree nuts: 4

Stone: 5

                                       
                                       
                                   Pome: 21
                                       
                                   Stone: 14
                                       
                                  Almonds: 25
                                       
                                 Tree Nuts: 14
Apply thoroughly as a foliar cover spray to both sides of plant leaves and surfaces.  Spray leaf surfaces to the point of drip but do not exceed 2 fl oz of product per 1,500ft[2]
Residential ornamentals
                       Homeowner Garden Spray Fungicide 
                            [EPA Reg. No. 7969-GLG]
                                       
                            SC 9.0% pyraclostrobin
                                       
                           Handheld spray equipment
                               0.0016 lb ai/gal
                                       
                                0.16 lb a/A[1]
                                       6

                                      NA
For manual spray applications: spray until foliage is wet.

For hose-end sprayers: typically hose-end applicators are designed to deliver the desired dial setting per gallon of water in 30 seconds.

Retreatment interval is 14 days.
1 Assumed 100 gallons treats 1 acre based on other similar labels; HED recommends that the Homeowner Garden Spray Fungicide (EPA Reg No. 7969-GLG) label should be clarified by including the spray volume (i.e., number of gallons of spray treated per acre).  This information is needed so that the application rate can be presented in terms of lbs ai/A as well as, lbs ai/gal (which is currently on the label).  
3.4	Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support proposed new uses of pyraclostrobin on the following: 1) agricultural crops sugarcane, artichoke, Belgium endive, and persimmon; 2) greenhouse tomato use for commercial production and for tomato transplants grown for the home consumer market; 3) residential fruit and nut trees; and 4) residential ornamentals and landscape gardens.  Humans may be exposed to pyraclostrobin in food and drinking water, since pyraclostrobin may be applied directly to growing crops and application may result in pyraclostrobin reaching surface and ground water.  There are residential uses of pyraclostrobin so there is exposure to residential handlers and those entering treated areas following application.  In occupational settings, applicators may be exposed while handling pyraclostrobin.  There is a potential for post-application exposure for workers re-entering treated fields and residents re-entering treated areas.  

Risk assessments have been completed for proposed and existing uses of pyraclostrobin.  This risk assessment considers all of the aforementioned exposure pathways based on the proposed new uses of pyraclostrobin, but also considers existing uses of pyraclostrobin, particularly in the dietary and residential exposure assessments.  

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 U.S. Department of Agriculture's National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age and ethnic group.  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 post-application 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

Pyraclostrobin, a strobilurin fungicide, blocks fungal growth by disrupting mitochondrial respiration through inhibiting Complex III electron transfer at the Cytochrome bc1 (ubiquinol oxidase) Q0 site.  There are no mammalian molecular data to specifically show this mode of action in the test animals.  

4.1	Toxicology Studies Available for Analysis

The pyraclostrobin toxicity database is complete.  The toxicity studies available for risk assessment include an acute toxicity battery; subchronic toxicity studies (oral, dermal, and inhalation) in rats, dogs or rabbits; chronic toxicity studies in dogs and rats; carcinogenicity studies in mice and rats; developmental toxicity studies in rats and rabbits; a 2-generation reproduction study in rats; a battery of mutagenicity studies; acute neurotoxicity studies in the rat; metabolism studies in rats; in vivo dermal penetration studies in rats, and an immunotoxicity study in mice. 

4.2	Absorption, Distribution, Metabolism and Excretion (ADME)

The available ADME data in rats indicated that orally-administered radiolabeled pyraclostrobin exhibits fast yet modest absorption, broad distribution with no specific tissue accumulation, extensive metabolism, and fast body clearance.  There was no evidence of bioaccumulation.

The data collected in male and non-pregnant female rats at two different dose levels (5 and 50 mg/kg) suggest a time to peak plasma levels (tmax) of 8.0/0.5 hrs [M/F] with absorption of 35% of the orally administered dose (AD). The plasma elimination half-life (t(1/2)) was biphasic at the low-dose with the initial t(1/2) of 9.0/10.5 hrs [M/F] and the terminal t(1/2) of 37.5/31.6 hrs [M/F]; at the high-dose the t(1/2) was 20.7/19.7 hrs [M/F]. Pyraclostrobin was rapidly and widely distributed in tissues.  The highest levels of radioactivity were measured in the liver, thyroid, kidney, lungs, adrenal glands, and pancreas; radioactivity was higher in females than in males.  Pyraclostrobin levels in the tissues decreased substantially over the first 24 hours and was essentially complete after 72 hours; feces was the primary route of elimination (>79% AD). There were no significant dose- or sex-dependent differences in tissue distribution or route of elimination.

Pyraclostrobin was extensively metabolized, resulting in 33 metabolites, in both male and female rats.  Pyraclostrobin underwent phase-I reactions such as N-demethoxylation, various hydroxylations, and cleavage of the ether bond with subsequent oxidation; these reactions were followed by phase II glucuronidation and sulfation.  The most abundant metabolite was 500M08 which resulted from N-demethoxylation and hydroxylation of the pyrazol ring.  The parent was quantified along with an N-demethylated metabolite and was less than 14% AD.

4.2.1	Dermal Absorption

The Agency evaluated an available dermal penetration study, but it was deemed initially unacceptable due to material on the dressings being unavailable for absorption.  In 2003 however, the HED re-evaluated the study and derived a dermal penetration rate of 14% (TXR# 0051553; 10 FEB 2003).  

4.3	Summary of Toxicological Effects

The most consistently observed effects of pyraclostrobin exposure across species, genders, and treatment durations were diarrhea and decreased body weight, body weight gain, and food consumption.  Pyraclostrobin also causes intestinal disturbance as indicated by increased incidence of diarrhea or duodenum mucosal thickening.  These intestinal effects appeared to be related to the irritating action on the mucus membranes as demonstrated by irritation seen in the primary eye irritation study. 

In the rat acute and subchronic neurotoxicity studies, neuropathology and behavior changes were not observed.

In the rat and rabbit developmental toxicity studies, developmental toxicity (i.e. skeletal variations, post-implantation loss, and fetal resorption) occurred at doses greater than or equal to those doses causing maternal toxicity (i.e. diarrhea, decreased body weight, body weight gain, food consumption, and clinical signs of toxicity).  In the reproduction studies (guideline and range-finding studies), systemic toxicity manifested as decreased body weight and body weight gain in both the parents and offspring; no reproductive toxicity was seen. 

Pyraclostrobin was classified by the Cancer Assessment Review Committee (CARC) as "Not Likely to be Carcinogenic to Humans" based on the lack of treated related increase in tumor incidence in adequately conducted carcinogenicity studies in rats and mice (CARC 01 FEB 2007).  Pyraclostrobin did not cause mutagenicity or genotoxicity in the in vivo and in vitro assays nor did it cause immunotoxicity in T-cell dependent antibody response (TDAR) assays in mice with preliminary review.

Pyraclostrobin has moderate to low acute toxicity via the oral, dermal, and inhalation routes of exposure (Toxicity Categories II-IV).  Pyraclostrobin is not a dermal sensitizer.  However, pyraclostrobin was determined to have a low effect dermal and eye irritant (Toxicity Category III).

4.4	Safety Factor for Infants and Children (FQPA Safety Factor)

For all assessment scenarios, the default 10X FQPA Safety Factor can be reduced to 1X because the toxicity database is complete and there is no neurotoxicity, and no residual uncertainty in the exposure data.  Although there are indications of qualitative susceptibility, the points of departure are protective of the effects in the developing organism.

4.4.1	Completeness of the Toxicology Database

The toxicology database is complete, acceptable, and sufficient for assessing susceptibility to infants and children as required by FQPA.

4.4.2	Evidence of Neurotoxicity

There are no indications in any of the studies available that the nervous system is a target for pyraclostrobin.  Effects seen in the acute and subchronic neurotoxicity studies in rats are considered to reflect perturbations in mitochondrial respiration leading to effects on energy production.

In the absence of frank neurotoxicity or neuropathology findings in the neurotoxicity battery or elsewhere in the database, a developmental neurotoxicity study is not required.

4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no evidence that pyraclostrobin results in increased susceptibility in in utero rats or rabbits in the prenatal developmental studies or in young rats in the 2-generation reproduction study.  Although there is qualitative evidence of increased susceptibility in the prenatal development study in rabbits, HED did not identify any residual uncertainties after establishing toxicity endpoints and traditional UFs to be used in the risk assessment of pyraclostrobin.  The degree of concern for prenatal and/or postnatal toxicity is low.

4.4.4	Residual Uncertainty in the Exposure Database

There are no residual uncertainties identified in the exposure databases.  The acute dietary exposure assessments were performed assuming 100% of the crops were treated with pyraclostrobin and tolerance-level or highest field trial residues.  The chronic dietary exposure assessments were performed using average percent crop treated estimates and tolerance-level or highest field trial residues.  EPA made conservative (protective) assumptions in the ground and surface water modeling used to assess exposure to pyraclostrobin in drinking water.  EPA used similarly conservative assumptions to assess post-application exposure of adults and children as well as incidental oral exposure of children.  The residential exposure assessment is based on the updated 2012 Residential SOPs employing surrogate study data, including conservative exposure assumptions based on Day 0 dermal/oral contact to turf and surfaces treated at the maximum application rate.  These data are reliable and are not expected to underestimate risks to adults or children.  The Residential SOPs are based upon reasonable "worst-case" assumptions are not expected to underestimate risk.  Although some of the residue values used in the dietary exposure assessment were refined, these assessments will not underestimate the exposure and risks posed by pyraclostrobin. 

4.5	Toxicity Endpoint and Point of Departure Selections

4.5.1	Dose-Response Assessment

A variety of oral toxicity studies were used for the different risk assessment scenarios including the rabbit developmental toxicity study, the acute neurotoxicity study in rats, the rat carcinogenicity study, and the 13-week study in dogs.  In addition, the 28-day inhalation study in rats will now be used for short- and intermediate-term occupational and residential inhalation risk assessments.  The endpoints in these studies are well characterized and are the most sensitive among available comparable toxicity studies in other species.  All dietary endpoints (i.e., acute and chronic RfDs), are calculated from the respective study's NOAEL after applying a 100-fold safety factor (10 X to account for interspecies extrapolation and 10X for intraspecies variation).  For all other scenarios, including dermal, inhalation, and incidental oral, an MOE approach will be used with a Level of Concern (LOC) at 100. 

The selected endpoint from the acute neurotoxicity study of 300 mg/kg/day for the acute dietary (general population) risk assessment is appropriate because the decreased body weight gain in males occurred during the first week after a single oral high dose of 1000 mg/kg. 

The rabbit developmental toxicity study findings are used for endpoint selections for acute dietary (Females 13+) as well as for short- and intermediate-term dermal exposures.  For the acute dietary endpoint (Females 13+), the rabbit developmental findings of increased resorptions/post-implantation loss at the LOAEL of 10 mg/kg/day are assumed to occur following a single in utero exposure.  These effects were dose-dependently increased at the next (high) dose of 20 mg/kg/day.  The same study and developmental endpoint are used for short- and intermediate-term dermal exposures after applying a dermal absorption factor of 14%.  Additionally, the maternal endpoints of decreased body weight gain and decreased food intake and food efficiency were found at the LOAEL of 10 mg/kg/day.  This selection mitigates any concern from the observed developmental toxicity findings in rabbits which are not assessed in the rat dermal toxicity study.

The rat carcinogenicity study findings are used for endpoint selections for chronic dietary and dermal exposures based on findings of decreased body weight/gain and kidney tubular casts/atrophy in both sexes in addition to liver necrosis and stomach lesions in males at the high dose (LOAEL) of 9.2 mg/kg/day.  This study has the lowest NOAEL (3.4 mg/kg/day) in the most sensitive species following chronic exposure.  The dermal absorption factors of 14% will be applied to the dermal long-term risk scenario.

The short- and intermediate-term incident oral exposures are from the subchronic toxicity study in the dog, and are based increased incidence of diarrhea, clinical chemistry changes, duodenum mucosal hypertrophy, and decreased body weight and food intake/efficiency at a LOAEL of 12.9 mg/kg/day, with an oral NOAEL of 5.8 mg/kg/day.

The short-, intermediate-, and long-term inhalation exposures are based on the 28-day inhalation toxicity study in rats which had dose-dependent adverse findings in the respiratory system and duodenum.  The study's oral equivalents NOAEL/LOAEL are 0.23/6.92 mg/kg/day (corresponding to study's air concentration of 0.001/0.03 mg/L air).  The findings are well characterized in that the severity, frequency, and location (e.g., along the respiratory tract) are dose-dependent ranging from no effects at the NOAEL of 0.001 mg/L air to severe respiratory effects and death at the highest dose of 0.3 mg/L air.

4.5.2	Recommendation for Combining Routes of Exposure for Risk Assessment

As per FQPA, 1996, when there are potential residential exposures to a pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures.  When common toxicity endpoints are selected for these routes of exposure they may be aggregated.  Aggregate assessments are required for acute and chronic dietary (food + water) exposures, and short-term residential exposures (i.e., chronic dietary plus incidental oral and dermal exposures).

Residential short-/intermediate-term dermal exposure for adults and toddlers were assessed using the NOAEL (5 mg/kg/day) from the rabbit developmental study.  While the developmental effect of increased resorptions is not applicable to toddlers, it should be noted that the maternal NOAEL from this study is also 5 mg/kg/day, and is based on reduced body weight gain, food consumption, and food efficiency at the LOAEL of 10 mg/kg/day; this more relevant endpoint was used to assess toddler dermal exposure.  For incidental oral ingestion, exposure was assessed using the endpoint from a 13-week feeding study in the dog.  The NOAEL from this study is 5.8 mg/kg/day, based on increased incidence of diarrhea, clinical chemistry changes, duodenum mucosal hypertrophy, and decreased body weight and food intake/efficiency at the LOAEL of 12.9 mg/kg/day.  A common effect (i.e., decreased body weight gain, food intake, and food efficiency) was seen in the studies selected to evaluate toddler dermal and incidental oral ingestion exposure; therefore, route-specific MOEs were aggregated for toddlers. 

4.5.3	Cancer Classification and Risk Assessment Recommendation

Pyraclostrobin was classified by the Cancer Assessment Review Committee (CARC) as "Not Likely to be Carcinogenic to Humans" based on adequate carcinogenicity and mutagenicity studies (CARC 01 FEB 2007).

4.5.4	Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

Table 4.5.4.1: 	Summary of Toxicological Doses and Endpoints for use in Dietary and Non-Occupational Human Health Risk Assessments
Exposure Scenario
Point of Departure (PoD)
Uncertainty / FQPA Safety Factors
RfD, PAD, Level of Concern for Risk Assessment
Study and Toxicological Effects
Acute Dietary
General population (including infants and children)
NOAEL = 
300 mg/kg/day
UFA = 10x
UFH = 10x
FQPA = 1x

aRfD =
3.0 mg/kg/day

aPAD = 
3.0 mg/kg/day

Acute Neurotoxicity  -  Rat
LOAEL = 1000 mg/kg/day based on decreased body weight gain in males.
Acute Dietary,
Females (13-49 years old)
NOAEL = 
5.0 mg/kg/day
UFA = 10x
UFH = 10x
FQPA = 1x

aRfD =
0.05 mg/kg/day

aPAD = 
0.05 mg/kg/day

Developmental Toxicity  -  Rabbit
LOAEL = 10.0 mg/kg/day based on developmental toxicity findings of increased resorptions.
Chronic Dietary
NOAEL = 
3.4 mg/kg/day
UFA = 10x
UFH = 10x
FQPA = 1x
cRfD = 
0.034 mg/kg/day

cPAD = 
0.034 mg/kg/day
Carcinogenicity  -  Rat
LOAEL = 9.2 mg/kg/day based on decreased body weight/body weight gain, kidney tubular casts and atrophy in both sexes; increased incidence of liver necrosis and erosion/ulceration of the glandular- stomach and fore-stomach in males.

Incidental Oral 
Short Term 
(1-30 days)

Intermediate Term
(1-6 months)

Oral NOAEL = 
5.8 mg/kg/day
UFA = 10x
UFH = 10x
FQPA = 1x

Residential LOC for MOE = 100
Subchronic Toxicity  -  Dog
LOAEL = 12.9 mg/kg/day based on increased incidence of diarrhea, clinical chemistry changes, duodenum mucosal hypertrophy, and decreased body weight and food intake/efficiency.

Dermal 
Short Term 
(1-30 days)

Intermediate Term
(1-6 months)

Oral NOAEL = 
5.0 mg/kg/day

(Dermal Absorption Rate = 14%)
UFA = 10x
UFH = 10x
FQPA = 1x

Residential LOC for MOE = 100
Developmental Toxicity  -  Rabbit
LOAEL = 10.0 mg/kg/day based on developmental toxicity findings of increased resorptions and maternal toxicity based on decreased body weight gain and decreased food intake/efficiency.

Dermal
Long Term
(>6 months)
Oral NOAEL =
3.4 mg/kg/day

(Dermal Absorption Rat = 14%)
UFA = 10x
UFH = 10x
FQPA = 1x

Residential LOC for MOE = 100
Carcinogenicity  -  Rat
LOAEL = 9.2 mg/kg/day based on decreased body weight/body weight gain, kidney tubular casts and atrophy in both sexes; increased incidence of liver necrosis and erosion/ulceration of the glandular- stomach and fore-stomach in males.

Inhalation 
Short Term 
(1-30 days)

Intermediate Term
(1-6 months)

Long Term
(>6 months)

NOAEL = 
0.23 mg/kg/day

(Air Concentration = 0.001 mg/L)

UFA = 10x
UFH = 10x
FQPA = 1x

Residential LOC for MOE = 100
Inhalation Toxicity  -  Rat
LOAEL = 6.9 mg/kg/day (air concentration = 0.03 mg/L) based on duodenum mucosal hyperplasia and respiratory system findings including alveolar histiocytosis and olfactory atrophy/necrosis in nasal tissue.
Cancer (oral, dermal, and inhalation)
Classification: "Not likely to be Carcinogenic to Humans" based on the absence of significant tumor increases in two adequate rodent carcinogenicity studies.

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.

Table 4.5.4.2: 	Summary of Toxicological Doses and Endpoints for use in Occupational Human Health Risk Assessments
Exposure Scenario
Point of Departure (PoD)
Uncertainty / FQPA Safety Factors
Level of Concern for Risk Assessment
Study and Toxicological Effects
Dermal 
Short Term 
(1-30 days)

Intermediate Term
(1-6 months)

Oral NOAEL = 
5.0 mg/kg/day

(Dermal Absorption Rate = 14%)
UFA = 10x
UFH = 10x
FQPA = 1x

Residential LOC for MOE = 100
Developmental Toxicity  -  Rabbit
LOAEL = 10.0 mg/kg/day based on developmental toxicity findings of increased resorptions and maternal toxicity based on decreased body weight gain and decreased food intake/efficiency.

Dermal
Long Term
(>6 months)
Oral NOAEL =
3.4 mg/kg/day

(Dermal Absorption Rat = 14%)
UFA = 10x
UFH = 10x
FQPA = 1x

Residential LOC for MOE = 100
Carcinogenicity  -  Rat
LOAEL = 9.2 mg/kg/day based on decreased body weight/body weight gain, kidney tubular casts and atrophy in both sexes; increased incidence of liver necrosis and erosion/ulceration of the glandular- stomach and fore-stomach in males.

Inhalation 
Short Term 
(1-30 days)

Intermediate Term
(1-6 months)

Long Term
(>6 months)

NOAEL = 
0.23 mg/kg/day

(Air Concentration = 0.001 mg/L)

UFA = 10x
UFH = 10x
FQPA = 1x

Residential LOC for MOE = 100
Inhalation Toxicity  -  Rat
LOAEL = 6.9 mg/kg/day (air concentration = 0.03 mg/L) based on duodenum mucosal hyperplasia and respiratory system findings including alveolar histiocytosis and olfactory atrophy/necrosis in nasal tissue.
Cancer (oral)
Classification: "Not likely to be Carcinogenic to Humans" based on the absence of significant tumor increases in two adequate rodent carcinogenicity studies.

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. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

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 (HED MARC, DP278044, L. Cheng, 10/9/01).  HED has concluded that the residues of concern in plants include pyraclostrobin and its desmethoxy metabolite (BF 500-3) for purposes of tolerance enforcement and risk assessment.  For livestock commodities, HED has determined that for purposes of tolerance setting and risk assessment the residues of concern consist of pyraclostrobin and its metabolites convertible to 1-(4-chlorophenyl)-1H-pyrazol-3-ol (BF 500-5) and 1-(4-chloro-2-hydroxyphenyl)-1H-pyrazol-3-ol (BF 500-8).  

For drinking water, the residue of concern for pyraclostrobin is the parent only.

Table 5.1. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression.
Matrix
                     Residues included in Risk Assessment
                   Residues included in Tolerance Expression
Plants
Primary Crop
                               parent, BF 500-3
                               parent, BF 500-3

Rotational Crop
                               parent, BF 500-3
                               parent, BF 500-3
Livestock
Ruminant
                          parent, BF 500-5, BF 500-8
                          parent, BF 500-5, BF 500-8

Poultry
                          parent, BF 500-5, BF 500-8
                          parent, BF 500-5, BF 500-8
Drinking Water
                                  parent only
                                Not Applicable

5.2	Food Residue Profile

Field trial data on sugarcane (MRID 48237401), artichoke (MRID 48897401), Belgium endive (MRID 48897402), and persimmon (MRID 48897403) have been submitted to support the proposed tolerances.  These data are adequate to support dietary risk assessment as well as the proposed tolerances of pyraclostrobin on sugarcane, artichoke, Belgium endive, and persimmon.  The number and geographic distribution of the field trials are adequate.  The analytical method was demonstrated to be acceptable via concurrent recoveries of fortified control samples.  The intervals of frozen storage of samples are covered by previous storage stability studies, and no corrections for loss of residue are needed.  The trials were conducted according to the proposed labels (single and seasonal application rates, PHI).  Summaries of the residue data from the crop field trials are presented in Appendix D, Table D-1 through D-4.

A processing study was submitted for sugarcane (MRID 48237401).  The study is adequate.  Residues of pyraclostrobin and BF 500-3 did not concentrate in blackstrap molasses or refined sugar, relative to the concentration in the raw agricultural commodity (sugarcane).  Therefore, tolerances are not necessary for these processed commodities.

Greenhouse Grown Tomato Transplants Grown for Home Consumer Market
BASF Corporation has requested the addition of greenhouse tomato use for commercial production and for tomato transplants grown for the home consumer market to the Pageant(TM) Fungicide label (EPA Reg. No. 7969-251).  This product is identical to Pristine(TM) Fungicide (EPA Reg. No. 7969-199), which includes use on greenhouse tomatoes, but does not cover tomato transplants for consumers or use of lath type structures.  No residue chemistry data were submitted with this request.

Residues on tomato fruits from such use of Pristine(TM) Fungicide (EPA Reg. No. 7969-199) for tomato transplants in green house, lath house, and other production structures would be expected to be less than those found in the greenhouse trials supporting the approved greenhouse use.  The existing tolerance for fruiting vegetables will cover the requested new uses of the Pageant(TM) Fungicide (EPA Reg. No. 7969-251) formulation.

Residential Use of FT09 (EPA File Symbol 4-UII) on Pome Fruit, Stone Fruit, and Tree Nuts
The submitted use directions are sufficient to allow for evaluation of the proposed residential use of FT09 based on comparison to the existing BASF Pristine[(R)] label for agricultural uses.  The BASF formulation is a water dispersible granule.  It is a solid material that forms a dispersion when mixed with water.  The Bonide formulation is a suspension concentrate or suspension of solid materials in water.  It also will form a dispersion when mixed with water.  The formulations are expected to behave similarly when applied in the same manner (same rate) to crops.  The Organization of Economic Cooperation and Development (OECD) Crop Field Trial Guidance recognizes such formulations as yielding the same residues at PHIs greater than 7 days.  All relevant Bonide PHIs exceed 7 days, and therefore the resulting residues based on formulation will not be greater than residues from the BASF formulation.

The PHIs for the Bonide formulation are equal to or longer/greater than the BASF Pristine(R) formulation PHIs.  Therefore, residues from use on the Bonide formulation are anticipated to be no more than or less than residues from the BASF formulation, based on comparison of the PHIs.  

The application rates (lbs ai/A) for the Bonide formulation, both per application and per season, are approximately equal to or less than the corresponding application rates for the BASF Pristine(R) formulation.  Therefore, residues from the use of the Bonide formulation are anticipated to be no more than or less than residues from the BASF formulation, based on comparison of the application rates.

Residential use of the Bonide FT09 per the proposed label will not yield residues in excess of those from agricultural use of the BASF formulation Pristine[(R)] per the approved label.  

Livestock
The livestock feedstuff associated with the proposed uses in these petitions is sugarcane blackstrap molasses.  Sugarcane blackstrap molasses is a carbohydrate concentrate (CC) feed item for dairy cattle and beef cattle and may comprise up to 10% of the diet of each.  The processing factor for conversion of sugarcane to blackstrap molasses is 0.3X (S. Funk, 48237401.der2).  No significant changes to the dietary burden result from the present considerations.  No changes to the existing livestock tolerances are indicated.  Additionally, sugarcane blackstrap molasses is not a poultry or swine feed item.

Rotational Crops
An adequate confined rotational crop study was reviewed in PP#0F6139 (DP278668, L. Cheng, 11/28/01).  The study showed that the metabolism of pyraclostrobin in rotated crops is similar but more extensive than that in primary crops.  Pyraclostrobin undergoes demethoxylation to yield BF 500-3, followed by further degradation to medium polar and polar metabolites, and subsequent conjugation reactions and incorporation into natural products.  The HED MARC has determined that the residues of concern in rotational crops consist of pyraclostrobin and metabolite BF 500-3.

A limited field rotational crop study was reviewed in PP#0F6139.  The results indicate that residues of pyraclostrobin and its metabolite BF 500-3 were each less than the method LOQ (<0.02 ppm) in/on rotational crop matrices (radish, roots and tops; cabbage, with and without wrapper leaves; and wheat forage, hay, and grain) planted 14 days following the last of six sequential foliar applications to the primary crop, cucumbers, of the 2 lb/gal EC formulation at 0.19 - 0.20 lb ai/A/application.  Residues of pyraclostrobin in/on one sample of wheat straw from the CA test site were at the LOQ (0.02 ppm), but residues of pyraclostrobin in/on a replicate sample from the same plot were below the LOQ (0.012 ppm) for an average residue of <0.02 ppm.  Residues of metabolite BF 500-3 were nondetectable (<0.02 ppm) in/on all samples of wheat straw.

The registered pyraclostrobin end-use product labels presently specify a 14-day plantback interval restriction for all crops that are not registered.  

5.3	Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by EFED (D403871, D405066, F. Khan, 04/04/2013) and incorporated directly into the dietary assessment.  Water residues were incorporated in the DEEM-FCID into the food categories "water, direct, all sources" and "water, indirect, all sources."

For surface water, the EDWCs were generated using EFED's standard suite of models.  Pesticide Root Zone Model (PRZM v3.12.2, May 12, 2005) and Exposure Analysis Modeling System (EXAMS v2.98.04.06, Apr. 25, 2005) are simulation models coupled with the input shell PRZM/EXAMS (PE v5.0, Nov. 15, 2006) to generate EDWCs of pyraclostrobin residues that may occur in surface water for drinking water.  For ground water, Screening Concentration in Ground Water (SCI-GROW v2.3, Jul. 29, 2003) is a regression model used as a screening tool to estimate pesticide concentrations found in ground water used as drinking water.  In addition, Tier 1 ground water EDWCs for pyraclostrobin, resulting from its use on various crops were also derived using the PRZM-GW model (Pesticide Root Zone Model for Groundwater, version 1.0, August 31, 2012), with the GW-GUI (Graphical User Interface, version 1.0, August 31, 2012).  

For the proposed uses of pyraclostrobin, the use on fruiting vegetables resulted in the highest surface water concentrations at 16.6 ug/L for the 1-10 year peak value from ground application and at 1.1 ug/L for the 1-10 annual year average value from aerial application.  The acute and chronic EDWCs resulting from the proposed application uses are lower than the EDWCs for surface water in the previously recommended drinking water assessments for pyraclostrobin for turf uses (USEPA 2007 D389729+).  Since the EDWCs for surface water for proposed uses are lower than the previously recommended EDWCs for this chemical, the EDWCs for surface water will not supersede the EDWCs previously recommended for turf use.

Table 5.3 provides a summary of the estimated concentrations of pyraclostrobin in surface water.  In the acute analysis, the 1-in-10 year peak surface water value of 35.6 ppb was used and in the chronic analysis the surface water value of 2.3 ppb was used.  Estimates of pyraclostrobin concentration in drinking water were less for ground water sources.  The models and their descriptions are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/. 

Table 5.3.  EDWCs of Pyraclostrobin 
                                 Crop Scenario
         PRZM/EXAMS Estimated Concentrations in Surface Water (g/L)
                                       
                               Acute[1] (ug/L)
                                Chronic (ug/L)
                                 Surface Water
NJ Nursery (no irrigation) Turf
                                     35.6
                                      2.3
                                Ground Water[2]
N/A
                                     0.06
                                     0.02
1 These are the highest EDWCs for previously evaluated use scenarios and the estimated acute and annual average surface water concentrations were 35.6 and 2.3 ug/L respectively.  Previously estimated ground water concentrations for acute was 0.02 ug/L 2007, D389729. 
[2] EDWCs based on PRZM-GW model

5.4	Dietary Risk Assessment

5.4.1	Description of Residue Data Used in Dietary Assessment

The dietary exposure analysis incorporates all current and proposed tolerances for residues of pyraclostrobin, including its metabolites and degradates.  

A slightly refined acute dietary exposure assessment was performed for pyraclostrobin.  The analysis used tolerance-level residues or highest field trial residues and empirical or default processing factors.  Experimentally derived processing factors were used for fruit juices, tomato, sugarcane, and wheat commodities.  For all other processed commodities, DEEM default processing factors were assumed.  Estimated drinking water concentrations (EDWCs) were also used.  The estimated acute drinking water concentration for pyraclostrobin (0.0356 ppm) was calculated based on a turf scenario for surface water.  

A refined chronic dietary analysis was conducted for this assessment, since some refinement was needed for the aggregate assessment.  The chronic dietary analysis included tolerance-level or average field trial residues, average percent crop treated estimates (2012) when available, and empirical processing factors.  Screening level estimates of agricultural uses of pyraclostrobin were provided by the Biological & Economic Analysis Division (BEAD).  Experimentally derived processing factors were used for fruit juices, tomato, sugar cane, and wheat commodities.  For all other processed commodities, DEEM default processing factors were assumed.  The estimated drinking water concentration for pyraclostrobin (0.0023 ppm) was calculated based on a turf scenario for surface water.  

Pyraclostrobin is classified as "not likely to be carcinogenic to humans".  Therefore, a cancer dietary exposure assessment was not conducted.

5.4.2	Percent Crop Treated Used in Dietary Assessment

The acute dietary assessment was based on 100% crop treated (%CT).

BEAD provided updated percent crop treated information for pyraclostrobin (S. Haddad, 11/18/2012).  For the chronic analyses, average %CT was incorporated.  One hundred percent crop treated was assumed for commodities with no %CT information, including sugarcane and Belgium endive. 

The following average percent crop treated estimates were used in the chronic dietary risk assessments for the crops that are currently registered for pyraclostrobin:  almonds 40%; apples 15%; apricots 25%; barley 10%; green beans 5%; blueberries 45%; broccoli 5%; cabbage 10%; caneberries 50%; cantaloupes 15%; carrots 35%; cauliflower 2.5%; celery 2.5%; cherries 50%; corn 10%; cotton 2.5%; cucumber 5%; dry beans/peas 10%; garlic 15%; grapefruit 25%; grapes 30%; hazelnuts (filberts) 15%; lemons 2.5%; lettuce 5%; nectarines 10%; onions 20%; oranges 5%; peaches 20%; peanuts 25%; pears 15%; green peas 5%; pecans 2.5%; peppers 10%; pistachios 30%; plums/prunes 5%; potatoes 15%; pumpkins 20%; soybeans 5%; spinach 5%; squash 15%; strawberries 65%; sugar beets 45%; sweet corn 5%; tangelos 15%; tangerines 10%; tomatoes 25%; walnuts 1%; watermelons 30%; wheat 5%.  

5.4.3	Acute Dietary Risk Assessment

The results of the acute dietary analysis for food and drinking water indicate that acute dietary risks are not of concern (<100% of the aPAD) for the U.S. population and all subgroups.  Combined dietary exposure from food and drinking water at the 95[th] percentile of exposure for the U.S. population is equivalent to 1.5% of the acute Population Adjusted Dose (aPAD).  The population subgroup with the highest estimated acute dietary exposure to pyraclostrobin is females 13-49 years, with an estimated exposure of 87% of the aPAD at the 95[th] percentile.

5.4.4	Chronic Dietary Risk Assessments

The results of the refined chronic dietary (food and drinking water) analysis are below the Agency's level of concern for all population subgroups.  The dietary exposure for food and drinking water for the general U.S. population is 8.0% of the chronic Population Adjusted Dose (cPAD) and 27% of the cPAD for children 1-2 years old, the population subgroup with the highest estimated chronic dietary exposure to pyraclostrobin.

5.4.5	Summary Table

 Table 5.4.5.  Summary of Dietary Exposure and Risk for Pyraclostrobin Food & Drinking Water.
 Population Subgroup
                                 Acute Dietary
                               (95th Percentile)
                                Chronic Dietary
                                        
                          Dietary Exposure (mg/kg/day)
                                     % aPAD
                                Dietary Exposure
                                  (mg/kg/day)
                                     % cPAD
 General U.S. Population
                                    0.044721
                                      1.5
                                    0.002707
                                      8.0
 All Infants (< 1 year old)
                                    0.061716
                                      2.1
                                    0.004353
                                       13
 Children 1-2 years old
                                    0.083049
                                      2.8
                                    0.009206
                                       27
 Children 3-5 years old
                                    0.074666
                                      2.5
                                    0.006204
                                       18
 Children 6-12 years old
                                    0.044251
                                      1.5
                                    0.003525
                                       10
 Youth 13-19 years old
                                    0.031506
                                      1.0
                                    0.001832
                                      5.4
 Adults 20-49 years old
                                    0.041724
                                      1.4
                                    0.002224
                                      6.5
 Adults 50-99 years old
                                    0.041722
                                      1.4
                                    0.002252
                                      6.6
 Females 13-49 years old
                                    0.043481
                                      87
                                    0.002005
                                      5.9
*The subpopulations with the highest risk estimates are bolded.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

The proposed residential uses for pyraclostrobin will result in residential handler and post-application exposures.  In addition, the existing use on residential turf (Insignia Fungicide label; EPA Reg. No. 7969-184) was reassessed in this document to reflect updates to HED's 2012 Residential SOPs along with policy changes for body weight assumptions, since the revisions to these exposures could impact the human health aggregate risk assessment for pyraclostrobin.  Registered and proposed products do not lead to any residential handler or post-application risk estimates of concern.


6.1	Residential Handler Exposure

The residential handler assessment includes short-term exposures via the dermal and inhalation routes.  Exposures occur from treating gardens, trees, and turf.  

HED's LOC for the MOE is defined by the uncertainty factors that are applied to the assessment.  HED applies a 10X factor to account for variability among species and a 10X factor to account for variability within species.  The total uncertainty factor that has been applied to the non-cancer assessment of pyraclostrobin is 100X for residential exposure.  Residential exposure and risk resulting in MOEs greater than or equal to 100 will not be of concern to HED (LOC = 100).  

Summaries of the inhalation and dermal risk estimates for residential handlers are included in Table 6.1.  The maximum application rate for each exposure scenario is presented as the worst case scenario.  The residential handler dermal MOEs range from 740 (hose end turf application of WDG formulation) to 13,000 (hose end sprayer application to trees using a liquid formulation).  The residential handler inhalation MOEs range from 590 (manually pressurized handwand turf application of WDG formulation) to 3,400,000 (hose end sprayer application to trees using a liquid formulation).  The dermal and inhalation risks to handlers are not of concern to HED for any of the residential handler scenarios.



Table 6.1.  Residential Handler Non-cancer Exposure and Risk Estimates for Pyraclostrobin.
                              Exposure Scenario 
                               Level of Concern
                        Dermal Unit Exposure (mg/lb ai)
                      Inhalation Unit Exposure (mg/lb ai)
                          Maximum Application Rate[1]
                    Area Treated or Amount Handled Daily[2]
                                    Dermal
                                  Inhalation






                                     Dose 
                                (mg/kg/day)[3]
                                    MOE[4]
                              Dose (mg/kg/day)[5]
                                    MOE[6]
                            Mixer/Loader/Applicator
                            Liquid Garden/Trees : 
                         manually pressurized handwand
                                      100
                                      63
                                     0.018
                               0.0041 lb ai/gal
                                     5 gal
                                    0.0026
                                     1,900
                                   0.0000046
                                    50,000
                            Liquid Garden/Trees : 
                         manually pressurized handwand
                                      100
                                      63
                                     0.018
                             0.0000028 lb ai/ft[2]
                                  1200 ft[2]
                                    0.00043
                                    12,000
                                  0.00000076
                                    300,000
                            Liquid Garden/Trees : 
                               hose-end sprayer
                                      100
                                      58
                                    0.0014
                             0.0000028 lb ai/ft[2]
                                  1200 ft[2]
                                    0.00040
                                    13,000
                                  0.000000059
                                   3,900,000
                            Liquid Garden/Trees : 
                               hose-end sprayer
                                      100
                                      58
                                    0.0014
                               0.0041 lb ai/gal
                                    11 gal
                                    0.0053
                                      940
                                  0.00000079
                                    290,000
                            Liquid Garden/Trees : 
                               backpack sprayer
                                      100
                                      130
                                     0.14
                             0.0000028 lb ai/ft[2]
                                  1200 ft[2]
                                    0.00089
                                     5,600
                                   0.0000059
                                    39,000
                            Liquid Garden/Trees : 
                               backpack sprayer
                                      100
                                      130
                                     0.14
                               0.0041 lb ai/gal
                                     5 gal
                                    0.0054
                                      920
                                   0.000036
                                     6,400
                            Liquid Garden/Trees : 
                                 sprinkler can
                                      100
                                      58
                                    0.0014
                             0.0000028 lb ai/ft[2]
                                  1200 ft[2]
                                    0.00040
                                    13,000
                                  0.000000059
                                   3,900,000
                            Liquid Garden/Trees : 
                                 sprinkler can
                                      100
                                      58
                                    0.0014
                               0.0041 lb ai/gal
                                     5 gal
                                    0.0024
                                     2,100
                                  0.00000036
                                    640,000
                               WDG Lawn/turf : 
                         manually pressurized handwand
                                      100
                                      69
                                      1.1
                               0.0057 lb ai/gal
                                     5 gal
                                    0.0040
                                     1,300
                                    0.00039
                                      590
                                WDG Lawn/turf :
                                hose-end sprayer
                                      100
                                     13.4
                                     0.022
                                  0.5 lb ai/A
                                     0.5 A
                                    0.0068
                                      740
                                   0.000069
                                     3,300
                                WDG Lawn/turf :
                                backpack sprayer
                                      100
                                      69
                                      1.1
                               0.0057 lb ai/gal
                                     5 gal
                                    0.0040
                                     1,300
                                    0.00039
                                      590
                               WDG Lawn/turf : 
                                 sprinkler can
                                      100
                                     13.4
                                     0.022
                             0.000011 lb ai/ft[2]
                                  1000 ft[2]
                                    0.00031
                                    16,000
                                   0.0000032
                                    73,000
1	Based on the proposed garden/tree use on Bonide FT09 label (EPA Reg. No. 4-UII) and registered turf use on Insignia(R) Fungicide label (EPA Reg. No. 7969-184).
2	Based on HED's 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential-exposure-sop.html).
3	Dermal Dose = Dermal Unit Exposure (mg/lb ai) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A/day or gallons/day) x Dermal Absorption Factor (%) / Body Weight (kg).
4	Dermal MOE = Dermal NOAEL (mg/kg/day) / Dermal Dose (mg/kg/day).
5	Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A/day or gallons/day) / BW (kg).
6	Inhalation MOE = Inhalation NOAEL (mg/kg/day) / Inhalation Dose (mg/kg/day).


6.2	Post-Application Exposure

There is the potential for post-application exposure for individuals as result of being in an environment that has been previously treated with pyraclostrobin.  Short-term dermal exposures were assessed for adults, youth 11 to 16 years old, and children 6 to 11 years old.  Short-term dermal and incidental oral exposures were assessed for children 1 to <2 years old.  A series of assumptions and exposure factors served as the basis for completing the residential post-application risk assessment.  Each assumption and factor is detailed in the 2012 Residential SOPs6.

Dislodgeable Foliar Residues
Chemical-specific dislodgeable foliar residue (DFR) data were previously submitted by the registrant to support earlier registration requests for food crops.  An overview of each study was provided in a previous assessment (D269670, K. O'Rourke, 9/30/2002).  Pyraclostrobin DFR studies were conducted on peaches, peanuts, strawberries, grapes.  The Canadian Pesticide Management Regulatory Agency (PMRA) performed the primary review of these data, and considered the results useful for risk assessment purposes; summaries of their reviews and a summary of the DFR study results is provided in a previous HED assessment (D269670, K. O'Rourke, 9/30/2002).  

It should be noted that PMRA only used the DFR data to calculate % dissipation per day and half-lives.  Therefore, HED went back to the initial study to calculate the DFR on day zero based on the results of the DFR study.   The calculated DFR values on day zero were used in the post-application dermal assessments.  The PA peach DFR data, which resulted in the highest DFR values of the three study sites, were used in the residential fruit/nut tree and garden assessments.  The CA strawberry DFR data, which also resulted in the highest DFR values of the three study sites, were used in the residential exposure to retail tomato transplants.  The DFR data used in this assessment are presented in Appendix F, Tables F-1 through F-3.

Turf Transferable Residues
Turf transferrable residue (TTR) data (MRID 45118725) are available from an earlier submission in support of a request for use on golf course turf.  This study was not used in the previous turf exposure assessments because the study used an emulsifiable concentrate formulation, rather than the water dispersible granule formulation that is currently registered.  The effect of formulation type on residue values can be significant.  At that time, HED concluded that using the results from the TTR study may be under protective due to formulation effects (D298017, K. O'Rourke, 8/19/2004).  However, HED has since determined that there is no statistical difference between residues resulting from liquid, wettable powder (applied as a spray), or water dispersible granular (applied as a spray) applications.  Therefore, the residue data from the pyraclostrobin-specific TTR study were used in this assessment (2012 Residential SOPs[6]).  

Combined Risks
Since the toxicological endpoints for dermal and incidental oral exposure routes are based on toxicity studies that have a common effect (i.e., decreased body weight gain and food efficiency), risk estimates have been combined for those routes.  The incidental oral scenarios (i.e., hand-to-mouth, object-to-mouth, and soil ingestion) should be considered inter-related and it is likely that they occur interspersed amongst each other across time.  Combining these scenarios with the dermal exposure scenario would be overly-conservative because of the conservative nature of each individual assessment.  Therefore, the post-application exposure scenarios that were combined for children (1 to <2 years old) are the dermal and hand-to-mouth scenarios.  This combination should be considered a protective estimate of children's exposure to pesticides used on turf.

Summary of Residential Post-application Non-Cancer Exposure and Risk Estimates
All the short-term MOEs for each scenario are greater than the LOC of 100, and therefore, are not of concern. 

Table 6.2. Residential Post-application Non-cancer Exposure and Risk Estimates for Pyraclostrobin.
                                   Lifestage
                      Post-application Exposure Scenario
                              Application Rate[1]
                              Dose (mg/kg/day)[2]
                                    MOEs[3]
                               Combined MOEs[4]
                                       
                                   Use Site
                               Route of Exposure
                                       
                                       
                                       
                                       
                                     Adult
                              Tomato Transplants
                                    Dermal
                                 0.18 lb ai/A
                                       
                             DFR = 0.379 ug/cm[2]
                                    0.0013
                                     3,800
                                      NA
                            Child (6-11 years old)
                                       
                                       
                                       
                                    0.00077
                                     6,500
                                       
                                     Adult
                                    Gardens
                                    Dermal
                                 0.12 lb ai/A
                                       
                             DFR = 0.457 ug/cm[2]
                                     0.017
                                      290
                                       
                            Child (6-11 years old)
                                       
                                       
                                       
                                     0.010
                                      490
                                       
                                     Adult
                              Fruit and Nut Trees
                                    Dermal
                                 0.12 lb ai/A
                                       
                             DFR = 0.457 ug/cm[2]
                                    0.0016
                                     3,200
                                       
                            Child (6-11 years old)
                                       
                                       
                                       
                                    0.00093
                                     5,400
                                       
                                     Adult
                                   Lawn/Turf
                                    Dermal
                                 High contact 
                                  0.5 lb ai/A
                                       
                             TTR = 0.035 ug/cm[2]
                                     0.019
                                      260
                                       
                                       
                                       
                                    Dermal
                                  Mowing turf
                                       
                                    0.00039
                                    13,000
                                       
                                       
                                       
                                    Dermal
                                    Golfing
                                       
                                    0.0015
                                     3,300
                                       
                            Youth (11-16 years old)
                                       
                                    Dermal
                                  Mowing turf
                                       
                                    0.00039
                                    13,000
                                       
                                       
                                       
                                    Dermal
                                    Golfing
                                       
                                    0.0015
                                     3,300
                                       
                            Child (6-11 years old)
                                       
                                    Dermal
                                    Golfing
                                       
                                    0.0018
                                     2,800
                                       
                           Child (1< 2 years old)
                                       
                                    Dermal
                                 High contact 
                                       
                                     0.033
                                      150
                                      130
                                       
                                       
                                Incidental Oral
                                 Hand to mouth
                                       
                                    0.0048
                                     1,200
                                       
                                       
                                       
                                Incidental Oral
                                Object to mouth
                                       
                                    0.00015
                                    40,000
                                      NA
                                       
                                       
                                Incidental Oral
                                Soil Ingestion
                                       
                                   0.000017
                                    340,000
                                      NA
1	Based on the proposed garden/tree use on Bonide FT09 label (EPA Reg. No. 4-UII); the proposed tomato transplant use on Pagent(R) Fungicide(EPA Reg. No.7969-251); and the registered turf use on Insignia(R) Fungicide label (EPA Reg. No. 7969-184).
2	Dose (mg/kg/day) equations:
	Dermal Dose (turf)
 	Dermal Dose (gardens/trees)
	Dermal Dose (tomato transplants)
	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 (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 (kg).
	Soil Ingestion = soil residue (ug/g) x ingestion rate (50 mg/day) x conversion factor (0.000001 g/ug) / body weight (11 kg).
	TTR = 0.035 μg/cm[2] (based on pyraclostrobin TTR study)
3	Dermal MOE = Dermal NOAEL (mg/kg/day) / Dermal Dose (mg/kg/day).
	Incidental Oral MOE = Oral NOAEL (mg/kg/day) / Incidental oral Dose (mg/kg/day).
4  Combined MOE = 1 / (1/dermal MOE) + (1/incidental oral MOE), where applicable

6.3	Combined Residential Risk Estimates (Multiple Exposure Scenarios)

Because dermal post-application exposures to treated gardens, fruit or nut trees, tomato transplants, and turf could conceivably co-occur within the same day for adults and children 6 to 11 years old, combined exposures from these scenarios were considered.  However, all four of these use sites/scenarios involved different labeled products, and therefore, the probability of co-occurrence is considered improbable.  Therefore, assessments of these combined exposures were not conducted. 

6.4	Residential Risk Estimates for Use in Aggregate Assessment

Since the toxicity effect from the inhalation route of exposure is different than the effect from the dermal route of exposure, inhalation and dermal exposures are not aggregated together.  Therefore, separate inhalation and dermal aggregate assessments are evaluated.  The scenarios with the highest exposures and corresponding lowest MOEs, provided in Tables 6.1 and 6.2, reflect the residential risk estimates that are recommended for use in the short-term aggregate assessment for pyraclostrobin.  Table 6.4 summarizes the residential risk estimates that are recommended for use in the short-term aggregate assessments for pyraclostrobin.
   * The recommended residential inhalation exposure for use in the adult aggregate assessment reflects inhalation exposure from application of the WDG formulation to turf via manually pressurized handwand or backpack sprayer.
   * The recommended residential dermal exposure for use in the adult aggregate assessment reflects dermal exposure from post-application activities on treated turf. 
   * The recommended residential dermal exposure for use in the child (11-16 yr) aggregate assessment reflects dermal exposure from post-application golfing on treated turf. 
   * The recommended residential dermal exposure for use in the child (6-11 yr) aggregate assessment reflects dermal exposure from post-application activities in treated gardens. 
   * The recommended residential exposure for use in the children (1<2 years old) aggregate assessment reflects dermal and hand-to-mouth exposures from post-application exposure to treated turf.


Table 6.4.  Recommendations for the Residential Exposures for the Pyraclostrobin Short-term Aggregate Assessments.
                                   Lifestage
                               Route of Exposure
                                   Scenario
                                     Dose
                                (mg/kg/day)[4]
                                    MOE[5]
Adult
                                  Inhalation
Applying WDG formulation to turf via manually pressurized handwand or backpack sprayer
                                    0.00039
                                      590

                                    Dermal
Post-application activities on treated turf
                                     0.019
                                      260
Child (11 -16 yr)
                                    Dermal
Post-application golfing on treated turf
                                    0.0015
                                     3,300
Child (6-11 yr)
                                    Dermal
Post-application activities in treated gardens
                                     0.010
                                      490
Child (1<2 years old)
                                   Combined
                          (incidental oral + dermal)
Post-application activities on treated turf
                                     0.038
                                      130

6.5	Residential Bystander Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for pyraclostrobin at this time primarily because of the low vapor pressure (1.9 x 10[-8] mm Hg at 20 degrees) and the low proposed use rate (0.2 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.  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 pyraclostrobin.

6.6	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 pyraclostrobin.  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 (see the Agency's Spray Drift website for more information).  The Agency has completed its evaluation of the new database 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 with specific products with significant risk estimates associated with drift.

It is noted that the 0.5 lb ai/acre application rate for turf was modeled to estimate post-application residential exposure of children.  As this rate is equal to or higher than many of agricultural application rates, this scenario is protective of any exposure of farm children via spray drift from agricultural pyraclostrobin applications.

Although a quantitative residential post-application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers.  This exposure scenario is representative of a worse 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 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 pyraclostrobin, potential exposures from food, drinking water, and residential scenarios were aggregated.  

7.1	Acute Aggregate Risk

The aggregate acute risk estimates include exposure to residues of pyraclostrobin in food and drinking water, and does not include dermal, inhalation, or incidental oral exposure.  The acute risk estimate for the U.S. population and all other population subgroups, resulting from aggregate exposure to pyraclostrobin in food and drinking water, is not of concern.  The food and drinking water exposure estimates are 1.5% of the aPAD for the U.S. general population, and 88% for the most highly exposed subgroup, females 13-49 years old.

47.2 Short-Term Aggregate Risk

There is potential short-term exposure to pyraclostrobin via dietary (which is considered background exposure) and residential (which is considered primary) exposure pathways.  For adults, these pathways lead to exposure via oral (background) as well as dermal and inhalation (primary) routes.  The most conservative scenarios were chosen for each population (e.g., hand-to-mouth exposure from treated turf for children 1-2 years old).  For a description of the residential exposure scenarios considered in the aggregate assessment, see Section 6.4.  

The adult greatest exposure non-cancer aggregate MOE is 230 and is not of concern to HED.  The aggregate MOE for children 1-2 years old, including incidental oral exposures from treated turf, is 120 and is not of concern to HED.  


Table 7.2.1.  Short-/Intermediate-Term Aggregate Risk Calculations 
Population
                                Dermal Exposure
                                 Oral Exposure
                             Total Combined MOE[2]

                                     NOAEL
                                   mg/kg/day
                                   Exposure
                                   mg/kg/day
                                    MOE[1]
                                NOAEL mg/kg/day
                      Incidental Oral Exposure mg/kg/day 
                   Chronic Dietary (Food + Water) mg/kg/day
                                    MOE[1]

                                 Child 1-2 yrs
                                       5
                                     0.033
                                      150
                                      5.8
                                    0.0048
                                   0.009206
                                      630
                                      120
                                Child 6-11 yrs
                                       5
                                     0.01
                                      490
                                       5
                                      NA
                                   0.003525
                                     1,400
                                      360
                                Youth 11-16 yrs
                                       5
                                    0.0015
                                     3,300
                                       5
                                      NA
                                   0.001832
                                     2,700
                                     1,500
                                 Adult Handler
                                       5
                                     0.004
                                     1,300
                                       5
                                      NA
                                   0.002707
                                     1,800
                                      760
                            Adult Post-application
                                       5
                                     0.019
                                      260
                                       5
                                      NA
                                   0.002707
                                     1,800
                                      230
[1] The Level of Concern MOE is 100.
[2] Total Combined MOE = 1/ [(1/MOEDermal) + (1/MOEOral)]

47.3 Intermediate-Term Aggregate Risk

Based on the registered residential uses of pyraclostrobin on residential and golf course turf, intermediate-term post application exposures are possible.  However, since the short- and intermediate-term endpoints and PODs for dermal and oral routes are the same, the short-term exposure and risk estimates are considered to be protective of potential intermediate-term exposure and risk.  

7.4	Chronic Aggregate Risk

Chronic exposure from the residential pathway is not anticipated based on the current pyraclostrobin use pattern. The chronic aggregate risk (food and drinking water) is below HED's LOC (i.e., <100% cPAD for the general U.S. population and all population subgroups).  The dietary exposure is estimated at 0.002944 mg/kg/day for the general U.S. population (8.7% of the cPAD) and 0.009888 mg/kg/day (29% of the cPAD) for children 1-2 years old, the population subgroup with the highest estimated chronic dietary exposure to pyraclostrobin.  See Section 5.4.4 for details.

6.0 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 pyraclostrobin and any other substances and pyraclostrobin 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 pyraclostrobin 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/.


7.0 Occupational Exposure/Risk Characterization

Pyraclostrobin is proposed for new occupational uses on sugarcane, globe artichoke, Belgium endive, persimmon, and greenhouse grown tomatoes.  Application methods, maximum application rates, and use sites are summarized in Section 3.3 and Table 3.3.  Based on the proposed use patterns, there is a potential for short- and intermediate-term occupational exposure to pyraclostrobin during handling (mixing, loading, and applying) and post-application activities.  Pyraclostrobin uses are proposed for multiple applications, with the retreatment intervals ranging from 7 to 28 days.  The proposed labels require occupational handlers to wear the following personal protective equipment (PPE): long-sleeved shirts, long pants, chemical resistant gloves, and coveralls in a few cases.  The 12 hour restricted entry interval (REI) listed on the labels is appropriate.  

9.1	Short-/Intermediate-Term Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide application process.  HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each task.  Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.  

Based on the anticipated use patterns from the proposed labels, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses.  HED's LOC for the MOE is defined by the uncertainty factors that are applied to the assessment.  HED applies a 10X factor to account for variability among species and a 10X factor to account for variability within species.  The total uncertainty factor that has been applied to the non-cancer assessment of pyraclostrobin is 100X for occupational exposure.  Occupational exposure and risk resulting in MOEs greater than or equal to 100 will not be of concern to HED.  Dermal and inhalation exposure estimates were not combined in this assessment, since the toxicological PODs are based on different toxicological effects.

Summaries of the short- and intermediate-term non-cancer risk estimates for occupational handlers applying pyraclostrobin are provided in Appendix E, Tables E-1 and E-2.  The dermal MOEs range from 47 (mixing/loading of SC formulation to support aerial applications to sugarcane) to 7,800 (applying with aerial equipment to typical acreage crops) at baseline PPE.  The proposed labels require occupational handlers to wear the following personal protective equipment (PPE): long-sleeved shirts, long pants, and chemical resistant gloves.  All of the dermal MOEs are greater than the LOC of 100 when assessed using labeled PPE (gloves) and are not a concern to HED.  

The inhalation MOEs range from 33 (mixing/loading of WDG formulation to support aerial and chemigation applications to artichoke and persimmon) to 8,500 (applying with manually pressurized handwand equipment to greenhouse tomatoes) at baseline PPE (no respirator).  The two inhalation scenarios with MOEs below 100 at baseline PPE [mixing/loading of WDG formulation to support aerial and chemigation applications to artichoke and persimmon (MOE=33); and M/L/A of WDG formulation using a mechanically pressurized handgun to treat greenhouse tomatoes (MOE=85)] were no longer a concern to HED when assessed with a PF5 respirator (MOEs >100).  A PF5 respirator needs to be proposed on the affected Pristine Fungicide [EPA Reg. No.7969-199] and Pagent(R) Fungicide [EPA Reg. No.7969-251] labels.

9.2	Short-and Intermediate-Term Post-Application Risk

HED uses the term post-application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re-entry exposure).  Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting.  Post-application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical's degradation properties.  In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post-application exposure. 

9.2.1	Dermal Post-Application Risk

Based on the proposed use patterns, short- and intermediate-term post-application dermal exposures to workers re-entering treated areas is possible.  Therefore, a post-application risk assessment for dermal exposures is needed.  It should be noted that there is no post-application dermal exposure anticipated for the proposed Belgium endive use, because the roots are treated with pyraclostrobin prior to forcing in the trays.  Thus there would be negligible exposure to the residue when the crop is harvested or maintained.

Dislodgeable Foliar Residues
Chemical-specific DFR data was previously submitted by the registrant to support earlier registration requests for food crops.  An overview of each study was provided in a previous assessment (D269670, K. O'Rourke, 9/30/2002).  Pyraclostrobin DFR studies were conducted on peaches, peanuts, strawberries, and grapes.  PMRA performed the primary review of these data, and considered the results useful for risk assessment purposes.  It should be noted that PMRA used the DFR data only to calculate percent dissipation per day and half-lives.  Therefore, HED went back to the initial study to calculate the DFR on day zero based on the results of the DFR study.   The calculated DFR values on day zero were used in the post-application dermal assessments.  The PA peach DFR data, which resulted in the highest DFR values of the three study sites, were used in the persimmon assessment.  The CA strawberry DFR data, which also resulted in the highest DFR values of the three study sites, were used in the artichoke and greenhouse tomato assessments.  The TX peanut DFR data, which resulted in the highest DFR values of the three study sites, were used in the sugarcane assessment.  The peanut DFR data were selected for use in the sugarcane assessment because the climate of regions where both of these crops are grown is very similar.  The DFR data used in this assessment are presented in Appendix F, Tables F-1 through F-3.

Occupational Post-application Non-Cancer Dermal Risk Estimates
The short- and intermediate-term non-cancer post-application risk estimates for workers are provided in Appendix E, Table E-3.  All post-application scenarios resulted in MOEs greater than 100 on day 0 (12 hours after application), and therefore, are not of concern to HED.  The MOEs for pyraclostrobin ranged from 120 to 12,000.

Restricted Entry Interval
The REI specified on the proposed label is based on the acute toxicity of pyraclostrobin. Pyraclostrobin is classified as Toxicity Category III via the dermal route and for skin and eye irritation potential.  It is not a skin sensitizer.  Under 40 CFR 156.208 (c) (2) (iii), ai's classified as Acute III or IV for acute dermal, eye irritation and primary skin irrigation are assigned a 12-hour REI.  Furthermore, the short- and intermediate-term post-application risk estimates were not a concern on day 0 (12 hours following application) for all post-application activities.  Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from post-application exposures to pyraclostrobin.

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 pyraclostrobin at this time primarily because of the low vapor pressure (1.9 x 10[-8] mm Hg at 20 degrees C) and the low proposed use rate (0.2 lb ai/A).  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields.  These potential sources include volatilization of pesticides and resuspension of dusts and/or 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. The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for pyraclostrobin.

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

S. Funk, 4/30/13, DP403449.  Pyraclostrobin:  Request for the Use on Sugarcane.  Summary of Analytical Chemistry and Residue Data.

S. Funk, 4/30/13, DP398877.  Boscalid and Pyraclostrobin:  Application by Bonide Products, Inc. to Register an End Use Product Containing Pyraclostrobin, Boscalid, and Lambda Cyhalothrin for Homeowner Use on Pome Fruit, Stone Fruit, and Tree Nuts.  

S. Funk, 4/30/13, DP406471.  Pyraclostrobin and Boscalid:   Request to Add Indoor Use on Greenhouse Tomato for Commercial Production and on Greenhouse/Lathhouse Transplants for Consumer Home Market. Pagent(TM) Fungicide Reg. No. 7969-251.

S. Funk, 6/24/13, DP410737.  Amended: Pyraclostrobin:  Petition for the Establishment of Permanent Tolerances and Registration for Use on Belgium Endive, Persimmon, and Globe Artichoke. Request for Crop Group Expansions/Revisions for Bulb Vegetable Group 3-07, Fruiting Vegetable 8-10,  Citrus Fruit Group 10-10, Pome Fruit Group 11-10, Berry Subgroups 13-07A, B, F, and G, and Oilseed Group 20. Summary of Analytical Chemistry and Residue Data

S. Funk, 4/30/13, DP410739.  Pyraclostrobin. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments to Support New Uses on Sugarcane, Persimmon, Globe Artichoke, and Belgium Endive.

C. Walls, 4/30/13, DP403449.  Pyraclostrobin.  Occupational and Residential Exposure Assessment for proposed new uses of pyraclostrobin on sugarcane, globe artichoke, Belgium endive, persimmon, greenhouse grown tomato transplants grown for home consumer market, and residential ornamentals, landscape gardens, fruit trees and nut trees.

F. Khan, 4/4/13, DP403871.  Addendum of Drinking Water Exposure Assessment for the Section 3 New Uses of Pyraclostrobin on Various Agricultural Crops and Residential Ornamentals.

S. Haddad, 11/18/2012, SIAB/BEAD, Screening Level Estimates of Agricultural Uses (SLUA) for the Fungicide Pyraclostrobin (099100)


Appendix A.  Toxicology Profile and Executive Summaries

A.1	Toxicology Data Requirements

The requirements (40 CFR 158.500) for food uses are in the table below. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1: Toxicology Studies
                                   Required
                                   Submitted
                                   Satisfied
870.1100	Acute Oral Toxicity	
870.1200	Acute Dermal Toxicity	
870.1300	Acute Inhalation Toxicity	
870.2400	Acute Eye Irritation	
870.2500	Acute Dermal Irritation	
870.2600	Skin Sensitization	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.3100	90-Day Oral Toxicity in Rodents	
870.3150	90-Day Oral Toxicity in Non-Rodents	
870.3200	21/28-Day Dermal Toxicity	
870.3250	90-Day Dermal Toxicity	
870.3465	90-Day Inhalation Toxicity	
                                      yes
                                      yes
                                      yes
                                    no (CR)
                                   yes (CR)
                                      yes
                                      yes
                                      yes
                                      no
                                      yes
                                      yes
                                      yes
                                      yes
                                      ---
                                      yes
870.3700	Prenatal Developmental Toxicity Study (Rodent)	
870.3700	Prenatal Developmental Toxicity Study (Non-Rodent)	
870.3800	Reproduction and Fertility Effects	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.4100	Chronic Toxicity (Rodent)	
870.4100	Chronic Toxicity (Non-Rodent)	
870.4200	Carcinogenicity (Two Rodent Species; Rat and Mouse)	
870.4300	Combined Chronic Toxicity/Carcinogenicity	
                                      yes
                                      no
                                      yes
                                      no
                                      yes
                                      yes
                                      yes
                                      no
                                      yes
                                      ---
                                      yes
                                      yes
870.5100	Bacterial Reverse Mutation Test	
870.5300	in vitro Mammalian Cell Gene Mutation Test	
870.5375	in vitro Mammalian Chromosome Aberration Test	
870.5385	Mammalian Bone Marrow Chromosomal Aberration Test	
870.5395	Mammalian Erythrocyte Micronucleus Test	
870.5550	Unscheduled DNA Synthesis in Mammalian Cells in Culture	
                                      yes
                                      yes
                                      yes
                                      ---
                                    yes
no
                                      yes
                                      yes
                                      yes
                                      no
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      ---
                                      yes
                                      ---
870.6100	Delayed Neurotoxicity of Organophosphorus Substances (Acute, Hen)	
870.6100	Delayed Neurotoxicity of Organophosphorus Substances (28-Day, Hen)	
870.6200	Neurotoxicity Screening Battery (Acute, Rat)	
870.6200	Neurotoxicity Screening Battery (Subchronic, Rat)	
870.6300	Developmental Neurotoxicity Study	
                                    no (CR)
                                    no (CR)
                                      yes
                                      yes
                                    no (CR)
                                      no
                                      no
                                      yes
                                      yes
                                      no
                                      ---
                                      ---
                                      yes
                                      yes
                                      ---
870.7200	Companion Animal Safety	
870.7485	Metabolism and Pharmacokinetics	
870.7600	Dermal Penetration	
	in vitro Dermal Penetration	
870.7800	Immunotoxicity	
                                    no (CR)
                                      yes
                                    no (CR)
                                      no
                                      yes
                                      no
                                      yes
                                      yes
                                      no
                                      yes
                                      ---
                                      yes
                                      ---
                                      ---
                                      ---
CR: Conditionally Required

A.2	Toxicity Profiles

 Table A.2.1.  Acute Toxicity of Pyraclostrobin
 
Table A.2.1: Acute Toxicity Profile
                                   Guideline
                                  Study Type
                                     MRID
                                    Results
                               Toxicity Category
                                   870.1100
Acute Oral Toxicity
                                   45118302
LD50 >= 5000 mg/kg
                                      IV
                                   870.1200
Acute Dermal Toxicity
                                   45118305
LD50 >2000 mg/kg
                                      III
                                   870.1300
Acute Inhalation Toxicity
                                   45118308
0.31 mg/L < LC50 < 1.07 mg/L
                                      II
                                   870.2400
Acute Eye Irritation
                                   45118311
Minimal Eye Irritation
Maximum Average Score (MAS): 4.6 / 110
24 hr Maximum Irritation Score (MIS): 6.3 / 110
                                      III
                                   870.2500
Acute Dermal Irritation
                                   45118314
Moderate Skin Irritation
Maximum Average Score (MAS): 2.2 / 8.0
24 h Maximum Irritation Score (MIS): 2.7 / 8.0
                                      III
                                   870.2600
Dermal Sensitization
                                   45118317
Not a dermal sensitizer
                                      N/A
 
 Table A.2.2.  Non-acute Toxicity Profile for Pyraclostrobin
 
Table A.2.2. Subchronic, Chronic, and Other Toxicity Profiles
                                   Guideline
                                  Study Type
                     MRID (year) / Doses / Classification
                                    Results
                                   870.3050
Repeated Dose 
28-Day Oral Toxicity in Rodents (Rat)

45118322 (1999)
Dietary Concentration (ppm):
		0,	20,	100,	500, 	1500
Intake Dose (mg/kg/day):
	M:	0,	1.8,	9.0,	42.3, 	120.2
	F:	0,	2.0,	9.6,	46.6, 	126.3
Acceptable / Guideline

NOAEL (mg/kg/day):	M =	9.0	F =	9.6
LOAEL (mg/kg/day):	M =	42.3	F =	46.6
Based on changes in hematology parameters, increased spleen weight (both absolute and relative), and histopathology in the spleen and liver, in addition to increased duodenal mucosal hyperplasia. 
                                   870.3100
90-Day Oral Toxicity in Rodents (Rat)
45118321 (1999)
45118322 (1999)  -  Dose Selection
Dietary Concentration (ppm):
		0,	50,	150,	500, 	1000	1500
Intake Dose (mg/kg/day):
	M:	0,	3.5,	10.7,	34.7, 	68.8,	105.8
	F:	0,	4.2,	12.6,	40.8, 	79.7, 	118.9
Acceptable / Guideline

NOAEL (mg/kg/day):	M =	10.7	F =	12.6
LOAEL (mg/kg/day):	M =	34.7	F =	40.8
Based on decreased body weights/body weight gains (males), decreased food consumption, increased relative liver weight and absolute and relative spleen weight in females, and histopathology of the duodenum, spleen and liver.

                                       
90-Day Oral Toxicity in Rodents (Mouse)
45118320 (1999)
Dietary Concentration (ppm):
		0,	50,	150,	500, 	1000	1500
Intake Dose (mg/kg/day):
	M:	0,	9.2,	30.4,	119.4, 	274.4,	475.5
	F:	0,	12.9,	40.4,	162.0, 	374.1, 	634.8
Acceptable / Guideline

NOAEL (mg/kg/day):	M =	9.2	F =	12.9
LOAEL (mg/kg/day):	M =	30.4	F =	40.4
Based on decreased body weights/body weight gains (males), changes in clinical chemistry (increased urea and decreased triglycerides), and increased incidences in females of lymph node apoptosis, thymus atropy, and ulcer/erosion in the glandular stomach.
                                   870.3150
90-Day Oral Toxicity in Non-Rodents (Dog)

45118323 (1999) 
Dietary Concentration (ppm):
		0,	100,	200,	450
Intake Dose (mg/kg/day):
	M:	0,	2.8,	5.8,	12.9
	F:	0,	3.0,	6.2,	13.6
Acceptable / Guideline

NOAEL (mg/kg/day):	M =	5.8	F =	6.2
LOAEL (mg/kg/day):	M =	12.9	F =	13.6
Based on an increased incidence of diarrhea, clinical chemistry changes and mucosal hypertrophy of the duodenum (both sexes) and body weight loss, decreased food intake and decreased food efficiency (females only).
                                   870.3200
21/28-Day
Dermal Toxicity (Rabbit)

45118324 (1999)
Applied Dose (mg/kg/day):
	M:	0,	40,	100,	250
	F:	0,	40,	100,	250
Unacceptable / Guideline

Unacceptable due to the lack of systemic effects at the highest dose tested (250 mg/kg/day); the limit dose is 1000 mg/kg/day.

Dermal
NOAEL (mg/kg/day):	M =	40	F =	40
LOAEL (mg/kg/day):	M =	100	F =	100
Based on scale formation, hyperkeratosis, and epidermal thickening at the site of application.

Systemic
NOAEL (mg/kg/day):	M =	250	F =	250
LOAEL (mg/kg/day):	M >	250	F >	250

                                   870.3465
28-Day 
Inhalation Toxicity
(Rat)


46638801 (2005)
Applied Dose (mg/L):
	M:	0,	0.001,	0.030,	0.300
	F:	0,	0.001,	0.030,	0.300
Acceptable / Guideline

NOAEL (mg/L):	M =	0.001	F =	0.001
LOAEL (mg/L):	M =	0.030	F =	0.030
Based on findings of hyperplasia in the duodenum, alveolar histiocytosis in the lungs, and olfactory atrophy/necrosis in the nasal tissues.
                                   870.3700
Prenatal Developmental Toxicity Study (Rat)
45118325 (1999) 
Gavage Dose (mg/kg/day):
	F:	0,	10,	25,	50
Acceptable / Guideline
Maternal
NOAEL (mg/kg/day) =	10
LOAEL (mg/kg/day) =	25
Based on decreased body weights and body weight gains and reduced food consumption and reduced food efficiency.

Developmental
NOAEL (mg/kg/day) =	25
LOAEL (mg/kg/day) =	50
Based on increased incidence of dilated renal pelvis and cervical ribs.

                                       
Prenatal Developmental Toxicity Study (Rabbit)
45118326 (1999)
45437001 (2001)
Gavage Dose (mg/kg/day):
	F:	0,	1,	3,	5, 	10, 	20
Acceptable / Guideline

Maternal
NOAEL (mg/kg/day) =	5
LOAEL (mg/kg/day) =	10
Based on body weight gains, reduced food consumption and reduced food efficiency.

Developmental
NOAEL (mg/kg/day) =	5
LOAEL (mg/kg/day) =	10
Based on increased resorptions per litter, increased post-implantation loss and dams with total resorptions.

                                   870.3800
Reproduction and Fertility Effects 
(Rat)
45118327 (1999) 
Dietary Concentration (ppm):
		0,	25,	75,	300
Intake Dose (mg/kg/day):
	M0:	0,	2.5,	7.4,	29.0
	F0:	0,	2.6,	7.8,	30.4

	M1:	0,	2.8,	8.6,	35.0
	F1:	0,	3.0,	9.0,	36.0
Acceptable / Guideline

Parental
NOAEL (mg/kg/day):	M =	29.0	F =	30.4
LOAEL (mg/kg/day):	M >	29.0	F >	30.4

Reproductive
NOAEL (mg/kg/day):	M =	29.0	F =	30.4
LOAEL (mg/kg/day):	M >	29.0	F >	30.4

Offspring
NOAEL (mg/kg/day):	M =	29.0	F =	30.4
LOAEL (mg/kg/day):	M >	29.0	F >	30.4

                                       

45596210 (2002) 
Dietary Concentration (ppm):
		0,	200,	400,	600
Intake Dose (mg/kg/day):
	M:	0,	20.5,	39.9,	59.1
	F:	0,	21.3,	42.5,	60.4
Acceptable / Non-Guideline

One-Generation Study
Parental
NOAEL (mg/kg/day):	M =	20.5	F =	42.5
LOAEL (mg/kg/day):	M =	39.9	F =	60.4
Based on reduced body weights and body weight gains.

Reproductive
NOAEL (mg/kg/day):	M <	20.5	F <	21.3
LOAEL (mg/kg/day):	M <=	20.5	F <=	21.3

Offspring
NOAEL (mg/kg/day):	M >=	59.1	F >=	60.4
LOAEL (mg/kg/day):	M >	59.1	F >	60.4
Based on a reduced pup body weights and body weight gains (a threshold body weight effect).

                                   870.4100
Chronic Toxicity (Rat)
45118329 (1999)
Dietary Concentration (ppm):
		0,	25,	75,	200
Intake Dose (mg/kg/day):
	M:	0,	1.1,	3.4,	9.0
	F:	0,	1.5,	4.6,	12.3
Unacceptable / Guideline

Unacceptable due to low dose selection

NOAEL (mg/kg/day):	M =	9.0	F =	12.3
LOAEL (mg/kg/day):	M >	9.0	F >	12.3

There was no evidence of carcinogenic potential
                                       
Chronic Toxicity (Dog)
45118328 (1999)
Dietary Concentration (ppm):
		0,	100,	200,	400
Intake Dose (mg/kg/day):
	M:	0,	2.7,	5.4,	10.8
	F:	0,	2.7,	5.4,	11.2
Acceptable / Guideline

NOAEL (mg/kg/day):	M =	5.4	F =	5.4
LOAEL (mg/kg/day):	M =	10.8	F =	11.2
Based on an increased incidence of diarrhea and clinical chemistry changes (both sexes) and decreased body weight gain, decreased food intake and decreased food efficiency (females only).
                                   870.4200
Carcinogenicity (Rat)

45118331 (1999)
Dietary Concentration (ppm):
		0,	25,	75,	200
Intake Dose (mg/kg/day):
	M:	0,	1.2,	3.4,	9.2
	F:	0,	1.5,	4.7,	12.6
Acceptable / Guideline

NOAEL (mg/kg/day):	M =	3.4	F =	4.7
LOAEL (mg/kg/day):	M =	9.2	F =	12.6
Based on differences in body weight and body weight gains, increased incidences of kidney tubular casts and atrophy in males and females, and in males, an increased incidence of necrosis of the liver, gross and microscopic evidence of erosion/ulcer of the glandular stomach and an increased incidence of acanthosis and ulcers of the forestomach.

Under the conditions of this study, there was no evidence of carcinogenic potential.

                                       
Carcinogenicity 
(Mouse)
45118330 (1999)
Dietary Concentration (ppm):
	M:	0,	10,	30,	120
	F:	0,	10,	30,	120,	180
Intake Dose (mg/kg/day):
	M:	0,	1.4,	4.1,	17.2
	F:	0,	1.6,	4.8,	20.5,	32.8
Unacceptable / Guideline

Unacceptable due to low dose selection

NOAEL (mg/kg/day):	M >=	17.2	F >=	32.8
LOAEL (mg/kg/day):	M >	17.2	F >	32.8

Under the conditions of this study, there was no evidence of carcinogenic potential.

                                   870.5100
Bacterial Reverse Mutation Test
(Salmonella typhimurium)
45118332 (1997)
Applied Dose (ug/plate):
	S9:	0,	20,	100,	500,	2500,			5000
Acceptable / Guideline

+-S9: Negative up to 2500 μg/plate in the absence of cytotoxicity with precipitation above this concentration.

There was no evidence of treatment-induced mutant colonies above background levels.

                                   870.5300
in vitro Mammalian Cell Gene Mutation Test
(Mouse Lymphoma Cells)

45118335 (1998)
Applied Dose (ug/mL):
	S9: 	0.625,	1.25,	2.5,	5.0,	10.0,			20.0
	S9: 	3,	4,	5,	6,	7,			8
	S9: 	1.25,	2.5,	5.0,	10.0,	20.0
Acceptable / Guideline

BAS 500 F was tested up to cytotoxic and solubility limit concentrations. The positive controls induced the appropriate response. There was no evidence of induced mutant colonies over background.
                                   870.5375
in vitro Mammalian Chromosome Aberration Test
(Chinese Hamster Ovary cells)

45118333 (1999)
Applied Dose (ug/mL):
	S9: 	0,	6.25,	12.5,	25.0		+S9: 	0,	3.125,	6.25,	12.5
	S9: 	0,	0.005,	0.010,	0.050,	0.100
Acceptable / Guideline

BAS 500 F was tested up to preciptating concentrations.  Positive controls induced the appropriate response. There was no evidence of an increase in the number of structural or numerical chromosomal aberrations induced over background.  It is therefore concluded that BAS  500 F is not a clastogenic agent under the conditions of this study.

                                   870.5395
Mammalian Erythrocyte Micronucleus Test
(Mouse)

45118334 (1998)
Gavage Dose (mg/kg/day):
	M:	0,	75,	150,	300
	F:	0,	75,	150,	300
Acceptable / Guideline

There was no significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow at any dose level tested, at any time after treatment. It is therefore concluded that BAS 500 F did not induce a clastogenic effect in either sex at any sacrifice time.

                                   870.5550
Unscheduled DNA Synthesis in Mammalian Cells in Culture
(Rat Hepatocytes)

45118336 (1998)
Applied Dose (ug/mL):
	Run 1: 	0.01,	0.03,	0.1, 	0.3, 	1.0	Run 2: 	0.004,	0.02,	0.5
Acceptable / Guideline

BAS 500 F was tested up to cytotoxic concentrations. The positive controls induced the appropriate response.  There was no evidence that BAS 500 F induced unscheduled DNA synthesis, as determined by net nuclear silver grain counts.

                                   870.6200
Acute Neurotoxicity Screening Battery
(Rat)

45118337 (1999)
Gavage Dose (mg/kg/day):
	M:	0,	100,	300,	1000
	F:	0,	100,	300,	1000
Acceptable / Guideline

Neurotoxicity
NOAEL (mg/kg/day):	M =	1000	F =	1000
LOAEL (mg/kg/day):	M >	1000	F >	1000

Systemic
NOAEL (mg/kg/day):	M =	300	F =	1000
LOAEL (mg/kg/day):	M =	1000	F >	1000
For males, based on 33% decreased body weight gain (p  0.01) on days 0-7; no similar effect was detected on days 0-14.

                                       
90-Day Neurotoxicity Screening Battery
(Rat)
45118401 (1999)
Dietary Concentration (ppm):
		0,	50,	250,	M: 750
					F: 1500
Intake Dose (mg/kg/day):
	M:	0,	3.5,	16.9,	49.9
	F:	0,	4.0,	20.4,	111.9
Acceptable / Guideline

Neurotoxicity
NOAEL (mg/kg/day):	M =	49.9	F =	111.9
LOAEL (mg/kg/day):	M >	49.9	F >	111.9

Systemic
NOAEL (mg/kg/day):	M =	16.9	F =	20.4
LOAEL (mg/kg/day):	M =	49.9	F =	111.9
Based on decreased body weight gain, food intake and food efficiency (both sexes) and decreased water intake (males only).

                                   870.7485
Metabolism and Pharmacokinetics (Rat)
45118403 (1998)
45118404 (1999)
Gavage Dose (mg/kg):
	Single: 		5,	50
	Repeated: 	50
Acceptable / Guideline
Nearly 35% of an oral dose of pyraclostrobin is absorbed with urinary and fecal excretions accounting for about 15% and 85%, respectively, and bile elimination accounted for about 30%. Two peak plasma concentrations were reached at 0.5-1 and 8 hours with lower plasma concentrations in males than females (by 16-38%) during the early peak phase. Elimination was biphasic at a low dose with plasma half lives of nearly 10/35 hours and monophasic at a high dose with a half-life of nearly 20 hours. 

Tissue distribution was fast, peaking at 0.5 hours, and was slightly higher among females. Some of the highest concentrations were found in the liver, thyroid, kidney, lung, adrenal glands, and pancreas but all levels dropped by more than 20-fold within 72 hours. 

About 33 metabolites were identified in urine, feces, and bile with no sex- or dose-related differences but the position of the label seemed to alter the profile, particularly in the urine. Desmethoxy pyraclostrobin (500M07) is one of the major metabolites in rat and is also found in large amounts in plants (BF 500-3) and livestock (500M07). The rat metabolic pathway included phase-I reactions such as N-demethoxylation, various hydroxylations, and cleavage of the ether bond with subsequent oxidation; these reactions were followed by phase II glucuronidation and sulfation.

                                   870.7600
Dermal Penetration (Rat)


45118402 (1999)
Applied Dose (mg/cm[2]):
	M: 		0.015,	0.075,	0.375
Unacceptable / Guideline

Unacceptable because the actual dose was indeterminate due to material retained on the dressings being unavailable for absorption. 

The HIARC calculated and recommended a dermal penetration rate of 14%. (TXR#0051553: 10 FEB 2003)

In all three doses the largest portion of the dose was found in the Dressings (72.38-84.36%, 78.51-81.58% and 76.38-80.24% for the respective doses) The dressings consisted of silicone ring, nylon mesh cover and porous bandage. This material must be considered unavailable for absorption.
 
Dermal penetration of [[14]C-tolyl]-pyraclostrobin was low for all dose groups and time intervals (0.44-2.60%). After an 8-hour exposure period, absorbed radioactivity accounted for 0.65%, 0.86% and 0.50% of the applied dose at nominal doses of 0.015, 0.075 and 0.375 mg/cm[2], respectively. After removal of the test substance and washing the site, absorption continued - an additional 0.93-1.74% of the dose in each dose group over the next 64 hours; however, there was no concomitant decrease in radioactivity in the skin.

The percent of the dose absorbed was not dose dependent; however, the actual amount of the test material absorbed did increase with increasing dose level. Immediately following the 8-hour exposure period, absorbed radioactivity accounted for 0.105, 0.757 and 2.27 ug/cm[2] at mean achieved doses of 0.017, 0.087 and 0.428 mg/cm[2]. Comparing the increases from the low to high-dose groups, the amount of actual absorption increased by 21.6x compared to the 25.2x increase in the dose level. This pattern of absorption is commonly seen with a chemical which directly damages the stratum corneum of the skin.

                                   870.7800
Immunotoxicity
(Mouse)

48830601 (1999)
Dietary Concentration (ppm):
		0,	50,	200,	750
Intake Dose (mg/kg/day):
	F:	0,	13,	50,	165
Unclassified

Preliminary review of the studies does not indicate any immunotoxicity or systemic toxicity below 165 mg/kg/day.
                                       

48830602 (2012)
Dietary Concentration (ppm):
		0,	50,	200,	750
Intake Dose (mg/kg/day):
	F:	0,	13,	50,	202
Unclassified


                                       

48830603 (2012)
Dietary Concentration (ppm):
		0,	50,	200,	750
Intake Dose (mg/kg/day):
	F:	0,	14,	55,	191
Unclassified



 
 
Appendix B.  Physicochemical Properties of Pyraclostrobin.

TABLE B.  Physicochemical Properties of Technical Grade Pyraclostrobin.
Parameter
                                     Value
                            References[1]  (MRID) 
Melting point/range
63.7-65.2ºC
                                   45118213
pH
Not applicable
                                       
Density
1.367 g/cm[3] 
                                   45118214
Water solubility at 20 ºC
1.9 +-  0.17 mg/L (deionized water, pH 5.8)

                                   45118233
Solvent solubility
n-heptane (0.37 g/100mL);  2-propanol (3.0 g/100mL); 1-octanol (2.42 g/100mL);  olive oil (2.80 g/100m/L);  methanol  (10.08 g/100mL); >50 g/100mL in acetone, ethyl acetate , acetonitrile, dichloromethane and toluene.
                                   45118228
Vapor pressure
2.6 x 10[-10] hPa at 20 ºC

                                   45118214
Dissociation constant, pKa
None (no dissociable moieties)
                                       
Octanol/water partition coefficient, Log(KOW) at room temperature
3.990 mean log Pow; Pow is 9772 

                                   45118215
UV/visible absorption spectrum
The structural identity of BAS 500 F was confirmed by NMR and MS spectra. UV molecular extinction (e [1 mol[-1] cm[-1]]): 2.5x10[4] at 205 nm; 2.4x10[4] at 275 nm.
                                 1996/10955[2]
[1]	Product Chemistry data were reviewed by the Registration Division (DP# 269848 and DP# 274191, 5/3/01, 5/15/01, and 6/7/01, S. Malak).  
[2]	BASF Document Number.

Appendix C.  Review of Human Research

The PHED Task Force, 1995.  The Pesticide Handlers Exposure Database, Version 1.1.  Electronic Database.  Task Force Members: Health Canada, U.S. EPA, and the National Agricultural Chemicals Associations, released February 1995.  

The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler Unit Exposure Surrogate Reference Table.  U.S. EPA.  Released June 21, 2011.  

Data from the Outdoor Residential Exposure Task Force (ORETF).  

HED Residential Standard Operating Procedures (2012).  



Appendix D.  Summaries of Field Residue Data

TABLE D-1.  Summary of Residue Data from Crop Field Trials with Pyraclostrobin on Sugarcane.
Commodity
                              Total Applic. Rate
                                   (lb ai/A)
                                  [kg ai/ha]
                                  PHI (days)
                                    Analyte
                               Residue Levels[1]
                                     (ppm)




                                       n
                                  SampleMin.
                                    Sample
                                     Max.
                                    LAFT[2]
                                    HAFT[2]
                                    Median
                                     Mean
                                   Std. Dev.
Sugarcane
                                   0.78-0.81
                                  (0.88-0.91)
                                     13-14
                                Pyraclostrobin
                                       8
                                   <0.02
                                    0.1049
                                   <0.02
                                     0.099
                                     0.058
                                   <0.060
                                     0.026

                                       
                                       
                                   BF 500-3
                                       8
                                   <0.02
                                    0.0267
                                   <0.02
                                     0.027
                                   <0.02
                                   <0.021
                                     0.002

                                       
                                       
                                   Combined
                                       8
                                   <0.04
                                   <0.125
                                   <0.040
                                   <0.119
                                   <0.076
                                   <0.076
                                     0.029
                                       
                                       
                                     27-28
                                Pyraclostrobin
                                       8
                                   <0.02
                                    0.0866
                                   <0.020
                                     0.068
                                     0.043
                                   <0.044
                                     0.016

                                       
                                       
                                   BF 500-3
                                       8
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                      N/A

                                       
                                       
                                   Combined
                                       8
                                   <0.04
                                  <0.1066
                                   <0.040
                                   <0.088
                                   <0.062
                                   <0.061
                                     0.017
Sugarcane
(for processing)
                                   3.94-3.99
                                  [4.42-4.47]
                                      14
                                Pyraclostrobin
                                       2
                                    0.0238
                                    0.2935
                                     0.028
                                     0.255
                                     0.141
                                     0.141
                                      N/A

                                       
                                       
                                   BF 500-3
                                       2
                                   <0.02
                                    0.0253
                                   <0.02
                                     0.025
                                   <0.022
                                   <0.022
                                      N/A

                                       
                                       
                                   Combined
                                       2
                                   <0.044
                                     0.319
                                   <0.048
                                     0.280
                                   <0.164
                                   <0.164
                                      N/A

                                       
                                      28
                                Pyraclostrobin
                                       2
                                    0.0203
                                   0.3811[3]
                                     0.026
                                     0.268
                                     0.147
                                     0.147
                                      N/A

                                       
                                       
                                   BF 500-3
                                       2
                                   <0.02
                                    0.0405
                                   <0.02
                                   <0.030
                                   <0.025
                                   <0.025
                                      N/A

                                       
                                       
                                   Combined
                                       2
                                   <0.040
                                     0.422
                                   <0.046
                                   <0.299
                                   <0.172
                                   <0.172
                                      N/A


TABLE D-2.  Summary of Residue Data from Globe Artichoke Crop Field Trials with Pyraclostrobin.
Commodity
                              Total Applic. Rate
                                   (lb ai/A)
                                  [kg ai/ha]
                                  PHI (days)
                                    Analyte
                               Residue Levels[1]
                                     (ppm)




                                       n
                                  SampleMin.
                                    Sample
                                     Max.
                                    LAFT[2]
                                    HAFT[2]
                                    Median
                                     Mean
                                   Std. Dev.
                             Artichoke Flower Head
                                  0.549-0.562
                                 (0.615-0.630)
                                       0
                                Pyraclostrobin
                                       3
                                     0.514
                                     1.110
                                     0.618
                                     1.045
                                     0.759
                                     0.807
                                     0.218

                                       
                                       
                                   BF 500-3
                                       3
                                   <0.02
                                     0.056
                                   <0.02
                                     0.056
                                   <0.028
                                   <0.035
                                     0.019

                                       
                                       
                                   Combined
                                       3
                                   <0.534
                                     1.166
                                   <0.638
                                     1.101
                                   <0.787
                                   <0.842
                                     0.236
[1]  Except for sample min/max, values reflect per trial averages; n = no. of field trials.  For calculation of median, mean, and standard deviation, the LLMV (0.02 ppm) was used for any results reported as <LLMV in Table C.3.
[2]  LAFT = lowest average field trial; HAFT = highest average field trial.


TABLE D-3.  Summary of Residue Data from Belgium Endive Crop Field Trials with Pyraclostrobin.
Commodity
                                    Rate[1]
                                  PHI (days)
                                    Analyte
                               Residue Levels[2]
                                     (ppm)


                                       
                                       
                                       n
                                  SampleMin.
                                    Sample
                                     Max.
                                    LAFT[3]
                                    HAFT[3]
                                    Median
                                     Mean
                                   Std. Dev.
            Treatment 02: One pre-cold-storage application to roots
Belgium endive heads
                       0.578-0.597 g ai/100 lb of roots
                                     25-27
                                Pyraclostrobin
                                       3
                                   <0.02
                                    0.0679
                                   <0.023
                                     0.059
                                   <0.040
                                   <0.041
                                     0.018

                                       
                                       
                                   BF 500-3
                                       3
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                      N/A

                                       
                                       
                                   Combined
                                       3
                                   <0.04
                                   <0.088
                                   <0.043
                                   <0.079
                                   <0.06
                                   <0.061
                                     0.018
      Treatment 03: One pre-forcing application to roots in packing tray
Belgium endive heads
                            0.089-0.097 g ai/ft[2]
                                     17-19
                                Pyraclostrobin
                                       3
                                    0.1239
                                    1.7620
                                     0.150
                                     1.347
                                     0.900
                                     0.799
                                     0.605

                                       
                                       
                                   BF 500-3
                                       3
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                      N/A

                                       
                                       
                                   Combined
                                       3
                                   <0.144
                                   <1.782
                                   <0.170
                                   <1.367
                                   <0.920
                                     0.819
                                     0.605
Treatment 04: One pre-cold-storage application to roots + One pre-forcing application to roots in packing tray
Belgium endive heads
                    0.584-0.591 g ai/100 lb of roots and[3]
                            0.092-0.101 g ai/ft[2]
                                     17-19
                                Pyraclostrobin
                                       3
                                    0.2250
                                    0.8710
                                     0.256
                                     0.771
                                     0.551
                                     0.526
                                     0.258

                                       
                                       
                                   BF 500-3
                                       3
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                      N/A

                                       
                                       
                                   Combined
                                       3
                                   <0.245
                                   <0.891
                                   <0.276
                                   <0.791
                                   <0.571
                                   <0.546
                                     0.258
[1]  Rate for pyraclostrobin, as calculated by the study reviewer based on the certificate of analysis of applied product in the study report.
[2]  Except for sample min/max, values reflect per trial averages; n = no. of field trials.  For calculation of median, mean, and standard deviation, the LLMV (0.02 ppm) was used for any results reported as <LLMV in Table C.3.  N/A = Not Applicable.
[3]  LAFT = lowest average field trial; HAFT = highest average field trial.


TABLE D-4.  Summary of Residue Data from Persimmon Crop Field Trials with Pyraclostrobin.
Commodity
                              Total Applic. Rate
                                   (lb ai/A)
                                  [kg ai/ha]
                                  PHI (days)
                                    Analyte
                               Residue Levels[1]
                                     (ppm)




                                       n
                                  SampleMin.
                                    Sample
                                     Max.
                                    LAFT[2]
                                    HAFT[2]
                                    Median
                                     Mean
                                   Std. Dev.
                                Persimmon Fruit
                                  0.564-0.573
                                 (0.632-0.642)
                                       0
                                Pyraclostrobin
                                       3
                                     0.421
                                     1.278
                                     0.092
                                     1.155
                                     0.437
                                     0.561
                                     0.542

                                       
                                       
                                   BF 500-3
                                       3
                                   <0.02
                                     0.077
                                   <0.02
                                     0.073
                                   <0.02
                                   <0.038
                                     0.031

                                       
                                       
                                   Combined
                                       3
                                   <0.103
                                     1.355
                                   <0.112
                                     1.228
                                   <0.457
                                   <0.599
                                     0.571
[1]  Except for sample min/max, values reflect per trial averages; n = no. of field trials.  For calculation of median, mean, and standard deviation, the LLMV (0.02 ppm) was used for any results reported as <LLMV in Table C.3.  N/A = Not Applicable.
[2]  LAFT = lowest average field trial; HAFT = highest average field trial.





Appendix E.  Summaries of Occupational Handler and Post-application Exposure and Risk Estimates

Table E-1.  Occupational Handler Non-Cancer Exposure and Risk Estimates for Pyraclostrobin.
                               Exposure Scenario
                                     Crop
                      Dermal Unit Exposure (μg/lb ai)[1]
                    Inhalation Unit Exposure (μg/lb ai)[1]
                                    Maximum
                              Application Rate[2]
                                   (lb ai/A)
                    Area Treated or Amount Handled Daily[3]
                                    Dermal
                                  Inhalation
                                       
                                       
                                   Baseline
                                   Baseline
                                       
                                       
                              Dose (mg/kg/day)[4]
                                    MOE[5]
                              Dose (mg/kg/day)[6]
                                    MOE[7]
                                 Mixer/Loader
                          Aerial applications of WDG
                                      and
                        Chemigation application of WDG
                                   Artichoke
                                   Persimmon
                                      227
                                     8.96
                                     0.18
                                      350
                                     0.029
                                      170
                                    0.0071
                                      33
                            Aerial applications of
                                      SC
                                   Sugarcane
                                      220
                                     0.219
                                     0.20
                                     1200
                                     0.11
                                      47
                                    0.00069
                                      350
                          Airblast application of WDG
                                   Persimmon
                                      227
                                     8.96
                                     0.18
                                      40
                                    0.0033
                                     1,500
                                    0.00081
                                      290
                        Chemigation application of WDG
                                      and
                         Groundboom application of WDG
                              Greenhouse tomatoes
                                      227
                                     8.96
                                     0.18
                                      60
                                    0.0050
                                     1,000
                                    0.0012
                                      190
                        Chemigation applications of SC
                                   Sugarcane
                                      220
                                     0.219
                                     0.20
                                      350
                                     0.031
                                      160
                                    0.00019
                                     1,200
                         Groundboom application of WDG
                                   Artichoke
                                      227
                                     8.96
                                     0.18
                                      80
                                    0.0066
                                      750
                                    0.0016
                                      140
                         Groundboom application of SC
                                   Sugarcane
                                      220
                                     0.219
                                     0.20
                                      200
                                     0.018
                                      280
                                    0.00011
                                     2,100
                                  Applicator
                              Aerial application
                                   Artichoke
                                   Persimmon
                                       5
                                     0.068
                                     0.18
                                      350
                                    0.00064
                                     7,800
                                   0.000054
                                     4,300
                              Aerial application
                                   Sugarcane
                                       5
                                     0.068
                                     0.20
                                     1200
                                    0.0024
                                     2,100
                                    0.00020
                                     1,100
                             Airblast application
                                   Persimmon
                                     1770
                                     4.71
                                     0.18
                                      40
                                     0.026
                                      190
                                    0.00042
                                      540
                            Groundboom application
                              Greenhouse tomatoes
                                     78.6
                                     0.34
                                     0.18
                                      60
                                    0.0017
                                     2,900
                                   0.000046
                                     5,000
                            Groundboom application
                                   Artichoke
                                     78.6
                                     0.34
                                     0.18
                                      80
                                    0.0023
                                     2,200
                                   0.000071
                                     3,200
                            Groundboom application
                                   Sugarcane
                                     78.6
                                     0.34
                                     0.20
                                      200
                                    0.0064
                                      780
                                    0.00017
                                     1,400
                                    Flagger
                                    Flagger
                                   Artichoke
                                   Persimmon
                                      11
                                     0.35
                                     0.18
                                      350
                                    0.0014
                                     3,500
                                    0.00028
                                      830
                                    Flagger
                                   Sugarcane
                                      11
                                     0.35
                                     0.20
                                      350
                                    0.0016
                                     3,200
                                    0.00031
                                      750
                            Mixer/Loader/Applicator
                          Backpack application of WDG
                              Greenhouse tomatoes
                                    13,200
                                      140
                                    0.0018
                                   lb ai/gal
                                      40
                                      gal
                                    0.0019
                                     2,600
                                    0.00013
                                     1,800
                   Manually pressurized handwand app of WDG
                              Greenhouse tomatoes
                                    100,000
                                      30
                                    0.0018
                                   lb ai/gal
                                      40
                                      gal
                                     0.015
                                      340
                                   0.000027
                                     8,500
                    Mechanically pressurized handgun of WDG
                                   Artichoke
                                   Persimmon
                                     1300
                                      3.9
                                    0.0018
                                   lb ai/gal
                                     1000
                                      gal
                                    0.0048
                                     1,100
                                    0.00088
                                     2,600
                    Mechanically pressurized handgun of WDG
                              Greenhouse tomatoes
                                     3500
                                      120
                                    0.0018
                                   lb ai/gal
                                     1000
                                      gal
                                     0.013
                                      390
                                    0.0027
                                      85
                    Mechanically pressurized handgun of WDG
                   Belgium Endive  -  prior to cold storage
                                     1300
                                      3.9
                                   0.000014 
                                lb ai/ lb root
                                    200,000
                                    lb root
                                    0.0074
                                      680
                                    0.00014
                                     1,700
                    Mechanically pressurized handgun of WDG
                      Belgium Endive  -  prior to forcing
                                     1300
                                      3.9
                                    0.0002
                                  lb ai/ft[2]
                                    10,890
                                     ft[2]
                                    0.0057
                                      870
                                    0.00011
                                     2,200

1	Based on the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (March 2013); 
2	Based on proposed label (See Table 4).
3	Exposure Science Advisory Council Policy #9.1.
4	Dermal Dose = Dermal Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount  Handled Daily (A or gal/day) x DAF (%) / BW (kg).
5	Dermal MOE = Dermal NOAEL (mg/kg/day) / Dermal Dose (mg/kg/day).
6	Inhalation Dose = Dermal Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount  Handled Daily (A or gal/day) / BW (kg).
7	Inhalation MOE = Inhalation NOAEL (mg/kg/day) / Inhalation Dose (mg/kg/day).


Table E-2.  Occupational Handler Non-Cancer Exposure and Risk Estimates for Pyraclostrobin with PPE.
                               Exposure Scenario
                                     Crop
                      Dermal Unit Exposure (μg/lb ai)[1]
                    Inhalation Unit Exposure (μg/lb ai)[1]
                                    Maximum
                              Application Rate[2]
                                   (lb ai/A)
                    Area Treated or Amount Handled Daily[3]
                                    Dermal
                                  Inhalation
                                       
                                       
                               Baseline + gloves
                                PF5 Respirator
                                       
                                       
                              Dose (mg/kg/day)[4]
                                    MOE[5]
                              Dose (mg/kg/day)[6]
                                    MOE[7]
                                 Mixer/Loader
                          Aerial applications of WDG
                                      and
                        Chemigation application of WDG
                                   Artichoke
                                   Persimmon
                                     51.6
                                     1.792
                                     0.18
                                      350
                                    0.0066
                                      760
                                    0.0014
                                      160
                            Aerial applications of
                                      SC
                                   Sugarcane
                                     37.6
                                    0.0438
                                     0.20
                                     1200
                                     0.018
                                      270
                                    0.00013
                                     1,800
                            Mixer/Loader/Applicator
                    Mechanically pressurized handgun of WDG
                              Greenhouse tomatoes
                                     2500
                                      24
                                    0.0018
                                   lb ai/gal
                                     1000
                                      gal
                                    0.0091
                                      550
                                    0.00054
                                      430
1	Based on the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (March 2013); 
2	Based on proposed label (See Table 4).
3	Exposure Science Advisory Council Policy #9.1.
4	Dermal Dose = Dermal Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount  Handled Daily (A or gal/day) x DAF (%) / BW (kg).
5	Dermal MOE = Dermal NOAEL (mg/kg/day) / Dermal Dose (mg/kg/day).
6	Inhalation Dose = Dermal Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount  Handled Daily (A or gal/day) / BW (kg).
7	Inhalation MOE = Inhalation NOAEL (mg/kg/day) / Inhalation Dose (mg/kg/day).


Table E-3.  Occupational Post-application Non-Cancer Exposure and Risk Estimates for Pyraclostrobin.
                                   Crop/Site
                                  Activities
                        Transfer Coefficient (cm[2]/hr)
                                    DFR[1]
                                 Dermal Dose 
                                (mg/kg/day)[2]
                                    MOE[3]
                                   Sugarcane
                                   Scouting
                                     1,100
                                     0.152
                                    0.0027
                                     1,800
                                       
                                Hand Harvesting
                                    17,600
                                       
                                     0.043
                                      120
                                       
                                 Hand Weeding
                                      70
                                       
                                    0.00017
                                    29,000
                                   Artichoke
                                Hand Harvesting
                                     1,100
                                     0.379
                                    0.0068
                                      740
                                       
                        Hand Weeding, Thinning, Pruning
                                      70
                                       
                                    0.00043
                                    12,000
                                       
                                  Irrigation
                                  (hand set)
                                     1,900
                                       
                                     0.012
                                      430
                                       
                                   Scouting
                                      210
                                       
                                    0.0013
                                     3,900
                                       
                                 Transplanting
                                      230
                                       
                                    0.0014
                                     3,500
                                   Persimmon
                       Scouting, Hand pruning, Training
                                      580
                                     0.686
                                    0.0065
                                      770
                                       
                  Hand weeding, Propping, orchard maintenance
                                      100
                                       
                                    0.0011
                                     4,500
                                       
                                Hand Harvesting
                                     1,400
                                       
                                     0.016
                                      320
                                       
                                 Transplanting
                                      230
                                       
                                    0.0026
                                     2,000
                                       
                                   Thinning
                                     3,600
                                       
                                     0.040
                                      120
                              Greenhouse Tomatoes
Hand harvesting, pinching, hand pruning, Scouting, Turning, Tying, Hand weeding, 
                                     1200
                                     0.379
                                    0.0074
                                      680
                                       
                   Irrigation (hand watering), Transplanting
                                      230
                                       
                                    0.0014
                                     3,500
1	DFR chemical-specific study (see Appendix D, Tables D4, D5, and D6)
2	Daily Dermal Dose = [DFR (ug/cm[2]) x Transfer Coefficient x 0.001 mg/ug x 8 hrs/day x dermal absorption (%)]  BW (kg).
3	MOE = POD (mg/kg/day) / Daily Dermal Dose.  Daily Dermal Dose = [DFR (ug/cm[2]) x TC x 0.001 mg/ug x 8 hrs/day x dermal absorption factor (%)]  BW (kg).



Appendix F. Summary of Pyraclostrobin DFR Study Results

Table F-1. Summary of DFR Values and Regression Analysis Results for Treated Peach Foliage with Pyraclostrobin
                                Input/Parameter
                                    Georgia
                                 Pennsylvania
                                  California
Application Rate (lb ai/A)
 (Study Target Rate = 0.12 lb ai/A)
                                     0.12
                                     0.12
                                     0.12
Spray Volume (GPA) 
                                      105
                                     92.2
                                      152
Measured Average Day 0 Residue (ug/cm[2])
                                     0.175
                                     0.29
                                     0.29
Predicted Day 0 Residue (ug/cm[2])
                                     0.176
                                     0.457
                                     0.389
Slope
                                    -0.0963
                                    -0.105
                                    -0.0297
Half-life (days)
                                      7.2
                                      6.6
                                      23
R[2]
                                     0.98
                                     0.90
                                     0.59


Table F-2. Summary of DFR Values and Regression Analysis Results for Treated Strawberry Foliage with Pyraclostrobin
                                Input/Parameter
                                North Carolina
                                  California
                                    Oregon
Application Rate (lb ai/A)
 (Study Target Rate = 0.18 lb ai/A)
                                     0.18
                                     0.18
                                     0.18
Spray Volume (GPA) 
                                     45.8
                                     45.8
                                     45.8
Measured Average Day 0 Residue (ug/cm[2])
                                     0.505
                                     0.431
                                     0.19
Predicted Day 0 Residue (ug/cm[2])
                                      0.1
                                     0.379
                                    0.0963
Slope
                                    -0.139
                                    -0.166
                                    -0.106
Half-life (days)
                                       5
                                      4.2
                                      6.5
R[2]
                                     0.62
                                     0.99
                                     0.85


Table F-3. Summary of DFR Values and Regression Analysis Results for Treated Peanut Foliage with Pyraclostrobin
                                Input/Parameter
                                     Texas
                                    Georgia
                                North Carolina
Application Rate (lb ai/A)
 (Study Target Rate = 0.25 lb ai/A)
                                     0.25
                                     0.25
                                     0.25
Spray Volume (GPA) 
                                 Not provided
                                 Not provided
                                 Not provided
Measured Average Day 0 Residue (ug/cm[2])
                                     0.497
                                     0.438
                                     0.511
Predicted Day 0 Residue (ug/cm[2])
                                     0.19
                                     0.104
                                     0.133
Slope
                                    -0.122
                                    -0.104
                                    -0.112
Half-life (days)
                                      5.7
                                      6.7
                                      6.2
R[2]
                                     0.78
                                     0.46
                                     0.63
Note: Bolded text indicates DFR values used in exposure assessments.





Appendix G.  International Residue Limits Status Sheet

                      Pyraclostrobin (099100; 02/19/2013)
Summary of US and International Tolerances and Maximum Residue Limits 
Residue Definition:
US
Canada
Mexico[2]
Codex[3]
40 CFR §180.582.  Plants:  Tolerances are established for residues of the fungicide pyraclostrobin, including its metabolites and degradates.  Compliance with the tolerance levels is to be determined by measuring on the sum of pyraclostrobin (carbamic acid, [2-[[[1-(4-chlorophenyl)-1H- pyrazol-3-yl]oxy]methyl]phenyl]methoxy-, methyl ester) and its desmethoxy metabolite (methyl N-[[[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy]methyl]phenyl carbamate), calculated as the stoichiometric equivalent of pyraclostrobin.
methyl [2-[[[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy]methyl]phenyl]methoxycarbamate, including the metabolite [2-[[[1-(4-chlorophenyl)-1H-pyrazol-3-
yl]oxy]methyl]phenyl]carbamate
-
Pyraclostrobin.  Residue is NOT fat soluble.
Commodity[1]
Tolerance (ppm) /Maximum Residue Limit (ppm)

                                      US
Canada
Mexico[2]
Codex[3]
Artichoke, globe
                                      3.0
                                     None

2. 
Belgium endive
(witloof chicory)
                                      4.0
                                     None

None
Persimmon
                                      3.0
                                     None

None
Vegetable, bulb, group 3-07
                                      0.9
                                      0.9

Garlic 0.15
Leek 0.7
Bulb onion 1.5
Spring onion 1.5
Vegetable, fruiting, group 8-10
                                      1.4
                                   Tomato 1
                                   Pepper 1

Tomato 0.3
Pepper 0.5
Eggplant (aubergine) 0.3
Fruit, citrus, group 10-10
                                      2.0
                                      2.0

2
Fruit, pome, group 11-10
                                      1.5
                                      1.5

Apple 0.5
Oilseed group 20
                                     0.45
                                     0.45

0.4
Caneberry subgroup 13-07A
                                      4.0
                                      3.5

Blackberry 3
Bushberry subgroup 13-07B
                                      4.0
                                      3.5

Blueberry 4
Small fruit, vine climbing subgroup (except fuzzy kiwi) 13-07F
                                      2.0
                                      2.0

Grape 2
Low growing berry subgroup 13-07G except cranberry
                                      1.2
                                      1.2

Strawberry 1.5
[1] Includes only commodities of interest for this action.  Tolerance values should be the HED recommendations and not those proposed by the applicant.
2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

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