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


MEMORANDUM

DATE:  	March 12, 2015

SUBJECT:	Pyraclostrobin  -  Human Health Risk Assessment for a Section 3 Registration of New Uses on Herb Subgroup 19A and Dill Seed, Plus Crop Group Conversions on Stone Fruit Group 12-12 and Tree Nut Group 14-12.

PC Code:  099100
DP Barcode:  D416700 
Decision No.:  484923 
Registration No.:  7969-199
Petition No.:  3E8216
Regulatory Action:  Section 3 Registration
Risk Assessment Type:  Single Chemical/Aggregate
Case No.:  7034
TXR No.:  NA
CAS No.:  175013-18-0
MRID No.:  NA
40 CFR:  180.582

FROM:	Barry O'Keefe, Senior Biologist
		Vincent Chen, Toxicologist
		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:		Andrew Ertman, Risk Manager
		Risk Integration, Minor Use and Emergency Response Branch (RIMUERB)
		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 Edom Seifu (EPA Environmental Fate and Effects Division (EFED)), the review of the residue chemistry data and dietary exposure assessment were conducted by Steve Funk, the occupational and residential exposure assessment was conducted by Cassi Walls, and the human health risk assessment was conducted by Barry O'Keefe.  


                               Table of Contents

1.0	Executive Summary	4
2.0	HED Recommendations	7
2.1	Data Deficiencies	7
2.2.1	Enforcement Analytical Method	7
2.2.2	Recommended Tolerances	8
2.2.3	Revisions to Petitioned-For Tolerances	8
2.2.4	International Harmonization	8
2.2.5	Label Recommendations	9
3.0	Introduction	9
3.1	Chemical Identity	9
3.2	Physical/Chemical Characteristics	9
3.3	Pesticide Use Pattern	10
3.4	Anticipated Exposure Pathways	10
3.5	Consideration of Environmental Justice	11
4.0	Hazard Characterization and Dose-Response Assessment	11
4.1	Summary of Toxicological Effects	11
4.2	Safety Factor for Infants and Children (FQPA Safety Factor)	12
4.2.1	Completeness of the Toxicology Database	12
4.2.2	Evidence of Neurotoxicity	12
4.2.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal	13
4.2.4	Residual Uncertainty in the Exposure Database	13
4.3	Toxicity Endpoint and Point of Departure Selections	13
4.3.1	Dose-Response Assessment	13
4.3.2	Cancer Classification and Risk Assessment Recommendation	15
4.3.3	Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment	16
5.0	Dietary Exposure and Risk Assessment	18
5.1	Residues of Concern Summary and Rationale	18
5.2	Food Residue Profile	18
5.3	Water Residue Profile	19
5.4	Dietary Risk Assessment	20
5.4.1	Description of Residue Data Used in Dietary Assessment	20
5.4.2	Percent Crop Treated Used in Dietary Assessment	20
5.4.3	Acute Dietary Risk Assessment	21
5.4.4	Chronic Dietary Risk Assessments	21
5.4.5	Summary Table	21
6.0	Residential (Non-Occupational) Exposure/Risk Characterization	22
6.1	Residential Bystander Post-application Inhalation Exposure	22
6.2	Spray Drift	23
7.0	Aggregate Exposure/Risk Characterization	23
7.1	Acute Aggregate Risk	23
7.2	Short-Term Aggregate Risk	24
7.3	Chronic Aggregate Risk	24
8.0	Cumulative Exposure/Risk Characterization	24
9.0	Occupational Exposure/Risk Characterization	25
9.1	Short-/Intermediate-Term Handler Risk	25
9.2	Short-and Intermediate-Term Post-Application Risk	26
9.2.1	Dermal Post-Application Risk	26
9.2.2	Inhalation Post-Application Risk	26
10.0	References	28
Appendix A.  Toxicology Profile and Executive Summaries	29
A.1	Toxicology Data Requirements	29
A.2	Toxicity Profiles	30
Appendix B. Methodologies for Human-Equivalent Concentration (HEC) Calculations.	36
Appendix C.  Physicochemical Properties of Pyraclostrobin.	41
Appendix D.  Review of Human Research	42
Appendix E.  Occupational Handler and Post-application Exposure and Risk Estimates	43
Appendix F.  Summaries of Field Residue Data	45
Appendix G.  International Residue Limits Status Sheet	46

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, on residential and golf course turf, residential ornamentals, landscape gardens, residential fruit and nut trees, and greenhouse grown tomato transplants for the home consumer market.

Use Profile
The Interregional Research Project No. 4 (IR-4) is proposing new uses on herb subgroup 19A and dill as additions to the Pristine[(R)] Fungicide label (EPA Reg. No. 7969-199).  Additionally, IR-4 is proposing crop group conversions for the stone fruit group 12-12 and the tree nut group 14-12.  The Pristine[(R)] Fungicide label also includes the active ingredient boscalid; therefore, a separate HED exposure and risk assessment document will be completed to evaluate the proposed new uses and crop conversions for boscalid.  The Pristine[(R)] label requires occupational handlers to wear the following personal protective equipment (PPE): long-sleeved shirts, long pants, shoes, socks, and chemical resistant gloves.  The 12 hour restricted entry interval (REI) listed on the label is adequate to protect workers.  

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

Hazard Assessment 
The primary target tissues following repeated pyraclostrobin exposure appear to be mucosal membranes, with histopathology or secondary effects (e.g., diarrhea) observed in different species.  The primary effects were decreased body weight and food consumption in addition to diarrhea.  The developmental study in rabbits indicated qualitative susceptibility where increased fetal resorptions, post-implantation loss, and total resorptions occurred at the same doses as maternal effects (i.e., decreased food consumption and food efficiency); however, toxicity endpoints and traditional UFs are protective of these effects and therefore, the degree of concern for prenatal and postnatal toxicity is low.  This assessment uses the results from a new inhalation toxicity study.  Pyraclostrobin is classified as "Not Likely to be Carcinogenic to Humans."  There was no observed 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.  The toxicity of pyraclostrobin through the inhalation route predominately consisted of portal of entry (POE) effects; therefore, a Human Equivalent Dose (HED) and a Human Equivalent Concentration (HEC) have been used to assess inhalation risks.  The Food Quality Protection Act (FQPA) Safety Factor (SF) 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.  Pyraclostrobin has moderate to low acute toxicity via the oral, dermal, and inhalation routes of exposure.  Pyraclostrobin is a mild dermal and eye irritant.  Pyraclostrobin is not a dermal sensitizer.  

Dietary Exposure
The residue chemistry 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.  

The results of the partially refined 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.  For children 1 to 2 years old, the population subgroup with the highest exposure for this aPAD, exposure is equivalent to 2.8% of the aPAD.  Additionally, the population subgroup females 13 to 49 years old are assessed with a different aPAD and have the highest estimated acute dietary risk estimate, 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 8.1% 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
No new residential uses were requested in this action.  However, pyraclostrobin is currently registered for use on residential and golf course turf, residential ornamentals and landscape gardens, and residential fruit and nut trees.  Residential exposure is expected to be short-term only.  Residential exposures from these existing residential uses were previously assessed 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 (LOCs <100).  The only new residential exposure assessment conducted in this current document was for handler inhalation exposure from applying WDG formulation to turf via manually pressurized handwand or backpack sprayer using the results from the new inhalation toxicity study and using HEDs/HECs.  This was from the previous highest exposure risk estimate MOE of 590, and using the HED/HEC method resulted in an MOE of 97 (LOC <30), which is still not of concern.  All previously assessed residential post-application dermal and incidental oral exposure risk estimates were also not of concern to HED, with MOEs ranging from 150 to 340,000.  
Aggregate Exposure 
There is potential for acute, short-term, and chronic aggregate exposure to pyraclostrobin.  The short-term aggregate exposure results from dietary (which is considered background exposure) and residential (which is considered primary) exposure pathways.  The acute and chronic aggregate exposures are the same as acute and chronic dietary exposures from food and drinking water, which are all below the HED's level of concern.  The adult short-term aggregate MOE is 230, which includes post-application exposure to treated turf and background dietary exposure and is not of concern to HED.  The short-term aggregate MOE for children 1-2 years old, including incidental oral exposures from treated turf and background dietary exposure, is 110, which is not of concern to HED.  The short-term aggregate MOE for children 6-11 years old, including post-application dermal exposures from treated gardens and background dietary exposure, is 380, which is not of concern to HED.  The short-term aggregate MOE for youths 11-16 years old, including post-application dermal exposures from treated turf from golfing and background dietary exposure, is 1,600, which is not of concern to HED.

Occupational Exposure
Based on the proposed agricultural uses, there is potential for short- and intermediate-term occupational exposure during handling and post-application activities.  The proposed label requires occupational handlers to wear the following PPE: long-sleeved shirts, long pants, shoes, socks, and chemical resistant gloves.

The dermal MOEs range from 63 (mixing/loading/applying of WG formulation to support mechanically pressurized handgun applications) to 2,600 (ground application to herbs) at baseline PPE.  When assessed with labelled PPE (e.g., including gloves), all dermal MOEs are >=210. Since all dermal MOEs at labelled PPE are greater than the LOC of 100, they are not a concern to HED.

The inhalation MOEs range from 34 (mixing/loading of WG formulation to support ground applications to dill seed) to 1,100 (ground application to herbs) at baseline PPE (no respirator).  All handler scenario MOEs at labelled PPE (e.g., no respirator) are greater than the LOC of 30, which are not a concern to HED.

All post-application scenarios resulted in dermal 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 380 to 10,000.  DFR studies are not required at this time for pyraclostrobin since the lowest dermal MOE (380) is greater than 2 times the LOC based on default input values.

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 REI listed on the label 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 Outdoor Residential Exposure Task Force (ORETF), and the Residential SOPs (lawns and turf) 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, residue chemistry, and exposure databases for pyraclostrobin.  Pending submission of a revised Section 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.  No additional data are needed.  The specific tolerance recommendations are discussed in Section 2.2.

0.1 Data Deficiencies

None.

2.2	Tolerance Considerations

2.2.1	Enforcement Analytical Method

There are adequate residue analytical methods for tolerance enforcement.  The analytical methods for plant commodities are liquid chromatography with tandem mass spectrometry (LC/MS/MS; BASF Method D9908) and high pressure liquid chromatography with ultraviolet detector (HPLC/UV; BASF Method D9904), which both measure pyraclostrobin and its desmethoxy metabolite (BF 500-3).  The validated method limit of quantitation (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.

The analytical methods for livestock commodities, gas chromatography with mass spectrometry (GC/MS) and LC/MS/MS, convert pyraclostrobin and related metabolites to chlorophenylpyrazolol (BF 500-5) and hydroxylated chlorophenylpyrazolol (BF 500-8) in goats and chlorophenylpyrazolol (BF 500-5) and a hydroxylated chlorophenylpyrazolol isomer of BF 500-8 (BF 500-9) in poultry. 

2.2.2	Recommended Tolerances

Sufficient data are available to support tolerances for residues of the fungicide pyraclostrobin, including its metabolites and degradates, in or on dill seed and the herb subgroup 19A.  The tolerance expression is aligned with the requirements of the S. Knizner 05/27/2009 memo.  A summary of the proposed and recommended tolerances may be found in Table 2.2.2 below.

Table 2.2.2.  Tolerance Summary for Pyraclostrobin
                                   Commodity
                           Proposed Tolerance (ppm)
                              Existing Tolerance
                        HED Recommended Tolerance (ppm)
                                   Comments
                        (correct commodity definition)
Herb subgroup 19A
                                      85
                                       -
                                      40
                                       
Dill, seed
                                      100
                                       -
                                      40
                                       
Fruit, stone, group 12
                                       
                                      2.5
                                    Revoke
                             Crop group conversion
Fruit, stone, group 12-12
                                      2.5
                                       -
                                      2.5
                             Crop group conversion
Nut, tree, group 14
                                       
                                     0.04
                                    Revoke
                             Crop group conversion
Nut, tree, group 14-12, except pistachio[1]
                                     0.04
                                       -
                                     0.04
                             Crop group conversion
[1]A separate tolerance exists for pistachio (0.7 ppm).

2.2.3	Revisions to Petitioned-For Tolerances

The proposed tolerances for the herb subgroup 19A and dill seed are based on the use of field trial data without adjustment for the exaggerated application rate (2.7X) represented by those trials.  Each of the two applications of pyraclostrobin were conducted at 2.7X the label rate, and the total seasonal rate was 2.7X the label rate.  Using the assumption of proportionality, i.e., that the residue levels are proportional to the rate of application, the residue results may be adjusted to the concentrations expected at the 1X rate.  The tolerance estimates at the 1X rate are 40 ppm for herb subgroup 19A and 40 ppm for dill seed.  A revised section F must be submitted.

2.2.4	International Harmonization

The Codex and US residue definitions for pyraclostrobin residues on plant commodities are different.  The Codex definition is pyraclostrobin, whereas the US definition is pyraclostrobin and its desmethoxy metabolite.  Codex has not established MRLs for pyraclostrobin on herbs or dill seed, and therefore there are no harmonization issues.  Codex has established MRLs for some members of the stone fruit group, i.e., cherries (3 mg/kg), peach/nectarine (0.3 mg/kg), and plums (0.8 ppm), but does not have a group tolerance.  Codex has established a tree nut group tolerance at 0.02 mg/kg.  The US tolerance cannot be lowered, as it includes parent and a metabolite, each at 0.02 ppm, or 0.04 ppm total.

The Canada and US definitions for the pyraclostrobin residue are harmonized.  Canada has not established MRLs for herbs or dill seed.  Canada has MRLs for tree nuts, and these are harmonized with the US.  Canada has established MRLs for various stone fruits at 0.7 ppm.  The US tolerance for stone fruits prior to 2009 was 0.9 ppm.  However, the tolerance was increased to 2.5 ppm to accommodate European Union import requirements (D359194, M. Negussie, 04/01/2009; PP#8F7390).  Refer to Appendix G for the International Residue Limits status table.

2.2.5	Label Recommendations

None.

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 numerous agricultural crops, as well as seed treatment use on oats, canola, and flax.  Additionally, it is registered for use on residential and golf course turf, residential fruit and nut trees, residential ornamentals and landscape gardens, and tomato transplants grown for the home consumer market.

With the current action, IR-4 is proposing new uses on herb subgroup 19A and dill seed as additions to the Pristine[(R)] Fungicide label (EPA Reg. No. 7969-199).  Additionally, IR-4 is proposing crop group conversions for the stone fruit group 12-12 and the tree nut group 14-12.  

3.1	Chemical Identity

The chemical structure and nomenclature of pyraclostrobin is presented in Table 3.1.

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)
Pristine(R) Fungicide, EPA Reg. No. 7969-199

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 C.  

3.3	Pesticide Use Pattern

Note:  An updated label was received; and therefore, the use pattern assessed in the occupational and residential exposure chapter and in the residue chemistry summary document are different from this comprehensive risk assessment document.  Applications by chemigation and aerial methods were removed on the updated label.

Interregional Research Project No. 4 (IR-4) is proposing new uses of pyraclostrobin on herb subgroup 19A and dill seed as additions to the Pristine[(R)] Fungicide label (EPA Reg. No. 7969-199).  Pristine[(R)] Fungicide is a multiple active ingredient water dispersible granule (WDG) fungicide containing 12.8% pyraclostrobin and 25.2% boscalid.  Herbs and dill may be treated at a maximum single application rate of 0.15 lb ai/A (18.5 fl oz/A) using ground application equipment.  Pristine[(R)] Fungicide may be applied two times per year at a maximum yearly application rate of 0.3 lb ai/A (37 fl oz/A).  The label requires occupational handlers to wear the following PPE: long-sleeved shirts, long pants, shoes and socks, and chemical resistant gloves.  The 12 hour REI listed on the label is appropriate.

Additionally, IR-4 is proposing crop group conversions for the stone fruit group 12-12 and the tree nut group 14-12.

The proposed uses of pyraclostrobin are summarized in Table 3.3.
TABLE 3.3.  Summary of Directions for the Proposed Uses of Pyraclostrobin.
                                   Use Site
                              Application Method
                        Maximum Single Application Rate
                                   (lb ai/A)
                     Maximum Number of Applications/ Year
                        Maximum Application Rate/Acre/
                                     Year
                                 (lb ai/A/yr)
                         Minimum Retreatment Interval
                                    (days)
                                      PHI
                                    (days)
                                 Herb Subgroup
                                    Ground
                                     0.15
                                       2
                                      0.3
                                       7
                                       0
                                   Dill Seed
                                       
                                     0.15
                                       2
                                      0.3
                                       7
                                       0

3.4	Anticipated Exposure Pathways

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 drinking water sources.  There are existing 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	Summary of Toxicological Effects

The most consistently observed effects of pyraclostrobin exposure across species, genders, and treatment durations were diarrhea, decreased body weight, and decreased 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 redness and chemosis (i.e., swelling of the conjunctiva) 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, food consumption, and clinical signs of toxicity).  In the reproduction study, systemic toxicity manifested as decreased body weight in both the parents and offspring; no reproductive or offspring toxicity was observed. 

In the rat subchronic inhalation toxicity studies, inhalation toxicity consisted of both portal of entry effects (i.e., olfactory atrophy/necrosis and histiocytosis in the lungs) and systemic effects (i.e., hyperplasia in the duodenum).

Pyraclostrobin was classified by the Cancer Assessment Review Committee (CARC) as "Not Likely to be Carcinogenic to Humans" based on the lack a of treatment-related increase in tumor incidence in adequately conducted carcinogenicity studies in rats and mice (CARC, 02/15/2007, TXR0054516).  Pyraclostrobin did not cause mutagenicity or genotoxicity in the in vivo and in vitro assays.  Pyraclostrobin did not cause immunotoxicity in T-cell dependent antibody response (TDAR) or Natural Killer (NK) assays in mice.

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

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

For all assessment scenarios, the 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.

4.2.1	Completeness of the Toxicology Database

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

4.2.2	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 be a reflection of the perturbations in mitochondrial respiration leading to effects on energy production.

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


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

There is no concern for pyraclostrobin causing an 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 some concern for qualitative susceptibility in the prenatal development study in rabbits the toxicity endpoints and traditional UFs are protective of these effects.  The degree of concern for prenatal and postnatal toxicity is low.

4.2.4	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 incorporating 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.  Although the acute and chronic assessments included minor refinements, the use of field trial and %CT estimates ensures that actual exposures/risks from residues in food will not be underestimated.  EPA used similarly conservative assumptions to assess post-application exposure of adults and children.  The residential exposure assessment is based on the updated 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 to pyraclostrobin.

4.3	Toxicity Endpoint and Point of Departure Selections

4.3.1	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, a new 28-day inhalation study in rats was 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.  

For acute dietary (general population) risk assessment, the point of departure (POD) is based on decreased body weight gain in males at the lowest observable adverse effect level (LOAEL) of 1,000 mg/kg/day seen in the acute neurotoxicity study ( no observable adverse effect level NOAEL) of 300 mg/kg/day).  This selected endpoint is appropriate for acute dietary risk assessment because the decreased body weight gain (33%) in males occurred during the first week after administration of the highest dose of 1000 mg/kg. 

For acute dietary (females 13-49), and short- and intermediate-term dermal exposures,  the POD is based on increased resorptions/post-implantation loss at the LOAEL of 10 mg/kg/day are assumed to occur following a single in utero exposure in the rabbit developmental toxicity study.  These effects were dose-dependently increased at the next and highest dose tested of 20 mg/kg/day.  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 dermal absorption factor of 14% will be applied to the dermal exposure assessments.

For chronic dietary, the POD is based on decreased body weight and kidney tubular casts/atrophy in both sexes, and liver necrosis and stomach lesions in males at the highest dose tested (LOAEL) of 9.2 mg/kg/day (NOAEL of 3.4 mg/kg/day).

For short- and intermediate-term incidental oral exposures, the POD is based on 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 in the 
subchronic toxicity study in the dog (NOAEL of 5.8 mg/kg/day).

The short- and intermediate-term inhalation PODs were derived from a route-specific 28-day inhalation study in rats where the NOAEL is 0.010 mg/L/day; the LOAEL is 0.030 mg/L/day for both sexes based on olfactory atrophy/necrosis in the nasal tissues.  In another subchronic inhalation study, the LOAEL at 0.030 mg/L/day for both sexes was based on findings of hyperplasia in the duodenum, alveolar histiocytosis in the lungs, and olfactory atrophy/necrosis in the nasal tissues.  In previous risk assessments, HED converted the NOAEL and LOAEL values from mg/L/day into mg/kg/day in rats only.  However, HED's standard operating procedure for the assessment of inhalation exposures have changed since the last risk assessment to account for rat-human pharmacokinetic differences thereby reducing uncertainty from 100x to 30x. Refinements were conducted to better match hazard reference values with exposure estimates for a more accurate estimation of inhalation risk.  Therefore, HED is translating an inhalation hazard reference concentration to a daily dose estimate for more accurate risk characterization.  Adjustments for species differences in breathing rates, respiratory tract architecture, and deposition fraction (aerosols) have been made.

The methods and dosimetry equations described in EPA's RfC guidance (1994) are suited for calculating HECs based on the inhalation toxicity NOAEL for use in MOE calculations.  The regional deposited-dose ratio (RDDR), which accounts for the particulate diameter (mass median aerodynamic diameter [MMAD] and geometric standard deviation [g] of aerosols), can be used to estimate the different dose fractions that are deposited along the respiratory tract.  The RDDR is also based on interspecies differences in ventilation and respiratory-tract surface areas.  Thus, the RDDR can be used to adjust an observed animal particulate inhalation exposure to the predicted inhalation exposure for a human.  For the 4-week inhalation study with pyraclostrobin, an RDDR was estimated at 0.131 based on the reported MMAD of 2.20 um and standard deviation (g) of 3.70 and the respiratory-tract surface area of the rat relative to the human (see Appendix B for detailed calculations).  Since the rat inhalation study was carried out for 6 hr/day for 5 days/week, the only exposure adjustment made was in the assumption of 8 hr/day for human occupational exposures.  The resulting HECs for residential and occupational exposures are presented in Tables 4.3.4.1 and 4.3.4.2.  The LOC is 30, which includes interspecies (3x) and intraspecies (10x) uncertainty factors.  The interspecies factor was reduced from 10x to 3x due to the HEC calculation accounting for pharmacokinetic interspecies differences, but the intraspecies factor is retained at 10x because HEC calculation does not account for pharmacodynamic intraspecies differences.

Using the reference concentration (RfC) methodology, human-equivalent concentrations (HECs) and human-equivalent doses (HEDs) were generated for residential and occupational inhalation risk assessments.  HECs were derived from the 28-day inhalation study in rats based upon the portal of entry effects in the extrathoracic (ET) region (i.e., olfactory atrophy/necrosis in the nasal tissues) which is considered a portal-of-entry effect and is protective for any systemic effects (HEC = 0.00098 mg/L for occupational handlers and HEC = 0.00131 mg/L for residential handlers).  HEDs were subsequently calculated for occupational handler exposure scenarios based upon ventilation rates of 8.3, 16.7, and 29 L/min (0.056, 0.113, and 0.195 mg/kg/day, respectively) and residential-handler exposure scenarios based upon a ventilation rate of 16.7 L/min (0.038 mg/kg/day).  For details regarding the calculation of the HECs and HEDs, see Appendix B. These HEDs are protective of the portal of entry and systemic effects observed through the inhalation route.  This study is thus appropriate for the route and duration of exposure, and is protective of adults in occupational and residential settings.

4.3.2	Recommendation for Combining Routes of Exposure for Risk Assessment

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 dermal and incidental oral exposures for toddlers were combined.

For occupational handlers, dermal and inhalation exposures were not combined, because there are no common endpoints.

4.3.3	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, 02/15/2007, TXR0054516).

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

Table 4.3.3.1.	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, 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 efficiency.
Dermal 
Short Term 
(1-30 days)

Intermediate Term
(1-6 months)
Oral NOAEL = 
5.0 mg/kg/day

DAF = 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 food efficiency.
Inhalation 
Short Term 
(1-30 days)

Intermediate Term
(1-6 months)
Inhalation NOAEL = 0.010 mg/L/day

fHandler = 
16.7 L/min
HECHandler =
0.00131 mg/L 

HECBystander =
0.00023 mg/L

HEDHandler = 
0.038 mg/kg/day
UFA = 3x
UFH = 10x
FQPA = 1x
Residential LOC for MOE = 30
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. DAF = Dermal Absorption Factor. HEC = Human Equivalent Concentration. HED = Human Equivalent Dose. f = Respiratory frequency

Table 4.3.3.2: 	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

DAF = 14%
UFA = 10x
UFH = 10x
FQPA = 1x
Occupational 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 food efficiency.
Inhalation 
Short Term 
(1-30 days)

Intermediate Term
(1-6 months) 
Inhalation NOAEL = 0.010 mg/L/day

HEC =
0.00098 m/L/day

f Applicators = 
8.3 L/min
HEDApplicators = 
0.056 mg/kg/day

f Handlers = 
16.7 L/min
HEDHandlers = 
0.113 mg/kg/day

fHandheld Spray = 
29 L/min
HEDHandheld Spray = 
0.195 mg/kg/day
UFA = 3x
UFH = 10x
FQPA = 1x
Occupational LOC for MOE = 30
Inhalation Toxicity  -  Rat
LOAEL = 0.03 mg/L/day 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. DAF = Dermal Absorption Factor. HEC = Human Equivalent Concentration. HED = Human Equivalent Dose. f = Respiratory frequency

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 (MARC, D278044, L. Cheng, 10/9/2001).  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
                           Pyraclostrobin, BF 500-3
                           Pyraclostrobin, BF 500-3

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

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

5.2	Food Residue Profile

IR-4 submitted field trial data on basil (MRID 47014803), chives (MRID 47014802), and dill (MRID 47014801).  All studies were conducted at a seasonal rate of 0.80 lb ai/acre (2 applications at 0.40 lb ai/acre) with a 0-day PHI.  The proposed use pattern is 0.30 lb ai/acre (2 applications at 0.15 lb ai/acre) with a 0-day PHI.  The trials were at a 2.7X exaggerated rate, for each application and for the seasonal application.  Proportionality was used to adjust the experimental data to the 1X rate.  The number of trials and geographic distribution are acceptable.  The analytical method used is adequate for determination of the residues of concern, and the samples were stored frozen for intervals supported by the storage stability results.  A summary of the residue data from the crop field trials is presented in Appendix F, Table F.1.  The existing field trial data for the crop group conversions are adequate.

Processed Food and Feed
Basil from each of the four field trials was dried.  The median processing factor (combined residues of pyraclostrobin and BF 500-3) is 6.2X.  These studies are adequate to estimate a processing factor for the combined residue of pyraclostrobin and BF 500-3.  In each of the trials, the fresh basil contained quantifiable residues of parent and metabolite.


Livestock
There are no feed items associated with dill seed or herbs from the herb subgroup 19A.  Therefore, the previous livestock dietary intake calculations and resulting tolerance recommendations are not changed.

Rotational Crops
Adequate limited field rotational crop studies are available supporting the existing tolerances for indirect residues in rotational crops.  These data support the label-specific plant-back interval of 14 days for crops without pyraclostrobin uses.  No additional rotational crop data are required for purposes of this petition.

5.3	Water Residue Profile

The new uses on herbs and dill seed were considered by EFED, and no change from the 2013 values was considered necessary (D417303, E. Seifu, 07/10/2014).  The drinking water residues used in the dietary risk assessment were provided by EFED (D403871, D405066, F. Khan, 02/13/2013, Addendum 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."  

EDWCs were generated using EFED's standard suite of models including the Pesticide Root Zone Model for Groundwater (PRZM- GW, version 1.0, August 31, 2012) and the Surface Water Calculator.  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 (D389729, 09/06/2007).  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.  The turf use is the same evaluation provided previously by EFED and originally used in a 2007 assessment (D389729, 9/6/2007).  All proposed new uses were considered.

Table 5.3 provides a summary of the estimated concentrations of pyraclostrobin in surface and ground 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
                                     0.02
                                     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 groundwater concentrations for acute was 0.02 ug/L 2007, D389729. 
[2] EDWCs are based on the 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, 100% crop treated, 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.  The estimated acute drinking water concentration for pyraclostrobin (0.0356 ppm) was calculated based on a turf scenario for surface water and included in the dietary exposure assessment.  

A refined chronic dietary analysis was conducted for this assessment in order to compensate for exposure resulting from residential uses in the aggregate assessment.  The chronic dietary analysis included tolerance-level or average field trial residues, average percent crop treated estimates (2014) when available, and empirical processing factors.  Screening level percent crop estimates of agricultural uses of pyraclostrobin were provided previously by the Biological & Economic Analysis Division (BEAD).  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.  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).

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 <2.5%; 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%; cotton (seed treatment) 10%; cucumber 10%; dry beans/peas 10%; garlic 10%; grapefruit 30%; grapes 30%; hazelnuts (filberts) 20%; lemons <2.5%; lettuce 5%; nectarines 10%; onions 25%; oranges 5%; peaches 20%; peanuts 25%; pears 15%; green peas 5%; pecans <2.5%; peppers 10%; pistachios 30%; plums/prunes 5%; potatoes 20%; pumpkins 20%; rice <1%; soybeans 5%; soybeans (seed treatment) 5%; spinach 5%; squash 15%; strawberries 65%; sugar beets 45%; sugarcane 10%; sweet corn 5%; tangelos 15%; tangerines 10%; tomatoes 25%; walnuts <1%; watermelons 30%; wheat 5%; wheat (seed treatment) <1%.  Note that the sugarcane estimate is from a time limited Section 18 (exp 12/2014) and not the Section 3 registration (2013).  Therefore, 100% crop treated was used for sugarcane.

5.4.3	Acute Dietary Risk Assessment

The results of the acute dietary analysis for food and drinking water indicate that acute dietary risks do not exceed the Agency's level 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).  A separate assessment was conducted for females 13-49 years to address the developmental toxicity concerns.  The estimated exposure is at the 95[th] percentile of 87% of the aPAD for this population.

5.4.4	Chronic Dietary Risk Assessments

Pyraclostrobin exposure from the existing uses and the proposed new uses on dill seed and the herbs of crop subgroup 19A results in estimated risks that are below the Agency's level of concern for food plus drinking water.  The highest exposure and risk estimates for food plus drinking water utilized 8.1% of the chronic population adjusted dose (cPAD) for the U.S. population and 27% for children 1 to 2 years old, the most highly exposed population subgroup.

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
                                    0.04687
                                      1.5
                                    0.002742
                                      8.1
 All Infants (< 1 year old)
                                    0.061725
                                      2.1
                                    0.004082
                                       12
 Children 1-2 years old
                                    0.083114
                                      2.8
                                    0.009231
                                       27
 Children 3-5 years old
                                    0.074744
                                      2.5
                                    0.006258
                                       18
 Children 6-12 years old
                                    0.044276
                                      1.5
                                    0.003566
                                       11
 Youth 13-19 years old
                                    0.031310
                                      1.0
                                    0.001869
                                      5.5
 Adults 20-49 years old
                                    0.041809
                                      1.4
                                    0.002269
                                      6.7
 Adults 50-99 years old
                                    0.041843
                                      1.4
                                    0.002282
                                      6.7
 Females 13-49 years old
                                    0.043510
                                      87
                                    0.002049
                                      6.0
*The subpopulations with the highest risk estimates are bolded.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no residential uses proposed for pyraclostrobin with this action.  However, there are existing residential uses on turf, ornamentals and garden landscapes, and on residential fruit and nut trees.  Residential exposure is expected to be short-term only.  These existing residential uses were assessed in the last HED exposure and risk assessment (D405065, B. O'Keefe, 07/03/2013) and the occupational and residential exposure risk assessment (D403449, C. Walls, 04/30/2013) to reflect updates to HED's 2012 Residential SOPs along with policy changes for body weight assumptions.  All registered products do not lead to any residential handler or residential post-application risk estimates of concern.  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 (LOCs <100).  The only new residential exposure assessment conducted in this current assessment was for handler inhalation exposure from applying WDG formulation to turf via manually pressurized handwand or backpack sprayer using the results from the new inhalation toxicity study and using HEDs/HECs.  This was from the previous highest exposure risk estimate MOE of 590, and using the HED/HEC method resulted in an MOE of 97 (LOC <30), which is still not of concern.  All previously assessed residential post-application dermal and incidental oral exposure risk estimates were also not of concern to HED, with MOEs ranging from 150 to 340,000.  In order to incorporate residential exposure into the short-term aggregate risk assessment, a summary of the scenarios that were previously determined to be most protective are presented in Table 6.1.  Note that inhalation exposure risk estimates to adults are not aggregated, since these are portal of entry effects.

Table 6.1.  Summary of Residential Exposures Used in the Pyraclostrobin Short-term Aggregate Assessments.
                                   Lifestage
                               Route of Exposure
                                   Scenario
                                     Dose
                                  (mg/kg/day)
                                      MOE
Adult
                                    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

6.1	Residential Bystander Post-application Inhalation Exposure

Volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications.  The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219).  
During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is required for pyraclostrobin.

6.2	Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications.  This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for pyraclostrobin.  The agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call-In issued by EPA), 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 also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk assessments for pesticides.  The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently.  The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs) - Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift.  This document outlines the quantification of indirect non-occupational exposure to drift.

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.  A separate assessment was conducted for females 13-49 years to address the developmental toxicity concerns.  The estimated exposure is at the 95[th] percentile of 87% of the aPAD for this population.


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.  For pyraclostrobin only oral and dermal exposures can be aggregated.  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 6.0.  

The greatest exposure non-cancer aggregate MOE for adults 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 110 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
                                   0.009231
                                      400
                                      110
                                Child 6-11 yrs
                                       5
                                     0.01
                                      490
                                       5
                                      NA
                                   0.003566
                                     1,600
                                      380
                                Youth 11-16 yrs
                                       5
                                    0.0015
                                     3,300
                                       5
                                      NA
                                   0.001869
                                     3,100
                                     1,600
                            Adult Post-application
                                       5
                                     0.019
                                      260
                                       5
                                      NA
                                   0.002742
                                     2,100
                                      230
[1] The Level of Concern MOE is 100.
[2] Total Combined MOE = 1/ [(1/MOEDermal) + (1/MOEOral)]

7.3	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 0.002742 mg/kg/day for the general U.S. population (8.1% of the cPAD) and 0.009231 mg/kg/day (27% of the cPAD) for children 1 to 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 uses on dill seed and herb subgroup 19A.  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 use is proposed for up to two applications, with a minimum retreatment interval of 7 days.  Additionally, for both dermal and inhalation exposures the same endpoint and point of departure were selected for short- and intermediate-term durations, and therefore, short-term exposure and risk estimates are considered to be protective of intermediate-term exposure and risk estimates.

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 label, 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 pyraclostrobin occupational dermal exposure assessment is 100X.  Occupational dermal exposure and risk resulting in MOEs greater than or equal to 100 will not be of concern to HED.  

For inhalation exposures, the LOC is 30, which includes interspecies (3X), and intraspecies (10X) uncertainty factors.  The interspecies factor was reduced from 10X to 3X due to the HEC calculation accounting for pharmacokinetic interspecies differences, but the intraspecies factor is retained at 10X because HEC calculation does not account for pharmacodynamic intraspecies differences.

Summaries of the short- and intermediate-term risk estimates for occupational handlers applying pyraclostrobin are provided in Appendix E, Tables E.1 and E.2.  The dermal MOEs range from 63 (mixing/loading/applying of WG formulation to support mechanically pressurized handgun applications) to 2,600 (ground application to herbs) at baseline PPE.  When assessed at labelled PPE (e.g., including gloves), the dermal MOE of 63 (mixing/loading/applying of WG formulation to support mechanically pressurized handgun applications) increased to 210.  Since all dermal MOEs at labelled PPE are greater than the LOC of 100, they are not a concern to HED.  

The inhalation MOEs range from 34 (mixing/loading of WG formulation to support ground applications to dill seed) to 1,100 (ground application to herbs) at baseline PPE (no respirator).  All handler scenario MOEs at labelled PPE (e.g., no respirator) are greater than the LOC of 30, which are not a concern to HED.

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.  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 380 to 10,000.  DFR studies are not required at this time for pyraclostrobin since all occupational dermal MOEs are >=380 and are greater than 2 times the LOC based on default input values.  The short- and intermediate-term non-cancer post-application risk estimates for workers are provided in Appendix E, Table E.3.  

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 eye and skin irritation potential.  Short- and intermediate-term post-application risk estimates were not a concern on day 0 (12 hours following application) for all post-application activities.  Under 40 CFR §156.208 (c) (2) (iii), active ingredients classified as toxicity category III or IV for acute dermal, eye irritation and primary skin irritation are assigned a 12-hour REI.  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

There are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219).  During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is required for pyraclostrobin.

In addition, the Agency is continuing to evaluate the available post-application inhalation exposure data generated by the Agricultural Reentry Task Force.  Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the agency's risk assessments.

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.

10.0	References

S. Funk, 06/30/2014, D421154.  Pyraclostrobin:  Petition for the Establishment of Permanent Tolerances and Registration for Use on Herb Subgroup 19A and Dill.  Request for Crop Group Expansions/Revisions for Stone Fruit Group 12-12 and Tree Nut Group 14-12. Summary of Analytical Chemistry and Residue Data.

S. Funk, 07/17/2014, D421148.  Pyraclostrobin. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments to Support New Uses on Dill Seed and Herbs Subgroup 19A.

C. Walls, 12/15/2014, D421149.  Pyraclostrobin.  Occupational and Residential Exposure Assessment for proposed new uses on dill seed and the herb subgroup 19A.

C. Walls, 04/30/2013, D403449.  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, 04/04/2013, D403871. Addendum of Drinking Water Exposure Assessment for the Section 3 New Uses of Pyraclostrobin on Various Agricultural Crops and Residential Ornamentals.

E. Seifu, 07/10/2014, D417303. Ecological Risk and Drinking Water Assessment Conclusions for Pyraclostrobin IR-4 Proposed New Use on Herb Subgroup 19A and Dill.



Appendix A.  Toxicology Profile and Executive Summaries

A.1	Toxicology Data Requirements

The requirements (40 CFR 158.500) for food uses of pyraclostrobin 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 Data Requirements of Pyraclostrobin.
                                     Study
                                   Technical

                                   Required
                                   Satisfied
870.1100    Acute Oral Toxicity	
870.1200    Acute Dermal Toxicity	
870.1300    Acute Inhalation Toxicity	
870.2400    Primary Eye Irritation	
870.2500    Primary Dermal Irritation	
870.2600    Dermal Sensitization	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.3100    Oral Subchronic (rodent)	
870.3150    Oral Subchronic (nonrodent)	
870.3200    21-Day Dermal	
870.3250    90-Day Dermal	
870.3465    90-Day Inhalation	
                                      yes
                                      yes
                                      yes
                                      no
                                      CR
                                      yes
                                      yes
                                      yes
                                      no
                                      yes
870.3700a  Developmental Toxicity (rodent)	
870.3700b  Developmental Toxicity (nonrodent)	
870.3800    Reproduction	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.4100a  Chronic Toxicity (rodent)	
870.4100b  Chronic Toxicity (nonrodent)	
870.4200a  Oncogenicity (rat)	
870.4200b  Oncogenicity (mouse)	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.5100    Mutagenicity -- Gene Mutation - bacterial	
870.5300    Mutagenicity -- Gene Mutation - mammalian	
870.5375    Mutagenicity -- Structural Chromosomal Aberrations	
870.5550    Mutagenicity -- Other Genotoxic Effects	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.6100a  Acute Delayed Neurotoxicity (hen)	
870.6100b  90-Day Neurotoxicity (hen)	
870.6200a  Acute Neurotoxicity Screening Battery (rat)	
870.6200b  90-Day Neurotoxicity Screening Battery (rat)	
870.6300    Develop. Neurotoxicity	
                                      CR
                                      CR 
                                      yes
                                      yes
                                      CR
                                      NA
                                      NA
                                      yes
                                      yes
                                      NA
870.7485    General Metabolism	
870.7600    Dermal Penetration	
870.7800    Immunotoxicity	
                                      yes
                                      CR
                                      yes
                                      yes
                                      NA
                                      yes
CR	Conditionally Required
NA	Not Applicable
[1]	Either guideline study type may be used to satisfy the data requirement (e.g., 870.5300 or 870.5375)


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 (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 (males), changes in clinical chemistry (increased urea and decreased triglycerides), and increased incidences in females of lymph node apoptosis, thymus atrophy, 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
Acceptable / Non-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/day):
	M:	0,	0.001,	0.030,	0.300
	F:	0,	0.001,	0.030,	0.300
Acceptable / Guideline

NOAEL (mg/L/day):	M =	0.001	F =	0.001
LOAEL (mg/L/day):	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.
                                       
4-Week 
Inhalation Toxicity
(Rat)
49459611 (2014)
Applied Dose (mg/L/day):
	M:	0,	0.030,	0.010,	0.030
	F:	0,	0.030,	0.010,	0.030
Acceptable / Guideline

NOAEL (mg/L/day):	M =	0.010	F =	0.010
LOAEL (mg/L/day):	M =	0.030	F =	0.030
Based on increased incidence of olfactory epithelium atrophy/necrosis in the nasal cavities of both sexes.
                                   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 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 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.

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 precipitating 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 (a.k.a., dermal absorption factor (DAF)) 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

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

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

Acceptable / Guideline

Immunotoxicity
NOAEL (mg/kg/day):	M =	NA	F =	165
LOAEL (mg/kg/day):	M =	NA	F >	165

Systemic
NOAEL (mg/kg/day):	M =	NA	F =	50
LOAEL (mg/kg/day):	M =	NA	F =	165
Based on decreased body weight, spleen weight, and thymus weight.



Appendix B. Methodologies for Human-Equivalent Concentration (HEC) Calculations.

B.1	Executive Summary: 4-week Inhalation Toxicity in Rats (MRID 49459611)

In an inhalation toxicity study (MRID 49459611), pyraclostrobin (99.02% a.i., batch number: COD-001236) was administered to Crl:WI(HAN) rats (10/sex/dose) nose-only via aerosol at dose levels 0, 3, 10, or 30 mg/m[3]/day (0, 0.003, 0.010, or 0.030 mg/L/day) for 6 hours/day on 20 work days during a 28-day period.  Additionally, a recovery group composed of Crl:WI(HAN) rats (10/sex/dose) were dosed at 0 or 30 mg/m[3]/day (0 or 0.030 mg/L/day) for the same duration as the main group but were given a 4-week post-exposure recovery period prior to necropsy.

There were no unscheduled mortalities in any treatment group.  In the treated animals, there were no test substance-related effects or findings with respect to clinical signs of toxicity, body weight, food consumption, ophthalmoscopic findings, hematology, clinical chemistry, organ weights, and macroscopic pathology.

At the 30 mg/m[3]/day dose of the main group, the test substance-related finding was increased incidences of olfactory epithelium atrophy/necrosis (nasal cavity levels II-IV) in both sexes.

The NOAEL is 10 mg/m[3]/day (0.010 mg/L/day) and the LOAEL is 30 mg/m[3]/day (0.030 mg/L/day) based on the increased incidence of olfactory epithelium atrophy/necrosis in the nasal cavities of both sexes.

This study is classified as Acceptable/Non-Guideline and satisfies the guideline requirement for a 90-day inhalation toxicity study (OCSPP 870.3465).  

B.2	Reference Concentration (RfC) Background

The RfC methodology applies a dosimetric adjustment that takes into consideration not only the differences in minute ventilation rate (VE) but also the physicochemical properties of the inhaled compound, the type of toxicity observed (e.g., systemic vs. portal of entry) and the pharmacokinetic (PK) but not pharmacodynamic (PD) differences between animals (A) and humans (H).  Based on the EPA's RfC guidance (1994), the methodology for RfCs derivations is an estimate of the quantitative dose-response assessment of chronic non-cancer toxicity for individual inhaled chemicals and includes dosimetric adjustment to account for the species-specific relationships of exposure concentration to deposited/delivered dose.  This adjustment is influenced by the physicochemical properties of the inhaled compound as well as the type of toxicity observed (e.g., systemic vs. portal of entry), and takes into consideration the PK differences between animals and humans.  To provide greater accuracy, the RfC also takes into account the effect of aerosols and gases on the extrathoracic (ET), tracheobronchial (TB), and pulmonary (PU) respiratory regions (r) as described in the figure below.

                                       
Figure B.2.1: Regions of the human respiratory tract used for HEC calculations 
               (Figure 3-1 of the 1994 RfC methodology document)

Though the RfC methodology was developed to estimate toxicity of inhaled chemicals over a lifetime, it can be used for other inhalation exposures (e.g., acute, short-term, and intermediate-term exposures) since the dosimetric adjustment incorporates mechanistic determinants of disposition that can be applied to shorter durations of exposures provided the assumptions underlying the methodology are still valid.  These assumptions, in turn, vary depending on the type of toxicity observed.  Thus, the derivation of a Human Equivalent Concentration (HEC) for inhaled chemicals is described by the following equation:

HECr = E x (DA / DH) x (WA / WH) x DAFr

HEC:	Human equivalent concentration (mg/L)
E:	Experimental exposure level (mg/L) or Point of Departure (POD)
D:	Number of hours exposed per 24 hours
W:	Number of days exposed per 7 days
DAF:	Dosimetric adjustment factor is a multiplicative factor used to adjust an observed inhalation exposure concentration of an animal (A) to the predicted inhalation exposure concentration for a human (H) that would be associated with the same dose delivered to a specific respiratory region (r) or target tissue.
A:	Test animals
H:	Humans

HECs can be determined using inhalation studies that are conducted using either aerosols or gases.  However, aerosols are assumed to be spherical, relatively insoluble, and non-hygroscopic particles in accordance with the 1994 RfC methodology and thus physically distinct from gases.  Therefore, the DAF for aerosols are determined differently from gases.

For inhalation studies using aerosols, the DAF is referred to as the regional deposited dose ratio (RDDR) and it is the ratio between the estimated regional deposited doses (RDD) in test animals (A) and humans (H).  The RDDR is determined through characterizing particulate exposure by defining the particulate diameter (mass median aerodynamic diameter [MMAD]) and the geometric standard deviation (σg); MMAD and GSD are used to describe the particle size distribution of any aerosol statistically based on the weight and size of the particles.  The RDDR is generally described by the following equation:

RDDRr	= (RDDr,A / RDDr,H) x (NFH / NFA)
= ((10[-6] x Ci,A x VE,A x Fr,A) / (10[-6] x Ci,H x VE,H x Fr,H)) x (NFH / NFA)
= (Ci,A / Ci,H) x (VE,A / VE,H) x (Fr,A / Fr,H) x (NFH / NFA)

Ci:	Inhaled concentration (mg/cm[3] = 10[-6] mg/m[3])
VE:	Minute volume (mL/min)
F:	Fractional deposition
NF:	Normalizing factor

However, the RDDR can be refined by applying the appropriate normalizing factor (NF) based on effects observed in the inhalation study.  The normalizing factor for respiratory (i.e., portal of entry) effects is the surface area (SA) of the specific respiratory region, but for extrarespiratory (i.e., systemic) effects it is the animal's body weight (BW).  The refined RDDR is described by the following equations:

Respiratory Effects
RDDRr	= (Ci,A / Ci,H) x (VE,A / VE,H) x (Fr,A / Fr,H) x (SAr,H / SAr,A)

Extrarespiratory Effects
RDDRER	= (Ci,A / Ci,H) x (VE,A / VE,H) x (FTOT,A / FTOT,H) x (BWH / BWA)

TOT:	Total respiratory tract

For inhalation studies using gases, the DAF is referred to as the regional gas dose ratio (RGDR) and it is the ratio between the estimated regional gas doses (RGD) in test animals (A) and humans (H).  The RGDR is determined through characterizing exposure by concentration, temperature, pressure, and gas category (i.e., Categories 1, 2 and 3). Category 1 gases are defined as gases that are highly water-soluble and/or rapidly irreversibly reactive in the respiratory tract; this category of gas does not significantly accumulate in the blood and thus has potential for respiratory but not extrarespiratory toxicity.  Category 2 gases are defined as gases that are moderately water-soluble that may be rapidly reversibly reactive or moderately to slowly irreversibly reactive in the respiratory tract; this category of gas has the potential for significant accumulation in the blood and thus has the potential for both respiratory and extrarespiratory toxicity.  Category 3 gases are defined as gases that are relatively water insoluble and unreactive in the ET and TB regions; this category of gas has the potential for extrarespiratory but not respiratory toxicity.  Reactivity is defined to include both the propensity for dissociation as well as the ability to serve as substrate for metabolism in the respiratory tract.  The RGDR for different gas categories and respiratory regions are described in the EPA's 1994 document: "Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry."

After the appropriate DAF has been applied to calculate the HEC, a route-to-route extrapolation is conducted to convert HEC inhalation units (mg/L) into human equivalent dose (HED) units (mg/kg/day).  The HED generated provide unique doses for different inhalation exposure scenarios. The route-to-route extrapolation is described with the following equation:

HEDr = HECr x A x CF x DH x AF

HED:	Human equivalent dose (mg/kg/day)
HEC:	Human equivalent concentration (mg/L)
A:	Absorption ratio through the respiratory tract as compared to the oral route; assumed to be unity
CF:	Human-specific value (L/hr/kg) that accounts for volume respired per unit time. CF equals 11.8 L/hr/kg based on the default breathing rate assumed for a typical human in the HEC calculation (i.e., the RfC Methodology's default breathing rate for HEC is 13.8 L/min for a 70 kg human; CF = 13.8 L/min / 70 kg = 11.8 L/hr/kg)
D:	Number of hours exposed per 24 hours for humans
AF:	Relative ratio that accounts for relative changes in respiratory rate due to activity level. Different AF values should be used for different occupational and residential scenarios

B.3	HEC Calculations for Short- and Intermediate-Term Inhalation Exposure Scenarios

Since pyraclostrobin is an aerosol, the HEC was determined using a RDDR for the DAF.  In turn, the RDDR for this chemical in Table B.2.1 was determined by applying the methodology above to information extracted from the pyraclostrobin subchronic inhalation toxicity study (MRID 49459611).

Table B.2.1 Regional Deposited Dose Ratio (RDDR) [MMAD = 1.6 m; g = 4.0]
                                    Species
                              Body Weight (BW, g)
                              Minute Ventilation 
                                   (VE, mL)
                              Extrathoracic (ET)
                                       
                                       
                                       
                           Surface Area (SA, cm[2])
                           Fractional Deposition (F)
Rat (R)
                                      198
                                     148.5
                                      15
                                     0.347
Human
                                     70000
                                     13800
                                      200
                                     0.381
Ratio
                                     0.003
                                     0.011
                                     0.075
                                     0.910
RDDR
                                      NA
                                      NA
                                     0.131

The magnitude of the uncertainty factors (UF) applied is dependent on the methodology used to determine the risk estimates.  The RfC methodology takes into consideration the PK differences, but not the PD difference. Consequently, the UF for interspecies extrapolation may be reduced to 3x (to account for the PD differences) while the UF for intraspecies variation is retained at 10x. Thus, the UF when using the RfC methodology is 30x.

B.4	HEC & HED Calculations for Occupational and Residential Inhalation Exposure Scenarios

HECs are calculated using DAFs, and DAFs are chosen based on the inhalation type and respiratory surfaces affected.  For pyraclostrobin, the RDDRET was chosen as the DAF because the subchronic inhalation toxicity study delivered the chemical via aerosol and the extrathoracic respiratory surface was protective of both the respiratory toxicity (i.e., olfactory atrophy and necrosis) and systemic toxicity (i.e., mucosal hyperplasia in the duodenum).  Table B.3.1 contains HECs for potential occupational and residential scenarios; residential bystander exposure was assumed to be 24 hours/day and 7 days/week.  The HECs in the table were generated using the following equation:

HECET	= E x (DA / DH) x (WA / WH) x RDDRET

HEC:	Human equivalent concentration (mg/L)
E:	Experimental exposure level (mg/L) or Point of Departure (POD)
D:	Number of hours exposed per 24 hours
W:	Number of days exposed per 7 days
DAF:	Dosimetric adjustment factor is a multiplicative factor used to adjust an observed inhalation exposure concentration of an animal (A) to the predicted inhalation exposure concentration for a human (H) that would be associated with the same dose delivered to a specific respiratory region (r) or target tissue.
A:	Test animals
H:	Humans

Table B.3.1  HEC Array for Occupational and Residential Risk Assessment
                                   Exposure
                                     Study
                                    POD / r
                                      DA
                                      DH
                                      WA
                                      WH
                                     RDDR
                                      HEC
                                      UF
                   Occupational Short and Intermediate Term
Applicators
Inhalation Toxicity
MRID 49459611
NOAEL = 0.010 mg/L
r = ET
                                       6
                                       8
                                       5
                                       5
                                     0.131
                                    0.00098
UFA = 3x
UFH = 10x
Handlers









Handheld Spray









                    Residential Short and Intermediate Term
Handler
Inhalation Toxicity
MRID 49459611
NOAEL = 0.010 mg/L
r = ET
                                       6
                                       2
                                       5
                                      N/A
                                     0.131
                                    0.00131
UFA = 3x
UFH = 10x
Bystander


                                       
                                      24
                                       
                                       7
                                       
                                    0.00023

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 (mg/L). LOAEL = lowest observed adverse effect level (mg/L). r = target respiratory region. DA = Number of hours exposed per 24 hours for animals. DH = Number of hours exposed per 24 hours for humans. WA = Number of days exposed per 7 days for animals. WH = Number of days exposed per 7 days for humans. RDDR = Regional deposited dose ratio. HEC = Human Equivalent Concentration (mg/L). UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies). N/A = not applicable. ET = Extrathoracic. TB = Tracheobronchial. PU = Pulmonary.

HED's route-to-route extrapolation converts human and animal values from mg/L concentrations to mg/kg oral-equivalent doses.  The equation uses a single conversion factor to account for default body weights and respiratory volumes.  An activity factor is used to account for increased exposure resulting from increased respiration.  More information and details in:  Memo, "Route-to-Route Extrapolations" J. Whalen and H. Pettigrew, 10/10/98.

Table B.3.2 contains HEDs for potential occupational and residential scenarios; residential exposure was assumed to be 24 hours/day and 7 days/week. The HEDs in the table were generated using the following equation:

HEDET [mg/kg/day] = HECET [mg/L] x A x CF [L/hr/kg] x D [hr/day] x AF

A:	Absorption ratio through the respiratory tract as compared to the oral route; assumed to be unity
CF:	Human-specific value that accounts for volume respired per unit time. CF equals 11.8 L/hr/kg based on the default breathing rate assumed for a typical human in the HEC calculation (i.e., the RfC Methodology's default breathing rate for HEC is 13.8 L/min for a 70 kg human; CF = 13.8 L/min / 70 kg = 11.8 L/hr/kg)
D:	Number of hours exposed per 24 hours
AF:	Relative ratio that accounts for relative changes in respiratory rate due to activity level. Different AF values should be suited for different occupational and residential scenarios

Table B.3.2  HED Array for Occupational and Residential Risk Assessment
                                   Exposure
                                      HEC
                                       A
                                      CF
                                      DH
                                      AF
                                      HED
                                      UF
                   Occupational Short and Intermediate Term
Applicators
                                    0.00098
                                      1.0
                                     11.8
                                       8
                                      0.6
                                     0.056
UFA = 3x
UFH = 10x
Handlers




                                      1.2
                                     0.113

Handheld Spray




                                      2.1
                                     0.195

                    Residential Short and Intermediate Term
Handler
                                    0.00131
                                      1.0
                                     11.8
                                       2
                                      1.2
                                     0.038
UFA = 3x
UFH = 10x
Bystander
                                    0.00023
                                      1.0
                                     11.8
                                      24
                                      N/A
                                      N/A

HEC = Human Equivalent Concentration (mg/L). HED = Human Equivalent Dose (mg/kg/day). A = Absorption ratio through the respiratory tract as compared to the oral route. CF = Human-specific value that accounts for volume respired per unit time. DH = Number of hours exposed per 24 hours for humans. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies). N/A = not applicable.

 
Appendix C.  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 D.  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 E.  Occupational Handler and Post-application Exposure and Risk Estimates

Table E.1.  Occupational Handler Non-Cancer Dermal Exposure and Risk Estimates for Pyraclostrobin.
                               Exposure Scenario
                                     Crop
                             Dermal Unit Exposure 
                                (μg/lb ai)[1]
                                      Max
                                Applic Rate[2]
                                   (lb ai/A)
                    Area Treated or Amount Handled Daily[3]
                                    Dermal
                                   Baseline
                                    Dermal
                               Baseline + gloves
                                       
                                       
                                   Baseline
                               Baseline + Gloves
                                       
                                       
                              Dose (mg/kg/day)[4]
                                    MOE[5]
                                   (LOC=100)
                              Dose (mg/kg/day)[6]
                                    MOE[7]
                                   (LOC=100)
                              Mixer/Loader of WDG
                            Groundboom application
                                    Herbs 
                                      227
                                      NA
                                     0.15
                                      80
                                    0.0055
                                      910
                                      NA
                                      NA
                            Groundboom application
                                     Dill
                                      227
                                      NA
                                     0.15
                                      200
                                     0.014
                                      360
                                      NA
                                      NA
                             Applicator of Liquids
                            Groundboom application
                                     Herbs
                                     78.6
                                      NA
                                     0.15
                                      80
                                    0.0019
                                     2,600
                                      NA
                                      NA
                            Groundboom application
                                     Dill
                                     78.6
                                      NA
                                     0.15
                                      200
                                    0.0048
                                     1,000
                                      NA
                                      NA
                        Mixer/Loader/Applicator of WDG
                       Mechanically pressurized handgun
                                     Herbs
                                     Dill
                                     1300
                                      390
                                     0.030
                                   lb ai/gal
                                     1000
                                      gal
                                     0.079
                                      63
                                     0.024
                                      210
NA: Not assessed
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).



Table E.2.  Occupational Handler Non-Cancer Inhalation Exposure and Risk Estimates for Pyraclostrobin.
                               Exposure Scenario
                                     Crop
                      Baseline Inhalation Unit Exposure 
                                (μg/lb ai)[1]
                                      Max
                                Applic Rate[2]
                                   (lb ai/A)
                    Area Treated or Amount Handled Daily[3]
                                  Inhalation
                                   Baseline 
                                (no respirator)
                                       
                                       
                                       
                                       
                                       
                                     Dose 
                                (mg/kg/day)[4]
                                    MOE[5]
                                   (LOC=30)
                              Mixer/Loader of WDG
                                  Groundboom 
                                    Herbs 
                                     8.96
                                     0.15
                                      80
                                    0.0014
                                      84
                                  Groundboom 
                                     Dill
                                     8.96
                                     0.15
                                      200
                                    0.0034
                                      34
                             Applicator of Liquids
                                  Groundboom 
                                     Herbs
                                     0.34
                                     0.15
                                      80
                                   0.000051
                                     1,100
                                  Groundboom 
                                     Dill
                                     0.34
                                     0.15
                                      200
                                    0.00013
                                      440
                        Mixer/Loader/Applicator of WDG
                       Mechanically pressurized handgun
                                     Herbs
                                     Dill
                                      3.9
                                     0.030
                                   lb ai/gal
                                     1000
                                      gal
                                    0.0015
                                      130

NA: Not assessed
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	Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount  Handled Daily (A or gal/day) / BW (kg).
5	Inhalation MOE = Inhalation HED (mg/kg/day) / Inhalation Dose (mg/kg/day).
	Where:
	Mixer/loader MOEs use HED (based on inhal rate 16.7 L/min) of 0.113 mg/kg/day
	Groundboom applicators MOEs use HED (based on inhal rate 8.3 L/min) of 0.056 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]
                                  (ug/cm[2])
                                 Dermal Dose 
                                (mg/kg/day)[2]
                                    MOE[3]
                                Dill and Herbs
                                  Irrigation
                                   (Hand Set)
                                     1,900
                                     0.42
                                     0.013
                                      380
                                       
                                   Scouting
                                     1,100
                                       
                                    0.0075
                                      660
                                       
                                 Hand weeding
                                      70
                                       
                                    0.00048
                                    10,000
1 DFR = Application Rate x F x (1-D)t x 4.54E8 ug/lb x 2.47E-8 acre/cm[2]; where F = 0.25 and D = 0.10 per day  
2	Daily Dermal Dose = [DFR (ug/cm[2]) x Transfer Coefficient x 0.001 mg/ug x 8 hrs/day x dermal absorption (14%)]  BW (69 kg).
3	MOE = POD (mg/kg/day) / Daily Dermal Dose.


Appendix F.  Summaries of Field Residue Data

Table F.1.   Summary of Residue Data from Field Trials with Pyraclostrobin.
Crop Matrix
                              Total Applic. Rate
                                   (lb ai/A)
                                  PHI (days)
Combined Residue Levels of Pyraclostrobin and its Metabolite BF 500-3 (ppm)[1]



                                       n
                                     Min.
                                     Max.
                                     HAFT
                                    Median
                                    (STMdR)
                                     Mean
                                    (STMR)
                                   Std. Dev.
BASIL.  Proposed use pattern:  Two foliar sprays at 0.15 lb ai/A/application for a seasonal rate of 0.3 lb ai/A with a 0-day PHI. 
Fresh Basil
                                   0.80-0.83
                                       0
                                       8
                                      7.2
                                     21.1
                                     16.1
                                      8.9
                                     10.9
                                      4.5
                                       
                                       
                                      3-4
                                       8
                                      1.3
                                      7.5
                                      7.4
                                      4.9
                                      4.8
                                      2.6
Dried Basil
                                       
                                       0
                                       4
                                     40.1
                                     80.6
                                     80.6
                                     74.7
                                     67.5
                                     18.5
CHIVES.  Proposed use pattern:  Two foliar sprays at 0.15 lb ai/A/application for a seasonal rate of 0.3 lb ai/A with a 0-day PHI.
Chives
                                   0.81-0.83
                                       0
                                       8
                                      0.7
                                      8.8
                                      7.8
                                      6.9
                                      5.8
                                      3.1
DILL.  Proposed use pattern:  Two foliar sprays at 0.15 lb ai/A/application for a seasonal rate of 0.3 lb ai/A with a 0-day PHI.
Dill weed
                                   0.81-0.82
                                       0
                                       8
                                     3.98
                                     19.54
                                     19.01
                                     9.66
                                     10.46
                                     5.79
Dill Seed
0.80-0.83
                                       0
                                       6
                                     3.60
                                     22.60
                                     21.20
                                     18.30
                                     14.45
                                     8.34
[1] n = number of samples, typically 2X number of trials.  Min = lowest replicate sample value.  Max = highest replicate sample value.  HAFT = highest average field trial.  STMdR = median of average field trials.  Mean = mean of average field trials.





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]
Herb, subgroup 19A
(fresh and dried)
                                      40
None

None 
Dill, seed 
                                      40
None

None
Nut, tree, group 14-12, except pistachio
                                     0.04
0.04

0.02 (*)
Fruit, stone, group 12-12
                                      2.5
0.7
(apricot, nectarine, peach, plumcot, plum cherries)

Cherries 3;
Peach/nectarine 0.3;
Plum 0.8
[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.
