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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

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. 
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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
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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
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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®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®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®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 
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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 95th 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 95th 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 Procedures1(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 

 

1

http://www.epa.gov/pesticides/science/residential-exposure-sop.html
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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. 
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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.

2.1 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 
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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 pistachio10.04 - 0.04 Crop group conversion

1A 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 
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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®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]-Nmethoxycarbamate

CAS registry number 175013-18-0

End-use product (EP) Pristine® 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 1.9×10-8 mm Hg at 20 oC limiting 

N

N

Cl

O

N O

H3C

O

OCH3
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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®Fungicide label (EPA Reg. No. 7969-

199). Pristine®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®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. 
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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.
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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.
Page 13 of 46

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.
Page 14 of 46

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 μm 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 
Page 15 of 46

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.
Page 16 of 46

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 = 

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.
Page 17 of 46

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

0.038 mg/kg/day

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
Page 18 of 46

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.
Page 19 of 46

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)

Acute1(μg/L) Chronic (μg/L)

Surface Water

NJ Nursery (no irrigation) Turf 35.6 2.3

Ground Water2

N/A 0.02 0.02
Page 20 of 46

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 μg/L respectively. Previously estimated groundwater concentrations for acute was 0.02 μg/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%; 
Page 21 of 46

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 95th

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 95th 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.
Page 22 of 46

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 SOPs2along with policy changes for body weight 

assumptions. All registered products do not lead to any residential handler or residential postapplication 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). 

 

2 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
Page 23 of 46

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). 3 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 95th percentile of 87% of the aPAD for this 

population.

 

3 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
Page 24 of 46

7.2 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 

MOE2

NOAEL

mg/kg/day

Exposure

mg/kg/day MOE1 NOAEL mg/kg/day

Incidental Oral 

Exposure 

mg/kg/day 

Chronic Dietary 

(Food + Water) 

mg/kg/day

MOE1

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.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to 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 
Page 25 of 46

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

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. 
Page 26 of 46

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 reentry 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 
Page 27 of 46

evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent 

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQOPP-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.
Page 28 of 46

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.
Page 29 of 46

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)
Page 30 of 46

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.
Page 31 of 46

Table A.2.2. Subchronic, Chronic, and Other Toxicity Profiles

Guideline Study Type MRID (year) / Doses / Classification Results

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 postimplantation loss and dams with total resorptions.
Page 32 of 46

Table A.2.2. Subchronic, Chronic, and Other Toxicity Profiles

Guideline Study Type MRID (year) / Doses / Classification Results

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.
Page 33 of 46

Table A.2.2. Subchronic, Chronic, and Other Toxicity Profiles

Guideline Study Type MRID (year) / Doses / Classification Results

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 (μg/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 (μg/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 (μg/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 (μg/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.
Page 34 of 46

Table A.2.2. Subchronic, Chronic, and Other Toxicity Profiles

Guideline Study Type MRID (year) / Doses / Classification Results

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 halflife 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.
Page 35 of 46

Table A.2.2. Subchronic, Chronic, and Other Toxicity Profiles

Guideline Study Type MRID (year) / Doses / Classification Results

870.7600 Dermal Penetration 

(Rat)

45118402 (1999)

Applied Dose (mg/cm2):

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 [14C-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/cm2, 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 μg/cm2at mean achieved doses of 0.017, 

0.087 and 0.428 mg/cm2. 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.
Page 36 of 46

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/m3/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/m3/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/m3/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/m3/day (0.010 mg/L/day) and the LOAEL is 30 mg/m3/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 speciesspecific 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.
Page 37 of 46

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 inhal ed chemicals over a 

lifetime, it can be used for other inhalation exposures (e.g., acute, short-term, and intermediateterm 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 × (DA ÷ DH) × (WA ÷ WH) × 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.
Page 38 of 46

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) × (NFH ÷ NFA)

= ((10-6× Ci,A × VE,A × Fr,A) ÷ (10-6× Ci,H × VE,H × Fr,H)) × (NFH ÷ NFA)

= (Ci,A ÷ Ci,H) × (VE,A ÷ VE,H) × (Fr,A ÷ Fr,H) × (NFH ÷ NFA)

Ci: Inhaled concentration (mg/cm

3

= 10-6 mg/m3)

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) × (VE,A ÷ VE,H) × (Fr,A ÷ Fr,H) × (SAr,H ÷ SAr,A)

Extrarespiratory Effects

RDDRER = (Ci,A ÷ Ci,H) × (VE,A ÷ VE,H) × (FTOT,A ÷ FTOT,H) × (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: 
Page 39 of 46

“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 × A × CF × DH × 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, cm2) 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 
Page 40 of 46

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 × (DA ÷ DH) × (WA ÷ WH) × 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

Bystander 24 7 0.00023 UFH = 10x

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, “Routeto-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] × A × CF [L/hr/kg] × D [hr/day] × 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
Page 41 of 46

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

Bystander 0.00023 1.0 11.8 24 N/A N/A UFH = 10x

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 References1(MRID)

Melting point/range 63.7-65.2oC 45118213

pH Not applicable

Density 1.367 g/cm345118214

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-1cm-1]): 2.5x104

at 205 nm; 2.4x104at 275 nm.

1996/109552

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.
Page 42 of 46

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). 
Page 43 of 46

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 Rate2

(lb ai/A)

Area Treated 

or Amount 

Handled 

Daily3

Dermal

Baseline

Dermal

Baseline + gloves

Baseline Baseline + 

Gloves

Dose 

(mg/kg/day)4

MOE5

(LOC=100)

Dose 

(mg/kg/day)6

MOE7

(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 0.030lb 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) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) × DAF (%) ÷ BW 

(kg).

5 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day).
Page 44 of 46

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) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × 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.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 Rate2

(lb ai/A)

Area Treated or 

Amount Handled 

Daily3

Inhalation

Baseline 

(no respirator)

Dose 

(mg/kg/day)4

MOE5

(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 0.030lb ai/gal

1000

gal 0.0015 130
Page 45 of 46

Table E.3. Occupational Post-application Non-Cancer Exposure and Risk Estimates for Pyraclostrobin.

Crop/Site Activities Transfer Coefficient 

(cm2/hr)

DFR1

(μg/cm2)

Dermal Dose 

(mg/kg/day)2 MOE3

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 × F × (1-D)t × 4.54E8 μg/lb × 2.47E-8 acre/cm2; where F = 0.25 and D = 0.10 per day 

2 Daily Dermal Dose = [DFR (μg/cm2) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × 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.
Page 46 of 46

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 Mexico2 Codex3

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)-1Hpyrazol-3-

yl]oxy]methyl]phenyl]met

hoxycarbamate, including 

the metabolite [2-[[[1-(4-

chlorophenyl)-1Hpyrazol-3-

yl]oxy]methyl]phenyl]car

bamate

- Pyraclostrobin. Residue is 

NOT fat soluble.

Commodity1 Tolerance (ppm) /Maximum Residue Limit (ppm)

US Canada Mexico2 Codex3

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.