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occupational, and aggregate exposure assessments, as needed, to estimate the risk to human health 

that will result from the proposed use of picoxystrobin.

HED has evaluated the toxicity and exposure databases for picoxystrobin, and has conducted a 

human health risk assessment in support of the proposed use. No risk concerns were identified. 

Based on this assessment, HED has recommended for an unconditional registration and permanent 

tolerances for the proposed uses, provided that a revised Section B is requested to allow use of a 

non-ionic surfactant only; remove the restriction of using forage and hay (sorghum and millet); 

specify a 10 month PBI for leafy vegetables and 12 month PBI for all other crops including root and 

tuber vegetables.

A summary of the findings and an assessment of human health risk resulting from the proposed use 

of picoxystrobin on various agricultural crops are provided in this document. The HED team 

members contributing to this risk assessment include Cassi Walls (risk assessment and 

occupational/residential assessments), Whang Phang and Vincent Chen (hazard evaluation), and 

Meheret Negussie (residue chemistry and dietary risk assessment).
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2.0 HED Recommendations ......................................................................................................... 7

2.1 Data Deficiencies/Conditions of Registration................................................................... 7

2.2 Tolerance Considerations................................................................................................... 8

2.2.1 Enforcement Analytical Method ....................................................................................... 8

2.2.2 International Harmonization............................................................................................. 9

2.2.3 Recommended Tolerances.................................................................................................. 9

2.2.4 Revisions to Petitioned-For Tolerances .......................................................................... 11

2.3 Label Recommendations.................................................................................................. 12

2.3.1 Recommendations from Residue Reviews...................................................................... 12

2.3.2 Recommendations from Occupational Assessment....................................................... 13

2.3.3 Recommendations from Residential Assessment........................................................... 13

3.0 Introduction........................................................................................................................... 13

3.1 Chemical Identity.................................................................................................................. 13

3.2 Structure and Nomenclature ........................................................................................... 13

3.3 Physical/Chemical Characteristics.................................................................................. 14

3.4 Pesticide Use Pattern ........................................................................................................ 14

3.5 Anticipated Exposure Pathways...................................................................................... 16

4.0 Hazard Characterization and Dose-Response Assessment............................................... 17

5.0 Dietary Exposure and Risk Assessment.............................................................................. 23

5.1 Metabolite/Degradate Residue Profile ............................................................................ 23

5.1.1 Summary of Plant and Animal Metabolism Studies ..................................................... 23

5.1.2 Summary of Environmental Degradation ...................................................................... 24

5.1.3 Comparison of Metabolic Pathways................................................................................ 24

5.1.4 Residues of Concern Summary and Rationale............................................................... 25

5.2 Food Residue Profile......................................................................................................... 27

5.3 Water Residue Profile....................................................................................................... 29

5.4 Dietary Risk Assessment .................................................................................................. 30

5.4.1 Description of Residue Data Used in Dietary Assessment ............................................ 30

5.4.2 Percent Crop Treated Used in Dietary Assessment....................................................... 31

5.4.3 Acute Dietary Risk Assessment ....................................................................................... 31

5.4.4 Chronic Dietary Risk Assessment ................................................................................... 32

5.4.5 Cancer Dietary Risk Assessment..................................................................................... 32

5.4.6 Summary Table................................................................................................................. 33

6.0 Residential (Non-Occupational) Exposure/Risk Characterization .................................. 34

6.1 Spray Drift......................................................................................................................... 34

7.0 Aggregate Exposure/Risk Characterization....................................................................... 34

8.0 Cumulative Exposure/Risk Characterization .................................................................... 34

9.0 Occupational Exposure/Risk Characterization ................................................................. 34

10.0 References.............................................................................................................................. 35

Appendix A. International Residue Limits.................................................................................... 36

Appendix B. Chemical Names and Structures of Picoxystrobin Metabolites/Degradates......... 38

Appendix C. Physical/Chemical Properties................................................................................... 52

Appendix D. Toxicology Profile and Executive Summaries ........................................................ 53

D.1 Toxicology Data Requirements........................................................................................ 53

D.2 Toxicity Profiles ............................................................................................................... 54

D.3 Dermal Absorption ............................................................................................................... 61
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Appendix E: Hazard Identification and Endpoint Selection................................................... 62

Appendix F: Executive Summaries................................................................................................ 65

Appendix G. Picoxystrobin Dietary Burden Calculation for Risk Assessment......................... 83

Appendix H. Human Equivalent Concentration and Dose Calculations ................................... 86
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1.0 Executive Summary

Use Profile:

DuPont has proposed uses for the new active ingredient, picoxystrobin, on cereal grains (Crop Group 

15) except rice, cereal forage/fodder (Crop Group 16) except rice, legume vegetables-dry, except 

soybean (Crop Group 6, Subgroup C), legume vegetables, foliage (Crop Group 7), soybeans, and 

canola. Picoxystrobin is a broad-spectrum fungicide which controls foliar and soil-borne plant 

diseases and has preventive, curative, and systemic activity. It inhibits mitochondrial respiration by 

blocking electron transfer at the Qo center of cytochrome bc1.

DuPont submitted their application for picoxystrobin registration as a North American Free Trade 

Agreement (NAFTA) Joint Review to USEPA and Canada (PMRA). These actions will be the first 

registrations in the U.S. Picoxystrobin is currently registered in European, African and Latin 

American countries for uses on cereal grains and other commodities.

In the U.S., the proposed picoxystrobin end use product is formulated as a suspension concentrate 

(SC) containing 22.5% active ingredient (2.08 lb ai/gal). The product is proposed for foliar 

applications at a maximum single application rate of 12 fl oz/A/application (0.2 lb ai/A/application) 

and seasonal application rate of 36 fl oz/A (0.6 lb ai/A) using ground, air or chemigation equipment. 

The proposed pre-harvest intervals (PHIs) range from 0 (legume vegetables – vines, hay, and corn 

forage) to 45 days (wheat and barley grain and straw). The restricted entry interval (REI) on the 

proposed label is 12 hours.

Exposure Profile:

The requested uses may result in human exposure to picoxystrobin and/or its metabolites in food and 

drinking water. The source of dietary exposure in food is from low level residues in cereal grains and 

secondary residues in livestock commodities resulting from the consumption of picoxystrobin 

treated feed items. Picoxystrobin residues may also reach drinking water; modeling indicates that 

surface water residues are likely to be higher than those in ground water. At this time, there are no 

existing, pending, or requested registrations that would result in exposure from use in a residential 

setting. In the occupational setting, dermal and/or inhalation exposure to agricultural workers is 

expected to be of short- and intermediate term durations based on the frequency of application to 

crops. 

Hazard Identification:

The most consistently observed effects of picoxystrobin exposure across species, genders, and 

treatment durations were decreased body weight, body weight gain and food consumption, and 

diarrhea.

Picoxystrobin toxicity following acute oral, dermal, and inhalation exposure is considered low to 

moderate (Toxicity Categories II-IV); there was no evidence of dermal irritation or sensitization. 

Picoxystrobin was, however, determined to be a severe eye irritant (Toxicity Category I).
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Developmental toxicity seen in the rat and rabbit was considered of low concern. In both species, the 

observed fetal effects consisted of slight skeletal variations that were seen at well-defined 

NOAELs/LOAELs and occurred in the presence of maternal toxicity. There was no evidence that 

picoxystrobin directly affects the nervous system; behavioral changes observed in the acute and 

subchronic neurotoxicity studies were attributed to general malaise. Picoxystrobin has no effects on 

the immune system in rats and mice, and is not mutagenic or genotoxic. No adverse dermal or 

systemic effects were identified in the rat following dermal exposure at the limit dose. In the 

inhalation toxicity study, rats showed no portal of entry, respiratory or systemic toxicity. 

Chronic picoxystrobin exposure induced a treatment-related increase in testicular interstitial cell 

benign tumors in male rats at the high dose only. No tumors were seen in female rats or in male and 

female mice, and there is no mutagenic concern. The carcinogenicity classification for picoxystrobin 

is “Suggestive Evidence of Carcinogenic Potential” and quantification of cancer risk is based on a 

non-linear approach (i.e., RfD) which adequately accounts for all chronic toxicity, including 

carcinogenicity, which could result from exposure to picoxystrobin.

FQPA Recommendation:

HED has retained the 10X FQPA safety factor in the form of a UFL for acute dietary risk assessment 

because a NOAEL was not established in the acute neurotoxicity study selected for this exposure 

scenario. The acute neurotoxicity study’s extrapolated NOAEL of 20 mg/kg is considered protective 

for all populations including potentially pregnant females. For all other risk assessment scenarios, 

the default 10X FQPA Safety Factor is reduced to 1X because: 1) the toxicology database is 

complete; 2) there are no indications that the nervous system is a target for picoxystrobin; 3) there is 

no evidence of increased susceptibility seen in the rat and rabbit developmental studies; and 4) there 

are no residual uncertainties in the exposure database.

End Points and Uncertainty Factors for Risk Assessment:

A Point of Departure (PoD) for acute dietary risk assessment was selected from the acute 

neurotoxicity study; behavioral effects and decreased bodyweight gain and food consumption were 

observed after a single oral administration at the LOAEL of 200 mg/kg/day. An Acute Reference 

Dose (aRfD) and acute Population Adjusted Dose (aPAD) of 0.2 mg/kg/day was derived from the 

LOAEL and the application of an Uncertainty Factor of 1000 which includes the conventional 10X 

inter-species extrapolation and the 10X intra-species variation factors, and a 10X UFL for the use of 

the LOAEL.

A PoD for chronic dietary risk assessment was selected from the 1-year dog study; decreased body 

weights, bodyweight gains, and food consumption were seen in both sexes of dogs at a LOAEL of 

15.7 mg/kg/day. A chronic RfD and chronic PAD (cPAD) of 0.046 mg/kg/day was derived from a 

PoD of 4.6 mg/kg/day and a UF of 100 which includes the conventional 10X inter-species 

extrapolation and the 10X intra-species variation factors.

An endpoint and dose were not selected for dermal risk assessment since no dermal systemic hazard 

was observed at the limit dose in a rat dermal toxicity study.
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A PoD for inhalation exposure risk assessment for the proposed uses was not identified since no 

portal of entry, respiratory or systemic toxicity was seen following repeated exposures at the highest 

concentration tested (0.025 mg/L/day, 6.78 mg/kg/day). Thus, for the proposed uses considered in 

this risk assessment, HED concluded that selection of an inhalation endpoint and quantitative 

inhalation risk estimates are not needed.

Human Health Risk Assessment:

For this action, the only risk assessments conducted were for aggregate acute and chronic dietary 

(food and water) exposures to picoxystrobin. There are no proposed residential uses of 

picoxystrobin; therefore, a residential exposure assessment was not necessary. In addition, since no 

hazard was identified for the dermal or inhalation routes of exposure, there are no occupational 

dermal and inhalation risks associated with the proposed uses.

Aggregate Acute Dietary: Exposure inputs included highest field trial residues for parent plus 

metabolites of concern for all proposed crops, 100% crop treated (CT), tolerance levels for livestock 

commodities, empirical or default processing factors, and a surface water residue estimate (7.95 ppb) 

modeled using a total residue method. Aggregate risk for the general U.S. population and all 

population subgroups is well below HED’s level of concern [<100% of the acute Population 

Adjusted Dose (aPAD)]. The aggregate acute dietary risk estimates are <1% of the aPAD for the 

general U.S. population and 1.3 % of the aPAD for children 1-2 years old, the most highly exposed 

population subgroup. 

Aggregate Chronic Dietary: Exposure inputs included highest average field trial residues for 

parent plus metabolites of concern for all proposed crops, 100% CT, tolerance levels for livestock 

commodities, empirical or default processing factors, and a surface water residue estimate (2.41 ppb)

modeled using a total residue method. Aggregate risk for the general U.S. population and all 

population subgroups is well below HED’s level of concern [<100% of the chronic Population 

Adjusted Dose (cPAD)]. The aggregate chronic dietary risk estimates are 1% of the cPAD for the 

general U.S. population and 2.8% of the cPAD for children 1-2 years old the most highly exposed 

population subgroup.

Aggregate Cancer Dietary: HED has concluded that assessments using a non-linear approach 

(e.g., a chronic RfD-based assessment) will adequately account for all chronic toxicity, including 

carcinogenicity that could result from exposure to picoxystrobin. Chronic dietary risk estimates are 

below HED’s level of concern; therefore, cancer risk is also below HED’s level of concern.

Environmental Justice Considerations: Potential areas of environmental justice concerns, to the 

extent possible, were considered in this human health risk assessment. Dietary and non-dietary 

exposures were considered.

2.0 HED Recommendations

2.1 Data Deficiencies/Conditions of Registration
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Provided revised Sections B (OPPTS 860.1200) and F (OPPTS 860.1550) are submitted, HED can 

recommend for an unconditional registration and permanent tolerances for the proposed uses of 

picoxystrobin.

Future proposed tolerances and uses should include the following residue chemistry data:

860.1300 Nature of the Residue – Livestock

The nature of the residue in poultry is adequately understood for the currently proposed uses, 

since tolerances are not needed for residues in poultry commodities. However, if additional 

crops are proposed in the future that are significant feedstuffs for poultry, 

characterization/identification of tissues (liver, muscle, and fat) and storage stability data 

(eggs and tissues) will need to be provided for the laying hen metabolism study (MRID 

48073858).

For future uses resulting in a higher livestock dietary burden, additional livestock metabolism 

studies may be needed to further characterize the metabolite residues in milk and poultry 

matrices. 

860.1300 Nature of the Residue – Plants

If additional crops are proposed in the future, a metabolism study on a root crop must be 

conducted.

860.1900 Field Rotational Crops

For future uses with shorter PBIs, additional field rotational studies may be needed to 

characterize metabolite residues, particularly compounds 11, 20, 29, and 30 (which were 

observed at high concentrations in the confined studies).

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate residue analytical method for tolerance enforcement and data collection was submitted. 

The liquid chromatography tandem mass spectrometry (LC/MS/MS) Method in report DuPont24868 was submitted for the determination of picoxystrobin and the metabolites (IN-QDK50 or 

Compound 3, IN-QDY62 or Compound 2 and IN-QDY63 or Compound 8) in/on cereal grains, 

cereal forage/fodder, legume vegetables-dry, legume vegetables foliage, soybeans, rapeseed, and 

associated processed commodities. Two mass ion transitions per analyte were monitored for the 

quantitation and confirmation. The confirmatory method was based on detection and the relative 

ratios of the two parent-to-daughter ion transitions monitored. The method limit of quantitation 

(LOQ) for each analyte was 0.010 ppm. The estimated limit of detection (LOD) is reported at onethird of the LOQ for each analyte. The method was adequately validated. The method uses the same 

extraction solvent and procedure as those used in the plant metabolism studies. Based on these 

results, the LC-MS/MS method is considered suitable for data-gathering and enforcement purposes. 
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The method may be forwarded to FDA for inclusion in the Pesticide Analytical Manual PAM, Vol. 

II. 

An LC/MS/MS method in report DuPont-25997 was submitted for the determination of residues of 

picoxystrobin in livestock commodities. The method was used for data collection in samples of 

livestock commodities from the cattle and hen feeding studies associated with the current petition. It 

is also the proposed enforcement method for animals. The method was adequately validated at the 

LOQ of 0.01 ppm, using animal tissues including poultry egg, bovine whole and skim milk, cream, 

muscle, liver, kidney, and fat.

The LC/MS/MS methods are suitable enforcement methods for plant and animal commodities. Both 

plant and livestock methods describe two mass ion transitions. 

The multi-residue method based on natural fluorescence is not suitable for the regulatory analysis of 

picoxystrobin and its three metabolites when using a C18 column. Acceptable recoveries of 

picoxystrobin from a non-fatty matrix (apple) were achieved under Protocol D and E. Acceptable 

recoveries from a fatty matrix (soybeans) were also achieved under Protocol F. The multiresidue 

methods testing data will be forwarded to FDA for further evaluation and inclusion of results in 

PAM Vol. I.

2.2.2 International Harmonization

Picoxystrobin is part of a joint review project with Canada. During the course of the review, the 

partners reached agreement on both the tolerance expression and the tolerance levels for 

commodities common to the reviewing countries. 

There are no Codex or Mexican maximum residue limits (MRLs) for picoxystrobin, and the 

recommended U.S. and Canadian MRLs are harmonized for all proposed crops. The U.S. has 

recommended tolerances for some livestock feed commodities, but by policy Canada does not 

establish MRLs for livestock feed commodities. Canada has established an MRL of 0.01 ppm for 

eggs and poultry commodities based on the existence of poultry feed commodities with finite 

residues. Even though there is no reasonable expectation of finite residues on eggs and poultry

commodities, the US is proposing tolerances on these commodities for harmonization purposes. 

Therefore, there are no issues with respect to international harmonization associated with the 

tolerances recommended in this action. An International Residue Limit Status sheet is attached 

(Appendix A).

The petitioner requested a tolerance for canola seed and not for subgroup 20A, for which canola is 

the representative commodity. Canada is establishing a tolerance at 0.08 ppm for subgroup 20A. 

For harmonization purposes, the petitioner is being requested to revise the tolerance request to 

subgroup 20A at 0.08 ppm as opposed to canola at 0.08 ppm.

2.2.3 Recommended Tolerances

Table 2.2.3 summarizes the registrant’s proposed tolerances and the Agency’s final tolerance 

recommendations. The tolerance expression for picoxystrobin should read as follows:
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Tolerances are established for residues of the fungicide picoxystrobin, including its 

metabolites and degradates, in or on the commodities listed below. Compliance with the 

tolerance levels specified below is to be determined by measuring only picoxystrobin, 

methyl (αE)-α-(methoxymethylene)-2-[[[6-(trifluoromethyl)-2-

pyridinyl]oxy]methyl]benzeneacetate.

Table 2.2.3. Tolerance Summary for Picoxystrobin

Commodity Proposed Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments; 

Correct Commodity Definition

Grain, cereal, except rice, 

(Group 15)

Proposed as Crop 

Group 15 at 0.2

0.04 Grain, cereal, group 15, except rice 

and barley

Grain, cereal, forage and 

fodder, except rice, (Group 

16)

Proposed as Crop 

Group 16 at 13.0

2.0 Grain, cereal, forage, fodder, and 

straw, group 16, straw 

Grain, cereal, forage and 

fodder, except rice, (Group 

16)

10 Grain, cereal, forage, fodder, and 

straw, group 16, stover 

Grain, cereal, forage and 

fodder, except rice, (Group 

16)

5.0 Grain, cereal, forage, fodder, and 

straw, group 16, hay 

Grain, cereal, forage and 

fodder, except rice, (Group 

16)

15 Grain, cereal, forage, fodder, and 

straw, group 16, forage 

Cereal grain oil 1.5 0.07 Corn, field, refined oil

Cereal (Wheat), aspirated 

grain fractions

4.5 10 Grain, aspirated grain fractions

Vegetable, legume, dried 

shelled, except soybean, 

(Group 6-C)

0.1 0.06 Pea and bean, dried shelled, except 

soybean, subgroup 6C

Vegetable, foliage of 

legume, (Group 7)

Proposed as Crop 

Group 7 at 18

40 Vegetable, foliage of legume, except 

soybean, subgroup 7A

Soybean, seed 0.05 0.05

Soybean forage 0.8 1.0 Soybean, forage

Soybean hay 2.5 3.0 Soybean, hay

Soybean, hulls 10.0 0.20

Soybean, aspirated grain 

fractions

3.2 10 Grain, aspirated grain fractions

Soybean, oil 0.08 None

Canola, seed 0.05 0.08

Additional Tolerance(s) on Primary Crop Commodities That Need to be Proposed/Established

Barley, grain Proposed as crop 

group at 0.2

0.30 Barley, grain

Wheat, bran Not proposed 0.06 Wheat, bran

Wheat, germ Not proposed 0.09 Wheat, germ

Barley, bran Not proposed 0.5 Barley, bran

Livestock Commodities That Need to be Proposed/Established

Cattle, fat 0.05 0.01
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Table 2.2.3. Tolerance Summary for Picoxystrobin

Commodity Proposed Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments; 

Correct Commodity Definition

Cattle, liver 0.8 None Tolerance is established as meat 

byproducts at 0.01

Cattle, meat 0.01 0.01

Cattle, meat byproducts, 

except liver

0.01 0.01 Cattle, meat byproducts, except 

kidney

Goat, fat 0.05 0.01

Goat, liver 0.8 None Tolerance is established as meat 

byproducts at 0.01

Goat, meat 0.01 0.01

Goat, meat byproducts, 

except liver

0.01 0.01 Goat, meat byproducts, except 

kidney

Hog, fat 0.05 Established at 0.01 

for harmonization 

purposes

Based on the transfer coefficients for 

livestock tissues and the relatively 

low dietary burden for swine of 

0.013 ppm for picoxystrobin, 

tolerances for hogs are not needed.

Hog, liver 0.8

Hog, meat 0.01

Hog, meat byproducts, 

except liver

0.01

Horse, fat 0.05 0.01

Horse, liver 0.8 None Tolerance is established as meat 

byproducts at 0.01

Horse, meat 0.01 0.01

Horse, meat byproducts, 

except liver

0.01 0.01 Horse, meat byproducts, except 

kidney

Sheep, fat 0.05 0.01

Sheep, liver 0.8 None Tolerance is established as meat 

byproducts at 0.01

Sheep, meat 0.01 0.01

Sheep, meat byproducts, 

except liver

0.01 0.01 Sheep, meat byproducts, except 

kidney

Poultry, eggs 0.01 Established at 0.01 

for harmonization 

purposes

Based on the transfer coefficients for 

poultry tissues and the relatively low 

dietary burden for poultry of 0.016

ppm for picoxystrobin, tolerances for 

poultry are not needed

Poultry, fat 0.01

Poultry, meat 0.01

Poultry, meat byproducts 0.01

Milk 0.01 0.01

Cream 0.03 Not needed

2.2.4 Revisions to Petitioned-For Tolerances

HED is recommending that tolerances be set at levels different than those requested by the registrant 

for a variety of food and feed commodities. Use of the Organisation for Economic Co-operation and 

Development tolerance calculation procedure (OECD TCP) resulted in differences between the 

recommended and proposed tolerance levels. Livestock tolerances are recommended based on the 

calculated dietary burden to account for the transfer of residues to livestock matrices (tissues and 

milk).
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For the cereal grain, except rice (crop group 15), crop group 16, and foliage of legume vegetables 

(7A) the proposed tolerance differ from the recommended because a crop group tolerance could not 

be established due to the fact that the minimum and maximum recommended tolerances differ by 

more than 5x. Therefore, separate tolerances listed above are recommended.

For wheat bran and wheat germ, based on the data from the wheat processing study, residues of 

picoxystrobin concentrate in wheat bran (2x) and germ (3.2x). The maximum expected residues of 

picoxystrobin are 0.06 ppm and 0.09 ppm, respectively. The recommended tolerance on barley bran 

at 0.5 ppm is derived using 2x concentration factor of wheat bran. Tolerances were not proposed for 

these commodities. 

For corn oil, based on the corn processing study, residues of picoxystrobin concentrate in refined oil 

and dry milled refined oil. The maximum expected residue of picoxystrobin in corn refined oil (0.07 

ppm) is the recommended tolerance, whereas the proposed tolerance is 1.5 ppm for Cereal (Corn) 

oil.

For soybean, based on the soybean processing study, residues of picoxystrobin concentrate in 

soybean hulls (3.9x) and refined oil (1.3x). The maximum expected residue of picoxystrobin in 

soybean hulls and soybean refined oil resulting from the proposed use is 0.152 ppm and 0.051 ppm, 

respectively. HED recommends a tolerance of 0.20 ppm for soybean hulls, whereas the proposed 

tolerance is 10 ppm for soybean hulls. The soybean oil residues will be covered by the soybean seed 

tolerance at 0.05 ppm, and a separate tolerance is not needed for soybean oil.

Aspirated grain fractions (AGF) Bulk corn grain, wheat grain, and soybean seed samples were 

processed into corresponding AGFs. Residues of picoxystrobin concentrate 14.3x in corn AGF, 

18.6x on wheat AGF, and 255x on soybean AGF. The maximum expected residue of picoxystrobin 

in/on field corn, wheat, and soybean aspirated grain fractions are 0.143, 0.521, and 9.945 ppm, 

respectively.

HED recommends a tolerance of 10 ppm for residues of picoxystrobin in/on grain, aspirated grain 

fractions (based on soybeans). OPPTS 860.1500(f)(3)(v) indicates that, if a pesticide is used on 

several crops, the raw agricultural commodity (RAC) with the highest residue in the dust will be 

used to establish the tolerance. The proposed tolerances for soybean aspirated fractions and cereal 

(wheat) AGF are 3.2 and 4.5 ppm, respectively. 

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

A revised Section B is requested to allow use of a non-ionic surfactant only; remove the restriction 

of using forage and hay (sorghum and millet); specify a 10 month plantback interval (PBI) for leafy 

vegetables and 12 month PBI for all other crops including root and tuber vegetables. These 

recommended label revisions are detailed below:

The submitted label should be revised to remove the statement that APROACHTM may be 

tank mixed with other physically compatible pesticides, non-ionic surfactants (NIS), crop oil 
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concentrates (COC), and methylated seed oils (MSO).

The submitted label should be revised to remove the statement that treated areas may be 

replanted immediately after harvest with any crop appearing on the label and all other crops 

may be planted 6 months following the last application. Based on the results of the rotational 

crop metabolism study, the label should include a 10 month PBI for leafy vegetables and 12 

month PBI for all other crops including root and tuber vegetables.

The submitted label should be revised to remove the statement “Do not use for hay or forage” 

(sorghum) since it is not enforceable.

The Section B/label must be revised to indicate use on rapeseed subgroup 20A rather than 

canola seed. 

2.3.2 Recommendations from Occupational Assessment

Because picoxystrobin is a Toxicity Category I (severe) for eye irritation, goggles must be included 

as personal protection equipment (PPE) and the restricted entry interval (REI) must be increased 

from 12 hours to 48 hours per the Worker Protection Standards (WPS).

2.3.3 Recommendations from Residential Assessment

None. There are currently no registered or proposed residential uses of picoxystrobin. 

3.0 Introduction

3.1 Chemical Identity

Picoxystrobin is the active ingredient in the end-use product DuPontTM ApproachTM Fungicide. It is 

a broad-spectrum fungicide, recommended for control of foliar and soil-borne plant diseases. It

inhibits mitochondrial respiration by blocking electron transfer at the Qo centre of cytochrome bc1. 

Picoxystrobin is a preventive and curative fungicide with unique distribution properties including 

systemic (acropetal) and translaminar movement, and diffusion in leaf waxes.

3.2 Structure and Nomenclature

The chemical structure and nomenclature of picoxystrobin are presented in Table 3.1. Chemical 

names and structures of the metabolites are presented in Appendix B.

Table 3.2. Picoxystrobin Nomenclature

Compound Chemical Structure

 

Common name Picoxystrobin

Company experimental name ZA1963, or DPX-YT699

CH3O

CO2CH3

F3C N O
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IUPAC name methyl (2E)-3-methoxy-2-{2-[6-(trifluoromethyl)-2-

pyridyloxymethyl]phenyl}acrylate 

CAS name methyl (αE)-α-(methoxymethylene)-2-[[[6-(trifluoromethyl)-2-

pyridinyl]oxy]methyl]benzeneacetate 

CAS # 117428-22-5

End-use product/EP DuPontTM AproachTM Fungicide (EPA Reg No. 352-IUN)

3.3 Physical/Chemical Characteristics

Picoxystrobin has a relatively low vapor pressure (5.5 x 10-6 Pa) and a Henry’s Law Constant of 6.5 

x 10-4Pa m3 mol-1which decreases its potential for volatility. Although the octanol/water partition 

coefficient (log KOW ~3.6) indicates that the compound may be fat soluble, a fish bioaccumulation 

study showed no indication of bioaccumulation. Picoxystrobin is moderately persistent in soil and 

stable to hydrolysis in water under normal environmental conditions. The physical and chemical 

properties of picoxystrobin are detailed in Appendix C.

3.4 Pesticide Use Pattern

Picoxystrobin is formulated as a suspension concentrate (SC) containing 22.5% active ingredient 

(equivalent to 2.098 lb ai/gal) in the end-use product (EP), DuPontTM AproachTM SC Fungicide 

(EPA Reg. No.352-IUN). The EP is proposed for a maximum of 36 fl oz/A (0.6 lb ai/A seasonal) 

foliar spray applications using ground, aerial, or chemigation equipment at a maximum single 

application rate of 0.195 lb ai/A. The proposed preharvest intervals (PHIs) range from 0 (field corn 

forage, pea vines and hay) to 45 days (wheat grain and straw).

The submitted label for use on crops is adequate to allow evaluation of the residue data relative to 

the proposed uses. Refer to Section 2.3 for recommended modifications to the proposed labels. 

Table 3.4. Summary of Directions for Use of Picoxystrobin.

Trade Name; 

Formulation;

[EPA File 

Symbol No.]

App. Equip. App.Rate 

(lb ai/A)

[fl oz /A]

Max. 

No. 

App. 

per 

Season

RTI1

(days)

Max. 

Seasonal 

App. Rate

(lb ai/A)

[fl oz /A]

PHI

(days)

Use Directions and other 

Limitations

Canola

DuPontTM 

AproachTM

2.08 lb ai/gal 

SC

[352-IUN]

Ground, air 

or 

chemigation

0.13-0.2

[8-12]

N/S 14 0.4

[24]

28 Begin applications prior to 

disease development or at 20-

50% bloom prior to disease 

development and continue on a 

7-14 day interval. Use higher 

rate and shorter interval when 

disease pressure is high. Make 

no more than 2 sequential 

applications before switching to 

a different mode of action. 

Cereal Grains, (except rice) (Barley, Wheat, Rye, Oats, Buckwheat, Teosinte, Triticale)
Picoxystrobin Human Health Risk Assessment DP No. 377690

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Table 3.4. Summary of Directions for Use of Picoxystrobin.

Trade Name; 

Formulation;

[EPA File 

Symbol No.]

App. Equip. App.Rate 

(lb ai/A)

[fl oz /A]

Max. 

No. 

App. 

per 

Season

RTI1

(days)

Max. 

Seasonal 

App. Rate

(lb ai/A)

[fl oz /A]

PHI

(days)

Use Directions and other 

Limitations

DuPontTM 

AproachTM

2.08 lb ai/gal 

SC

[352-IUN]

Ground, air 

or 

chemigation

0.05-0.2

[3-12]

N/S 14 0.6

[36]

45-grain and 

straw

14-hay

7-forage

Apply early season for 

preventive disease control. Begin 

applications prior to disease 

development and continue on a 

7-14 day interval. Use higher 

rate and shorter interval when 

disease pressure is high. For 

optimizing yield and flag leaf

disease control, apply at Feeke’s 

9, ‘flag leaf out’. Do not apply 

after flowering (Feekes 10.5). 

Make no more than 2 sequential 

applications before switching to 

a different mode of action.

Cereal Grains, (except rice) (Millet (pearl, proso), Sorghum (milo), Sorghum spp. (sudangrass and hybrids)

DuPontTM 

AproachTM

2.08 lb ai/gal 

SC

[352-IUN]

Ground, air 

or 

chemigation

0.1-0.2

[6-12]

N/S 14 0.6

[36]

Begin applications prior to 

disease development and 

continue on a 7-14 day interval. 

Use higher rate and shorter 

interval when disease pressure is 

high. Make no more than 2 

sequential applications before 

switching to a different mode of 

action.

Do not apply after flowering; Do 

not use for hay or forage.

Corn (Field, Sweet, Seed, Popcorn)

DuPontTM 

AproachTM

2.08 lb ai/gal 

SC

[352-IUN]

Ground, air 

or 

chemigation

0.05-0.2

[3-12]

N/S 14 0.6

[36] 

7-grain and ear

0-forage or 

grazing 

Apply a single 3-4 oz application 

between V4 to V7 for early 

season disease control. 

Make additional 6-12 fl oz 

applications (between VT to R3) 

prior to disease development at 

7-14 day intervals. Use higher 

rate and shorter interval when 

disease pressure is high. Make 

no more than 2 sequential 

applications before switching to 

a different mode of action.

Legume Vegetables (dry shelled beans and peas) 

Broad Bean (dry); chickpea (garbanzo); guar; lablab bean; lentil; pigeon pea; (Lupinus) grain lupin, sweet 

lupin, white lupin, and white sweet lupin; ( Phaseolus ) field bean, kidney bean, lima bean, navy bean, pinto 

bean, tepary bean; ( Vigna ) adzuki bean, blackeyed pea, catjang, cowpea, crowder pea, moth bean, mung 

bean, rice bean, southern pea, urd bean, ( Pisum) field pea
Picoxystrobin Human Health Risk Assessment DP No. 377690

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Table 3.4. Summary of Directions for Use of Picoxystrobin.

Trade Name; 

Formulation;

[EPA File 

Symbol No.]

App. Equip. App.Rate 

(lb ai/A)

[fl oz /A]

Max. 

No. 

App. 

per 

Season

RTI1

(days)

Max. 

Seasonal 

App. Rate

(lb ai/A)

[fl oz /A]

PHI

(days)

Use Directions and other 

Limitations

DuPontTM 

AproachTM

2.08 lb ai/gal 

SC

[352-IUN]

Ground, air 

or 

chemigation

0.13-0.2

[8-12]

N/S 14 0.4

[24]

14-seed 

0-vines and 

hay

Begin applications prior to 

disease development and 

continue on a 7-14 day interval. 

Use higher rate and shorter 

interval when disease pressure is 

high.

For white mold: make initial 

preventive application at 

beginning bloom and follow 

with 2nd application 7-10 days 

later at full bloom. Make no 

more than 2 sequential 

applications before switching to 

a different mode of action. 

Soybeans

DuPontTM 

AproachTM

2.08 lb ai/gal 

SC

[352-IUN]

Ground, air 

or 

chemigation

0.1-0.2

[6-12]

N/S 14 0.6

[36]

0.2 [12] 

For forage 

and Hay

14-Soybean 

Seed, Forage 

and Hay

Begin applications prior to 

disease development and 

continue on a 7-14 day interval. 

Use higher rate and shorter 

interval when disease pressure is 

high.

For white mold: make initial 

preventive application at 100% 

bloom (1 flower blooming on all 

plants) and follow with 2nd

application 7-10 days later at full 

bloom. Make no more than 2 

sequential applications before 

switching to a different mode of 

action.

Do not exceed 12 fl. oz./A/crop 

if grown for forage and hay; 36 

fl. oz./A/crop for grain (seed).

3.5 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed 

new use of picoxystrobin on canola, cereal grains (except rice), dried shelled peas and beans, and 

soybeans. The requested uses may result in human exposure to picoxystrobin and/or its metabolites 

in food and drinking water. At this time, there are no existing, pending, or requested registrations 

that would result in exposure from use in a residential setting. In the occupational setting, dermal 

and/or inhalation exposure to agricultural workers is expected to be of short- and intermediate term 

durations based on the frequency of application to crops. 

3.6 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," 
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(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, season of the year, ethnic group, and region of the country. 

Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure 

assessments are performed when conditions or circumstances warrant. Whenever appropriate, nondietary 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

Picoxystrobin, 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; 

however, effects such as decrease body weight, food consumption, and food efficiency are 

frequently found in test animals treated with compounds which disrupt mitochondria respiration with 

the subsequent disruption of energy production, and similar effects are also demonstrated in 

picoxystrobin treated animals.

4.1 Toxicology Studies Available for Analysis

A full suite of picoxystrobin toxicity studies has been submitted to support proposed food-use 

registrations. The toxicology database is acceptable for characterizing picoxystrobin hazard and 

includes 90-day oral toxicity studies in rats and dogs, 28-day dermal and inhalation studies in rats, a 

combined chronic/carcinogenicity study in rats, a 1-year toxicity study in dogs, a carcinogenicity 

study in mice, developmental toxicity studies in rats and rabbits, a 2-generation reproduction study 

in rats, a neurotoxicity battery in rats, a mutagenicity battery, immunotoxicity studies in rats and 

mice, metabolism and pharmacokinetics studies in rats, and in-vivo and in vitro dermal absorption 

studies.

4.2 Absorption, Distribution, Metabolism and Excretion (ADME)

Following oral dosing with low (10 mg/kg) and high doses (100 mg/kg) in rats, 70-80% of the 

administered picoxystrobin was absorbed with moderate speed and exhibited bimodal peaks; the first 

peak occurred within 1 hour of dosing and the second peak occurred between 8-24 hours postdosing. Mean Tmax values for low dose groups were 0.6 to 7.1 hours; for high dose groups, 9.3 to 

12.3 hours. The mean values for area under curve (AUC) appeared to be slightly higher for males 
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(102 hr*μg/g) than for females (86 hr*μg/g) in low dose animals. The elimination half-lives of 

radioactivity from plasma were similar regardless of sex and dose level and were in the range of 

30.5-45.8 hours.

Based on the whole body autoradiography results, the absorbed picoxystrobin was distributed into 

the heart, lungs, and nasal passages and other tissues. The highest levels were found in the liver, 

kidneys, and GI tract each containing less than 0.3% of the administered dose. Picoxystrobin was 

extensively metabolized and does not accumulate. Approximately 42 metabolites were measured 

and 34 metabolites were identified, representing approximately 63% of the administered dose 

(Appendix B). Parent compound was identified only in fecal excretion profile and was low (≤9%). 

Over 120 hours, approximately 92% of the administered dose was eliminated for both males and 

females. The majority of the administered dose was eliminated within 48 hour post dosing (73-89% 

of the administered dose). The predominant route of elimination was via feces for both males and 

females accounting for 74% and 65% of the administered dose in males and females, respectively. 

Females showed a higher rate of urinary elimination than males (26% and 18% of the dose for 

females and males, respectively). The bile duct cannulation data indicate that enterohepatic 

circulation was more pronounced in males (approximately 15% of the dose) than in females 

(approximately 2% of the dose). 

4.2.1 Dermal Absorption

The dermal absorption for picoxystrobin was low. Using the results from an in vivo dermal 

absorption study and those from the in vitro dermal absorption studies with isolated human and rat 

skin, a dermal absorption factor was estimated to be 2%.

4.3 Toxicological Effects

The most consistently observed effects of picoxystrobin exposure across species, genders, and 

treatment durations were decreased body weight, body weight gain and food consumption, and 

diarrhea. The effects on body weight and food consumption were consistent with the commonly 

observed findings for compounds which disrupt mitochondria respiration system and the resulting 

disruption of energy production. Similar to some other strobilurins, picoxystrobin 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 severe eye irritation effect seen in the primary eye irritation study on picoxystrobin.

Picoxystrobin caused changes in behavioral effects in both the acute and subchronic neurotoxicity 

studies with no neuropathological findings. The effects observed with acute exposure were transient 

(i.e. lasted for a day) and consisted of low arousal and decreased motor activities in males and

decreased rearing in females, and with subchronic exposure included decreased male forelimb grip

and increased female hindlimb splay. In the absence of any neuropathological findings, the 

behavioral effects were attributed to general malaise (probably related to energy production 

perturbations) as evidenced by the associated decreased body weight and body weight gain.
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In the rat and rabbit developmental toxicity studies, developmental toxicity was expressed as skeletal 

variations at doses causing maternal toxicity (i.e. diarrhea, decreased body weight, body weight gain, 

food consumption, and clinical signs of toxicity). In the reproduction study, parental/systemic 

toxicity manifested as decreased body weight and body weight gain in both the parents and 

offspring; no reproductive toxicity was seen. 

Picoxystrobin did not cause mutagenicity or genotoxicity in in vivo and in vitro assays nor did it 

cause immunotoxicity in T-cell dependent antibody response (TDAR) assays in mice or rats.

Picoxystrobin induced treatment-related increase in testicular interstitial cell benign tumors in the 

high dose male rats. No increase in any type of tumor incidence was seen in female rats or in male 

and female mice. As indicated before, the genotoxicity battery was negative. Picoxystrobin was 

classified by the Cancer Assessment Review Committee (CARC) as “Suggestive Evidence of 

Carcinogenic Potential” based on tumors observed in one species (rat) and one sex (males) (CARC 

Repot Nov. 15, 2011).

Picoxystrobin has low to moderate acute toxicity via the oral, dermal, and inhalation routes of 

exposure (Toxicity Categories II-IV). Picoxystrobin is not a dermal irritant or sensitizer. However, 

picoxystrobin was determined to be a severe eye irritant (Toxicity Category I).

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

HED has retained the 10X FQPA safety factor in the form of a UFL for acute dietary risk assessment 

because a NOAEL was not established in the acute neurotoxicity study selected for this exposure 

scenario. The acute neurotoxicity study’s extrapolated NOAEL of 20 mg/kg is considered protective 

for all populations including potentially pregnant females. 

For all other risk assessment scenarios, the default 10X FQPA Safety Factor can be reduced to 1X 

because the toxicity database is complete and there is no evidence of sensitivity/susceptibility in the 

developing organism, no neurotoxicity, and no residual uncertainty in the exposure data. Clear 

NOAELs/LOAELs have been identified for critical effects. Finally, the exposure assessment 

includes conservative assumptions, such that exposure will not be underestimated.

4.4.1 Completeness of the Toxicology Database

The toxicology database is complete, acceptable, and sufficient for assessing susceptibility to infants 

and children as required by FQPA.

4.4.2 Evidence of Neurotoxicity

There are no indications in any of the studies available that the nervous system is a target for 

picoxystrobin. Effects seen in the acute and subchronic neurotoxicity studies in rats are considered 

to reflect perturbations in mitochondrial respiration leading to effects on energy production. 

In the absence of frank neurotoxicity or neuropathology findings in the neurotoxicity battery or 

elsewhere in the database, a developmental neurotoxicity study is not required.
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4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

The prenatal and postnatal toxicity studies include rat and rabbit prenatal developmental studies in 

addition to reproduction and fertility effects studies in rats. No evidence of increased 

susceptibility/sensitivity is seen in any of these studies.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. Since the dietary exposure estimates 

were based on several conservative assumptions, HED does not believe that the exposure estimates 

are underestimated. The dietary assessments conducted with DEEM-FCID were a partially refined 

analysis. The assessment utilized the highest field trial residues for all crops in the acute assessment 

and the highest average field trial residues for all crops in the chronic assessment. In addition, 

default processing factors and 100% crop treated were assumed for all commodities. The DEEM 

analysis also assumed that all drinking water will contain picoxystrobin at the highest Estimated 

Drinking Water Concentrations (EDWC) levels modeled by EFED for ground water or surface 

water. For these reasons it can be concluded that the dietary exposure analysis does not 

underestimate risk from acute or chronic exposure to picoxystrobin. 

4.5 Toxicity Endpoint and Point of Departure Selection

4.5.1 Dose-Response Assessment

After oral administration, picoxystrobin was rapidly absorbed, widely distributed, extensively 

metabolized, and completely eliminated. Among the species tested (i.e. rats, dogs, and rabbits), the 

primary toxicological effects observed were decreased body weight, body weight gain, and food 

consumption. The toxicological database indicates that picoxystrobin toxicity does not progress 

with duration of exposure (i.e., NOAELs/LOAELs are not lower with longer exposure durations nor 

do the effects seen progress in severity). No frank neurotoxicity or neuropathology was seen 

following a single gavage or repeated dietary administrations to rats. The alterations seen in the 

functional observational battery are attributable to the systemic toxicity seen in these rats. There was 

no evidence of increased susceptibility neither following in utero exposures to rats and rabbits nor 

following pre/post natal exposure to rats for two generations. No evidence of functional 

immunotoxicity was seen in TDAR assays conducted in mice and rats. Picoxystrobin shows 

“Suggestive Evidence of Carcinogenic Potential” based on tumors observed in one species (rat) and 

one sex (males): a treatment-related increase in testicular interstitial cell benign tumors in the high 

dose only.

The doses and endpoints selected for dietary risk assessments are shown in Table 4.5.4.1. The 

Agency has selected an acute neurotoxicity study for acute dietary risk assessment. The LOAEL of 

200 mg/kg based on low arousal and decreased motor activity (males), decreased rearing (females)

and decreased bodyweight gain and food consumption (both sexes) seen on Day 1of the study was 

selected as the Point of Departure (PoD). This endpoint is appropriate for this exposure scenario 

since the effects were seen after a single oral administration. A LOAEL was used since a NOAEL 

was not established in the critical study. An Acute Reference Dose (aRfD) of 0.2 mg/kg/day was 

derived from the LOAEL and the application of an Uncertainty Factor of 1000 which includes the 
Picoxystrobin Human Health Risk Assessment DP No. 377690

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conventional 10X inter-species extrapolation and the 10X intra-species variation factors, a 10X UFL

for the use of the LOAEL. The application of the 10X factor for LOAEL to NOAEL extrapolation is 

considered conservative as the magnitude of observed effects in the acute study are marginal and 

also resolved quickly.

A separate endpoint of concern for pregnant females (13-49 years of age) was not selected since no 

endpoints attributable to a single dose were identified in the developmental toxicity studies in rats 

and rabbits.

The Agency has selected the decreased body weights, body weight gains, and food consumption 

seen in both sexes of dogs in the chronic toxicity as the endpoint of concern for chronic dietary risk 

assessment. This study/endpoint is appropriate for this exposure scenario since the effects were seen 

in the most sensitive species following long term exposure. A chronic RfD of 0.046 mg/kg/day was 

derived from a PoD of 4.6 mg/kg/day and a UF of 100 which includes the conventional 10X interspecies extrapolation and the 10X intra-species variation factors.

Quantification of risk via dermal exposure is not required since no dermal or systemic toxicity was 

seen following repeated dermal applications at the Limit Dose for 28 days to rats. Furthermore, as 

noted above, there are no concerns for developmental-, reproductive, or immunotoxicity. Since the 

effects reported in the acute and subchronic neurotoxicity studies were considered to be the result of 

systemic effects assessed in the dermal toxicity study, the critical effects of concern were adequately 

evaluated in the dermal toxicity study. 

Quantification of risk via inhalation exposure for the proposed uses considered in this risk 

assessment is not required since no portal of entry, respiratory, or systemic toxicity was seen 

following repeated exposures at the highest concentration tested (0.025 mg/L/day, 6.78 mg/kg/day). 

Furthermore, there are no developmental, reproductive, or immunotoxicity concerns and critical 

effects of concern were evaluated in the available inhalation toxicity study. The highest 

concentration tested (0.025 mg/L/day) was converted to a human equivalent dose (2.4 mg/kg/day) 

and compared to the anticipated inhalation exposure levels (0.00066 mg/kg/day) for the proposed 

uses (see Appendix E). The human equivalent dose is approximately 4,000 times greater than 

potential inhalation exposure scenarios associated with this action. Thus, for the proposed uses 

considered in this risk assessment, HED concluded that selection of an inhalation PoD and 

quantitative inhalation risk estimates are not needed for the exposure scenarios associated with this 

action.

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

In the absence of toxicity via the dermal and inhalation routes, there is no need to combine any 

exposures. Only the risk from oral route is assessed quantitatively.

4.5.3 Cancer Classification and Risk Assessment Recommendation

In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), 

picoxystrobin shows “Suggestive Evidence of Carcinogenic Potential” based on tumors observed in 

one species (rat) and one sex (males): a treatment-related increase in testicular interstitial cell benign 
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tumors in the high dose only. No tumors were seen in female rats. No treatment-related increase in 

tumor incidence was seen in male or female mice at doses that were considered to be adequate for 

the assessment of carcinogenicity of picoxystrobin. There is no mutagenic concern.

The evidence from animal data is suggestive of carcinogenicity which raises a concern for 

carcinogenic effects but is judged not sufficient for quantification of cancer risk in humans using a 

linear low dose approach. Also, when there is suggestive evidence, the Agency does not attempt a 

linear dose-response assessment as the nature of the data generally would not support one. 

Therefore, the Agency has determined that quantification of risk using a non-linear approach (i.e., 

RfD) will adequately account for all chronic toxicity, including carcinogenicity, which could result

from exposure to picoxystrobin. The NOAEL (4.6 mg/kg/day) used for establishing the Chronic 

RfD is approximately 30-fold lower than the dose (162 mg/kg/day) that induced testicular tumors in 

male rats.

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

Assessment

Table 4.5.4.1: Summary of Toxicological Doses and Endpoints for use in Dietary and Non-Occupational Human Health 

Risk Assessments

Exposure Scenario Point of 

Departure (PoD)

Uncertainty / 

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary

general population, 

including infants and 

children 

LOAEL = 

200 mg/kg/day

UFA = 10x

UFH = 10x

FQPA = 10x (UFL)

aRfD =

0.2 mg/kg/day

aPAD = 

0.2 mg/kg/day

Acute Neurotoxicity – Rat

LOAEL = 200 mg/kg based on low 

arousal and decreased motor activities 

in males, decreased rearing in females, 

in addition to decreased bodyweight 

gain and food consumption in both 

sexes on Day 1.

Acute Dietary,

Females (13-49 years 

old)

N/A; There was no toxicity attributable to a single dose in the relevant studies

Chronic Dietary NOAEL = 

4.6 mg/kg/day

UFA = 10x

UFH = 10x

FQPA = 1x

cRfD = 

0.046 mg/kg/day

cPAD = 

0.046 mg/kg/day

Chronic Toxicity – Dog

LOAEL = 15.7 mg/kg/day based on

decreased body weights, body weight 

gains, and food consumption in both 

sexes

Dermal Short 

(1-30 ) Term 

Quantification of risk is not required because there is no identified hazard for this scenario.

Dermal Intermediate 

(1-6 months) Term 

Inhalation Short 

(1-30) Term 

Quantification of risk is not required because there is no identified hazard for this scenario.

Inhalation 

Intermediate (1-6 

months) Term 

Cancer (oral, dermal, 

and inhalation)

Classification: “Suggestive Evidence of Carcinogenic Potential” based on tumors in one species and 

one sex: a treatment-related increase in testicular interstitial cell benign tumors in high dose male rats.

Quantification of cancer risk is based on a non-linear (i.e., RfD) approach.
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Point of Departure (PoD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the 

beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no 

observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from 

animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies). 

FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of 

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

Table 4.5.4.2: Summary of Toxicological Doses and Endpoints for use in Occupational Human Health Risk Assessments

Exposure 

Scenario

Point of 

Departure 

(PoD)

Uncertainty / FQPA 

Safety Factors

RfD, PAD, Level 

of Concern for 

Risk Assessment

Study and Toxicological Effects

Dermal Short 

(1-30 ) Term 

Quantification of risk is not required because there is no identified hazard for this scenario. 

Dermal 

Intermediate 

(1-6 months) 

Term 

Inhalation 

Short 

(1-30) Term 

Quantification of risk is not required because there is no identified hazard for this scenario.

Inhalation 

Intermediate 

(1-6 months) 

Term 

Cancer (oral, 

dermal, and 

inhalation)

Classification: “Suggestive Evidence of Carcinogenic Potential” based on tumors in one species and one sex: 

a treatment-related increase in testicular interstitial cell benign tumors in high dose male rats. Quantification 

of cancer risk is based on a non-linear (i.e., RfD) approach.

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.

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The nature of the residue in plants, livestock, and rotational crops is adequately understood for the 

purposes of this petition. Metabolism studies were conducted in plants (apples (non-GLP), canola, 

soybean, and wheat), rotational crops (spring wheat, lettuce, and carrots), and livestock (goats and 

hens). These studies were conducted using test substances radio-labeled separately in the pyridine 

and phenyl rings of picoxystrobin. 

In primary crops (canola, apples, and wheat (forage and straw)), unchanged picoxystrobin was the 

major residue for both radiolabels. Metabolism in soybean was extensive; metabolites/glucose 

conjugates were predominant. Most of these metabolites are similar in structure to the parent. The 

parent was detected at low levels in soybean seed. In wheat grain, parent residue levels were low. 

In the phenylacrylate label, Compound 24, Compound 15, and PAG3 were the major residues 

detected. Compound 15 and 24 derive from Compound 9 which was present in the rat metabolism 

study, but is oxidized in a different form in the plant and rat systems. Compound PAG3 was 
Picoxystrobin Human Health Risk Assessment DP No. 377690

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identified as R730529, an acidic compound. Chemical names and structures of the metabolites are 

depicted in Appendix B. 

Rotational crop studies indicate extensive degradation of picoxystrobin. The parent was identified in 

all rotational crops, except in wheat grain. In the confined rotational crop studies, total radioactive 

residues (TRRs) exceeded 0.01 ppm at the 30-day and 197-day plantback intervals (PBIs). 

Picoxystrobin (only in carrot), conjugates of Compound 3, Compound 30, and a conjugate of 

Compound 2 (PAF1) were major metabolites detected at greater than 10% at PBIs of 197-days. 

Compound 30 is a soil metabolite and was detected only in confined rotational study. 

In addition to the traditional confined rotational crop studies, radiolabeled field accumulation studies 

were conducted at 107-day (winter wheat) and 305-days (spring wheat) PBIs. The TRRs were 

greater than 0.01 ppm at 305-day PBI in spring wheat forage and straw, and carrot foliage 

(pyridinyl). Residues identified were similar as the confined study; conjugates of Compound 3 were 

detected at greater than 10% at 305-day PBI. 

In ruminants, the majority of the administered dose (AD) was excreted via urine. Picoxystrobin was 

the only residue detected in the fat. Compound 2 and Compound 7 were the predominant 

metabolites detected in the liver and kidney respectively, with minor residues of the parent. TRRs in 

skim milk and muscle were <0.01 ppm thus metabolites were not characterized or identified. 

The hen metabolism study indicated that the majority of the administered dose was excreted. The 

highest TRRs were observed in the liver and Day 10 egg yolk. TRRs were low in muscle, fat, and 

Day 10 egg white. Residues in tissues were not characterized in the hen metabolism study because 

the residues were <0.01 ppm. 

There were no plant or livestock metabolites identified that were unaccounted for in the rat 

metabolism study.

5.1.2 Summary of Environmental Degradation

Picoxystrobin is moderately persistent in aerobic and anaerobic conditions, and is moderately mobile 

(mean Koc = 924). Picoxystrobin’s half-lives range from 29 to 73 days in aerobic soil. There is no 

evidence of degradation via hydrolysis across environmental pHs (pH 5, pH 7, and pH 9 @ 25o C). 

Picoxystrobin degraded under the conditions of aerobic aquatic metabolism with half-lives ranging 

from 39 to 41 days; and under anaerobic aquatic systems with a half-life of 83 days. The primary 

route of degradation is aqueous photolysis (half-life of 16 days); however photolysis only plays a 

significant role in shallow clear waters. Under other conditions, aerobic 

biometabolism/biotransformation is expected to be the primary route of degradation.

The major environmental degradates of picoxystrobin include Compound 2, Compound 3, 

Compound 4, Compound 7, Compound 8, and Compound 12. However, Compounds 4 and 12 were 

only major degradates under aqueous photolysis conditions and exposure is not anticipated except in 

shallow clear waters. See Appendix B for degradate structures.

5.1.3 Comparison of Metabolic Pathways
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Picoxystrobin is metabolized in plants via ester hydrolysis, cleavage of the ether link followed by 

conjugation, photoisomerization (minor pathway), oxidative cleavage of the parent and subsequent 

oxidation, O-demethylation, decarboxylation, and metabolism of picoxystrobin’s side chain that 

proceeds through a series of hydrolytic, reductive, oxidative and/or conjugation steps. In primary 

crops parent picoxystrobin was the predominant major residue. In several primary crops, 

Compounds 2, 3, and 8 were also major residues. Compounds 2 and 8 are similar in structure to 

parent picoxystrobin while, Compound 3 is a cleavage product.

In rotational crops, extensive degradation of picoxystrobin was observed which shows the potential 

for substantially more exposure to various metabolites compared to parent picoxystrobin. The 

significant residues identified were picoxystrobin, conjugates of Compound 3, Compound 30, and a 

conjugate of Compound 2 (PAF1). Compounds 30 and 31 were observed, predominantly at the 

longer interval of 197 days after treatment (DAT). 

In the environment, the primary route of degradation may include aqueous photolysis; however 

photolysis only plays a significant role in shallow clear waters. Under other conditions, aerobic 

biometabolism is expected to be the primary route of degradation. Major degradates Compounds 2, 

3, 4, 7, 12, 8, and CO2 were identified in the environmental fate studies at concentrations >10% of 

the applied radioactivity. 

In livestock, metabolism of picoxystrobin proceeds via ester hydrolysis, cleavage of the ether link, 

O-demethylation, and hydroxylation of the phenyl ring. In ruminants, picoxystrobin was the major 

residue in fat, but only a minor residue in liver and kidney. Extensive metabolism was observed in 

the liver and kidney with the primary metabolite being Compound 2 in goat liver and Compound 7 

in goat kidney. The submitted goat metabolism study did not characterize or identify metabolites in 

milk.

In poultry, the residues in tissues (liver, fat, and muscle) whose values were greater than 0.01 ppm 

were not characterized or identified. In hen excreta, parent picoxystrobin and Compounds 2, 3, 7, 

10, 33, 34, and 48 were identified. In the egg yolk, the parent was identified while Compounds 3, 7, 

and 10 were identified at low levels. 

In the rat, the metabolism proceeded via hydrolysis and glucuronide conjugation resulting in 42 

different metabolites some of which includes compounds seen in plant and livestock metabolism 

studies, and a few products produced in significant quantities. Parent and Metabolites 2, 32, and 42 

were found in the feces of all groups. Except in bile duct-cannulated groups, Metabolite 2 was 

isolated in the greatest quantity. In the bile duct-cannulated groups, Metabolite 40 was isolated in 

the greatest amount. 

5.1.4 Residues of Concern Summary and Rationale

HED has concluded that for plants (primary and rotational crops) and livestock commodities, parent 

picoxystrobin should be the residue of concern for the tolerance expression. For risk assessment 

purposes, Compounds 2, 3 and 8 should be included in primary crops and livestock commodities. 

For drinking water, a total residue approach for parent, and compounds 2, 3, 7 and 8 should be used 

for the risk assessment.
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Table 5.1.4 Summary of Metabolites and Degradates to be included in the Risk Assessment 

and Tolerance Expression for Picoxystrobin.

Matrix Residues included in Risk Assessment1 Residues included in Tolerance 

Expression 

Plants Primary Crop Picoxystrobin + Compounds 2, 3, and 8 Picoxystrobin

Rotational Crop Picoxystrobin2Picoxystrobin

Livestock Ruminant Picoxystrobin + Compounds 2, 3, and 8 Picoxystrobin

Poultry Picoxystrobin + Compounds 2, 3, and 8 Picoxystrobin

Drinking Water Picoxystrobin + Compounds 2, 3, 7, and 8 Not Applicable

1

See attached Appendix B for parent and metabolite names and structures. 

2 Assuming a plant-back interval (PBI) of 10 months

Hazard Considerations: A structure activity analysis of picoxystrobin and its major metabolites 

using DEREK v.12 did not raise any concerns for toxic effects that were not evaluated in the toxicity 

database. 

Compounds 2, 3, and 8 were major residues in primary crops, including peas. Toxicological data are

not available for these metabolites and thus they cannot be excluded from risk assessment on the 

basis of toxicological impacts. Compounds 2 and 8 are similar in structure to parent picoxystrobin 

and are therefore assumed to have the same toxicological MOA and potency as the parent. 

Compound 3 is a cleavage product and structurally dissimilar from the parent. Similarity and QSAR 

searches do not indicate that this structure will result in greater toxicity than the parent compound. 

Therefore, for the purpose of the residues of concern recommendation, compound 3 is considered to 

have equivalent toxicity as parent picoxystrobin.

Primary Crops: The use of parent picoxystrobin is an adequate measure for tolerance enforcement 

purposes in primary crops for the proposed uses. For risk assessment purposes parent picoxystrobin 

and Compounds 2, 3, and 8 should be included, an approach that is conservatively protective.

Rotational Crops: The confined rotational crop studies and radiolabeled field accumulation studies 

show extensive degradation of picoxystrobin and indicate that there is the potential for substantially 

more exposure to various metabolites compared to parent picoxystrobin. In the rotational crop 

studies, the significant residues identified at >0.01 ppm at 197-DAT and 305-DAT were 

picoxystrobin (carrot root only), conjugates of Compound 3, Compound 30, and a conjugate of 

Compound 2 (PAF1). Compound 30 is a soil metabolite and was detected only in confined 

rotational crop study, predominantly at the longer PBI. The parent was identified in all rotational 

crops, except wheat grain. Parent picoxystrobin is an adequate measure for tolerance expression and 

risk assessment assuming a plantback interval of 10 months. Based on the results of the study, the 

label should include a 10 month PBI for leafy vegetables and 12 month PBI for all other crops 

including root and tuber vegetables. In the event of future uses with shorter PBI’s, additional field 

studies may be needed to characterize metabolite residues, particularly conjugates of Compound 3 

(compounds 11, 20, 29), and 30 which were observed at high concentrations in the confined studies.

Livestock Commodities: Parent picoxystrobin is an adequate measure for tolerance enforcement 

purposes in livestock commodities. For risk assessment purposes, compounds 2, 3, and 8 should be 

included in these commodities. For dietary burden calculations, parent picoxystrobin and 
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Compounds 2, 3, and 8 should be included assuming that these metabolites are equivalent to parent 

in terms of transferring to livestock tissues and milk. 

Drinking Water: A total residue approach should be used in the drinking water assessment, including 

parent and the following major environmental degradates: Compound 2, Compound 3, Compound 7, 

and Compound 8. 

5.2 Food Residue Profile

Adequate residue data are available to support dietary risk assessment as well as the proposed 

tolerances for the fungicide picoxystrobin in/on cereal grains, legume vegetables, soybeans, and 

canola. Residues are quantifiable in all crops treated in accordance with the proposed label. 

Residues of picoxystrobin on the foliage of livestock feeds such as cereal grain forage/hay/straw and 

legume hay/vines were generally higher (1-23 ppm) than residues in cereal grains and soybean seeds 

(≤ 0.05 ppm), except barley grain at 0.22 ppm. Upon processing, residues concentrate in corn and 

soybean oil as well as wheat bran and germ. 

Livestock feeding studies indicate low transfer of residues to meat and milk with the highest transfer 

in liver. Quantifiable residues were detected in the fat. No quantifiable residues were found in any 

poultry commodity. 

Crop Field Trials

The submitted magnitude of the residue data, summarized in Table 5.2.1, are adequate for risk 

assessment and tolerance assessment. For all crops, the number and locations of field trials are 

adequate. Adjuvants were used in all the field trials, mostly nonionic surfactants (NIS)s. The data 

reflect the proposed 1x single application rate and pre-harvest interval. The OECD statistical 

calculation spreadsheet was used to determine appropriate tolerance levels. 

Based on the available data, an adjustment to the proposed tolerance is required for most of the 

RACs (or crop groups) in order to reflect the appropriate tolerance levels recommended by the 

OECD statistical calculation spreadsheet. 

Table 5.2.1 Summary of the Picoxystrobin Residue Data from Crop Field Trials

Commodity

Total Applic. 

Rate 

g a.i./ha 

(lb a.i./A)

PHI 

(days)

Picoxystrobin Residue1 Levels (ppm)

N Min. Max. HAFT Median Mean Std. Dev.

Field Corn

Corn Forage 639-676 

(0.570-0.603)

0 13 0.83 8.1 8.1 3.3 3.9 1.8

Corn Stover 6-75 <0.013 6.6 6.6 1.9 2.1 1.8

Corn Grain 15 <0.01 <0.01 <0.01 <0.01 <0.01 0.0

Sweet Corn

Sweet Corn 

Forage

864-906 

(0.77-0.81) 6-9 11 <0.01 2.2 2.2 0.53 0.74 0.69

Sweet Corn Ears 6-9 11 <0.01 <0.01 <0.01 <0.01 <0.01 0.0

Wheat and Barley

Wheat Forage 217-231 

(0.19-0.21) 6-9 26 0.17 4.45 4.45 0.81 1.24 1.09

Wheat Hay 655-685 

(0.58-0.61)

14-17 26 0.14 3.05 3.05 0.73 1.03 0.86

Wheat Straw 35-56 26 0.012 1.5 1.5 0.16 0.30 0.38
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Wheat Grain 26 <0.01 0.028 0.028 <0.01 <0.012 0.005

Barley Hay 655-693 

(0.58-0.62)

9-17 21 0.16 3.65 3.65 0.63 1.01 0.95

Barley Straw 44-77 21 0.027 0.74 0.74 0.15 0.19 0.20

Barley Grain 21 <0.01 0.22 0.22 <0.016 <0.034 0.05

Soybean

Soybean Forage 213-224 

(0.19-0.20)

13-21 21 <0.01 0.76 0.76 0.20 0.25 0.17

Soybean Hay 13-21 21 <0.01 1.9 1.9 0.8 0.78 0.52

Soybean Seed 646-717 

(0.58-0.64) 13-17 21 <0.01 0.039 0.039 <0.01 0.014 0.009

Canola

Canola Seed 437-461 

(0.39-0.41) 19-28 20 <0.01 0.047 0.047 0.02 0.023 0.013

Bean and Peas

Pea Seed 433-455 

(0.39-0.41) 13-14 11 <0.01 0.033 0.033 0.012 0.015 0.007

Pea Vine 448-455 

(0.40-0.41)

0 6 3.35 9.35 9.35 5.98 6.02 2.5

Pea Hay 0 6 3.35 23 23 9.23 10.4 6.8

Bean Seed 430-451 

(0.38-0.40) 14-15 11 <0.01 0.038 0.038 <0.01 0.016 0.01

1

 The average of replicates from the same trial was reported.

Processing Studies

Adequate processing studies were conducted on canola, corn, soybean, and wheat. Residues of 

picoxystrobin concentrate in cereal grain and soybean processed commodities. A tolerance for 

residues of picoxystrobin is recommended for corn oil, wheat bran, wheat germ, soybean hulls, and 

aspirated grain fractions.

Storage Stability

Adequate storage stability data for picoxystrobin are available to validate the storage conditions and 

durations of storage of samples from the crop field trial and processing studies. Corrections to 

residue values from the residue trials to account for dissipation during storage are not necessary 

since residues did not decline during storage.

Meat, Milk, Poultry, and Eggs

The livestock feedstuff associated with the proposed crop uses in this action are cereal grain 

commodities (grain, forage, hay, straw, stover, cannery waste, milled byproducts); canola meal; 

legume vegetables-dry commodities (seed, vines, hay, silage, forage); soybean (seed, forage, hay, 

meal, hulls, silage); and aspirated grain fractions. For risk assessment purposes, the livestock dietary 

burdens of picoxystrobin are presented in Appendix G, and reflect the most recent guidance 

“Revisions of Feedstuffs in Table 1 of OPPTS Test Guideline 860.1000 and Guidance on 

Constructing Maximum Reasonably Balanced Diets (MRBD)”. 

Based on the dietary exposure levels and the residue data from the feeding study, tolerances are 

needed for residues of picoxystrobin at 0.01 ppm in the meat; meat byproducts, except kidney; milk; 

liver; and fat of cattle, goats, horses, and sheep. No tolerances are needed for residues in kidney of 

cattle, goats, horses and sheep, or in any swine commodities. Tolerances for eggs and poultry are 

not needed based on the conclusion that there is no reasonable expectation of finite residues in 
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poultry commodities. However, tolerances for livestock commodities including kidney, eggs, and 

poultry commodities are recommended as listed on Table 2.2.3, for harmonization purposes.

Rotational Crops

The nature and magnitude of the residue in rotational crops is adequately understood for currently 

proposed uses based on an acceptable confined rotational crop study and radiolabeled field 

accumulation studies; no traditional field accumulation studies were conducted. TRR accumulated 

at >0.01 ppm in all rotated crop matrices following treatment at all plant back intervals (PBI). 

Picoxystrobin (except carrot root 0.01 ppm) and most metabolites were less than 0.01 ppm, except 

conjugates of Compound 3 and Compound 30 which were identified at greater than 0.01 ppm at 197-

DAT. 

Radiolabeled field accumulation studies were conducted at 107-day (winter wheat) and 305-days 

(spring wheat) PBIs. The TRRs were greater than 0.01 ppm at 305-day PBI in spring wheat forage 

and straw, and carrot foliage (pyridinyl). Residues identified were similar as the confined study; 

conjugates of Compound 3 were detected at greater than 10% at 305-day PBI. 

Based on the results of the study, the label should include a 10 month PBI for leafy vegetables and 

12 month PBI for all other crops including root and tuber vegetables (ChemSAC 09/28/2011). A 

revised Section B is requested. For future uses with shorter PBI’s, additional field studies may be 

needed to characterize metabolite residues, particularly compounds 11, 20, 29, and 30 (which were 

observed at high concentrations in the confined studies) (ROCKS memo DP# 392813, 09/16/2011). 

5.3 Water Residue Profile

Estimated surface water and groundwater concentrations shown in Table 5.3 were provided by the 

Environmental Fate and Effects Division (EFED; DP401564, 08/01/2012). The surface drinking 

water assessment is based on Tier II aquatic models PRZM (Pesticide Root Zone Model) and 

EXAMS (Exposure Analysis Modeling Systems) for all proposed picoxystrobin uses. The drinking 

water assessment used a total toxic residue (TTR) approach to include parent and the major 

environmental degradates: Compound 2, Compound 3, Compound 7, and Compound 8 (See 

Appendix B for structures of the degradates). The sweet corn application rate resulted in the highest 

EDWC. The drinking water estimates incorporated label modifications that included early season

treatment, low rate applications, as well as the percent cropped area adjustment. Due to the lack of 

fate data on degradates, most of the fate parameters for the parent were assumed for the degradates. 

However, EFED’s Total Residue (TR) model was used to calculate half-lives as model inputs. This 

modeling strategy requires an assumption that all residues of concern have similar physical, 

chemical, and partitioning characteristics. Application rates for the parent pesticide are used to 

represent the total mass loading of pesticide and its transformation product. Tier I groundwater 

EDWCs were estimated using SCI-GROW (Screening Concentration in Groundwater, version 2.3). 

The estimated surface water concentrations are 7.95 μg/L and 2.41 μg/L (acute and chronic 

assessment, respectively) and ground water concentration is estimated to be 0.052 μg/L (for acute 

and chronic). Typically, HED uses the higher of the surface or ground water estimates when 
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assessing dietary risk; therefore, the surface water EDWCs were used in the acute and chronic 

dietary assessment.

Table 5.3. Estimated Drinking Water Concentrations (EDWC) of Picoxystrobin Residues in 

Surface Water and Ground Water.

Scenario

Peak (acute)

(ppb)

Yearly average

(Chronic noncancer)

(ppb)

30-year average

(cancer)

(ppb)

Surface water

(PRZM 3.12.2/EXAMS 2.98.04.06)

Early season application

1 application (4 fl oz and ) on May 26

Additional applications

1st applications (12 fl oz) on July 9

2nd application (12 fl oz) on July 16

3rd application (8 fl oz) on July 23 

Application dates*

7.95 2.41 1.62

Groundwater

(SCI-GROW 2.3)

3 applications (12 oz)

Acute and chronic 0.041

*: Dates of applications were chosen based on label directions and corn growth stages:

V4 (19-26 days after seeding)

V7 (28-35 days after seeding)

VT (65-72 days after seeding)

R3 (91-98 days after seeding)

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Conservative acute and chronic dietary exposure assessments for picoxystrobin were conducted

using the Dietary Exposure Evaluation Model DEEM-FCIDTM, Version 3.16 which uses food 

consumption data from the U.S. Department of Agriculture’s National Health and Nutrition 

Examination Survey, What We Eat in America, (NHANES/WWEIA). The residues of concern for 

risk assessment purposes are picoxystrobin, Compounds 2, 3, and 8. Tolerance level residues were 

not used in the dietary assessment since the tolerance does not include the metabolites. The total 

highest field trial residues for parent plus metabolites of concern for all proposed crops were used in 

the acute assessment. The total highest average field trial residues for parent plus metabolites of 

concern (Compounds 2, 3, and 8) for all proposed crops were used in the chronic assessment. Both 

the acute and chronic assessment utilized tolerance levels for livestock commodities. Additionally, 

DEEM version 7.81 default processing factors were assumed except for where tolerances were 

established for processed commodities or when processing studies showed no concentration.

Table 5.4.1 summarizes the picoxystrobin residue levels and processing factors for the proposed 

crops used in the acute and chronic dietary assessments. 
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Table 5.4.1. Residue Data and Processing Factors used for Acute and Chronic Dietary Risk Assessments.

Commodity Tolerance 

(ppm) 1

Acute

Total Highest Field 

Trial Residue 

(ppm)2

Chronic

Total Highest Average

Field Trial Residue 

(ppm)3

Processing 

Factors4

Barley, bran (used wheat bran 

processing factor)

0.50 N/A N/A 1

Barley, grain 0.30 0.29 0.28 N/A

Bean, seed 0.06 0.11 0.10 N/A

Canola, seed 0.08 0.10 0.10 N/A

Corn, grain 0.04 0.06 0.06 N/A

Corn, oil 0.07 N/A N/A 1

Pea, seed 0.06 0.16 0.13 N/A

Soybean, seed 0.05 0.09 0.09 N/A

Wheat, bran 0.06 N/A N/A 1

Wheat, germ 0.09 N/A N/A 1

Wheat, grain 0.04 0.07 0.07 N/A

Fat, liver, meat and meat by 

products, except kidney of cattle, 

goat, horse, and sheep

0.01 N/A N/A N/A

Milk 0.01 N/A N/A N/A

1 Tolerance level was used for livestock commodities. 

2 Total highest field trial residue of picoxystrobin, compounds 2, 3, and 8.

3 Total highest average field trial residue of picoxystrobin, compounds 2, 3, and 8.

4 Tolerance determined using processing study (HAFT-highest average field trial residue x (processing factor)

N/A-Not applicable

The surface drinking water residue levels used in the dietary assessment were estimated using Tier II 

PRZM/EXAMS modeling. The EDWC for total toxic picoxystrobin residues are surface water 

residues based on applications to sweet corn. The EDWC for total toxic residues is 7.95 ppb for 

acute and 2.41 ppb for the chronic assessments. The water residues were directly incorporated in the 

DEEM-FCID into the categories “water, direct, all sources” and “water, indirect, all sources.” 

5.4.2 Percent Crop Treated Used in Dietary Assessment

The acute and chronic dietary analyses assumed that 100% of the crop was treated (100% CT). 

5.4.3 Acute Dietary Risk Assessment

A conservative acute dietary assessment was conducted. The assumptions of this dietary assessment 

included total highest field trial total residues (parent + metabolite) for all proposed crops. In 

addition, 100% crop treated (CT) was assumed. DEEM version 7.81 default processing factors were 

assumed except for where tolerances were established for processed commodities or when 

processing studies showed no concentration. A conservative EDWC derived through EFED 

modeling which is unlikely to underestimate the concentration of picoxystrobin in drinking water 

was utilized. The surface water EDWC (7.95 μg/L) was incorporated directly into the dietary 

assessment (D401564, I. Abdel-Saheb, 08/01/2012).

As shown in Table 5.4.6, the acute dietary (food and drinking water) exposure to picoxystrobin is 

below HED’s level of concern [i.e., <100% of the acute Population Adjusted Dose (aPAD)] for the 
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general U.S. population and all population subgroups. The acute dietary exposure estimates are <1% 

of the aPAD for the general U.S. population and 1.3% of the aPAD for children 1-2 years old, the 

most highly exposed population subgroup. 

5.4.4 Chronic Dietary Risk Assessment

A conservative chronic dietary assessment was conducted. The assumptions of this dietary 

assessment included total highest average field trial total residues (parent + metabolite) for all 

proposed crops. In addition, 100% crop treated (CT) was assumed. DEEM version 7.81 default 

processing factors were assumed except for where tolerances were established for processed 

commodities. A conservative EDWC derived through EFED modeling which is unlikely to 

underestimate the concentration of picoxystrobin in drinking water was utilized. The surface water 

EDWC (2.41 μg/L) was incorporated directly into the dietary assessment.

As shown in Table 5.4.6, the chronic dietary (food and drinking water) exposure to picoxystrobin is 

below HED’s level of concern [i.e., <100% of the chronic Population Adjusted Dose (cPAD)] for the 

general U.S. population and all population subgroups. The chronic dietary exposure estimates are 

1.0% of the cPAD for the general U.S. population and 2.8% of the cPAD for children 1-2 years old,

the most highly exposed population subgroup. 

5.4.5 Cancer Dietary Risk Assessment

Picoxystrobin is classified as having "suggestive evidence of carcinogenicity" and HED has 

concluded that assessments using a non-linear approach (e.g., a chronic RfD-based assessment) will 

adequately account for all chronic toxicity, including carcinogenicity that could result from exposure 

to picoxystrobin. Chronic dietary risk estimates are below HED’s level of concern; therefore, cancer 

risk is also below HED’s level of concern.
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5.4.6 Summary Table

Table 5.4.6. Summary of Dietary Exposure and Risk for picoxystrobin – Food & Drinking 

Water.

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% 

aPAD

Dietary 

Exposure

(mg/kg/day)

% 

cPAD

Dietary 

Exposure

(mg/kg/day) Risk

General U.S. Population 0.001376 0.69 0.000475 1.0

A separate 

quantitative cancer 

risk assessment is not 

required. 

All Infants (< 1 year old) 0.002395 1.2 0.000729 1.6

Children 1-2 years old 0.002536 1.3 0.001296 2.8

Children 3-5 years old 0.002115 1.1 0.001072 2.3

Children 6-12 years old 0.001568 0.78 0.000723 1.6

Youth 13-19 years old 0.001046 0.52 0.000448 1.0

Adults 20-49 years old 0.001119 0.56 0.000417 0.90

Adults 50+ years old 0.000849 0.42 0.000317 0.70

Females 13-49 years old 0.000962 0.48 0.000369 0.80

1The population subgroup with the highest estimated dietary (food + drinking water) exposure and risk is indicated by 

bold text.
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6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no residential uses of picoxystrobin; therefore, a residential exposure assessment was not 

necessary.

6.1 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This 

is particularly the case with aerial application, but, to a lesser extent, could also be a potential source 

of exposure from the ground application method employed for picoxystrobin. The Agency has been 

working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for 

pesticide regulation and other parties to develop the best spray drift management practices (see the 

Agency’s Spray Drift website for more information at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed on 

product labels/labeling. The Agency has completed its evaluation of the new database submitted by 

the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on 

how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for 

pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in 

place, the Agency may impose further refinements in spray drift management practices to reduce 

off-target drift with specific products with significant risks associated with drift.

7.0 Aggregate Exposure/Risk Characterization

As there are no registered or requested residential uses of picoxystrobin, aggregate exposure is 

equivalent to the dietary exposure discussed in Section 5. Since the dietary risk estimates are all 

below HED’s level of concern, aggregate risk estimates are also below HED’s level of concern.

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 

picoxystrobin and any other substances and picoxystrobin 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 picoxystrobin has a common mechanism of toxicity with other substances. For 

information regarding EPA’s efforts to determine which chemicals have a common mechanism of 

toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released 

by EPA’s Office of Pesticide Programs concerning common mechanism determinations and 

procedures for cumulating effects from substances found to have a common mechanism on EPA’s 

website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

Occupational short-term (1 - 30 days) and intermediate-term (1 - 6 months) dermal and inhalation 

exposures are expected from picoxystrobin handler and post-application activities associated with 
Picoxystrobin Human Health Risk Assessment DP No. 377690

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the proposed agricultural uses. Since no hazard was identified for the dermal or inhalation routes of 

exposure, there are no dermal or inhalation risks associated with the proposed uses. 

The restricted entry interval (REI) specified on the proposed label is based on the acute toxicity of 

picoxystrobin. Picoxystrobin is classified as Toxicity Category IV via the dermal route and for skin 

irritation potential. It is not a skin sensitizer. Picoxystrobin is classified as Toxicity Category I for 

eye irritation. Under Worker Protection Standards (WPS) for agricultural pesticides, active 

ingredients that are classified as Acute III or IV for acute dermal, eye irritation and primary skin 

irrigation are assigned a 12-hour REI. Since picoxystrobin is a Tox Category I for eye irritation, 

HED is recommending that the proposed REI of 12 hours be revised on the label to 48 hours per the 

WPS. Additionally, since picoxystrobin is a severe eye irritant, goggles need to be included as 

personal protection equipment (PPE) on the label. 

10.0 References

Abdel-Saheb, I., 08/01/12, D401564, Revised Tier I Estimated Surface Drinking Water 

Concentrations (EDWCs) for Picoxystrobin Use in Human Health Risk Assessment (PP# 0F7722).

Abdel-Saheb, I., 12/01/11, D377700, Tier I Estimated Surface Drinking Water Concentrations and 

Estimated Ground Water Concentrations (EDWCs) for Picoxystrobin Use on Sweet Corn for Use in 

Human Health Risk Assessment (PP# 0F7722).

Brunsman, L., 08/25/11, Picoxystrobin. Qualitative Risk Assessment Based On Crlj:CD1(ICR) 

Mouse and CD[Crl:CD(SD)] Rat Dietary Studies.

Holman, E., 09/22/11, D392813, Picoxystrobin. Report of the Residues of Concern Knowledgebase

Subcommittee (ROCKS). 

Kidwell, J., 11/15/11, TXR No. 0056121, Picoxystrobin: Report of the Cancer Assessment Review 

Committee

Negussie, M., 07/09/12, D378233, Picoxystrobin. Petition for the Establishment of Permanent 

Tolerances for Uses on Cereal Grains (Crop Group 15), Except Rice; Cereal Forage/Fodder (Crop 

Group 16), Except Rice; Legume Vegetables-Dry, Except Soybean (Crop Group 6, Subgroup C); 

Legume Vegetables, Foliage (Crop Group 7); Soybeans; Canola; and Livestock Commodities. 

Summary of Analytical Chemistry and Residue Data.

Negussie, M., 08/03/12, D378235, Picoxystrobin: Acute and Chronic Aggregate Dietary (Food and 

Drinking Water) Exposure and Risk Assessments for the First Food Uses in Support of a Section 3 

Registration Action on Cereal Grains (Crop Group 15), Except Rice; Cereal Forage/Fodder (Crop 

Group 16), Except Rice; Legume Vegetables-Dry, Except Soybean (Crop Group 6, Subgroup C); 

Legume Vegetables, Foliage (Crop Group 7); Soybeans, Canola, and Livestock Commodities. 
Picoxystrobin Human Health Risk Assessment DP No. 377690

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Appendix A. International Residue Limits 

Picoxystrobin (129200; 10/11/2011)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3

40 CFR 180.xxx:

Plants/Livestock: Picoxystrobin, 

including its metabolites and degradates, 

in or on the commodities listed below. 

Compliance with the tolerance levels 

specified below is to be determined by 

measuring only picoxystrobin, methyl 

(αE)-α-(methoxymethylene)-2-[[[6-

(trifluoromethyl)-2-

pyridinyl]oxy]methyl]benzeneacetate

picoxystrobin, methyl (αE)-

α-(methoxymethylene)-2-

[[[6-(trifluoromethyl)-2-

pyridinyl]oxy]methyl]benze

neacetate

None

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

US Canada4 Mexico2 Codex3

Barley, grain 0.30 0.30

Corn, field, refined oil 0.07 0.07

Grain, aspirated grain fractions 10 10

Wheat, bran 0.06 0.06

Wheat, germ 0.09 0.09

Barley, bran 0.5 0.5

Grain, cereal, group 15, except 

rice and barley

0.04 0.04

Grain, cereal, forage, fodder, and 

straw, group 16, straw 

2.0

Grain, cereal, forage, fodder, and 

straw, group 16, stover 

10

Grain, cereal, forage, fodder, and 

straw, group 16, hay 

5.0

Grain, cereal, forage, fodder, and 

straw, group 16, forage 

15

Pea and bean, dried shelled, 

except soybean, subgroup 6C

0.06 0.06

Vegetable, foliage of legume, 

except soybean, subgroup 7A

40

Soybean, seed 0.05 0.05

Soybean, forage 1.0

Soybean, hay 3.0

Soybean, hulls 0.20 0.20

Canola, seed 0.08 0.08

Cattle fat, meat, meat 

byproducts, except kidney

0.01 0.01

Goat fat, meat, meat byproducts, 

except kidney

0.01 0.01
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Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3

Horse fat, meat, meat 

byproducts, except kidney

0.01 0.01

Sheep fat, meat, meat 

byproducts, except kidney

0.01 0.01

Milk 0.01 0.01

Cream 0.01

Completed by: M. Negussie; 07/09/2012

1

Includes only commodities of interest for this action. Tolerance values are 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.

4 Canadian MRLs are recommended MRLs.
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Appendix B. Chemical Names and Structures of Picoxystrobin Metabolites/Degradates

Tabular Summary of Metabolites and Degradates.

Chemical Name

(other names in parentheses)

and Structure

Matrix Percent TRR (PPM) 1

Matrices - Major 

Residue (>10%TRR)

Matrices - Minor 

Residue (<10%TRR)

Picoxystrobin (ZA1963)

methyl (E)-2-{2-[6-(trifluoromethyl)pyridin2-yloxymethyl]phenyl}-3-methoxyacrylate

Canola (Py) Foliage/Pods Mature 70 

(8.3)

Seed 89 (1.5)

Canola (Ph) Foliage/Pods Mature 72 

(9.4)

Seed 94 (2.3)

Soybean (Py) Forage 10 (0.18)

Seed 5.9 (0.004)

Soybean (Ph) Forage 7.4 (0.12)

Seed 1.5 (0.002)

Wheat (Py) Forage 50 (2.0)

Straw 20 (2.0)

Grain 7.6 (0.006

Wheat (Ph) Forage 56 (3.3)

Straw 21 (2.3)

Grain 3.5 (0.011)

Apple (Py) 53 (0.035)

Apple (Ph) 55 (0.110)

Wheat (Py)-Rot Forage 2.5 (0.024) 1

Straw 0.8 (0.034) 1

Wheat (Ph)-Rot Forage 3.4 (0.012) 1

,

 1.3 

(<0.001) 2

Straw 0.8 (0.015) 1

Lettuce (Py) 1.1 (0.002) 1

Lettuce (Ph) 3.6 (0.002) 1

Carrot (Py) Root 11 (0.021) 1

Foliage 1.0 (0.007) 1

Foliage 1.1 (0.0006) 2

Carrot (Ph) Root 29 (0.010) 1

Foliage 8.6 (0.004) 1

Goat (Py) Liver 2.7 (0.003)

Kidney 3.8 (0.002)

Fat (Omental) 81 (0.024)

Fat (Perirenal) 72 

(0.021)

Fat (Subcutaneous) 70 

(0.022)

Goat (Ph) Liver 1.0 (0.003)

Kidney 2.5 (0.004)

Fat (Omental) 76 (0.018)

Fat (Perirenal) 75 

(0.018)

Fat (Subcutaneous) 55 

(0.012)

Hen (Py) Egg Yolk 2.2 (0.005)

Excreta 4.3 NR

Hen (Ph) Egg Yolk 1.3 (0.003)

Excreta 8.2 NR

Rat Phenyl: Feces 19.2

Compound 2 IN-QDY62 (R403092) Canola (Py) Foliage/Pods Mature 0.4

(0.05)
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Tabular Summary of Metabolites and Degradates.

Chemical Name

(other names in parentheses)

and Structure

Matrix Percent TRR (PPM) 1

Matrices - Major 

Residue (>10%TRR)

Matrices - Minor 

Residue (<10%TRR)

(E)-3-methoxy-2-{2-[6-

(trifluoromethyl)pyridin-2-

yloxymethyl]phenyl}acrylic acid

Canola (Ph) Foliage/Pods Mature 0.9

(0.11)

Wheat (Py) Straw 6.1 (0.60)

Wheat (Ph) Straw 4.8 (0.53)

Wheat (Py)-Rot Forage 0.1 (0.001) 1

Straw 0.9 (0.038) 1

Wheat (Ph)-Rot Straw 1.7 (0.032) 1

Lettuce (Ph) 1.2 (<0.001) 1(30-d)

Carrot (Py) Foliage 1.2 (0.0006) 2

Carrot (Ph) Root 0.5 (<0.0001) (30-d)

Goat (Py) Liver 6 (0.007)

Kidney 3.1 (0.002)

Goat (Ph) Liver 5.2 (0.017)

Kidney 2.6 (0.004)

Hen (Py) Excreta 1.7 NR

Hen (Ph) Excreta 2.5 NR

Rat Phenyl: Feces 26.5 Phenyl: Urine 4.1

Pyridinyl: Bile 2.1

Compound 3 IN-QDK50 (R403814)

6-(trifluoromethyl)pyridin-1H-2-one (6-

(trifluoromethyl) pyrindin-2-ol (preferred 

name))

Goat (Py) Liver 4.4 (0.005)

Hen (Py) Egg Yolk 1.4 (0.003)

Excreta 7.8 NR

Canola (Py) Foliage/Pods Mature 2.9 

(0.34)

Wheat (Py) Straw 2.0 (0.20)

Apple (Py) 0.4 (<0.001)

Wheat (Py)-Rot Forage 0.1 (0.001) 1

;Forage 

3.1 (0.002) 2

Straw 6.7 (0.285) 1; Forage 

2.0 (0.003) 2

Grain 0.9 <0.0011(30-d)

Carrot (Py) 1.7 (0.021) 1

(30-d)

Rat Pyridinyl: Urine 1.3

Compound 4 IN-QCD12 (R407782)

Methyl (Z)-2-{2-[6-(trifluoromethyl) pyridin-2-

yloxymethyl]phenyl}-3-methoxyacrylat

Canola (Py) Foliage/Pods Mature 0.7 

(0.08)

Canola (Ph) Foliage/Pods Mature 0.6 

(0.08)

Seed 0.6 (0.02)

Wheat (Py) Forage 1.5 (0.059)

Straw 1.3 (0.129)

Wheat (Ph) Forage 1.0 (0.059)

Straw 1.3 (0.143)

Compound 7 (R408631)

2-[2-[6-trifluoromethyl) pyridin-2-

yloxymethyl] phenyl] acetic acid

Wheat (Ph)-Rot Straw 0.5 (0.009) 1

Carrot (Ph) Root 0.5 (<0.001) 1

(30-d)

Goat (Py) Kidney 15 (0.008) Liver 3.3 (0.004)

Goat (Ph) Kidney 14 (0.020) Liver 3.9 (0.013)

Hen (Py) Egg Yolk 2.2 (0.005)

Excreta 0.8 NR

Hen (Ph) Egg Yolk 0.9 (0.002)
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Tabular Summary of Metabolites and Degradates.

Chemical Name

(other names in parentheses)

and Structure

Matrix Percent TRR (PPM) 1

Matrices - Major 

Residue (>10%TRR)

Matrices - Minor 

Residue (<10%TRR)

Excreta 1.1 NR

Soybean (Ph) 

(R408631-

glucoside) 

Forage 6.5 (0.109)

Rat Pyridinyl: Bile 1.6

N O

O

F3C

HO
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Tabular Summary of Metabolites and Degradates.

Chemical Name

(other names in parentheses)

and Structure

Matrix Percent TRR (PPM) 1

Matrices - Major 

Residue (>10%TRR)

Matrices - Minor 

Residue (<10%TRR)

M8 (R408631-glucoside) Soybean (Ph) Forage 6.5 (0.109)

Seed 2.8 (0.004)

Compound 8 IN-QDY63 (R408509)

2-[6-(trifluoromethyl)pyridin-2-

yloxymethyl]phenyl]benzoic acid

Canola (Py) Foliage/Pods Mature 7.6 

(0.90)

Canola (Ph) Foliage/Pods Mature 7.4 

(0.96)

Soybean (Ph) Forage 1.5 (0.026)

Seed 0.6 (<0.001)

Wheat (Py) Forage 1.1 (0.043)

Straw 4.3 (0.43)

Wheat (Ph) Forage 0.9 (0.053)

Straw 3.5 (0.385)

Apple (Ph) 0.8 (0.002)

Wheat (Ph)-Rot Straw 3.3 (0.001) 2

107-d

Carrot (Ph) 1.0 (<0.001) 1

Goat (Py) Liver 0.2 (<0.001)

Kidney 0.5 (<0.001)

Goat (Ph) Kidney 0.9 (0.001)

Rat Pyridinyl: Bile 0.1

Compound 9 (R233331 or CGA-320298)

Methyl (E)-2-[2-(hydroxymethyl)phenyl]-

3methoxyacrylate

HO

O

MeO OMe

Canola (Py) Foliage/Pods Mature 7.6 

(0.90)

Canola (Ph) Foliage/Pods Mature 7.4 

(0.96)

Wheat (Ph) Straw 0.4 (0.044)

Goat (Ph) Liver 0.3 (0.001)

Kidney 0.9 (0.001)

Compound 10 (R404843)

methyl 2-[2-[6-(trifluoromethyl) pyridin-2-

yloxymethyl] phenyl] acetate

Goat (Py) Liver 0.7 (0.001)

Kidney 2.9 (0.002)

Goat (Ph) Liver 1.1 (0.004)

Kidney 3.0 (0.004)

Hen (Py) Egg Yolk 0.5 (0.001)

Excreta 1.9 NR

Hen (Ph) Excreta 1.4 NR

Rat Pyridinyl: Bile 0.1

Compound 11 IN-QGS45 (R409465)

6-trifluoromethyl-2-glucosylpyridine

Canola (Py) Foliage/Pods Mature 0.2 

(0.03)

Wheat (Py) Forage 2.9 (0.114)

Straw 0.2 (0.020)

Wheat (Py)-Rot Straw 36 (0.052) 2

Forage 3.4 (0.033) 1; 

Forage 5.4 (0.004) 2

Straw 4.2 (0.179) 1 

N O

O

F3C

O

H3C
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Tabular Summary of Metabolites and Degradates.

Chemical Name

(other names in parentheses)

and Structure

Matrix Percent TRR (PPM) 1

Matrices - Major 

Residue (>10%TRR)

Matrices - Minor 

Residue (<10%TRR)

N O O

HO

OH

OH

OH

F

F

F

Wheat (Ph)-Rot Forage 

Lettuce (Py) 8.5 (0.016) 1

Carrot (Py) Foliage 10.2 (0.076)1

; 6.4 

(0.003) 2

Root 2.6 (0.005) 1

Compound 12 (R410101)

methyl 2-hydroxy-{2-[6-(trifluoromethyl) 

pyridin-2-yloxymethyl] phenyl} acetate

Wheat (Py) Forage 0.7 (0.028)

Straw 2.5 (0.248)

Wheat (Ph) Forage 0.5 (0.029)

Straw 2.8 (0.308)

Apple (Py) 6.1 (0.004)

Apple (Ph) 5.3 (0.011)

Rat Pyridinyl: Bile 0.1

Compound 13 (R407748)

methyl 2-oxo-{2-[6-(trifluoromethyl) pyridin-2-

yloxymethyl] phenyl} acetate

Wheat (Py) Forage 1.3 (0.051)

Straw 1.5 (0.149)

Wheat (Ph) Forage 1.3 (0.076)

Straw 2.0 (0.220)

Apple (Py) 2.4 (0.002)

Apple (Ph) 2.4 (0.005)

Goat (Py) Liver 1.1 (0.001)

Kidney 2.0 (0.001)

Goat (Ph) Liver 1.1 (0.004)

Kidney 3.9 (0.006)

Rat Pyridinyl: Bile 0.1

Compound 14 (R410639)

2-hydroxy-[2-(6-{trifluoromethyl}pyridine2-yloxymethyl)phenyl]acetic acid

Soybean (Ph) Forage 1.6 (0.027) 

Seed 2.0 (0.003)

Wheat (Py) Seed 0.5 (<0.001)

Straw 4.6 (0.455)

Wheat (Ph) Forage 0.5 (0.029)

Straw 3.0 (0.330)

Apple (Ph) <0.1 (<0.001)

Goat (Ph) Liver 0.6 (0.002)

Rat Pyridinyl: 

Bile 0.1; Urine 0.1

M2 (R410639- glucoside) Soybean (Py) Forage 14 (0.26) Seed 6.2 (0.005)

Soybean (Ph) Forage 8.4 (0.140)

Seed 0.7 (<0.001)

M7 (Malonyl-glucose conjugatedecarboxylated ( R410639)

Soybean (Ph) Forage 9.9 (0.166) 

Seed 0.5 (<0.001)

N O

O

F3C

O

H3C OH

F3C N O

HO

OH

O
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Tabular Summary of Metabolites and Degradates.

Chemical Name

(other names in parentheses)

and Structure

Matrix Percent TRR (PPM) 1

Matrices - Major 

Residue (>10%TRR)

Matrices - Minor 

Residue (<10%TRR)

Compound 15 Phthalic Acid (R001731) Soybean (Ph) Seed 21.3 (0.03) Forage 1.2 (0.020)

Wheat (Ph) Forage 1.6 (0.094)

Straw 1.8 (0.198)

Grain 7.4 (0.023)

Apple (Ph) 1.3 (0.003)

Compound 18 (R206576) Isochromen-3-one Goat (Ph) Liver 0.1 <0.001

Rat Phenyl: Urine 1.9

Compound 20 (R415833)

6-trifluoromethyl-2-(6-

malonylglucosyl)pyridine

N O O

HO

OH

OH

O

O

OH

F O

F

F

Wheat (Py) Forage 3.3 (0.130)

Wheat (Py)-Rot Forage 44 (0.43) 1

Forage 31 (0.022) 2

Straw 2.4 (0.003) 2

Straw 20 (0.861) 1

Lettuce (Py) 46 (0.086) 1

Carrot (Py) Foliage 23 (0.171) 1

Foliage 14 (0.008) 2

Root 5.4 (0.011) 1

Compound 21 (R277643)

2-(hydroxymethyl)benzoic acid

Wheat (Ph) Forage 0.2 (0.012)

Straw 1.0 (0.110)

Compound 24 (R135305)

1,3-dihydro-isobenzofuran-3-one-1-

carboxylicacid

O

O

COOH

Soybean (Ph) Forage 1.7 (0.028)

Seed 2.5 (0.003)

Wheat (Ph) Grain 14.9 (0.046) Forage 1.5 (0.088)

Straw 1.8 (0.198)

Grain 7.9 (0.024)

Wheat (Ph)-Rot Grain 1.7 (0.002)1

Compound 29 (R414535) Soybean (Py) Forage 4.6 (0.083)

Seed 6.8 (0.005)

O

O
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Tabular Summary of Metabolites and Degradates.

Chemical Name

(other names in parentheses)

and Structure

Matrix Percent TRR (PPM) 1

Matrices - Major 

Residue (>10%TRR)

Matrices - Minor 

Residue (<10%TRR)

Note: Mixture of 3,4 and 6-isomers

2-{n-(3-hydroxy-3-

methylglutaryl)glucosyl}-6-

{trifluoromethyl)pyridine, where n is a 

mixture of 3, 4 and 6

Carrot (Py) Foliage 43 (0.322) 1

Root 7.6 (0.015) 1

Foliage 43 (0.023) 2

Compound 30 (R409665)

2-(6-(trifluoromethyl)pyridin-2-yloxyacetic 

acid

Wheat (Py)-Rot Grain 13 (0.005) 1

Forage 9.6 (0.093) 1

Straw 6.6 (0.281) 1

Wheat (Ph)-Rot Forage 40.8 (0.146) 1

Straw 9.7 (0.181) 1

Grain 17.8 (0.016) 2

Lettuce (Py) 9.0 (0.017) 1

Lettuce (Ph) 31 (0.014) 1

Carrot (Py) Root 1.7 (0.003) 1

Carrot (Ph) Foliage 7.4 (0.004) 1

Root 5.9 (0.002) 1

Compound 31 (R416021)

2-oxo-{2-[6-(trifluoromethyl)pyridin-2-

yloxymethyl]phenyl} acetic acid

Rat Pyridinyl: Bile 0.1

Compound 32

Methyl 3-hydroxy-2-[2-[6-(trif1uoromethyl) 

pyridin-2-yloxymethyl] phenyl] propionate

Wheat (Py) Straw 2.3 (0.228)

Wheat (Ph) Straw 1.4 (0.154)

Goat (Py) Liver 1.5 (0.002)

Kidney 2.9 (0.002)

Goat (Ph) Liver 2.4 (0.008)

Kidney 3.4 (0.005)

Rat Phenyl: 

Feces 8.3; Urine 0.2

Pyridinyl:

Urine 0.2; Bile 0.1

Compound 33

methyl 2-{2-[n-(hydroxy-6-

(trifluoromethyl)pyridin-2-

Wheat (Py) Straw 2.2 (0.218)

Wheat (Ph) Straw 2.7 (0.297)

Hen (Py) Excreta 3.1 NR

N O

O

F3C

O OH

H3C
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Tabular Summary of Metabolites and Degradates.

Chemical Name

(other names in parentheses)

and Structure

Matrix Percent TRR (PPM) 1

Matrices - Major 

Residue (>10%TRR)

Matrices - Minor 

Residue (<10%TRR)

yloxymethyl]phenyl}-3-hydroxypropionate

n is an unknown locant

N O

F

F

F

O

MeO OH

OH

Hen (Ph) Excreta 4.9 NR

Compound 34

methyl (E)-2-(n-(hydroxy-2-[6-

(trifluoromethyl)pyridin-2-

yloxymethyl]phenyl}-3-methodyacrylate

n is an unknown locant

N O

F

F

F

O

MeO OMe

OH

Goat (Py) Liver 0.5 (0.001)

Kidney 1.0 (0.001)

Goat (Ph) Liver 2.1 (0.007)

Kidney 0.5 (0.001)

Hen (Py) Excreta 6.7 NR

Hen (Ph) Excreta 9.6 NR

Compound 36

N O

F

F

F

O

HO

OH

Goat (Py) Liver 2.3 (0.003)

Goat (Ph) Liver 0.9 (0.003)

Compound 38

2-glucuronidyl-6-(trifluoromethyl) pyridine

Rat Pyridinyl: Urine 1.0

Compound 39 (PYST2-conf study)

2-sulphooxy-6-(trifluoromethyl) pyridine

Wheat (Py)-Rot Straw 19 (0.016) 2 (107-

d)

Rat Pyridinyl: Urine 2.3
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Tabular Summary of Metabolites and Degradates.

Chemical Name

(other names in parentheses)

and Structure

Matrix Percent TRR (PPM) 1

Matrices - Major 

Residue (>10%TRR)

Matrices - Minor 

Residue (<10%TRR)

Compound 40

glucuronidyl (E)-3-methoxy-2-{2-[6-

(trifluoromethyl) pyridine-2-yloxymethyl] 

phenyl} acrylate

Rat Pyridinyl: Bile 28.9 Phenyl: Urine 7.4

Pyridinyl: Urine 2.2

Compound 42

methyl (E)-2-{4-hydroxy-2-[6-

(trifluoromethyl) pyridin-2-yloxymethyl]

Rat Phenyl: Feces 11.4 Phenyl: Urine 0.7

Pyridinyl:

Urine 0.2; Bile 0.1

Compound 43

methyl (E)-2-{4-glucuronidyl-2-[6-

(trifluoromethyl) pyridin-2-yloxymethyl] 

phenyl}-3-methoxyacrylate

Rat Phenyl: Urine 0.1

Pyridinyl: Bile 6.1

Compound 44

methyl (E)-3-hydroxy-2-{4-hydroxy-2-[6-

(trifluoromethyl) pyridin-2-yloxymethyl] 

phenyl}-3-methoxyacrylate

Rat Phenyl: 

Feces 8.4; Urine 1.3

Pyridinyl: Bile 1.0

Compound 45 (R290458)

methyl (E)-3-hydroxy-2-{2-[6-

(trifluoromethyl) pyridin-2-yloxymethyl] 

phenyl} acrylate

Rat Pyridinyl: Bile 0.1
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Tabular Summary of Metabolites and Degradates.

Chemical Name

(other names in parentheses)

and Structure

Matrix Percent TRR (PPM) 1

Matrices - Major 

Residue (>10%TRR)

Matrices - Minor 

Residue (<10%TRR)

Compound 46

methyl (E)-3-glucuronidyl-2-{2-[6-

(trifluoromethyl) pyridin-2-yloxymethyl] 

phenyl} acrylate

Rat Phenyl: Urine 0.3

Pyridinyl: Bile 2.1

Compound 47

methyl (E)-3-glucuronidyl-2-{4-hydroxy-2-

[6-(trifluoromethyl) pyridin-2-

yloxymethyl]phenyl} acrylate

Rat Phenyl: Urine 0.1

Pyridinyl: Bile 3.2

Compound 48 (R290461)

Methyl 2,3-dihydroxy-2-[6-

(trifluoromethyl)pyridin-2-

yloxymethyl]phenyl] propionate

Goat (Py) Liver 1.2 (0.001)

Kidney 2.6 (0.001)

Goat (Ph) Liver 1.8 (0.006)

Kidney 2.0 (0.003)

Hen (Py) Excreta 0.9 NR

Hen (Ph) Excreta 1.2 NR

Rat Phenyl: Urine 2.0

Pyridinyl: Urine 0.1

M1 (R290461-glucoside) Soybean (Py) Forage 24 (0.44) Seed 7.7 (0.006)

Soybean (Ph) Forage 22 (0.37) Seed 3.8 (0.005)

M4 (Malonyl-glucose conjugate of 

R290461) 2-[n-(,3-hydroxy-3-

methylglutaryl)glucosal]-6-

(trifluoromethyl)pyridine

Soybean (Py) Forage 10 (0.18) Seed 6.3 (0.005)

M5 (R290461-glucoside) Soybean (Py) Forage 6.2 (0.112) 

Seed 3.5 (0.003)

Soybean (Ph) Forage 4.1 (0.068) 

M6 (R290461) 2,3-dihydroxy-2-[2-(6-

{trifluoromethyl}pyridine-2-

yloxymethyl)phenyl]propionic acid

Soybean (Py) Seed 4.5 (0.003)

N O

O

F3C

O

H3C

OH

OH
Picoxystrobin Human Health Risk Assessment DP No. 377690

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Tabular Summary of Metabolites and Degradates.

Chemical Name

(other names in parentheses)

and Structure

Matrix Percent TRR (PPM) 1

Matrices - Major 

Residue (>10%TRR)

Matrices - Minor 

Residue (<10%TRR)

Compound 49

methyl 2-hydroxy-3-glucuronidyl-2-{2-[6-

(trifluoromethyl) pyridin-2-yloxymethyl] 

phenyl} propionate

Rat Phenyl: Urine 0.7

Compound 50

3-hydroxy-2-{2-[6-(trifluoromethyl) pyridin-2-

yloxymethyl] phenyl} propionic acid

Goat (Py) Liver 0.7 (0.001)

Kidney 2.8 (0.002)

Goat (Ph) Liver 3.1 (0.010)

Kidney 3.0 (0.004)

Rat Phenyl: Urine 1.2

Pyridinyl: 

Urine 0.3; Bile 0.1

Compound 51

2,3-dihydroxy-2-{2-[6-(trifluoromethyl) 

pyridin-2-yloxymethyl] phenyl} propionic 

acid

Rat Phenyl: Urine 3.7

Pyridinyl:

Bile 1.5; Urine 1.3

Compound 52

methyl 2-hydroxy-3-sulphooxy-2-{2-[6-

(trifluoromethyl) pyridin-2-yloxymethyl] 

phenyl} propionate

Rat Phenyl: Urine 6.5

Pyridinyl: Urine 3.1

Compound 53

methyl 3-glucuronidyl-2-{2-[6-

(trifluoromethyl) pyridin-2-yloxymethyl] 

phenyl} propionate

Rat Pyridinyl: Bile 0.1
Picoxystrobin Human Health Risk Assessment DP No. 377690

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Tabular Summary of Metabolites and Degradates.

Chemical Name

(other names in parentheses)

and Structure

Matrix Percent TRR (PPM) 1

Matrices - Major 

Residue (>10%TRR)

Matrices - Minor 

Residue (<10%TRR)

Compound 54

N-carboxymethyl 2-{2-[6-(trifluoromethyl) 

pyridin-2-yloxymethyl] phenyl} acetamide

Rat Phenyl: Urine 8.9

Pyridinyl: Urine 1.4

Compound 55

(E)-2-[2-(hydroxymethyl) phenyl]-3-

methoxyacrylic acid

Rat Phenyl: Urine 3.4

Compound 56

methyl (E)-2-[2-(glucuronidylmethyl) 

phenyl]-3-methoxyacrylate

Rat Phenyl: Urine 2.5

Compound 57

2-{n-hydroxy-2-[6-(trifluoromethyl) 

pyridin-2-yloxymethyl] phenyl} malonic 

acid

Rat Phenyl: Urine 1.4

Compound 58

n-(sulfooxy) iso-chromanone

Rat Phenyl: Urine 1.9

Compound 59

[Nomenclature and Structure Not Provided]

Rat Pyridinyl: Bile 3.3

Compound 60

[Nomenclature and Structure No Provided]

Rat Phenyl: Urine 0.8

Pyridinyl: Urine 0.1

Compound A

[Unknown Nomenclature and Structure]

Rat Phenyl: Feces 10.5 Phenyl: Urine 1.0

Pyridinyl: Bile 2.1

Compound C

[Unknown Nomenclature and Structure]

Rat Phenyl: Feces 3.0
Picoxystrobin Human Health Risk Assessment DP No. 377690

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Tabular Summary of Metabolites and Degradates.

Chemical Name

(other names in parentheses)

and Structure

Matrix Percent TRR (PPM) 1

Matrices - Major 

Residue (>10%TRR)

Matrices - Minor 

Residue (<10%TRR)

Compound D

[Unknown Nomenclature and Structure]

Rat Phenyl: Urine 2.1

Pyridinyl: Urine 0.4

Compound E

[Unknown Nomenclature and Structure]

Rat Phenyl: Urine 4.2

Compound F

[Unknown Nomenclature and Structure]

Rat Phenyl: Urine 0.6

Compound G

[Unknown Nomenclature and Structure]

Rat Phenyl: Urine 0.9

Pyridinyl: Urine 0.3

Compound H

[Unknown Nomenclature and Structure]

Rat Phenyl: Urine 0.9

Pyridinyl: Urine 0.3

Compound (R414535) M3

2-(n-(3-hydroxy-3-methylglutaryl)glucosyl)-

6-(trifluoromethyl)pyridine

Soybean (Py) Forage 4.6 (0.083)

Soybean (Ph) Seed 6.8 (0.005)

M13 (2-formyl-phenyl)-oxo-acetic acid Soybean (Ph) Seed 25.5 (0.036)

PAG3

HO

O

HO

O

Wheat (Ph) Straw 0.8 (0.088)

Grain 7.9 0.024

PAF1 Wheat (Ph)-Rot 13 (0.028) (30-day)

Lettuce (Ph) 27 (0.012) 1

Carrot (Ph) Foliage 17 (0.008) 1

Root 14 (0.005) 1

PYCR2 Carrot (Py) Root 15 (0.055) 1 (30-d)

Root 15 (0.030) 1 (197-d)

PYCR3 Carrot (Py) Root 24 (0.090) 1(30-d)

Root 15 (0.030) 1 (197-d)

PYST2 Wheat (Py)-Rot Straw 19 (0.016) 2 (107-

d)
Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 51 of 89

Tabular Summary of Metabolites and Degradates.

Chemical Name

(other names in parentheses)

and Structure

Matrix Percent TRR (PPM) 1

Matrices - Major 

Residue (>10%TRR)

Matrices - Minor 

Residue (<10%TRR)

Canola: 48073852; 0.4 lb ai/A (Two Broadcast foliar spray) at BBCH-80 and BBCH-85; Forage-7-day after 1st application, 14-

day after 2nd application, and 21 day after second application (mature); Seed-21-day PHI.

Soybean: 48073856; 0.1 lb ai/A (Two Broadcast foliar spray) at R3 and R5 (14-days after 1st application); Total-0.2 lb ai/A and 

1.0 lb ai/A (metabolite isolation only); Forage-14-day PHI, Seed-61-day PHI (mature).

Wheat: 48073854; ~0.4 lb ai/A (Two Broadcast foliar spray) at BBCH 32 and BBCH-65-69; Forage-14-day PHI; 48-day PHI 

(straw and grain- mature).

Apple: 48073857; ~0.16 lb ai/A (Three Broadcast foliar spray) at BBCH 69 and 21nad 85 days after 1st application; 14-day 

PHI.

Confined Rotational Crops (Carrot, Lettuce and Wheat): 48073883; ~0.8 lb ai/A , applied to bare sandy loam soil; 30,197-days 

PBI. Radio labeled Field Accumulation: 48073884; ~0.8 lb ai/A , (Two Broadcast foliar spray) at BBCH 32 and BBCH-65-69; 

305-days PBI. Radio labeled Field Accumulation: 48073885; ~0.8 lb ai/A , (Two Broadcast foliar spray) at BBCH 32 and

BBCH-55-59; 107-days PBI. 

1

Confined Rotational wheat (PBI 197 days)

2

Field Rotational wheat (PBI 304 days)

Goat: 48073859; 10 ppm; oral dose daily for 7-days; sacrificed 16-hour after last dose administration.

Hen: 48073858; 10 ppm; oral dose daily for 10-days; sacrificed 16-hour after last dose administration.
Picoxystrobin Human Health Risk Assessment DP No. 377690

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Appendix C. Physical/Chemical Properties

Physicochemical Properties of the Technical Grade Test Compound: Picoxystrobin

Parameter Value Reference

Melting point 75 °C PMRA Chemistry Evaluation 

pH Not indicated Section (CES) Review

Density at 20 °C 1.4 g/mL

Water solubility at 20 °C 3.1 mg/mL

Vapor pressure at 20 °C 5.5X10-3 mPa

Octanol/water partition 

coefficient Log(KOW) at 20 °C 3.6
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Appendix D. Toxicology Profile and Executive Summaries

D.1 Toxicology Data Requirements

The requirements (40 CFR 158.500) for picoxystrobin food uses are found below (Table D.1). Use 

of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table D.1: Toxicology Studies Required Submitted Satisfied

870.1100 Acute Oral Toxicity ...................................................................................................

870.1200 Acute Dermal Toxicity ..............................................................................................

870.1300 Acute Inhalation Toxicity ..........................................................................................

870.2400 Acute Eye Irritation....................................................................................................

870.2500 Acute Dermal Irritation..............................................................................................

870.2600 Skin Sensitization ......................................................................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 90-Day Oral Toxicity in Rodents...............................................................................

870.3150 90-Day Oral Toxicity in Non-Rodents.......................................................................

870.3200 21/28-Day Dermal Toxicity .......................................................................................

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

870.3465 90-Day Inhalation Toxicity (28-Day) ........................................................................

yes

yes

yes

no (CR)

yes (CR)

yes

yes

yes

no

yes

yes

yes

yes

---

yes

870.3700 Prenatal Developmental Toxicity Study (Rodent)......................................................

870.3700 Prenatal Developmental Toxicity Study (Non-Rodent) .............................................

870.3800 Reproduction and Fertility Effects.............................................................................

yes

yes

yes

yes

yes

yes

yes

no

yes

870.4100 Chronic Toxicity (Rodent).........................................................................................

870.4100 Chronic Toxicity (Non-Rodent).................................................................................

870.4200 Carcinogenicity (Rat).................................................................................................

870.4200 Carcinogenicity (Mouse)............................................................................................

870.4300 Combined Chronic Toxicity/Carcinogenicity (Rat) ...................................................

yes

no

yes

yes

yes

no

yes

yes

yes

yes

yes

---

yes

yes

yes

870.5100 Bacterial Reverse Mutation Test................................................................................

870.5300 in vitro Mammalian Cell Gene Mutation Test ...........................................................

870.5375 in vitro Mammalian Chromosome Aberration Test ...................................................

870.5395 Mammalian Erythrocyte Micronucleus Test..............................................................

870.5550 Unscheduled DNA Synthesis in Mammalian Cells in Culture...................................

yes

yes

yes

yes

no

yes

yes

yes

yes

yes

yes

yes

yes

yes

---

870.6100 Delayed Neurotoxicity of Organophosphorus Substances (Acute, Hen)....................

870.6100 Delayed Neurotoxicity of Organophosphorus Substances (28-Day, Hen) .................

870.6200 Neurotoxicity Screening Battery (Acute, Rat) ...........................................................

870.6200 Neurotoxicity Screening Battery (Subchronic, Rat)...................................................

870.6300 Developmental Neurotoxicity Study..........................................................................

no (CR)

no (CR)

yes

yes

no (CR)

---

---

yes

yes

---

---

---

yes

yes

---

870.7200 Companion Animal Safety.........................................................................................

870.7485 Metabolism and Pharmacokinetics.............................................................................

870.7600 Dermal Penetration ....................................................................................................

OECD 428 in vitro Dermal Penetration........................................................................................

870.7800 Immunotoxicity..........................................................................................................

no (CR)

yes

no (CR)

no

yes

---

yes

yes

yes

yes

---

no

---

---

yes

CR: Conditionally Required
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D.2 Toxicity Profiles

Table D.2.1: Acute Toxicity for Picoxystrobin Technical

Guideline Study Type MRID Conclusion Toxicity Category

870.1100 Acute Oral Toxicity 48073718 Female LD50 > 5000 mg/kg IV

870.1200 Acute Dermal Toxicity 48073721 Both sexes LD50 > 5000 mg/kg IV

870.1300 Acute Inhalation Toxicity 48073723 LC50: =0.11 mg/L II

870.2400 Acute Eye Irritation 48073725 Severe reaction observed I

870.2500 Acute Dermal Irritation 48073727 Not a dermal irritant in rabbits IV

870.2600 Dermal Sensitization 48073729 Not a dermal sensitizer in guinea pigs Negative

Table D.2.2: Acute Toxicity for Technical Grade Picoxystrobin Metabolites

Guideline Study Type (Metabolite) MRID Conclusion Toxicity Category

870.1300 Acute Inhalation Toxicity (26) 48258033 LC50: M > 26.24 / F > 26.24 mg/L IV

Table D.2.3: Subchronic, Chronic, and Other Toxicity Profiles for Picoxystrobin Technical

Guideline Study Type MRID (year) / Doses / Classification Results (NOAEL, LOAEL, and LOAEL Effects)

870.3100 90-Day Oral Toxicity 

in Rodents (Rat)

48073731 (1999) 

Dietary Concentration (ppm):

0, 100, 500, 1250

Intake Dose (mg/kg/day):

M: 0, 8.5, 41.7, 104.9

F: 0, 9.7, 8.1, 120.1

Acceptable / Guideline

NOAEL (mg/kg/day) = M: 41.7 F: 48.1

LOAEL (mg/kg/day) = M: 104.9 F: 120.1

Based on decreased body weight, body weight gains and 

food consumption in both sexes

90-Day Oral Toxicity 

in Rodents (Mouse)

48073732 (1996)

Dietary Concentration (ppm):

0, 200, 800, 1600, 2400

Intake Dose (mg/kg/day):

M: 0, 33.2, 137.3, 290.8, 421.6

F: 0, 43.8, 176.1, 358.5, 534.8

Unacceptable / Non-Guideline

NOAEL (mg/kg/day) = M: 33.2 F: 43.8 

LOAEL (mg/kg/day) = M: 137.3 F: 176.1

Based on decreases in body weights, body weight gains 

and food utilization

Unacceptable: Hematology and clinical chemistry were 

not evaluated, numerous organs were not weighed, and 

numerous tissues were not evaluated microscopically

870.3150 90-Day Oral Toxicity 

in Non-Rodents (Dog)

48073734 (1998)

Dietary Concentration (ppm): 

0, 125, 250, 500

Intake Dose (mg/kg/day): 

M: 0, 4.3, 8.9, 16.5

F: 0, 4.3, 8.5, 16.9

Acceptable / Guideline

NOAEL (mg/kg/day) = M: 8.9 F: 8.5

LOAEL (mg/kg/day) = M: 16.5 F: 16.9

Based on decreased body weights and body weight gains 

in the males and food consumption in males and females 

870.3200 21/28-Day Dermal 

Toxicity (Rat)

48073735 (2009)

0, 100, 300, 1000 mg/kg/day

Acceptable / Guideline

NOAEL (mg/kg/day) = 1000

LOAEL (mg/kg/day) = Not Established

48073736 (1999)

0, 200, 500, 1000 mg/kg/day

Unacceptable / Guideline

NOAEL (mg/kg/day) = 1000

LOAEL (mg/kg/day) = Not Established

Unacceptable due to numerous submission deficiencies

870.3465 28-Day Inhalation 

Toxicity

48697401 (2011)

Dietary Concentration (mg/L): 

0, 0.0017, 0.012, 0.025

Intake Dose (mg/kg/day): 

M: 0, 0.46, 3.25, 6.78

F: 0, 0.46, 3.25, 6.78

Acceptable / Non-Guideline

NOAEL (mg/kg/day) = 6.78

LOAEL (mg/kg/day) > 6.78
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Table D.2.3: Subchronic, Chronic, and Other Toxicity Profiles for Picoxystrobin Technical

Guideline Study Type MRID (year) / Doses / Classification Results (NOAEL, LOAEL, and LOAEL Effects)

870.3700 Prenatal 

Developmental

(Rat)

48073738 (1998)

0, 10, 30, 100 mg/kg/day

Acceptable / Guideline

Maternal 

NOAEL (mg/kg/day) = 30

LOAEL (mg/kg/day) = 100

Based on decreased body weight gain, food 

consumption, and increased incidence of clinical signs 

(diarrhea and urine staining).

Developmental

NOAEL (mg/kg/day) = 30

LOAEL (mg/kg/day) = 100

Based on misaligned 5th sternebrae on GD 22

Prenatal 

Developmental 

(Rabbit)

48073737 (1999)

0, 8, 25, 100 mg/kg/day

Acceptable / Guideline

Maternal

NOAEL (mg/kg/day) = 8

LOAEL (mg/kg/day) = 25

Based on decreased food consumption accompanied by 

clinical signs of diarrhea

Developmental

NOAEL (mg/kg/day) = 25

LOAEL (mg/kg/day) = 100

Based on incomplete ossification of the odontoid, 27 prepelvic vertebrae and 13th ribs of long length

870.3800 Reproduction and 

Fertility Effects 

(Rat)

48073739 (2010)

Dietary Concentration (ppm)

0, 75, 300, 1000, 2500

Intake Dose (mg/kg/day)

M: 0, 4.2, 16.9, 55.5, 137.5

F: 0, 5.4, 21.7, 70.3, 173.4

Acceptable / Guideline

Parental 

NOAEL (mg/kg/day) = M: 55.5 F: 70.3

LOAEL (mg/kg/day) = M: 137.5 F: 173.4

Based on decreases in body weight, body weight gain, 

and food consumption in the P and F1 generation during 

pre-mating; increased body weight gains in the P and F1 

females at the end of the lactation period; organ weight 

differences; and minimal to moderate lymphoid atrophy 

in the thymus in P generation females

Offspring

NOAEL (mg/kg/day) = M: 55.5 F: 70.3

LOAEL (mg/kg/day) = M: 137.5 F: 173.4

Based on decreased mean pup body weights/litter and 

body weight gains in the F1 and F2 generations

Reproductive

NOAEL (mg/kg/day) = M: 137.5 F: 173.4

LOAEL (mg/kg/day) = Not Established

48073740 (1998)

Dietary Concentration (ppm)

0, 50, 200, 750

Intake Dose (mg/kg/day)

M: 0, 5.4, 21.5, 80.0

F: 0, 5.8, 23.4, 87.2

Acceptable /guideline

Parental

NOAEL (mg/kg/day) = M: 5.4 F: 5.8

LOAEL (mg/kg/day) = M: 21.5 F: 23.4

Based on decreased body weights, body weight gains, 

and food consumption in the F1 males

Offspring

NOAEL (mg/kg/day) = M: 21.5 F: 23.4

LOAEL (mg/kg/day) = M: 80.0 F: 87.2

Based on decreased body weights in the F1 and F2 pups

Reproductive

NOAEL (mg/kg/day) = M: 80.0 F: 87.2

LOAEL (mg/kg/day) = Not Established
Picoxystrobin Human Health Risk Assessment DP No. 377690

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Table D.2.3: Subchronic, Chronic, and Other Toxicity Profiles for Picoxystrobin Technical

Guideline Study Type MRID (year) / Doses / Classification Results (NOAEL, LOAEL, and LOAEL Effects)

870.4100 Chronic Toxicity 

(Dog)

48073741 (1999)

Dietary Concentration (ppm): 

0, 50, 150, 500

Intake Dose (mg/kg/day): 

M: 0, 1.6, 4.8, 16.1

F: 0, 1.6, 4.6, 15.7

Acceptable / Guideline

NOAEL (mg/kg/day) = M: 4.8 F: 4.6

LOAEL (mg/kg/day) = M: 16.1 F: 15.7

Based on decreased body weights, body weight gains, 

and food consumption in both sexes

870.4200 Carcinogenicity 

(Mouse)

48457401 (2011)

Dietary Concentration (ppm):

0, 100, 600, 2400, 4800

Intake Dose (mg/kg/day):

M: 0, 12, 71, 293, 583

F: 0, 16, 99, 412, 799

Acceptable / Guideline

NOAEL (mg/kg/day) = M: 71 F: 99

LOAEL (mg/kg/day) = M: 293 F: 412

Based on duodenal mucosal hyperplasia, mucosal gland 

dilatation, and stomach glandular mucosal hyperplasia in 

male mice.

Carcinogenicity:

At 2400 ppm and above, picoxystrobin produced 

gastrointestinal (GI) effects in male mice; these effects 

included increased incidence of hyperplasia of duodenal 

mucosa (0 ppm: 3/50; 2400 ppm: 6/59; 4800 ppm: 

10/58) and increased incidence of stomach glandular 

mucosal hyperplasia (0 ppm: 10/53; 2400 ppm: 26/59; 

4800 ppm: 18/58).

48073744 (1999)

Dietary Concentration (ppm): 

0, 50, 200, 800

Intake Dose (mg/kg/day): 

M: 0, 6.6, 26.2, 108.8

F: 0, 8.8, 35.6, 144.7

Unacceptable / Guideline

NOAEL (mg/kg/day) = M: 26.2 F: 35.6

LOAEL (mg/kg/day) = M: 108.8 F: 144.7

Based on slight increase in the incidence of ulceration 

and inflammation of the stomach.

Carcinogenicity: 

Unacceptable, doses were inadequate to assess 

carcinogenic potential
Picoxystrobin Human Health Risk Assessment DP No. 377690

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Table D.2.3: Subchronic, Chronic, and Other Toxicity Profiles for Picoxystrobin Technical

Guideline Study Type MRID (year) / Doses / Classification Results (NOAEL, LOAEL, and LOAEL Effects)

870.4300 Combined 

Chronic Toxicity/

Carcinogenicity 

(Rat)

48457402 (2011)

Dietary Concentration (ppm):

0, 50, 200, 1000, 3500

Intake Dose (mg/kg/day):

M: 0, 2.2, 8.8, 45.3 162.1

F: 0, 2.8, 11.0, 57.1, 203.3

Acceptable / Guideline

NOAEL (mg/kg/day) = M: 45.3 F: 57.1

LOAEL (mg/kg/day) = M: 162.1 F: 203.3

Based on reduced body weight and food consumption in 

addition to increased incidence of interstitial cell 

hyperplasia in male rats.

Carcinogenicity:

There were no treatment-related microscopic findings 

following one year of treatment. With two years of 

treatment, picoxystrobin induced an increase in testicular 

interstitial cell adenomas in male rats. The testicular 

interstitial cell tumors in male rats demonstrated a 

statistically significant trend at p < 0.01 and a significant 

pair-wise comparison of the 3500 ppm dose group with 

the controls at p < 0.05 with Peto’s test. When compared 

to historical control data from the testing laboratory, the 

tumor incidence (7/70, 10%) was above the majority of 

the incidence of this tumor (0 to 8.3%). In comparison 

to the Charles River Laboratory historical control data 

for CD®[Crl:CD®(SD)] rats which show an overall 

mean of 2.4% with a range of 1.1% to 9.3%, the 

testicular interstitial cell adenoma incidence induced by 

picoxystrobin is above this overall mean. Therefore, the 

increased incidence of testicular tumors in male rats was 

treatment-related. A compound-related increase in 

testicular interstitial cell hyperplasia was also seen in 

3500 ppm males. 

48073745 (2010) [1-year Interim Results]

Dietary Concentration (ppm): 

0, 50, 200, 1000, 3500

Intake Dose (mg/kg/day): 

M: 0, 2.6, 10.4, 52.3, 186.3

F: 0, 3.2, 13.1, 65.0, 229.6

Acceptable / Non-guideline

NOAEL (mg/kg/day) = M: 26.2 F: 35.6

LOAEL (mg/kg/day) = M: 108.8 F: 144.7

Based on decreased body weights, body weight gains, 

and food consumption.

Carcinogenicity: 

Unacceptable, duration was inadequate to assess 

carcinogenic potential

48073746 (1999)

Dietary Concentration (ppm): 

0, 50, 200, 750

Intake Dose (mg/kg/day): 

M: 0, 3.1, 12.2, 45.6

F: 0, 3.8, 14.8, 57.8

Acceptable / Guideline

NOAEL (mg/kg/day) = M: 45.6 F: 57.8

LOAEL (mg/kg/day) = Not Established

Carcinogenicity: 

Unacceptable, doses were inadequate to assess 

carcinogenic potential

870.5100 Bacterial Reverse 

Mutation Test

(Salmonella 

typhimurium and

Escherichia coli)

48073747 (1996)

0, 100, 200, 500, 1000, 2500, 5000 g/plate

Acceptable / Guideline

E1963 did not induce gene mutation in any of the strains 

employed, either with or without metabolic activation.

870.5300 in vitro

Mammalian Cell Gene 

Mutation Test

(Mouse lymphoma 

cells)

48073748 (1996)

Trial 1 ( S9): 0, 4, 8, 16, 32, 64 g/mL 

Trial 2 ( S9): 0, 24, 32, 42, 56, 75 g/mL 

Acceptable / Guideline

E1963 was not mutagenic in this test system
Picoxystrobin Human Health Risk Assessment DP No. 377690

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Table D.2.3: Subchronic, Chronic, and Other Toxicity Profiles for Picoxystrobin Technical

Guideline Study Type MRID (year) / Doses / Classification Results (NOAEL, LOAEL, and LOAEL Effects)

870.5375 in vitro Mammalian 

Chromosome 

Aberration Test

(Human lymphocytes)

48073749 (1996)

-S9: Range between 0.5-20.0 g/mL

+S9: Range between 1-60 g/mL

Acceptable / Guideline

Negative for inducing structural chromosome aberrations

870.5395 Mammalian 

Erythrocyte 

Micronucleus Test

(Mouse)

48073750 (1996)

0, 2000, 3200, 5000 mg/kg/day

Acceptable / Guideline

E1963 did not induce the formation of micronucleated 

polychromatic erythrocytes at dose levels up to the limit 

dose which was overtly toxic to the test animals (both 

male and female) and slight cytotoxic to the target cell 

(males only). Accordingly, there was no evidence of 

clastogenicity or inhibition of spindle formation under 

the conditions of this study.

870.5550 in vivo Genotoxicity 

Testing-Unscheduled 

DNA Synthesis

(Rat hepatocytes)

48073751 (1996)

0, 3200, 5000 mg/kg/day

Acceptable / Non-Guideline

E1963 did not induce DNA repair, as assessed by NNG 

counts and proportion of cells in repair, at doses up to 

and including the limit dose of 5000 mg/kg , under the 

conditions employed in this study

870.6200 Neurotoxicity 

Screening Battery

(Acute Rat)

48073753 (2009)

0, 200, 1000, 2000 mg/kg 

Acceptable / Guideline

NOAEL (mg/kg/day) = Not Established

LOAEL (mg/kg/day) = 200 mg/kg 

Based on low arousal and decreased motor activities in 

males, decreased rearing in females, in addition to 

decreased bodyweight gain and food consumption in 

both sexes on Day 1.

Neurotoxicity 

Screening Battery

(Subchronic Rat)

48073752 (2010)

Dietary Concentration (ppm): 

0, 100, 600, 3500

Intake Dose (mg/kg/day):

M: 0, 6, 36, 207

F: 0, 8, 46, 246

Acceptable / Guideline

NOAEL (mg/kg/day) = M: 36 F: 46

LOAEL (mg/kg/day) = M: 207 F: 246

Based on decreased male forelimb grip and increased 

female hindlimb splay in addition to decreased body 

weight, body weight gain, and food consumption in both 

sexes.
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Table D.2.3: Subchronic, Chronic, and Other Toxicity Profiles for Picoxystrobin Technical

Guideline Study Type MRID (year) / Doses / Classification Results (NOAEL, LOAEL, and LOAEL Effects)

870.7485 Metabolism and 

Pharmacokinetics (Rat)

48073754 (2010)

10, 100 mg/kg

Acceptable / Guideline

Absorption: Rats absorbed 77-82% of the orally 

administered dose (AD) and was comparable in both 

sexes. Absorption in both the single-low and singlehigh dose groups was bimodal with an initial peak in 

both sexes at ~1 hr. However, the second peak in the 

single-low dose group (12 hrs) appeared sooner than in 

the single-high dose group (24 hrs). 

Distribution: Picoxystrobin residues were found in low 

levels throughout the rat with detectable levels in a 

broad range of organs (i.e. brain, gonads, heart, kidneys, 

liver, lungs, and spleen) as well as in the residual 

carcass. The highest residue levels observed in the rat 

organs were found in the liver (0.12-0.24% AD) and 

kidneys (0.014-0.019%AD). The rat carcass without the 

previously mentioned organs only contained 0.36-

0.63% AD.

Metabolism: The major metabolic reactions were ester 

hydrolysis and glucuronide conjugation. Parent was 

found in significant quantities in the feces (5-19%) but 

none was found in the urine; indicative of thorough 

metabolism of the parent. The parent metabolized into 

42 different products (Appendix B: Table B.1 and 

Figure B.1) with a few products produced in significant 

quantities; one product’s structure was not identified 

(i.e. Product A). In non-bile duct cannulated rats, 

product 2 (Parent methyl-ester hydrolysis) was found in 

the greatest quantity (17-30% AD) with the majority 

relegated to the feces and only 1-4% AD found in the 

urine. In bile-duct cannulated groups however, product 

40 (Product 2 glucuronide conjugation) was isolated in 

the greatest quantity (29-32%) with the majority found 

in the bile and only 2% AD found in the urine. There 

were observable sex differences for a select group of 

products, whereby only females through urine released 

Products 52 (Parent phenyl ring hydroxylation para to 

acrylate moiety) and 54 (Parent acrylate to acetamide 

conversion), and males via feces formed substantially 

more Product 44 (Parent methoxy group 

demethylation).

Elimination: The majority of picoxystrobin elimination 

(i.e. combined feces and urine) in the rat occurred 

within 48 hours (73-89% AD) and was essentially 

complete at 120 hours (92-99% AD). Elimination was 

predominately through the fecal route for males (74-

78% AD) and females (61-65% AD) with bile being the 

primary route of excretion (66-72% AD). Urinary 

excretion was also a significant route of elimination in 

males (18-21% AD) and females (26-34% AD).

48073755 (1999)

Single: 100 mg/kg

48073756 (1998)

Single: 10 mg/kg

48073757 (1998)

Single: 100 mg/kg

48073758 (1998)

Repeated: 10 mg/kg

48073759 (1997)

Single: 10 mg/kg

Acceptable / Guideline
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Table D.2.3: Subchronic, Chronic, and Other Toxicity Profiles for Picoxystrobin Technical

Guideline Study Type MRID (year) / Doses / Classification Results (NOAEL, LOAEL, and LOAEL Effects)

870.7600 Dermal Absorption D383984

48073760 (1999)

48073761 (1999)

Dermal Absorption Factor (DAF) = 2%

The Triple Pack specifies that when laboratory studies 

demonstrate that the ratio of the animal in vitro to in vivo

DAF is close to 1, a human in vitro study conducted 

under the same condition as the animal test is likely to be 

a good predictor of human dermal absorption

Exposure scenarios in the rat (in vitro / in vivo):

24 h exposure, no wash (33.08/20.59): 1.61

24 h exposure, wash at 10 hr (55.06/4.75): 11.59

Since the 24 h exposure with no wash ratio in rats was 

close to 1, therefore the 24 h exposure with no wash 

human in vitro data was accepted as the refined DAF 

(1.98%). The value was subsequently rounded to 2%.

OECD 428

in vitro

Dermal Penetration

(Human & Rat) 

48073760 (1999)

5.45, 1279 g/mL

Acceptable / Guideline

Rat: 24 h exposure, wash at 10 hr: 55.06 11.67%

24 h exposure, no wash: 33.08 6.04%

Human: 24 h exposure, wash at 10 hr: 2.17 0.79%

24 h exposure, no wash: 1.98 0.68%

Dermal Penetration

(Rat)

48073761 (1999)

6.17, 1219 g/mL

Acceptable / Guideline

Dermal Absorption Factor: 10 hour exposure = 4.75%

24 hour exposure = 20.59%

Experimentally determined that skin bound residues are 

not likely to be absorbed

870.7800 Immunotoxicity

(Rat)

48073762 (2010)

Dietary Concentration (ppm): 

0, 50, 200, 1000, 3500

Intake Dose (mg/kg/day): 

M: 0, 3.5, 15, 68, 231

F: 0, 3.9, 16, 75, 225

Acceptable / Guideline

NOAEL (mg/kg/day) = M: 231 F: 225

LOAEL (mg/kg/day) = Not Established

Immunotoxicity

(Mouse)

48073763 (2010)

Dietary Concentration (ppm): 

0, 100, 600, 2400, 4800

Intake Dose (mg/kg/day): 

M: 0, 16, 95, 358, 727

F: 0, 20, 127, 449, 931

Acceptable / Guideline

NOAEL (mg/kg/day) = M: 727 F: 931

LOAEL (mg/kg/day) = Not Established
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D.3 Dermal Absorption

Rat in vivo Study: Absorption was quantified as the sum of radioactivity found in urine, feces,

gastrointestinal contents, carcass, and cage wash (Table D.3.1). 

 

Table D.3.1: Results for a 14C-Picoxystrobin in vivo Dermal Absorption Study in Male Rats

Test Conditions

Dose ( g/cm2) 10 hrs treated 10 hrs treated, wash, and then 14 hrs untreated 24 hrs treated

6.17 4.44% 4.75% 20.59%

1219 0.33% 0.45% 0.88%

Human and Rat in vitro Study: Absorption was quantified as the percentage of radioactivity that 

passed through an epidermal membrane (Table D.3.2).

Table D.3.2: Results for a 14C-Picoxystrobin in vitro Dermal Absorption Study using Rat and Human Epidermis

Test Conditions

Dose ( g/cm2) 10 hrs treated, wash, and 14 hrs untreated 24 hrs treated

Rat Epidermis Human Epidermis Rat Epidermis Human Epidermis

5.45 55.06% 2.17% 33.08 1.98%

1279 1.49% 0.06% 0.77% 0.04%

The dermal absorption factor (DAF) was estimated in accordance with “Estimating Dermal 

Absorption Factors for use in Human Health Risk Assessment” (HED, 29JUN2010). The guidance

specifies that the test conditions yielding similar animal in vitro and in vivo DAFs will also be the 

best test conditions in a human in vitro study to estimate the human DAF. The most relevant data 

with respect to human exposure was the 24 hr exposure with no wash, as demonstrated below:

Rat 24 h exposure with no wash (in vitro : in vivo) = 33.08/20.59 ≈ 1.61

Based on the above ratio, the human in vitro data from the 24 h exposure with no wash (1.98% 

rounded to 2%) provides a reliable dermal absorption estimate for risk assessment [D383984, 

22NOV2010, J. Ryman].
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Appendix E: Hazard Identification and Endpoint Selection

E.1 Acute Reference Dose (aRfD) – General Population 

Includes: Females 13-49 Years Old

Study Selected: Acute Neurotoxicity Study in Rats

MRID: 48073753

Executive Summary: See Appendix §D.21 (Guideline 870.6200)

Endpoints: LOAEL = 200 mg/kg

Comments about the Study, Endpoint, or Uncertainty Factors:

The ACN study was chosen since the study demonstrates adverse effects following a single oral dose. 

The adverse effects observed were low arousal and decreased motor activities in males, decreased 

rearing in females, in addition to decreased bodyweight gain and food consumption in both sexes on 

Day 1. The developmental studies in rats and rabbits were not selected as end points since neither 

maternal nor fetal effects could be attributed to one or two doses. 

E.2 Chronic Reference Dose (cRfD)

Study Selected: Chronic Toxicity in Dogs

MRID: 48073741

Executive Summary: See Appendix §D.11 (Guideline 870.4100) 

Endpoint: NOAEL = 4.6 mg/kg/day (LOAEL = 15.7 mg/kg/day)

Comments about the Study, Endpoint, or Uncertainty Factors:

The Chronic Dog Study exhibits similar effects (i.e. decreased body weight and body weight gain) 

seen in other tested species and the endpoint selected is protective of the effects seen in other studies

(e.g. both the rat and mouse chronic exposure NOAELs are ≥26.2 mg/kg/day). Additionally, the 

results found in the subchronic dog study are comparable to the chronic dog study and support this 

selection. Therefore, the dog has been selected as the most sensitive species for this exposure 

scenario.

E.3 Incidental Oral Exposure (Short & Intermediate Term) 

Includes: Occupational and Residential Exposure Scenarios

Study Selected: Subchronic Toxicity in Dogs

MRID: 48073734

Executive Summary: See Appendix §D.3 (Guideline 870.3150) 

Endpoint: NOAEL = 8.5 mg/kg/day (LOAEL = 16.5 mg/kg/day)

Comments about the Study, Endpoint, or Uncertainty Factors:

The Subchronic Dog Study exhibits similar effects (i.e. decreased body weight and body weight 

gain) seen in other tested species and provides the most protective point of departure for risk 

assessment; this study is also appropriate for the duration and route of exposure for the population of 

concern. The lower NOAEL (4.6 mg/kg/day) in the chronic dog is an artifact of dose selection. 

Additionally, the LOAELs are comparable between the Subchronic (16.5 mg/kg/day) and Chronic 

(15.7 mg/kg/day) dog studies. Therefore, the higher NOAEL (8.5 mg/kg/day) was selected. The 

offspring toxicity (i.e. decreased body weight & bodyweight gain) in the two Reproduction & 

Fertility studies would be appropriate end point for the population of concern (i.e. infants & 
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children). However, these end points were not utilized for endpoint selection since data for offspring 

toxicity is unavailable for the most sensitive species, non-rodents. Therefore, the dog has been 

selected as the most sensitive species for this exposure scenario. The relevant NOAELS of the 

subchronic mouse & rat, subchronic neurotoxicity in rats, reproduction & fertility studies in rats 

(2010 & 1998), and immunotoxicity studies were between 2-100x greater than the NOAEL found in 

the subchronic dog study. Accordingly, these studies were not utilized for endpoint selection.

E.4 Dermal Exposure (Short & Intermediate Term)

In the dermal toxicity study, rats were treated at the limit dose with no observed dermal or systemic 

toxicity. Additionally, developmental, neurotoxicity, reproductive and immunotoxicity effects were 

not observed in the database. Thus, there is no identified hazard for this scenario. 

E.5 Inhalation Exposure (Short & Intermediate Term)

Study Selected: Subchronic Inhalation Toxicity

MRID: 48697401

Executive Summary: See Appendix §D.6 (Guideline 870.3465)

Comments about the Study, Endpoint, or Uncertainty Factors:

In the inhalation toxicity study, rats were treated at the “limit dose” with no observed inhalation or 

systemic toxicity. Thus, there is no identified hazard for this scenario. 

The “limit dose” or tolerable concentration level for the repeated inhalation exposure study was 

determined based on the results of the acute inhalation toxicity study and two range finding studies. 

No compound-related adverse effects were observed in the 28-day inhalation toxicity study in rats. 

Although there was an increase in the incidence of retinal atrophy in both mid- (0.01 mg/L) and 

high-dose (0.025 mg/L) groups relative to the controls, HED concluded that the retinal atrophy is not 

compound related. Retinal atrophy was observed in both control animal and all test animals in the 

satellite study. Historical control data for retinal atrophy showed a relative high background 

incidence of retinal atrophy. In addition, subchronic and chronic oral toxicity studies in rats as well 

as acute inhalation toxicity studies did not show retinal atrophy in any picoxystrobin treated groups. 

Thus, considering all these data together, HED concluded that the retinal atrophy is not compound 

related.

Furthermore, a human equivalent dose (HED) of 2.4 mg/kg/day was calculated based on the NOAEL 

of 25 mg/m3from the 28-day inhalation toxicity study in rats (see Appendix H). This HED was 

compared to the exposure levels for the proposed uses (see table below) showing that the HED is at 

least 4,000 times greater than the potential inhalation exposure (0.00066 mg/kg/day). Thus, for these 

proposed uses, HED concluded that an inhalation endpoint will not be selected at this time. Further, 

a quantitative inhalation risk assessment is not necessary at this time.

Summary Of Proposed Short- And Intermediate-Term Occupational Handler Exposures
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Exposure Scenario Crop Grouping

Application 

Ratea

(lb ai/A)

Area 

Treated 

Dailyb

(acres/day)

Baseline 

Inhalationc 

Unit 

Exposure 

(μg/lb ai)

Baseline 

Inhalation 

Dosed

(mg/kg/day)

Mixer/Loader

Mixing/Loading Liquid Concentrates for 

Aerial Applications

Legume vegetables, 

canola, cereal grains, 

sorghum, corn (field, 

sweet, pop)

0.2 350 0.219 0.00019

Soybeans 0.2 1200 0.219 0.00066

Mixing/Loading Liquid Concentrates for 

Chemigation Applications

Legume vegetables, 

canola, cereal grains, 

sorghum, corn (field, 

sweet, pop), soybeans

0.2 350 0.219 0.00019

Mixing/Loading Liquids Concentrates for 

Groundboom Applications

Legume vegetables, 

canola, cereal grains, 

sorghum, corn (field, 

sweet, pop)

0.2 80 0.219 0.00004

Soybeans 0.2 200 0.219 0.00011

Applicator

Applying Sprays via Aerial Equipment 

(enclosed cockpit)

Legume vegetables, 

canola, cereal grains, 

sorghum, corn (field, 

sweet, pop)

0.2 350 0.068 0.000060

Soybeans 0.2 1,200 0.068 0.00020

Applying Sprays via Groundboom Equipment 

(open cab)

Legume vegetables, 

canola, cereal grains, 

sorghum, corn (field, 

sweet, pop)

0.2 80 0.34 0.000068

Soybeans 0.2 200 0.34 0.00017

Flagger

Flagging for Aerial Sprays Applications

Legume vegetables, 

canola, cereal grains, 

sorghum, corn (field, 

sweet, pop), soybeans

0.2 350 0.35 0.00031

a Application rates are the maximum application rates determined from proposed labels for picoxystrobin

b Amount handled per day values are HED estimates of acres treated per day based on Exposure SAC SOP #9 “Standard Values 

for Daily Acres Treated in Agriculture,”

c Unit exposure source: “Occupation Pesticide Hander Unit Exposure Surrogate Reference Table – Revised March 2012” 

http://www.epa.gov/pesticides/science/handler-exposure-table.pdf

d Inhalation dose = daily unit exposure (μg/lb ai) x application rate x amount handled per day / body weight (80 kg adult)
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Appendix F: Executive Summaries

F.1 90-Day Oral Toxicity Study in Rats (OPPTS 870.3100)

MRID 48073731 (1999)

In a subchronic oral toxicity study (MRID 48073731), picoxystrobin (ZA1963; 93.3% a.i.; Batch 

No. P25) was administered in the diet to Wistar rats (12/sex/dose) at doses of 0, 100, 500, or 1250 

ppm (equivalent to 0/0, 8.5/9.7, 41.7/48.1, and 104.9/120.1 mg/kg/day for males/females) for 13 

weeks. 

No adverse, treatment-related effects were observed on mortality, clinical signs, ophthalmoscopic 

examination, hematology, clinical chemistry, urinalysis, organ weights, or gross or microscopic 

pathology.

At 1250 ppm, decreased (p<=0.05) body weights were observed throughout the study in males (decr. 

7-10%) and females (decr. 5-9%). Body weight gain during the initial week of treatment was 

decreased by 27-28%, and overall (Weeks 1-14) body weight gains were decreased by 14-15%. 

Decreased food consumption was observed each week during Weeks 1-10 in males (decr. 7-15%) 

and during Weeks 3-7 and 10 in females (10-15%). Food utilization was decreased during Weeks 1-

4 in the females (11.9% treated vs 14.1% controls). 

The LOAEL is 1250 ppm (104.9 mg/kg/day in males/females) based on decreased body weight, 

body weight gains and food consumption. The NOAEL is 500 ppm (41.7 mg/kg/day in 

males/females).

This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.3100; OECD 408) for a subchronic oral toxicity study in the rat. 

F.2 90-Day Oral Toxicity Study in Mice (OPPTS 870.3100)

MRID 48073732 (1996)

In a subchronic oral toxicity study (MRID 48073732), picoxystrobin (ZA1963; 99% a.i.; Batch No. 

P13) was administered in the diet to C57BL/10JfAP/Alpk mice (10/sex/dose) at doses of 0, 200, 800, 

1600, or 2400 ppm (equivalent to 0/0, 33.2/43.8, 137.3/176.1, 290.8/358.5, and 421.6/534.8 

mg/kg/day for males/females) for 13 weeks.

No adverse, treatment-related effects were observed on mortality, clinical signs, food consumption, 

organ weights, or gross or microscopic pathology.

Body weights were decreased (p<=0.05; except as noted) as follows: (i) sporadically throughout the 

study in the 800 ppm males (not statistically significant [NS]) and in the females (decr 3-7%); (ii) 

sporadically throughout the study in the 1600 ppm males (decr 2-7%) and females (decr 3-5%); and 

(iii) in the 2400 ppm males sporadically throughout the study (decr 2-6%) and females often 

throughout the study (decr 4-10%). At 800 ppm and above, body weight gains were decreased in 

males and in females during the initial week, contributing to decreased overall (Days 1-92) body 

weight gains of 10-28% in males and 18-34% in females. 
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At 1600 and 2400 ppm, food utilization (g food/100 g body weight gain) was decreased (p<=0.05; 

except as noted) during Days 1-28 in males by 38-52% and in females by 15-44%. The initial effects 

on food utilization in 1600 and 2400 ppm groups contributed to an overall (Days 1-91) decrease of 

25-32% in males and 10-25% in females. At 800 ppm, a slight decrease in food utilization was also 

found demonstrating a threshold treatment-related effect.

The LOAEL is 800 ppm (137.3 mg/kg/day) based on decreases in body weights, body weight gains 

and food utilization. The NOAEL is 200 ppm (33.2 mg/kg/day).

This study is classified as unacceptable/non-guideline and does not satisfy the guideline 

requirements (OPPTS 870.3100; OECD 408) for a subchronic oral toxicity study in the mouse. 

Hematology and clinical chemistry were not performed. Numerous organs were not weighed, and 

numerous tissues were not evaluated microscopically. However, this study provides useful data for 

dose-selection for longer term studies.

F.3 90-Day Oral Toxicity Study in Dogs (OPPTS 870.3150)

MRID 48073734 (1998)

In a subchronic oral toxicity study (MRID 48073734), ZA1963 (Picoxystrobin; 94.4% a.i.; Batch 

No. P27) was administered in the diet to four beagle dogs/sex/dose group at concentrations of 0, 125, 

250, or 500 ppm (equivalent to 0, 4.3/4.3, 8.9/8.5, or 16.5/16.9 mg/kg/day in males/females) for at 

least 90 days.

No adverse effects of treatment were observed on mortality, clinical signs, ophthalmoscopic 

examinations, hematology, clinical chemistry, organ weights, or gross or microscopic pathology.

At 500 ppm, body weights were decreased during Weeks 2-14 by 4-7% (p≤ 0.05, except Weeks 13

and 14) in the males and by 3-7% (p≤0.05, except Week 6) in the females, resulting in decreased 

overall body weight gains in both males and females. Additionally at this dose, food consumption 

was decreased (p≤0.05; except during Week 5) during Weeks 1-6 by 7-27% in the males and by 8-

26% in the females. 

At 250 ppm and 125 ppm, treatment-related effects were not observed.

The LOAEL is 500 ppm (16.5 mg/kg/day), based on decreased body weights and body weight gains 

in the males and food consumption in males and females. The NOAEL is 250 ppm (8.5 mg/kg/day).

This study is classified acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.3150; OECD 409) for a subchronic oral toxicity study in dogs.

F.4 28-Day Dermal Toxicity Study in Rats (OPPTS 870.3200)

MRID 48073735 (2009)
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In a 28-day dermal toxicity study (MRID 48073735), Picoxystrobin Technical (99.3% ai, batch 

number: SEP07AS013) was administered to 10 Crl:CD(SD) rats/sex/dose via repeated dermal 

exposure at dose levels of 0, 100, 300, or 1000 mg/kg/day for 6 hours/day for 29 consecutive days. 

In the treated animals, there were no dose-related effects on body weight, body weight gain, food 

consumption, food efficiency, hematology, clinical chemistry, and urinalysis. In addition, there were 

no treatment-related findings for clinical signs of toxicity, dermal irritation, ophthalmoscopic 

evaluations, gross pathology, and microscopic pathology. There were no adverse effects on organ 

weight and no test substance-related mortalities observed in the study.

There were four test-substance unrelated mortalities during the course of the study: one male at the 

1000 mg/kg/day dose, one male and one female at the 300 mg/kg/day dose, and one male at the 100 

mg/kg/day dose. Although the necropsy results were inconclusive, the determination that the 

mortalities were caused by the rats being wrapped too tightly is acceptable.

The study did not include neurological evaluations. However, the guideline requirement for 

neurological evaluations was satisfied with data from two neurotoxicity-specific studies (MRIDs 

48073752 and 48073753).

The LOAEL was not established. The NOAEL was 1000 mg/kg/day.

This 28-day dermal toxicity study in rats in conjunction with submitted neurotoxicity studies in the 

rat (MRIDs 48073752 and 480873753) is Acceptable / Guideline and satisfies the guideline 

requirement for a 21/28-day dermal toxicity study (OPPTS 870.3200; OECD 410) in rodents.

F.5 28-Day Dermal Toxicity Study in Rats (OPPTS 870.3200)

MRID 48073736 (1999)

In a 28-day dermal toxicity study (MRID 48073736), ZA1963 (93.3% a.i., batch number: P25) was 

administered to 5 Alpk:APfSD (Wistar-derived) rats/sex/dose via repeated dermal exposure at dose 

levels of 0, 200, 500, or 1000 mg/kg/day, 6 hours/day on days 1-2, 5-9, 12-16, 19-23, and 26-28.

In the treated animals, there were no dose-related effects observed on body weight, food 

consumption, food efficiency, hematology, clinical chemistry, and organ weights. In addition, there 

were no treatment-related findings observed with respect to clinical signs of toxicity, dermal 

irritation, gross pathology, and microscopic pathology. There were no unscheduled mortalities 

during the study. 

The study did not include neurological evaluations. However, the guideline requirement for 

neurological evaluations was satisfied with data from two neurotoxicity-specific studies (MRIDs 

48073752 and 48073753).

The LOAEL was not established. The NOAEL was 1000 mg/kg/day.
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This 28-day dermal toxicity study in rats is Unacceptable / Guideline and does not satisfy the 

guideline requirement for a 21/28-day dermal toxicity study (OPPTS 870.3200; OECD 410) in 

rodents.

F.6 Subchronic Inhalation Toxicity - Rat (OPPTS 870.3465)

MRID 48697401 (2011)

In a subchronic inhalation toxicity study (MRID 48697401), Picoxystrobin (99.6% a.i., batch/lot 

#SEP07AS013) was administered to 5 Wistar/(CRL:WI) rats/sex/group by dynamic nose-only 

exposure at analytical (i.e. gravimetric) concentrations of 0, 0.0017, 0.012 or 0.025 mg/L/day

(equivalent to 0, 0.46, 3.25 and 6.78 mg/kg/day) for 6 hours per day, 5 days/week for a total of 20 

exposures. Satellite groups of 5 Wistar/(CRL:WI) rat/sex were exposed to 0 or 0.012 mg/L/day

picoxystrobin for a total of 20 exposures and were allowed to recover for 2 weeks. 

In the treated animals there were no unscheduled mortalities; there were no treatment-related effects 

on food consumption; there were no treatment-related findings for clinical signs of toxicity, and 

gross pathology; there were no toxicologically relevant effects on body weight, hematology, clinical 

chemistry, urinalysis, and organ weight. Microscopic changes, indicative of retinal atrophy, were 

observed in the retina of several animals including the control group. These changes were not 

considered to be test substance related based on the fact that these retinal lesions were observed in 

all groups (except at 0.00l mg/L), including controls, and in all rats in the control recovery/satellite 

groups in this study, also in a previous 2 year chronic study with picoxystrobin, no test substancerelated retinal changes were present at any dose in rats.

The NOAEL is 0.025 mg/L/day (6.78 mg/kg/day). The LOAEL is >0.025 mg/L/day. 

This 28-day inhalation toxicity study in rats is Acceptable / Non-Guideline and satisfies the 

guideline requirement for a 90-day inhalation toxicity study in rats (OPPTS 870.3465; OECD 413).

F.7 Prenatal Development Study in Rabbits (OPPTS 870.3700)

MRID 48073737 (1999)

In a developmental toxicity study (1999, MRID 48073737), ZA1963 (picoxystrobin; Lot/Batch # 

P25; 93.3% a.i.) was administered in 1% carboxymethylcellulose via gavage, in a dose volume of 1 

mL/kg, to 20 female New Zealand White (NZW) rabbits/group, at dose levels of 0, 8, 25, or 100 

mg/kg/day, on gestation days (GD) 8 through 20. All surviving does were sacrificed on GD 30 and 

their fetuses were removed by cesarean and examined.

No treatment-related effects on mortality, gross pathology or cesarean section data were observed in 

the dams at any dose.

At 25 mg/kg bw/day clinical signs of diarrhea, were observed in 13 animals beginning on Day 13 

and lasting until termination, and there was also a decrease in food consumption throughout the 

dosing period (12-28%). At 100 mg/kg/day, clinical signs of diarrhea were observed in 14 animals 

beginning on Day 9. A slight (2 – 3%) but significant body weight decrement which correlated with 
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decreased food consumption (12 – 63%) was observed in the high-dose group. Overall body weight 

gain was decreased by 31% in the high-dose group.

The maternal LOAEL is 25 mg/kg bw/day based on decreased food consumption accompanied by 

clinical signs of diarrhea. The maternal NOAEL is 8 mg/kg bw/day.

There were no abortions or premature deliveries. One complete litter resorption was observed in one 

low-dose animal. The number of dead fetuses was neither reported nor obvious from the individual 

data; while the number of live fetuses does not account for all implantation sites less resorptions, 

there is no apparent effect of treatment on fetal mortality. Sex ratio and post-implantation losses of 

the treated groups were comparable to control values. 

There were slight effects on growth attributable to picoxystrobin. While fetal weights of the treated 

groups were similar to control values, the small increase in incomplete ossification observed in 

rabbits cannot be dismissed as an adverse effect of treatment.

No treatment-related external or visceral variations or malformations were observed at the highest 

dose tested, 100 mg/kg/day. At 100 mg/kg/day, slightly increased incidence rates of the skeletal 

variations, incompletely ossified odontoid, 13th rib of long length and 27 pre-pelvic vertebrae, were 

observed and cumulatively regarded as adverse effects of treatment.

The developmental LOAEL for this study is 100 mg/kg/day based on incomplete ossification of the 

odontoid, 27 pre-pelvic vertebrae and 13th ribs of long length. The developmental NOAEL is 25 

mg/kg bw/day.

The developmental toxicity study in the rabbit is classified acceptable/non-guideline and does not 

satisfy the current guideline requirement for a developmental toxicity study in rabbits, OPPTS 

870.3700; this study was satisfactorily performed under FIFRA Subdivision F 83-3 guidelines for 

teratogenicity and does satisfy the requirements of OECD 414.

F.8 Prenatal Development Study in Rats (OPPTS 870.3700)

MRID 48073738 (1998)

In a developmental toxicity study (MRID 48073738), ZA1963 (Picoxystrobin; 99%; Batch No. P9)

in corn oil was administered via daily oral gavage in a dose volume of 10 mL/kg to 24 time-mated 

Alpk:APfSD (Wistar-derived) rats/dose group at doses of 0, 10, 30, or 100 mg/kg/day from gestation 

days (GD) 7-16 inclusive. On GD 22, all dams were euthanized; each dam’s uterus was removed via 

cesarean section and its contents examined. Fetuses were examined for external, visceral, and 

skeletal malformations and variations.

No treatment-related effects on mortality, gross pathology, or cesarean section data were observed in 

the dams at any dose. 

At 100 mg/kg/day, clinical signs including signs of diarrhea, diarrhea, and urine staining were 

observed in 6-9 dams during the dosing period. Also in this group, body weight gains (calculated by 

reviewers) were decreased by 22% compared to controls during the dosing period (GD 7-16) and 7% 
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for the overall (GD 1-22) study; body weights were decreased (p<0.01) by 3-4% at all intervals 

during dosing and on GD 19; and food consumption values were decreased (p<0.01) by 13-35% 

compared to controls throughout the dosing period.

The maternal LOAEL is 100 mg/kg/day based on decreased body weight gain, food consumption, 

and increased incidence of clinical signs (diarrhea and urine staining). The maternal NOAEL is 30 

mg/kg/day.

There were no abortions, premature deliveries, complete litter resorptions, or dead fetuses and no 

effects of treatment on the numbers of litters, live fetuses, early resorptions, or late resorptions. 

Similarly, sex ratio and post-implantation losses of the treated groups were comparable to controls.

There were no effects of treatment on growth or development of the fetuses. Fetal weights of the 

treated groups were comparable to controls, and there were no treatment-related effects on 

ossification of the skeleton.

There were no adverse treatment-related external or visceral variations or malformations. At 100 

mg/kg/day, an increased incidence of misaligned 5th sternebrae was observed and regarded as an 

adverse effect of treatment.

The developmental LOAEL is 100 mg/kg/day based on misaligned 5th sternebrae. The 

developmental NOAEL is 30 mg/kg/day.

This study is classified acceptable/guideline and satisfies the guideline requirement for a 

developmental toxicity study (OPPTS 870.3700a; OECD 414) in rats.

F.9 Reproduction and Fertility Effects Study in Rats (OPPTS 870.3800) 

MRID 48073739 (2010)

In a two-generation reproduction toxicity study (MRID 48073739), Picoxystrobin (99.3%; Lot # 

DPX-YT669-028) was administered continuously in the diet to 30 Sprague-Dawley (Crl:CD[SD]) 

rats/sex/dose group for two consecutive generations at dietary levels of 0, 75, 300, 1000, or 2500 

ppm (equivalent to 0/0, 4.2/5.4, 16.9/21.7, 55.5/70.3, and 137.5/173.4 mg/kg/day in males/females, 

respectively). The P generation animals (30/sex/dose group) were exposed to the test diets 

beginning at approximately 8-9 weeks of age, for at least 10 weeks prior to mating to produce the F1 

litters. F1 offspring selected to be parents of the next generation (30/sex/dose group) were fed the 

same test diet concentrations as their parents. F1 parents were fed the test diets for at least 10 weeks 

prior to mating to produce the F2 generation. The F2 offspring were terminated after weaning.

Parent animal toxicity: The treatment-related effects produced by picoxystrobin were mainly seen in 

the 2500 ppm P and F1 parental rats. The effects were on body weights, body weight gains, food 

consumption, food efficiency changes, organ weight changes, and histopathology. The effects on 

body weights, body weight gains, food consumption, and food efficiency are tabulated below.

Percent Change Relative to the Controls (%) in P & F1 Generation Rats at 2500 ppm

Periods Body Weights Body Weight Gains Food Consumption Food Efficiency

Males Females Males Females Males Females Males Females

P Generation
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Pre-mating ↓4-7% ↓5-7% ↓18% ↓26% ↓7% ↓8% ↓11% ↓19

Gestation ↓7-8% ↓8% ↓10% −

Lactation ↓7-8% ↑223% ↓16-20% −

F1 Parental Rats

Pre-mating 10-26%↓ 9-27%↓ ↓8% ↓5% ↓9% ↓9% − ↑5%

Gestation ↓8% ↓9% ↓8% −

Lactation ↓6-10% ↑304% ↓12% at 

LD 11-15

↑64%

Additionally at 2500 ppm, the following differences in organ weights compared to controls were 

noted in the P generation females: (i) absolute and relative (to body and to brain weight) liver 

weights were increased by 6-10%; (ii) absolute and relative (to body and to brain weight) thymus 

weights were decreased by 29-32%; (iii) absolute and relative (to body and to brain weight) nongravid uterus weights were decreased by 30-32%; (iv) absolute and relative (to body and to brain 

weight) pituitary weights were decreased by 13-20%; (v) absolute brain weight was decreased by 

3%; and (vi) absolute and relative (to body weight) right ovary weights were decreased by 13% 

each. Findings in the P generation males were limited to increased relative (to body weight) liver 

weight (incr. 10%) at this dose. Microscopic findings were limited to minimal to moderate 

lymphoid atrophy in the thymus in the 2500 ppm females (11/30 treated vs. 0/30 controls).

The LOAEL for parental toxicity is 2500 ppm (137.5/173.4 mg/kg/day in males/females, 

respectively) based on decreases in body weight, body weight gain, and food consumption in the P 

and F1 generation during pre-mating; increased body weight gains in the P and F1 females at the end 

of the lactation period; organ weight differences; and minimal to moderate lymphoid atrophy in the 

thymus in P generation females. The NOAEL is 1000 ppm (55.6/70.3 mg/kg/day in males/females, 

respectively).

Offspring toxicity: There were no treatment-related effects on: mortality; clinical signs; live birth, 

viability, and lactation indices; or pup sex ratio for either generation. There were no treatmentrelated gross or microscopic findings in the F1 or F2 pups.

At 2500 ppm, overall (PND 1-22) pup body weight gains (calculated by reviewers) were decreased 

in both the F1 and F2 generations by 17-26%. Mean pup body weights/litter at this dose were 

decreased by 13-23% on PND 8, 15, and 22 in the F1 generation and by 12-14% on PND 15 and 22 

in the F2 generation. Organs weights such as thymus, spleen, and thyroid were decreased in F1 and 

F2 pups.

The LOAEL for offspring toxicity is 2500 ppm (137.5/173.4 mg/kg/day in males/females, 

respectively) based on decreased mean pup body weights/litter and body weight gains in the F1 and 

F2 generations and decreased organ weights including spleen, thymus, and thyroid. The NOAEL is 

1000 ppm (55.6/70.3 mg/kg/day in males/females, respectively).

Reproductive toxicity: There were no effects of treatment in either generation on: estrous cycle; 

sperm parameters; mating, fertility, litter sizes, sex ratio, pup birth weights, or gestation indices; precoital interval; or gestation duration.

The LOAEL for reproductive toxicity was not observed. The NOAEL is 2500 ppm (137.5/173.4 

mg/kg/day in males/females, respectively) (HDT).
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This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.3800; OECD 416) for a two-generation reproduction study in the rat.

F.10 Reproduction and Fertility Effects Study in Rats (OPPTS 870.3800) 

MRID 48073740 (1998)

In a two-generation reproduction toxicity study (MRID 48073740), ZA1963 (Picoxystrobin; 93.3% 

a.i.; Batch No. P25) was administered in the diet to 26 Alpk:APfSD rats/sex/dose group at dietary 

levels of 0, 50, 200, or 750 ppm (equivalent to 0/0, 5.4/5.8, 21.5/23.4, and 80.0/87.2 mg/kg in 

males/females during pre-mating) for two successive generations with one litter per generation. The 

P generation animals were fed the test diets for ten weeks prior to mating to produce the F1 litters. 

On post-natal day (PND) 29, 26 pups/sex/dose group were selected and fed the same test diet 

concentration as their dam. These F1 parents were fed the test diets for at least ten weeks prior to 

mating to produce the F2 litters.

No treatment-related effects were observed on mortality, clinical signs, organ weights, or 

macroscopic or microscopic findings.

At 750 ppm, pre-mating body weights were decreased during Weeks 2-11 in the P and F1 parental 

males and during Weeks 4/5-11 in the P and F1 parental females. Body weight was also decreased 

during gestation and lactation at day 1 in males and females. Pre-mating (Weeks 1-11) body weight 

gains (calculated by reviewers) were also decreased, and food consumption was generally decreased 

during this period in both sexes and generations. There were also decreases in body weights and 

food consumption in 200 ppm F1 parental males.

The LOAEL for parental toxicity is 200 ppm (21.5 mg/kg), based on decreased body weights, body 

weight gains, and food consumption in the F1 males. The NOAEL is 50 ppm (5.4 mg/kg).

There were no effects of treatment on the survival indices, numbers of pups born or born live, 

numbers of litters or litters with all pups born live, mean litter size, litters with all pups live on PND 

22, whole litter losses, or clinical observations, organ weights, or macroscopic or microscopic 

findings in either the F1 or F2 offspring.

At 750 ppm, body weights were decreased in both the F1 males and females on PND 29, and in both 

the F2 males and females on PND 22 and 29. No treatment-related effect was seen in 200 ppm or 

lower.

The LOAEL for offspring toxicity is 750 ppm (80 mg/kg ), based on decreased body weights in the 

F1 and F2 pups. The NOAEL is 200 ppm (21.5 mg/kg ).

Reproductive performance was not affected by treatment at any dose level. All the reproductive 

parameters measured were comparable among the treated and control groups.

The LOAEL for reproductive toxicity was not observed. The NOAEL is 750 ppm (equivalent to 

87.2 mg/kg) (HDT).
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This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.3800; OECD 416) for a two-generation reproduction study in the rat.

F.11 Chronic Toxicity Study in Dogs (OPPTS 870.4100)

MRID 48073741 (1999)

In a chronic toxicity study in dogs (MRID 48073741), picoxystrobin (ZA1963; 94.4% a.i., Batch No. 

P27) was administered in the diet to 4 beagle dogs/sex/dose for 1 year at doses of 0, 50, 150, or 500 

ppm (equivalent to 0/0, 1.6/1.6, 4.8/4.6, and 16.1/15.7 mg/kg/day in males/females). 

No adverse, treatment-related effects were observed on mortality, ophthalmology, hematology, 

clinical chemistry, urinalysis, organ weights, or gross or histological pathology.

At 500 ppm, females were considered thin (3/4 dogs, 62 total observations) compared to controls 

(1/4 dog, 11 total observations). Body weights were decreased by 5-11% in the males during Weeks 

2-30. Body weights were decreased by 3-15% in the females throughout the study, with the 

exception of the final week. Males lost weight during the first 2 weeks, and females lost weight 

during the first week. Body weight gains for the interval of Weeks 1-13 were decreased by 75-77% 

in both sexes, contributing to overall (Weeks 1-53) decreased body weight gains of 27% in the males 

and 38% in the females. Generally throughout the study, food consumption decreased by 5-34% in 

males and by 6-36% in females.

The LOAEL is 500 ppm (equivalent to 16.1/15.7 mg/kg/day in males/females), based on decreased 

body weights, body weight gains, and food consumption in both sexes. The NOAEL is 150 ppm 

(equivalent to 4.8/4.6 mg/kg/day in males/females).

This study is classified as acceptable/guideline and satisfies the guideline requirement (OPPTS 

870.4100b, OECD 452) for a chronic oral toxicity study in dogs. 

F.12 Carcinogenicity Study in Mice (OPPTS 870.4200) 

MRID 48073744 (1999)

In a carcinogenicity study (MRID48073744), picoxystrobin (ZA1963) (93.3%) was administered to

C57BL/10Jf AP Alpk mice (50/sex/dose) in the diet at concentrations of 0, 50, 200 or 800 ppm

(M/F: 0/0, 6.6/8.8, 26.2/35.6, or 108.8/144.7 mg/kg/day) for at least 80 weeks.

Under the conditions of the study picoxystrobin produced no treatment-related effects on survival, 

clinical signs of toxicity, hematology, or organ weights. It appeared to cause, at best, a marginal 

decrease in body weight (4%) in 800 ppm males only. There was a slight increase in the incidence of 

macroscopic and microscopic changes in the stomach of females only. The macroscopic finding was 

described as ulceration. The microscopic finding was inflammation (control: 4/50; 800 ppm: 8/50) 

and erosion of the stomach (control: 3/50; 800 ppm:7/50). The LOAEL might be established at 800 

ppm (144.7 mg/kg/day) based on slight increase in the incidence ulceration and inflammation of the 

stomach. NOAEL was 200 ppm (35.9 mg/kg/day). Under the condition of the study, there was no 
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increase in treatment-related tumor incidence. However, the test animals could have tolerated higher 

dose levels.

This study is classified as unacceptable/guideline as a carcinogenicity study in mice because the dose 

levels employed in this study are insufficient in evaluating the carcinogenic potential of 

picoxystrobin. 

F.13 Combined Chronic Toxicity/Carcinogenicity Study in Rats (OPPTS 870.4300) 

MRID 48073745 [interim study] (2010)

In a combined chronic / carcinogenicity study (MRID: 48073745), picoxystrobin (99.3% a.i; batch #: 

SEP07A013).) was administered to 70 CD®[Crl:CD®(SD)] rats/sex/dose in the diet at the 

concentrations of 0, 50, 200, 1000, & 3500 ppm (equivalent to 0, 2.6, 10.4, 52.3, & 186.3 mg/kg

bw/day for males; 0, 3.2, 13.1, 65.0, & 229.6 mg/kg bw/day for females; respectively) for 2 years. 

The current report presents the results of test animals treated for 12-months.

At 12-month, 10 rats/sex/dose were sacrificed and examined grossly and microscopically. The data 

showed no treatment-related effects on mortality, hematology, clinical chemistry, organ weights, 

gross exanimation and histological changes. No increase in tumor incidence. There appeared to be 

treatment-related findings in clinical observations characterized by increased incidence of soft feces 

(i.e., increases in frequency of occurrence/# of animals) at 1000 and 3500 ppm groups (control: 13/8; 

1000 ppm: 97/25; 3500 ppm: 257/39). However, It was not associated with any histological or

clinical chemistry changes; the adversity if this observation could not be determined. The body 

weight, body weight gains, food consumption, and food efficiency were consistently decreased at 

various intervals of examination in 3500 ppm males and females. The decreases also showed 

statistical significance. Based on the 12-months results on body weights, body weight gains, food 

consumption, and food efficiency, the LOAEL was 3500 ppm (M/F: 186.3/229.6mg/kg/day). The 

NOAEL was 1000 ppm (M/F: 52.3/65.0 mg/kg/day).

The interim (12-month) report is considered acceptable/non-guideline at this time. 

F.14 Combined Chronic Toxicity/Carcinogenicity Study in Rats (OPPTS 870.4300) 

MRID 48073746 (1999)

In a combined chronic /carcinogenicity study (MRID 48073746) ZA1963 (picoxystrobin) (99.3% 

purity) was administered to Alpk:APf SD rats (64/sex/dose) in the diet at concentrations of 0, 50, 

200, or 750 ppm (equivalent to 0, 3.1, 12.2, or 45.6 mg/kg bw/day for males; 0, 3.8, 14.8, or 57.8 

mg/kg bw/day for females) for 2 years. 12 rats/sex/dose group were designated for interim sacrifice 

at 53 weeks. 

Under the conditions of this study picoxystrobin produced no treatment-related changes in mortality, 

clinical signs, hematological parameters, clinical chemistry parameters, urinalyses, organ weights, 

and non-neoplastic histopathology. The survival rates in the mid and high dose males were better 

than the concurrent controls. In females, the survival rates in all the treated groups were better than 

the controls. There was no apparent finding to support a specific reason for this discrepancy. 

However, picoxystrobin at 750 ppm consistently produced slight decreases (<10%) in body weight 
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and food consumption in males and females. Food efficiency was slightly reduced in 750 ppm 

males. The decrease in body weights might positively influence the survival in rats at high dose 

males and females. 

There was a slight increase in the incidence of large granular lymphocyte leukemia in 750 ppm 

males (7/52) relative to the controls (2/52). The increase showed a statistically significant trend. The 

individual animal data showed that the first incidence occurred at week 97, and all of the tumors 

were observed between 97 weeks and 105 weeks. There was no decrease in time to tumor 

occurrence in treated males relative to the controls. This increase was marginally above the historical 

background range for males (0/52 - 5/52) while it was within control range for females (0/52 -

11/52). There was no increase in tumor incidence in females, and there were no associated changes 

in other hematological parameters. Therefore, a slight increase in the incidence of large granular 

lymphocyte leukemia seen in 750 ppm males only was not considered to be treatment-related. Since 

the highest dose tested (750 ppm) produced marginal effects in body weight, food consumption, and 

food utilization, it was not high enough to assess the carcinogenic potential of picoxystrobin. 

It should be noted that recently this rat chronic/carcinogenicity study has been repeated at higher 

concentrations (3500 ppm, highest concentration), and 12-month interim sacrifice data do not show

any tumor incidence in treated animals at any dose group (MRID 48073745). Consistent with the 

1999 study, no changes in any of the hematological parameters are found in the 12-month interim 

results.

Although the body weight decreases and reduced food consumption showed statistically significant 

difference from controls, these two effects, in this study, appeared to have a positive impact on the 

survival in rats in high dose groups of both males and females. It is notable that the reduction in 

body weight is one of the consistent effects seen in other studies with picoxystrobin; however, in this 

study, this finding is slight and seems not to be adverse in the context of survival rates and the 

general health of picoxystrobin treated animals. Therefore, the LOAEL for this chronic study cannot 

be established. The NOAEL is 750 ppm (57.8 mg/kg/day) (HDT).

The study is considered acceptable/guideline for the chronic toxicity part of the combined study, but 

it is unacceptable for the carcinogenicity part of the study because the highest dose tested is not 

sufficient to properly assess the carcinogenic potential of the chemical. 

F.15 Mutagenicity
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Study Dose Levels Result

In vitro studies 

870.5100

Bacterial Reverse Mutation

MRID 48073747 (1996)

0-5000 μg/plate Negative

870.5375

In vitro Cytogenetics

MRID 48073749 (1996)

0 – 60 μg/mL Negative at cytotoxic 

concentrations

870.5300

Mammalian cell gene mutation (mouse 

lymphoma)

MRID 48073748 (1998)

0-64 μg/mL Negative

In vivo studies

870.5395

Mouse Bone Marrow Micronucleus 

Assay

MRID 48073750 (1996)

0-5000 mg/kg bw No evidence of 

clastogenicity or inhibition 

of spindle formation 

870.5550

Unscheduled DNA synthesis – Rat Liver

MRID 48073751 (1996)

0-5000 mg/kg bw Negative

F.16 Subchronic Neurotoxicity Study in Rats (OPPTS 870.6200) 

MRID 48073752 (2010)

In a 90-day subchronic neurotoxicity study (MRID 48073752) Picoxystrobin Technical (99.3% a.i., 

batch number: SEP07AS013) was administered to 12 Crl:CD(SD) rats/sex/dose via diet at dose 

levels of 0, 100, 600, and 3500 ppm (equivalent to 0/0, 6/8, 36/46, and 207/246 mg/kg/day for 

males/females, respectively) for 91 days. Neurobehavioral assessment (functional observational 

battery and motor activity assessment) was performed in 12 animals/sex/dose during weeks 4, 8, and 

13. At study termination, 6 animals/sex/dose were perfused in situ for neuropathological 

examination.

In the treated animals, there were no dose-related effects on motor activity and there were no 

treatment-related observations for clinical signs of toxicity, gross pathology or neuropathology.

Adverse treatment-related effects were only observed at the highest dose tested (3500 ppm), and the 

effects that were identified include: decreased body weight, body weight gain, food consumption, 

male forelimb grip, and increased female hindlimb splay. 

The LOAEL was 3500 ppm (207/246 mg/kg/day for males/females, respectively) based on 

decreased male forelimb grip and increased female hindlimb splay in addition to decreased body 

weight, body weight gain, and food consumption in both sexes. The NOAEL was 600 ppm (36/46 

mg/kg/day for males/females, respectively).
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This subchronic neurotoxicity study is classified as Acceptable / Guideline and satisfies the 

guideline requirement for a subchronic neurotoxicity study in rats (870.6200b; OECD 424).

F.17 Acute Neurotoxicity Study in Rats (OPPTS 870.6200) 

MRID 48073753 (2009)

In an acute neurotoxicity study (MRID 48073753), Picoxystrobin Technical (99.3% a.i., batch 

number: SEP07AS013) was administered to 12 Crl:CD(SD) rats/sex/dose via a single oral (gavage) 

at doses levels of 0, 200, 1000, or 2000 mg/kg and observed for 15 days. Neurobehavioral 

assessments (functional observational battery and motor activity assessment) were performed on 12

rats/sex/dose on days 1, 2, 8, and 15 except in the high dose females (only 9 females remained as a 

result of 3 mortalities on day 1). At study termination, 6 rats/sex/dose were perfused in situ for 

neuropathological examination. 

In the treated groups, there were no dose-related effects on body weight and there were no treatmentrelated neuropathological or gross pathological findings. Dose-related effects were first observed at 

the 200 mg/kg/day dose and mortalities were observed at the 2000 mg/kg dose.

Adverse effects that were observed at the low dose (200 mg/kg) in both sexes were: decreased body 

weight gain and food consumption; in males only: decreased motor activity and low arousal; and in 

females only: decreased rearing.

In addition to effects seen at the low dose, the treatment-related effects observed at 1000 mg/kg were 

stained skin/fur, drooping eyelids, diarrhea, stained cageboard and curled up posture, abnormal 

posture, and high carriage. 

In addition to effects seen in the lower doses, the treatment-related effects observed at the 2000 

mg/kg dose were red nasal discharge, soiled skin/fur, wet perineum fur, uncoordinated gait, and 

decreased body temperature. Additionally, two females were found dead and another was sacrificed 

in a moribund condition.

The LOAEL (LDT) was 200 mg/kg based on low arousal and decreased motor activities in males, 

decreased rearing in females, in addition to decreased bodyweight gain and food consumption in 

both sexes on Day 1. The NOAEL could not be established.

This acute neurotoxicity study is classified as Acceptable / Non-Guideline and satisfies most of the 

guideline requirements for an acute neurotoxicity study in rats (870.6200; OECD 424).

F.18 Metabolism and Pharmacokinetics Study in Rats (OPPTS 870.7485) 

MRID 48073754 (2010)

In a plasma kinetics study (MRID: 48073754), four groups of Crl:CD(SD) rats (4/sex/group) 

received a single oral gavage dose of [Phenyl(U)-

14C] DPX-YT669 (96.9% radiochemical purity; 

Lot# H-22705-153) or [Pyridine-3-

14C] DPX-YT669 (96.4% radiochemical purity; Lot# H-22705-

154) in polyethylene glycol (PEG) at nominal doses of 10 and 100 mg/kg bw. Samples of whole 

blood were collected from each rat at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours 
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post-dose, and separated into plasma and red blood cell (RBC) fractions for radioassay. Samples of 

urine and feces were also collected daily from each animal for up to 7 days post-dose and stored at 

<-10°C, but excreta samples were not further analyzed in the current study.

For each dose group, concentrations of radioactivity were generally higher (ca 2.5x) in plasma than 

in the RBC fraction for up to 72 hours post-dose. Although there was a high degree of variability 

between individual rats, concentrations of radioactivity in plasma over time were generally similar 

for each dose level, regardless of sex or 14C-label position. Based on the mean plasma 

concentrations for each dose group, the calculated Cmax in plasma was in the range of 2.35-4.36 μg/g 

for the low-dose groups and 8.89-10.84 μg/g for the high-dose groups. When the data are pooled to 

include both 14C-labels, the Tmax generally occurred at 0.5-1 hours post-dose for the low-dose group 

and at 24 hours for the high-dose. Variability in Tmax values was confounded by the fact that the 

concentration vs. time curves for each dose group generally showed two peaks of radioactivity, one 

typically occurring within 1 hour of dosing and a second peak occurring between 8 to 24 hours postdose. The two peaks of radioactivity in plasma were most pronounced in the high-dose group and 

may be indicative of enterohepatic circulation of metabolites, which is supported by excretion data 

from bile-duct cannulated rats in an earlier study.

The terminal elimination half-lives (1⁄2Tel) of radioactivity from plasma were similar regardless of 

sex, dose level and 14C-label position. Elimination half-lives were in the range of 33.4-47.2 hr for 

the low-dose groups and 30.5-45.8 hr for the high-dose groups. The area-under-the-curve (AUC) 

range values were also similar between the sexes and 14C-labels, although the values for low-dose 

males (101.8-110.2 hr*μg/g) were slightly higher than for the low-dose females (85.9-86.7 hr*μg/g). 

For the high-dose groups, AUC(0-∞) values were in the range of 579.3-605.0 hr*μg/g for males and 

453.4-709.6 hr*μg/g for females. Because the increase in AUC values between the low and high 

dose groups (5.2-8.3x) is lower than the 10-fold increase in the dose level, therefore absorption 

and/or metabolism of DPX-YT669 may be approaching saturation at the 100 mg/kg dose level.

In conjunction with the available Tier I metabolism data (MRIDs 48073755-48073759), this plasma 

kinetic study in the rat is classified Acceptable / Guideline. The current study satisfies the Tier II

guideline requirement for a plasma kinetics study in the rat [OPPTS 870.7485].

F.19 Metabolism and Pharmacokinetics Study in Rats (OPPTS 870.7485) 

MRID 48073755 (1999), 48073756 (1998), 48073757 (1998), 

48073758 (1998), 48073759 (1997)

In a series of metabolism studies (MRIDs 48073755-48073759), Alpk:APfSD rats were dosed orally 

by gavage using [14C] ZA1963 (radiochemical purity >97%) in polyethylene glycol (PEG) 600.

A preliminary study (MRID 48073759) was conducted in which two groups of rats (1 sex/dose 

group) were dosed once by gavage with [14C-pridinyl]- or [14C-phenyl]- ZA1963 at a nominal rate of 

10 mg/kg bw in order to examine the recovery of the dosed radioactivity in excreta and expired air 

over 24 hours and tissue distribution.

An excretion and tissue distribution study was conducted using two groups of rats (5 sex/dose group) 

that were dosed once by gavage with [14C-phenyl] ZA1963 at a nominal rate of 10 or 100 mg/kg 
Picoxystrobin Human Health Risk Assessment DP No. 377690

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body weight in order to examine the recovery of radioactivity in excreta and tissues. Additionally, a 

third group of 5 rats/sex received 14 consecutive daily doses by gavage of unlabeled ZA1963 (10 

mg/kg bw) followed by a single 10 mg/kg labeled dose of [

14C-phenyl] ZA1963 on Day 15. In these 

studies, urine, feces, and cage washes were collected at intervals up to 120 hours post-dose, and 

selected tissues and the residual carcasses were collected at termination. The metabolic profile was 

also determined using pooled samples of excreta. 

Additional studies were apparently performed including a bile duct-cannulation study; however, 

many details of these studies were not provided as these studies were mentioned only in regards to 

determining the metabolic profile in the bile, urine, and feces.

In the preliminary study (MRID 48073759), the total recovery of radioactivity ([

14C-pyridinyl] & 

[

14C-phenyl] ZA1963) in excreta and expired air of during the first 24 hours post-dose for males was 

38.0 & 41.2% administered dose (AD) for males and for females was 48.3 & 53.7% AD. The 

recovery of radioactivity in combined 14C-labels ([

14C-pyridinyl] & [14C-phenyl] ZA1963) and in 

both sexes for urine was 17.8-30.2% AD and for feces 13.4-19.6% AD, and <0.4% of the AD was 

recovered in expired air. Whole body autoradiographs showed that the highest concentrations of 

radioactivity were associated with the gastrointestinal (G.I.) tract, liver and kidneys at 24 hours postdose.

Based upon the amount of radioactivity recovered in the bile and urine of rats treated with 100 mg 

[

14C-pyridinyl] ZA1963/kg bw, approximately 77-82% AD was absorbed by both sexes. Excretion 

through bile represented a primary route of excretion, but no biliary excretion data were available for 

review at doses of 10 mg/kg.

In the excretion and tissue distribution studies at 10 mg/kg (both single and repeated doses), the 

highest concentrations of radioactivity in tissues by 120 hours post-dose were found in the liver 

(males, 0.400-0.470 μg equiv/g; females, 0.248-0.258 μg equiv/g), kidneys (0.184-0.206 μg 

equiv/g), and G.I. tract (0.113-0.251 μg equiv./g). For the 100 mg/kg dose group, the levels of total 

radioactive residues (TRR) were also highest in liver (3.056-3.756 μg equiv/g), kidneys (1.907-2.329 

μg equiv/g), and the G.I. tract (1.646-2.990 μg equiv./g). The TRR levels in the remaining tissues 

and in the residual carcass were generally less than in whole blood. The distribution and 

concentration of 14C-residues in tissues were generally similar between the sexes within each group 

and between the single and repeated low-dose groups. The distribution of 14C-resdiues in tissues 

was also similar between the single low and high dose groups, but the concentration of 14C-residues 

in tissues were generally 9 to 22-fold higher in the high dose, which generally reflected the 10-fold 

increase in the dose level.

In the main mass balance studies, 94-100% AD was recovered was from all groups, with most of the 

dose (73-89% AD) being excreted within 48 hours. The major route for elimination was feces for all 

groups, accounting for 74-78% AD in males and 61-65% AD in females. Urinary excretion in all 

dose groups accounted for 18-21% AD in males and 26-34% AD in females. Thus, there was a 

slight sex-related difference in the amounts excreted in urine and feces. The carcass and tissues 

(excluding the GI tract with contents) accounted for <1% AD.

The test compound was extensively metabolized; a total of 42 metabolites were isolated from 

excreta, of which 34 were structurally identified. The identified 14C-residues accounted for 61.9-
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78.2% of the AD in the 10 and 100 mg/kg single dose groups and the 10 mg/kg repeated dose group, 

and 89.3-100.3% of the AD in bile-duct cannulated rats dosed at 100 mg/kg. Nine to ten of the 

identified compounds were major metabolites accounting for >5% AD. Parent and Metabolites 2, 

32, and 42 were found in the feces of all groups. Except in bile duct-cannulated groups, Metabolite 

2 was the major metabolite, accounting for 11-17% AD in males and 18-30% AD in females. 

However, in the bile duct-cannulated groups, Metabolite 40 was isolated in the greatest amount (29-

32% AD). The only unidentified metabolite found at >5% of the AD was Metabolite A, which was 

recovered primarily in feces. Unknown A accounted for 4.5-10.5% of the AD in all groups, except 

the bile-duct cannulated rats in which it accounted for ≤2.1% of the AD. The general metabolic 

profile was similar regardless of sex, dose level, radiolabel, or number of doses administered. The 

major route of metabolism for picoxystrobin in rats was via ester hydrolysis and glucuronide 

conjugation.

This metabolism study in the rat is classified Acceptable/Guideline and satisfies the guideline 

requirement for a Tier I metabolism study [OPPTS 870.7485, OECD 417] in rats.

F.20 in vitro Dermal Penetration (OPPTS 870.7600) 

MRID 48073760 (1999)

In an in vitro dermal penetration study (MRID 48073760), unlabelled ZA 1963 (purity 99.8%, 

Lot/Batch No. Y08467/012) spiked with radiolabeled ZA 1963 (purity >97%, Lot/Batch No. 

Y08467/045) was applied to rat or human epidermal membranes in static diffusion cells (5 

replicates/dose/time) at doses of 1279 μg/cm

2

or 5.45 μg/cm

2

. Receptor fluid (50% v/v 

water/ethanol) was sampled over a 10 hour exposure, a 24 hour exposure, or a 10 hour exposure with 

a wash that was continued out to 24 hours. At the end of the exposure period, epidermal membranes 

were washed and radioactivity quantified via mass balance. Data were expressed in units of flux or 

as percentage of dose recovered. 

The overall recovery of the radiolabel was acceptable for all experiments using rat epidermis (>88%) 

and human epidermis (>83%). The amount of radioactivity in the receptor fluid (an indication of 

dermal penetration) was always greater for rat epidermis than human epidermis under otherwise 

identical experimental conditions. This result indicated a greater permeability of rat skin and/or 

greater interaction of ZA1963 with rat skin than human skin. The amount of radioactivity in human 

and rat epidermis after washing was also measured, and results showed that amount of radioactivity 

in the epidermis was greater in rat epidermis than in human epidermis under all conditions except for 

the low dose with a 24 hour contact period, in which the amounts were similar. This result 

supported the idea of greater interactions of ZA1963 with rat than human skin under conditions of 

shorter exposures (e.g. 10 hours) and higher concentrations (e.g. 1279 μg/cm

2

). 

These dermal penetration studies with in vitro rat and human skins and in vivo live rats are 

considered acceptable, guideline. There is no OPPTS guideline, but the studies were done according 

to OECD 428. 

F.21 in vivo Dermal Penetration in Rats (OPPTS 870.7600) 

MRID 48073761 (1999)
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In a dermal penetration study (MRID 48073761) 14C-ZA1963 (98% a.i., phenylacrylate label, 

radiochemical purity >97%, batch Y08467/045) was reconstituted in the formulation blank and 

administered to 4 male AlpkAPfSD (Wistar-derived)rats/dose/time at dose levels of 1219 μg/ cm2

and 6.17 μg/ cm2. Three exposure groups were used: a group in which skin was washed and the 

experiment terminated at 10 hours, a group in which the skin was washed at 10 hours and the 

experiment terminated at 24 hours, and a group in which the skin was washed and the experiment 

terminated at 24 hours. Excreta for all exposure groups were collected throughout exposure, 

however, exhaled CO2 was not examined. 

Recoveries for all treatment groups were acceptable and were in excess of 96%. The absorbed dose 

was determined by adding the percentages of radioactivity in the urine, feces, cage wash and 

contents, and carcass. For the high dose, the total absorbed dose was greatest for the 24 hour 

exposure (0.88 0.99 %) followed by a 10 exposure and wash before termination at 24 hours (0.45 

0.22 %), which was apparently greater than the 10 hour exposure with termination at 10 hours 

(0.33 0.22 %). However, consideration of the variability in both of the 10 hour measurements 

indicates that that absorption was similar, as these values are not likely significantly different. A 

similar pattern was observed for the low dose, in which the absorbed dose was highest for a 24 hour 

exposure (20.59 7.05%), followed by a 10 hour exposure and wash before termination at 24 hours 

(4.75 0.88 %), which was similar in magnitude to the 10 hour exposure and termination (4.44 

1.33%). The similarities in the absorbed dose for the 10 hour exposure data with termination at 10 

hours or at 24 hours after washing at 10 hours for both dose groups indicate that the skin-bound 

residue is hardly bioavailable. Therefore, skin-bound residues should not be added to the absorbed 

dose to calculate a DAF.

This rat in vivo study indicates that the dermal absorption factor for a 10 hour exposure is 4.75%. 

The DAF for a 24 hour exposure is 20.59%. These DAFs do not include skin-bound residues. 

However, it was experimentally determined that skin-bound residues are not likely to be absorbed. 

This study in the rat is acceptable, guideline and satisfies the guideline requirement for a dermal 

penetration study (870.7600) in rats. 

F.22 Immunotoxicity Study in Rats (870.7800) 

MRID 48073762 (2010)

In an immunotoxicity study (MRID 48073762) Picoxystrobin (99.3% a.i., batch/lot SEP07AS013)

was administered to CRL:CD(SD) rats (10/sex/dose) in diet at dose levels of 0, 50, 200, 1000 or 

3500 ppm (0, 3.5, 15, 68 or 231 mg/kg bw/day for males and 0, 3.9, 16, 75 or 225 mg/kg bw/day for 

females,) for 28 days. Systemic toxicity parameters were evaluated, and immunotoxicity was 

investigated by performing an enzyme-linked immunosorbent assay (ELISA) to measure serum IgM 

responses to sheep red blood cells (SRBC) following immunization with SRBC.

For systemic toxicity, there were no compound related effects on mortality, clinical signs, requisite 

organ weights or gross pathology. Significantly reduced body weight was observed in high-dose 

animals throughout the study resulting in a 22% reduction in overall body weight gain in males and 

40% reduction in females. Decreased food consumption was also observed in the high-dose group 

males and females. The systemic LOAEL was 3500 ppm (231 mg/kg/day in males and 225 
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mg/kg/day in females) based on decreased body weight, body weight gains, food consumption and 

food efficiency. The NOAEL was 1000 ppm (68 mg/kg/day in males or 75 mg/kg/day in females).

For immunotoxicity, there was no evidence of immunotoxicity under the study conditions. Spleen 

and thymus weights were unaffected by the treatment. No effect was observed in the humoral 

immune response as measured by the T-dependent antibody response against sheep red blood cells 

with an ELISA assay. The available toxicity database revealed no abnormal findings in organ 

weights and histopathology in the immune organs. By the weight of evidence, the immune system is 

not a primary target organ for picoxystrobin exposure. A NK cell activity assay is not needed. 

Similar results were also observed in an immunotoxicity study in mice (MRID 48073763). 

The LOAEL for immunotoxicity was not established and the NOAEL is 3500 ppm (equivalent to 

231 mg/kg/day in males and 225 mg/kg/day in females).

This immunotoxicity study is classified acceptable, guideline and satisfies the guideline requirement 

for an immunotoxicity study (OPPTS 870.7800). 

F.23 Immunotoxicity Study in Mice (OPPTS 870.7800)

MRID 48073763 (2010)

In an immunotoxicity study (MRID 48073763) Picoxystrobin (99.3% a.i., batch/lot SEP07AS013)

was administered to CRl:CD1(ICR) mice (10/sex/dose) in diet at dose levels of 0, 100, 600, 2400 or 

4800 ppm (0, 16, 95, 358 or 727 mg/kg bw/day for males; 0, 20, 127, 449 or 931 mg/kg bw/day for 

females) for 28 days. Systemic toxicity parameters were evaluated, and immunotoxicity was 

investigated by performing an enzyme-linked immunosorbent assay (ELISA) to measure serum IgM 

responses to sheep red blood cells (SRBC) following immunization with SRBC.

For systemic toxicity, there were no compound related effects in mortality, clinical signs, body 

weight or body weight gain, food consumption or efficiency, requisite organ weights or gross 

pathology. The LOAEL was not established. The NOAEL was 4800 ppm (727 mg/kg/day in males 

or 931 mg/kg/day in females).

For immunotoxicity, there was no evidence of immunotoxicity under these study conditions. Spleen 

and thymus weights were unaffected by the treatment. No effect was observed in the humoral 

immune response as measured by the T-dependent antibody response against sheep red blood cells 

with an ELISA assay. The available toxicity database revealed no abnormal findings in organ 

weights and histopathology in the immune organs. By the weight of evidence, the immune system is 

not a primary target organ for picoxystrobin exposure. A NK cell activity assay is not needed. 

Similar results were also observed in an immunotoxicity study in rats (MRID 48073762). 

The LOAEL for immunotoxicity was not established and the NOAEL is 4800 ppm (727 mg/kg/day 

in males and 931 mg/kg/day in females).

This immunotoxicity study is classified acceptable, guideline and satisfies the guideline requirement 

for an immunotoxicity study (OPPTS 870.7800) in the mouse.
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Appendix G. Picoxystrobin Dietary Burden Calculation for Risk Assessment

Table G.1. Calculation of Dietary Burdens of Picoxystrobin to Livestock for Risk Assessment.

Feedstuff Type1 % Dry 

Matter2 % Diet2

Highest Residue 

Median Residue

(ppm) 3

Dietary Contribution 

(ppm)4

Beef Cattle

Corn, field, forage (silage) R 40 15 10 3.75

Barley, grain CC 88 50 0.06 0.0341

Wheat, Grain CC 88 25 0.06 0.0171

Grain aspirated fractions CC 85 5 2.55 0.15

Canola, meal PC 88 5 0.06 0.0034

TOTAL BURDEN -- -- 100 3.96

Dairy Cattle

 Corn, field, forage/silage R 40 35 10 8.75

 Pea, field, vine R 25 10 12 4.8

 Barley, grain CC 88 45 0.06 0.031

Canola, meal PC 88 10 0.06 0.0068

TOTAL BURDEN -- -- 100 -- 13.6

Poultry

Barley, grain CC 88 75 0.06 0.045

Canola, meal PC 88 15 0.06 0.009

Soybean, meal PC 92 10 0.06 0.006

TOTAL BURDEN -- -- 100 -- 0.06

Swine

Barley, grain CC 88 20 0.06 0.012

Wheat, grain CC 88 65 0.06 0.039

Canola, meal PC 88 15 0.06 0.009

TOTAL BURDEN -- -- 100 -- 0.06

1

 R: Roughage; CC: Carbohydrate concentrate; PC: Protein concentrate.

2

 Revision of feedstuffs in OPPTS 860.1000 Table 1 referenced as “Table 1 Feedstuffs (October 2006)”. 

3

 Highest residue: Total max residue of picoxystrobin (feed items); For blended commodities –Total median residue of 

picoxystrobin

4

 Contribution = ([highest residue /% DM] X % diet) for beef and dairy cattle; contribution = ([highest residue] X % 

diet) for poultry and swine.
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Expected secondary residues in meat and milk

To determine the need for tolerances for residues of picoxystrobin in milk and tissues, the 

anticipated secondary residues in cattle matrices were estimated using transfer coefficient factors 

calculated from the maximum residues of picoxystrobin observed at the dose level closest to the 

RBDB in the dairy cattle feeding study. The transfer coefficients (calculated as residue level to feed 

level ratios) are presented in Table G2. The transfer coefficient for each matrix was then used to 

calculate the expected secondary residues by multiplying the transfer coefficient by the calculated 

dietary burden. The expected residues of picoxystrobin and the recommended tolerances based on 

expected residues are presented in Table G3.

Table G. 2. Residue-Level-to-Feed Ratios (Transfer Coefficients) in Dairy Cattle Milk and Tissues.

Matrix Maximum Residue of 

picoxystrobin (ppm)

Feeding Level

(ppm)

Transfer

Coefficient 1

Milk <0.01 40 <0.00025

Milk fat <0.01 40 <0.00025

Liver 0.005 40 0.000125

Kidney N/D 40 N/A

Muscle N/D 40 N/A

Fat 0.004 40 0.0001

1 Calculated from the maximum residues observed at the dose level closest to the RBDB divided by the dose level.

Table G.3. Expected Secondary Residues of picoxystrobin in Meat and Milk.

Matrix Dietary Burden

(ppm)

Secondary Residues 1

(ppm)

Recommended Tolerance

(ppm)

Dairy Cattle

Milk 13.6 0.0034 0.01

Milk fat 13.6 0.0034 0.01

Liver 13.6 0.0017 0.01

Kidney 13.6 N/A N/A

Muscle 13.6 N/A N/A

Fat 13.6 0.00136 0.01

Swine

Liver 0.06 0.0000075 Not required

Kidney 0.06 N/A N/A

Muscle 0.06 N/A N/A

Fat 0.06 0.000006 Not required

1

Calculated from dietary burden x transfer coefficient from Table G2.

Expected secondary residues in poultry eggs and tissues

To determine the need for tolerances for residues of picoxystrobin in poultry eggs and tissues, the 

anticipated secondary residues in poultry matrices were estimated using transfer coefficient factors 

calculated from the maximum residues of picoxystrobin observed at the dose level closest to the 

RBDB in the poultry feeding study. The transfer coefficients (calculated as residue level to feed 

level ratios) are presented in Table G4. The transfer coefficient for each matrix was then used to 

calculate the expected secondary residues by multiplying the transfer coefficient by the calculated 

dietary burden. The expected residues of picoxystrobin and the recommended tolerances based on 

expected residues are presented in Table G5.
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Table G.4. Residue-Level-to-Feed Ratios (Transfer Coefficients) in Poultry Eggs and Tissues.

Matrix Maximum Residue of 

Picoxystrobin (ppm)

Feeding Level

(ppm)

Transfer

Coefficient 1

Eggs <0.01 15 <0.00067

Fat <0.01 15 <0.00067

Liver 0.027 15 0.0018

Muscle <0.01 15 <0.00067

1 Calculated from the maximum residues observed at the dose level closest to the RBDB divided by the dose level.

Table G. 5. Expected Secondary Residues of Picoxystrobin in Poultry Eggs and Tissues

Matrix Dietary Burden

(ppm)

Secondary Residues 1

(ppm)

Recommended Tolerance

(ppm)

Eggs 0.06 0.0000402 Not required

Fat 0.06 0.0000402 Not required

Liver 0.06 0.000108 Not required

Muscle 0.06 0.0000402 Not required

1 Calculated from dietary burden x transfer coefficient from Table G4.
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Appendix H. Human Equivalent Concentration and Dose Calculations

Appendix H/Table 1: HEC Array for Occupational Risk Assessment§ 

Relevant Study LOAEL

(mg/m3)

NOAEL

(mg/m3)

Da Dh Wa Wh RDDR HEC 

(mg/m3)

inter intra UF

Short-& Intermediate-Term Exposure

Inhalation – Rat

(MRID 48697401 ) 

28-day

ER Not Obs. 25 6 8 5 5 2.8 0.05 3 10 NA

Long Term Exposure: Not appropriate for picoxystrobin

§ Bolded studies used for endpoint selection.

Appendix H/Table 2: HEC Array for Non-Occupational Risk Assessment§ 

Relevant Study LOAEL

(mg/m3)

NOAEL

(mg/m3)

Da Dh Wa Wh RDDR HEC 

(mg/m3)

inter intra UF

Short-& Intermediate-Term Exposure

Inhalation – Rat

(MRID 48697401 ) 

28-day

ER Not Obs. 25 6 24 5 7 2.8 0.0125 3 10 NA

Long Term Exposure: Not appropriate for picoxystrobin

§ Bolded studies used for endpoint selection.

Key for Array Tables

LOAEL: Lowest observed adverse effect level

Da: Daily animal exposure (hrs/day)

Wa: Weekly animal exposure (days/week)

RRDR: Regional Deposited Dose Ratio

inter: interspecies extrapolation uncertainty factor

Dh: Anticipated daily human exposure (hrs/day)

Wh: Anticipated weekly human exposure (days/week)

HC: Human Concentration

HEC: Human Equivalent Concentration

intra: intraspecies variation uncertainty factor

UF: Other uncertainty factor(s)

§ Bolded studies used for endpoint selection.

Using the HEC calculated, a conversion of the inhalation concentration to a dose (mg/L to 

mg/kg/day) was conducted as follows: 

dose (systemic HEC value) mg/L x A x CF (L/hr/kg) x D (hours) x AF = mg/kg;

Occupational: (0.0525 mg/L) x 1 x 6 x 8 x 1 = 2.4 mg/kg/day 

Residential: (0.0125 mg/L) x 1 x 6 x 24 x 1 = 1.8 mg/kg/day 

 

Where: 

A absorption: ratio of deposition and absorption in respiratory tract compared to absorption by 

the oral route.

CF Conversion Factor: A L/hr/kg factor which accounts for respiratory volume and body weight 

for a given species and strain (Table 1 of guidance document).
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D Duration: Duration of daily animal or human exposure (hours).

AF Activity Factor: Animal default is 1.

When conducting inhalation risk assessments, the magnitude of the UFs applied is dependent on the 

methodology used to calculate risk. For studies in this risk assessment with inhalation animal data, 

UFs are based on the RfC methodology developed by the Office of Research and Development 

(ORD) for the derivation of inhalation reference concentration s (RfCs) and human equivalent 

concentrations (HECs) for use MOE calculations. Since the RfC methodology takes into 

consideration the pharmacokinetic (PK) differences but not pharmacodynamic (PD) differences, 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 10X1. Thus, the UF when using the RfC methodology is 

customarily 30X.

Based on proposed picoxystrobin Labels, HED believes exposures can be short- (1-30 days) or 

intermediate- (1 to 6 months) term in duration. Long-term exposures are not anticipated for 

picoxystrobin based on proposed labeled uses. Acute exposures are not expected but were 

calculated. 

For the acute, short- and intermediate-term scenarios, inhalation data from the 28-day inhalation 

rodent study were most appropriate for determining HECs. In the RfC methodology, different HECs 

may be calculated for the same experimental NOAEL due to:

1. Different algorithms are used to derive HECs for systemic versus portal-of-entry 

effects. Typically, HECs are calculated separately for systemic versus portal-of-entry 

effect. 

2. Time adjustments are traditionally needed for non-occupational (bystander) versus 

occupational exposure scenarios. Traditionally, HECs for non-occupational exposure 

are based on the number of hours an individual may be at home. Therefore, the most 

conservative estimate of hours spent at home would be 24 hours/day and 7 

days/week. In comparison, the average work week for an occupational worker is 8 

hours/day and 5 days/week. The HEC array table reflects the time adjustment in the 

calculations.

Methodologies for Human-Equivalent Concentration (HEC) Calculations.

The RfC methodology applies a dosimetric adjustment that takes into consideration not only the 

differences in ventilation rate (MV) 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 and humans. Based on the 

EPA’s RfC guidance (1994), the methodology for RfCs derivation is an estimate of the quantitative 

dose-response assessment of chronic non-cancer toxicity for individual inhaled chemicals and 

includes dosimetric adjustment to account for the species-specific relationships of exposure 

concentration to deposited/delivered dose. This adjustment is influenced by the physicochemical 

properties of the inhaled compound as well as the type of toxicity observed (e.g. systemic vs. portal

of entry), and takes into consideration the PK differences between animals and humans. Though the 

RfC methodology was developed to estimate toxicity of inhaled chemicals over a lifetime, it can be 

 

1 A 3X UF for interspecies extrapolation is retained to account for the PD differences between animals and humans 

which are not accounted for in the RfC methodology. 
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used for other inhalation exposures (e.g. acute and short-term exposures) since the dosimetric 

adjustment incorporates mechanistic determinants of disposition that can be applied to shorter 

duration 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 HEC 

for inhaled gases is described by the following equation:

Where:

PODstudy: Point of departure identified in the critical toxicology study

Danimal exposure: Duration of animal exposure (hrs/day; days/wk)

Danticipated exposure: Anticipated human duration of exposure (hrs/day; days/wk)

RDDR: Regional Dose Deposited Ratio

Calculations used to estimate the inhalation risk to humans from aerosols are dependent not on the 

RGDR as for gases, but on the regional deposited dose ratio (RDDR). Inhalation studies using 

aerosols characterize particulate exposure by defining the particulate diameter (mass median 

aerodynamic diameter [MMAD]) and the geometric standard deviation (σg), which is then used to 

determine the RDDR. The RDDR is a multiplicative factor used to adjust an observed inhalation 

particulate exposure concentration of an animal (A) to the predicted inhalation particulate exposure 

concentration for a human (H) that would be associated with the same dose delivered to the rth 

region or target tissue.

RDDRr = (RDDr/Normalizing Factor)A

 (RDDr/Normalizing Factor)H 

As with calculations for gases, the r regions and potential target tissues are the three respiratory 

regions (ET, TB, PU). The RDDR is easily calculated by using a software program designed 

specifically for computing the RDDR from the MMAD and σg defined from an aerosol inhalation 

study. The values for the species-specific parameters used to calculate the RDDR are provided in 

the EPA document “Methods for Derivation of Inhalation Reference Concentrations and Application 

of Inhalation Dosimetry.” 

Regional Deposited Dose Ratio (RDDR) for bifenazate

MMAD = 2.12

Sigma g = 2.79

 Body Minute 

SPECIES Weight (g) Ventilation (VE, ml) 

-----------------------------------------------------------------------------

 rat 187 141.7 

 human 70000 13800.0 

-----------------------------------------------------------------------------

 

 deposited fraction 

HEC = POD * D 

D 

* W

W

study * RGDR animal exposure (hrs/ day)

human exposure (hrs/ day)

animal exposure (days / wk)

human exposure (days/ wk)
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--------------------------------------------------------------------------------

 rat 0.491 

 human 0.669 

--------------------------------------------------------------------------------

RATIO 0.734

RDDR = (VE/SA)animal/(VE/SA)human * deposited fractionanimal/deposited fractionhuman

= (141.7/187)animal/(13800/70000)human * 0.491/0.669

= 2.8

The magnitude of the UFs applied is dependent on the methodology used to calculate risk. The RfC 

methodology takes into consideration the PK differences but not the PD differences. 

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 customarily 30X.