### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 2 of 89 occupational, and aggregate exposure assessments, as needed, to estimate the risk to human health

that will result from th e 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 fora ge 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 evalu ation) , and Meheret Negussie (residue chemistry and dietary risk assessment).

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 3 of 89 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 Struct ure 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

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 4 of 89 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

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 5 of 89 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, foli age (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 respiratio n by blocking electron tra nsfer at the Qo cent er 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, A frican and Latin American countries for uses on cereal grains and other commodities.

In the U.S., the proposed p icoxystrobin end use product is formulated as a suspension concentrate (SC) containing 2 2.5% 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 g round , air o r 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.

Expos ure 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 indi cates 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, de rmal 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 a cross species, genders, and

treatment durations were decrease d body weight, body weight gain and food consumption

, and

diarrhea.

Picoxystrobin toxicity f

ollowing acute oral, dermal, and inhalation exposure is considered low to moderate (Toxicity C ategorie s II

- IV); there was no evidence of dermal irritation or sensitization. Picoxystrobin was, however, determined to be a severe eye irritant (Toxicity Category I).

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 6 of 89 Developmental toxicity seen in the rat and rabbit was considered of low concern. In both spec ies , 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 a ffects the nervous system; b ehavioral changes observed in the acute and subchronic neurotoxicity studies were attributed to general malaise

. P icoxystrobin has no effects on the immune system in rats and mice, and is not mutagenic or genotoxic. N o adverse dermal or systemic effects were iden tified 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 carc inogenicity classification for p icoxystrobin is “Suggestive Evidence of Carcinogen ic 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 UF L 

### for acute die tary risk assessment

because a N OAEL 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) t he toxicology database is complete; 2) t here are no indicati ons that the nervous system is a target for p icoxystrobin ; 3) t here 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

int er

- species extrapolation and the 10X intra

- species variation factors, a nd a 10X UF L 

### for the use of

the LOAEL.

A PoD for chronic dietary risk assessment was selected from the 1

- year dog study; decreased body weights, body weight 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 int ra

- species variation factors.

An endpoint and dose were not selected for dermal risk asse ssment since no dermal systemic hazard was observed at the limit dose in a rat dermal toxicity study.

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 7 of 89 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 ex posures at the highest concentration tested (0.025 mg/L/day, 6.78 mg/kg/day )

. Thu s, for the proposed uses considered in this risk assessment, HED concluded tha t selection of an inhalation endpoint and quantitative

inhalation risk estimates are not needed.

Human Health Risk Assessment:

For this action, the only risk assessments conduc ted 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 assessm ent was not necessary

. In addition, since no

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

dermal and inhalation risks associated with the proposed uses.

Aggregate Acute D ietary : E xposure 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 facto rs, and a surface water residue estimate (7.95 ppb) modeled using a total residue method. Aggregate risk for the gener al 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 , t olerance 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 conside red in this human health risk assessment . Dietary and non

- dietary exposures were considered.

2.0 HED Recommendations

2.1 Data Deficiencies/Conditions of Registration

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 8 of 89 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 na ture of the residue in poultry is adequately understood for the currently proposed uses, since tolerances are not needed for residues in poultry commodities

. However, i f 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 met abolism 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 cro ps 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 com pounds 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 subm itted. The liquid chromatography tandem mass spectrometry (LC/MS/MS) Method in report DuPont

24868 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 c ereal 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 m ethod 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 one

third 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 en forcement purposes.

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 9 of 89 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. T he 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

LO Q 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 f or plant and animal commodities . Both plant and livestock method s describ e 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 m atrix (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 i n 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 harmo nized 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 Int ernational 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 20 A. 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 th e Agency’s final tolerance recommendations. The tolerance expression for picoxystrobin should read as follows:

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 10 of 89 Tolerances are established for residues of the fungicide picoxystrobin, including its metabolites and degradates, in or on the commodities list ed below. Compliance with the tolerance levels specified below is to be determined by measuring only picoxystrobin, methyl (α E )

- 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

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 11 of 89 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

calc ulated dietary burden to account for the transfer of residues to livestock matrices (tissues and milk).

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 12 of 89 For the cereal grain, except rice (crop g roup 15) , crop group 16, and foliage of legume vegetables (7A) the proposed tolerance differ from the recommen ded because a crop group tolerance could not

be established due to the fact that the minimum and maximum recom mended tolerances differ by more than 5x. Therefore, separate tolerance s listed above are recommended.

For wheat bran and wheat germ, based on th e data from the wheat processing study, residues of picoxystrobin concentrate in wheat bran (2x) and germ (3.2x). The maximum expected residue s of picoxystrobin are 0.06 ppm and 0.09 ppm, respectively. The recommended tolerance on barley bran at 0.5 ppm i s derived using 2x concentration factor of wheat bran. Tolerances were not proposed for

these commodities.

For c orn oil , b ased on the corn processing study, residues of picoxystrobin concentrate in refined oil

an d dry milled refined oil. The maximum expected residue of picoxystrobin in corn refined oil (0.07 ppm) is the recommended tolerance, whereas t he proposed tolerance is 1.5 ppm for Cereal (Corn)

oil.

For s oybean , based on t he soybean processing study, residues of picoxystrobin conc entrate 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 toleran ce of 0.20 ppm for soybean hulls, whereas t he 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 ) Bul k corn grain, wheat grain, and soybean seed samples were processed into corresponding AGFs. R esidues of picoxystrobin concentrat e 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 1 0 ppm for residues of picoxystrobin in/on grain, aspirated grain

fractions (based on soybeans). OPPTS 860.1500(f)(3)(v) indi cates 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

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 13 of 89 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

cro p metabolism study, the label should include a 10 month PBI for leafy vegetables and 12 month PBI for all other crops inclu ding 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 Tox icity 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 f rom Residential Assessmen t

None. There are currently no registered or proposed residential uses of picox y strobin.

3.0 Introduction

3.1 Chemical Identity

Picoxystrobin is the active ingredient in the end

- use product DuPontTM Approach TM 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 p reventive and curative fungicide with unique distribut ion properties including systemic (acropetal) and translaminar mo vement, and diffusion in leaf waxes.

3.2 Structure and Nomenclature

T he chemical structure and nomenclature of picoxystrobin are presented in Table 3. 1. Chemical

names and structures of th e metabolites are presented in Appendix B.

Table 3.2

. Picoxystrobin Nomenclature Compound Chemical Structure

Common name Picoxystrobin Company experimental name ZA1963, or DPX

- YT699

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 14 of 89 IUPAC name methyl (2 E )

- 3

- methoxy

- 2

- {2

- [6

- (trifluoromethyl)

- 2

- pyridyloxymethyl]phenyl}acrylate

CAS name methyl (α E )

- α

- (methoxymethylene)

- 2

- [[[6

- (trifluoromethyl)

- 2

- pyridinyl]oxy]methyl]benzeneacetate

CAS # 117428

- 22

- 5

End

- use product/EP DuPontTM Aproach TM 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 - 4 

### Pa m 3 

### mol - 1 

### w hich decreases its potential for volatility. Although t he octanol/water partition coefficient ( log K OW 

### ~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 t he 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 sp ray 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 e valuation 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 RTI 1

(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 swit ching 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

Page 15 of 89 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 RTI 1

(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 App ly a single 3

- 4 oz application

bet ween V4 to V7 for early

season disease control.

Make additional 6

- 12 fl oz applications (between VT to R3)

p rior 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 Vege tables (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, li ma 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

Page 16 of 89 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 RTI 1

(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 2 nd 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 2 nd
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 c anola, c ereal g rains (e xcept r ice )

, d ried s helled p eas and b eans, and

s oybeans. 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 inha lation 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 Lo w

- Income Populations,"

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 17 of 89 ( 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 accord ing 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 ris k 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, sp ecialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, a nd 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 f ung al growth by disrupt ing mitochondrial respiration through inhibit ing Complex III electron transfer at the Cytochrome bc1 (ubiquinol oxidase) Q 0 

### site. There are no mammalian molecular data to specifically show this mode of action in the test animals; however, effects such as decrease body weig ht, 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 tre ated animals

.

4.1 Toxicology Studies Available for Analysis

A full suite of picoxystrobin toxicity studies ha s 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 Absorp tion, Distribution, Metabolism and Excretion (ADME)

Fol lowing oral dosing with low (10 mg/kg) and high dose s (100 mg/kg) in rats, 70

- 80% of the administered picoxystrobin was absorbed with moderate speed and exhibited bimodal peaks; the first

p eak occurred within 1 hour of dosing and the second peak occurred between 8

- 24 hours post

dosing. Mean T
max 

### values for low dose groups were 0.6 to 7.1 hours; for high dose group s , 9.3 to

12.3 hours. The mean values for area under curve (AUC) appeared to be slightly higher for males

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 18 of 89 (102 hr*μg/g) than for female s (8 6 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 who le 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 d ose. 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 o nly 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% a nd 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 Abs orption

The dermal absorption for picoxystrobin was low. Using the results from an in vivo dermal absorption study and those from the in vit r o 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 f ood 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

disturb ance 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 ir ritation 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

.

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 19 of 89 In the rat and rabbit developmental toxicity studies, deve lopmental 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 ma nifested 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 i n male

and female mice. As indicated before, the genotoxicity battery was negative. P icoxystrobin 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 I I

- IV). Picoxystrobin is not a dermal irritant or sensitizer. However, pi coxystrobin 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 UF L 

### 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 includ ing 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 organis m, 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 assess ing susceptibility to infants and children as required by FQPA.

4.4.2 Evidence of Neurotoxicity

There are no indications in any of the s tudies 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.

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 20 of 89 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 studie s

.

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 assessment s 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 cr ops 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 Conce ntrations ( 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 Po int 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), th e 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 wi th 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 batt ery 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. P icoxystrobin shows “Suggestive Evidence of Carcinogenic Potential” based on tumors observed in one species (rat) and one sex (males): a treatment

- related increase in testicula r 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. T he LOAEL of

200 mg/kg based on low arousal and decreased motor activit y ( 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 appropria te 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 app lication of an Uncertainty Factor of 1000 which includes the

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 21 of 89 conventional 10X inter

- species extrapolation and the 10X intra

- species variation factors, a 10X UF L 

### 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 singl e 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/d ay and a UF of 100 which includes the conventional 10X inter

species 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 der mal 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 t o 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 ris k 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 m g/kg/day )

. Furthermore, there ar e 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 t o 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 th e 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

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 22 of 89 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 quantif ication 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 appr oximately 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 (P o D) Uncertainty /

FQPA Safety

Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Acute Dietary general population, including infants and

children L OAEL =

20 0 mg/kg/day UF A = 10x

UF H = 10x FQPA = 10 x (UF L ) a RfD =

0.2 mg/kg/day

aPAD = 0.2 mg/kg/day Acute Neurotoxicity

– Rat

LOAEL = 200 mg/kg ba sed 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 t oxicity attributable to a single dose in the relevant studies

Chronic Dietary NOAEL =

4.6 mg/kg/day UF A = 10x

UF H = 10x FQPA = 1x c RfD =

0.046 mg/kg/day

cPAD = 0.046 mg/kg/day Chronic Toxicity

– Dog

LOAEL = 15.7 mg/kg/day b ased 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.

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 23 of 89 Point of Departure (P o D) = 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 = uncertaint y factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). Rf D = 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 (P o D) 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 (P o D) = 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. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the hu man 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 Assessm ent

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 phen yl 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

d etected. 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 system s . Compound PAG3 was

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 24 of 89 identified as R730529, an acidic compound. Chemical names and structure s 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 radioacti ve 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 P BIs 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, r adiolabeled field accumulation studies

were conducted at 107

- day (winter wheat) and 3 05

- 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 tha n 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 r espectively, 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 TR Rs 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 metabol ites 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 (hal f

- life of 16 days ); however photolysis only plays a significant role in shallow clear waters. Under other condi tions, 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

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 25 of 89 P icoxystrobin is metabolized in plan ts 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 step s

. In primary

crops parent picoxystrobin was the predominant major residue. In several primary crops, Compounds 2, 3, and 8 were also major re sidues

. 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. T he 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 treatmen t (DAT).

In the environment, t he 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 CO 2 

### were identified in the environmental fate studies at concentrations >10% of the applied radioactivity

.

In livestock, metabolism of picoxystrobin proceeds via este r 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 t he primary metabolite being Compound 2 in goat liver and C om pound 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 C ompounds 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 identifie d 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 product s produced in signifi cant 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 f or 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 co mmodities. For drinking water, a total residue approach for parent, and compounds 2, 3, 7 and 8 should be used

for the risk assessment

.

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 26 of 89 Table 5. 1. 4 Summary of Metabolites and Degradates to be included in th e Risk Assessment

and Tolerance Expression for P icoxystrobin.

Matrix Residues included in Risk Assessment 1 Residues included in Tolerance Expression

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

Rotational Crop Picoxystrobin 2 Picoxystrobin

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 S ee 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, includin g 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 t o 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 co mpound. 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

pu rposes 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 ro tational crop studies and radio labeled 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 significa nt 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 cr op 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 o n 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 ch aracterize 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: P arent 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

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 27 of 89 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 foll owing 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 w ell as the proposed

tolerances f

or 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 gra in 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 a nd 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

. T he OECD statistical calculation spreadsheet was used to determine appropriate tolerance levels

.

Based on the available data, an adjustmen t to the proposed tolera nce 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 Residue 1 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

- 7 5 <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

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 28 of 89 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 conditio ns 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 d uring 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) ; a nd aspirated grain fractions. For risk assessment purposes, t he 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 feedin g 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 sh eep, 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

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 29 of 89 poultry commodities. However, tolerances for livestock commodities including kidney, eg gs, 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 con fined 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)

. Picoxystro bin (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 dete cted 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 i s 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 Effe cts 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

. Th e drinking

water assessment used a total toxic residue (TTR) approach to include parent and the ma jor environmental degradates: Compound 2, Compound 3, Compound 7, and Compound 8 (See Appendix B for structures of the degradates). T he 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

. D ue 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 a re used to represent the total mass loading of pesticide and its transformation product

. Tier I groundwater EDWCs were estimated using S CI

- GROW (Screening Concentration in Groundwater, version 2.3).

The estimated sur face water concentrations are 7.95 μg /L and 2.41 μ g/L (acute and chronic assessment, respectively) and ground water concentr ation is estimated to be 0.052 μ g/L (for acute and chronic). Typically, HED uses the higher of the surface or ground water estimates when

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 30 of 89 assessing dietary risk; theref ore, 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) Y early average

(Chronic non

cancer) (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 chroni c 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 al l 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.

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 31 of 89 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

Factors 4

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 det ermined 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 re sidues are surface water residues based on applications to sweet corn. T he EDWC for total toxic residues is 7.95 ppb for

acute and 2.41 ppb for the chronic assessment s. T he water residues were directly incorporated in the

DEEM

- FCID into the categories “w ater, 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 t he concentration of picoxystrobin in drinking water

was utilized. The surface water EDWC (7.95 μ g/L) was incorporated directly into th e dietary assessment (D401564, I

. Abdel

- Saheb, 08/01 /2012 ).

As shown in Table 5.4 .6, the acute dietary (food and drinkin g water) exposure to picoxystrobin is below HED’s level of concern [i.e., <100% of the acute Population Adjusted Dose (a PAD)] for the

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 32 of 89 general U.S. population and all population subgroups. The acute dietary exp osure estimates are <1%

of the a PAD for the general U.S. population and 1.3 % of the aP AD 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 defa ult processing factors were assumed except for where tolerances were established for processed

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

underestimate the concentration of picoxystrobin in drinking water was utili zed. The surface water
EDWC (2.41 μ g/L) was incorporated directly into th e 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 c hronic Population Adjusted Dose (cPAD)] for the general U.S. population and all population subgroups. The chronic dietary exp osure estimates are

1 .0 % of the c PAD for the general U.S. population and 2.8 % of the cP AD for children 1

- 2 years old

, the most hig hly 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.

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 33 of 89 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

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

bold text.

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 34 of 89 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no residential uses of picoxystrobin; therefore, a residential exposure assessm ent 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 metho d 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 si gnificant 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 to lerance 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 cumula tive 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

exposure s are expected from picoxystrobin handler and post

- application activities associated with

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 35 of 89 the proposed agricultural uses. Since no hazard was identified for the dermal or inhalation route s 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 p esticides, 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.

1 0 .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 As sessment (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 G rains (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 Ana lytical 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

Page 36 of 89 Ap pendix A. International Residue Limits



## Picoxystrobin ( 129200; 10/11/2011 )

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 

### Codex 3



### 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 (α E )

- α

- (methoxymethylene)

- 2

- [[[6

- (trifluoromethyl)

- 2

- pyridinyl]oxy]methyl]benzeneacetate picoxystrobin, methyl (α E )

-

α

- (methoxymethylene)

- 2

- [[[6

- (trifluoromethyl)

- 2

- pyridinyl]oxy]methyl]benze

neacetate None



### Commodity 1 

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

US Canada 4 

### Mexico 2 

### Codex 3



### Barley, grain 0.3 0 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, forag e, fodder, and straw, group 16, hay 5.0

Grain, cereal, forag e, 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 0.2 0 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

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 37 of 89 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 

### Codex 3



### 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 0.0 1

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.

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 38 of 89 A ppendix 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)

m ethyl (E)

- 2

- {2

- [6

- (trifluoromethyl)pyridin

2

- 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 (R40 3092 ) Canola (Py) Foliage/Pods Mature 0.4 (0. 05 )

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 39 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)
(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 (P y) Foliage 1.2 (0.0006) 2

Carrot (P h) 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 <0.001 1 (30

- d)

Carrot (P y) 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)

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 40 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)

Excreta 1.1 NR Soybean (Ph) (R408631

- glucoside) Forage 6.5 (0.109)

Rat Pyridinyl: Bile 1.6

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 41 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)
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 (0.0 01 )

Rat Pyridinyl: Bile 0. 1
Compound 9 (R233331 or CGA

- 320298) Methyl (E)

- 2

- [2

- (hydroxymethyl)phenyl]

- 3methoxyacrylate 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

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 42 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)
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 1 2 (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 (R40 77 48) 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}pyridine

2

- 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 ; Urin e 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 conjugate

decarboxylated ( R410639) Soybean (Ph) Forage 9.9 (0.166)

Seed 0.5 (<0.001)

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 43 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) Compound 15 Phthalic Acid (R001731) Soybean (Ph) Seed 21.3 (0.03) Forage 1

. 2 (0.0 20 )

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 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 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 (P y) Forage 4.6 (0.083)
Seed 6.8 (0.005)

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 44 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)
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 (P y) 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 (P h) 31 (0.014) 1

Carrot (P y) Root 1.7 (0.003) 1

Carrot (P h) 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

m ethyl 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

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 45 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) yloxymethyl]phenyl}

- 3

- hydroxypropiona te
n is an unknown locant Hen (Ph) Excreta 4.9 NR

Compound 34

m ethyl (E)

- 2

- (n

- ( hydroxy

- 2

- [6

- ( trifluoromethyl)pyridin

- 2

- yloxymethyl]phenyl}

- 3

- methodyacrylate

n is an unknown locant 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 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

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 46 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) 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

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 47 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) 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)

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 48 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) 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

Page 49 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) 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

Page 50 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) 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)pyridin e 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 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 1 st application, 14

- day after 2 nd 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

- da ys after 1 st 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 (stra w and grain

- mature). Apple : 4807385 7 ; ~0. 16 lb ai/A (T hree Broadcast foliar spray) at BBCH 69 and 21nad 85 days after 1 st 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

Page 52 of 89 Appendix C. Physical/Chemical Properties

Physicochemical Properties of the Technical Grade Test Compound: Picoxystrobin

Parameter Value Reference
Melting point 75 °C PMRA Chemistry Evaluation Section (CES) Review pH Not indicated 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(K OW ) at 20 °C 3.6

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 53 of 89 A ppendix 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 i n vitro Mammalian Cell Gene Mutation Test

................................ ........................... 870.5375 i n 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

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 54 of 89 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 LD 50 > 5000 mg/kg IV

870.1200 Acute Dermal Toxicity 48073721 Both sexes LD 50 > 5000 mg/kg IV

870.1300 Acute Inhalation Toxicity 48073723 LC 50 : =0.11 mg/L II

870.2400 Acute Eye Irritation 48073725 Severe r eaction o bserved 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 LC 50 : 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, n umerous organs were not weighed, and

numerous tissues were not eval uated microscopically

870.3150 90

- Day Oral Toxicity

in Non

- R odents (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

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 55 of 89 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 5 th 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 pre

pelvic vertebrae and 13 th 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 b ody 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

Page 56 of 89 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 T oxicity

(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; 2 400 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

Page 57 of 89 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) 484574 02 (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, pic oxystrobin induced an increase in testicular

interstitial cell adenomas in male rats. The testicular

interstitial cell tu mors 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 laborat ory, 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 inte rstitial 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, d uration w as inadequate to assess carcinogenic poten tial

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 i n vitro

Mammalian Cell Gene

Mutation Test (Mouse l ymphoma

c ells) 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

Page 58 of 89 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 i n vitro Mammalian

Chromosome

Aberration Test ( Human l ymphocytes) 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.

870.555 0 in vivo Genotoxicity

Testing

- Unscheduled DNA Synthesis ( Rat h epatocytes) 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

Ba sed on low arousal and decreased motor activities in males, decreased rearing in females, in addition to

decr eased 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.

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 59 of 89 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 single

high dose groups was bimodal with an initial peak in both sexes at ~1 hr. However, the second peak in the single

- l ow 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 contain ed 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; indic ative of thorough

metabolism of the pare nt. 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 isolat ed 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 h ydroxylation 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 f

eces 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

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 60 of 89 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 D 383984 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 de rmal 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 h r: 55.06 11.67 % 24 h exposure

, no wash : 33.08 6.04 %

Human : 24 h exposure

, wash at 10 h r: 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

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 61 of 89 D

. 3 Dermal Absorption

Rat in vivo S tudy : 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 14 C

- P icoxystrobin in vivo Dermal Absorption Study in Male Rat s
Test Conditions
Dose ( g/cm 2 ) 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 S tudy : 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 14 C

- P icoxystrobin in vi tr o Dermal Absorption Study using Rat and Human Epidermis

Test Conditions
Dose ( g/cm 2 ) 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, 29JUN 2010)

. 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%) pro vides a reliable d ermal absorption estimate for risk assessment [D383984,

22NOV 2010, J. Ryman].

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 62 of 89 A ppendix E : Hazard Identification and Endpoint Selection

E .1 Acute Reference Dose (aRfD)

– General Population

Includes : Females 13

- 49 Years Old

Study Selected : Acute Neurotoxicity S tudy 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 demons trates 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 attribut ed 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 t he rat and mouse chronic exposure NOAELs are ≥26.2 mg/kg/day ) . Additionally, the results found in the subchronic dog s tudy 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 R esidential 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 durat ion 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. infant s &

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 63 of 89 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 ex posure 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, d evelopmental, 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 To xicity

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 “ li mit 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 re tinal 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 st udy. 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, c onsidering 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/m 3 

### from th e 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/da y) . Thus, for these proposed uses, HED concluded that an inhalation endpoint will not be selected at this time. Further, a quantit ative inhalation risk assessment is not necessary at this time.

Summary Of Proposed Short

- And Intermediate

- Term Occupational Handler Exposures

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 64 of 89 Exposure Scenario Crop Grouping Application

Rate a (lb ai/A) Area

Treated Daily b
(acres/day) Baseline

Inhalation c

Unit Exposure (μg/lb ai) Baseline

Inhalation

Dose d
(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 I nhalation dose = daily unit exposure (μg/lb ai) x applicatio n rate x amount handled per day / body weight (80 kg adult)

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 65 of 89 A ppendix 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, ur inalysis, 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

decrea sed by 27

- 28%, and overall (Weeks 1

- 14) body weight gains were decreased by 14

- 15%.

D ecreased f

ood 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/10J f 

### AP/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.

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 66 of 89 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 femal es 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 thre shold 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 microscopica lly. 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 4 8073734 ), 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 tr eatment 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 mal es 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 Rat s (OPPTS 870.3200)

MRID 48073735 (2009)

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 67 of 89 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 mort alities 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 t he 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 evaluat ions 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 studie s 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 4807 373 6 (1999)

In a 28

- day dermal toxicity study (MRID 48073736 ), ZA1963 (93.3% a.i., batch number: P25) was

a dministere d to 5 Alpk:AP f 

### SD (Wistar

- derived) rats/s ex/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, th ere

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 eva luations. 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.

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 68 of 89 This 28

- day dermal tox icity study in rats is Unacceptable / Guideline and does not satisf y 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) rat s /sex/group by dynamic nose

- only exposure at analytical (i.e. gravimetric) concentrations of 0, 0.0017, 0.01 2 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 a nd 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 patholog y; 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 r etinal lesions were observed in all groups (except at 0.00 l mg/L), including controls, and in all rats in the control recovery/satellite groups in this study , als o i n a previous 2 year chronic study with p icoxystrobin, no test substance

related 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 ra t s 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 Ra bbi ts (OPPTS 870.3 7 00)

MRID 4807373 7 (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

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 69 of 89 decreased food consumption (12

– 63%) was observed in the high

- dose group. Overall body weight

g ain 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 treat ed 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 h ighest dose tested, 100 mg/kg/day. At 100 mg/kg/day, slightly increased incidence rates of the skeletal variations, incompletely ossified odontoid, 13 th 

### rib of long length and 27 pre

- pelvic vertebrae, were observed and cumulatively regarded as adverse eff ects 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 13 th 

### 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

satisf y 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 guidelin es for teratogenicity and does satisfy the requirements of OECD 414

.

F

. 8 Prenatal Development Study in Rats (OPPTS 870.3 7 00)

MRID 4807373 8 (1998)

In a developmental toxicity study (MRID 48073738 ), ZA1963 ( Picoxystrobin ; 99%; Batch No. P9)

in corn oil wa s administered via daily oral gavage in a dose volume of 10 mL/kg to 24 time

- mated Alpk:AP f 

### SD (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 2 2% compared to controls during the dosing period (GD 7

- 16) and 7%

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 70 of 89 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%

compa red 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 w ere 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 trea ted 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 5 th 

### sternebrae was observed and regarded as an

adverse effect of treatment.

The developmental LOAEL is 100 mg/kg/day based on misaligned 5 th 

### 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 ra ts

.

F .9 Reproduction and Fertility Effects Study in Rats (OPPTS 870.3800) MRID 48073739 (2010)

In a two

- generation reproduction toxicity study (MRID 4 8073739 ), Picoxystrobin ( 9 9.3 % ; Lot #

DPX

- YT669

- 028 ) was administered continuously in the diet to 30 Sprague

- Dawley (Crl:CD[SD]) rats/sex/dose group for two consec utive 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 ge neration 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

- r elated 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

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 71 of 89 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) non

gravid 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. Findin gs 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).

Offspr ing 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 treatment

related 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 an d 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 w ere no effects of treatment in either generation on : estrou s cycle;

sperm parameters; mating, fertility, litter sizes, sex ratio, pup birth weights, or gestation indices; pre

coital 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).

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 72 of 89 This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 870.3800; OECD 416) for a two

- generation reproduction stud y 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:AP f 

### SD 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 a nimals 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 wei ght 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).

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 73 of 89 This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 870.3800; OECD 416) for a two

- generatio n 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 do gs/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, ur inalysis , 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. G enerally throughout the study, f ood 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 cl assified 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 (MRID 48073744 )

, picoxystrobin (ZA1963) (93.3%) was administered to

C57BL/10J f 

### 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 condition s 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 incre ase 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

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 74 of 89 increas e 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 insufficien t 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 micr oscopically. 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 o bservations 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) Z A1963 (picoxystrobin) (99.3% purity) was administered to Alpk:AP f 

### 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) fo r 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, picox ystrobin at 750 ppm consistently produced slight decreases (<10%) in body weight

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 75 of 89 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 hi storical 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 sac rifice 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 decreas es 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 re duction 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 an imals. 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 carcino genicity part of the study because the highest dose tested is not sufficient to properly assess the carcinogenic potential of the chemical.

F .15 Mutagenicity

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 76 of 89 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

- 5 000 mg/kg bw N o evidence of clastogenicity or inhibition of spindle formation

870.5550
Unscheduled DNA synthesis

– Rat Liver

MRID 48073751 (1996) 0

- 5 000 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 w eight 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 de creased 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).

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 77 of 89 This subchronic neurotoxicity study is classified as Acceptable / Guideline and satisfies the guideline requirement for a subchronic neurotoxic ity 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 Tech nical (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

assessment s (functional observational battery and motor activity assessment ) w ere performed on 12

rat s/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 rat s/sex/ dose were perfused in situ for

neuro pathological examination.

In the treated groups, there were no dose

- related effects on body weight and there were no treatment

related 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 effect s 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 1 000 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 wer e 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

- G uideline and satisfies most of the guideline requirement s 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 kinetic s study (MRID: 480 73754)

, four groups of Crl:CD(SD) rats (4/sex/group) received a single oral gavage dose of [ P henyl ( U )

- 14 

### C] DPX

- YT669 ( 96 .9 % radiochemical purity ; Lot# H

- 22705

- 153) or [ P yridin e

- 3

- 14 

### C] DPX

- YT669 ( 96 .4 % radiochemical purity ; Lot# H

- 22705

- 154) i n 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

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 78 of 89 post

- dose, and separated into plasma and red blood cell (RBC) fra ctions 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, c oncentrations of radio activity were generally higher (ca 2.5x) in plasma than

in the RBC fraction for u p 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

f or each dose level, regardless of sex or 14 

### C

- label position. Based on the mean plasma concentrations for each dose group, the calculated C

max 

### 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 14 

### C

- labels, the T

max 

### generally occurred at 0.5

- 1 hours post

- dose for the low

- dose group and at 24 hours for the high

- dose. Variability in T

max 

### values was confounded by the fact that the

concentration vs. time cur ves 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 post

dose. The two peaks of radioactivity in plasma were most pronounced in the high

- dos e 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 ( 1⁄2T el 

### ) of radioactivity from plasma were similar regard less of sex, dose level and 14 

### C

- 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 an d 14 

### C

- 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 ) , th is plasma kinetic study in the rat is classified Acceptable / Guideline

. T he 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:AP f 

### SD rats were dosed orally by gavage using [ 14 

### C] 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 gav age with [ 14 

### C

- pridinyl]

- or [ 14 

### C

- 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 [ 14 

### C

- phenyl] ZA1963 at a nominal rate of 10 or 100 mg/kg

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 79 of 89 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 un labeled ZA1963 ( 10 mg/kg b w) followed by a single 10 mg/kg labeled dose of [ 14 

### C

- 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.

A dditional studies were apparently performed including a bile duct

- cannul ation 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 ( [ 14 

### C

- pyridinyl] &
[ 14 

### C

- 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 combi ned 14 

### C

- labels ( [ 14 

### C

- pyridinyl] & [ 14 

### C

- 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

radioa ctivity were associated with the gastrointestinal (G.I.) tract, liver and kidneys at 24 hours post

dose.

Based upon the amount of radioactivity recovered in the bile and urine of rats treated with 100 mg
[ 14 

### C

- 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 re peated 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

an d in the residual carcass were generally less than in whole blood. The distribution and

concentration of 14 

### C

- residues in tissues were generally similar between the sexes within each group and between the single and repeated low

- dose groups. The distribut ion of 14 

### C

- resdiues in tissues was also similar between the single low and high dose groups, but the concentration of 14 

### C

- residues in tissues were generally 9 to 22

- fold higher in the high dose, which generally reflected the 10

- fold

increase in the dose le vel.

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
, account ing 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 wi th 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 14 

### C

- residues accounted for 61.9

-

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 80 of 89 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% A D. 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

th e 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 e ster 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 .2 0 in vitro Dermal Penetration (O PPTS 870.7600) MRID 48073760 (1999)

In an in vitro dermal penetration stud y (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 q uantified 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 radioa ctivity 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 intera ction 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 un der 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) an d 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. The re is no OPPTS guideline, but the studies were done according

to OECD 428.

F .2 1 in vivo Dermal Penetration in Rats (OPPTS 870.7600) MRID 48073761 (1999)

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 81 of 89 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 blan k and

administered to 4 male AlpkAP f 

### SD (Wistar

- derived) rats/dose/time at dose levels of 1219 μ g/ cm 2



### and 6.17 μ g/ cm 2 

### . 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 CO 2 

### 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 high est 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 f or 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 .2 2 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, t here 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 througho ut 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

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 82 of 89 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 immunoto xicity 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 4807376 3 ) Picoxystrobin (99.3% a.i., batch/lot SEP07AS013)

was administered to CR l :CD 1 ( ICR ) mice (10 /sex/dose ) in diet at dose levels of 0, 10 0, 6 00, 24 00 or

48 00 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, t here 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 NOAE L 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

.

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 83 of 89 Appendix G

. Picoxystrobin Dietary Burden Calculation for Risk Assessmen t

Tab le G .1. Calculation of Dietary Burdens of Picoxystrobin to Livestock for Risk Assessment.

Feedstuff Type 1 % Dry

Matter 2 % Diet 2 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 blend ed 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.

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 84 of 89 Expected secondary residues in meat and milk

To deter mine 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 do se 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 G 2. The transfer coefficient for each matrix was then used to calculate the expected secon dary 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 G 3.

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 G 2

.



### 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 o bserved 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 G 4. The transfer coefficient for each matrix was then used to

calculate the ex pected 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 G 5.

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 85 of 89 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 t ransfer coefficient from T able G 4.

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 86 of 89 Appendix H. Human Equivalent Concentration and Dose Calc u l ations

Appendix H /Table 1: HEC Array for Occupational Risk Assessment §

Relevant Study LOAEL (mg/m 3 ) NOAEL

(mg/m 3 ) Da Dh Wa Wh RDDR HEC (mg/m 3 ) inter intra UF

Short

- & Intermediate

- Term Exposure

Inhalation

– Rat ( MRID 48 697401 )

28

- day E R 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/m 3 ) NOAEL

(mg/m 3 ) Da Dh Wa Wh RDDR HEC (mg/m 3 ) inter intra UF

Short

- & Intermediate

- Term Exposure

Inhalation

– Rat ( MRID 48 697401 )

28

- day E R 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)

W h : 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).

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 87 of 89 D Duration: Duration of daily animal or human exposure (hours).

AF Activity Factor: Animal default is 1.

When conducting inhalation risk asses sments, 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) d ifferences , 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 1 

### . Thus, the UF when using the RfC methodology is customarily 30X.

Based on proposed pico xystrobin Labels, HED believes exposures can be short

- (1

- 30 days) or

intermediate

- (1 to 6 months) term in duration. Long

- term exposures are n ot anticipated for picoxystrobin based on proposed labeled uses. Acute exposures are not expected but were

calc ulated.

For the acute, short

- and intermediate

- term scenario s, 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 d ue to:

1. Different algorithms are used to derive HECs for systemic versus port al

- of

- entry effects. Typically, HECs are calculated separately for systemic versus port al

- of

- entry
effect.

2. 

## Ti me adjustments are traditionally needed for non

- occupational (bystan der) 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 day s/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. port al of entry) a nd 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 inh aled compound as well as the type of toxicity observed ( e.g. systemic vs. port al 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.

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 88 of 89 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 assumpti ons 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:

POD study 

### : Point of departure iden tified in the critical toxicology study

D animal exposure 

### : Duration of animal exposure (hrs/day; days/wk)

D anticipated 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

aer odynamic diameter [MMAD]) and the geometric standard deviation (σ g 

### ), 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 i nhalation particulate exposure concentration for a human (H) that would be associated with the same dose delivered to the rth region or target tissue.

RDDR

r 

### = (RDD

r



### /Normalizing Factor) A 

### (RDD

r 

### /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 σ g 

### defined from an aerosol inhalation

stud y. 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) f or bifenazate

MMAD = 2

. 12 Sigma g = 2. 79

Body Minute

SPECIES Weight (g) Ventilation (VE, ml)

----------------------------------------------------------------------------- rat 187 1 41

. 7

human 70000 13800.0

-----------------------------------------------------------------------------

deposited fraction

### Picoxystrobin Human Health Risk Assessment DP No. 377690

Page 89 of 89 -------------------------------------------------------------------------------- rat 0. 491

human 0. 669

-------------------------------------------------------------------------------- RATIO 0.7 34

RDDR = (VE/ SA ) animal 

### /(VE/ SA ) human 

### * deposited fraction animal 

### /deposited fraction human



### = ( 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 ri sk. 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 retain ed at 10X. Thus, the UF when using the RfC methodology is customarily 30X.