Fenpyrazamine Human Health Risk Assessment DP No

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Page 2 of 56 Table of Contents

1.0 Executive Summary

................................................................................. 4
2.0 HED Recommendations

................................ ................................ ................................ .... 6
2.1 Data Deficiencies

................................ ................................ ................................ ............ 6
2.2 Tolerance Considerations

................................ ................................ .............................. 6
2.2. 1 Enforcement Analytical Method

................................ ................................ ............... 6
2.2.2 Recommended Tolerances

................................ ................................ ......................... 7
2.2.3 Revisions to Petitioned

- For Tolerances

................................ ................................ .... 8
2.2.4 International Harmonization

................................ ................................ ..................... 8
2.3 Label Recommendations

................................ ................................ ................................ 8
3.0 Introduction

................................ ................................ ................................ ........................ 9
3.1 Chemical Ide ntity

................................ ................................ ................................ ........... 9
3.2 Physical/Chemical Characteristics

................................ ................................ ............... 9
3.3 Pesticide Use Pattern

................................ ................................ ................................ ...... 9
3.4 Anti cipated Exposure Pathways

................................ ................................ ................. 12
3.5 Consideration of Environmental Justice

................................ ................................ .... 12
4.0 Hazard Characterization and Dose

- Response Assessment

................................ .......... 13
4.1 Toxicology Studies Available for Analysis

................................ ................................ . 13
4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

............................. 14
4.2.1 Dermal Absorption

................................ ................................ ................................ ... 14
4.3 Toxicological Effects

................................ ................................ ................................ .... 14
4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

............................... 16
4.4.1 Completeness of the Toxicology Database

................................ .............................. 16
4.4.2 Evidence of Neurotoxicity

................................ ................................ ........................ 16
4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

........ 16
4.4.4 Residual Uncertainty in the Exposure Databas e

................................ ................... 16
4.5 Toxicity Endpoint and Point of Departure Selections

................................ .............. 17
4.5.1 Dose

- Response Assessment

................................ ................................ ...................... 17
4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

..... 19
4.5.3 Cancer Classification and Risk Assessment Recommendation

............................ 19
4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk
Assessment

................................ ................................ ................................ ............................... 19
5.1 Metabolite/Degradate Residue Profile

................................ ................................ ....... 21
5.1.1 Summary of Plant and Animal Metabolism Studies

................................ ............. 21
5.1.2 Summary of Environmental Degradation

................................ .............................. 22
5.1.3 Comparison of Metabolic Pathways

................................ ................................ ....... 2 2
5.1.4 Residues of Concern Summary and Rationale

................................ ...................... 22
5.2 Food Residue Profile

................................ ................................ ................................ .... 23
5.3 Water Residue Profile

................................ ................................ ................................ .. 24
5.4 Dietary Risk Assessment

................................ ................................ .............................. 25
5.4.1 Description of Residue Data Used in Dietary Assessment

................................ .... 25
5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ .............. 25
5.4.3 Acute Dietary Risk Assessment

................................ ................................ ............... 25
5.4.4 Chronic Dietary Risk Assessment

................................ ................................ ........... 25
5.4.5 Cancer Dietary Risk Assessment

................................ ................................ ............. 25Fenpyrazamine Human Health Risk Assessment DP No

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Page 3 of 56 5.4.6 Summary Table

................................ ................................ ................................ ......... 26
6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

............................. 26
6.1 Residential Bystander Post

- application Inhalation Exposure

................................ . 26
6.2 Spray Drift

................................ ................................ ................................ .................... 26
7.0 Aggregate Exposure/Risk Characterization

................................ ................................ .. 27
8.0 Cumulative Exposure/Risk Characterization

................................ ............................... 27
9.0 Occupational Exposure/Risk Characterization

................................ ............................ 28
9.1 Short

- /Intermediate

- Term Handler Risk

................................ ................................ ... 28
9.2 Short

- /Intermediate

- /Long

- Term/Cancer (if needed) Post

- Application Risk

........ 32
9.2.1 Dermal Post

- application Risk

................................ ................................ .................. 32
9.2.2 Inhalation Post

- application Risk

................................ ................................ ............. 32
10.0 References

................................ ................................ ................................ ......................... 33 Appendix A. Toxicology Profile and Executive Summaries

................................ .................. 35
A.1 Toxicology Data Requirements

................................ ................................ ................... 35
A.2 Toxicity Profiles

................................ ................................ ................................ ............ 36
A.3 Hazard Identification and Endpoint Selection

................................ .......................... 41
A.4 Summaries (obtained from Austria Monograph on Fenpyrazamine)

.................... 43 Appendix B. Metabolism Summary

................................ ................................ .......................... 51 B.1. Summary of the total radioactive residues of fenpyrazamine, metabolites and degradates.

................................ ................................ ................................ ................................ ... 51 B.2. Nomenclature of fenpyrazamine, the metabolites and degradates.

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

................................ ................................ ............. 55 Appendix D. Review of Human Research

................................ ................................ ................ 56Fenpyrazamine Human Health Risk Assessment DP No

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Page 4 of 56 1.0 Executive Summary

Fenpyrazamine is a new pyrazole fu ngicide used to control grey mo ld diseases caused by Botrytis cinerea

. It shows its fungicidal activity through inhibition of germ tube elongation and mycelium elongation. The petitioners, Valent U.S.A. Corporation and IR

- 4, are proposing registration and /or establishment of permanent tolerances of fenpyrazamine on almond, sm all fruit climbing subgroup 13

- 07F, head and leaf lettuce, low growing berry subgroup 13

- 07G, bushberry subgroup 13

- 07B, caneber ry subgroup 13

- 07A, ginseng, pistachio and ornamentals

. Foliar, aerial and chemigation applications of the aqueous

- based suspen sion concentrate, V

10135 4SC Fungicide, are proposed on these crops. The European Food Safety Authority (EFSA) recommended registration of fenpyrazamine in Europe for treatment of grapes and vegetables.

The toxicological database for fenpyrazamine is complete. The principal toxicological findings for repeated dose studies in rodents, rabbits, and dogs were reduced bodyweights/ bodyweight weight gains. In addition, thyroid follicular cell hypertrophy was observed in rats in the subchronic, chronic/carcinogenicity and reproduction toxicity (parental animals only) studies. The increased liver weights, hepatocellular hypertrophy, and alterations in hematology and clinical chemistry parameters observed in se veral studies, were not considered to be toxicologically relevant since the magnitude of the changes was within normal variability. The liver alterations were therefore considered adaptive rather than adverse effects.

In both the rat and rabbit developme ntal studies, maternal effects ( ↓ body weight) occurred at doses lower than or equal to those eliciting developmental effects (↓ fetal weight, skeletal variations in rats and late abortions and premature deliveries in rabbits). In the multi

generation reproduction toxicity study, thyroid toxicity was observed in parental animals at same doses eliciting decreased body weights in the offspring. Reproductive effects manifested as decreases in implantations and increases in post

- implantation loss occurred at a dose level ≈4x higher than the parental and offspring LOAELs.

The only potential sign of neurotoxicity was a decrease in total distance time and total number of rearings observed in the acute neurotoxicity study in rats. However, given that the live r is the target tissue, these effects may be nonspecific effects secondary to general toxicity. These effects were not observed in the subchronic neurotoxicity study or any other studies in the database.

There are no mutagenicity concerns for fenpyrazam ine. Based on the lack evidence of carcinogenicity in mice and rats, fenpyrazamine is classified a "Not Likely to be Carcinogenic to
Humans".

The HASPOC (July 19, 2012 meeting) waived the need for a 28

- day inhalation toxicity study in rats
to support t he proposed uses of fenpyrazamine.

For the acute dietary risk assessment, an acute reference dose (aRfD) of 0.8 mg/kg/day was selected for assessment of all populations, based on a NOAEL of 80 mg/kg/day in the rat acute neurotoxicity study with decreases in motor activity on day 1 observed at 400 mg/kg/day. Since the FQPA 10X safety factor is being reduced to 1X, the acute population adjusted dose (aPAD)Fenpyrazamine Human Health Risk Assessment DP No

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Page 5 of 56 is equal to the aRfD. For the chronic dietary risk assessment, a chronic reference dose (cRfD) of
0. 3 mg/kg/day was selected for assessments of all populations, based on a NOAEL of 30 mg/kg/day from the developmental toxicity study in rabbits. The LOAEL of 50 mg/kg/day is based on decreased maternal body weight and food consumption

. Since the FQPA 10X safety
factor is b eing reduced to 1X, the c PAD is equal to the cRfD. Short

- and Intermediate

- Term Incidental Oral endpoints were not established since there are no residential uses being proposed which would raise the concern for hand to mouth exposure of children. A dermal hazard was not identified for fenpyrazamine in the dermal toxicity study. The short

- and intermediate

- term inhalation endpoints were derived from the developmental rabbit study in which the maternal LOAEL was 50 mg/kg/day based on de creased body weight and food consumption (NOAEL = 30 mg/kg/day).

The risk assessments conducted for fenpyrazamine were based on the most sensitive endpoints in the toxicity database, and the NOAELs selected for risk assessment are considered protective of potential developmental, neurotoxic, and immunotoxic effects for infants and children.

The residue chemistry database is considered complete for fenpyrazamine. The nature and magnitude of the residue in primary crops have been adequately delineated. The residue of concern for tolerance enforcement is parent fenpyrazamine only and tolerances were recommended accordingly. For dietary assessment purposes, parent fenpyrazamine and the
metabolite S

- 2188

- DC are the residues of concern . The metabolite S

- 21 88

- DC is assumed to have similar toxicity to the parent . The nature of residues in rotational crops and ruminants has also been adequately delineated; however, there is no reasonable expectation of quantifiable residues in these matrices under the propose d use pattern. Adequate method validation data and processing studies have been submitted.

Fenpyrazamine is a moderately mobile chemical that is expected to reach water resources through runoff, infiltration and/or erosion. As this is a new chemical, there is no drinking water monitoring data available; however, a conservative estimate of the concentrations in drinking water was obtained using models.

Unrefined acute and chronic dietary (food and water) assessments using tolerance level residues
of parent fenpyrazamine plus maximum residues of S

- 2188

- DC, assuming 100% crop treated and incorporating Tier I modeled water exposure estimates demonstrated that estimated risks were ≤ 9.2% of the aPAD at the 95 th percentile exposure and ≤ 7.3 % of the cPAD f or the general U.S. population and all modeled populations.

There are no exposures expected for fenpyrazamine via non

- occupational pesticide use; therefore, the aggregate risk estimate for this chemical is equivalent to the dietary risk estimate.

Occupational handler inhalation margins of exposure (MOEs) are not of concern (MOEs are greater than the level of concern of 100) for all scenarios associated with the proposed uses. The
label

- required PPE on the proposed label is that all handlers must w ear long

- sleeved shirt and long pants, chemical

- resistant gloves, and socks and shoes. No additional personal protective equipment (PPE) is required. The proposed restricted

- entry interval (REI) for fenpyrazamine is 12 hours; based on the acute toxicity of the chemical, this REI meets the Worker ProtectionFenpyrazamine Human Health Risk Assessment DP No

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Page 6 of 56 Standard (WPS) requirement. No quantification of dermal post

- application risk is required as no
dermal hazard was identified. Based on the Agency's current practices, a quantitative non

- cancer post

- application inhalation exposure assessment is not needed for fenpyrazamine at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quan titative
post

- application inhalation exposure assessment for fenpyrazamine.

The occupational risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; and the Outdoor Residential Exposure Task Force (ORETF) database, are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. Refer to Appendix D for additional information.

Potential areas of environmental justice concerns, to the extent possible, were considered in this
human health risk assessment; refer to Section 3.5 for detailed discussion.

2.0 HED Recommendations

D 406080

, I. Negrón, 10/31/2012

Provided that the data deficiencies mentioned in Section 2.1 are fulfilled there are no deficiencies in the residue chemistry, toxicity and occupational exposure database that would preclude granting the requested Section 3 registration for fenpyrazamine for all.

2.1 Data Deficiencies

860.1340 Residue Analytical Method

• Confirmation that the laboratory personnel performing th e Independent Laboratory Validation had no previous knowledge/experience with the method.

860.1550 Proposed Tolerances

• The registrant needs to submit a revised Section 7 in which the recommended tolerances
listed in Table 2.2.2 are proposed.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Multiresidue Method (MRM)

- The FDA MRM was reported by the registrant as unsuitable for analysis of fenpyrazamine based on low recoveries.Fenpyrazamine Human Health Risk Assessment DP No

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Page 7 of 56 Enforcement Method

- Parent fenpyrazamine only is the residu e of concern for tolerance enforcement purposes. Valent U.S.A. Corporation has submitted the results of an independent laboratory validation (ILV) by LC/MS/MS, Method RM

- 45C

- 1, titled “Determination of S

- 2188
and S

- 2188

- DC in crops”. The method is consid ered adequate for enforcement of tolerances in plant commodities. However, the Health Effects Division ( HED ) requires confirmation that the laboratory personnel conducting the ILV had no previous knowl edge/experience with the
method

.

Briefly, homogenize d samples, stabilized with 1 M sodium ascorbate solution, are extracted (2x) with acetone:water (4:1, v:v) and filtered; the extracts are combined. Prior to further clean

- up, the filtered extracts are evaporated to remove acetone. For samples with matrix interference (e.g., grapes and lettuce), the filtered extracts are partitioned with dichloromethane (DCM), combined with water and then the DCM is evaporated. The aqueous extracts following either procedure are cleaned

- up using an Oasis HLB cartridge. Residues are eluted with acetonitrile:water (1:1, v:v). The eluted sample is analyzed by Liquid Chromatography / Tandem Mass Spectrometry ( LC/MS/MS ) and two ion transitions of fenpyrazamine are monitored (331.8 m/z → 229.9 m/z and 331.8 m/z → 188.9 m/z) ; therefore, no confirmatory method is required. The validated limit of quantitation (LOQ) is 0.02 ppm and the estimated limit of detection (LOD) is 0.01 ppm, in t he crop matrices.

2.2. 2 Recommended Tolerances

HED recommends that 40 CFR be amended by establishing tolerances for fenpyrazamine in/on the plant commod ities listed in Table 2.2.2 . Tolerances for livestock commodities and rotational crops are not neede d to support the proposed uses of fenpyrazamine. The tolerances for plant
commodities should be defined as follows:

Tolerances are established for residues of the fungicide fenpyrazamine, including its metabolites and degradates, in or on the commoditi es in the table below. Compliance with the tolerance levels for fenpyrazamine is to be determined by measuring only fenpyrazamine (S

- 2

- propen

- 1

- yl

5

- amino

- 2,3

- dihydro

- 2

- (1

- methylethyl)

- 4

- (2

- methylphenyl)

- 3

- oxo

- 1H

- pyrazole

- 1

- carbothioate).

Table 2.2.2. Tolerance Summary for Fenpyrazamine 1

Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments (correct commodity

definition)

Almond 0.02 0.02 Almond, hulls 1.5 1.5

Pistachio 0.02 0.02
Lettuce, head 2.5 1.5
Lettuce, leaf 2.5 2 Caneberry subgroup 13

- 07A 7.0 5 Bushberry subgroup 13

- 07B 7.0 5 Small fruit vine climbing subgroup, except fuzzy kiwi fruit, crop subgroup 13

- 07F 3.5 3

Grape, Juice 7.0 4 Grape, Raisins 4.5 None Adequately covered under the tolerance of Subgroup 13

- 07F.Fenpyrazamine Human Health Risk Assessment DP No

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Page 8 of 56 Table 2.2.2. Tolerance Summary for Fenpyrazamine 1

Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments (correct commodity

definition)
Low growing berry subgroup 13

- 07G 3.0 3

Ginseng 0.80 0.7

1 The tolerances recommended by HED were established for parent fenpyrazamine only while those proposed by the registrant were based on residues of parent fenpyrazamine and the metabolite S

- 2188

- DC expressed as fenpyrazamine.

2.2. 3 Revisions to Petitioned

- For Tolerances

The Agency is recommending that tolerances be set for the commodities requested by the registrant at the levels established in Table 2.2.2. The tolerances recommended by HED are based on parent fenpyrazamine only (the residue of concern f or tolerance enforcement) while those proposed by the registrant were based on residues of parent fenpyrazamine and the
metabolite S

- 2188

- DC expressed as fenpyrazamine. In addition, HED used the Organization for the Economical Cooperation and Development (OECD) calculation procedures to establish the tolerances recommended. The registrant should submit a revised Section 7 in which the proposed tolerances are the same as those recommended by HED.

2.2.4 International Harmonization

Fenpyrazamine Maximum Residue Limits ( MRLs ) have not been established by Codex, Canada, or Mexico for the commodities proposed for registration in the US.

2.3 Label Recommendations

The labels are considered adequate to support the registration of V

- 10135 4SC Fungicide pending the modification described below

.

The label instructions for use on ornamentals specify a maximum application rate per growing cycle of 48 oz/A. Based on the maximum single application rate (16 oz/100 gal) and number of applications per growing cycle (3), the maximum application rate per growing cycle would be 48 oz/100 gal. For consistency HED recommends to specify a maximum application rate per growing cycle of 48 oz/100 gal in the label.Fenpyrazamine Human Health Risk Assessment DP No

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Page 9 of 56 3.0 In troduction

3.1 Chemical Identity

TABL E 3

. 1 Test Compound Nomenclature. 1
Compound Chemical Structure

Empirical Formula C 17 H 21 N 3 O 2 S

Common name Fenpyrazamine Company experimental name S

- 2188

IUPAC name S

- allyl

- 5

- amino

- 2,3

- dihydro

- 2

- isopropyl

- 3

- oxo

- 4( o

- tolyl)pyrazole

- 1

- carbothioate

CAS name S

- 2

- propenyl

- 1 yl

- 5

- amino

- 2,3

- dihydro

- 2

- (1

- methylethyl)

- 4

- (2

- methylphenyl)

- 3

-

oxo

- 1 H

- pyrazole

- 1

- carbothioate

CAS # 473798

- 59

- 3

End

- use product/(EP) V

- 10135 4SC Fungicide

Chemical Class Pyrazole

1 Shyam Mathur, D388255, 4/27/2012

3.2 Physical/Chemical Characteristics

The physical and chemical properties, as well as a summary of relevant environmental fate parameters are detailed in Appendix C1.

Fenpyrazamine has a very low vapor pressure of 2.17x10 - 10 mmHg at 25 oC; therefore, is not a volatile pesticide. The octanol water partition coefficient (Kow = 3300) suggests that it is slightly lipophilic

. Fenpyrazamine is soluble in water (20.4 mg/L at 20 °C) and does not
dissociate under environmental relevant c onditions. Based on the environmental fate properties of fenpyrazamine it may bind moderately to soil particles and may reach surface water bodies or ground water drinking water sources via runoff water, erosion and/or leaching. Upon reaching
water bodie s, aqueous photolysis (half life of 1.64 days) is expected to be the main degradation mechanism for fenpyrazamine in reservoir surface waters followed by degradation in aerobic alkaline environments (half life of 18.92 days).

3.3 Pesticide Use Pattern

The proposed use pattern for V

- 10135 4SC Fungicide on the various crops for which registration is sought are summarized in Table 3.3. In general, the end use product is a suspension concentrate to be applied as a foliar spray up to 3

- 4 times per season w ith maximum seasonal rates from 1.1 to 2 lb ai/A followed by harvest from 0 to 21 days after the last application. Crops may be rotated 365 days after the last application.Fenpyrazamine Human Health Risk Assessment DP No

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Page 10 of 56 Table 3.3 Summary of Directions for Use of V

- 10135 4SC Fungicide.

Applic. Timing , Type, and Equip. Formulation Applic. Rate (lb ai/A) Max. No.

Applic. per
Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and Limitations

Almond

Aerial, Chemigation,
Ground

Foliar Spray V

- 10135 4

SC Fungicide Suspension
Concentrate 4 lb ai/gal 8

- 12 fl

oz (0.25

- 0.375 lb ai/A) 2 Sequential Applications,
3 Applications per Season 36 fl oz

(1.125 lb ai/A) 21 For Aerial Application: use a

minimum of 20 gal of water / acre. For Ground Application: use a minimum of 100 gal of wa ter/acre.
Immediate Rotational Interval
For Brown Rot and Blossom Blight: Begin applications at pink bud (approx. 5% of bloom). If
conditions are favorable for disease development, make additional applications at full bloom and at petal fall. For Green F ruit
Rot/Jacket Rot: Begin applications prior to disease development. Generally, a single application at
full bloom is most effective.
Small Fruit Vine Climbing Subgroup, Except Fuzzy Kiwifruit, 13

- 07F (Representative Crop: Grape)

Aerial, Chemigation,
Ground

Foliar Spray V

- 10135 4

SC Fungicide Suspension
Concentrate 4 lb ai/gal 12

- 16 fl

oz (0.375

- 0.5 lb ai/A) 2 Sequential Applications,
3 Applications per Season 48 fl oz (1.5

lb ai/A) 3 For Aerial Application: use a

minimum of 20 gal of water / acre.

Fo r Ground Application: use a minimum of 100 gal of water/acre.
Immediate Rotational Interval For Botrytis Bunch Rot : First application at early bloom. Second application at pre

- bunch closure. Third application at veraison. Up to 3 days prior to harvest.

Head and Leaf Lettuce

Aerial, Chemigation,
Ground

Foliar Spray V

- 10135 4

SC Fungicide Suspension
Concentrate 4 lb ai/gal 12

- 16 fl

oz (0.375

- 0.5 lb ai/A) 2 Sequential Applications,
3 Applications per Season 48 fl oz (1.5

lb ai/A) 14 For Aerial Application: use a

minimum of 5 gal of water / acre. For Ground Application: use a minimum of 20 gal of water / acre.
Immediate Rotational Interval For Lettuce Drop and Gray Mold : Apply from planting to just after thinning and again 10 days later. If

con ditions still favor disease development, a third application
should be made 7

- 10 days after the

second spray.

Lo w Growing Berry Subgroup 13

- 07G (Representative Crop: Strawberry)

Aerial, Chemigation,
Ground

Foliar Spray V

- 10135 4

SC Fungicide Suspension
Concentrate 4 lb ai/gal 12

- 16 fl

oz (0.375

- 0.5 lb ai/A) 2 Sequential Applications,

4 Applications per Season 64 fl oz (2 lb

ai/A) 0 For Aerial Application: use a

minimum of 5 gal of water / acre. For Ground Application: use a minimum of 20 gal of water / a cre. Immediate Rotational Interval For Gray Mold : First application at early bloom and continue on a 7 toFenpyrazamine Human Health Risk Assessment DP No

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Page 11 of 56 Table 3.3 Summary of Directions for Use of V

- 10135 4SC Fungicide.

Applic. Timing , Type, and Equip. Formulation Applic. Rate (lb ai/A) Max. No.

Applic. per
Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and Limitations

14 day interval until last harvest.

Ornamentals (Greenhouse and Nursery)

Aerial, Ground, Chemigation,
Handheld V

- 10135 4

SC Fungicide Suspension
Concentrate 4 lb ai/gal 12

- 16 fl

oz/100 gal (0.375

- 0.5 lb
ai/100 gal) 2 Sequential Applications,
3 Applications per Growing Cycle 48 oz/A per

growing cycle N/A For chemigation to ornamental sites

apply this product only through microirrigation, overhead irrigation or motorized calibrated irrigation

equipment. For Botrytis Blight and Gray Mold : Apply before disease development. Reapply after 7 to 14 days. 100 gal of spray solution will treat approximately 20,000 sq ft of area. Apply the spray solution t o all plant surfaces and to the point of run

- off.
Bushberry Subgroup 13

- 07B (Representative Crop: Blueberries)

Aerial, Chemigation,
Ground

Foliar Spray V

- 10135 4

SC Fungicide Suspension
Concentrate 4 lb ai/gal 12

- 16 fl

oz (0.375

- 0.5 lb ai/A) 2 Sequential Applications,
3 Applications per Season 48 fl oz (1.5

lb ai/A) 0 For Aerial Application: use a

minimum of 5 gal of water / acre. For Ground Application: use a minimum of 20 gal of water / acre.
Immediate Rotational Interval For Gray Mold and Mum my Berry : Apply when conditions favor disease development and prior to infection. Continue applications on

a 7 to 14

- day interval.
Caneberry Subgroup 13

- 07A (Representative Crops: Blackberries and Raspberries)

Aerial, Chemigation,
Ground

Foliar Spray V

- 10135 4

SC Fungicide Suspension
Concentrate 4 lb ai/gal 12

- 16 fl

oz (0.375

- 0.5 lb ai/A) 2 Sequential Applications,
3 Applications per Season 48 fl oz (1.5

lb ai/A) 0 For Aerial Application: use a

minimum of 5 gal of water / acre. For Ground Application: use a minimum of 20 gal of water / acre.
Immediate Rotational Interval For Gray Mold : First application at early bloom and continue on a 7 to 14 day interval until last harvest.

Ginseng

Ground, Chemigation

Foliar Spray V

- 10135 4

SC Fungicide Suspension
Concentrate 4 lb ai/gal 12

- 16 fl

oz (0.375

- 0.5 lb ai/A) 2 Sequential Applications,

4 Applications per Season 64 fl oz (2 lb

ai/A) 2 For Ground Application: use a

minimum of 50 gal of water / acre.
Immediate Rotational Interval For Gray Mold Blight : Begin applications when conditions favor disease development (cool, wet weather and high humidity). Repeat

at 7

- to 14

- day intervals if favorable conditions persist.

Pistachio
Aerial, Chemigation, V

- 10135 4

SC Fungicide 12 fl oz

(0.375 lb 2 Sequential

Applications, 36 fl oz

(1.125 lb 21 For Aerial Application: use a

minimum of 20 gal of water / acre.Fenpyrazamine Human Health Risk Assessment DP No

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Page 12 of 56 Table 3.3 Summary of Directions for Use of V

- 10135 4SC Fungicide.

Applic. Timing , Type, and Equip. Formulation Applic. Rate (lb ai/A) Max. No.

Applic. per
Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and Limitations

Ground

Foliar Spray Suspension

Concentrate 4 lb ai/gal ai/A) 3 Applications per Season ai/A) For Ground Application: use a minimum of 100 gal of water/acr e. Immediate Rotational Interval For Blossom, Shoot and Fruit Blight : Begin applications at 5 to
10% bloom. If conditions are favorable for disease development, make additional applications at full bloom then every 7 to 10 days or
when conditions favor di sease development.

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new use of fenpyrazamine on almond, small fruit climbing subgroup 13

- 07F, head and leaf lettuce, low growing berry subgroup 13

- 07G, bushberry subgroup 13

- 07B , caneberry subgroup 13

- 07A, ginseng, p istachio and ornamentals . Humans may be exposed to residues of fenpyrazamine in food and drinking water, since fenpyrazamine may be applied directly to growing crops

, and application may result in residues reaching s urface and ground water sources of drinking water. There are no residential uses of fenpyrazamine, so there is not likely to be exposure in residential or non

- occupational settings. In an occupational setting, applicators may be exposed while handling th e pesticide prior to application, as well as during application. There is a potential for post

- application exposure for workers re

- entering treated fields.

These are the first registrations proposed for fenpyrazamine; therefore, this is the first risk assessment prepared by the Agency to address potential risks associated with the use of this new fungicide. This risk assessment considers all of the aforementioned exposure pathways (dietary and occupational) based on the proposed new uses of fenpyrazami ne.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions
to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part of every pesticide risk assessment, OPP co nsiders a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in A merica,Fenpyrazamine Human Health Risk Assessment DP No

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Page 13 of 56 (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, and ethnic group. Additionally, OPP is able to assess dietary exposure to sm aller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risk
estimates for adult applicators and for t oddlers, youths, and adults entering or playing on treated

areas post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and tradition al dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicological database for fenpyrazamine is complete and adequate for FQPA evaluation,
selection of PODs for the various routes of exposure, and for dose

- response evaluation. The routes of administration for the toxicity studies are consistent with the potential exposure scenarios. Appendix A provides a summary of the fenpyrazamine toxicological datab ase which includes the
studies listed below

.

Acute lethality studies (oral, dermal, inhalation, primary eye and dermal irritation, and dermal sensitization) Subchronic oral toxicity studies (rat, mouse, and dog) Developmental (rat and rabbit) and repro ductive toxicity (rat) studies Dermal toxicity (21

- day dermal toxicity in rat) Neurotoxicity (acute and subchronic) and immunotoxicity studies (rat and mouse) Chronic oral toxicity studies (dog) Carcinogenicity studies [rat (chronic combined) and mouse]

Me tabolism studies (rat) Mutagenicity battery (parent) Immunotoxicity Study (28

- day oral in rat)

The Hazard and Science Policy Committee (July 19, 2012 meeting) waived the need for a 28

- day inhalation toxicity study in rats to support the proposed uses of fenpyrazamine. The weight of evidence approach considered all of the available hazard and exposure information for fenpyrazamine, including: (1) the physical/chemical properties, including its low volatility; (2) the low acute inhalation toxicity (Toxicity Category IV); (3) the target organs appear to be the liver and thyroid not the nervous system , and the toxicity data indicate lack of progression of toxicity and that LOAELs identified in short

- term toxicity studies would be protective of effects
seen af ter prolonged ( e.g., chronic) exposures; and (4) b ased on an oral NOAEL of 30 kg/kg/day, occupational handler inhalation MOEs range from 3,400 for the proposed use in greenhouses to 1,000,000 for the proposed use in nurseries.Fenpyrazamine Human Health Risk Assessment DP No

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Page 14 of 56 4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

The available ADME data in rats indicate that orally

- administered radiolabeled fenpyrazamine
exhibits fast and extensive absor ption, extensive metabolism, and relatively fast body clearance.

The data collected in male and non

- pregnant female rats at two different dose levels (5 and 300 mg/kg bw) suggests a time to peak plasma levels (tmax) of 1 hr and a plasma elimination half

life (t 1/2 ) of 2

- 3 hours at the low dose. At the high dose tested, a prolonged tmax of 6 hours, a longer t 1/2 of 14

- 17 hours, and more than proportional increases in the area under the plasma
concentration

- time curve (AUC) with respect to administered dose suggest that saturation of body clearance could be reached at high dose levels.

Fenpyrazamine was rapidly and widely distributed in tissues. The highest levels of radioactivity were measured in the stomach, small intestines (including contents), liver, and kidney. The highest concentrations in most tissues coincided wi th tmax, having been measured at 1 and 6 hours for the low and high dose tested. Radioactivity increases in caecum and large intestine contents (being highest at 12 hours) were explained by elimination via fecal excretion.

Urine was the predominant route of elimination (> 80% for males and females) followed by fecal excretion. There were no significant dose

- or sex

- dependent differences in tissue distribution or route of elimination. A repeated oral dosing study did not reveal any differences in excretio n patterns as compared to single dose studies.

Based on characterization of metabolites, metabolism was mostly the result of dealkylation and hydroxylation. There was gender dependent difference s in metabolism depending on the dose
level administered. Me tabolism studies indicate that S

- 2188

- DC, a metabolite resulting from dealkylation, was the major metabolite in both sexes but was more pronounced in females. Another major metabolite observed in the rat meta bolism study was identified as S

- 2188

- CH2OH

- DC. An uncharacterized metabolite noted as “RT 31 min” was quantified only in male rats and only at the low dose tested. No attempt was made to characterize RT 31 particularly because the gender differences disappear at the higher dose, i.e., it was not dete cted in either sex. For both sexes and doses, the parent fenpyrazamine was minor in plasma at each time point.

4.2.1 Dermal Absorption

Since no hazard was identified via the dermal route, a dermal absorption factor ( DAF) is not
needed at this time.

4.3 Toxicological Effects

Fenpyrazamine (S

- 2188) is a pyrazole fungicide used to control grey mold diseases which are caused by Botrytis cinerea . Fenpyrazamine shows its fungicidal activity through inhibition of germ tube elongation and mycelium elongatio n. Mechanistic data indicate that it is an inducer of CYP2B in the liver of rats. Hepatic effects, consistent with induction of CYP2B, were observed in a number of rodent and dog studies. Although increased liver weights, hepatocellularFenpyrazamine Human Health Risk Assessment DP No

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Page 15 of 56 hypertrophy, an d alterations in hematology and clinical chemistry parameters were observed in several studies, they were not considered to be toxicologically relevant since the magnitude of the changes was within normal variability. Repeated exposures produced changes in the liver , some of these changes (at higher doses) are adverse while some (in particular at lower doses) are adaptive. With repeated dosing, consistent findings of mild to moderate increases in liver weights across multiple species (rats, mice, dogs) were observed. The increases in liver weights were accompanied by hepatocellular hypertrophy and increase in metabolic liver enzymes (cytochrome P450). Most of the liver effects seen in the subchronic toxicity studies consisted of increases in liver weigh ts and hepatocellular hypertrophy in the absence of biologically significant changes in clinical chemistry parameters ( e.g., alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase) and were considered adaptive. Based on the available

m echanistic data, the increase in liver weights and hepatocellular hypertrophy are related to an induction of liver metabolizing cytochrome P

- 450 CYP2B enzymes. The mechanistic data indicated that fenpyrazamine induces CYP2B activity and marginally enhance s hepatocellular proliferation. In addition, the hepatic effects are mediated through a constitutive androstane receptor (CAR).

The principal toxicological findings for repeated dose studies in rodents, rabbits, and do gs were reduced bodyweights/ bodywei ght gains. In addition, thyroid follicular cell hypertrophy was observed in rats in the subchronic, chronic/carcinogenicity and reproduction toxicity (parental animals only) studies. Fenpyrazamine technical has a low order of acute toxicity via the oral

, dermal and inhalation routes of exposure.

There was no evidence of increased susceptibility of the developing organism after in utero or post

- natal exposure to fenpyrazamine in the developmental toxicity studies (rats and rabbits) or
the multi

- generati on reproduction toxicity study. In both the rat and rabbit developmental studies, maternal effects ( ↓ body weight) occurred at doses lower than or equal to those eliciting developmental effects (↓ fetal weight, skeletal variations in rats and late aborti ons and premature
deliveries o n rabbits). Since the late abortions and premature deliveries occurred at doses higher than the maternal LOAEL, this finding is not considered to be indicative of susceptibility. In the
multi

- generation reproduction toxicit y study, thyroid toxicity was observed in parental animals at
the same dose eliciting decreased body weights in the offspring. Reproductive effects manifested as decreases in implantations and increases in post

- implantation loss occurred at a
dose level ≈ 4x higher than the parental and offspring LOAELs.

The only potential sign of neurotoxicity was a decrease in total distance time and total number of rearings observed in the acute neurotoxicity study in rats. However, given that the liver is the target tissue, these effects may be nonspecific effects secondary to general toxicity. These effects were not observed in the subchronic neurotoxicity or any other stu dies in the database.

In a 28

- day dermal toxicity study, no hazard was identified at the limit dose (1000 mg/kg/day). Similarly, an immunotoxicity study in rats did not indicate that the immune system is a target for fenpyrazamine toxicity.

Although an increase in the incidence of hepatocellular and thyroid follicular carcinomas was noted in the chronic/carcinogenicity study in rats, the concern for these findings is low based onFenpyrazamine Human Health Risk Assessment DP No

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Page 16 of 56 the following weight of evidence considerations: 1) the margina l increases occurred only at the high dose, 2) there was no reduction in the latency period (i.e., tumors were seen only at the terminal sacrifice)

, and 3) the incidences were only slightly outside the historical control range of the testing laboratories. In addition, no neoplastic lesions attributable to treatment were observed in the carcinogenicity study in mice and no indication of mutagenicity was noted in the mutagenicity battery. Based on the lack evidence of carcinogenicity in mice and rats, in accordance with the Agency's 2005 Guidelines for Cancer Risk Assessment, fenpyrazamine is classified a "Not Likely to be Carcinogenic to Humans".

The HASPOC (July 19, 2012 meeting) waived the need for a 28

- day inhalation toxicity study in rats
to suppor t the proposed uses of fenpyrazamine.

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

The fenpyrazamine risk assessment team evaluated the quality of the hazard and exposure data and determined that based on the hazard and exposure data , the FQPA SF should be reduced to 1X from 10X. This recommendation is based on the following:

4.4.1 Completeness of the Toxicology Database

The toxicology database for fenpyrazamine is complete and the Agency has concluded that the FQPA safety factor c an be reduced to 1x. The following acceptable studies are available for FQPA consideration: (1) Developmental toxicity studies in rats and rabbits; (2) Two

- generation reproduction study in rats; and (3) Acute and subchronic neurotoxicity studies.

4.4.2 Evidence of Neurotoxicity

The only potential sign of neurotoxicity was a d ecrease in total distance time and total number of rearings observed in the acute neurotoxicity study in rats. However, given that the liver is the target tissue, these effects may be nonspecific effects secondary to general toxicity. These effects were not observed in the subchronic neurotoxicity or any other studies in the database.

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

There is no evid ence of increased pre

- and/or postnatal susceptibility based on the results of the rat and rabbit prenatal developmental toxicity studies, and the rat 2

- generation reproductive toxicity study.

4.4.4 Residual Uncertainty in the Exposure Database

There i s no residual uncertainty in the exposure database for fenpyrazamine with respect to dietary (food and water) exposure. The dietary risk assessment was conducted using the the most sensitive endpoints for points of departure for aPAD and cPAD, tolerance l evel residues of parent fenpyrazamine plus the maximum residue of the metabolite S

- 2188

- DC, 100% of crop treated assumptions, empirical concentration factors and default processing factors. Further,Fenpyrazamine Human Health Risk Assessment DP No

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Page 17 of 56 highly conservative, modeled drinking water estimates of exposure were included in the assessments. This assessment is conservative and will not underestimate dietary exposure to fenpyrazamine. No residential uses of fenpyrazamine are proposed at this time; therefore, that exposure route is not germane to thi s action.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose

- Response Assessment

A detailed description of the toxicity studies used for selecting toxicity endpoints and points of departure for various exposure scenarios, as well as a d etailed rationale for selection of the toxicity endpoints are presented in Appendix A.

In general, the toxicity profile for fenpyrazamine demonstrates a pattern of generalized systemic toxicity primarily manifested as decreases in body weight. In additi on, thyroid follicular cell hypertrophy was observed in rats in the subchronic, chronic/carcinogenicity and reproduction toxicity (parental animals only) studies. Decreases in total distance time and total number of rearings were noted in an ACN study in the rat.

Consistent with the ADME profile that metabolism and clearance of fenpyrazamine is rapid, there is no progression of toxicity with duration of exposure. The severity of effects did not increase with time nor were the LOAELs for longer term stud ies lower than those for the subchronic length studies. For example, the NOAEL from the ACN rat study was comparable to
both the SCN and combined chronic

- oncogenicity studies in the rat. The same pattern of lack of progression of toxicity with duration wa s noted for the mouse and dog studies. Thus, the toxicity
data indicate that LOAELs identified in short

- term toxicity studies would be protective of effects seen after prolonged ( e.g., chronic) exposures. Consequently, the main considerations in the endpo int selection decisions are: (i) toxicological significance of the findings and (ii)
identification of a dose

- spread that is not too wide (> 2X dose spread), which would provide a clearer description of the dose response relationship.

The ACN is the onl y toxicity study in the database that identified a toxicologically relevant effect after a single exposure. Decreases in total distance time and total number of rearings were reported at 400 mg/kg/day (LOAEL) with a NOAEL of 80 mg/kg/day. This study, the refore, is the basis for the acute reference dose for the general population. An acute reference dose specific for females of reproductive age was not selected since no developmental effects that could be attributed to a single exposure were identified. The abortions seen in the developmental study in rabbits did not occur until gestation days 24

- 27

, suggesting the effect was not likely the result of a single exposure. Similarly, fetal weight decrements and skeletal variations seen in the rat development al study were not considered to be due to an acute exposure.

The maternal body weight decrements reported in the developmental toxicity study in rabbits serves as the basis for establishing the chronic reference dose. Although acceptable/guideline long

- term toxicity studies were available in several species (rats, mice, and dogs), the maternal NOAEL of 30 mg/kg/day identified in the developmental toxicity study would be protective ofFenpyrazamine Human Health Risk Assessment DP No

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Page 18 of 56 the effects seen in the chronic studies at doses ≥ 69 mg/kg/day. Furthermore, the dose selection in the developmental toxicity study in rabbits (NOAEL = 30 mg/kg/day, LOAEL = 50 mg/kg/day) provides a clearer description of the dose

- response relationship curve for fenpyrazamine compared to other studies because of the tighter dose spread. While the NOAEL and LOAEL in this study are 30 a nd 50 mg/kg/day, respectively (a dose

- spread of ≈1.5X), the dose selection in other studies results in dose spreads of 4

- 10X. Given that the NOAEL in the developmental toxicity study in rabbits is protective of the effects seen after long

- term exposure

a nd that the dose

- selection in this study provides the most accurate description of the dose

response curve for fenpyrazamine, an additional uncertainty factor for extrapolation from a short

- term study to a long

- term exposure scenario is not warranted.

Acu te Dietary Endpoint for All Populations: The endpoint used for establishing the aPAD for the general population was selected from the acute neurotoxicity study in rats. An aPAD of 0.8 mg/kg/day was derived from a NOAEL of 80 mg/kg/day and a 100

- fold fac tor that included a
10x

- UF for inter

- species extrapolations, 10x

- UF for intra

- species variations, and a 1x FQPA SF. The LOAEL of 400 mg/kg/day was based on decreases in total distance time and total number of rearings on day 1 which resolved by the next e valuation (day 7). The NOAEL of 80 mg/kg/day would be protective of the potential developmental effects observed in the developmental rat study (NOAEL = 125 mg/kg/day which is higher than 80 mg/kg/day). The developmental effects (abortions/premature deli veries) noted in the developmental rabbit study are not attributable to a single dose administration as these effects were observed later in the study.

Chronic Dietary Endpoint for the General Population: Th e endpoint used for deriving the cPAD

was se lected from the developmental toxicity study in rabbits. The cPAD of 0.3 mg/kg/day was derived from a NOAEL of 30 mg/kg/day and a 100

- fold factor that included a 10x

- UF for inter

species extrapolations, 10x

- UF for intra

- species variations, and a 1x FQPA SF. The LOAEL of
50 mg/kg/day is based on decreased maternal body weight and food consumption

. The developmental rabbit NOAEL of 30 mg/kg/day is supported by NOAELs identified in the 2

- generation reproduction study (NOAEL = 27.4 mg/kg/day; LOAEL =68.6 mg /kg/day), and the
90

- day dog (NOAEL = 25.0 mg/kg/day ; LOAEL =50.0 mg/kg/day ).

Short

- and Intermediate

- Term Incidental Oral: This endpoint was not established since there are no residential uses being proposed which would raise the concern for hand to mouth exposure of
children.

Short

- (1

- 30 days), Intermediate

- (1

- 6 months) and Long

- Term Dermal Endpoints: An acceptable/guid eline dermal toxicity study is available. No effects were observed at the limit dose (1000 mg/kg/day). Since there is no evidence of enhanced susceptibility of the young and all critical effects of concern were evaluated in the dermal study, a dermal haz ard was not identified and therefore no quantification of risk is required.

Short

- (1

- 30 days) and Intermediate

- (1

- 6 months) Term Inhalation Endpoints: The short

- and
intermediate

- term inhalation endpoints were derived from the developmental rabbit study in which the maternal LOAEL was 50 mg/kg/day based on decreased body weight and food consumption (NOAEL = 30 mg/kg/day). The developmental rabbit NOAEL of 30 mg/kg/day isFenpyrazamine Human Health Risk Assessment DP No

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Page 19 of 56 supported by NOAELs identified in the 2

- generation reproduction study (NOAEL = 27.4 mg/kg/day; LOAEL =68.6 mg/kg/day), and the 90

- day dog (NOAEL = 25.0; LOAEL =50.0).

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

As part of conducting a human health risk assessment, HED has considered the potential f or concurrent fenpyrazamine exposure via oral, dermal, and inhalation routes. When there are potential occupational and/or residential exposures to a pesticide, the risk assessment must address exposures from oral, dermal and inhalation routes and determin e whether the individual exposures may be combined across several exposure pathways. No residential uses are proposed at this time. With regards to occupational exposure, the only endpoint identified was for the inhalation route of exposure. Based on fen pyrazamine's current use pattern and toxicological profile, combining routes of exposure is not appropriate. Should different use patterns be proposed in the future, the need for an aggregate risk assessment may be reevaluated.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Based on the lack evidence of carcinogenicity in mice and rats, in accordance with the Agency's 2005 Guidelines for Cancer Risk Assessment, fenpyrazamine is classified a "Not Likely to be Carcinogenic to Humans".

4.5. 4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk
Assessment

Table 4.5.4.1 summarizes the toxicological doses and endpoints selected for the acute and chronic dietary risk assessments for fenpyrazamine. Table 4.5.4.2 summarizes the toxicological doses and endpoints selected for the short

- and intermediate

- term occupational inhalation exposure scenarios for fenpyrazamine.

Table 4.5.4.1 Summary of Proposed Toxicological Doses and Endpoints for Fenpyrazamine for Use in Dietary

an d Non

- Occupational Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD,

Level of
Concern for
Risk
Assessment Study and Toxicological Effects

Acute Dietary (General Population, including
Infants and
Children and
Females 13

- 49 years of

age ) NOAEL= 80

mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Acute RfD =

0.8 mg/kg/day

aPAD = 0.8 mg/kg/day Acute Neurotoxicity Screening

Battery

- Rats
LOAEL = based on a statistically significant decrease in total motor activity (total distance) in males at 400 and 2000 mg/kg/day on day 1. Number of rearings was statistically decreased in males at 400 and 2000 mg/kg/day, and in females at 2000 mg/kg/day on day 1.Fenpyrazamine Human Health Risk Assessment DP No

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Page 20 of 56 Table 4.5.4.1 Summary of Proposed Toxicological Doses and Endpoints for Fenpyrazamine for Use in Dietary

an d Non

- Occupational Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD,

Level of
Concern for
Risk
Assessment Study and Toxicological Effects

Chronic Dietary (All Populations) NOAEL = 30

mg/kg/day
UF = 100 UF A = 10x

UF H =10x FQPA SF= 1x Chronic RfD

= 0..3 mg/kg/day

cPAD = 0.3mg/kg/day Developmental Toxicity Study in

Rabbits Maternal LOAEL = 50 mg/kg/day [based on decreased body weight and
food consumption.

Incidental Oral, Short

term (1

- 30 days) and
Intermediate

Term (1

- 6 months) No residential uses of fenpyrazamine are proposed at this time.

Dermal Short

and
Intermediate

Term (1

- 30 days and 1

- 6 months) No residential uses of fenpyrazamine are proposed at this time.

Inhalation
Short

- and
Intermediate

Term (1

- 30 days, and 1

- 6 months) No residential uses of fenpyrazamine are proposed at this time.

Cancer (oral, dermal, inhalation) Based on the lack evidence of carcinogenicity in mice and rats, in accordance with the Agency's

2005 Guidelines for Cancer Risk Assessment, fenpyrazamine is classified a "Not Likely to be Carcinogenic to Humans".
Point of Departure (POD) = A data point o r 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 adver se effect level.
LOAEL = low est 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 human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. LOC = level of concern. N/A = not applicable.

T able 4.5.4.2 Summary of Toxicological Doses and Endpoints for Fenpyrazamine for Use in Occupational
Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk
Assessment Study and Toxicological Effects

Dermal Short

- ,Intermediate

- , and Long

Term (1

- 30 days and 1

- 6 months) No hazard was identified. No quantification required.Fenpyrazamine Human Health Risk Assessment DP No

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Page 21 of 56 T able 4.5.4.2 Summary of Toxicological Doses and Endpoints for Fenpyrazamine for Use in Occupational
Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk
Assessment Study and Toxicological Effects

Inhalation
Short

- and
Intermediate

Term (1

- 30 days, and 1

- 6 months) NOAEL =

30 mg/kg/day UF A = 10 x

UF H = 10x Occupational

LOC for MOE =
100 Developmental Toxicity Study

- Rabbit

LOAEL = 50 mg/kg/day based on decreased body weight and food consumption

Cancer (oral, dermal, inhalation) Based on the lack evidence of carcinogenicity in mice and rats, in accordance with the Agency's

2005 Guidelines for Cancer Risk Assessment, fenpyrazamine is classified a "Not Likely to be Carcinogenic to Humans".
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adver se effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapo lation 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). RfD = reference dose. LOC = level of concern. N/A = not applicable.

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

E. Holman, D403378, 08/31/2012 I. Negrón, D 406080

, 10/31/2012 G. Rothman; D388319; 09/07/ 2012

5.1.1 Summary of Plant and Animal Metabolism Studies

Adequate studies are available to establish the metabolism of fenpyrazamine in plants and
livestock. The metabolism of [phenyl

14 C]

- and [pyrazolyl

- 5

- 14 C]

- fenpyrazamine in plants was studied in grapevines (fruit crop), lettuce (leafy crop) and oilseed rape (pulses/oilseed). The metabolism of fenpyrazamine was similar with both radiolabels and is comparable in all crops investigated. More than 90.2% of the total radioactive residue (TRR) was extractable in all commodities excep t in rapeseed, where >31.2% of the TRR was associated with radioactive residues in protein, starch and lignin. T he majority of the radioactivity was identified as parent fenpyrazamine

. The metabolite S

- 2188

- DC is common to all crop metabolism studies an d was found in lettuce leaves and oilseed rape haulm at levels >10% TRR. In addition, the lettuce field trials show it at similar concentration as parent fenpyrazamine. The metabolite S

- 2188

- OH is common to all crop metabolism studies, but was not detect ed at levels above 10% TRR.

Uses of fenpyrazamine on strawberries and lettuce are proposed by the petitioner. Therefore,
studies of residues in succeeding crops (wheat, lettuce and carrot) were evaluated . Parent fenpyrazamine and the metabolites S

- 2188

- OH and S

- 2188

- (OH)2 were found in all crops. The only major residues found were parent fenpyrazamine in carrot tops and roots at 30 and 120 DAT, and S

- 2188

- (OH)2 in carrot tops at 120 DAT. A 365

- day plant

- back interval (PBI) is proposed by the registran t. Although the TRR is >0.01 ppm in some commodities planted 365

- days after treatment, all the residues of fenpyrazamine in mature commodities harvested fromFenpyrazamine Human Health Risk Assessment DP No

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Page 22 of 56 plants planted 365

- days after treatment were below the limit of detection (LOD; 0.01 ppm) of the proposed enforcement method.

Metabolism studies of fenpyrazamine in lactating goat are available to establish the residues of
concern in ruminants. The TRR levels were higher in goat liver and kidney and lower in other edible tissues and milk. The major metabolites found in goat commodities were (1) unchanged parent (S

- 2188) in the liver and fat , (2) S

- 2188

- DC in milk, muscle, liver, kidney and heart

, and (3) S

- 2188

- CH 2 OH

- DC in muscle, kidney and liver.

5.1.2 Summary of Environmental Degradation

Fenpyrazamine appears to be moderately persistent in alkaline environments to persistent in acidic environments. In general, degradates were not observed at significant levels in the aerobic soil metabolism studies. This is most likely due to the large levels of unextracted unidentified residues bound to soil in the aerobic soil metabolism studies, accounting for approximately up to
70% of the material b alance in two alkaline soils in aerobic soil metabolism studies. Upon reaching water bodies, aqueous photolysis is expected to be the main degradation mechanism for fenpyrazamine in reservoir surface waters, with an environmentally relevant half

- life of 1 .64 days. Degradates which formed to significant levels included S

- 1288

- DC at 65.6% of the applied radioactivity (AR) and MCNI at 19.9% of the AR. Other important degradation pathways include biodegradation in alkaline environments. In aerobic alkaline environments, the
S

- 2188

- OH and S

- 2188

- DC degradates form in significant quantities encompassing material balances of up to 17.3% and 23.5% of the material balance in submitted studies.

5.1.3 Comparison of Metabolic Pathways

The proposed metabolism p athways of fenpyrazamine in plants, livestock and rats are summarized in Appendix B.3

. In primary and rotational crops the metabolic pathway of fenpyrazamine proceeds via cleavage of the carbamate linkage on the pyrazolyl ring to give S

2188

- DC. Subsequen t hydroxylation at the 4

- position of the pyrazolyl ring and tautomerisation
forms S

- 2188

- OH. In rotational crops the metabolite S

- 2188

- (OH)2 was also observed, probably formed by enzyme

- mediated deamination of S

- 2188

- OH. The metabolites S

- 2188

- DC and S

2 188

- CH2OH

- DC were identified as major metabolites in rats and lactating goat . C leavage
between the phenyl and pyrazolyl rings was not observed in the any of the metabolism studies.

5.1.4 Residues of Concern Summary and Rationale

The Residues of Concern Knowledgebase Sub

- committee (ROCKS) considered the available data on the nature and magnitude of residues in fenpyrazamine and has recommended parent fenpyrazamine as the residue of concern in plants for tolerance enforcement and ri sk assessment

purposes. In addition, inclusion of S

- 2188

- DC for dietary assessment purposes is recommended based on limited data indicating that the S

- 2188

- DC metabolite has similar toxicity as parent fenpyrazamine. The residues of concern in ruminants w ere recommended as parent fenpyrazamine and S

- 2188

- DC based on a metabolism study with lactating goat. In addition, S

2188

- CH2OH

- DC is included for risk assessment purposes as it is a major metabolite in muscle, liver, and kidney. For rotational crops, b ased on the 365

- day plant back interval proposed by theFenpyrazamine Human Health Risk Assessment DP No

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Page 23 of 56 registrant, parent fenpyrazamine only is an adequate residue of concern for dietary risk assessment and tolerance enforcement. For drinking water, the ROCKS recommended including the parent, and the degradates S

- 2188

- DC, S

- 2188

- OH, and MCNI. Toxicity data are not
available for the meta bolites/degradates S

- 2188

- OH, S

- 2188

- CH2OH

- DC and MCNI; h owever, based on structural similarity to the parent, ROCKS assume s that the toxicity for these
metabolites wil l also be similar to parent fenpyrazamine.

The residues of concern are summarized in Table 5.1.4 and the structures /nomenclature are summarized in Appendix B.

Table 5.1.4 Summary of Metabolites and Degradates to be included in the Risk Assessment

and T olerance Expression of Fenpyrazamine.

Matrix Residues included in Risk

Assessment Residues included in Tolerance Expression

Plants Primary Crop Parent + S

- 2188

- DC Parent

Rotational Crop Parent Parent

Livestock Ruminant Parent + S

- 2188

- DC + S

2188

- CH2OH

- DC Parent + S

- 2188 DC

Poultry Not Applicable 1 Not Applicable 1

Drinking Water Parent + S

- 2188

- DC +
S

- 2188

- OH + MCNI Not Applicable

1 No poultry feedstuff is associated with the proposed uses of fenpyrazamine.

5 .2 Food Residue Profile

D 406080

, I. Negrón, 10/31/2012

The submitted data on the metabolism of fenpyrazamine in grapes, oilseed rape and lettuce
demonstrate that residues are detectable in all commodities and these are primarily o n the surface of the commodity. Moreover, t he highest residue levels are generally found in the foliage or forage portions of plants, and are lower in the fruit and seeds of these commodities. Crop field
trial data submitted showed maximum residues of parent fe npyrazamine ranging from 0.08 ppm
in hea d lettuce without wrapper leaves to 2.86 ppm in caneberries. Maximum residues of the
metabolite S

- 2188

- DC ranged from levels below the limit of quantitation (LOQ ; 0.02 ppm) in ginseng to 1.08 ppm in lettuce leaf. Moreover, a higher concentration in almon d hulls feedstuff (up to 0.94 ppm) than in almond nutmeat (< LOQ) is evident

. The concentration of residues at different pre

- harvest intervals was assessed in the d ecline studies

. These studies show ed that
residues of parent fenpyrazami ne and the combin ed residues ( parent fenpyrazamine and the
metabolite S

- 2188

- DC ) decrease or are relatively constant through the sampling period. The
residue s of parent fenpyrazamine and the metabolite S

- 2188

- DC in grapes showed concentration upon processing to grape juice and raisin

.

All the tolerances recommended by HED were determined via the OECD tolerance calculation procedure, see Table 2.2.2

. Tolerances are not needed for rotational crops or livestock
commodities. The registrant has provided confin ed rotational studies on carrots, wheat and lettuce that demonstrate there is uptake of radioactivity into aerial portion of those plants;
h owever, quantifiable residues are not likely to be present in edible commodit ies harvested from crops planted 365

- da ys after treating the primary crop. With respect to livestock commodities,Fenpyrazamine Human Health Risk Assessment DP No

. 388322 and 389274

Page 24 of 56 t he Agency has determined that the newly proposed uses of fenpyrazamine are classified as 180.6 (a) (3), no reasonable expectation of finite residues in livestock commodities.

Ad equate residue chemistry data have been provided. Field trials are of adequate number and geographic representation, were generated using adequate analytical methods. S torage stability issues were discussed in the residue chemistry chapter; however, the d ata is considered adequate to support registration in all crops. Adequate studies were submitted for grapes to elucidate the
fate of fenpyrazamine in processed commodities derived from these crops.

5.3 Water Residue Profile
D388319, G. Rothman, 09/07/2012

Fenpyrazamine is a new chemical; therefore, there are no monitoring data currently available for this active ingredient or its residues of concern in drinking water. E stimated drinking water concentrations (EDWCs) were generated using OPP’s standard suite of models. The screening model FIRST (FQPA Index Reservoir Screening Tool) was used to calculate the surface water EDWCs. Estimated groundwater EDWCs were calculated using the screening model SCI

GROW (Screening Concentrations in Ground Wa ter) but this was significantly lower than that
obtained for surface water . The drinking water residues used in the dietary risk assessment were provided by the Environme ntal Fate and Effects Division

.

The EDWCs were obtained from FIRST analysis using th e highest supported use rate for fenpyrazamine of 3 aerial applications of 1.089 lbs ai/A every 7 days for a maximum seasonal
rate of 3.267 lb ai/A in ornamentals. Acute and chronic exposure of fenpyrazamine total residues (e.g., S

- 2188, S

- 2188

- OH, S

- 2188

- DC, and MCNI) in surface drinking water sources is represented by annual peak concentrations and annual average concentrations, respectively. Upper

- bound Tier I modeling predicts that the concentrations of fenpyrazamine in surface drinking water sources a re not likely to exceed 213

. 5 ppb for the acute peak concentration and
72

. 5 ppb for the chronic and cancer annual average concentrations.

Table 5.3 Summary of Estimated Surface Water and Groundwater Concentrations for

Fenpyrazamine

Scenario Surface Wat er Conc., ppb a Groundwater Conc., ppb b

Acute 213.5 1.31 Chronic (non

- cancer) 72. 5

a From the Tier I FIRST

- Index Reservoir model.

b From the SCI

- GROW model. Input parameters for FIRST and SCI

- GROW are based on 3 aerial applications of 1.089 lbs ai/A every 7 days for a
maximum seasonal rate of 3.267 lb ai/A in ornamentals. EDWC are based on the residues of concern including fenpyrazamine and the degradates S

- 2188

- OH, S

- 2188

- DC, and MCNI. Highest value for use in risk assessment is shown in bold. Highest values result from ornamentals use in each

case.Fenpyrazamine Human Health Risk Assessment DP No

. 388322 and 389274

Page 25 of 56 5.4 Dietary Risk Assessment D406081, I. Negrón, 10/31/2012

5.4.1 Description of Residue Data Used in Dietary Assessment

The residue definition for tolerance enforcement in plants is parent fenpyrazamine only while for risk assessment is the parent compound and the S

- 2188

- DC metabolite. To account for all the residues of concern in plants tolerance level residues of parent fen pyrazamine plus the maximum
residue of S

- 2188

- DC (expressed as parent fenpyrazamine) observed in the crop field trials were incorporated in the acute and chronic dietary assessments. Moreover, default and empirical processing factors were used. Drinking water was incorporated directly in the dietary assessment using the Tier I acute and chronic EDWCs for surface water generated by the FIRST model

. Based on the above Tier 1 FIRST modeling analysis, the residue levels included in the dietary

assessment are considered significantly conservative.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The acute and chronic dietary risk assessment assumed 100% crop treated for all commodities
included in the assessment.

5.4.3 Acute Dietary Risk Assessment

An unrefined acute dietary risk assessment for fenpyrazamine showed that acute dietary risk
estimates at the 95 th percentile of exposure are below HED’s level of concern (i.e. <100% aPAD) for the general U.S. popu lation and all population subgroups

. The r esults are summarized in
table 5.4.6

. The highest risk was observed for children 1

- 2 years old (9.2% of the aPAD).

5.4.4 Chronic Dietary Risk Assessment

An unrefined chronic dietary risk assessment for fenpyrazamine showed that chronic dietary risk

es timates are below HED’s level of concern (i.e. <100% cPAD) for the general U.S. popu lation
and all population subgroups . The results are summarized in table 5.4.6

. C hildren 1

- 2 year old were the highest exposed population subgroup ( 7.3 % of the cPAD).

5.4.5 Cancer Dietary Risk Assessment

Fenpyrazamine was classified as "Not Likely to be Carcinogenic to Humans", based on the results of mice and rat carcinogenicity studies; therefore, a cancer risk assessment is not needed.Fenpyrazamine Human Health Risk Assessment DP No

. 388322 and 389274

Page 26 of 56 5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Fenpyrazamine.

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 0.023720 3.0 0.008022 2.7

N/A N/A All Infants (<1 year old) 0.053592 6.7 0.016624 5.5

Children 1

- 2 years old* 0.073511 9.2 0.021792 7.3

Children 3

- 5 years old 0.050147 6.3 0.015293 5.1

Children 6

- 12 years old 0.027948 3.5 0.008542 2.8

Youth 13

- 19 years old 0.016521 2.1 0.005348 1.8

Adults 20

- 49 years old 0.020282 2.5 0.007058 2.4
Adults 50+ years old 0.019653 2.5 0.007401 2.5

Females 13

- 49 years old 0.020894 2.6 0.007268 2.4 The subpopulation with the highest risk estimates is in bold

.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no proposed residential uses of fenpyrazamine at this time.

6. 1 Residential Bystander Post

- application Inhalation Exposure

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for ( f enpyrazamine at this time primarily because of the low acute inhalation toxicity (Toxicity Category III) and low vapor pressure ( 2.17x10 - 10 mmHg at 25 oC ). However, volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Roden ticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/sap/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

application inhalation exposure into the Agency's risk assessment s. If new policies or procedures are developed, the Agency may revisit the need for a quantitative post

- application inhalation exposure assessment for fenpyrazamine.

6. 2 Spray Drift

Spray drift is always a potential source of exposure to residents near by to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be aFenpyrazamine Human Health Risk Assessment DP No

. 388322 and 389274

Page 27 of 56 potential source of exposure from the ground application method employed for fenpyrazamine. The Agency has been working with the Sp ray 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 as sessments 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 sign ificant risks
associated with drift.

Although a quantitative residential post

- application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation
exposure assessment was p erformed for flaggers. This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post

- application inhalation exposure scenarios

.

7.0 Aggregate Exposur e/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and
risk estimates from three major sources: food, drinking water, and residential exposures. There are no residential uses for fenpyrazamine; therefore the aggregate exposure and risk assessments include acute and chronic dietary (food and water) only and are shown in Sec tion 5.4.3 and 5.4.4, respectively. There are no aggregate risk estimates of concern for the proposed new uses of fenpyrazamine.

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 fenpyrazamine and any other substances and fenpyrazamine does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that fenpyrazamine has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have
a common mechanism on EPA’s websit e at http://www.epa.gov/pesticides/cumulative/.Fenpyrazamine Human Health Risk Assessment DP No

. 388322 and 389274

Page 28 of 56 9.0 Occupational Exposure/Risk Characterization D404560, A. LaMay, 10 / 30 /12

An occupation al exposure and risk assessment was conducted to support the new uses on almond, small fruit climbing subgroup 13

- 07F, h ead and leaf lettuce, low growing berry subgroup 13

- 07G, bushberry subgroup 13

- 07B, caneberry subgroup 13

- 07A, ginseng, pistachio
and ornamentals . Full details of that assessment are included in the memorandum cited above and the results are briefly summa rized here.

9.1 Short

- /Intermediate

- Term Handler Risk

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses of fenpyra zamine. The occupational exposure and risk assessment addresses risk estimates to pesticide handlers exposed in an occupational setting via the dermal and inhalation routes of exposure. However, for fenpyrazamine a quantitative dermal risk assessment is not required;
therefore risk estimates were quantitatively assessed for inhalat ion exposure only. For fenpyrazamine, , short

- and intermediate

- term exposures are anticipated for the following reasons: (1) 3 to 4 applications of the fungicide can be made to crops per season, and (2) commercial applicators could apply and re

- apply the fungicide to multiple crops over a period of weeks (e.g., completing multiple applications for multiple clients for multiple crops within a region). The quantitative exposure/risk assessment developed for occupational handlers includes the following scen arios:

Mixing/Loading suspension concentrate for ground, air, and chemigation application; Applying spray by aerial and ground equipment; Flagging in support of aerial application; and Mixing/Loading/Applying suspension concentrate for handheld equipment application.

Application rates on the labels are as follows: The maximum single application rate for almonds and pistachio is 0.375 lb ai/acre. The maximum single application rate for grapes, lettuce, low growing berry subgroup, bushberry subg roup, caneberry subgroup, and ginseng is 0.5 lb ai/acre. The application rate for ornamentals grown in greenhouse and nursery is 0.5 lb ai/100 gallons. Directions on the label indicate that for ornamental applications, 100 gallons of spray solution will treat approximately 20,000 ft 2 of area. At a rate of 0.5 lb/100 gallons, this equates to an approximate application rate of 1.09 lb ai/acre for ornamentals grown in greenhouses and nursery.

It is the policy of HED to use the best available data to asses s handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical

- specific data, include PHED 1.1, the AHETF database, the ORETF database, or other registrant

- submitted occupational exposure studies. Some of these dat a are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures”, areFenpyrazamine Human Health Risk Assessment DP No

. 388322 and 389274

Page 29 of 56 outlined in the “Occupati onal Pesticide Handler Unit Exposure Surrogate Reference Table” ( http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf ), which, along with additional information on HED p olicy on use of surrogate data, including descriptions of the various sources, can be found at http://www.epa.gov/pesticides/science/handler

- exposure

data.html

.

Estimates of in halation exposure were calculated. Results are presented for “baseline,” defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator. The product label directs mixers, lo aders, applicators and other handlers to wear long

- sleeved shirt and long pants, chemical

- resistant gloves, socks and
shoes.

Occupational handler inhalation risk estimates are not of concern (MOEs > LOC) for all proposed uses assessed with baseline inhala tion protection (no respirator) . Inhalation MOEs range from 4,000 (mixing/loading/applying soluble concentrate formulation by mechanically

pressurized handwand) to 550,000 (mixing/loading soluble concentrate in support of airblast application). A summary of inhalation risk estimates for occupational handlers can be found in
Table 9.1.Fenpyrazamine Human Health Risk Assessment DP No

. 388322 and 389274

Page 30 of 56 Table 9.1. Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Fenpyrazamine

.

Exposure Scenario Crop or Target Inhalation Unit Exposure (ug/lb ai) 1 Maximum

Application Rate 2 Area

Treated or

Amount
Handled Daily 3 Inhalation

Baseline Dose (mg/kg/day) 4 MOE 5

Mixer/Loader

M/L, L/SC/EC, Aerial, Broadcast Nursery

0.219 1.09 lb ai/acre 60 acres 0.000179 170,000

Orchard, Field Crop 0.5 lb ai/acre 350 acres 0.000479 63,000

M/L, L/SC/EC, Airblast,
Broadcast Nursery 1.09 lb ai/acre 20 acres 0.0000596 500,000

Orchard 0.5 lb ai/acre 40 acres 0.0000548 550,000

M/L, L/SC/EC, Chemigation,
Broadcast Orchard, Field Crop 0.5 lb ai/acre 350 acres 0.00479 63,000

Greenhouse, Nursery 1.09 lb ai/acre 60 acres 0.000179 170,000

M/L, L/SC/EC, Groundboom,

Broadcast Field

- grown ornamentals 1.09 lb ai/acre 40 acres 0.000119 250,000

Nursery, Greenhouse 1.09 lb ai/acre 60 acres 0.000179 170,000

Field Crop 0.5 lb ai/acre 80 acres 0.00011 270,000

Applicator

Applicator, Spray, Aerial,
Broadcast Nursery Engineering Control:
0.068 1.09 lb ai/acre 60 acres 0.0000556 540,000

Orchard, Field Crop 0.5 lb ai/acre 350 acres 0.000149 200,000

Applicator, Spray, Airblast,
Broadcast Nursery 4.71 1.09 lb ai/acre 20 acres 0.00129 23,000

Orchard 0.5 lb ai/acre 40 acres 0.00118 25,000

Applicator, Spray, Groundboom,

Broadcast Field

- grown ornamentals

0.34 1.09 lb ai/acre 40 acres 0.000185 160,000

Nursery, Greenhouse 1.09 lb ai/acre 60 acres 0.000278 110,000

Field Crop 0.5 lb ai/acre 80 acres 0.00017 180,000

Flagger

Flagger, Spray, Aerial, Broadcast Nursery 0.35 1.09 lb ai/acre 60 acres 0.000286 100,000

Orchard, Field Crop 0.5 lb ai/acre 350 acres 0.000766 39,000

Mixer/Loader/Applicator

M/L/A, L/SC/EC, Backpack,
Broadcast Greenhouse, Nursery 140

0.005 lb ai/gallon 40 gallons 0.00035 86,000

M/L/A, L/SC/EC, Manually

pressurized handwand, Broadcast Greenhouse, Nursery 30 40 gallons 0.000075 400,000

M/L/A, L/SC/EC, Mechanically

- Nursery 3.9 1000 0.000244 120,000Fenpyrazamine Human Health Risk Assessment DP No

. 388322 and 389274

Page 31 of 56 Table 9.1. Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Fenpyrazamine

.

Exposure Scenario Crop or Target Inhalation Unit Exposure (ug/lb ai) 1 Maximum

Application Rate 2 Area

Treated or
Amount
Handled Daily 3 Inhalation

Baseline Dose (mg/kg/day) 4 MOE 5

pressurized handwand, Broadcast Greenhouse 120 gallons 0.0075 4,000 M/L = Mixer/Loader. M/L/A = Mixer/Loader/Applicator. L/SC/EC = Liquid/Suspension Concentrate/Emulsifiable Concentrate

1 Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2012); includes data from PHED/ORETF/AHETF (level of mitigation: Baseline, no respirator).

2 Based on proposed label. The maximum single application rate for almonds and pistachios is 0.375 lb ai/A; however this use i s covered by the assessed maximum application rate of 0.5 lb ai/A for other orchard crops.

3 Exposure Science Advisory Council Pol icy #9.1.

4 Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal ) x Area Treated or Amount Handled Daily (A or gal/day) /BW (80 kg).

5 Inhalation MOE = Inhalation NOAEL (30 mg/kg/day )/ Inhalation Dose (mg/kg/day).Fenpyrazamine Human Health Risk Assessment DP No

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Page 32 of 56 9.2 Short

- /Intermediate

- /Long

- Term/Cancer (if needed) Post

- Application Risk

9.2.1 Dermal Post

- application Risk

HED uses the term postapplication to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re

- entry exposure). Such exposures may occur when workers enter previo usly treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting.

For the occupational dermal exposure pathway, short

- and intermediate

- term quantitative risk
estimates were not calc ulated since quantification of dermal risk is not required for fenpyrazamine. Therefore

, no occupational dermal risk estimates of concern have been identified for fenpyrazamine.

In accordance with the updated 40 CFR Part 158 data requirements (2007), o ne or more dislodgeable foliar residue (DFR) studies are required when a pesticide has residential or occupational uses that could result in postapplication dermal exposure. However, as quantification of dermal risk is not required for fenpyrazamine, a DF R study is not required for fenpyrazamine at this time. Additionally, a turf transferable residue (TTR) study is required for all occupational (e.g., sod farms, golf courses, parks, and recreational areas) or residential turf uses. As there are no propos ed uses on turf, a TTR study is not required for fenpyrazamine at
this time.

The REI specified on the proposed label is based on the acute toxicity of fenpyrazamine. Fenpyrazamine is classified as Toxicity Category III via the dermal route, Toxicity Cate gory IV for acute eye irritation, and Toxicity Category IV for acute dermal irritation. It is a skin
sensitizer. Under WPS for agricultural pesticides, ai’s classified as Acute III or IV for acute dermal, eye irritation and primary skin irrigation are as signed a 12

- hour REI. Therefore, the WPS interim REI of 12 hours is adequate to protect agricultural workers from post

- application exposures to fenpyrazamine.

9.2.2 Inhalation Post

- application Risk

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for fenpyrazamine at this time primarily because of the low acute inhalation toxicity (Toxicity Category III) and the low vapor pressure ( 2.17x10 - 10 torr at 25 oC ). However, th ere are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or par ticulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/sap/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as avail able post

- application inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policiesFenpyrazamine Human Health Risk Assessment DP No

. 388322 and 389274

Page 33 of 56 and procedures, to identify the need for and, subsequently, the way to incorporate occupational
post

- application inhal ation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational
post

- application inhalation exposure assessment for fenpyrazamine.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.

T he Worker Protection Standa rd for Agricultural Pesticides contains requirements for protecting workers from inhalation exposures during and after greenhouse applications through the use of ventilation requirements. [40 CFR 170.110, (3) (Restrictions associated with pesticide applic ations)].

10.0 References

D404560 ; Fenpyrazamine. Occupational and Residential Exp osure Assessment for a Proposed Use on Almond, Grape, Lettuce, Strawberry, and Ornamentals; and IR

- 4 Use on Bushberry,
Ca neberry, Ginseng, and Pistachio; A. LaMay; October 3 1 , 2012.

D 406080 ; Fenpyrazamine. Petition for the Section 3 Registration and Establishment of Tolerances for Uses on Almond, Small Fruit Climbing Subgroup 13

- 07F, Head and Leaf Lettuce, and Low Growing Berry Subgroup 13

- 07G, Bushberry Subgroup 1 3

- 07B, Caneberry Subgroup
13

- 07A, Ginseng, and Pistachio

. Summary of Analytical Chemistry and Residue Chemistry Data; I. Negrón; October 3 1 , 2012.

D 406081 ; Fenpyrazamine. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Ass essments for the Section (3) Registration Action for Domestic Uses on Almond, Pistachio, Caneberry Subgroup 13

- 07A, Bushberry Subgroup 13

- 07B, Small Fruit Climbing Subgroup 13

- 07F, and Low Growing Berry Subgroup 13

- 07G, Head Lettuce, Leaf Lettuce, and Gins eng

. ; I. Negrón; October 3 1 , 2012.

D403378 ; Fenpyrazamine. Report of the Residues of Concern Knowledgebase Subcommittee (ROCKS).; E. Holman; August 31, 2012.

D388319; Tier I Drinking Water Assessment for the new chemical Fenpyrazamine (P.C. Code:
090109 ) proposed Section 3 uses on almonds, grapes, lettuce, strawberries, and ornamentals; and

IR

- 4 uses on pistachios, bushberries, caneberries, and ginseng (DP Barcode 388319); G. Rothman; September 7, 2012.

ToxSAC memo; FENPYRAZAMINE

- Summary of Toxicology Science Advisory Council (ToxSAC) Meeting of August 2, 2012; Jessica Kidwell; September 26, 2012.Fenpyrazamine Human Health Risk Assessment DP No

. 388322 and 389274

Page 34 of 56 HASPOC memo; Fenpyrazamine : Summary of Hazard and Science Policy Council (HASPOC) Meeting of July 17, 2012: Recommendations on the Requirement of a 28

- Day I nhalation Study.; Julie Van Alstine; September 17, 2012.Fenpyrazamine Human Health Risk Assessment DP No

. 388322 and 389274

Page 35 of 56 Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for (food and non food use) for Fenpyrazamine are in the table below. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Primary Eye Irritation

................................ .................... 870.2500 Primary Dermal Irritation

................................ .............. 870.2600 Dermal Sensitization

................................ ...................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent)

................................ ......... 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 28

- Day Inhalation

................................ .......................... yes

yes

yes

CR

CR yes

yes

yes

-

yes

870.3700a Developmental Toxicity (rodent)

................................ ... 870.3700b Developmental Toxicity (nonrodent)

............................. 870.3800 Reproduction

................................ ................................ . yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (nonrodent)

................................ ........ 870.4200a Oncogenicity (rat)

................................ .......................... 870.4200b Oncogenicity (mouse)

................................ .................... 870.4300 Chronic/Oncogenicity

................................ .................... yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

................ 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations

... 870.5xxx Mutagenicity

— Other Genotoxic Effects

....................... yes

yes

yes

yes yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)

............................... 870.6100b 90

- Day Neurotoxicity (hen)

................................ ........... 870.6200a Acute Neurotoxicity Screening Battery (rat)

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

............... 870.6300 Develop. Neurotoxicity

................................ ................. no

no

yes

yes

CR -

-

yes

yes

-

870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

CR

yes yes

yes

yesFenpyrazamine Human Health Risk Assessment DP No

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Page 36 of 56 A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile

– Fenpyrazamine Technical

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [rat] 48400106 LD 50 > 2000 mg/kg (♀) III

870.1200 Acute dermal [rat] 48400109 LD 50 > 2000 mg/kg (♂,♀) III

870.1300 Acute inhalation [rat] 48400111 LC 50 > 0.61 mg/L (♂, ♀) III

870.2400 Acute eye irritation [rabbit] 48400112 Minimally irritating IV

870.2500 Acute dermal irritation [rabbit] 48400115 Not irritating IV

870.2600 Skin sensitization [Guinea pig] 48400117 Dermal
sensitizer N/A

Table A.2.2 Fenpyrazamine: Subchronic, Chronic and Other Toxicity Profile

Guideline
No. Study Type MRID No. (year)/
Classification /Doses Results

870.3100 90

- day rat study

(diet) 48400119 (2006)

Acceptable/Guideline 0, 300, 600, 1000 ppm (males 0, 19.1, 37.7, 64, 196.1; females 0, 20.5, 42.0, 68.6, 207.3 mg/kg/day) NOAEL = 64 /68.6 mg/kg/day (♂/♀)

LOAEL = 196.1/207.3 (♂/♀) mg/kg/day based
on d ecreased body weight/body weight gains (♂),and thyroid follicular cell hyperthrophy (♂).

870.3100 90

- day mouse

study (diet) 48400118 (2007)

Acceptable/Guideline

0, 200, 2000, 4000, 6000 ppm (males 0, 28, 296.2, 639.5, 1022.6 females 0, 33.5, 363.3, 719.6, 1098.3 mg/kg/day). NOAEL = 296.2/363.3 (♂/♀)

LOAEL = 639.5/719.6 (♂/♀) mg/kg/day decreased body weight gain (♂), and decreased bilirubin , creatinine, pr otein, albumin and A/g ratio (♂).

870.3100 90

- Day oral

toxicity (dog) 48400120(2008)

Acceptable/Guideline 0, 25, 50, 150 mg/kg/day (capsules) NOAEL = 25 mg/kg/day ♂; 50 mg/kg/day ♀

LOAEL = 50 mg/kg/day (♂) based on decreases in BW/BWgain , ↓CA, ↓Alb, ↓A/G at 50 & 150 mg/kg/day ♂. ↑ALP at 150 mg/kg/day in ♂/♀. ↓ RBC, Hb conc, MCHC & ↑MCV in 150 mg/kg/day ♂. ↓ MCHC & ↑MCV in 150 mg/kg/day ♀.

870.3200 21

- Day dermal

toxicity (rat) 48400121 (2008)

Acceptable/Guideline

0, 100, 300, 1000 mg/kg/day NOAEL = 1000 mg/kg/day

LOAEL = not observedFenpyrazamine Human Health Risk Assessment DP No

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Page 37 of 56 Table A.2.2 Fenpyrazamine: Subchronic, Chronic and Other Toxicity Profile

Guideline
No. Study Type MRID No. (year)/
Classification /Doses Results

870.3465 28

- Day

inhalation toxicity (rat) Not Available Not Available

870.3700a Prenatal

developmental in (rat) 48400123 (2009)

Acceptable/Guideline

0, 30, 125, 500 mg/kg/day Maternal NOAEL = 30 mg/kg/day
LOAEL = 125 mg/kg/day based on decreased body weight/BW gain, corrected BW gain. Developmental NOAEL = 125 mg/kg/day
LOAEL = 500 mg/kg/day based on decreased body weight, increased visceral and skeletal variations, delayed ossification

.

870.3700b Prenatal Dose

Range Finding

- developmental in (rabbit) 48400122 (2008)

Acceptable/Guideline

0, 60, 90, 120, 150 mg/kg/day Materna l NOAEL = 60 mg/kg/day
LOAEL = 90 mg/kg/day based on food refusal, abortions/premature deliveries. Developmenta l NOAEL = 60 mg/kg/day

LOAEL = 90 mg/kg/day based on abortions/premature deliveries.

870.3700b Prenatal

developmental in (rabbit) 48400125 (2008)

Acceptable/Guideline

0, 30, 50, 90 mg/kg/day Materna l NOAEL = 3 0 mg/kg/day
LOAEL = 5 0 mg/kg/day based on decreased food consumption, decreased body weight,. Developmenta l NOAEL = 5 0 mg/kg/day
LOAEL = 9 0 mg/kg/day based on abortions/premature deliveries.

870.3800 Reproduction

and fertility
effects (rat) 48400127 (2009)

Acceptable/Guideline

0, 400, 1000, 3000 ppm (premating: males

– 27.4, 68.6, 213 mg/kg/day;
females

– 32.0, 79.9, 237 mg/kg/day) Parental/Systemic NOAEL = 68.6/79.9 (♂/♀)

LOAEL = 213/237 (♂/♀) based on ↑ thyroid cell hypertrophy and hyperplasia (♂/♀ ) and liver histology (inflammation , bile duct pigmentation, hyperplasis) Reproductive NOAEL = 213/79.9 (♂/♀)

LOAEL = not identified/237 mg/kg/day (♂/♀) based on ↓ no. of implantations; ↑ postimplantation (♀) Offspring NOAEL = 68.6/79.9 (♂/♀)

LOAEL = 213/237 (♂/♀) based on ↓ pup BW in F1 and F2 pups, and ↑ thyroid cell hypertrophy and hyperplasia in F2 pups.

870.4100b Chronic toxicity

(dog) 48400128 (2009)

Acceptable/Guideline
0, 5, 25, 100 mg/kg/day NOAEL = 25 mg/kg/day (♂/♀)

LOAEL = 100 mg/kg/day (♂/♀) based on ↑MCV, ↓MCHC in ♂; ↑ platelet counts in ♀; ↑ALP in ♂;Fenpyrazamine Human Health Risk Assessment DP No

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Page 38 of 56 Table A.2.2 Fenpyrazamine: Subchronic, Chronic and Other Toxicity Profile

Guideline
No. Study Type MRID No. (year)/
Classification /Doses Results

870.4300 Combined

Chronic/Carcino genicity

- Rat (diet) 48400130 (2009)

Acceptable/Guideline

Males & Females: 0, 100, 300, 1200, or 2400 ppm Males: 0, 4.25, 12.7, 51.9 & 107 mg/kg/day) Females: 0, 5.29, 15.6, 63.6, & 130 mg/kg/day) NOAEL = 51.9/63.6 mg/kg/day (♂/♀)

LOAEL = 107/130 mg/kg/day (♂/♀) based on decreased body weight, hepatocyte fatty change ( ♀ ), and vacuolated foci ( ♂ )

No carcinogenic effects of biological significance

870.4300 Carcinogenicity

– Mouse (diet) 48400129 (2009)

Acceptable/Guideline

Males: 0, 100, 1500, or 3000 ppm (0, 11.1, 176 & 349 mg/kg/day) Females: 0, 100, 2000 or 4000 ppm ( 0, 13.9, 283, & 552 mg/kg/day) NOAEL = 176/283 mg/kg/day (♂/♀)

LOAEL = 349/552 mg/kg/day (♂/♀) based on increased MCV and MCH (♂), decreased RBC (♂), and decreased RBC, HB and HCT (♀)

No evidence of carcinogenicity

870.5100 Bacterial Reverse

Mutation

- Salmonella typhimurium (TA100, TA98, TA1535, TA1537) and one
strain of E. coli (WP2uvrA)
(technical grade
S

- 2188) 48400132

Acceptable/Guideline

+/

- S9: 156, 313, 625, 1250, 2500, 5000 μg/plate(48 hr) Negative with and without metabolic activation

Gene
Mutation
870.5300 Mammalian Cell

Gene Mutation Assay

In vitro
mammalian cell gene mutation
with Chinese hamster lung cells (CHL/IU) 48400133

Acceptable/Guideline

- S9: 2.81, 5.63, 11.3, 22.5, 45, 90 μg/ml ( 24 hr, repeat 6 hrs) +S9: 40, 80, 120, 160 μg/ml ( 24 hr, repeat 6 hrs) Negative with and without metabolic activationFenpyrazamine Human Health Risk Assessment DP No

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Page 39 of 56 Table A.2.2 Fenpyrazamine: Subchronic, Chronic and Other Toxicity Profile

Guideline
No. Study Type MRID No. (year)/
Classification /Doses Results

Cytogenetics
870.5375 In vitro

chromosomal
aberration test
with Chinese
Hamster V79
cells

- HPRT 48400134

Acceptable/Guideline

- S9:2.5, 5.0, 10, 20, 30, 40, 50, 60 μg/mL (4 hr); 25, 40, 55, 70, 85, 100, 115, 130 μg/mL (24 hr)

+S9: 12.5, 25, 50, 75, 100, 150, 175, 200 μg/mL (4 hr); 20, 40, 60, 80, 100, 120, 140, 160 μg/mL (24 hr) Negative with and without metabolic activation

Micronucleus

870.5385 Mouse Bone

Marrow (males)
Micronucleus Assay 48400135

Acceptable/Guideline

0, 500, 1000, 2000 mg/kg [M] Negative; 0, 500, 1000, 2000 mg/kg (male)

870.6200 Acute

neurotoxicity screening battery

Han Wistar Rats (Gavage) 48400137

Acceptable/Guideline

80, 400, 2000 mg/kg bw NOAEL = 80/400 mg/kg/day (♂/♀)

LOAEL = 400/2000 (♂/♀) mg/kg/day based on
d ecreased total distance time (♂), decreased total number of rearings (♂/♀).

870.6200 Acute Oral

Neurotoxicity
Peak Effect Study in Han
Wistar Rats (Gavage) 48400138

Acceptable/Guideline

100, 1000, 2000 mg/kg NOAEL = 1000/>2000 mg/kg/day (♂/♀)

LOAEL = 2000 mg/kg/day (♂) based on >10% body weight gain decrement, LOAEL not observed in (♀)

870.6200b Subchronic

neurotoxicity screening battery
(diet) 48400136 (2008)

Acceptable/Guideline

0, 500, 1200, 3000 ppm (males: 0, 36.8, 87.6, 223.6 mg/kg/day; females: 0, 41.7, 100.2, 248.4 mg/kg/day) NOAEL = 87.6/100.2 mg/kg/day (♂/♀)

LOAEL = 223.6/248.4 mg/kg/day (♂/♀) based
on d ecreased body weight/body weight gain.Fenpyrazamine Human Health Risk Assessment DP No

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Page 40 of 56 Table A.2.2 Fenpyrazamine: Subchronic, Chronic and Other Toxicity Profile

Guideline
No. Study Type MRID No. (year)/
Classification /Doses Results

870.7485 Metabolism and

excretion in the

Rat

– Single Oral High and Low

Doses 48400139

acceptable/guideline Absorption of fenpyrazamine was extensive, and almost totally metabolized. Excretion of low dose was almost complete within 24 hrs and of the high dose within 48 hrs. Urine was the most important route of elimination (>80%) for both sexes, and elimation as CO2 almost insignificant. After 168 hrs the proportion of dose remaining in tissues was very low. Elimination of the allylsulfanylcarbonyl group was the initial step in metabolism to form S

2188

- DC. The latter underwent oxidation. Dealkylation of fe npyrazamine to MPPZ was important in both sexes. MPPZ was conjugated both with sulphate and with glucuronide.

870.7485 The Metabolism,

Excretion and
Tissue
Distribution of [14C] S

- 2188 in the Rat Upon
Administration of Repeated oral

Doses. 48400140

acceptable/guideline During repeated oral dosing for 14 days, readiolabel concentrations in tissues plateaued from approximately day 7, and declined after cessation of dosing. Highest concentrations
were found in the GI tract and liver. There was no majo r accumulation of radioactivity in any tissue. The results of excretion (route of excretion and metabolite pattern) obtained in repeated dose study were in ine with those from single dose study.

870.7485 The

Pharmacokinetic s of [14C] S

2188 in the Rat Upon
Administration of Single Oral High and Low

Doses 48400141

Acceptable/Guideline Absorption of [14C]

- fenpyrazamine was more rapid at low tha high doses. Maximum blood and plasma 14C concentrations were observed 1 hr after administration of the low dose, and 6 hrs after that of the high dose. The kinetic half

lives (elimination) were 2

- 3 hrs for the low
dose and 14

– 17 hrs for the high dose . The AUC for the high dose (300 mg/kg) was
calculated to be 150

- 170 fold greater than that for the low dose (3 mg/kg), indicating some saturation of the elimination processes at the high dose.

870.7485 The Tissue

Distribution of [14C] S

- 2188 in
the Rat Upon
Administration of Single Oral High and Low

Doses 48400142

Acceptable/Guideline Fenpyrazamine was rapidly and widely distributed into tissues. Highest concentration of tissue residues were seen in the GI tract, and in liver and kidney. Tissue concentrations rapidly declined from peak values. The major
metabolite extracted from tissues was S

- 2188

- DC. Other major metabolites included S

- 2188

- CH 2 OH

- DC and MPPZ. S

- 2188

- CH 2 OH

- DC was more abundant in the liver and kidneys of male rats; MPPZ tended to be more abundant in females compared to males.Fenpyrazamine Human Health Risk Assessment DP No

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Page 41 of 56 Table A.2.2 Fenpyrazamine: Subchronic, Chronic and Other Toxicity Profile

Guideline
No. Study Type MRID No. (year)/
Classification /Doses Results

870.7600 In Vivo Dermal

Absorption Study
in the Male Rat 48793502 Combing the absorbed and potentially systemically bioavailable (absorbable) radioactivity, the absorption for spray dilution
was 17.91% and 1.9% for concentrate 168 hours post

- dosing.

Note: This study is based on a 50WG formulation used in Europe.

Nonguideline In Vitro Human

and Rat Dermal Absorption Study 48793501 Regarding absorption and distribution of S

2188 through human and rat skin, the results
from the in the in vitro rat and human skin study show that rat skin in vitro is about 20 times more permeable for concentrate and 23 times more permeable for diluted f ormulation
than the human skin.

Note: This study is based on a 50WG formulation used in Europe.

870.7800 28

- Day Dietary

Immunotoxicity Study in Female
Hans Wistar Rat 48400143 (2010)

Acceptable/Guideline

0, 500, 1500, & 4000 ppm (0, 36, 123 & 392 mg/kg/day) Systemic NOAEL = 123 mg/kg/day

LOAEL = 392 mg/kg/day based on decreased body weight/body weight gain, increased liver and spleen weights (both sexes).

There were no immunotoxic effects.

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD)

- Females age 13

- 49

Not established. An endpoint attributable to a single dose was not available in the data base, including the pre

- natal toxicity studies in rats and rabbits.

A.3.2 Acute Reference Dose (aRfD)

- General Population

Selected Study: Acute Neurotoxicity Study in the Rat

MRID No : 48400137 Executive Summary: See Appendix A, Guideline 870.6200a Dose and Endpoint for Establishing aRfD: NOAEL = 80 mg/kg based on a statistically significant decrease in total motor activity (total distance) observed in males at 400 on day 1. Uncertainty Factor (UF) : 100 (10x intraspecies, 10x interspecies); FQPA SF = 1xFenpyrazamine Human Health Risk Assessment DP No

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Page 42 of 56 Comments about Study/Endpoint/Unce rtainty Factor : The ACN study is appropriate for aPAD since the effects were observed on day 1 and are attributed to a single dose. It is also appropriate for the route of exposure, i.e., oral. The NOAEL of 80 mg/kg/day would be protective of the potenti al developmental effects observed in the developmental rat study (NOAEL = 125 mg/kg/day). The developmental effects (abortions/premature deliveries) noted in the developmental rabbit study are not attributable to a single dose administration as these effe cts were observed later in the study on GD24.

A.3.3 Chronic Reference Dose (cRfD)

Study Selected : Developmental Toxicity Study in Rabbits

MRID No.: 48400125

Executive Summary: See Appendix A, Guideline 870.3700b

Dose and Endpoint for Establishin g cRfD: Maternal NOAEL = 30 mg/kg/day. The maternal LOAEL = 50 mg/kg/day based on decreased body weight and food consumption.

Uncertainty Factor (UF) : 100 (10x intraspecies, 10x interspecies); FQPA SF = 1x

Comments about Study/Endpoint/Uncertainty Factor : The use of the developmental toxicity study in the rabbit is appropriate for the chronic dietary endpoint since there is no progression of toxicity over time with this chemical. The lack of progression of toxicity is also consistent with
the ADME d ata. The liver effects (hypertrophy and increased liver weights) seen in the subchronic and chronic studies were considered to be adaptive and not adverse because they were only associated with minimal changes in clinical chemistry and did not progress in severity over time. The endpoint chosen represents the most sensitive population and is protective of any potential developmental effects.

A.3.4 Incidental Oral Exposure (Short

- and Intermediate

- Term)

There are no residential uses proposed for this chemical.

A.3.5 Dermal Exposure (Short

- , Intermediate

- and Long

- Term)

Quantification of short

- , intermediate, or long

- term dermal risk is not required. No systemic toxicity was seen at the limit dose in an acceptable dermal toxicity study in rats (MRID 48400121). The developmental or reproductive effects only occurred in the presence of parental toxicity manifested as effects that would have been evaluated in the dermal toxicity study ( e.g., decreased bo dy weight, food consumption, and increased incidence of liver hypertrophy and thyroid follicular cell hyperplasia), Additionally, the potential for neurotoxicity was evaluated in the dermal toxicity study and no treatment

- related effects were seen in any of the neurological parameters. Although the duration of the dermal toxicity study in rats is only 28 days, this study is considered appropriate for long

- term dermal hazard assessment since no increase in toxicity with duration was observed throughout the toxicology database for fenpyrazamine.Fenpyrazamine Human Health Risk Assessment DP No

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Page 43 of 56 A.3.6 Inhalation Exposure (Short

- , Intermediate

- and Long

- Term)

Study Selected : Developmental Toxicity Study in Rabbits

MRID No.: 48400125

Executive Summary: See Appendix A, Guideline 870.3700b

Dose and End point: Maternal NOAEL = 30 mg/kg/day. The maternal LOAEL = 50 mg/kg/day based on decreased body weight and food consumption.

Uncertainty Factor (UF) : The occupational level of concern for MOE is 100.

Comments about Study/Endpoint/Uncertainty Factor : The use of the developmental toxicity study in the rabbit is appropriate for the inhalation exposure scenario (all durations) since there is no progression of toxicity with duration. The lack of progression of toxicity is also consistent
with the ADME data. T he liver effects (hypertrophy and increased liver weights) seen in the subchronic and chronic studies were considered to be adaptive and not adverse because they were only associated with minimal changes in clinical chemistry and did not progress in severi ty over time. The endpoint chosen represents the most sensitive population and is protective of any potential developmental effects.

A.4 Summaries (obtained from Austria Monograph on Fenpyrazamine)

A.4.1 Subchronic Toxicity

870.3100 90

- Day Oral Toxicity

- Rat
Summary: The LOAEL = 196.1/207.3 (♂/♀) mg/kg/day based on d ecreased body weight/body weight gains (♂),and thyroid follicular cell hyperthrophy (♂). NOAEL = 64 /68.6 mg/kg/day (♂/♀).

870.3100 90

- Day Oral Toxicity

– Mouse Summary: In the 90 days study in mice, the NOAEL for fenpyrazamine is 296.2/363.3 (♂/♀).

The LOAEL = 639.5/719.6 (♂/♀) mg/kg/day decreased body weight gain (♂), and decreased bilirubin , creatinine, protein, albumin and A/g ratio (♂).

870.3150 90

- Day Oral Toxicity

- Dog Summary: In the 90 day study in dog, the NOAEL for males is 25 mg/kg bw/d, based on decreased BW/BW gain, decreased CA, Alb and A/G at 50 mg/kg/day and 150 mg/kg/day. The NOAEL for females is 50 mg/kg/day based on decreased MCHC and increased MCV in at 150 mg/kg/day.

870.3200 21/28

- Day Dermal Toxicity

– RatFenpyrazamine Human Health Risk Assessment DP No

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Page 44 of 56 Summary: In the dermal 28

- days study in rats dosed at 100, 300, and 1000 mg/kg, the NOAEL was considered to be 1000 mg/kg bw/day for male and female rats.

870.3465 28

- Day I nhalation

– Rat

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study

– Rat Summary: In the main developmental study in rats fenpyrazamine at dose levels of 0, 30, 125, and 500 mg/kg bw/day was well tolerated. All animals survived to the scheduled sacrifice and did not show any adverse clinical signs. No malformations were observed in the study. At 125 and 500 mg/kg dose level, mean body weight gains of dams were statistically significantly lower when compared to the control group, thus indicating the occurrence of maternal toxicity. No visceral or skeletal malformations were observed in the study. The increased incidences of visceral (dilated kidney pelvis, dilated ureters, distended uri nary bladder, and of additional liver lobes in fetuses) and skeletal (zygomatic arch fusions, sternebra offset or sternebra with misshapen ossification site, incomplete ossification of the frontal bone and costal cartilages asymmetrically aligned at sternu m) fetal findings in high dose animals were considered related to observed maternal toxicity in this dose group.

In conclusion, the No Observed Adverse Effect Level ( NOAEL) for maternal animals is proposed at 30 mg/kg bw/day (lowest tested dose), based o n statistically significantly lower body weight gain in mid

- and high dose dose animals during pregnancy. The developmental NOAEL is proposed at 125 mg/kg bw/day (mid

- dose), based on significant decrease of mean fetal weight,
visceral and skeletal variation s and delayed ossifications (above historical control data) in fetuses of high dose group (500 mg/kg bw/d).

870.3700b Prenatal Developmental Toxicity Study

- Rabbit Summary: In the range finding rabbit developmental study, five presumed

- pregnant female rabbits per group were administered fenpyrazamine at doses of 0, 60, 90, 120 or 150 mg/kg bw/day as a suspension in 1% aqueous CMC from days 6 to 2 7 o f pregnancy. Mortality was observed at 120 mg/kg bw/d (one doe). Reduced food consumption/refusal of food was observed in three high dose groups (90, 120 and 150 mg/kg bw/day), followed by abortion and/or premature deliveries. As a result, there was a reduced litter number for further examination. Clinical findings among affected does were largely restricted to orange discolored urine and/ or a red fluid beneath the cage, mainly observed in 120 and 150 mg/kg bw group. No effect on development of the fetuses was detected. Although the study was only a range

- finding study, maternal and fetal NOAELs are proposed at 60 mg/kg bw/d, based on food refusal of does, and subsequent abortions/premature deliveries at next higher dose.

Summary: In the developmental study in rabbit presumed

- pregnant female rabbits were administered fenpyrazamine at doses of 0, 30, 50, or 90 mg/kg bw/day as a suspension in 1% aqueous CMC from days 6 to 27 of pregnancy, sacrificed shortly before term, and fetuses examined for indications of effects on development. Seven females of the high dose, and one of
the mid

- dose either aborted or ga ve birth prematurely and as a result, were sacrificed before theFenpyrazamine Human Health Risk Assessment DP No

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Page 45 of 56 end of the study. The abortions/early deliveries were attributed to severely reduced food consumption and markedly reduced body weight which was seen in each affected doe. The
number of litte rs available for detailed examination at the high dose was consequently lower. No effect on development of examined fetuses was detected. Incidence of variations and malformations observed in the treated groups was either comparable or lower than in the c ontrol animals. Regarding observed effects, it is proposed to set maternal NOAEL at 30 mg/kg bw/d, based on severely reduced food consumption, and markedly reduced body weight at 50 mg/kg/day. The offspring NOAEL is 50 mg/kg bw/, based on abortions/premat ure deliveries at 90 mg/kg/day.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects

- Rat Summary: In the 2

- generation study, fenpyrazamine was administered continuously in the feed to rats at dietary concentrations of 0, 400, 1000, and 3000 ppm. The toxicological response of the treated animals was principally characterized by increase in thyroid weigh t and histological findings (cell hypertrophy) and reduced food consumption and decreased body weight gain throughout the whole study period. Significantly lower number of implantations, significantly increased post implantation loss and significantly inc reased post natal loss in the high dose group of F1 generation is considered to be the effect of systemic toxicity in maternal animals (body weight gain loss, body weight reduction, thyroid enlargement , and thyroid cell hypertrophy). Fenpyrazamine showed no effects on fertility. Sperm evaluation and ovary staging did not reveal any test substance related findings.

A No

- Observed

- Adverse

- Effect Level (NOAEL) for parental effects is 68.6/79.9 mg/kg/day (♂/♀), based on ↑ thyroid cell hypertrophy and hyperplasia (♂/♀) and hepatic histology (inflammation, bile duct pigmentation, hyperplasia) at 213/237 mg/kg/day (♂/♀).

A No

- Observed

- Adverse

- Effect Level (NOAEL) for offspring effects is 68.6/79.9 mg/kg/day (♂/♀) based on ↓ pup BW in F1 and F2 pups, and ↑ thyroid cell hypertrophy and hyperplasia in F2 pups at 213/237 mg/kg/day (♂/♀).

A No

- Observed

- Adverse

- Effect Level (NOAEL) for reproductive effects is 213/79.9 mg/kg/day (♂/♀) based on ↓ no. of implantations and ↑ postimplantation (♀) at 237 mg/kg/day.

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity

– Rat Summary: In the combined chronic and carcinogenicity study (2 years) in rat, the LOAEL is 107/130 mg/kg/day (male/female) based on decreased body weight, hepatocyte fatty change (female), and vacuolated foci (male). The NOAEL is 51.9/63.6 mg/kg/day (male/female).

870.4100b Chronic Toxicity

- Dog Summary: In the 1

- year dog study the NOAEL for males and females is proposed at 25 mg/kgFenpyrazamine Human Health Risk Assessment DP No

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Page 46 of 56 bw/d, based on ↑MCV, ↓MCHC in ♂; ↑ platelet counts in ♀; ↑ALP in ♂ at 100 mg/kg/day.

A.4.5 Carcinogenicity

870.4200a Carcinoge nicity Study

– rat (see above)

870.4200b Carcinogenicity (feeding)

– Mouse Summary: In the carcinogenicity study in CD

- 1 mouse (78 weeks), the NOAEL is 176/283 mg/kg/day (♂/♀) based on increased MCV and MCH (♂), decreased RBC (♂), and decreased
RBC, HB and HCT (♀) at 349/552 mg/kg/day (♂/♀).

In the mouse carcinogenicity study, no carcinogenic potential of fenpyrazamine could be
observed.

A.4.6 Mutagenicity

Gene Mutation

Guideline 870.5100, Ames assay

MRID 48400132

Classification: acceptable/guideline Negative with and without metabolic activation.

Salmonella typhimurium (TA100, TA98, TA1535, TA1537) and one strain of E. coli (WP2uvrA).

+/

- S9: 156, 313, 625, 1250, 2500, 5000 μg/plate(48 hr)

Guideline 870.5300, Mammalian Cell Gene Mutation Assay

MRID Classification: 48400133
acceptable/guideline Negative with and without metabolic activation

Chinese hamster lung cells (CHL/IU)

- S9: 2.81, 5.63, 11.3, 22.5, 45, 90 μg/ml ( 24 hr, repeat 6 hrs) +S9: 40, 80, 120, 160 μg/ml ( 2 4 hr, repeat 6 hrs)

Cytogenetics

Guideline 870.5375

, chromosomal
aberration test

MRID

classification: acceptable/guideline Negative with and without metabolic activation

Chinese Hamster V79 cells

– HPRT

- S9:2.5, 5.0, 10, 20, 30, 40, 50, 60 μg/mL (4 hr); 25, 40, 55, 70, 85, 100, 115, 130 μg/mL (24 hr)

+S9: 12.5, 25, 50, 75, 100, 150, 175, 200 μg/mL (4 hr); 20, 40, 60, 80, 100, 120, 140, 160 μg/mL (24 hr)Fenpyrazamine Human Health Risk Assessment DP No

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Page 47 of 56 Other Genotoxicity

Guideline 870.5385

, Micronucleus Assay

MRID 48400134

classification : acceptable/guideline Negative; 0, 500, 1000, 2000 mg/kg (male)

Mouse Bone Marrow (males)

0, 500, 1000, 2000 mg/kg [M]

A.4.7 Neurotoxicity

870.6100 Delayed Neurotoxicity Study

- Hen

870.6200 Acute Neurotoxicity Screening Battery Summary: In the acute oral neurotoxicity study the NOAEL is set at 80 mg/kg bw for males, based on statistically significantly reduced total distance time and total number of rearings at day 1 of treatment in 400 mg/kg bw male group. For females, the NOAEL is set a t 400 mg/kg bw, based on statistically significantly reduced total number of rearings at day 1 of treatment in 2000 mg/kg bw group.

870.6200 Subchronic Neurotoxicity Screening Battery Summary: In the subchronic (90 days) oral neurotoxicity study in rats no clinical signs or mortality, no significant changes during FOB or motor activity and no microscopic pathology indicative of neurotoxicity was found at necropsy. The only treatment

- related finding was a decrease in body weight and bodyweight gain in bot h sexes at 3000 ppm. On the basis of the body weight and body weight gain decrease at 3000 ppm (223.6/248.4 mg/kg/day

– male/female), the NOAEL in this study was determined to be 1200 ppm for both males and females (87.6 and 100.2 mg/kg bw /day , respectivel y).

870.6300 Developmental Neurotoxicity Study

A.4.8 Metabolism

870.7485 Metabolism

- Rat Summary (MRID 48400139 ) : Absorption of fenpyrazamine was extensive, and S

- 2188 almost totally metabolised. Excretion of the low dose was almost complete within 24 hours and of the high dose within 48 hours. Urine was the most important route of elimination (>80% for males and females, at low or high doses), and elimination as CO 2 almost insignificant.

After 168 hours the proportion of dose remaining in tissues was very low. Distribution of radioactivity into tissues was very even. There was no evidence of accumulation into tissues, with the exception of stom ach and caecum (including contents). The higher residues in stomach and caecum seem to be unusual but no explanation for this finding is given. There were no significant dose or sex differences in tissue distribution or routes of elimination.
The amount of radioactivity found in urine (80.4 to 87.2% of dose) indicates a high resorption
from GI tract.Fenpyrazamine Human Health Risk Assessment DP No

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Page 48 of 56 Elimination of the allylsulfanylcarbonyl group to produce S

- 2188

- DC was the initial step in metabolism. This metabolite was eliminated as a significant fract ion in males and females at high and low doses (particularly in females at the low dose). S

- 2188

- DC was hydroxylised to form S

2188

- OH in only small amounts. Dealkylation of S

- 2188

- DC to MPPZ was important in both sexes at high and low doses. MPPZ was conj ugated with sulphate and with glucuronide (sulphation was more important at the low dose). The proportion of dose identified as metabolites was satisfactory (> 68% in all groups), however no attempts were made to identify the unknown metabolites (none exce eding 5% of dose).

Summary (MRID 48400140 ) : During repeated dosing, the concentration of radioactivity in most tissues maximised approximately up to day 7 and then remained relatively constant for the rest of the dosing period. Tissue residues declined after finishing of dosing period. There was no evidence of unusual accumulation into any tissue and of sex differences.

A mixture of S

- 2188

- CH 2 OH

- DC and MPPZ was the major identified metabolite fraction in plasma, kidney, and lung. Parent fenpyrazamine w as a major component only in liver (max 9.6% of liver TRR).

In urine, the relative amounts of identified metabolites were similar for both sampling periods and both sexes. In males, MPPZ sulphate and S

- 2188

- CH 2 OH

- DC contributed mostly to the
identified rad ioactivity in urine, while S

- 2188

- DC was present < 10%. In urine of females, MPPZ, MPPZ sulphate and S

- 2188

- DC contributed evenly to the identified radioactivity. In
feces S

- 2188

- CH 2 OH

- DC was the major metabolite in males (max. 25.1%) and MPPZ (max. 26.6%) in females. MPPZ sulphate was not identified in feces , neither in males nor in females.
Considerable radiolabel was unextractable from feces

.

Recovery of eliminated radioactivity in excreta after 24 days was 96.5% of administered dose in males and 97.2% in females. The majority of radioactivity was recovered in urine (74.6% in males and 78.7% in females) and feces (13.6% in males and 11.2% in fe males). While the excretion up to day 15 (one day after last dose administration) was high and constant, it declined rapidly after the dosing was finished. From day 15 to the end of the study, only very low amounts of radioactivity were found in urine, cag e wash and feces . The results of excretion (route of excretion and metabolite pattern) obtained in repeated dose study were in line with those from single dose study.

Summary (MRID 48400141 ) : Fenpyrazamine orally administered of either 3 mg/kg body weight or 300 mg/kg body weigh was rapidly absorbed and than rapidly eliminated whereby the absorption of [ 14 C] S

- 2188 was more rapid at low than at high dose. Based on the toxicokinetic parameters investigated (AUC), the systemic availability increased wi th dose level applied. Longer T 1⁄2 and over proportionally higher AUC at high dose might indicate that in the high dose
animals the saturation of elimination could be reached.

Summary (MRID 48400142) : In low dose animals the highest concentration in most tissues (except stomach including content) was reached 1 hour post

- dosing. The increase of
concentration in caecum and large intestine contents in low dose animals within 12 hours after dosing can be explained by elimination via f ecal excretion.

In high d ose animals the highest concentration in most tissues (except stomach and smallFenpyrazamine Human Health Risk Assessment DP No

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Page 49 of 56 intestine, including contents) was reached 6 hour post

- dosing. This is supported by the previous pharmacokinetic study showing higher T
max in blood/plasma compared to low dose animals. The
decrease of concentration in caecum and large intestine contents between 6 up to 24 hours can be explai ned by excretion via f eces.

Regarding the metabolite pattern in plasma of low and high dose animals, there were some
differences in sex an d doses. While S

- 2188

- DC was the major metabolite in both sexes (but much higher amount were measured in females) and for both doses applied, the unknown metabolite “RT 31 min” was present at high amounts in low dose males but not quantified in low
dose fe males, which may indicate slightly different metabolite pattern in low dose males and females. No attempt was made to identify “RT 31 min”. For both sexes and doses, fenpyrazamine was minor in plasma, liver and kidney at each time point showing a rapid

met abolisation process. In high dose animals the difference in metabolites occurrence and amount measured in males and females was less pronounced.

In liver, additional unknown metabolites occurred compared to plasma samples, but no identification was perfor med. These unidentified metabolites made max. 30% and 17% in low dose males, respectively females and 13% and 15% in high dose males and females. The metabolite pattern of kidney was similar to that of liver. The results of plasma, liver and kidney

measure ment indicate that there are differences between sexes in metabolic degradation pathway of fenpyrazamine, as well as in metabolite pattern depending on the dose applied.

870.7600 Dermal Absorption

– Rat Summary (MRID 48793502): The highest amount of ra dioactivity was detected in the skin wash, showing a very low penetration of both spray dilution and concentrate. Absorption of
radiolabel occurred in a time

- dependent manner at both dose levels up to 168 hours post dose. After 168 hours the absorption was 1.74% for the concentrate and 13.35% for the spray dilution. Major part of radioactivity was detected in urine . The amount of radiolabel that may have been available for further absorption after 168

- hours post

- dose ranged from was 0.16% for the

concentrat e and 4.56% for the spray dilution . Since 10 tape strips were pooled, it is considered necessary to include radioactivity from all tape strips and skin at application site as becoming systemically bioavailable 1 . This is supported by the fact that no decline in excreta was observed up to 168 hours post

- dosing. Total recovery of radiolabel was 95.4 to 102.9%. Combing the absorbed and potentially systemically bioavailable (absorbable) radioactivity, the absorption for spray dilution was 17.91% and 1.9% for concentrate 168 hours post

- dosing.

A.4.9 Immunotoxicity

870.7800 Immunotoxicity In an immunotoxicity study (MRID 48400143 ), S

- 2188 Technical (Fenpyrazamine, 94.7% a.i.,
Batch 030

- 050914

- 1G) was administered in the diet to female HsdHan WIST rats ( 10/dose) at concentrations of 0, 500, 1500, or 4000 ppm (equivalent to 0, 36, 123, or 392 mg/kg bw/day, respectively) for at least 28 days. On Day 25, animals in all groups were immunized with a

1 Scientific report submitted to EFSA: Proposal for a Revision of the Guidance Document on Dermal Absorption. Dewhurst I., Samu els, S., Leslie, W. 2010.Fenpyrazamine Human Health Risk Assessment DP No

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Page 50 of 56 suspension of sheep red blood cells (2x10 8 SRBC) by intraveno us injection (1.0 mL/animal dose volume). Eight animals in the positive control group received an intraperitoneal injection of cyclophosphamide on Days 27 (two day prior to sacrifice) at a dose of 50 mg/kg bw (10 mL/kg bw application volume). On Day 29, a nimals were sacrificed by carbon dioxide asphyxiation followed by exsanguination. Spleens were harvested for evaluation of T

- cell dependent antibody response (TDAR) with an anti

- SRBC plaque

- forming

- cell (PFC) assay (Jerne 1963 2 ). Other parameters evaluat ed were: mortality, clinical signs, body weight changes, food and water consumption, gross pathology, and selected organ weights (liver, spleen, and thymus).

There were no test substance

- related effects on mortality, clinical signs, food, water consumption, and gross pathology at dose levels of 4000 ppm and below. Test substance

- related decreases in mean body weights (↓10%) and body weight gains (↓50

- 55%) were noted at necropsy in the 4000 ppm group. Increased absolute and relative to body weights values occurred in liver (↑22%), (↑34%) and spleen (↑10%), (↑23%) respectively. Liver weight was also increased at 1500 ppm by ↑11% absolute, and ↑13% (p<0.01) for rel ative weight. Absolute thymus weights were reduced (↓17%) at 4000 ppm. These changes occurred in the presence of a slight increase in food intake in week 4 at the highest dose. The liver weight changes at the 1500 ppm dose are not considered to be adverse since the terminal body weight was lower than the
control.

The systemic toxicity LOAEL is 4000 ppm, (equivalent to 392 mg/kg bw/day, highest dose tested) based on reduced body weights and body weight gains. The NOAEL for systemic toxicity is 1500 ppm ( equivalent to 123 mg/kg bw/day).

There was no statistically significant treatment

- related effect on the mean splenic cell count or
anti

- SRBC PFC activity measured by specific activity (PFC/10 6 spleen cells) or total activity (PFC/spleen) when compared wit h the control. A high inter

- individual variability was noted in all the treatment groups as well as in the control group. Evaluation of individual animal data of this study did not show any trend or distribution that would demonstrate significant suppressi on of anti

- SRBC PFC response. Animals in the positive control group showed marked decreases in splenic cell counts and specific activity (PFC/10 6 spleen cells) and total activity PFC/spleen). The positive control group confirmed the ability of the test sys tem to detect immuno

- suppressive effects and confirmed the validity of the study design.

The Natural Killer (NK) cells activity was not evaluated in this study. The toxicology database for Fenpyrazamine does not reveal any evidence of treatment

- related ef fects on the immune
system. The overall weight of evidence suggests that this chemical does not directly target the immune system. Under HED guidance, a NK cells activity assay is not required at this time.

Under the conditions of this study, the immunoto xicity NOAEL is 4000 ppm (equivalent to 392 mg/kg bw/day, highest dose tested); a LOAEL for immunotoxicity was not established.

This immunotoxicity study is classified as acceptable/guideline and satisfies the guideline requirement for an immunotoxicity study (OPPTS 870.7800) in the rat.

2 JERNE, N.K., NORDIN, A.A. (1963) Plaque formation in agar by single antibody producing cells

, Science 1 40 p 405.Fenpyrazamine Human Health Risk Assessment DP No

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Page 51 of 56 Appendix B. Metabolism Summary

B.1. Summary of the total radioactive residues of fenpyrazamine, metabolites and degradates.

Table B.1. Tabular Summary of Metabolites and Degradates 1

Chemical Name and
Structure Matrix Percent TRR (PPM)

Matrices

- Major Residue (>10%TRR) Matrices

- Minor Residue (<10%TRR)
Parent Fenpyrazamine ( S

- 2188 ) Grape 88

- 95%TRR, 13.8

- 41.5 mg/kg

Lettuce 81

- 82% TRR, 9.14

- 9.96 mg/kg
Rapeseed 16.2

- 21.8% TRR, 0.005

- 0.007 mg/kg
Rotational Crops 46.4%, 0.20 ppm (30 DAT, M Carrot Tops)

67.9%, 0.57 ppm (30 DAT, M Carrot Roots) 30.2%, 0.16 ppm (120 DAT, M Carrot Tops) 58.7%, 0.17 ppm (120 DAT, M Carrot Roots) 6.7%, 0.09 ppm (30DAT, W Forage) 0.4%, 0.007 ppm (30 DAT, W Hay)
0.7%, 0.008 ppm (120 DAT, W Hay) 0.2%, 0.008 ppm (30DAT, W Straw) 2.9%, 0.008 ppm (30 DAT, M Lettuce) 5.8%, 0.01 ppm (120 DAT, M Lettuce)

Ruminant 0.033 mg/kg, 13.7% TRR (liver)

0.002 mg/kg, 17.5% TRR (fat)

Rat 4.3% AD (Single dose) 1.1% AD (Repeated dose)

S

- 2188

- DC Grapes 1

- 5% TRR, 0.22

- 1.17 mg/kg

Lettuce 9

- 11% TRR, 1.05

- 1.24 mg/kg
Rapeseed 1.9

- 3.7% TRR, 0.001 mg/kg
Rotational Crops 1.0%, 0.1 ppm (30 DAT, W Forage)

Ruminant 0.041 mg/kg, 17.1% TRR (liver)

0.067 mg/kg, 41.0% TRR (kidney, free and conjugated) 0.003 mg/kg, 24.9% TRR (muscle) 0.004 mg/kg, 23.1% TRR (heart) 8.6% TRR, 0.002 mg/kg (milk)

Rat 44.9% AD (Single dose)

34.6% AD (Repeated dose)

S

- 2188

- OH Grapes 0.2

- 0.6% TRR, 0.05

- 0.18 mg/kg

Lettuce 0.2

- 0.3% TRR, 0.02

- 0.04 mg/kg
Rapeseed 1.6

- 4.0% TRR, 0.001 mg/kg
Rotational Crops 9.9%, 0.13 ppm (30 DAT, W Forage) 1.2%, 0.006 ppm (120 DAT,W Forage) 0.5%, 0.007 ppm (30 DAT, W Hay) 0.7%, 0.008 ppm (120 DAT, W Hay) 1.1%, 0.04 ppm (30DAT, W Straw) 2.0%, 0.03 ppm (120DAT, W Straw) 7.5%, 0.02 ppm (30 DAT, M Lettuce) 3.8%, 0.009 ppm (120 DAT,M Lettuce) 4.0%, 0.002 ppm (365 DAT,M Lettuce) 1.2%, 0.005 ppm (30 DAT, M Carrot Tops) 1.1%, 0.006 ppm (120 DAT,M Carrot Top) 0.3%, 0.002 ppm (30 DAT,M Carr ot Roots) 1.4%, <0.001 ppm (365 DAT, M Carr Root)

Rat 0.7% AD (Single dose) 2.7% AD (Repeated dose)Fenpyrazamine Human Health Risk Assessment DP No

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Page 52 of 56 S

- 2188

- (OH)2 Rotational Crops 10.8%, 0.06 ppm (120 DAT,M Carrot Top) 4.8%, 0.06 ppm (30 DAT, W Forage) 3.9%, 0.02 ppm (120 DAT,W Forage) 8.5%, 0.006 ppm (365 DAT,W Forage) 0.7%, 0.010 ppm (30 DAT, W Hay) 0.8%, 0.01 ppm (120 DAT (W Hay) 5.1%, 0.18 ppm (30DAT, W Straw) 3.7%, 0.05 ppm (120DAT, W Straw) 6.9%, 0.02 ppm (30 DAT, M Lettuce) 4.5%, 0.002 ppm (120 DAT,M Lettuce)

2. 3%, 0.01 ppm (30 DAT, M Carrot Tops) 7.7%, 0.006 ppm (365 DAT,M Carrot Top) 2.9%, 0.001 ppm (365 DAT, M Carr Root)
S

- 2188

- CH 2 OH

- DC Ruminant 0.003 mg/kg, 29.2% TRR (muscle) 0.039 mg/kg, 16.2% TRR (liver) 0.043 mg/kg, 26.3% TRR (kidney, free and conjugated)

Rat 18.4% AD (Single dose)

32.3% AD (Repeated dose) 3

1 For simplicity, only the residue levels in mature commodities of the rotational crops were included.

2 The repeated dose oral dosing study was performed for 14 days and the metabolism, excretion and tissue distribution were
studied.

3 Sum of MPZZ and S

- 2188

- CH 2 OH

- DC.

B.2. Nomenclature of fenpyrazamine, the metabolites and degradates.

Table B

. 2

. Chemical structure, codes and chemical names of fenpyraza m ine metabolites/degradates.

Common name/code

ID No. Chemical name (IUPAC, unless otherwise noted) Chemical structure

Fenpyrazamine (S

2188) S

- allyl 5

- amino

- 2,3

- dihydro

- 2

- isopropyl

- 3

- oxo

- 4

- ( o

tolyl)pyrazole

- 1

- carbothiaote

CAS: S

- 2

- propen

- 1

- yl 5

- amino

2,3

- dihydro

- 2

- (1

- methylethyl)

- 4

- (2

- methylphenyl)

- 3

- oxo

- 1 H

pyrazole

- 1

- carbothioate

S

- 2188

- DC 5

- amino

- 2

- isopropyl

- 4

- (o

- tolyl)

- 1 H

- pyrazol

- 3

- one

S

- 2188

- OH 5

- amino

- 4

- hydroxy

- 2

- isopropyl

4

- ( o

- tolyl)pyrazol

- 3

- oneFenpyrazamine Human Health Risk Assessment DP No

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Page 53 of 56 Table B

. 2

. Chemical structure, codes and chemical names of fenpyraza m ine metabolites/degradates.

Common name/code

ID No. Chemical name (IUPAC, unless otherwise noted) Chemical structure

S

- 2188

- (OH)2 4,5

- dihydroxy

- 4

- (2

- methylphenyl)

- 2

- (propan

- 2

- yl)

- 2,4

- dihydro

- 3 H

- pyrazol

- 3

- one

MCNI 2

- cyano

- N

- isopropyl

- 2

- ( o

tolyl)acetamide

S

- 2188

- CH 2 OH

- DC 5

- amino

- 1,2

- dihydro

- 4

- (2

- hydroxymethylphenyl)

- 2

- isopropyl

- pyrazol

- 3

- oneFenpyrazamine Human Health Risk Assessment DP No

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Page 54 of 56 B.3. Proposed metabolism pathways of fenpyrazamine in various matrices.Fenpyrazamine Human Health Risk Assessment DP No

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Page 55 of 56 Appendix C. Physical/Chemical Properties

Table C1. Physico

- Chemical Properties of Technical Grade Fenpyrazamine.

Parameter Value Reference 1,2

Molecular Weight 331.43 g/mol
pH (1% aqueous solution at 25°C) 5.47 483999

- 07
Water solubility (20°C) 20.4 mg/L (reagent grade water, pH 6.61) 483999

- 15

Solvent solubility (20°C) n

- hexane: 811 mg/L

n

- octanol: 99.174 and 105.230 g/kg toluene: 126.297 and 132.262 g/kg acetone, methanol, dichloromethane, and ethyl acetate: >250 g/L 483999

- 06 to
483999

- 07, 483999

- 09 to 483999

- 16,
and 484001

- 47

Vapor pressure at 25°C (Computer Modeling) 2.89x10 - 8 Pa (2.17x10 - 10 mmHg ) 483999

- 16

Dissociation constant, pKa No Results Reported 483999

- 13 Octanol/water partition coefficient, log K OW (25°C) 3.52 483999

- 14

Mobility (leaching, adsorption, desorption)

UK Clay Loam:
UK Silt Loam:

UK Loam: UK Loamy Sand: Japan Sandy Loam:
NJ Silt Loam: CA Loamy Sand: Koc = 250 mL/g; Kd = 8.7 mL/g; OC = 4.8% Koc = 343 mL/g; Kd = 7.4 mL/g; OC = 2.7%

K

oc = 123 mL/g; K d = 4.2 mL/g; OC = 3.8%

K

oc = 766 mL/g; K d = 5.7 mL/g ; OC = 0.8 %

K

oc =269 mL/g; K d = 6.6 mL/g ; OC = 3.2 %

K

oc = 366 mL/g; K d = 3.5 mL/g ; OC = 1.4%

K

oc = 585 mL/g; K d = 0.87 mL/g ; OC = 0.2% 48399919
48399919
48399919
48399919
48399919
48399922
48399922

Aqueous photolysis t 1/2 1.64 days (SFO) 48399924

Aerobic Soil Metabolism t 1/2 UK Sandy Loam: UK Sandy Loam:

UK Loam:
UK Silt Loam:
NJ Silt Loam: 49.3 days (alkaline, DFOP) 801 days (acidic, IORE) 37.7 days (alkaline, IORE) 230 days (acidic, DFOP) 201 days (acidic, IORE) 48399920
48399920
48399920
48399920
48399927

Anaerobic Soil Metabolism t 1⁄2 NJ Silt Loam: 128 days (acidic, SFO) 48399928

Aerobic aquatic metabolism t 1/2 UK Silty Clay Loam Sediment:
Swiss Lake Sand Sediment: 18.93 days (alkaline, SFO) 280 days (acidic, IORE) 48399929

Anaerobic aquatic metabolism t 1/2 MS Clay Sediment: 12.2 days (neutral, SFO) 48399930

1 Shyam Mathur, D388255, 4/27/2012

2 Gabe Rothman, D388319, 09/07/2012

3 Half life ( t 1/2 ) degradation kinetics scheme determinations: SFO = Single First Order; IORE = Indeterminate Order Rate Equation; DFOP = Double First Order in ParallelFenpyrazamine Human Health Risk Assessment DP No

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Page 56 of 56 Appendix D. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from PHED 1.1; the AHETF database; and the ORETF database, are (1) subjec t to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data so urces, as well as guidance on their use,
can be found at http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

.