Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

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 Identity ........................................................................................................... 9

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

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

3.4 Anticipated 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 Database ................................................... 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....................................................................... 22

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............................................................................. 25
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

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................................................................................ 56
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

Page 4 of 56

1.0 Executive Summary

Fenpyrazamine is a new pyrazole fungicide used to control grey mold 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, 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, pistachio and ornamentals. 

Foliar, aerial and chemigation applications of the aqueous-based suspension concentrate, V10135 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 several 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 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 abortions and premature deliveries in rabbits). In the multigeneration 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 liver 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 fenpyrazamine. 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 the 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. 388322 and 389274

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 being reduced to 1X, the cPAD 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 decreased 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-2188-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 proposed 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 95th percentile exposure and ≤ 7.3% of the cPAD for 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 wear 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 Protection 
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

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 quantitative 

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

D406080, 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 the 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. 388322 and 389274

Page 7 of 56

Enforcement Method - Parent fenpyrazamine only is the residue 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 considered 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 knowledge/experience with the 

method. 

Briefly, homogenized 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 the crop matrices. 

2.2.2 Recommended Tolerances

HED recommends that 40 CFR be amended by establishing tolerances for fenpyrazamine in/on 

the plant commodities listed in Table 2.2.2. Tolerances for livestock commodities and rotational 

crops are not needed 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 commodities 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 Fenpyrazamine1

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. 388322 and 389274

Page 8 of 56

Table 2.2.2. Tolerance Summary for Fenpyrazamine1

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 for 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. 388322 and 389274

Page 9 of 56

3.0 Introduction

3.1 Chemical Identity

TABLE 3.1 Test Compound Nomenclature.1

Compound Chemical Structure

Empirical Formula C17H21N3O2S

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-1yl-5-amino-2,3-dihydro-2-(1-methylethyl)-4-(2-methylphenyl)-3-

oxo-1H-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 conditions. 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 bodies, 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 with 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.

N

N

H2N

O

S

O
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

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 water/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 Fruit 

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.

For 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 

conditions still favor disease 

development, a third application 

should be made 7-10 days after the 

second spray.

Low 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 / acre.

Immediate Rotational Interval

For Gray Mold: First application at 

early bloom and continue on a 7 to 
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

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 to 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 Mummy 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. 388322 and 389274

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/acre.

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 disease 

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, pistachio 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 surface 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 the 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 fenpyrazamine. 

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption,

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the U.S. Department of 

Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, 
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

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 smaller, specialized subgroups and 

exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated risk 

estimates for adult applicators and for toddlers, youths, and adults entering or playing on treated 

areas post-application are evaluated. Further considerations are currently in development as OPP 

has committed resources and expertise to the development of specialized software and models 

that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 

patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

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 database 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 reproductive 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]

Metabolism 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 after prolonged (e.g., chronic) exposures; and (4) based 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. 388322 and 389274

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 absorption, 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 halflife (t1/2) of 2-3 hours at the low dose. At the high dose tested, a prolonged tmax of 6 hours, a 

longer t1/2 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 with 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 excretion 

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 differences in metabolism depending on the dose 

level administered. Metabolism 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 metabolism 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 detected 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 elongation. 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, hepatocellular 
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

Page 15 of 56

hypertrophy, and 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 weights 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 

mechanistic 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 enhances 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 dogs were 

reduced bodyweights/bodyweight 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-generation 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 abortions and premature 

deliveries on 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 toxicity 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 studies 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 on 
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

Page 16 of 56

the following weight of evidence considerations: 1) the marginal 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 support 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 can 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 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 studies in the database. 

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

There is no evidence 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 is 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 level 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. 388322 and 389274

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 this 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 detailed 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 addition, 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 studies 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 was 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 

endpoint 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 only 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, therefore, 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 developmental 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 of 
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

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 and 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 

and that the dose-selection in this study provides the most accurate description of the doseresponse curve for fenpyrazamine, an additional uncertainty factor for extrapolation from a 

short-term study to a long-term exposure scenario is not warranted.

Acute 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 factor 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 evaluation (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 deliveries) 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: The endpoint used for deriving the cPAD 

was selected 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 interspecies 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/guideline 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 hazard 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 is 
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

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 for 

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 determine 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 fenpyrazamine'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 

and 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

UFA= 10x

UFH= 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. 388322 and 389274

Page 20 of 56

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

and 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

UFA= 10x

UFH=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, Shortterm (1-30 

days) and 

IntermediateTerm (1-6 

months)

No residential uses of fenpyrazamine are proposed at this time.

Dermal Shortand 

IntermediateTerm (1-30 

days and 1-6 

months)

No residential uses of fenpyrazamine are proposed at this time.

Inhalation 

Short- and 

IntermediateTerm (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 or an estimated point that is derived from observed dose-response data and used to mark the beginning 

of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. 

LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = 

potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population 

adjusted dose (a = acute, c = chronic). RfD = reference dose. LOC = level of concern. N/A = not applicable.

Table 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 LongTerm (1-30 

days and 1-6 

months)

No hazard was identified. No quantification required.
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

Page 21 of 56

Table 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 

IntermediateTerm (1-30 

days, and 1-6 

months)

NOAEL = 

30 

mg/kg/day

UFA= 10x 

UFH= 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 adverse effect level. 

LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = 

potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population 

adjusted dose (a = acute, c = chronic). RfD = reference dose. 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, D406080, 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 [phenyl14C]- and [pyrazolyl-5-

14C]- 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 except in rapeseed, where >31.2% of the TRR was associated with radioactive 

residues in protein, starch and lignin. The majority of the radioactivity was identified as parent 

fenpyrazamine. The metabolite S-2188-DC is common to all crop metabolism studies and 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 detected 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 registrant. Although the TRR is >0.01 ppm in some commodities planted 365-

days after treatment, all the residues of fenpyrazamine in mature commodities harvested from 
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

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-CH2OH-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 balance 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 pathways 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 S2188-DC. Subsequent 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 S2188-CH2OH-DC were identified as major metabolites in rats and lactating goat. Cleavage 

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 risk 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 were recommended as parent 

fenpyrazamine and S-2188-DC based on a metabolism study with lactating goat. In addition, S2188-CH2OH-DC is included for risk assessment purposes as it is a major metabolite in muscle, 

liver, and kidney. For rotational crops, based on the 365-day plant back interval proposed by the 
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

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 metabolites/degradates S-2188-OH, S-2188-CH2OH-DC and MCNI; however, 

based on structural similarity to the parent, ROCKS assumes that the toxicity for these 

metabolites will 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 Tolerance 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 + S2188-CH2OH-DC Parent + S-2188 DC

Poultry Not Applicable1 Not Applicable1

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

D406080, 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 on the surface 

of the commodity. Moreover, the 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 fenpyrazamine ranging from 0.08 ppm 

in head 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 almond 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 decline studies. These studies showed that 

residues of parent fenpyrazamine and the combined residues (parent fenpyrazamine and the 

metabolite S-2188-DC) decrease or are relatively constant through the sampling period. The 

residues 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 confined rotational studies on carrots, wheat and 

lettuce that demonstrate there is uptake of radioactivity into aerial portion of those plants; 

however, quantifiable residues are not likely to be present in edible commodities harvested from 

crops planted 365-days after treating the primary crop. With respect to livestock commodities, 
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

Page 24 of 56

the 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. 

Adequate residue chemistry data have been provided. Field trials are of adequate number and 

geographic representation, were generated using adequate analytical methods. Storage stability 

issues were discussed in the residue chemistry chapter; however, the data 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. Estimated 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 SCIGROW (Screening Concentrations in Ground Water) 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 Environmental Fate and Effects Division.

The EDWCs were obtained from FIRST analysis using the 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 are 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 Water 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 fenpyrazamine 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 95th percentile of exposure are below HED’s level of concern (i.e. <100% aPAD) 

for the general U.S. population and all population subgroups. The results 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 

estimates are below HED’s level of concern (i.e. <100% cPAD) for the general U.S. population

and all population subgroups. The results are summarized in table 5.4.6. Children 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 (fenpyrazamine 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 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 and may, as appropriate, develop policies 

and procedures to identify the need for and, subsequently, the way to incorporate postapplication inhalation exposure into the Agency's risk assessments. 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 nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 
Fenpyrazamine 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 Spray Drift Task Force, EPA Regional Offices and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information at 

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

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

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

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT computer model to 

its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. 

After the policy is in place, the Agency may impose further refinements in spray drift 

management practices to reduce off-target drift with specific products with significant risks 

associated with drift.

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 performed 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 Exposure/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 Section 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 website 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 occupational exposure and risk assessment was conducted to support the new uses 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, pistachio

and ornamentals. Full details of that assessment are included in the memorandum cited above 

and the results are briefly summarized 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 fenpyrazamine. 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 inhalation 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 scenarios: 

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 subgroup, 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 ft2of 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 assess 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 data 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”, are 
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

Page 29 of 56

outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” 

(http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), which, along with 

additional information on HED policy on use of surrogate data, including descriptions of the 

various sources, can be found at http://www.epa.gov/pesticides/science/handler-exposuredata.html.

Estimates of inhalation 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, loaders, 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 inhalation protection (no respirator). Inhalation MOEs 

range from 4,000 (mixing/loading/applying soluble concentrate formulation by mechanicallypressurized 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 Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

Inhalation

Baseline Dose (mg/kg/day)4 MOE5

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

M/L/A, L/SC/EC, Mechanically- Nursery 3.9 1000 0.000244 120,000
Fenpyrazamine 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 Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

Inhalation

Baseline Dose (mg/kg/day)4 MOE5

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 is covered by the assessed 

maximum application rate of 0.5 lb ai/A for other orchard crops.

3 Exposure Science Advisory Council Policy #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. 388322 and 389274

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 previously 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 calculated 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), one 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 DFR 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 proposed 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 Category 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 assigned 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, there are multiple potential sources of post-application inhalation exposure to 

individuals performing post-application activities in previously treated fields. These potential 

sources include volatilization of pesticides and resuspension of dusts and/or particulates that 

contain pesticides. The Agency sought expert advice and input on issues related to volatilization 

of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory 

Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/sap/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 
Fenpyrazamine 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 inhalation 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.

The Worker Protection Standard 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 

applications)].

10.0 References

D404560; Fenpyrazamine. Occupational and Residential Exposure Assessment for a Proposed 

Use on Almond, Grape, Lettuce, Strawberry, and Ornamentals; and IR-4 Use on Bushberry, 

Caneberry, Ginseng, and Pistachio; A. LaMay; October 31, 2012.

D406080; 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 13-07B, Caneberry Subgroup 

13-07A, Ginseng, and Pistachio. Summary of Analytical Chemistry and Residue Chemistry 

Data; I. Negrón; October 31, 2012.

D406081; Fenpyrazamine. Acute and Chronic Aggregate Dietary (Food and Drinking Water) 

Exposure and Risk Assessments 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 Ginseng.; I. Negrón; October 31, 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 Inhalation 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

yes
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

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 LD50 > 2000 

mg/kg (♀) III

870.1200 Acute dermal [rat] 48400109 LD50 > 2000 

mg/kg (♂,♀) III

870.1300 Acute inhalation [rat] 48400111 LC50 > 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 decreased 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, protein, 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 observed 
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

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 DoseRange Finding -

developmental in 

(rabbit)

48400122 (2008)

Acceptable/Guideline

0, 60, 90, 120, 150 

mg/kg/day

Maternal NOAEL = 60 mg/kg/day

LOAEL = 90 mg/kg/day based on food refusal, 

abortions/premature deliveries.

Developmental 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

Maternal NOAEL = 30 mg/kg/day

LOAEL = 50 mg/kg/day based on decreased 

food consumption, decreased body weight,.

Developmental NOAEL = 50 mg/kg/day

LOAEL = 90 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. 388322 and 389274

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 activation
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

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 

decreased 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 decreased body weight/body weight gain.
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

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 S2188-DC. The latter underwent oxidation. 

Dealkylation of fenpyrazamine 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 major 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] S2188 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 halflives (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-

CH2OH-DC and MPPZ. S-2188-CH2OH-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. 388322 and 389274

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 S2188 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 formulation 

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 = 1x
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

Page 42 of 56

Comments about Study/Endpoint/Uncertainty 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 

potential 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 effects 

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 Establishing 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 data. 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 body 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. 388322 and 389274

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 Endpoint: 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. 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.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 decreased 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 – Rat
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

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 Inhalation – 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 urinary 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 sternum) 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 on 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 variations 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 27 of 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 gave birth prematurely and as a result, were sacrificed before the 
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

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 litters 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 control 

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/premature 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 weight 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 increased 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/kg 
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

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 Carcinogenicity 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 ( 24 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. 388322 and 389274

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 at 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 both 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, respectively). 

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 CO2 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 stomach 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. 388322 and 389274

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 fraction in males and females at high 

and low doses (particularly in females at the low dose). S-2188-DC was hydroxylised to form S2188-OH in only small amounts. Dealkylation of S-2188-DC to MPPZ was important in both 

sexes at high and low doses. MPPZ was conjugated 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 exceeding 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-CH2OH-DC and MPPZ was the major identified metabolite fraction in 

plasma, kidney, and lung. Parent fenpyrazamine was 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-CH2OH-DC contributed mostly to the 

identified radioactivity 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-CH2OH-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 females). 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, cage 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 [14C] S-2188 was more rapid at low than at high dose. Based on the toxicokinetic 

parameters investigated (AUC), the systemic availability increased with dose level applied. 

Longer T1⁄2 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 fecal excretion. 

In high dose animals the highest concentration in most tissues (except stomach and small 
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

Page 49 of 56

intestine, including contents) was reached 6 hour post-dosing. This is supported by the previous 

pharmacokinetic study showing higher Tmax 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 

explained by excretion via feces. 

Regarding the metabolite pattern in plasma of low and high dose animals, there were some 

differences in sex and 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 females, 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 

metabolisation 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 performed. 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 

measurement 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 radioactivity 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 

concentrate 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 bioavailable1. 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., Samuels, S., 

Leslie, W. 2010.
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

Page 50 of 56

suspension of sheep red blood cells (2x108SRBC) by intravenous 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, animals 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 19632). Other 

parameters evaluated 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 relative 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/106spleen cells) or total activity 

(PFC/spleen) when compared with 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 suppression 

of anti-SRBC PFC response. Animals in the positive control group showed marked decreases in 

splenic cell counts and specific activity (PFC/106spleen cells) and total activity PFC/spleen).

The positive control group confirmed the ability of the test system 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 effects 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 immunotoxicity 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 140 p 405.
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

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 Carrot 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. 388322 and 389274

Page 52 of 56

S-2188-(OH)2

N

N

O

CH3

HO

HO

H3C

CH3

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-CH2OH-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-CH2OH-DC.

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

Table B.2. Chemical structure, codes and chemical names of fenpyrazamine 

metabolites/degradates.

Common name/code

ID No.

Chemical name 

(IUPAC, unless otherwise noted)

Chemical structure

Fenpyrazamine (S2188)

S-allyl 5-amino-2,3-dihydro-2-

isopropyl-3-oxo-4-(otolyl)pyrazole-1-carbothiaote

CAS: S-2-propen-1-yl 5-amino2,3-dihydro-2-(1-methylethyl)-4-

(2-methylphenyl)-3-oxo-1Hpyrazole-1-carbothioate

S-2188-DC 5-amino-2-isopropyl-4-(o-tolyl)-

1H-pyrazol-3-one

S-2188-OH 5-amino-4-hydroxy-2-isopropyl4-(o-tolyl)pyrazol-3-one
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

Page 53 of 56

Table B.2. Chemical structure, codes and chemical names of fenpyrazamine 

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-3H-pyrazol-3-one

N

N

O

CH3

HO

HO

H3C

CH3

MCNI 2-cyano-N-isopropyl-2-(otolyl)acetamide

S-2188-CH2OH-DC 5-amino-1,2-dihydro-4-(2-

hydroxymethylphenyl)-2-

isopropyl-pyrazol-3-one
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

Page 54 of 56

B.3. Proposed metabolism pathways of fenpyrazamine in various matrices.
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

Page 55 of 56

Appendix C. Physical/Chemical Properties

Table C1. Physico-Chemical Properties of Technical Grade Fenpyrazamine.

Parameter Value Reference1,2

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 KOW (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%

Koc = 123 mL/g; Kd = 4.2 mL/g; OC = 3.8%

Koc = 766 mL/g; Kd = 5.7 mL/g ; OC = 0.8 %

Koc =269 mL/g; Kd = 6.6 mL/g ; OC = 3.2 %

Koc = 366 mL/g; Kd = 3.5 mL/g ; OC = 1.4%

Koc = 585 mL/g; Kd = 0.87 mL/g ; OC = 0.2%

48399919

48399919

48399919

48399919

48399919

48399922

48399922

Aqueous photolysis t1/2 1.64 days (SFO) 48399924

Aerobic Soil Metabolism t1/2

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 t1⁄2

NJ Silt Loam: 128 days (acidic, SFO) 48399928

Aerobic aquatic metabolism t1/2

UK Silty Clay Loam Sediment: 

Swiss Lake Sand Sediment: 

18.93 days (alkaline, SFO)

280 days (acidic, IORE)

48399929

Anaerobic aquatic metabolism t1/2

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 (t1/2) degradation kinetics scheme determinations:

SFO = Single First Order; IORE = Indeterminate Order Rate Equation; DFOP = Double First Order in Parallel
Fenpyrazamine Human Health Risk Assessment DP No. 388322 and 389274

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) subject 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 sources, as well as guidance on their use, 

can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

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