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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

Date: 31-JUL-2013

SUBJECT: Prometryn: Human-Health Risk Assessment for the Proposed Uses on Snap Bean 

and Dill.

PC Code: 080805 DP Barcode: D403975

Decision No.: 467531 Registration No.: 100-620

Petition No.: 2E8052 Regulatory Action: Section 3 Registration

Risk Assessment Type: Single Chemical/Aggregate Case No.: 467

TXR No.: NA CAS No.: 7287-19-6

MRID No.: NA 40 CFR: §180.222

FROM: Kelly M. Lowe, Environmental Scientist 

Anwar Y. Dunbar, Ph.D., Pharmacologist

Sarah J. Levy, Chemist

Lata Venkateshwara, Environmental Scientist

Risk Assessment Branch 1 (RAB1)

Health Effects Division (HED, 7509P)

THROUGH: Dana M. Vogel, Associate Director

George F. Kramer, Ph.D., Senior Chemist

RAB1/HED (7509P)

TO: Laura Nollen

Barbara Madden

Registration Division (RD, 7505P)

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human 

health from exposure to pesticides. The Interregional Research Project No. 4 (IR-4) has 

requested registration of the active ingredient (ai) prometryn for use on snap bean and dill. The 

RD of OPP has requested that HED evaluate hazard and exposure data and conduct dietary, 

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

health that will result from the proposed/registered uses of prometryn. 

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

and registered uses of prometryn are provided in this document. The risk assessment was 

provided by Kelly Lowe (RAB1); the residue chemistry and dietary assessments by Sarah Levy 

(RAB1); the hazard characterization and endpoint selection by Anwar Dunbar (RAB1); the 

occupational and residential exposure assessment by Lata Venkateshwara (RAB1); and the 
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drinking water exposure assessment by Mohammed Ruhman of the Environmental Fate and 

Effects Division (EFED).
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Table of Contents

1.0 Executive Summary........................................................................................................... 5

2.0 HED Recommendations.................................................................................................... 8

2.1 Data Deficiencies ............................................................................................................ 8

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

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

2.2.2 Recommended Tolerances...................................................................................... 9

2.2.3 Revisions to Petitioned-For Tolerances .............................................................. 10

2.2.4 International Harmonization............................................................................... 10

2.3 Label Recommendations.............................................................................................. 10

2.3.1 Recommendations from Residue Reviews.......................................................... 10

2.3.2 Recommendations from Occupational Assessment........................................... 10

3.0 Introduction...................................................................................................................... 11

3.1 Chemical Identity ......................................................................................................... 11

3.2 Physical/Chemical Characteristics ............................................................................. 12

3.3 Pesticide Use Pattern.................................................................................................... 12

3.4 Anticipated Exposure Pathways................................................................................. 13

3.5 Consideration of Environmental Justice.................................................................... 13

4.0 Hazard Characterization and Dose-Response Assessment.......................................... 14

4.1 Toxicology Studies Available for Analysis................................................................. 14

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)............................. 14

4.2.1 Dermal Absorption ............................................................................................... 15

4.3 Toxicological Effects .................................................................................................... 15

4.4 Safety Factor for Infants and Children (FQPA SF).................................................. 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.............................................. 16

4.5.1 Dose-Response Assessment .................................................................................. 16

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment. 18

4.5.3 Cancer Classification and Risk Assessment Recommendation ........................ 18

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

Assessment........................................................................................................................... 18

5.0 Dietary Exposure and Risk Assessment......................................................................... 19

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

5.1.1 Summary of Plant and Livestock Metabolism Studies...................................... 19

5.1.2 Summary of Environmental Degradation .......................................................... 20

5.1.3 Comparison of Metabolic Pathways.................................................................... 20

5.1.4 Residues of Concern Summary and Rationale................................................... 20

5.2 Food Residue Profile .................................................................................................... 21

5.3 Water Residue Profile.................................................................................................. 22

5.4 Dietary Risk Assessment.............................................................................................. 23

5.4.1 Description of Residue Data Used in Dietary Assessment ................................ 23

5.4.2 Percent Crop Treated Used in Dietary Assessment........................................... 23

5.4.3 Acute Dietary Risk Assessment ........................................................................... 23

5.4.4 Chronic Dietary Risk Assessment ....................................................................... 23

5.4.5 Cancer Dietary Risk Assessment......................................................................... 23

5.4.6 Summary Table..................................................................................................... 23

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 24
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6.1 Residential Bystander Post-application Inhalation Exposure ................................. 24

6.2 Spray Drift.................................................................................................................... 24

7.0 Aggregate Exposure/Risk Characterization.................................................................. 25

7.1 Acute Aggregate Risk................................................................................................... 25

7.2 Chronic Aggregate Risk .............................................................................................. 25

8.0 Cumulative Exposure/Risk Characterization ............................................................... 25

9.0 Occupational Exposure/Risk Characterization ............................................................ 26

9.1 Short-/Intermediate-Term Handler Risk................................................................... 26

9.2 Short-/Intermediate-Term Post-Application Risk .................................................... 27

9.2.1 Dermal Post-application Risk.............................................................................. 27

9.2.2 Inhalation Post-application Risk ......................................................................... 28

10.0 References......................................................................................................................... 29

Appendix A. Toxicology Profile and Executive Summaries .................................................. 31

A.1 Toxicology Data Requirements................................................................................... 31

A.2 Toxicity Profiles............................................................................................................ 32

Appendix B. Physical/Chemical Properties............................................................................. 35

Appendix C. Review of Human Research................................................................................ 36
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1.0 Executive Summary

Background: Prometryn [2,4-bis(isopropylamino)-6-methylthio-s-triazine] is a substituted 

thiomethyl triazine herbicide (Group 5) registered in the U.S. for the control of weeds in a 

number of agricultural crops, such as celery, cotton, dill, pigeon peas, carrot, celeriac, cilantro, 

okra, parsley, and leaf petioles (crop subgroup 4B). Permanent tolerances for the residues of 

prometryn are currently established in/on a variety of crops (40 CFR §180.222). There are no 

residential uses registered for prometryn. 

IR-4 and the registrant, Syngenta, have submitted a petition proposing a tolerance for prometryn 

use on snap bean and dill. Proposed end-use product labels were not submitted with this petition 

due to indemnification concerns. Indemnification allows registrants to place a waiver of liability

statement on their product label. It is currently only available through the Section 24(c) process, 

and is intended mainly for minor-use crops. According to the petition, Syngenta does intend to 

allow this use via a Section 24(c) in the future. 

Section B of the petition provides indemnified label language for the IR-4 submission of the enduse product Caparol®

4L (EPA Reg. #100-620). The language indicates that the user is to follow 

all applicable directions, restrictions, Worker Protection Standard (WPS) requirements, and 

precautions on the EPA-registered end-use product label. Caparol®4L is a selective herbicide 

that may be applied either before or after weeds emerge for control of most annual broadleaf 

weeds and grasses. The proposed use directions allow for one application per year on snap beans 

and dill at rates ranging up to 1.6 pounds (lbs) ai per acre (A) using ground equipment. 

Preharvest intervals (PHIs) of 52 and 30 days are proposed for snap bean and dill, respectively. 

In conjunction with this petition, IR-4 has requested the establishment of permanent tolerances 

for the residues of prometryn in or on the commodities summarized in Table 2.2.2.1.

Hazard Assessment: Prometryn was categorized as having minimal acute toxicity via the oral, 

dermal, and inhalation routes (Category III or IV). It was mildly irritating to the eyes and 

slightly irritating to the skin, but not a sensitizer of the skin. Prometryn is distributed primarily

to the blood, spleen, and lungs. It is extensively metabolized in rats, with <2% of recovered 

material representing the parent compound, and is excreted predominantly in the urine and feces.

No evidence of local or systemic toxicity was observed in a 21-day dermal toxicity study in 

rabbits. The only subchronic oral feeding study available for prometryn is a 28-day feeding 

study in mice, in which prometryn caused decreased body weight and/or mortality at doses that 

exceeded the limit dose. In chronic oral toxicity studies, effects primarily occurred only at the 

highest doses tested for dogs (degenerative hepatic changes, renal tubule degeneration, and bone 

marrow atrophy), rats (decreased body weight, decreased body-weight gains, and renal toxicity), 

and mice (decreased body-weight gain), with the dog considered to be the most sensitive species. 

In developmental studies with prometryn, effects were observed primarily at the highest doses 

tested. Furthermore, fetal effects (decreased fetal body weight, incomplete ossification of 

sternebrae and metacarpals in rats, and a decreased number of viable litters and live fetuses in 

rabbits) were observed at the same doses as maternal toxicity (decreased body weight, decreased 

food consumption, and clinical signs of toxicity in rats, and decreased food consumption and an 

increased incidence of resorptions, abortions, and post-implantation loss in rabbits). In the twogeneration rat reproductive study, no evidence of toxicity to the reproductive organs was 

observed and the effects that were observed in the offspring (decreased body weights) occurred 
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at the same dose as those observed in parental animals (decreased food consumption, body

weight, and body-weight gain). 

Preliminary review of the rat acute and subchronic neurotoxicity studies reveals lower mean total 

and/or ambulatory locomotor activity counts noted for both sexes on the first day of treatment in 

the acute study, and no signs of neurotoxicity in the subchronic study. In the immunotoxicity

study, there was a decreased humoral response in the sheep red blood cell assay, though this 

effect is not expected to impact the risk assessment. There was no evidence of carcinogenicity in 

either mice or rats, and prometryn was non-mutagenic. 

Since the last risk assessment, HED’s Hazard and Science Policy Council (HASPOC) evaluated 

all existing hazard and exposure data, and current use patterns for prometryn, and used a weightof-evidence approach to require a subchronic inhalation toxicity study. In the absence of a routespecific inhalation study, the HASPOC recommends that a 10X database uncertainty factor be 

applied when assessing risks for inhalation exposure scenarios.

Dose-Response and Food Quality Protection Act (FQPA) Assessments: The prometryn risk 

assessment team has recommended that the FQPA Safety Factor (SF) be reduced to 1X for the 

following reasons: (1) there is an adequate toxicity database for prometryn; (2) preliminary

review of the neurotoxicity studies show some indication of neurotoxicity in the acute study;

however, the level of concern (LOC) is low since the point of departure (POD) chosen for risk 

assessment is lower and considered protective of these effects; (3) there is no evidence of 

susceptibility, and no residual uncertainties concerning pre- or post-natal toxicity; and (4) there 

are no residential uses for prometryn, and the dietary assessments will not underestimate 

exposure.

A no-observed adverse-effect level (NOAEL) of 12 mg/kg/day from the developmental toxicity

study in rabbits was chosen for the acute reference dose (aRfD) for females 13-49 years of age. 

A NOAEL of 3.75 mg/kg/day from the chronic toxicity study in the dog was chosen for the 

chronic reference dose (cRfD). Since the FQPA SF has been reduced to 1X, both the acute 

population-adjusted dose (aPAD) and the chronic population-adjusted dose (cPAD) are equal to 

the aRfD and the cRfD, respectively. The short- and intermediate-term dermal and inhalation 

PODs are based on the NOAEL of 12 mg/kg/day from the oral developmental toxicity study in 

the rabbit. The LOC is for margins of exposure (MOEs) <100 for dermal (10X interspecies 

factor and 10X intraspecies factor) and <1000 for inhalation (10X interspecies factor, 10X 

intraspecies factor, and 10X database uncertainty factor). 

Metabolism and Food Residue Profile: Acceptable plant and livestock metabolism studies have 

been submitted, with the exception of a root crop metabolism study. The studies already

submitted and reviewed indicate that the metabolic pathway involves N-dealkylation and 

hydrolysis of prometryn. HED determined that the residue of concern in plants and livestock is 

the parent, prometryn per se, which is the currently regulated residue. The submitted residue 

analytical methods data are adequate to satisfy data requirements for the proposed uses. 

Acceptable enforcement methodology is available for tolerance enforcement purposes for the 

proposed uses, and adequate data-collection methods were used in the submitted field trial and 

processing studies. 

Dietary Exposure and Risk Assessment: Acute and chronic risk assessments were conducted 

for dietary exposure based on the existing and proposed uses. The acute and chronic assessments 

directly incorporated drinking water estimates. Assumptions for the acute and chronic 
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assessments included tolerance-level residues for all foods, Dietary Exposure Evaluation Model 

(DEEM) 7.81 default processing factors (where provided), and 100% crop-treated (CT). All 

exposure and risk estimates were not of concern. The resulting acute dietary (food + drinking 

water) risk estimates utilized 17% of the aPAD for the females 13-49 years old population 

subgroup, the only acute population subgroup of concern for this assessment. The resulting 

chronic dietary (food + drinking water) risk estimates utilized 8.6% of the cPAD for the general 

U.S. population and 23% of the cPAD for all infants (<1 year old), the most highly exposed 

population subgroup. A cancer dietary assessment was not conducted because prometryn is 

classified as “Group E: Evidence of non-carcinogenicity for humans.”

Residential (Non-Occupational) Exposure/Risk Assessment: There are no registered or 

proposed residential uses for prometryn; therefore, a residential exposure assessment was not 

conducted.

Aggregate Exposure/Risk Assessment: Since there are no residential uses, only acute and 

chronic aggregate risk assessments were conducted, and are made up only of dietary sources 

(food and drinking water). The dietary exposure analyses represent acute and chronic aggregate 

exposure, respectively. Prometryn is classified as “Group E: Evidence of non-carcinogenicity 

for humans”; therefore, cancer aggregate risk assessments were not performed.

Occupational Exposure/Risk Assessment: Based on the proposed use patterns, there is potential 

for short- and intermediate-term occupational exposure to prometryn during mixing, loading, 

applying, and other handling tasks for groundboom and chemigation applications; and during 

post-application activities. Additionally, since the same endpoint and POD were selected for 

short- and intermediate-term durations, short-term exposure and risk estimates are considered to 

be protective of potential longer-term exposure and risk. Chronic exposure is not expected for 

the proposed agricultural uses. For the proposed uses, all occupational handler scenarios, except 

mixing/loading liquids for chemigation applications, result in MOEs greater than the LOC (i.e., 

MOEs ≥100 for dermal and ≥1,000 for inhalation) at baseline (i.e., single layer of clothing, no 

gloves, no respirator) and the combined dermal and inhalation risk estimates, expressed as an 

aggregated-risk index (ARI), are greater than 1 with baseline attire. HED has determined that 

gloves are required to reach acceptable MOEs and ARIs for the mixing/loading liquids for 

chemigation applications scenario. The registered label for Caparol®4L (EPA Reg. #100-620) 

already requires the use of chemical-resistant gloves as personal-protective equipment (PPE) for 

applicators and other handlers; therefore, there is no risk of concern for this scenario with the 

current label PPE. 

HED has determined that short- and intermediate-term risk estimates are not of concern (i.e., 

MOEs ≥100) on the day of treatment (i.e., day 0) for most post-application exposure activities. 

However, there were risk estimates of concern related to one post-application activity for snap 

beans and dill: hand-set irrigation (MOEs of 81 and 86 on Day 0 for snap bean and dill, 

respectively). It should be noted that the transfer coefficient used to represent the hand-set 

irrigation activity is based on a study in which wet foliage was contacted by volunteers, and in 

addition, the volunteers performing the activities in the study (potato irrigation) did not wear 

waterproof boots, which would normally be worn. Therefore, the use of this transfer coefficient 

to represent activity associated with hand-set irrigation is considered a conservative assumption. 

This is particularly true for the proposed uses being assessed here, snap bean and dill, where the 

applications are to be made early season (pre-emergence or soon after emergence), while the 

applications in the transfer coefficient study were made late season when the crop (potato) was 

fairly tall.
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This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. Please refer to Appendix C for a 

discussion of the human study data used in this risk assessment. 

2.0 HED Recommendations

HED can recommend for a registration and tolerance for the use of prometryn on snap bean and 

dill. Additional data are needed as outlined in Section 2.1 below. The specific tolerance 

recommendations are discussed in Section 2.2, and label modifications are discussed in Section 

2.3.

2.1 Data Deficiencies

The following data gaps have been identified: 

 Nature of the Residue Study in a root crop (OCSPP 860.1300): This is an outstanding 

data request from the 2009 risk assessment (W. Wassell et al., 05-AUG-2009; D367830).

The registrant submitted a metabolism study in rice with rationale as to why this study

was submitted instead of the requested study in a root crop. HED reviewed this study

and while it is adequate, it presents a qualitatively different metabolic profile than the 

other submitted studies on celery and cotton; therefore, HED is still requesting the root 

crop metabolism study in this current risk assessment. Depending on results of the root 

crop metabolism study, additional field trial data could be required.

 90-Day Inhalation Toxicity Study (OCSPP 870.3465): This is a new requirement based 

on an evaluation by HED’s HASPOC. 

 Dislodgeable Foliar Residue (DFR) Study (OCSPP 875.2100): This is a new requirement 

based on HED’s Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and 

Dislodgeable Foliar Residue (DFR) Studies (Memo, J. Housenger, 12-DEC-2012). In 

addition, there are risk estimates of concern for post-application activities for the 

proposed uses using our default assumptions at the 12-hour restricted entry interval (REI)

currently on the label. The REI on the label will need to be changed to 48 hours based on 

the current assessment.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate enforcement methodology is available to enforce the proposed tolerances. Prometryn 

is completely recovered (>80% recovery) using the Food and Drug Administration’s (FDA’s) 

Multiresidue Section 302 and partially recovered (22-87% recovery) using Sections 303 and 304, 

with the recovery varying depending upon the choice of Florisil system used.

In addition, an acceptable gas chromatography (GC) method with flame-photometric detection in 

the sulfur mode (FPD/S), Ciba-Geigy Method AG-559, is available for use as a single-analyte 

confirmatory method. Method AG-559 has undergone a successful independent laboratory

validation (ILV; Memo, E. Zager, 24-MAY-1991; D160100). This method was radiovalidated 

using samples from the celery metabolism study; however, these samples contained no 

detectable residues of prometryn. HED previously concluded that Method AG-559 is acceptable 

for enforcement purposes, pending completion of a successful Agency method validation trial. 
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The Residue Chemistry Chapter of the Prometryn RED also required radiovalidation of the 

method using samples from the cotton metabolism study.

In response to the radiovalidation data requirements, Syngenta submitted a method description 

and validation data for a GC/nitrogen phosphorous detector (NPD) method, Method AG-673, for 

the determination of prometryn residues in/on cotton matrices. The method adequately 

determines residues of prometryn, and its metabolites GS-11354 and GS-26831, in cottonseed

and gin byproducts. Method AG-673 specifies that analyte residues may be confirmed by 

equipping the GC system with a flame-photometric detector (FPD), as described for Method AG559. The extraction procedures of Method AG-673 are similar to those of AG-559. No ILV data 

were submitted for Method AG-673; however, since adequate ILV data have been submitted for 

Method AG-559, HED will not require additional ILV data for Method AG-673. Method AG673 and Method AG-559 are both considered adequate for enforcement purposes.

2.2.2 Recommended Tolerances

Pending submission of a revised Section F (see requirement in Section 2.2.3), HED recommends

granting a registration and tolerance for the use of prometryn on the requested crops. The 

proposed uses and the submitted data support the tolerances identified in Table 2.2.2.1 for 

residues of the herbicide prometryn in or on the commodities. Compliance with the tolerance 

levels specified below is to be determined by measuring only prometryn [2,4-

bis(isopropylamino)-6-methylthio-s-triazine]. 

Table 2.2.2.1. Tolerance Summary for Prometryn

Commodity Established/Proposed 

Tolerance (ppm)

HEDRecommended 

Tolerance (ppm)

Comments

Correct Commodity Definition

Bean, snap, succulent 0.05 0.05

Bean, forage 0.09 0.09 A tolerance is not necessary for this 

commodity.

Dill, leaves 0.3 0.30

Concurrent with granting a national 

registration, the removal of the 

regional restrictions on dill should be 

removed.

Dillweed, fresh leaves

Dill, dried leaves 1.1 1.1

Dill, oil 1.3 --

A tolerance is not necessary for this 

commodity.

In accordance with the most recent guidance concerning tolerance expressions, HED 

recommends that the tolerance expression for 40 CFR §180.222 be changed as indicated below. 

“(a) General. Tolerances are established for residues of the herbicide prometryn, including its 

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

tolerance levels specified below is to be determined by measuring only prometryn ([2,4-

bis(isopropylamino)-6-methylthio-s-triazine] in or on the following raw agricultural 

commodities:

and

(d) Indirect or inadvertent residues. Tolerances are established for indirect or inadvertent 

residues of the herbicide prometryn, including its metabolites and degradates, in or on the 
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commodities in the table below. Compliance with the tolerance levels specified below is to be 

determined by measuring only prometryn ([2,4-bis(isopropylamino)-6-methylthio-s-triazine] in 

or on the following raw agricultural commodities:”

Note to PM: Concurrent with the establishment of the HED-recommended tolerances for 

residues in/on dillweed, fresh leaves and dill, dried leaves, the established tolerance of 0.3 ppm 

in/on dill with regional restriction should be removed in 40 CFR §180.222(c).

2.2.3 Revisions to Petitioned-For Tolerances

In accordance with Agency guidance on tolerance expressions, the tolerance expressions for 

prometryn were revised by clarifying that the tolerances cover “residues of prometryn, including 

its metabolites and degradates.” There were no additional revisions needed to the petitioned-for 

tolerances for bean, snap, succulent or dill, dried leaves. There is currently a prometryn 

tolerance established in/on dill, leaves at 0.3 ppm with a regional restriction. This tolerance level 

is adequate and HED agrees with the petitioner to remove the regional restriction for this crop. 

However, the commodity definition should be changed from dill, leaves to dillweed, fresh 

leaves. The petitioner also proposed tolerances for residues of prometryn in/on bean, forage and 

dill, oil; however, tolerances are not necessary as bean, forage is an insignificant livestock feed 

item and dill, oil is not a regulated commodity. 

2.2.4 International Harmonization

There are currently no established Codex maximum residue limits (MRLs) for prometryn; 

therefore, harmonization is not an issue. 

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

There are no label recommendations based on the residue chemistry reviews.

2.3.2 Recommendations from Occupational Assessment

HED recommends that RD ensure the appropriate REI for prometryn be included on the product 

label based on the results of the occupational post-application exposure assessment. MOEs are 

not of concern for the hand-set irrigation activity for the proposed crops 2 days (48 hours) after 

application. Chemical-specific DFR data are not available for prometryn, and could be used to 

refine the assessment. 
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N

N

N

OH

N N

CH

H

CH3

CH3

CH

H

H3C

CH3

3.0 Introduction

3.1 Chemical Identity

Table 3.1.1. Prometryn Nomenclature.

Chemical structure

Common name Prometryn

Company experimental name G-34161

IUPAC name N,N'-diisopropyl-6-(methylthio)-1,3,5-triazine-2,4-diamine

CAS name N,N'-bis(1-methylethyl)-6-(methylthio)-1,3,5-triazine-2,4-diamine 

CAS registry number 7287-19-6

End-use product (EP) Caparol®4L (4 lb/gal FlC; EPA Reg. No. 100-620)

GS-11354

2-amino-4-iospropylamino-6-methylthio-s-triazine

GS-26831

N

N

N

NH2

NH2S

H C3

2,4-bis-amino-6-methylthio-s-triazine

GS-11526 

4,6-bis-isopropylamino-[1,3,5]triazine-2-ol

N

N

N

S

CH3

N N

CH

H

CH3

CH3

CH

H

H3C

CH3

N

N

N

S

CH3

N

CH

H

CH3

CH3

N

H

H
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Table 3.1.1. Prometryn Nomenclature.

GS-16141

4,6-bis-isopropylamino-2-methanesulfinyl-[1,3,5] triazine

GS-17794

4 arnino-6-isopropylarnino-(1,3,5jtriazine-2-ol) 

3.2 Physical/Chemical Characteristics

Prometryn is a substituted thiomethyl triazine herbicide. Its vapor pressure is 8.54 x 10-7 mm Hg 

at 25oC. Prometryn and its degradates are mobile to very mobile in soil. Potential transport 

mechanisms include runoff to surface water, leaching to ground water, spray drift, and secondary 

drift of volatilized or soil-bound residues leading to deposition onto nearby or more distant 

ecosystems. According to the submitted physical-chemical and environmental fate data, the 

degradation of prometryn is driven by microbial (biotic) activity and not by abiotic processes; 

however, biotransformation is slow. The major biotransformation product is GS-11526. The 

low Freundlich adsorption coefficient of prometryn suggests that the chemical has the potential 

to run off and/or leach to ground water. Prometryn is stable to hydrolysis and direct photolysis 

in aqueous media. A table of the physicochemical properties can be found in Appendix B. 

3.3 Pesticide Use Pattern

The petitioner has submitted a petition proposing a tolerance for prometryn use on snap bean and 

dill. Proposed end-use product labels were not submitted with this petition due to 

indemnification concerns (i.e., waivers of liability statements on the product label). The intent of 

the company is to allow this use via a Section 24(c) in the future. 

Section B of the petition provides indemnified Caparol®4L label language for the IR-4 

submission. The language indicates that the user is to follow all applicable directions, 

restrictions, WPS requirements, and precautions on the EPA-registered end-use product label

(EPA Reg. #100-620). The information pertaining to the proposed uses is listed in Table 3.3.1.

A summary of the recommended label changes can be found in Section 2.3. 

It should be noted that prometryn is already registered for use on dill; however, the current 

registration is limited to a regional tolerance. The petitioner has submitted additional data to 

expand the regional tolerance to a national tolerance.

N

N

N

S

CH3

N N

CH

H

CH3

CH3

CH

H

H3C

CH3

O
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Permanent tolerances for the residues of prometryn are currently established in/on a wide variety 

of crops and crop groups in 40 CFR §180.222 (a), ranging from 0.05 ppm for okra and celeriac

roots to 9 ppm for the dried leaves of coriander. A tolerance with a regional exemption is

established in 40 CFR §180.222(c) for dill at 0.3 ppm. Additionally, indirect tolerances are 

established in 40 CFR §180.222(d) for a variety of food commodities including barley, oat, rye, 

triticale, and wheat, ranging from 0.3 to 1.0 ppm. 

Table 3.3.1. Summary of Directions for Use of Prometryn

Applic. 

Timing, Type, 

and Equip.

Formulation 

[EPA Reg. 

No.]

Max. 

Applic. 

Rate (lb 

ai/A)

Max. No. 

Applic. 

per Season

Max. 

Seasonal 

Applic. Rate 

(lb ai/A)

PHI 

(days)

Use Directions and 

Limitations

Snap Bean

Groundboom

Chemigation

Caparol®4L, 

44% prometryn 

(ai), 4 lb ai/gal 

liquid 

formulation

[100-620]

1.5 1

1.5 per crop 

cycle 52 

Can be applied 

preemergence (post 

planting). Do not use on 

sand or loamy sand soil.

Dill

Groundboom

Chemigation

Caparol®4L, 

44% prometryn 

(ai), 4 lb ai/gal 

liquid 

formulation

[100-620]

1.6 1

1.6 per crop 

cycle 30 

Can be applied either preemergence (post planting) 

or post-emergence. Do 

not use on sand or loamy 

sand soil.

3.4 Anticipated Exposure Pathways

RD has requested an assessment of human health risk to support the proposed new use of 

prometryn on snap bean and dill. Humans may be exposed to prometryn in food and drinking 

water, since prometryn may be applied directly to growing crops and application may result in 

prometryn reaching surface and ground water sources of drinking water. There are no residential 

uses of prometryn, so exposure is not likely 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. 

Risk assessments have been previously prepared for the existing uses of prometryn. This risk 

assessment considers all of the aforementioned exposure pathways based on the proposed new 

uses of prometryn, but also considers the existing uses as well for the dietary exposure 

assessment. 

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."

1

 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 

 

1

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf
Prometryn Human-Health Risk Assessment D403975

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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 United 

States Department of Agriculture (USDA) under the National Health and Nutrition Examination 

Survey, What We Eat in America (NHANES/WWEIA; 2003-2008), and are used in pesticide 

risk assessments for all registered food uses of a pesticide. These data are analyzed and

categorized by subgroups based on age, season of the year, ethnic group, and region of the 

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

and exposure assessments are performed when conditions or circumstances warrant. Whenever 

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

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

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

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

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

patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicology database for prometryn is adequate for characterization of its hazard, toxicity

endpoint selection, and FQPA consideration. In the last Section 3 risk assessment (W. Wassell et 

al., 05-AUG-2009; D367830), immunotoxicity and neurotoxicity screening battery test studies 

were reported as data gaps. These studies have since been submitted and are pending formal 

review. Preliminary review suggests that they will not affect the endpoints selected for assessing 

dietary and occupational risks of concern. 

Since the last risk assessment, HED’s HASPOC evaluated all existing hazard and exposure data, 

and current use patterns for prometryn, and used a weight-of-evidence approach to require a 

subchronic inhalation toxicity study (Memo, J. Van Alstine, 21-FEB-2013; TXR#005625). In 

the absence of a route-specific inhalation study, the HASPOC recommends that a 10X database 

uncertainty factor be applied when assessing risks for inhalation exposure scenarios.

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

In the rat metabolism study, animals received a single dose of prometryn at 0.46 mg/kg (low 

dose) and 467 mg/kg (high dose). Animals were also repeatedly dosed at 0.46 mg/kg for 14 

days. Absorption from the gastrointestinal (GI) tract was not experimentally measured; however, 

estimates were made based upon the urinary excretion profile; 47.06-53.3% of the 0.46 mg/kg 

single oral dose was estimated to have been absorbed. A bile duct ligation experiment was not 

performed, so it is unclear whether there was a greater amount of absorption from the GI tract 

than the fraction detected in the urine. Prometryn is distributed primarily to the blood, spleen, 

and lungs. There was a dose-related increase in tissue levels. Prometryn is extensively

metabolized in rats, with <2% of recovered material representing the parent compound. 

Prometryn is excreted predominantly in the urine (47.06-53.3%) and feces (33.13-45.48%) out to 

7 days post-dosing. These values were similar following 14 days of repeated low dosing, and for 

the high-dose group at 7 days. Greater than 90% of the radiolabel was excreted by both sexes in 

the low-dose groups by 24 hours. Urinary and fecal excretion was greater than 90% complete 

for the high-dose animals at 72 hours post dosing. 
Prometryn Human-Health Risk Assessment D403975

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4.2.1 Dermal Absorption

A dermal absorption study is not available for evaluation. An absorption factor of 15% was 

estimated based on comparison of data from the developmental and dermal studies in rabbits 

(Memo, J. Rowland, 24-OCT-1997; TXR#0012371). In the oral developmental toxicity study in 

rabbits, the lowest-observed adverse-effect level (LOAEL) was 72 mg/kg/day based on 

decreased food consumption, increased resorptions, abortions, and post implantation loss as well 

as a decreased number of viable litters and fetuses. In the dermal toxicity study in non-pregnant 

adult rabbits, no dermal or systemic toxicity was observed at the limit-dose of 1000 mg/kg/day. 

Due to the uncertainties in extrapolating from the oral to dermal route from the available data, a 

conservative dermal-absorption factor of 15% was selected (72 mg/kg/day ÷ 1000 mg/kg/day * 

2), in the absence of definitive dermal-absorption data.

4.3 Toxicological Effects

Prometryn was categorized as having minimal acute toxicity via the oral, dermal, and inhalation 

routes (Category III or IV). It was mildly irritating to the eyes and slightly irritating to the skin, 

but not a sensitizer of the skin.

The only subchronic oral feeding study available for prometryn is a 28-day feeding study in 

mice. In this study, prometryn caused decreased body weight and/or mortality at doses that 

exceeded the limit dose (1000 mg/kg/day). 

In chronic oral toxicity studies, effects primarily occurred only at the highest doses tested for 

dogs, rats, and mice, though the dog is considered the most sensitive species. Effects in the dog 

included degenerative hepatic changes, renal tubule degeneration, and bone marrow atrophy. In 

a combined chronic toxicity/carcinogenicity study in rats, effects included decreased body 

weight and body-weight gains and renal toxicity (mineralized concretions). In a carcinogenicity

study in mice, the only effect was decreased body-weight gain.

In developmental studies with prometryn, effects were observed primarily at the highest doses 

tested. Furthermore, fetal effects were observed at the same doses as maternal toxicity. In rats, 

decreased body weight and food consumption, and clinical signs of toxicity were observed in 

dams. Decreased fetal body weight and incomplete ossification of sternebrae and metacarpals 

were observed at the same dose in offspring. In rabbits, decreased food consumption and an 

increased incidence of resorptions, abortions, and post-implantation loss were observed in 

maternal animals and corresponded with a decreased number of viable litters and live fetuses. 

In the two-generation rat reproductive study, decreased food consumption, body weight, and 

body-weight gain were observed in parental animals, and decreased body weights were observed 

in offspring at the same dose. There was no evidence of toxicity to the reproductive organs.

Preliminary review of the rat acute and subchronic neurotoxicity studies reveals lower mean total 

and/or ambulatory locomotor activity counts noted for both sexes on the first day of treatment in 

the acute study and no signs of neurotoxicity in the subchronic study. In the immunotoxicity

study, there was a decreased humoral response in the sheep red blood cell assay, though this 

effect is not expected to impact the risk assessment. 

No evidence of local or systemic toxicity was observed in a 21-day dermal toxicity study in 

rabbits. 
Prometryn Human-Health Risk Assessment D403975

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4.4 Safety Factor for Infants and Children (FQPA SF)

The prometryn risk assessment team has recommended that the FQPA SF be reduced to 1X for 

the following reasons: (1) there is an adequate toxicity database for prometryn; (2) preliminary

review of the neurotoxicity studies show some indication of neurotoxicity in the acute study;

however, the LOC is low since the POD chosen for risk assessment is lower and considered 

protective of these effects; (3) there is no evidence of susceptibility, and no residual uncertainties 

concerning pre- or post-natal toxicity; and (4) there are no residential uses for prometryn, and the 

dietary assessments will not underestimate exposure.

4.4.1 Completeness of the Toxicology Database

The toxicology database is adequate for characterizing prometryn toxicity and quantification of 

hazard for dietary exposures. Developmental toxicity studies in rats and rabbits, and a twogeneration reproduction study in rats are available to assess potential fetal/offspring sensitivity.

4.4.2 Evidence of Neurotoxicity

Preliminary reviews of the rat acute and subchronic neurotoxicity studies show some indication 

of neurotoxicity in the acute study and no signs in the subchronic study. The LOC is low for the 

effects identified in the preliminary review of the acute study because the endpoint chosen for 

the acute dietary exposure scenario for females 13-49 occurs at a lower dose and is considered 

protective. The effects observed in the acute neurotoxicity study occur at higher doses than those 

being used for risk assessment.

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

There is no evidence of increased quantitative prenatal susceptibility for prometryn. In both rats 

and rabbits, there are fetal and offspring effects which occur at maternal/parental doses. The 

LOC for all of these effects is low because: (1) the effects are well characterized, (2) clear 

NOAELs were established, and (3) the developmental rabbit study is being used in endpoint 

selection.

4.4.4 Residual Uncertainty in the Exposure Database

There are no currently registered residential uses for prometryn. The acute and chronic dietary

(food + water) exposure assessments utilize tolerance-level residues, DEEM 7.81 default 

processing factors (where provided), 100% CT information for all commodities, and screening 

level drinking water estimates. By using these screening-level assessments, actual 

exposures/risks will not be underestimated.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

Tables 4.5.4.1 and 4.5.4.2 summarize the toxicological doses and endpoints selected for human 

health risk assessment. 

Acute Dietary Endpoint (Females 13-49 years of age): The aRfD for females 13-49 years of age 

was established based on the NOAEL of 12 mg/kg/day from the developmental toxicity study in 
Prometryn Human-Health Risk Assessment D403975

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rabbits. The LOAEL of 72 mg/kg/day is based on an increased incidence of resorptions, 

abortions, and post-implantation loss leading to a decreased number of viable litters and live 

fetuses. The endpoints in this study are the most appropriate for single-dose effects for this 

population of concern. For reasons outlined in Section 4.4, the FQPA SF has been reduced to 1X 

for this exposure scenario; therefore, the aPAD is the same as the aRfD.

Acute Dietary Endpoint (General Population): There were no effects observed in oral toxicity

studies that could be attributable to a single dose (exposure) for the general population. 

Therefore, a dose and an endpoint were not selected for this exposure scenario.

Chronic Dietary Endpoint (General Population): The cRfD was established based on the 

NOAEL (3.75 mg/kg/day) from the chronic toxicity study in the dog. The LOAEL of 37.5 

mg/kg/day is based on degenerative hepatic changes, renal tubule degeneration, and bone 

marrow atrophy. The NOAEL of 3.75 mg/kg/day was chosen because it is the lowest in the 

database and because the study duration is appropriate for the duration of exposure. This study

also protects for similar renal effects in the rat. For reasons outlined in Section 4.4, the FQPA 

SF has been reduced to 1X for this exposure scenario; therefore, the cPAD is the same as the 

cRfD.

Short- and Intermediate-Term Incidental Oral Exposure: There are no proposed or registered 

residential uses for prometryn. Therefore, an endpoint for incidental oral exposure was not 

chosen. 

Short- and Intermediate-Term Dermal Endpoints: The oral developmental toxicity study in the 

rabbit was chosen for the short- and intermediate-term dermal occupational exposure scenarios. 

Even though there is a route-specific study available in which no effects were observed, the 

NOAEL and endpoint from the oral developmental toxicity study in rabbits was selected for the 

dermal route since developmental parameters were not evaluated in the dermal toxicity study.

Effects observed in the oral developmental toxicity study included an increased incidence of 

resorptions, abortions, and post-implantation loss in maternal animals leading to a decreased 

number of viable litters and live fetuses occurring at the maternal LOAEL of 72 mg/kg/day

(NOAEL = 12 mg/kg/day).Since an oral dose was selected, a dermal-absorption factor of 15% 

should be used for dermal risk assessment. The effects in this study are considered to be due to a 

“single dose”; however, the excretion data show that the compound is mostly cleared within 24 

hours at lower doses, and thus this study is protective of daily exposures. This study also 

protects for the parental/offspring decreased body weights in the two-generation reproduction 

study that were seen at similar doses. The two-generation reproduction study was considered for 

these scenarios as well, but not chosen because the low NOAELs in that study are believed to be 

an artifact of the dose spacing. Based upon the standard 10X interspecies and the 10X 

intraspecies uncertainty factors, the LOC for the dermal exposure scenarios is for MOEs <100. 

This study is protective of pregnant females in occupational settings. 

Short- and Intermediate-Term Inhalation Endpoints: Similar to the dermal scenarios, the 

developmental rabbit study was chosen for the short- and intermediate-term inhalation 

occupational scenarios and the POD for the maternal effects is being used. Because an oral 

study is being used for inhalation exposure scenarios, and an inhalation study is required, a 10X 

database uncertainty factor will be combined with the 10X interspecies and 10X intraspecies 

uncertainty factors for a LOC for MOEs of <1000. For inhalation exposures scenarios, 100% 

absorption of the oral dose should be assumed. 
Prometryn Human-Health Risk Assessment D403975

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4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

For occupational exposure, dermal and inhalation exposures should be combined since the 

toxicological effects of concern are the same and were identified from the same study. 

Currently, there are no registered residential uses of prometryn.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Prometryn was classified by the HED Peer Review/Cancer Committee (July 26, 1994 Report) as 

a Group E chemical (“Evidence of non-carcinogenicity for humans”), based on the lack of 

oncogenic effects at any dose in both rats and mice. Prometryn was determined to be nonmutagenic and non-clastogenic in in vitro and in vivo genotoxicity assays.

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

Assessment

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Prometryn for Use in Dietary HumanHealth Risk Assessments. 

Exposure Scenario POD Uncertainty/ 

FQPA SFs

RfD, PAD, LOC 

for Risk 

Assessment

Study and Toxicological 

Effects

Acute Dietary 

(Females 13+)

NOAEL = 12

mg/kg/day

UFA = 10X

UFH = 10X

UFFQPA = 1X 

aRfD = aPAD =

0.12 mg/kg/day

Developmental toxicity 

(rabbit)

LOAEL = 72 mg/kg/day based 

on increased incidence of 

resorptions, abortions, and 

post-implantation loss leading 

to decreased number of viable 

litters and live fetuses.

Chronic Dietary (All 

populations)

NOAEL = 

3.75

mg/kg/day

UFA = 10X

UFH = 10X

UFFQPA = 1X

cRfD = cPAD = 

0.04 mg/kg/day

Chronic toxicity (dog; dietary)

LOAEL = 37.5 mg/kg/day 

based on degenerative hepatic 

changes, renal tubule 

degeneration, and bone 

marrow atrophy.

Cancer (oral, 

dermal, inhalation)

Classification: “Group E: Evidence of non-carcinogenicity for 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 = populationadjusted dose (a = acute, c = chronic). RfD = reference dose (a = acute, c = chronic). 

Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for Prometryn for Use in Occupational 

Human-Health Risk Assessments.

Exposure 

Scenario POD Uncertainty Factors

LOC for Risk 

Assessment

Study and Toxicological 

Effects

Dermal

Short- and 

IntermediateTerm (1-30 

days and 1-6 

months)

NOAEL = 12

mg/kg/day 

Dermalabsorption 

factor = 15%

UFA = 10X

UFH = 10X

Occupational LOC for 

MOE <100

Developmental toxicity 

(rabbit)

LOAEL = 72 mg/kg/day based 

on increased incidence of 

resorptions, abortions, and postimplantation loss leading to 

decreased number of viable 

litters and live fetuses.
Prometryn Human-Health Risk Assessment D403975

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Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for Prometryn for Use in Occupational 

Human-Health Risk Assessments.

Exposure 

Scenario POD Uncertainty Factors

LOC for Risk 

Assessment

Study and Toxicological 

Effects

Inhalation

Short- and 

IntermediateTerm (1-30

days and 1-6 

months)

NOAEL = 12

mg/kg/day 

100% 

inhalation 

assumed

UFA = 10X

UFH = 10X

UFDB = 10X

Occupational LOC for 

MOE <1000

Developmental toxicity 

(rabbit)

LOAEL = 72 mg/kg/day based 

on increased incidence of 

resorptions, abortions, and postimplantation loss leading to 

decreased number of viable 

litters and live fetuses.

Cancer (oral, 

dermal, 

inhalation)

Classification: “Group E: Evidence of non-carcinogenicity for 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). UFDB = database uncertainty factor. MOE = margin of 

exposure. LOC = level of concern. 

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Livestock Metabolism Studies

Memo, S. Levy, 31-JUL-2013; D408525

Acceptable cotton and celery metabolism studies were previously reviewed (Residue Chemistry 

Chapter of the Prometryn RED, C. Swartz 08-DEC-1994; D207139; Memo, W. Wassell, 22-

DEC-2010; D382622). The results of the metabolism studies showed metabolic pathways 

involving N-dealkylation and hydrolysis of prometryn. HED determined that the residue of 

concern in cotton and celery consists of the parent, prometryn per se, which is the currently 

regulated residue.

The petitioner recently submitted a metabolism study in rice, which has been reviewed (Memo, 

S. Levy, 13-MAR-2013; D398563). Although the rice metabolism study was deemed adequate, 

it presents a qualitatively different metabolic profile than the celery and cotton profiles (Memo, 

C. Swartz, 05-DEC-1994; D208880 and 09-DEC-1995; D207139, respectively). In the celery

and cotton metabolism studies, parent is the major residue and in the rice metabolism study

metabolite GS-17794 is the major residue. 

The available cotton, celery, and rice metabolism data are adequate to support the proposed uses; 

however, no data are available reflecting metabolism in a root crop to support the existing uses 

on carrot and celeriac. OCSPP 860.1300 specifies that a metabolism study should be submitted 

for each type of plant for which use is proposed, or metabolism studies on three dissimilar crops 

must be provided which indicate a similar metabolic route. Note that IR-4 and Syngenta 

submitted a letter stating that they were working together to plan and conduct a nature of the 

residue study of prometryn on carrots or another root crop and asked for additional time to 

conduct this study (with a deadline of January 5, 2012). HED responded that this request was 

reasonable, considering the length of the study (Memo, W. Wassell, 22-DEC-2010; D382622). 

HED has not received this root crop metabolism study and, therefore, this deficiency remains 

outstanding. Depending on the results of the root crop metabolism study, additional field trial 

data could be required.
Prometryn Human-Health Risk Assessment D403975

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The nature of the residue in livestock is adequately understood based on acceptable poultry and 

ruminant metabolism studies. The residue of concern (and that which should be regulated) in 

livestock is the parent, prometryn per se. As in plants, the metabolism of prometryn in livestock 

involves N-dealkylation along with hydrolysis and/or amino acid conjugation.

5.1.2 Summary of Environmental Degradation

According to the submitted physical-chemical and environmental fate data, the degradation of 

prometryn is driven by microbial (biotic) activity and not by abiotic processes; however, 

biotransformation is slow. The major biotransformation product is GS-11526. The low 

Freundlich adsorption coefficient of prometryn suggests that the chemical has the potential to run 

off and/or leach to ground water. Prometryn is stable to hydrolysis and direct photolysis in 

aqueous media.

Prometryn and its degradates are mobile to very mobile in soil. Potential transport mechanisms 

include runoff to surface water, leaching to ground water, spray drift, and secondary drift of 

volatilized or soil-bound residues leading to deposition onto nearby or more distant ecosystems. 

The US Geological Survey (USGS) has reported data on the presence of pesticides in rain and 

wet deposition in four US agricultural watersheds. Among other pesticides, prometryn was 

detected in rain and wet deposition in California.

5.1.3 Comparison of Metabolic Pathways

The primary routes of metabolism in livestock and plants and degradation in the environment 

were basically the same and involves dealkylation along with hydrolysis and/or amino acid 

conjugation. The metabolism of prometryn in rotational crops is similar to that of the primary

crops and involves N-dealkylation, oxidation, hydroxylation, deamination, and conjugation. In

the environment, prometryn is stable to abiotic hydrolysis, soil photolysis, direct hydrolysis 

aerobic soil metabolism, and anaerobic soil metabolism. 

5.1.4 Residues of Concern Summary and Rationale

In the previous risk assessment for prometryn (Memo, W. Wassell et al., D367830, 05-AUG2009), the residues of concern in drinking water were listed as parent plus all degradates, while

the residues of concern identified in the EFED drinking water memo were parent only (Memo, S. 

Termes, 06/19/2009; D357096). In the recent scoping document for prometryn (Memo, K. Lowe 

et al., D407422, 28-FEB-2013), HED determined that the residues of concern for prometryn 

drinking water estimates should be parent plus the degradate, hydroxypropazine (GS-11526). 

This decision was based on information on the degradates of prometryn provided by EFED 

(Memo, M. Ruhman and N. Mastrota, 08-JAN-2013, D408043), which showed that the only 

major degradate of prometryn identified in the submitted environmental fate studies was

hydroxypropazine (GS-11526). This transformation product accounted for 27% of the maximum 

percent applied radioactivity in the aerobic soil study. It also accounted for 16-18% in the 

aerobic aquatic study and 15-31% in the terrestrial field dissipation study. All other 

transformation products identified in these studies were ≤7% of the applied radioactivity. There 

is limited information regarding the toxicity of hydroxypropazine; therefore, in the scoping 

document, HED proposed to include both parent plus hydroxypropazine (GS-11526) in the 

drinking water estimates.
Prometryn Human-Health Risk Assessment D403975

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In the drinking water memo supporting the proposed uses (Memo, M. Ruhman, D403977, 13-

MAR-2013), EFED proposed that the previous drinking water estimates be used even though 

those drinking water estimates represent parent only. HED has determined that this will be 

adequate for risk assessment purposes. Having limited information regarding the toxicity of the 

degradate, HED would make the assumption of equivalent toxicity for the parent and major 

degradate. Drinking water estimates based on parent only should then be similar to estimates 

based on a combination of parent and degradate (totaling 100%). Therefore, for the current risk 

assessment, the residue of concern in drinking water is prometryn per se.

Table 5.1.4.1. Summary of Metabolites and Degradates to be Included in the Risk Assessment and 

Tolerance Expression.

Matrix Residues Included in Risk 

Assessment

Residues Included in 

Tolerance Expression

Plants

Proposed/registered 

Primary Crops Prometryn Prometryn

Rotational Crop

Livestock Ruminant Prometryn Prometryn Poultry

Drinking Water Prometryn Not Applicable

5.2 Food Residue Profile

Memo, S. Levy, 31-JUL-2013; D408525

Crop Field Trials: Crop field trials were conducted for both dill and snap bean in support of the 

proposed uses. These studies were deemed adequate for risk assessment and tolerance 

assessment. Two dill field trials were conducted with applications made at approximately the 

same rate as that being proposed when plants were at the vegetative growth stage. Fresh dill 

leaves with stems were harvested at commercial maturity (pre-bloom) at PHIs of 27 or 29 days, 

and dill seed was harvested at seed maturity at PHIs of 62 or 68 days. At one trial, additional 

fresh dill leaves with stems were harvested and dried to generate dried dill leaves with stems. 

Residue decline was not evaluated. Prometryn residues were <0.05-0.10 ppm in/on fresh dill 

leaves/stems, 0.26-0.29 ppm in/on dried dill leaves/stems, and below the LOQ (<0.05 ppm) in/on 

dill seed. Seven snap bean field trials were conducted with applications made to the soil at either 

the same or slightly less rate than that being proposed. Snap beans (pods with seed) and snap 

bean plants (foliage with pods and seed) were harvested at commercial maturity at PHIs of 52-68 

days. Residue decline was not evaluated. Prometryn residues were below the LOQ (<0.05 ppm) 

in/on all samples of snap beans, and ranged from <0.05-0.077 ppm in/on snap bean plants.

Processing Studies: The IR-4 submitted a processing study for prometryn on dill, which showed 

that following the processing of the raw agricultural commodity samples (i.e., dill fresh 

leaves/stems), which did not have quantifiable residues (i.e., all residues <LOQ), total residues of 

prometryn concentrated in dill oil (>6.6X). The petitioner recommended a tolerance for residues 

of prometryn in/on dill, oil; however, a tolerance is not necessary since dill oil is not a regulated 

commodity. 

Storage Stability: Storage stability data are available for fortified samples of celery, cottonseed, 

fresh and dried parsley, pigeon peas, and sesame seed. In addition, concurrent storage stability

data were generated with snap beans, snap bean plants, fresh and dried dill and seed matrices, as 

well as dill oil. These data are adequate to support the storage conditions and durations of 

samples from the magnitude of the residue and processing studies on snap beans and dill. These 
Prometryn Human-Health Risk Assessment D403975

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data show that corrections for storage degradation of residues are not required for the submitted 

studies. 

Meat, Milk, Poultry, and Eggs: The 1994 Residue Chemistry Chapter concluded that residues of 

prometryn per se in meat and milk can be classified under Category 3 of 40 CFR §180.6(a): 

“That it is not possible to establish with certainty whether finite residues will be incurred, but 

there is no reasonable expectation of finite residues.” No tolerances were required, and 

therefore, livestock feeding studies were not needed. In the current petition, there are no 

significant livestock feed items; therefore, a newly constructed dietary burden was not warranted

for this petition. Pending submission of an additional plant metabolism study, HED tentatively 

concludes that the Category 3 situation remains valid for this registration request. 

Rotational Crops: The nature of the residue in rotational crops is adequately understood. The 

metabolism of prometryn in rotational crops is similar to that of celery and cotton and involves 

dealkylation, oxidation, hydroxylation, deamination, and conjugation. Based on the results of a

confined rotational crop study submitted previously, where residues from all plant back intervals 

(PBIs) were greater than 0.01 ppm, the registrant also submitted limited field rotational crop 

studies. Based on the results of these studies, HED previously determined that the minimum 

plant back restrictions for crops not listed on prometryn labels should be as follows: 

1) Following maximum application to any primary crop at up to 3.2 lb ai/A: a 5-month PBI 

for leafy vegetables, an 8-month PBI for root crops, and a 9-month PBI for small grains 

and all other crops. 

2) Following application at rates higher than 3.2 lb ai/A and up to 6.0 lb ai/A: an 8-month 

PBI for root crops; rotation to all other crops is prohibited. 

The PBI restrictions listed on the EPA-registered Caparol®4L Label remain appropriate for the 

proposed crops.

5.3 Water Residue Profile

Memo, M. Ruhman, 13-MAR-2013; D403977

In the drinking water assessment prepared for the proposed uses of prometryn on snap bean and 

dill (Memo, M. Ruhman, 13-MAR-2013, D403977), EFED indicated that the currently

established estimated drinking water concentrations (EDWCs) for prometryn based on the last 

assessment (Memo, S. Termes, 19-Jun-2009, D357096) can be used for the new use. In the 

previous assessment, EDWCs were established for uses on carrots, okra, parsley, cilantro, 

celeriac, and leafy petioles using the Tier I FIRST (FQPA Index Reservoir Screening Tool; 

Version 1.1.1) model for surface water and the Tier I SCI-GROW (Screening Concentration In 

Ground Water; Version 2.3) regression model for groundwater. 

The driver for both surface and groundwater was the use on carrots (three ground applications at 

2 lbs ai/A, 30 days apart). EDWCs for okra and cilantro were also estimated, and were much 

lower than EDWCs from the carrot use. The proposed application rate for snap beans is the 

same as that for previously modeled okra (one ground application at 1.5 lbs a.i/A) and gives the 

same Tier I EDWCs. In addition, the proposed application rate for dill is the same as that for 

previously modeled cilantro (one ground application at 1.6 lbs a.i/A) and gives the same Tier I 

EDWCs. Therefore, it was concluded that the previous drinking water assessment would be 

protective for the proposed uses. Water residues were incorporated directly into the DEEMFCID into the food categories “water, direct, all sources” and “water, indirect, all sources.”
Prometryn Human-Health Risk Assessment D403975

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Table 5.3.1. Summary of Estimated Surface Water and Groundwater Concentrations for Prometryn.

Scenario Surface Water Conc., ppb1 Groundwater Conc., ppb2

Acute 377.4 23.2 Chronic (non-cancer) 157.9

1

From the Tier I FIRST model. Input parameters are based on three ground applications to carrots @ 2 lb ai/acre, 30 days apart.

2

From the SCI-GROW model.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Acute and chronic dietary-exposure (food plus water) and risk assessments were conducted using 

DEEM-FCID, Version 3.16, which uses food consumption data from the USDA’s 

NHANES/WWEIA survey from 2003 through 2008. The assessments were performed for the 

general U.S. population and all population subgroups. Assumptions for the acute and chronic 

assessments include tolerance-level residues for all foods, DEEM 7.81 default processing factors 

(where provided), and 100% CT. Drinking water estimates were provided by EFED. The 

EDWC values were generated using the registered carrot use pattern and the Tier I FIRST model. 

The resulting acute EDWC estimate of 377.4 ppb was used for the acute assessment, and the 

chronic EDWC estimate of 157.9 ppb was used for the chronic assessment. 

5.4.2 Percent Crop Treated Used in Dietary Assessment

The acute and chronic dietary analyses assumed 100% CT for all commodities. 

5.4.3 Acute Dietary Risk Assessment

Acute dietary risk estimates (food and drinking water) are not of concern at the 95th percentile of 

the exposure for females 13 to 49 years old, the only acute population subgroup of concern for 

this assessment. The resulting acute risk estimate is 17% of the aPAD of the exposure 

distribution. A summary table of dietary exposure and risk for prometryn can be found in 

Section 5.4.6. 

5.4.4 Chronic Dietary Risk Assessment

Chronic dietary risk estimates (food and drinking water) are not of concern for the general 

population or any other population subgroup. The most highly exposed population was all 

infants (<1 year old), utilizing 23% of the cPAD. The chronic exposure estimate for the general 

U.S. population utilized 8.6% of the cPAD. A summary table of dietary exposure and risk for 

prometryn can be found in Section 5.4.6. 

5.4.5 Cancer Dietary Risk Assessment

A cancer dietary assessment was not performed because prometryn was classified as “Group E: 

Evidence of non-carcinogenicity for humans.”

5.4.6 Summary Table

The acute and chronic analyses assumed tolerance-level residues, 100% CT, and DEEM (ver. 

7.81) default processing factors. These analyses are considered very conservative and could be 
Prometryn Human-Health Risk Assessment D403975

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refined using anticipated-residue estimates (ARs), percent market share data, and/or empirical 

processing factors. However, at this time, refinement is not necessary.

Table 5.4.6.1. Summary of Dietary (Food + Drinking Water) Exposure and Risk for Prometryn.

Population Subgroup1

Acute Dietary2

(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

N/A N/A

0.003426 8.6

N/A N/A

All Infants (<1 year old) 0.009081 23

Children 1-2 years old 0.005136 13

Children 3-5 years old 0.004274 11

Children 6-12 years old 0.003041 7.6

Youth 13-19 years old 0.002484 6.2

Adults 20-49 years old 0.003390 8.5

Adults 50-99 years old 0.003366 8.4

Females 13-49 years old 0.020659 17 0.003377 8.4

1

 The values for the highest exposed population for each type of risk assessment is bolded.

2

 An acute dietary endpoint (aPAD = 0.12 mg/kg/day) was only determined for females 13-49 years old (see Table 2).

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

The proposed uses are not expected to result in residential exposure, and there are no currently

registered residential uses of prometryn; therefore, a quantitative residential exposure assessment 

was not conducted.

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 prometryn at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV) and low vapor pressure (8.54 x 10-7 mm Hg at 25oC). 

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 

(FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report 

on March 2, 20102. The Agency is in the process of evaluating the SAP report and may, as 

appropriate, develop policies and procedures to identify the need for and, subsequently, the way

to incorporate post-application inhalation exposure into the Agency's risk assessments. If new 

policies or procedures are developed, the Agency may revisit the need for a quantitative postapplication inhalation exposure assessment for prometryn.

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 

potential source of exposure from the ground application method employed for prometryn. 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-

 

2 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
Prometryn Human-Health Risk Assessment D403975

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management practices (see the Agency’s Spray Drift website for more information3). 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 risk estimates associated with drift.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks 

from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure.

For prometryn, aggregate exposure risk assessments were performed for the following scenarios: 

acute aggregate exposure (food and drinking water), and chronic aggregate exposure (food and 

drinking water). Short- and intermediate-term aggregate assessments, which are used to evaluate 

aggregate dietary and residential exposures, were not performed because there are no registered 

or proposed residential non-food uses. Prometryn is classified as “Not Likely to be Carcinogenic 

to Humans”; therefore, cancer aggregate risk assessments were not performed.

7.1 Acute Aggregate Risk

The acute aggregate risk assessment takes into account exposure estimates from dietary

consumption of prometryn (food and drinking water). The acute dietary exposure estimates are 

not of concern to HED (<100% aPAD) at the 95th exposure percentile for females 13-49 years 

old (see Table 5.4.6). The dietary exposure assessment utilized tolerance-level residues, 100% 

CT information for all proposed agricultural uses, DEEM 7.81 default processing factors (where 

provided), and Tier 1 acute surface water EDWCs. 

7.2 Chronic Aggregate Risk

The chronic aggregate risk assessment takes into account average exposure estimates from 

dietary consumption of prometryn (food and drinking water). The chronic dietary exposure 

estimates are not of concern to HED (<100% cPAD) for the general U.S. population and all 

population subgroups (see Table 5.4.6). The dietary exposure assessment utilized tolerance-level 

residues, 100% CT information for all proposed agricultural uses, DEEM 7.81 default processing 

factors (where provided), and Tier 1 chronic surface water EDWCs. 

8.0 Cumulative Exposure/Risk Characterization

Prometryn is a triazine, and certain triazine pesticides were identified as a common mechanism 

group (CMG) by the Agency in a 2002 paper entitled, “The Grouping of a Series of Triazine 

Pesticides Based on a Common Mechanism of Toxicity.

4

” However, prometryn was excluded 

 

3 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 

4

http://www.epa.gov/oppsrrd1/REDs/triazine_cumulative_risk.pdf
Prometryn Human-Health Risk Assessment D403975

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from the triazine CMG because it does not share the toxicity profile of the CMG triazines. 

Therefore, for the purposes of this action, EPA is assuming that prometryn does not have a 

common mechanism of toxicity with other substances. 

9.0 Occupational Exposure/Risk Characterization

9.1 Short-/Intermediate-Term Handler Risk

Occupational handler exposure is expected from the proposed uses, based on the anticipated use 

patterns, proposed labeling, types of equipment, and techniques that can potentially be used. The 

quantitative exposure/risk assessment developed for occupational handlers is based on the 

following scenarios: (1) mixing/loading liquids for ground application, (2) mixing/loading 

liquids for chemigation application, and (3) applying by ground application. Short- and 

intermediate-term exposures are anticipated for the following reasons: (1) the product can be 

applied once per season, (2) the product can be applied to multiple application sites, and (3) there 

may be a large agribusiness and/or commercial applicators who may apply a product over a 

period of weeks. The short- and intermediate-term dermal and inhalation endpoints are the same 

for prometryn; therefore, the short-term assessment is protective of longer durations of exposure.

Application rates used in the occupational handler assessment are identified in Table 3.3.1 

(Summary of Use Directions). Generic handler data were used as surrogate data in the absence 

of chemical-specific data, and were based on the Pesticide Handlers Exposure Database (PHED)

1.1, the Agricultural Handlers Exposure Task Force (AHETF) database, the Outdoor Residential 

Exposure Task Force (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. 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, as well as baseline plus gloves for certain scenarios. 

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates: Table 9.1.1 

provides a summary of the estimated exposures and risks to occupational pesticide handlers. All 

occupational handler scenarios, except mixing/loading liquids for chemigation applications, 

result in MOEs greater than the LOC (i.e., MOEs ≥100 for dermal and ≥1,000 for inhalation),

and the combined dermal and inhalation risk estimates, expressed as an ARI, are greater than 1 

with baseline attire (i.e., single layer of clothing, no gloves, no respirator). 

HED has determined that risks are of concern for short-and intermediate-term exposures (i.e., 

MOEs <100 for dermal) for mixing/loading liquids for chemigation applications at baseline, and 

require gloves to reach acceptable MOEs and ARIs. The registered label for Caparol®4L (EPA 

Reg. #100-620) already requires the use of chemical-resistant gloves as PPE for applicators and 

other handlers; therefore, there is no risk of concern for this scenario with the current label PPE. 
Prometryn Human-Health Risk Assessment D403975

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Table 9.1.1. Short- and Intermediate-Term Occupational Exposure and Risk Estimates for Prometryn.

Exposure 

Scenario

Crop 

or 

Target

Unit Exposure 

(ug/lb ai)1 Maximum 

Application 

Rate (lb 

ai/A)2

Area 

Treated 

(acres)3

Dermal Inhalation

ARI8

Dermal Inhalation Dose 

(mg/kg/day)4

MOE5

LOC = 100

Dose 

(mg/kg/day)6

MOE7

LOC = 1000

Mixer/Loader

Liquid -

Chemigation

Dill

Baseline: 

220 Baseline: 

0.219 1.6 350

0.267 45

0.00178 6700

0.42

SL Gloves:

37.6 0.0459 260 1.9

Snap 

Bean

Baseline: 

220 Baseline: 

0.219 1.5 350

0.252 48

0.00167 7200

0.45

SL Gloves:

37.6 0.0428 280 2.0

Liquids –

Groundboom 

Applications

Dill Baseline: 

220

Baseline: 

0.219 1.6 80 0.0613 200 0.000406 30,000 1.9

Snap 

Bean

Baseline: 

220

Baseline: 

0.219 1.5 80 0.0574 210 0.000381 31,000 2

Applicator

Groundboom 

Applications

Dill Baseline: 

78.6

Baseline: 

0.34 1.6 80 0.022 550 0.00063 19,000 4.3

Snap 

Bean

Baseline: 

78.6

Baseline: 

0.34 1.5 80 0.0205 590 0.000591 20,000 4.6

Bolded values indicate risk estimates are less than the LOC.

1 Unit Exposures are taken from “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table,” September 2012. Baseline = single 

layer of clothing, no gloves, no respirator. SL Gloves = single layer of clothing, gloves, no respirator.

2 Based on proposed label (Reg. No. #100-620).

3 Units Treated are taken from “Standard Values for Daily Acres Treated in Agriculture”; ExpoSAC SOP No. 9.1, revised 25 September 2001.

4 Dermal Dose = Dermal Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre) x Area Treated (A/day) x 

DAF (15%)/BW (69 kg).

5 Dermal MOE = Dermal NOAEL (12 mg/kg/day)/Dermal Dose (mg/kg/day).

6

Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre) x Area Treated 

(A/day)/BW (69 kg).

7

Inhalation MOE = Inhalation NOAEL (12 mg/kg/day)/Inhalation Dose (mg/kg/day).

8 Combined risks were calculated using the ARI Index method. ARI total = 1/[(1/ARIdermal) + (1/ARIinhal)], where ARIdermal = MOEdermal/100 and 

ARIinhal = MOEinhal/1000. ARIs greater than 1 are not of concern.

9.2 Short-/Intermediate-Term Post-Application Risk

9.2.1 Dermal Post-application Risk

Based on the anticipated use patterns and proposed labeling, occupational post-application 

exposure is expected from the proposed uses. Post-application exposure is expected to be shortand intermediate-term based on information provided on proposed labels; however, since both 

the short- and intermediate-term PODs are the same, the short-term assessment is protective of 

longer exposure durations. Application rates used in the occupational post-application

assessment are identified in Table 3.3.1 (Summary of Use Directions). Generic post-application 

exposure data were used as surrogate data in the absence of chemical-specific data, and are 

derived from the Agricultural Reentry Task Force (ARTF) exposure monitoring studies and, as 

proprietary data, are subject to the data protection provisions of FIFRA. Chemical-specific 

dislodgeable foliar residue data have not been submitted for prometryn. Therefore, this 

assessment uses HED’s default assumption that 25% of the application rate is available for 

transfer on day 0 following the application, and that the residues dissipate at a rate of 10% each 

following day.
Prometryn Human-Health Risk Assessment D403975

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Occupational Post-application Non-Cancer Dermal Risk Estimates: HED has determined that 

short- and intermediate-term risk estimates are not of concern (i.e., MOEs ≥100) on the day of 

treatment (i.e., day 0) for most post-application exposure activities. However, there were risk 

estimates of concern related to one post-application activity for snap beans and dill: hand-set 

irrigation. It should be noted that the transfer coefficient used to represent the hand-set irrigation 

activity is based on a study in which wet foliage was contacted by volunteers and, in addition,

the volunteers performing the activities in the study (potato irrigation) did not wear waterproof 

boots, which would normally be worn. Therefore, the use of this transfer coefficient to represent 

activity associated with hand-set irrigation is considered a conservative assumption. This is 

particularly true for the proposed uses being assessed here, snap bean and dill, where the 

applications are to be made early season (pre-emergence or soon after emergence), while the 

applications in the transfer coefficient study were made late season when the crop (potato) was 

fairly tall. Table 9.2.2.1 presents a summary of occupational post-application risk estimates 

associated with use of prometryn.

Table 9.2.2.1. Summary of Short- and Intermediate-term Occupational Post-application Risk Estimates for 

Prometryn.

Crop/Site Activities Transfer Coefficient 

(cm2/hr)

DFR

(μg/cm2)

1 Day Dermal Dose

(mg/kg/day)2 MOE3

Bean, snap (Crop 

Grouping 6A)

Irrigation (hand set) 1,900

4.21 0 0.139 86

3.79 1 0.125 96

3.41 2 0.113 110

Hand harvesting 1,100 4.21 0 0.0805 150

Scouting 210 4.21 0 0.0154 780

Weeding, hand 70 4.21 0 0.00513 2300

Dill (Crop Group 

19A)

Irrigation (hand set) 1,900

4.49 0 0.148 81

4.04 1 0.133 90

3.63 2 0.12 100

Scouting 1,100 4.49 0 0.0859 140

Weeding, hand 70 4.49 0 0.00547 2200

1 DFR (dislodgeable-foliar residue) = Application Rate × F × (1-D)t × 4.54E8 μg/lb × 2.47E-8 acre/cm2

; where F = 0.25 and D = 0.10 per day. 

2 Daily Dermal Dose = [DFR (μg/cm2

) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (%)]/BW (69 kg).

3 MOE = POD (mg/kg/day) / Daily Dermal Dose. Daily Dermal Dose = [DFR/TTR (μg/cm2

) × TC × 0.001 mg/μg × 8 hrs/day × dermal 

absorption factor (%)]/BW (69 kg).

REI: Prometryn is classified as Toxicity Category IV via the dermal route and Toxicity

Category IV for skin irritation potential. It is not a skin sensitizer. Short- and intermediate-term 

post-application risk estimates were not a concern on day 0 (12 hours following application) for 

most activities. However, there were risk estimates of concern related to one post-application 

activity for snap beans and dill: hand set irrigation. As stated above, the transfer coefficient for 

the hand-set irrigation is considered a conservative estimate for the hand-set irrigation activity. 

The WPS minimum REI is 12 hours based on acute toxicity of the active ingredient; however,

HED is noting that there are risk estimates of concern for some post-application scenarios based 

on default assumptions. There are no chemical-specific DFR data available to refine the postapplication assessment. MOEs are not of concern for the hand-set irrigation activity 2 days (48 

hours) after application. 

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 prometryn at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV) and low vapor pressure (8.54 x 10-7 mm Hg at 25oC). 

However, there are multiple potential sources of post-application inhalation exposure to 
Prometryn Human-Health Risk Assessment D403975

Page 29 of 36

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 FIFRA SAP in December 2009, and received the SAP’s final report on 

March 2, 20105. The Agency is in the process of evaluating the SAP report as well as available 

post-application inhalation exposure data generated by the ARTF and may, as appropriate, 

develop policies 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 prometryn.

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.

10.0 References

Previous Risk Assessment: W. Wassell et al., 05-AUG-2009; D367830

Scoping Document: Memo, K. Lowe et al., 28-FEB-2013, D407422

EFED Document Supporting Residues of Concern Decision: Memo, M. Ruhman and N. 

Mastrota, 08-JAN-2013, D408043

HASPOC Memo: J. Van Alstine; 21-FEB-2013; TXR # 0056525

Chemistry Memo: S. Levy; 31-JUL-2013; D408525

Previous Chemistry Memos: Memo, E. Zager, 24-MAY-1991; D160100

Residue Chemistry Chapter of the Prometryn RED, C. Swartz 08-DEC-1994; D207139

Memo, W. Wassell, 22-DEC-2010; D382622

Memo, S. Levy, 13-MAR-2013; D398563

Memo, C. Swartz, 05-DEC-1994; D208880 

Memo, C. Swartz, 09-DEC-1995; D207139

Drinking Water Memo: M. Ruhman; 13-MAR-2013; D403977

Previous Drinking Water Memo: Memo, S. Termes, 19-JUN-2009; D357096

Dietary Memo: S. Levy; 31-JUL-2013; D408528

Occupational Exposure Memo: L. Venkateshwara; 31-JUL-2013; D408529

 

5 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
Prometryn Human-Health Risk Assessment D403975

Page 30 of 36

cc: S. Levy, A. Dunbar, L. Venkateshwara

RDI: RAB1 (08-MAY-2013) 

K. Lowe: S-10947: Potomac Yard 1 (PY1): (703) 347-8989: 7509P: RAB1
Prometryn Human-Health Risk Assessment D403975

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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for a food use for prometryn are in Table 1. 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 90-Day Inhalation..........................................................

yes

yes

yes

no

yes1

yes

no

yes

--

no

1

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................

870.5400 Mutagenicity—Structural Chromosomal Aberrations...

870.5500 Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

no

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

no

no

-

-

yes

yes

-

870.7485 General Metabolism ......................................................

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

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

yes

no

yes

yes

-

yes

Special Studies for Ocular Effects

Acute Oral (rat)...........................................................

Subchronic Oral (rat) ..................................................

Six-month Oral (dog)..................................................

no

no

no

-

-

-

1. The HASPOC met on 21-FEB-2013 (TXR# 005625) and concluded that a repeated exposure inhalation toxicity study is required for 

prometryn at this time. 
Prometryn Human-Health Risk Assessment D403975

Page 32 of 36

A.2 Toxicity Profiles

Table A.2.1. Acute Toxicity Profile – Prometryn.

Guideline 

No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral (rat) 00060314 LD50 = 1802 (1265-2568)/

2076 (1654-2607) mg/kg (M/F) III

870.1200 Acute dermal (rat) 00060647 LD50 > 3170 mg/kg III

870.1300 Acute inhalation (rat) 42325503 LC50 = 4.96 mg/L IV

870.2400 Primary eye irritation (rabbit) 40776601 Mild Irritation III

870.2500 Primary dermal irritation (rabbit) 00060317 Slight Irritation IV

870.2600 Dermal sensitization (Guinea pig) 00256682 Not a sensitizer N/A

Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile – Prometryn.

Guideline 

No. Study Type MRID No./ Classification /Doses Results

870.3100 28-Day oral 

toxicity (mouse)

40457 515 (1977)

Acceptable/non-guideline

0, 30, 100, 300, 600, 

1,000, 3,000, 10,000 or 

30,000 ppm

NOAEL = 3000 ppm (~450 mg/kg/day).

LOAEL = 10000 ppm (~1500 mg/kg/day) 

based on decreased body weight.

870.3200 21-Day dermal 

toxicity (rabbit)

40573702 (1988)

Acceptable/guideline

0, 10, 100, or 1000 mg/kg 

bw/day (limit dose)

NOAEL = 1000 mg/kg/day.

LOAEL not established.

870.3700a Prenatal 

developmental (rat)

404574517 (1987)

Acceptable/guideline

0, 10, 50, or 250 mg/kg 

bw/day

Maternal NOAEL = 50 mg/kg/day.

LOAEL = 250 mg/kg/day based on salivation 

and decreases in body-weight and food 

consumption.

Developmental NOAEL = 50 mg/kg/day.

LOAEL = 250 mg/kg/day based on decreased 

fetal body-weight and incomplete ossification 

of sternebrae & metacarpals.

870.3700b Prenatal 

developmental 

(rabbit)

00157995 (1985)

Acceptable/guideline

0, 2, 12, or 72 mg/kg 

bw/day

Maternal NOAEL = 12 mg/kg/day.

LOAEL = 72 mg/kg/day based on decreased 

food consumption and increased incidence of 

resorptions, abortions, and post-implantation 

loss leading to decreased number of viable 

litters and live fetuses.

Developmental NOAEL = 12 mg/kg/day.

LOAEL = 72 mg/kg/day based on increased 

incidence of resorptions, abortions, and postimplantation loss leading to decreased number 

of viable litters and live fetuses.

870.3800 2-gen. reproduction 

and fertility effects

(rat)

41445101 (1990)

Acceptable/guideline

0, 10, 750, or 1500 ppm 

(0/0, 0.6/0.7, 47.8/53.6, or 

96.7/105.6 mg/kg bw/day 

[M/F])

Parental NOAEL = 10 ppm (0.6/0.7 mg/kg/day 

[M/F]).

LOAEL = 750 ppm (47.8/53.6 mg/kg/day 

[M/F]) based on decreased food consumption, 

body weight & body-weight gain.

Reproductive NOAEL = 750 ppm (47.8/53.6 

mg/kg/day [M/F]).

LOAEL not observed.

Offspring NOAEL = 10 ppm (0.6/0.7 

mg/kg/day [M/F]).

LOAEL = 750 ppm (47.8/53.6 mg/kg/day 

[M/F]) based on decreased pup weight.
Prometryn Human-Health Risk Assessment D403975

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Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile – Prometryn.

Guideline 

No. Study Type MRID No./ Classification /Doses Results

870.4100 Chronic toxicity (2-

year; dog)

00042794 (1965)

Acceptable/guideline

0, 15, 150, or 1500 ppm 

(0.0, 0.375, 3.75, or 37.50 

mg/kg/d) 

NOAEL = 150 ppm (3.75 mg/kg/day).

LOAEL = 1500 ppm (37.5 mg/kg/day) based 

on degenerative hepatic changes, renal tubule 

degeneration, and bone marrow atrophy.

870.4300 Combined Chronic 

Toxicity/

Carcinogenicity

(rat)

41901201 (1991)

Acceptable/guideline

0, 10, 100, 750 or 1500 

ppm (males: 0, 0.38, 3.90, 

29.45, or 60.88 mg/kg/d; 

females: 0, 0.49, 4.91, 

37.25, or 80.62 mg/kg/d) 

NOAEL = 750 ppm (29.45/37.25 mg/kg/day 

[M/F]).

LOAEL = 1500 ppm (60.88/80.62 mg/kg/day 

[M/F]) based on decreased body-weight and 

body-weight gains (both sexes) and renal 

lesions (mineralized concretions) (M).

No evidence of oncogenicity

870.4200 Carcinogenicity

(mouse)

40466201 (1981)

Acceptable/guideline

0, 10, 1000, or 3000 ppm 

(0, 1, 100, or 300 

mg/kg/d)

NOAEL = 1000 ppm (100 mg/kg/day).

LOAEL = 3000 ppm (300 mg/kg/day) based on 

decreased body-weight gain (F).

No evidence of oncogenicity.

870.5100 Bacterial Gene 

Mutation

40457518 (1987)

Acceptable/guideline

Up to 1000-2000 ug/plate

Negative

870.5100 Bacterial Gene 

Mutation

40457519 (1979)

Acceptable/guideline

Up to 1000 ug/plate

Negative

870.5385 In vivo bone 

marrow

chromosomal 

aberration assay 

(Chinese hamster)

40457520 (1986)

Acceptable/guideline

Up to 5000 mg/kg bw

Negative

870.5550 In vitro UDS assay 

(rat hepatocytes)

40457522 (1984)

Acceptable/guideline

Up to 156.25 ug/ml

Negative

870.6200a Acute neurotoxicity 

screening battery 

(rat)

49021204 (2012)

Classification: Pending

0, 150, 500, 1500 mg/kg 

[M/F]

Preliminary Systemic NOAEL = 500 mg/kg.

Preliminary Systemic LOAEL = 1500 mg/kg 

based upon decreased defecation, mean body 

weight losses with corresponding reductions in 

food consumption, and lower mean absolute 

body weights.

Neurotoxic NOAEL = 150 mg/kg/day.

Neurotoxic LOAEL = 500 mg/kg/day was 

based upon lower mean total and/or ambulatory 

locomotor activity counts noted for males and 

females in the 500 and 1500 mg/kg groups 

during the 0-10 minute interval t the time of 

peak effect on study day 0. 

870.6200b Subchronic 

neurotoxicity 

screening battery 

(rat)

48306973 (2012)

Classification: Pending

0, 250, 500, 1000, 2000 

ppm

(0, 19, 33/40, 67/79, and 

135 mg/kg/day [M/F])

Systemic NOAEL = 33/79 mg/kg/day).

Systemic LOAEL = 67/135 ([M/F]) mg/kg/day 

based upon decreased absolute body weights. 

Neurotoxic NOAEL = 135 mg/kg/day.

Neurotoxic LOAEL was not observed. 
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Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile – Prometryn.

Guideline 

No. Study Type MRID No./ Classification /Doses Results

870.7485 Metabolism and 

pharmacokinetics

(rat)

41255901 (1989)

Acceptable/guideline

0.46 or 467 mg/kg bw

(single)

0.46 mg/kg bw (repeat)

Prometryn is distributed in blood > spleen > 

lungs (the three highest tissues measured). 

Distribution is not dosage-dependent. It is 

extensively metabolized with <2% of recovered 

14C radioactivity representing the parent 

compound. Twenty-eight metabolites were 

identified in the urine, and 28 in the feces. Ten 

metabolites were identified in both urine and 

feces. Prometryn is excreted predominantly in 

the urine and feces, with slightly higher 

concentrations in the urine. The 7-day recovery 

of 14C radioactivity averaged 95% for all dosing 

groups.

870.7485 Immunotoxicity 

(mouse)

48936501 (2012)

Classification: Pending

0, 500, 2000, 5000 ppm

(0, 105.8, 413.1, 1044.5 

mg/kg/day)

Preliminary NOAEL = 413.1 mg/kg/day.

Preliminary LOAEL = 1044.5 mg/kg/day based 

upon a reduced humoral immune response 

using the sheep red blood cell assay.
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Appendix B. Physical/Chemical Properties

Table C.1. Physico-Chemical Properties of Prometryn.

Parameter Value Reference

Melting range 118-120C DP# 207139, 12/8/94, C. Swartz

pH 6.7 at 20oC (saturated solution) RCB# 2907, 12/4/87, G. Makhijani

Density 1.16 g/mL at 20oC

Water solubility 33 ppm at 20oC DP# 207139, 12/8/94, C. Swartz

Solvent solubility 10-30 g/100 mL in acetone,

dichloromethane, methanol, 

octanol, and toluene at 20oC

Vapor pressure 8.54 x 10-7 mm Hg at 25oC DP#s 196116 & 196123, 4/25/94, K. 

Dockter

Dissociation constant, pKa 4.09 at 20oC RCB# 2907, 12/4/87, G. Makhijani

Octanol/water partition 

coefficient

KOW = 2140 at 25oC DP#s 196116 & 196123, 4/25/94, K. 

Dockter

UV/visible absorption spectrum Not available
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Appendix C. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

the PHED 1.1, the AHETF database, and the ARTF 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 the Agency website6. 

 

6

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

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