
                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
\* MERGEFORMAT
                                                           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 drinking water exposure assessment by Mohammed Ruhman of the Environmental Fate and Effects Division (EFED).






                               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
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


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 end-use product Caparol[(R)] 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[(R)] 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 two-generation 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 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 weight-of-evidence approach to require a subchronic inhalation toxicity study.  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.

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 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[(R)] 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.
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.  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 AG-559.  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 AG-673 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)
                        HED-Recommended 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 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.        


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[(R)] 4L (4 lb/gal FlC; EPA Reg. No. 100-620)
GS-11354










2-amino-4-iospropylamino-6-methylthio-s-triazine
GS-26831

2,4-bis-amino-6-methylthio-s-triazine
GS-11526 









4,6-bis-isopropylamino-[1,3,5]triazine-2-ol
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[(R)] 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.
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[(R)] 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[(R)] 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 pre-emergence (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."  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the 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.  
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.  
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 two-generation 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 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.  

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 non-mutagenic 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 Human-Health 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 = population-adjusted 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 Intermediate- Term (1-30 days and 1-6 months)
NOAEL = 12
mg/kg/day 

Dermal-absorption 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 post-implantation loss leading to decreased number of viable litters and live fetuses.
Inhalation
Short- and Intermediate- Term (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 post-implantation 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.
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-AUG-2009), 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.

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 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[(R)] 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 DEEM-FCID into the food categories "water, direct, all sources" and "water, indirect, all sources."

Table 5.3.1.  Summary of Estimated Surface Water and Groundwater Concentrations for Prometryn.
                                   Scenario
                          Surface Water Conc., ppb[1]
                           Groundwater Conc., ppb[2]
                                     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 95[th] 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 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 Subgroup[1]
                               Acute Dietary[2]
                               (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, 2010.  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 post-application 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-management practices (see the Agency's Spray Drift website for more information).  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[(R)] 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 95[th] 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."  However, prometryn was excluded 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[(R)] 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.   

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
                                    ARI[8]
                                       
                                       
                                    Dermal
                                  Inhalation
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                              Dose (mg/kg/day)[4]
                                    MOE[5]
                                   LOC = 100
                              Dose (mg/kg/day)[6]
                                    MOE[7]
                                  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 short- and 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.

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 (cm[2]/hr)
                                      DFR
                                (ug/cm[2])[1]
                                      Day
                                  Dermal Dose
                                (mg/kg/day)[2]
                                    MOE[3]
                         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 x F x (1-D)[t] x 4.54E8 ug/lb x 2.47E-8 acre/cm[2]; where F = 0.25 and D = 0.10 per day.  
[2] Daily Dermal Dose = [DFR (ug/cm[2]) x Transfer Coefficient x 0.001 mg/ug x 8 hrs/day x dermal absorption (%)]/BW (69 kg).
[3] MOE = POD (mg/kg/day) / Daily Dermal Dose.  Daily Dermal Dose = [DFR/TTR (ug/cm[2]) x TC x 0.001 mg/ug x 8 hrs/day x 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 post-application 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 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, 2010.  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















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
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
                                    yes[1]
                                      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.  
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 post-implantation 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.
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.  
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 [14]C 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 [14]C 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.



Appendix B.  Physical/Chemical Properties

Table C.1.  Physico-Chemical Properties of Prometryn.
Parameter
Value
Reference
Melting range
118-120C
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





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 website.  


