Pr o m etryn Re gistr ation R eview Human-Health A ssessment**~coping** Docum ent

· -- ·---

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460



### MEMORANDUM

Date: 2 8-FEB-201 3 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### SUBJECT : Prometryn. Human-Health Assessme nt Scoping Document in Support of Registration Review.

PC Code: 080805 Decision No.: 

### l/121C.> Petition No.: NIA 

### DP Barcode: D40742 2 Registration No.: N /A Regulatory Action: Registration Review Scoping Document Case No.: 467 Risk Assessment Type: N/ A TXRNo.: N/A CAS No.: 7287-19-6 40 CFR: § 180.222 MRID No.: N / A

FROM: Kelly M. Lo we, Senior Environme ntal

### Scientist~**. ~**  Anwar Y. 

### Dunbar,

## Ph.D.**,J armac** **olo i**  

# {k1'1/ fj

, t/t·/c_,/ Sa rah J. 

### Levy, C hemi st 

## bvt 

# :?\ f
Risk Assessment Branch 1 (RAB 1) Health Effects Division ( HED

, 7509P )

THROUGH: Charles W. Smith III

, Acting Branch Chiee:::: 

### C

## )~5. "'> George F. Kramer, Ph.D., Senior

### Cherni**~.....,- ~**  RAB 1 / HED (7509P)

TO: C hristina Schle t e ma, Chemical Review Manager Pestic ide R e-Eval uation Di visio n (P RD ) (75 08P )

Attached i s HED's human-heal t h risk asse ssme nt scoping document for prom etry n to support registration review.

Page 1 of21 

# -______**Pr~me!!Y._~ ~e~J.~tra** **t_i_~~_Re-:~~** Human-Health Assessment Scoping**D~cume~ ---**  _ ____ _ Executive Summary

Prometryn [2,4-bis(isopropylamino )

- 6 -m ethylthio-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). There are no residential uses registered for prometryn. There are currently six prometryn containing end-use products sold under the following names: Caparol® 4L (100

- 620), SuprenlM Herbicide (100

- 1163), Prometryne 4L Herbicide (two different Registrants : 9779-297 and 3 4704-692), Prometryn 4L Herbicide (66222

- 15), and Cotton-Pro® ( 66222-116). In addition, there are several Special Local Need (SLN) labe l s, which include applications to carrots, ce l ery, cotton, dill, parsnip, and parsley.

The Prometryn Reregistration Eligibility Decision (RED) document was issued in 1996, at which time prometryn was registered for use on celery, cotton, dill, and pigeon peas (Memo, J. Redden


### et al., 16

- MAR -1 995) . I n 1998, a tolerance without a US registration was issued for the use of prometryn on carrots (Memo, W. Wassell 

### et al., D224645, 20 -J AN-1998). In 2009, a humanhealth risk assessment was conducted for registration of prometryn on carrots in the US, as we ll

as new food use registrations on celeriac, cilantro, okra, parsley, and leaf petioles (crop subgroup 4B) (Memo, W. Wasse ll 

### et al., D367830, 05-AUG-2009). There is one pending Pesticide Registration Improvement Extension Act (PRIA) action (petition # 2E8052) for new food uses on

s nap beans and dill.

HED has eva l uated the status of the human-health assessments for prometryn to determine whether sufficient data are available and whether any updates are needed to support Registration Review

. HED has considered all avai l able data and human-health risk assessments for prometryn with respec t to its toxicity, exposure, and usage databases, and the most updated Agency science policy and risk assessment methodologies to determine the scope of work
necessary to support Registration Review

.

The toxicity database for prometryn is nearly complete at the present t ime with the exception of the neurotoxicity battery as required by t he 2007 r evised 40 CFR §158 Toxicology Data Requirements. These studies have been submitted to the Agency and will be reviewed during the pending PRIA action for new food uses on snap beans and d ill

. HED 's Hazard and Science Polic y Council (HASPOC) has determined that an inhalation toxicity study is required for prometryn at this time. Prometryn demonstrated minimal acute toxicity via the oral, dermal, and inhalation routes (Toxicity Category III or IV). It is mildl y irritat i ng to the eyes and slightly irritating to the skin and is a non

- sensitizer of the skin. Effec ts in the subchron i c and chronic oral studies in mice, dogs, and rats primarily occurred at the highest doses tested. No evidence of toxicity was observed in the dermal toxicity study in rabbits for prometryn. In rats and rabbits, feta l effects occurred at doses where maternal toxicity was seen. Parental and offspring effects occurred at similar doses, and there were no reproductive effec ts. In accordance with the 1986 EPA Carcinogen Risk Assessment Guidelines, Prometryn is classified as a Group E chemical (Evidence of non-ca rcinogenicity for humans) based on the lack of evidence for

carc i nogenicity in mice or rats. During Regis tr ation Re view, HED will reevaluate the poin ts of departure (PODs) and uncertainty factors (Ufs) for the dietary and occupational exposure
assessments.

Adequate metabolism (crops, livestock, and rotational crops) and magnitude of the r esidue data

are avai l able to support the currently registered uses of prometryn, except for a metabo li sm study in a root crop. In the 2009 h uman -heal th assessment, two data gaps were iden tifi e d: a Page 2 of21Prometryn Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 3 of 21 

### magnitude of residue study in carrots and a metabolism study in carrots (or other root crop). Since then, a magnitude of residue study in carrots has been submitted, along with a metabolism study in rice. These studies will be reviewed as part of the pen ding PRIA action for new food uses on snap beans and dill

. After preliminary review of the metabolism in rice study, it appears that the metabolism in rice presents a different metabolic profile than the celery and cotton profiles; therefore, HED is still requ est ing a root crop metabolism study. HED is also requesting a ruminant feeding study at this time since the livestock dietary burden could change significantly pending the results of the root crop metabolism study. Based on available data, HED concl uded that the residue of concern in cotton and celery , rotational crops, and livestock, for purposes of tolerance enforcement and risk assessment, is prometryn per se

. Adequate methods are available for enforcement of the currently established tolerances.

The dietary

- exposure database is adequate to support current registration requirements. The most recent dietary

- exposure assessment was performed in the August 2009 human

- health risk assessment conducted by HED. As part of Registration Review, a r evi sed dietary risk assessment may be necessary to reflect potential revised estimated drinking water concentrations (EDWCs), the most recent dietary exposure models, and/or revised toxicological PODs.

There is sufficient information available to assess occu pational and residential exposure and risk from the registered uses. There are no residential uses currently registered for prometryn; therefore, a quantitative residential exposure/risk assessment is not necessary during Registration Review. Based on ex isting registrations, the previous assessments identified most of the anticipated occupational handler and post

- application exposure scenarios with the exception of handler scenarios associated with a dry

- flowable (DF) formulation. These scenarios may be included in Registration Review. Additionally, all occupational scenarios may need to be reassessed to address updates to HED’s exposure policies, including updates to default exposure data and assumptions for body weights.

The following data deficiencies were identified for prometryn:

Toxicology:

o 870.6200: Acute Neurotoxicity Study 1



### . o 870.6200: Subchronic Neurotoxicity Study 1



### . o 870. 7800 : Immunotoxicity Study 1



### . o 87 0.3465 : 90

- day Inhalation study 2



### . Residue Chemistry:

o 860.1300: Metabolism Study in Carrots (or other root crop) 3



### . o 860.1500: Magnitude of the Residue in C arrots 1



### . o 860.1 48 0: Magnitude of the Residue Study in Ruminants

. Dietary Exposure: None

. Occupational/Residential Exposure:

o 875.2100: Dislodgeable Foliar Residue (DFR) study

.

1 These data have been submitted to the Agency and will be reviewed during the pending PRIA action for new food uses on snap beans and dill.
2 28

- day inhalation study will be sufficient.
3 This study was required as conditional data per the 2009 HED risk as sessment and has not been fulfilled at this time.Prometryn Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 4 of 21 

### EPA anticipates conducting the following risk assessment updates during Registration Review: Toxicology:

o Reevaluat ion of the toxicity endpoint/dose selection, along with the Food Quality Protection Act (FQPA) Safety Factor (SF) may be required. Residue Ch emistry:

o The tolerance expression for prometryn in 40 CFR §180.222 needs to be updated as follows to reflect current Agency policy: “Tolerances are established for residues of the herbicide prometryn, including its metabolites and degradates, in
or on t he commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only prometryn ( N,N'

- bis(1

- methylethyl)

- 6

- (methylthio)

- 1,3,5

- triazine

- 2,4

- diamine )

..... ” Dietary Exposure:

o Revised dietary risk assessment may be necessary to reflect the potential revised EDWCs, dietary exposure models, and/or toxicological PODs. Occupational/Residential Exposure:

o Revised occupational handler and post

- application risk assessment may be
necessary based on the most recent exposure data and Agency policies, and should include an assessment of all registered formulations.

1.0 Introduction

Prometryn [2,4

- bis(isopropylamino)

- 6

- methylthio

- s

- triazine] is a substituted thiomethyl triazine herbicide (Group 5) registered i n 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). There are no residential uses registered for prometryn. The re are currently six end

- use products sold under the following names: Caparol ® 

### 4L (100

- 620), Suprend TM 

### Herbicide (100

- 1163), Prometryne 4L Herbicide (two different Registrants: 9779

- 297 and 34704

- 692), Prometryn 4L Herbicide (66222

- 15), and Cotton

- Pro ® 

### (66222

- 116). In addition, there are several SLN labels, which include application s to carrots, celery, cotton, dill, parsnip, and parsley. All products are liquid formulations and contain prometryn as the sole active ingredient, except for Suprend TM 

### Herb icide, which is a DF formulation and contains another active ingredient, trifloxysulfuron

- sodium. This memo only evaluates the status of the human

- health assessments for prometryn.

The Prometryn RED document was issued in 19 96

, at which time prometryn wa s registered for use on celery, cotton, dill, and pigeon peas (Memo, J. Redden et al.

, 16

- MAR

- 1995 ) . In 1998, a tolerance without an U.S. registration was issue d for the use of prometryn on carrots (Memo, W. Wassell et al.

, D224645, 20

- JAN

- 1998 )

. The mos t recent human

- health risk assessment was conducted in 2009 in support of registration of prometryn on carrots, as well as celeriac, cilantro, okra, parsley, and leaf petioles (crop subgroup 4B) (Memo, W. Wassell et al.

, D367830

, 05

- AUG

- 2009 ).

2.0 Hazard Identification/Toxicology

Prometryn is a substituted thiomethyl triazine herbicide that acts by inhibiting photosynthesis at photosystem II. For a summary of the acute, subchronic, and chronic toxicity profile, see Attachment 2

. For a summary of the relevant toxicological endpoints used in risk assessment, see Attachment 3.Prometryn Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 5 of 21 

### In the rat metabolism study for prometryn, absorption from the gastrointestinal (GI) tract was not directly measured. However, based upon the urinary excretion profile, it ca n be estimated that 47.06

- 53.3% of the 10

- mg/kg single oral dose was absorbed. Because no bile duct ligation experiment was performed, it cannot be reasonably estimated how much of the fraction from feces was absorbed from the GI tract. Prometryn is dist ributed primarily to the blood, spleen, and lungs. There was a dose

- dependent increase in tissue levels at 168 hours post dosing. 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 168 hours post dosing. These values were similar following 14 days of repeated low dosing, and for the high

- dose group (500 mg/kg) at 168 hours. Greater than 90% of the ra diolabel in the urine and feces was excreted by both sexes in the low dose groups by 24 hours. Seventy

- two hours were required for urinary and fecal excretion to be greater than 90% complete for the high

- dose animals, suggesting saturation of either absor ption or excretion. Prometryn demonstrated minimal acute toxicity via the oral, dermal, and inhalation routes (Toxicity Category III or IV). It is mildly irritating to the eyes and slightly irritating to the skin and is a non

- sensitizer of the skin.

Th e 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)

. Regarding chronic oral exposure , effects primarily occurred only at the highest doses tested for dogs, rats, and mice. 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 sole effect was decreased body

- weight gain.

In the developmental and reproductive studies for prometr yn, effects were observed primarily at the highest doses tested. Furthermore, fetal and offspring effects were observed at the same doses as maternal/parental toxicity. In rats, decreased body weight and food consumption and clinical signs of toxicity we re observed in dams, and 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
po st

- implantation loss were observed in maternal animals and led to 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 in the study.

No evidence of local or systemic toxicity was observed in a 21

- day dermal toxicity study in rabbit s. There was no evidence of carcinogenicity in either mice or rats , and prometryn was non

genotoxic or mutagenic. In accordance with the 1986 EPA Carcinogen Risk Assessment Guidelines , Prometryn is classified as a Group E chemical (Evidence of non

- carcinogenicity for humans) ; therefore, EPA is not likely to re

- evaluate the carcinogenicity of prometryn

. In the last risk assessment, three toxicity data gaps were identified: (1) an immunotoxicity study, (2) an acute neurotoxicity study, and (3 ) a subchronic neurotoxicity study. A 28

- day dietary immunotoxicity study in female mice has been submitted to the Agency. Upon preliminary review, it was determined that prometryn caused a transient decrease in body weights, as well as a decrease in ant ibody formation response at the highest dose tested. The neurotoxicity screening battery tests have been conducted and will be reviewed during the pending PRIAPrometryn Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 6 of 21 

### action for new food uses on snap beans and dill

. The HED HASPOC has determined that a subchron ic repeated dose inhalation study for prometryn is needed based on weight of evidence considerations, including the available toxicity data and the potential for exposure to prometryn via the inhalation route.

Conclusions: The toxicity database for prome tryn is complete at the present time as required by the 2007 revised 40CFR Toxicology Data Requirements

. HED’s HASPOC has determined tha t an inhalation toxicity study is required for prometryn at this time b ased on weight of evidence considerations, inclu ding the available toxicity data and the potential for exposure to prometryn via the inhalation route

. During registration review, the endpoints, doses, and safety factors used in the most recent human health risk assessments should be reconsidered based on current HED policy, recen tly submitted studies, and any other outstanding data

.

3.0 Residue Chemistry

Tolerances are established for residues of prometryn per se in/on carrots, celeriac, cilantro, cotton, leaf petioles (crop subgroup 4B), okra, parsley, and pigeon peas at 0.05

- 9.0 ppm (40 CFR § 180.222). Additionally, a permanent tolerance with regional registration is established under 40 CFR §180.222(c) for residues o f prometryn per se in/on dill at 0.3 ppm. Tolerances are also established for indirect or inadvertent residues of prometryn per se in/on the forage and straw of barley, oat, rye, triticale, and wheat at 0.3 ppm and the hay of barley, oat, rye, triticale, and wheat at 1.0 ppm.

The petitioner submitted adequate celery and cotton metabolism studies for prometryn

, with these data indicating that metabolism proceeds via N

- dealkylation and hydrolysis of prometryn. These data are sufficient for all registered c rops , excluding carrot and celeriac . In the most recent assessment, a root crop metabolism study was requested as a condition of registration (Memo, W. Wassell et al

. , D367830 , 05

- AUG

- 2009). The petitioner has not submitted a root crop metabolism study

, therefore, this conditional data is still considered outstanding. A metabolism study in/on rice was recently submitted to the Agency, along with justi fication to explain why this study was submitted instead of the requested metabolism study in/on a root

c rop . HED is in the process of reviewing these data in conjunction with the pending PRIA action for new uses on snap beans and dill

. However, after preliminary review, it appears that the rice metabolism study presents a different metabolic profile than t he celery and cotton profiles; therefore, HED is still requesting a root crop metabolism study.

The nature of the residue in livestock is adequately understood based on acceptable poultry and ruminant metabolism studies. The residue of concern (and tha t which should be regulated) in livestock is the parent, prometryn per se . As in plant commodities, the metabolism of prometryn in livestock involves N

- dealkylation along with hydrolysis and/or amino acid conjugation. 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) ; t hat is, there is no reasonable expectation of finite residues in meat and milk

. Thus, n o tolerances we re required, and ruminant feeding studies were not required at that time

. HED tentatively concluded in the 2009 assessment (Memo, W. Wassell et al. , D367830, 05

- AUG

- 2009) that the Category 3 situation is still applicable with the carrot registration as lo ng as a metabolism study was submitted in/on a root crop. HED is requesting a ruminant feeding study at this time since the livestock dietary burden could change significantly pending the results of the root crop metabolism study and this study requiremen t has not been fulfilled

.Prometryn Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 7 of 21 

### The nature of the residue in rotational crops is also adequately understood. The metabolism of prometryn in rotational crops is similar to that of the primary crops and involves dealkylation, oxidation, hydroxylation, deaminati on, and conjugation. The residue of concern in rotational crops is prometryn per se

. Excluding carrot, adequate crop field trial an d processing data are available . Previously, three additional carrot trials were requested in several regions reflecting a pplication according to the maximum proposed use pattern, including use of a surfactant; with one of the trials generating residue

- decline data. These data have been submitted

, and HED is in the process of reviewing these data in conjunction with the pend ing PRIA action. HED notes that if the review of a future root crop metabolism study may indicate a major metabolite which was not monitored

, then additional carrot field tr ia l data could be required.

There are no outstanding issues related to the use directions and/or tolerances. Adequate methods are available for enforcement of all currently e stablished tolerances . In addition, the FDA PESTDATA database (dated 06/05) indicates that prometryn is completely recovered (>80% recovery) using the multiresidue method (MRM) in the Pesticide Analytical Manual, volume I (PAM, Vol. I) 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.

Conclusio ns : A metabolism study in/on a root crop is still required per the 2009 risk assessment. HED is requesting a ruminant feeding study at this time since the livestock dietary burden could change significantly pending the results of the root crop metabolism study. A carrot magnitude of the residue stud y (MRID 48727501) ha s been received by the Agency and will be reviewed as part of the pending PRIA action. Depending on the conclusions concerning the residues of concern in root crops, additional carrot and celeriac field tr ia l data may be requested

.

4.0 Dietary Exposure

HED has previously conducted acute and chronic dietary exposure analyses, which considered all currently registered uses (Memo, W. Wassell et al.

, D367830 , 05

- AUG

- 2009). The analyses

were conducted using the Dietary Exposure Evaluation Model

– Food Consumption Intake Database (DEEM

- FCIDTM, ver. 2.03), which incorporates the food consumption data from the United States Department of Agriculture (USDA) Continuing Surveys of Food Intakes by Ind ividuals (CSFII; 1994

- 1996 and 1998) and assumed tolerance

- level residues and 100% crop treated. Dietary risk estimates were determined considering exposures from food plus drinking water using EDWCs for surface water sources provided by the Environmental Fate and Effects Division ( EFED ; Memo, S. Termes, 06/19/2009; D357096). In the 2009 risk assessment, EDWCs of 0.1579 ppm and 0.3774 ppm were incorporated directly in the acute and chronic analysis, respectively into the food categories “water, direct, all sources” and “water, indirect, all sources.”

The residues of concern in drinking water identified in the 2009 EFED memo indicated that EDWCs were modeled for parent only. Recently, EFED provided information regarding the degradation products of prometryn (Memo, M. Ruhman and N. Mastrota, 01/08/2013, D408043), which indicat ed that t he 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 thePrometryn Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 8 of 21 

### % applied radioactivity. Since there is limited information regar ding the toxicity of hydroxypropazine, HED has taken a conservative approach and determined that the residues of concern for prometryn drinking water estimates should be parent pl us hydroxypropazine (GS

11526)

. Updated drinking water estimates will be ca lculated as part of the pending PRIA action.

In the 2009 assessment, the resulting acute food plus water exposure estimates were not of concern to HED (<100% acute population

- adjusted dose (aPAD)) at the 95 th 

### percentile of the exposure distribution for females 13 to 49 years old (only subgroup of interest). Specifically, the resulting acute exposure estimate for this subgroup was 16% of the aPAD. The resulting chronic exposure estimates were also not of concern to HED (<100% chronic PAD). The most hig hly exposed population subgroup was all infants (<1 year old) utilizing 30% of the chronic PAD (cPAD).

Conclusions: The dietary

- exposure database is adequate to support current registration requirements. In the most recent risk assessment, neither acute nor chronic dietary exposures were of concern to HED. However, as part of Registration Review, revised dietary exposure analyses may be required to reflect the most recent dietary exposure models, potential revised EDWCs, and/or changes to the toxicologi cal PODs.

5.0 Residential Exposure

The registered uses for prometryn are not expected to result in residential exposure; therefore, a quantitative residential exposure assessment has not been conducted and would not be required for Registration Review.

Spray Drift Residential exposures resulting from off

- site transport (e.g., spray drift or volatilization) may occur as a result of applications of prometryn

. The Agency is in the process of evaluating these types of exposures and may, as appropriate, deve lop policies and procedures to identify the need for and, subsequently, the way to incorporate these post

- application exposures into the Agency's risk assessments. The need for spray drift and volatilization risk assessment for prometryn will be examined during registration review

.

Conclusions : There are no residential uses currently registered for prometryn; therefore, a quantitative residential exposure/risk assessment is not necessary during Registration Review.

6.0 Aggregate

- Risk Assessment

The mos t recent aggregate

- risk assessment was performed in conjunction with the August 2009 human

- health risk assessment conducted by HED (Memo, W. Wassell et al.

, D367830

, 05

- AUG

2009 ). Since there are no residential uses for prometryn, only acute and chronic a ggregate assessments were conducted, which only took into consideration dietary food plus water

e xposures. Neither the acute nor chronic aggregate risk assessments showed risks of concern (aPAD for females 13 to 49 years old (only subgroup of interest) = 16% and cPAD for most highly exposed population subgroup (all infants <1 year old ) = 30%).

Conclusions : A new aggregate risk assessment may be required during Registration Review to incorporate potential changes to the prometryn toxicological PODs and dietary assessment

.

7 .0 Occupational ExposurePrometryn Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 9 of 21 

### Occupational handler and post

- application exposures are expected b ased on the registered agricultural uses of prometryn

. Attachment 4 provides a summary of the occupational use pattern. The current registr ations include several SLN registrations. Current formulations include one dry flowable product and several liquid products. The application rates range from 0.75

- 4 lb ai/A, and applications can be made either pre

- or post

- emergence. Most labels appear to restrict over

- the

- top sprays or allow them only up to an early crop stage (i.e., when few leaves

are present).

Occupational Handlers There is the potential for dermal and inhalation exposure to occupational handlers from the currently registered use pattern of prometryn . In all past risk assessments, no chemical

- specific data were available with which to assess potential exposure to pesticide handlers; therefore, occupational handler assessments were based primarily on surrogate unit exposures from the Pesticide Handlers Exposure Database (PHED). Previous risk calculations were based on the maximum application rates and assum ed maximum area treated per day or gallons handled. Handler's exposure and risk were calculated at baseline (long pants, a long

- sleeved shirt, no chemical

- resistant gloves, and no respirator) and with personal protective equipment (PPE) when necessary (e.g., chemical

- resistant gloves, respirators, and engineering controls).

In the 1995 RED, which assessed the uses on celery, cotton, dill

, and pigeon peas, occupational handler scenarios were assessed for wettable powder and liquid formulations at rates ranging from 0.8

- 3.2 lb ai/A. The mixer/loader scenarios for aerial ( liquids and wettable powder) and groundboom (wettable powder) applications resulted in risks of concern. Currently, there are no wettable powder formulations registered for prometryn, and all but one of the liquid formulation product labels require some t ype of respirator and an apron as required PPE for mixer/loaders of aerial applications. In the 2009 assessment, which assessed the uses on carrots, celeriac, cilantro, okra, parsley, and leaf petioles (crop subgroup 4B), occupational handler scenarios we re assessed for liquid formulations at rates ranging from 3.2

- 4 lb ai/A. None of the scenarios result ed in risks of concern as long as handlers wore protective gloves. Gloves are currently required as PPE on all registered prometryn labels.

Based on e xisting registrations, the previous assessments identified most of the anticipated occupational handler exposure scenarios with the exception of those associated with a DF formulation. These scenarios may be included in Registration Review. Additionally, all occupational handler scenarios may need to be reassessed to address updates to HED’s exposure policies, including updates to default exposure data used for handler scenarios and assumptions for body weights.

Occupational Post

- Application There may be the potential for post

- application dermal exposure to workers following applications of prometryn to agricultural crops. As noted above, applications can be made either
pre

- or post

- emergence, but most labels appear to restrict over

- the

- top s prays or allow them only up to an early crop stage (i.e., when few leaves are present). Therefore, any post

- application exposure is expected only for early season activities (i.e., scouting, irrigation).

In the 1995 RED, similar conclusions were made as to the diminished potential for post

application exposure except for applications to celery

, which could be made over the crop. It was noted that celery is often thinned by hand and , therefore, there could be potential post

application dermal exposure. A quantitative assessment was not conducted since no data werePrometryn Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 10 of 21 

### available ; however, the RED required a DFR study on celery and determined that entry to treated areas should not be permitted immediately following application. The RED established a 24

- hour restricted

- entry interval (REI) for celery and a 12

- hour REI for all other crops.

In the 2009 risk assessment for prometryn

, early season post

- application activities were assessed for celeriac and the leafy petioles crop group. No risk estimates of c o ncern were identified and a 12

- hour REI was proposed.

Since the previous reviews, there have been several updates to HED’s exposure policies, including updates to post

- application transfer coefficients, transferable residue assumptions, and assumptions for body weights. Thus, these scenarios may need to be updated in the Registration R eview assessment to be sure they are assessed using current policies and recommended exposure data.

In accordance with the updated Part 158 data requirements (2007), one or more DFR studies are required when a pesticide has occupational uses that could result in post

- application dermal exposure. HED analyzed a number of DFR studies and selected a new default value for the fraction of the application rate available to be d islodged after a foliar application (FAR). This default value is 25%. Of the analyzed DFR studies, the maximum FAR value seen was 89% or 3.6 times higher than the default residue transfer value. Therefore , HED has decided that a calculated MOE of approx imately four times higher than the level of concern (e.g., an MOE > 400 if the LOC = 100) using the default dislodged residue values would provide an adequate margin of safety for any potentially higher residues seen in a chemical

- specific DFR study . This policy is described in Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) Studies ( Memo, J. Housenger, 12/12 /12). A new DFR study for prometryn is required since estimated dermal MOEs for occupational workers exposed to treated foliage are not greater than 400.

Conclusions: The occupational exposure database is adequate to support the Registration Review process for prometryn. Previous occupational handler exposure assessments did identify risks of c oncern and additional PPE is currently required on some labels. Registration R eview
may include updated risk estimates based on revised surrogate unit exposures. Previous occupational post

- application exposure assessments did not identify risks of concer n; applications are mostly pre

- emergent or early seaso n post

- emergent. Registration R eview may include updated post

- application risk estimates based on revisions to ExpoSAC Policy 3. Additional DFR data are necessary based on existing and anticipated occ upational post

application risk estimates.

8.0 Public Health and Pesticide Epidemiology Data

The Agency has reviewed the available incident data for prometryn ( Memo, S. Recore and E. Evans

, D406671 , 13

- NOV

- 2012) and concludes that based on the low freque ncy and severity of incident cases reported for prometryn, there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the risk
assessment.

9 .0 Tolerance Assessment and International HarmonizationPrometryn Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 11 of 21 

### U.S. permanent tolerances (listed in 40 CFR 180. 222 ) are summarized in Attachment 5

. There

are no Codex or Mexican maximum residue limits (MRLs) in/on the registered crops.

10 .0 Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in the
most recent prometryn human

- health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low

Income Populations,” (http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf). The OPP typically considers the highest potential exposures from the legal use of a pesticide when conducting human

- health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diets within the U.S., and people who may be exposed when harvesting crops. Should these highest exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure that the risk estimates are based on the best available information.

11.0 Cumulative

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

- mechanism group (CMG) by the Agency in a 2002 paper entitled, “ The Grouping of a Series of Triazine Pesticides Based on a Common Mechanism of Toxicity

. 4 

### ” However, promet ryn was excluded from the triazine CMG because it does not share the toxicity profile of the CMG triazines. Therefore, f

or the purposes of the prometryn registration review , EPA is assuming that prometryn does not have a common mechanism of toxicity with other substances.

12.0 Endocrine Disruption

As required by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal Food, Drug, and Cosmetic Act (FFDCA), EPA reviews nu merous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general o r systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its most recent registration decision , EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), prometryn is subject to the endocrine screening part of the Endocri ne Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the est rogen, androgen, or thyroid (E, A, or T) hormonal

4 http://www.epa.gov/oppsrrd1/REDs/triazine_cumulative_risk.pdfPrometryn Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 12 of 21 

### systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine whic h, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and establish a dose

- response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 in ert ingredients. Prometryn is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Accordingly, as part of Registration R eview, EPA will issue future EDSP orders/data call

- ins, requiring the submission of EDSP screening assays for prometryn. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.

1 3 .0 Human Studies

Past prometryn risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation expo sure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as PHED, the Outdoor Residential Exposure Task Force (ORETF) Database, and the Agricultural Reentry Task Force (ARTF) Database. E PA has reviewed all the studies supporting these multi

- pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethica l standards prevailing at the time the research was conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued reliance on the se studies.

1 4 .0 Risk Assessment Updates, Data Deficiencies, and Label Revisions

The following data deficiencies were identified for prometryn:

Toxicology:

o 870.6200: Acute Neurotoxicity Study 5



### . o 870.6200: Subchronic Neurotoxicity Study 4



### . o 870.7 800 : Immunotoxicity Study 4



### . o 870.3465 : 90

- day Inhalation study 6



### . Residue Chemistry:

o 860.1300: Metabolism S tudy in C arrots (or other root crop) 7



### . o 860.1500: Magnitude of the Residue in Carrots 4



### . o 860.1 480: Magnitude of the Residue Study in Ruminants. Diet ary Exposure: None.

5 These data have been submitted to the Agency and will be reviewed during the pending PRIA action for new food uses on snap beans and dill.
6 28

- day inhalation study will be sufficient.
7 This study was required as conditional data per the 2009 HED risk assessment and has not been fulfilled at this time

.Prometryn Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 13 of 21 

### Occupational/Residential Exposure:

o 875.2100 : DFR study.

EPA anticipates conducting the following risk assessment updates during Registration Review:

Toxicology:

o Reevaluation of the toxicity endpoint/dose selection, along with the FQPA SF may be required. Residue Chemistry:

o The tolerance expression for prometryn in 40 CFR §180.222 needs to be updated as follows to reflect current Agency policy: “Tolerances are established for residues of the herbicide prometryn, including its met abolites 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 ( N,N'

- bis(1

- methylethyl)

- 6

- (methylthio)

- 1,3,5

- triazine

- 2,4

- diamine ).....” Dietary Expo sure:

o Revised dietary risk assessment may be necessary to reflect the potential revised EDWCs, dietary exposure models, and/or toxicological PODs. Occupational/Residential Exposure:

o Revised occupational handler and post

- application risk assessment may be necessary based on the most recent exposure data and Agency policies, and should include an assessment of all registered formulations.

1 5 .0 References

Table 3 . Memoranda Relevant to Registration Review. Author Barcode Date Title

J. Redden N/A 16

- MAR

- 1995 The HED Chapter of the Reregistration Eligibility Decision Document (RED) for Prometryn, Case #0467 (Pesticide Chemical Code 080805; Reg. Group A).

J. Redden N/A 27

- JUL

- 1995 The 2nd revised Mixer/Loader Exposure Assessment for the Reregistration Eligibility Decision Document (RED) for Prometryn, Case #0467 (Pesticide Chemical Code 080805).

W. Wassell et al. D237148,

D224645 20

- JAN

- 1998 PP#6E4691. Prometryn in or on Carrots. Tolerance with no U.S. Registration. U.S. Harmonization of Pesticide Tolerances with Canada.

W. Wassell et al. D367830 05

- AUG

- 2009 Prometryn. Section 3 Registration Request to Add New Uses on Carrot, Celeriac, Cilantro, Okra, Parsley, and Leaf Petioles (Crop Subgroup 4B). Human

- Health Risk Assessment.

W. Wassell D382622 22

- DEC

- 2010 Prometryn (080805). Section 3 Registration Request to Add New Uses on Carrot, Celeriac, Cilantro, Okra, Parsley, and Leaf Petioles (Crop Subgroup 4B). Response (Dated 09/03/2010) to Conditions of Registration.



### Attachments:

Attachment 1: Chemical Identity Table. Attachment 2: Prometryn Acute, Subchronic, and Chronic Toxicity Profile Attachment 3: Prometryn Endpoint Selection Tables.Prometryn Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 14 of 21 

### Attachment 4: Summary of Occupational Registered Uses Pulled From LUIS Report (dated 8/2 2/12). Attachment 5: Prometryn International Residue Limit Status Sheet.

cc: K. Lowe (RAB1), S. Levy (RAB1), A. Dunbar (RAB1) RDI: RAB1 ( 11/16/ 12 ), D. Vogel ( 11/16 /12 ), J. Rowland ( 11/16 /12 ) K.Lowe :S109 4 7:PY

- S:(703)3 47

- 8989 :7509P:RAB1Prometryn Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 15 of 21 

### Attachment 1: Chemical Identity Table

.

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

Physicochemical Properties of Prometryn.
Parameter Value Reference Melting range 118

- 120 C DP# 207139, 12/8/94, C. Swartz pH 6.7 at 20oC (saturated solution) RCB# 2907, 12/4/87, G. Makhijani Density 1.16 g/mL at 20oC Water solubility 33 ppm at 20oC DP# 207139, 12/8/94, C. Swartz Solvent solubility 10

- 30 g/100 mL in acetone, dichloromethane, methanol, octanol, and toluene at 20oC Vapor pressure 8.54 x 10 - 7 mm Hg at 25oC DP#s 196116 & 196123, 4/25/94, K. Dockter Dissociation constant, pK a 4.09 at 20oC RCB# 2907, 12/4/87, G. Makhijani Octanol/water partition coefficient K OW = 2140 at 25oC DP#s 196116 & 196123, 4/25/94, K. Dockter UV/visible absorption spectrum Not availablePrometryn Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 16 of 21 

### Attachment 2: Prometryn Acute, Subchronic, and Chronic Toxicity Profile

Acute Toxicity Profile

– Prometryn

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

870.1100 Acute oral (rat) 00060314 LD 50 = 1802 (1265

- 2568)/ 2076 (1654

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

870.1200 Acute dermal (rat) 00060647 LD 50 >3170 mg/kg III

870.1300 Acute inhalation (rat) 42325503 LC 50 = 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

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

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 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

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 inc omplete ossification of sternebrae & metacarpals. 870.3700b Prenatal

developmental (rabbit) 00157995

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 i ncidence 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

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. Offsp ring 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 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.Prometryn Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 17 of 21 Subchronic and Chronic Toxicity and Genotoxicity Profile

– Prometryn

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

870.4300 Combined Chronic

Toxicity/ Carcinogenicity (rat) 41901201

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 b ody

- weight gains (both sexes) and renal lesions (mineralized concretions) (M).

No evidence of oncogenicity

. 870.4200 Carcinogenicity

(mouse) 40466201

Acceptable/guideline 0, 10, 1000, or 3000 ppm (0, 1, 100, or 300 mg/kg/d) NOAEL = 1000 ppm (100 mg/kg/d ay)

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

- weight gain (F).

No evidence of oncogenicity. 870.5100 Bacterial Gene

Mutation 40457518 Acceptable/guideline Up to 1000

- 2000 ug/plate Negative

870.5100 Bacterial Gene

Mutation 40457519 Acceptable/guideline Up to 1000 ug/plate Negative

870.5385 In vivo bone marrow

chromosomal aberration assay (Chinese hamster) 40457520

Acceptable/guideline Up to 5000 mg/kg bw Negative

870.5550 In vitro UDS assay

(rat hepatocytes) 40457522

Acceptable/guideline Up to 156.25 ug/ml Negative

870.7485 Metabolism and

pharmacokinetics (rat) 41255901

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

(mice) 48936501

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

.Prometryn Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 18 of 21 

### Attachment 3: Prometryn Endpoint Selection Tables.

Summary of Toxicological Doses and Endpoints for Prometryn for Use in Dietary Human

- Health Risk Assessments. Exposure Scenario Point of Departure Uncertainty/FQPA Safety Factors RfD, PAD, LOC for

Risk Assessment Study and Relevant Toxicological Effects Acute Dietary (Females 13+) NOAEL = 12

mg/kg/day UF A = 10X

UF H = 10X UF FQPA = 1X aRfD = aPAD = 0.12

mg/kg/day Developmental toxicity (rabbit) LOAEL = 72 mg/kg 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 UF A = 10X

UF H = 10X UF FQPA = 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

- car cinogenicity for humans

. ”

Abbreviations: UF = uncertainty factor, UF A = extrapolation from animal to human (interspecies), UF H = potential variation in sensitivity among members of the human population (intraspecies), UF FQPA = FQPA Safety Factor, NOAEL = no

- observed adverse

- effect level, LOAEL = lowest

observed adverse

- effect level, RfD = reference dose (a = acute, c = chronic), PAD = population

- adjusted dose.

Summary of Toxicological Doses and Endpoints for Prometryn for Us e in Occupational Human

- Health Risk Assessments. Exposure Scenario Point of Departure Uncertainty Factors Level of Concern

for Risk Assessment Study and Toxicological Effects

Dermal Short

- and Intermediate

Term (1

- 30 days and 1

- 6 months) NOAEL = 12

mg/kg/day

Dermal

- absorption factor = 15% UF A = 10X

UF H = 10X Occupational LOC

for MOE <100 Developmental toxicity (rabbit)

LOAEL = 72 mg/kg based on increased incidence of resorptions, abortions, and post

- implantation loss leading to decreased number of viable litters and live fetuses. Dermal Long

- Term (>6 months) NOAEL = 3.75

mg/kg/day

Dermal

- absorption factor = 15% UF A = 10X

UF H = 10X Occupational LOC

for MOE <100 Chronic toxicity (dog; dietary)

LOAEL = 37.5 mg/kg/day based on degenerative hepatic changes, renal tubule degeneration, and bone marrow atrophy. Inhalation Short

- and Intermediate

Term (1

- 30 days and 1

- 6 months) NOAEL = 12

mg/kg/day

100% inhalation assumed UF A = 10X

UF H = 10X Occupational LOC

for MOE <100 Developmental toxicity (rabbit)

LOAEL = 72 mg/kg based on increased incidence of resorptions, abortions, and post

- implantation loss leading to decreased number of viable litters and live fetuses. Inhalation Long

- Term (>6 months) NOAEL = 3.75

mg/kg/day

100% inhalation assumed UF A = 10X

UF H = 10X Occupational LOC

for MOE <100 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”

Abbreviations: UF = uncertainty factor, UF A = extrapolation from animal to human (interspecies), UF H = potential variation in sensitivity among members of the human population (intraspecies), UF FQPA = FQPA Safety Factor, NOAEL = no

- observed adverse

- effect level, LOAEL = lowest

observed adverse

- effect level, MOE = margin of exposure , LOC = level of concern.Prometryn Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 19 of 21 

### Attachment 4: Summary of Occupational Registered Uses Pulled From LUIS Report (dated 8/22/ 12).

Formulation Use Site Application Equipment Application Timing Max App Rate REI Comments

Liquid Carrot

(including tops) Groundboom Postemergence. Apply after crop has 3

- 5 true leaves. 1 lb ai/A

12 hr SLN use. Used on carrot seed. Preemergence and postemergence (make through 6

- leaf stage of carrot development). 2 lb ai/A

Liquid Celeriac Groundboom Postemergence. Up to the 6

- to 8

- leaf stage. 4 lb ai/A

12 hr Groundboom and Chemigation Transplant. Apply after the

crop has 6

- 8 leaves. 2 lb ai/A

Liquid Celery Groundboom Post

- transplant

. 2

- 6 weeks after transplant 3.2 lb ai/A 24 hr

Pre

- and Post

- transplant

. 2

- 6 weeks after transplant 2 lb ai/A 12 hr SLN use

Groundboom and Chemigation Preemergence 1.6 lb ai/A 12 hr

Seed bed. Applications may be made over the crop after the crop has 2

- 5 true leaves. 0.8 lb ai/A 12 hr

Liquid Cilantro Groundboom Post

- plant, preemergence 1.6 lb ai/A 12 hr

Liquid

Cotton Groundboom Preplant 1 lb ai/A 12 hr SLN use.
Aerial, Groundboom, Chemigation Preemergence 2.8 lb ai/A 12 hr

Groundboom Postemergence. Do not

allow contact of spray with cotton leaves, or injury may occur. Direct spray to base of cotton plants. 1.6 lb ai/A 12 hr

Dry Flowable Groundboom Postemergence (avoid contact with cotton leaves) 1.2 lb ai/A 12 hr

Liquid Dill Groundboom Postemergence. Apply after crop has 3

- 5 true leaves. 1 lb ai/A 12 hr SLN use. Used on dill seed. Preemergence and Postemergence 1.6 lb ai/A 12 hr

Liquid Fennel Groundboom and Chemigation Post

- transplant . 2

- 6 weeks

after transplant 2 lb ai/A 12 hr

Groundboom Preemergence and Post

plant 1.6 lb ai/A 12 hr

Groundboom and Chemigation Preemergence 1.6 lb ai/A 12 hr SLN use.

Groundboom and Chemigation Seed bed. Applications

may be made over the crop after the crop has 2

- 5 true leaves. 0.8 lb ai/A 12 hrPrometryn Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 20 of 21 Formulation Use Site Application Equipment Application Timing Max App Rate REI Comments

Liquid Leafy petioles

crops (cardoon, celery, chinese celery, celtuce, florence fennel, rhubarb, Swiss chard) Groundboom Post

- transplant . 2

- 6 weeks after transplant 3.2 lb ai/A 12 hr

Groundboom and Chemigation Preemergence 1.6 lb ai/A 12 hr

Groundboom and Chemigation Postemergence. Apps can

be made over the top of the crop when celery has 2

- 5 true leaves. 1 lb ai /A 12 hr

Groundboom Seed bed. Applications

may be made over the crop after the crop has 2

- 5 true leaves. 0.8 lb ai/A 12 hr

Liquid Okra Groundboom Preemergence. After planting before crop emergence for 1 app. 1.5 lb ai/A 12 hr

Postemergence. Directed spray when plants at 7

- 9 leaf stage. 0.75 lb ai/A 12 hr

Liquid Parsnip Groundboom Postemergence. Apply after crop has 3

- 5 true leaves. 1 lb ai/A 12 hr SLN use. Used on parsnip seed.

Liquid Parsley Groundboom Postemergence. Apply after crop has 3

- 5 true leaves. 1 lb ai/A 12 hr SLN use. Used on parsley seed. Preemergence. Before crop
emergence. 2 lb ai/A 12 hr

Liquid Pigeon peas Groundboom Preemergence. Before crop
emergence. 3 lb ai/A 12 hr

Liquid Rhubarb Groundboom Dormant. Before leaves have emerged from crown. 2 lb ai/A 12 hrPrometryn Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 21 of 21 

### Attachment 5: Prometryn International Residue Limit Status Sheet.

Prometryn (080805); current as of 11/5/12

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 Codex 40 CFR 180.222: Prometryn (2,4

- bis(isopropylamino)

- 6

- methylthio

- s

– triazine) None None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 Codex General Tolerances Carrot, roots 0.45 Celeriac, roots 0.05 Celeriac, tops 0.20 Cilantro, leaves 3.5 Coriander, dried leaves 9.0 Cotton, gin byproducts 1.0 Cotton, undelinted seed 0.25 Leaf petioles subgroup 4B 0.50 Okra 0.05 Parsley, dried leaves 1.5 Parsley, leaves 0.60 Pea, pigeon, seed 0.25 Tolerances with regional registration Dill 0.3 Indirect or inadvertent residues Barley, forage 0.3 Barley, hay 1.0 Barley, straw 0.3 Oat, forage 0.3 Oat, hay 1.0 Oat, straw 0.3 Rye, forage 0.3 Rye, hay 1.0 Rye, straw 0.3 Triticale, forage 0.3 Triticale, hay 1.0 Triticale, straw 0.3 Wheat, forage 0.3 Wheat, hay 1.0 Wheat, straw 0.3 Completed: M. Negussie; 11/06/2012

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.