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



### MEMORANDUM DATE: August 5, 20 14 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### SUBJECT: Diclofop-methyl: Human Health Assessment Scoping Document in Support of Registration Review. PC Code: 110902 Decision Nos.: 490582 Petition Nos.: NA Risk Assessment Type: Single Chemical Aggregate TXRNo.: NA MRIDNo.: NA 

### FROM: Sheila Piper, Chemist

# bh~~ DP Barcodes: 0419904 Registration No.: 241-427 Regulatory Action: Registration Review CaseNo.: NA CAS No. : 51338-27-3 40 CFR: 180.385 Yung Yang, Ph.D., Toxicologist 

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### 1 • Monica Hawkins, Ph.D., M.P.H.,

### Bbv1ronme~tal Health Scientist 

### AA

### \}~fin»J~ Risk Assessment Branch VI 1

## v~ Health Effects Division (7509P) 

### THROUGH: Donna Davis, Acting Branch Chief

# ~tJ**J. ./2~**  Risk Assessment Branch VI Health Effects Division (7509P) 

### TO: Marianne Mannix, Chemical Review Manager Pesticide Re

-Evaluation Division (7505P) Risk Management 

### & Implementation Branch 3 (RMIB3)


### Executive Summary The Health Effects Division (HED) Diclofop-methyl Registra tion Review Team has evaluated the status ofthe human health risk assessment for diclofop

-methyl to determine the scope of work necessary to support Registration Review. The primary source ofinformation for this evaluat ion was the most recent human health risk assessment written for diclofop-methyl (Memo, D268403, C. Jarvis, 08/1 0/2000).

Page I of20Diclofop-methyl Registration Review Human Health Seeping Document Diclofop-methyl was first registered in 1982 as an herbicide that controls wild oats and annual grassy weeds in wheat and barley, as well as in established bermuda grass turf on golf courses. Exposures can be expected to occur via the dietary, drinking water , and occupational (handler and post-app li ca t ion) routes . There are no registered residential uses of diclofop-methyl; however , there is the potential for r esidential e x posure to golfers f r om co n tact with turf treated by commercial applicators. The toxicology da t abase for diclof o p-methyl is complete; no addi t ional data are required to support the registration review. The diclofop

- methyl registration r e view team has evaluated the toxicity database and reviewed the endpoints , doses and safety/uncertain t y factors selected for this chemical and finds them to reflect current policies. No new data is anticipated and no further rev ie w of the points of departure of SFIUFs are required for this chem ical.

There are no outstanding residue c h emis t ry data. The dietary exposure database is adequate to support the registration review of diclofop methyl. No dietary (food and water) risks of concern were identified; however , E F E D has indicated that an updated drinking water assessment is required. Shou ld the revised dr i nking water concentrations significantly i ncrease, a revised

dietary risk assessment may be r equired.

Based on current HED policy, a tu r f transferrable residue (TTR) study is required for diclofopmethyl to support the use on go l f courses. An updated residential exposure assessment will be required under registration review which incorporates the findings of t he TTR study and the most updated residential standard operating procedures (SOPs) to address post-application exposure to

adults and children go lfin g on commercially treated turf. An updated aggregate risk assessment will be required in registrat i on review wh ich incorpora t es updated drinking water estimates and revised residential post-application exposure estimates from the established golf course u s e.

The current tolerance expression s h ould be updated to comply with HED's current policy on tolerance expressions du r ing registration review. The residue defini t ion in the US is harmoni ze d with the Canadian Maximum Residue Limit (MRL) expression; Codex has no MRLs for diclofopmethyl. The barley and wheat tolerances at 0.1 ppm are harmonized with Canada. Mexico adopts the

standa r ds of the US for it s export p u rposes. Dislodgeable Foliar Residue ( DFR) studies (wheat/barley) are req u ired for diclofop-methyl at this time based on HED policy. An updated occupational handler e x posure assessments will be required based upon revisions to the Agency's scenario-specific surrogate handler exposure data. Introduction HED has evaluated the most recent complete human health risk assessment for diclofop-methyl to determine if sufficient data are a vailable and if updates are nee d ed to support registration review. The latest risk assessment was conducted in 2000 (C. Jarvis, 0268403, 08/1 0 / 2000). H E D has also considered updates to i ts toxicity , exposure and usage databases, and the latest Agency science policy and risk as s essment methodologies. Page 2 of20Diclofop-methyl Registration Review Human Health Scoping Document Diclofop-methyl is classified by the Agency as a restricted use pesticide due to carcinogenicity in laboratory mice, and may be purchased and used only by certified applicators. Diclofop-methyl may be applied pre-plant, pre-emergent, or post-emergent, and is applied by fixed-wing aircraft and tractor-drawn equipment, as well as by hand held equipment. The registered product is emulsifiable concentrate (EC) formulations and the maximum la bel rate is 1.0 lb. ai!acre for wheat and barley, and 1. 02 lb. ai/acre for golfcourse turf. There is a maximum ofone application per growing season. Information on the chemical identify ofdiclofop-methyl is included in Attachment 1
. 

### Hazard l dentificationffoxicology Diclofop Methyl Herbicide is a member ofthe aryloxphenoxypropionate class ofherbicides that is an inhibitor ofacetyl CoA carboxylase. The toxicology database for diclofop-methyl is complete, no additional data are required. While the current 40 CFR Part 158 Toxicology Data Requirements include subchronic inhalation, immunotoxicity, and neurotoxicity (acute and subchronic) studies, these studies were not submitted for diclofop-methyl. However, the Hazard and Science Policy Council (HASPOC) determined that based on a weight-of-evidence (WOE) approach, considering all the available hazard and exposure information for diclofop-methyl, subchronic inhalation, immunotoxicity, and neurotoxicity (acute and subchronic) studies are not required to support the registered uses of diclofop-methyl (TXR#0056963, 5/8/2014). Diclofop-methyl exhibits moderate to low acute toxicity via the oral and dermal routes of exposure (toxicity category II and III, respectively), but is less toxic by the inhalation route of exposure (toxicity category IV). In primary irritation studies, diclofop-methyl produced moderate ocular irritation (toxicity category III) and slight dermal irritat ion (toxicity category IV). It was considered to be a moderate to severe sensitizer in a maximization test; the Buehler test was negative. Diclofop-methyl toxicity database identified the liver as the target organ. Liver weights were increased in treated animals in all ofthese studies
. 

### In the two-generation study, increased liver weights were observed across generations in both sexes; in some cases, pup liver weights were also affected. Histological examination ofthe livers revealed an increased incidence ofhepatic lesions following subchronic oral and dermal exposure and multi-generational exposure. Carcinogenicity studies in the rat and mouse showed increased incidence ofadenomas and carcinomas ofthe liver. No evidence ofmutagenicity was seen in any study. The Agency' s Cancer Assessment Review Committee classified diclofop-methyl as a Group C carcinogen (possible human carcinogen) with a Q1* of2.3 x 10- 1(mg/kg/ dayy 1 based on hepatocarcinogenesis in the mouse carcinogenicity study. Developmental toxicity studies were conducted in the rat and rabbit. In the rat study, developmental toxicity was observed only at maternally toxic doses. Systemic maternal toxicity was observed at the lowest dose tested and consisted ofincreased absolute and relative liver weights. At the mid-dose level, decreased fetal body weight and decreased crown-rump length,
Page 3 of20Diclofop-methyl Registration Review Human Health Scoping Document distended ureters, and skeletal abnormalities were observed. In the rabbit s tudy no developmental

toxicity was seen; maternal toxicity, consisting of increased liver and kidney weights, decreased body weights, and reduced food consumption, was observed only at the high do se .

The acute reference dose (RID) ofO.l mg/kg/day (NOAEL =10 mg/kg/day) for females 13-50 years old is derived from th e developmental toxicity study in the rat, base d on significant decreases in fetal body weight and crown-rump length, distended ureters, and skeletal abnormalities at the LOAEL of 32 mg/kg/day. No appropriate endpoint was identified for the U.S. ge neral population, including infants and children. The chronic RID of 0.0023 mg/kg/day (NOAEL= 0.23 mglkg/day) is derived from a combined chronic feed ing /carcinogen icity study in the rat, based on increased abso l ute and relative liver and kidney weights, increased ALT (alan ine aminotransferase), AST (aspartate aminotransferase), and AlkP (alkaline phosphatase) activities, impaired lipid and protein metabolism, and histopathology (hypertrophy, lipofuscin s torage) in males and females at the LOAEL of2.3 mg/kg/day. The short- and intermediate-term dermal risk assessment was based on a 21 -day dermal toxicity study in the rat w i th a NOAEL of 5 mg/kg/day, the LOAEL was 25 mg/kg/day based on increased liv er enzymes, proteins, and absolute and relative liver weights. A dermal absorption factor (after 10 hours of exposure) of 15% will be used to convert the oral dose to an equivalent dermal dose for the cancer risk assessment on ly. No inhalation s tudy i s available except t he acute inhalation study. The subc hronic feedi ng study in the rat with NOAELILOAEL of 1.6/6.3 mg/kg/day, respectively is selecte d for short- and intermediate-term inhalation risk assessm en t since the effect (liver toxicity) is consistent with the other studies in both rats and mice. The current use pattern for diclofop-methyl does not indicate a concern for long-term inhalation or dermal exposure. There is no evidence for increased quantitative or qualitative susceptibility of the young following in utero and pre-and post-natal exposure to diclofop-methyl b ased on t he re su lts from developmental stu die s conducted with rats and rabbits, as well as a two-generation reproduction study conducted with rats. The risk assessment team concluded that the FQPA Safety Factor could be reduced to 1. Metabolism studies in the rat indicate that diclofop-methyl is extensively absorbed, metabolized and excreted through the feces (69.7 to 77.9%) while less was eliminated i n the urine (16.4 to

18 .9%); no measurable amount(< 0.01%) ofradioactivity was found in expired air. Residual radioactivity was found mainly in t he li ve r, kidney and digesti ve tract; the highest le vels of radioactivity were found in the fat. Two metabolites were identified in bo t h the urine and feces as hydroxylated and de-esterified parent compounds. Conclusions for Hazard Identifica t ion/Toxicology The toxicology database for diclofop-methyl is complete, no additional data are requ ired. The HASPOC determined that based on a weight-of-evidence (WOE) approach considering all the available hazard and exposure in format ion for diclofop-methyl, subc hron ic inhala t ion , immunotoxicity, and neurotoxicity (acute and subchron ic) studies are no t required to support registered use of diclofop-methyl at thi s time. The selected PODs and tox i cological endpoints from the most recent human heal th risk assessment are summarized in t he attachment. Page 4 of20Diclofop-methyl Registration Review Human Health Scoping Document
No new data have been reviewed since the last toxicological assessment for diclofop

-methyl. Additionally, the team has reviewed the points ofdepartures and safety factors and concluded that they consider all appropriate data and are consistent with current science policy. Dietary Exposure The existing residue chemistry database for diclofop-methyl is adequate for risk assessment purposes. Tolerances are established for diclofop

-methyl under 40 CFR 

### §180.385 in/on barley and wheat commodit ies. The nature ofthe residue in plants is adequately understood
. The residues ofconcern in plants is diclofop-methyl (parent), diclofop acid, and hydroxyl diclofop (free and conjugated). Based on the results ofmetabolism studies in ruminants, and a poultry feeding study, tolerances are required for residues in meat and milk as a result ofingestion of diclofop-methyl residues in the livestock feed. Tolerances have been proposed for barley hay, wheat forage, wheat hay, and livestock commodities and should be included in the 40 CFR for diclofop

-methyl. Tolerances are not required for residues ofdiclofop

-methyl in eggs and poultry tissues. Acceptable
_ analytical methods are available to enforce tolerances for residues of diclofop-methyl in p lant and livestock commodities. The most recent dietary exposure and risk assessment was conducted in 2000 (D267649, 

### R. Griffin, 08/03/00). HED conducted a partially refined, acute and chronic dietary risk assessments for diclofop-methyl using anticipated residues, percent crop treated, and included modeled estimated drinking water concentrations. The Environmental Fate and Effects Division (EFED) provided a refined surface water and a Tier 1 groundwater analysis for diclofop-methyl, using computer modeling, existing monitoring data, and a small scale prospective groundwater study which were incorporated into the most recent risk assessment for this chemical. The residues ofconcern for drinking water are diclofop-methyl (parent) and its metabolite, 2- [ 4

-(2,4

- dichlorophenoxy)phenoxy]propanoic acid. PRZMIEXAMS and SCI-GROW modeling estimates, as well as monitor ing data from the prospective groundwater study, are based on parent diclofop

-methyl and its acid metabolite. EFED has indicated that updated drinking wa ter exposure estimates are needed for diclofop-methyl during registration review. The acute dietary assessment was limited to the females 13

-49 years ofage population subgroup. This is the only population subgroup for which an appropriate toxic endpoint attributable to a single dose was ident ified
. For females 13-49 years ofage, acute dietary (food and water) risk was S 8% ofthe acute population adjusted dose (aPAD). Estimated chronic dietary (food and water) risks for the U.S population and all regulated population subgroups were S 1% ofthe chronic PAD (cPAD). Carcinogenic risk for diclofop-methyl is quantified, based on the estimated average dietary exposure ofthe general U.S. population (5x 1o-6 mg/kg bw /day) multiplied by the upper-bound potency factor 

### (Q1*) of2.3 x10- 

### 1(mg/kg/dayy 

### 1

. On this basis, the upper-bound carcinogenic risk estimate for diclofop

-methyl is calculated to be 1.2 x 1

# o-6). Conclusions for Dietary Exposure The residue chemistry database is considered comple te and the dietary exposure database is adequate to support the existing registration. Tolerances have been proposed for barley hay (6 ppm); wheat forage (12 ppm); wheat hay (1 ppm); meat by-products, excluding kidney (7 ppm);
Page 5 of20Diclofop

- methyl Registration Review Human Health Scoping Document kidney (25 ppm); m i lk (4 ppm); and in the meat and fat of cattle, goat, horses, and sheep (1 ppm) and shou l d be included in the 40 CFR for diclofop

- methy l. An updated dietary (food and drinking water) risk assessment may be conducted during registration review process should the updated drinking water exposure values vary significantly from th e values used in the current assessment. Residential (Non-Occupational) Ex posure and Risk Diclofop-methyl, an emulsifiable concentrate, is a restricted use pesticide that is currently registered for use on go l f course turf. Dic l ofop-methyl is restricted from use on residentia l turf/lawns, however there is the potential for residential exposure fro m contact with turf treated by commercial applicators during golfing activities; however, based on the use on golf courses, adults and older children may experience exposure to diclofop-methyl as a result of contacting commercia ll y treated turf (i . e., residential post-application exposure) . Residential Handler Diclofop-me thy l is a restricted use pesticide. Label language restricts the sale and use of this pesticide to licensed applicators. There are no residential handler exposure scenarios expected for diclofop

- methyl and residentia l handler exposure assessments were not conducted and are not required. Residential Post-Application In accordance with 40CFR158, TTR data are required for all occupational (e.g., sod farms, golf courses, parks, and recreational areas) or residential turf uses that c ould result in post

- application exposure to turf. HED developed a waiver policy for TTR studies. The MOEs from the assessment, using default TTR val u es are evaluated . If those are 1 0 times higher th an the l evel of concern (LOC) the TTR studies can be waived. Residential MOEs for post

- app l ication exposure are shown in the tab l e be l ow.

Golfing Formulation Lifestage TTR , Weight Transfer Hours of E xpos ure Absorbed Dermal Dermal (ug/cm 2 ) unit Coefficient Exposure (mg/day) Dose MOE MOE conversio (cm 2 / hr) (hr) (mglkg/day) (rounded) n f actor (mg/ug) Liquid s Adult 0.11 0.001 5 , 300 4 2.3564 0.02945475 169 .75 170 11 to 0 . 11 0.001 4 , 400 4 1.9562 0.03432 145 . 69 150 < 16 years 6 to < 11 0 . 11 0 . 001 2,900 4 1.2893 0 .04 029185 124.09 120 years Since the estimated residentia l turf post-application exposure for golf cou r se using default TTR values for diclofop-methyl is not minimal in compar i son to the level of concern (i.e., the calculated MOE is not greater than 10 times higher than the l e v el of concern, MOE= 120 Page 6 of20Diclofop-methyl Registration Review Human Health Seeping Document compared to the LOC of 100, future refmements ofthis post-application exposure for diclofopmethyl may be necessary due to increased use ofdiclofop-methyl or advances in EPA risk assessments. Therefor e, EPA is requiring the 40CFR TTR data requirement for diclofop-methyl as part ofregistration review. An updated residential post-a pplication assessment will be required for registration review which incorporates the required TTR data using the updated 2012 residential SOPs (http://www.epa.gov/pesticides/science /residential-exposure-sop.html). Spray Drift /Volatilization Residential bystander exposures resulting from off-site transport (e.g., spray drift or volatilizat ion) may occur as a result ofapplications ofdiclofop-methyl. The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs)

- Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift ( http://www.regulations.gov /#!docketDetail;D=EPA-HQ-OPP-2013-0676). This document outlines the quantification ofindirect non-occupational exposure to drift. In terms of volatilization, the agency has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http: //www.regulations.gov/# !docketDetail;D=EPA

-HQ

OPP

-2014

-0219). During Registration Review, the agency will utilize this analysis to determine ifdata (i.e. , flux studies , route-specific inhalation toxicological studies) or further analysis is required for dicloflop-methyl. Conclusions for Residential Exposure There is insufficient information available to assess residential post-application exposure. In accordance with the updated Part 158 data requirements (2007), a ITR study is required for all occupational (e.g., sod farms , golfcourses, parks, and recreational areas) or residential turfuses that could result in post-application exposure to turf. Based on HED policy, a TTR study is required for diclofop

-methyl. The study will affect the occupational post
-application assessment that will be conducted for golfcourses. A revised residential exposure assessment (cancer and non-cancer) may be required under registration review that includes post-application exposure to adults and children golfing on commercially treated turf. This assessment should incorporate, as necessary, updated human factors (e.g., body weight) assumptions , and the 2012 Revised Residential SOPs. The potential for residential exposures resulting from off-site transport (e.g., spray drift or volatilization) will need to be evaluated for diclofop-methyl during the registration review process. Aggregate Risk Assessment In accordance with the Food Quality Protection Act (FQPA), HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and direct residential exposures.

Page 7 of20Diclofop-methyl Registration Review Human Health Scoping Document The acute (females only) and chronic aggregate risk assessments for diclofop-methyl included food and drinking water only. As discussed above, there were no aggregate acute or chronic risks identified in the most recent dietary assessment. An updated dietary risk assessment will only be required if there is a signi fi cant change to the drinking wa t er concentration. A shortterm aggregate risk assessment considering exposure from food, water, and non-occupational (residential) sources of exposure d i d not exceed HED ' s level of concern. An intermediate-term aggregate risk assessment was not conducted for diclofop-methyl. The cancer aggregate risk

estimate to diclofop-methyl addresses carcinogenic exposure from food, drinking water, and residential exposure to golferS is 3 . 2 X 1 o- 6 . Conclusions for Aggregate Risk Assessment No acute or chronic aggregate ri sk s have been identified for diclofop-me t hyl. An updated dietary risk assessment will only b e required during registration review if there is a significant change to the drinking water concentration. While there are no registered residential uses for diclofop-methyl, there is the poten t ial to residential post-application exposure from contact with turf from commercial application to golf courses. Therefore, an updated short- and intermediateterm as well as cancer aggregate ri s k assessments will be required for registration review for diclofop-methyl. Occupational Exposure As previously mentioned , diclofop

- methyl is currently registered fo r use on agricultural crops such as wheat and barley and on golf course turf. It is applied pre-p l ant, pre-emergent, or postemergent by groundboom and aerial for wheat/barley and han d- held equipment for golf courses. The maximum application rate is 1 lb ai / A for wheat and barley and 1.0 lb ai / A for golf course turf. Occupational handler and post-application exposures are expected based on the registered uses of diclofop-methyl. For labels where diclofop-methyl is applied to wheat and barley, engineering controls are used by applicators and flaggers. Mixer/loaders must use a closed system as instructed by the currently approved labels. Mixer/loaders mus t also use a chemicalresistant apron and chemical-resistant gloves. For labels where diclofop-methyl is applied to golf courses, the PPE for mixers/loaders is baseline PPE (long

- sleeved shirt, and long pants, chemical-resistant footwear plus socks), chemical-resistant apron and gloves, and a NIOSH approved respirator with an organic vapor cartridge or canister. Occupational Handlers For occupational handlers, the major exposure scenarios identifie d and assessed previously include: mixing/loading liquids for groundboom application, mixing/loading liquids for aerial application, mixing/loading liquids for hand gun sprayer application, applying liquids wi t h a groundboom sprayer, applying liquids with fixed-wing aircraft, applying liquids with hand gun sprayer, and flagging for liquids application. Occupational handler exposures are expected to be short- and intermediate-term in du r ation. All of the MOEs for the combined dermal and inhalation exposure are greater t han 1 00 with maximum risk reduction measures (personal Page 8 of20Diclofop-methyl Registration Review Human Health Scoping Document protective equipment (PPE) or engineering controls) for all ofthe short- and intermediate-term occupational exposure scenarios listed above (D267650, Tadayon, S., 8/2 /2000). The cancer risk estima tes for occupational handler dermal and inhalation exposure range from 1.4 x 10·2 to 5.1 x 10·6 at the baseline level, 8.4 x 10·5 to 6.0 x 10-7 with PPE, and 5.8 x 10·5 to 1.4 x 10-6 at the engineering control level (D267650, Tadayon, S. , 8/2/2000). In 2000, diclofopmethyl was classified as a "possible human carcinogen" by the Carcinogenicity Peer Review Committee (CARC) based on liver adenomas and carcinomas with significant trend and pairwise comparisons, as seen in a mouse carcinogenicity study. The 

### Q1 

## * was determined to be 2.3 x 10- 1 (mg/kg/day)" 1 human equivalents to assess its cancer risks. The CARC reconvened on January 5, 2000 and it was decided that the 

### Q1 

## * remain unchanged (D267650, Tadayon, S., 8/2/2000). Recommended unit exposures for occupational handler assessments have generally been derived only from the Pesticide Handlers Exposure Database (PHED). However, recently both the Outdoor Residential Exposure Task Force (ORETF) and the Agricultural Handler Exposure Task Force (AHETF) have produced pesticide handler exposure monitoring data that the Agency is using in place ofPHED (http: //www.epa.gov/pesticides/science/handler-exposure-data.html). As more reliable data become available, the Agency will continue to replace existing data. Reviewers should incorporate new exposure monitoring data, as necessary, during registration rev1ew. Occupational Post-Application In accordance with 40CFR158 , DFR data are required for all occupational (e.g., crop, nursery, greenhouse use sites) or residential (e.g., ornamental and vegetable gardens, pick your own farms , retail tree farms) uses that could result in post-application exposure to foliage. HED developed a waiver policy for DFR studies. The MOEs from the assessment, using default values are evaluated. Ifthose are 2 times higher than the LOC the DFR studies can be waived. Occupational MOEs for post-application exposure are shown in the table below. Occupational Post-application Non-Cancer Dermal Exposure and Risk Estimates Crop/Site Activities Transfer Coefficient ·Dermal Dose MOE (cm2 /hr) (mglkglday) Barley Scouting 1,100 0.278 18 Wheat, Spring Scouting 1,1 00 0.278 18 Wheat, Winter Scouting 1,100 0
.278 18 Since the highest estimated occupational post-application exposure using default DFR values for diclofop-methyl is not minimal in comparison to the level ofconcern (i.e., the calculated MOE is not greater than 2 times higher than the level ofconcern, MOE = 18 (at Day 1 (restricted-entry interval (REI) = 24 hours) compared to the LOC of 1 00); EPA is requiring the 40CFR DFR data. Therefore, EPA is requiring the 40CFR DFR data requirement to facilitate any necessary exposure assessments refinements and to further EPA's general understanding ofthe availability ofdislodgeable foliar pesticide residues.
Page 9 of20Diclofop-methyl Registration Review Human Health Seeping Document There may be the potential for pos t -application dermal exposure to worke r s following applications of diclofop-methyl to agricultural crops (wheat/barley) and to golf course turf. As noted above, application can be made either pre-plant, pre-emergent , or post-emergent. Recommended transfer coefficient s for occupational post-applicat i on assessments are derived from Agricultural Reentry Task F o rce (ARTF) exposure monitoring studies ( http://www . epa.gov/pesticides /s cience/post-app-exposure-data.html ). These transfer coefficients have been updated in 2012 based on a reanalysis and submission of new monitoring data. Reviewers should incorporate new exposure monitoring data, as necessary, during registration review.Conclusions for Occupational Exposure There is insufficient information available to assess occupational exposure. In accordance with the updated Part 158 data requirements (2007), one or more Dislodgeable Foliar Residue (DFR) studies are required when a pestici de has residential or occupational uses that could result in post-application dermal exposure. Based on HED policy, a DFR is required for diclofop-methyl at this time for wheat/barley. In accordance with the updated Part 158 data requirements (2007) ,

a TurfTransferrable Residue (TTR) study is required for all occupa t ional (e.g. , sod farms, golf courses, parks , and recreational areas) or residential turf uses that could result in post-application exposure t o turf. Based on HED policy, a TTR study is required for diclofop-methyl. An

updated occupational handler and post-application assessment will be required under registration

review if warranted by any significant changes in exposure assessment methodology and any new data that is submitted. Public Health and Pesticide Epidemiology Data

HED has completed its review of incident data that were reported to the Agency, the findings in the Agricultural Health Study (AHS) as part of the diclofop-methyl seeping process (S. Recore, 05/29 / 14, D420493). There does not appear to be a concern at this time that would warrant further investigation, sincere there were no incidents involving diclofop-methyl. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the preliminary risk assessment. Page 10 of20Diclofop-methyl Registration Review Human Health Scoping Document
Tolerance Assessment and International Harmonization Tolerances are currently established under 40 CFR §180.385 for the herbicide diclofop-methyl (methyl 2-[4-(2,4-dichlorophenoxy)phenoxy ]propanoate) and its metabolites 2-[ 4-(2,4- dichlorophenoxy)phenoxy]propanoic acid and 2-[4-(2,4-dichloro-5- hydroxyphenoxy)phenoxy]propanoic acid in or on barley grain, barley straw, wheat grain and wheat straw at 0.1 ppm. Only tolerances for plant commodities are presently established, and none have been established for livestock commodities. Tolerances have been proposed for barley hay (6 ppm); wheat forage ( 12 ppm); wheat hay (1 ppm); meat by-products, excluding kidney (7 ppm) ; kidney (25 ppm); milk ( 4 ppm); and in the meat and fat ofcattle, goat, horses, and sheep (1 ppm) and should be included in the 40 CFR for diclofop-methyl. Tolerances are not required for residues ofdiclofop-methyl in eggs and poultry tissues. HED recommend that 40 CFR §180.385(a) should be further subdivided into 40 CFR §180.385(a)(1) and 40 CFR § 180.385 (a)(2) for separate designations ofdiclofop residues of concern in plants and animals, respectively. The current tolerance expressions are not in compliance with BED's Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner) and should be revised during registration review. The residue definitio· n in the 

### US is harmonized with the Canadian Maximum Residue Limit (MRL) expression; Codex has no MRLs for diclofop-methyl. The barley and wheat tolerances at 0.1 ppm are harmonized with Canada. Mexico adopts the standards ofthe 

### US for its export purposes. Therefore, there are no harmonization issues with Canada, Codex, or Mexico. The International Residue Limit Status Sheet is attached to the document as Attachment 5. International or Intergovernmental Work Sharing HED is not currently involved in any joint interna tional review projects that involve the active ingredient, diclofop-methyl. Additionally, HED is unaware of any ongoing international assessments for diclofop-methyl. Given the limited use pa ttern for this chemical and the lack of any identified new work, HED has not identified any potential work sharing opportunities for diclofop-methyl. Cumulative The Food Quality Protection Act (FQPA) requires the Agency to consider the cumulative risks of chemicals sharing a common mechanism oftoxicity. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism oftoxicity, EPA has not made a common mechanism of toxicity finding as to diclofop

-methyl and any other substances, and diclofop-methyl does not appear to produce a toxic metabolite produced by other substances. Therefore, a cumulative risk assessment has not been performed for these compounds. Human Studies There are no diclofop-methyl specific human studies that require an ethics review at this time. Previous HED risk assessments relied in part on data from studies in which adult human subjects · Page 11 of20Diclofop-methyl Registration Review Human Health Scop ing Document were i n tentiona ll y exposed to a pesticide or other chemical. The se data, which include studies from PHED 1.1; the AHETF database; the Outdoor Res id entia l Exposure Task Force (ORETF) database; the ARTF database; are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that rev iew, and (3) are compliant with applicable ethics r eq uireme nts. 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 b e found at the Agency website' Data Requirements Toxicity Studies • NoneResidue Chemistry Stud ies • None Occupational/Residential Studies • Chemical-specific TTR study (875.2100) • Chemical-specific DFR study (875 . 2100) References Table 1: HED Memoranda Relevant to Registration Review

Author BarcodeffXR # Date Title Uma Habiba TXR No. 0056963 06/14 Diclofop -m ethyl: Summary of Hazard and Science Policy Council (HASPOC) Meeting of May 8, 2014: Recommendations on th e Requirement of a Subchronic Inhala t ion Study, Neurotoxicity (acute and subchronic) Studies, and an lmmunotoxicity Study Shanna Recore D420493 05/29/14 Diclofop-methyl: Tier 1 Review of Human Incident s Seyed Tadayon D267650 08/02/00 Revised Occupational and Residentia l Exposure Assessment and Recommendations for the Reregistration Eligibility Document for Diclofop-methyl 1 http: // www.epa . gov / pesticides / science/handler-exposure-data.html and http: // www.epa.gov / pesticides / science / post-app-exposure-data . html Page 1 2 of20Diclofop

-methyl Regist ration Review Human Healt h Seeping Document
Table 1: HED Memoranda Relevant to Registration Review Author BarcodeffXR # I Date Chr istina Jarvis D268403 08/ 10 /00
Richard Griffin D267649 08/03/00
Sheila Piper D265277 05/02/00

Attachments Attachment 1. Chemical Identity Attachment 2. Toxicology Data Requirement Attachment 3. Toxicity Profile Tables Attachment 4. Endpoint Tables Attachment 5. International Residue Limits Table

Attachment 1. Diclofop-methyl Chemical Identity

Table 1.1 Diclofop

- methyl Nomenclature Compound

Common name Diclofop-methyl Title Diclofop-methyl Revised HED Chapter ofthe Reregistration Eligibility Decision Document (RED) Diclofop-methyl. Revised Anticipa ted Residue Estimates and Dietary Risk Assessment Diclofop-met hyl. Product and Residue Chemistry Chapters for the Reregistration Eligibility Decision Document (RED)

TUPAC name methyl (RS)-2-[4-(2,4-dichlorophenoxy)phenoxy)propionate CAS name methyl 2-[4-(2,4-dichlorophenoxy)phenoxy]propanoate CAS registry number 51338-27

-3

Page 13 of20Diclofop

- methyl Registration Review Human Hea lth Scoping Document Table 1.2 . Physicochemical Properties of the Technical Grade of Diclofop

- methyl Parameter Value Reference

Melting point (range) 39-41 c pH 5.7 Density 1.30 + 0.05 g/cm 3 at 40 C

Water solubility 0.005g/l00mL So l vent solub i lity xy l ene - 253 g/1 OOmL ethanol - 11 g/1 OOmL acetone- 249 g/IOO mL D265277, S . Piper, 5 / 02 / 00 Vapor pressure 1. 9 x 1**0~** mm Hg at 20 C Dissoc i ation constant, pKa pKa = 3.43 Octanol / water partit i on 37 , 800 coefficient, Log(Kow) UV / visible absorption spectrum Not available Page 1 4 of20Diclofop-methyl Registration Review Human Healt h Scoping Document
Attachment 2. Toxicology Data Requirement
Test Technical Required Conducted 870
. 1100 Acute Oral Toxicity yes yes 870.1200 Acute Dermal Toxicity yes yes 870
. 1300 Acute Inhalation Toxicity yes yes 870
.2400 Primary Eye Irritation yes yes 870.2500 Primary Dermal I rritation yes yes 870.2600 Dermal Sensitization yes yes 870.3100 Oral Subchronic (rodent) yes yes 870
.3150 Oral Subchronic (non

-rodent) yes yes 870
.3200 21 /28

-Day Dermal yes yes 870.3250 90-Day Derma l no no 870.3465 90-Day Inhalation no waived 870.3700a Developmenta l Toxicity (rodent) yes yes 870.3700b Developmenta l Toxicity (non-rodent) yes yes 870
.3800 Reproduction yes yes 870.4100a Chronic Toxicity (rodent) yes yes 870.41 OOb Chronic Toxicity (non

-rodent) yes yes 870.4200a Oncogenicity (rat) yes yes 870.4200b Oncogenicity (mouse) yes yes 870.4300 Chronic /Oncogenicity yes yes 870
.5100 Mutagenicity

- Gene Mutation (bacterial) yes yes 870
.5300 Mutagenicity

- Gene Mutation (mammalian) yes yes 870.5375 Mutagenicity

- Structural Chromosoma l Aberrations yes yes 870.5395 Mutagenicity-Other Genotoxic Effects yes yes 870.5500 Mutagenicity-Other Genotoxic Effects yes yes 870.6100a Acute Delayed Neurotoxicity (hen) no no 870
.6100b 90-Day Neurotoxicity (hen) no no 870.6200a Acute Neurotoxicity Screening Battery (rat) yes waived 1 870.6200b 90

-Day Neurotoxicity Screening Battery (rat) yes waived 1 870
.6300 Developmental Neurotoxicity no no 870.7485 General Metabolism yes yes 870.7600 Dermal Penetration no yes 870.7800 Immunotoxicity yes waived 1

. . . . 1The 90-day mha1at10n, acute /subchromc neurotoxicity, and 1mmunotoXICity studies are not requrred at th1s trrne.

Page 15 of20Diclofop-methyl Registration Review Human Heal th Scoping Document Attachment 3. Toxicity Profile Tables Table 3.1. Acute Toxicity Profile for Diclofop-metbyl Guideline Study Type MRID(s) Results Toxicity Number Category 870.1100 Acute oral [Rat] 41476001 LDso = 512 ( 428 - 636) mg/kg (M/F) II 92036052 870.1200 Acute dermal [Rat] 00071522 LDso > 2000 mg/kg (M/F) III 92036013 870.1300 Acute inhalation [Rat] 41573304 LCso > 4.75 mg/ L (MIF) IV 870.2400 Acute eye irritation [Rabbi t ] 42428601 Slight ocular irritant, conjunctival redness III and discharge at 24 hr , cleared by 72hr 870.2500 Acute dermal irritation [Rabbit] 40213506 Slight irritation reported IV 870 . 2600 Skin sens it ization [Guinea pig] 41476003 Buehler : Nega ti ve 41476002 Maximizati o n: Moderate to severe sensitizer 41476003 Table 3.2. Subcbronic, Chronic and Other Toxicity Profile for Diclofop-metbyl Guideline Number/ MRID(s)/ Results Study Type Classification 870 . 3150 4257330 1 -02 NOAEL = l.6/1.8 mg/kg/day [MIF ] 90-Day oral toxicity Acceptable / G u ideline LOAEL = 6.317.1 mg/kg/day (M!F] based on clinical [rat ] chem , perox proliferation, liver hypertrophy 870 . 3150 42593901 NOAEL not established 90-Day oral t oxicity Accep t able / G u ideline LOAEL = 0.3 / 0.4 mg/k g/day [MIF ] based on clinical [mouse] chem , perox proliferation, liver necrosis 870 . 3200 41476004 Systemic NOAEL = 5 mg/kg/day 28-day dermal toxicity Acceptable / gu i deline Systemic LOAEL = 25 mg/kg/day ba sed on [rat) increased liver enzymes, proteins, and absolute and relative liver w ei ghts

D ermal irritation N OAE L = 125 mg/kg/day; LOAEL>l25 mg/kg/day 870 . 3700a 92036043 Maternal NOAE L = 0.3 mg/kg/day Prenatal Acceptable / G u id eline LOA EL = 3.0 mg/kg/day Based on significantly developmental increased absolute l i ver and kidney weights, [rabb i t] decreased body weight gain, and reduced food consumption. Developmental NOAE= 3.0 mg/kg/day. LOAEL could no t be determined. 870 . 3700c 92036042 Maternal NOAE L =not es tab l i shed. Prenatal Acceptable / G u ideline LOAEL = 10 mg/kg/day based on reductions in food developmental consumption, mean body weights and body weight ga in. [ra t ] Developmental NOAEL= I 0 mg/kg/day LOA EL = 32 mg/kg/day based on decreased fetal body weights and crown-rump l ength, distended ureters, skeletal abnormalities . Page 16 of20Diclofop-methyl Registra tion Review Human Health Scoping Document
Table 3.2. Subcbronic Chronic and Other Toxicity Profile for Diclofop-metbyl

Guideline Number/ MRID(s) / Results Study Type Classification 870.3800 42543 101 Parental/Systemic NOAEL = 0.3 mglkglday Reproduction and Acceptable/Guideline LOAEL = 3.0 mglkglday based on liver weight incr eases fertility effects and histopathological lesions in liver and kidney. [rat] Reproductive /Developmental NOAEL = 3.l/2.5 mglkg/day [M/F] LOAEL = 7.3/8
.4 mglkglday [M/F] based on reduced fetal body weights and delayed !>hysical development. 870.4100b 92036039 NOAEL = 2.0/0.2 mglkg/day [MIF] Chronic toxicity (dog] Acceptable /Guideline LOAEL = not established/0.63 mglkg/day [M/F] based on Clinical chem, perox proliferation, liver histopathology. 870.4100a 43927302 NOAEL = 0.23/0.3 mglkglday [M/F] Chronic toxicity/ Acceptable /Guideline LOAEL = 2.32/3.05 m g/kglday [M/F] based on Increased Carcinogenicity liver and kidney weights, hepatocellular hypertorphy , [rat] histopathology (lipofusin storage). Evidence ofsignificant (p<O.O I) increases (both pair-wise and trend) ofhepatocellular adenomas and carcinomas in males as well as combined adenomas /ca rcinomas in both sexes. 870.4300 92036058 NOAEL = 0.24 /0.25 mglkglday (M/F] Carcinogenicity Acceptable /Guideline LOAEL [systemic] = 0.76/0.77 mglkg/day [MIF] based on [mouse] Clinical chem, perox proliferation, liver hypertrophy
. Statistically significant trends were evident in both sexes for hepatocellular adenomas, carcinomas and combined adenomas/ca rcinomas. 870.5100a 000719004 Dose range: 0 to 500 uglmL, +/- S9 Gene Mutation Acceptable Negative Bacterial reverse mutation test in Salmonella typhimurim 870.5300a 4 1573305 Dose range: 2 to 500 J.lg/mL +/

- S9 In vitro mammalian Acceptable Test was negative up to cytotoxic doses (200 J.lg/mL, - cell gene mutation test S9; 300 J.lg/mL, +S9). in Chinese hamster lung f V79] cells 870.5375a 41476004 Dose range: I to 500 J.lg/mL +/- S9 ln vitro mammalian Acceptable Test was negative over the dose range ( +S9) chromosome aberration test in primary human hepatocytes 870.5385 4 1737901 Dose range: 0, 200, 1000, and 2000 mg/kg In vitro Acceptable Chromosomal analysis did not show any treatmentcytogenetic related cytogenetic aberrations test in bone marrow cells ofthe Chinese hamster 870.5550 41996902,42437801 Dose range: 0.5 to 50 J.lg/mL, cytotoxicity at 100 J.lg/mL Unscheduled Acceptable Did not induce sig nificant increases in nuclear labeling DNA synthesis in ofprimary rat hepatocytes. A549 human lung
Page 17 of20Diclofop-methyl Regis tr ation Review Human Hea l th Scop in g Document Table 3.2. Subchronic, Chronic and Other Toxicity Profil e for Diclofop - m ethyl Guideline Number/ MRID(s)/ Results Study Type Classification carcinoma i n vitro 870 . 5550 41996902 ,42437801 Dose range: 0.03 to 1 00 J.lg/mL ± S9 Unschedu l ed Acceptable Did no t induce significant increases i n nucl e ar label i ng D NA synthesis in human l ung cancer ce lls. A549 human l ung carcinoma i n vitro Mutagenicity 0087820 Dose range : 250, 500, 1000 J.lg/mL ± S9

-Ot h er Acceptable Mitotic gene conversions not i nc reased in yeas t strain

ge n otoxic over spontaneous rate ± S9 effects 870.7485 41573306 D iclofop-methyl is extensive ly absorbed , metabolized and Metabolism Accep t ab le / Gu id eline excreted through the feces and the urine ; no measurable [ra t ) amount( < 0 .0 1%) of radioac t ivity was found in exp i red ai r. R es idual radioactivity was found mainly in the li ver, kidney and d igestive tract; t he highes t leve ls of radioactivity were found i n the fat. Two metaboli t es were identified i n both the urine and feces as hydroxyla te d and

de-ester ified paren t compounds . 870 . 7600 42364601 De r ma l absorption factor = 15% at 10 hours Dermal pene t ration Acceptable/gu i deline [rat] Page 18 of20Diclofop

-methyl Registration Review Human Health Scoping Documen t Attachment 4: Diclofop-methyl Endpoint Selection Table

Table 4. Toxicolotdcal Doses and Endpoints for Use in Diclofop-metby) Human Health Risk Assessments. Exposure Point ofDeparture, RID, PAD, Level Study and Toxicological Effects Scenario Uncertainty/FQPA Safety ofConcern for Factors Risk Assessment Acute Dietary NOAEL

- 10 mg/kg/day aPAD= 0.1 Developmental toxicity study in the rat (Females 13-49) UFA =l Ox mg/kg/day (MRlD 92036042) UFH = lOx Developmental LOAEL= 32 FQPA SF= I mg/kg/day based on decreased fetal body wts, distended ureters, skeletal abnormalities. These effects could be attributed to a single dose. Acute Dietary No endpoint attributable to a single dose was identified. (General Population) Chronic Dietary NOAEL

- 0.23 mglkg/day cPAD = 0.0023 Carcinogenicity study in rats. (All Populations) UFA =lOx mglkg/day (MRID 43927302) UFH = lOx LOAEL = 2.32 mglkg/day, based on FQPA SF = lx increased relative liver and kidney wts, liver enzymes, liver histopathology (hypertrophy, lipofuscin storage). Effects and NOAEL consistent with other studies in mouse and dog. Dermal Short

- and NOAEL= 5 mg/kg/day LOC for 21-Day Dermal Toxicity Study in the Intermediate-Term UFA = lOx MOE=IOO Rat UFH = lOx (MRID 41476004) FQPASF = lx LOAEL= 25 mglkg/day based on Dermal absorption factor: increased liver enzymes, proteins, and 15% absolute and relative liver weights. Dermal Long-Term No long-term exposure anticipa ted from currently use pattern. (>6 Months) Inhalation Short- Oral, NOAEL= 1
.6 mg/kg/day LOC for Subchronic Oral Toxicity Study in the and intermediated

- (inhalation toxicity assumed MOE= IOO Rat (MRID 42573301) Term to be equivalent to oral LOAEL= 6
.3 mglkg/day based on toxicity 100%) increased liver enzymes, proteins, and absolute and relative liver weights. Inhalation Long- No long-term exposure anticipated from currently use pattern. Term {>6 Months) Cancer (Oral, Classification: Group C carcinogen (possible human carcinogen) with a Q l 

### * of2.3 x 10· 1 Dermal, Inhalation) (mg/kg/day)- 1 based on hepatocarcinogenesis in the mouse carcinogenicity study. Pomt ofDeparture (POD) = data pomt or estimated pomt, denved from observed dose-response data, and used to mark the beginning ofextrapolation 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 ofthe human population (intraspecies)
. FQPA SF= FQPA Safety Factor
. PAD= population adjusted dose (a = acute, c = chronic). MOE = margin ofexposure. LOC = level ofconcern.

Page 19 of20Diclofop-met hy l Registration Review Human Health Scoping Document Attachment 5. International Residue Limits Table Table 5. Summary of US and Inte rn ational Tolerances and Maximum Residue L i mits for Diclofop-Methyl Residue Definition: us Canada Mexico 1 Codex 40 CFR § 180.385 propanoic acid , 2-[ 4-(2,4- None Plant: Diclofop-methyl (methyl 2-[ 4- dich l orophenoxy) phenoxy )-, (2,4-dichlorophenoxy) methyl ester , including the phenoxy ]propanoate) and its metabolites propanoic acid, 2- metabolites 2-[ 4-(2,4- [4-(2,4- dichlorophenoxy)phenoxy ]propanoic dichlorophenoxy)phenoxy ]- and acid and 2 -[ 4 -( 2,4-dichloro-5- propanoic ac i d, 2- [ 4-(2 ,4
- hydroxyphenoxy)phenoxy]propanoic dichloro-5 - hyd roxy phenoxy) acid phenoxy]- Livestock: None Commodity T o ler a nce (ppm) /Maximum Residue Lim i t (m vkg) us Canada Mexico' Codex Barley , grain 0 . 1 0.1 Barley , straw 0 . 1 Wheat, grain 0 . 1 0.1 0 .1 triticale Wheat, st raw 0 .1

Comp l eted: M . Negussie; 05 / 29/14 1 Mex1co adopts US tolerances and/or Codex MRLs for 1ts export purposes. Page 20 of20