UNITED STATES ENVIRONMENTAL PROTE CTION AGENCY WASHINGTON , D.C. 20460

MEMORANDUM
DATE: 12 / 05 / 20 1 3 OFFI CF- OF C HEMICAL SAFETY AND POLL U TION PR E V E NTION

SUBJECT: Dithiopyr. Human Health Assessment Scopin g Document in S upport of Registration Review

PC Code: 128994 MRID No.: Not Applicable Petition No. : Not App licable Assessme nt Type: Single Chemical Aggregate TXR No.: Not Applicable
FROM: DP Barcode: 041 365 9 Registration No.: Not Applicabl e Regulatory Action: Registration Review Scop ing Rere g istration Case No. : Not App licable CAS No
. : 97886-45-8

T HROUGH: An a Rivera-Lupiariez, Chemi st 

# JtJJ/
. /'""'\ '**-~~­** Michael Metzger, Branch Chief

-

### ~**~** Ri s k Assessm ent Branches V & VII
TO: Health Effects Division (75 09P ) Veronica Du tch, Chemical Review Manager Ri sk Managem e nt and Impl e mentation Branch V Pe stic ide Re- eval ua tio n Di vision ( 7508P )
Executive Summary The HED Dithi op yr Registration Review Team ha s evaluated the scientific database for the pe st ic ide dithiopyr to de termine the scope of work nec essary to support the exi stin g registrati on. Dithiopyr (S,S ' -dime thyl 2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3 , 5

- pyridinedicarbothi oate), a substituted pyridine herbicide , is reg is tered by EPA for use to control crabgrass and broad leaf weeds in turf and ornamental s. Curr en tl y, there-are no agricultural food Page 1 of 10uses for dithiopyr. Although a tolerance petition to support the import of treated brown rice was considered in 1992 , no tolerances were established. Disciplinary and peer review documents in the EPA databases were the primary resources for this document. Drinking water, occupational, and residential exposures to dithiopyr are possible; therefore , a qu an t itative human health risk assessment is required under reg istr ation re view for the existing uses of dithiopyr. HED notes that dithiopyr has not been through a comprehensive endpoint se lect ion process (chronic RID and carcinogenicity assessments have been completed); a Toxicology Science Advisory Council (ToxSAC) meeting is needed during registration review to determine toxicity endpoints for this chemical. The HED Hazard and Science Policy Council (HASPOC) met on l l/7/13 and determined that an inhalat ion study is required ; however , the requirements for acute and subchronic neurotoxicity and immunotoxicity studies were waived. At this time , no aggregate , dietary , occupational or re sidenti al risks of concern have been identified for this chemical. Introduction The HED Dithiopyr Registration Review Team has eval uated the potential for human exposure from use of this herbicide. The purpose ofthis screen is to determine whether sufficient data are available and whether a human health risk assessment is required to support regis tration review. In preparation of this memo, HED considered all relevant dithiopyr reports in th e E PA databases. A full list is presented in the reference sect ion of this document. Dithiopyr is used as a pesticide to control crabgrass and broadleaf weeds in turf and ornamental plants. Dithiopyr is formulated as an emulsifiable concentrate, water soluble packets, and as a granular product ; it can be applied by groun d-based and handheld equipment to residential turf/ornamentals, industr i al areas , commercial turf, and gol f courses. Short-term and intermediate-term occupational exposures are expected based on the registered use pattern. Short-term re sidenti al exposures are expected based on the registered use pattern. Hazard Identification/Toxicology The tox ici ty database for dithiopyr is complete except for an inhalation study. HASPOC has determined that the inhalation study is required (TXR 0056812, J. Les hin, 1 1119/20 13). The HASPOC also recommended waiving the requirem ents for the ACN/ SCN and immunotoxicity studies. The toxicity DERs will be re-assessed for establishing LOAEL and NOAEL values based on current toxi city policies, and then reviewe d by the To x SAC. There are no recent comprehensive human -health risk assessments available for dithiopyr. Other than the oral RID , endpoi nts for other exposure scenarios (i.e ., inhalation, dermal, incid e ntal oral) have not been identified in these previous assessments. Dithiopyr underwent an RID Committee review meeting in 1997 , and a CARC review in 1993. The RID Committee recommended that a chronic RID be established based on a combined chronic toxicity/ carcinogenicity study in the rat. A NOAEL of 0 .36 mg/kg/ day was iden tified from the Page 2 of 10rat study based on liver and kidney toxicity obse r ved at 3.63 mg/kg/day. An uncertainty factor of 100 was applied to the NOAEL to account for inter

- and intra-spec ie s variation, resul tin g in a chronic RID of 0.0036 mg/kg/day. Dithiop yr was classified as GroupE- no evidence for carcinogenicity in humans. As a basis for the carcinogenic ity decision, the CARC indicated that there was no increase in malignancy, a lack of genotoxic ity , and that dithiopyr does not have any structural similarity to known chem ica l carcinogens. On the basis of a preliminary review of the toxicity database for dithiopyr, the follow i ng tentative co n c lu sions regarding the toxicity of this ch emical can be drawn. Technical grade dithiopyr has low acute toxicity via oral, dermal and inhalation routes of exposure. Technical dithiopyr is not a dermal sensit izer. A primary eye irritation study in rabbits indicated no corneal opacity but the re was irrit at io n that was rever sible. Mi ld or s light irritati on was noted in a primary sk in irritation study in the rabb i t. The subchronic and chron i c oral toxicity studies in revealed liver and kidney toxicity in rats, mice and dogs. A LOAEL of 1000 mglkg/day, based on increased absolute and relative (to body weight) liver weights was identified in a 21-day dermal toxicity study in the rat. The NOAEL was 500 mg/kg/day. Limited to transient mild irritation was noted in some animals in all dose groups. Developmental toxicity studies in rabbits and rats ide n tified developmental NOAELs = 1,000 mg/kg/day , the highest dose tested. No treatment-related adverse effects on reproductive parameters (i.e. , mating, fertility, gestation indices , and length of gestatio n) were observed in the 2-generati on reproducti ve toxicity study in the rat. In addition, there were no indications of treatment-related effects on mean number of pups/litter, sex ratio or pup viability in both ge nerati ons . The res ul ts of mutagen i c i ty studies (Ames assay, CHO/HGPRT mutation assay , and an unscheduled DNA sy nth es is in rat hep atocyte culture) indicated that dith i opyr was not mutagenic under test conditions. Conclusions: The toxicity database for dithiopyr is complete except for a s ub chronic inhalation toxicity study. A ToxSA C meeting will be scheduled for endpoint se lection during reg i stration review. Residue Chem ist ry Dithiopyr is not currently registered as a pesticide for use in any food commodities; therefore , eval u ation of residues i n c rops is not needed. A searc h of the dithiopyr residue chemistry database indicates that a p et it ion to establi s h a tolerance o n imported brown rice was submi tte d in 1 992. Although no tolerance was establi shed, the residue of concern in rice was determined to be parent dithiopyr and it s dicarboxylic acid metabolite , for both enforcement and risk assessme nt purposes. Deficiencies identified included an insufficient numb er of field trials and inadequate storage stability data (D 16945 2, J. Stokes, 30

- JUL-1992). These deficiencies will be of concern o nly if new dithiopyr uses on agricu ltural crops are proposed
. Conclusions: The res idue chemistry databa se sup ports the registered uses of dithiopyr.

Pa ge 3 of 10

### Dietary Exposure The established pesticide uses on turf and ornamentals may result in dietary expos ure through drinking water consumption. No food-based exposure is anticipated as th ere are no registered food uses in agricultural commodities. A dietary exposure assessment for dithiopyr will be conducted in registration review, once estimated drinking water concentrations (EDWCs) are determined by the Environmental Fate and Effects Division (EFED). Conclusions: A dietary exposure assessment to include drinking water exposure will be conducted registration review
. Residential Exposure Based on a review of past dithiopyr document reviews and risk assessments, no quantitative or qualitative non-occupational exposure assessment has bee n conducted to date. Therefore , a quantitative residential exposure assessment to address residential handler, pos t -application, and bystander exposure is needed during registration r eview
. Residential Handlers Based on the current use pattern, there is potential for residential handler exposure. Dithiopyr is mainly applied to residential and industrial turf (e.g., go l f courses and other non-residential turf areas such as industrial parks , sod farms, seed farms, and professionally managed sports fields), although it i s registered for use on nonbearing fruit and nut trees. It is not restricted from purchase or use by residential handlers. Therefore, during regi stration re view HED a nticipates conducting a residential handler assessment to address dermal and inhalation exposure using the most recent exposure methodology and toxico logical endpoints/points of departu re . Residential Post-Application Based on the current use pattern, there is potential for post-application exposure (dermal, incidental oral) to individuals coming into contact with treated resident ial turf, for recreational golfers, and individuals contacting treated turf in commercially treated areas. Since dithiopyr i s formulated as a granu lar product, HED also intends to address incidental ingestion of granules as part of the residential post-application assessment. In accordance with th e updated Part 158 data requirements (2007), a turf-tr ansferrable residue (TTR) study i s required for a ll occupational (e.g., sod farms) or residential turf uses; TTR data are not available for dithiopyr. As part of the recent revision to the Health Effects Division's 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment, HED analyzed all of the available TTR data and selected new liquid and granular default values for the fraction of the applica t ion rate available for transfer after a turf application (FAR)· Thi s default is 0.2% for granular formulations. Of the available TTR stud i es submitted to the Agency, the maximum FAR value seen using a granular product was 0.69% or 3.5 tim es higher than th e default residue transfe r value. Therefore , HED has decided that a calculated MOE of approximately 10 t imes higher than the LOC (e.g., an MOE > 1 ,000 if the LOC = 100) using the default residue transfer values would provide an adequate margin of safety for any potentially Page 4 of 10higher res idu es see n in a c hemical-specific TTR study (HED Memo, 12/12/12, 

### "Gu idance/or Requiring /Waiv ing TurfTr ansfe rrable Residu e (ITR) and Disiodge abfe Foliar Residue (DFR) Studies"). While a chemical-specific TTR study is avai lable, substant ive data quality issues were identified du ring Agenc y review. Because of the issues identified , HED completed screenin g level risk est imates based on default TTR values. For the current uses of dithiopyr , a TTR study will not be required for Registration Review since estima t ed derma l (and inc idental oral) MOE s for all residentia l post-appli cation scenario s are greater than 1000. Ifthe use pattern and/or to xicol ogical points of departure change in th e fu ture , this requirement may be revisited. R

esi denti a l Bystander Exposw-es Residential exposures resulting from off-site transport (e.g., spray drift or vo latilization) might occur as a resu lt of applicati ons of dithiopyr. The Agency is in the process of eval uating these types of ex pos ures and as appropri ate , plans to de velop policie s and procedure s to iden tify the need for and , s ubsequently , the way to inc orporate these post-application expo s ures into the Agency 's risk assessments. The need fo r spray drift and volatilization ri sk assessment fo r dithiopyr will be examined during registration review, although HED anticipates a qualitati ve residentia l bystander exposure assessment based on the high turf appl i cation rate relative to th e agricultural application r ate. 

### Co nclusion s: HED anticipate s cond uct in g a new risk assessment to address the short

- term handler and post-application dermal exposure potential for recreational golfers and indiv iduals (ad ults and children) contacting residential and commerc ially treated turf. Additionally , HED intends to assess inci d ental oral exposure potential based on turf contact and the incidental i nge st io n of dithiopyr formulated as granule s . TTR data are not req uired for d it h iopyr based on a preliminary sc reen of estimated risks from contacting treated turf, and based o n tentative endpoint se lection and 2012 Residential SOPs. The potential for resi d e n tial expos ures resultin g from o ff

- site transport (e.g. , spray drift or volatilization) may need to be quantitatively evaluated for dithi opyr during the registration re view p rocess. 

### C ombined Drinking Wate r Plus Residential Exp osure Risk Assessment Comb in ed drinking wat er plu s residential exposu re to dithiopyr will be examined as part of registration review. These routes of exposure are anticipated given the use pattern 

### (i.e., turf and ornamentals) of the chemical and , the refore, the risk from both so urces will be assessed as part of the regi stration review of dithiopyr. 

### Occupational Exposure Dithiopyr is not currently re giste red for use on agricu ltura l crops , although it is registered for use on commercial turf , go lf courses , and other professio nally managed turf areas. There is potenti al for short- and intermediate-te rm occupational exposure to dithiopyr during hand ling ( mixing , load ing, and apply ing) and po s t-application activ i ti es . The LOC for dermal and inhalation risk estimates is an MOE of le ss than 100 for short- and intermed iate
- term exposure. Occupation al Handlers HED conducted occupational expos ure calculations 

### in 1991 based on two dith iopyr stu die s: a P age 5 of 10passive dos i metry and b io logical mon itori ng study. While those stu dies were class i fied as "supplementary" , data fro m the bio l ogica l mon itorin g study was u sed to estima te Margins of Exposure (MOEs); M OEs were estimated to be greate r than 100 (and therefore "not of co n cern") for occupational han d lers. A revised occ u pationa l handle r risk assessment may be needed f o r di thi opyr. Updated occupational handler exposure assessment may be required under registration review based upon revisions to the scenario-specific surrogate handler exposure data changes i n toxicological endpoint se l ect i on . Furthermore, Agency r eviews of the t w o occupational applicator stud i es used f or es t imating occupati on al ex p osure and risk noted a number of m ethodological deficiencies in the studies. Occupational Pos t-App licat ion A revised occupational post
- applicati on risk assessment may be needed for d i th i opyr . There is a possibility for worke rs to have pos t-app li ca t ion de rm a l exposure to dithiopyr treated turf follow i ng i ts uses. A chemical-specific transferable turf residue study is availab l e, although the Agency identified substantive me th odo l ogical issues in the 1 991 study review
. G iven the age of the available study and the methodological issues noted in the Agency reviews, HED used sc reening methods to evaluate the need for a chemical-specific TIR study. Tur.fTrans.ferable Residue (7TR) : B ased on t h e d i scuss i o n in the res i dential post
- application sect i on, a TT R study wi ll n ot be required for Registration Review since es t imated dermal MOEs for all occup ational post
- app li cation scenarios are greate r than 1

### OX the LOC (i.e., calculated MOEs of 1000)
. If the use pattern and/ or t oxicological point s of departure change in the fu ture, this requ irement may be revisited
. Based on the Agency's current practices, a quanti tati ve occupational post
- ap plication inhalation exposure assessment h as not been performed fo r dithiopyr. However, there are m u ltiple potentia l sources of post-application i nhalati on exposure t o indiv id ual s performing postapplication acti vities in previously treated fie l ds. Th ese potential sources include volatilizat ion of pesticides an d resuspens i on of dusts and/or particulates that contain pestic i des. The Agency sought expert advice and i nput on issues related to vo l atili zation of pesticides from its Feder al Insecti c id e, Fungici de, and Rodenti c i de Act Scientific Adv i sory Pane l (SAP) 

### in December 2009. The Agency received the SAP's final report on March 2 , 20 1 0 1 • T he Agency i s i n the process of evaluating the SAP report as we ll as availab l e pos t -application inhalation exposure data generated by the Agri cu ltural Reentry Task Force and may, as appropriate, develop po licies and procedures to identify the need for and, subsequently, the way to i ncorporate occupational postapplication inhalation exposure i nto th e Agency's r i sk assessments. If new policies or proce d ures are put into p l ace, the Agen cy may revisit the need for a quantitat ive occupati on al post
- application inhalat ion exposure assessment for d i thiopyr. Conclusions: There is sufficient informat i on avail able to assess occup ational h and l er an d pos t
applicatio n exposures , al tho u gh no t all relevant occupati o n al exposure scenarios were assessed i n the last Agency risk assessment ( 1991) based on current ORE policies
. During registration review, H E D w ill consider the need for hand ler and post-applica tion occupationa l assessments to

1 Available: http: //www.epa . gov / scipoly/ SAP / meetings / 2009/120 I 09meeting.html Page 6 of 10account for these policy changes; if a new a ssess ment is n eeded, potential changes to the e ndpoints and safety factor s wi ll be includ ed. Public Health and Pesticid e Epidem i ology Data The eva lu ation of the OPP Main Incident Data Sys tem (IDS) indicated 4 incide nt s ide n tified in the Un i ted States from January 1, 2008, through June 11, 2013 , fo r the single chemical dithiopyr , plus 8 additional incid ents i nvo lving dithiopyr plus more than o ne chemica l. In Aggregate ID S , from January I , 2008 to June 11, 2013, there were 108 incident s reported fo r dithiopyr. For dithiopy r, there appears t o be a low potential fo r exposure . Dithiop yr is not included i n the Agricultural Health S t udy (AHS), and ther efore, does not provide information for this report . There doe s not appear to be a co nc ern at thi s time that would warrant furth er inv es tigat ion. T he Agency will co ntinue to monitor the incid e n t informa t i on and if a concern is triggered, add i tional ana lysis wi ll be included in the risk a ssessmen t. Cumulative The Foo d Q ua li ty Protection Act (F QPA) requires the Agency to cons ider the cumu lative risks of chemicals s haring a common mechanism of toxicity
. Di th i opyr is a member of the s ubsti tuted pyridine class of pesticides. Thi s class a l so includes fluro xypy r , imazapyr , thiazo pyr , and triclopyr. Although the various pyridine herbi cides have similar str uctural components , HED has not made a d etermi nation that they have a common mode of toxic action
. Therefore, a cumu lative risk assessment has not been performed for these compounds. Human St udies The pre vious risk ass e ssments re ly in part on data from studies in which adult human subjects were in tentionally ex p osed to a pesticide or other chemical. These studies , which comprise the PHED, the Outdoor Residential Exposure Task Force (ORETF) , and the Agricultural Reen try Task Fo rc e (ARTF), have been determined to requ ire a review of the i r et hica l conduct, and have rece i ved th at review. Beyond the generic pesticide exposure database stu dies , there were two data reviews for chemical-specific dith iopyr occupational exposure studies; a passive dosimetry study and a biomonitoring study for lawn care applicators handling dithiop yr. HED intend s to su bmit those two exposure studies for OPP ethics review during the reg i stration review proc ess. Data N eeds and Risk Assessment Updates

• Subchron ic inhal atio n toxicity study • ToxSAC Meeting for endpo int selection • Dietary e xposure assessment to inc lud e drinking water • Occupational/residential ex po sure assessment

Page7of10References Auth or Barcode/ MRID Date Title Dithiopyr: Summary of the Hazard and Science Policy Council November (HASPOC) M eeting ofNovember 7 , 2013: Recommendations on J
. Leshin TXR 0056812 19,2013 the Requirement of a Subchronic Inhalation Study, an Immunotoxicity Study, a.nd the Acute and Subchronic Neurotoxicity Studies for Dithiopyr. E
. Evans and 0415250 September Dithiopyr: Review of Human Incidents S
. Recore 24,2013

J.B
. Stokes D169452 Ju ly 30, Dithiopyr in / on Imported Brown Rice
. Evaluation of Analytical 1992 Method and Residue Data.

P. Chin and TXR #010631 October 13, Carcinogenicity Peer Review of Dithiopyr. E. Rinde 1993

G
.Z. Ghali TXR # 012243 May29 , RID /Peer Review Report ofDithopyr. 1997

S.B
. Mathur 0334268 Aprill6, FEE: Product Chemistry Review on Dithiopyr Technical. 2007 Chow, Flora N/A March, Risk Assessment for Dithiopyr R044377 1991
Schlosser, August, Evaluation of Monsanto Response to OREB Review of the Passive Arthur R118561 1992 Dosimetry Portion of Applicator Exposure Study of Dithiopyr Use on Lawns
James D
... September
.. . Post Application Exposure to Dithiopyr
. . . Rl48135 29 , 1994 Note: ellipse denotes illegible text. W ebsi tes http://chem.sis.nlm.nih.gov/ chemidplus/ cas/97886-45-8 http:/ / www.epa . gov/ pesticides/science/residential-exposure-sop.html htto :// www.eoa.swv/scioolv/ SAP / meetin!:!s/2009/120109meeting.html h ttp://www.eh .doe. Q.ov/neoa/ tools/ !!uidanceNolumel/2-6-EO 12898enviustice.pdf http: // www.eoa.Qov/ endo/

Page 8 of 10Attachmen t 1: Chemical Identity Tab l e Chemicalldentity of Dithiopyr.

Structu re I UPACName N**~**

S,S'

- dimethyl 2-d itluoromethyl-4-i so buty l-6-

tritluoromethylpyridin e-3,5-d icarbothio ate S,S'-dimethyl 2-(ditluoromethyl)-4

-(2-methylpropyl)- Reference: CAS Name 6-(trifluoromethyl)-3 ,5 -pyridinedicarbothioate 0334268, S.**lt-C~o-m_m_o_n_N_a_m_e --** **---- --+------** **--"--0-it-h•...;..o...;..pyr ----** **---~** Mathur, 16-APR**I~ ----~--~----** **------ --~------** **----------~------------~2007** Molecular Formula C 15 1-1 16F 5N0 2 S 2 Molecu lar Weight 401.40 glmole CAS Registry Number 97886-45

- 8 PC Cod e Number 128994 Physical State Powder Density 0.593 ± 0.005 glmL @20"C [Tap method] Color Tan Odor Characteristic of s ulfur contain in g compounds Melting Point 65°C UV/Vis 254 nm p H 5.66@ 20"C Henry 's Law Constant 1.51 x I0..() atm-m3 / mol @25"C Reference: II-V-ap_o.;_r_P-re-s-su_r_e**--------+------4-_-0_x_I_O'""",-b_m_•_n_H @-::-2.::.5"** **,--, ,..---** **-- ~**  http: //chem.sis
.nI**l~-"-------------1 --** **-- ---** **-,..-,..-,-"--=----- ----l**  m.nih.gov / chemi II-L_o....;g;....K_o_w

________ --1

_________ 4 _·7

_

5

________ --t dplus/cas/97886- Water solubility 1.4 mg!L @20"C 45-8

lie Acid.

HOOC COOH

Page 9 of 10

### Attachment 2. Dithiopyr Use P roducts and S ites Summary

Attachment 2. Representative Use Patterns of Sec. 3/24C End-use Product For mula ti ons of Dithiopyr
. Registered Use Sites and Applicat
. ion products & %AI Applicable ORE Rev iew s equipment C omm ents F ormu l. Types 84886-3 0.08 granular .25 lb Residential turf Drop spreader ai/acre Established lawns Ground Turf areas equipment, Industrial sites 81927

- 10 0.625 lb Golf course turf Hand wand, No WSB ail acre Nonbearing fruit an d nut trees backpack , chemigation handgun
73327-5 .2 granular .25 lb Residential turf Drop sp reader ai/ acre 73327-6 .17 gran ul ar .25 lb Residential turf Drop spreader ai/ acre Conflicting Estab lished lawns ra te 66222-213 40 Turf info rmation WSB .625 lb Ornamental landscapes -li sted as ailacre Nonbearing fru it and nut trees 0.5 and .625 in d ifferent

places Established lawns Ground 12.7 Turf equipment, 62719-426 0.5 lb Ornamental landscapes Ha nd wand , No EC ai /acre Nonbearing fruit and nut trees backpack , chemigation handgun Es t ablished lawns 53883-208 .25 Turf Dro p s preader granu lar .5 lb ai/ A Ornamental landscapes Illegibl e 32802-69 label

Page 10 of 10