### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHING TON , D.C. 20460

MEMORANDUM DATE: Final

- May 2 1 , 2 014 OFFICE OF CH EMJCAL SAFETY**D** POLUIT ION PREVENTION



### SUBJECT: Propargite: Human Health Risk Assessment Scoping Document in Support of R eg i s tration Review PC Co de : 097601 MRlD No.: Not Appl.icab l e Peti tion No.: Not Applicable Assessment Type: Scoping TXR No.: Not A pp licable DP Bar code: 0416480 Registration No.: Not Applicable Regu latory Acti on: Registration Review Rereg i s trati on Case No.: 0243 CAS 

### No.: 2312

- 35-8
FROM: Marqu ea D
. King , Ph.D. , Toxico l ogist/Risk Asses Bonnie Cropp-Kohlligian , Env ir o nmental Scientist I van Nieves, ORE

### ~ 

### /V"(}) · Risk A s sessment Branch 

# I V'
. Health Effects Divi s ion (7509P ) THROUGH: E li ss a Reaves, Ph.D., Branch Chief

# f~ Risk Assessment Branch 

### IV
TO: Health E ffects Division (7509P) Wilhelmena Livingston, Chemica l Review Manager Risk Management and Imp l ementation Branch IV Pesti cide Re-Evaluation Divisio n (7508P) Attached i s th e Health Effects Division 's (HE D) human health ri sk assessment scoping doc um e nt for propargite to support the registration rev iew process. Executive S ummary HED has co n s id ere d t h e available risk assessments f or propargite and it s toxicity , exposure and usage databases , as well as the most current Agency scien ce and assess me nt po lic ies. HED performed this eval uation i n order to determine the scope of work necessary to s upport the established tole rances and existing registratio ns during re gis tration review. The primary source of informati on for thi s evaluation was the most recent comprehensive Propargite Human HealthPropargite: Hum an Health Risk Assessment Scoping Document in Support of Regis trati on Review Risk Assessme nt 1 conducted to support the September 2001 USEPA Registration E ligibility Deci s ion ( RED) for Propargite2

. Propargite [2-(p-tert-butylphenoxy) cyclohexy l-2-propynyl sulfite] is an organosulfite acaricide 

### used for the control of agricultural pests. It is regi s tere d for u se on a v ariety of field , 

### frui t, and vegetab l e crops , as well as ornamentals. To lerances are establi she d i nion a number of crop and livestock commodities under 40 CFR §180.259 and are expr e ssed in tem1S ofpropargite 

### per se. There are no res id ential uses regi s tere d for propargite
. Formulations ofpropargite include e mul sifiabl e conce ntrates (EC) and wettab l e powders (WP). Depending on th e crops, the se formulat ions ma y be applied as broadcast, banded or direc ted spray or chemigation fo liar treatments pre- or postharvest using ground or aerial e quipment. T h e toxicity , residue chemistry and occupational e xposure databases for propargite are adequate for re g i s tration review and no additional data are r equired. T he toxicity database for propargit e i s considered comp lete and suffi cient f or characterization of potential dev e lop men tal , reprodu c ti ve , carcinoge ne tic , mutageni c, neurotoxic , and immunotoxic effects. As part of registration r eview , however, the endpoints , do s es , and safet y fac tors (SFs) u sed in th e mo st recent human health risk assessment may nee d to b e re-evaluated accordin g to current HED policy
. Update d exposure and ri sk ass ess m e nts may be conducted if there are any significant chan ges to the estimated drinking water conc e nt r ations (EDWCs), and/ or to the current scenariospecifi c s urrogate handler- ex posure data. The mo s t prevalent clinical s igns associate d with thi s chemical are we ight l oss and GI (stomach and jejunum) perturbation s . There was no indication of quantitative or qualita t ive susceptibi lity in the de velopmental or reproduction s tudie s. A b atte ry of mutagenicity studies adequate ly demon strates the lack of mutag enic effe c t s exerted by this chemical. Proparg i t e i s classifi e d as a B 2 Chemical ( Probabl e Human Carcinogen) (TXR No. 0 0 1 046 1) based up on the presence of rar e mali gn ant tumor s 

### in the jejunum of mal e and female C rl :CDBR rats. No evidence of carcinogenicity was found in the carcinogenic ity studies with C D-l mouse or Wistar rats. Acute and chronic dietary risk assessm e nts 3 were last performed to support the 2 001 Proparg ite RED
. Previously assessed highly refined acute , chronic non-cancer, and cancer dietary exposure and ri sk anal yses were performed on food onl y. At the 99.9th percentile , 2% of the acute Population Adjusted Dose (aPAD ) was used for fe male s 13-49 ye ars (the o nl y population subgroup identified as relevant for the acute dietary endpoint), and less than 1 % of the chronic Population Adjusted Dose (cPAD) was u sed for the general U.S. population and all other population s ubgroups. Cancer dietary risk from food alone was 1.8 x 10 -? for the general U.S. population. Risks fro m potential expo s ure to propargite in drinking water from all sources were evaluated by comparing m ode l ed estimated environmental concentrations (EECs) again st calcu late d drinking water leve ls of compari son ( DWLO Cs). The modeled acute and chronic non-cancer EECs for propargite in drinking water did not exceed the Agency ' s ca lcula t ed DWLOC values
. The modeled cancer EEC for s urface water and availabl e s urface water

1 Propa rgite Revised H uman H ealth Risk Assessment. T. Morton. 9/ 13 /200 I
. 0276544 2 http ://www . epa.gov/pesticides/ reregistrationlpropargi te / 3 Propargite Revised Cancer D ietary Exposure and Ri s k Analysis f or the HED Human Health R isk Assessment. T
. Morton. 8 /28/200 I. 0276547. Page 2 of20Propargite : Human Health Risk Assessment Scoping Document in Support of Registration Review monitoring data di d indi cate a concern for cancer from drinking water alone; however, the Agency considers these drinking water estimates to be conservative and likely overestimate the actual exposure to propargite in fmished drinki ng water. While there are currently no registered residential uses of propargite, residential bystander exposures resulting from off-site transport (i.e. , spray drift or volatilization) may occur as a result of occupational applications of propargite. The need for a bystander risk assessment for propargite will be considered during registration review. The previous occupational exposure assessment 4 covered all exposure scenarios relevant to propargite and no occupational handler or post
- app lication risks of concern were identified with use of appropriate personal protective equipment (PPE).
Chemical Use Profile Propargite i s an organosulfite acaricide used for t he control of agricultural pests and its mode of action is believed to be inhibition of mitochondrial ATP synt hase
. It is a non -systemic compound causing morta lity of mites from interrup tion of normal metabolism and respiration. It is currently registered for food/feed uses on the following: almond, dry beans , com (field, pop and sweet), cotton, grape, grapefruit, hops , lemon , nectarine, orange, peanut , peppermint/spearmint, potato , sorghum, tea and walnut; however, lemon and tea are not currently on end-use products registered in the U .S. Registered commercial use sites for propargite i nclude ornamentals and roses not for homeowner use or purchase. Propargite formu lations include emulsifiable concentrate and as a wettable powder which is applied b y aerial application, ground boom, chemigation, air blast sprayer, and high pressure hand wand. Propargite labels have been amended as required under the propargite RED process with the following exception: EPA Registration Number 400-427 still allows application to cherry orchards after fruit harvest. This use should be deleted since it is considered a food use (ChemSAC 8/25 /99) and there is no established tolerance in/on this crop. The nomencla ture and physiochemical properties of propargite are presented in Tables 1 and 2 of Attachment 1.
Hazard Identificationrr oxicology T he toxici ty database for propargite is complet e and sufficient for characterization of potential developmental, reproductive , carcinogenetic, mutagenic, neurotoxic , and immunotoxic effects. There were no qualitative differences found in the formation of metabolites in mouse versus rat. Pharmacokinetic studies revealed that propargite i s absorbed through the GI tract 5-7 times faster in mice than in rats. Mice also eliminated th e material twice as fast as rats.

4 Propargite: Revised Occupational and Residential Exposure and Risk Assessment for the Reregistration Eligibility Decisio n (RED) Document. S
. Tadayon. 7 /31/2001. D276513
. Page 

### 3 of20Propargite: Human Health Risk Assessment Scoping Docu m ent in Support of Registration Review Propargite is considered cor ros i ve and is irritating in both the eye and dermal rabbit studies , with a Tox Category I rat in g for both. These chemical properties are consistent with incidents of workers in the field d eve lop ing dermal and eye irritation (D419224). Ev idence of dermal sensitization potential has been noted but due to th e irritating properties of the chemical conclusive results have not been generated. There is low acute toxicity via the oral and dermal routes of exposure. The most prevalent clinical signs is wei ght loss and target organ for propargite is the GI tract (stomach). Adverse effe cts of overall body weight decreases are consistent across time and species. The available s tudies demonstrate no incre ased sensitivit y to rats or rabbits in utero and/or postnatal exposure to propargite. The lOx Food Quality Protection Act (FQPA) Safety Factor (SF) for the protection of infants and children has been reduced to IX for the following reasons: (1) The toxicology and expos ure databases are complet e and 2) There is no increased qualitative or quantitative suscept ibility in the rat or rabbit developmental toxicity studies Propargite is classified as a B2 chemical (Probable Human Carcinogen) based upon the presence of rare malignant tumors of the jejunum in male and female Crl:CDBR rats. There was no carcinogenicity seen in CD -I mice nor Wistar rats . An oral s l ope factor (Q I *) of0.033 x 

### 10" 1 was used for quantification of human cancer ri sk. Cell proliferation studi e s were conducted in an effort to establish a mode of action for the carcinogenic effects. It was concluded that there was insufficient evid ence to warrant a re-evaluation of the classification of Propargite or the method of quantification of human cancer risk reassessment (MRID 43766801 ). A battery of mutagenicity studies demonstrates lack of mutagenic effec ts upon exposure to propargite. Acute and subchronic neurotoxicity studie s in rats and an immunotoxicity st ud y , which are required in accordance with new data requirements for convent io na l pesticide re g i stration ( 40 CFR Part I 58), have not been submitted. However , based on a weight-of-evidence (WOE) approach, considering all the available propargite hazard and exposure informat ion , the HED Hazard and Science Policy Council (HASPOC) con cluded that the acute and subchronic neurotoxicity studies and the immunotoxicity study are not needed for propargite at thi s time 5

. The acute, s ubchronic , a nd chronic toxicity profile tables for propargite are included in Attachment 2. Toxicity endpo ints , po int s of departure (PODs ), and uncertainty/ safety facto rs (UF / SFs) were selected for oral, dermal, and inhala t ion expo sure pathway s for the Human Health Risk Assessment conducted in 2001 (D276544) , and these are shown in Attachme nt 3. Upon review of the toxicology data and consideration of all available data including the open literature, the endpoints for risk assessment and all uncertainty factors may be re-evaluated during registration revi ew to reflect current HED p o lici es. 

### Conclusions: The toxicity data base for propargite is considered complete and is adequate for assessing potential carc ino genetic , mutagenic, deve lopmental , neurotoxic , immunotoxic , and

5 Propargite : Summary of Hazard and Science Policy Coun c il ( HA S POC ) Meetin g of Ap r il I 0, 2014: Recommendations on the Requirement of an Immunotoxicity S tudy, and the Acute and S ubchronic Neurotoxicity Studie s for Propargite
. U
. Habiba
. 4/10/2014. TXR No. 0056943
. Page 

### 4 of20Propargite: Human Health Risk Assessment Scoping Document in Support of Registration Review 

### reproductive effects. During registration review, the endpoints and safety factors for risk assessment may be updated to reflect current policies. 

### Res idue Chemistry The qualitat ive nature of the residue of propargite in plants and livestock is adequately understood. The HED Metabolism Assessment Review Committee (MARC; D256182) determined that propargite is the residue of concern for tolerance expression and/or risk assessment in plants, livestock, rotational crops and drinking water. Additional data required by the HED MARC concerning the fate of the propynyl side chain has been reviewed (D259994) and, neither the propynyl fragment nor any metabolites of this side chain are considered a residue of concern. Adequate analytical enforcement methods are available. Multiresidue method testing data (GLN 860.13 60), storage stability data (GLN 860.1380) and cotton gin byproducts field trial data (GLN 860
. 1500) were submitted in response to the Propargite Reregistration Eligibility Decision (RED). Additional sweet corn field trial data (GLN 860 .1 500) were submitted under Section 6(a)(2) notification regarding above tolerance residues of propargite in/on sweet corn forage and were considered by ChemSAC (6/3/09). These data will be reviewed during registration review
. A tolerance for residues ofpropargite in/on cotton gin byproducts will need to be esta blished and the currently established tolerance in/on sweet corn forage may need to be increase d. 

### Conclusions : No additional residue chemistry data are required for the propargite registration review
. Residue chemistry data submitted since the RED will be reviewed and relevant tolerances will be re assessed. Additionally. tolerance expressions will be updated to reflect current guidance (Knizner, 5/27 /09). 

### Dietary Exposure and Risk Assessment The most recent dietary exposure and risk asse s sments (D266001 and D276547) used the Dietary Exposure Evaluation Model (DEEMTM) software and consumption data from USDA's Continuing Surveys of Food In t akes by Individuals (CSFII), 1989-92. Highly refined acute (D266001) , chronic non-cancer (D266001) and cancer (D276547) dietary exposure and risk analyses were performed on food only using available United States Department of Agriculture (USDA) Pesticide Data Program (PDP) monitoring data, magnitude of the residue data and percent crop treated data. At the 99
. 9 t h percentile of exposure, 2% of the acute Population Adjusted Dose (PAD) was used for females 13-49 years (the only population subgroup identified as relevant for the acute di etary endpoint), and less than 2% of the chronic PAD was used for the general U.S. population and all other population subgroups. Dietary cancer risk for propargite was 1.8 X 

### 1 0" 7 

### based on the QI* 

### for propargite Of 0.033 X 

### 1 o·l 

### (mglkg/day)" 1 • 

### Risks from potential exposure to propargite re sidues in drinking water from all sources was comprehensively discussed in the 2005 Revised Propargite RED and risks were evaluated by comparing estimated environmental concentrat i on (EEC) levels against calculated drinking water levels of comparison (DWLOCs). The potential groundwater and surface water exposures to
Page 5 

### of20Propargite: Human Health Risk Assessment Scoping Document in Support of Registration Review propargite were assessed based on Tier 1 and Tier 2 mode ls, respectively. The acute and chronic values were be low the acute and chronic DWLOCs and not of concern. However, the cancer value exceeded the cancer DWLOC. EPA investigated the available United States Geologic Survey (USGS) National Water Quality Assessment (NAWQA) monitoring data for propargite to evaluate how it compared to the modeling resul ts. Although the cancer drinking water risk estimates from surface water were above the Agency's level of concern, the Agency deemed the mode ling and monitoring data upon which the estimates were based to be conservative and likely overestimate the actual exposure to propargite in drinking water. 

### Conclusions: A new dietary exposure and risk assessment may need to be conducted if there are changes to the propargite toxicological PODs or UFs or significant changes to the EDWCs. The assessment, if conducted, will use the newest version of DEEM and reflect updated consumption information. 

### Residential Exposure The registered uses for propargite 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. Residential exposures resulting from off-site transport (e.g., spray drift or volatilization) may occur as a result of applications ofpropargite. The Agency is in the process of evaluating these types of exposures and may , as appropriate, develop policies and procedures to identify the need for and, subsequently , the way to incorporate these post-app lication exposures into the Agency's risk assessments. 

### Conclusions: There are no residential uses currently registered for propargite; t herefore, a quantitative residential exposure risk assessment is not necessary during registration review. The need for spray drift and vo latilization risk assessment for propargite will be examined during registration review. 

### 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 residential exposures. The aggregate risk assessment evaluates the combined risk from dietary exposure (food and water) and any non-occupational (residential) uses. However , there are currently no residential uses for propargite ; therefore the propargite aggregate risk assessment includes on ly dietary exposure (food and water). 

### Acute The 2001 Human Health Risk Assessment acute aggregate risk assessment addressed exposure to propargite residues in food and water using the DWLOC approach described above. The resulting surface and ground water acute EDWCs of 34 ppb and 0.006 ppb were found to be

Page 6 of20Propargite: Human Health R isk Assessment Scoping Document in Support of Registration Review 

### below the calculated acute DWLOC of2400 ppb for females 13-49 years old, and are therefore not of concern. Chronic Chronic DWLOCs were calculated based on chronic dietary exposures to propargite in food and water. Chronic EDWCs of 8.7 ppb and 0.006 ppb for surface and groundwater were likewise found to be below the chronic DWLOCs of 1400 ppb for the general U.S. population and 400 ppb for all infants < 

### 1 year old, and are therefo re not of concern. Conclusions : In 2001 there were no aggregate (food and water) risk estimates of concern for propargite
. During registration review, updated aggregate assessments may be conducted as required to include any significant change that might occur for toxicological PODs, FQPA and uncertainty factors, dietary exposure estimates , or EDWCs. Emerging policies related to pesticide drift and volatilization assessments may d ictate further changes to the existing aggregate risk assessment. Occupational Exposure 

### Occupational handler and post-application exposures are expected based on the registered agricultural uses of propargite. Propargite is currently formulated as an emulsifiable concentrate liquid and a wettable powder. The application rates range from 0
. 5 to 4.8 lbs propargite/acre. It 

### can be applied 2 to 3 times per year to agricultural crops from early season up to harvest time. Equipment used include aerial, cherniga t ion, groundboom, airblast, and high pressure handwand
. The most current occupational and residential memo is a revised assessment for the re-registration eligibility decision (RED) document in 2001 (D276513; 7/31/01; S. Tadayon). The Reregistration Eligibility Decision (RED) document for propargite was signed on September 2001
. Subsequent to the Agency's review of public comments, the propargite RED was revised in December 2005. In September 2007, the propargite RED was amended to lower airblast maximum spray application rate (from 4.5 ai/ A to 4.05 ai/ A), and require enclosed cab applicators to wear additional personal protect i ve equipment (PPE) (long-sleeved shirt, long pants, coveralls, shoes and socks) p lus chemical resistant head gear. Occupational Handlers There is the potential for dermal and inhal ation exposure to occupational handlers from the currently registered use pattern ofpropargite. Chemical

- specific data was submi tted by the registrant to assess potential exposure to pest i cide handlers. These data included the following studies: • Airblast applicator exposure studies (MRID Nos. 418486-05 and 420997-02) • Groundboom applicator exposure study (MRID No. 418486-05)

Page 7 of20Propargit e : Human Health Risk As sess m e nt Scoping Document in Support of Registration Review Occupational handler exposure based on surrogate unit exposures from the Pesticide Handlers Exposure Database (PHED) was u sed when no che mical specific data were available. Previous risk calculation s we re based on the maximum appl i cation rates and assumed maximum area treated p e r day. Handl er expo s ure and risk were c a lculated at baseline (long pants , a longs leeved shirt, no chemi cal-resistant g loves, and no respirator) and with personal protective equipment (PP E) when necessary (e.g., chem ical-resi st ant gloves , re spirators, and engine ering controls). Short-and intermediate-term exposure durations re sulted in margin of expo sures (MOE s) from less than 1 to 2 , 600. However, MOEs were grea ter than the leve l of concern (LO C = 100) at the maximum level of protection as thus not of concern (e.g. , various le v els of PPE or engine erin g control s ). Cancer potential risk est imates resulted in val ues ranging from 3.2 x 10 · 3 to 2.7 x 10· 6 at baseline , 2.8 x 104 to 5.3 x 10· 7 at various level o f PPE and 6.1 x 10· 5 to 6.9 x 1 

## o-s with engineering controls. Occupat ional Post

- App li cation There are potentially s ignificant sh ort and intermed iate-term post-application exposure s to workers e ntering treated fields for post-treatment ac t ivities , e.g., weeding , pruning , irrigating , harvest ing. For the 2001 RED , post app li cation exp o s ure studies were condu cted by the registrant and subm i tted to the Agency. These studies were acceptable and included passive dosimetry data, along w ith dislodgeable foliar res i d ues (DFRs). Duration of exposure acti vi ti es (i.e. , days engaged i n sort ing/packing , irr igation , harvesting , etc.) were presumed to be of short (1 to 7 days) and intermediate (7 to 90 day s )-tenn duration s . Reentry intervals (REis) for the potential dermal contact ranged from 0 to 42 days
. For cance r , a s c reening estimate was developed be c ause lifetime u s e data wer e n ot available. Based on screening leve l assumptions , the cancer p r obab iliti es on t he day the REis were e s timated used the subchronic endpoints and ranged from 9
. 74xl0 -6 to 1.00x l 0 4

. 

### Conclusions: T he occupational exposure database is adequate to support the regi stration r eview process for propargite. Previous occupational hand ler and post-a pplication expo sure assessments did id entify risks of concern based on chemical-spe c ific d ata. Registration review may includ e updated handler and po st applicati on risk est imates based on current policies. During re gistration review , the validity and applicability of t hese data will be co n s idered pending anal ys is.


### Public Health and Pesticide Epidemiology Data For thi s evalu ation, both the OPP Incident Data Sys tem (IDS) and the Centers for Diseas e C ontrol and Prevention/National In stitute for Occup ational S afety and H e alth (CDC/NIO S H) S entinel Event Notification System for Occupationa l Risk-Pesticides (S EN SOR ) databases were consult e d for p esticide incident data on the active i n gredient propargite (P C codes : 097 6 0 l ). Th e purpo s e o f the database search is to i dentify potenti a l patterns 

### in the frequency and severity of

Page 

### 8 of20Propargite: Human Health Risk Assessment Scoping Docu ment in Support of Registration Review 

### the health effects attributed to propargite exposure. Propargite is not included in the AHS, and therefore t his study does not provide information for this report. 

### Conclusions: The Agency has reviewed the available incident data and concludes that based on the low frequency and severity of incident cas es reported for propargite in both IDS and SENSOR-Pesticides, there does not appear to be a concern at t his time that would warran t 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 (0419224).


### Tolerance Assessment and International Harmonization U.S. permanent tolerances are established under 40 CFR 

### § 180.259 for the registered uses of propargite inion a number of commodities. Codex and Canadian maximum residue limits (MRLs) for residues ofpropargite have been e stablished for some of the same commodities which have tolerances in the United States (U.S.). Mexico adopts U.S
. tolerances and/or Codex MRLs for its export purposes. While residue definitions are compatible, a number of U.S. tolerances are not numerically compatible with Codex or Canadian MRLs. The tolerance residue levels may need to be examined during regis tratio n review to determine if further harmonization can be achieved
. See Appendix 4
. 

### Environmental J ustice Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," http://www.epa.gov/compliance/resources/po licies/ej/exec order 1 2898.pdf The Office of Pesticide Programs (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 high exposures indicate potential risks of concern, OPP will further refine the risk assessments to ensure that the risk estimates are based on the best available information. 

### Cumulative Risk Assessment Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to propargite and any other substances and propa rgite does not appear to produce a toxic metabolite produced by other substances. For the purposes ofthis tolerance action, therefore, EPA has not assumed that propargite has a c o mmon mechanism of toxicity with other substances. For information regarding EPA 's efforts to determine which chemicals have a common mechanism of toxicit y and to evaluate the cumulative effects of such chemical s, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http: //www.epa.gov/pes ticides/cumulative/.

Page 9 of20Propargit e: H uman Health Ri s k Ass es sment Scoping Docum ent in Support of Re gistration Rev i ew Human Stu dies The 2 001 RED and 2001 risk assessment reli ed in part on data from stu di es in which adult human s ubj ects were in te ntion a ll y exposed to a pesticide or other c hem i cal. These data, wh i ch inc lude studies fro m P esticide Handler Ex po su re Database (PHED) 1.1; the Agricultural Han dl er Ex posure Task Force (AHETF) d atabase; the Agric u ltural Reentry Exposure Task Force (ARTF) database ; an d Exposure Sc ience A dvi sory Comm i tte e (ExpoSAC) Policy 14 (Standard Operating Procedures for See d Treatment), are ( 1) subject to ethic s r eview pursuant to 40 CFR 26, ( 2) ha ve rece ived that review, and (3) ar e comp li ant with applicable ethics requirements. For certain studies, the ethics review ma y have inc luded review by the Human St udie s Review Board. Descriptions of data sources , as well as gu id ance on their use, can be found at the Agency w eb site 6

.

Endocrine Disruption As require d by Fe deral Insecticide, Fungicide , and Rodenticide Act (FI FRA) and Fe deral Fo od , Drug , and Cosme tic Act (FFDCA), EPA re views n umerous studies to assess potential adve rse o u tcomes from expos ur e to chemicals. Co llectiv ely , these st udies include acute , subchronic and chronic tox icity, includin g assess ments of carci n ogenic i ty , neurotoxicity, d evelopmenta l, reproductive, and general or sys temic toxicity. Thes e stu di es include endpoints which m ay be s u sceptibl e to endocrine influence , inc ludin g effe ct s o n endocrine targ et organ hi stopatho l ogy, organ we ights , estrus cycl icity , sexua l maturation , f ertility , pregnancy rates , r eproduct i ve loss , a

nd sex ra tios in offsprin g. For ecological h azard a s sessment s, EPA evaluates acute tests and chronic s tudies that assess growth, developmental and reproductive ef fect s in di fferent taxo n om ic gro up s. As part of it s mo st recent registration decision for pr opargite , EPA r ev i ewed these data and se lected th e mo s t se nsitive endpoint s for relev ant risk assessment scen ari os from th e existing hazard database. However, as required by FFD CA section 408(p), propargi te is subject to the e nd ocrin e sc reeni n g part of the Endo c rine Disrupter Scree ning Program (EDSP)
. EPA has deve loped the EDSP to determine w h ether c ertain sub stances (incl uding pesticide ac tive and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a " naturally occurring estrogen , or other suc h endocrine effects as th e Admin i strator may de s i gnate . " The EDSP employs a two-tiered approach to makin g the sta tutoril y required determinations. Tie r 1 co nsist s o f a b attery of 11 screening assays to identi fy the p otenti a l of a c he mi cal substance to inter act w ith the estrogen , andro gen , or thyro id (E , A , or T) hormonal syste m s. C hemi ca ls that go through T ier 1 screeni n g and are found to have the potential to interact wi th E , A , or T hormonal syste ms wi ll proce e d to the next stage of the ED SP where EP A w ill determine which, if any , ofthe Tier 2 tests are ne cessary based on the avai lab l e data. Tier 2 testing is designed to identify any adve rse endocrine

- related eff ects caused by the substance, and establis h a dose-response relationship between the dose and the E , A, or T effect. Under FFDCA sect ion 408(p ) , the Age nc y must scre e n all pest icid e chemicals. Between

6 http:/ /ww w . epa . g ov/ pesticides / science /handl er- exposu re -data .html and http ://ww w.epa.gov/ pesticides/ sci e nce/ post-app
-expo s ure-data .html Page 

### 1 0 of2 0Propargite: Human Health Risk Assessment Scoping Document in Support of Registration Rev iew October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of67 chemicals, which contains 58 pesticide active ingredi ents and 9 inert ingredients. A second li st of chemicals iden ti fied for 

### EDSP screening was published on June 14, 2013 7 and includes some pesticides schedule d for registration review and chemicals found in water. For further information on the status of the EDSP , the po licies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website. 8 Propargite is on List 1 for which EPA has rec ei ved all the required Tier I assay data. The Agency i s currently reviewing all the assay d a ta received for the appropriate L i s t 1 chemicals and planning to make the conclusions of those reviews available in early 2015. 

### Risk Assessment Updates and Data Deficiencies 

# • • There are no data deficiencies for propargite. • Updated exposure and risk assessments may be conducted if there are any significant changes to propargite toxicological endpoints, points of departure, Food Quality Protection Act safety factor or other uncertainty factors , standard operating procedures, or exposure data or assumptions. • Residue chemistry data submitted since the RED will be reviewed and relevant to lerances will be reassessed. Additionally, tolerance expressions will be updated to reflect current guidance (Knizner, 5/27 /09). • E PA Registration Number 400-427 allows application to cherry orchards (a food use) after fru it harvest. This use should be deleted since there is no established tolerance inion this crop (ChemSAC 8/25/99).

7 See http: //www.regulations.gov/# !documentDetail:D='EPA-HO

-OPPT

-2009

- 0477

-0074 for the final se co n d list of chem icals. 8 http: //www.epa.gov /endo / Page 11 of20Propargi te: Human Health Risk Assessment Scoping Docum e nt in Support of Registration Review
References

Table 1. Memoranda Relevant to Registration Review•. Author Barcode Date T itl e E. Evans and S. 0419224 4/09/2014 Propargite: Tier 1 Review of Human I nci dents Recore Dodd,N. D25618 2 06/07 /99 Propargite. HED Metabolism Assessment Review Committee Meeting on 5/ 18/ 99. Res idues of Concern in P l ants, Animals , and Water. Dodd , N
. D256206 06/07/99 Pro pargite. Plant and Anima l Metabo lism Data Req uested by the Metaboli sm Assessment Review Committee on 5/ 18/ 99. Shalla!, S. D259994 !l/02 / 99 Information on the fate of the sulfide si de chain of Propargite (MRID 44920901 )
. Stokes , J. D250257 01 /2 0/00 Resi d ue Chemistry Chapter For The Propargite Rer egi stration Eligibility Decision (RED) Document. Morton , T
. D266001 05/24/00 Revised Anticipated Re sidues and Acute , C hronic , and Cancer Dietary Exposure and Risk Analy ses for the HED Human Health Risk Assessment. Morton, T. D276547 08 /28/ 01 Revi se d Cancer Dietary Exposure and Risk Analysis for the HED Human Health Risk Assessment. S. Tadayon D27651 3 7 / 31 /0l Propargite: Occupational and Re sid ential Exposure and Ri sk Asse ssment for the R ereg istratio n Elig ibili ty Deci s ion (RED) Document. Morton , T
. D276544 09/ 13 /01 HED's Revised Human Health Risk Assessmen t for Propargite. Lin , J
. 0350518 06/18/ 08 Revi e w of the Small-Scale Drinking Water Monitoring Andrews , N
. Study for Propargite. (MR1D 473141 0 1 ) Kni z ner, S. None 05/27/ 09 Interim Guidance on Tol erance Expres s ions Morton , T. 0373907 3/31 / 11 Propargite: Storage Stabi li ty Data for Co m Processed Commodities, Peanut Processed Commodities , and Alm o nd Raw Agricultural Commodities
.
I
. Thi s table o nl y includes referen ces to final versions
. Previo us versions of these documents are ava ilable, but have been superseded.

Page 

### 12 of20Pro p argite: Human Health R isk Assessment Scoping Document in S upport o f Registration Revi ew 

### Attachments: Attachment 1: Chemica l Id e ntity and Physicochemical Properties Attach ment 2 : Propargite Acute, Subchronic, and Chronic Toxicity Profi l e Attachment 3: Propargite Toxico logical Doses and En dpoints Attachment 4: Propargite International Residue Limits 

### Attachment 1. 

### Chemical Identity and Physicochemical Properties Table 1. Test Compound Nomenclature. Compound Chemical Structure

# "·'~ // 0 (;'

## ,o~~ 's

II 0
Common name Propargite Company experimental name NA IUPAC name 2

- (4

- tert
- butylphenoxy)cyclohexyl prop-2-ynyl sulfite CAS name 2-[4-(1, 1 -dimet hylethyl) phenoxy ] cyclohexyl 2-propynyl sulfite CAS# 23 12-35-8

Table 2. Physicochemical Properties of Proparg ite. Parameter Value Reference Boiling point/range Decomposes before boiling 40171201 & 42585202 pH 6.3 (1% dispersion in distilled water) 4017120 1 & 42861203 Density 1.12 g/m 1 22°C 473916-03 Water solubility ( 25 ° C) 1
. 9ppm 40358403 , 42319303 , & 423 1 9304 Solvent solubility (mg/L) >200 giL in acetone , dichloromethane, 40358403 , 42319303 , & hexane , m ethanol, an d toluene 42319304 Vapor pressure at 25 ° C 4.49 x J0 · 9 mm Hg 4 1003603 & 45920501 D i ssociation constant (pK. ) pKa > 1 2. No deprotonation (i.e. , ionization) 423 19302 was observed in water solutions Octano1 / water partition coefficient Log(Kow) 5.8 @ 2 5 

### c 40171201 , 42319302& 42861202 UV / visible absorption spectrum E = 1387 (log E = 3
. 14) at 276 nm 45905506


### Page 

### 13 of20Proparg ite : Human Hea lt h Risk Assessment Scoping Docume nt in Su p port of Registration Review



### Attachment 2. Propargite Acute, Subchronic, and Chronic Toxicity Profile Acute Toxicity- Propargite

-- 

### --- 

## -- - ! G uidelin e Study Type MRID(s) Results Toxicity No. Category !----

-

870.1100 Acute Oral 42857001 LD 50 = 2639 mglkg for males III 2947 mglkg for femal es 2800 mglkg combined

870.1200 Acute Dermal 42857002 LD 5 0 > 2000 mglkg lii f--
- 870.1300 Acute inhalation 42857003 LC 50 = 0.95 mg/L for males lii 0.95 mg/L for females 0.89 m g/L combined 870.2400 Primary Eye Irritation 42857004 Corrosive I
870.2500 Primary Skin I rritation 42857005 Corrosiv e I 870.2600 Dermal Sensitization 42857006 Sensitizer N/A

Subch ronic , C hronic , and Other Toxicity Profile- Propargite Guideline No./ MRID No. (year)/ Results

Study Type Class ification /Doses
870.3700a MRID 41346501 ( 1990 ) No t r eatment -related changes were see n in gravid uterine acceptable / guideline Prenatal developmental 0 , 6 , 12 , 18 ,2 5 , 105 wei g ht , post implantati on loss, fetal viab ili ty, sex ratio , or in rats mglk glday soft t issue variations / malformations
870
. 3700b MRJD4133630 1 ( 1989) No tre atment-related changes were see n in post Prenata l developm ental acceptable/guideline implantation loss , fetal viabi lity , sex ratio, or soft ti ss ue in rabbits 0 , 2 , 4, 6, 8, I 0 mglkglday variation s/ malformation s

Page 

### 14 of20Propargite: Human Hea l th Risk Assessment Scoping Document in Support of Registration Review
No treatment-related effects were seen in male fertility index, fema le fertil ity index, or gestation index
. . Pup viability, sex ratio, gross or histopathological changes in the testes, ep id idymides, seminal vesicle, coagulating gland, prostate , ovaries, uterus, cervix, vagina, or pituitary. 870.3800 MRID 41352401 (1990) Reproduction and acceptable / guideline NOTE: Tab le 3 on Page 5 of the OSRI presents incidence fertility effe
. cts 0 , 4 , 20, or 40 mglkg/day data for microscopic observations in this study. Observations in the uterus indicate "not remarkable" for 7 / 24 controls and 6 / 25 high dose animals. The DER, however, states that "there were no compoundrelated increases in gross necropsy or microscopic abnormalities
. " No treatment-re l ated changes were seen in testes weights. Th e absolute mean ovarian weight was decreased (54%) in females only at the high dose (44 rn/k/d) and the absolute kidney weigh t s were decreased in males (35%) and females (34%) at the high dose. The increase in relative weights of 870.4100 b MRID41751401 (1991) adrenals , liver , kidneys, thyroid, and ovaries at the high Chronic tox i city in acceptable / guideline dose were attributed to the severe body weight loss in both 0, 5 , 38 or 44 mglkg/day males (23.3%) and females (25%) at the high dose. The dogs (beag le) for l year initial high dose of2500 ppm was reduced to 1875 ppm (44 rn/k/d) after fir st 9 weeks due to severe weight loss (29%), decreased food consumption and reduced heart and kidney weights. No treatment-related histopathological lesions were seen in the, testes , epididymides, prostate , mammary g lands, ovaries, uterus, pituitary, adrenal , or thyroid glands
. No treatment-related changes were seen on the testes and epididymides
. At t he interim sacrifice (week 52) , relative liver and kidney weights were increased in both sexes when MRID 41750901 (1991) compared to controls but at termination the relati ve weights of these organs were comparable to controls
. Ovarian and 870.4300 acceptable/gu ideline uterus weights were not obtained. Chronic Toxicity / M: 0 , 2 .38 , 3.83 , 19
.24, No treatment-related histopathological lesions were seen in Carcinogenicity in rats 38
. 87 mglkg/day the testes , epididymides, seminal vesicle, prostate, penis, F: 0, 2 .9 5 , 4.68 , 23.58, preputial gland , mammary glands, ovaries, cervix, vag in a , 49
. 36 mg/kg/day clitoral g lands , pituitary, adrenal or th yroid g land s. Endometrial polyps of the uterus were seen in 2%, 0%, 12% , 15%, and 3% at the control, low, mid, mid-high and high dose groups , respectively
.

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### 15 of20Propargite: Hu man H ealth Ri s k Assess m ent Sco p ing Doc um ent in Su pp o rt of Registratio n Review


### A ttachm ent 3 . Toxico logical 

### Doses and E ndpoints

EXPOSURE DOSE ENDPOINT STUDY TYPE / SC ENARIO (mg/k g /day) MRID

A c ut e D i etar y - NOAEL=8 In c r eased i n c id ence o f fused sternebrae i n fetuses at Deve l opmental Toxicity females 13-50 UF = 100 I 0 mg/ k glday (LOAE L ). in Rabbits FQ P A= I 4133630 1

Ac u te Dietary

- NOAEL= N / A No r e l evant si n gle ex po s u re e ndp o int w a s ide n ti fi ed. ge n e r a l p opu l a ti o n 

### u r = N/A N / A FQPA = I

Acute RID (female s 13-50) == 0.08 mg/ kg/ day Acut e RID ( Ge n . Pop.) = N/A aPAD = 0.08 mglk glday

Chro n ic Dietary NOAEL = 4 Decreased body weight / body weight gain and C hronic Feeding and UF = 100 increased morta li t y at 19 m glkglday (LOAEL) for C a r cinogenicity in Rats FQ P A= I m a le s . 41 750901

C hronic R ID = 0.0 4 mglkg/ d a y c PAD = 0
. 04 mglk glday
Can c e r Risk - 1 · I Q 1 • = 0.33 X tO (m glkgld ay)

Short-Term I NOAE L=6 Decreased maternal body weight gain at 8 mg/ kg/day Developmen t al Toxicity

( Dermal) MOE = 100 ( L O AEL). i n Rabb it s 4 1 33630 1

Intermed i ate- Term I NOAE L = 4 Red u ction in body weight gain and food consumption Re productive Toxicit y ( Dermal ) MOE = 100 at 20 mg/ kglday (pa rental LOA E L)
. i n Ra t s 41 352 40 1
Long-T e r m I NO A EL= 4 Dec re ased body weig h t I body weight gain a n d Ch r onic Feedi n g and

(Derm al) MOE = 100 increased mortali ty at 20 mg / kg/da y (L OAEL ). Carcinogenic i ty in Rats 4 1

7509 01

Sho r t T erm 2 LOA EL= Ac ut e In ha latio n in



### Page 1 6 

### of2 0Propargite : Human Health Risk Assessment Scoping Document in Support of Registrat ion Review

l Intermediate Term 0.31 mg/L or 50 mg/kg Increased mortality at 0.3 I mg/L (LOAEL) in mal es . MO E = 1000 Long Term l

I A 14% derma l absorption f.tctor will be used fo r risk assessment and an MOE of 1 00. z An MOE of 1000 was selected for inhalation, includ ing a lOX factor due to lack of a NOAEL, severi ty of effects at the lowest dose tested , and 4 hour durat ion. 3 [conversion mg/L t o mg/kg : 0.3 1 mg/L X 10 Uh r X 4 hrs = 12.4 mg; 12
.4 mg /0. 25 kg= 49
.6 mg/kg] 

### Attachment 4 . Internati onal Residue Limits 

### Propargite (097 60 1; 12/11113) S u mmary ofUS and International To l erances and Maximum Residue Limits Residue Definition: 

## us Canada Mexico 2 

### Codex 3 40 CFR § 180.2 59 : 2

- (4-tert

- Propargi te Plan ts/Livestock: Propargite (2-(p- butylphen o xy)cycloh The resi due is fat solub l e. exy l prop-2-ynyl tert-buty lphenoxy) cyclohexyl 2- sulphite propynyl sulfite) Commodity 1 Tolerance (ppm) ! Maximum Residue Limit (mgl kg) 

### Canada Mexico2 

### Codex 

# us Almond 0.1 0.1 (*) A lmond, hulls 55.0 50 B e an, dry, seed 0.2 5 bean s 0.3 beans; broad bean; ch ickpea; li pin (all dry) Cattle, fat 0 .1 Cattle, mea t 0.1 0
. 1 (*)(fat) meat (from mammals other than marine mammals Cattle, meat byproducts 0
. 1 0.1 (*)edible offal (mamma l ian) Citrus, oil 30.0 Com, fie ld , forage 10.0 Com, field, grain 0 .1 0.1 (*)maize Com, fie ld, stover 1 0.0



### Page 1 7 

### of20 Rats 42 857003Propargite : Human Health Risk Assessment Scoping Document in Support of Registration Review Summary of US and International To l erances and Maximum Residue Limits Residue Definition: 

## us 

# I Canada Mex i co 2 Co dex3 Com , pop , grain 0
. 1 Com, pop, stover 10.0 Com , s weet, forage 10.0 Corn , sweet , stover 10
. 0 Cotton , undelinted seed 0
. 1 I . I
. cotton seed 1 .2. cotton see d oil, ed ible Egg 0.1 0.1 (*) Goat, fat 0
. 1 Goat , meat 0. 1 0.1 (*)(fat) meat (from mammal s o th er than marine mammals Goat, meat byproducts 0.1 0
. 1 (*)edib l e offal ( mammalian) Grain, asp irated fractions 0.4 Grap e 10.0 7 7 Grapefruit 5.0 5 citrus fruits 3 citrus fruits Ho g, fat 0
. 1 Hog , meat 0. 1 0
. 1 (*)(fat) meat (from mammal s other than marine mammal s Hog , meat byproducts 0.1 0.1 (*)edible offal (mammalian) Hop , dried cones 100.0 30 hop s (dried) 100 hop s dry Horse , fat 0.1 Horse , meat 0.1 0
. 1 (*) ( fat) meat (from mammal s other than marine mammals Horse , meat byproducts 0.1 0
. 1 (* ) edible offal (mammalian) Lemon 5
. 0 5 citrus fruits 3 citrus fruits Milk, fat (0
. 08 ppm in mi lk) 2.0 0.1 (*)milks F


### Page 18 of20Propargite: Human H ealth Risk Assessment Scoping Document in Support of Registration Review Summary of US and International Tolerances and Maximum Res idue Limits Residue Definition: 

## us 

# ICanada Mexico 2 Codex3 Nectarine 4
. 0 7 4 stone fruits Orange 1 0
. 0 5 citrus fruits 3 citrus fruits
Peanut 0.1 0.1 (*) Peppermint, tops 50.0 Poultry, fat 0. 1 Potato 0.1 0.03 Sheep, fat 0.1 Sheep, meat 0
. 1 0.1 (*)(fat) meat (from mammals other than marine mammals Sheep, meat byproducts 0
. 1 0.1 (*) edible offal (mammalian) Sorghum, grain, forage 10.0 Sorghum, grain, grain 5.0 Sorgh um, grain, stover 10
. 0 Spearmint, tops 50.0 Tea, dried 10.0 5 tea, green , b l ack (b l ack fermented and dried) Walnu t 0.1 0.3 MRLs With No US Equivalent Apples 3 3 Apple jui ce 0.2 Citrus pulp, dry 10 Dried grapes ( = c urrants, 12 raisins and sultanas) Grape juice 1 Grape pomace, dry 40 Maize flour 0.2

Page 19 

### of20Propargite: Hum an Heal th Risk Assessment Scopin g Docum ent in S upport of Regi stratio n Revi ew Summary of US and International Tolerances and Maximum Residue Limi ts R esid ue Definition: 

# us 

# ICanada Me x i co2 Codex3 Maize oil , crude 0.7 Maize oil , edible 0.5 Orange juice 0.3 Peac he s 7 P

ea nut oil, crude 0. 3 Peanut o il , edible 0.3 Plu ms 5 Po ultry , meat 0
. I ( * )(fat) Poultry, edible offal of 0.1 (*) T o mato 2

Complete d : M. Negussie/ 12 / 12/2013

1 Include s only commodi tie s of intere s t for thi s action
. Tolerance values should be the H ED r eco mm e ndation s and not those proposed by th e applicant. 2 Mexi co adopts US tolerances and/or C odex MRLs for its export purposes. 3 * = absent at the limit of quantitation; Po = postharvest treatment, s uch as treatment of stored grains. Po P = processe d postharve st treated commodity, suc h as processin g of treated stored wheat. (fat) = to b e m eas ure d on the fat portion of the sample. MRLs indicated a s propo se d have not been finalized by the CCPR and the CA C. (c) Tolerances with regional r egistrations. Tolerances with reg ional registration, a s defined in § 180.1 (1), are establi s hed for res idu es of propargite in or on the followin g raw agricultural commodities: Co mmodi ty Parts per million Com, sweet, kernel plus cob with husks remove d 0.1



### Page 20 of20