### IMA Z O SU LF U RO N Hum an H ea lth Ri sk Assessment DP No. D427999


### UNITED STATES ENVIRONM E NTAL PROTECTION AGENCY WASHINGTON, D .C. 20460



### MEM ORANDUM DATE: July 7 , 20 1 5 OFFICE OF CH EM ICAL SAFETY AND POLLUT ION PREVENTION



### SUBJECT: Imazosulfuron. Human Health Draft Ri s k Assessment for Reg i stration Review. 

### PC Code : I 18602 

### Decision No.: 506476 

### Petit ion No.: NA 

### Ri s k Assess m ent Ty p e : Single Chemica l / Agg re gate 

### TXRNo
. : NA 

### MRIDNo.: NA 

### DP Barcode: D4 279 99 

### Registration Nos.: 59639 -1 54, 155, 166 , 1 8 9 

### R egul atory Actio n : Re g istration Review 

### Case No. : 7285-1 

### CAS No.: 122548-33-8 

### 40 CFR: 180.651 

### F RO M: Nancy J. K e ller , Risk**,** 

### Chemist N ancy Dodd , Chemist**"1~ "'**  

### Whang Phang,**Tox ic** **og st~\?**  

### Risk Assess ment Branch 3 G 

### Health Effects Division (7509 P) 

### THROUGH: C

. hristine O linger, C hi ef 

# (F/ " /

, /
Risk Assess ment Bran c h 3 

# rf ,,,, "---_ '" H ea lth Effects Di vis i on (7509 · 

### TO: Cai tlin Newcamp , Chem ical Review Manager Risk Management and Impl e m entat ion Branch 1 Pesticide Re-Eva lu atio n Di v ision (7508 P ) The Pesticide Re-Evaluation Div is ion (P RD ) ha s requested a Draft Risk Assess me nt (D RA) from the Health Effects Di v is ion ( HED ) to pro v ide information that supports the r eg istration rev iew of imazosulfuron. Thi s assessment ad dr esses the exposur es and risk esti m ates assoc iated w ith all curre ntl y reg i s te red u ses . S in ce the la st risk assessment, there h ave bee n n o c han ges to the im azosu lfuron u se profi le, hazard profile, o r residue profile ( DP4 09228 , S. Healy , 02115 / 20 1 3). Furthermore, there have been no policy c han ges that would warrant an updat e t o dietary, res idential , aggregate, or occupational risk estimates. However , a new assessme nt fo r indirec t non-occupational spray dri ft h as been conducted for regi stra tion revi ew. T h ere are no outstanding data deficienci es or conditions of registration for im azosulfuron at this time.

P age 1 of 15IMAZOSULFURON Human H e alth Ri sk Assessment DP No. D4 27999


### T a bl e o f Co ntent s 1.0 

### E xecutiv e S ummary . ................. ..... ..... ............................ . .... ............ ... . ...... .. ..... .. ..... ... ....... 2 2.0 

### Us e Profile

...... .. ...... .. .. ....... . .... ..... .... . .............................................................. . ...... . ..... . .. ... .. 2 3.0 Hazard ldentificationff oxicology

.................. . .......................................... . .. .. .. . .... . ..... .. . . .. 3 3.1 S ummary of Toxicological Effec t s .. .... . .. ... ... ... .. ............ ... ...... .. ...... . ...... . ....................... 3 3 .2 Safety Factor for Infant s and C hildre n (FQPA Safety Factor)

.... ... .. ...................... . . 3 3

. 3 Toxicity En dpoint and Point of Dep a rture Se le ction s .... . ... ... ............ .. ............ . .......... 3 4.0 

### Residue C h emi stry
..... ... .. .. .. .. .. .... .. .... . ......... .. . ........................................................... .. ....... 6 5.0 

### Dieta ry Ri s k Asse ss m ent
..................................................... .. ....... . .. .. ...... . .................... ..... 7 6.0 

### Residential (No n-Occup a tional) Ex p osure/Ris k Characterization

. ........ .. .... .. .... ...... . ... 7 7.0 

### Aggregat e Ex p os ure/ Ri s k C har acterization

....... .. ............ .. ...... .. ..... .. ... ......... . .. ............... 8 8.0 

### C umulative Exposure/Risk C haracterization

.................................. .. ..... .. ..... .. ..... .. ........ 9 9
. 0 

### Occupational Expos ur e/Ris k Characterization

.............................. .. ..... .. ..... .. .............. 10 10.0 

### Refere nc es ...................................................................... . ...... .. .................. . ....................... 10 

### Appendix A. Toxico lo gy Profile for Ima zos ulfuron

... ...... . ............................................ .. ..... 11


### 1.0 Exec utive S ummary l m azosulfuron(2-chloro- N- [[ 4 ,6 -dim et ho xy - 2- pyri midi ny 1 )

-ami no]c arbon y l]imid azo [ 1 , 2- 

### a ]p yridi ne - 3-sulfo namid e ) , a sulfonylurea (SU) herbicide , i s currently re gistered for u se on agric ultural crops includin g me lo n s (crop s ub g roup 9A) , p e pper s , ric e, tomato es, and tub e rou s and corm vegetables (crop s ub gro up 1 C) , as well as ornamentals and established turf grass in residential and recreational areas. Va lent U.S.A. (Valent) is the o nl y re gis trant wi th im azos ulfuron end- u se product s at thi s time. Si nce the la s t risk assess men t , th e r e have bee n no c han ges to the im azosu l furon u se profile, hazard profil e, or res idue profil e (DP409 228, S. H ealy , 02115 / 20 1 3). Furthermo re , there have been no policy c h anges that would warrant an update to di etary , reside ntia l, aggregate , or occupational ri sk es timate s. Howev e r, a new assessme nt fo r indirect non- occupational s pray drift has been conducted fo r registrat ion review. T here are no ou t standing data deficiencies or conditions of registration fo r im azosu lfuron a t this tim e. 2.0 

### Us e Profile C urre n tly, im azos ulfuron is on ly formulated as a wate r-di spe rsible granule (WG). T hi s formulation is to be added to water, r es ulting in a d is p ers io n of finely div ided he rbi c id e particl es s u spe nd e d in wate r to be app li e d for weed co nt ro l. Currently reg is te re d labe ls include o ne t ech ni cal lab e l, three agricultural labels , three state labels , and one experimental u se p en nit la b e l. In ge neral, imazos ul furon may be applied up to twice a year . A ppli cation timing varies depending o n the target weed (pre-/ post-emergent to weeds o r p re-/ p os t
- e merge n t to crop p lant in gs). The app li ca ti on rates ran g e from 0.0 1 0 lb a i / A to 0. 3 0 lb ai/ A for all reg istered u ses. D e p e nding on th e u se s ite , imazosulfuron may be ap pli e d v ia ground. aeri al, chernigation , o r handheld equipment.
Pa ge 2 of 15

### IMA ZOSUL FURON Hum an H ea lth Risk Assessment DP No. D427999



### 3.0 Hazard ld e ntific ationffox i co lo gy The toxicology database fo r im azos ulfuron is complete and adequate for ri sk asses s ment. HED ha s previously determined that a subchronic inhalation study is not required at this time for imazo s ulfuron (TXR#0056566, Hazard and Sc ienc e Polic y Council , 02/ 20/ 20 13). Ne w toxicity a nd/or metabolism data h ave not been received since the l ast ri sk assessment , and the se lec ted toxicity endpoints and points of departure (PODs ) remain the same. A summary of the acute, subchronic , and chronic tox ici ty profile is presented in Appendix A. 

### 3.1 Summary of Toxicological Effects The toxicity database for im azosulfuron suggests that thi s herbicide possesses relatively low toxicity. Many of the effects of s ingl e or rep eated dosing are observed near or be yo nd the respective limit doses. The primary target organ of imazo su lfuron toxicity was the liver in a ll spec ie s tested. Mild to moderate thyroid effects were apparent only in the chronic toxicity study in dog s . Dramat ic eye effects (ret inal degeneration , lens vasc ul arization , cataracts and corneal scarri ng) were observed in rats fed greater than the limit dose beginning at 3 month s in the chronic toxicity/ carcinogenicity s tudy. Ocular effects , in creased incidence of eye opacity , co rneal edema , inflammation, and neovascularization , were also observed at a dose s ubstantially greater than the limit dose in a s ubchronic oral toxicity study in rats. Decr eased body weight was a frequent finding throughout th e toxicology databa se for imazo s ulfuron. Imazosulfuron did not induce ne u rotoxic ity in e i ther acute or subchro ni c neurotoxicity sc reening battery or in any other rep eat-do se study. Developmental effects were not found in 

### rats or rabbits with prenatal treatment. Decreased pup viability was observed in the rat two-generation r eprod uction s tudy at a dose approaching the limi t dose in both the Fl and F2 offspring; increased mortality was also observed in the parental animals at the same do se level. Therefore , n e ither qualitative nor quantitati ve susceptibi li ty were apparent in fetuses or pups w i th pre natal o r postnatal treatment. Imazosulfuron produced no evidence of being a carcinogen , mutagen , or clastogen. Acutely , 

### this pesticide also demonstrated rather low toxicity by oral, dem1al , or inh alation route of administration ( mo stly Toxicity Category 

### IV ). 

### 3.2 Safety Factor for Infant s a nd C hildren (FQPA Safety Factor) The FQPA Safety Factor has been reduced to IX 

### for the following rea so ns: (I) 

### the toxicity database of imazosulfuron is complete and adequate to assess the qualitative or quantitative s usc eptibi lity in the young; (2) There i s no evi denc e of increased qualitat ive or quantitative s usceptibility in the young; (3) imazosulfuron produced no evidence of neurotoxicity; and (4) exposure estimates are unlikely to und e restimate risk. 

### 3.3 Toxicity E ndpoint a nd Point of D epa rture Se le c tion s

Page 

### 3 of 15IMAZOSU LFURO N Human H ealth Risk Assessment DP N o. D427 999
There ha ve been no changes to the prior dose-response a sse ssment and cance r clas s ification. It should be noted that the previously se lected PODs m ay be conservat iv e relati ve to the current s tandards for evaluating toxic it y studies and d e termining adverse effects fo r estab li s hin g NOA E Ls and LOAELs. F urth ermore, the risk estim ates calc ul ated with thes e POD s do es not prese nt any risk es timate s of concern at thi s time.



### Tab l e 3.3. Summary of Toxico l ogical Dos es and Endpoints for Ima z o s u lfuron for Use in Dietary , Non-Occupational and Occu pational Human Health Risk Assessments
U

nc ertainty/ RfD , Leve l of Expos ure/ Point of Safety Co ncern for Study and Toxicolo g ical Effects Scenario Departure Factors Ri sk Assessment Acute n eurotoxi c i ty sc reenin g b attery (rat; Acute Dietary MRJD 47305319). Acute RID = LOA EL = 2000 m g/kg/ day based on th e (Ge ne r a l NOAE L = UF A = IOX 4 mg/k g/day following c l inical s i g n s: abnormal ga it , Population , 400 UFH = !O X decreased activ ity, pil oerec tion and upward includin g mg/k g/ d ay FQPA SF = a PAD = 4 curvature of th e s pin e; and incide nts of irre gu tar I nfant s and IX Childre n) mg/k g/day breathing, redu ced ri ghting reflex , tremors, de creased visua l placement r es pon se in male s and inc reased respon s e to sou nd in one fe m ale. Acute Dietary An acute reference dose was n ot identified for females age 13-49 because there was no prenatal ( Females 1 3

- or fetal toxicity observed in d eve lopm ental o r r e productiv e animal s tudies fo llo wing a s ingle 49 years of oral d ose. ag e) Chronic RID Chroni c NOAEL = UF A = !O X = 0.75 Ch ronic tox ic ity ( do g; MRlD 47305305) Dietary (All 75 UFH = IOX mg/k g/day L OAEL = 150 m g/kg/day based on mode rat e Population s) m g/kg/day FQPA S F = th y roid hype rtr oph y (mal es at mid- and hi g hIX c P AD = 0

. 75 do se : mild h ypertrophy in fe mal es at hi g h-do se). mg/kg/day Reproduction , 2 generation (rat; MRJD 47305304) Incid en ta l NOAEL= 88 m g/kg/day Oral S hort- NOAEL = UF A = IOX LOA EL = 777 mg/kg/day based o n in creased Term (1

- 30 266 UFH = !OX LOC for MOE pup mortality (decrease pup v iabilit y) an d day s) and m g/kg/day FQPA SF = = 1 00 deceased body weights. lnt e nn ediate- ( MRID IX Te nn ( 1-6 47 3 05 232) 90-day oral toxicity (r a t ; MRJD 47305232). month s) NO AEL = 266 m g/kg/day LOAEL = 956 mg/k g/day based o n decreased bod y weight ga in s and food efficiency

Page 

### 4 of 15

### IMAZOSULFURON Human H ealth Risk Assessment DP No. D427999


### Table 3.3. Summary of Toxicological Doses and En dpoints for Imazo s ulfuron for Us e in 

### Di etary , Non-Occupational a nd Occupational Human Health Risk Assessments

Ex posure/ Scenario

DennaI Short -Term (1-30 day s) and lnt e nnedi ate T e nn (I-6 months )

Inhalation Short- Term (1-30 days) and lnt e m1ed iateTenn (1 -6 months)

Ca ncer (o r al, dennal , inhalation) Point of Departure Unce rtainty / Safety Factors RID , Level of Conce rn for Ri sk Asses s ment Study and Toxico logical Effects

No sys temic toxicity occurr e d at the limit do se and the primary toxic effec ts of concern (liver, eye) wer e adequatel y assessed in a 2 1-da y dermal toxicit y study ( MRJD 47305236). It is concluded that thi s compound is not o r poorly abso rb ed throug h the skin and, th e refo re , a quantitativ e risk assessment for thi s route and duration i s not necess ary.

NOAEL = 266 m g/ kg/ day UFA = IOX UFH = IOX FQPA SF= IX LOC for MOE = 100 Reproduction , 2 ge neration ( rat ; MRID 47305304) NOAEL= 88 m g/kg/da y LOAEL = 777 mg/k g/day based on parental effects: increase d mortali ty , decreased bod y weight s, & food consumption

. 90-day o ral toxicity ( rat ; MRJD 47305232). NOA EL = 266 mg/kg/da y LOAEL = 956 m g/kg/ da y based on decrea se d body weights and food efficiency Classification: "No t likely t o be Carcinogenic to Human s" based on th e absence of significant tumor increases in two adequate r ode nt ca rcin oge ni c i ty st udi es (M RJD 47305307 , mouse ; MRJD 47305306 , rat). Point of D eparture ( POD) = A data p o int or an es timat e d point that is d e rived from o b se rv e d dos e- res pon se data and used to mark the beginning of ex trapolation to determine risk a ssoc iated with lowe r environmentally relevant human exposures. NOAEL = no ob se rved adverse effect level. LOAEL = lowest observed adverse effec t leve l. UF = unc e rtainty factor

. UFA = ex trapolation from animal to human ( interspe c ies). UFu = potential variation in sen s itivity among members o f th e human populati o n (i ntr as peci es). MO E = marg in of expos ure. LO C = le ve l of concern. 

### 3.4 E n d ocrine Di s ruption As re quire d by FIFRA and FFDCA , EPA rev i ews numerou s s tudies to assess potentia l adverse outcomes from expos ure to chemicals. Co ll ective ly, these st udies include acute, s ubc h ron ic and chronic toxicity , includin g asse ss ment s of carcinogenicity , ne urotoxicity , dev elopmental, reproductive, and general or systemic toxicity. These studies include e ndpoints which may be susceptible to endocrine influence , includin g effects on endocrine target organ histopathology, o rg an we i ghts, estrus cyclicity , sex ual maturation , ferti li ty, preg nan cy rates , reproductive loss , a nd sex ratios in 

### offspri ng. For eco logi cal hazard assessments, EPA evaluates acute tests and chronic studie s that asse ss growth , dev e lopmental and reproductive effec t s in different taxonomic g roup s . As part of it s most recent registration decision fo r mets ul furon-methyl , EPA r e viewed these data and se lected the most sensitive e ndpoint s for rel evant risk assessment Page 5 of 15

### IMAZOSULFURON Human Health Risk Assessment DP No. 0427999
scenarios from the existing hazard database. However, as required by FFDCA sec tion 408(p ), metsulfuron-methyl is subject to the endocrine screening part of the Endocrine Disrupto r Screening Pro gram (EDS P). E PA has de veloped the EDS P to determin e whet h er certain substances (including pesticide active and othe r ingred ient s) may ha ve an effec t in hwnans or wi ldli fe similar to an effect produced by a " naturally occurring estrogen, or other such endocrine effects as the A dministrator may designate. " The E D SP employs a two-tiered approach to making th e statuto ril y required determinations

. Tier I con sis ts of a battery of 11 screening assays to identify the potential of a chemica l substance to interact with the estrogen , androgen , or thyroid (E , A , o r T) hormonal sys tems. chemicals that go through Tier I 

### screening and are found to have the potentia l to interact with E , 

### A , or T hormonal sys t ems will proceed to the next stage of the EDSP where E P A will d e termine which , if any , of the Tier 2 tests are necessary based on the availabl e data. Tier 2 tes ting is d es ign e d to identify any adverse endoc rin e-related effects caused b y the s ub stance , and estab li sh a dose-response r ela ti onsh ip between the dose and the E , A, or T effect. Under FFDCA section 408(p) , the Agency mu s t screen all pesticide chemical s . B etween October 2009 and February 2010, EPA issued test orders/ data call-ins for the fi rst g roup of 67 chemica l s, whic h contains 58 pesticide active in gredients and 9 

### inert ingredients. A second list of che mical s id e ntifi ed for EDSP screeni ng was published on June 14 , 2013 1 

### and includes so me pesticides sc hedu led for Reg istration Re v iew and chemicals found in water. Neit h er of these li sts sho uld be construed as a li s t of known or likely endocrine disruptors. For further information on the s tatu s of the EDSP, the policies and procedures , the lists of chemica ls, future list s, the test guidelines and the Tier I 

### sc reening batter y, please visit our website. 2 

### 4.0 Res idue C he mi stry An 

### adequate high performance liqui d chromatography method with tandem mass spectroscopy detection (LC/ M S/MS), Method RM-42 C-3, i s availabl e for to lerance enforcement in plant commodities. The method determines re s idue s of imazo s ulfuron and metabolite UDPM , or 

### (4 , 6- dimethoxy-pyrimidin-2-y l)-urea. The method has been adeq uately validated by an independent laboratory for the determination of imazo s ulfuron. The nature of the residue in plants is adequately und e rstood ba se d similar metaboli s m of imazosulfuron in three dissimilar crops (rice grain , pepper and tomato): hydrolysis of the su lfon y lurea linkage i s the major metabo li c process. The residue of concern for tolerance e nfor cement for plant s is imazosulfuron. The residue of concern for dietary ri s k a ssess ment for plants is the sum of imazosulfuron and the metabo l ite 

### UDPM , expressed as equivalents of imazo s ulfuron. The residue of co ncern for toleranc e enforcement in livestock is imazo s ulfuron

1 See http: //www.rcgulations.gov/#! documentDetail;D =E PA-HO

- OPPT

- 2009

- 0477

-0074 for the final second li st of chemica ls. 2 http :// www.epa.gov/ endo/ 

### Page 

### 6 of 15IMAZOSULFURON Human H ealth Ri sk Assessment DP No. D427999
and the re s idue of concern for dietary ri sk assessment in live s tock i s the sum of imazosulfuron and the metabolite IP SN , ex pressed as eq ui va le nts of imazo sul furon

. There are currently no Cod ex , Canadian , or Mexican maximum re s idue limit s (MRLs) estab lished for imazosulfuron

. B ased on a risk assessmen t from 20 I 0 , there are three conditions ofregistration that were pending res olution: (I) s torage s tability data, (2) confined acc u m ul atio n in rotationa l crops data , and (3) field accumulation in rotational crops data (DP362653 , 

### S. Healy , 11 / 03 / 2010). Th ese data have all been subm i tted and , based on a preliminary revi ew, H E D believes the submi ss ions are suffic i ent. The exis tin g imaz osulfuron risk es timates and tolerances are not expected to change upon 

### full re v iew of th ese data. 

### 5.0 Diet ary Ri s k Assessment The residue chemistry data and e nvironmental fate data are adequate to assess human exposure. The previously conducted dietary exposure assessments are considered conservative and are based on re liabl e data wh ich do not und e restimate expos ure/ri sk

. Unrefined acute a n d chronic di e tary assessments were conducted using assuming I 00% of the crops wer e treated and that all treated crops contained res idue s at tol e rance l eve ls

. Default processing factors were assumed for the registered crop uses. The hi g hest est imated dri nking water concentration (E DWC ) of 27 8.9 μg/L was incorporated into both ac ut e a nd chronic assessments. Thi s recommend ed EDWC re s ulted from th e T ier I Rice model, and is ba se d on aerial spray application of 0.30 lb ai/ A per year for rice. Acute Ri s k estimates for all population s ubgroups did not exceed H E D 's l evel of co n cern at the 

### 95' 11 percentile of exposure for food and d r inking water. The 

### U.S. population resu l ted in < 1.0 % of the acute popu lation-adjusted dose (aPAD) , while the most highly exposed popu lat ion s ubgroup, all infants( < I year old), resulted in 1.2 % o f the a PAD. Chronic Ri sk estimates for all population subgroups did not exceed HED 's level of concern for dietary expos ure from food and drinking water. The U.S. popu lation res ul ted in < l % of the chronic population-adjusted dos e (c P AD) , wh il e the most highl y exposed population subgroup, all infants ( < 1 year old), re s ulted in 2

. 0% of the cPA D. 

### 6 .0 Residential (No n -O ccup a tional) Ex po s ure/ Ri s k C haracterizatio n There are ex istin g res idential u ses that ha ve been pre v iousl y assessed according to HE D 's 2012 R es idential SOPs 3 along with policy changes fo r body weight ass u mptions (DP403362, C. Walls , 0I / 18/ 2013 ). Re s idential handler scenarios re s ulted in margin s of exposure ( MOEs) greater than the leve l of concern (i

. e. the LOC is an MOE < l 00) and therefore are not of concern to HED. The residential short -term post-application incidental oral scenario for c hil dren re su lted in an

3 A vai I able: hrtp: // www.epa . gov / pest ic id es / s ci e nce/ residential- e xposure- sop. htm I Pag e 

### 7 of JSIMAZOSULFURON Human Health Risk Assessment DP No. 0427999
MOE g reater than the LOC of 

### 100 and therefore is not of concern to HED (MO Es ranged from 

### 2, l 00 to 

### 9,300,000). Spray Drift Off-target movement of pesticides can occur via man y types of pathways and it is governe d b y a variety of factors. Sprays that are released and do not deposit in the application area end up offtarget an d can lead to expos ure s to those it may directly contact. They can al so deposit on surface s where contact with residue s can eve ntually lead to indirect exposures (e.g. children playin g on lawn s where residues have deposited next to treated fields). T he potential risk est imates from these residues can be calculated usin g drift mod e ling coupled with methods em ployed for re s idential ri sk assessments for turf products. The approach to be u se d for quantitatively incorporating sp ra y drift into ri s k assessment is based o n a premise of co mpliant applications which , by definition , s ho uld not result in direct exposures to individuals becau se of existing label langua ge and oth er regulatory requirement s intended to prevent them. 4 Direct exposures would includ e inhalation of the spray plume or being sprayed directly. Rather, the ex po s ures addressed here are thought to occur indirectly through contact with impacted areas, such as re s idential lawns , when compliant applications are conducted. Given this premi se , exposures for children 

### (1 to 2 years old) and adults who have contact with turf where residues are assumed to have deposited via spray drift thus resulting in an indirect ex po s ure are the focus of this analysis analogous to how exposures to turf products are considered in r is k as sess m e nt. EPA Reg. No. 59639-155 i s an existing label for use on turf, thus it was evaluated to determine whether the risk assessment for that use may be considered protective of any type of exposure that would be associated with spray drift. 

### If the maximum application rate on crops , adjusted by the amount of drift expected, is less than or equal to existing turf application rates , the ex istin g turf assessment is considered protective of spray drift exposure. For imazosulfuron , the registered residential uses on turf result in estimated exposure level s that are greater than the potential ex po sure from s pray drift; therefore , no ne w residential assessment needs to be completed. The currently registered maximum single application rate of ima zos ulfuron for all reg iste red crops is 

### 0.30 lb ail 

### A The highest degree of sp ra y drift noted for any application method immediatel y adjacent to a treated field (Tier 1 output from the aerial application usin g fine to medium s pray quality) results in a deposition fraction of 0.26 of the application rate. A quantitative spray drift assessment for imazosulfuron is not required because the maximum application rate to a crop/ target site multiplied by th e adjustment factor for drift of 0.26 is less than the maximum direct spray residential turf application rate 0.75 lb ai / A 5 for any imazo s ulfuron products. The turf post-application MOEs have been previous ly assessed and are based on the 2012 Residential SO P s. 

### 7. 0 Aggregate Ex p os u re/Ris k C h a r ac t er izati o n Aggregate acute risk i s equivalent to acute dietary risk via food and drinking water exposure

4 This approach i s consistent with the re qu irement s of the EPA ' s Worker Pro te ctio n Standard which, when included o n all labe ls. precludes direct exposure pathways. 5 0.30 lb ai/A x 0.26 ::; 0.75 lb ai/A Page 8 of 1 5

### IMAZOSULFURON Human H ea lth Risk Assessme n t DP No. 0 427999 path ways and co mpri ses 1 .2% of the aP AD for the most hig hl y exposed popu l atio n , infants < 1 year old. Likewise, chronic d ietary risk comprises 2.0% of the cPAD 

### for the most highly exposed po pul atio n , in fants < l year o ld. Short

- and Intem1e d iate Term The re is po tentia l s hort- and inte rmed iate -te rm expos w- e to imazos ul furon via t h e dietary pathway (w hi ch is cons idered background exposure) and the residential path way (which is considered the pri m ary pathway). F or adu lts, since a de rm al hazard was no t id e n tifi ed, th e exposure pathways include only the dietary and inhalation (residentia l hand le r) r outes. For children , the exposure pathway includes the dietary exposure and the incide n tal ora l pos t
app li ca ti o n r es i de nti al pathway. A ll aggregate M OEs are g reate r than 1 00; the refore , aggregate exposure to irnazosulfuron is not of risk concern.



### Table 7.0. Short- and Intermediate-Term A22regate Ri s k Calcu lations Population L OC for Dietary MOE Residential MOEc Aggregate MOE Aggregate Ri sk 3 (food + drinki ng water)b (foo d and res ident ial)d Adults 100 43,000 N IA 140,000 33,000 Children 100 27,000 21,000 NI A 12, 0 00 (I to 2 years old) a Adults and Children Level of Concern = 100 (base d on inter- and intra- s pecie s uncenainty factors, each at IOX). b Dietary MOE = NOAE L + chronic dietary exposure. NOAEL = 235 mg/kg/day. Adult chron ic dietary exposure =

0.005957 mg/kg/day (Gene ra l U.S. population). Children dietary expo s ure = 0.008712 m g/

kg/day (Chi ldren 1

-2 years old). c Residential MOE based on residential handler exposure and post-application exposure from app lication to

re s idential l awns. d Aggregate MOE = I + [(I/dietary MOE) -r (I / residentia l MOE)]. 

### 8.0 C umulative E xposure/ Risk C h aracterization In 2015, E PA's Office of Pes t icide Program s released a guidance doc ume n t e n ti tled , 

### Peslicide Cumulative Risk Assessment: Framework for Screening Analysis [http: //www . epa.gov/ oppfead l/c b /csb _page / updates /2015 / framework-for

- screeningana lys i s. h tm l]. T h is d oc ume nt prov id es gu idance on how to scree n groups of pestic ides for cumulative evaluation u s ing a two
- step approach beginning with the evaluation of available toxicolog i cal i nfo nnati on and if necessa r y, fo ll owed by a risk-based sc ree nin g a pp ro ac h

. Thi s framework supplements the ex i sting guidance documents for estab l ishing common mechanism groups (CMGs)lll and conducting cumulative risk assessments (CRA)l2 1. 

### The Agency h as util ized thi s fram ework to eval ua t e the SUs of w hi ch imazosulfuron is a member (D P4 28798, J
. 

### D. Agostino, 09 1 09 12015). Althoug h the SUs s hare some chemica l and toxicological characteristics, the toxicologica l database does not support a tes tab le hypothes i s fo r a co m mo n mechanism of act ion. No further mechanist ic data are required and no further cumu lative eva luation is nec ess ary.

fll 

### G uidance For Identifying Pes1icide Chemicals and Other Substances That Have a Common Mechanism of Toxicity (USEPA , 1999) r 2 1 

### Guidance on C umulative Risk Assessment of Pesticide Chemicals That Have a Common Mechanism of Toxicity (USE PA , 2002) Page 9 of 15

### IMAZO SULF U RO N Human H ealth Ri s k A s ses s ment DP N o. 0427999


### 9.0 Occupational Exposu re/Ris k C haracterizati on Dermal exposure during handling activities was not consider e d b e cau s e s ystemic toxicity was not o bse rv ed at the limit d ose in the de rmal s tud y . Th e occupational handler e xpo s ure a nd ri s k estimate s indicate that short

- and inte rmediate-te rm non-cancer inhalation MO E s are not of con c ern to HED (i. e . , MOEs 

### 2: 100) at base li ne (no re s pirator) attire (DP403362 , C

. Wall s , 01 / 1 8/ 2013). The lowest MOE of 6 , 600 represents th e most protectiv e worst-case occupational s c e nario: mixin g/ loadin g dry fl owabl es (wate r-di s per s ible g ranu le s) to s upport ae r ia l applicati o ns to high acreag e c rops (i.e. rice). The se risk estim ates ar e n ot of concern to HED. D erma l exposure during post-application activ iti es was not consid e red becau se no s ystemic to x ic ity wa s o b s e rved at th e limit do s e in 

### th e dermal s tud y . B as ed on th e A g ency 's curre nt practices , a quantit at ive occupat ional post-application inhalation e xpo s ure a sse ssm e nt w as not p e rform e d for imazos ulfuron at this time. If new poli c ies or proc e dures are put into plac e , the Ag e ncy may revis it the n ee d fo r a quantitative occupatio na l post-applic ation inhalation e x po s ure a ss e s sment for irnazo s ul fu r o n . 

### 10 . 0 Refer e n ces H eal y, S. , 02/ 1 5 /201 3, DP409 2 28 , 

### lmazo sulf uron : Human Health Ri s k Assessm e nt f or Propo sed Uses on Me lon ( Crop Subg roup 9A) and Tuberou s and C orm V ege tables ( Crop Sub g roup I C)

. Healy , S. , 11 / 0 3/20 I 0 , DP362653 , 

### lmazo s ulfuron : Human H e alth Risk Assessm e nt for Propo se d Uses on Ri ce. Pe ppe rs and T o ma toes .

Page JO 

### of JS

### IMAZOSULFURON Human Health Ri sk Assessment 

### DP No. 04 27999 Appendix A. Toxicology Profile for lmazo s ulfuron Technical Table A.1. Toxicology Data Requirements Required Submitted 870.1100 Acute Oral Toxicity

................ ...... ................................. yes yes 870.1200 Acute Dennal Toxicity

........................ ... ........... ... ......... yes yes 870. 1 300 Acute Inhalation Tox i city

..................... .. ..... . ..... ... ....... .. ye s yes 870.2400 Primary Eye Irritation

.................... . .............. ... ........... .. . yes yes 870.2500 Prim ary Dennal Irritation

.............................................. yes yes 870.2600 Dermal Sensitizatio n ............. .. ........................ .. ............ yes yes 870.3100 O ral Subchronic ( rodent )

...... ................... ........ .............. yes yes 870 .3 150 Oral Subchronic ( n on - rodent)

.............. ... ........... ... ......... yes yes 870.3200 2 1-0ay Den11al

...................................................... .. ...... yes yes 870.3250 90 -D ay Dennal

....................... .... ......... . ............ ...... ... .... no no 8 70.34 65 90-Day Inhalation

............................................... ... ........ cR• waived b 870.3700a Deve l opmental Toxicity ( rodent)

......... .. ........... ... .......... yes yes 870.3700b Developmental Toxicity ( non - rodent)

....... ... .......... .. ..... yes yes 870 .3 800 Reproduction

................................................................. yes yes 870.4 lOOa Chronic Toxicity (rodent)

................................ .... .......... n/a 

## - 870.4 IOOb C hronic Toxicit y (non-roden t)

....... . ...................... .. .. . .... yes yes 870.4200a Oncogen icity (rat)

.. ..... ......... ... ........... .. . ... ....... ...... ......... n / a 

### - 870.4200b Oncogenicity (mouse)

................................................... yes yes 870.4300 Chronic/Oncoge nicity (ra t )

............................................ yes yes 870.5100 Mutagenicity -Ge ne Mutation

- bacterial

..... .. ............ .. yes yes 870.5300 Mutagenicity -Ge ne Mutation

- mammalian

................ yes yes 870.5375 Mutagenicity -S tructural C hromo somal Aberrations

... yes yes 870.5395 Mutagenicity

- Other Genotoxic Effects

........... ...... ...... yes yes 870.6100a Acute Delayed Neurotoxicity (hen)

............... . .. . ............ no no 870.6100b 90-Day Neurot oxic ity (hen)

........................................... no no 870.6200a Acute Neurotoxicity Scre e ning Battery (rat)

.. ........... .. .. yes yes 870.6200b 90- Da y Neurotoxicity Screening Battery (rat)

... .. .......... yes yes 870.6300 Develop. Neuro
..... ...... ......... ...... ........................ .. .......... no no 870.7485 General Metabolism

...... ...... .................................... . ..... no yes 870.7600 Denna! Penetration

.. .. .. ..... ...... . .......................... .. .......... no no 870.7800 lr nmunotoxicity

.................... ...... ....................... .... ........ yes yes a C R = conditionally required. b The Ha zard and Science Policy Cou nc il (HASPOC) detem1ined th at a s ubchronic inhalation s tu dy is not requ ired

at this time for im azos ulfuron (TXR#0056566, 02/ 20/ 2013). 

### Tab l e A . 2. Acute T oxicity Profile - Test Substa nc e Guideline No. Study Type MRID(s) Results Toxicity Category 870.1100 Acu te oral

- rat 47305221 LD so > 5000 mg/kg IV 870.1200 Acute dennal

- rat 47305227 LD so > 2000 mg/kg Ill 870.1300 Acute inhalation

- rat 47305228 LC so > 2.12 mg/L IV 870.2400 Acute eye irritation

- rabbit 47305229 Non-irritating IV 

### Page 11 of 15

### IMAZOSULFURON Human H ealth Ri sk Assess me nt 

### DP No. 042 7999

870 .2500 Acute dermal irritation

- rabbit 47305230 No n-irrit at in g IV 870.2600 S kin se n s iti za tion

- guine a pi g 47 30523 1 Negative NI A Metabolit es 870.1100 IHOA 47305222 LD so > 5000 mg/kg IV 870.1100 UD PM 47305223 LD so = 677 mg/kg Ill 870.1100 IP SN 47305224 LD so 

### = 4 15 mg/ kg , male s; II 445 mg/kg. fema l es 870

. 1100 M-1 47305225 LD so > 5000 m g/

k

g IV 8 70. 1100 ADPM 47305226 LD so = 8 36 mg/kg I II

P age 

### 12 of 15

### IMAZO SU LFU RON Human H ea lth Ri s k Assess me nt DP No
. D427999



### Table 

### A.3 S ubchronic , C hronic and Other Toxicity Profile of Imazosulfuron

Guideline S tudy Type MRID Nu mb e r (yea r )/ Result s Number C lass ifi cation/Doses 47305232 ( 1991) NOA EL= 235 /266 mg/kg/day (MJF) 90-Day oral Acceptab le / G uidelin e LO AEL = 95611081 ( M /F) bas ed on 870.3100 to xic ity (rat) 0. 2500. I 0000. 45000 ppm: reduced mean body weights and food M: 0 , 234.7. 956.3

. 4577.2 mg/kg/day: F: 0. 265.7. 1081.4. 5 135.7 mg/k !!lday efficiency. 47305233 ( 1991 ) NOA EL= I 820 /2727 mg/kg/day (M/F) 90-Day oral Acceptable/Guideline LOAEL = 9776/ 12695 mg/kg/day 870.3 JOO toxicity (mouse) 0 , 2500. I 0000. 45000 ppm: (M/F) based on central lobular M: 0 , 456 , I 820, 9776 mg/k g/day; hepatocyte hypertrophy and increased F: 0, 692 , 2727, 12695 mg/k g/ day liver weie.hts. 870.3 I 50 90-Day oral No ava il able toxicity (dog) 2 112 8-Day 4 7305236 (20 06) 870.3200 dermal toxicity Acceptable /Guideline NOAEL = 1000 mg/kg/day (HOT). (rat) 0 , I00 , 300, I000 mg/kg/day
870.3465 90-Day Waived (TX R : 0056566 ; 2 1 20 1 2 013 ) inhalation study 4 7305238 ( 1989) Maternal NOA EL = I000 mg/kg/day Acceptable/Guide lin e ( limit); Pren atal 0 , 250 , 500 , I 000 mg/kg/day . Since LOA EL = 1500 mg/k g/ day base d on 8 70.37 00a developmental n o maternal t ox icity was observed in the decrease d body weight gain and food (rat) ori g inal treatmen t group s. an additi onal consump ti on. treatment gro up o f 15 00 mg/kg/ day was D eve lo pmenta l NOAEL = 1500 added to th e s tud y . mg/k g/ day { HOT ; > limit dose) 4 730530 I ( I 990) Maternal NOA EL = I 25 mg/kg/ day Prenatal Acceptabl e/No n - Guideline• 870.3700b developmental 0 , 25, 50 , 1 25 mg/k g/day ( HDT ) (rabbit) Developmenta l NOAEL = 125 •t

est

e d und e r FIFRA S11 bd 1v1sio11 F mg/k g/ day ; flwdelines P are nt a l NOA EL = 78/ 88 mg/k g/day (MIF) 47305304 ( 1990) ; LOAEL = 777 / 869 mg/kg/day (M/F) Acceptab le / Guideline based on mortality , clinical s igns , Reproduction 0 , 1 00, 1 , 000 , 10 , 000 ppm: decrease d body weights and food 870.3800 and fenility F o consumption

. effec ts M: 0 , 7.7, 77.8, 777.4 mg/ kg/day ; R e pro du ctive NOAEL = 777/ 869 {rat ) F: 0 , 8.93 , 88.4 , 868.5 mg/k g/day ; mg/k g/ day (M/ F) ( HOT) Off s pring NOA EL = 78 / 88 mg/kg/day ( M/ F) LOAEL = 777/ 869 mg/k g/day (MJF) based on decreased pup viability a nd body weie.hts. NOA EL = 75 mg/kg/day Chronic t ox icity 4 7305305 ( 1990) LOAEL = 150 mg/k g/ day based on 870.4 IOOb Acceptable/Guidel in e moderate thyroid hy pertroph y (males at (dog) 0 , 75, I 50 , 300 mg/k g/day mid- and hi gh-dose; mild hype rtrophy in females at hi.e.h-dose).



### Page 13 of15

### IM AZ O SU LFURO N Human Health Risk Assessment DP No. D427999



### T a ble A.3 S ubchronic , C hroni c a nd Other Toxici ty Profil e of lm azos ulfuron

Guideli n e Study Type MRID N umb e r (yea r)/ Re s ults Number Classification/Doses 47305307 (1991) NOA EL = 73 / 8 7 mg/kg/day (M/F) Acceptable/ Guid e lin e Carcinogenicity 0,450,4500,45000ppm; LOAEL = 741 / 870 mg/k g/day (M/F) 870 .4200b (mo u se) M: 0 , 72.7 , 741.3 , 7848.1 based on centrilob ular swelling of mg/kg/day: hepatocytes. F: 86.8 , 870.0 , I0303.5 mg/k g/day No ev id ence o f carc in oge n ici t y 47305306 (199 1): NOA EL = I 061132 mg/kg/d ay ( M/F) 0 , 20 0 , 2000, 20000 ppm ; LOA EL = 1124 /1554 mg/kg/day ( M /F) Chronic M : 0 , 10.39 , 106.10 , 1123.99 based on increased mortality , decreased 870.4300 toxicity/ Ca rcinog mg/kg/day ; bod y weight , and clinical ophthalmic en ic ity F: 0 , 12 .94 , 132.46 , 1 554.35 observations (ca t aracts and retin a l (rat) mg/kg/ da y. degeneration) and hepatotoxicity in fema le s. Acceptable/ Guideline No ev id ence of carc in oge ni c ity Bacterial reverse 47305308 ( 1988) TH -913 Technical: Test article has no 870.5100 rev erse mutageni c potentia l und er these mutation test Accept able/Guideline experimen t al conditions Bacterial r everse 4 7305309 ( 19 90) UDPM: Tes t article has no reve r se 870.5100 mutagenic potential under thes e mutation test Acceptable / Guideline experim en t a l condition s Bacterial reverse 47305310 (1993) TH OA: T est article h as n o rev e rse 870.5100 mutation t es t Acceptable/Guideline mutagenic potential under the se experimental conditions Bacterial reverse M-1: Test artic le has no reverse 870.5 100 mutation test; 4 73 05 3 11 ( 198 9) mut age ni c potential under these 870.5500 DNA repair tes t Acce ptable/Guideline experimental condi tions: negative with or without S9 metabolic activat ion Bacterial reverse 47305312 (1988) IP SN: Test art i c l

e ha s no re v erse 870.5100 mutagenic potential under these mutat io n te s t Acceptable/ Guideline experimental condition s B acterial r eve r se 47305313 ( 1990) ADPM: Te s t article has no reverse 870.5100 mut age ni c potential un der th ese mutation test Acceptable/Guideline experimental condit i ons In v itr o 870.5300 mammalian cell 473053 1 4 ( 19 99) T est article is not mutagenic in test ge n e mut at ion Accep t able/Guideline system test Te s t article "was con sidered to induce no ch rom oso m a l abe rratio n because the In vitro test s ubstance s h owed a s uspect 870.5375 mamm a li an cell 47305315 (1988) po sitive by the direct method but th e chromosome Acce pt able /Guideline same results were not reproduced. " aberrat ion test T est article did not induce chromosomal aberrations at any conce ntration in presence of S9. Mamm a lian 4 73053 16 (2007) Te s t article ha s no potential to indu ce 870.5395 erythrocyte Acce pt able/Guideli n e micronuclei in mouse bone marrow micronucleus test cells under the conditions of this test



### Page 14 of 1 5

### lMAZOSULFURON Human Health Risk Assessment 

### DP No. 0427999

T a bl e 

### A .3 Sub chronic, C hro nic and Oth e r T o xi ci ty Profil e o f Im azo s u lfuron

Guideline Study Type MRJD Number (year)/ Re sults Number Clas s ification/Doses NOA EL = 400 mg/k g/ day; Acute 4 7305319 (2007); LOA EL = 2000 mg/kg/ day based on 870.6200a neurotoxicity Acceptable/ Guideline the clinical sig ns: abnonnal gait , screening battery 0, 80 , 400 , 2000 mg/kg decreased activity, piloerection and upward curvature of the spine and decreased motor activity in mal es. 47305320 (2007) NOA EL = 169 / 201 mg/ kg/ day (M/F) 870.6200b Subchronic Acceptable/Guideline LOAEL = 57 1 / 655 mg/kg/day (M/F) neurotoxicity**80~2500 8000ppm;**  based on decreased body weight and screening battery M: 0, 54.0 , I 69.2, 571.3 mg/kg/day ; food efficiency. F: 0, 6 1 .9, 200. 8 , 655.3 mg/k !!/ da y No neurotoxicity was found

. Parent and 5 metabolites were identified and quantified. Parent was detected on l y in feces and amounted to 0.9% of the admi n istered dose (AD). Metaboli s m and HM S, the predominant metabolite , was 870.7485 pharmacokinetic 47305322 (2007) found in the urine at 6 , 12 and 24 hours s Acceptable/Guideline amounting to 3 1.1 , 18.4 and 6.2 % of (rat) the dos e, r espe ctively, and in less e r amounts , in the feces (6.5)

. The le sser metabolite s(< 5% AD) , IHD U. HOS , IPSN and ACIS were identified in urine and feces. Metaboli s m and The absorption rate was estimated to be 870.7485 phannacokinetic 47305323 (2007) - I 00 %
. Near complete elimination (66.4% urine , 34.0% bile , 2.4% feces) s Acceptable/Guideline within 24 hours after administration of (rat) radiolabel ed compound was observed. Systemic NOA EL = 222 mg/k g/day Systemic LOAEL 

### = 710 mg/kg/day based on decreased body weight, body weight gain, an d re lat ive thymu s Immunotoxicity 48691003 (2011) weights ; and increased relative spleen 870.7800 and adrenal weigh ts ( rat) Acceptable/Guideline lmmunotoxicity NOA EL = 222 mg/kg/day) l mmunotoxicity LOAEL = 710 mg/k g/day based on reduced thymus weights and decreased antiSRBC PFC response



### Page 15 of 15