### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON , D .C. 20460 OFFICE OF CHEMICAL SAFE TY AND POLLUTION PREVE NT ION



### M E MORAND UM D a te: May 

### 12 , 2015 

### SUB.JECT: Ch lorimuron

- ethyl: Tier I Re vi ew of Human In c ident s for Draft Ri s k Assessment

P C Co de: 128901 DP Barcode: D-126223 Dec i s ion No
. : 5 0 21 7 5 P e ti t io n No. : NA Reg is tration No.: NA Reg ul atory Act i on : NA Case No .: A Ri s k A ssess m e nt T y pe: N A TX R No .: I J\ CAS No .: 90982-32

- 4 40 C FR : NA .MRIO No.: NA 

### FROM:

THROUGH :

TO: Shanna Reco re, Industrial Hyg ie ni st T ox ico logy and Epidem iology Branch Health Effects Di vis ion 

### (7509 P) and E li zabeth Eva n s, Env ironmental Protection Specia li st Toxicology a nd E pidemi o logy B r a nch H ea lth Effec t s Di vision 

### (7509 P ) 

# c

Carol

# C~**~· 1s** **se ,**  E pid e mi o log is t

# i Toxicolog y and Epidemiology Branch H ealth Effec t s Di v is ion 

### (7509P ) /}**y//~** David 

### J. Miller, Act in g Branch

# hief**}** T oxico logy a nd E pidemi o logy B r an ch Health Effec t s Di v isio n 

### (7509 P ) K arly n Midd le to n , R isk Assesso r Risk Assessment Branch fl Hea lth Effec t s Di v is ion 

### (750 9P ) and Wilhelmena Livin gs ton , C he mi cal Re v i ew Manager Ri s k Management 

### & Impl ementat io n B ranch 4 Pesticide Re-evaluation Di vision 

### (7508P)

Page 1 of 6 Vcr.J\pr.08Summary a nd Conc lu s io n s C hlorimuron-eth y l was previously rev iewed in 20 I 0 ( K . M iddl eto n c t a l. , 08 / 19 120 10, 0380339). At th e tim e, there were no incident s r eported for the s in g le c hemi cal chlorimuron-ethyl only in Main ID S and three incide nt s r eported to Agg re gate ID S from Janu a r y 1. 2000 to May 25
. 20 l 0. In addition, th ere two cases r e ported for ch lo rimuron- e th y l to N IO S H SENSOR-Pesticides from 1998 to 2007. U p o n rev i ew of these incidents
. it was co ncl ud ed that ·' B ased on the lo w freq ue ncy a nd seve rity of incident cases, there does not app ea r to be a concern a t th i s time that w ould warra nt further in vest igat i on." The c urrent IDS a n al ysis from January 1 , 20 10 through March I 0 , 2015 , s how s one incid e nt reported involving chlorimuron-ethyl in Main IDS in vo lvi ng multiple c hem ical s a nd six incidents r epo rte d to A gg r ega te lDS
. There we re no s in g le chemica l incid e nt s r e p o rted to ID S. The query of SENS OR-P es ti c ide s I 99 8- 2011 identifies th e same two c a ses. both involving multiple act ive in g redi e nt s, th at were previously identified in 20 10
. Base d on th e lo w fr e qu e ncy and mo s tly low severity of incident cases rep o rted fo r c hlorimurone thy l in both IDS and N lOSH SENSO R-P es ticid es. th e re doe s not appear to be a co ncern at this tim e that would warrant further inves ti g ation. Several initial in ves ti gat ion s w ithin the A H S h ave made an epi demiol og ic a l risk es tim a te of th e association between chlo rimu ron ethyl and variou s anatomical c anc e r endpoints; however, th ese cancer s ites we re e ither not related to u se of chlorimuron e th y l (prostate or lun g cancers, NHL , and c uta neo u s melanoma), or the as soc iation m easured was no n- s ta ti s tically s i g nifi ca ntl y modest in size (< I .5 ) (breast, colorectal, pancreatic cancers). Th e Age ncy w ill conti nu e to m onitor the incide nt in fo rmati o n and if a co ncern is triggered, add iti o n a l anal ys i s wi ll be con du cte d. Detai led Rev ie w 

### J. ACT IO N REQUESTED Chlorimuron-ethyl are being co nsid e r e d und e r th e FQPA-mandated Reg is trat ion Rev i ew program es ta bli s he d to review, o n a 1 5 year cycle, pesticides for w hi c h a Re- re g is tration Eli gib ili ty Decision ha s been made. One co mp one nt of th e Age nc y"s Regi s tration Re v i ew Pro g ram i s co nsid e ration of human incident data. ln conjunction with a human health ri s k assess ment based o n other data sources . such human in cident data can assi st the Agency in better defining and characteri z in g th e risk of pe s ticide s/ pe s ticide products. Reports of adverse health effects all ege dl y due to a s p ec ific p esticide exp osu re 

### (i.e., an

· ' incident'') are la rge ly se lf-repo 1ted and th erefo r e. ge nera ll y speakin g, neither exposure to a pe s ti c ide or re porte d symptom (o r the connection between th e two) i s va lid ated or othe r wise co nfirmed. T ypi ca ll y, ca u sati on cannot b e determined based on in cident d ata. H owev e r, incid e nt inf ormati o n can be an imp o rt ant so urc e of feedback to th e Agency: incidents of severe outcome , o r a suggested pattern or tre nd among less severe in c idents. can s ig nal the A ge ncy to furt her invest igate a particular c hemi cal o r product. Ob se rvational ep idemio logy s tudie s relate the ri s k of di sease. 

### e.g., canc e r . and ex posure to an age nt s uch as a p es ticid e product in th e ge nera l population o r spec ifi c s ub-groups l i ke pe s t icide ap pli cators.

Page 2of6

### II. BA C KGRO UN D Chlo rimuron - ethyl is a s ul fo ny lurea class herbicide with a mode of act ion of inhibiting aceto lactat e synthatase. Chlorimuron-cthyl contro l s grasses and broadleaf weeds. C hlorimuronethyl is registered for use on soybeans, field co m , peanuts, low growing berries and no n -crop areas such as fence rows and roadsides. Soybean is the predominant agricultural usage. There are no registered residential uses for chlorimuron-ethyl methyl. For this evaluat io n, both OP P Incident Data System (IDS) and the Centers for Disea se Co ntrol and Prevention/National Institute for Occupational Safety and He alth (CDC/N IO SH) Sentine l Event Notification System for Occupational Risk-Pesticides (SENSO R) databases were consulted for pesticide incident data on the active ingredient chlorimu r on-ethyl ( PC Code: 128901). The purpose of the database searc h is to identify po t e nti a l patte rn s in the frequency and severit y of the health effects attributed to ch lo rimu ron - ethy l exposure . In addition. findings from the Agricultural Health Study (AI-IS) were reviewed. The AHS is a high quality, prospective ep idemiolog y s tud y evaluating the link between pesticide u se and various health outcomes in clud in g cancer. Chlorimuron

- ethyl is included in the AI-IS and the findings are s ummari zed in this re port.


### lll. RESU LT S/DIS CUSS IO N a. IDS (Incident Data System) OPP's ID S includes reports of alleged human health incident s from various so urce s, i ncl udin g mandatory Federal Insecticide, Fungicide and Rodenticide Ac t (F IFRA ) Sect io n 6(a)(2) reports from registrants, other federal and state health and e nvironmental agencies, and indi vidua l consumers. Since 1992, OPP has compiled th ese reports in ID S. ID S contains reports from across the U
. S
. and mo st incidents hav e a ll re levant product infom1ation recorded
. R e port s submitted to the IDS represent anecdotal reports or a lle gations only, unless otherwise stat ed in the report. IDS records incid ents in one of two mod ul es: Main IDS a nd Aggregate ID S :
o Main I DS contains incide nts resulting in hi gher severity outcomes and provide s more detail with regard to case specific. This system stores incident data for death, major and moderat e incident s. and it include s information about the location. date and nature of the incident. Main IDS incid en ts in vo lv in g only one pestic ide are co n s id ered to prov id e mo re certa in informati o n about th e pote ntial effects of exposure from the pesticide.
o Aggregate ID S contains incidents resulting in less severe human incid e nt s ( min or, unknown , or no effects o utcomes). These are repo rted by reg is trants on ly as counts in what 

### arc aggregate summar ie s.

Page3of6From January 

### 1. 2010 to March 18. 2015. there were no incidents reported to Main ID S in vo l v in g the s ingle acti ve in gre di e nt , chlorimuron-ethyl. There was one incident reported to Main ID S. invol v ing multiple active ingre dient s includin g c hl o rimuron-ethyl. thifensulfuronmethyl , flumioxazin , s -m etolac h lor , and so dium sa lt of fomesafe n. Thi s incident involved a 54 year m ale w h o died five days following inhalation exposure to two products ( Re g istration numbers 100-1 268 and 352 -7 56). He was loading th e product s into a tru ck a nd it blew back into his face
. Hi s initial symptoms included fever, no appetite, body aches, and difficulty wa lkin g w hich were fo ll owed by renal fai lure. and hypovolem ic s hock. The patient req uired intubation. but eve ntu a ll y died. The radiologist's r ead in g of the case·s chest x-ray indic a ted "s uspiciou s for mu lti-l obular pneumonia ." No autopsy was conducted and causat i o n cannot be determined based on th e in c ide nt data prov id ed
. From Janu ary I, 20 I 0 to M arc h 18 , 20 1 5. there were s ix incid e nt s r eported to Agg regate ID S in vo lving chlo rimu ro n - ethyl. T he se incident s were classified as minor seve rit y. Overall th ere were few incidents re port e d to ID S involving c hl o rimu ron - ethy l. 

### b. SENSO R -Pes ticid es The SENSO R-P esticides database covers 12 s tate s from 1998-2011. although reporting varies from s tate to state
. Cases of pe s ticide-related illnesses are ascerta in ed from a varie ty of so urces , including: reports from local Po ison Control Ce nter s . state Department of Labor workers' co m pensation claim s w hen reported by physicians, reports from S tate Departments of Agric ulture, and phy s i c i an rep or ts to s tate D epartments of Health. A lth oug h both occupational an d non - occupational in cidents are included in the database. SENSOR focuses on occupat iona l pes ti c id e incidents , a nd is of p articular value in providing that in forma tion. A state SENSOR co n tact specia li s t attempts to fo ll ow-up with cases and obta in s medical records to ver i fy sy mptom s . circumstance s s un- o undin g th e exposure , seve rity, and outco me . Us in g s tandardi zed protoco l and case definitions derived from poi son ce nter reporting. SE SOR coord in ators at State D epa rtments of Hea lth e nter the incident interview de sc ripti o n provided by the case, medical r epo rt , phy s ic ian and patient into the SENSO R data syste m. Th e SENSOR data system is accessible to partici p ating s tates and E PA. A query of SENSOR- P esticides from 1998-2011 id entifies a tota l of two ca ses in vo lv in g c hlorimuron (pc code 12890 I ); no s ing le a i cases we r e identified
. Both cases were low in severity. O ne case ex perienc ed dermal irri tatio n and r edness and the other case was a bystander in hi s car who sa w a nd was sp r ayed by an aerial app lic ation and repo rted cough a nd headache.


### c . Ag ri cultural Health S tud y (A HS) The A H S is a hi g h quality, prospective epide mi o logy study evalu ating th e link between pesticide u se a nd vario u s health outcom es in clud in g cancer. The AHS incl udes private and commercial pesticide app li cators and their s pou ses. If there are AHS findings re l evant to a particular pesticide go in g throu gh reg i stra tion r ev iew, th e Age nc y w ill e nsure the y a re co n s idered in the problem fo rmulation/ scopi ng phase of th e process and, if approp riate. fully rev i ewed in the risk assessment pha se of the proce ss. Th e AHS includ es in formati o n on u se of 50 diff e rent pesticide ac ti ve ingredients commonly u sed in agricu lture.

Page 4of6Authors with the AHS have reported risk estimates regarding the association between chlorimuron-ethyl and several s pecific anatom ical cancer s ites. Tn nested case control analyses of breast. colorectal and pancreatic cancer. authors estimated the assoc iation between chlorimuron ethyl and cancer. Rega rding breast cancer. among 30,434 wives of AHS applicators there were 309 cases. Chlori mu ron-e th yl use modestly non-statistically significantl y increased the odd s of breast cancer by 30% ( 1.3 (95% confidence interval (95% CI) 0.6
. 2.8), amo ng only 7 chlorimuro n-eth y l ex posed cases (E ngel e t al., 2005). In a study of pancreatic cancer risks , ever use of chlorimuron-ethyl was re lated to a 40% increased odds of pancreatic cancer ( l.4 (95% CI 0.7, 3.0), a mon g I I exposed cancer cases (Andreotti et al., 2009). Among 56, 813 A HS applicators. there were 305 cases of colorcctal cancer: however. use of chlorimuro n- ethyl was not related to this cancer (0 .8 0 (95% CI 0
. 6
. 1.2)) (Lee et al., 2007)
. Ov e rall , from these preliminary, hypothesis generating studies w ithin the AHS, chlorimuron-ethyl i s not strong ly linked to these anatomical cancer sites
. For other anatomica l cancer sites eva luated within the A f IS including prostate. lung , non-Hodgkin lymphoma and cutaneous melanoma , au thors did not present an ep idemiol og ical risk es timate for chlorimuron-ethyl because a risk estimate with this compound was not calculated (too few exposed case s) or not presented (Alavanja et a l. , 2004: Alavanja et al.. 2014; Alavanja e t al., 2003: Denni s. Ly nch , Sandler, & Alavanja, 2010; Koutros et a l.. 2013). Hoppin et al. (2002) eva luated the association betw ee n agricultura l pesticide u se and wheeze among 20.468 applicators within the AHS. Us ing se lf-reported information concerning pesticide use and ph ys ician diagnosis of wheeze, authors reported a significantly increased odds of wheeze among chlorimuron-ethyl u sers ( 1.14 (95% CI 1.0 2, 1.29), p for trend 0.0 I across four exposure categories. Several other pesticides were also related to this outcome; however the plausibility for a role of this chemical in ad verse respiratory outcomes remains uncl ear. 

### IV. CONCLUS IO N Based on the low frequency and mostl y low severity of incident cases reported for chlorimu ronethyl in both IDS and NIOSH SENSOR-Pestic ides. there does not appear to be a concern at thi s time that would warrant further investigation. Severa l initial investigations within the AHS have made an epidemiological risk estimate of th e association between chlorimuron ethyl and various anatomical cancer endpoints; however , these cancer s ites were either not related to use of chlorimuron ethy l (prostate o r lung cancer s, NHL, and cutaneou s melanoma) , or the association measured was non- sta ti s ticall y s i g nificantl y modest in size ( < 1.5) (brea s t , colorectal, pancreatic cancers). The Agency will continue to mo nifor the incident information and if a concern is triggered, additional ana l ys is will be conducted.

Page 5of6Ci tation s: Alavanja, M. C., Dosemeci, M., Samanic, C., Lubin , J., Lynch, C. F., Knott, C.,

... Blair, A. (2004). Pesticides and lung cancer risk in the agricultural health study cohort. Am J Epidemiol, 160(9), 876 -885. doi: 10.1093/aje/kwh290 Alavanja, M. C., Hofmann, J. N ., Lynch, C. F., Hines , C. J., Barry, K. H ., Barker, J.,
... Beane Freeman, l. E. (2014). Non-hodgkin lymphoma risk and insecticide, fungicide and fumigant use in the agricultura l health study. PLoS One, 9(10), e109332. doi: 10.1371/journal.pone.0109332 Alavanja, M. C., Samanic, C., Dosemeci, M., Lubin, J., Tarone, R., Lynch, C. F.,

... Blair, A. (2003). Use of agricultural pesticides and prostate cancer risk in the Agricultural Health Study cohort. Am J Epidemiol, 157(9) , 800-814. Andreotti, G., Freeman, l. E., Hou , l., Coble, J. , Rusiecki, J., Hoppin, J. A.,

... Alavanja, M. C. (2009). Agricultural pesticide use and pancreatic cancer risk in the Agricultural Health Study Cohort. Int J Cancer, 124(10), 2495-2500. doi: 10.1002/ijc.24185 Dennis, l. K., Lynch, C. F., Sandler, D. P., & Alavanja, M

. C. (2010). Pesticide use and cutaneous melanoma in pesticide applicators in the agricultural heath study. Environ Health Perspect, 118(6), 812-817. doi: 10.1289/ehp.0901518 Engel, l. S., Hill, D. A., Hoppin, J. A., Lubin, J. H., Lynch, C. F., Pierce, J.,
... Alavanja, M

. C. (2005). Pesticide use and breast cancer risk among farmers' wives in the agricultural health study. Am J Epi demiol, 161(2), 121 -13 5. doi: 161/2/121 [pii]10.1093/aje/kwi022 Hoppin, J. A ., Umbach, D. M., London, S. J., Alavanja, M. C. R

. , & Sandler, D. P. (2002). Chemical predictors of wheeze among farmer pesticide applicators in the agricultural health study. American Journal of Respiratory and Critical Care Medicine, 165(5), 683-689. doi: 10.1164/rccm.2106074 Koutras, S., Beane Freeman, l. E., Lubin, J. H., Heltshe, S. L., Andreotti, G., Barry, K. H.,

... Alavanja, M. C. (2013). Risk of total and aggress iv e prostate cancer and pesticide use in the Agricultural Health Study. Am J Epidemiol, 177(1), 59-74. doi: 10.1093/aje/kws225 Lee, W. J., Sandler, D. P., Blair, A., Samanic, C. , Cross, A. J. , & Alavanja, M

. C.R. (2007). Pesticide use and colorectal cancer risk in the Agricultural Health Study. International Journal of Cancer, 121(2), 339-346. doi : 10.1002/ijc.22635



### Page 6of6