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



### MEMORANDUM Date: 13-JAN-20 15 O FFI CE OF C HEM ICAL SA FETY AND POLLUTION PREVENTION



### SUBJECT: Benalaxyi
- M. Chronic and Cancer Dietary (Food Only) Exposure and Risk Assessments to Support Import Uses on Grape and Tomato . PC Code : 113510 Decision No.: 476296 Petition No.: 3E8162 DP Barcode: 0416584 Registration No. : NA Regulatory Action: T oleran ce without U.S. Registration Risk Assessment Type: Dietary Ri sk TXRNo.: NA Case No.: NA CAS No. : 98243-83-5 MRIDNo.: NA 40 CFR: New Active Ingredient 

### FROM:

THROUGH:

TO: William H. Donovan, Ph.D. , Chemist 

# W ;JJ..;.._ }:{ ,**{)~** Risk Assessment Branch V Health Effects Division (7509P) / 

# /'/

# Lt~~~A-4~ Mohsen Sahafeyen, Chemist 

# ff · - "**~** 

## 1 · / David Hrdy, Senior Biologist 

# vJtwi/ 

# f.
- ?([!j\ / / Dietary Exposure Science Advi sory Council (**ES~)** HED (7509P)
Karen Samek, Ri sk Manager Reviewe r Fungicide Branch Reg istration Division (7505P)

Page 1 of 10Benalaxyl-M (113510) Dietary Exposure and Risk Assessment 0416584 Executive Summary Chronic and cancer dietary (food only) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model with the Food Commodity Intake Database (DEEM-FCID) Version 3.16. This software incorporates 2003-2008 food consumption data from the U.S. Department of Agriculture's National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWE IA) . The analyses were performed to support an import tolerance request for uses of the new active ingredient, benalaxyl-M , on grape and tomato. This memo was reviewed by two members ofthe DESAC, per the current DESAC SOP . Acute Dietary Exposure Assessment Because no appropriate acute endpoint was identified in the toxicity database, no acute dietary analysis was conducted. Chronic Dietary Exposure Assessment Partially refined chronic dietary assessments were conducted using anticipated residue levels and 100% crop treated . All processing factors were set to 1 excep t for raisin and dried tomato, where empirical and default values, respectively, were used. The estimated risk is :S 7% of the chronic population adjusted dose (cPAD) for the U.S. population and all population subgroups. Cancer Dietary Assessment The cancer dietary assessment made use of the same input assumptions as the chronic analysis. Benalaxyl-M has been classified as "Likely to be Carcinogenic to Humans" (TXR No. 0057093, L. Brunsman, 04
- DEC
- 2014). A linear low
- dose extrapolation model (Q1*) was used to estimate cancer risk, w ith a Q1 

## * = 5.90 x 10 · 3 (mg/kg/day)" 1

. The cancer risk estimate to the U . S. population is 1. 7 x 10· 6

. I . Introduction Dietary risk assessment incorporates both exposure and toxicity of a given pesticide. For acute and chronic assessments, the ri sk is expressed as a percentage of a maximum acceptable dose (i.e., the dose which HED has concluded will result in no unreasonab le adverse health effects). Thi s dose is referred to as the population adjusted dose (PAD). The PAD is equivalent to the point of departure (PoD) (e.g., no observed adverse effect level ; NOAEL, lowest observed adverse effect level; LOAEL) divided by the required uncertainty or safety factors. For acute and chronic exposures, HED is concerned when estima ted dietary ri sk exceeds 100% of the PAD. References which discuss the acute and chronic risk assessments in more detail are available on the EPA/pesticides web site : "Available Information on Assessing Exposure from Pesticides, A User's Guide, " 21-JUN-2000 , web link: http://www.epa . gov/fedrgstr/EPA
PEST/2000/July/Day
- 12 / 606l.pdf; or see SOP 99.6 (20-AUG- 1 999). This memo reports the first dietary exposure analysis for bena laxyl-M.
Page 2 of 10Benalaxyi-M (113510 ) 

### II. Residue Information D416583 , W. Donovan , 0 2-DEC-20 14 Dietary Exposure and Risk Assessment D416584

No tolerances have been establis hed for benalaxyl-M as this is a new active ingredient. The residue of concern in plants consists of the parent compound (D421423, E. Holman , 09-SEP-2014). Because a screening approach using recommended tolerance level residues resulted in cancer risk estimates to the U.S. population of 1 x 10· 5, it was determined that anticipated residues should be used for the chronic and cancer dietary analyses. There are no livestock feedstuffs associated with grape or tomato. Therefore , no residue estimates for meat , milk, poultry or eggs were included in the analyses. For the current petition, the anticipated residues used in the analyses, as well as the recommended benalaxyl-M to lerances, are shown in Table 1 (D416583, W. Donovan, 02-DEC2014). Table 1. Recommended Toler ance Levels a n d Anticip ated Residues for Benalaxy i-M. Com modi ty HED-Recommended To lerance (ppm) Antic ipated Residue (ppm) Grape 3.0 0 . 398 Tomato 0.2 0.058 The residue chemistry database for benalaxyl-M included processing studies for all relevant processed commodities from grape and tomato except for dried tomato. Thus , the DEEM default processing factor of 14. 3 x was used for dried tomato . The onl y process ed co mmodity showing re s idue concentration was for raisin, with an average concentration factor of 2.3 x. All other processed commodities showed residue reducti on upon processing ; for these commodities a processing factor of 1.0 was used in the analysis. Table 2 summarizes the processing factor information for benalaxyl-M. Table 2. P r ocessing F acto rs (PFs) Used for Benalax' 1-M. Processed E mp iri cal Processing DEEM Default Processing PF Used in Commod ity Factor Factor C hronic/ Cancer Ana ly s is Raisin 2 . 3 4.3 2.3 Grape juice <0.7 1.2 1.0 Wine <0 .7 

### -- 1.0 Tomato puree 0.4 3.3 1.0 Tomato paste 0 . 75 5.4 1.0 T omato juice 0.45 1.5 1. 0 Dried tomato 

### -- 14 . 3 14 .3 The USDA Pesticide Data Program (PDP) monitored pesticide residu es in catfish in 2008, 2009, and 20 10 . In general, pesticide residues would not be expected to be found in fish unless the pesticide bio accumulates or has an aquatic use. To determine whether or n ot residues are present in fish, HED now routinely checks PDP monitoring data re gardless of the pesticide's uses and physicochemical properties. However, PDP did not analyze catfish samples for benalaxyl-M. As a result, residues in fish were not included in the assessment.
Page 3 of 10Benalaxyl-M ( 11351 0) Dietary Exposure and Risk Assessment D416584 

### III. Percent Crop Treated Information The chronic and cancer dietary exposure assessments assumed 100% crop treated for grape and tomato. IV. Drinking Water Data As the proposed uses are limited to countries outside the United Sta tes , no residues of benalaxyl-M are expected in drinking water. V. DEEM-FCID Program and Consumption Information Benalaxyl-M acute and chronic dietary exposure assessments were conducted using the Dietary Expos ure Evaluation Model softwa re with the Food Commodity Intake Database DEEM-FCID, Version 3.16. This software incorporates 2003-2008 food consumption data from USDA's NHANES/WWEIA. The data are based on the reported consumption of more than 20,000 individuals over two non-consecutive survey days. Foods "as consumed'' (e .g., apple pie) are linked to EPA-defined f ood commodities (e.g . , apples, peeled fruit- cooked; fresh or N/S; baked; or wheat flour
- cooked; fres h or N/S, baked) using publicly available recipe translation files developed jointly by USDA/ARS and EPA. For chronic exposure assessment, consumption data are averaged for the entire U.S. population and within population subgroups. However, fo r acute exposure assessment, consumption data are retained as individual consumption events. Based on analysis of the 2003- 2008 WWEIA consumption data, which took into account dietary patterns and survey respondents, HED concluded that it is most appropriate to report risk for the following population subgroups: the general U.S. population, all infants (<1 year old), children 1-2 , children 3-5, children 6-12, youth 13- 19 , adults 20-49, females 13-49, and adults 50-99 years old. For a chronic dietary exposure assessment, an estimate ofthe residue level in each food or food-form (e.g., orange or orange juice) on the food commodity residue lis t is multiplied by the average daily consumption estima te for that food/food form to produce a residue intake estimate. The re sulting residue intake estimate fo r each food/food form is summed with the residue intake estimates for all other food/food forms on the commodity residue list to arrive at the total average estimated exposure . Exposure is expressed in mglkg body weight/day and as a percent of the cPAD. This procedure is performed for each population subgroup. VI. Toxicological Information The benalaxyl-M risk assessment team in consultation with the ToxSAC (Toxicology Science Advisory Council) selected doses and endpoints for risk assessment. On August 13, 2014, the Carcinogenicity Assessment Review Committee recommended that a low dose extrapo lation model be applied to the experimental animal tumor data and that quantifications of risk be estimated for benalaxyl-M. The most potent unit risk, Q1 *, is that for male mouse liver tumor ra tes at 5.90 x 1 

# o- 3 (mg/kg/day)- 1 in human equiva lents (TXR 0057093, L. Brunsman, 04-DEC-2014). The toxicological doses and endpoints used for dietary risk assessment are summarized in Table 3.
Page 4 of 10Benalaxyl
- M ( 113 51 0) Dietary Exposure and Risk Assessmen t D416584 Tab le 3. Summary of Toxico log ical Doses and Endpoints for Be o a l axyi-M for Use in Dietary Hum a n Hea lth Risk As sess ments RID , PAD, E xpo s ure/ Point of Uncertainty/ Level of S c e nari o Departur e FQPA Safety Co n ce rn for Study and Tox icolog ical Effects Factors R isk Assessment Acute Dietary ( Gener a l Population , including No appropriate acute endpoint was identified . Infants and Chi ldren and fema les 13 + ) C hro n ic Tox ic ity/Carci no ge ni c ity Study
- rat ( 49040634) LOAEL = 136 mg/kg/day bas ed o n based on an increase in GGT in males, slight increases liver weight in both sexes, Chronic UFA= lOx Chronic RID= increased incidence of hepatoce ll ular Dietary (All NOA EL=20 UFH = lOx cPAD = 0.02 hypertrophy in both sexes, increased Populations) mglkg/day FQ PA UFos= mglkg/day incidence of thyroid follicular cell lOx hypertrophy in both sexes, increased incidence of thyroid cell hyperp lasia in f e males, increased incide nce of thyroid fo lli cular ectasia in fema le s, and an incr eased incidence of ova r ian stromal cell hyp

_ e rplasia in females. Cancer (oral) C lassification: "Likely to be Carcinogenic to Humans" based on male mouse liver tumors . Q , * = 5.90 X I

## o· 3 (mg/kg/day)" 1 Pomt of Departure (POD)
- A data pomt or an estimated pomt that tS denved from observed dose-response data and used to mark the beginning ofextrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL =no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertain ty factor . UFA =extrapolation from animal to human (interspecies). UFH =potential variation in sensitivity among members of the human population (intraspecies). UFoa = to account for the absence of key data (i.e., lack of a critical stu dy). FQPA SF= FQPA Safety Factor. PAD = population adjusted dose (a = acute , c = chronic). RID = reference. dose. D ue to uncertainti es in the tox icity d atab ase of benalaxy l-M , the Agen cy r ecommend s that th e 1 

### OX FQPA safety factor for the protection of infants and chi ldren be retained. 

### VII . R es ul ts/D isc u ss ion As stated above, for acu t e and chronic assessme nts, HED i s co n cerned when dietary risk exceeds 100% of the PAD . The DEEM -FCID analyses es timate the d ietary exposure of th e U .S. p op ulation a nd various pop ul atio n subgro up s . T he res ul ts repo rted in T a ble 4 are f or the general U . S. Popu latio n , a ll infants ( < 1 year old), chi ldren 1-2, children 3
- 5, chil dre n 6-12, yo u th 1 3
- 19 , females 13-49, adu lts 20
-49, and adu lts 50
- 99 years. Cancer ri sk is de termined for t he general U.S. population only. Results of Chronic Dietary (Food Only) Exposure and Risk Analysis Partially refined chronic and cance r dietary assessments were conducted using anticipated residue level s, 100% crop treated assumptions, and processing factors of2.3 x and 14.3 x fo r raisi n and dried Page 5 of 10Benalaxyi-M (113510) D ietary Exposure and Risk As sessment D4 16584 tomato, respectively. The es timated risk is S 7 % ofthe chronic p op ul ation adjusted dose (cPAD) f o r the 

### U.S. population and all popul ation subgroups. Results are shown in Table 4. Results of Cancer Dietary (Food Only) Exposure and Risk Analys i s The es timated expos ure of th e general U.S. population to benalaxyl -M is 0 . 000287 mg/kg/day. Apply ing the 

### Q1 

## * of 5.90 x 10· 3 (mg/ kg/day)" 1 to the expo sure value resu lts in a cancer risk es timate of 1 . 7 x 1

# o- 6

. Results are sho wn in Ta ble 4. A commodity contribution analysis was performed to identify the ri sk drivers. Thus, the contrib utions from grape, r a isi n, and tomato were 76, 8, and 16%, respectively.

Table 4. Summary of Dietary (Food Only) Expos ure an d Risk for Benalaxyi -M. 1 Acute Dieta ry Chronic Dietary Cancer (95th Percentile) Population Subgroup Dietary Dietary D ietary Expos ure %aPAD Exposure %cPAD Exposure Ris k (mglkg/day) (mglkglday) (mglkgld ay) Genera l U.S. P o pu la tion 0.000287 1. 4 0.000287 1.1 x to- 6 All Infants (< I year ol d) 0.000477 2.4 Childre n 1
- 2 years old 0.001416 7.1 Children 3-5 years old 0.000901 4 . 5 Children 6
- 12 years old NA NA 0.000381 1.9 NA NA Youth 13-19 years old 0 .000148 <I Adults 20-49 years old 0.000201 1.0 Adults 50-99 years old 0.000225 1.1 Females 13-49 years old 0.000206 1.0 H1ghest exposure 1dent1fi ed m bold.

Page 6 of 10Benalaxyi-M (113510) Dietary Exposure and Risk Assessment 0416584 VIII . Characte rization of Inputs/O utputs For the chronic and cancer dietary risk estimates, partia ll y refined dietary ri sk assessments were conduc t ed. Th e refinement consisted of the use of anticipated residue levels, based on the average residues found in the field trials. This refinement was included because unrefined cancer risk estimates us ing tolerance level residues were 1 x 1 

# o- 5

. If furthe r refinements become necessary for future assessments, percent crop treated estimates may be considered based on import data. IX. Conclus ion s HED conducted chronic and cancer dietary risk assessments, which made use of anticipated residues, conservative determinations ofprocessing factors , and assumin g all grapes and tomatoes consumed in the U . S. were treated (100% crop treated). C hronic dietary ri sks to all population subgroups**were ~**  7% of the cPAD. Additionally , cancer ri sk to the US population was estimated at 1.7 x 10· 6

. HED is confident that these assessments do not underestimate risk to the general U.S . population o r any population subgroup. X. List of Attachments Attachment I . Chro ni c Residue Input F ile Attachment 2. Chro nic Results Fi le Attachment 3. Cancer Results File

P age 7 of 10Benalaxyi- M (113510) Dietary Exposure and Risk Assessment Attachment 1. Chronic Res idue Inp ut Fil e
Filename: C : \Users\wdonovan\Documents\DEEM Ve rsion 3.16\113510.r08 Chemical: Benalaxyl
- M RfD(Chronic): .02 mg/kg bw/day NOEL(Chronic): 0 mg/kg bw/day RfD(Acu t e) : 0 mg/kg bw/day NOEL(Acu t e): 0 mg/ kg bw/day Q * = .005 9 Date c r eated/last mod ifi ed: Ol-02-2015/ 1 2: 1 S:03 P r og r am ve r . 3.16, 03
- 0S
- d Commen t : Grape, t omato import uses (food only) EPA Crop Def Res Adj .Factors Commen t Code Grp Commodi t y Name (ppm) Ill 112

- - -------- ----- ------------ ----- - ---- - --- 

### - - - ------- 

## - ... 

## -- ........ 1304175000 13 D Grape 0.39SOOO 1 . 000 l. 000 mean res 130 4 1 76000 13 0 Grape, juice 0.39SOOO l. 000 l. 000 mean res 130 4176001 13D Grape, ju i ce -babyfood 0.39SOOO 1.000 1 . 000 mean res 9500 1770 00 0 Grape, l eaves 0.39SOOO 1.000 1.000 mean r es 9500 17 SOOO 0 G r ape, raisin 0.39SOOO 2.300 1.000 mean r es 13 04 1 79000 130 G r ape, wine and sherry 0.39SOOO 1 . 000 1.000 mean r es OS01375000 SA Tomato 0 . 05SOOO 1.000 1.000 mean r es OS0137SOOO SA Tomat o, dried 0 . 05SOOO 14.300 1 .000 mean res OS0137S001 SA Tomat o, dried-babyfood 0.05SOOO 1 4.300 1 .000 mean res OS01379000 SA Tomato, juice 0.05SOOO 1 .000 1. 000 mean res OS0 13 76000 SA Tomato, paste 0.05SOOO 1. 000 1 .000 mean r es OS0137600 1 SA Tomato, paste-babyfood 0.05SOOO 1.000 1 . 000 mean res OS013 77000 SA Toma t o, puree 0.05SOOO 1.000 1.000 mean res OS0 137 7001 SA Tomato, puree-babyfood 0 .0 5SOOO 1 .000 1 .000 mean res OS01375001 SA Tomat o - babyfood 0 . 05SOOO 1 .000 1 .000 mean r es

Page 8 of 10 0416584

D4165S3 D4 1 65S3 D4 1 65S3 04165S3 04165S3 04165S3 04165S3 04165S3 D4 1 65S3 04 1 65S3 0416583 0416583 0 4 16583 0 4 16583 0416583Benalaxy i-M (113510) Dietary Ex po sur e and Risk Assessment 0416584 Attachment 2 . C hronic Resu lts Fil e
US EPA Ver. 3.16, 03
- 08
- d DEEM-FCID Chronic anal ysis for BENALAXYL-M NHANES 2003 -200 8 2
- day Residue file name: C:\Users\wdonovan\Documents\DEEM Version 3.16\113510.r08 Adjustment fac t o r ij2 NOT used . Ana l ys is Date 0 1- 05
- 20 1 5/07:25:24 Resid ue f ile dated: 01-05
- 2 0 1 5/07:24:32 Refe rence dose (RfD , Chronic) 

### = . 02 m g/kg bw/day COMMENT 1: Grape, tomato import uses . (food only) 

### ======= ==== ======= ==== ==================== ==== ====== === === = =========== ===== ==== Total exposure by population subgroup Total Exposure Popula t ion

Subgroup Tot al US Population Hispanic Non
- Hisp-White Non- Hisp
- Black No n-H isp-Other Nursing Infants Non-Nursing Infant s Female 13+ PREG Children 1-6 Children 7-12 Male 13
- 19 Female 13
- 19/ N P Ma le 20+ Fe ma l e 20+/NP Seniors 55+ All Infants Female 13-50 Children 1-2 Children 3
- 5 Childre n 6-12 Youth 13- 19 Adu l ts 20-49 Adults 50-99 Female 13-49 mg / kg Percen t of body wt/day Rfd



### --- --------- - ------- ----- -- -- 0 . 000287 1.4% 0 . 000255 1. 3\ 0 .000296 1.5% 0.000 2 80 1.4% 0 .0 0 02 66 1. 3% 0.00 0 172 0.9% 0.000613 3.1% 0.000183 0.9% 0 . 001059 5.3% 0 . 000315 1. 6% 0.000 142 0. 7% 0.000154 0.8% 0.00 0 197 1. 0% 0.000225 1.1% 0.000236 1.2\ 0 .00 0 47 7 2.4% 0 .0002 05 1. 0\ 0.001416 7 . 1% 0.000901 4.5% 0.000381 1 . 9% 0.000 1 48 0.7% 0.000 2 01 1.0% 0.000 225 1.1% 0.000206 1.0%

Page 9 of 10Benalaxyi-M (11351 0) Dietary Exposure and Risk Assessment 0416584 Attachment 3 0 Cancer Results File US EPA Vero 3ol6, 03
- 08
- d DEEM -FCID Chronic ana l ys i s for BENALAXYL-M NHANES 2003-2008 2-day Res idue fi l e nam e: C :\Users\wdonovan\ Documents\ DEEM Version 3o l 6\1 1 35l0or08 Adjustm ent factor #2 NOT used. Analys i s Date 01-05-20 1 5/07 : 25 : 43 R esidue fi l e d a ted : 01-05-2015/07 :2 4:32 Q* = Oo0059 COMMENT 1 : Grape, tomato import uses (food on l y ) 

### =================== ========= ============= ========= ==================== ========= Tot al exposure by population subgroup Total Exposure Popu l ation

Subgroup Total US Po p ula tio n m g/Jcg body wt/day O o 000287

Page 10 of 10 Lifet i me risk (Q* = 0 0059}

1o 69E
- 06