UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: 13-JAN-20 15 

OFFICE OF 

CHEMICAL SAFETY 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: Tolerance without U.S. 

Registration 

Risk Assessment Type: Dietary Risk 

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) 

/ /'/ 

Mohsen Sahafeyen, Chemist ff Lt~~~A-4~ ·-" ~ 1 · / 

David Hrdy, Senior Biologist vJtwi/ f.- ?([!j\/ / 

Dietary Exposure Science Advisory Council ( ES~) 

HED (7509P) 

Karen Samek, Risk Manager Reviewer 

Fungicide Branch 

Registration Division (7505P) 

Page 1 of 10 
Benalaxyl-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/WWEIA). 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 except 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 ( cP AD) 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, with 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 risk is expressed as a percentage of a maximum acceptable dose (i.e., the 

dose which HED has concluded will result in no unreasonable adverse health effects). This 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 estimated dietary risk 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/EPAPEST/2000/July/Day-12/606l.pdf; or see SOP 99.6 (20-AUG-1999). 

This memo reports the first dietary exposure analysis for benalaxyl-M. 

Page 2 of 10 
Benalaxyi-M (113510) 

II. Residue Information 

D416583, W. Donovan, 02-DEC-20 14 

Dietary Exposure and Risk Assessment D416584 

No tolerances have been established 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 tolerances, are shown in Table 1 (D416583, W. Donovan, 02-DEC2014). 

Table 1. Recommended Tolerance Levels and Anticipated Residues for Benalaxyi-M. 

Commodity HED-Recommended Tolerance (ppm) Anticipated 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 only processed commodity showing 

residue concentration was for raisin, with an average concentration factor of 2.3 x. All other 

processed commodities showed residue reduction 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 rocessing Factors (PFs) Used for Benalax' 1-M. 

Processed Empirical Processing DEEM Default Processing PF Used in 

Commodity Factor Factor Chronic/Cancer Analysis 

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 

Tomato juice 0.45 1.5 1.0 

Dried tomato -- 14.3 14.3 

The USDA Pesticide Data Program (PDP) monitored pesticide residues 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 not residues are present in fish, 

HED now routinely checks PDP monitoring data regardless 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 10 
Benalaxyl-M ( 11351 0) Dietary Exposure and Risk Assessment D416584 

III. Percent Crop Treated Information 

The chronic and cancer dietary exposure assessments assumed 1 00% crop treated for grape and 

tomato. 

IV. Drinking Water Data 

As the proposed uses are limited to countries outside the United States, 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 

Exposure Evaluation Model software 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 food commodities (e.g., apples, peeled fruit- cooked; fresh or N/S; baked; or wheat 

flour - cooked; fresh 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, for 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 of the residue level in each food or food-form 

(e.g., orange or orange juice) on the food commodity residue list is multiplied by the average daily 

consumption estimate for that food/food form to produce a residue intake estimate. The resulting 

residue intake estimate for 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 extrapolation 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 rates at 5.90 x 1 o-3 

(mg/kg/day)-1 in human equivalents (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 10 
Benalaxyl-M ( 113 51 0) Dietary Exposure and Risk Assessment D416584 

Table 3. Summary of Toxicological Doses and Endpoints for Beoa laxyi-M for Use in Dietary Huma n Health Risk 

Assessments 

RID, PAD, 

Exposure/ Point of Uncertainty/ Level of 

Scenario Departure FQPA Safety Concern for Study and Toxicological Effects 

Factors Risk 

Assessment 

Acute Dietary 

(Genera l 

Population, 

including No appropriate acute endpoint was identified. 

Infants and 

Children and 

fema les 13+) 

Chronic Toxicity/Carcinogenicity Study -rat 

(49040634) 

LOAEL = 136 mg/kg/day based on based 

on an increase in GGT in males, slight 

increases liver weight in both sexes, 

Chronic UFA= lOx Chronic RID= increased incidence of hepatocellular 

Dietary (All NOAEL=20 UFH= lOx cPAD = 0.02 hypertrophy in both sexes, increased 

Populations) mglkg/day FQPA UFos= mglkg/day incidence of thyroid follicular cell 

lOx hypertrophy in both sexes, increased 

incidence of thyroid cell hyperplasia in 

females, increased incidence of thyroid 

follicular ectasia in fema les, and an 

increased incidence of ovarian stromal cell 

hyp_erplasia in females. 

Cancer (oral) Classification: "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 of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL =no 

observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty 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 study). FQPA SF= FQPA Safety Factor. PAD = population 

adjusted dose (a = acute, c = chronic). RID = reference. dose. 

Due to uncertainties in the toxicity database of benalaxyl-M, the Agency recommends that the 1 OX 

FQP A safety factor for the protection of infants and children be retained. 

VII. Results/Discussion 

As stated above, for acute and chronic assessments, HED is concerned when dietary risk exceeds 

100% of the PAD. The DEEM-FCID analyses estimate the dietary exposure of the U.S. population 

and various population subgroups. The results reported in Table 4 are for the general U.S. 

Population, all infants (<1 year old), children 1-2, children 3-5, children 6-12, youth 13-19, females 

13-49, adults 20-49, and adults 50-99 years. Cancer risk is determined for the general U.S. 

population only. 

Results of Chronic Dietary (Food Only) Exposure and Risk Analysis 

Partially refined chronic and cancer dietary assessments were conducted using anticipated residue 

levels, 100% crop treated assumptions, and processing factors of2.3 x and 14.3 x for raisin and dried 

Page 5 of 10 
Benalaxyi-M (113510) Dietary Exposure and Risk Assessment D4 16584 

tomato, respectively. The estimated risk is S 7 % ofthe chronic population adjusted dose (cPAD) 

for the U.S. population and all population subgroups. Results are shown in Table 4. 

Results of Cancer Dietary (Food Only) Exposure and Risk Analysis 

The estimated exposure of the general U.S. population to benalaxyl-M is 0.000287 mg/kg/day. 

Applying the Q1* of 5.90 x 10·3 (mg/kg/day)"1 to the exposure value results in a cancer risk estimate 

of 1. 7 x 1 o-6. Results are shown in Table 4. A commodity contribution analysis was performed to 

identify the risk drivers. Thus, the contributions from grape, raisin, and tomato were 76, 8, and 16%, 

respectively. 

Table 4. Summary of Dietary (Food Only) Exposure and Risk for Benalaxyi-M.1 

Acute Dietary Chronic Dietary Cancer (95th Percentile) 

Population Subgroup Dietary Dietary Dietary 

Exposure %aPAD Exposure %cPAD Exposure Risk 

(mglkg/day) (mglkglday) (mglkglday) 

General U.S. Population 0.000287 1.4 0.000287 1.1 x to-6 

All Infants ( < I year old) 0.000477 2.4 

Children 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 1dent1fied m bold. 

Page 6 of 10 
Benalaxyi-M (113510) Dietary Exposure and Risk Assessment 0416584 

VIII. Characterization of Inputs/Outputs 

For the chronic and cancer dietary risk estimates, partially refined dietary risk assessments were 

conducted. The 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 using tolerance level residues were 1 x 1 o-5. If further refinements become necessary for 

future assessments, percent crop treated estimates may be considered based on import data. 

IX. Conclusions 

HED conducted chronic and cancer dietary risk assessments, which made use of anticipated 

residues, conservative determinations of processing factors, and assuming all grapes and tomatoes 

consumed in the U.S. were treated (100% crop treated). Chronic dietary risks to all population 

subgroups were ~ 7% of the cPAD. Additionally, cancer risk 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 or any population subgroup. 

X. List of Attachments 

Attachment I . Chronic Residue Input File 

Attachment 2. Chronic Results File 

Attachment 3. Cancer Results File 

Page 7 of 10 
Benalaxyi-M (113510) Dietary Exposure and Risk Assessment 

Attachment 1. Chronic Residue Input File 

Filename: C : \Users\wdonovan\Documents\DEEM Version 3.16\113510.r08 

Chemical: Benalaxyl- M 

RfD(Chronic): .02 mg/kg bw/day NOEL(Chronic): 0 mg/kg bw/day 

RfD(Acut e) : 0 mg/kg bw/day NOEL(Acut e): 0 mg/kg bw/day Q* = .005 9 

Date c r eated/last modified: Ol-02-2015/1 2: 1S:03 Pr ogr am ver . 3.16, 03 - 0S - d 

Comment : Grape, t omato import uses (food only) 

EPA Crop Def Res Adj .Factors Comment 

Code Grp Commodit y Name (ppm) Ill 112 

---------- ------------------------------- ---------- -... --........ 

1304175000 13D Grape 0.39SOOO 1 . 000 l. 000 mean res 

1304 1 76000 130 Grape, juice 0.39SOOO l. 000 l. 000 mean res 

1304176001 13D Grape, jui ce -babyfood 0.39SOOO 1.000 1 . 000 mean res 

9500177000 0 Grape, l eaves 0.39SOOO 1.000 1.000 mean r es 

950017SOOO 0 Gr ape, raisin 0.39SOOO 2.300 1.000 mean r es 

1304 1 79000 130 Gr 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 

OS01376001 SA Tomato, paste-babyfood 0.05SOOO 1.000 1 . 000 mean res 

OS013 77000 SA Tomat o, puree 0.05SOOO 1.000 1.000 mean res 

OS0 1377001 SA Tomato, puree-babyfood 0 .05SOOO 1 .000 1 .000 mean res 

OS01375001 SA Tomato - 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 165S3 

041 65S3 

0416583 

0416583 

0 416583 

0 4 16583 

0416583 
Benalaxyi-M (113510) Dietary Exposure and Risk Assessment 0416584 

Attachment 2. Chronic Results File 

US EPA Ver. 3.16, 03 - 08 - d 

DEEM-FCID Chronic analysis for BENALAXYL-M NHANES 2003 -2008 2 - day 

Residue file name: C:\Users\wdonovan\Documents\DEEM Version 3.16\113510.r08 

Adjustment fac t o r ij2 NOT used . 

Anal ysis Date 01-05 - 2015/07:25:24 Residue f ile dated: 01-05 - 2015/07:24:32 

Refe rence dose (RfD, Chronic) = . 02 mg/kg bw/day 

COMMENT 1: Grape, tomato import uses. (food only) 

======================================================= ======================== 

Total exposure by population subgroup 

Total Exposure 

Populat ion 

Subgroup 

Total US Population 

Hispanic 

Non - Hisp-White 

Non- Hisp- Black 

Non-Hisp-Other 

Nursing Infants 

Non-Nursing Infants 

Female 13+ PREG 

Children 1-6 

Children 7-12 

Male 13 - 19 

Female 13 - 19/NP 

Male 20+ 

Fema l e 20+/NP 

Seniors 55+ 

All Infants 

Female 13-50 

Children 1-2 

Children 3 - 5 

Children 6-12 

Youth 13-19 

Adul ts 20-49 

Adults 50-99 

Female 13-49 

mg/ kg Percent of 

body wt/day Rfd 

------------- -------------- -- 0 . 000287 1.4% 

0 . 000255 1. 3\ 

0 .000296 1.5% 

0.0002 80 1.4% 

0 .00 0266 1. 3% 

0.000172 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% 

0.000197 1. 0% 

0.000225 1.1% 

0.000236 1.2\ 

0 .00047 7 2.4% 

0 .000205 1. 0\ 

0.001416 7 . 1% 

0.000901 4.5% 

0.000381 1 . 9% 

0.000148 0.7% 

0.000201 1.0% 

0.000225 1.1% 

0.000206 1.0% 

Page 9 of 10 
Benalaxyi-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 anal ysi s for BENALAXYL-M NHANES 2003-2008 2-day 

Residue fil e name: C:\Users\wdonovan\Documents\DEEM Version 3o l 6\1135l0or08 

Adjustment factor #2 NOT used. 

Analysi s Date 01-05-2015/07 : 25 : 43 Residue fil e d a ted : 01-05-2015/07 :24:32 

Q* = Oo0059 

COMMENT 1 : Grape, tomato import uses (food onl y ) 

=============================================================================== 

Total exposure by population subgroup 

Total Exposure 

Popul ation 

Subgroup 

Total US Popula tion 

mg/Jcg 

body wt/day 

Oo000287 

Page 10 of 10 

Lifeti me risk 

(Q* = 0 0059} 

1o 69E- 06