Isoxaben Dietary Exposure and Risk Assess ment DP Number: 4 21 116

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICA L SA F ETY AND POLLU T ION PREVEN T ION



### MEMORANDUM

Date: Aug 28, 20 14



### SUBJECT: lsoxaben. Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Ri sk Assessments for Regi st ration R eview

.



### PC Code: 1258 51 

### Decision N o.: 482026 

### DP Barcode: D4 21116 

### Registration Nos.: 62719-580

, 62710-659

, 627 1 9-6 1 2 

### Petition No.: NA 

### Regulatory Action: Registration Revie w 

### Case No.: 7219 

### Risk Assessment Type : Dietary 

### T XRNo. : NA 

### CAS No.: 82558-50-7 40 

### CFR: § 180.650 

### MRIDNo.: NA



### FROM: D ennis McNeilly, Chemist 

# ?J..,----- fr(

._ 

# 1

Ri sk Assessment Branch II (RAB II ) Hea l th Effects Division (HED; 7509P)



### THROUGH: Nancy D odd, C hemist -/

# 4~**,8t:,--,4~ .**  

# - . Bill C utchin

, Chemist 

# :£-.**;U_ (;** **~** 

# (!_ (')**t~** Di eta ry Expos ure Science Advisory 

### Coun'cr(

and

. 1

## ;J~£4 Michael Doherty, Ph.D, Senio r Scie nti st**~ (lt.~**  Ri sk Assessment Bran ch II (RA BII ) Health Effects Division ( HED ; 7509 P )



### TO : Christina Sche l te ma , RM Team 53 Risk Management and Implem entat ion Branch 1 (RMIB 1) Pe s ticid e R eeva luation Division (PRD; 7508P)



### Executive Summary

A chronic aggregate d i etary (food and drinkin g water) exposure and risk assessment was

con duc t ed u si n g the Dietary Expo sur e Evaluation Model software w i th the Food C ommodi ty Intake Database (DEEM-FCID) Version 3.16, which uses 2003-2008 food consum ption datafrom the U.S. Department of Agriculture's National He alth and Nutrition Examination Survey, What We Eat in America (NHANES/WWEIA). No appropriate endpoint attributable to a single dose was identified. As no acute dietary endpo int was identified, an acute exposure analysis was not performed. The analysis was conducted in support of a human health risk assessment for registration review (D414154, D. McNeilly). This memorandum was reviewed by two peer reviewers ofthe DESAC, per DESAC SOP 2012.1.

The chronic analysis is based on tolerance level residues, 100% crop treated assumptions, and a screening l eve l drinking water assessment. Based on these highly conservative assumptions, chronic dietary (food and drinking water) risk estimates are less than or equal to 98% of the chronic population-adjusted dose (cPAD) for all popu l at ion subgroups. Genera ll y, HED i s concerned when risk estimates exceed 100% of the PAD; therefore, all chronic dietary risk estimates are below HED's level of concern (LOC).

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 that 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, NOAEL, LOAEL, e.g.) divided by the required uncertainty or safety factors.

For acute and non-cancer chronic exposures, HED is concerned when estimated dietary risk exceeds 100% of the PAD

. References that 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-AUG1999).

The most recent dietary risk assessment for thiamethoxam was conducted by Dennis McNeilly (D375246, 13 July 201 0).



### II. Residue Information

Isoxaben is a benzamide herbicide (Group 21) used for control ofbroadleafweeds. Isoxaben reportedly acts via inhibition of cell wall synthesis

. The herbicide is registered for non-food uses

on turf, ornamentals, non-bearing fruit and nut trees, and non-bearing vineyards. It is a l so registered for food use on grapes, tree nuts (crop group 14 ), and pistachios.

Tolerances for residues of isoxaben are listed in 40 CFR 

### § 180.650 and are expressed in terms of isoxaben residues in or on grape, tree nuts (crop group 14), pistachio and almond hulls. Compliance with the tolerance levels is determined by measuring only isoxaben, N-[3-(1-ethyl

- 1- methylpropyl)-5-isoxazolyl]-2,6

- dimethoxybenzamide, in or on the commodity. See Table 1 below for a summary of the existing tolerances. As part of registration review, the crop group 14 tolerance will be updated to a tolerance for the current crop group 14-12.

Page 2 of 11

### Page 3 of 11

Table 1. Summary of Tolerances

– HED Recommendation s for Tolerance Rev i sions Commodity Recommended Tolerance (ppm) Almond, hulls 0.40 Grape 0.01 Nut

, tree, group 14 0.02 (update to crop group 14

- 12*) Pistachio * Delete *Pistachio is included in crop group 14

- 12.


### HED is making the conservative assumption of 100% crop treated.

Processing Factors:

The grape processing study was c onducted at 5x the proposed maximum seasonal application rate, the submitted processing study on grapes showed residues <LOQ (0.01 ppm) in/on all samples of grapes, raisins, and grape juice; therefore, processing factors could not be calculated. It is rea sonable to assume (because of the exaggerated treatment) that no residues will concentrate. The RAC tolerance should suffice for the processed commodities. Therefore

, processing factors of 1

. 0x were used for grape juice and raisins (summarized in Table 2)

. This is a change from the previous dietary assessment.

Table 2. Summary of Processing Factors for Isoxaben

RAC Processed Commodity Processing Factor Grape Grape juice 1. 0 x Raisins 1.0 x



### Liv estock : HED continues to conclude that residues in eggs and the meat, fat, and meat byproducts of ruminants and poultry remain a 40 CFR §180.6[a][3] situation (there is no expectation of finite residues in these commodities). As a result, tolerances are still not required in any livestock commodities

.

Fish: The USDA Pesticide Data Program (PDP) monitored pesticide residues in catfish in 2008, 2009, and 2010; however, the samples were not analyzed for isoxaben . As a result, residues in fish were not included in the assessment.

I I I. Percent Crop Treated Information

Percent crop treated information was not used in the chronic analysis (100% crop treated assumed)

. IV. Drinking Water Data

The drinking water residues used in these dietary risk assessments were provided by EFED (D 420998

, A. Shelby

, 8 / 11 /2014 ), and incorporated directly into the DEEM

- FCID TM dietary assessments via entry into the food categories “water, direct, all sources” and “water, indirect, all sources.”

### Page 4 of 11

Th e drinking water assessment provide d a total toxic residue (TTR) screening level approach assuming stability of toxic residues to biotic and abiotic degradation. Major degradates include hydroxy isoxaben, dimethoxy benzamide, methoxyphenyl pyrimidinol, and AEM hexenoyl. Degradates are charact erized in detail in the drinking water degradates identification memo (D374526

, C Peck, 23 Feb 2010 ) . Hydroxy isoxaben, methoxyphenyl pyrimidinol, AEM hexenoyl isoxaben, and dimethoxy benzamide are included with parent isoxaben as residues of

conce rn as i dentified by HED . Unidentified degradates from the aqueous photolysis study were not noted as residues of concern.

Due to the persistence and moderate mobility of isoxaben, groundwater estimated drinking water concentrations (EDWCs) were higher than surf ace water EDWCs. Based on modeling results, the maximum estimated groundwater exposure concentrations for TTR and the recommended concentrations for use in HED’s dietary assessment are:

1,010 μg/L for the peak concentration 909 μg/L for the post

- breakt hrough average

The maximum estimated 1

- in

- 10 year peak surface water exposure concentration for TTR of isoxaben is 89.6 μg/L derived from the Surface Water Concentration Calculator (SWCC v1.106).

Surface water and groundwater EDWCs are presented below (Table 3a and Table 3b) with highest representative EDWCs highlighted in bold. All relevant surface water scenarios that are relatable to isoxaben uses were selected and parameterized at maximum application rates and with the maximum number of reapplicat ions.

Table 3 a : EDWCs for Total Toxic Residues of Isoxaben

in Surface Water. Crop Scenario 1

- in

- 10 Y ear Acute C oncentration (ppb) 1

- in

- 10 Y ear

A nnual A verage (ppb) 30

- year A nnual

A verage (ppb)

CA Almond 24.1 16.2 14.6 CA Citrus 13.9 10.7 9.7 CA Fruit 20.4 16.2 12.6 CA Grapes 18.8 13.9 10.9 CA Nursery 28.3 19.9 11 FL Citrus 89.6 32.2 21.6 FL Nursery 60.4 19.3 13.5 FL Turf 24.1 15 11.3 MI Nursery 54.3 30.7 24.7 NC Apple 69.5 28.1 17 NJ Nursery 59.2 28 20.1 NY Grape 77.1 43.6 33.6 OR Apple 35.8 21.5 16.3 OR Nursery 26.5 18.6 16.1

### Page 5 of 11 Table 3 a : EDWCs for Total Toxic Residues of Isoxaben

in Surface Water. Crop Scenario 1

- in

- 10 Y ear Acute C oncentration (ppb) 1

- in

- 10 Y ear

A nnual A verage (ppb) 30

- year A nnual

A verage (ppb)

OR Xmas Tree 21.7 14.7 12.8 PA Apple 59.7 31.7 21.9 PA Turf 39.8 24.1 16.9 TN Nursery 60.6 22.4 15.3

All currently available groundwater scenarios were run in a screening level approach to assess for vulnerable groundwater conditions. Groundwater EDWCs are substantially higher than surface water EDWCs due to isoxaben’s moderate mobility and high persiste nce.

Table 3b : EDWCs for Total Toxic Residues of Isoxaben in Groundwater Scenario Peak (ppb) Post Breakthrough Average (ppb) Delmarva 739 673 Florida Citrus 805 721 Florida Potato 126 125 Georgia Coastal 301 259 North Carolina Coastal 971 867 Wisconsin Sands 1010 909

Typically, HED uses the higher of the surface or groundwater estimates for each duration when assessing dietary risk. For isoxaben, the results f or groundwater are the highest estimates and were used in the dietary assessments.

The model s and their description s are available at the EPA internet website via the web link, http://www.epa.gov/oppefed1/models/water/

.
Water Monitoring Data



### Isoxaben is not included as one of the analytes monitored in U.S. surface and groundwater under the USGS’s National Water Quality Assessment (NAWQA) program ( http://water.usgs.gov/nawqa ). There were no detections in six surface water and sediment samples collected and analyzed for isoxaben by California Department of Pesticide Regulation (CDPR) in 2006 in Stanislaus County.

V. DEEM

- FCID Program and Consumption Information

A chronic dietary exposure assessment w as conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database DEEM

- FCID, Version 3.16 , which incorporates consumption data from USDA’s NHANES/W WEIA. This dietary survey was conducted from 2003 to 2008. 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)

### Page 6 of 11

are linked to EPA

- defined food commodit ies (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 ave raged 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 accou nt 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, adu lts 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 dail y 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 a rrive at the total average estimated exposure. Exposure is expressed in mg/kg body weight/day and as a percent of the cPAD. This procedure is performed for each population subgroup.

VI. Toxicological Information

The Health Effects Division (HED) has evaluated the toxicology database for isoxaben. The RAB II risk assessment team reviewed the toxicology data for isoxaben with regard to the acute and chronic reference doses and the toxicological endpoint selection. Table 4 below provides a summary of th e doses and endpoints recommended for use in the dietary exposure assessments. In accordance with EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), the Cancer Assessment Review Committee (CARC) classified isoxaben as having “Suggestive Evidence of Carcinogenicity

, ” but concluded that quantification of carcinogenic potential is not required. The cRfD is protective of cancer effects. The FQPA safety factor was reduced to 1x for all exposure scenarios.

In addition, the NOAELs selected for risk assessment are protective of all toxicological effects observed in the database including treatment

- related changes in the adrenal gland, thyroid, testes and ovaries. Thus, the Agency believes the FQPA safety factor can be reduced to 1X and still be conservatively protective of human health risk.

### Page 7 of 11

Table 4 . Toxicological Doses and Endpoints for Isoxaben for Use in Human Health Risk Assessments. Exposure/ Scenario Point of

Departure Uncertainty/

FQPA Safety Factors Level of

Concern for Risk Assessment Study and Toxicological

Effects

Acute Dietary All populations including infants and children Appropriate endpoints for this risk assessment were not identified.

Chronic Dietary All populations including infants and children NOAEL= 5.0

mg/kg/day UF A = 10x

UF H = 10x SF FQPA =1 cRfD=0.0 5

mg/kg/day

cPAD=0.0 5 mg/kg/day Chronic oral

toxicity/carcinogenicity in the rat LOAEL = 50.7 mg/kg/day, based on renal toxicity in males.

Cancer (oral, dermal, inhalation) Classification: Suggestive Evidence of Carcinogenic Potential, based on increased incidence

of hepatocellular adenomas in male and female mice. A quantitative assessment of cancer risk is not required.

Point of Departure (POD) = A data point or an estimated point that is derived 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. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose.



### VII. Results/Discussion

The DEEM

- FCID analyses estimate the dietary exposure of the US population and various population subgroups. The results of the assessments are sho wn in Table 5 , below.

### Page 8 of 11

Table 5 . Summary of Estimated Dietary (Food + Drinking Water) Exposures and Risk for Isoxaben

.

Population Subgroup aPAD,

mg/kg/day Acute Estimates (95 th



### Percentile) cPAD,

mg/kg/day Chronic Estimates 1


### Exposure, mg/kg/da
y Risk,

% aPAD Exposure,

mg/kg/da
y Risk, % cPAD

U.S. Population

NA NA NA 0.0 5 0.0 1904 0 3 8 All infants (< 1 year) 0.0 5 0.0 490 8 9 98

Children 1

- 2 yrs 2 0.0 5 0.0 2749 0 55 Children 3

- 5 yrs 0.0 5 0.0 2315 4 46 Children 6

- 12 yrs 0.0 5 0.01669 2 33 Youth 13

- 19 yrs 0.0 5 0.01388 3 28 Adults 20

- 49 yrs 0.0 5 0.0 1899 5 38 Adults 50

- 99 yrs 0.0 5 0.0 187 79 38 Females 13

- 49 yrs 0.0 5 0.0 1892 5 38
1

- The population subgroup with the highest estimated exposure/risk is bolded.



### The results reported in Table 5 are for the general U.S. population, all infants (<1 year old), children 1

- 2 years old , children 3

- 5 years old , children 6

- 12 years old , youth 13

- 19 years old

, females 13

- 49 years old , adults 20

- 49 years old , and adults 50

- 9 9 years old

. A complete listing of chronic exposure and risk estimates can be found in Attachment 2

. As previously stated, for chronic assessments, HED is concerned when dietary risk exceeds 100% of the PAD. The analyses indicate that the currently regi stered uses, with the updated tree nuts crop group, will result in chronic dietary (food + drinking water) exposures that are below HED’s level of concern for all population subgroups, including those of infants and children.

The chronic assessment indica tes that a ll i nfants are the most highly exposed subgroup, utilizing 9 8 % of the c PAD, while the general US population utilizes 38 % of the c PAD; all risk estimates are below HED’s level of concern (Table 5 ).

VIII. Characterization of Inputs/Outputs

This assessment is based on tolerance

- level residues and assumes 100% CT. The exposure values represent high

- end estimates and should be considered to be highly conservative, health

protective estimates of dietary exposure and risk.

T he model used to generate the EDWCs is a screening level assessment and is expected to produce conservative estimates of pesticides in groundwater.

Various other refinements could be made to the assessments . H owever, as there are no risk estimates of concern (including aggregate risk concerns) , no additional refinements were incorporated.

### Page 9 of 11

IX. Conclusions

B ased on highly conservative assumptions, there are no dietary (food + drinking water) risk estimates of concern for isoxaben

.

HED is confident that th e assessment does not underestimate risk to the general U.S. populat ion or any population subgroup. There are no dietary risk considerations that would preclude maintaining tolerance s for residues of isoxaben at the current level s

.

X. List of Attachments

Attachment 1 . Input file for the chronic dietary exposure analys i s of isoxaben

. Attachment 2 . Summary of the chronic dietary exposure analysis for isoxaben

.

### Page 10 of 11

Attachment 1. Input File for the Chronic Dietary Exposure Estimates.

US EPA Ver. 3.16, 03

- 08

- d
DEEM

- FCID Chronic analysis for ISOXABEN Residue file: J: \ Isoxaben \ DEEM \ Isoxaben_chronic

- 14_12.r08 Adjust. #2 NOT used Analysis Date 09

- 04

- 2014 Residue file dated: 09

- 04

- 2 014/11:40:53 Reference dose (RfD) = 0.05 mg/kg bw/day

---------------------------------------------------------------------------------- Food Crop Residue Adj.Factors EPA Code Grp Food Name (ppm) #1 #2

---------- ---- ------------------------------- ---------- ------ ------ 1400003000 14 Almond 0.020000 1.000 1.000 1400003001 14 Almond

- babyfood 0.020000 1.000 1.000 1400004000 14 Almond, oil 0.020000 1.000 1.000 1400004001 14 Almond, oil

- babyfood 0.020000 1.000 1.000 1400059000 14 Brazil nut 0.020000 1.000 1.000 1400068000 14 Butternut 0.020000 1.000 1.000 1400081000 14 Cashew 0.020000 1.000 1.000 1400092000 14 Chestnut 0.02000 0 1.000 1.000 9500111000 O Coconut, meat 0.020000 1.000 1.000 9500111001 O Coconut, meat

- babyfood 0.020000 1.000 1.000 9500112000 O Coconut, dried 0.020000 1.000 1.000 9500113000 O Coconut, milk 0.020000 1.000 1.000 9500114000 O Coconut, oil 0.020000 1.000 1.000 2003114001 20C Coconut, oil

- babyfood 0.020000 1.000 1.000 1400155000 14 Hazelnut 0.020000 1.000 1.000 1400156000 14 Hazelnut, oil 0.020000 1.000 1.000 1304175000 13D Grape 0.010000 1.000 1.000 130417 6000 13D Grape, juice 0.010000 1.000 1.000 1304176001 13D Grape, juice

- babyfood 0.010000 1.000 1.000 9500177000 O Grape, leaves 0.010000 1.000 1.000 9500178000 O Grape, raisin 0.010000 1.000 1.000 1304179000 13D Grape, wine and sherry 0.010000 1.000 1.000 1400185000 14 Hickory nut 0.020000 1.000 1.000 1400213000 14 Macadamia nut 0.020000 1.000 1.000 1400269000 14 Pecan 0.020000 1.000 1.000 1400278000 14 Pine nut 0.020000 1.000 1.000 1400282000 14 Pistachio 0.020000 1.000 1.000 1400391000 14 Walnut 0.020000 1.000 1.000 8601000000 86A Water, direct, all sources 0.909000 1.000 1.000 8602000000 86B Water , indirect, all sources 0.909000 1.000 1.000

### Page 11 of 11

Attachment 2. Summary of the chronic dietary exposure analysis for thiamethoxam

.

US EPA Ver. 3.16, 03

- 08

- d
DEEM

- FCID Chronic analysis for ISOXABEN NHANES 2003

- 2008 2

- day Residue file name: J: \ Isoxaben \ DEEM \ Isoxaben_chronic

- 14_12.r08 Adjustment factor #2 NOT used. Analysis Date 09

- 04

- 2014/13:50:43 Residue fil e dated: 09

- 04

- 2014/11:40:53 Reference dose (RfD, Chronic) = .05 mg/kg bw/day

=============================================================================== Total exposure by population subgroup

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

Total Exposure

----------------------------------- Population mg/kg Percent of Subgroup body wt/day Rfd

-------------------------------------- ------------- ---------------- Total US Population 0.019040 38.1% Hispanic 0.018179 36.4%
Non

- Hisp

- White 0.019584 39.2%
Non

- Hisp

- Black 0.015712 31.4%
Non

- Hisp

- Other 0.021944 43.9% Nursing Infants 0.017224 34.4%
Non

- Nursing Infants 0.063321 126.6% Female 13+ PREG 0.017926 35.9% Children 1

- 6 0.024403 48.8% Children 7

- 12 0.015876 31.8% Male 13

- 19 0.013087 26.2% Female 13

- 19/NP 0.014 665 29.3% Male 20+ 0.017737 35.5% Female 20+/NP 0.019997 40.0% Seniors 55+ 0.018408 36.8% All Infan ts 0.049089 98.2% Female 13

- 50 0.018947 37.9% Children 1

- 2 0.027490 55.0% Children 3

- 5 0.023154 46.3% Children 6

- 12 0.016692 33.4% Youth 13

- 19 0.013883 27.8% Adults 20

- 49 0.018995 38.0% Adu lts 50

- 99 0.018779 37.6% Female 13

- 49 0.018925 37.9%

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