Isoxaben Dietary Exposure and Risk Assessment DP Number: 421 116 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: Aug 28, 2014 

SUBJECT: lsoxaben. Chronic Aggregate Dietary (Food and Drinking Water) Exposure and 

Risk Assessments for Registration Review. 

PC Code: 125851 

Decision No.: 482026 

DP Barcode: D421116 

Registration Nos.: 62719-580, 62710-659, 

62719-612 

Petition No.: NA Regulatory Action: Registration Review 

Risk Assessment Type: Dietary Case No.: 7219 

TXRNo.: NA CAS No.: 82558-50-7 

MRIDNo.: NA 40 CFR: § 180.650 

FROM: Dennis McNeilly, Chemist ?J..,----- fr( ._ 1 

Risk Assessment Branch II (RABII) 

Health Effects Division (HED; 7509P) 

THROUGH: Nancy Dodd, Chemist -/ 4~ ,8t:,--,4~. -. Bill Cutchin, Chemist :£-. ;U_(;~ (!_ (') t~ Dietary Exposure Science Advisory Coun'cr( 

and . 1 ;J~£4 Michael Doherty, Ph.D, Senior Scientist ~ (lt.~ 

Risk Assessment Branch II (RABII) 

Health Effects Division (HED; 7509P) 

TO: Christina Scheltema, RM Team 53 

Risk Management and Implementation Branch 1 (RMIB 1) 

Pesticide Reevaluation Division (PRD; 7508P) 

Executive Summary 

A chronic aggregate dietary (food and drinking water) exposure and risk assessment was 

conducted using the Dietary Exposure Evaluation Model software with the Food Commodity 

Intake Database (DEEM-FCID) Version 3.16, which uses 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). No appropriate endpoint attributable to a single 

dose was identified. As no acute dietary endpoint 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 level 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 population subgroups. Generally, HED is 

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 also 

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 
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Table 1. Summary of Tolerances – HED Recommendations for Tolerance Revisions

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 conducted 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 reasonable 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 1.0x

Raisins 1.0x

Livestock: 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.

III. 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 

(D420998, A. Shelby, 8/11/2014), and incorporated directly into the DEEM-FCIDTM dietary 

assessments via entry into the food categories “water, direct, all sources” and “water, indirect, all 

sources.” 
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The drinking water assessment provided 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 characterized 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 

concern as identified 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 surface 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-breakthrough 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 reapplications. 

Table 3a: EDWCs for Total Toxic Residues of Isoxaben

in Surface Water.

Crop Scenario 1-in-10 Year 

Acute 

Concentration 

(ppb)

1-in-10 Year 

Annual 

Average 

(ppb)

30-year Annual 

Average (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
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Table 3a: EDWCs for Total Toxic Residues of Isoxaben

in Surface Water.

Crop Scenario 1-in-10 Year 

Acute 

Concentration 

(ppb)

1-in-10 Year 

Annual 

Average 

(ppb)

30-year Annual 

Average (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 persistence. 

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 for groundwater are the highest estimates and 

were used in the dietary assessments. 

The models and their descriptions 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 was 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/WWEIA. 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) 
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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 foodform (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 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 

RABII 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 the 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.
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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 

UFA= 10x

UFH= 10x

SFFQPA=1

cRfD=0.05

mg/kg/day

cPAD=0.05

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. UFA = extrapolation from animal to human (interspecies). UFH = 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 shown in Table 5, below.
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Table 5. Summary of Estimated Dietary (Food + Drinking Water) Exposures and Risk 

for Isoxaben.

Population 

Subgroup

aPAD, 

mg/kg/day

Acute Estimates (95th

Percentile) cPAD, 

mg/kg/day

Chronic Estimates1

Exposure, 

mg/kg/da

y

Risk,

% 

aPAD

Exposure, 

mg/kg/da

y

Risk, 

% cPAD

U.S. Population

NA NA NA

0.05 0.019040 38

All infants (< 1 

year) 0.05 0.049089 98

Children 1-2 yrs2 0.05 0.027490 55

Children 3-5 yrs 0.05 0.023154 46

Children 6-12 yrs 0.05 0.016692 33

Youth 13-19 yrs 0.05 0.013883 28

Adults 20-49 yrs 0.05 0.018995 38

Adults 50-99 yrs 0.05 0.018779 38

Females 13-49 yrs 0.05 0.018925 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 50-99 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 registered 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 indicates that all infants are the most highly exposed subgroup, utilizing 

98% of the cPAD, while the general US population utilizes 38% of the cPAD; 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, healthprotective estimates of dietary exposure and risk. 

The 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. However, as there are no risk 

estimates of concern (including aggregate risk concerns), no additional refinements were 

incorporated.
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IX. Conclusions

Based on highly conservative assumptions, there are no dietary (food + drinking water) risk 

estimates of concern for isoxaben.

HED is confident that the assessment does not underestimate risk to the general U.S. population 

or any population subgroup. There are no dietary risk considerations that would preclude 

maintaining tolerances for residues of isoxaben at the current levels.

X. List of Attachments

Attachment 1. Input file for the chronic dietary exposure analysis of isoxaben.

Attachment 2. Summary of the chronic dietary exposure analysis for isoxaben.
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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: 09-04-2014/11:40:53

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 0.020000 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 

1304176000 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 
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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 file 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 0.014665 29.3%

Male 20+ 0.017737 35.5%

Female 20+/NP 0.019997 40.0%

Seniors 55+ 0.018408 36.8%

All Infants 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%

Adults 50-99 0.018779 37.6%

Female 13-49 0.018925 37.9%

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