Isoxaben Dietary Exposure Assessment DP Barcode: 375246

PC Code: 125851

 Page 1 of 10

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND

 POLLUTION PREVENTION

MEMORANDUM

DATE: July 13, 2010

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

Risk Assessment for the Section 3 Registration on Grapes and Tree Nuts.

PC Code: 125851 DP Barcodes: D375246

Decision No.: 379577 Registration No.: 62719-LIN

Petition No.: 7F7222 Regulatory Action: Section 3 Registration

Risk Assessment Type: Single Chemical 

Aggregate, Dietary

Case No.: NA

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

MRID No.: NA 40 CFR: §180.xxx (not yet established)

 

REVIEWER: Elizabeth Holman, Chemist

Dennis McNeilly, Chemist

Risk Assessment Branch II (RAB2)

Health Effects Division (HED; 7509P)

THROUGH: Julie VanAlstine, MPH, Environmental Health Scientist

Douglas Dotson, Ph.D., Chemist

Dietary Exposure Science Advisory Council

Health Effects Division (HED; 7509P)

and

Richard Loranger, Ph.D., Branch Senior Scientist

Risk Assessment Branch II (RAB2)

Health Effects Division (HED; 7509P)

TO: Kathryn V. Montague, PM-23

 Herbicide Branch

 Registration Division (RD; 7505P)
Isoxaben Dietary Exposure Assessment DP Barcode: 375246

PC Code: 125851

 Page 2 of 10

Executive Summary

A chronic aggregate dietary risk assessment (food and drinking water) was conducted using the 

Dietary Exposure Evaluation Model (DEEM-FCID, Version 2.03), which uses food consumption 

data from the U.S. Department of Agriculture (USDA’s) Continuing Surveys of Food Intakes by

Individuals (CSFII) from 1994-1996 and 1998. The analysis was performed to support a Section 

3 registration for use of isoxaben [N-[3-(1-ethyl-1-methylpropyl)-5-isoxazolyl]-2,6-

dimethoxybenzamide] on grapes and tree nuts.

Acute Dietary Exposure (Food and Drinking Water) Results and Characterization

No appropriate endpoint attributable to a single dose was identified. As no acute dietary

endpoint was identified, an acute exposure analysis was not performed.

Chronic Dietary (Food and Drinking Water) Exposure Results and Characterization

The chronic analysis is based on tolerance level residues and 100% crop treated assumptions. 

Default processing factors were used for grape juice (1.2x), and grapes, raisin (4.3x). The HEDrecommended tolerance level for each raw agricultural commodity (RAC) was entered as listed 

below: 

Grape...........................................................................0.01 ppm

Nut, tree, group 14 ......................................................0.02 ppm

Pistachio......................................................................0.02 ppm

The general U.S. population and all population subgroups have risk estimates that are well below 

HED’s level of concern (i.e., 100% of the chronic population adjusted dose (cPAD)). The most 

highly exposed population subgroup is Infants <1 yr, which utilizes 17% of the cPAD. The 

general U.S. population utilizes 5.1% of the cPAD.

Cancer Dietary (Food and Drinking Water) Exposure Results and Characterization

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 CARC determined that the cRfD is protective of cancer effects. As a result, a 

separate cancer dietary exposure analysis was not performed. Cancer risk from dietary exposure 

to isoxaben is not of concern to HED. 

I. Introduction

Dietary risk assessment incorporates both exposure and toxicity of a given pesticide. For acute 
Isoxaben Dietary Exposure Assessment DP Barcode: 375246

PC Code: 125851

 Page 3 of 10

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, 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. HED is generally concerned when estimated cancer risk exceeds one 

in one million. 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,” 6/21/2000, web link: 

http://www.epa.gov/fedrgstr/EPA-PEST/2000/July/Day-12/6061.pdf ; or see SOP 99.6 

(8/20/99).

This is the first food use and first dietary risk assessment to be conducted for isoxaben. 

II. Residue Information

Isoxaben is a benzamide herbicide (Group 21) used for control of broadleaf weeds. Isoxaben 

reportedly acts via inhibition of cell wall synthesis. The herbicide is currently registered for nonfood uses on turf, ornamentals, non-bearing fruit and nut trees, and non-bearing vineyards.

The petitioner has proposed a new Section 3 use on grapes, tree nuts, and pistachios. See Table 1 

below for a summary of the HED-recommended tolerances. 

Table 1. Summary of HED- Recommended Tolerances for Proposed New Use

Commodity Recommended Tolerance (ppm)

Grape 0.01

Nut tree, group 14 0.02

Pistachio 0.02

For grapes and tree nuts (including pistachio), isoxaben parent serves as an adequate measure of 

misuse based on its percentage of the total radioactive residues (TRR) in the metabolism studies 

and the residues seen in crop field trials. 

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

Processing Factors:

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 
Isoxaben Dietary Exposure Assessment DP Barcode: 375246

PC Code: 125851

 Page 4 of 10

grape juice; therefore, processing factors could not be calculated. Therefore default processing 

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

Table 2. Summary of Processing Factors for Isoxaben

RAC Processed Commodity Processing Factor (Default)

Grape Grape juice 1.2x

Raisins 4.3x

III. Drinking Water Data

The drinking water residues used in the dietary risk assessment were provided by the 

Environmental Fate and Effects Division (EFED) in the following memorandum: “Tier I

Drinking Water Assessment for the Isoxaben Proposed New Use on Bearing Nut Trees and 

Vineyards” (341497, C. Peck, 3/18/2010) and incorporated directly into this dietary assessment. 

Water residues were incorporated in the DEEM-FCID into the food categories “water, direct, all 

sources” and “water, indirect, all sources.” 

The estimated drinking water concentrations (EDWCs) are based on the maximum proposed 

application rates specified in the product labels. The EDWCs for the human health risk 

assessment are presented in Table 3. Because isoxaben has a number of major degradates whose 

toxicity is similar to that of isoxaben, a total toxic residue (TTR) approach was used in the 

modeling. The Residue of Concern Knowledge-based Subcommittee (ROCKS) recommended 

that the drinking water assessment for isoxaben include hydroxyisoxaben, dimethoxybenzamide, 

methoxyphenylpyrimidinol, and AEM hexenoylisoxaben. 

The drinking water exposure assessment for isoxaben and total isoxaben residues is based on 

modeling. Estimated drinking water concentrations for isoxaben and total isoxaben residues are 

shown in Table 3. 

The estimated drinking water concentrations (EDWC) were calculated using a Tier I model for 

surface water (FQPA Index Reservoir Screening Tool or FIRST) and a Tier I model for 

groundwater (Screening Concentration in Ground Water or SCI-GROW). The surface water 

values were higher than the groundwater values in all scenarios. Two sets of modeling runs were 

completed: one set using the mobility estimates of the parent and one set using mobility estimates 

derived from the isoxaben degradate study. RAB2 has selected the most conservative estimate in 

order to be sufficiently protective of human health. The maximum annual mean FIRST EDWC 

in surface water (from the modeling of the isoxaben degradates) was 120 μg/L for ornamental 

use. 
Isoxaben Dietary Exposure Assessment DP Barcode: 375246

PC Code: 125851

 Page 5 of 10

Table 3. Tier I Estimated Drinking Water Concentrations (EDWCs) resulting 

from applications of isoxaben on ornamentals and bearing nut trees.

Drinking water source 

(model)

Use 

(modeled rate)

Chronic 

(μg/L)

Parent Kd Data

Surface water (FIRST) Ornamental 54.7

Groundwater (SCIGROW) Ornamental 2.13

Surface water (FIRST) Bearing nut trees and vineyards 16.9

Groundwater (SCIGROW) Bearing nut trees and vineyards 0.71

Degradate Kd Data

Surface water (FIRST) Ornamental 120

Groundwater (SCIGROW) Ornamental 43.6

Surface water (FIRST) Bearing nut trees and vineyards 37.0

Groundwater (SCIGROW) Bearing nut trees and vineyards 14.5

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.

IV. DEEM-FCID Program and Consumption Information

An isoxaben chronic dietary exposure assessment was conducted using the DEEM-FCID, 

Version 2.03, which incorporates consumption data from USDA’s CSFII, 1994-1996 and 1998. 

The 1994-96, 98 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 EPAdefined 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, but for acute exposure assessment 

are retained as individual consumption events. Based on analysis of the 1994-96, 98 CSFII 

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+ years old.

For 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. 
Isoxaben Dietary Exposure Assessment DP Barcode: 375246

PC Code: 125851

 Page 6 of 10

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.

V. Toxicological Information

The Health Effects Division (HED) has evaluated the toxicology database for isoxaben. The 

RAB2 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. 

Table 4 Summary of Toxicological Doses and Endpoints for Isoxaben for Use in Dietary 

Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary, 

General 

Population, 

including 

Infants, 

Children and 

Females Age 13 

to 49

Not required. Appropriate endpoints for this risk assessment were not identified.

Chronic Dietary 

(All 

Populations)

NOAEL= 

5.0 

mg/kg/day

UFA= 10x

UFH= 10x

FQPA SF= 1x 

Chronic RfD = 

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. 
Isoxaben Dietary Exposure Assessment DP Barcode: 375246

PC Code: 125851

 Page 7 of 10

VI. Results/Discussion

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

100% of the PAD. The DEEM-FCID analysis estimates the dietary exposure of the U.S. 

population and various population subgroups. The results reported in Table 5 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+ years.

Results of Acute Dietary (Food and Drinking Water) Exposure Analysis

No appropriate endpoint attributable to a single dose was identified. As no acute dietary

endpoint was identified, an acute exposure analysis was not performed.

Results of Chronic Dietary (Food and Drinking Water) Exposure Analysis

The summary table below lists the results of the chronic dietary exposure analysis. The chronic 

dietary risk estimates for the general U.S. population utilized 5.1% of the cPAD. The most 

highly exposed population subgroup was all infants (<1 yr old), which utilized 17% of the cPAD. 

All population exposures are well below HED’s level of concern. 

Table 5. Summary of Dietary Exposure and Risk for Isoxaben1

Population Subgroup*

Acute Dietary Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day) % aPAD

Dietary 

Exposure

(mg/kg/day) % cPAD

Dietary 

Exposure

(mg/kg/day) Risk

General U.S. Population N/A

No acute 

dietary 

endpoint 

was 

identified

N/A 0.002536 5.1

N/A N/A All Infants (< 1 year old) 0.008303 17

Children 1-2 years old 0.003794 7.6

Children 3-5 years old 0.003539 7.1

Children 6-12 years old 0.002434 4.9

Youth 13-19 years old 0.001832 3.7

Adults 20-49 years old 0.002366 4.7

Adults 50+ years old 0.002489 5.0

Females 13-49 years old 0.002356 4.7

1The value for the highest exposed population in this chronic risk assessment is bolded. 
Isoxaben Dietary Exposure Assessment DP Barcode: 375246

PC Code: 125851

 Page 8 of 10

VII. Characterization of Inputs/Outputs

As the exposure estimates to all population subgroups were so low, it was not necessary to make 

refinements to the chronic dietary analysis. If it had been necessary to refine the analysis, 

average field trial values could have been used in place of tolerance level residues. In addition, 

estimates of percent crop treated could have been used.

VIII.Conclusions

Based on very conservative assumptions, the chronic dietary risk estimates are well below HED’s 

level of concern for the general U.S. population and all population subgroups, including those 

comprised of infants and children. In addition, cancer risk from dietary exposure to isoxaben is 

not of concern to HED (the cRfD is protective of cancer effects). Based on the conservative 

nature of the chronic dietary endpoint and the drinking water assessment, exposure and risk to 

isoxaben are not expected to be underestimated. 

IX. List of Attachments

Attachment 1: Residue Input File for Chronic Analysis

Attachment 2: Results of Chronic Dietary Exposure Analysis
Isoxaben Dietary Exposure Assessment DP Barcode: 375246

PC Code: 125851

 Page 9 of 10

Attachment 1: Isoxaben Residue Input File

Filename: C:\Documents and Settings\EHOLMAN\My Documents\isoxaben0414.R98

Chemical: Isoxaben

RfD(Chronic): .05 mg/kg bw/day NOEL(Chronic): 5 mg/kg bw/day

RfD(Acute): 0 mg/kg bw/day NOEL(Acute): 0 mg/kg bw/day

Date created/last modified: 04-14-2010/17:33:53/8 Program ver. 2.03

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

 EPA Crop Def Res Adj.Factors 

Comment

 Code Grp Commodity Name (ppm) #1 #2 

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

-

95001750 O Grape 0.010000 1.000 1.000 

95001760 O Grape, juice 0.010000 1.200 1.000 

95001761 O Grape, juice-babyfood 0.010000 1.200 1.000 

95001770 O Grape, leaves 0.010000 1.000 1.000 

95001780 O Grape, raisin 0.010000 4.300 1.000 

95001790 O Grape, wine and sherry 0.010000 1.000 1.000 

86010000 O Water, direct, all sources 0.120000 1.000 1.000 

86020000 O Water, indirect, all sources 0.120000 1.000 1.000 

14000030 14 Almond 0.020000 1.000 1.000 

14000031 14 Almond-babyfood 0.020000 1.000 1.000 

14000040 14 Almond, oil 0.020000 1.000 1.000 

14000041 14 Almond, oil-babyfood 0.020000 1.000 1.000 

14000590 14 Brazil nut 0.020000 1.000 1.000 

14000680 14 Butternut 0.020000 1.000 1.000 

14000810 14 Cashew 0.020000 1.000 1.000 

14000920 14 Chestnut 0.020000 1.000 1.000 

14001550 14 Filbert 0.020000 1.000 1.000 

14001560 14 Filbert, oil 0.020000 1.000 1.000 

14001850 14 Hickory nut 0.020000 1.000 1.000 

14002130 14 Macadamia nut 0.020000 1.000 1.000 

14002690 14 Pecan 0.020000 1.000 1.000 

14002820 14 Pistachio 0.020000 1.000 1.000 

14003910 14 Walnut 0.020000 1.000 1.000 
Isoxaben Dietary Exposure Assessment DP Barcode: 375246

PC Code: 125851

 Page 10 of 10

Attachment 2: Results of Isoxaben Chronic Dietary Exposure Analysis

U.S. Environmental Protection Agency Ver. 2.00

DEEM-FCID Chronic analysis for ISOXABEN (1994-98 data)

Residue file name: C:\Documents and Settings\EHOLMAN\My 

Documents\isoxaben0414.R98

 Adjustment factor #2 NOT used.

Analysis Date 04-16-2010/16:15:54 Residue file dated: 04-14-2010/17:33:53/8

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 

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

U.S. Population (total) 0.002536 5.1%

U.S. Population (spring season) 0.002514 5.0%

U.S. Population (summer season) 0.002724 5.4%

U.S. Population (autumn season) 0.002451 4.9%

U.S. Population (winter season) 0.002452 4.9%

Northeast region 0.002315 4.6%

Midwest region 0.002564 5.1%

Southern region 0.002410 4.8%

Western region 0.002905 5.8%

Hispanics 0.002876 5.8%

Non-hispanic whites 0.002475 4.9%

Non-hispanic blacks 0.002407 4.8%

Non-hisp/non-white/non-black 0.003105 6.2%

All infants (< 1 year) 0.008303 16.6%

Nursing infants 0.003079 6.2%

Non-nursing infants 0.010285 20.6%

Children 1-6 yrs 0.003560 7.1%

Children 7-12 yrs 0.002306 4.6%

Females 13-19 (not preg or nursing) 0.001784 3.6%

Females 20+ (not preg or nursing) 0.002530 5.1%

Females 13-50 yrs 0.002452 4.9%

Females 13+ (preg/not nursing) 0.002462 4.9%

Females 13+ (nursing) 0.003508 7.0%

Males 13-19 yrs 0.001864 3.7%

Males 20+ yrs 0.002270 4.5%

Seniors 55+ 0.002488 5.0%

Children 1-2 yrs 0.003794 7.6%

Children 3-5 yrs 0.003539 7.1%

Children 6-12 yrs 0.002434 4.9%

Youth 13-19 yrs 0.001832 3.7%

Adults 20-49 yrs 0.002366 4.7%

Adults 50+ yrs 0.002489 5.0%

Females 13-49 yrs 0.002356 4.7%