Isoxaben Dietary Exposure Assessment DP Barcode: 3 75246

PC Code: 125851

Page 1 of 10

UNITED STA

TES ENVIRONMENTA L PROTECTION A GENCY WASHINGTON, D.C. 20460
OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION MEM ORANDUM DATE: July

13, 2010 SUBJECT: Is oxaben : 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: D 375246 Decision No.: 379577 Registr ation No. : 62719
- LIN Petition No.: 7F7222 Regulatory Action: Section 3 Registration Risk Assessment Type: Single Chemical Aggregate, Dietary Case No.: NA T XR No.: NA CAS No.: 82558
- 50
- 7 MRID No.: NA 40 CFR: § 180. xxx (not y et established)
REVI EWER: Elizabeth Holman, Chemist

D ennis McNeilly , Chemist R isk Assessment Branch II (RAB2) Health Effects Division ( HED; 7509 P ) THROUGH: Julie VanAlstine , MPH, Environmental Health Scientist

Douglas Dotson , Ph.D., Chemist Dietary E xposure Science Advisory Council Health Effects Division ( HED; 7509P ) and Richard L oranger, Ph. D., Branch Senior Scientist Risk Assessment Branch I I (RAB2) Health Effects Division ( HED; 7509P ) TO: Kathry

n V. Montague , PM
- 23 Herbicide Branch Registration Division ( RD; 7505P)Isoxaben Dietary Exposure Assessment DP Barcode: 3 75246

PC Code: 125851

Page 2 of 10 Executive Summary A chronic aggregate dietary risk assessment (food and drinking water) w as conducted using the Dietary Exposure Evaluation Model (DEEM
- FCI D, Version 2.03), which uses food consumption data from the U.S . Department of Agriculture ( USDA’s ) Continuing Survey s of Food I ntakes by In dividuals (CSFI I) from 1994
- 1996 and 1998. The analy s i s w as performed to support a Section 3 registration for use of isoxaben [ N
- [3
- (1
- ethyl
- 1
- methylpropy l)
- 5
- isoxazolyl]
- 2,6
- dim ethoxy

benzamide ] 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 analy sis was not performed. Chronic Dietary (Food and Drinking Water) Exposure Results and Characterization T he chronic analy sis is based on tolerance level residues and 100% crop treated a ssumption s . Default processing factors were used for grape juice ( 1.2x ), and grapes , raisin (4.3x )
. The HE D
recommended tolerance level for each raw agricultural commodity ( RAC ) w as entered as listed below: Grape
................................ ................................ ........... 0.01 ppm

Nut, tree, group 14
................................ ...................... 0.0 2 ppm Pistachio
................................ ................................ ...... 0.0 2 ppm The general U.S. population and all populatio n 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 In fants <1 y r , which utilizes 17 % of the cPAD. The general U.S. populat ion utilizes 5.1 % of the cPAD. Cancer Dietary (Food and Drinking Water) Exposure Results and Characterization Inaccordance with EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), the Cancer Assessment Review Commi ttee (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 analy sis 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 acuteIsoxaben Dietary Exposure Assessment DP Barcode: 3 75246

PC Code: 125851

Page 3 of 10 and chronic asse ssments, 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 equival ent 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 wh en 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). Th is is the first food use and first dietary risk assessment to be conducted for isoxaben. II. Residue Information Is oxaben is a ben zamide herbicide (Group 21) used for control of broadleaf weeds. I soxaben reportedly

acts via inhibition of cell wall sy nthesis. The herbicide is currently registered for non
food uses on turf, ornamentals, non
- bearing fruit and nut trees, and non
- bearin g viney ards. The petitioner has proposed a new Section 3 use on grape s , 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 Com mo dity Reco mme nded 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 stud ies 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 grape s showed residues <L OQ (0.01 ppm) in/on all samples of grapes, raisins, andIsoxaben Dietary Exposure Assessment DP Barcode: 3 75246

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 1.2 x Raisins 4. 3 x III. Drinking Water Data The drinking water residues used in the dietary risk assessment wer e provided by the Environmental Fate and Effects Division (EFED) in the following memorandum: “ Tier I Drinking Water Assessment for the I soxaben Proposed New Use on Bearing Nut Trees and Viney ards ” ( 341497 , C. Peck, 3 / 18 / 2010 ) and incorporated directly int o this dietary

assessment. Water residues were incorporated in the DEEM
- FCI D into the food categories “water, direct, all sources” and “water, indirect, all sources.” The estimated drinking water concentrations (EDWCs) are based on the maximum propose d 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 w hose toxicity is similar to that of isoxaben, a total toxic residue (TTR) app roach was used in the modeling. The Residue of Concern Knowledge
- based Subcommittee (ROCKS) recommended tha t the drinking water assessment for isoxaben include hy droxyisoxaben, dimethoxy benzamide, methoxy phenylpy rimidinol, and AEM hexenoy lisoxaben. 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 estima ted drinking water concentrations ( EDWC ) were calculated using a Tier I model for surface water ( FQPA I ndex Reservoir Screening Tool or FIRST) and a Tier I model for groundwater ( Screening Concentration in Ground Water or SCI
- GROW). The surface water valu es were higher than the groundwa ter 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 der ived from the isoxaben degradate study
. RAB2 has selected th e 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: 3 75246

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Page 5 of 10 Table 3. Tier I Estim ated Drinking Water Concentrations (EDWCs) resulting fromapplications of isoxaben on ornam entals and bearing nut trees. Drinking water source (m odel) Use (m odeled rate) C hronic ( μg/L ) Parent K d Data Surface water (FIRST) Ornamental 54.7 Groundw ater (SCIGROW) Orn amental 2.13 Surface water (FIRST) Bearing nut trees and vineyards 16.9 Groundw ater (SCIGROW) Bearing nut trees and vineyards 0.71 Degradate K d Data Surface water (FIRST) Ornamental 120 Groundw ater (SCIGROW) Ornamental 43.6 Surface water (FIRST) Bear ing nut trees and vineyards 37.0 Groundw ater (SCIGROW) Bearing nut trees and vineyards 14.5 Monitoring Data Is oxaben is not included as one of the analy tes monitored in U.S. surface and groundwater under the USGS’s National Water Quality Assessment (NA WQA) program ( http://water.usgs.gov/nawqa ). There were no detections in six surface water and sediment samples collected and analy zed for isoxaben by

California Department of Pesticide Regulation (CDPR) in 2006 in Stanislaus County
. IV. DEEM - FCID  Program and Consumption Information A n isoxaben chronic dietary exposure assessment w as conducted using the DEEM
- FCI D  , Version 2.03 , which incorporates consumption data from USDA’s CSFI I , 1994
- 1996 and 1998. The 199 4
- 96, 98 data are based on the reported consumption of more than 20,000 individuals over two non - consecutive survey day s. Foods “as consumed” (e.g., apple pie) are linked to EPA
defined food commodities (e.g. apples, peeled fruit
- cooked; fresh or N/S; b aked; 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 populatio n subgroups, but for acute exposure assessment are retained as individual consumption events. Based on analy sis of the 1994
- 96, 98 CSFI I consumption data, which took into account dietary patterns and survey

respondents, HED concluded that it is most appro priate to report risk for the following population subgroups: the general U.S. population, all infants (<1 y ear old), children 1
- 2, children 3
- 5, children 6
- 12, y outh 13
- 19, adults 20
- 49, females 13
- 49, and adults 50+ y ears old. For chronic dietary

exposu re 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
.Isoxaben Dietary Exposure Assessment DP Barcode: 3 75246

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. Inaccordance 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 R isk 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 N ot required. Appropriate endpoints for this risk assessment were not identified.

Chronic Dietary (All Populations) NOAEL=

5.0 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Chronic RfD =

0.05 mg/kg/day cPAD = 0.05 mg/kg/day Chronic oral toxicity/carcinogen icity 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 aden om as 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 lowe r 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 sensitiv ity 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: 3 75246

PC Code: 125851

Page 7 of 10 VI. Results/Discussion As stated above, for acute and chronic assessments, HED is c oncerned when dietary risk exceeds 100% of the PAD. The DEEM
- FCI D  analy s i s estimate s 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 y ear old), children 1
- 2, children 3
- 5, children 6
- 12, y outh 13
- 19, females 13
- 49, adults 20
- 49, and adults 50+ y ears. Results of Acute Dietary (Food and Drinking Water) Exposure Analy sis No appropriate endpoint attributable to a single dose was identified. A s no acute dietary endpoint was identified, an acute exposure analy sis was not performed
. Results of Chronic Dietary (Food and Drinking Water) Exposure Analy sis The summary

table below lists t he results of the chronic dietary exposure analy sis
. The chro nic 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 y r 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 Isoxaben 1

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 wa s 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 0.0035 39 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 0.0024 89 5.0 Females 13
- 49 years old 0.002356 4.7 1 The value for the highest exposed population in this chronic risk assessm ent is bolded.Isoxaben Dietary Exposure Assessment DP Barcode: 3 75246

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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 analy sis. I f it had been necessary to refine the analy sis, average field trial val ues could have been used in place of tolerance level residues. I n 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 o f concern for the general U.S. population and all population subgroups, including those comprised of infants and children. Inaddition, cancer risk from dietary exposure to isoxaben is not of concern to HED (the cRfD is protective of cancer effects). Bas ed 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. I X. List of Attachments Attachment 1: Residue Input File for Chronic Analy s i s Attachme nt 2: Results of Chronic Dietary Exposure Analy sisIsoxaben Dietary Exposure Assessment DP Barcode: 3 75246

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(A cute): 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 0.1 20000 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 1.0 00 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 1.000Isoxaben Dietary Exposure Assessment DP Barcode: 3 75246

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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 us ed. 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 popul ation subgroup

------------------------------------------------------------------------------- Total Exposure

----------------------------------- Popula tion 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 0.00227 0 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%