Isoxaben D376428

Page 1 of 90

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

Office of Chemical 

Safety and Pollution 

Prevention

Date: July 28, 2010

MEMORANDUM

SUBJECT: Isoxaben. Human Health Risk Assessment for the First Food Uses of the Herbicide 

on Grapes, Tree Nuts and Pistachios.

PC Code: 125851 DP Barcode: D376428

Decision No.: 379577 File Symbol: 62719-LIN, 62719-ARE

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

Risk Assessment Type: Single Chemical 

Aggregate

Case No.: NA

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

MRID No.: NA 40 CFR: 180.xxx (first food use)

FROM: Dennis McNeilly, Chemist/Risk Assessor

Elizabeth Holman, Chemist

William T. Drew, Chemist

Linnea Hansen, Ph.D., Toxicologist

Suku Oonnithan, Biologist

Risk Assessment Branch II (RAB2)

 Health Effects Division (HED) (7509P)

THROUGH: Christina Swartz, Chief

Risk Assessment Branch II (RAB2)

 Health Effects Division (HED) (7509P)

and

Michael S. Metzger, Designated Reviewer

P.V. Shah, Ph.D., Designated Reviewer

Risk Assessment Review Committee

Health Effects Division (7509P)

TO: Kathryn V. Montague, PM-23

 Herbicide Branch

 Registration Division (7505P)
Isoxaben D376428

Page 2 of 90

Table of Contents

1.0 Executive Summary.......................................................................................................... 4

2.0 Ingredient Profile.............................................................................................................. 7

2.1 Summary of Proposed Uses.................................................................................... 7

2.2 Structure and Nomenclature ................................................................................... 9

2.3 Physical and Chemical Properties........................................................................... 9

3.0 Hazard Characterization/Assessment........................................................................... 10

3.1 Hazard and Dose-Response Characterization....................................................... 10

3.1.1 Database Summary ................................................................................... 10

3.1.1.1 Studies available and considered (animal, human, general 

literature)................................................................................................... 10

3.1.1.2 Mode of action, metabolism, toxicokinetic data........................ 10

3.1.1.3 Sufficiency of studies/data......................................................... 10

3.1.2 Toxicological Effects................................................................................ 11

3.1.3 Dose-response ........................................................................................... 12

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)................................. 12

3.3 FQPA Considerations ........................................................................................... 13

3.3.1 Adequacy of the Toxicity Database.......................................................... 13

3.3.2 Evidence of Neurotoxicity ........................................................................ 13

3.3.3 Developmental Toxicity Studies............................................................... 13

3.3.4 Reproductive Toxicity Study .................................................................... 14

3.3.5 Additional Information from Literature Sources...................................... 15

3.3.6 Pre-and/or Postnatal Toxicity ................................................................... 15

3.3.6.1 Determination of Susceptibility................................................. 15

3.3.6.2 Degree of Concern Analysis and Residual Uncertainties for Preand/or Postnatal Susceptibility.................................................................. 16

3.3.7 Recommendation for a Developmental Neurotoxicity Study................... 16

3.4 Safety Factor for Infants and Children.................................................................. 16

3.5 Hazard Identification and Toxicity Endpoint Selection........................................ 17

3.5.1 Acute Reference Dose (aRfD) .................................................................. 17

3.5.2 Chronic Reference Dose (cRfD)............................................................... 17

3.5.3 Incidental Oral Exposure, Short-Term (1 to 30 days)............................... 17

3.5.4 Incidental Oral Exposure, Intermediate-Term (1 to 6 months)................. 17

3.5.5 Dermal Absorption.................................................................................... 18

3.5.6 Residential/Occupational Dermal Exposure, Short-Term (1 to 30 days) . 19

3.5.7 Residential/Occupational Dermal Exposure, Long-Term (>30 days) ...... 19

3.5.8 Residential/Occupational Inhalation Exposure, Short-Term.................... 19

3.5.9 Residential and Occupational Inhalation Exposure (Intermediate-Term) 19

3.5.10 Residential and Occupational Inhalation Exposure (Long-Term).......... 20

3.5.11 Level of Concern for Margin of Exposure.............................................. 20

3.5.12 Recommendation for Aggregate Exposure Risk Assessments............... 20

3.5.13 Classification of Carcinogenic Potential................................................. 21

3.5.14 Summary of Toxicological Doses and Endpoints for Use in Human Risk 

Assessments.......................................................................................................... 22

3.6 Endocrine disruption............................................................................................. 25

4.0 Public Health and Pesticide Epidemiology Data and Incident Reports .................... 25

5.0 Dietary Exposure/Risk Characterization ..................................................................... 25
Isoxaben D376428

Page 3 of 90

5.1 Pesticide Metabolism and Environmental Degradation........................................ 26

5.1.1 Metabolism in Primary Crops................................................................... 26

5.1.2 Metabolism in Rotational Crops............................................................... 27

5.1.3 Metabolism in Livestock........................................................................... 27

5.1.4 Analytical Methodology ........................................................................... 28

5.1.5 Environmental Degradation...................................................................... 29

5.1.6 Comparative Metabolic Profile................................................................. 30

5.1.7 Toxicity Profile of Major Metabolites and Degradates ............................ 30

5.1.8 Pesticide Metabolites and Degradates of Concern.................................... 31

5.1.9 Drinking Water Residue Profile................................................................ 31

5.1.10 Food Residue Profile............................................................................... 33

5.1.11 International Residue Limits................................................................... 34

5.2 Dietary Exposure and Risk ................................................................................... 34

5.2.1 Acute Dietary Exposure/Risk ................................................................... 34

5.2.2 Chronic Dietary Exposure/Risk ................................................................ 35

5.2.3 Cancer Dietary Risk.................................................................................. 35

5.3 Anticipated Residue and Percent Crop Treated (%CT) Information.......................... 36

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................ 36

6.1 Residential Postapplication Exposure................................................................... 38

6.2 Other (Spray Drift, etc.)........................................................................................ 40

7.0 Aggregate Risk Assessments and Risk Characterization............................................ 41

7.1 Acute Aggregate Risk........................................................................................... 41

7.2 Short- and Intermediate-Term Aggregate Risk..................................................... 41

7.3 Chronic Aggregate Risk........................................................................................ 42

7.4 Aggregate Cancer Risk ......................................................................................... 42

8.0 Cumulative Risk Characterization/Assessment........................................................... 43

9.0 Occupational Exposure/Risk Pathway.......................................................................... 43

9.1 Short- and Intermediate-Term Handler Risk ........................................................ 43

9.2 Short- and Intermediate-Term Postapplication Risk............................................. 45

10.0 Data Needs, Label Recommendations & Environmental Justice............................... 45

10.1 Toxicology ............................................................................................................ 45

10.2 Residue Chemistry................................................................................................ 46

10.3 Occupational and Residential Exposure ............................................................... 46

10.4 Label Recommendations....................................................................................... 46

10.5 Environmental Justice........................................................................................... 47

References:................................................................................................................................... 47

Appendix A: Toxicology Assessment ........................................................................... 49

A.1 Toxicology Data Requirements ................................................................................ 49

A.2 Acute Toxicity Profile for Isoxaben.......................................................................... 50

A.3 Executive Summaries................................................................................................ 55

A.4 Rationale for Toxicology Data Requirements .......................................................... 71

Appendix B: Metabolism Assessment.......................................................................... 74

B.1 Metabolism Guidance and Considerations ........................................................... 74

B.2 Tabular Summary of Metabolites and Degradates................................................ 76

Appendix C: Tolerance Reassessment Summary and Table..................................... 90

Appendix D: Review of Human research .................................................................... 90
Isoxaben D376428

Page 4 of 90

1.0 Executive Summary

Dow AgroSciences has submitted a petition, 7F7222, proposing the establishment of tolerances 

for residues of the herbicide isoxaben [N-[3-(1-ethyl-1-methylpropyl)-5-isoxazolyl]-2,6-

dimethoxybenzamide] in/on the following raw agricultural commodities:

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

Grape, juice .................................................................0.01 ppm

Grape, raisin................................................................0.01 ppm

Nut, tree, group ...........................................................0.03 ppm

Pistachio......................................................................0.03 ppm

Almond, hulls..............................................................0.35 ppm

The petitioner has also requested a waiver from the requirement for a tolerance for isoxaben in or 

on cattle meat byproducts, meat, and milk.

In conjunction with this petition, Dow AgroSciences has submitted a request to register an enduse product, FN-3133 Specialty Herbicide, a 75% dry flowable (DF) formulation of isoxaben. 

The product is proposed for use on grapes and tree nuts with multiple soil applications ranging 

from 0.5 - 1.0 lb. ai/A/application, and a maximum of 1.0 lb. ai/A per crop year (harvest to 

harvest). No minimum retreatment interval (RTIs) is specified on the label. Preharvest intervals 

(PHIs) of 60 days for tree nuts and 165 days for grapes have been proposed. Isoxaben is already 

registered for non-food uses on turf, ornamentals, non-bearing fruit and nut trees, and nonbearing vineyards.

A human health risk assessment scoping document was completed for isoxaben in conjunction 

with Registration Review in August 2007 (D341567). An addendum to the scoping document 

was completed in June, 2008 (D341543) to incorporate new toxicology data requirements under 

current 40 CFR Part 158 guidelines.

For the purposes of this petition only, the nature of the residue in grapes and tree nuts (early 

season use only) is adequately understood based on grape and barley metabolism studies. This 

use is considered to fall under 40 CFR 180.6 (a)(3), i.e., no expectation of finite residue in meat, 

milk, poultry and eggs; tolerances are therefore not required. 

Isoxaben has low acute toxicity via all routes. No toxicity was observed in subchronic oral or 

dermal studies. The liver and kidney were target organs in chronic studies. Significant liver 

toxicity was seen in mice but was limited to adaptive (non-adverse) changes in rats and dogs. 

Nephropathy was observed in the rat. Body weight and/or body weight gain were reduced in all 

species. Rat acute and subchronic neurotoxicity studies and an immunotoxicity study have not 

been submitted and are required; however, there was no evidence for these effects in the 

available data. The cancer classification is “Suggestive Evidence of Carcinogenic Potential,” 

based on an increased incidence of benign liver tumors in mice at the highest dose. Concern for 

genotoxicity is low based on generally negative studies. Cancer risk was not quantified because 

the RfD is considered protective.
Isoxaben D376428

Page 5 of 90

No developmental toxicity was observed in the rat or rabbit. In the rat reproductive toxicity

study, decreased corpora lutea and offspring toxicity (decreased body weight and survival) 

occurred in the presence of maternal effects. Malformations (microphthalmia, coloboma) and 

hydroureter were observed in later offspring generations. Although offspring lineage suggested 

a genetic predisposition for these effects, a relationship to treatment could not be conclusively 

ruled out and the malformations were considered a possible treatment-related effect. However, 

they are not considered single-dose effects since they were only increased in F2 offspring.

The FQPA safety factor was reduced to 1X. The degree of concern for neurotoxicity and 

immunotoxicity data gaps is low due to lack of evidence for these effects in the available studies. 

Concern for increased qualitative susceptibility in the rat reproductive study is low, since a clear 

offspring NOAEL was identified; malformations were seen only at the limit dose and did not 

occur in developmental studies, and the exposure assessment does not underestimate exposure. 

The proposed use on grapes and tree nuts is supported by adequate field trial data, storage 

stability and processing studies. Detectable residues in grapes and tree nuts are not expected as a 

result of the proposed uses, except for almond hulls, a livestock feed item.

No acute dietary endpoint was identified; therefore, no acute dietary risk assessment was 

conducted. HED performed a chronic dietary assessment using HED recommended tolerance 

level residues in grapes and tree nuts, and assumed 100% crop treated. The dietary exposure 

estimates are based on highly conservative, health-protective assumptions regarding residue 

levels in food and water. For the general U.S. population and all population subgroups, the 

chronic dietary exposure estimates are below HED’s level of concern (LOC), 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.

The proposed use of isoxaben in orchards of tree nuts and grapes is expected to result in shortand intermediate-term occupational exposures to mixers, loaders, and applicators. The registrant 

did not submit a chemical-specific exposure study for assessing occupational exposures. Instead, 

surrogate unit exposures from the Pesticide Handlers Exposure Database (PHED) were used. 

Short- and intermediate-term dermal risks were not calculated due to the absence of respective 

endpoints. Short- and intermediate-term inhalation margins of exposure (MOEs) are not of 

concern (MOEs ≥2,700).

Only one application of isoxaben is allowed per season at the maximum rate per application 

(two at lower rates) on tree nuts and grapes. Risks to workers are not of concern because of the 

soil-directed application method proposed for applying isoxaben formulations, thereby 

minimizing inhalation exposure, and due to the lack of a dermal endpoint. The labels also 

recommend incorporation of the spray by rainfall or irrigation for maximum efficacy as a 

preemergence herbicide, thereby further minimizing postapplication exposures.

With respect to existing residential uses, risks to homeowners who apply isoxaben are not of 

concern. Postapplication risk to adults are also not of concern. HED assumed that incidental 

ingestion of soil represents the worst case for oral postapplication exposure to young children, 

since no other oral scenarios would be expected to have an equivalent duration of exposure to 
Isoxaben D376428

Page 6 of 90

residues, or residues as high as those possible in soil. The MOE associated with soil ingestion is 

1300000 with an LOC of 100, and therefore is not of concern. This scenario is expected to be 

protective of all other oral postapplication risks for children in residential settings. 

Postapplication inhalation exposures are expected to be negligible based on the low volatility of 

isoxaben and label instructions to incorporate after application. Dermal exposures are not of 

concern due to the absences of toxicity by this route. 

For the U.S. population and all population subgroups, short- and intermediate-term aggregate 

risk estimates do not exceed HED’s level of concern for any of the residential exposure 

scenarios. The short-term aggregate MOEs range from 62,000 to 66,000, for the U.S. population 

and females 13-49, respectively. The intermediate-term aggregate risk MOE estimate is 51,000

for children 1-2 years old. The chronic aggregate assessment is equivalent to the chronic dietary

(food + water) risk assessment, which indicates chronic dietary/aggregate risks are below HED’s 

LOC as described above.

For the purposes of this tolerance action, HED has not assumed that isoxaben has a common 

mechanism of toxicity with other substances.

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations,”

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.

CONCLUSIONS & RECOMMENDATIONS

There are no data deficiencies that would preclude establishing tolerances for isoxaben as shown 

below in Table 1. HED recommends the registration be made conditional, pending receipt of the 

required acute and subchronic neurotoxicity studies in the rat, 90-day inhalation toxicity in the 

rat and an immunotoxicity study, as required in the registration review scoping document 

addendum for isoxaben. In response to the scoping document, the Registrant has requested a 

waiver for the inhalation study, which is currently under review.

Additional residue chemistry data requirements and label recommendations are described in 

detail in Section 10 of the document. Additional tolerance recommendations are described 

below:

1) HED recommends the isoxaben tolerance expression be established as follows: “Tolerances 

are established for residues of the herbicide isoxaben, including its metabolites and degradates, 

in or on the commodities in the table below. Compliance with the tolerance levels is to be 

determined by measuring only isoxaben (N-[3-(1-ethyl-1-methylpropyl)-5-isoxazolyl]-2,6-

dimethoxybenzamide) in or on the commodity.”

2) The tolerance for grape should be set at the LOQ, 0.01 ppm. The maximum residues 

observed in almond and pecan were 0.015 ppm; therefore, the proposed tolerance of 0.03 ppm 

for the tree nut group is too high. A tolerance of 0.02 ppm would be appropriate for the tree nut 

crop group.
Isoxaben D376428

Page 7 of 90

3) HED has determined that pistachio should be added to the tree nut crop group; almond and 

pecan would remain the representative commodities for this group. Until the crop is officially

added to the crop group listings in 40 CFR, residue data for almond and pecan may be used to 

establish a tolerance for pistachio, which is to be set at the same level as the tree nut tolerance. 

Therefore, the proposed tolerance of 0.03 ppm for pistachio is too high; a tolerance of 0.02 ppm 

would be appropriate. 

4) The available data indicate that a 0.40 ppm tolerance for almond hulls is appropriate.

5) The available processing data indicate that residues of isoxaben do not concentrate in grape 

juice or raisins. Therefore, separate tolerances are not needed for grape processed commodities. 

The proposed tolerances should be removed from Section F. 

6) HED concludes that residues in milk, eggs and ruminant and poultry meat, fat, and meat 

byproducts remain a 40 CFR §180.6[a][3] situation (there is no expectation of finite residues in 

these commodities). Therefore, no tolerances are needed for livestock commodities.

Table 1. Tolerance Summary for Isoxaben. 

Commodity Proposed Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Grape 0.01 0.01

Grape, juice 0.01 Remove A separate tolerance for grape juice 

is not needed.

Grape, raisin 0.01 Remove A separate tolerance for raisin is not 

needed.

Nut, tree, Group 14 0.03 0.02 Nut, tree, Group 14

Pistachio 0.03 0.02

Almond, hulls 0.35 0.40

2.0 Ingredient Profile

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

acts via inhibition of cell wall synthesis. The herbicide is currently registered for non-food uses 

on turf, ornamentals, non-bearing fruit and nut trees, and non-bearing vineyards. The chemical 

structure and nomenclature of isoxaben are presented in Table 2.2, and the physicochemical 

properties of the technical grade of isoxaben are presented in Table 2.3.

2.1 Summary of Proposed Uses

Dow AgroSciences has submitted a request to register an end-use product, FN-3133 Specialty

Herbicide, with EPA File Symbol No. 62719-LIN. The product is proposed for use on grapes 

and tree nuts (including pistachio) with up to two soil applications at application rates ranging 

from 0.5–1.0 lb. ai/acre. The proposed label limits the seasonal application rate to no more than 

1.0 lb ai/acre per crop year (i.e., harvest to harvest). No minimum retreatment interval (RTI) was 

specified on the proposed label. The proposed pre-harvest intervals (PHIs) are 60 days for tree 
Isoxaben D376428

Page 8 of 90

nuts, and 165 days for grapes. The product is also being proposed for use on nonbearing fruit 

and nut trees and nonbearing vineyards. HED also evaluated the proposed product AmoreTM DF, 

which contains 75% isoxaben and 3.12% penoxsulam. This product is also proposed for use on 

non-bearing tree nuts and non-bearing vineyards. A summary of the proposed use pattern is 

presented in Table 2.1.

Table 2.1 Summary of Directions for Use of Isoxaben.

Applic. Timing, 

Type, and Equip.

Formulation

[EPA File 

Symbol No.]

Applic. 

Rate 

(lb ai/A)

Max. No. 

Applic. 

per Season

Max. 

Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations

Grape (American, European, Muscadine)

Soil application,

equipment type 

not specified

75% DF

[62719-LIN] 0.50-1.0 2

1.0 per crop 

season 

(harvest to 

harvest)

165

The label states: Not to be 

used in NY. Application is 

to be made prior to 

germination of target weeds 

or immediately after 

cultivation. Application is 

to be made in a minimum of 

10 gal/A.

Almond; Beech Nut; Brazil Nut; Butternut; Cashew; Chestnut; Chinquapin; Filbert (Hazelnut); Hickory Nut; 

Macadamia Nut (Bush Nut); Pecan; Pistachio; and Walnut (Black, English/Persian)

Soil application,

equipment type 

not specified

75% DF

[62719-LIN] 0.50-1.0 NS

1.0 per crop 

season 

(harvest to 

harvest)

60

The label states: Not to be 

used in NY. Application is 

to be made prior to 

germination of target weeds 

or immediately after 

cultivation. Application is 

to be made in a minimum of 

10 gal/A.

Non-bearing tree nuts and nonbearing grape vines

Soil application,

equipment type 

not specified

75%DF 

[62719-ARE, 

62719-LIN]

Single 

appl. rate 

= 1.0-1.33 

lbs 

product/A 

Max. 

single 

appl. rate 

=1.0 lb 

ai/A)

1 1.0 lb ai/A NA

The label states: Not to be 

used in NY. Application is 

to be made prior to 

germination of target weeds 

or immediately after 

cultivation. Application is 

to be made in a minimum of 

10 gal/A. Note: with 3.12% 

Penoxsulam.

The product is not to be applied through any type of irrigation system or to crops grown in 

containers. The draft label of FN-3133 Specialty Herbicide has CAUTION as Signal Word and 

the following PPE: Applicators and other handlers must wear a long sleeved shirt and long pants, 

chemical resistant gloves made of any waterproof material and shoes plus socks. In addition, the 

label has a 12 hour restricted entry interval (REI) per the worker protection standards (WPS).

Conclusions. The proposed use directions are adequate to allow evaluation of the crop field trial 

data submitted with this petition. The proposed use directions represent maximum seasonal rates 
Isoxaben D376428

Page 9 of 90

at 1x those used in the crop field trials. The available crop field trial data support a maximum 

seasonal rate of 1 lb ai/A. The label should specify that non-bearing means trees or vines where 

nuts and/or fruit are not harvested for food within one year of treatment.

2.2 Structure and Nomenclature

Table 2.2. Isoxaben Nomenclature.

Compound

OCH3

N

H

O

O

N

CH3

CH3

CH3

OCH3

Common name Isoxaben

Company experimental name EL-107

IUPAC name N-[3-(1-ethyl-1-methylpropyl)isoxazol-5-yl]-2,6-dimethoxybenzamide

CAS name N-[3-(1-ethyl-1-methylpropyl)-5-isoxazolyl]-2,6-dimethoxybenzamide

CAS registry number 82558-50-7

End-use products (EPs) FN-3133 Specialty Herbicide (75% DF formulation; EPA File Symbol, 62719-

LIN), Gallery 75 Dry Flowable (75% DF, EPA Registration Number, 62719-145)

Amore DF (75% DF formulation; EPA File Symbol, 62719-ARE), which also 

contains 3.12% penoxsulam

2.3 Physical and Chemical Properties

Table 2. 3. Physicochemical Properties of Isoxaben.

Parameter Value Reference

Melting range 173-176.5oC MRID 47140001

Density (relative) 0.580 g/ml at 22oC MRID 47140001

Water solubility 1.42 mg/L at 20oC MRID 47140001

Solvent solubility, at 20oC Acetone 270 g/L

Methanol 98 g/L

1-Octanol 29 g/L

Ethyl acetate 88 g/L

1,2-Dichloroethane 51 g /L

Xylene 4.0 g/L

Hexane 0.028 g/L

MRID 47140001

Vapor pressure 1.3 x 10-8Pa at 25oC Email from

DowAgrosciences (5/19/10) 

revising vapor pressure

Dissociation constant, pKa 9.78 ± 0.06 at 20oC EFSA1(May 2006 Draft 

Report)
Isoxaben D376428

Page 10 of 90

Table 2. 3. Physicochemical Properties of Isoxaben.

Parameter Value Reference

Octanol/water partition coefficient, 

Log(KOW)

3.83 at 20oC MRID 47140001

UV/visible absorption spectrum max1 = 202 nm / 26000 mol-1

cm-1

max2 = 252 nm / 16500 mol-1cm-1

max3 = 275 nm / 20800 mol-1cm-1

EFSA1(May 2006 Draft 

Report)

1- European Food Safety Authority (EFSA)

3.0 Hazard Characterization/Assessment

This hazard characterization updates the previous assessment for isoxaben, prepared in 

December, 1987 for the New Chemical Registration Standard. However, a human health risk 

assessment scoping document was completed for isoxaben in conjunction with Registration 

Review in August 2007 (D341567). An addendum to the scoping document was completed in 

June, 2008 (D341543) to incorporate new toxicology data requirements under 40 CFR Part 158.

3.1 Hazard and Dose-Response Characterization

3.1.1 Database Summary

3.1.1.1 Studies available and considered (animal, human, general literature)

Studies considered for this assessment included acute lethality (oral, dermal and inhalation 

routes); primary eye and dermal irritation, dermal sensitization, subchronic oral toxicity (rat, 

mouse and dog), rabbit 21-day dermal toxicity, dog chronic toxicity, rat chronic toxicity and 

combined chronic toxicity/carcinogenicity, mouse carcinogenicity, developmental toxicity (rat 

and rabbit), rat multigenerational reproductive toxicity, genotoxicity, rat metabolism and a 

dermal absorption study in the monkey (see Appendix A).

3.1.1.2 Mode of action, metabolism, toxicokinetic data

Isoxaben is a pre-emergent benzamide herbicide that is used for control of broadleaf weeds. In 

plants, it inhibits growth via inhibition of cellulose biosynthesis in dicots, but does not affect 

germination. Its mode of action for mammalian toxicity has not been characterized. 

In metabolism studies conducted in the rat, oral absorption of isoxaben is limited. The majority

of the administered radioactivity was excreted as unmetabolized parent compound. 

3.1.1.3 Sufficiency of studies/data

The available toxicity data are considered adequate for conducting this risk assessment for the 

proposed first food use of isoxaben. However, in accordance with the recently revised 40 CFR 

Part 158, an immunotoxicity study and rat acute and subchronic neurotoxicity studies are 

required. A 90-day inhalation toxicity study in the rat is also required to support registration of 

isoxaben, based on the potential for inhalation exposure and potential portal of entry effects. The 
Isoxaben D376428

Page 11 of 90

required studies were requested during the registration review scoping process (D341543). 

Rationales for data requirements are provided in Appendix A.4. In the absence of inhalation 

data, an inhalation point of departure was selected for this assessment using route-to-route 

extrapolation of oral data, i.e., assuming toxicity via the inhalation route is similar to the oral 

route. In response to the scoping document, the Registrant has submitted a waiver request for the 

inhalation study, which is under review.

3.1.2 Toxicological Effects

The primary target organs identified for isoxaben are the liver and kidney. Although liver effects 

were observed in all species tested (rat, dog, mouse), adverse changes were only observed in the 

mouse following chronic oral exposure. These effects included histopathology and increased 

blood alkaline phosphatase and alanine aminotransferase activities at high doses. In the dog and 

rat, liver effects were considered adaptive and consisted of enlargement, hepatocellular 

hypertrophy and induction of hepatic microsomal enzymes. Increased incidence and severity of 

nephropathy was observed in the rat following chronic (two-year) exposure. No adverse renal 

effects were reported in the dog or mouse. There was no indication of neurotoxicity or 

immunotoxicity in the available studies, which generally tested up to or above the limit dose. 

No maternal or developmental effects were seen in the rabbit or rat developmental studies. In 

the rat reproductive toxicity study, two matings (a and b generations) per F0 and F1 parental

generations were conducted, plus two additional matings (F2c and F3a) to examine 

developmental effects on gestation day 20. Effects included a decrease in corpora lutea, 

resulting in a decrease in the mean number of implantations and mean live fetuses per litter. 

Nursing pups showed decreased body weight gain at the highest dose tested. An increase in the 

incidence of several malformations (exencephaly, microphthalmia/coloboma and hydroureter) 

was seen in the F2b, F2c and F3a mating generations at the limit dose of 1000 mg/kg/day (HDT), 

but not in the F1a, F1b or F2a offspring. The relationship of these findings to treatment is 

unclear because an examination of the genealogy of these offspring suggests a possible heritable 

component. A large percentage of the affected litters were the result of either cousin matings or 

had in common F0 progenitors derived from several F0 litters from the supplier. However, 

because the relationship to treatment could not be ruled out, the malformations were considered a 

possible treatment-related effect.

No effects of treatment were reported in a 21-day repeated application dermal toxicity study in 

the rabbit. This is consistent with relatively low dermal absorption (≤11% of administered dose) 

observed in a dermal penetration study in the monkey and the low oral toxicity observed in 

subchronic oral studies in the rat, mouse and dog. 

Isoxaben is classified as having “suggestive evidence of carcinogenicity to humans.” An 

increased incidence of benign liver tumors was observed in male and female mice at the high 

dose only. Isoxaben was negative in most genotoxicity studies: weak positive increases in bone 

marrow micronucleus formation were seen in two out of three studies but may have been due to 

low concurrent control values. 

Isoxaben is of low acute toxicity when administered orally (Toxicity Category IV), dermally 

(Category III), or via inhalation (Category III). It is not a dermal sensitizer or irritant (Category
Isoxaben D376428

Page 12 of 90

IV) and causes only minor transient irritation to the eye (Category III).

3.1.3 Dose-response

An acute reference dose (aRfD) was not selected for any population, including females ages 13-

49 because there were no toxic effects resulting from a single dose. Although malformations 

were observed in the rat reproductive study, they were not considered single-dose effects because 

no malformations were observed in the F1 of F2a offspring, or in developmental studies in rat 

and rabbit. The offspring effects were, however, the basis for short- and intermediate-term 

inhalation exposure assessment. 

There were no effects seen in the developmental toxicity studies or from subchronic oral 

exposure. Therefore, for short-term residential incidental oral exposure to young children, an 

appropriate endpoint was not identified. For occupational and residential short- and 

intermediate-term dermal exposure, an appropriate endpoint was not identified, due to a lack of 

dermal toxicity. 

Although toxicity was not observed in subchronic oral studies, body weight decreases in females 

were observed following exposures of several months in both the rat reproductive study and at 

six months in the rat one year dietary study. Offspring effects were also observed in the 

reproductive study. Therefore, these two studies were selected as co-critical for assessment of 

intermediate-term residential and occupational risk, including incidental oral exposure to young 

children and intermediate-term inhalation exposure. In the reproductive study, decreased body 

weight gain in F1 females at Day 70 was seen at 1000 mg/kg/day, but not at 200 mg/kg/day. 

This effect level was supported by decreased body weight gain in females at around six months 

at 625 mg/kg/day in the rat one year dietary study (NOAEL = 62.5 mg/kg/day). This endpoint 

provided a protective exposure level for developmental toxicity based on the offspring NOAEL 

of 200 mg/kg/day, which was based on decreased offspring weights, gestation survival and live 

litter size at 1000 mg/kg/day. This approach is considered to be conservative, given the lack of 

other effects and absence of findings in oral studies up to 90 days.

Toxicity was observed at lower dose levels with long-term oral administration. For chronic 

dietary exposure, the chronic reference dose RfD was based on a NOAEL of 5.0 mg/kg/day in 

male rats from the two-year chronic toxicity/carcinogenicity feeding study. This provided the 

lowest NOAEL and the most sensitive point of departure (POD) available for long-term dietary

exposure. Males were affected with progressive glomerulonephrosis, which showed increased

incidence and severity with increasing dose. Female rats showed this effect, along with 

decreased body weight and weight gain, but only at the highest dose tested (647 mg/kg/day). In 

mice, liver effects (including hepatocellular tumors) were observed but only at the highest dose 

tested, which exceeded the limit dose. However, only adaptive liver changes were observed in 

the dog following one year oral administration.

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)

Oral absorption of isoxaben was incomplete, particularly at higher doses, where it appeared to 

achieve saturation based on increased percent dose excreted in feces and decreased urinary and 

biliary excretion observed at increasing dose levels. The primary route of excretion was fecal 
Isoxaben D376428

Page 13 of 90

(up to about 90% of administered radioactivity). Urinary excretion accounted for 2-13% of the 

administered radioactivity and decreased with increasing dose. Biliary excretion was observed 

in both sexes, at the lower dose of 10 mg/kg representing about 23% and 39% of the dose in 

males and females, respectively but decreasing to 17% and 15% at the higher dose of 250 mg/kg, 

consistent with rate-limiting absorption. The majority of radioactivity was excreted by 24 hr 

postdosing, with some additional excretion seen between 24-72 hr. The total radioactivity 

excreted tended to be slightly lower in males (71 to 95%) than females (88 to 106%). Exhalation 

of radiolabeled carbon dioxide was limited to <3% of the administered radioactivity. Repeated 

dosing did not significantly affect the excretion pattern of isoxaben and by 7 days, the amount of 

radioactivity left in the carcass was 0.4% or less of the administered dose with negligible 

radioactivity remaining in tissues. In tissue distribution studies, most of the radioactivity

remained in the intestinal tract, but the radioactivity that was absorbed was widely distributed, 

with the majority of the examined tissues showing tissue:plasma ratios greater than one at 4 hrs. 

Except for the GI tract, tissue levels were greatest in the liver, pituitary, thyroid, kidney, adrenals

and prostate. At 24 hrs postdosing, tissue:plasma ratios generally decreased, but radioactivity

remained in most tissues; radioactivity was not assessed at later times. The majority of 

radioactivity excreted in the feces was unmetabolized isoxaben (up to 90% of fecal 

radioactivity); other fecal metabolites were not characterized. In the urine, 15 to 20 metabolites 

were observed. The major routes of metabolism were oxidation of position 2 of the alkyl side 

chain yielding either an alcohol or a ketone, hydroxylation of the aromatic ring adjacent to one of 

the methoxy groups or O-demethylation of the methoxy groups. Overall metabolite profiles 

were similar for males and females, with minor quantitative differences observed.

3.3 FQPA Considerations

3.3.1 Adequacy of the Toxicity Database

The database is considered adequate for the purpose of assessment of susceptibility of infants 

and children to the effects of isoxaben. Acceptable developmental toxicity studies in two species 

(rat, rabbit) and a multigeneration reproductive toxicity study (rat) are available. There is no 

evidence of neurotoxicity or immunotoxicity. Therefore, although neurotoxicity and 

immunotoxicity studies have not been submitted, these studies are not considered likely to 

identify more sensitive endpoints (and lower points of departure) than those already selected for 

isoxaben, and an additional safety factor to account for data gaps is not required. For inhalation 

exposure, oral endpoints were selected and 100% inhalation absorption assumed. 

3.3.2 Evidence of Neurotoxicity

Isoxaben did not show evidence of neurotoxicity in the available studies. Rat acute and 

subchronic neurotoxicity studies have not been submitted and are required.

3.3.3 Developmental Toxicity Studies

Acceptable developmental toxicity studies in the rat and rabbit are available (see Appendix A.3 

for executive summaries). Both studies tested at 0, 100, 320 and 1000 mg/kg/day. No 

developmental or maternal toxicity was observed in either species at doses up to the limit dose of 

1000 mg/kg/day.
Isoxaben D376428

Page 14 of 90

3.3.4 Reproductive Toxicity Study

An acceptable multigeneration reproductive toxicity study in the rat is available (see Appendix 

A.3 for the executive summary) in which Wistar rats were dosed at 0, 40, 200 or 1000 mg/kg/day

in the diet. Maternal toxicity was observed at 200 mg/kg/day as mildly decreased body weight 

gain in F2 females during the growth phase and decreased body weight in F2b females during 

gestation. At 1000 mg/kg/day, F1 and F2 females showed pronounced weight decrements during 

growth phases, gestation and postpartum. Pup/fetal effects were observed at 1000 mg/kg/day in 

F2b, F2c and F3 offspring, especially F2b pups, and included decreased pup weight during 

lactation. An increase in the incidence of microphthalmia, coloboma and/or exencephaly and 

hydroureter, was also reported. In the F2b litters there was a decrease in live pups/litter and 

gestation survival which was associated with decreased corpora lutea. In additional litters used 

for prenatal assessments of the malformations (F2c and F3a litters), decreases in corpora lutea, 

implantations and live fetuses were seen. 

There were no malformations observed in either developmental study at doses up to the limit 

dose of 1000 mg/kg/day. The malformations in the reproductive toxicity study were therefore 

examined more closely. In the reproductive toxicity study, a dose-response was not observed: 

no increases were seen at 40 or 200 mg/kg/day. No increases were observed in the first three 

matings (F1a, F1b, F2a): the F2b litters were the first to show the increase. The subsequent 

additional F2c and F3a matings also showed increases, but the incidence did not increase relative 

to the F2b generation. Based on an assessment of the pup lineage and several interrelationships 

among affected offspring, there appeared to be a heritable component to these malformations. 

The study report provided genealogy charts showing the F0 lineage of the litters affected with 

the malformations and noting offspring that were descendents of cousin matings. Details of 

these lineages may be found in the Appendix to the supplemental DER for this study (TXR# 

0051626). The genealogy evaluation shows a high percentage of the litters affected with 

malformations were descended from a relatively small number of F0 litters. An examination of 

offspring lineage shows several interrelationships, including the following:

(1) Of the 17 affected high dose litters/38 offspring, 8 litters/17 offspring (F1, F2 and 

F3 offspring generations) were derived from a single F0 mating pair. Cousin 

matings involving this pair produced 5 of the affected high dose litters;

(2) The same F0 mating pair noted in (1) were among the progenitors of 3 of the 4 

affected high dose litters in the F3a generation, and of abnormal litters in four F2 

matings. Another F0 female was also associated with a severely affected F2c 

litter and 3 of the 4 affected F3a litters (total of 11 affected offspring); 

(3) Two high dose F0 siblings from F0 litter 9 were progenitors of four affected litters 

(F2b, F2c, F3a), including those described in (4);

(4) Two high dose F1 siblings produced two of the most severely affected F2b litters, 

with 4/4 and 7/10 abnormal progeny, respectively, most with both exencephaly 

and microphthalmia. 

(5) Sibling relationships were observed for some F0 animals that produced affected 

litters but were in different dose groups. For example, littermates from F0 litter 5 

produced affected litters in the control group, the 40 mg/kg/day group and the 

1000 mg/kg/day group.
Isoxaben D376428

Page 15 of 90

The overall findings indicate a high percentage of affected fetuses/litters were derived from a 

relatively small number of F0 progenitor animals and/or matings of cousins. In some instances, 

several generations of affected litters were derived from the same progenitors. The data suggest 

that there may have been a genetic predisposition to these abnormalities and that affected 

animals may have been more susceptible as a result of genetic factors. Exposure to high doses of 

isoxaben may have enhanced the effect in these more susceptible offspring. 

The relationship of the malformations to treatment is unclear, since no abnormalities were 

observed in the developmental studies and they were only seen at a high dose. However, the 

malformations are considered a potential effect of treatment in the absence of conclusive 

evidence to the contrary. For example, epigenetic effects such as spindle disruption, could 

potentially cause effects in later generations of offspring. HED cannot discount that the adverse 

effects discussed above are treatment related, but they are unlikely to have resulted from a single 

dose exposure. Therefore, an acute dietary assessment is not needed. HED has selected a 

chronic dietary point of departure with a NOAEL of 5.0 mg/kg/day which would be protective of 

these effects observed at much higher doses, i.e., 1000 mg/kg/day. 

The European Food Safety Commission (European Economic Community, prepared by

Rapporteur Member State Sweden) also reviewed the toxicity of isoxaben in a draft document 

published in May, 2006. For the malformations in the reproductive toxicity study, the report 

concluded that the weight-of-the-evidence indicated that congenital abnormalities were 

associated with genetic, i.e. heritable, factors that were traced back to specific litters from which 

the F0 generation was derived, rather than to administration of isoxaben.

3.3.5 Additional Information from Literature Sources

The European Union Food Safety Authority (EFSA) published a draft assessment report which 

evaluated toxicology and metabolism in May 2006: http://www.efsa.europa.eu/

en/scdocs/scdoc/58r.htm.

A screening-level literature search was conducted for information on the toxicity of isoxaben. 

No relevant studies providing additional information were identified.

3.3.6 Pre- and/or Postnatal Toxicity

3.3.6.1 Determination of Susceptibility

There was no evidence of increased quantitative susceptibility for pre- and/or postnatal effects in 

developmental toxicity studies in two species and a rat multigeneration reproductive toxicity

study. 

Increased qualitative susceptibility was observed in the rat reproductive toxicity study as 

decreased live pups/litter and decreased gestation survival in F2b litters (relative to body weight 

effects in mothers). However, concern for qualitative susceptibility is low because these effects 

may have been partly due to decreases in corpora lutea and they were only observed at the limit 

dose (1000 mg/kg/day) in the presence of maternal effects. The NOAEL/LOAEL for these 

effects is well-defined, and risk assessment points of departure (PODs) were selected to be 
Isoxaben D376428

Page 16 of 90

protective for these effects. Increases in fetal malformations (microphthalmia, coloboma and/or 

exencephaly) were also noted in later offspring generations (see Section 3.3.4 for discussion). 

3.3.6.2 Degree of Concern Analysis and Residual Uncertainties for Pre- and/or Postnatal 

Susceptibility

There is low concern for postnatal susceptibility for the reasons discussed above (Section 

3.3.6.1).

3.3.7 Recommendation for a Developmental Neurotoxicity Study

A developmental neurotoxicity study is not recommended for isoxaben. No developmental 

abnormalities were observed in either the rat or rabbit developmental toxicity studies at doses up 

to the limit dose. No evidence of neurotoxicity was observed in the available toxicology

database. As noted previously, malformations in the rat reproductive toxicity study were wellcharacterized, increased only at the limit dose (1000 mg/kg/day) in later generations and 

appeared due, in part, to heritable factors. 

3.4 FQPA Safety Factor for Infants and Children

It is recommended that the 10x FQPA safety factor for infants and children be reduced to 1x for 

isoxaben, for the following reasons:

 The toxicology database for isoxaben is largely complete, missing only the 

neurotoxicity, immunotoxicity and subchronic inhalation studies; however, there 

is no evidence that isoxaben targets the nervous system or the immune system.. 

Overall the toxicity of isoxaben is low: the available oral studies of short-term 

(e.g., developmental toxicity) or subchronic exposure duration did not show 

toxicity up to the limit dose. Effects observed at exposures of intermediate-term 

duration were minimal in adult animals (decreased body weight) and 

malformations seen in offspring of the rat reproduction study were of uncertain 

relationship to treatment. The endpoints selected were therefore considered 

conservative but were assumed to be treatment-related to be protective of 

potential effects. Based on these considerations, the required studies are not 

expected to provide lower PODs than those currently selected.

 Based on the lack of neurotoxicity in the database, a developmental neurotoxicity

study is not needed.

 There is a low degree of concern for the increased qualitative susceptibility 

observed in the multigenerational reproductive toxicity study, due to evidence that

observed malformations were due in part to heritable factors and additionally

were only seen at the limit dose in later generations, and not observed in the 

developmental studies. The relationship of these effects to treatment is unclear. 

There are low concerns for effects on offspring viability because they were only

observed at the limit dose and may have been secondary to effects on the dams. 

The endpoints for risk assessment are protective of these effects.
Isoxaben D376428

Page 17 of 90

 The exposure assessments for food, drinking water and residential uses will not 

underestimate potential exposure to isoxaben, and a conservative approach was 

used for aggregate risk assessment. 

3.5 Hazard Identification and Toxicity Endpoint Selection

3.5.1 Acute Reference Dose (aRfD) – All Populations (Including Females Age 13 to 49, 

Infants and Children)

An acute reference dose was not determined. An appropriate endpoint was not identified 

that could occur following a single exposure. Malformations in the reproductive study

were only observed after several matings and were not seen in either the rat or rabbit 

developmental studies. Therefore, HED concluded these effects, if treatment-related,

were unlikely to result from a single dose.

3.5.2 Chronic Reference Dose (cRfD)

Study Selected: Chronic Toxicity/Carcinogenicity in the Rat (Dietary)

MRID No: 00164553

Dose and Endpoint for Risk Assessment: NOAEL = 5.0 mg/kg/day, based on renal 

toxicity in males observed at the LOAEL of 50.7 mg/kg/day.

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)

Chronic RfD = 

100 ( )

5.0 / /

UF

mg kg day = 0.05 mg/kg/day

Comments about Study/Endpoint/Uncertainty Factors: The study is of the 

appropriate duration and exposure route (i.e., long-term oral exposure) and represents the 

most conservative available endpoint and dose available in the database for assessment of 

chronic dietary exposure. 

3.5.3 Incidental Oral Exposure, Short-Term (1 to 30 days)

An appropriate endpoint was not identified. No maternal toxicity was observed in the rat 

or rabbit, both of which tested up to the limit dose of 1000 mg/kg/day. Offspring effects

relevant to postnatal exposure (e.g., decreased body weights, clinical effects in young 

pups) identified in the reproductive toxicity study were not observed within the shortterm exposure time frame. Subchronic toxicity studies did not report effects. There is no 

hazard associated with short-term incidental oral exposure, and therefore, no risk.

3.5.4 Incidental Oral Exposure, Intermediate-Term (1 to 6 months)

Studies Selected: Reproductive toxicity in the rat and chronic toxicity (1 year dietary) in 

the rat, co-critical studies.

MRID No: 00153529, 00164552
Isoxaben D376428

Page 18 of 90

Dose and Endpoint for Risk Assessment: The NOAEL of 200 mg/kg/day is based on 

decreased body weight gain in F1 females at Day 70 at 1000 mg/kg/day and decreased 

pup weight, gestation survival and live pups/litter in the F2b generation in the rat 

reproductive toxicity study. This dose selection is supported by the co-critical rat one 

year dietary study, where females showed decreased body weights by six months at 625 

mg/kg/day and a NOAEL of 62.5 mg/kg/day.

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)

Comments about Study/Endpoint/Uncertainty Factors: The endpoint selected for 

this risk assessment is based on a study of the appropriate duration and route, and 

represents a conservative endpoint for this duration. The endpoint is protective of 

potential postnatal effects, based on the offspring NOAEL/LOAEL of 200/1000 

mg/kg/day in the rat reproductive toxicity study. Although the NOAELs for subchronic 

toxicity and maternal toxicity (in the developmental toxicity studies) were much higher 

(at or above the limit dose of 1000 mg/kg/day), in the rat reproductive toxicity study

decreased body weight and weight gain were observed in F1 females at 1000 mg/kg/day. 

Body weight effects in the rat chronic toxicity/carcinogenicity study were observed in 

females by six months at 625 mg/kg/day, with a NOAEL of 62.5 mg/kg/day. The higher 

NOAEL of 200 mg/kg/day (reproduction study) together with the lower LOAEL of 625 

mg/kg/day (chronic study) was used to establish the dose and endpoint. Although the 

low dose of 40 mg/kg/day in the reproduction study was identified as a parental NOAEL, 

it was not selected because body weight changes at 200 mg/kg/day were minimal and 

only seen at later times in the study (F2 animals’growth period and later). The mid dose 

of 200 mg/kg/day was therefore considered a more robust endpoint.

3.5.5 Dermal Absorption

Dermal absorption of 11% was estimated, based on absorption values obtained from an in 

vivo dermal absorption study in the monkey (MRID 00153113). This value was obtained 

from a comparison of the area under the curve (AUC) of intravenous vs. dermal dosing 

with radiolabeled isoxaben. The low absorption value is consistent with the lack of 

systemic effects seen in the rabbit 21-day dermal toxicity study.

A relative dermal absorption value was estimated since oral absorption was shown to be 

incomplete. Relative dermal absorption was calculated to determine whether endpoints 

from the available oral data adjusted for dermal absorption were more sensitive than the 

21-day dermal study. In the rat metabolism study at the low dose, a total oral absorption 

of 47% was calculated by adding urinary + biliary + exhaled CO2 excretion of 

radioactivity (using the average percent dose for male and female excretion values). 

Absorption values from the low dose were selected as more appropriate than the higher 

dose for human exposure and to provide a more conservative value. The average values 

were as follows: 

13% (urinary) + 31% (biliary) + 2.6% (CO2) = 47%

To estimate a relative dermal absorption factor for comparison of doses in oral studies 

with those in dermal studies, the average oral absorption of 47% was compared to the 
Isoxaben D376428

Page 19 of 90

dermal absorption of 11%, a difference of approximately four-fold. A dermal absorption 

factor of 23% is therefore used to adjust oral studies for percent dermal absorption. 

3.5.6. Residential and Occupational Dermal Exposure, Short-Term (1 to 30 days) and 

Intermediate-Term (1 to 6 months)

Quantitative short- and intermediate-term dermal exposure assessments were not 

performed for isoxaben. No effects were observed in the rabbit 21-day dermal toxicity

study at 1000 mg/kg/day. An appropriate dose and endpoint from an oral study were 

identified (NOAEL of 200 mg/kg/day from the rat reproductive toxicity study, based on 

offspring and parental effects at 1000 mg/kg/day). However, route-to-route extrapolation 

with adjustment of the oral NOAEL for relative dermal absorption (23%; see 3.5.5) 

resulted in a NOAEL of 870 mg/kg/day, comparable to the NOAEL of 1000 mg/kg/day

in the dermal study, with a LOAEL of 2300 mg/kg/day, a value above the limit dose. 

Therefore, significant dermal hazard does not exist, and quantitative assessment of 

dermal risk is not required.

3.5.7 Residential and Occupational Dermal Exposure, Long-Term (>6 months)

A long-term residential or occupational risk assessment is not required because long-term 

dermal exposure is not anticipated from the proposed or existing uses.

3.5.8 Residential and Occupational Inhalation Exposure, Short-Term (1 to 30 days)

Study Selected: Rat reproductive toxicity

MRID No: 00153529

Dose and Endpoint for Risk Assessment: 200 mg/kg/day, based on an increased 

incidence of malformations at 2000 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors: See Section 3.5.4. The 

malformations seen in the reproductive study are considered potential developmental 

effects in offspring that may result from short-term exposure. In the absence of 

inhalation data, inhalation absorption of 100% is assumed for route-to-route extrapolation 

from oral to inhalation exposure, i.e., inhalation toxicity is assumed to be equivalent to 

toxicity via the oral route. An additional uncertainty factor for lack of the 90-day rat 

inhalation study is not needed, based on the low vapor pressure and frequency of 

application, and persistence in soil (i.e., not volatilizing from the soil). When conducting 

the risk assessment, a body weight of 60 kg should be used to protect for offspring 

effects.

3.5.9 Residential and Occupational Inhalation Exposure, Intermediate-Term (1 to 6

months)

Study Selected: Rat reproduction toxicity and rat chronic toxicity (1 year dietary), cocritical.

MRID Nos: 00153529, 00164552

Dose and Endpoint for Risk Assessment: 200 mg/kg/day, based on decreased body 

weight gain in F1 females at Day 70 at 1000 mg/kg/day in the reproductive study. 
Isoxaben D376428

Page 20 of 90

Decreased pup weight and decreased corpora lutea, live pups/litter, gestation survival in 

F2 offspring and malformations in F2 and F3 offspring were also observed. This 

endpoint is supported by decreased body weight gain in females at 625 mg/kg/day by six 

months in the one year rat dietary study, with a NOAEL of 62.5 mg/kg/day.

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)

Comments about Study/Endpoint/Uncertainty Factors: See Section 3.5.4. In the 

absence of inhalation data, inhalation toxicity is assumed to be equivalent to toxicity via 

the oral route. An additional uncertainty factor for lack of the 90-day rat inhalation study

is not needed, based on the low vapor pressure and frequency of application, and 

persistence in soil (i.e., not volatilizing from the soil). When conducting the risk 

assessment, 60 kg body weight should be used to protect for offspring effects. 

3.5.10 Residential and Occupational Inhalation Exposure, Long-Term (> 6 months)

A long-term residential or occupational risk assessment is not required because long-term 

inhalation exposure is not anticipated from the proposed or existing uses.

3.5.11 Level of Concern for Margin of Exposure (MOE)

Table 3.5.12 Summary of Levels of Concern for Risk Assessment.

Route

Short-Term

(1 - 30 Days)

Intermediate-Term

(1 - 6 Months)

Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal N/A N/A N/A

Inhalation 100 100 N/A

Residential Exposure

Dermal N/A N/A N/A

Inhalation 100 100 N/A

3.5.12 Recommendation for Aggregate Exposure Risk Assessments

For the chronic dietary assessments, exposure from food and drinking water should be combined. 

For children, intermediate-term aggregate assessment should combine incidental oral exposure 

from soil ingestion with exposure to average food and water exposure (chronic dietary exposure). 

An appropriate short-term incidental oral endpoint was not identified. For adults, short- and 

intermediate-term aggregate exposure assessments should combine residential inhalation 

exposure with exposure to average food and water exposure (chronic dietary exposure). 

Although there is a potential for short- or intermediate-term residential dermal exposure based on 

the existing uses on turf, there is no short-term dermal hazard, and therefore dermal exposure 

should not be included in the aggregate assessment. For intermediate-term exposure the oral and 

inhalation points of departure are based on the same toxic effects. Therefore, combining such 

exposures and risks is appropriate.
Isoxaben D376428

Page 21 of 90

3.5.13 Classification of Carcinogenic Potential

Isoxaben was reviewed by the Cancer Assessment Review Committee (CARC) to determine the 

cancer classification under the current (2005) US EPA Guidelines for Assessment of 

Carcinogenicity. Isoxaben is classified as “Suggestive Evidence of Carcinogenic Potential,” 

based on an increased incidence of benign hepatocellular tumors in male and female mice 

(Isoxaben: Second Report of the Cancer Assessment Review Committee, dated October 7, 2008). 

The liver tumors were observed only in one species, were not malignant and were observed in 

the presence of liver toxicity at dietary levels exceeding the limit dose (1000 mg/kg/day). The 

chronic RfD/PAD is based on the chronic toxicity NOAEL of 5 mg/kg/day in the rat, which is 

more than 200-fold lower than the dose at which tumors were observed in the mouse. Therefore, 

the cRfD/PAD is considered to be protective of potential carcinogenicity.
Isoxaben D376428

Page 22 of 90

3.5.14 Summary of Toxicological Doses and Endpoints for Use in Human Risk 

Assessments

Table 3.5.2a. Summary of Toxicological Doses and Endpoints for Isoxaben for Use in 

Dietary and Non-Occupational 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, 

All Populations

including 

Females Age 13 

to 49, Infants 

and Children 

Not required. An appropriate endpoint for this risk assessment was 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.

Incidental Oral 

Short-term (1 to 

30 days) 

Not required. An appropriate endpoint was not identified.

Incidental Oral 

Intermediateterm (1 to 6 

months)

NOAEL = 

200 

mg/kg/day

UFA=10x

UFH=10x

FQPA SF= 1x 

LOC for MOE 

= 100

Reproductive toxicity in the rat (oral).

Offspring LOAEL = 1000 mg/kg/day, 

based on decreased body weight gain in 

F1 females on Day 70. 

One year dietary study in the rat (cocritical supporting study)

LOAEL = 625 mg/kg/day based on 

decreased body weight gain in females 

during the first six months with a NOAEL 

of 62.5 mg/kg/day.

Dermal ShortTerm (1 to 30 

days) and 

IntermediateTerm (1 to 6 

months)

Not required. An appropriate endpoint was not identified.

Dermal LongTerm (>6 

months)

Not required. Long-term dermal exposure is not anticipated from current and proposed uses.

Inhalation 

Short-Term (1 

to 30 days)

NOAEL = 

200 

mg/kg/day

(inhalation 

toxicity 

assumed to be 

equivalent to 

oral toxicity)

UFA=10x

UFH=10x

FQPA SF= 1x 

LOC for MOE 

= 100

Reproductive toxicity in the rat (oral).

Offspring LOAEL = 1000 mg/kg/day, 

based on increased incidence of

malformations.
Isoxaben D376428

Page 23 of 90

Table 3.5.2a. Summary of Toxicological Doses and Endpoints for Isoxaben for Use in 

Dietary and Non-Occupational 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

Inhalation 

IntermediateTerm (1 to 6 

months)

NOAEL = 

200 

mg/kg/day

(inhalation 

toxicity 

assumed to be 

equivalent to 

oral toxicity )

UFA=10x

UFH=10x

FQPA SF= 1x 

LOC for MOE 

= 100

Reproductive toxicity in the rat (oral).

Offspring LOAEL = 1000 mg/kg/day, 

based on decreased body weight gain in 

F1 females on Day 70, decreased F2 pup 

weights, gestation survival and live 

pups/litter, and increased incidence of 

malformations. 

One year dietary study in the rat (cocritical supporting study), 

LOAEL = 625 mg/kg/day based on 

decreased body weight gain in females 

during the first six months in the one year 

dietary study with a NOAEL of 62.5 

mg/kg/day.

Inhalation 

Long-Term (> 6 

months)

Not required. Long-term inhalation exposure is not anticipated from current and proposed uses.

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 

using a cancer potency factor is not required. The chronic RfD is protective of potential cancer 

risk.

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). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = 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). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.
Isoxaben D376428

Page 24 of 90

Table 3.5.2b Summary of Toxicological Doses and Endpoints for Isoxaben for Use in 

Occupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Dermal ShortTerm (1 to 30 

days) and 

IntermediateTerm (1 to 6 

months)

Not required. An appropriate endpoint was not identified.

Dermal LongTerm (> 6 

months)

Not required. Long-term dermal exposure is not anticipated from current and proposed uses.

Inhalation 

Short-Term (1 

to 30 days)

NOAEL = 

200 

mg/kg/day

(inhalation 

toxicity 

assumed to 

be 

equivalent 

to oral 

toxicity )

UFA=10x

UFH=10x Occupational LOC 

for MOE = 100

Reproductive toxicity in the rat (oral).

Offspring LOAEL = 1000 mg/kg/day, 

based on decreased F2 pup weights, 

gestation survival, live pups/litter and 

increased malformations. 

Inhalation 

IntermediateTerm (1 to 6 

months)

NOAEL = 

200 

mg/kg/day

(inhalation 

toxicity 

assumed to 

be 

equivalent 

to oral 

toxicity)

UFA=10x

UFH=10x Occupational LOC 

for MOE = 100

Reproductive toxicity in the rat (oral).

Offspring LOAEL = 1000 mg/kg/day, 

based on decreased body weight gain in F1 

females on Day 70, decreased F2 pup 

weights, gestation survival, live pups/litter 

and incidence of malformations. 

One year dietary study in the rat (cocritical supporting study)

LOAEL = 625 mg/kg/day based on 

decreased body weight gain in females 

during the first six months with a NOAEL 

of 62.5 mg/kg/day.

Inhalation 

Long-Term (> 

6 months)

Not required. Long-term inhalation exposure is not anticipated from current and proposed uses.

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 

using a cancer potency factor is not required. The chronic RfD is protective of potential cancer 

risk..

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). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

data (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.
Isoxaben D376428

Page 25 of 90

3.6 Endocrine disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor 

Screening Program (EDSP) to determine whether certain substances (including all pesticide 

active and other ingredients) “may have an effect in humans or wildlife similar to an effect 

produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designated to identify any adverse endocrine related effects caused by the substance, 

and establish a dose-response relationship between the dose and the E, A, or T effect.

Between October, 2009 and early 2010, EPA issued test orders/data call-ins for the first group of 

67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. This list of 

chemicals was selected based on the potential for human exposure through pathways such as 

food and water, residential activity, and certain post-application agricultural scenarios. This list 

should not be construed as a list of known or likely endocrine disruptors. Isoxaben is not among 

the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. 

Under FFDCA sec. 408(p), the Agency must screen all pesticide chemicals. Accordingly, EPA 

anticipates issuing future EDSP test orders/data call-ins for all pesticide active ingredients. 

For further information on the status of the EDSP, the policies and procedures, the list of 67 

chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/.

4.0 Public Health and Pesticide Epidemiology Data and Incident Reports

Seventeen human incidents were reported in the Isoxaben Scoping Document (Nov. 2007). Four 

were in an occupational setting with 3 symptomatic cases, two of which visited a health care 

facility. The non-occupational group had 8 exposures with two symptomatic cases. Four 

exposures were found in a group of children 5 and under, with two symptomatic cases. One 

involved a 67 year old woman who reported respiratory problems after an application near her 

home. There were no hospitalizations or Intensive Care Unit treatments reported for these 

incidences (See Review of Isoxaben Incident Reports, M. Hawkins; Aug 30, 2007). 

5.0 Dietary Exposure/Risk Characterization

For the purposes of this petition only, the nature of the residue in grapes and tree nuts is 

adequately understood based on grape and barley metabolism studies. With respect to future 

uses, HED concludes that the submitted plant metabolism studies are adequate for uses on cereal 

grains, grasses, and tree nuts. For grapes and tree nuts the grape metabolism study is adequate 

only for early season uses (i.e., prior to or at bloom). Additional radiolabeled studies would be 

needed for later season uses on tree nuts or grapes and for any uses on other crops beyond grains 

and grasses.
Isoxaben D376428

Page 26 of 90

The petitioner provided adequate grape and tree nut field trial data and processing studies in 

support of the proposed tolerances. The available processing data indicate that residues of 

isoxaben do not concentrate in grape juice or raisins; therefore, no tolerances are needed for 

grape processed commodities. There are no processed commodities for tree nuts and pistachios.

For dietary risk assessment purposes, HED concludes that the tolerance based on the parent will 

be adequate. In the grape metabolism study, the TRR was <0.008 ppm in the fruit, after a single 

application of isoxaben ranging from 1.79-1.97 lbs ai/A (1.8-2.0x proposed seasonal rate). 

Grapes harvested 60 days following a single broadcast application of the 75% DF formulation of 

isoxaben to the soil at 5.0 lb ai/A (5x the proposed rate) had residues below the LOQ (0.01 ppm) 

in/on all samples of grapes and raisins. Therefore, use of the LOQ (0.01 ppm) for the parent in 

grapes represents a conservative estimate of dietary exposure. Although radiolabeled data have 

not been provided for tree nuts to make a similar comparison with field trial results, it is unlikely

that at the requested PHIs significant uptake of residues from a soil-directed application into the 

edible nutmeat would occur. 

5.1 Pesticide Metabolism and Environmental Degradation

5.1.1 Metabolism in Primary Crops

DER Reference: 47140006.der.doc (Barley)

47175101.der.doc (Grape)

Residue Chemistry Memo PP#5G3216, 5/17/85, J. Worthington

Grape. Dow AgroSciences submitted a study investigating the metabolism of [isoxazole-5-

14C]isoxaben and [phenyl14C]isoxaben in grape. The radiolabeled test substances were applied 

as a single broadcast application to the soil surrounding grape vines at the dormant stage at 1.97 

lb ai/A for the isoxazole label and 1.79 lb ai/A for the phenyl label. The application rates used in 

the study are approximately 1.8x-2.0x the proposed maximum seasonal rate and maximum 

individual application rate of 1.0 lb ai/A.

TRR were below the LOQ (<0.008 ppm) in/on grape fruit harvested 165 days following soil 

treatment with isoxazole- or phenyl-labeled isoxaben at 1.79 or 1.97 lb ai/A. TRR were 0.304 

and 0.288 ppm in grape foliage following soil treatment with isoxazole- or phenyl-labeled 

isoxaben, respectively. Because TRR were <LOQ in/on grape fruit, no attempts were made to 

characterize or identify metabolites in the fruit.

Based on the submitted grape metabolism study, the petitioner proposed that following 

application of isoxaben to the soil, low levels of radioactivity are taken up by the grape vine 

roots, and even lower levels of radioactivity are translocated into the edible fruit. The 

metabolism of isoxaben in grape leaves appears to proceed through hydroxylation of the 

methylpropyl group. Ultimately, the soil degradation/plant metabolism proceeds to low level, 

multiple, polar components, presumably through cleavage of the benzamide bridge. 
Isoxaben D376428

Page 27 of 90

Barley. Dow AgroSciences submitted a study investigating the metabolism of [isoxazole-5-

14C]isoxaben and [phenyl14C]isoxaben in barley. Each radiolabeled test substance was

formulated with blank suspension concentrate (SC) formulation, diluted with water, and applied 

as a single foliar application at 0.178 lb ai/A (200 g ai/ha) to barley at the BBCH 13 growth stage 

(3 unfolded leaves) grown outdoors. The application rate used in the study is 0.1x the proposed 

maximum seasonal rate of 1.3 lb ai/A for grapes and tree nuts. (Note: This is a new study, not 

the study reviewed by HED in 1985.)

TABLE 5.1.1 Total Radioactive Residues (TRR) in Barley at 0.178x Application Rate.

Matrix Application rate

(lb ai/A)

PHI

(days)

Isoxazole label Phenyl label

ppm ppm

Immature plant 0.178 0 5.731 4.718

7 3.129 1.307

14 0.376 0.341

28 0.084 0.052

Grain 87 0.019 (0.019) 0.012 (0.011)

Straw 0.281 (0.298) 0.222 (0.213)

Chaff 0.458 (0.475) 0.279 (0.295)

Based on the submitted barley metabolism studies, the petitioner proposed that isoxaben is 

significantly metabolized in summer barley. Hydroxylation of the aliphatic side chain of the 

intact molecule is the major route of metabolism in barley; cleavage of the amide bond was not 

observed. Isoxaben and metabolites were also present as acid-hydrolyzable conjugates. 

Isoxaben and metabolites, as well as conjugates/polar compounds, were partly incorporated into 

the nonextractable residues of barley matrices. (See Figures in Appendix B2.)

The metabolism of isoxaben was similar in both plant types and confirms the major metabolic 

pathway is hydroxylation of the aliphatic side chain of the parent compound, followed by further 

conjugation reactions. The grape metabolism study suggested cleavage of the benzamide bridge, 

which was not reflected in the barley study. The difference may be due to the longer PHI 

reflected in the grape study, compared to the barley study (165 vs. 87 days).

Additional details for the plant and animal metabolism studies can be found in the Isoxaben 

Chemistry Summary (D341694, D. McNeilly, 21 July 2010). 

5.1.2 Metabolism in Rotational Crops

Data depicting the metabolism of isoxaben in rotational crops have not been submitted. Grape 

vines and tree nuts are perennial and under normal practices there are no succeeding crops. 

Therefore, such data are not required at this time.

5.1.3 Metabolism in Livestock

DER Reference: 47825501.der.doc
Isoxaben D376428

Page 28 of 90

Dow AgroSciences LLC has submitted a study investigating the metabolism of [isoxazole-5-

14C]isoxaben and [phenyl14C]isoxaben in goats. Based on the results of the study, isoxaben 

metabolism in the lactating goat is proposed to occur by hydroxylation to form the 3-hydroxy

isoxaben metabolite and the hydroxylated isoxaben metabolite (with the hydroxylation occurring 

on the methyl pentanyl moiety). Oxidation of these hydroxylated metabolites is hypothesized to 

result in the carboxylic acid metabolite of isoxaben. Two oxime metabolites (of unclear 

stereochemistry) are then formed by hydryolytic cleavage of the isoxazole ring. Finally, cleavage 

of the amide link in isoxaben causes the formation of the 2,6 dimethoxybenzamide, 2,6-

dimethoxybenzoic acid, and 2-hydroxy-6-methoxybenzamide metabolites (minor residues 

identified in liver, kidney, and muscle in the phenyl-label goat matrices). 

The majority of the administered isoxaben (74% in the isoxazole label, 63% in the phenyl label) 

was excreted in urine and feces. Only a small portion of the administered dose was recovered in 

milk, with less than 0.22% of the dose recovered in the isoxazole label and 0.09% in the phenyl

label. The highest concentration was observed in liver matrices, with the maximum TRR of 

2.026 ppm observed in the isoxazole label (accounting for 2% of the administered dose). The 

parent isoxaben was only identified as a major metabolite in fat matrices. An oxime isomer was 

found to be a major metabolite in liver and kidney matrices, whereas a second oxime isomer was 

identified as a major metabolite only in kidney. A carboxylic acid metabolite was also identified 

as a major metabolite, but only in kidney matrices. Minor metabolites of 2,6-

dimethoxybenzamide (muscle, liver, kidney, milk), 2,6-dimethoxybenzoic acid (kidney), and 2-

hydroxy-6-methoxy-benzamide (liver and kidney) were also identified A significant portion of 

the TRR (14-68% TRR across matrices) could not be conclusively identified, either because the 

components were <LOQ or the components were tentatively identified as being one to four 

possible metabolites (oxime isomer, 3-hydroxy isoxaben, carboxylic acid metabolite, 

hydroxylated isoxaben). This metabolism study is sufficient for the purposes of the new 

proposed uses on tree nuts and vineyards currently under review. However, future new uses 

involving significant livestock feed items may need additional metabolism studies given the 

inconclusive results of metabolite identification for a large portion of the TRR across matrices.

5.1.4 Analytical Methodology

DER References: 47140007.der.doc (Method GRM 02.26)

47492601.der.doc (revised Method GRM 02.26.S.1)

Enforcement method: Dow AgroSciences has proposed an LC/MS/MS method, GRM 02.26.S.1, 

for the enforcement of tolerances for residues of isoxaben in/on crop commodities. The method 

is entitled “Determination of Residues of Isoxaben in Cereals, Chicory, Endives, Almonds, 

Pecans and Grapes by Liquid Chromatography with Tandem Mass Spectrometry.”

Briefly, residues of isoxaben are extracted from crop samples with ACN:water (70:30, v:v). An 

aliquot of the extract is diluted with water and subjected to liquid-liquid extraction on a 

diatomaceous column, using dichloromethane to elute the residues. The eluate is evaporated to 

dryness, redissolved in methanol:water (50:50, v:v) containing 5 mM ammonium acetate, and 

analyzed by liquid chromatography with positive-ion atmospheric pressure chemical ionization 

tandem mass spectrometry (LC/MS/MS). The validated LOQ is 0.01 ppm for isoxaben in each 

matrix.
Isoxaben D376428

Page 29 of 90

An independent laboratory validation (ILV) study was not submitted for the enforcement method 

GRM 02.26.S.1. However, an ILV was submitted for the initial method GRM 02.26 with wheat 

grain and endive leaves fortified with isoxaben at 0.01 ppm, 0.02 ppm, and 0.10 ppm. Adequate 

recoveries were obtained for both commodities using the method as written.

Data collection: The originally proposed enforcement method, LC/MS/MS method GRM 02.26, 

was used for data collection in samples of grape and tree nut commodities from the crop field 

trial and processing studies associated with this petition.

Conclusions. The plant commodity analytical method data are adequate for both data collection 

and tolerance enforcement.

No multiresidue method testing data were submitted with this petition. The FDA PESTDATA 

database (dated 06/05) indicates that isoxaben is completely recovered using multiresidue 

method Section 302. The database did not include any information for any of the other test 

methods.

5.1.5 Environmental Degradation

D341497, C. Peck, 18 March 2010

There is no significant evidence that isoxaben degrades by hydrolysis. Isoxaben does not readily 

undergo aerobic or anaerobic degradation in soil, half lives are greater than 150 days. Isoxaben 

degrades via soil photolysis with a half life of 49 days. Primary routes of degradation are

aqueous photolysis, aerobic aqueous metabolism and anaerobic aqueous metabolism with half 

lives ranging from 6 to 18 days. Isoxaben is not expected to volatize based on its low vapor 

pressure. Isoxaben is classified as moderately mobile based on adsorption Kd values in five types 

of soils ranging from 0.81 to 6.63 ml/g. Major degradates of isoxaben include hydroxyisoxaben, 

dimethoxybenzamide, methoxyphenylpyrimidinol, and AEM hexenoylisoxaben. Based on 

structural analysis of these degradates in EPISuite, three of the degradates (hydroxyisoxaben, 

dimethoxybenzamide, and AEM hexenoylisoxaben) have the potential to be more mobile than 

isoxaben (Koc values ranging from 4.6 to 102 ml/goc), with methoxyphenylpyrimidinol appearing 

to be very immobile (Koc values from 4,800 to 38,000 ml/goc).

There is a potential for isoxaben and its degradates to reach surface water through spray drift, as 

products may be applied via ground spray. Because isoxaben and its degradates are persistent in 

surface soils, there is also the potential for them to reach surface water through surface runoff 

either in solution or adsorbed to the soil. Isoxaben and its degradates have the potential to leach 

to ground water when applied to certain soils, where high water tables are present, and high 

rainfall/ irrigation occurs.

Isoxaben residues accumulated in bluegill sunfish with maximum bioconcentration factors of 

14x in edible tissue, 134x in non-edible tissue, and 70x in whole fish tissue during 28 days of 

exposure. The residues accumulated by day 28 were depurated quickly; at day 14 of dupuration, 

isoxaben residues had been reduced by 92-99% in the edible, non-edible, and whole fish tissue. 
Isoxaben D376428

Page 30 of 90

Isoxaben is not expected to accumulate in aquatic or terrestrial food chains as used under the 

currently registered and/or proposed uses.

5.1.6 Comparative Metabolic Profile

In rats, the major routes of metabolism were oxidation of position 2 of the alkyl side chain 

yielding either an alcohol or a ketone, hydroxylation of the aromatic ring adjacent to one of the 

methoxy groups or O-demethylation of the methoxy groups. Overall metabolite profiles were 

similar for males and females, with minor quantitative differences observed.

Hydroxylated metabolites (e.g., 1-hydroxyl, 2-hydroxyl, 3-hydroxyl) were major residues in the 

plant metabolism studies. Similar metabolic pathways were also observed in the livestock

metabolism and the rat metabolism study.

5.1.7 Toxicity Profile of Major Metabolites and Degradates

Plants: For dietary risk assessment purposes, Residues of Concern Knowledgebase 

Subcommittee (ROCKS) concluded that the tolerance based on the parent will be adequate. In 

the grape metabolism study, the TRR was <0.008 ppm in the fruit, after a single application of 

isoxaben ranging from 1.79-1.97 lbs ai/A (roughly 1.8-2.0x proposed seasonal rate). Grapes 

harvested 60 days following a single broadcast application of the 75% DF formulation of 

isoxaben to the soil at 5.0 lb ai/A (5x the proposed rate) had residues below the LOQ (0.01 ppm) 

in/on all samples of grapes and raisins. Therefore, use of the LOQ (0.01 ppm) for the parent in 

grapes represents a conservative estimate of dietary exposure. Although radiolabeled data have 

not been provided for tree nuts to make a similar comparison with field trial results, it is unlikely

that significant uptake of residues from a soil-directed application into the edible nutmeat would 

occur. 

For the primary crops grapes and tree nuts, isoxaben parent can serve as an adequate measure of 

misuse based on its percentage of the total radioactive residue (TRR) in the barley metabolism 

study and the field trial residues observed in almond hulls and nutmeat. ROCKS recommended 

using the parent only for compliance purposes.

Three hydroxylated metabolites (1-hydroxyl, 2-hydroxyl, 3-hydroxyl) were major residues in the 

barley metabolism study. Structure-activity relationship (SAR) analysis (DEREK) did not reveal 

any alerts for the parent compound or the 1-hydroxyl metabolite. Due to structural similarity, all 

of the hydroxylated metabolites are assumed to have comparable toxicity to the parent; therefore, 

for any future uses on grains or grasses, the petitioner is advised to include residue data on the 

three hydroxylated metabolites as they are likely to be included (at least for risk assessment 

purposes) on those crops.

Livestock: HED concludes that residues in milk, ruminant and poultry meat, fat, and meat 

byproducts and eggs remain a 40CFR §180.6[a][3] situation (i.e., no expectation of finite 

residues in these commodities). Although the goat metabolism study identified low percentages 

of the total radioactive residues in most matrices, it is adequate for the proposed uses, based on 

the very low dietary burden for cattle. Another goat metabolism study with better identification 
Isoxaben D376428

Page 31 of 90

and characterization of the residues will be needed to support any additional uses of isoxaben 

that result in significantly higher dietary burdens.

Drinking Water: Major degradates (>10% of total residues) detected during aerobic and 

anaerobic soil metabolism studies and aerobic and anaerobic aqueous metabolism studies include 

hydroxy isoxaben, dimethoxy benzamide, methoxyphenyl pyrimidinol, and AEM hexenoyl 

isoxaben. These degradates are more mobile than the parent, except for methoxyphenyl

pyrimidol. SAR analysis (DEREK) did not reveal any alerts for the parent compound but did 

produce alerts for the methoxyphenyl pyrimidinol (carcinogenicity, skin sensitization) and AEM 

hexenoyl isoxaben (skin sensitization) metabolites. ROCKS is not concerned for these alerts 

because substituted pyrimidine/purine carcinogenicity is only seen at very high doses (as a result 

of bladder calculi) and dermal exposure to metabolites is not expected to be significant. None of 

the environmental degradates are thus expected to be more toxic than the parent compound, but 

data are not available to exclude them as residues of concern.

5.1.8 Pesticide Metabolites and Degradates of Concern

Table 5.1.8 Summary of Metabolites and Degradates to be included in the Risk 

Assessment and Tolerance Expression

Matrix Residues included in Risk 

Assessment

Residues included in Tolerance 

Expression for Compliance 

Monitoring

Plants Primary Crop Isoxaben Isoxaben

Rotational Crop Not Applicable Not Applicable

Livestock Ruminant Not Applicable Not Applicable

Poultry Not Applicable Not Applicable

Drinking Water Isoxaben + Hydroxy isoxaben + 

Methoxyphenyl pyrimidinol + AEM 

hexenoyl isoxaben + Dimethoxy 

benzamide.

Not Applicable

Isoxaben = N-[3-(1-ethyl-1-methylpropyl)-5-isoxazolyl]-2,6-dimethoxybenzamide.

Hydroxy isoxaben = N-[3-(1-hydroxyl-1-methylpropyl)-5-isoxazoyl]-2,6-dimethoxy-benzamide.

Methoxyphenyl pyrimidinol =6-(1-ethyl-1-methylpropyl)-2-(2-hydroxy-6-methoxyphenyl)-4-pyrimidinol.

AEM hexenoyl isoxaben = N-[3-amino-4-ethyl-4-methyl-2-hexenoyl]-2,6-dimethoxybenzamide.

Dimethoxy benzamide = 2,6-Dimethoxybenzamide.

5.1.9 Drinking Water Residue Profile

D341497, C. Peck, 3/18/2010

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 New Use on Bearing Nut Trees and Vineyards” 

(D341497, C. Peck, 3/18/2010) and were incorporated directly into the dietary assessment. 

Monitoring data are not available to assess isoxaben residue concentrations in surface and 

groundwater sources of drinking water.
Isoxaben D376428

Page 32 of 90

Estimated drinking water concentrations (EDWCs) were generated using EFED’s standard suite 

of models. The FQPA Index Reservoir Screening Tool (FIRST) is a surface water model that is 

used to estimate both acute and chronic potential pesticide concentrations in untreated drinking 

water. EDWCs from FIRST represent concentrations which might occur from a single 1-in-10-

year storm event following the last application of pesticide at a location more vulnerable than 

most locations in the United States to runoff, regardless of the crop being produced. The model 

considers reductions in dissolved concentration due to the percentage of the watershed which is 

cropped (percent cropped area - PCA), due to adsorption of pesticide to field soil and to reservoir 

bottom sediment, due to incorporation of the pesticide at the time of application, due to 

degradation in soil before washoff to the reservoir, and due to degradation of the pesticide within 

the water body. A more detailed description of the index reservoir watershed can be found in 

Jones et al., 1998. Percent Cropped Areas (PCA) that account for the maximum area within a 

watershed that may be planted with the modeled crop are applied to concentrations predicted by

PRZM/EXAMS (Pesticide Root Zone Model/Exposure Analysis Modeling System).

Screening Concentration in Ground Water (SCI-GROW v2.3, Jul. 29, 2003) is a regression 

model used as a screening tool to estimate pesticide concentrations found in ground water used 

as drinking water. SCI-GROW was developed by fitting a linear model to ground water 

concentrations with the Relative Index of Leaching Potential (RILP) as the independent variable. 

The RILP is a function of aerobic soil metabolism and the soil-water partition coefficient. The 

output of SCI-GROW represents the concentrations of isoxaben residue that might be expected 

in shallow unconfined aquifers under sandy soils, which is representative of the ground water 

most vulnerable to pesticide contamination and likely to serve as a drinking water source. The 

SCI-GROW model and user’s manual may also be downloaded from the EPA Water Models 

web-page (http://www.epa.gov/oppefed1/models /water/#scigrow). 

The EDWCs are based on the maximum proposed application rates specified in the product 

labels. Because the maximum annual application rate for the new uses assessed here is less than 

the application rate for ornamentals on the label for Isoxaben 75DF (EPA Reg. No. 34704-917), 

the values for ornamentals are recommended for use in the human health risk assessment. The 

annual application rate for ornamentals, which is used in this current assessment, is 3 lbs 

ai/A/year with a 60 day re-treatment interval. The EDWCs for the human health risk assessment 

are presented in Table 5.1.9. Because isoxaben has a number of major degradates predicted to 

have similar toxicity as isoxaben, a total toxic residue (TTR) approach was used in the modeling. 

In the TTR approach, half-lives are calculated for the combined isoxaben and degradate residue 

and modeling runs are conducted using these half-lives. Additionally, a mobility study and 

EPISuite analysis indicated that several of the isoxaben degradates were more mobile than the 

parent. As such, 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 degradate study. The 

maximum 1-in-10-year peak and annual mean EDWCs in surface water were 284 and 120 μg/L, 

respectively, for ornamental use. The maximum estimated acute concentration in groundwater 

was 43.6 μg/L for ornamental use. The maximum 1-in-10-year peak and annual mean EDWCs 

in surface water were 87.6 and 37 μg/L, respectively, for bearing nut trees and vineyards. The 

maximum estimated acute concentration in groundwater was 14.5 μg/L for bearing nut trees and 

vineyards.
Isoxaben D376428

Page 33 of 90

Table 5.1.9. Tier I Estimated Drinking Water Concentrations (EDWCs) resulting from applications 

of isoxaben and its degradates on ornamentals and bearing nut trees.

Drinking water source 

(model)

Use 

(modeled rate)

Acute1

(μg/L)

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 1202

Groundwater (SCIGROW) Ornamental 43.6

Surface water (FIRST) Bearing nut trees and vineyards 37.0

Groundwater (SCIGROW) Bearing nut trees and vineyards 14.5

1- An acute dietary analysis was not conducted due to the absence of an appropriate end-point.

2- The value used in the chronic dietary assessment.

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.

5.1.10 Food Residue Profile

DER Reference: 47140008.der.doc (Almond)

47140009.der.doc (Pecan)

47040010.de1.doc (Grape)

To support the proposed uses on grapes and tree nuts, Dow AgroSciences has submitted crop 

field trial data for grapes, a grape processing study, and crop field trial data for almonds and 

pecans, the representative commodities of the tree nut crop group. The submitted studies are 

adequate to satisfy data requirements. Both table and wine grape varieties were included in the 

grape field trials. A suitable method was used for determination of residues of isoxaben, and 

adequate storage stability data were included. The grape processing study indicates residues do 

not concentrate in raisins or juice. A recommended tolerance summary for isoxaben is presented 

in Appendix C.

Grape 

Residues of isoxaben were below the LOQ of 0.01 ppm in/on all grape samples.

Tree nut, group 14

Almond: Residues of isoxaben were <LOQ in/on all almond nutmeat samples from Treatment 

Plot Nos. 2 and 3, with the exception of two samples collected from Treatment Plot No. 3 in the 
Isoxaben D376428

Page 34 of 90

decline trial (sampling interval of 68 days) which bore residues of 0.014 and 0.015 ppm. 

Residues of isoxaben were below the LOQ in/on all samples of almond hulls from Treatment 

Plot No. 2, including samples from the decline trials. Residues of isoxaben were <0.01-0.301 

ppm in/on almond hull samples (including samples from decline trials) from Treatment Plot No. 

3. 

In the decline trial for Treatment Plot No. 2, isoxaben residues were below the LOQ in/on all 

samples of almond nutmeat and hulls. In the decline trial from Treatment Plot No. 3, residues of 

isoxaben were <LOQ in/on all samples of nutmeat except those harvested at the 68-day sampling 

interval (as noted above). For almond hulls from Treatment Plot No. 3, residues of isoxaben 

increased from the 54-day sampling interval (average of 0.103 ppm) to the 68-day sampling 

interval (average of 0.267 ppm) and then decreased at the 75-day sampling interval (average of 

0.123 ppm). 

Pecan: Residues of isoxaben were <LOQ in/on all pecan nutmeat samples.

Grape Processing

DER Reference: 47140010.de2.doc

Dow AgroSciences submitted a processing study with isoxaben on grapes. Samples used for 

processing were generated from one trial conducted in NY during the 2006 growing season. 

Grapes were harvested 60 days following a single broadcast application of the 75% DF 

formulation of isoxaben to the soil at 5.0 lbs ai/A (5x the field trial rate). Application was made 

using ground equipment in 25 gal/A spray volumes without an adjuvant. Whole grapes were 

processed into raisins and juice using simulated commercial processes. All residues were below 

the LOQ in/on all samples of grapes, raisins, and grape juice; therefore, processed commodity 

tolerances are not required and the data indicate that residues in processed commodities treated at 

1x would be well below the LOQ.

5.1.11 International Residue Limits

No Codex, Canadian, or Mexican MRLs have been established for isoxaben.

5.2 Dietary Exposure and Risk

D375246, E. Holman, 7/13/2010

A chronic dietary risk assessment was conducted using the Dietary Exposure Evaluation Model 

(DEEM-FCID, Version 2.03), which uses food consumption data from the USDA’s Continuing 

Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998. This analysis is 

based on tolerance level residues and 100% crop treated assumptions.

5.2.1 Acute Dietary Exposure/Risk

An acute reference dose has not been established for either the general population (including 

infants and children) or for females ages 13-49 years. There were no studies that demonstrated 
Isoxaben D376428

Page 35 of 90

evidence of toxicity attributable to a single dose. As a result, a quantitative acute dietary

exposure assessment has not been performed.

5.2.2 Chronic Dietary Exposure/Risk

The chronic dietary (food + water) risk estimates are below HED’s LOC for the general U.S. 

population and all population subgroups, including those comprised of infants and children. The 

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

HED’s LOC (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.

Table 5.2.2 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 0.003540 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 0.002490 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. 

5.2.3 Cancer Dietary Risk

Isoxaben was reviewed by the Cancer Assessment Review Committee (CARC) to determine the 

cancer classification under the current (2005) US EPA Guidelines for Assessment of 

Carcinogenicity. Isoxaben is classified as “Suggestive Evidence of Carcinogenic Potential,” 

based on an increased incidence of benign hepatocellular tumors in male and female mice 

(Isoxaben: Second Report of the Cancer Assessment Review Committee, dated October 7, 2008). 

The liver tumors were observed only in one species, were not malignant and were observed in 

the presence of liver toxicity at dietary levels exceeding the limit dose (1000 mg/kg/day). The 

chronic RfD/PAD is based on the chronic toxicity NOAEL of 5 mg/kg/day in the rat, which is 

more than 200-fold lower than the dose at which tumors were observed in the mouse. Therefore, 

the cRfD/PAD is considered to be protective of potential carcinogenicity and quantification of 

cancer risk using a cancer potency factor is not required.
Isoxaben D376428

Page 36 of 90

5.3 Anticipated Residue and Percent Crop Treated (%CT) Information

No Percent Crop Treated (PCT) information was incorporated into the current dietary exposure 

and risk assessment; that is, HED assumed 100 %CT for grapes and tree nuts. Tolerance level 

residue levels were assumed; no anticipated residues were used in this assessment. 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

D368834, S. Oonnithan, 7/26/10

With the proposed first food use of isoxaben (EPA File Symbol 62719-LIN), the registrant did 

not propose any new residential uses. There are several registered liquid and solid end-use 

product formulations available for weed control on home lawns, recreational turf areas and 

ornamental plantings. Some products are labeled for use by homeowners and others are for use 

by professional applicators. No new residential uses for isoxaben are being requested with this 

application. 

Even though isoxaben is already registered for weed control in residential areas, quantitative 

homeowner (handler) and postapplication exposure assessments were not previously conducted 

due to the lack of short-term incidental oral, dermal and inhalation endpoints needed to estimate 

these risks. Based on the current hazard characterization and in order to complete an aggregate 

risk assessment in conjunction with the proposed first food use of isoxaben, residential exposures 

were estimated, taking into consideration all end-use products registered for residential uses. 

For assessing residential handler exposure, two representative product formulations having the 

highest single application rates were selected. They are an EC (Lawn 3iP Herbicide Concentrate, 

Reg. No. 72155-87) and a granule (T&O Fertilizer-Contains Gallery plus Team, EPA Reg. No. 

62719-280). The liquid and granule have maximum single application rates of 0.49 and 1.0 lb 

ai/A, respectively. The granule product is packaged and marketed individually as homeowner 

and commercial products and both labels have almost identical use patterns (Table 6a).
Isoxaben D376428

Page 37 of 90

Table 6a. Use Pattern of Isoxaben End-use Products Selected for Residential Handler and Postapplication 

Exposure Assessments.

EPA 

Reg. No.1

Application 

Equipment Appl. rates

No. appls./ 

season & 

interval 2 Comments

Lawn 3iP 

Herbicide 

Conc., Reg. 

No. 72155-87 

(EC, Isoxaben 

= 2.63%)

Homeowner/Commercial Label

After mixing with water

- pump style hand held sprayer

- concentrate plus water hose-end 

sprayer

Without mixing with water

- dial-style hose-end sprayer 

- single-rate or dual- rate hose-end 

sprayer

Rate/appl.= 1.6-3.2 

fl. oz. /500 sq. ft 

Max/appl.= 0.49 lb 

ai/A

Max/year = 0.98 lb 

ai/A

2/year 

60 days

NA

T&O Fertilizer, 

EPA Reg. No. 

62719-280 

(Granule) 

Isoxaben = 

0.38%) 

Homeowner/Commercial Label

- drop or rotary-type granule spreader 

Rate/appl.= 174-265 

lbs/A 

Max/appl.= 1.0 lb 

ai/A 

Max/year = 2.0 lb 

ai/A 

2-7/year

56 days 

Sprinkler 

irrigation or 

rainfall within a 

few hours is 

recommended 

Isoxaben 75DF 

Specialty 

Herbicide

EPA Reg. No. 

34704-917, DF

Isoxaben=75%

Commercial Label 

- herbicide sprayer 

- spray volume ≥10 gal/A 

Rate/appl.= 0.66-

1.33 lbs/A 

Max/appl.= 1.0 lb 

ai/A

Max/year = 4 lbs/A 

(3.0 lb ai/A)

3 or more

60 days 

Sprinkler 

irrigation or 

rainfall after 

application is 

recommended

Abbreviations used: DF = dry flowable, EC = emulsifiable concentrate, NA = not applicable 

1. Lawn 3iP Herbicide Concentrate/Ready-to-Spray (Reg. No. 72155-87) is an EC containing isoxaben (2.63%), 

2,4-D dimethylamine salt (4.73%), dicamba (0.52%) and mecoprop-p potassium salt (1.1%). T&O FertilizerContains Gallery plus Team (EPA Reg. No. 62719-280) is a granule + fertilizer containing isoxaben (0.38%), 

trifluralin (0.39%) and benefin (0.76%). 

2. Repeat applications may represent rates that are lower than the maximum single rate/A. 

Exposure and Risk to Homeowners: 

The use patterns used for a quantitative assessment of homeowner exposures are from EC and 

granule products (Table 6a).

Potential Exposure Scenarios: The following scenarios were assessed:

1. mixing/loading/applying EC using a hose-end sprayer 

2. mixing/loading/applying EC using a hand-held pump sprayer 

3. loading/applying granules using a granular push-type spreader

Application Rate and Exposure Durations: For residential handler exposure assessment, HED 

uses maximum single application rates and frequency of treatments for determining short- and 

intermediate-term exposures. The EC product label recommends two applications per year for 

weed control on home lawns at a single maximum rate of 0.49 lb ai/A. The minimum interval 

between treatments is 60 days. Therefore, homeowners have the potential for only short-term 

dermal and inhalation exposure. The granule product label recommends repeat applications at an 
Isoxaben D376428

Page 38 of 90

interval of 56 days on cool season grass and 70 days on warm season grass at a single maximum 

single rate of 0.99 lb ai/A, resulting in short-term exposures. There are some distributor products 

sold in Florida (both homeowner and commercial labels) that recommend up to 7 applications 

per year on Bermuda grass with a maximum rate of 2 lb ai/A/year. These repeated applications 

are assumed to be made at an average rate of 0.3 lb ai/A/application taking into account an 

annual limit of 2.0 lb ai/A. Despite the potential for repeated applications, HED continues to 

consider residential handler exposures to be short-term in duration based on the 56 day

retreatment interval.

Exposure and Risk to Residential Handlers: No chemical specific exposure data have been 

submitted by the registrant to estimate the inhalation unit exposures for residential handlers. 

Therefore, surrogate unit exposures from the Outdoor Residential Exposure Task Force database 

(ORETF) were selected. Short-term dermal risks were not estimated due to the lack of a dermal 

endpoint. The short-term inhalation MOEs ranged from 2.9E+06 to 2.8E+07 (LOC=100) and 

are not of concern (Table 6b).

Table 6b. Exposures and Risks to Homeowners Resulting from Applying Liquid and Solid Formulations of 

Isoxaben on Residential Lawns. 1

Exposure 

Scenarios

Max. Single 

Appl. rate, 

lb ai/A 2

Area 

treated 

A/day 3

Inhal. U.E.

mg/kg/day

(ORETF)

Inhalation 

dose

mg/kg/day 4

Short-term 

Inhal. MOE5

M/L/A, liquid,

hose-end sprayer 0.49 0.5 0.017 6.94 E-05 2.9 E+06

M/L/A, liquid,

hand-held sprayer 0.49 0.5 0.0038 1.55 E-05 1.3 E+07

L/A, granules, pushtype spreader 0.99 0.5 0.00088 7.2 E-06 2.8 E+07

Abbreviations used: A= applicator, L= loader, M= mixer, ORETF = Outdoor residential exposure task force. 

1. Short-term dermal exposures were not estimated due to the absence of a dermal endpoint. 

2. The maximum single application rates are from Table 6a.

3. The area treated (acres per day) are assumed to be 0.5 A/day for hose-end and hand-held sprayers and for

 granules. 

4. Inhalation dose (mg/kg/day) = (application rate * area treated/day * inhalation unit exposure * inhalation 

 absorption rate) / body wt. (60 kg).

5. Inhalation MOE = Short-term Inhalation NOAEL (200 mg/kg/day)/inhalation dose

6.1 Residential Postapplication Exposure.

For evaluating the residential postapplication exposure of isoxaben, EC, granule and solid 

formulations were considered (Table 6a). Since the Isoxaben 75 DF Specialty Herbicide, EPA 

Reg. No. 34704-917, had the highest application rate/year, it was assumed that the estimated 

risks would be protective of those associated with other formulations and application rates. This 

solid formulation is labeled for use by professional applicators on established turf, landscape, 

container and field grown ornamentals, non-cropland, non-bearing fruit and nut trees and nonbearing vineyards. It has a maximum single application rate of 1.0 lb ai/A (similar to EC and 

granule), with a yearly rate of 3.0 lb ai/A. 
Isoxaben D376428

Page 39 of 90

Dermal Exposures to Children, Youth and Adults: Dermal endpoints were not selected for 

isoxaben, for any duration of exposure, due to the lack of toxic effects via the dermal route; 

therefore, the risk associated with dermal postapplication exposure is not of concern.

Short-Term Incidental Oral Exposures to Children from Hand-to-Mouth and Object-to-Mouth 

Events: It is likely that children playing in treated turf areas would ingest residues of isoxaben 

from hand-to-mouth and objects-to-mouth events. However, there is no endpoint applicable to 

short-term oral exposure, and therefore, there are no risks of concern associated with hand-tomouth and object-to-mouth exposure.

Episodic Oral Exposures to Children from Ingestion of Granules: Ingestion of isoxaben granules 

following application of T&O Fertilizer-Contains Gallery plus Team to turf is considered to be 

an episodic event for children playing on treated lawns. The granules are not likely to be present 

on treated turf for up to 30 days (i.e., short-term durations) due to the label recommendation for 

irrigation/watering within hours of application. Further, in the absence of an acute dietary

endpoint attributable to a single exposure, episodic ingestion of granules was not assessed. 

Bystander Inhalation Exposure: Based on the Agency's current practices, residential 

postapplication inhalation risk to children is not assessed; however, bystander exposure could 

occur for children playing in areas adjacent to pesticide applications. For adult bystanders, 

postapplication inhalation exposure is expected to be negligible because (i) technical isoxaben 

has low inhalation toxicity (Category III); (ii) label recommended incorporation by rainfall or 

irrigation after application; (iii) isoxaben has low volatility (vapor pressure of 1.3E-8 Pa at 25 ̊ C, 

McNeilly, July 2010); and (iv) products are not applied using air blast or aerial equipment that 

would result in significant inhalation exposure. However, volatilization of pesticides may be a 

potential source of postapplication inhalation exposure to individuals nearby to pesticide 

applications. The Agency sought expert advice and input on issues related to volatilization of 

pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel 

(SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings /2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, develop policies and procedures to 

identify the need for and, subsequently, the way to incorporate postapplication inhalation 

exposure into the Agency's risk assessments. If new policies or procedures are put into place, the 

Agency may revisit the need for a quantitative postapplication inhalation exposure assessment 

for isoxaben.

Intermediate-term Incidental Oral Exposure to Children resulting from Soil Ingestion: HED 

does not typically consider soil ingestion to occur over intermediate-term durations, i.e., from 1-

6 months, largely due to use pattern and the fact that residues are removed by precipitation or 

through microbial degradation in soil. In the case of isoxaben, HED estimated incidental oral 

exposure from ingestion of soil because the use pattern calls for repeat applications, and because

the environmental fate data indicated that isoxaben is persistent in the soil, with a half life of 

≥150 days (C. Peck., D341497, 3/18/2010). Because of the likely persistence of isoxaben in 

soil, HED conducted a conservative assessment of potential intermediate-term oral risk from soil 

ingestion by using an yearly application rate of 3.0 lb ai/A from Isoxaben 75 DF instead of the 

maximum single rate of 1.0 lb ai/A. 
Isoxaben D376428

Page 40 of 90

To address the persistence of isoxaben in the soil, HED assumed that exposure resulting from 

incidental oral ingestion of soil (intermediate-term) at an exaggerated rate of 3.0 lb ai/A/year 

would be a conservative estimate that would address the potential build up of isoxaben in the 

soil. The exposure and risk from incidental oral ingestion of soil was calculated using the 

following formula:

ADD = (SR * IgR2 * CF4) / BW where, SR = AR * F3 * CF1 * CF2 * CF3 

MOE = NOAEL / ADD

SR = 3.0 lb ai/A * 100%/cm * 4.54E+08 μg/lb * 2.47E-08 A/cm2 * 0.67 cm3 /g soil = 22.54 μg ai/g 

ADD = [22.54 μg ai/g * 100 mg/day * 0.000001 g/μg] / 15 kg = 1.50E-04 mg/kg/day

MOE = 200 mg/kg/day / 1.50E-04 mg kg/day = 1.30E+06

where, 

ADD = Average daily dose (mg/kg/day)

AR = Application rate (3.0 lb ai/A/year) 

BW = Body weight of child (15 kg)

CF1 = Conversion factor for μg/lb (4.54E+08)

CF2 = Conversion factor for A/cm2 (2.47E-08)

CF3 = conversion factor for volume to weight (0.67 cm3/g soil) 

CF4 = conversion factor for g/μg (0.000001)

F3 = Percent of ai available in uppermost cm of soil (100% assumed)

IgR2 = Ingestion rate of soil (100 mg/day)

MOE = NOAEL (intermediate-term, mg/kg/day) / ADD (mg/kg/day)

NOAEL (intermediate-term) = 200 mg/kg/day

SR = Soil residue at intermediate-term (μg ai/g soil) 

t = postapplication day on which exposure is assessed (intermediate-term) 

It is emphasized here that the application rate of 3.0 lb ai/A/year used for estimating the 

intermediate-term exposure is an exaggerated rate when compared with the single application 

rate of 1.0 lb ai/A of granule and DF formulations. At the intermediate-term exposure duration, 

the risk was found to be not of concern to children who may ingest soil treated with isoxaben 

(MOE = 1.30E+06, LOC =100).

6.2 Other (Spray Drift, etc.)

Spray drift is a potential source of exposure for residents living in close proximity to spraying 

operations. This situation is particularly the case with aerial application. However, to a lesser 

extent, spray drift resulting from the ground application of isoxaben could also be a potential 

source of exposure. The Agency has been working with the Spray Drift Task Force (a 

membership of US pesticide registrants), EPA Regional Offices, State lead Agencies for 

pesticide regulation, and other parties to develop the best spray drift management practices. The 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, and is developing a policy on how to appropriately 

apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied 

by air, orchard airblast, and ground hydraulic methods. After the policy is in place, the Agency

may impose further refinements in spray drift management practices to reduce off-target drift

and risks associated with pesticide application.
Isoxaben D376428

Page 41 of 90

7.0 Aggregate Risk Assessments and Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks

from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure. 

7.1 Acute Aggregate Risk

An acute reference dose has not been established for either the general population (including 

infants and children) or for females ages 13-49 years. There were no studies that demonstrated 

evidence of toxicity attributable to a single dose. As a result, a quantitative acute dietary

exposure assessment has not been performed, and acute aggregate risk is not of concern.

7.2 Short-Term and Intermediate-Term Aggregate Risk

Short- and intermediate-term aggregate exposure takes into account residential exposure plus 

average exposures levels from food and water (considered to be a background exposure level). 

Isoxaben residential uses constitute short- and intermediate-term exposure scenarios; endpoints 

have been selected for intermediate-term incidental oral (children only), and short- and 

intermediate-term inhalation exposures. The target MOEs for short-term and intermediate-term 

exposures are both 100.

For children, an intermediate–term aggregate assessment was conducted by adding the incidental 

soil ingestion exposure (see Section 6.1) and average food and water exposure (chronic dietary

exposure). A short-term aggregate assessment for children was not conducted due to the absence 

of an appropriate end-point. For adults, a short-term aggregate assessment was conducted by

adding inhalation exposure (assuming that the inhalation exposure is toxicologically equivalent 

to oral exposure), resulting from residential lawn treatment, with the average food and water 

exposures. Since exposures from the use of the granular formulation in a push-type applicator 

resulted in the highest exposure, that short-term exposure scenario was evaluated. The liquid 

formulation applied in a hose-end sprayer also reflects short-term exposure (only two 

applications per year) and has less exposure and risk. Children are not expected to make 

pesticide treatments with isoxaben.

For all of the population subgroups shown in Table 7.1., short- and intermediate-term aggregate 

risk estimates do not exceed HED’s level of concern (i.e., an MOE < 100) for any of the 

residential exposure scenarios examined. The short-term aggregate risk MOEs range from 

62,000 to 66,000, for the U.S. population and females 13-49, respectively. The intermediateterm aggregate risk estimate is 51,000 for children 1-2 years old. The incidental oral residential 

exposure value selected for the aggregate analysis is based on children ingesting soil particles 

containing pesticide residues while playing in treated turf. Due to the persistence of isoxaben in 

the soil, HED took a conservative approach by using the maximum seasonal application rate for 

estimating soil ingestion by children rather than the standard maximum single application rate. 

This scenario resulted in the highest calculated exposure levels, and, therefore, is protective for 
Isoxaben D376428

Page 42 of 90

all other postapplication risk for children in residential settings.

Table 7.1. Aggregate Risk Calculations

Population NOAEL

mg/kg/day LOC1

Max 

Allowable

Exposure2

mg/kg/day

Average

Food & 

Water

Exposure

mg/kg/day

Residential

Exposure3

mg/kg/day

Aggregate MOE

(food and

residential)4

US Population 200 100 2.0 0.002536 6.94E-04 62, 000

Females 13-49 200 100 2.0 0.002356 6.94E-04 66, 000

Children 1-2 

years old5

200 100 2.0 0.003794 0.00015 51,000

1

The LOC includes the standard inter- and intra species uncertainty factors for a total of 100.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure (adults and reproductive females) = [ Inhalation Exposure]. See Table 6b. Residential 

Exposure (children) = [ Incidental Soil Ingestion] See Section 6.1. 

4 Aggregate MOE = [(NOAEL(Avg. Food & Water Exposure + Residential Exposure)]

5 Children 1-2 were selected for the aggregate risk evaluation as the sentinel population, i.e., a subpopulation more 

likely to be exposed than infants <1 year old. Infants <1 year old did have a higher background (chronic dietary)

exposure, and the MOE for that population subgroup is 24,000.

A short- and intermediate-term dermal risk was not estimated due to the lack of an appropriate 

end-point.

7.3 Chronic Aggregate Risk

Since there are no long-term or chronic residential scenarios associated with isoxaben uses, the

chronic aggregate risk is equivalent to the chronic dietary (food and drinking water) risk. As 

shown in Table 5.2.2, these risks are not of concern.

7.4 Aggregate Cancer Risk

Isoxaben was reviewed by the Cancer Assessment Review Committee (CARC) to determine the 

cancer classification under the current (2005) US EPA Guidelines for Assessment of 

Carcinogenicity. Isoxaben is classified as “Suggestive Evidence of Carcinogenic Potential,” 

based on an increased incidence of benign hepatocellular tumors in male and female mice 

(Isoxaben: Second Report of the Cancer Assessment Review Committee, dated October 7, 2008). 

The liver tumors were observed only in one species, were not malignant and were observed in 

the presence of liver toxicity at dietary levels exceeding the limit dose (1000 mg/kg/day). The 

chronic RfD/PAD is based on the chronic toxicity NOAEL of 5 mg/kg/day in the rat, which is 

more than 200-fold lower than the dose at which tumors were observed in the mouse. Therefore, 

the cRfD/PAD is considered to be protective of potential carcinogenicity. As noted above, 

chronic aggregate risk estimates do not exceed HED’s level of concern. 
Isoxaben D376428

Page 43 of 90

8.0 Cumulative Risk Characterization/Assessment

FQPA (1996) stipulates that when determining the safety of a pesticide chemical, EPA shall base 

its assessment of the risk posed by the chemical on, among other things, available information 

concerning the cumulative effects to human health that may result from dietary, residential, or 

other non-occupational exposure to other substances that have a common mechanism of toxicity. 

The reason for consideration of other substances is due to the possibility that low-level exposures 

to multiple chemical substances that cause a common toxic effect by a common mechanism 

could lead to the same adverse health effect as would a higher level of exposure to any of the 

other substances individually. A person exposed to a pesticide at a level that is considered safe 

may in fact experience harm if that person is also exposed to other substances that cause a 

common toxic effect by a mechanism common with that of the subject pesticide, even if the 

individual exposure levels to the other substances are also considered safe.

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to isoxaben and any other substances, and isoxaben does not appear to produce a toxic metabolite 

produced by other substances. For the purposes of this tolerance action, therefore, EPA has not 

assumed that isoxaben has a common mechanism of toxicity with other substances. For 

information regarding EPA’s efforts to determine which chemicals have a common mechanism 

of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements 

released by EPA’s Office of Pesticide Programs concerning common mechanism determinations 

and procedures for cumulating effects from substances found to have a common mechanism on 

EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Pathway

D374750, S. Oonithan, 7/16/2010.

No chemical-specific data for assessing handler exposures were submitted to the Agency in 

support of the proposed uses associated with the subject petition. Therefore, when estimating 

occupational exposures, HED used: 1) surrogate data from the Pesticide Handlers Exposure 

Data Base (PHED v1.1); 2) standard assessment variables established by the Health Effects 

Division Science Advisory Council for Exposure (e.g. maximum application rates, standard acres 

treated per day, 60 kg body weight for workers); and, 3) standard protection factors assumed 

with specified personal protective equipment. The estimated exposures are believed to be 

reasonable high-end estimates.

The proposed use pattern for isoxaben in orchards of tree nuts and grapes is expected to result in 

short- and intermediate-term occupational inhalation and dermal exposures to mixers, loaders, 

and applicators. Short- and intermediate-term dermal MOEs were not calculated due to the 

absence of respective endpoints.

9.1 Short-Term and Intermediate-Term Handler Risk

The registrant has not submitted a chemical specific exposure study to determine the dermal and 

inhalation unit exposures (exposed ai per lbs of ai handled per day) needed to estimate the 

exposure to handlers. In the absence of chemical-specific data, surrogate unit exposures were 
Isoxaben D376428

Page 44 of 90

selected from PHED that are specific to the formulation, application equipment and personal 

protective equipment (PPE). ExpoSAC Policy No. 9 estimates that 40-200 acres can be 

treated/day with a tractor mounted ground boom sprayer depending upon the crop treated. For 

this assessment, 80 A/day was selected as a high end average for the orchard setting based on 

treatment of one row at a time, thereby reducing the acreage treated on a given day. Areas not 

covered with a ground-boom sprayer or spot treatments may be treated using a tractor mounted 

low-pressure hand wand sprayer. It is assumed that a handler (M/L/A) can mix, load and apply

40 gal/day (ExpoSAC Policy No. 9); at the label recommended spray volume of 10 gal/A (4 

acres/day), HED estimates 4 acres/day could be treated for the low-pressure hand wand (tractor 

mounted) scenario.

Baseline PPE (long sleeved shirt, pants and shoes with socks) was used as a starting point to 

calculate handler exposures. For the present assessment, additional protection (e.g., respirators, 

and engineering controls (enclosed cab and cockpit, closed systems)) was not needed to obtain 

an MOE that is higher than the LOC.

The label allows only 1 application of FN-3133 (a 75% DF formulation) at the maximum single 

rate of 1.0 lb ai/A (harvest to harvest) on tree nuts, grape, and non-bearing fruit tree and 

grapevine orchards, resulting in short-term exposure to occupational handlers. However, it is 

possible that contract applicators may use FN-3133 Herbicide on several fields, with sequential 

applications lasting longer than a month during the weed growing season, resulting in 

intermediate-term exposure to handlers.

A bodyweight of 60 kg was used for handlers because the toxicity endpoints selected for 

assessing inhalation risks are based on offspring effects in the reproductive toxicity study.

Summaries of the short- and intermediate-term inhalation risks for handlers are included in Table 

9.1. The maximum application rate for each exposure scenario is presented as the worst case 

scenario. All handler scenarios resulted in total MOEs greater than the LOC (MOEs ≥ 100) at 

baseline. The intermediate-term combined dermal and inhalation MOEs ranged from 2,700 to 

200,000 for handlers, which are not of concern.

Table 9.1. Short- and Intermediate-term Exposures Resulting from the Use of FN-3133 Specialty Herbicide and 

AmoreTM DF Herbicide in Orchards of Bearing and Non-bearing Fruit and Nut Trees and Grape Vines 1.

Exposure Scenario Appl. rate

Area 

treated

(A/day)

PPE & 

Eng.

Control 2

Inhal. unit 

exposure 

(mg/lb ai) 3

Inhalation, Short- and 

Intermediate-term 

Exposure 

mg/kg/day 4 MOE 5

1. Mixing/loading DF 

for ground boom

spray (open mixing)

1.0 lb al/A

80 Baseline 0.00077 0.00103 190,000

2. Applying spray 

using ground boom

Baseline & 

open cab. 0.00074 0.00099 200,000

3. Mixing, loading, 

and applying using a 

tractor powered lowpressure hand wand

4

Baseline 1.1 0.07333 2,700

1. MOE = Margin of exposure and PPE = Personal protective equipment. The inputs used for calculations are 

explained under Exposure Scenarios, Inputs and Assumptions. 
Isoxaben D376428

Page 45 of 90

2. Baseline PPE includes long sleeved shirt, long pants and shoes with socks. Engineering controls include open cab 

(tractor) for applicators. 

3. Lacking unit exposures in PHED for a DF formulation, unit exposures for mixing, loading and applying a 

wettable powder formulation with a low-pressure handwand were used as surrogate. 

4. Inhalation exposure = [Inhalation unit exposure (mg/lb ai) * appl. rate (lb ai/A) * area treated/day (acres) * 

inhalation absorption 100 %] / body wt (60 kg).

5. MOE = Short- and intermediate-term NOAEL (200 mg/kg/day) /inhalation exposure (mg/kg/day).

9.2 Short-/Intermediate-Term Postapplication Risk

Workers entering treated areas to do crop-related cultural practices such as irrigation, scouting, 

pruning, etc., may be exposed to isoxaben residues via dermal and inhalation routes for shortterm durations. However, postapplication dermal risk for workers is not of concern because of 

the absence of a short-term dermal endpoint. 

Based on the Agency's current practices, a quantitative occupational postapplication inhalation 

exposure assessment was not performed for isoxaben at this time. However, there are multiple 

potential sources of postapplication inhalation exposure to individuals performing 

postapplication activities in previously treated fields. These potential sources include 

volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. 

The Agency sought expert advice and input on issues related to volatilization of pesticides from 

its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in 

December 2009. The Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available postapplication inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

postapplication inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

postapplication inhalation exposure assessment for isoxaben.

Restricted Entry Interval: A 12-hour REI for isoxaben was set based on the acute toxicity

properties of the technical material which is classified as Categories III (acute dermal, inhalation 

and eye irritation) and IV (acute oral and skin irritation). Isoxaben is not a dermal sensitizer. 

The 12-hour REI is appropriate for isoxaben based on the WPS for agricultural pesticides.

10.0 Data Needs, Label Recommendations & Environmental Justice

10.1 Toxicology

Additional toxicology data are required to support registration of isoxaben. Although isoxaben 

did not show evidence of neurotoxicity or immunotoxicity in the available studies, in accordance 

with the revised 40 CFR Part 158 Guidelines, acute and subchronic neurotoxicity studies in the 

rat and an immunotoxicity study are required. The registrant in a May 20, 2010 letter to the EPA 

stated that they were developing these data for submission. A 90-day inhalation toxicity study in 

the rat is required based on the potential for inhalation exposure. These study requirements were 

identified during the Registration Review Scoping process for isoxaben. In response to the 

scoping document, the Registrant has submitted a waiver request for the inhalation study, which 
Isoxaben D376428

Page 46 of 90

will be reviewed by the Agency. (Note: One of the incidents discussed in Section 4 involved 

potential post-application inhalation exposure.)

10.2 Residue Chemistry

A revised Section F should be submitted with grape juice and raisins removed and the tolerance 

for almond hulls revised to 0.40 ppm. The proposed tolerances for the tree nut group and 

pistachios should be revised to 0.02 ppm and the commodity definition for the tree nut group 

should be revised to “Nut, tree, Group 14.” 

NOTES: The submitted livestock metabolism study is sufficient for the proposed uses currently 

under review. However, additional ruminant metabolism data with better identification and 

characterization of the residue will be needed for any additional uses of isoxaben that result in 

significantly higher livestock dietary burdens. 

HED’s review of the livestock metabolism indicates that a cattle feeding study is not needed for 

the proposed uses currently under consideration. However, a cattle feeding study may be needed 

for any additional uses of isoxaben that result in significantly higher livestock dietary burdens.

NOTE: The hydroxylated metabolites of isoxaben are assumed to have comparable toxicity to 

the parent due to structural similarity; therefore, for any future uses on grains or grasses, the 

petitioner is advised to include residue data on the three hydroxylated metabolites as they are 

likely to be included (at least for risk assessment purposes) on those crops.

10.3 Occupational and Residential Exposure

Based on the Agency's current practices, a quantitative postapplication inhalation exposure 

assessment was not performed for isoxaben at this time because of (i) the absence of a short-term 

inhalation endpoint; (ii) the low acute inhalation toxicity of isoxaben (Toxicity Category III); and 

(iii) the soil-directed application method, which does not include the use of air blast or aerial 

equipment that could result in higher postapplication inhalation exposures. However, 

volatilization of pesticides may be a source of postapplication inhalation exposure to individuals 

nearby pesticide applications. The Agency sought expert advice and input on issues related to 

volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report 

on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies 

and procedures to identify the need for and, subsequently, the way to incorporate postapplication 

inhalation exposure into the Agency's risk assessments. If new policies or procedures are 

developed, the Agency may revisit the need for a quantitative postapplication inhalation 

exposure assessment for isoxaben. 

10.4 Label recommendations

The label should specify that non-bearing nut tree or vines means trees or vines where nuts 

and/or grapes are not harvested for food/wine within one year of treatment.
Isoxaben D376428

Page 47 of 90

10.5 Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations,”

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED estimates 

risks to population subgroups from pesticide exposures that are based on patterns of that 

subgroup’s food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Extensive data on food consumption patterns are compiled 

by the USDA under the Continuing Survey of Food Intakes by Individuals (CSFII) and are used 

in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed 

and categorized by subgroups based on age, season of the year, ethnic group, and region of the 

country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups 

and exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, nondietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 

postapplication are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary

patterns among specific subgroups.

References: 

European Union Food Safety Authority (EFSA), Draft Report for Isoxaben; May, 2006. 

http://www.efsa.europa.eu/en/scdocs/scdoc/58r.htm.

Jones, R. D., S. Abel, W. R. Effland, R. Matzner, R. Parker. 1998. An Index Reservoir for Use 

in Assessing Drinking Water Exposure. Proposed Methods for Basin-scale Estimation of 

Pesticide Concentrations in Flowing Water and Reservoirs for Tolerance Reassessment. 

Presentation to FIFRA Science Advisory Panel, June 29-30, 1998. Online at: 

http://www.epa.gov/scipoly/sap/1998/index.htm

USEPA. 2002. SCIGROW: Users Manual. Online at: http://www.epa.gov/oppefed1/models/ 

water/#scigrow

D341567. Isoxaben: Registration Review Scoping Document for Human Health Assessments; 

PC Code: 125851; Registration Review Case Number: 7219. August 16, 2007. Charles Smith

D341543. Isoxaben. Addendum to the Registration Review Scoping Document for Human 

Health Assessments. June 10, 2008. Linnea Hansen, Ph.D.

 

PP #5G3216. EL-107® on wheat and barley. Comments on the analytical method and residue 

data. RCB #591, J. Worthington, 5/17/85. MRIDs: 073291 and 072296
Isoxaben D376428

Page 48 of 90

D341497, C. Peck; March 18, 2010. Tier I Drinking Water Assessment for the Isoxaben 

Proposed New Use on Bearing Nut Trees and Vineyards.

D340895, D. McNeilly, July 21, 2010. Isoxaben. Petition for Establishment of Tolerances for 

Residues of Isoxaben in/on Grapes and Tree Nuts (including Pistachio). Summary of Analytical 

Chemistry and Residue Data.

D375246, E. Holman; July 13, 2010. Isoxaben: Chronic Aggregate Dietary Exposure (Food and 

Drinking Water) and Risk Assessment for the Section 3 Registration on Grapes.

D368834, S. Oonithan; July 26, 2010. Isoxaben: Occupational and Residential Exposure 

Assessment for the Registration of a New End-use Product Formulation for Use in Orchards of 

Nut Trees, Grapes and Non-bearing Fruit and Nut Trees. 

D353925, S. Oonnithan, 4/13/09. Isoxaben: Occupational and Residential Exposure Assessment 

for the Registration of Two New Formulations for Use on Residential Lawns.

Isoxaben: Second Report of the Cancer Assessment Review Committee. October 7, 2008.

Review of Isoxaben Incident Reports, M. Hawkins; Aug 30, 2007
Isoxaben D376428

Page 49 of 90

Appendix A: Toxicology Assessment

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use for are shown below in Table 1. Use of the new guideline numbers 

does not imply that the new (1998) guideline protocols were used.

Test Isoxaben Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity ..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Primary Eye Irritation....................................................

870.2500 Primary Dermal Irritation ..............................................

870.2600 Dermal Sensitization......................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)...............................................

870.3150 Oral Subchronic (nonrodent).........................................

870.3200 21-Day Dermal ..............................................................

870.3250 90-Day Dermal ..............................................................

870.3465 90-Day Inhalation..........................................................

yes

yes

yes

no

yes

yes

yes

yes

-

no

1

870.3700a Developmental Toxicity (rodent)...................................

870.3700b Developmental Toxicity (nonrodent).............................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200a Oncogenicity (rat)..........................................................

870.4200b Oncogenicity (mouse)....................................................

870.4300 Chronic/Oncogenicity....................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.....................

870.5300 Mutagenicity—Gene Mutation - mammalian................

870.5375 Mutagenicity—Structural Chromosomal Aberrations...

870.5550 Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)...............................

870.6100b 90-Day Neurotoxicity (hen)...........................................

870.6200a Acute Neurotoxicity Screening Battery (rat) .................

870.6200b 90-Day Neurotoxicity Screening Battery (rat)...............

870.6300 Develop. Neurotoxicity .................................................

no

no

yes

yes

no

--

--

no

no

--

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration........................................................

yes

yes

yes

yes

870.7800 Immunotoxicity series......................................................... yes no

Special Studies for Ocular Effects

Acute Oral (rat)...........................................................

Subchronic Oral (rat) ..................................................

Six-month Oral (dog)..................................................

no

no

no

--

--

--

1 - A recent study waiver request from the registrant is being evaluated.
Isoxaben D376428

Page 50 of 90

A.2.1 Acute Toxicity Profile for Isoxaben (95.86%)

A.2.1 Acute Toxicity Profile - Test Substance 

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral - rat 00132126 LD50 > 10,000 

mg/kg (both 

sexes)

IV

870.1200 Acute dermal - rabbit 00153112 LD50 > 2000 

mg/kg (both 

sexes)

III

870.1300 Acute inhalation - rat 00132127 LC50 > 1.99 mg/L 

(both sexes)

III

870.2400 Acute eye irritation - rabbit 00132127 Slight irritation at 

28 mg on eye

III

870.2500 Acute dermal irritation - rabbit 00132127 Non-irritating IV

870.2600 Skin sensitization - guinea pig 00137846 Not a sensitizer 

(Buehler method)

N/A
Isoxaben D376428

Page 51 of 90

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral 

toxicity (rat)

MRID 00153116 (1984)

Acceptable/guideline

0, 0.05, 0.14, 0.42 or 

1.25% via diet (0/0, 

32/36, 94/104, 285/312 or

853/946 mg/kg/day in 

males/females)

LOAEL was not observed (> 853/946 

mg/kg/day). 

NOAEL = 853/946 mg/kg/day in 

males/females (HDT).

870.3100 90-Day oral 

toxicity (rat)

MRID 00134493 (1982)

Acceptable/guideline

0, 1.25, 2.5 or 5.0% via 

diet (0/0, 905/964, 

1813/1939 or 3701/3962 

mg/kg/day in 

males/females)

LOAEL (females) = 1939 mg/kg/day, based on 

slightly decreased body weight gain and food 

efficiency. LOAEL (males) was not observed

(> 3701 mg/kg/day). 

NOAEL = 964 mg/kg/day NOAEL (males = 

3701 mg/kg/day (HDT).

870.3100 90-Day oral 

toxicity (mouse)

MRIDs 00164549 and 

00164550 (1985)

Acceptable/guideline

0, 0.001, 0.01, 0.14 or 

1.25% via diet (0, 1.5, 15, 

210 or 1875 mg/kg/day)

LOAEL was not observed (>1875 mg/kg/day). 

NOAEL = 1875 mg/kg/day (HDT).

Assays of hepatic enzymes showed treatmentrelated induction that recovered after cessation 

of exposure and was considered adaptive.

870.3150 90-Day oral 

toxicity (dog)

MRID 00153115 (1984)

Unacceptable/guideline; 

not upgradable (the dogs 

could have tolerated a 

higher dose)

0, 25, 100 or 500 

mg/kg/day by capsule

LOAEL was not observed (>500 mg/kg/day). 

NOAEL = 500 mg/kg/day (HDT).

870.3150 90-Day oral 

toxicity (dog)

MRID 00132134 (1982)

Acceptable/guideline

0, 250, 500, or 1000 

mg/kg/day by capsule

LOAEL was not observed (>1000 mg/kg/day). 

NOAEL = 1000 mg/kg/day.

870.3200 21-Day dermal 

toxicity (rat)

MRID 00137849 (1983)

Acceptable/guideline

250, 500 or 1000 

mg/kg/day

LOAEL was not observed (1000 mg/kg/day). 

NOAEL = 1000 mg/kg/day (HDT).

870.3700a Prenatal 

developmental in 

(rat)

MRID 00153119 (1984)

Acceptable/guideline

0, 100, 320 or 1000 

mg/kg/day by gavage

Maternal LOAEL was not observed (>1000 

mg/kg/day).

Maternal NOAEL = 1000 mg/kg bw/day

Developmental LOAEL was not observed 

>1000 mg/kg/day).

Developmental NOAEL = 1000 mg/kg /day

870.3700b Prenatal 

developmental in 

(rabbit)

MRID 00153118 (1984)

Acceptable/guideline

0, 100, 320 or 1000 

mg/kg/day by gavage

Maternal LOAEL was not observed ( >1000 

mg/kg/day). 

Maternal NOAEL = 1000 mg/kg/day (HDT).

Developmental LOAEL was not observed

(>1000 mg/kg/day). Developmental NOAEL = 
Isoxaben D376428

Page 52 of 90

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

1000 mg/kg/day (HDT).

870.3800 Reproduction and 

fertility effects

(rat) 

MRID 00153529 (1984)

Acceptable/guideline

0, 0.05, 0.25 or 1.25% in 

the diet (0, 40, 200 or

1000 mg/kg/day)

Matings conducted twice 

with F0 parental animals 

(F1a and F1b litters); 

three times with F1 

parental animals (F2a, 

F2b and F2c litters) and 

once with F2 parental 

animals (F3a litters). The 

F2c and F3a litters were 

assessed in utero on GD 

20 for developmental 

effects. All other litters 

were assessed following 

delivery according to 

standard reproductive 

toxicity study procedures.

Parental LOAEL = 200 mg/kg/day, based on 

decreased body weights/body weight gains

during the growth phase in F2 females; 

decreased body weights in F2a and F2b females 

during gestation and F2b females during 

lactation; and decreased feed efficiency in F2 

females during the growth phase. 

Parental NOAEL = 40 mg/kg/day.

Offspring LOAEL = 1000 mg/kg/day, based on 

decreased pup body weights during lactation 

(all generations), possible increased incidence 

of microphthalmia, exencephaly and 

hydroureter, decreased gestation survival (F2b) 

and live fetuses/litter (F2c and F3a).

Offspring NOAEL = 200 mg/kg/day

Reproductive LOAEL = 1000 mg/kg/day, 

based on decreased corpora lutea (F2c and 

F3a), implantations (F2c and F3a), mean 

number of live pups/litter (F2b), gestation 

survival (F2b) and live fetuses/litter (F2c and 

F3a). 

Reproductive NOAEL = 200 mg/kg/day.

870.4100a Chronic toxicity

(rat) – One year 

duration (also see 

two-year chronic 

toxicity/carcinogen

icity study, MRID 

00164553)

MRID 00164552 (1984)

Acceptable/guideline

0, 0.0125, 0.125 or 1.25%

in the diet 

(0, 6.25, 62.5 or 625 

mg/kg/day)

LOAEL = 625 mg/kg/day, based on decreased 

body weight gain and food efficiency in 

females.

NOAEL = 62.5 mg/kg/day.

870.4100b Chronic toxicity 

(dog)

MRID 00164551 (1985)

Acceptable/guideline

0, 10, 100 or 1000 

mg/kg/day by capsule

LOAEL was not observed (>1000 mg/kg/day). 

NOAEL = 1000 mg/kg/day (HDT).

870.4200a Carcinogenicity

(rat) See 870.4300, below

870.4200b Carcinogenicity

(mouse)

MRID 00164554 (1985)

Acceptable/guideline

0, 100, 1000 or 12,500 

ppm in the diet (0, 15, 150 

or 1875 mg/kg/day)

LOAEL = 1875 mg/kg/day, based on decreased 

body weights and body weight gains in males 

and hepatotoxicity in both sexes.

NOAEL = 150 mg/kg/day

At 1875 mg/kg/day, increased incidences of 

hepatocellular adenoma were noted in both 

sexes.

870.4300 Combined 

carcinogenicity/chr

MRID 00164553 (1985)

Acceptable/guideline

LOAEL = 50.7 mg/kg/day in males, based on 

gross whole tissue alteration in the kidney and 

progressive glomerulonephrosis . 646.6 
Isoxaben D376428

Page 53 of 90

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

onic toxicity (rat) 0, 0.0125, 0.125 or 1.25% 

in the diet (0/0, 5.0/6.2, 

50.7/61.8 or 526.5/646.6 

mg/kg/day in 

males/females)

mg/kg/day in females, based on decreased body 

weight gain and progressive 

glomerulonephrosis.

NOAEL = 5.0 mg/kg/day in males (61.8 

mg/kg/day in females).

870.5100 Bacterial Gene 

Reverse Mutation 

S. typhimurium

Ames Assay, 

strains TA 98, 100, 

1535, 1537, 1538

MRID 00132136 (1984) 

Acceptable/guideline

31, 62.5, 125, 250 or 500 

μg/plate (with or without

activation)

Negative. There was no evidence of induced 

reverse mutations with or without activation up 

to precipitating doses.

870.5100 Bacterial Gene 

Reverse Mutation

S. typhimurium

TA98, 100, 1535, 

1537

E. coli WP2uvrA40485701 (1987)

Acceptable/guideline

31 to 500 μg/plate with and 

without S9 activation

Negative. There was no evidence of induced 

reverse mutation with or without activation.

870.5100 Bacterial Gene 

Reverse Mutation

E. coli WP2uvrA40485702 (1987)

Acceptable/guideline

31 to 500 μg/plate with 

and without S9 activation

Negative. There was no evidence of induced 

reversed mutation with or without activation.

870.5300 In Vitro

Mammalian Cell 

Forward Gene 

Mutation

Mouse lymphoma 

L5178Y cells

00132138 (1983) 

Acceptable/guideline

1, 10, 50, 75, 100, 150, 

200 or 250 μg/mL (nonactivated)

0.5, 1, 2, 4, 6, 8, 10 or 12 

μg/mL (activated)

Negative. There was no evidence of induced 

forward mutations with or without activation up 

to cytotoxic concentrations.

870.5375 In Vitro

Mammalian 

Chromosome 

Aberration 

CHO cells

40435901 (1987)

Acceptable/guideline

10, 20, 40 or 80 μg/mL 

without S9

25, 50, 100, 200 μg/mL 

with S9

Negative. There was no treatment-related 

increase in the frequency of chromosomal 

aberrations up to precipitating concentrations.

870.5395 In vivo Mammalian 

Micronucleus 

Assay 

Mouse (male)

00164555 (1984)

Unacceptable/guideline 

(results inconclusive)

5000 mg/kg

Inconclusive. Slight, significant increases in 

the frequency of micronucleated polychromatic 

erythrocytes were noted at 24 and 48 h, but not 

at 72 h.

870.5395 In vivo Mammalian 

Micronucleus 

Assay 

Mouse (male)

40485704 (1984)

Acceptable/guideline 

(results inconclusive)

800, 2000 or 5000 mg/kg

Weakly positive. Slight, statistically significant

increases in the frequency of micronucleated 

polychromatic erythrocytes were noted at 24 

hrs.

870.5395 In vivo Mammalian 

Micronucleus 

47170002 (1992)

Acceptable/guideline

0, 1250, 2500 or 5000 

Negative. There was no significant increase in 

the frequency of micronucleated polychromatic 

erythrocytes in bone marrow of mice up to the 
Isoxaben D376428

Page 54 of 90

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

Assay 

Mouse (male and 

female)

mg/kg limit dose.

870.5450 Rodent Dominant 

Lethal Assay

Rat

00164556 (1985)

Unacceptable/guideline 

(upgradable, pending 

submission of positive 

control data)

0, 34, 173, 932 mg/kg/day

Negative. There was no evidence of a 

dominant lethal effect in the progeny of male 

rats.

870.5550 Unscheduled DNA 

synthesis

Rat cultured 

hepatocytes

00132137 (1982)

Acceptable/guideline

eight concentrations 

ranging from 0.5-1000 

nmoles/mL

Negative. There was no evidence that 

unscheduled DNA synthesis, as determined by 

radioactive tracer procedures [nuclear silver 

grain counts], was induced. Cytotoxicity was 

not observed.

870.5915 In Vivo Sister 

Chromatid 

Exchange in

Chinese hamster

40485703 (1987)

Acceptable/guideline

800, 2000 or 5000 mg/kg

Negative. There was no increase in sister 

chromatid exchange frequency up to the limit 

dose.

870.7485 Metabolism and 

pharmacokinetics

(rat)

00153114; 00164557; 

00164558; 00164559 

(1984-1986)

Acceptable/guideline

250 mg/kg, single oral 

dose for expired air, 

excretion and metabolite 

identification and multiple 

oral dose for excretion

1000 mg/kg, single oral 

dose, tissue distribution

After 72 hours, 90% of the dose was recovered 

in the feces, mostly as parent. Approximately 

half the absorbed dose was excreted in the urine 

and the other half in the feces as metabolites. 

The urine contained 15-20 metabolites. 

Identification of urinary metabolites led to the 

conclusion that the major metabolic 

transformation involved oxidation of the test 

compound at position 2 of the alkyl side chain 

to produce either an alcohol or a ketone, 

hydroxylation of the aromatic ring adjacent to 

one of the methoxy substituents, and Odemethylation of one of the methoxy 

substituents. Fecal metabolites were not 

identified. Generally, there were no major 

differences in the excretion or metabolism of 

the test compound between sexes. Excluding 

the GI tract and residual carcass, highest tissue 

levels were isolated in the liver at 4 and 24 

hours post-dose. Tissue levels were lower at 24 

hrs than 4 hrs except for the colon. Predosing 

of the animals with cold 250 mg/kg isoxaben, 

did not significantly change the pattern of 

urinary and fecal excretion of isoxaben. 

Significant amounts of radioactivity did not 

remain in the organs and tissues at 7 days postdose. Expired air accounted for <3% of the 

dose.

870.7485 Metabolism and 

pharmacokinetics 

(rat)

00132131; -32; -33 (1982)

Acceptable/guideline

10, 100, 250, 500 or 1000 

Most of the administered radioactivity was 

excreted by 24 hrs postdosing. The major route 

of elimination was via feces (>85%), with a 
Isoxaben D376428

Page 55 of 90

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

mg/kg, single dose 

excretion;

10 or 250 mg/kg, biliary 

excretion

250 mg/kg-tissue 

distribution

dose-related decrease in urinary excretion due 

to poor gastrointestinal absorption. Urine and 

fecal excretion ranged from 70.8%-94.9% of 

dose (males) and 88.2% to 106.3% (females) of 

dose. Biliary excretion was observed at 10 

mg/kg (23.1% and 38.8% of dose in males and 

females, respectively) but was decreased as a 

percent of dose at 250 mg/kg (17.5% and 

15.3%, males and females, respectively), 

indicating rate-limiting gastrointestinal 

absorption. Following a single 250 mg/kg 

dose, radioactivity was widely distributed with 

the highest levels seen in liver (except for the 

intestinal tract). Most tissue levels decreased 

between 4 and 24 hr postdosing except for 

pituitary and thyroid in females. Tissue:plasma 

ratios decreased by 24 hr except in the thyroid, 

adrenals, eyes and pituitary of both sexes, and 

ovaries in females. Tissue levels were not 

analyzed at later times.

870.7600 In Vivo Dermal 

Penetration

Rhesus Monkey

MRID 00153113 (1983)

Acceptable/non-guideline

2 mg/kg by intravenous 

injection compared to 2 

mg/kg by dermal 

application

Dermal absorption was estimated to be between 

7.5 and 11%.

A.3 Executive Summaries

A.3.1 Subchronic Toxicity

870.3100 90-Day Oral Toxicity - Rat

(1) In a subchronic oral toxicity study (MRID 00134493), 15 Fischer 344 rats/sex/dose group 

were administered EL-107 (Isoxaben technical; 92.4% a.i.; Lot No. B31-72C-88) in the diet at 

doses of 0, 1.25, 2.5, or 5.0% (equivalent to average daily intakes of 0/0, 905/964, 1813/1939, 

and 3701/3962 mg/kg/day in males/females) for 3 months. In addition to standard subchronic 

study parameters, hepatic p-nitroanisole O-demethylase activity was analyzed at necropsy.

No adverse, treatment-related effects were observed on mortality, clinical signs, food 

consumption, hematology, clinical chemistry, organ weights, or gross or histological pathology.

At 2.5% and 5.0%, mean body weight gain and food efficiency in females were decreased by 10-

11% (p≤0.05%) during the last weeks of the study, but no significant changes were observed in 

males. The following differences (p≤0.05, except as noted) were noted between the treated 

groups and the control groups: (i) decreased mean serum alkaline phosphatase levels in the 2.5% 
Isoxaben D376428

Page 56 of 90

and 5.0% groups; (ii) decreased serum creatinine in all treated female groups; (iii) increased 

blood glucose in the 5.0% females; (iv) increased hepatic p-nitroanisole O-demethylase activity

in all treated groups (but the increase was not statistically significant in the 5.0% males); (v) 

increased absolute and relative to body liver weights in all treated groups; and (vi) increased 

relative to body kidney weights in all treated groups (but the increase was not statistically

significant at 5.0% in either sex). The effect on hepatic enzyme induction and corresponding 

liver weight increase, without any corroborating clinical chemistry or pathological support for 

hepatotoxicity, suggests that the effect on the liver was adaptive and not adverse. The effects 

observed on clinical chemistry parameters were unconvincing without corroborating pathological 

evidence of an adverse effect.

The LOAEL is 2.5% (1939 mg/kg/day in females), based on slightly decreased body weight gain 

and food efficiency in females. The LOAEL in males is >5.0% (3701 mg/kg/day). The NOAEL 

is 1.25% (905/964 mg/kg/day in females). The NOAEL in males is 5.0% (3701 mg/kg/day). 

This study is classified acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.3100; OECD 408) for a subchronic oral toxicity study in rats.

(2) In a subchronic oral toxicity study (MRID 00153116), 25 Fischer 344 rats/sex/dose group 

were administered EL-107 (Isoxaben technical; 86.7-92.5% a.i.; Lot No. H02-2G6-118) in the 

diet at doses of 0, 0.05, 0.14, 0.42 or 1.25% (equivalent to 0/0, 32/36, 94/104, 285/312, and 

853/946 mg/kg/day in males/females) for 3 months. Fifteen rats/sex/dose group were terminated 

at this time, and subgroups of 10 rats/sex/dose group were fed control diet for 1 month to 

evaluate recovery.

No adverse, treatment-related effects were observed on mortality, clinical signs, body weights, 

food consumption, food efficiency, hematology, organ weights, or histological pathology. 

The following observations were noted and were statistically significant (p≤0.05), but were not 

considered adverse as there were only minor differences from controls: (i) body weights at three 

months were decreased by 5% in both the 0.42% and 1.25% males (females were unaffected); 

(ii) food efficiency was decreased 4% in the 1.25% males and decreased 6-9% in the >=0.14% 

females; and (iii) serum glucose increased by 14% in both the 1.25% males and females. 

Increased (p≤0.05) absolute and relative to body liver weights were noted in all treated female 

groups, and increased (p≤0.05) relative to body liver weights were observed in the 0.42% and 

1.25% males. Increased (p≤0.05) hepatic p-nitroanisole O-demethylase activity was observed in 

the 0.42% males (incr 41%) and the >=0.14% females (incr 30-33%). These differences 

generally returned to normal after the recovery period. Effects on liver weight and enzymes 

were considered adaptive in the absence of other evidence of hepatotoxicity.

The effect on hepatic enzyme induction and corresponding liver weight increase, without any

corroborating clinical chemistry or pathological support for hepatotoxicity, suggests that the 

effect on the liver was adaptive and not adverse.

The LOAEL was not observed. The NOAEL is 1.25% (HDT; equivalent to 853/946 mg/kg/day

in males/females; approximately the limit dose).
Isoxaben D376428

Page 57 of 90

This study is classified acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.3100; OECD 408) for a subchronic oral toxicity study in rats.

870.3100 90-Day Oral Toxicity - Mouse

In a subchronic oral toxicity study (MRID 00164549), 25 B6C3F1 mice/sex/dose group were 

administered EL-107 (Isoxaben technical; 93.7-94.2% a.i.; Lot No. H02-2G6-118) in the diet at 

doses of 0, 0.001, 0.01, 0.14, or 1.25% (approximately equivalent to 0, 1.5, 15, 210, and 1875 

mg/kg bw/day based on a conversion factor of 1 ppm = 0.150 mg/kg bw/day). Up to 15 

mice/sex/dose group were terminated after 3 months, and subgroups of 10 mice/sex/dose group 

were fed control diet for an additional month prior to sacrifice in order to evaluate recovery.

No adverse treatment-related effects were observed on mortality, clinical signs, body weights, 

body weight gains, ophthalmology, hematology, clinical chemistry, organ weights, or gross or 

histological pathology. Food consumption was not measured in this study.

At 0.14% and 1.25%, increased (p≤0.05) absolute liver weights were observed in males, and 

increased (p≤0.01) relative to body liver weights were noted in both sexes. An increased 

incidence of minimal hepatic hypertrophy was noted in males at 0.14% (3/15 treated vs. 0/15 

controls) and 1.25% (9/15 treated). Increased (p≤0.05) hepatic p-nitroanisole O-demethylase 

activity was observed in the 0.14% and 1.25% dose groups. Without further evidence of 

toxicity, these changes were considered adaptive and not adverse. These differences generally

returned to normal after the recovery period.

The LOAEL was not observed. The NOAEL is 1.25% (approximately equivalent to 1875 mg/kg 

bw/day).

This study is classified acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.3100; OECD 408) for a subchronic oral toxicity study in the rodent. An acceptable study in 

the rat is also available (MRID 00153116; TXR#s 005372, 0051626).

870.3150 90-Day Oral Toxicity – Dog

(1) In a subchronic oral toxicity study (MRID 00132134), 4 beagle dogs/sex/dose group were 

administered EL-107 (Isoxaben technical, 93.3% a.i., Lot No. H02-2G6-021) in gelatin capsules 

at doses of 0 (capsule only), 250, 500 or 1000 mg/kg bw/day for 3 months. In addition to 

standard subchronic study parameters, hepatic p-nitroanisole-O-demethylase activity was 

analyzed at necropsy.

No adverse, treatment-related effects were observed on mortality, clinical signs, body weights, 

body weight gains, food consumption, ophthalmology, hematology, clinical chemistry, 

urinalysis, organ weights, or gross or histological pathology. 

One 1000 mg/kg/day male lost 10% of its initial body weight during the study, but had regained 

some of the loss by the end of the test. As no other dogs had significant body weight changes 

and no other evidence of toxicity was noted, this effect was considered incidental (in addition, no 
Isoxaben D376428

Page 58 of 90

body weight effects were reported in the one year dog study at 1000 mg/kg/day; MRID 

00164551). Increased hepatic p-nitroanisole O-demethylase activity was observed in all treated 

groups (between about +60% to +100% of control values), indicating induction of hepatic 

microsomal enzyme activity. Minimal hepatocellular centrilobular hypertrophy was observed in 

one male at 500 mg/kg/day and one at 1000 mg/kg/day. The effects on the liver were considered 

adaptive rather than adverse in the absence of other clinical chemistry and microscopic findings.

It was reported that many dogs in the 500 and 1000 mg/kg/day groups intermittently vomited 

food and/or test compound. These findings were attributed to the large volume of test compound 

administered (up to the limit dose via capsule dosing).

The LOAEL was not observed. The NOAEL is 1000 mg/kg bw/day (the limit dose).

This study is classified acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.3150; OECD 409) for a subchronic oral toxicity study in dogs. 

(2) In a subchronic oral toxicity study (MRID 00153115), 4 beagle dogs/sex/dose group were 

administered EL-107 (Isoxaben technical; 95.5%; Lot No. Z10025) in gelatin capsules at doses 

of 0 (capsules only), 25, 100 or 500 mg/kg bw/day for 3 months. 

No adverse, treatment-related effects were observed on mortality, clinical signs, body weights, 

body weight gains, food consumption, hematology, clinical chemistry, urinalysis, organ weights, 

or gross or histological pathology. Significant treatment-related changes were not found for 

hepatic p-nitroanisole O-demethylase activity.

Absolute and relative to body liver weights were increased (p≤0.05) in the 500 mg/kg/day males. 

In the absence of corroborating evidence of hepatotoxicity, this effect was considered an 

adaptive response. 

The LOAEL was not observed. The NOAEL is 500 mg/kg bw/day.

This study is classified unacceptable/guideline, not upgradeable and does not satisfy the 

guideline requirements (OPPTS 870.3150; OECD 409) for a subchronic oral toxicity study in 

dogs. The animals could have tolerated a higher dose, and the limit dose was not tested. The 

previously conducted subchronic study in dog (MRID 00132134; see this TXR# and TXR# 

003434 for DER and executive summary) indicated that the limit dose should have been selected 

for the high dose and satisfies the guideline requirement for a subchronic oral toxicity study in 

the dog.

870.3200 21-Day Dermal Toxicity – Rabbit

In a 21-day dermal toxicity study (MRID 00137849), EL-107 (Isoxaben technical grade; 94.8% 

a.i.; Lot No. Z10025) was applied to the clipped skin of rabbits (5 sex/dose; New Zealand White) 

for 6 hours/day for 21 consecutive days. One dose group was treated with EL-107 technical 

equivalent to 1000 mg active technical EL-107/kg bw. Group 2 (also 5 animals/sex/dose) was 

treated with 500 mg/kg bw suspension concentration formulation (FN-7033) containing 50% EL-
Isoxaben D376428

Page 59 of 90

107 (250 mg/kg bw). Groups 3 and 4 were treated with 1000 mg/kg of FN-7033 (500 mg/kg bw 

EL-107). All groups were sacrificed after 21 days, except group 4, which was maintained 

without treatment for an additional 2 weeks before sacrifice in order to monitor recovery.

No adverse, treatment-related effects were observed on mortality, clinical signs, dermal effects, 

body weight, food consumption, hematology, clinical chemistry, organ weights, or gross or 

histological pathology.

Systemically, relative to body thyroid/parathyroid weight was increased (p≤0.01) by 77% in the 

1000 mg/kg FN-7033 group. No increase was noted in the recovery group and only slight 

increases (not statistically significant) of 21-23% were observed in the other treated groups. 

Pathological examination did not corroborate thyroid toxicity, and thyroid toxicity was not 

demonstrated in the concurrently submitted toxicity studies. Consequently, the increased thyroid 

weights were considered an equivocal finding.

Systemically, the LOAEL was not observed. The systemic NOAEL was 1000 mg/kg bw/day 

(the limit dose).

Transient dermal irritation was observed in the 1000 mg/kg FN-7033 group (4/20 treated vs. 0/20 

controls) during the first week of treatment. This effect was not observed in the animals treated 

with EL-107 technical and could have been related to some other compound in the formulation. 

There was no morphologic evidence of dermal irritation, and as the incidence of irritation was 

slight and the effect was transient, this effect was not considered adverse.

The dermal LOAEL was not observed. The dermal NOAEL was 1000 mg/kg bw/day (the 

limit dose).

This study is classified as acceptable/guideline and satisfies the guideline requirement for a 21-

day dermal toxicity study (OPPTS 870.3200; OECD 410) in rabbits. 

A.3.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study - Rat

In a developmental toxicity study (MRID 00153119), EL-107 (Isoxaben technical; 95.5%; Lot 

No. Z10025) in 10% aqueous acacia oil was administered by daily gavage (10 mL/kg) to 

presumed pregnant Wistar rats (25/dose group) at dose levels of 0, 100, 320 or 1000 mg/kg 

bw/day on gestation days (GD) 6-15. On GD 20, all dams were euthanized. The uterus was 

removed via cesarean section, and its contents examined. Fetuses were examined for external, 

visceral, and skeletal malformations and variations.

Maternal Toxicity: No treatment-related effects were observed. At 1000 mg/kg/day, mean 

maternal body weight gain was decreased by 15% compared to controls (not analyzed 

statistically) during the interval GD 6-16 (treatment occurred on GD 6-15). Recovery occurred 

post-treatment (GD 17-20), with a cumulative weight gain for GD 0-20 of 7% (p≤0.05). Net 

weight gains of 78.5, 79.6, 75.9 and 76.2 g (control to high dose, respectively) were calculated 

by subtraction of gravid uterine weight from total body weight gain, indicating that by GD20, 
Isoxaben D376428

Page 60 of 90

much of this decrease was secondary to lower gravid uterine weight. Based on the marginal 

changes observed, this was not considered a treatment-related effect. 

The maternal LOAEL was not established (>1000 mg/kg bw/day). The maternal NOAEL 

is 1000 mg/kg bw/day.

Developmental Toxicity: No treatment-related effects were observed. At 1000 mg/kg bw/day, 

slightly increased mean resorptions (control to high dose 0.7, 0.5, 1.1 and 1.6), increased 

postimplantation loss (8.4, 12.6, 8.4 and 16.5%) and a decreased mean number of live fetuses per 

litter (11.5, 11.4, 11.5 and 10.0) were observed. Post-implantation loss increased to 13.8% vs. 

5.7% in controls. A slight increase in incidence of runts was observed (4/240 in 4 litters vs. 

1/265 controls). These effects were not considered treatment-related because values for 

resorptions and postimplantation loss were within published MARTA historical control range. 

Decreases in fetal weights were marginal and not considered treatment-related. Male fetal 

weights were decreased (p≤0.05) by 5% in all treated groups; thus, this effect was unrelated to 

dose. A similar effect was not observed in females. 

The developmental LOAEL was not established (>1000 mg/kg bw/day). The 

developmental NOAEL is 1000 mg/kg bw/day.

This study is classified acceptable/guideline and satisfies the guideline requirement for a 

developmental toxicity study (OPPTS 870.3700; OECD 414) in rats. 

870.3700b Prenatal Developmental Toxicity Study – Rabbit

In a developmental toxicity study (MRID 00153118), EL-107 (Isoxaben technical; 95.5%; Lot 

No. Z10025) in 10% aqueous acacia oil was administered by daily oral gavage (10 mL/kg) to 

inseminated Dutch Belted rabbits (20/dose group) at dose levels of 0, 100, 320, or 1000 mg/kg 

bw/day on gestation days (GD) 6-18. On GD 28, all dams were euthanized. The uterus was 

removed via cesarean section, and its contents examined. Fetuses were examined for external, 

visceral, and skeletal malformations and variations.

There were no treatment-related effects on survival, clinical signs, body weight, food 

consumption, or cesarean parameters. 

One mortality occurred on GD 28 in a 1000 mg/kg/day pregnant dam. Another 1000 mg/kg/day

dam aborted on GD 22 and was sacrificed. This abortion and death were attributed to nutritional 

deprivation as a result of partial or complete blockage of the digestive system by hair.

The maternal LOAEL was not observed. The maternal NOAEL is 1000 mg/kg bw/day (the 

limit dose).

There were no treatment-related effects on developmental parameters. There were no effects of 

treatment on numbers of litters, live fetuses, dead fetuses, or sex ratio. There were no treatmentrelated external, visceral, or skeletal malformations or variations. There were no effects of 

treatment on fetal body weights. 
Isoxaben D376428

Page 61 of 90

The developmental LOAEL was not observed. The developmental NOAEL was 1000 

mg/kg bw/day (the limit dose).

This study is classified acceptable/guideline and satisfies the guideline requirement for a 

developmental toxicity study (OPPTS 870.3700; OECD 414) in rabbits. 

A.3.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects - Rat

In a three-generation reproduction study (MRID 00153529), 25 Wistar rats/sex/dose group were 

administered EL-107 (Isoxaben technical; 93.7-94.5% a.i.; Lot Nos. H02-2G6-118 and Z10025) 

continuously in the diet at doses of 0, 0.05, 0.25 or 1.25% (equivalent to 0, 40, 200 or 1000 

mg/kg/day). Each generation was maintained on the test diets for a growth period of 

approximately 10 weeks prior to mating (1 male: 1 female). Rats from the P, F1 and F2 

generations were continued on the test diets for 2, 3 and 1 breeding trial(s), respectively. From 

the F1a and F2b weanlings, 25 rats/sex/dose were selected to be parents of the F2 and F3 

generations, respectively. Selected weanlings were fed the same test diet concentrations as their 

parents. At sacrifice, livers and reproductive organs were collected for histological examination. 

In addition, eyes from F2 parental animals were saved and examined histologically.

Additionally from the F2b litters, high-dose progeny with microphthalmia (8 rats/sex), 10 control 

weanlings with linear retinal dysplasia (diagnosed during ophthalmic examinations), and 10 

normal control weanlings from each sex were retained as F2 parental animals. These additional 

animals were also maintained on the test diets for approximately 10 weeks prior to mating. The 

study also contained a developmental assessment: F2c and F3a litters were subjected to 

complete teratological evaluation. Females were grossly examined and livers and reproductive 

organs were collected for histological examination. The uterus was removed via cesarean 

section, and its contents examined. Fetuses were weighed, sexed, and examined for external, 

visceral, and skeletal malformations and variations. 

Parental toxicity: At 0.25%, decreased (p≤0.05) body weight gain (Days 0-70) was observed in 

the F2 females (decr 16%) and decreased (p≤0.05) body weights were noted in the dams on PND 

21 of the F2b generation (decr 6%). Decreased (p≤0.05) food efficiency was also observed in 

the F2-generation females. 

At 1.25%, decreased (p≤0.05) maternal body weights were observed on gestation day (GD) 7, 

14, and 20 in the F1 generation (decr 9-10%), resulting in a decreased (p≤0.05) total body weight 

gain of 17%. Decreased (p≤0.05) maternal body weights were observed at PND 0, 7, and 14 in 

the F2 generation (decr 17-19%), resulting in a decreased (p≤0.05) total body weight gain of 

29%.

Body weight gains (Days 0-70) were decreased (p≤0.05) by 15-20% in the F1 and F2 parental 

females during pre-mating. Decreased (p≤0.05) food efficiency was observed in the F2-

generation females. In the dams, mean body weight gain was decreased (p≤0.05) by 12-29% 

during gestation of the F1a, F1b, F2a, and F2b litters. Decreased (p≤0.05) mean body weight 

was noted in the 1.25% dams on postnatal day (PND) 21 of the F1b, F2a, and F2b litters (decr 8-
Isoxaben D376428

Page 62 of 90

14%) and at 0.25% in the F2b litter (decr 6%). There were no treatment-related effects on 

survival, clinical signs or histology.

Slight increases (p≤0.05) in parental mean relative liver weight were observed in the 0.25% 

females (incr 8-13%) and generally in the 1.25% males and females (incr 10-13%) from P, F1, 

and F2 generations. Subchronic oral toxicity studies in rats (MRIDs 00153116 and 00134493; 

concurrently submitted) indicated that the increased liver weight was an adaptive effect. No 

adverse treatment-related effect was observed on mortality, clinical signs or histology.

The LOAEL for parental toxicity is 0.25% (200 mg/kg bw/day), based on decreased body 

weights, body weight gains and food efficiency. The NOAEL is 0.05% (40 mg/kg bw/day).

Offspring Toxicity: At 1.25%, the mean number of live pups/litter was decreased (not 

statistically significant [NS]) by 10-14% in the F1a, F1b, and F2a litters, and decreased (p≤0.05) 

by 34% in the F2b litter. Gestation survival (percentage of newborn progeny alive on PND 0) 

was decreased (NS) in the 1.25% F2b generation (88.6% treated vs. 98.3% controls).

At 1.25%, decreases (p≤0.05) in pup body weight were observed on PND 4 in the F1b generation 

(decr 12%), on PND 14 in the F1b, F2a, and F2b generations (decr 14-19%), and on PND 21 in 

the F1a, F1b, F2a, and F2b generations (decr 13-25%). Decreases in pup body weights were 

generally also observed at 0.25%, but only obtained significance (p≤0.05) on PND 14 in the F2a 

generation (decr 9%). Therefore, the effect on body weights at 0.25% was not considered 

adverse.

In the 1.25% F2b weanlings, the incidence of uni- or bilateral microphthalmia was increased 

(8.6% treated vs. 0% controls). Equivocally treatment-related slight increases in incidence of 

coloboma optic disc (3.4% treated vs. 0.6% controls) and uni- or bilateral linear retinal dysplasia 

(8.6% treated vs. 6.1% controls) were also noted. Exencephaly was observed in the F2b 

generation (9 fetuses in 2 litters) and in one fetus each from the F1a and F2a generations Most 

affected fetuses showed more than one malformation. The significance of these malformations 

is unclear because many of the affected litters were associated with specific progenitor animals 

and/or cousin matings, but they are considered potentially treatment-related. An increased 

incidence of hydroureter was noted at 1.25% in both F1 and F2 generations (10-13% fetuses; 

59% litters) compared to controls (2% fetuses; 19-22% litters). In the developmental toxicity

phase of the study, slightly increased incidences in hydroureter were also noted in the F1 

generation at 0.05% (4% fetuses; 42% litters) and 0.25% (5% fetuses; 33% litters). Slightly

increased incidences of microphthalmia were noted at 1.25% in the F1 generation (2% fetuses; 

14% litters) compared to controls (0.5% fetuses; 6% litters) and in the F2 generation (3% fetuses; 

11% litters) compared to controls (0% fetuses; 0% litters). The historical control ranges were not 

reported. In summary, fetal incidence was 5% or less, except for the incidence of hydroureter in 

the 1.25% F1 and F2 generations. Consequently, the increased incidence of hydroureter is 

conservatively considered a possible treatment-related effect. there was no evidence of 

teratogenicity in the concurrently submitted developmental study in Wistar rats (MRID 

00153119). It also must be noted that the latter developmental study followed the suggested 

guidelines for a developmental study (including daily gavage treatment from GD 6-15), unlike 

the present study. The findings of hydroureter at 0.05% and 0.25% and microphthalmia were 
Isoxaben D376428

Page 63 of 90

considered equivocal, because the incidence was minor and there was no indication of 

teratogenicity in the developmental study. 

The LOAEL for offspring toxicity is 1.25% (1000 mg/kg bw/day), based on decreased pup 

body weights, decreased live pups/litter and gestation survival in F2b litters and possibly 

increased incidence of malformations including microphthalmia, coloboma and/or 

exencephaly, and hydroureter, in some litters beginning in the F2b generation. The 

NOAEL is 0.25% (200 mg/kg bw/day).

Reproductive Toxicity: At 1.25%, the following decreases (p≤0.05) in cesarean section 

parameters were observed in the F2c and F3a generations and in the additional animals with 

microphthalmia that were mated and killed on GD20: (i) mean number of corpora lutea (decr 13-

21%); (ii) mean number of implantations (decr 10-23%); and (iii) mean number of live fetuses 

(decr 20-41%). In the F2b litters, the mean number of live pups per litter and gestation survival 

were decreased (-35% and -10%, respectively, p≤0.05). At 1.25%, insufficient milk production 

was noted in at least four dams and their progeny were not thriving in the F1b, F2a, and F2b 

litters. 

The LOAEL for reproductive toxicity is 1.25% (equivalent to 1000 mg/kg bw/day), based 

on decreased mean number of live pups/litter, gestation survival, corpora lutea, 

implantations, and reduced milk production seen in some nursing dams. The NOAEL is 

0.25% (equivalent to 200 mg/kg bw/day in males/females).

This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.3800; OECD 416) for a multiple-generation reproduction study in the rat. 

A.3.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity – Rat

In a chronic toxicity study (MRID 00164552; interim report on two-year chronic dietary

toxicity/carcinogenicity study reported in MRID 00164553), 30 Fischer 344 rats/sex/dose group 

were administered EL-107 (Isoxaben technical; 92-95% a.i.; Lot No. Z10025) in the diet at doses 

of 0, 0.0125, 0.125, or 1.25% (approximately equivalent to 0, 6.25, 62.5, and 625 mg/kg 

bw/day). Ten rats/sex/dose group were terminated after exposure for 3, 6, and 12 months. 

No adverse, treatment-related effects were observed on mortality, clinical signs, ophthalmology, 

hematology or gross or histological pathology. 

In the 1.25% females, decreased (p≤0.05) mean body weight gain was observed during Months 

0-3, 0-6, and 0-12 (decr 8-15%) and decreased (p≤0.05) food efficiency was noted during 

Months 0-3 and 0-12 (decr 7-13%). During Months 0-3, the 0.125% females also had decreased 

body weight gain and food efficiency (decr 6% each), but this effect was considered minor.

Increased serum glucose was observed in the 0.125% and 1.25% groups at 6 months and males at 

12 months (incr 15-18%); however, this slight difference was not considered adverse in the 

absence of corroborating evidence of toxicity.
Isoxaben D376428

Page 64 of 90

Increased (p≤0.05) absolute and relative to body liver weights were generally noted in the 1.25% 

group at Months 3, 6, and 12 (incr 9-29%). At Months 6 and 12, increased (p≤0.05) hepatic pnitroanisole O-demethylase activity was observed in the 0.125% females (incr 29-36%), the 

1.25% males (incr 34-35%), and the 1.25% females (incr 57-88%). The effect on hepatic 

enzyme induction and corresponding liver weight increase, without any corroborating clinical 

chemistry or pathological support for hepatotoxicity, suggests that the effect on the liver was 

adaptive and not adverse.

The LOAEL was 1.25% (approximately equivalent to 625 mg/kg bw/day), based on decreased 

body weight gain and food efficiency in females. The NOAEL is 0.125% (approximately

equivalent to 62.5 mg/kg bw/day).

This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.4100; OECD 452) for a chronic toxicity study in rats.

870.4100b Chronic Toxicity – Dog

In a chronic toxicity study (MRID 00164551), 4 beagle dogs/sex/dose group were administered 

EL-107 (Isoxaben technical; 92-95% a.i.; Lot No. Z10025) in gelatin capsules at doses of 0, 10, 

100 or 1000 mg/kg bw/day for 12 months. In addition to standard chronic study parameters, 

hepatic p-nitroanisole O-demethylase activity was analyzed at necropsy.

No adverse, treatment-related effects were observed on mortality, clinical signs, body weight, 

food consumption, ophthalmology, electrocardiograms, hematology, clinical chemistry, 

urinalysis, organ weights, or gross or histological pathology. 

Increases in serum alkaline phosphatase levels relative to controls were observed at 100 and 

1000 mg/kg/day for various time periods (analyzed pretest, weeks 1, 2 and 4; monthly

thereafter). A statistically significant increase (generally about 2-fold; 3-fold in last months of 

study) was seen in males at 1000 mg/kg/day at most analyses, beginning on Day 118. At 100 

mg/kg/day, increases of about 2-fold were seen at later months and were not significant. 

Increases in females were also seen at these dose levels but were generally less pronounced and 

statistical significance was only seen occasionally at 1000 mg/kg/day during the later half of the 

study. In both sexes, alkaline phosphatase levels did not show an age-related decrease in the 

treated dogs as was seen in the control dogs. At 1000 mg/kg/day, increased (p≤0.05) pnitroanisole O-demethylase activity (+31%) was noted in males. Increased (p≤0.05) relative to 

brain liver weights were observed in both sexes (incr 27-38%), and increased (p≤0.05) relative to 

body liver weight was noted in the females (incr 29%). There was minimal to slight 

hepatocellular hypertrophy observed in 1 male and 2 females (vs. 0 controls). Overall, the 

findings are considered evidence of adaptive change and are attributed to treatment, but are not 

considered adverse in the absence of other supporting evidence of hepatotoxicity.

The LOAEL was not observed. The NOAEL is 1000 mg/kg/day (the limit dose).
Isoxaben D376428

Page 65 of 90

This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.4100; OECD 452) for a chronic toxicity study in dogs.

A.3.5 Carcinogenicity

870.4200a Carcinogenicity Study - rat

In a combined chronic toxicity/carcinogenicity study (MRID 00164553), 60 Fischer 344 

rats/sex/dose (in study report, stated to be two replicate test groups of 30 rats/sex/dose group that 

were considered as one test group), EL-107 (Isoxaben; 92-95% a.i.; Lot No. Z10025) was 

administered in the diet at doses of 0, 0.0125%, 0.125% or 1.25% (equivalent to 0/0, 5.0/6.2, 

50.7/61.8, and 526.5/646.6 mg/kg bw in males/females). 

No adverse, treatment-related effects were observed on clinical signs, hematology or urinalysis. 

In the 1.25% males at Month 24, decreased survival was noted (combined study survival rates of 

48% treated vs. 66% control), and an increased incidence of general thinning of the body was 

also observed. At 1.25%, mean weight at termination and cumulative mean weight gain over the 

entire treatment period were each decreased (p≤0.05) by 12-19% in both sexes. The decreases 

were associated with reduced efficiency of food utilization, which was decreased (p≤0.05) by 15-

23%. In males, statistically significant decreases in weight gain were primarily observed in the

first and last 6 months of the study; the decreases did not reach 10% until the last months of the 

study. In females, statistically significant (p≤0.01) reductions in both bodyweight and weight 

gain were observed throughout most of the study, with cumulative gain generally decreased by 

10%. At 0.125%, statistically significant reductions in mean weight gain were also observed in 

females for many weeks of the study, but the decreases were marginal (between 5-7% below 

controls) and not considered adverse.

Treatment-related nephrotoxicity was observed in males at 0.125% and 1.25%. At 0.125% and 

above, nephrotoxicity was evident in males as an increased incidence and severity of minimal to 

severe progressive glomerulonephrosis (from control to high dose, respectively 44%, 55%, 67% 

and 85%; mean severity 1.8, 1.7, 2.0 and 2.5). 

At 1.25%, urea nitrogen levels in the terminal blood samples were increased (p≤0.05) by 32-67% 

at termination in the males of both replicate studies and increased (p≤0.05) by 34% in the 

females of one study. In both replicate studies, relative to body kidney weights were increased 

(p≤0.05) by 25-39% in males and by 15-23% in females. Grossly, increased incidences of whole 

tissue alterations were noted in the kidney of the males (39/60 vs. 16/59, controls) and females 

(38/60 vs. 21/61 controls), and increased incidences and severity of minimal to severe 

progressive glomerulonephrosis were observed in the females (from control to high dose, 

respectively 56%, 45%, 58% and 78%; mean severity 1.4, 1.6, 1.5 and 2.0). 

The LOAEL in males is 0.125% (50.7 mg/kg/day), based on increased incidence and severity of 

progressive glomerulonephrosis. The NOAEL is 0.0125% (equivalent to 5.0 mg/kg bw/day in 

males). The LOAEL in females is 1.25% (646.6 mg/kg/day), based on increased incidence and 

severity of progressive glomerulonephrosis and decreased body weight/weight gain. The 

NOAEL is 0.125% (61.8 mg/kg/day).
Isoxaben D376428

Page 66 of 90

At the doses tested, an increased incidence of adrenal pheochromocytomas was observed in the 

1.25% males (18/60 treated vs. 10/59 controls). The increase was not seen in females. Dosing 

was considered adequate based on decreased survival in males, decreased body weights, body 

weight gains, and food efficiency in both sexes, and nephrotoxicity in both sexes. 

This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.4300; OECD 453) for a combined chronic toxicity/carcinogenicity study in rats.

870.4200b Carcinogenicity (feeding) - Mouse

In an oral carcinogenicity study (MRID 00164554), 60 B6C3F1 mice/sex/dose group (in study

report listed as two replicate studies of 30 mice/sex/dose considered as one test group) were 

administered EL-107 (Isoxaben technical, 95.5% a.i.; Lot No. Z10025) in the diet for 24 months 

at doses of 0, 100, 1000 or 12,500 ppm. Food consumption was not measured for this study: 

using in-house control food consumption data, average daily intakes were estimated at 0, 11.5, 

113.7 or 1476.4 mg/kg/day for males and 0, 12.2, 123.9 or 1567.1 mg/kg/day in females. 

Because no weight loss was observed in the early weeks of the study, palatability did not appear 

to be affected and these surrogate food consumption values were considered acceptable for use. 

(Using the standard conversion factor of 1 ppm = 0.150 mg/kg/day for mice, daily intakes were 

calculated at 0, 15, 150 or 1875 mg/kg bw/day. The estimates obtained using in-house control 

food consumption were therefore used to provide more conservative values). The combined 

groups (60 mice/sex/dose group) were subjected to statistical analyses. An interim 12-month 

sacrifice cohort was not included in this study.

The findings of the two replicate studies showed similar results. No adverse, treatment-related 

effects were observed on mortality, clinical signs, ophthalmology or hematology. 

Systemically in the 12,500 ppm males, decreased (p≤0.05) mean body weights were noted at 

Weeks 25-79, and decreased (p≤0.05) bodyweight gains (about 10 to 15% below controls) were 

noted at Weeks 25-73. No effects on body weight or weight gain were reported in females and 

in high dose males, body weight/weight gain was not significantly lower at the end of the study. 

Hepatotoxicity was observed at 12,500 ppm. In the males, serum alkaline phosphatase and 

alanine aminotransferase were increased (p≤0.05) by 97 and 139%, respectively in the two-year 

measurements (clinical chemistry was not evaluated at earlier times). Absolute and relative to 

body liver weights were increased (p≤0.05) in both sexes. Increased incidences of hepatic 

nodules were observed grossly in the males (35/60 treated vs. 26/60 controls) and females (16/60 

treated vs. 4/60 controls). Increased incidences of the following non-neoplastic hepatic lesions 

were observed: (i) cytomegaly in the males (33/59 treated vs. 9/60 controls) and females (4/60 

treated vs. 0/60 controls); (ii) hyperplasia in the males (27/59 treated vs. 19/60 controls) and 

females (20/60 treated vs. 3/60 controls); and (iii) minimal to moderate vacuolation in the males 

(22/59 treated vs. 5/60 controls) and females (40/60 treated vs. 4/60 controls). Minimal to 

moderate vacuolation was also noted at 1000 ppm in males (10/60 treated) and females (11/59 

treated); however, this effect was not considered adverse at this dose level due to the nature of 

this lesion and the lack of corroborating evidence of toxicity. The systemic toxicity LOAEL 

was 12,500 ppm (approximately equivalent to 1476/1567 mg/kg bw/day in M/F), based on 
Isoxaben D376428

Page 67 of 90

decreased body weights and body weight gains in males and hepatoxicity (as detailed 

above) in both sexes. The NOAEL is 1000 ppm (approximately equivalent to 114/124

mg/kg bw/day in M/F).

At the doses tested, there was a treatment-related increase in tumor incidence when compared to 

controls. At 12,500 ppm, incidences of hepatocellular adenoma were increased in the males 

(12/59 treated vs. 3/60 controls) and females (7/60 treated vs. 0/60 controls). Increased 

incidence of hepatocellular carcinomas in females (2/60 treated vs. 0/60 controls) was expected 

to be within the range of historical controls. Dosing was considered adequate based on

decreased body weights and body weight gain in males and hepatotoxicity observed in both 

sexes. 

This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.4300; OECD 453) for a combined chronic toxicity/carcinogenicity study in mice.

A.3.6 Mutagenicity

Gene Mutation

870.5100 Bacterial Gene Reverse 

Mutation in S. typhimurium TA 98, 

100, 1535,1537, 1538

MRID 00132136

Acceptable/guideline

31, 62.5, 125, 250 or 500 μg/plate with and without S9 activation.

Negative up to precipitating concentrations.

870.5100 Bacterial Gene Reverse 

Mutation, S. typhimurium TA98, 100, 

1535, 1537 and E. coli WP2uvrAMRID 40485701

Acceptable/guideline

31 to 500 μg/plate with and without S9 activation.

Negative up to precipitating concentrations.

870.5100 Bacterial Gene Reverse 

Mutation, E. coli WP2uvrAMRID 40485702

Acceptable/guideline

31 to 500 μg/plate with and without S9 activation.

Negative up to precipitating concentrations.

870.5300 in Vitro Forward Mutation, 

Mouse Lymphoma L5178Y cells

MRID 00132138

Acceptable/guideline

1 to 250 μg/mL (without activation) and 0.5 to 12 μg/mL (with 

activation).

Negative up to cytotoxic concentrations.

Cytogenetics

870.5375 In Vitro Chromosomal 

Aberration in CHO Cells

MRID 40435901

Acceptable/guideline

10 to 80 μg/mL (without activation) and 25 to 200 μg/mL (with 

activation).

Negative up to precipitating concentrations.

870.5395 In Vivo Micronucleus Assay

in Male Mice

MRID 00164555

Unacceptable/guideline (results 

inconclusive)

5000 mg/kg

Inconclusive. Slight, significant increases in frequency of micronucleated 

polychromatic erythrocytes at 24 and 48 hrs but not 72 h.
Isoxaben D376428

Page 68 of 90

870.5395 In Vivo Micronucleus Assay

in Male Mice

MRID 40485704

Acceptable/guideline (results 

inconclusive)

800, 2000 or 5000 mg/kg

Weakly positive. Slight, statistically significant increase in the frequency of 

micronucleated polychromatic erythrocytes were noted at 24 h.

870.5395 In Vivo Micronucleus Assay

in Mice

MRID 47140002

Acceptable/guideline 

0, 1250, 2500 or 5000 mg/kg

Negative up to the limit dose.

870.5450 Rodent Dominant Lethal in 

male rats

MRID 00164556

Unacceptable/guideline (upgradeable; 

no positive control data provided)

0, 34, 173 or 932 mg/kg/day.

Negative for dominant lethal effects in male rats

Other Genotoxicity

870.5550 Unscheduled DNA Synthesis 

in Cultured Rat Hepatocytes

MRID 00132137

Acceptable/guideline

0.5 to 1000 nmoles/mL

Negative. No cytotoxicity observed.

870.5915, In Vivo Sister Chromatid 

Exchange, Chinese Hamster

MRID 40485703

Acceptable/guideline

800, 2000 or 5000 mg/kg

Negative up to the limit dose.

A.3.7 Metabolism

870.7485 Metabolism – Rat

(1) In a series of three metabolism studies (MRID 00132131, -32, -33), isoxaben (14C-EL-107 

technical, lot # 553-02V-094; label located on the 5 position of the isoxazole ring and 

radiochemical purity 100%) and unlabeled isoxaben (EL-107 technical, 92.4%, lot B31-72C-88)

were administered to Fischer 344 rats according to the following protocols: (1) biliary excretion

- to 5 rats/sex/dose by gavage in 10% aqueous acacia (w/v) at 10 or 250 mg/kg 14C-EL-107 

(dosing volume 10 mL/kg bw). All rats had surgically installed exteriorized bile duct cannulae 

and collection of bile was continued for 24 hrs following dosing; (2) excretion - to 5 

rats/sex/dose by gavage in 10% aqueous acacia (w/v) at 10, 100, 250, 500 or 1000 mg/kg 14CEL-107 (10 mL/kg dosing volume). Urine and feces were collected for 72 hours; (3) tissue 

distribution - to 5 rats/sex/sampling time, a single gavage dose of 250 mg/kg 14C-EL-107 in 10% 

aqueous acacia (10 mL/kg bw dosing volume). At 4 or 24 hrs postdosing, rats were sacrificed 

under ether anesthesia, blood samples were collected and tissues and organs collected for 

radioassay. 

Total excretion of radiolabel in urine and feces by 72 hrs ranged from 70.8% to 94.9% in males 

and 88.2% to 106.3% in females. The majority of radioactivity was excreted within the first 24 

hrs. The lowest recoveries in males (≈71-74%) were observed at 10, 100 and 250 mg/kg. The 

major route of excretion of isoxaben was fecal, ranging from 57.2% to 81.8% of dose in males 
Isoxaben D376428

Page 69 of 90

and 81.7 to 104.3% in females. Urinary excretion ranged from 2.0% at high dose levels to about 

12-13% of the dose at the lower doses. With increasing dose, the percent of dose excreted in the 

urine decreased and fecal excretion increased, suggesting oral absorption may be a rate-limiting 

process. At 10 mg/kg, biliary excretion was observed in males and females at 23.1% and 38.8% 

of the dose, respectively. At 250 mg/kg, the percent radioactivity excreted was 17.5% and 

15.3%, respectively, consistent with rate-limiting oral absorption. Radioactivity was widely 

distributed to tissues. At 4 hrs postdosing, the tissues with the greatest amount of radiolabel were 

liver, pituitary, thyroid, kidney, adrenals and prostate, with 12/20 tissues in males and 13/20 

tissues in females. At 24 hrs postdosing, the tissue to plasma ratios were increased compared to 

4 hrs in pituitary, thyroid, ovaries and eyes of females. Males showed slightly higher levels in 

adrenals and pituitary. However, radioactivity in tissues was not assessed at times later than 24 

hrs postdosing to evaluate levels through 72 hrs. It is not known whether the lower recoveries in 

males were due to increased retention in tissues or experimental artifact, such as quenching or 

problems with a suspension dosing solution.

This metabolism study in the rat is classified Acceptable/guideline and satisfies the guideline 

requirement for a metabolism study [OPPTS 870.7485, OECD 417] in the rodent when 

considered together with additional metabolism studies in the rat that include repeated dosing, 

exhaled air excretion and identification of metabolites (TXR # 005732).

(2) In a series of metabolism studies (MRIDs 00153114, 00164557, -58, -59),

14C-EL-107 

(isoxaben technical, lot # 553-3N1-056, radiochemical purity of 98.6%-99.9% and unlabeled EL107, lot no. Z10025, purity 95%) was administered to male and female rats according to one of 

the following protocols: (1) single gavage dose of 250 mg/kg 14C-EL-107 to 5 Wistar rats/sex 

for evaluation of fecal and urinary excretion and analysis of metabolites; (2) single gavage dose 

of 1000 mg/kg 14C-EL-107 to 5 Fischer 344 rats/sex/time point for analysis of tissue levels of 

radioactivity at 4 and 24 hrs postdosing; (3) repeated daily gavage doses of 250 mg/kg unlabeled 

EL-107 for 14 days, followed by a single oral dose of 250 mg/kg 14C-EL-107 on day 15 for 

assessment of excretion and carcass and tissue levels by 7 days following the radioactive dose; 

and (4) single gavage doses of 250 mg/kg 14C-EL-107 to 5 Fischer 344 rats/sex for collection of 

expired air 14CO2 over a 48 hr period postdosing. Carcasses and cage rinses were also assayed.

Following a single dose of 250 mg/kg, radioactivity was rapidly eliminated in both males and 

females, with almost all the administered dose excreted by 48 hrs. The major route of excretion 

was fecal, with 81.8% and 91.8% of the dose excreted in males and females, respectively. 

Urinary excretion of radioactivity accounted for 8.5% in both sexes. About 90% of the 

radioactivity present in the feces was unmetabolized EL-107. Absorption of EL-107 was poor, 

with about 8-10% of the dose absorbed and extensively metabolized. In the urine, 15 to 20 

metabolites were recovered. The major metabolic pathways involve oxidation at the 2-position 

of the alkyl side chain to yield either an alcohol or ketone, hydroxylation of the aromatic ring 

next to one of the methoxy groups, and O-demethylation of one of the methoxy groups.

Radiolabel was widely distributed among tissues by 4 hrs postdosing after administration of 

1000 mg/kg. By 24 hrs most tissue levels decreased compared to 4 hrs, with the exception of the 

colon in both sexes. Tissues with levels of radioactivity higher than plasma at 4 and 24 hrs 

included the GI tract, liver, kidneys, fat, prostate, pancreas (females), adrenal glands and carcass. 

Levels were not assessed at later times. The ratio of red cell to plasma radioactivity was 0.4 to 
Isoxaben D376428

Page 70 of 90

0.8. The study author noted that the high levels of radiocarbon at 24 hrs in the previous study

(MRID 00132133) may have been an artifact of counting small tissues than may have caused 

overestimation of radioactivity due to undetected chemiluminescence.

Predosing with unlabeled isoxaben did not significantly change the pattern of urinary and fecal 

excretion of radioactivity. Urinary excretion was 5.6% and 7.5% and fecal excretion 75% and 

88.6% for males and females, respectively, with the greatest amount excreted by 24 hrs. 

Combined seven day urine and fecal recoveries were 80.6% in males and 96.1% in females. At 7 

days after the final, radiolabeled dose, residual carcass levels of radioactivity were 0.3% and 

0.4% in males and females, respectively. All tissue levels at 7 days postdosing were less than 

0.01% of dose except for liver, which was 0.01% and 0.02% in males and females, respectively. 

All tissues samples were at or below 0.32 μg equivalents/g tissue.

Excretion of 14CO2 was limited to 2.4% (males) and 2.8% (females) of the dose. At 48 hrs 

postdosing in the expired air study, urinary and fecal excretion represented 78.1% and 73.8% of 

the dose and carcasses 1.5% and 14.4% of the dose in males and females, respectively.

This series of metabolism studies in the rat is classified acceptable/guideline and satisfies the 

guideline requirement for a metabolism study [OPPTS 870.7485, OECD 417] in the rodent. 

870.7600 Dermal Absorption - Monkey

In an in vivo dermal absorption study (MRID 00153113), two male and two female Rhesus 

monkeys were administered a single IV dose of 2.0 mg/kg 14C-EL-107 (isoxaben technical, lot # 

553-02V-094, radiochemical purity 100% and lot # 558-1X7-018 radiochemical purity 98.4%, 

radiolabel on the 5 carbon of the isoxazole ring) and samples of plasma were collected at 0, 0.25, 

0.5, 1, 2, 4, 6, 24, 48, 72, 96, 120, 144 and 168 hrs postdosing for analysis of levels of 

radioactivity. Urine and feces were also collected twice daily for 7 days and analyzed. One 

month later the same animals were treated topically for 24 hr with 2.0 mg/kg 14C-EL-107 (6 cm2

on shaved are of right ventral forearm). Serum, urine and feces were collected and analyzed as 

described for the IV dosing.

The results indicated limited dermal absorption of EL-107. Comparison of IV and topical dosing 

plasma AUCs indicated that about 11% of the dermal dose was absorbed. A dermal absorption 

value of 7.5% was obtained by comparison of the urinary excretion data. EL-107 was rapidly

distributed to a second compartment (half life 1.4 hrs) with a half life for the terminal elimination 

phase from plasma of 30.9 hrs. Based on volume of distribution estimates, the study authors 

suggested that the radioactivity was partially bound to plasma protein.

This dermal absorption study in the monkey is classified acceptable/guideline and satisfies the 

guideline requirement for an in vivo dermal absorption study (OPPTS 870.7600).
Isoxaben D376428

Page 71 of 90

A.4 Rationale for Toxicology Data Requirements

Table A.4.1 Guideline Number: 870.3465

Study Title: 90-Day Inhalation Toxicity 

Rationale for Requiring the Data

This study is required if there is the likelihood of significant repeated inhalation exposure to the pesticide as 

a gas, vapor or aerosol. The Agency has determined that there are potential inhalation exposures to mixers, 

loaders and applicators, as well as potential postapplication exposures, associated with isoxaben 

applications. The inhalation study may potentially be shortened (i.e., 28-day exposure) as appropriate to 

exposures from current use patterns. 

Because toxicity via the inhalation route may differ from that observed following oral dosing, the study is 

required to better assess potential effects resulting from inhalation exposure and provide a refined 

assessment of risk from inhalation exposure.

Practical Utility of the Data

How did the Agency make its re-registration decision without these data? 

In the absence of inhalation toxicity studies for any given pesticide active ingredient, The Agency 

estimates occupational risk from inhalation exposure by using the most sensitive oral endpoint appropriate 

for a given exposure scenario. To account for route-to-route extrapolation, 100% absorption is assumed.

How will the data be used? 

An inhalation study may result in changes to the endpoints and how the risks are quantified. These animal 

studies can be used to select endpoints and doses for use in risk assessment for all exposure scenarios and 

are considered a primary data source for reliable reference dose calculation for the inhalation route of 

exposure.

How could the data impact the Agency’s future decision-making?

The Agency does not have a full picture of the potential effects which could occur as a result of exposure 

via the inhalation route. In some cases, toxicity observed via the inhalation route is higher than toxicity 

observed via oral exposure, which means that route-to-route extrapolation could result in an 

underestimation of risks from inhalation. The study may be used to confirm that no further mitigation is 

needed for uses where inhalation exposure occurs.

Table A.4.2 Guideline Number: 870.6200

Study Title: Neurotoxicity Battery (Acute and Subchronic Studies)

Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for 

registration of a pesticide (food and non-food uses). 

The Neurotoxicity Screening Battery (OPPTS 870.6200) is designed to evaluate the potential 

adverse effects on the nervous system from exposure to pesticide chemicals. The Agency

believes that the guideline studies are inadequate in their assessment of behavioral effects and 

do not use optimal methods to evaluate the potential toxicity to the nervous tissue structure and 

function. To detect and characterize these potential effects more fully, a battery of more 

sensitive testing is required. The objective of this neurotoxicity battery testing is to evaluate the 

incidence and severity of the functional and/or behavioral effects, the level of motor activity, 

and the histopathology of the nervous system. The acute neurotoxicity study is required to 
Isoxaben D376428

Page 72 of 90

detect possible effects resulting from a single exposure. The subchronic neurotoxicity study is 

intended to detect possible effects resulting from repeated or long-term exposures.

Practical Utility of the Data

How will the data be used?

The acute and subchronic neurotoxicity studies provide critical scientific information needed to 

characterize potential hazard to the human population on the nervous system from pesticide 

exposure. These studies can provide data on a wide range of functional tests for evaluating 

neurotoxicity including sensory effects, neuromuscular effects, learning and memory and 

histopathology of the nervous system For example, animal studies with organophosphorous 

chemicals have shown neurotoxicity to be the primary toxic endpoints (e.g., cholinesterase 

inhibition) of concern in rodents and non-rodents. These animal studies can be used to select 

endpoints and doses for use in risk assessment of all exposure scenarios and are considered a 

primary data source for reliable reference dose calculation. The Agency has established an oral 

reference dose (RfD) for assessing dietary risks for a number of chemicals (e.g., 

organophosphates and carbamates) where neurotoxicity was the most sensitive endpoint of 

concern.

How could the data impact the Agency's future decision-making?

If the acute or subchronic neurotoxicity studies show that isoxaben poses either a greater or a 

diminished risk than that given in the interim decision’s conclusion, the risk assessment for 

isoxaben may need to be revised to reflect the magnitude of potential risk derived from the new 

data.

If the Agency does not have this data, a 10X database uncertainty factor may be applied when

conducting a risk assessment using the currently available studies.
Isoxaben D376428

Page 73 of 90

Table A.4.3 Guideline Number: 870.7800

Study Title: Immunotoxicity

Rationale for Requiring the Data

The immunotoxicity study is a new data requirement under 40 CFR Part 158 as a part of the data 

requirements for registration of a pesticide (food and non-food uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity testing and 

is designed to evaluate the potential of a repeated chemical exposure to produce adverse effects (i.e., 

suppression) on the immune system. Immunosuppression is a deficit in the ability of the immune system 

to respond to a challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired 

Respiratory Syndrome (SARS), or neoplasia. Because the immune system is highly complex, studies 

assessing functional immunotoxic endpoints are helpful in fully characterizing a pesticide’s potential 

immunotoxicity. These data will be used in combination with data from hematology, lymphoid organ 

weights, and histopathology in routine chronic or subchronic toxicity studies to characterize potential 

immunotoxic effects. 

Practical Utility of the Data

How will the data be used?

These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure 

scenarios and are considered a primary data source for reliable reference dose calculation. For example, 

animal studies have demonstrated that immunotoxicity in rodents is one of the more sensitive 

manifestations of TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental, reproductive, and 

endocrinologic toxicities. Additionally, the EPA has established an oral reference dose (RfD) for 

tributyltin oxide (TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Agency's future decision-making? 

If the immunotoxicity study shows that the test material poses either a greater or a diminished risk than 

that given in the interim decision’s conclusion, the risk assessments for the test material may need to be 

revised to reflect the magnitude of potential risk derived from the new data.

If the Agency does not have these data, a 10X database uncertainty factor may be applied for conducting a 

risk assessment from the available studies.
Isoxaben D376428

Page 74 of 90

Appendix B: Metabolism Assessment

B.1 Metabolism Guidance and Considerations

Plants: For the primary crop grapes and tree nuts, isoxaben parent can serve as an adequate 

measure of misuse based on its percentage of the total radioactive residue (TRR) in the barley

metabolism study and the field trial residues observed in almond hulls and nutmeat. In addition, 

the FDA multiresidue method Section 302 completely recovers the parent (PESTDATA 06/05). 

Therefore, ROCKS recommends using the levels of the parent for compliance purposes.

For dietary risk assessment purposes, ROCKS concludes that the tolerance based on the parent 

will be adequate. In the grape metabolism study, the TRR was <0.008 ppm in the fruit, after a 

single application of isoxaben ranging from 1.79-1.97 lbs ai/A (1.8-2.0x proposed seasonal rate). 

Grapes harvested 60 days following a single broadcast application of the 75% DF formulation of 

isoxaben to the soil at 5.0 lb ai/A (5x the proposed rate) had residues below the LOQ (0.01 ppm) 

in/on all samples of grapes and raisins. Therefore, use of the LOQ (0.01 ppm) for the parent in 

grapes represents a conservative estimate of dietary exposure. Although radiolabeled data have 

not been provided for tree nuts to make a similar comparison with field trial results, it is unlikely

that significant uptake of residues from a soil-directed application into the edible nutmeat would 

occur. 

Three hydroxylated metabolites (1-hydroxyl, 2-hydroxyl, 3-hydroxyl) were major residues in the 

barley metabolism study. Structure-activity relationship (SAR) analysis (DEREK) did not reveal 

any alerts for the parent compound or the 1-hydroxyl metabolite. Due to structural similarity, all 

of the hydroxylated metabolites are assumed to have comparable toxicity to the parent; therefore, 

for any future uses on grains or grasses, the petitioner is advised to include residue data on the 

three hydroxylated metabolites as they are likely to be included for at least risk assessment 

purposes on those crops.

Livestock: Although the goat metabolism study identified low percentages of the TRR in most 

matrices, it is adequate for the proposed uses based on the very low dietary burden for cattle. 

Only one commodity associated with the proposed uses, almond hulls, is a cattle feed item. 

There are no poultry or swine feed items associated with the proposed uses. HED/RAB2 review 

of the livestock metabolism study indicates that a cattle feeding study, and tolerances for 

livestock commodities are not needed. A ROCKS decision on the residues of concern is thus not 

required at this time. However, another goat metabolism study with better identification and 

characterization of the residues will be needed for any additional uses of isoxaben that result in 

significantly higher dietary burdens.

Table B.1. DEREK Alerts for Major Biodegradates.

Compound Alerts

Isoxaben Nothing to report

Hydroxy isoxaben

Methoxyphenyl pyrimidinol 121 Substituted pyrimidine or purine. Carcinogenicity. Number of 

matches = 1

440 Resorcinol or precursor. Skin sensitization. Number of matches 

= 1

AEM hexenoyl isoxaben 444 Imine or alpha, beta-unsaturated imine. Skin sensitization. 

Number of matches = 1
Isoxaben D376428

Page 75 of 90

Table B.1. DEREK Alerts for Major Biodegradates.

Compound Alerts

Dimethoxy benzamide Nothing to report

Drinking Water: Major degradates (>10% of total residues) detected during aerobic and 

anaerobic soil metabolism studies and aerobic and anaerobic aqueous metabolism studies include 

hydroxy isoxaben, dimethoxy benzamide, methoxyphenyl pyrimidinol, and AEM hexenoyl 

isoxaben. SAR analysis (DEREK) did not reveal any alerts for the parent compound but did 

produce alerts for the methoxyphenyl pyrimidinol (carcinogenicity, skin sensitization) and AEM 

hexenoyl isoxaben (skin sensitization) metabolites. ROCKS is not concerned for these alerts 

because substituted pyrimidine/purine carcinogenicity is only seen at very high doses (as a result 

of bladder calculi) and dermal exposure to metabolites is not expected to be significant. None of 

these environmental degradates are thus expected to be more toxic than the parent compound, 

but data are not available to exclude them as residues of concern.

Four major photolytic degradates (Unk 3, Unk 3i, Unk 5a, and Unk 5b) were detected but not 

conclusively identified. SAR analysis triggered an alert for Unk 3 (carcinogenicity), but was 

based on bladder tumors from saturating urinary levels of pyrimidines, considered an unlikely 

occurrence in humans. SAR analysis triggered an alert for Unk 3i for mutagenicity based on the 

presence of an oxime moiety. The mutagenicity discussion indicated that some oximes were 

positive in Ames and mouse lymphoma tests, but that results were often conflicting depending 

on which laboratory performs the test. Unk3i also had a carboxyl group that will be ionized 

under environmental and most physiological conditions. The presence of the group was likely to 

enhance excretion and interfere with any potential mutagenic activity. In the absence of other 

data that might support the mutagenicity alert, ROCKS was not concerned with this mutagenicity 

alert for Unk 3i. Lastly, SAR analysis triggered alerts for Unk 3i, Unk 5a, and 5b for skin 

sensitivity. ROCKS was not concerned with these alerts because dermal exposure of metabolites 

was not expected to be significant. Therefore, because aqueous photolysis was not expected to 

be a dominant degradation pathway of isoxaben and these degradates were not observed in any 

other study, the formation of the photodegradates was considered minimal, and none of these 

degradates were expected to be more toxic than the parent compound, these major degradates 

were excluded as residues of concern.

Recommended Tolerance Expression:

The ROCKS recommends the following language for the tolerance expression for plant 

commodities:

Tolerances are established for residues of the herbicide isoxaben, including its metabolites and 

degradates, in or on the commodities listed below. Compliance with the tolerance levels 

specified below is to be determined by measuring only isoxaben, N-[3-(1-ethyl-1-methylpropyl)-

5-isoxazolyl]-2,6-dimethoxybenzamide.
Isoxaben D376428

Page 76 of 90

B.2 Tabular Summary of Metabolites and Major Degradates

Figure 1. Isoxaben Metabolism in/on Grape.
Isoxaben D376428

Page 77 of 90

Figure 2. Isoxaben Metabolism in/on Barley.
Isoxaben D376428

Page 78 of 90

FIGURE 3. Proposed Metabolic Profile of Isoxaben in the Lactating Goat

APPENDIX B.2.1 Chemical Names and Structures of Isoxaben and Plant Metabolites. 

Common name;

Company code

Chemical name Chemical structure

Isoxaben N-[3-(1-ethyl-1-methylpropyl)-5-

isoxazolyl]-2,6-dimethoxybenzamide

OCH3

N

H

O

O

N

CH3

CH3

CH3

OCH3
Isoxaben D376428

Page 79 of 90

APPENDIX B.2.1 Chemical Names and Structures of Isoxaben and Plant Metabolites. 

Common name;

Company code

Chemical name Chemical structure

Metabolite I12,6-dimethoxybenzoic acid OCH3

OCH3

OH

O

Isoxaben-2-hydroxy/ 

Metabolite II

(mixture of two 

diastereomers)

N-[3-(1-ethyl-2-hydroxy-1-

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

dimethoxybenzamide

OCH3

OCH3

N

H

O

O

N

CH3

CH3

CH3

OH

Isoxaben-3-hydroxy/ 

Metabolite III

N-[3-(3-hydroxy-1-ethyl-1-

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

dimethoxybenzamide

OCH3

OCH3

N

H

O

O

N

CH3

CH3

OH

Isoxaben-1-hydroxy/ 

Metabolite IV

N-[3-(1-hydroxy-1-methylpropyl)-5-

isoxazolyl]-2,6-dimethoxybenzamide

OCH3

N

H

O

O

N

HO CH3CH3

OCH3

2-OH-6-OMe benzamide 2-hydroxy-6-methoxy benzamide OCH3

NH2

O

OH

2,6-dimethoxy benzamide OCH3

OCH3

NH2

O

1 Suspected to be an artifact formed during acid hydrolysis.
Isoxaben D376428

Page 80 of 90

Appendix B.2.2 Chemical Names and Structures of Isoxaben and Livestock Metabolites.

Common name/code

 Figure C.3.1 ID No.

Chemical name Chemical structure

Isoxaben N-(3-(1-ethyl-1-methylpropyl)-5-

isoxazolyl)-2,6-dimethoxybenzamide

3-Hydroxy isoxaben N-(3-(1-hydroxy-1-ethyl-1-

methypropyl)-5-isoxazolyl)-2,6-

dimethoxybenzamide

2,6 Dimethoxybenzamide 2,6 Dimethoxybenzamide

2,6 Dimethoxybenzoic acid 2,6 Dimethoxybenzoic acid

Isoxaben Desmethyl 

metabolite

Benzamide, N-[3-(1-ethyl-1-

methypropyl)-5-isoxazolyl]-2-hydroxy6-methoxy
Isoxaben D376428

Page 81 of 90

2-Hydroxy-6-

methoxybenzamide

2-Hydroxy-6-methoxybenzamide

Oxime Metabolite

Carboxylic Acid Metabolite

Hydroxylated Isoxaben
Isoxaben D376428

Page 82 of 90

Appendix B.2.3 Chemical Names and Structures of Isoxaben and Rat Metabolites (copied from 

EL-107 Metabolic Study In Rats, Accession # 073293).
Page 83 of 90

B.3 Environmental Fate Summary 

Table B.3.1. Summary of Maximum Degradate Amounts in Environmental Fate Studies of Isoxaben

Degradate 1

Max. Degradate % of Applied (Time of Peak) Analyzed Degradates

Hydrolysis

Aqueous 

Photolysis

Soil

Photolysis Aerobic Soil Anaerobic Soil

Aerobic 

Aquatic

Anaerobic 

Aquatic TFD PGW

Source MRID 47140003 47428403 47140004 41106302 46393202 46393201 No study

Dimethoxy 

benzamide - 21.9% (12 days) 8.5% (30 days) - - 10.7% (44 days) 12.9% (30 days)

Hydroxy isoxaben

- - - 10.8% (122 days) 16.8% (60 days) 1.1% (84 days) -

8.6% 

(224 days)

Methoxyphenyl 

pyrimidinol - - - - - 0.1% (61 days) 33.1% (93 days)

AEM hexenoyl 

isoxaben - - - - - 8.4% (30 days) 60.1% (14 days)

Unk1 - 27.6% (36 days) - - - - -

Unk3 - 24.2% (36 days) - - - - -

Unk3i - 14.8% (14 days) - - - - -

Unk 4a/4b - 8.0% (14 days) - - - - -

Unk5a - 23.2% (1 days) - - - - -

Unk5b - 17.6% (14 days) - - - - -

Oxypropyl isoxaben

- - - 7.3% (90 days) 4.4% (30 days) 1.6% (30 days) 1.4% (121 days)

Desmethyl isoxaben

- - - 1.6% (122 days) 2.2% (60 days) - 2.5% (7 days)

Hydroxyethyl 

isoxaben - - - 0.4% (90 days) 1.9% (60 days) - -

3.9%

(602 days)

Hydroxymethoxy 

benzamide - - - - - 1.1% (84 days) 7.7% (61 days)

CO2- 11.5% (36 days) 15.9% (23 days) 8.6% (122 days) - 18.7% (103 days) -

1 - 2,6-DMB - 2,6-dimethoxybenzamide (127992); Unk3 - 6-(1-ethyl-1-methylpropyl)pyrimidine-2,4(1H,3H)-dione; Unk3i - 4-ethyl-3-(hydroxyimino)-4-methylhexanoic acid; Unk5a - 2-(2,6-

dimethoxybenzoyl)-5-(1-ethyl-1-methylpropyl)1,2-dihydro-3H-pyrazol-3-one; Unk5b - 4,6-diethyl-4a,8-dimethoxy-4-methyl-4a,8a-dihydropyrazolo[1,5-b]isoquinoline-2,9(1H,4H)-dione; 

Unk1 and Unk 4a/4b – composites of several minor transformation products, each < 6.5% of applied. Unk4a - N-(2,6-dimethoxybenzoy1)-3-(1-ethyl-1-methylpropyl)-2H-azirene-2-carboxamide; Unk4b 

- N-[2-(1-ethyl-1-methylpropy1)-1,3-oxazo1-5-yl]-2,6-dimethoxybenzamide
Isoxaben D376428

Page 84 of 90

Table B.3.2 Maximum Reported Amounts of Isoxaben Degradation Products1

Degradate Maximum % of Applied % of Applied at Study 

Termination

Study Type MRID Monitoring 

Data

Isoxaben (parent) Not applicable 96.5-98 (30 d, pH4,7,9)

1.2 (36 days)

83.8 - 89.5 (30 days)

54.3-70.4 (122 days)

55.8 (60 days)

0.2-2.4 (103 days)

0.5 (121 days)

3 (313 days, 0-6”, autumn FL app)

5 (127 days, 0-6”, spring FL app)

18 (127 days, 0-6”, spring IN app)

35 (182 days, 0-6”, autumn TX app)

2.9 (299 days, 0-15 cm, FL app)

5.8 (322 days, 0-15 cm, IN app)

14.4 (483 days, 0-15 cm, TX app)

9.1 (700 days, 0-15 cm)

Hydrolysis

Aqueous Photolysis

Soil Photolysis

Aerobic Soil Metabolism

Anaerobic Soil Metabolism

Aerobic Aquatic Metabolism

Anaerobic Aquatic Metabolism

Terrestrial Field Dissipation

Terrestrial Field Dissipation

Terrestrial Field Dissipation

Terrestrial Field Dissipation

Terrestrial Field Dissipation

Terrestrial Field Dissipation

Terrestrial Field Dissipation

Terrestrial Field Dissipation

00250449

47140003

47428403

47140004

41106302

46393202

46393201

40059508

40059508

40059508

40059508

40532101

40532101

40532101

00250449

No

Dimethoxy benzamide 21.9 (12 days)

8.5 (30 days)

10.7 (44 days)

12.9 (30 days)

14.1 (36 days)

8.5 (30 days)

2.5-5.7 (103 days)

5.2 (121 days)

Aqueous Photolysis

Soil Photolysis

Aerobic Aquatic Metabolism

Anaerobic Aquatic Metabolism

47140003

47428403

46393202

46393201

No

Hydoxy isoxaben 10.8 (122 days)

16.8 (60 days)

1.1 (84 days)

5 (36 days, 0-6”, autumn FL app)

9 (60 days, 0-6”, spring FL app)

7 (41 days, 0-6”, spring IN app)

3 (182 days, 0-6”, autumn TX app)

4.2 (299 days, 0-15 cm, FL app)

3.2 (322 days, 0-15 cm, IN app)

2.1 (375 days, 0-15 cm, TX app)

11 (66 days, 0-6”, IL app)

8.6 (224 days, 0-7.5 cm)

7.6 (539 days, 0-15 cm)

10.8 (122 days)

18.8 (60 days)

0.1-0.3 (103 days)

3 (313 days, 0-6”, autumn FL app)

5 (127 days, 0-6”, spring FL app)

3 (127 days, 0-6”, spring IN app)

3 (182 days, 0-6”, autumn TX app)

4.2 (299 days, 0-15 cm, FL app)

3.2 (322 days, 0-15 cm, IN app)

1.0 (483 days, 0-15 cm, TX app)

2.0 (211 days, 0-6”, IL app)

4.6 (700 days, 0-15 cm)

4.6 (700 days, 0-15 cm)

Aerobic Soil Metabolism

Anaerobic Soil Metabolism

Aerobic Aquatic Metabolism

Terrestrial Field Dissipation

Terrestrial Field Dissipation

Terrestrial Field Dissipation

Terrestrial Field Dissipation

Terrestrial Field Dissipation

Terrestrial Field Dissipation

Terrestrial Field Dissipation

Terrestrial Field Dissipation

Terrestrial Field Dissipation

Terrestrial Field Dissipation

47140004

41106302

46393202

40059508

40059508

40059508

40059508

40532101

40532101

40532101

40532102

00250449

00250449

No

Methoxyphenyl pyrimidinol 0.1 (61 days)

33.1 (93 days)

0 (103 days)

27.8 (121 days)

Aerobic Aquatic Metabolism

Anaerobic Aquatic Metabolism

46393202

46393201

No

AEM hexenoyl isoxaben 8.4 (30 days)

60.1 (14 days)

2.5 (103 days)

36.0 (121 days)

Aerobic Aquatic Metabolism

Anaerobic Aquatic Metabolism

46393202

46393201

No

Unk1 27.6 (36 days) 27.6 (36 days) Aqueous Photolysis 47140003 No

Unk3 24.2 (36 days) 24.2 (36 days) Aqueous Photolysis 47140003 No

Unk3i 14.8 (14 days) 11.8 (36 days) Aqueous Photolysis 47140003 No

Unk 4a/4b 8.0 (14 days) 1.2 (36 days) Aqueous Photolysis 47140003 No

Unk5a 23.2 (1 days) 0.0 (36 days) Aqueous Photolysis 47140003 No
Isoxaben D376428

Page 85 of 90

Degradate Maximum % of Applied % of Applied at Study 

Termination

Study Type MRID Monitoring 

Data

Unk5b 17.6 (14 days) 13.6 (36 days) Aqueous Photolysis 47140003 No

Oxypropyl isoxaben 7.3 (90 days)

4.4 (30 days)

1.6 (30 days)

1.4 (121 days)

3.3-5.7 (122 days)

4.2 (60 days)

0.4 (103 days)

1.4 (121 days)

Aerobic Soil Metabolism

Anaerobic Soil Metabolism

Aerobic Aquatic Metabolism

Anaerobic Aquatic Metabolism

47140004

41106302

46393202

46393201

No

Desmethyl isoxaben 1.6 (122 days)

2.2 (60 days)

2.5 (7 days)

0.5-1.6 (122 days)

2.2 (60 days)

0.0 (121 days)

Aerobic Soil Metabolism

Anaerobic Soil Metabolism

Anaerobic Aquatic Metabolism

47140004

41106302

46393201

No

Hydroxyethyl isoxaben 0.4 (90 days)

1.9 (60 days)

2.3 (350 days, 0-7.5 cm)

3.9 (602 days, 0-15 cm)

<0.1-0.3 (122 days)

1.9 (60 days)

3.8 (700 days, 0-15 cm)

3.8 (700 days, 0-15 cm)

Aerobic Soil Metabolism

Anaerobic Soil Metabolism

Terrestrial Field Dissipation

Terrestrial Field Dissipation

47140004

41106302

00250449

00250449

No

Hydroxymethoxy benzamide 1.1 (84 days)

7.7 (61 days)

0.1-0.6 (103 days)

6.8 (121 days)

Aerobic Aquatic Metabolism

Anaerobic Aquatic Metabolism

46393202

46393201

No

1 - Major degradates and maximum amounts >10% are in bold. Unacceptable data were not reported.
Page 86 of 90

Table B.3.3. Chemical Names and Structures of isoxaben and degradation products detected in submitted environmental fate studies

Name(s) Structure Occurrence Fate Properties1

Isoxaben (parent)

Pseudonyms- EL-107

IUPAC name

N- [3-(methylpent-3-yl)isoxazol -5-yl]-

2,6-dimethoxy-benzamide

CAS #-82558-50-7

See Table 2.3

Dimethoxy benzamide

2,6-Dimethoxybenzamide

Aqueous photolysis (major)

Aerobic Aquatic Metabolism (major)

Anaerobic Aquatic Metabolism (major)

Soil Photolysis (minor)

VP = 1.6x10-5torr

Sol = 8.4x104 mg/L

Log KOW = -0.22

KOC = 4.9 – 10 mL/g

Hydroxy isoxaben 

Pseudonyms- AA-045

N-[3-(1-hydroxyl-1-methylpropyl)-5-

isoxazoyl]-2,6-dimethoxy-benzamide

Aerobic Soil Metabolism (major)

Anaerobic Soil Metabolism (major)

Aerobic Aquatic Metabolism (minor)

Terrestrial Field Dissipation (minor)

VP = 9.8x10-12 torr

Sol = 462 mg/L

Log KOW = 1.53

KOC = 17 – 31 mL/g

KOC = 21 – 73

(MRID 4110603)

Methoxyphenol pyrimidinol

6-(1-ethyl-1-methylpropyl)-2-(2-

hydroxy-6-methoxyphenyl)-4-

pyrimidinol

Anaerobic Aquatic Metabolism (major)

Aerobic Aquatic Metabolism (minor)

VP = 4x10-10 torr

Sol = 41.2 mg/L

Log KOW = 3.56

KOC = 4800 – 38,000 mL/g
Isoxaben D376428

Page 87 of 90

Table B.3.3. Chemical Names and Structures of isoxaben and degradation products detected in submitted environmental fate studies

Name(s) Structure Occurrence Fate Properties1

AEM hexenoyl isoxaben

N-[3-amino-4-ethyl-4-methyl-2-

hexenoyl]-2,6-dimethoxybenzamide

Anaerobic Aquatic Metabolism (major)

Aerobic Aquatic Metabolism (minor)

VP = 3.1x10-13 torr

Sol = 265 mg/L

Log KOW = 1.71

KOC = 21 - 102 mL/g

Oxypropyl isoxaben

N-[3-(1 -ethyl-methyl-2-oxopropyl)-

isoxazolyl-5-yl]-2,6-

dimethoxybenzamide

Aerobic Soil Metabolism (minor)

Anaerobic Soil Metabolism (minor)

Aerobic Aquatic Metabolism (minor)

Anaerobic Aquatic Metabolism (minor)

VP = 5x10-10 torr

Sol = 148 mg/L

Log KOW = 1.93

KOC = 112 - 148 mL/g

Desmethyl isoxaben

N-[3-(1-ethyl-1-methylpropyl)-5-

isoxazolyl]-2-hydroxy-6-

methoxybenzamide

Aerobic Soil Metabolism (minor)

Anaerobic Soil Metabolism (minor)

Anaerobic Aquatic Metabolism (minor)

VP = 1.6x10-10 torr

Sol = 5.32 mg/L

Log KOW = 4.5

KOC = 2400 - 2500 mL/g

Hydroxyethyl isoxaben

N-[3-(1-hydroxyethyl)-5-isoxazolyl]-2,6-

dimethoxybenzamide

Aerobic Soil Metabolism (minor)

Anaerobic Soil Metabolism (minor)

Terrestrial Field Dissipation (minor)

VP = 2.9x10-11 torr

Sol = 4322 mg/L

Log KOW = 0.58

KOC = 5 – 11 mL/g
Isoxaben D376428

Page 88 of 90

Table B.3.3. Chemical Names and Structures of isoxaben and degradation products detected in submitted environmental fate studies

Name(s) Structure Occurrence Fate Properties1

Hydroxymethoxybenzamide

2-hydroxy-methoxy benzamide

Aerobic Aquatic Metabolism (minor)

Anaerobic Aquatic Metabolism (minor)

VP = 1.7x10-6torr

Sol = 7.7x104 mg/L

Log KOW = 0.58

KOC = 15 – 17 mL/g

6-(1-ethyl-1-methylpropyl)pyrimidine2,4(1H,3H)-dioneAqueous Photolysis (major) VP = 5.6x10-8torr

Sol = 853 mg/L

Log KOW = 2.0

KOC = 80 – 113 mL/g

4-ethyl-3-(hydroxyimino)-4-

methylhexanoic acid

Aqueous Photolysis (major) VP = 3.8x10-6torr

Sol = 698 mg/L

Log KOW = 2.8

KOC = 51 – 126 mL/g

N-(2,6-dimethoxybenzoy1)-3-(1-ethyl-1-

methylpropyl)-2H-azirene-2-carboxamide

Aqueous Photolysis (minor) VP = 6.6x10-12 torr

Sol = 1.1 mg/L

Log KOW = 4.5

KOC = 362 – 2014 mL/g

N-[2-(1-ethyl-1-methylpropy1)-1,3-

oxazo1-5-yl]-2,6-dimethoxybenzamide

Aqueous Photolysis (minor) VP = 2.5x10-9torr

Sol = 3.2 mg/L

Log KOW = 4.0

KOC = 972 – 1262 mL/g
Isoxaben D376428

Page 89 of 90

Table B.3.3. Chemical Names and Structures of isoxaben and degradation products detected in submitted environmental fate studies

Name(s) Structure Occurrence Fate Properties1

2-(2,6-dimethoxybenzoyl)-5-(1-ethyl-1-

methylpropyl)1,2-dihydro-3H-pyrazol-3-

one

Aqueous Photolysis (major) VP = 2.0x10-10 torr

Sol = 29 mg/L

Log KOW = 2.85

KOC = 222 – 228 mL/g

4,6-diethyl-4a,8-dimethoxy-4-methyl4a,8a-dihydropyrazolo[1,5-

b]isoquinoline-2,9(1H,4H)-dione

Aqueous Photolysis (major) VP = 1.3x10-10 torr

Sol = 2221 mg/L

Log KOW = 0.65

KOC = 12 – 331 mL/g

CO2

Carbon dioxide

O C O Aqueous Photolysis (major)

Soil Photolysis (major)

Aerobic Soil Metabolism (minor)

Aerobic Aquatic Metabolism (major)

1. Fate properties for degradates estimated using EPISuite 4.0.
Page 90 of 90

Appendix C: Tolerance Summary Table

Appendix C. Tolerance Summary for Isoxaben. 

Commodity Proposed Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Grape 0.01 0.01

Grape, juice 0.01 Remove A separate tolerance for grape juice 

is not needed.

Grape, raisin 0.01 Remove A separate tolerance for raisin is not 

needed.

Nut, tree, Group 14 0.03 0.02 Nut, tree, Group 14

Pistachio 0.03 0.02

Almond, hulls 0.35 0.40 Tolerance should be 0.40 ppm and 

not 0.35 ppm, based on evaluation 

using the NAFTA Tolerance 

Spreadsheet. 

No Codex, Canadian, or Mexican MRLs have been established for isoxaben.

Appendix D: Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to determine their dermal and inhalation exposures. Many such studies,

involving exposure to many different pesticides comprise generic pesticide exposure databases 

such as Pesticide Handlers Exposure Database (PHED), the Outdoor Residential Exposure Task

Force (ORETF) database and the Agricultural Reentry Task Force (ARTF) database. EPA has 

reviewed all the studies in these multi-pesticide generic exposure databases, and on the basis of 

available evidence has found them to have been neither fundamentally unethical nor significantly

deficient relative to standards of ethical research conduct prevailing when they were conducted. 

There is no regulatory barrier to continued reliance on these studies, and all applicable 

requirements of EPA's Rule for the Protection of Human Subjects for Research (40 CFR part 26) 

have been satisfied.