-Page 2 of 74- 

anticipated from exposure to isoxaben. Acute risk to mammals is not anticipated, but there is the 

potential for chronic risk to mammals on a chronic dose-basis (RQs ≤3.84). Risk to listed and 

non-listed species of terrestrial plants (RQs≤80.1) and aquatic vascular plants (RQs ≤14.7) may 

occur. 

Table 1 summarizes the representative uses assessed and the taxa that may potentially be directly 

at risk from exposure to isoxaben. 

Table 1. Risk Resulting from Isoxaben Exposure Presented by Taxon 

Use Pattern 

Category

Aquatic 

Invertebrates 

Fish 

(surrogate 

for aquaticphase 

amphibians)

Birds, 

(surrogate 

for 

terrestrialphase 

amphibians 

and 

reptiles)

Mammals Plants Terrestrial 

Invertebrates

Turfgrass / 

Groundcover/ 

perennials / 

Non-cropland / 

Christmas 

tree/conifer 

plantations, 

hardwood nursery / 

Ornamentals/ 

Non-bearing fruit & 

nut trees & 

vineyards / 

Bearing fruit and 

nut trees and 

vineyards / 

Eucalyptus 

Acute risk: 

Not expected; 

acute toxicity 

is limited by 

solubility 

Chronic risk: 

Not expected 

Acute risk: 

Not 

expected; 

acute toxicity 

is limited by 

solubility 

Chronic risk: 

Not expected 

Acute risk: 

Not 

expected 

Chronic 

risk: 

Not 

expected 

Acute risk: 

Not 

expected 

Chronic 

risk: 

Potential 

risk; RQs 

(dosebased) 

exceed 

LOC for 

all uses 

based on 

foliar 

application 

(RQs 

≤3.84) 

Terrestrial: 

Potential 

risk to 

listed and 

non-listed 

plants; 

RQs 

exceed 

LOC (RQs 

≤80.1) 

Aquatic 

Vascular: 

Potential 

risk to 

listed and 

non-listed 

plants; 

RQs 

exceed 

LOC (RQs 

≤14.7) 

Aquatic 

nonvascular: 

Not 

expected 

Non-listed 

and Listed: 

Not expected 
-Page 3 of 74- 

Environmental 

Fate and Ecological 

Risk Assessment for the Registration Review of Isoxaben 

 

Isoxaben 

N- [3-(methylpent-3-yl)isoxazol-5-yl]-2,6-dimethoxy-benzamide 

CAS Registry Number 82558-50-7

PC Code 125851

 

Prepared by:

Andrew Shelby, Physical Scientist 

Amy Blankinship, Chemist 

U. S. Environmental Protection Agency

Office of Pesticide Programs

Environmental Fate and Effects Division

Environmental Risk Branch VI

1200 Pennsylvania Ave., NW

Mail Code 7507P

Washington DC 20460

Reviewed by: 

Brian Kiernan, Biologist, ERB VI 

Ibrahim Abdel-Saheb, Physical Scientist, ERB VI 

Mark Corbin, Branch Chief, ERB VI 

September 3, 2014 
Page 4 of 74 

Table of Contents

1. Executive Summary ........................................................................................................................................... 5

2. Problem Formulation ........................................................................................................................................ 8

2.1. Nature of Regulatory Action ......................................................................................................................... 8

2.2. Nature of the Chemical Stressor ................................................................................................................... 9

2.3. Use Characterization ...................................................................................................................................... 9

2.4. Conceptual Model ......................................................................................................................................... 12

Analysis Plan ............................................................................................................................................................... 14

Residues of Concern ..................................................................................................................14

Measures of Exposure ..............................................................................................................15

Measures of Effect ....................................................................................................................16

3. Analysis ............................................................................................................................................................. 16

3.1. Exposure Characterization .......................................................................................................................... 16

3.2. Ecological Effects Characterization ............................................................................................................ 32

4. Risk Characterization ...................................................................................................................................... 37

4.1. Risk Estimation ............................................................................................................................................. 37

4.2. Risk Description............................................................................................................................................ 43

4.2.1. Risks to Aquatic Organisms ................................................................................................................... 44

4.2.2. Risks to Terrestrial Organisms ............................................................................................................. 46

5. Federally Threatened and Endangered (Listed) Species Concerns .................................................................... 52

6. Endocrine Disruptor Screening Program .......................................................................54

7. Literature Cited ................................................................................................................................................ 55
Page 5 of 74 

1. Executive Summary 

The Environmental Fate and Effects Division (EFED) has completed the registration review 

preliminary ecological risk assessment for isoxaben (N- [3-(methylpent-3-yl)isoxazol-5-yl]-2,6-

dimethoxy-benzamide; CAS No. 82558-50-7; PC Code 125851) and its end-use products. 

Isoxaben is a pre-emergent benzamide herbicide used for the control of broadleaf (dicotyledonous) 

weeds. Isoxaben is formulated as a dry flowable, granule, and suspension concentrate. Isoxaben 

is registered for use on a variety of non-agricultural uses including: turfgrass, ornamentals 

(landscape, container and field), groundcovers/perennials, conifer plantations/hardwood nurseries, 

non-bearing fruit and nut trees, non-bearing vineyards, and other non-cropland. It is also registered 

for agricultural use on bearing fruit and nut trees, vineyards, and eucalyptus. The majority of uses 

have a maximum application rate of 1.0 lb a.i./A/application (pounds of active ingredient per acre 

per application), with three applications per year and a 60-day reapplication interval (i.e., yearly 

application of 3.0 lb a.i./A). However, there is at least one label (EPA reg. no. 62719-658) where 

the maximum yearly application rate is 4.0 lb a.i./A. Isoxaben products are generally registered for 

both non-residential and residential use. Recent isoxaben ecological risk assessments include the 

Section 3 new use assessment for bearing nut trees and vineyards (USEPA, 2010; D341496). 

Isoxaben is moderately persistent and mobile. Isoxaben does not hydrolyze and does not appear to 

readily degrade in terrestrial environments. Primary routes of degradation appear to be 

biodegradation in aerobic and anaerobic water bodies and photolysis in shallow, clear water 

bodies. 

 

Isoxaben is not acutely toxic to freshwater and estuarine/marine fish and invertebrates at its limit 

of solubility. On a chronic exposure basis, isoxaben resulted in decreased reproduction (number 

of young/female) and growth of freshwater invertebrates and decreased reproduction (number of 

young/female) of estuarine/marine invertebrates at test concentration levels greater than estimated 

environmental concentrations. Chronic toxicity data for freshwater fish indicate it is not toxic near 

the limit of solubility. Chronic data for estuarine/marine fish are not available, however, the 

freshwater fish chronic toxicity data was considered sufficient to evaluate potential risk to 

estuarine/marine fish. Isoxaben is practically nontoxic to birds, mammals, and beneficial insects 

(i.e., honey bees) on an acute exposure basis as no effects were recorded in the available studies 

(i.e., the no effect level was greater than the highest concentration tested). Chronic toxicity testing 

with birds did not identify an adverse response threshold (i.e., no effects observed at highest 

concentration tested). In the chronic mammalian reproduction study, significant treatment-related 

reductions in parental bodyweight and decreases in viable pups were observed. Based on the 

available plant toxicity data, isoxaben exhibited low toxicity to aquatic non-vascular plants, but 

exhibited toxicity to terrestrial and aquatic vascular plants. 

Potential effects to federally-listed endangered and threatened species (listed species) based on 

level of concern (LOC) exceedances require an in-depth listed species evaluation determining the 

potential co-occurrence of listed species and use patterns of isoxaben. Identified potential risks to 

listed species are summarized in Table 1.
Page 6 of 74 

Table 1. Potential Effects to Federally Listed Taxa Associated with Direct Effects from the 

Registered Uses of Isoxaben.

Listed Plant Taxon Potential Direct Effects 

Terrestrial and semi-aquatic 

plants – monocots and dicots Yes1

Aquatic nonvascular plants No2

Aquatic vascular plants Yes1

Listed Animal Taxon Potential Direct Effects 

Acute Chronic 

Terrestrial invertebrates No3 No 

Mammals No3 Yes4 

Birds No3 No3 

Reptiles No3 No3

Amphibians No3 No3

Freshwater fish No3 No3

Freshwater invertebrates No3 No3

Estuarine/marine fish No3 No3

Estuarine/marine invertebrates No3 No3

1

 RQs exceed the listed LOC based on toxicity data for both terrestrial plants and aquatic vascular plants. 2

 Risk of direct effects from isoxaben exposure expected to be below the LOC 3 Risk of direct effects from acute and chronic exposure to terrestrial and aquatic animals is expected to be below the LOC, except for chronic 

risk to mammals. 

4 Chronic risk to mammalian species may occur as the LOC was exceeded for all registered uses from exposure to isoxaben on a chronic dosebasis, but not on a dietary basis.

Based on this screening-level assessment, acute risk resulting from direct effects is not expected 

for listed birds (surrogates for terrestrial-phase amphibians and reptiles), mammals, freshwater and 

estuarine/marine fish (surrogates for aquatic-phase amphibians), freshwater and estuarine/marine 

invertebrates and terrestrial invertebrates (using honeybees as a surrogate) from the use of isoxaben 

on all of its registered use sites. Chronic risk resulting from direct effects to listed birds, freshwater 

and estuarine/marine fish, freshwater and estuarine/marine invertebrates is not expected from the 

use of isoxaben on all of its registered use sites. Direct effects to aquatic non-vascular plants are 

not anticipated. Potential direct effects on listed terrestrial and aquatic vascular plants and 

mammals (chronic exposure) from the use of isoxaben may be associated with modification of 

primary constituent elements (PCEs) of designated critical habitat, where such designations have 

been made. However, at this current stage of the Registration Review process, it is premature to 

make effects determinations until further refinements are conducted. In order to make speciesspecific effects determinations, useful refinements include more detailed 1) species-specific 

ecological and biological data; 2) information on use patterns for isoxaben; and 3) sub-county level 

spatial proximity analyses for the co-occurrence of potential areas of effects and listed 

species/designated critical habitats of concern. Examples of such refinements are described below. 

EFED is currently developing tools that are expected to further refine the species-specific 

assessment and designed to aid in making effects determinations for individual listed species 

and/or their designated critical habitats (if applicable). Information obtained from the U.S. Fish & 

Wildlife Service (USFWS), the National Marine Fisheries Service (NMFS), and other reliable 

sources is being collated by EFED to address all currently listed species. The information will be 

stored in an Office of Pesticide Programs Pesticide Registration Information System (PRISM) 

knowledgebase, which consists of an information repository for biological and behavioral data 
Page 7 of 74 

relevant to specific species and/or their habitats and a document repository that contains supporting 

documents (e.g., USFWS recovery plans) and electronic information (e.g., GIS data files). These 

data will be relied upon to provide information on habitat, diet, life history variables, and temporal 

and spatial data. For terrestrial taxa specifically, the biological information relevant to Risk 

Quotient (RQ) calculations (e.g., diet and body weight) will be used to parameterize exposure 

estimates to derive species-specific RQs consistent with currently used methods in the T-REX and 

T-HERPS models. 

Refinements may also include more detailed analyses of the registered uses and their use patterns 

that result in level of concern (LOC) exceedances for listed species in the screening-level 

assessment. The analyses may include more information on where, when, and how isoxaben is 

used on turfgrass, groundcover, perennials, non-cropland, Christmas tree/conifer plantations, 

hardwood nursery, ornamentals, non-bearing fruit & nut trees & vineyards, bearing fruit and nut 

trees and vineyards, and eucalyptus. Actual usage data (when available) and national land-cover 

datasets that indicate potential use sites (e.g., national land cover dataset (NLCD), crop data layer 

(CDL)) may be used to support a more refined analysis of where isoxaben is reasonably expected 

to be used. Similarly, refinements for the timing of applications and how isoxaben is used may 

involve an analysis of reported usage data (if available) and a more in-depth exploration of 

agronomic practices. 

The U.S. Environmental Protection Agency (EPA), along with the U.S. Department of Agriculture 

(USDA), the U.S. Fish and Wildlife Service (FWS), and the National Marine Fisheries Service 

(NMFS), have announced the availability of a report developed by the National Academy of 

Sciences’ (NAS) National Research Council (NRC) outlining recommendations on specific 

scientific and technical issues related to the development of endangered and threatened species 

risk assessments for pesticides that are compliant with the Endangered Species Act (ESA) and the 

Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). The EPA, USDA, FWS and NMFS 

asked the NRC to consider a range of scientific and technical issues including: 

• identifying best available scientific data and information; 

• considering sub-lethal, indirect and cumulative effects; 

• assessing the effects of chemical mixtures and inert ingredients; 

• analyzing the effects of pesticide use through the use of models; 

• incorporating uncertainties into the evaluations; and 

• using geospatial information and datasets that can be employed by the agencies in the 

course of these assessments. 

After reviewing the NRC’s recommendations on these scientific and technical issues, the EPA 

and its federal partners will determine how these recommendations can be implemented and 

incorporated into the scientific approaches for developing listed species risk assessments. It is 

anticipated that any draft guidance and/or science policies developed by EPA and its federal 

partners as a result of the NAS recommendations would be released for public comment prior to 

implementation. 

The refinements based on species-specific data and detailed usage information, when available, 

are expected to help to more accurately identify potential areas of effect and to better inform effects 
Page 8 of 74 

and habitat determinations for listed species and any designated critical habitats. For example, if 

isoxaben is used when a particular species of concern is not present (e.g., it is migratory) or is not 

co-located in space, then risk to the species may often be precluded. If LOCs are still exceeded 

for mammals, and terrestrial and aquatic vascular plants after conducting the refined analyses, then 

further analyses of the potential spatial/temporal co-occurrence of listed species of concern (and 

any designated critical habitat) may be conducted. The extent of possible refinement in the 

analyses of spatial/temporal co-occurrence will largely depend on the scale and quality of the 

available sub-county level use site (e.g., NLCD, CDL) and species location data. 

2. Problem Formulation 

The purpose of problem formulation is to provide the foundation for the environmental fate and 

ecological risk assessment in support of the registration review of the herbicide isoxaben (N- [3-

(methylpent-3-yl)isoxazol-5-yl]-2,6-dimethoxy-benzamide; CAS No. 82558-50-7; PC Code 

125851). The problem formulation sets the objectives for the risk assessment, establishes a risk 

hypothesis and conceptual model depicting potential risk, and provides a plan for analyzing the 

data and characterizing the risk associated with the uses of isoxaben (USEPA, 1998). 

2.1. Nature of Regulatory Action 

Under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), all pesticides distributed 

or sold in the United States must be registered by the United States Environmental Protection 

Agency (EPA or the Agency). To determine whether a pesticide can be registered, the EPA 

evaluates the product’s safety to non-target species based on a wide range of environmental and 

health effects studies. In 1996, FIFRA was amended by the Food Quality Protection Act (FQPA), 

and EPA was mandated to implement a new program for the periodic review of pesticides, i.e., 

Registration Review1

. The registration review program is intended to ensure that as the ability to 

assess risk evolves and as policies and practices change, all registered pesticides continue to meet 

the statutory standard of no unreasonable adverse effects to human health and the environment. 

Changes in science, public policy, and pesticide use practices will occur over time. Through the 

registration review program, the Agency periodically reevaluates pesticides to make sure that as 

changes occur, products in the marketplace can be used safely. 

Additionally, potential effects to Federally-listed endangered and threatened species (hereafter 

referred to as “listed”) and their designated critical habitat are also considered under the 

Endangered Species Act (ESA) in order to ensure that the continued registration of isoxaben is not 

likely to jeopardize the continued existence of listed species or adversely modify their critical 

habitat. In order to meet the requirements of FIFRA and the ESA, this assessment follows EPA 

guidance on conducting ecological risk assessments (USEPA, 1998) and Office of Pesticide 

Program’s Overview Document, which contains guidance for assessing pesticide risks to nonlisted and listed species (USEPA, 2004). 

 

1 http://www.epa.gov/oppsrrd1/registration_review/
Page 9 of 74 

Recent isoxaben ecological risk assessments include the Section 3 new use assessment for bearing 

nut trees and vineyards (USEPA, 2010; D341496). 

2.2. Nature of the Chemical Stressor 

Isoxaben is a pre-emergent benzamide herbicide used for the control of broadleaf (dicotyledonous) 

weeds. Isoxaben has been shown to inhibit the conversion of glucose to cellulose in cell wall 

synthesis in sensitive species, with grasses (Family: Poaceae) tending to be more tolerant than 

other plant groups (Salihue et al. 1998). Isoxaben is not thought to be highly mobile in adult plant 

tissues, apparently limiting its toxicity to older plants, but allowing increased efficacy in emerging 

seedlings. The vegetative vigor of early growth plants, particularly ryegrass, is affected by 

isoxaben, as discussed in the Ecological Effects Characterization. Chemical properties of isoxaben 

are presented in Table 2. 

Table 2. Nature of the Chemical Stressor 

Common name Isoxaben (EL-107) 

Chemical Name N- [3-(methylpent-3-yl)isoxazol-5-yl]-2,6-

dimethoxy-benzamide 

Chemical Structure 

Pesticide type Herbicide 

Chemical class Benzamide 

CAS number 82558-50-7 

Empirical formula C18H24N2O4

Molecular Mass (g/mol) 332.39 g · mol-1

Vapor pressure (torr) <3.9 X 10 -7

Henry’s Law Constant at 20oC 

(atm-m3

/mole) 8.5x10-10

Solubility in water (ppm) 1.42 

Log Kow 2.64

pKa at 25oC 9.78 

2.3. Use Characterization 

Isoxaben is formulated as a dry flowable, granule, and suspension concentrate. Isoxaben is 

registered for use on a variety of non-agricultural uses including: turfgrass, ornamentals 

(landscape, container and field), groundcovers/perennials, conifer plantations/hardwood nurseries, 

non-bearing fruit and nut trees, non-bearing vineyards, and other non-cropland. It is also registered 

for agricultural use on bearing fruit and nut trees and vineyards. The majority of uses have an 
Page 10 of 74 

application rate of 1.0 lb ai/A/application, three applications per year with a 60-day reapplication 

interval. However, there is at least one label where the maximum yearly application rate is 4.0 lb 

a.i./A (EPA reg. no. 62719-658). Isoxaben products are generally registered for both nonresidential and residential use. Current labels allow for broadcast and spot treatment applications 

with spot treatments potentially resulting in less exposure; however, in this assessment exposure 

modeling was based on a per acre basis. Based on label instructions for the registered isoxaben 

product labels, most prohibit aerial application; it is not clear whether all of the current product 

labels prohibit aerial application (e.g. usage on conifer seed orchards). While there are reported 

geographical (U.S.state) restrictions for some registered uses on some of the labels, other labels 

for the same registered uses do not indicate any geographical restrictions. As such, where there 

was not a consistent geographical restriction, potential environmental exposures were estimated 

assuming no geographic restrictions. There appears to be consistent label prohibitions on direct 

applications to water. Warnings regarding the potential toxicity to aquatic organisms and 

avoidance of spray drift are on the labels. Labeled use patterns for isoxaben are summarized in 

Table 3, below. 

Table 3 Summary of the Maximum Isoxaben Application Rates by Use Site 

Use Application 

method

Residential 

or 

Agricultural

Max. 

Single 

app rate 

(lb 

a.i./A) 

Max # 

apps per 

year 

Max 

App rate 

per year 

(lb a.i/A) 

Min. App 

interval 

(days) 

Comment 

Turfgrass (Established) Ground 

(spray) 

Both 1.02 NS/4 4.03 56-60 AZ and NY 

use restriction 

inconsistent 

among labels, 

as well as for 

chemigation

Granule Residential 1.08 2 2.16 56-84 

Lawns (turfgrass) Ground 

(spray) 

Agricultural 1.0 NS 1.0 60 No use in NY, 

AZ 

Granule Both 1.0 NS/4 3.2 60/NS 

Ornamentals (landscape, 

container, field) 

Ground 

(spray) 

Both 1.02 NS/4 4.03 NS/56-60 AZ 

restrictions for 

commercial 

use 

Granule Both 1.0 3 3.0 60 

Groundcovers/perennials Ground 

(Spray) 

Both 1.02 NS/4 4.03 60 AZ use 

restriction 

inconsistent 

among labels. 

Not for 

commercial 

use. 

Granule Both 1.0 NS/3 3.0 60 

Non-cropland Ground 

(spray) 

Both 1.02 NS/4 4.03 60 AZ restriction 

inconsistent 

among labels. 

Not for 

commercial 

use. 

Granule 1.0 NS/3 3.0 60 

Non-bearing fruit & nut 

trees & non-bearing 

vineyards 

Ground 

(spray) 

Both 1.0 NS/3 3.0 60/NS Restrictions in 

AZ 

Granule Agricultural 1.0 NS/3 3.0 60 

Christmas tree/conifer 

plantations, hardwood 

nursery 

Ground 

(spray) 

Both 1.02 NS/4 4.03 60 Not for 

commercial 

Granule NS 1.0 NS/3 3.0 60 use in AZ 
Page 11 of 74 

Fruit and nut trees and 

vineyards 

Ground 

(spray) 

NS 1.02 2 1.0 30/NS Not for use in 

NY 

Eucalyptus Ground 

(spray) 

NS 0.75 2 1.0 30 62719-612: 

Not for use in 

NY; do not 

apply w/in 

200ft of 

susceptible 

non-target 

plants 

NS= the number of application was not specifically reported on label but rather calculated using the single maximum application

rate and yearly rate. 

NS/# - the number of applications was not specified on some labels while others provided a discrete number of applications 

A screening level estimate of current usage of isoxaben is presented in Table 4. This screening 

level usage assessment from the Biological and Economic Analysis Division (BEAD) presents 

usage data on an annual basis from USDA’s National Agricultural Statistics Service, the California 

Department of Pesticide Regulation, and private pesticide market research, with data updated to 

2012. This analysis indicates that on an annual basis, grapes and pistachios (based on pounds a.i. 

used) along with caneberries are the dominant agricultural use patterns. Non-agricultural uses, 

which comprise the majority of registered uses for isoxaben, are not represented in this table. 

Table 4. Isoxaben Screening Level Usage Analysis (SLUA) for 2004-2012 

Average Percent Crop Treated 

Crop Lbs. A.I. Average Maximum 

Almonds <500 <1 <2.5 

Apples <500 <1 <2.5 

Apricots <500 <1 <2.5 

Caneberries <500 5 5 

Grapes 8,000 <2.5 5 

Hazelnuts <500 <1 <2.5 

Nectarines * <500 NC NC 

Olives * <500 NC NC 

Peaches <500 <1 <2.5 

Pecans <500 <1 <2.5 

Pistachios 3,000 <2.5 <2.5 

Plums/Prunes <500 <1 <2.5 

Walnuts <500 <1 <2.5 

All numbers are rounded. 

<500: less than 500 pounds of active ingredient. 

<2.5: less than 2.5 percent of crop is treated. 

<1: less than 1 percent of crop is treated. 

* Based on CA DPR data only (80% or more of U.S. acres grown are in California) 

NC: not calculated, only pounds a.i. available. 
Page 12 of 74 

In addition to the screening level use information from BEAD, the U.S. Geological Survey 

(USGS) also provides use data with geographical mapping. As shown in Figure 1, based on 

USGS National Water Quality Assessment Program (NAWQA) from 2011, isoxaben agricultural 

uses appear to be used predominately on orchards and grapes in California and Oregon. 

NAWQA does not consider non-agricultural uses in its data. 

Figure 1 . Reported Isoxaben Use from USGS NAWQA database

http://water.usgs.gov/nawqa/pnsp/usage/maps/show_map.php?year=2011&map=ISOXABEN&hilo=L&disp=

Isoxaben (accessed June 26, 2014). 

2.4. Conceptual Model 

The potential terrestrial and aquatic exposure pathways and effects of the registered uses of 

isoxaben are shown in Figure 2. The conceptual model used to depict the potential ecological risk 

associated with the registered uses of isoxaben assumes that, as an herbicide, isoxaben is capable 

of adversely affecting terrestrial and aquatic animals and plants, provided that environmental 

concentrations are sufficiently elevated as a result of the labeled uses. Solid arrows in Figure 2

depict the most likely routes of exposure and effects; dashed lines depict potential routes of 

exposure that are not considered likely for isoxaben. 
Page 13 of 74 

STRESSOR Foliage applied Isoxaben and its resulting degradates 

Volatilization/ 

Wind Suspension 

Spray Drift Runoff/ Erosion 

Direct Deposition SOURCE/ TRANSPORT 

PATHWAYS

Terrestrial Food 

Residues (foliage, fruit, 

seeds, insects, 

granules) 

Upland 

Foliage/ Soil 

Riparian/ 

Wetland 

Foliage/ Soil 

Receiving 

Water Body

Sediment 

Terrestrial 

Upland 

Plants 

Riparian/ 

Wetland 

Plants 

Terrestrial Vertebrates 

(Birds, Mammals, 

Reptiles, Terrestrial Phase 

Amphibians) 

Aquatic 

Plants 

Plant 

Population: 

Reduced 

Population 

Growth, 

Biomass 

Individual Animals: Reduced 

Survival, Growth, 

Reproduction, 

Ind

Inver

Vert

Re

Surviva

Repr

Individual Plants: 

Reduced Seedling 

Emergence, 

Vegetative Vigor 

Ingestion Direct Contact 

Root Uptake 

Uptake/ 

Adsorption

In

Direct Contact 

Root Uptake

SOURCE/ EXPOSURE MEDIAEXPOSURE ROUTERECEPTORSATTRIBUTE CHANGE

Epibenthic, and Benthic Invertebrates 

Epibenthic and 

Benthic Animals: 

Reduced Survival, 

Growth, 

Reproduction 

Ingestion/ 

Gill/ 

Integument 

Uptake

Figure 2. Conceptual Model of the Transport and Effects of Isoxaben in Terrestrial and Aquatic Environ*Dotted lines indicate that, although this exposure route/media was considered, its contribution to the fate is expected to be negligible 
Page 14 of 74 

The hypothesis for the risks of isoxaben to non-target animals focuses on both aquatic and 

terrestrial environments via potential exposure to the parent from direct spray, spray drift, and 

runoff. Volatility is not considered a significant route of transport considering isoxaben’s vapor 

pressure. For terrestrial organisms, the major route of exposure is via diet, such as through 

consumption of plant leaves or insects, which contain isoxaben residues as a result of direct 

application and/or spray drift, or from consumption of isoxaben granules directly. For aquatic 

animal species, the major routes of exposure are direct contact via the respiratory surface (gills) or 

the integument. Aquatic vascular and non-vascular plants may also be exposed via direct uptake 

and adsorption. Risk to terrestrial plants is also considered in this screening-level assessment. 

Estimated exposure concentrations for all organisms are obtained through the use of several 

Agency exposure models.

The following risk hypothesis is presumed for this screening level assessment: 

Based on the application methods, mode of action, direct toxicity to non-target aquatic and 

terrestrial species, the registered uses of isoxaben have the potential to reduce survival, 

reproduction, and/or growth in listed and non-listed terrestrial and aquatic organisms. 

Analysis Plan 

Residues of Concern 

The stressors of ecological concern for aquatic and terrestrial organisms are isoxaben and 

degradates of similar chemical structure to the parent (other residues of concern). Therefore, 

these degradates can be available to runoff and translocated to water bodies based on their 

observed formation due to the biodegradation of isoxaben in aerobic and anaerobic soil 

metabolism studies. Major degradates, those occurring at more than 10% of applied isoxaben, 

detected during aerobic and anaerobic soil metabolism studies and aerobic and anaerobic 

aqueous metabolism studies include: hydroxyisoxaben; dimethoxybenzamide; 

methoxyphenylpyrimidinol and amino ethyl methyl (AEM) hexenoylisoxaben. Mobility studies 

(MRIDs 41106303 and 48533302) indicate that several of these isoxaben degradates are more 

mobile than the parent. Additionally, four major photolytic degradates (Unk 3, Unk 3i, Unk 5a, 

and Unk 5b) were detected but not conclusively identified (MRID 47140003). 

The Health Effects Division (HED) evaluated the isoxaben residues of concern for human health. 

Because the formation of the unidentified degradates was considered inconsequential (i.e., 

formed only during aqueous photolysis) and a structural activity relationship (SAR) analysis 

performed by HED concluded that none of these degradates were expected to be more toxic than 

the parent compound, these photodegradates were not of exposure concern and were excluded as 

residues of concern for human health. HED concluded that the major degradates detected during 

the aerobic and anaerobic soil and aqueous metabolism studies were not expected to be more 

toxic to humans than the parent compound, but data were not available to exclude them as 

residues of concern. As such, the degradates hydroxy isoxaben, dimethoxybenzamide, 

methoxyphenylpyrimidinol, and AEM hexenoyl isoxaben were included as residues of concern 

for human health (USEPA, 2010a). 
Page 15 of 74 

For this ecological risk assessment, in the absence of ecotoxicity data, these degradates were also 

included as residues of concern for aquatic organisms using a total toxic residue (TTR) analysis. 

Additionally, Unk 3, Unk 3i, Unk 5a, and Unk 5b from the aqueous photolysis study are also 

included in the TTR approach as HED’s method of exclusion using SAR does not necessarily 

reflect ecological endpoints. 

Mixtures 

Evaluation of pesticide environmental mixtures is beyond the scope of this assessment because of 

myriad factors that cannot be quantified based on the available data. Those factors include 

identification of other possible co-contaminants and their concentrations, differences in the pattern 

and duration of exposure among contaminants, and the differential effects of other 

physical/chemical characteristics of the receiving waters (e.g. organic matter present in sediment 

and suspended water). Evaluation of factors that could influence additivity/synergism is beyond 

the scope of this assessment and the capabilities of the available data to allow for an evaluation. 

However, it is acknowledged that not considering mixtures could over- or under-estimate risks 

depending on the type of interaction and factors discussed above. 

Measures of Exposure 

EFED uses standard available models to evaluate potential exposures to aquatic and terrestrial 

organisms as described at http://www.epa.gov/pesticides/science/models_db.htm.

Since the previous exposure assessments were completed, four main changes in standard 

procedures have occurred: 

1) Transformation rates for environmental fate studies were recalculated according to the North 

American Free Trade Agreement (NAFTA) Guidance for Evaluating and Calculating 

Degradation Kinetics in Environmental Media (Bohaty et al., 2012; NAFTA, 2012). These 

updated results will be used in estimating model inputs for estimating aquatic exposure. 

2) A new model for estimating concentrations in groundwater was developed called the 

Pesticide Root Zone Model – Groundwater (PRZM-GW) (Baris et al., 2013). This model 

will be used along with SCI-GROW to estimate concentrations in ground water. 

3) Surface Water Concentration Calculator (SWCC) replaces PE5 (linked PRZM and EXAMS) 

with the primary difference being an improved user interface. However, PRZM5 replaces 

PRZM 3.12 and daily average concentrations are being used to produce EECs and EDWCs 

whereas PE5 used daily peak concentrations. This results in small differences in 

concentration but not substantially and should not change risk conclusions. 

4) Revised spray drift values (USEPA, 2013b) for aquatic exposure in ecological risk 

assessment are increased from previous values and accurately reflect edge-of-field spray drift 

exposure. 

 
Page 16 of 74 

The most up to date procedures and models are used in the registration review exposure 

assessments. 

Measures of Effect 

Selected toxicity data are used to calculate risk estimates. Any additional information submitted 

by the registrant or found in the open literature are also considered. The open literature studies are 

identified using EPA’s ECOTOXicity (ECOTOX)2

 database, which employs a literature search 

engine for locating chemical toxicity data for aquatic life, terrestrial plants, and wildlife. The 

evaluation of both sources of data can also provide insight into the direct and indirect effects of 

pesticides on biotic communities from loss of species that are sensitive to the chemicals and from 

changes in structure and functional characteristics of the affected communities. 

During the registration review process for isoxaben (USEPA, 2007), additional ecological toxicity 

data were submitted by the registrants and subsequently reviewed by EFED. These data include: 

1) OCSPP 850.1350 - Mysid shrimp life-cycle toxicity study (MRID 49090201); 

2) OCSPP 850.2100 - Acute avian oral toxicity study (MRID 48952601); 

3) OCSPP 850.2300 - Avian reproduction toxicity study (MRID 49091601); 

4) OCSPP 850.4250 – Vegetative Vigor toxicity study (MRID 47428405); 

5) OCSPP 850.4400 – Aquatic vascular plant toxicity study (MRID 47428401,47428402, 

4748406); and 

6) OCSPP 850.5400 - Non-vascular aquatic plant toxicity studies (MRIDs 48533202, 

48533203, 48534801, 4853802, and 48952602). 

The toxicity studies above were classified as either acceptable or supplemental, and no additional 

studies are requested for these taxa. 

3. Analysis 

3.1. Exposure Characterization 

3.1.1.Environmental Fate and Transport Characterization 

 

The environmental fate data from submitted studies for isoxaben are summarized in Table 5. 

Environmental fate and transport properties of isoxaben and its degradates are characterized in 

further detail in the following sections. 

Table 5. Environmental fate data for parent isoxaben 

Property Value Source Comments and 

Study Status 

Chemical Name N- [3-(methylpent-3-yl)isoxazol-5-

yl]-2,6-dimethoxy-benzamide - 

 

2 http://cfpub.epa.gov/ecotox/
Page 17 of 74 

Property Value Source Comments and 

Study Status 

Hydrolysis Half-life 

(pH 5, 7, and 9; 25°C) Stable MRID 

00250449 Acceptable 

Aqueous Photolysis Half-life 

(days) 6 MRID 

47140003 Acceptable 

Soil Photolysis Half-life 

(days) 49 MRID 47428403 Acceptable 

Aerobic Soil Metabolism 

Half-life (days) 

161 (sandy loam) 

210 (silt loam) 

277 (silt loam) 

866 (sand) 

MRID 

47140004 Supplemental 

Anaerobic Soil Metabolism 

Half-life (days) 224 (loam) MRID 

41106302 Acceptable 

Aerobic Aquatic Metabolism 

Half-life (days) 21 (2 systems; sand and sandy loam) MRID 

46393202 Acceptable 

Anaerobic Aquatic 

Metabolism Half-life (days) 18 (sandy clay loam) MRID 46393201 Acceptable 

Soil-Water Partition 

Coefficients (mL/g) (Kd) 

0.81 (sand) 

2.18 (loamy sand) 

2.48 (sandy loam) 

4.41 (loam) 

6.63 (clay loam) 

MRID 

41106303 Acceptable 

Henry’s Law Constant (atmm3

/mol) 8.5x10-10 – 

Calculated from 

vapor pressure, 

molecular weight, 

and solubility. 

Log Kow 2.64 Product 

Chemistry 

Bioaccumulation 

At 0.25 ppm: 

14x for edible, 134x for non-edible, 

70x for whole fish tissues 

92-99% of 14C residues eliminated by 

14 days 

MRID 

40059509 Supplemental 

Terrestrial field dissipation 

half-life (soil texture) in top 

6 inches of soil 

34-55 days in spring treated sand soil 

(Florida) and loam soil (Indiana) 

78-174 days in autumn treated sand 

soil (Florida) and sandy loam soil 

(Texas) 

72 days in clay loam soil (Illinois) 

122-134 days in silt loam soil 

(Indiana) 

MRID 

40059508 

MRID 

40059508 

MRIDs 

40532102 & 

40532103 

MRID 

00250449 & 

00153107 

Supplemental 

--- 

Supplemental 

--- 

Acceptable & 

Acceptable 

--- 

Supplemental & 

Supplemental 

 Transport and Mobility 

Isoxaben is not volatile, with a vapor pressure of less than 3.9 x 10-7 torr at 26oC (MRID 

40059506). The compound exhibits weak acid behavior (pKa = 9.8), at neutral environmental 
Page 18 of 74 

pHs, and is moderately soluble in water (1 mg/L; MRID 40059506). The reported Kow for 

isoxaben is 434 (MRID 40059506). 

Isoxaben is considered mobile, with reported soil-water partition coefficients (Kd) from five soils 

ranging from 0.81 to 6.63 mL/g (MRID 41106303). A regression analysis of the adsorption 

coefficients versus the organic carbon content yielded a p-value >0.1; as such, the Koc model 

was deemed inappropriate and Kd values were used in the modeling. 

Leaching and adsorption/desorption studies were conducted on three of the identified major 

degradates: hydroxy isoxaben, AEM hexenoyl isoxaben, and 2,6-dimethoxybenzamide. With 

reported Kds ranging from 0.06 to 0.84, 4.8 to 10.9, and 0.09 to 0.24 mL/g, respectively, 

hydroxy isoxaben and AEM hexenoyl isoxaben are more mobile than parent isoxaben while 2,6-

dimethoxybenzamide is less mobile (MRID 41106303, 48533301, 48533302). 

Compounds with Kd values <5 mL/g present a potential concern for ground water (USEPA, 

2008a). Therefore, isoxaben and its major degradates, based on study data, present a potential 

ground water concern in some soils, especially those that are sandy and have low organic carbon 

content (all Kd values for both compounds, except for clay loam soil, were less than 5; MRID 

41106303). 

Degradation 

Isoxaben is stable to hydrolysis at pH 5, 7 and 9 (MRID 00250449). It is rapidly photolyzed in 

shallow, clear water, with a corrected environmental half-life of 6 days at pH 7 (MRID 

47140003). Major photodegradates include dimethoxybenzamide and four degradates that were 

detected but not conclusively identified; a uracil (Unk 3), an oxime (Unk 3i), a pyrazolone (Unk 

5a), and an isoquinolone (Unk 5b). Study authors indicated that extensive efforts were made to 

identify the compounds, but in the end the best that could be done was to identify structural and 

functional group changes that occurred during photodegradation. The names and structures of 

these unknowns that were proposed by the study authors based on this analysis are provided in 

Table 7. Isoxaben photodegrades comparatively slowly in soil, with a corrected environmental 

photodegredation half-life in soil of 49 days in sandy loam soil at pH 7.0 and 0.99% organic 

carbon (MRID 47428403). 

Isoxaben does not readily biodegrade in soil under aerobic or anaerobic conditions, with half 

lives of greater than 150 days. In four foreign soils held under aerobic conditions, isoxaben 

degraded with half-lives of 161 days (sandy loam), 210 days (silt loam), 277 days (silt loam), 

and 866 days (sand) (MRID 47140004). Overall recoveries were greater than 90%. The only 

major degradate identified in the study was hydroxy isoxaben. The study was classified as 

supplemental, as all of the soils were foreign and it was unclear if the soil microbial communities 

were comparable to those in the United States. 

Loam soil was incubated anaerobically for 60 days after 60 days of aerobic incubation (MRID 

41106302). Isoxaben degraded with a half-life of 224 days. Overall recoveries were greater 
Page 19 of 74 

than 90%. The only major degradate identified in the study was hydroxy isoxaben. The study 

was classified as acceptable. 

Primary routes of biodegradation are in aerobic and anaerobic water bodies. In two aerobic 

aquatic systems (brook water-sand sediment and brook water-sandy loam sediment), isoxaben 

degraded with a half-life of 21 days (MRID 46393202). Major degradates include 

dimethoxybenzamide and AEM hexenoyl-isoxaben. The study was classified as acceptable. In 

an anaerobic aquatic system (water and sandy clay loam soil), isoxaben degraded with a half-life 

of 18 days (MRID 46393201). Overall recoveries were above 90%. Major degradates include 

dimethoxybenzamide, methoxyphenylpyrimidinol, and AEM hexenoyl-isoxaben. The study was 

classified as acceptable. 

Field Studies 

Three terrestrial field dissipation studies were conducted for isoxaben using five sites in the 

United States. Two of the studies were conducted on turf plots (MRIDs 40059508 and 

40532102); the spring and autumn treated turf plots in Florida (sand) were level grade while the 

plot in Illinois (clay loam) had a slope of 5-10%. The remaining plots were bare ground (MRID 

40059508); the plot in Indiana (loam sand) had a slope of 2% and the Texas (sandy loam) plot 

was level grade. Of the five sites, only the Indiana site reported subsurface drainage. Turf 

applications were made using a backpack sprayer while bare soil applications were made using a 

tractor-drawn boom. Isoxaben, as a 75% dry flowable concentrate, was applied to all plots at a 

rate of 1.0 lbs ai/A. Florida sites were irrigated with 0.2 inches (spring) and 0.5 inches (fall) of 

water following treatment, with additional irrigation applied during the May to September 

timeframe if less than 0.1 inches per day occurred. A total of 74 inches of rain (plus irrigation) 

were received in Florida over 313 days, 28 inches in Illinois over 211 days, 13 inches in Indiana 

over 127 days, and 21 inches in Texas over 182 days. Samples were collected to a maximum 

depth of 24 inches in Florida and 12 inches in Indiana and Texas. Samples were analyzed for 

isoxaben and the degradate hydroxy isoxaben. In the majority of terrestrial field dissipation 

studies, isoxaben was equal to or less than 1% in soil samples collected at depths greater than 6 

inches. However, one sample in Florida (MRID 40531202) had an isoxaben level of 2% at a 

depth of 6-12 inches at 129 days after application. The study noted that the water table at the site 

was within 10 inches of the surface and that potential groundwater contamination could have 

occurred. In all but one of the terrestrial field dissipation studies, hydroxy isoxaben was ≤1% of 

the applied in all soil samples collected below 6 inches. However, in a supplemental Florida 

study (MRID 40532101), hydroxy isoxaben was detected in four soil samples at depths of 15-30 

cm at levels ≤2% of the applied. The limit of detection (LOD) in the studies was 0.01 lbs ai/A 

(MRID 40059508) and 0.02 lbs ai/A (MRID 40532102). Half-lives for isoxaben ranged from 34 

to 147 days. These half-lives compare well to aerobic soil metabolism half-lives ranging from 

161 days to 866 days as metabolism is the primary route of dissipation with run-off and leaching 

also contributing substantially considering the precipitation in the field studies. 

A third field dissipation study (MRID 00250449/00153107) was conducted using two outdoor 

lysimeter-enclosed bareground plots (0.656 m2

) of silt loam soil in Indiana. In the first test, 

isoxaben (14C isoxaben labeled on the carbonyl carbon) was applied at a target rate of 250 g ai/ha 
Page 20 of 74 

(0.22 lbs ai/A) to two plots seeded with winter barley in October, 1980. In a second test, 

isoxaben was applied at a target rate of 150 g ai/ha (0.13 lbs ai/A) to two plots (one plot received 

14C isoxaben labeled on the carbonyl carbon while the second plot received 14C isoxaben labeled 

in the 5-position on the isoxazole ring) which were maintained free of vegetation in November, 

1981. Soil samples were collected to a depth of 15 cm in the first test and 37.5 cm in the second 

test. In the second test radiolabeled isoxaben was not detected below 15 cm until week 50 and 

was always below 4%. The half-life for isoxaben ranged from 122 to 134 days. In the second 

test, two degradates were identified in samples collected to a depth of 15 cm: hydroxy isoxaben 

and hydroxy ethyl isoxaben. The maximum amount of hydroxyisoxaben occurred on Day 32 at 

8.6% of the applied amount and declined to 4.6% at Day 100. The maximum amount of 

hydroxyisoxaben occurred on Day 86 at 3.9% of the applied amount and declined to 3.8% at Day 

100. This study was classified as supplemental, as the use of lysimeter plots were not truly 

representative of field plots due to their limited size. 

Monitoring and Clean Water Act 

Isoxaben is not included as an analyte in the National Water Quality Assessment (NAWQA) and 

monitoring data has not been submitted to EPA; therefore, surface water and groundwater 

monitoring data is not readily available. Additionally, isoxaben is not responsible for any 

impaired waterbodies under 303(d) of the Clean Water Act. 

Bioconcentration 

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 (MRID 40059509). Residues accumulated by exposure day 28 were depurated 

quickly; at day 14 of depuration, isoxaben residues had been reduced by 92-99% in the edible, 

non-edible, and whole fish tissues. The study was classified as supplemental because isoxaben 

residues were incompletely characterized and residues in the whole fish tissue were not 

determined experimentally. Due to the relatively low KOW and bioconcentration factors in fish, 

isoxaben is not expected to accumulate in aquatic or terrestrial food chains. 

Degradates 

Major biodegradates of isoxaben include hydroxyisoxaben, dimethoxybenzamide, 

methoxyphenylpyrimidinol, and AEM hexenoyl-isoxaben. Additionally, four major photolytic 

degradates (Unk 3, Unk 3i, Unk 5a, and Unk 5b) were detected but not conclusively identified 

(MRID 47140003). Chemical names, structures, and fate data for these degradates are provided 

in Table 6. Based on recently submitted data, three of the biodegradates (hydroxy isoxaben, 

dimethoxy benzamide, and 2,6-dimethoxybenzamide) are incrementally more mobile than 

isoxaben, with methoxyphenylpyrimidinol appearing to be very immobile. As mentioned above, 

hydroxy isoxaben was detected in all of the terrestrial field studies. In two of the studies 

(MRIDs 40059508 and 40532102), hydroxy isoxaben was ≤1% of the applied in all soil samples 

collected below 6 inches. However, in the Florida study (MRID 40532101), it was detected in 

four soil samples at depths of 15-30 cm at levels ≤2% of the applied. In a third study (MRID 
Page 21 of 74 

00250449/00153107), the degradate hydroxy isoxaben was detected in samples collected to a 

depth of 15 cm. Hydroxy isoxaben was ≤9% of the applied in all soil samples collected below 

15 cm. Degradates vary in mobility with dimethoxy benzamide and hydroxy isoxaben being 

more mobile than parent isoxaben and Methoxyphenolpyrimidinol and AEM hexenoyl isoxaben 

being less mobile than parent isoxaben. 

Residues of Concern 

For this assessment, in the absence of ecotoxicity data, the degradates hydroxy isoxaben, 

dimethoxybenzamide, methoxyphenylpyrimidinol, AEM hexenoylisoxaben, and the unidentified 

degradates from the aqueous photolysis study were included as residues of concern for aquatic 

organisms using a total toxic residue (TTR) analysis. Parent only EECs are also provided for 

characterization. 
Page 22 of 74 

Table 6. Environmental Degradates of Isoxaben. 

Name(s) Structure Occurrence 

Dimethoxy benzamide 2,6-Dimethoxybenzamide 

Aqueous photolysis (major) Aerobic Aquatic Metabolism (major) Anaerobic Aquatic Metabolism (majoSoil Photolysis (minor) 

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 

Methoxyphenolpyrimidinol 6-(1-ethyl-1-methylpropyl)-2-(2-hydroxy-6-methoxyphenyl)-4-pyrimidinol 

Anaerobic Aquatic Metabolism (majoAerobic Aquatic Metabolism (minor) 

AEM hexenoyl isoxaben N-[3-amino-4-ethyl-4-methyl-2-hexenoyl]-2,6-dimethoxybenzamide 

Anaerobic Aquatic Metabolism (majoAerobic Aquatic Metabolism (minor) 
Page 23 of 74 

Name(s) Structure Occurrence 

Unk32

6-(1-ethyl-1-methylpropyl)pyrimidine2,4(1H,3H)-dione 

Aqueous Photolysis (major) 

Unk3i 4-ethyl-3-(hydroxyimino)-4-methylhexanoic acid 

Aqueous Photolysis (major) 

Unk5a 2-(2,6-dimethoxybenzoyl)-5-(1-ethyl-1-methylpropyl)1,2-dihydro-3H-pyrazol-3-one 

Aqueous Photolysis (major) 

Unk5b 4,6-diethyl-4a,8-dimethoxy-4-methyl4a,8a-dihydropyrazolo[1,5-b]isoquinoline-2,9(1H,4H)-dione 

Aqueous Photolysis (major) 
Page 24 of 74 

3.1.2. Measures of Aquatic Exposure 

Aquatic exposures are quantitatively estimated for all of the assessed uses using scenarios that 

represent high exposure sites for isoxaben use. Each of these sites represents a 10-hectare field 

that drains into a 1-hectare pond that is 2 meters deep and has no outlet. Exposure estimates 

generated using the standard pond are intended to represent a wide variety of vulnerable water 

bodies that occur at the top of watersheds including prairie pot holes, playa lakes, wetlands, 

vernal pools, man-made and natural ponds, and intermittent and first-order streams. As a group, 

there are factors that make these water bodies more or less vulnerable than the standard surrogate 

pond. Static water bodies that have larger ratios of drainage area to water body volume would be 

expected to have higher peak estimated environmental concentrations (EECs) than the standard 

pond. These water bodies will be either shallower or have large drainage areas (or both). Shallow 

water bodies tend to have limited additional storage capacity, and thus, tend to overflow and 

carry pesticide in the discharge whereas the standard pond has no discharge. As watershed size 

increases beyond 10 hectares, at some point it becomes unlikely that the entire watershed is 

planted to a single crop, which is all treated with the pesticide. Headwater streams can also have 

peak concentrations higher than the standard pond, but they tend to persist for only short periods 

of time and are then carried downstream. 

Isoxaben environmental fate data used for generating model parameters for the Pesticide Root 

Zone Model (PRZM) and the Exposure Analysis Model System (EXAMS) and use specific input 

parameters are in Table 7. Chemical property input values were chosen in accordance with 

current input parameter guidance (USEPA, 20093). SWCC with the variable volume pound is 

used. Initial application was set for pre-emergence in the PRZM scenario as isoxaben is a preemergence herbicide. However, given the maximum number of applications (4) and 

reapplication interval (56 to 60 days) subsequent applications are assumed to be made 

substantially after emergence. All uses are modeled assuming ground application (i.e., 99% 

application efficiency and 6.2% spray drift). 

Table 7. Summary of SWCC Environmental Fate Data Used for Aquatic Exposure Inputs for 

Isoxaben and Isoxaben Total Toxic Residues (TTR). 

PARAMETER (units) VALUE(S) SOURCE COMMENT

Application Rate (kg a.i./ha) 1.12 Product 

labels 

1.02 lbs a.i./A; Maximum application rate for 

turfgrass, ornamentals, groundcover/perennials, noncropland, Christmas tree/conifer plantations, 

hardwood nursery, fruit and nut trees and vineyards. 

Number of Applications 4 Product 

labels 

Maximum number of applications for turfgrass, 

ornamentals, groundcover/perennials, non-cropland, 

Christmas tree/conifer plantations, and hardwood 

nursery 

 

3 http://www.epa.gov/oppefed1/models/water/input_parameter_guidance.htm
Page 25 of 74 

PARAMETER (units) VALUE(S) SOURCE COMMENT

Interval between Applications 

(days) 

56 Product 

labels 

Minimum application interval for use patterns with 4 

applications per year (turfgrass and ornamentals). 

Most labels specify a 60 day interval but some allow 

for a 56 day interval 

Molecular weight (g/mol) 332.39 

Henry’s Law Constant (atmm3

/mol) 

1.26*10-9 Calculated (VAPR/760)/ (SOL/MWT), 

where 

VAPR is vapor pressure in torrs, 

MWT is the molecular weight in g mol-1, 

and SOL is the solubility in water in mg L-1. 

Vapor Pressure (torr) 4.1*10-9 IUPAC 

Footprint 

MRID 153106 reports a value of <3.9*10-7 torr 

Solubility in Water @ 20 OC, 

(mg/L or ppm) 

1.42 MRID 

47140001 

Soil Partition Coefficient 

(KOC)(mL/g) 

38 MRID 

41106303 

The most mobile degradate is hydroxy isoxaben. 

Average of 21, 26, 27, 42, and 73 mL/g o.c.1 

Chemical Application Method Ground Broadcast, applied to bareground and unincorporated. 

Application efficiency 

(decimal) 

0.99 Ground Application 

Spray drift fraction (decimal) 0.0616 Ground Application with high boom and ASAE very 

fine to fine droplet spectrum (default) (EPA, 2013b) 

Application date (day/month) 

March 1 

April 26 

June 23 

August 20 

Product 

Labels 

4 applications with 56 day retreatment intervals. 

Initial application is in early season to allow for allow 

applications to be within growing season. 

Hydrolysis Half-life (days) Stable MRID 

250449 

Aqueous Photolysis Half-life 

@ pH 7 (days) 

Parent 6.0 

TTR 93.5 

MRID 

47140003 

Aerobic Aquatic Metabolism 

Half-life (days) 

Parent 22.0 

TTR 282 

MRID 

46393202 

63 (TTR) and21.5 (parent) days in Water-sand; SFO 

171 (TTR) and 21 (parent)Stable in Water-sandy 

loam; N/A 

90th percentile mean of values used as input1 
Page 26 of 74 

PARAMETER (units) VALUE(S) SOURCE COMMENT

Anaerobic Aquatic 

Metabolism Half-life (days) 

Parent 17.4 

TTR 1608 

 Anaerobic soil input = single t1/2 x 31

 

Anaerobic aquatic input = anaerobic soil input x 21

 

Aerobic Soil Metabolism 

Half-life (days) 

Parent 443 

TTR 723 

MRID 

47140004 

MRID 

49090101 

274 (TTR) and 150 (parent)days in Sandy Loam; 

DFOP; isoxazole label 

264 (TTR) and 199(parent) days in Sandy Loam; 

SFO; phenyl label 

340 (TTR) and 207 (parent)days in Silt Loam; SFO; 

phenyl label 

360(TTR) and 280 (parent)days in Silt Loam; SFO; 

phenyl label 

1123(TTR) and 891(parent) days in Sand; SFO; 

phenyl label 

185 days in Sandy clay loam; DFOP; combined label 

90th percentile mean of values used as input1 

Anaerobic Soil Metabolism 

Half-life (days) 

Parent 2.9 

TTR 268 

MRID 

46393201 

Sandy clay loam; SFO; total system 

1 “Input Parameter Guidance” refers to Guidance for Selecting Input Parameters in Modeling the 

Environmental Fate and Transport of Pesticides; Version 2.1, October 22, 2009. 

DFOP – Double first order in parallel degradation kinetics 

SFO – Single first order degradation kinetics

Aquatic exposure modeling, using SWCC, was performed to estimate exposures for registered 

uses of isoxaben. Many isoxaben uses can be represented by various aquatic modeling scenarios. 

To organize which scenarios are representative of which uses, the modeling scenarios for each 

registered use category are presented in Table 8 and the results from the highest PRZM scenario 

for each use pattern are presented in Table 9. Output that generates peak EECs are reported in 

Appendix 1. 
Page 27 of 74 

Table 8. EECs for Use Pattern Categories. Scenario from which EECs used in the 

assessment for RQs are in bold (scenario with highest EECs)

Modeling Scenarios 

used to Represent 

Registered Uses 

Registered Uses of Isoxaben 

FL turf 

PA turf 

Turfgrass / Groundcover/ perennials / Non-cropland 

CA Almond 

CA Citrus 

CA Fruit 

CA Grapes 

CA Nursery 

FL Citrus 

FL Nursery 

MI Nursery 

NC Apple 

NJ Nursery 

NY Grape 

OR Apple 

OR Nursery 

OR Xmas Tree 

PA Apple 

TN Nursery 

Ornamental / Christmas tree/ conifer plantations, hardwood 

nursery / Non-bearing fruit & nut trees & vineyards 

Bearing fruit and nut trees and vineyards / Eucalyptus 
Page 28 of 74 

Table 9. Tier II Concentrations of Isoxaben (using Total Toxic Residues and Parent Only) 

in Surface Water modeled with SWCC. 

Registered 

Use 

EECs (TTR) EECs (Parent) 

App Rate (lb 

a.i./A) x No. of 

Apps 

(modeling 

scenario used 

to represent 

registered use) 

Peak 

(μg/L)

21-day 

average 

(μg/L)

60-day 

average 

(μg/L)

Peak 

(μg/L)

21-day 

average 

(μg/L)

60-day 

average 

(μg/L)

Turfgrass 

1.0 x 4 

(PA turf) 43.6 42.7 41.6 10.2 7.9 5.48 Groundcover/ perennials 

Non-cropland 

Christmas 

tree/conifer 

plantations, 

hardwood 

nursery 

1.0 x 4 

(FL citrus) 88.4 86.0 81.5 36.5 27.6 15.8 

Ornamentals 

Non-bearing 

fruit & nut 

trees & 

vineyards 

1.0 x 3 

(FL citrus) 76.0 73.9 69.7 32.4 23.4 15.6 

Bearing fruit 

and nut trees 

and vineyards 

1.0 x 1 

(FL citrus 

(TTR) / MI 

Nursery 

(Parent)) 

32.8 32.6 32.2 19.8 14.3 11.2 

Eucalyptus 0.75 x1, 0.25 x 

1 

(FL citrus/ MI 

Nursery) 

30.6 26.2 17.9 16.2 13.6 9.28 

Data in Table 9 indicate that the maximum surface water EECs for total toxic residues of isoxaben 

were generated with the Florida (FL) Citrus scenario and are as follows: 

88.4 μg/L for the 1 in 10 year annual peak concentration; 

86.0 μg/L for the 21-day average concentration; and 

81.5 μg/L for the 60-day average concentration 

3.1.3.Measures of Terrestrial Exposure 

3.1.3.1. Terrestrial Animals 

 Ingestion of Food Items Based on Foliar Application 
Page 29 of 74 

Exposure estimates for terrestrial animals assumed to be in the target area or in an area exposed to 

spray drift are derived using the T-REX4

 model (version 1.5.1., 10/12/2012). This model 

incorporates the Kenaga nomograph, as modified by Fletcher et al. (1994), which is based on a 

large set of actual field residue data. The upper limit values from the nomograph represent an 

approximation of the highest residue value observed in the data set (Hoerger and Kenaga 1972). 

Consideration is given to different types of feeding strategies for mammals and birds, including 

herbivores, insectivores and granivores. For dose-based exposures, three weight classes of birds 

(20, 100, and 1000 g) and mammals (15, 35, and 1000 g) are considered. The dose-based 

calculation takes into account that different-sized animals have to consume different amounts of 

food. The dose-based risk quotients do account for the fact that small animals need to consume 

more food relative to their body weight than large animals or that differential amounts of food are 

consumed depending on the water content and nutritive value of the food. 

Given that no acceptable data for evaluating dissipation from foliar surfaces are available for 

isoxaben, a default foliar dissipation half-life of 35 days is used based on the work of Willis and 

McDowell (1987). The EECs modeled in this assessment are based on parent isoxaben. For 

isoxaben, there are two main use scenarios, a ground spray and a granule application. The isoxaben 

application rates are similar between the non-agricultural registered uses in that for ground spray 

application, the maximum single application rate is 1 lb a.i./A with a yearly maximum rate of 3 or 

4 lb a.i./A at a minimum of 56-60 days between applications. For registered uses with granular 

application, the maximum single application rate is 1 lb a.i./A with a yearly maximum rate of 3 lb 

a.i./A. Finally, for the bearing fruit and nut trees and vineyards the single maximum application 

is the same as the yearly maximum rate at 1 lb a.i./A, and while the yearly maximum for the 

eucalyptus use is 1 lb a.i./A, the single maximum rate is 0.75 lb a.i./A. The dietary-based EECs 

on a variety of food items from the use of isoxaben applied at the maximum label rates are provided 

in Table 10; dose-based EECs are provided in Table 11. 

Table 10. T-REX Calculated Dietary-Based EECs of Isoxaben on Terrestrial Food 

Residues for the Maximum Use Scenario (Ground Spray Application). 

Registered Use Application 

Scenario (registered use) Food Type Maximum Dietary-based EECs (mg/kg) 

1.02 lb a.i./A w/4 applications @ 56-d 

retreatment interval 

(Turfgrass/Ornamentals/ Noncropland/ conifers plantations& 

hardwood nursery) 

Short Grass 354 

Tall Grass 162 

Broadleaf plants 199 

Fruits/pods/seeds 22.1 

Arthropods 139 

1.0 lb a.i./A w/3 apps @ 60-d interval Short Grass 335 

Tall Grass 154 

 

4

 USEPA. 2013. Pesticides: Science and Policy. Terrestrial Models, T-REX Version 1.5/1. 

http://www.epa.gov/oppefed1/models/terrestrial/ 
Page 30 of 74 

(non-bearing fruit & nut trees and 

vineyards) 

Broadleaf plants 189 

Fruits/pods/seeds 21.0 

Arthropods 131 

1.0 lb a.i/A w/1 app 

(bearing fruit & nut trees and 

vineyards) 

Short Grass 240 

Tall Grass 110 

Broadleaf plants 135 

Fruits/pods/seeds 15.0 

Arthropods 94.0 

0.75 lb a.i/A then 0.25 lb a.i/A @ 30-d 

interval 

(eucalyptus) 

Short Grass 180 

Tall Grass 82.5 

Broadleaf plants 101 

Fruits/pods/seeds 11.3 

Arthropods 70.5 

Table 11. T-REX Calculated Dose-Based EECs of Isoxaben Uses on Terrestrial Food 

Residues for the Maximum Use Scenario (Ground Spray Application). 

Registered Use 

Application Scenario 

(registered use) 

Food Type 

Dose-based EECs 

(mg/kg-bw) 

(birds)

Dose-based EECs 

(mg/kg-bw) 

(mammals) 

Small 

(20 g) 

Medium 

(100 g) 

Large 

(1000 g) 

Small 

(15 g) 

Medium 

(35 g) 

Large 

(1000 g) 

1.02 lb a.i./A w/4 

applications @ 56-d 

retreatment interval 

(Turfgrass/Ornamentals/ 

Non-cropland/ conifers 

plantations& hardwood 

nursery) 

Short grass 403 230 103 337 233 54.1 

Tall grass 185 105 47.2 155 107 24.8 

Broadleaf 

plants 227 129 57.9 190 131 30.4 

Fruits/pods 25.2 14.4 6.43 21.1 14.6 3.38 

Arthropods 158 90.0 40.3 132 91.3 21.2 

Seeds 

(granivore) 5.60 3.19 1.43 4.69 3.24 0.75 

1.0 lb a.i./A w/3 apps @ 

60-d interval 

(non-bearing fruit & nut 

trees and vineyards) 

Short grass 382 218 97.5 320 221 51.2 

Tall grass 175 99.9 44.7 147 101 23.5 

Broadleaf 

plants 215 123 54.9 180 124 28.8 

Fruits/pods 23.9 13.6 6.10 20.0 13.8 3.20 

Arthropods 150 85.3 38.2 125 86.6 20.1 

Seeds 

(granivore) 5.31 3.03 1.35 4.40 3.10 0.70 

1.0 lb a.i/A w/1 app 

(bearing fruit & nut 

trees and vineyards) 

Short grass 273 156 69.8 229 158 36.7 

Tall grass 125 71.4 32.0 105 72.5 16.8 

Broadleaf 

plants 154 87.7 39.3 129 89.0 20.6 

Fruits/pods 17.1 9.74 4.36 14.3 9.88 2.29 

Arthropods 107 61.1 27.3 89.6 61.9 14.4 

Seeds 

(granivore) 3.80 2.16 0.97 3.18 2.2 0.51 
Page 31 of 74 

0.75 lb a.i/A then 0.25 

lb a.i/A @ 30-d interval 

(eucalyptus) 

Short grass 205 117 52.3 172 119 27.5 

Tall grass 94.0 53.6 24.0 78.7 54.4 12.6 

Broadleaf 

plants 115 65.8 29.4 96.5 66.7 15.5 

Fruits/pods 12.8 7.31 3.27 10.7 7.41 1.72 

Arthropods 80.3 45.8 20.5 67.2 46.5 10.8 

Seeds 

(granivore) 2.85 1.62 0.73 2.38 1.65 0.38 

Ingestion of Food Items Based on Granular Application 

As mentioned, isoxaben is registered for several uses that employ a granular application. The 

EEC for acute exposure for this application method was calculated using T-REX and the LD50/ft2

methodology. Conceptually, an LD50/ft2 is the amount of a pesticide estimated to kill 50% of 

exposed animals in each square foot of applied area. Although a square foot does not have 

defined ecological relevance, and any unit area could be used, risk presumably increases as the 

LD50/ft2

 value increases. The LD50/ft2 value is calculated using a toxicity value (adjusted LD50) 

and the EEC (mg a.i./ft2) and is directly compared with the Agency’s levels-of-concern (LOCs). 

For isoxaben, a broadcast application with no incorporation was modeled using a single 

maximum application rate of 1.0 lb a.i./A. The EEC for this use scenario is 10.41 mg a.i./ft2. 

3.1.4. Terrestrial Plants 

Isoxaben exposure to terrestrial and semi-aquatic plants is estimated using the TerrPlant5 (version 

1.2.2) model and AgDrift (v2.1.1). The TerrPlant model generates EECs for plants residing near a 

use area that may be exposed via runoff and/or spray drift. The EECs are generated from one 

application at the maximum rate for a particular use and compound-specific solubility information. 

Only a single application is considered because it is assumed that for plants, toxic effects are likely 

to manifest shortly after the initial exposure and that subsequent exposures do not contribute to the 

response. Hence, the model estimates EECs based on application rate, the solubility factor, and 

default assumptions of drift. The EECs for terrestrial and semi-aquatic plants for a single 

application of isoxaben at the maximum label rate are presented in Table 12. AgDrift provides 

point estimates of mass deposition at distances from the application site. 

 

5

 USEPA. 2013a. Pesticides: Science and Policy. Terrestrial Models, TerrPlant Version 1.2.2. 

http://www.epa.gov/oppefed1/models/terrestrial/ 
Page 32 of 74 

Table 12. EECs for Terrestrial and Semi-Aquatic Plants near Isoxaben Use Areas 

(TerrPlant and AgDrift model). 

Single Max. Application 

Rate 

(lbs a.i./A) 

 

TerrPlant Model 

EECs (lb a.i./A) 

Total Loading to Adjacent 

Dry Areas (sheet runoff + 

drift) 

Total Loading to SemiAquatic Areas 

(channelized runoff + 

drift) 

Drift 

Ground spray 

1.02 

0.02 0.11 0.01 

Granular application 

0.01 0.10 0.0 

AgDrift Model (ground spray) 

Distance in feet from edge of field Drift EEC (lb/A) 

0 1.02 

50 0.051 

100 0.025 

200 0.0122 

500 0.004 

995 0.0014 

3.2. Ecological Effects Characterization 

The ecological effects characterization for isoxaben is based on data generated from guideline 

studies submitted by the registrant and from open literature studies in the ECOTOX database 

(http:/www/epa.gov/ecotox). 

A brief description of available aquatic and terrestrial toxicity data used to calculate RQs is 

provided below in Sections 3.2.1 and 3.2.2. Additional details on the available toxicity data for 

isoxaben are provided in Appendix 2. 

3.2.1.Aquatic Effects Characterization 

Toxicity data for aquatic animals and plants are summarized in Table 13. For freshwater and 

estuarine/marine fish and invertebrates, the acute toxicity of the compound (in terms of an 

LC/EC50) is limited by its solubility, i.e., 1.0 mg/L, as none of the studies established a definitive 

LC/EC50. In the acute toxicity test with Quahog clam larvae (Mercenaria mercenaria; MRID 

40531302) there was a 40% reduction in normally developed larvae after 48-h at the limit 

concentration of 0.96 mg a.i./L. On a chronic exposure basis, isoxaben resulted in decreased 

growth and reproduction for water fleas (Daphnia magna) and decreased reproduction for 

estuarine/marine shrimp (Americamysis bahia), with NOAEC values for freshwater and 

estuarine/marine invertebrates at 0.69 and 0.24 mg a.i./L, respectively. Chronic toxicity data are 

available for two species of freshwater fish with no effects on survival or growth up to 

approximately 0.4 mg a.i./L, which appears to be lower than the reported water solubility (i.e., 1 

mg/L). Chronic toxicity data are not available for estuarine/marine fish, but data from freshwater 

fish will be used to evaluate exposure of isoxaben to estuarine/marine fish. 
Page 33 of 74 

The 7-day IC50 for the vascular aquatic plant duckweed (Lemna gibba) was 0.010 mg a.i./L, based 

on a reduction in biomass. Similar to the aquatic animals, for aquatic non-vascular plants, 

definitive IC50 values were not established up to the isoxaben’s limit of solubility (i.e., IC50 values 

greater than 1.0 mg a.i./L). Toxicity data were available for green algae, freshwater and saltwater 

diatoms, and cyanobacteria. The available aquatic non-vascular plant data were classified as 

supplemental, and given the lack of a definitive IC50 value or classified for only qualitative use, 

they were not used quantitatively in the assessment. Four of the six available studies were 

conducted at test concentrations well above the reported water solubility of isoxaben (isoxaben 

formulations used in three studies), and in all studies, the IC50 values are greater than the reported 

limit of solubility of isoxaben. Two studies using green algae tested an isoxaben formulation and 

derived 72-h EC50 values of 17 and 43 mg a.i./L based on measured concentrations. While 

isoxaben may be more soluble when testing a formulation, in these studies, the test solutions were 

not centrifuged/filtered prior to analysis; therefore, there is uncertainty in the actual dissolved 

concentration of isoxaben. While these studies were classified as supplemental, collectively they 

provided sufficient information to adequately assess potential direct effects to aquatic non-vascular 

plants, and this evaluation is discussed in the risk description section. 

Degradate toxicity data for aquatic organisms were not available. 

Table 13. Summary of Most Sensitive Acute and Chronic Toxicity Data for Aquatic 

Animals and Plants Exposed to Isoxaben.

Species 

Acute Toxicity Chronic Toxicity 

96-hr 

LC50/EC50

(mg a.i./L) 

48-hr EC50

(mg a.i./L) 

Toxicity 

Classification

/Study 

Classification 

(MRID) 

NOAEC/ 

LOAEC 

(mg a.i./L) 

Endpoints / 

Study 

Classification

(MRID) 

Rainbow trout 

(Oncorhynchus mykiss) > 1.0 -- 

NA1 / 

Supplemental 

(00132146) 

0.42/ >0.42 

None affected / 

Supplemental 

(00137847) 

Fathead minnow 

(Pimphales promelas) NA -- -- 0.40 / >0.40 

None affected / 

Supplemental 

(00137848) 

Waterflea 

(Daphnia magna) -- > 1.3 

NA1

 / 

Supplemental 

(00132144) 

0.69/1.01 

Growth, 

reproduction / 

Supplemental 

(00137845) 

Sheepshead minnow

(Cyprinodon 

variegatus) 

> 0.86 -- 

NA1 / 

Supplemental 

(40531304) 

NA -- 

Quahog clam 

(Mercenaria 

mercenaria

-- >0.96 

NA1 / 

Supplemental 

(40531302)2 

NA -- 

Mysid shrimp 

(Americamysis bahia) NA -- -- 0.238 / 0.460 

Reproduction / 

Acceptable 

(49090201) 
Page 34 of 74 

Species 

Acute Toxicity Chronic Toxicity 

96-hr 

LC50/EC50

(mg a.i./L) 

48-hr EC50

(mg a.i./L) 

Toxicity 

Classification

/Study 

Classification 

(MRID) 

NOAEC/ 

LOAEC 

(mg a.i./L) 

Endpoints / 

Study 

Classification

(MRID) 

Duckweed 

(Lemna gibba) -- 

7-day IC50

= 0.010 / 

NOAEC = 

0.006 

Supplemental / 

47428402 -- -- 

Saltwater diatom 

toxicity (Skeletonema 

costatum )

96-hr IC50 

= 0.922; 

NOAEC = 

0.922 

-- Supplemental / 

48952602 -- -- 

1

No mortality was observed up to the practical solubility limit of the compound in water; therefore, the toxicity of the compound appears to be 

limited by its solubility. 

2 A 40% decrease in normal larvae was reported at the limit concentration (0.96 mg a.i./L). 

NA = Not available 

 

3.2.2.Terrestrial Effects Characterization 

Toxicity values for terrestrial animals and plants are summarized in Table 14. Isoxaben is 

practically non-toxic to mammals, birds (used as surrogates for reptiles and terrestrial-phase 

amphibians), and honey bees (Apis mellifera) (surrogates for terrestrial invertebrates) on an acute 

exposure basis. No sublethal effects were observed in either the acute bird or mammalian studies 

up to the limit doses/concentrations. In chronic avian studies, no treatment-related effects were 

observed in the northern bobwhite (Colinus virginianus) & mallard duck (Anas platyrhynchos) 

studies up to dietary concentrations of 1073 and 1035 mg a.i./kg-diet, respectively. There is an 

additional avian reproduction study with the mallard duck in which there was a reported decrease 

in the percent hatch of offspring (relative to 3-wk live embryos) at 946 mg a.i./L (MRID 

00153109). However, there were concerns with this study regarding control performance (high 

variability, high % of cracked eggs) and possible husbandry conditions. Therefore this study is 

classified as supplemental for qualitative use. In the chronic mammalian study using the rat (Rattus 

norvegicus), there were decreases in parental bodyweight at 2500 mg/kg-diet (200 mg/kg-bw) and 

decreases in number of viable pups and bodyweight at 12,500 mg/kg-diet (1000 mg/kg-bw); the 

overall NOAEL for the study was 500 mg/kg-diet (40 mg/kg-bw). On an acute exposure basis, 

isoxaben is classified as ‘practically nontoxic’ to non-target terrestrial invertebrates including 

young adult honey bees (honeybee acute contact LD50 >101.7 μg a.i./bee). 

Seedling emergence testing (MRID 47428404) indicate monocot grass species (Family: Poaceae) 

tested were unaffected at treatment rates equivalent to an application rate of 0.888 lbs ai/A, the 

highest rate tested. However, only three monocot species were tested. Among broadleaf plants 

(dicots), lettuce (Lactuca sativa) was the most sensitive (EC25 = 0.0095 lbs ai/A). A NOAEC was 

not established in this study, thus the lettuce EC05 (0.0014 lbs ai/A) is used in lieu of a NOAEC. 

For vegetative vigor testing (MRID 47428405), among the tested monocots (only three species 

tested), ryegrass (Lolium perenne) was the most sensitive species tested (EC25 = 0.014 lbs ai/A; 
Page 35 of 74 

NOAEC 0.0034 lbs ai/A). For the dicots, cucumber (Cucumis sativus) was the most sensitive 

species, with an EC25 of 0.089 lbs ai/A, and the NOAEC was 0.028 lbs ai/A. 

Degradate toxicity data were not available for terrestrial organisms. 

Table 14. Isoxaben Terrestrial Animal and Plant Toxicity Summary 

Taxa Study Type Species Exposure 

Duration 

Toxicity 

Value 

Reference 

(Study 

Classification) 

Birds 

(surrogates for 

terrestrial-phase 

amphibians and 

reptiles) 

Acute (Dosebased) 

Northern Bobwhite 

(Colinus 

virginianus) Single oral 

dose 

>2000 mg/kg 

bw (LD50) 

00132146 

(acceptable) 

Zebra finch 

(Taeniopygia 

guttata) 

>2000 mg/kg 

bw (LD50) 

48952601 

(acceptable) 

Acute 

(Dietarybased) 

Northern Bobwhite 

(Colinus 

virginianus) & 

Mallard duck 

(Anas 

platyrhynchos) 

8-Day dietary 

>4500 

(bobwhite) & 

>4800 

(mallard) 

mg/kg diet 

(LC50) 

00132142; 

00132143 

(acceptable) 

Chronic 

(Dietarybased) 

Northern Bobwhite 

(Colinus 

virginianus) & 

Mallard duck 

(Anas 

platyrhynchos) 

Avian 

reproduction 

study 

1073 

(bobwhite) & 

1035 

(mallard) 

mg/kg diet 

(NOAEC) 

00153110 

(bobwhite; 

supplemental); 

49091601 

(mallard; 

acceptable) 

Mammals 

 Acute Rat (Rattus 

norvegicus) 

Single oral 

dose 

>10,000 

mg/kg bw 

(LD50) 

00132126 

(acceptable) 

Chronic Rat (Rattus 

norvegicus) 

2-Generation 

reproduction 

study 

500 mg/kgdiet (40 

mg/kg-bw) 

(NOAEL); 

2500 mg/kgdiet (200 

mg/kg-bw ) 

(LOAEL) 

00153529 

(acceptable) 

Terrestrial 

invertebrates Acute Contact Honey Bee (Apis mellifera) 48 hours > 101.7 μg/bee 

0015311 

(acceptable) 

Terrestrial 

Plants 

Seedling 

Emergence 

Monocot: Oat, 

ryegrass, wheat 

21-days 

IC25: >0.888 

lb ai/A; 

NOAEC: 

0.888 lb ai/A 47428404 

(supplemental) 

Dicot: Lettuce 

IC25: 0.0095 

lb ai/A; 

NOAEC: 

0.0014 lb ai/A 

Vegetative 

Vigor Monocot: ryegrass 22-days 

IC25: 0.014 

lb ai/A; 

NOAEC: 

0.0034 lb ai/A 

4748405 

(supplemental) 
Page 36 of 74 

Taxa Study Type Species Exposure 

Duration 

Toxicity 

Value 

Reference 

(Study 

Classification) 

Dicot: cucumber 

IC25: 0.089 

lb ai/A; 

NOAEC: 

0.028 lb ai/A 

3.2.3.Review of Incident Data 

A review of the Environmental Incident Information System (EIIS, version 2.1) database, which 

is maintained by the Agency’s Office of Pesticide Programs, and the Avian Monitoring 

Information System (AIMS), which is maintained by the American Bird Conservancy, for 

ecological incidents involving isoxaben was completed on June 30, 2014. In addition to the 

incidents recorded in EIIS and AIMS, a search of the Agency’s incident data system (aggregated 

reports) was conducted on July 1, 2014 with no reported incidents. 

Six incidents involving plants are reported for isoxaben in EIIS (Table 15). For the incidents 

reported as registered uses or undetermined, five of the incidents have a certainty index of 

‘Possible’ and one as ‘Unlikely’ to involve the use of isoxaben. The ‘Possible’ incidents span 

1994 to 2003 and involved ornamental and tree farm applications. The reported numbers of 

affected plants range from 298,346 to 676,000, and included woody plants. All incidents report 

the application rate as 1.0 lbs ai/A. There was one incident reported in 2010 as a misuse for use 

on roses for which the application rate was not reported. 

Incident reports for isoxaben have not been received by the Agency since 2010 and only 6 incidents 

total have been reported to the Agency; however, the absence of reported incidents should not be 

construed as the absence of incidents. Incident reports for non-target organisms typically provide 

information only on mortality events and plant damage. Sublethal effects in organisms such as 

abnormal behavior, reduced growth and/or impaired reproduction are rarely reported, except for 

phytotoxic effects in terrestrial plants. EPA’s changes in the registrant reporting requirements for 

incidents in 1998 may account for a reduced number of reported incidents. Registrants are now 

only required to submit detailed information on ‘major’ fish, wildlife, and plant incidents. Minor 

fish, wildlife, and plant incidents, as well as all other non-target incidents, are generally reported 

aggregately and are not included in EIIS. In addition, there have been changes in state monitoring 

efforts due to a lack of resources. However, the incident data that are available suggest that 

exposure pathways for isoxaben are complete and that exposure levels are sufficient to result in 

field-observable effects for terrestrial plants. 
Page 37 of 74 

Table 15. Summary of incident information reported to the Agency as of 6/30/2014. 

Incident ID Use Site Legality Certainty State County Year Total 

No. 

Total 

Area 

I014702-017 Ornamental, 

woody 

Registered 

use 

Possible CA Santa Cruz 2003 35000 NR* 

I013636-027 Ornamental Registered 

use Possible OR Washington 2002 NR 6 acres 

I001485-001 Tree 

farm/plantation 

Undetermi

ned Possible NR NR 1994 676000 NR 

I010414-002 Ornamental Registered 

Use Possible CA Santa Cruz 2000 627405 6.5 acres 

I006865-001 Nursery Registered 

Use Unlikely OR Multnomah NR 298346 NR 

I023787-532 Roses Misuse Possible IL Clinton 2010 

100% of 

all 

plants 

NR 

*NR=not reported 

4. Risk Characterization 

4.1. Risk Estimation 

4.1.1.Aquatic Organisms 

The peak EECs in surface water generated from the PRZM/EXAMS model represents acute 

exposure to fish, aquatic invertebrates, and aquatic plants, and the highest 21-day and 60-day 

average EECs represents chronic exposure to aquatic invertebrates and fish, respectively. Acute 

and chronic RQs for freshwater and estuarine/marine animals are summarized in Table 16 . RQs 

for aquatic vascular plants are presented in Table 17.

4.1.1.1. Aquatic Animals 

Fish (surrogates for aquatic-phase amphibians) 

Acute RQs were not calculated for freshwater or estuarine/marine fish because the LC/EC50 

values for the acute studies were greater than the limit of solubility (Table 16). 

For chronic exposure, the RQs for freshwater fish were below the LOC. No effects to freshwater 

fish from chronic exposure to isoxaben were reported up to the maximum concentration tested for 

fathead minnows and rainbow trout, i.e., NOAECs of 400 and 420 μg ai/L, respectively. While 

these test concentrations are below the reported solubility of isoxaben (approximately 1 mg/L), the 

maximum 60-day EEC (using TTR approach) is 81.5 μg ai/L (FL citrus scenario) and the resulting 

RQ is 0.20. The highest chronic RQ for freshwater fish is 5X below the chronic risk LOC of 1.0, 
Page 38 of 74 

and, therefore, chronic risk to freshwater fish is anticipated to be low. While there are no chronic 

toxicity data available for estuarine/marine fish, based on the available acute and chronic 

freshwater fish data along with the lack of effects from acute exposure, up to the limit of solubility, 

for estuarine/marine fish, effects to estuarine/marine fish from chronic exposure are not 

anticipated. 

Aquatic invertebrates 

As with the fish, acute RQs could not be calculated for freshwater invertebrates because no effects 

were reported to the limit of solubility. For estuarine/marine invertebrates, the acute EC50 value 

was also greater than the limit of solubility. However, for the estuarine/marine clam, a 40% 

reduction in normal larvae was reported at the solubility limit. In the estuarine/marine grass 

shrimp (Palaemonetes pugio) toxicity test, no effects were reported up to the limit of solubility, 

1.0 mg/L. 

Chronic RQs for freshwater invertebrates are below the LOC and therefore, chronic risk to 

freshwater invertebrates is anticipated to be low (RQs ≤ 0.12). Similarly, the RQs for 

estuarine/marine invertebrates are below the LOC (RQs ≤0.36), and chronic risk is anticipated to 

be low. 
Page 39 of 74 

Table 16. Summary of Acute and Chronic RQs for Freshwater and Estuarine/Marine Fish and InvertebraIsoxaben (Maximum EECs by use pattern, assuming TTR) 

Toxicity Value (μg a.i./L) >860 (LC50) 400 (NOAEC) -- >1300 (EC50) >960 (EC50) 

Registered 

Uses 

App Rate 

(lb a.i./A) 

x No. of 

Apps 

Peak 

EEC 

(μg 

a.i./L) 

21-day 

EEC (μg 

a.i./L) 

60-day 

EEC (μg 

a.i./L) 

Acute FW 

and E/M 

Fish 

Chronic 

FW Fish 

Chronic 

E/M 

Fish 

Acute 

FW 

Invert 

Acute 

E/M 

Invert 

RQ 

Turfgrass 

1.0 x 4 43.6 42.7 41.6 

NO EFFECS UP TO SOLUBILITY LIMIT 0.10 

NO TOXICITY DATA AVAILABLE 

NO EFFECS UP TO SOLUBILITY LIMIT 

EC50 > LIMIT of SOLUBILITY 

Groundcover/ perennials Non-cropland Christmas tree/conifer plantations, hardwood nursery 

1.0 x 4 88.4 86.0 81.5 0.20 

Ornamentals Non-bearing fruit & nut trees & vineyards 

1.0 x 3 76.0 73.9 69.7 0.17 

Bearing fruit and nut trees and vineyards 

1.0 x 1 32.8 32.6 32.2 0.08 

Eucalyptus 0.75 x1, 

0.25 x 1 30.6 26.2 17.9 0.04 

All exposure scenarios modeled ground application LOCs: Non-listed acute 0.5; listed acute 0.05; chronic 1.0, for non-listed and listed species. Acute RQs use peak EEC; Chronic invertebrate RQs use 21-day EEC; Chronic vertebrate RQs use 60-day EEC
Page 40 of 74 

4.1.1.2. Aquatic Plants 

As shown in Table 17, RQs for vascular plants exceed the listed and non-listed species LOC (1.0) 

for all of the currently registered uses of isoxaben. The RQs exceed the LOC using EEC values 

using the TTR approach as well as EECs from parent isoxaben only (RQ=1.02-14.7). 

For aquatic non-vascular plants, the available toxicity data were classified as supplemental for 

qualitative use only and/or did not provide definitive IC50 values, and were not used quantitatively 

in the assessment. Therefore, RQs were not calculated. An evaluation of potential risk to aquatic 

non-vascular plants is discussed in the risk description section. 

Table 17. RQs for Aquatic Vascular Plants Exposed to Isoxaben 

Registered 

Use 

App 

rate 

lbs ai/A 

/ #app 

TTR EECs Parent Only EECs 

Peak 

EECs 

(ppb) 

Vascular Aquatic Plant 

RQs 

EC50 = 10 μg a.i./L 

NOAEC = 6 μg a.i./L 

Peak 

EECs 

(ppb) 

Vascular Aquatic Plant 

RQs 

EC50 = 10 μg a.i./L 

NOAEC = 6 μg a.i./L 

Non-listed 

Species 

Listed 

Species 

Non-listed 

Species 

Listed 

Species 

Turfgrass 

1.0 x 4 43.6 4.36 7.27 10.2 1.02 1.7 

Groundcover

/ perennials 

Noncropland 

Christmas 

tree/conifer 

plantations, 

hardwood 

nursery 

1.0 x 4 88.4 8.84 14.7 36.5 3.65 6.08 

Ornamentals 

Non-bearing 

fruit & nut 

trees & 

vineyards 

1.0 x 3 76.0 7.60 12.7 32.4 3.24 5.40 

Bearing fruit 

and nut trees 

and 

vineyards 

1.0 x 1 32.8 3.28 5.47 19.8 1.98 3.3 

Eucalyptus 0.75 x1, 

0.25 x 1 30.6 3.06 5.1 16.2 1.62 2.7 

Bolded values exceed the non-listed or listed LOC of 1 

4.1.2.Terrestrial Organisms 

4.1.2.1. Birds and Mammals 

Ingestion of Food Items Based on Ground Spray Application 

Based on the available toxicity data, no acute mortality and/or sublethal effects were observed in 

any of the avian or mammalian studies at the highest levels tested. Only non-definitive acute and 
Page 41 of 74 

sub-acute toxicity endpoints are available for birds and mammals; therefore, acute RQs were not 

calculated. Further discussion of the predicted exposure values relative to the levels at which no 

mortality occurred is provided as part of the risk description in Section 4.2.2. 

In the acceptable chronic avian reproduction studies, there were no effects reported at the highest 

concentration tested, resulting in a NOAEC of 1035 or 1073 mg ai/kg-diet. Chronic RQ values 

did not exceed the LOC for birds for any registered use (Table 18). 

For the chronic mammalian toxicity data, effects on parental bodyweight were reported at 200 

mg/kg-bw for a NOAEL of 40 mg/kg-bw. There were no LOC exceedances for chronic exposure 

on a dietary basis for mammals; however, there were exceedances on a dose basis for all registered 

uses for all size classes (Table 19). 

Table 18. Chronic Dietary-Based RQs Derived Using T-REX for Birds (Surrogates for 

Reptiles and Terrestrial-Phase Amphibians) and Mammals Exposed to Ground Spray 

Applications of Isoxaben* 

Uses 

(represents the highest 

EECs from ground 

application) 

Application 

Rate (lb a.i./A) 

x No. of Apps 

RQs for Birds RQs for Mammals 

Chronic Dietary Based1 Chronic Dietary Based2

Turfgrass / ornamentals / 

Groundcover/ perennials / 

Non-cropland / Christmas 

tree/conifer plantations, 

hardwood nursery 

1.0 x 4 (56-d 

retreatment 

interval) 

≤ 0.34 ≤ 0.71 

*No LOC exceedances (chronic RQ ≤ 1.0). RQs calculated using default foliar dissipation half-life of 35 days using 

T-REX version 1.5.1. 

1

Based on dietary-based EEC and mallard duck NOAEC = 1035 mg/kg diet, highest concentration tested (MRID 

49091601). 

2

Based on dietary-based EEC and Norway rat NOAEC = 500 mg/kg diet (MRID 00153529). 

Table 19. Chronic Dose-Based RQs Derived Using T-REX for Mammals Exposed to 

Ground Spray Applications of Isoxaben* 

Application Rate 

(Crop) 

Functional Feeding Group 

Dietary Item 

15 g mammals 35 g mammals 1000 g mammals 

Chronic1 Chronic1 Chronic1

0.75 lb a.i./A then 

0.25 lb a.i./A/30-d 

interval 

(eucalyptus) 

Herbivores/Insectivores 

 Short Grass 1.95 1.67 0.89 

 Tall Grass 0.89 0.76 0.41 

 Broadleaf plants 1.10 0.94 0.50 

 Fruits/pods 0.12 0.10 0.06 

 Arthropods 0.76 0.65 0.35 

Granivore

Seeds 0.03 0.02 0.01 
Page 42 of 74 

Application Rate 

(Crop) 

Functional Feeding Group 

Dietary Item 

15 g mammals 35 g mammals 1000 g mammals 

Chronic1 Chronic1 Chronic1

1 lb a.i./A @ 1 app 

(bearing fruit & nut 

trees and vineyards) 

Herbivores/Insectivores 

 Short Grass 2.60 2.22 1.19 

 Tall Grass 1.19 1.02 0.55 

 Broadleaf plants 1.46 1.25 0.67 

 Fruits/pods 0.16 0.14 0.07 

 Arthropods 1.02 0.87 0.47 

Granivore

Seeds 0.04 0.03 0.02 

1 lb a.i./A @3 

apps/60-d interval 

(non-bearing fruit & 

nut trees and 

vineyards) 

Herbivores/Insectivores 

 Short Grass 3.64 3.11 1.67 

 Tall Grass 1.67 1.42 0.76 

 Broadleaf plants 2.05 1.75 0.94 

 Fruits/pods 0.23 0.19 0.10 

 Arthropods 1.42 1.22 0.65 

Granivore

Seeds 0.05 0.04 0.02 

1 lb a.i./A @ 4 apps 

/ 56-d interval 

(Turfgrass / 

ornamentals / 

Groundcover/ 

perennials / Noncropland / Christmas 

tree/conifer 

plantations, 

hardwood nursery) 

Herbivores/Insectivores 

 Short Grass 3.84 3.28 1.76 

 Tall Grass 1.76 1.50 0.81 

 Broadleaf plants 2.16 1.84 0.99 

 Fruits/pods 0.24 0.20 0.11 

 Arthropods 1.50 1.28 0.69 

Granivore

Seeds 0.05 0.05 0.02 

* LOC exceedances in bold (chronic RQ > 1.0). RQs calculated using default foliar dissipation half-life 

of 35 days using T-REX version 1.5.1. 

1 Chronic RQ = (upper bound dose-based EEC, mg/kg-bw) / (NOAEL; mg/kg-bw). 

4.1.2.2. Terrestrial Invertebrates 

On an acute exposure basis, isoxaben is classified as ‘practically nontoxic’ to non-target terrestrial 

invertebrates including honey bees (honeybee acute contact LD50 >101.7 μg ai/bee). Therefore, 

RQs were not calculated but evaluation of potential risk is discussed in the Risk Description 

section. 

4.1.2.3. Terrestrial Plants 

At the maximum single application rate, RQs for both listed and non-listed dicots exceed the 

terrestrial plant LOC for species exposed to runoff plus drift in adjacent upland and wetlands as 

well as drift alone for foliar applications and from runoff alone for granular applications (Table 
Page 43 of 74 

20). The LOC for nonlisted dicot plants is exceeded by more than 11-fold and exceeded for listed 

dicot species by 80-fold. The RQ for listed monocots exceeds the LOC by 3-fold. 

Table 20. Risk quotients (RQs) for non-listed and listed terrestrial plants for ground spray 

and granular application of isoxaben at the maximum single application rate (1.02 lbs 

ai/A).1 

Terrestrial Plant 

Group

Ground Spray

Adjacent uplands Adjacent wetlands Drift Only

Monocots2 <0.1 0.13 0.73 

Dicots2 2.151 11.8 1.07 

Listed Monocots <0.1 0.13 3.0 

Listed Dicots 14.6 80.1 7.29 

Terrestrial Plant 

Group Granular Application 

Adjacent uplands Adjacent wetlands Drift Only 

Monocots2

<0.1 0.11 NA 

Dicots2

1.07 10.7 NA 

Listed Monocots <0.1 0.11 NA 

Listed Dicots 7.29 72.9 NA 

1

Bold values denote an exceedance of the LOC (RQ≥1.0). 2

In the seedling emergence study, no monocots were affected (EC25 >0.888 lb ai/A); most sensitive dicot was lettuce 

(EC25 = 0.0095 lbs ai/A; NOAEC = 0.0014 lb ai/A). Rye grass is the most sensitive monocot in the vegetative vigor 

study (EC25 = 0.014 lbs ai/A; NOAEC = 0.0034 lb ai/A); cucumber is the most sensitive dicot, with an EC25 0.089 lbs 

ai/A (NOAEC = 0.028 lbs ai/A) 

4.2.Risk Description 

Isoxaben is characterized as a moderately persistent and mobile compound. Although primary 

routes of degradation include aqueous photolysis, aerobic aqueous metabolism and anaerobic 

aqueous metabolism, uncertainty regarding the potential toxicity of its residues increases aquatic 

estimated environmental concentrations. 

 

Additionally, the compound is characterized as practically nontoxic to terrestrial animals on an 

acute exposure basis. For aquatic animals, the acute toxicity of isoxaben appears to be limited by 

its solubility, with the exception of estuarine/marine invertebrates. Although chronic effects on 

survival, growth, and/or reproduction were observed for freshwater and estuarine/marine 

invertebrates, chronic toxicity data for freshwater fish suggest that no effects on survival or growth 
Page 44 of 74 

may occur near the limit of solubility. As expected, isoxaben is toxic to terrestrial plants and to 

aquatic vascular plants, but for aquatic non-vascular plants, toxicity appears to be limited by 

solubility. 

4.2.1. Risks to Aquatic Organisms 

Animals 

For freshwater and estuarine/marine fish and invertebrates, the acute toxicity of isoxaben (in terms 

of an LC/EC50) is limited by its solubility (1.0 mg/L (1000 μg/L)) as none of the studies were able 

to establish a definitive LC/EC50. Except for the estuarine/marine invertebrate (clam larvae), no 

mortality or sublethal effects were observed at the limit of solubility. The highest peak EEC (FL 

citrus using TTR) is 88.4 μg a.i./L which is 9.7X lower than the lowest non-definitive acute toxicity 

value reported (LC50 > 860 μg a.i./L for sheepshead minnow). A 40% decrease in normal larvae 

was reported in the estuarine/marine clam study at a limit test concentration of 960 μg a.i./L which 

is 11X greater than the highest peak EEC. Therefore, given the general lack of acute effects to 

fish and aquatic invertebrates up to the limit of solubility and the difference between the EECs and 

isoxaben’s solubility, acute risk to aquatic animals is considered unlikely. 

The chronic LOC for freshwater fish and freshwater and estuarine/marine invertebrates was not 

exceeded for any registered use. While chronic toxicity data were not available for 

estuarine/marine fish and the freshwater fish studies were conducted below the reported solubility 

limit, given the difference between the highest EECs (81.5 μg a.i./L) and the no effect 

concentration (400 μg a.i./L), chronic risk to fish is not anticipated. 

Given that isoxaben has a log Kow of < 3 and is characterized as mobile in soils, it is not anticipated 

to partition to sediment. Therefore, while there are no data for sediment-dwelling organisms, given 

the potential lack of exposure, risk to these animals is not anticipated. 

Plants 

While RQs were not calculated for aquatic non-vascular plants, based on the available data, the 

toxicity of isoxaben appears to be limited by its solubility. In the studies using technical grade 

isoxaben, the IC50 values are greater than the solubility limit. The highest peak EEC (using TTR) 

is 88.4 μg a.i./L, which is 10X lower than the lowest non-definitive IC50 value (IC50 > 922 μg a.i./L 

for saltwater diatom). For the two studies that tested an isoxaben formulation and derived 72-h 

IC50 values (17 and 43 mg a.i./L), a comparison of potential exposures from spray drift of an 

isoxaben formulation to the IC50 values was conducted using AgDrift (v2.1.1). The concentration 

of isoxaben in a receiving water body (standard EPA farm pond) immediately adjacent to the field 

from the maximum single application rate of 1.0 lb a.i./A is 3.45 μg a.i./L6

. This drift EEC is over 

4900X lower than the lowest definitive IC50 value. Based on these comparisons, potential risk to 

aquatic non-vascular plants from isoxaben exposure from runoff and spray drift is not anticipated. 

 

6

 Initial average water concentration modeled using ground application using high boom, very fine to fine droplet 

size, and 90th percentile 
Page 45 of 74 

For aquatic vascular plants, the RQs exceeded both the listed and non-listed LOC for all registered 

uses for isoxaben, (RQ=1.02-15.2). As discussed above, the water concentration in an adjacent 

water body exposed to spray drift is 3.45 μg a.i./L, which is 1.7X lower than the NOAEC from the 

most sensitive aquatic vascular plant study (NOAEC = 6 μg a.i./L). Therefore, potential exposure 

from runoff is likely the main exposure route of concern. While the RQs were calculated using 

the maximum EECs (derived using either FL citrus or PA turf scenario), EECs were calculated 

using other scenario types (i.e., other geographic locations and/or application sites including 

nurseries and fruit/nut trees). EECs were grouped by use type (i.e., nut and fruit trees, nurseries, 

turf, etc.) and broad U.S. geographic regions (i.e., west, south, etc.). EECs based on one 

application at the maximum single application rate of 1.0 lb a.i./A as well as 3 applications at 1 lb 

a.i./A and the resulting non-listed and listed RQs are presented in Table 21. It is noted that the 

maximum yearly application rate is 4 lb a.i./A for some uses, but several registered labels state 

that the maximum yearly rate is only 3 lb a.i./A for many uses. Therefore, EECs using 3 

applications were used for characterization. Overall, the results in the table indicate that there are 

both non-listed and listed LOC exceedances when evaluating both on a use type basis as well as 

across several geographic areas. Therefore, this evaluation supports the conclusion of potential 

risk to aquatic vascular plants. 

Aquatic EECs were calculated based on a total toxic residue approach as well as based on parent 

only. Degradate toxicity data were not available for aquatic vascular plants. Toxicity values for 

aquatic vascular plants were not calculated using Quantitative Structure Activity Relationship 

(QSAR) methodology as the current tools do not calculate toxicity values for aquatic vascular 

plants. EECs using the TTR approach included degradates resulting from the aqueous photolysis 

study. While there are no aquatic plant toxicity data available on these degradates, inclusion of 

these degradates may be more relevant for shallow or clearer water bodies that contain isoxaben 

as they may be more susceptible to photolysis. However, the RQs based on parent alone exceed 

the listed LOC for all registered uses and exceed the non-listed LOC for all. Hence, based on the 

lines of evidence, there is a potential for risk to aquatic vascular plants from exposure via runoff 

from both isoxaben parent as well as a combination of isoxaben and its degradates of concern. 
Page 46 of 74 

Table 21. Aquatic Vascular Plant RQs when Using EECs Grouped by Use Type or U.S. 

Geographic Area. 

App Rate 

(lb a.i./A) x 

No. of 

Apps

Use Type or 

Geographic 

Area 

Aquatic Vascular Plant RQs1 

TTR Approach Parent Only 

Peak 

EECs 

(TTR) 

(μg/L) 

Nonlisted 

RQs 

Listed 

RQs 

Peak EECs 

(Parent) 

(μg/L) 

Non-listed 

RQs Listed RQs

Specific Registered Use 

1.0 x 3 

Nut, fruit trees 20-76 2.0-7.9 3.4-13 4.8-32 0.48-3.2 0.8-5.4

Grapes 24-60 2.4-6.0 4-10 6.6-15 0.7-1.5 1.1-2.4 

Nursery 29-82 2.9-8.2 4.8-14 8-24 0.8-2.4 1.3-3.9 

X-mas trees 31.3 3.1 5.2 6.6 0.7 1.1 

Turf 23-30 2.3-3.0 3.8-5 6.7-7.7 0.7-0.8 1.1-1.3 

1.0 x 1 

Nut, fruit trees 7.3-31 0.7-3.0 1.2-5.1 3.7-20 0.4-2 0.6-3.3

Grapes 11-24 1.1-2.4 1.8-2.8 5.4-7.6 0.5-0.8 0.9-1.3

Nursery 14-33 1.4-3.3 2.4-5.5 5.4-16 0.5-1.6 0.9-2.7

X-mas trees 11.3 1.1 1.9 5.0 0.5 0.8 

Turf 7.6-10.7 0.76-1.1 1.3-1.8 3.5-4.4 0.4-0.4 0.6-0.7 

Specific Geographical Region 

1.0 x 3 

 West Coast 

(CA, OR) 20-45 2.0-4.5 3.4-7.5 4.8-9.5 0.5-0.95 0.8-1.6

East Coast 

(PA, NY, NJ) 30-60 3.0-6.0 5-10 13-21 1.3-2.1 2.2-3.5 

Mid-West 

(MI, TN) 57-82 5.7-8.2 9.5-14 13-24 1.3-2.4 2.1-3.9 

Southeast 

(FL, NC) 23-52 2.3-5.2 3.8-8.7 6.7-32 0.7-3.2 1.1-5.4 

1.0 x 1 

CA, OR 7.3-19 0.7-1.9 1.2-3.2 3.7-9.4 0.4-0.9 0.6-1.6

PA, NY, NJ 11-27 1.1-2.7 1.8-4.5 4.4-14 0.4-1.4 0.7-2.3

MI, TN 26-33 2.6-3.3 4.3-5.5 7-16 0.7-1.6 1.2-2.7 

FL, NC 7.6-31 0.8-3.1 1.3-5.1 3.5-20 0.4-2.0 0.6-3.3 1

 RQs based on the most sensitive aquatic vascular plants toxicity values (EC50 = 10 μg/L; NOAEC = 6 μg/L); Bold 

values exceed the LOC 

4.2.2.Risks to Terrestrial Organisms 

Animals 

Based on the results of the screening-level assessment, the registered uses of isoxaben result in no 

direct acute effects to birds and mammals. Furthermore, for two avian reproduction studies, there 

were no effects at the highest dietary concentrations tested. 

In an effort to evaluate potential risk from acute exposure for birds and mammals, the maximum 

EECs were compared to the acute toxicity data currently available. T-REX was used to compare 

EECs to the highest value in the avian acute oral study (i.e., adjusted acute LD50 = 1,441 mg a.i./kgbw for a 20-g bird) and the highest value in the avian sub-acute dietary study (i.e., acute LC50 = 

4,500 mg a.i./kg-diet). If RQs were calculated assuming the LD50 to be 2,000 mg/kg-bw, the 
Page 47 of 74 

resulting RQs would be ≤0.28, which is less than the acute non-listed LOC of 0.5, but exceeds the 

acute listed LOC of 0.1. However, there were no effects observed at 2,000 mg/kg-bw in either the 

bobwhite quail or zebra finch acute oral study. The highest dose-based EEC is 403 mg/kg-bw 

and is 3.6X lower than the adjusted LD50 (20-g bird). For the avian dietary-based acute 

comparison, RQs, based on the highest EEC and assumption of an LC50 value of 4,500 mg/kg-diet, 

were <0.08, all of which are less than the listed species LOC of 0.1. A similar comparison was 

conducted for mammals assuming an acute LD50 value of 10,000 mg/kg-bw (highest dose tested 

which resulted in no effects), and the resulting RQs were ≤0.02. Overall, potential risk from acute 

exposure to birds and mammals is not anticipated. 

The RQs for birds did not exceed the chronic LOC based on no effects reported at the highest 

concentration tested in both a bobwhite quail (NOAEC = 1073 mg/kg-diet) and mallard duck 

reproduction (NOAEC = 1035 mg/kg-diet) study. There is an additional reproduction study with 

mallard duck that was not adequate for quantitative use (MRID 00153109). This study was deemed 

insufficient to provide a definitive endpoint as there were concerns with control performance (high 

percentage of cracked eggs, high variability in egg production). In this study there was also a 

significant decrease in the percent of eggs hatched relative to live 3-week old embryos at 946 

mg/kg-diet with an apparent effect on hatchling survival per egg set and the number of hatchlings 

per pen. However, these effects were not observed in the mallard study conducted at a later date 

at a concentration of 1035 mg/kg-diet (MRID 49091601), where control performance was deemed 

adequate. Therefore, the results from the later study were used to evaluate potential effects to 

mallard ducks. 

While risk of mortality from acute exposure to isoxaben is expected to be low for mammals from 

the registered uses of isoxaben, there is a potential for chronic risk. Although dietary-based RQs 

do not exceed the chronic risk LOC of 1.0 (RQs ≤0.71), dose-based RQs exceed the LOC for all 

registered uses (RQs ≤ 3.84). The dose-based calculation takes into account that different-sized 

animals have to consume different amounts of food. The dose-based risk quotients do account for 

the fact that small animals need to consume more food relative to their body weight than large 

animals or that differential amounts of food are consumed depending on the water content and 

nutritive value of the food. Overall, small- and medium-sized mammals foraging on short grass, 

tall grass, broadleaf plants and arthropods exceed the LOC for all uses except eucalyptus and 

medium mammals consuming arthropods for the use on bearing fruit and nut trees. Large-sized 

mammals consuming short grass exceed the LOC for all uses, except eucalyptus. For eucalyptus, 

chronic LOCs were exceeded for small and medium mammals consuming short grass and small 

mammals consuming broadleaf plants. 

In the modeling scenario for ground spray application for birds and mammals, the default foliar 

dissipation rate (i.e., 35 days) was used due to lack of adequate dissipation data. However, there 

are still LOC exceedances for all mammal size classes when a single application at the maximum 

single application rate is modeled (i.e., bearing fruit and nut trees; RQs ≤2.60). Also, given the 

large retreatment interval of 56-60 days for most uses, the default dissipation rate had limited 

impact on increasing the EECs and resultant RQs. While the maximum single application rate (1.0 

lb a.i./A) was used to calculate RQs, based on information in the available incident reports, this 

was the application rate generally reported, suggesting that users may be applying at the maximum 
Page 48 of 74 

single application rate. The minimum single application rate reported on several labels is 0.5 lb 

a.i./A, and the LOC is exceeded slightly for small and medium mammals (RQs ≤1.30) when a 

single application at this minimum application rate is used. Furthermore, while RQs were 

calculated based on upper bound Kenaga EECs, the LOC is still exceeded for small and medium 

mammals using the mean Kenaga EECs when using an annual rate of 3 or 4 lb a.i./A (RQs ≤1.36), 

and are just below the LOC for a single application rate of 1.0 lb a.i./A (RQs ≤0.92).While the 

RQs were calculated using the NOAEL value (40 mg/kg-bw; based on reductions in parental body 

weight), if the LOAEL was used (200 mg/kg-bw), there were no LOC exceedances for any 

mammalian size class. Additionally, in prenatal developmental studies in the rat and rabbit, no 

effects on development or maternal toxicity were observed at doses up to 1000 mg/kg/day (dosed 

by oral gavage for 10-12 days; MRID 00153119 and 00153118). However, overall, based on the 

application rate and resultant EECs and RQs, there may be a potential for chronic risk to mammals. 

In addition to the evaluation of potential risk to birds and mammals from ground spray, isoxaben 

is also applied as a granule, therefore potential acute risk to birds and mammals from this exposure 

route was also examined. Using the maximum single application rate (1.0 lb a.i./A), the EEC is 

10.41 mg a.i./ft2

. Similar to the evaluation for acute exposure from ground spray, if RQs were 

calculated assuming the LD50 to be 2,000 mg/kg-bw for birds, the resulting RQs would be ≤0.36, 

which is less than the acute non-listed LOC of 0.5, but exceeds the acute listed LOC of 0.1. For 

mammals assuming an acute LD50 value of 10,000 mg/kg-bw (highest dose tested which resulted 

in no effects), and the resulting RQs were ≤0.03. However, these RQs would be lower than the 

estimated values because no effects were identified at 2,000 mg a.i./kg-bw or 10,000 mg/kg-bw in 

the acute oral studies. Therefore, potential for acute risk from ingestion of granular isoxaben is 

considered low. 

Acute risk from inhalation was also evaluated for birds and mammals using the STIR model (v1.0). 

Isoxaben is not anticipated to be volatile and the results of the STIR model indicate that potential 

risk to birds and mammals via this exposure route is not anticipated (APPENDIX 3). 

There are no reported incident reports for terrestrial animals for isoxaben. However, the lack of 

reported incidents does not necessarily imply an absence of adverse effects in the field. 

Overall, potential risk from acute exposure for birds (and their surrogates) and mammals is not 

anticipated. Additionally, chronic risk to birds is not anticipated. However, based on the lines of 

evidence, there appears to be a potential for chronic risk to mammals. 

For terrestrial invertebrates, only non-definitive acute contact toxicity data were submitted for 

terrestrial arthropods (honeybees). If an RQ were calculated for terrestrial invertebrates7

, 

conservatively assuming the LD50 to be 101.7 μg ai/bee and the exposure equal to the application 

rate multiplied by 2.7 μg ai/bee per 1 lb ai/A, the resultant acute contact RQ would be 0.11 (using 

an annual maximum rate of 4 lb a.i/A). This RQ value is more than four times below the terrestrial 

invertebrate LOC (0.4). In an acute oral toxicity study with adult honeybees (unreviewed; EFSA 

 

7

 The employed methodology for calculating a honey bee acute contactRQ was proposed in the 2012 Pollinator Risk 

Assessment Framework SAP White Paper. The White Paper is accessible online at regulations.gov, under docket 

EPA-HQ-OPP-2012-0543 
Page 49 of 74 

2010), there was no mortality or behavioral abnormalities reported at an oral dose of 100 μg 

a.i./bee, suggesting low toxicity from oral exposure. Therefore, risk to non-target terrestrial 

invertebrates is considered unlikely. 

 

Plants 

Although the seedling emergence RQs which are derived from runoff plus drift are much higher 

than those for drift alone (derived using the vegetative vigor endpoint), RQs for listed and nonlisted 

dicots and listed monocots also exceed the LOC for terrestrial plants from drift alone as well as 

from a combination of runoff and drift. While grasses do not appear to be affected by isoxaben 

based on seedling emergence, some grasses appear to be susceptible to injury by isoxaben at later 

growth stages as evidenced by observed effects in the vegetative vigor toxicity studies. 

Runoff is a major factor in nontarget terrestrial plant exceedances based on TerrPlant. It is difficult 

to estimate how far from the application site adverse effects may occur. While RQs cannot be 

directly used to estimate the magnitude or likelihood of effects, it is true that lower application 

rates result in lower EECs. However, given that the LOC for listed dicots would be exceeded 80-

fold at a single application of 1.0 lbs ai/A, the potential for nontarget plant effects would remain 

even with a reduction in application rate. RQs were based on the most sensitive monocot and 

dicot, and it is noted that there is a range of sensitivities to isoxaben among the dicots tested in the 

seedling emergence study. In the available data, isoxaben did not appear to be toxic to cucumber 

in the seedling emergence test at the highest concentration tested (0.88 lb a.i./A, which is slightly 

lower than the maximum single application rate of 1.0 lb a.i./A), but cucumber was the most 

sensitive dicot tested in the vegetative vigor study. If RQs are calculated in TerrPlant using the 

second most sensitive dicot in the seedling emergence study (i.e., pea), the LOC is exceeded for 

listed dicots under semi-aquatic conditions (RQ=2). 

It is also important to consider that modeled runoff is only compared to endpoints from the seedling 

emergence study. The method of pesticide application in the guideline studies allows for analysis 

of effects to seedlings from both spray drift and runoff, but the guideline vegetative vigor studies 

are only analyzed for effects from spray drift (pesticide applied by overspray in toxicity studies 

and exposure from runoff is not considered). The potential for effects on older plants, such as 

those in the vegetative vigor study, from runoff through stem contact or root uptake remains an 

uncertainty and plant risk may be underestimated in this assessment. 

For isoxaben, the only monocots tested in the submitted toxicity studies were grass species 

(Family: Poaceae), which did not appear to be particularly sensitive to isoxaben at the application 

rates tested (most IC25s greater than highest concentration tested), especially in the seedling 

emergence study. Typically, onion (Family: Liliaceae) is the tested species representing the other 

monocot families (e.g. Orchidaceae, Smilacaceae). The lack of a second monocot family tested 

results in considerable uncertainty about the potential risk to non-grass species. While not at the 

maximum single application rate, an application of isoxaben at 0.25 lb ai/A prior to bulb 

emergence reported minimal visual injury 5-7 months after application to Golden Apeldoorn tulips 

(0-5% reported injury) and 0% injury to Ice Follies daffodils and Ideal irises (Al-Khatib et al. 

1996). In this study, the total bulb dry weight after isoxaben exposure for tulips, daffodils, and 

irises were 96, 104, and 110% of the control. 
Page 50 of 74 

Effects to sensitive trees and other perennial species may occur that cannot be accounted for by 

current modeling and phytotoxicity studies. However, the reported incidents included effects to 

woody plants. Changes in plant community composition may occur due to differences in species 

sensitivity. Such changes could lead to local reductions in biodiversity and influence animal 

species through changes in available habitat and preferred food sources. 

The AgDRIFT model was used to refine the potential effect of isoxaben drift to nontarget plants. 

Ground applications at the single application rate, 1.0 lbs ai/A, were modeled for all of the species 

tested in the seedling emergence and vegetative vigor studies (Table 22). This table indicates the 

distance from the edge of the application area where the RQ for that endpoint falls below the risk 

to terrestrial plant LOCs. For lettuce, the most sensitive species tested, effects on seedling 

emergence may be seen at out to 249 ft from the application area, and beyond 997 ft for listed 

species. For vegetative vigor, effects may be seen out to 174 ft from the application area, and out 

to 554 ft for listed species. 

Table 22 Distance (feet) from the edge of field where the RQ falls below the risk to 

terrestrial plant LOC for seedling emergence endpoints for ground application, based on 

Tier 1 AgDRIFT EECs. 

Plant 

Species 

Seedling Emergence Vegetative vigor 

Listed Nonlisted Listed Nonlisted 

Monocots

Oat 3.3 <3.3 325 <3.3 

Ryegrass 3.3 <3.3 554 174 

Wheat 3.3 <3.3 3.3 <3.3 

Dicots 

Oilseed rape 125 92 6.6 >3.3 

Pea 46 10 46 <46 

Cucumber 3.3 <3.3 92 30 

Carrot 177 59 554 <3.3 

Lettuce >997 249 46 <3.3 

Tomato 331 154 3.3 <3.3 

Sugarbeet 46 36 6.6 3.3 
Page 51 of 74 

The distance estimates are derived using EFED’s AgDRIFT default values, which include the use 

of a high-boom (50 in height) ground application and ASABE droplet size spectrum ‘very fine to 

fine.’ However, if isoxaben was applied using larger droplets sizes and/or a lower boom height, 

then the distances off-field would presumably be lower. AgDRIFT modeling was also conducted 

using low boom (20 in height) and ASAE droplet size spectrum ‘fine to medium/coarse’. Using 

these parameters, the longest distance to an exposure value equal to the vegetative vigor NOAEC 

is 144 ft and to the seedling emergence NOAEC is 430 ft. While this is still a considerable distance 

from the edge of the application area, it is appreciably less than the undefined >997 ft distance 

predicted using the default parameters. 

Current labels do not have specific droplet size distributions or boom heights. Larger droplet sizes 

or lower boom heights may reduce the drift distance off-field for isoxaben, however, it is noted 

that potential risk may still occur from runoff alone based on LOC exceedances. 

Because isoxaben is moderately persistent and moderately mobile, contamination of ground water 

used as irrigation was considered as a possible route of exposure to terrestrial plants. The highest 

peak estimated groundwater concentration value from PRZM-GW (1010 ppb; WI sands scenario) 

applied in one inch of water on an acre of land corresponds to an application rate of 0.22 lbs ai/A, 

roughly 24 times the most sensitive terrestrial plant endpoint, lettuce seedling emergence (0.0095 

lb a.i./A; Appendix 4). The peak EEC represents the groundwater concentration after 30 years 

assuming 4 applications per year at 1 lb a.i./A for 30 years; the time to breakthrough to the water 

table for isoxaben was calculated as approximately 19 years. If a single application at 1 lb a.i./A 

is applied, the 30 year estimated peak concentration is 20 ppb, with a breakthrough time of 19 

years. This single application EEC corresponds to an application rate of 0.0045 lb a.i./A (based 

on 1-in of irrigation water over an acre), which is roughly one-half the most sensitive plant toxicity 

value suggesting that a limited number of applications over that time until breakthrough (19 years) 

may pose a potential risk to nontarget terrestrial plants. Additionally, should this estimated ground 

water concentration result in exposure to aquatic plants via ground water recharge, the aquatic 

plants may be affected. 

The incident data discussed earlier suggest that, at least for plants, exposure pathways for isoxaben 

are complete and that exposure levels are sufficient to result in field-observable effects. Therefore, 

based on the lines of evidence, there is a potential for adverse effects to terrestrial plants. 

4.3. Overall conclusions 

The results of this screening-level risk assessment indicate that the registered uses of isoxaben are 

unlikely to cause potential direct adverse acute or chronic effects to freshwater and 

estuarine/marine fish and invertebrates nor effects to aquatic non-vascular plants. Isoxaben is not 

acutely toxic to avian, mammalian, or honeybee species, nor do data indicate likelihood of chronic 

effects to birds. Chronic effects to mammals were identified on a dose-based exposure but not on 

a dietary-based exposure basis. There is also potential risk to terrestrial and aquatic vascular plants. 

Therefore, this analysis (i.e., the preliminary registration review risk assessment) failed to reject 

the risk hypothesis for terrestrial and aquatic vascular plants and mammals (chronic risk). 
Page 52 of 74 

5. Federally Threatened and Endangered (Listed) Species Concerns 

In November 2013, the EPA, along with the U.S. Fish & Wildlife Service (USFWS), the National 

Marine Fisheries Service (NMFS) (collectively, the Services), and the U.S. Department of 

Agriculture (USDA) released a summary of their joint Interim Approaches for assessing risks to 

listed species from pesticides. The Interim Approaches were developed jointly by the agencies in 

response to the National Academy of Sciences’ (NAS) recommendations and reflect a common 

approach to risk assessment shared by the agencies as a way of addressing scientific differences 

between the EPA and the Services. The NAS report outlines recommendations on specific 

scientific and technical issues related to the development of pesticide risk assessments that EPA 

and the Services must conduct in connection with their obligations under the Endangered Species 

Act (ESA) and FIFRA. 

The joint Interim Approaches were released prior to a stakeholder workshop held on November 

15, 2013. In addition, the EPA presented the joint Interim Approaches at the December 2013 

Pesticide Program Dialogue Committee (PPDC) and State-FIFRA Issues Research and Evaluation 

Group (SFIREG) meetings, and held a stakeholder workshop in April 2014, allowing additional 

opportunities for stakeholders to comment on the Interim Approaches. As part of a phased, 

iterative process for developing the Interim Approaches, the agencies will also consider public 

comments on the Interim Approaches in connection with the development of upcoming 

Registration Review decisions. The details of the joint Interim Approaches are contained in the 

white paper “Interim Approaches for National-Level Pesticide Endangered Species Act 

Assessments Based on the Recommendations of the National Academy of Sciences April 2013 

Report,” dated November 1, 2013. 

Given that the agencies are continuing to develop and work toward implementation of the Interim 

Approaches to assess the potential risks of pesticides to listed species and their designated critical 

habitat, this preliminary risk assessment for isoxaben does not contain a complete ESA analysis 

that includes effects determinations for specific listed species or designated critical habitat. 

Although EPA has not yet completed effects determinations for specific species or habitats, for 

this preliminary assessment EPA conducted a screening-level assessment for all taxa of non-target 

wildlife and plants that assumes for the sake of the assessment that listed species and designated 

critical habitats may be present in the vicinity of the application of isoxaben. This screening level 

assessment will allow EPA to focus its future evaluations on the types of species where the 

potential for effects exists once the scientific methods being developed by the agencies have been 

fully vetted. This screening-level risk assessment for isoxaben indicates potential risks of direct 

effects to listed mammals, terrestrial and aquatic vascular plants from registered use sites. Listed 

species of birds (surrogates for aquatic-phase amphibians and reptiles) and aquatic animal taxa 

may also be affected through indirect effects because of the potential for direct effects on listed 

and non-listed species upon which such species may rely. Potential direct effects on listed 

mammals, terrestrial and aquatic vascular plants from the use of isoxaben may be associated with 

modification of Primary Constituent Elements (PCEs) of designated critical habitats, where such 

designations have been made. Once the agencies have fully developed and implemented the 
Page 53 of 74 

scientific methods necessary to complete risk assessments for endangered and threatened (listed) 

species and their designated critical habitats, these methods will be applied to subsequent analyses 

for isoxaben as part of completing this registration review (Table 23). 
54

Table 23. Potential Effects to Federally Listed Taxa Associated with Direct Effects from 

the Registered Uses of Isoxaben. 

Listed Plant Taxon Potential Direct Effects 

Terrestrial and semi-aquatic 

plants – monocots and dicots Yes1

Aquatic nonvascular plants No2

Aquatic vascular plants Yes1

Listed Animal Taxon Potential Direct Effects 

Acute Chronic 

Terrestrial invertebrates No3 No 

Mammals No3 Yes4 

Birds No3 No3 

Reptiles No3 No3

Amphibians No3 No3

Freshwater fish No3 No3

Freshwater invertebrates No3 No3

Estuarine/marine fish No3 No3

Estuarine/marine invertebrates No3 No3

1

 RQs exceed the listed LOC based on toxicity data for both terrestrial plants and aquatic vascular plants. 2

 Risk of direct effects from isoxaben exposure expected to be below the LOC 3 Risk of direct effects from acute and chronic exposure to terrestrial and aquatic animals is expected to be below the LOC, except for chronic 

risk to mammals. 

4 Chronic risk to mammalian species may occur as the LOC was exceeded for all registered uses from exposure to isoxaben on a chronic dosebasis, but not on a dietary basis.

6. Endocrine Disruptor Screening Program 

As required by FIFRA and the Federal Food Drug and Cosmetic Act (FFDCA), EPA reviews 

numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, 

these studies include acute, subchronic and chronic toxicity, including assessments of 

carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. 

These studies include endpoints which may be susceptible to endocrine influence, including effects 

on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, 

fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard 

assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and 

reproductive effects in different taxonomic groups. As part of its registration review decision, 

EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment 

scenarios from the existing hazard database. However, as required by FFDCA section 408(p), 

isoxaben is subject to the endocrine screening part of the Endocrine Disruptor Screening Program 

(EDSP). 

EPA has developed the EDSP to determine whether certain substances (including 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 
55

the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed 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. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 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. A second list 

of chemicals identified for EDSP screening was published on June 14, 20138

 and includes some 

pesticides scheduled for registration review and chemicals found in water. Neither of these lists 

should be construed as a list of known or likely endocrine disruptors. 

Isoxaben is on List 2. List 2 represents the next set of chemicals for which EPA intends to issue 

test orders/data call-ins in the near future. For further information on the status of the EDSP, the 

policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 

screening battery, please visit our website.9

7. Literature Cited 

Al-Khatib, K. 1996. Tulip (Tulipa spp), daffodil (Narcissus spp.) and iris (Iris spp.) response to 

preemergence herbicides. Weed Tech. 10:710-715. 

Fletcher, J.S., J.E. Nellessen, and T.G. Pfleeger. 1994. Literature review and evaluation of the 

EPA food-chain (Kenaga) nomogram, an instrument for estimating pesticide residues on 

plants. Environ. Tox. Chem. 13:1383-1391. 

Hoerger, F. and E. E. Kenaga. 1972. Pesticide Residues on Plants: Correlation of 

Representative Data as a Basis for Estimation of their Magnitude in the Environment. In 

F. Coulston and F. Korte, eds., Environmental Quality and Safety: Chemistry, 

Toxicology, and Technology, Georg Thieme Publ., Stuttgart, West Germany, pp. 9-28. 

Salihue, S., Hatzios, K.K., Derr, J.F. 1998. Comparative Uptake, Translocation, and Metabolism 

of Root-Applied Isoxaben in Ajuga (Ajuga reptans) and Two Ornamental Euonymus 

Species. Pesticide Bidchemistry and Physiology, 60:2 pp. 1 19-1 3 1 

United States Environmental Protection Agency. 1998. Guidelines for Ecological Risk 

Assessment. Risk Assessment Forum, Office of Research and Development, 

Washington, D.C. EPA/630/R-95/002F. April 1998. 

http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=30759 

 

8

 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of 

chemicals. 9

 http://www.epa.gov/endo/ 
56

USEPA, 2004. Overview of the Ecological Risk Assessment Process in the Office of Pesticide 

Programs. Office of Prevention, Pesticides, and Toxic Substances. Office of Pesticide 

Programs. Washington, D.C. January 23, 2004. 

USEPA, 2007. Problem Formulation for Isoxaben in Isoxaben Summary Document: 

 Registration Review. Office of Pesticide Programs, January, 2007. 

USEPA, 2009. Input Parameter Guidance. Version 2.1. Environmental Fate and Effects 

 Division. October 22, 2009 

http://www.epa.gov/oppefed1/models/water/input_parameter_guidance.htm 

USEPA, 2010. Environmental Fate and Ecological Risk Assessment for the Section 3 New Uses 

of Isoxaben on Bearing Nut Trees and Vineyards. Environmental Fate and Effects 

Division. Office of Pesticides. June 7, 2010. DP Barcode D341496. 

USEPA, 2010a. The Drinking Water Degradates Identification Memorandum for Isoxaben. 

 Memo to Dennis McNeilly. DP Barcode 374529. 

USEPA 2012. Ecological Structure Activity Relationships (ECOSAR) version 1.11. 

http://www.epa.gov/oppt/newchems/tools/21ecosar.htm 

USEPA. 2013. Pesticides: Science and Policy. Terrestrial Models, T-REX Version 1.5/1. 

http://www.epa.gov/oppefed1/models/terrestrial/ 

USEPA. 2013a. Pesticides: Science and Policy. Terrestrial Models, TerrPlant Version 1.2.2. 

http://www.epa.gov/oppefed1/models/terrestrial/ 

USEPA. 2013b. Guidance on Modeling Offsite Deposition of Pesticides via Spray Drift for 

Ecological and Drinking Water Assessments. Environmental Fate and Effects Division. 

Decemeber 20, 2013. 

 Willis G.H. and L.L. McDowell (1987) Pesticide persistence on foliage. Rev Environ Contam 

 Tox: 100:23-62. 

 
57

Appendix 1 – PRZM/EXAMS output from scenario with highest EECs 

Variable Volume Water Model, SWCC Compatible Version

  

*******************************************

Performed on:  8/15/2014  at 16:19

  

Peak 1‐in‐10       =   88.4     ppb

Chronic 1‐in‐10    =   64.0     ppb

Simulation Avg     =   49.8     ppb

4‐day avg 1‐in‐10  =   87.8     ppb

21‐day avg 1‐in‐10 =   86.0     ppb

60‐day avg 1‐in‐10 =   81.5     ppb

90‐day avg 1‐in‐10 =   78.3     ppb

  

Benthic Pore Water Peak 1‐in‐10       =   71.0     ppb

Benthic Pore Water 21‐day avg 1‐in‐10 =   70.9     ppb

Benthic Conversion Factor             =   1.89     ‐Pore water (ug/L) to (total mass, ug)/(dry sed mass,kg)

Benthic Mass Fraction in Pore Water   =  0.196     

  

YEAR    Peak      4‐day      21‐day     60‐day     90‐day   Yearly Avg Benthic Pk  Benthic 21‐day

  1    1.94E+01   1.92E+01   1.87E+01   1.78E+01   1.71E+01   1.08E+01   1.51E+01   1.51E+01

  2    4.63E+01   4.60E+01   4.48E+01   4.27E+01   4.21E+01   2.95E+01   3.71E+01   3.70E+01

  3    7.06E+01   7.03E+01   6.88E+01   6.57E+01   6.39E+01   4.71E+01   5.48E+01   5.48E+01

  4    8.58E+01   8.52E+01   8.30E+01   7.83E+01   7.52E+01   6.02E+01   7.04E+01   7.03E+01

  5    6.20E+01   6.22E+01   6.32E+01   6.59E+01   6.83E+01   5.02E+01   6.61E+01   6.70E+01

  6    5.59E+01   5.55E+01   5.45E+01   5.17E+01   4.97E+01   4.33E+01   4.73E+01   4.73E+01

  7    5.18E+01   5.16E+01   5.10E+01   4.86E+01   4.78E+01   4.24E+01   4.52E+01   4.52E+01

  8    4.65E+01   4.62E+01   4.51E+01   4.34E+01   4.36E+01   3.83E+01   4.12E+01   4.11E+01

  9    5.80E+01   5.77E+01   5.65E+01   5.42E+01   5.44E+01   4.54E+01   5.03E+01   5.03E+01

10    6.58E+01   6.55E+01   6.43E+01   6.30E+01   6.16E+01   5.42E+01   5.88E+01   5.87E+01

11    6.97E+01   6.94E+01   6.78E+01   6.41E+01   6.31E+01   5.18E+01   5.75E+01   5.74E+01

12    7.31E+01   7.27E+01   7.10E+01   6.90E+01   6.77E+01   5.60E+01   6.34E+01   6.33E+01

13    5.16E+01   5.14E+01   5.03E+01   5.11E+01   5.32E+01   4.43E+01   5.30E+01   5.40E+01

14    5.72E+01   5.69E+01   5.57E+01   5.29E+01   5.22E+01   4.43E+01   4.87E+01   4.87E+01

15    4.71E+01   4.68E+01   4.58E+01   4.36E+01   4.30E+01   3.75E+01   4.22E+01   4.29E+01

16    5.16E+01   5.13E+01   5.04E+01   4.79E+01   4.74E+01   4.04E+01   4.42E+01   4.41E+01

17    8.56E+01   8.51E+01   8.35E+01   7.99E+01   7.78E+01   5.68E+01   6.71E+01   6.70E+01

18    8.40E+01   8.35E+01   8.13E+01   7.67E+01   7.48E+01   6.00E+01   6.72E+01   6.72E+01

19    5.97E+01   5.94E+01   5.83E+01   5.77E+01   5.98E+01   5.19E+01   5.91E+01   6.01E+01

20    8.87E+01   8.81E+01   8.63E+01   8.16E+01   7.84E+01   6.27E+01   7.10E+01   7.10E+01

21    7.87E+01   7.82E+01   7.66E+01   7.27E+01   7.04E+01   6.42E+01   6.77E+01   6.85E+01
58

22    7.29E+01   7.24E+01   7.09E+01   6.88E+01   6.86E+01   6.04E+01   6.55E+01   6.54E+01

23    4.82E+01   4.79E+01   4.72E+01   4.90E+01   5.09E+01   4.24E+01   5.10E+01   5.21E+01

24    5.96E+01   5.94E+01   5.84E+01   5.54E+01   5.33E+01   4.38E+01   5.04E+01   5.04E+01

25    6.45E+01   6.42E+01   6.29E+01   6.08E+01   6.10E+01   5.27E+01   5.75E+01   5.75E+01

26    5.11E+01   5.09E+01   5.03E+01   4.92E+01   4.87E+01   4.36E+01   4.75E+01   4.84E+01

27    5.67E+01   5.65E+01   5.52E+01   5.23E+01   5.14E+01   4.29E+01   4.77E+01   4.77E+01

28    1.45E+02   1.44E+02   1.39E+02   1.30E+02   1.25E+02   7.89E+01   1.07E+02   1.07E+02

29    9.95E+01   9.97E+01   1.01E+02   1.06E+02   1.10E+02   8.31E+01   1.04E+02   1.05E+02

30    6.30E+01   6.31E+01   6.39E+01   6.64E+01   6.88E+01   5.37E+01   6.91E+01   7.03E+01

***********************************************************************************

*****************

Effective compartment halflives averaged over simulation duration:

  

zero washout                          0

water col metab halflife (days) =      303.336213300958      

zero hydrolysis                       0

photolysis halflife (days)  =          7952.62695872797      

volatile halflife (days)  =            169345.374914618      

total water col halflife (days) =      291.687912334577      

  

zero burial                           0

benthic metab halflife (days) =        1729.66181201397      

zero benthic hydrolysis               0

total benthic halflife (days) =        1729.66181201397      

***********************************************************************

Fractional Contribution of Transport Processes to Waterbody & Total Mass (kg):

  

Due to Runoff  =     0.7005           19.42     

Due to Erosion =     0.0008          0.2236E‐01

Due to Drift   =     0.2987           8.279     

***********************************************************************

Flow in/out Characteristics of Waterbody:

Average Daily Runoff Into Waterbody (m3/s) =   1.294828998867743E‐003

Baseflow Into Waterbody (m3/s)             =   0.000000000000000E+000

Average Daily Flow Out of Waterbody (m3/s) =   1.294828998867728E‐003

***********************************************************************

Inputs:

   38.00     = oc partitioning coefficient

   282.0     = water column half Life

   25.00     = reference temp for water column degradation

   1608.     = benthic Half Life
59

   25.00     = Reference temp for benthic degradation

   2.000     = Q ten value

   93.50     = photolysis half life

   40.00     = reference latitude for photolysis study

   0.000     = hydrolysis half life

   332.4     = molecular wt

  0.4100E‐08 = vapor pressure

   1.420     = solubility

  0.1000E+06 = field area

  0.1000E+05 = water body area

   2.000     = initial depth

   2.000     = maximum depth

   2         1=vvwm, 2=usepa pond, 3 = usepa reservoir, 4 = const vol no flow, 5 = const vol w/flow  

F  T = burial, else no burial

  0.1000E‐07 = mass transfer coefficient  

  0.5000     = PRBEN

  0.5000E‐01 = benthic compartment depth

  0.5000     = benthic porosity

   1.350     =  benthic bulk density

  0.4000E‐01 = OC frcation in benthic sediment

   5.000     = DOC in benthic compartment

  0.6000E‐02 = benthic biomass

   1.190     = DFAC

   30.00     = SS

  0.5000E‐02 = chlorophyll

  0.4000E‐01 = OC frcation in water column SS

   5.000     = DOC in water column

  0.4000     = biomass in water column

FRACTION AREA CROPPED =    1.00000000000000      

 
60

Appendix 2. Isoxaben Ecological Effects Summaries 

Many of the following study summaries were presented in previous risk assessment on bearing 

fruit and nut trees (D341496). 

1. Aquatic Effects Characterization 

 

The registrant has submitted a suite of studies, as required by CFR 40 Part 15810, which 

examine the toxicity of isoxaben to representative aquatic organisms that serve as surrogates for 

organisms that may be exposed. Both acute and chronic effects were determined for freshwater 

fish and invertebrates. Acute effects on marine/estuarine fish and invertebrates and aquatic 

vascular and nonvascular plants were also examined. 

 

 a. Aquatic Animals 

 i. Effects from Acute Exposure 

 Most of the available aquatic effects studies were conducted at nominal concentrations of 

0 (control) and 100 mg ai/L. Very few were conducted with a co-solvent, and the water 

solubility of isoxaben is 1 mg/L. There was no reported effort to centrifuge or filter the solute. 

If the solutions were actually prepared with a nominal concentration of 100 mg ai/L and the 

measured concentration is roughly 1 mg ai/L in the acute studies, a precipitate should have been 

reported. However, no precipitate is reported for any of the available studies. 

Freshwater Fish 

 In 96-h acute toxicity studies, rainbow trout (Oncorhynchus mykiss; MRID 00132146), 

bluegill sunfish (Lepomis macrochirus; MRID 00132145) and common carp (Cyprinus carpio; 

MRID 00137844) were exposed to isoxaben at mean-measured concentrations of 0 (negative 

control) and 1.0 mg ai/L. No sub-lethal effects were observed in any study. The LC50 and NOAEC 

values (Table 1), based on a lack of mortality and sub-lethal effects, were >1.0 and 1.0 mg ai/L. 

Table 1. Freshwater fish and amphibian acute toxicity for technical grade isoxaben.

Species 96-hour 

LC50 mg ai/L 

Toxicity 

Category MRID No. Study Classification

Rainbow trout 

(Oncorhynchus mykiss) >1.0 NA (no effects up to solubility 

limit) 

00132146 Supplementa 

Bluegill sunfish 

(Lepomis macrochirus) >1.0 NA (no effects up to solubility 

limit) 

00132145 Supplemental 

 

10 Code of Federal Regulations 40, Part 158.subpart 630. Terrestrial and aquatic nontarget organism data requirements. 

http://ecfr.gpoaccess.gov/cgi/t/text/textidx?c=ecfr;sid=fe712efed37d095118c7637457e011b3;rgn=div5;view=text;node=40%3A23.0.1.1.9;idno=40;cc=ecfr#40:23.0.1.1.9.7.1.1
61

Species 96-hour 

LC50 mg ai/L 

Toxicity 

Category MRID No. Study Classification

Common carp 

(Cyprinus carpio) >1.0 NA (no effects up to solubility 

limit) 

00137844 Supplemental 

Estuarine/marine Fish 

In a 96-h acute toxicity study, sheepshead minnows (Cyprinodon variegatus; MRID 

40531304) were exposed to isoxaben at time-weighted average (TWA) concentrations were 

<0.02 (<LOQ; controls) and 0.86 mg ai/L. The 96-h LC50 was >0.86 mg ai/L. The LC50 and 

NOAEC values (Table 2), based on a lack of mortality and sub-lethal effects, were 0.86 and 

>0.86 mg ai/L, respectively. 

Table 2. Estuarine/marine fish acute toxicity to technical grade isoxaben.

Species

96-hour 

LC50 mg 

ai/L 

Toxicity Category MRID 

No. 

Study 

Classification

Sheepshead minnow 

(Cyprinodon 

variegatus)

>0.86 NA (no effects up to solubility 

limit) 

40531304 Supplemental 

Freshwater Invertebrates 

Water fleas, Daphnia maga (MRID 00132444), were exposed to isoxaben at meanmeausured concentrations of 0 (control) and 1.3 mg ai/L. No effects were seen in either the 

control or treatment groups. Therefore the 48-h EC50 and NOAEC were >1.3 mg ai/L and 1.3 

mg ai/L, respectively (Table 3). 

Table 3. Freshwater invertebrate acute toxicity for technical grade isoxaben.

Species 96-hour 

LC50 mg ai/L Toxicity Category MRID No. Study Classification

Waterflea 

(Daphnia magna) >1.3 NA (no effects up to 

solubility limit) 

00132444 Supplemental 

*at the limit of solubility 

Estuarine/marine 

 

 Quahog clam larvae (Mercenaria mercenaria; MRID 40531302) were exposed to 

isoxaben at for 48-h under static conditions. Larvae were exposed to mean-measured 

concentrations of <0.02 (<LOQ; negative control) and 0.96 mg ai/L. The 48-hr EC50 was >0.96 

mg ai/L (Table 4). The NOAEC was <0.96 mg ai/L, based on a 40% reduction in normally 

developed larvae. The only observed toxic effect was an inhibition of normal larval 

development. It is not clear from the study how ‘normal larvae’ is differentiated from ‘abnormal 

larvae’. 
62

 Grass shrimp (Palaemonetes pugio; MRID 40531303) demonstrated no effect from 

exposure to a measured concentration of 1 mg ai/L of isoxoaben. 

Table 4. Estuarine/marine invertebrate acute toxicity for technical grade isoxaben.

Species

96-hour 

LC50 

mg ai/L Toxicity Category MRID 

No. 

Study 

Classification

Quahog clam 

(Mercenaria 

mercenaria)

>0.96 NA (EC50 > solubility limit) 40531302 Supplemental 

Grass shrimp 

(Palaemonetes pugio) >1.0 NA (no effects up to solubility 

limit) 

40531303 Supplemental 

ii. Effects from Chronic Exposure 

 Aquatic vertebrates 

 A 66-day early-life stage study of the effect of chronic exposure of isoxaben to rainbow trout 

(MRID 00137847) was conducted under flow-through conditions. Fertilized eggs/embryos 

(100/level, early-eyed stage) of rainbow trout were exposed to mean-measured concentrations of 

<0.002 (<LOD, controls), 0.024, 0.048, 0.093, 0.19, and 0.42 mg ai/L, respectively. No treatmentrelated effects were observed on any measured parameter during the study. The 66-day NOAEC 

and LOAEC were 0.42 and >0.42 mg ai./L, respectively (Table 5). 

 A 33-day early-life stage study of isoxaben with fathead minnows (Pimephales promelas; 

MRID 00137848) was conducted under flow-through conditions. Fertilized eggs/embryos 

(100/level, <48 hours old) of fathead minnow were exposed to mean-measured concentrations of 

<0.002 (<LOD, controls), 0.025, 0.048, 0.095, 0.18, and 0.40 mg ai/L, respectively. No treatmentrelated effects were observed on any measured parameter during the study. The 33-day NOAEC 

and LOAEC values were 0.40 and >0.40 mg ai/L, respectively. 

Table 5. Early life-stage toxicity of technical grade isoxaben to freshwater fish.

Species NOAEC 

mg ai/L

LOAEC 

mg ai/L Endpoints Affected

MRID 

No. Study 

Classification

Rainbow trout 

(Oncorhynchus 

mykiss) 

0.42 >0.42 None 00137847 Supplemental 

Fathead minnow 

(Pimphales 

promelas)

0.40 >0.40 None 00137848 Supplemental 

 No chronic toxicity data were submitted for estuarine/marine fish. 

 Aquatic Invertebrates 
63

 In a 21-day static renewal life-cycle study, first instar daphnids (MRID 00137845) were 

exposed to isoxaben at mean-measured concentrations of 0 (control), 0.13, 0.69 and 1.01 mg 

ai/L. No effects were observed in the control, 0.13 or 0.69 mg ai/L treatment groups (Table 6), 

but 13% of the daphnids were immobilized in the highest treatment group. Additionally, 

statistically significant effects were reported for growth and reproduction (brood size) at the 

highest treatment concentration. The NOAEC and LOAEC for the study are 0.69 mg ai/L and 

1.01 mg ai/L, respectively, based on impaired growth and reproduction.

Table 6. Freshwater invertebrate full life-cycle toxicity for technical grade isoxaben.

Species NOAEC 

mg ai/L

LOAEC 

mg ai/L Endpoints Affected

MRID 

No. Study 

Classification

Waterflea 

(Daphnia 

magna)

0.69 1.01 Growth and 

Reproduction 

00137845 Supplemental 

 In a 28-day flow-through life-cycle study, <24-hr old mysid shrimp (MRID 49090201) 

were exposed to isoxaben at mean-measured concentrations of 0 (control), 0 (solvent control 

DMF 0.01%), 0.0581, 0.121, 0.238, 0.460 and 0.841 mg ai/L. Statistically significant effects 

were reported for reproduction (# of young per female) at the two highest treatment 

concentration. The NOAEC and LOAEC for the study are 0.238 mg ai/L and 0.841 mg ai/L, 

respectively, based on impaired reproduction (Table 7).

Table 7. Estuarine/marine invertebrate full life-cycle toxicity for technical grade isoxaben.

Species NOAEC 

mg ai/L

LOAEC 

mg ai/L

Endpoints 

Affected

MRID 

No.

Study 

Classification

Mysid Shrimp 

(Americamysis 

bahia)

0.238 0.841 Reproduction 49090201 Acceptable 

 

 b. Aquatic Plants 

 Three studies assessing the effect of isoxaben on the aquatic vascular plant duckweed,

Lemna gibba, are available (Table 8). In a 14-day toxicity study, the freshwater floating aquatic 

vascular plant duckweed (MRID 47428401) was exposed to isoxaben (technical grade active 

ingredient;TGAI) at mean-measured concentrations of<0. 5 (<LOQ, control), 5.8, 13, 24, 46, and 

93 μg ai/L. A NOAEC was not defined in the study. The EC05 and EC50 values for decreased 

biomass, the most sensitive endpoint, were 2.9 and 13 g ai/L, respectively. Inhibition in 

biomass in the treatment groups ranged from 13 to 96%. 

 In a 7-day acute toxicity study, duckweed (MRID 47428402) was exposed to isoxaben 

TGAI at mean-measured concentrations of <0.50 (<LOQ, control), 3.1, 6.0, 12.3, 23.6, and 45.9 
64

g ai/L. The 7-day NOAEC and EC50 values for biomass inhibition, the most sensitive endpoint, 

were 6.0 and 10 g ai/L, respectively. The inhibition in biomass in the treatment groups ranged 

from -1 to 95%. 

 In a 14-day acute toxicity study (MRID 47428406), duckweed was exposed to Isoxaben®

500 SC (formulation) at mean-measured concentrations of <0.5 (<LOD, control), 5.1, 10.1, 20.3, 

38.5, 84.2 and 172.1 g ai/L. The 14-day NOAEC and EC50 values for biomass inhibition, the 

most sensitive endpoint, were 10.1 and 15 g ai/L, respectively. A hormetic (low-dose 

stimulatory) effect of 18% increased biomass was seen at the lowest test concentration. In the 

remaining treatment groups, percent inhibition in biomass ranged from 6 to 95%. 

 Studies of nonvascular plants are also required and typically involve microalgae. In a 

supplemental (quantitative use) 96-hour acute toxicity study, cultures of marine diatom, 

Skeletonema costatum, were exposed to technical grade isoxaben at initial measured 

concentrations (test material unstable during exposure) of <0.03 (<LOD, negative and solvent 

controls), 0.640, 0.127, 0.256, 0.492, and 0.922 mg ai/L. The NOAEC and EC50/IC50 values 

based on all endpoints (yield, growth rate, and AUC) were 0.922 and >0.922 mg ai/L, 

respectively. 

 In a supplemental (qualitative use) 72-hour acute toxicity study (MRID 48534802), cultures 

of the freshwater diatom (Navicula pelliculosa) were exposed to isoxaben technical at meanmeasured concentrations of <0.035 (<LOD; controls), 3.2, 5.1, 11, 20, 47, and 86 mg ai/L. The 

IC50 values for cell density, biomass, and growth rate were >86 mg ai/L, while the NOAEC 

values were 47, 20, and 20 mg ai/L, respectively. 

 A supplemental (qualitiative use) 14-day static study reports a NOAEC of 1.4 mg ai/L for the 

green algae Pseudokirchneriella subcapitata (formerly Selenastrum capricornutum) (MRID 

00153111). The study is from 1984, before microalgae studies were routinely submitted to the 

Agency; raw data were not included and the study is not consistent with Agency guidelines. 

 In a supplemental (qualitative use) 72 hour acute toxicity study (MRID 48533202), cultures 

of the unicellular green alga (Chlorella vulgaris) were exposed to Isoxaben 500 SC (Flexidor 50 

SC) at mean-measured concentrations of <0.002 (<LOQ; control), 2.30, 4.99, 9.56, 20.1, and 

43.4 mg ai/L. The NOAEC was 9.56 mg ai/L for cell density, growth rate, and biomass and the 

most sensitive endpoints were cell density and biomass, both with IC50 values of 43 mg ai/L. 

 A supplemental (qualitiative use) 96-hour acute toxicity study (MIRD 48533203), cultures 

of blue-green algae (Anabaena sp.,) were exposed to Isoxaben 500 SC (Flexidor 50 SC) at meanmeasured concentrations of <0.002 (<LOQ, control) and 36.6 mg ai/L. The NOAEC and IC50

values based on cell density, biomass (area under the growth curve), and the specific growth 

rates were 36.6 and >36.6 mg ai/L, respectively. 

 In a supplemental (qualitative use) 72-hour acute toxicity study (MRID 48534801), cultures 

of the unicellular algae (Scendesmus subspicatus) were exposed to Flexidor at nominal 
65

concentrations of 0 (negative control), 0.430, 1.376, 4.30, 13.76, 43.0, and 137.6 mg ai/L under 

static conditions. The 72-hr mean-measured concentrations were <0.11 (<LOD; control), 0.46, 

1.51, 4.60, 14.4, 43.7, and 142.7 mg ai/L. Cell density was the most sensitive endpoint, with a 

NOAEC of 4.6 mg ai/L and an IC50 value of 17 mg ai/L. 

Table 8. Toxicity of technical grade isoxaben to aquatic plant species.

Species/ 

 (duration) % ai

IC50

g ai/L

NOAEC 

g ai/L

MRID Study 

Classification

Duckweed (Lemna gibba) 

 (14 days) 

Technical 13 2.9 47428401 Supplemental 

Duckweed (Lemna gibba) 

(7 days) 

Technical 10 6 47428402 Supplemental 

Duckweed (Lemna gibba) 

 (14 days) 

Formulation 15 10.1 47428406 Supplemental 

Marine diatom (Skeletonema 

costatum) (96-hrs) 

Technical >922 922 48952602 Supplemental 

Freshwater diatom (Navicula 

pelliculosa) (72-hr) 

Technical >86000 20,000 48534802 Supplemental 

Green algae 

(Pseudokirchneriella 

subcapitata) (14-d) 

Technical >1400 1400 00153111 Supplemental 

Green algae (Chlorella 

vulgaris) (72-hr) 

Formulation 43,000 9,560 48533202 Supplemental 

Green algae (Scendesmus 

subspicatus) (72-hr) 

Formulation 17,000 4,600 48534801 Supplemental 

Blue-gree algae (Anabaena 

sp.) (96-hr) 

Formulation >36,600 36,600 48533203 Supplemental 
Page 66 of 74 

 

 2. Terrestrial Effects Characterization 

The registrant has submitted a battery of studies that examine the toxicity of isoxaben to 

representative terrestrial organisms that stand as surrogates for animals and plants at risk of 

exposure. Effects of acute and chronic exposure were evaluated for mammals; data are also 

available for birds which serve as a surrogate for terrestrial-phase amphibians and reptiles. Data 

on the effects of isoxaben on terrestrial invertebrates are available with studies of the honeybee 

(Apis mellifera). The toxicity of isoxaben to terrestrial plants was evaluated using representative 

monocotyledonous (monocots) and dicotyledonous (docots) plants.

a. Terrestrial Animals 

 i. Effects from Acute Exposure 

 Birds 

 The acute oral toxicity of isoxaben to 20-wk-old bobwhite quail (Colinus virginianus; 

MRID 00132146) was assessed over 14 days. Isoxaben was administered by oral gavage at 

nominal doses of 0 (vehicle control), 125, 250, 500, 1000 and 2000 mg/kg. The 14-day acute oral 

LD50 was >2000 mg/kg-bw (Table 9). Since no effects were observed in any of the treatment 

levels, the 14-day NOAEL, based on a lack of treatment-related effects, was 2000 mg/kg-bw. 

Isoxaben is classified as practically non-toxic to bobwhite quail (Colinus virginianus) on an acute 

oral exposure basis. 

 The acute oral toxicity of Isoxaben to 8- to 10-month old Zebra finches (Taeniopygia 

guttata) (MRID 48952601) was assessed over 14 days in a limit-dose study. Isoxaben was 

administered to the birds via gavage (5 mL/kg) at nominal concentrations of 0 (control) and 2000 

mg ai/kg bw. No mortality, clinical signs of toxicity, or effects on body weight or food 

consumption were observed in the 2000 mg ai/kg bw group. The acute oral LD50 was >2000 mg 

ai/kg bw. Isoxaben is classified as practically non-toxic to Zebra finches (Taeniopygia guttata) on 

an acute oral exposure basis 

Table 9. Avian acute oral toxicity for technical grade isoxaben.

Species

LD50

(mg ai/kg 

bw)

Toxicity 

Category MRID Study Classification

Northern bobwhite quail (Colinus 

virginianus) >2000 Practically 

 non-toxic 

00132146 Acceptable 

Zebra finches (Taeniopygia guttata) 

>2000 

Practically 

 non-toxic 

48952601 Acceptable 

 The subacute dietary toxicity of isoxaben to 12-d old bobwhite quails (Colinus virginianus; 

MRID 00132142) was assessed over 8 days (5 days with treated feed and 3 days with basal diet). 

Isoxaben was administered to the birds in their diet at measured concentrations of 0 (negative 
67

control), 56, 180, 480, 1500, and 4500 mg ai/kg diet. The 8-day subcute dietary LC50 was >4500 

mg ai/kg diet (Table 10). The NOAEC, based on a lack of treatment-related effects, was 4500 mg 

ai/kg-diet. Isoxaben is considered to be practically nontoxic to bobwhite quail on an subacute 

dietary exposure basis. 

The subacute dietary toxicity of isoxaben to 10-d-old mallard ducks (Anas platyrhynchos; 

MRID 00132143) was assessed over 8 days. Measured concentrations were 0 (negative control), 

63, 190, 540, 1600, and 4800 mg ai/kg diet. The 8-day subacute dietary LC50 was >4800 mg 

ai/kg diet. The NOAEC, based on a lack of treatment-related effects, was 4800 mg ai/kg diet. 

Isoxaben is considered to be practically nontoxic to mallard ducks on an subacute dietary 

exposure basis 

Table 10. Avian subacute dietary toxicity for technical grade isoxaben.

Species

LC50

(mg ai/kg 

diet) 

Toxicity 

Category MRID Study Classification

Northern bobwhite quail 

(Colinus virginianus)

>4500 Practically 

 non-toxic 00132142 Acceptable 

Mallard duck 

(Anas platyrhynchos)

>4800 Practically 

non-toxic 00132143 Acceptable 

 Mammals 

 The aucte LD50 used in this assessment is >10,000 mg ai/kg-bw (Table 11) and is 

classified as practically nontoxic to mammals on an acute oral exposure basis. 

Table 11. Acute oral mammalian toxicity for isoxaben.

Species LD50 Toxicity 

Category

Affected 

Endpoints MRID No. Classification

Wistar rat

Rattus rattus >10000 mg 

ai/kg-bw 

practically nontoxic none 00132126 Acceptable 
68

 Terrestrial Invertebrates 

 Honeybees (Apis mellifera) were exposed via contact to doses of isoxaben technical at 0 

(control), 33.9, 67.4 and 101.7 μg ai/bee (MRID 0015311). No mortality or other subeffects were 

reported at any of the doses tested. The LD50 for isoxaben is >101.7 μg ai/bee and isoxaben is 

classified as practically nontoxic to honeybees on an acute contact exposure basis. 

 ii. Chronic Effects 

 Birds 

 The one-generation reproductive toxicity study of isoxaben to 20 pairs per level of 17-

week old northern bobwhite quail (Colinus virginianus; MRID 00153110) -was assessed over 24 

weeks. Isoxaben was administered to the birds in the diet at mean-measured concentrations of 

<LOD (control), 105, 313, and 1073 mg ai/kg-diet, respectively. No treatment-related effects 

were observed on any adult or offspring parameter at any treatment level. Therefore the NOAEC 

and LOAEC for the study are 1073 and >1073 mg ai/kg-diet, respectively (Table 12). 

 The one-generation chronic toxicity of isoxaben to 12 pairs per level of 20-week old 

mallard duck (Anas platyrhynchos; MRID 00153109) was assessed over 23 weeks. Isoxaben 

was administered to the birds in their diet at mean-measured concentrations of <LOD (control), 

100, 298, and 946 mg ai/kg-diet, respectively. The study is classified as ‘Supplemental’, because 

it provides insight into the potential for effects of chronic exposure of isoxaben to avian species, 

but the study is insufficient to provide a definitive endpoint. There was a significant reduction in 

the proportion of eggs hatched to live 3-wk old embryos, indicating reproductive effects at least 

as low as 298 mg ai/kg diet. There was a high percentage of cracked eggs in the control (11%), 

nearly double the high-end normal value (6%) as stated in the OPPTS 850.2300 harmonized 

guideline11; the elevated number of cracked eggs in the control raises uncertainty regarding the 

conditions under which the study was conducted. Furthermore, the number of eggs laid per hen 

was higher than expected (59 vs 38), and the mean percentage of viable embryos per eggs set 

was very low in the control (71% vs 85-98%). There was also an apparent effect on hatchling 

survival per egg set and the number of hatchlings per pen, but high control variability did not 

allow for statistical detection. Additionally, data for two important growth endpoints, hatchling 

weight and 14-d survivor weight were not provided. While these problems are not enough to 

invalidate the study, a definitive endpoint could not be determined. 

The one-generation reproductive toxicity of Isoxaben to 16 pairs per level of 24-week old 

mallard duck (Anas platyrhynchos) was assessed over 20 weeks (MRID 49091601). Isoxaben 

was administered to the birds in the diet at nominal concentrations of 0 (negative control), 100, 

300, and 1000 mg ai/kg diet. Mean-measured concentrations were <25 (LOD, control), 103 

3.41, 313  16.5, and 1035  37.8 mg ai/kg diet. 

 

11 USEPA 1996. Ecological Effects Test Guideline 850.2300 Avian Reproduction Test. 

http://www.epa.gov/opptsfrs/publications/OPPTS_Harmonized/850_Ecological_Effects_Test_Guidelines/Drafts/85

0-2300.pdf 
69

There were no treatment-related mortalities, overt signs of toxicity, or treatment-related effects 

upon body weight or feed consumption in the control and treatment groups. No significant 

treatment-related effects upon any of the reproductive parameters were observed. No treatmentrelated differences upon egg shell thickness were observed at any treatment level. The NOEC 

was 1035 mg ai/kg diet (mean-measured concentration). 

Table 12. Avian reproduction chronic toxicity for technical grade isoxaben. 

Species % a.i. NOAEC 

(mg ai/kg diet) 

LOAEC 

(mg ai/kg-diet) 

MRID Study Classification

Northern bobwhite quail 

(Colinus virginianus) 

94.5 

Technical 

1073 >1073 00153110 Supplemental 

Mallard duck 

(Anas platyrhynchos) 

94.5 

Technical 

Not established 100 00153109 Supplemental 

Mallard duck 

(Anas platyrhynchos) 

93.5 

Technical 

1035 >1035 49091601 Acceptable 

 Mammals 

In a three-generation reproduction study (MRID 00153529) (Table 13), 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. 

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). 

The LOAEL for offspring toxicity is 1.25% (1000 mg/kg bw/day), based on decreased pup 
70

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). 

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). 

Table 13. Chronic toxicity of isoxaben to mammals.

Species % a.i. NOAEL 

(mg ai/kg-bw) 

LOAEL 

(mg ai/kg-bw) MRID Study Classification

Wistar rat 

(Rattus norvegicus) 

93.7-94.5 

Technical 

40 200 00153529 Acceptable 

 b. Terrestrial Plants 

 Seedling emergence testing (MRID 47428404) indicate moncot grass species (Family: 

Poaceae) tested were unaffected at treatment rates equivalent to an application rate of 0.888 lbs 

ai/A, the highest rate tested. However, only three monocot species were tested. Corn (Zea 

mays), a required test species, was not included in the study. Onion (Allium cepa), which 

typically represents non-graminoid monocot species such as lilies and orchids, was also not 

included. Among broadleaf plants (dicots), cucumber (Cucumis sativus) was unaffected at the 

highest rate tested, while fresh weight was affected in pea (Pisum sativum) and sugarbeet (Beta 

vulgaris). Emergence was the most sensitive endpoint for carrot (Daucus carota), lettuce 

(Lactuca sativa), oil seed rape (Brassica napus), and tomato (Solanum lycopersicum). Lettuce 

was the most sensitive dicot (EC25 = 0.0095 lbs ai/A); a NOAEC was not established in the 

study, but the lettuce EC05 (0.0014 lbs ai/A) is used in lieu of a NOAEC. 

Vegetative vigor testing (MRID 4748405) indicated that all species tested except wheat 

(Triticum aestivum) and tomato were at least somewhat sensitive to isoxaben. Among monocots, 

ryegrass (Lolium perenne) was particularly sensitive to isoxaben and was the most sensitive 

species tested (EC25 = 0.014 lbs ai/A; NOAEC 0.0034 lbs ai/A. As with the seedling emergence 

study, only three monocot species were tested. Corn, a required test species, was not included in 

the study. Onion, which typically represents non-graminoid monocot species such as lilies and 

orchids, was also not included. Among broadleaf plants, cucumber was the most sensitive 

species, with an EC25 of 0.089 lbs ai/A, and the NOAEC was 0.028 lbs ai/A. Table 14 provides 

the most sensitive endpoints from all plant species tested. 

Table 14. The most sensitive terrestrial plant endpoints (lbs ai/A) in the studies submitted 

for isoxaben. 

Species Seedling emergernce Vegetative vigor 
71

Endpoint NOAEC EC25 Endpoint NOEC EC25

Oat None 0.888 >0.888 Fresh weight 0.0069 >0.888 

Ryegrass None 0.888 >0.888 Fresh weight 0.0034 0.014

Wheat None 0.888 >0.888 None 0.888 >0.888 

Oilseed rape Emergence 0.020* 0.028 Survival 0.444 <0.888

Pea Fresh weight 0.056 0.29 Fresh weight 0.056 >0.056 

Cucumber None 0.888 >0.888 Fresh weight 0.028 0.089

Carrot Emergence 0.0138 0.043 Fresh weight 0.0034 0.888 

Lettuce Emergence 0.0014* 0.0095 Fresh weight 0.056 >0.888 

Tomato Emergence 0.0067 0.016 Fresh weight 0.888 >0.888 

Sugarbeet Fresh weight 0.056 0.073 None 0.444 0.73 *

-EC05 is used when calculated EC25 is less than derived NOAEC. 

 
72

Appendix 3. STIR results 

Welcome to the EFED 

Screening Tool for Inhalation Risk

This tool is designed to provide the risk assessor with a rapid method for determining the potential

significance of the inhalation exposure route to birds and mammals in a risk assessment.

Input

Application and Chemical Information

Enter Chemical Name isoxaben

Enter Chemical Use non-ag

Is the Application a Spray? (enter y or n) y

If Spray What Type (enter ground or air) ground

Enter Chemical Molecular Weight (g/mole) 332.39

Enter Chemical Vapor Pressure (mmHg) 3.90E-07

Enter Application Rate (lb a.i./acre) 1

Toxicity Properties

Bird

Enter Lowest Bird Oral LD50 (mg/kg bw) 2000

Enter Mineau Scaling Factor 1.15

Enter Tested Bird Weight (kg) 0.178

Mammal

Enter Lowest Rat Oral LD50 (mg/kg bw) 10000

Enter Lowest Rat Inhalation LC50 (mg/L) 1.99

Duration of Rat Inhalation Study (hrs) 4

Enter Rat Weight (kg) 0.35

Output

Results Avian (0.020 kg )

Maximum Vapor Concentration in Air at Saturation (mg/m3) 6.98E-03

Maximum 1-hour Vapor Inhalation Dose (mg/kg) 8.77E-04

Adjusted Inhalation LD50 2.22E+00

Ratio of Vapor Dose to Adjusted Inhalation LD50 3.95E-04 Exposure not Likely Significant

Maximum Post-treatment Spray Inhalation Dose (mg/kg) 1.06E-01

Ratio of Droplet Inhalation Dose to Adjusted Inhalation LD50 4.76E-02 Exposure not Likely Significant

Results Mammalian (0.015 kg )

Maximum Vapor Concentration in Air at Saturation (mg/m3) 6.98E-03

Maximum 1-hour Vapor Inhalation Dose (mg/kg) 1.10E-03

Adjusted Inhalation LD50 1.18E+02

Ratio of Vapor Dose to Adjusted Inhalation LD50 9.30E-06 Exposure not Likely Significant

Maximum Post-treatment Spray Inhalation Dose (mg/kg) 1.33E-01

Ratio of Droplet Inhalation Dose to Adjusted Inhalation LD50 1.12E-03 Exposure not Likely Significant

**NOTE**: When entering values, press the "Enter" key 

in order to update linked cells.
73

 
74

Appendix 4. Calculations for Irrigation Exposure

To estimate exposure to plants when ground water contaminated by isoxaben is applied to crops, 

the following method was used. 

Assume a field is irrigated with one inch of water containing 1010 μg/L isoxaben (concentration 

estimate from PRZM-GW). 

This results in 6,272,640 cubic inches of water on each acre of the field (one acre = 6,272,640 

in2), or 1.0 × 105 L/acre of water (6,272,640 in3 ÷ 61 in3/L = 1.0 × 105 L). Therefore, 1.01 × 108

μg isoxaben are applied to each acre of the field (1010 μg/L × 1.0 × 105 L = 1.01 × 108 μg), 

which is equivalent to an application rate of 0.22 lbs isoxaben/acre (1.01 × 108

 μg = 0.22 lbs)