- 2 of 31

- 

# Problem Formulation for the Ecological Risk and Endangered Species in Support of the Registration

Review of Dihydro

- 5

- pentyl

- 2(3H)

- furanone and Dihydro

- 5

- heptyl

- 2(3H)

- furanone (Furanones/Tanol Derivatives)

Dihydro

- 5

- pentyl

- 2(3H)

- furanone

Dihydro

- 5

- heptyl

- 2(3H)

- furanone



### CAS Registry Numbers: 000104

- 61

- 0

, 000104

- 67

- 6 PC Codes: 122301, 122302

Authors : Anita Ullagaddi, Biologist Robert Miller, Environmental Scientist Edward Odenkirchen, Senior Advisor U. S. Environmental Protection Agency Office of Pesticide Programs Environmental Fate and Effects Division

Environmental Risk Branch I 1200 Pennsylvania Ave., NW

Mail Code 7507P Washington, DC 20460 Reviewers : Sujatha Sankula, Lead Biologist Faruque Khan, Senior Fate Scientist Nancy Andrews, Branch Chief

September 16, 2011- 3 of 31

- Table of Contents

1. Purpose

................................ ................................ ................................ ................................ ....... 4

2. Problem Formulation

................................ ................................ ................................ ................. 4

2.1. Natu re of Regulatory Action

................................ ................................ ............................... 4

2.2. Previous Assessments

................................ ................................ ................................ ......... 5 2.2.1. Ecological Risk Assessments

................................ ................................ ....................... 5 2.2.2. Drinking Water Exposure Assessments

................................ ................................ ....... 5

3. Stressor Source and Distribution

................................ ................................ ............................... 5

3.1. Mode of Action

................................ ................................ ................................ ................... 5 3.2. Overview of Pesticide Use and Usage

................................ ................................ ................ 6 3.3. Environmental Fate and Transport

................................ ................................ ...................... 7 4. Receptors

................................ ................................ ................................ ................................ .... 7 4.1. Effects to Aquatic Organisms

................................ ................................ ............................. 8 4.2. Effects to Terrestrial Organisms

................................ ................................ ......................... 9

4.3. Incident Databases Review

................................ ................................ ............................... 11 4.4. Ecosystems Potentially at Risk

................................ ................................ ......................... 11 5. Assessment Endpoints

................................ ................................ ................................ ............. 12 6. Conceptual Model

................................ ................................ ................................ .................... 12

6.1. Risk H ypothesis

................................ ................................ ................................ ................ 12 6.2. Conceptual Diagram

................................ ................................ ................................ ......... 12 7. Analysis Plan

................................ ................................ ................................ ........................... 15

7.1. Stressors of Concern

................................ ................................ ................................ ......... 16 7.2. Measures of Exposure

................................ ................................ ................................ ....... 16

7.3. Measures of Effect

................................ ................................ ................................ ............ 17 7.4. Integration of Exposure and Effects

................................ ................................ ................. 18

7.5. Deterministic and Probabilistic Assessment Methods

................................ ...................... 18

7.6. Endangered Species Assessment

................................ ................................ ...................... 18 7.7. Drinking Water Assessment

................................ ................................ ............................. 19 7.8. Preliminary Identification of Data Gaps

................................ ................................ ........... 19

7.8.1. Fate Data Ga ps

................................ ................................ ................................ ........... 19 7.8.2. Effects Data Gaps

................................ ................................ ................................ ...... 20

8. References

................................ ................................ ................................ ................................ 23 Appendix A. Incidents

................................ ................................ ................................ .................. 25 Appendix B. The Risk Quotient Method and Levels of Concern

................................ ................. 27 Appe ndix C. STIR Input/Output

................................ ................................ ................................ ... 29- 4 of 31

- 1. Purpose

The purpose of this problem formulation is to provide the status of the environmental fate and ecologica l effects of dihydro

- 5

- pentyl

- 2(3H)

- furanone and dihydro

- 5

- heptyl

- 2(3H)

- furanone, which are commonly known as the furanones or tanol derivatives, considering their currently registered uses

. The furanones are classified as lactones, which are cyclic esters of alpha

h ydroxy acids. The furanones are registered nationally as insect, cat, and dog repellents. The insect repellent is formulated into a product called Bugchaser ( dihydro

- 5

- pentyl

- 2(3H)

- furanone:

0.024% ; dihydro

- 5

- heptyl

- 2(3H)

- furanone: 0.049% ; d

- limonene: 4.01 5%) that is worn on humans as a wristband. The dog and cat repellent is formulated into a granule called Doo

- Not for use in outdoor residential areas to discourage defecation ( dihydro

- 5

- pentyl

- 2(3H)

- furanone:

0.024% ; dihydro

- 5

- heptyl

- 2(3H)

- furanone: 0.049% ; d

- limonene: 4.015%). Both products also contain the active ingredient d

- limonene. This document will provide a plan for analyzing

environmental fate and effects data relevant to the furanones and for conducting ecological risk and endangered species asse ssments for their registered uses. Additionally, this problem formulation is intended to identify data gaps, uncertainties, and potential assumptions used to address those uncertainties relative to characterizing the ecological risk associated with the

reg istered uses of the furanones.

The Health Effects Division (HED) informed the Environmental Fate and Effects Division (EFED) that a drinking water assessment would not be necessary for the furanones because human exposure due to the registered uses as pesticides is expected to be low and there are no

food tolerances associated with either of the furanones.

2. Problem Formulation

2.1. Nature of Regulatory Action

Under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), all pesticides distributed or sold in the United States generally must be registered by the Environmental Protection Agency (EPA). In determining whether a pesticide can be registered in the United States, EPA evaluates its 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, and the Agency was mandated to implement a new program f or the periodic review of pesticides, i

. e ., registration review. 1

As part of the implementation of the new Registration Review program pursuant to Section 3(g) of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), th e Agency is beginning its evaluation of the furanones to determine whether they continue to meet the FIFRA standard for registration. This problem formulation for the ecological risk and endangered species 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 statut ory 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 new Registration Review program, the Agency periodically reevaluates pes ticides to make sure that as change occurs, products in the marketplace can be used safely.

1 http://www.epa.gov/oppsrrd1/registration_review/- 5 of 31

- assessment chapter in support of the registration review will be posted in the initial docket, which will open the public phase of the review process.

2.2. Previous Assessments

2.2.1. Ecological Risk Assessments

The furanones were first registered as a pesticide in the United States in 1983 for use as a cat repellent. The Agency conducted an ecological risk assessment as part of the Reregistration Eligibility Decision (RED), which was finalized in 1996. Because all of the submitted ecotoxicity tests were conducted using a formulated product, data requirements were not satisfied. However, it was determined that the data for the formulated product was useful and would be relevant for other products with similar co ncentrations of the active ingredient. Data gaps were identified for the aquatic mosquito larvicide use; however, this use is no longer registered. Because no fate data had been submitted, aquatic exposure and, consequently, risk could not be quantified. Due to the low toxicity of the formulated products to birds and mammals, risk was not anticipated for terrestrial organisms, but risk could not be precluded for aquatic organisms.

2.2.2. Drinking Water Exposure Assessments

No prior drinking water exposure assessments have been conducted for the furanones because human exposure due to the registered uses as pesticides is expected to be low and there are no

food tolerances associated with either of the furanones.

3. Stressor Source and Distributi on

The furanones, along with the active ingredient d

- limonene, are formulated into the product Bugchaser, which is an impregnated wristband worn by people to repel insects. However, t he Bugchaser wristband product will not be evaluated in the ecological r isk or endangered species assessments because environmental exposure is expected to be negligible. Doo

- Not dog and cat repellent is a formulated product, which also contains both the furanones and d

- limonene. It is a granule, which is sprinkled onto reside ntial areas such as lawns, flowerbeds, driveways and sidewalks to discourage defecation.

3.1. M ode of Action

The furanones, as well as d

- limonene, are botanicals; however, the mode of action is not known

. Because they are also used as a fragrance in cos metics, the odors of the compounds are presumably undesirable to the target pests. As such, the furanones are presumed to be volatile. Although d

- limonene is classified by the United States Food and Drug Administration to be “Generally Recognized as Safe” as a food additive, the furanones have not received this

classification.- 6 of 31

- 3.2. Overview of Pesticide Use and Usage

Table 3.1 summarizes the formulated products that are currently registered in the United States. There are no new pending uses for the furanones at this time. Table 3.2 presents the uses and corresponding application rates (single and maximum), application interval, and methods of application that will be considered in the registration review assessment.

Because there were no limitations made on the amount that could be applied in a given area in a year, EFED conservatively extrapolated the label rates (per 100 squ are feet) to determine the amount active ingredient applied per acre (435.6 lb product/acre; 0.1045 lb diyhdro

- 5

- pentyl

2(3H)

- furanone & 0.2134 lb dihydro

- 5

- heptyl

- 2(3H)

- furanone). In addition, EFED conservatively assumed that this amount would be applied once per week for 52 weeks. Although it is unlikely that 435.6 lb product would be applied on one acre since the product is sold in 2.5 lb bags, there were no label restrictions to prevent this conservative estimation of application rate. If the registran t revises the label prior to initiation of the risk assessment, EFED will certainly take the restrictions into consideration and revise the application rate if needed.

Table 3.1. Summary of Furanones Products Registered in the United States

Product Name EPA Reg.

No. Percent Active Ingredient Formulation

Bugchaser Insect Repellent Wristband Strip 66617

- 1 dihydro

- 5

- pentyl

- 2(3H)

- furanone: 0.024% dihydro

- 5

- heptyl

- 2(3H)

- furanone: 0.049%

d

- limonene: 4.015% Impregnated

Wristband

Doo

- Not Dog and Cat Repellent 45987

- 1 dihydro

- 5

- pentyl

- 2(3H)

- furanone: 0.024% dihydro

- 5

- heptyl

- 2(3H)

- furanone: 0.049%

d

- limonene: 4.015% Granule

Table 3.2. Maximum Labeled Application Rates for Doo

- Not Dog and Cat Repellent

Use Formulation Type Application

Method Maximum Single Application Rate (lb a.i./A)* Maximum

Number of Applications

per Year (#) Maximum

Seasonal Application

Rate (lb a.i./A) Application

Interval (days)**

Residential Areas

– lawns, flowerbeds, driveways,

sidewalks Granule Sprinkle dihydro

- 5

- pentyl

2(3H)

- furanone:

0.1045 dihydro

- 5

- heptyl

2(3H)

- furanone:

0.2134 NS (52) NS NS (7)

NS

– Not specified. The number in parentheses is EPA’s conservative assumption. *Label states that 1 lb product per 100 square feet should be used for cats and 1 lb product per 100 square feet should be us ed for dogs for heavy infestations (1 lb product per 800 square feet for light infestations for dogs). These rates have been extrap olated to determine the application rate in terms of lb a.i./acre when considering the percent active ingredient. However, these extrap olated rates are likely an overestimation because they are based on 435.6 lb product applied per acre, which is unlikely because the product is sold in 2.5 lb bags. **Because the number of applications and application interval are not precisely specified (interval specified on label as aft er rains and at least once per week until problem behavior stops and to resume treatme nt if behavior recurs), 52 applications per year are assumed. Again, this is likely an overestimation considering the size of the bag.- 7 of 31

- There is no national pesticide usage data available for the furanones, and there is no Screening Level Usage Analysis (SLUA) due to the lack of agricultural usage. Additionally, no usage data was available in the California Department of Pesticide Regulation Pesticide Use Reports for

Doo

- Not in 2009.

3.3. Environmental Fate and Transport

No fate data have been submitte d for the furanones. However, open literature data has been previously explored to determine physicochemical properties of lactones (the furanones belong to this chemical class) and their possible effect on environmental behavior

.

This previous search sh owed that the furanones ar e classified as lactones. Lactones are cyclic

esters

, which can be synthesized by acidification of alpha

- hydroxy acids (Morrison and Boyd, 1973). Detoxification mechanisms of lactones can be accomplished through base

- catalyzed

h ydrolysis or microbial

- mediated degradation of reactive groups (Anderson et al ., 1991). De

esterification may be catalyzed by metal ions, enzymes, and nucleophilic attack ( e.g. , OH

- ) (March, 1968 ). A new open literature search conducted on June 27, 2011 did not locate additional environmental fate data on the furanones. In summary, the Agency currently has no useable quantitative data on the fate and transport properties of the furanones.

For the purposes of the proposed Registration Review risk assess ment, the absence of environmental fate data will be addressed through the consultation of available structure

- based predictors of environmental fate, a search for fate parameters associated with any chemical analogs, or assumption of stability for the var ious biotic and abiotic processes commonly considered for aquatic and terrestrial exposure modeling. At this point in time, the extent to which any or all of these approaches meets minimal confidence needs cannot be determined.

4. Receptors

Consistent with the proces s described in the Overview Document (U.S. EPA, 2004), the risk assessment for the furanones will rely on a surrogate species approach. T oxicological data generated from surrogate test species, which are intended to be representative of broad taxonomic groups, are used to extrapolate the potential effects on a variety of species (receptors) included under these taxonomic g roupings.

A cute and chronic toxicity data from studies submitted by pesticide registrants along with the available open literature are used to evaluate the potential direct and indirect effects of the

furanones to aquatic and terrestrial receptors. This includes toxicity on the technical grade active ingredient, degradates, and

, when available, form ulated products ( e.g. , “Six

- Pack” studies). The open literature studies are identified through EPA’s ECOTOXicology (ECOTOX) database

, which employs a literature search engine for locating chemical toxicity data for aquatic life, terrestrial plants, and wi ldlife. The evaluation of both sources of data may also provide insight

into the direct and indirect effects of the furanones on biotic communities from loss of species that are sensitive to the chemical and from changes in structure and functional charac teristics of

the affected communities. A search of the open literature data on the public version of- 8 of 31

- ECOTOX 2 on June 23, 2011 did not yield any data. A more complete review of the ECOTOX database may be conducted for evaluat ion for possible quantitative a nd/or qualitative inclusion in

this risk assessment.

A summary of the submitted data representing non

- target organisms exposed to the furanones in aquatic and terrestrial habitats is provided in Sections 4.1 and 4.2 , respectively. The incident

database review for the furanones and a description of ecosystems potentially at risk are provided

in Sections 4.3 and 4.4 , respectively

.

4.1. Effects to Aquatic Organisms

A summary of aquatic toxicity data for the furanones from registrant

- submitted studies is provided in Table 4.1

. All of the studies were conducted using the formulated product NO

- GO Dog Repellent (4.015% d

- limonene; 0.024% dihydro

- 5

- pentyl

- 2(3H)

- furanone; 0.049% dihydro

5

- heptyl

- 2(3H)

- furanone). All three of the aquatic studies were revisited during the problem formulation phase to recalculate toxicity values (DP 391731; September 15, 2011). They retain their supplemental classification because they were conducted with a formulated product that

contains an other active ingredient, d

- limonene. It is important to note that the formulated product did not stay in solution throughout the studies, as evidenced by the observed precipitate, and this lends to the inherent uncertainty of the ability of the formulated product to predict the toxicity of

the tec hnical grade active ingredient. However, that fact that the formulation tested was a clay granule (likely source of the observed precipitate) and that structure based models for estimating organic chemical water so lubility suggest furanone solubilities in excess of 1 g/L, the data still provide a reasonable though somewhat uncertain estimation of toxicity.

EFED consulted the database for d

- limonene technical grade active ingredient to determine if

this mixture cons tituent adequately accounts for observed toxicity of the above formulated product. EFED concludes that d

- limonene alone does not account for observed toxicity in the available fish and aquatic invertebrate studies. Therefore, it is not possible to confiden tly determine if the effects observed were based solely on the furanones, and it is not possible to rule out effects that may have been attenuated by antagonism or enhanced by synergism. However, in the absence of furanones toxicity data for technical grad e active ingredient, the Registration Review risk assessment will conservatively (as long as antagonism is a rare event) assume the

furanones are the sole contributor for observed acute toxicity for freshwater fish and invertebrate endpoints generated with formulated product. This is believed to be conservative as it is empirically known that the d

- limonene constituent does exert some toxic contribution to the

mixture.

Table 4.1

. Summary of the Endpoints from S ubmitted A quatic T oxicity S tudies for the Fur anones
Study Type Species Toxicity Value Toxicity Classification MRID & Status

Acute

– Freshwater Fish Rainbow trout ( Oncorhynchus mykiss ) 96

- hr LC 50 : 737.11 mg product /L NOAEC: 600 mg product/L Not applicable due to

use of formulation 00109343 Supplemental

2 http://cfpub.epa.gov/ecotox/- 9 of 31

- Table 4.1

. Summary of the Endpoints from S ubmitted A quatic T oxicity S tudies for the Fur anones
Study Type Species Toxicity Value Toxicity Classification MRID & Status

Acute

– Freshwater Fish Fathead minnow ( Pimephales promelas ) 96

- hr LC 50 : 966.49 mg product/L NOAEC: 600 mg product/L Not applicable due to

use of formulation 00109344 Supplemental

Acute

– Freshwater

Invertebrate Water flea ( Daphnia magna ) 48

- hr LC 50 : 17.12 mg product/L NOAEC: 10 mg product/L Not applicable due to

use of formulation 00109345 Supplemental

There are no estuarine/marine effects data for fish or invertebrates. Exposure to these organisms cannot be precluded due to the use patt erns. For the purposes of the proposed Registration Review risk assessment, the absence of acute effects data for estuarine/marine fish and invertebrates will be addressed through the consultation of available structure

- based predictors of aquatic organism toxicity, a search for effect endpoints associated with any chemical analogs, or an assumption of a conservative generalized adjustment factor that relates the available freshwater endpoints to estuarine/marine endpoints. At this point in time, the extent to which any or all of these approaches meets minimal confidence needs cannot be determined.

There are no chronic data available for any fish or invertebrate regardless of habitat type. Given expected assumptions of stability of the compound, in the abse nce of data to the contrary, it is reasonable at this time to assume that the compound will be present in the environment for extended periods of time. This suggests the need for chronic effects endpoints for aquatic organisms. For the purposes of the prop osed Registration Review risk assessment, the absence of data on chronic effects to aquatic organism will be addressed through the consultation of

available structure

- based predictors of aquatic organism toxicity, a search for effect endpoints

associated w ith any chemical analogs, or an assumption of a conservative generalized adjustment factor that relates the available acute endpoints to chronic endpoints. At this point in time, the extent to which any or all of these approaches meets minimal confidence n eeds cannot be determined. In addition, should fate property extrapolation efforts discussed above indicate that the furanones are more reasonably assumed to be highly instable, the risk assessment may reevaluate this chronic effects extrapolation approach

.

There are no aquatic plant toxicity data for the furanones. For the purposes of the proposed Registration Review risk assessment, the absence of data on aquatic plant effects will be addressed through the consultation of available structure

- based predictor s of aquatic plant toxicity, a search for effect endpoints associated with any chemical analogs, or an assumption of a conservative generalized toxicity value from all available toxicity data. At this point in time, the extent to which any or all of these approaches meets minimal confidence needs cannot be

determined.

4.2. Effects to Terrestrial Organisms

Table 4.2 summarizes the terrestrial toxicity endpoints for the furanones based on an evaluation

of submitted studies. All of the studies were conduc ted using the formulated product NO

- GO Dog Repellent (4.015% d

- limonene; 0.024% dihydro

- 5

- pentyl

- 2(3H)

- furanone; 0.049% dihydro

5

- heptyl

- 2(3H)

- furanone). All three of the avian studies were revisited during the problem formulation phase and reclassified as supplemental because they were conducted with a- 10 of 31

- formulated product that contains another active ingredient, d

- limonene (DP 391731; September 15, 2011).

The indeterminate nature of the endpoints for available formulated product for birds precludes an

eva luation against d

- limonene technical grade active ingredient as was done for aquatic organisms. Therefore, it is not possible to confidently determine if the effects observed were based solely on the furanones, and it is not possible to rule out effects precluded by antago nism.

Given that d

- limonene is not demonstrated to be toxic at the limit dose tested (5,600 mg/kg

- diet), the Registration Review risk assessment will conservatively assume the furanones are the sole contributor for observed acute toxicity for avian endpoi nts generated with formulated product.

The submitted mammalian studies were conducted using the formulated product rather than the TGAI. However, EFED is aware that there may be useful open literature regarding the toxicity of

the furanones to mammals f or both acute oral and reproductive toxic effects. EFED defers to HED for review of this data and selection of endpoints.

Table 4.2

. Summary of the Endpoints from S ubmitted Terrestrial T oxicity S tudies for the

Furanones
Study Type Species Toxicity Value Toxicity Classification MRID & Status

Acute

– Avian

Oral Bobwhite q uail (Colinus virginianus ) LD 50 : >2000 mg product/kg

bw/day Not applicable due to

use of formulation 00109340 Supplemental

Acute

– Avian Dietary Mallard duck ( Anas platyrynchos ) LC 50 : > 5,000 mg product/kg

- diet Not applicable due to

use of formulation 00103341 Supplemental

Acute

– Avian Dietary Bobwhite quail ( Colinus virginianus ) LC 50 : >5,000 mg product/kg

- diet Not applicable due to

use of formulation 00109342 Supplemental

Acute

– Mammalian Oral Rat LD 50 : >5,000 mg product/kg Category IV 1996 RED

Acute

– Mammalian

Inhalation Rat LC50: >5 mg product/L

, using particle size of 297

microns or less Category IV 1996 RED

There are no chronic endpoints for birds or mammals identified at the time of drafting this problem formulation. Environmental instability is assumed for this chemical at this time. For the purposes of the proposed Registration Review risk assessment, the absence of effects data for chronic avian and mammalian organ isms will be addressed through the consultation of available

structure

- based predictors of avian and mammalian toxicity (if any), a search for effect endpoints associated with any chemical analogs, or an assumption of a conservative generalized adjustment factor that relates the available acute endpoints to chronic endpoints. At this point in time, the extent to which any or all of these approaches meets minimal confidence needs cannot be determined. In addition, should fate property extrapolation efforts discussed above indicate that the furanones are more reasonably assumed to be highly instable, the risk assessment may reevaluate this chronic effects extrapolation approach.

There are neither terrestrial plant nor terrestrial invertebrate toxicity data for the furanones. For the purposes of the proposed Registration Review risk assessment, the absence of effects data for terrestrial plant and invertebrate will be addressed th rough the consultation of available

structure

- based predictors of toxicity (if any), a search for effect endpoints associated with any chemical analogs, or an assumption of a conservative generalized toxicity value from all- 11 of 31

- available pesticide data. At thi s point in time, the extent to which any or all of these approaches

meets minimal confidence needs cannot be determined.

4.3. Incident Databases Review

Preliminary reviews of the Ecological Incident Information System (EIIS, version 2.1 ) and the

Avian Incident Monitoring System (AIMS) 3 were conducted on June 23, 2011 for the furanones,

as well as d

- limonene. There were no avian incidents reported in the AIMS database. There were no incidents reported in the EIIS database.

In addition to the incidents recorded in EIIS and AIMS, additional incidents can be reported to the Agency in an aggregated format. Pesticide registrants report certain types of incidents to the Agency as aggregate counts of incidents occurring per product per quarter. Eco logical incidents reported in aggregate reports include those categorized as ‘minor fish and wildlife’ (W

- B), ‘minor plant’ (P

- B), and ‘other non

- target’ (ONT) incidents. ‘Other non

- target’ incidents include reports of adverse effects to insects and other terrestrial invertebrates. One minor aggregate incident report involving plants has been submitted to the Agency for the furanones; however, the product used was Home Defense Indoor Insect Killer, which is not currently registered for

the furanones.

Due to limitations with data in the EIIS, a lack of reported incidents in the database cannot be used as evidence that additional incidents have not occurred. Incident reports for non

- target plants and animals typically provide information on mortality event s only. Reports for other adverse effects, such as reduced growth or impaired reproduction, are rarely received. EPA’s changes in the registrant reporting requirements of incidents may also account for the reduced number of reported incidents. Registran ts are now only required to submit detailed information on ‘major’ incidents. Minor incidents are generally reported aggregately and are not included in EIIS. In addition, there have been changes in state monitoring efforts due to lack of resources.

4. 4. Ecosystems Potentially at Risk

The ecosystems at risk are often extensive in scope; therefore, it may not be possible to identify specific ecosystems during the development of a nation

- wide ecological risk assessment. However, in general terms, terre strial ecosystems potentially at risk could include the treated area and immediately adjacent areas that may receive runoff. Areas adjacent to the treated area could include cultivated fields, fencerows and hedgerows, meadows, fallow fields or grasslands, woodlands, riparian habitats and other uncultivated areas.

Aquatic ecosystems potentially at risk include water bodies adjacent to or downstream from the treated area and could include impounded bodies such as ponds, lakes and reservoirs, or flowing

wa terways such as streams or rivers. For uses in coastal areas, aquatic habitat also includes marine ecosystems, including estuaries.

3 http://www.abcbirds.org/abcprograms/policy/pesticides/aims/aims/index.cfm- 12 of 31

- 5. Assessment Endpoints

Assessment endpoints represent the actual environmental value that is to be protected, defined by an ecological entity (species, community, or other entity) and its attribute or characteristics (U.S. EPA, 1998). For the furanones, the ecological entities may include the following: birds, mammals, terrestrial

- phase amphibians, reptiles, freshwater f ish and invertebrates, aquatic

- phase amphibians, estuarine/marine fish and invertebrates, terrestrial plants, terrestrial invertebrates, and aquatic plants. The attributes for each of these entities include survival, growth, and reproduction.

6. Conceptu al Model

For a pesticide to pose an ecological risk, it must reach ecological receptors in biologically significant concentrations. An exposure pathway is the means by which a pesticide moves in the environment from a source to an ecological receptor. For an ecological pathway to be complete, it must have a source, a release mechanism, an environmental transport medium, a point of exposure for ecological receptors, and a feasible route of exposure.

The conceptual model for the furanones provides a writ ten description and visual representation of the predicted relationships between the furanones, potential routes of exposure, and the predicted effects for the assessment endpoint. A conceptual model consists of two major components: risk hypothesis and a conceptual diagram (U.S. EPA, 1998).

6.1. Risk Hypothesis

A risk hypothesis describes the predicted relationship among the stressor, exposure, and assessment endpoint response along with the rationale for their selection. For the furanones, the

followi ng ecological risk hypothesis is being employed for this ecological risk assessment:

Based on the application methods , the assumed fate and transport, and the assumed sensitivity of non

- target aquatic and terrestrial species, the furanones have the potential to reduce survival, reproduction, and/or growth in non

- target terrestrial and aquatic organism s when used in accordance with the current labels

. These non

- target organisms include Federally

- listed threatened and endangered species as well a s non

- listed species.

6.2. Conceptual Diagram

Runoff and direct consumption of the granules are the potential transport mechanisms of the

furanones to aquatic and terrestrial habitats where non

- target organisms may be exposed. These transport mechani sms ( i .e ., sources) are depicted in the conceptual models below ( Figures 6.1

, 6.2 , and 6.3 ) along with the receptors of concern and the potential attribute changes in the receptors due to exposure to the furanones.- 13 of 31

- Generally, the Screening Imbibition Pro gram model (SIP v.1.0) 4 is used to determine whether dew and puddles, utilized as drinking water, on the field is a significant exposure route for birds and mammals ( Figure 6.3 ). However, the model was not used for the furanones because chronic

avian and m ammalian toxicity data was not submitted. Therefore, drinking water is conservatively assumed to be a significant route of exposure to terrestrial animals given the use

pattern.

Figure 6.1. Conceptual Model for Furanones Exposure and Effects to Aquatic Organisms. Dotted Lines Indicate Exposure Pathways that Have a Low Likelihood of Contributing to Ecological Risk.

4 http://www.epa.gov/oppefed1/models/te rrestrial/sip/sip_user_guide.html ** Route of exposure includes only ingestion of fish and aquatic 

### Stressor

Source

Receptors

Attribute Change Furanones applied to use site

Pesticide drift

Aquatic animals

Invertebrates

Vertebrates
**Piscivorous mammals

and birds

Individual organisms

Reduced survival Reduced growth Reduced reproduction Food chain Reduction in algae and

vascular plants Reduction in prey
Modification of PCEs

related to prey availability Habitat integrity Reduction in primary productivity

Reduced cover Community change
Modification of PCEs related to

habitat Surface water/
Sediment Runoff

Aquatic Animals

Invertebrates

Vertebrates 

### Exposure

Media

Uptake/gills or integument

Ingestion Ingestion Atmospheric transport

Wet/dry deposition Soil Leaching to
Groundwater

Uptake/gills or integument

Aquatic Plants

Non

- vascular
Vascular Uptake/cell, roots, leaves Riparian plants

terrestrial

exposure pathways see

Figure 6.2- 14 of 31

- Figure 6.2. Conceptual Model for Furanones Exposure and Effects to Terrestrial Organisms. Dotted Lines Indicate Exposure Pathways that Have a Low Likelihood of Contributing to Ecological Risk.

Stressor

Source

Attribute Change Furanones applied to use site

Direct application Pesticide
drift

Terrestrial

vertebrates* Terrestrial

Inverts*

Individual organisms

Reduced survival Reduced growth Reduced reproduction Food chain Reduction in prey and food
Modification of PCEs

related to prey availability Habitat integrity Reduction in primary productivity
Reduced cover Community change
Modification of PCEs related

to habitat Terrestrial plants grasses/forbs, fruit, seeds (trees, shrubs ) Runoff

Terrestrial

vertebrates* Exposure
Media & Receptors Soil

Ingestion Ingestion Dermal uptake/Ingestion Atmospheric transport

Root uptake/contact

Wet/dry deposition

Ingestion Leaching to
Groundwater Irrigation

water

* See Figure 6.3 for drinking water and inhalation exposure pathways for terrestrial vertebrates and ingestion of residues in dew by terrestrial invertebrates.- 15 of 31

- Figure 6.3. Drinking W ater and I nhalation E xposure P athways for T errestrial V ertebrates

and I ngestion of R esidues in D ew by T errestrial I nvertebrates. Dotted Lines Indicate Exposure Pathways that Have a Low Likelihood o f Contributing to Ecological Risk.

7. Analysis Plan

In order to address the risk hypothesis, the potential for adver se effects on the environment will

be estimated. The use, environmental fate, and e cological effects of the furanones will be characterized and integrated to assess the risks . R isk quotients (RQs) will be derived for the

furanones by dividing estimated environmental concentrations (EEC) by the most sensitive endpoint from the relevant, available toxicity data for the furanones

.

This analysis plan will be revisited and may be revised depending upon a full review of the data available in the open literature and the information submitted by the public in response to the opening of the Registration Review docket. Stressor

Source

Attribute Change Furanones applied to use site

Direct application Pesticide drift

Terrestrial

vertebrates Terrestrial

invertebrates

Individual organisms

Reduced survival Reduced growth Reduced reproduction Food chain Reduction in prey and
food
Modification of PCEs

related to prey availability Habitat integrity Reduction in primary productivity
Reduced cover Community change
Modification of PCEs related

to habitat Runoff

Exposure Media Dew (formed on terrestrial plants) Atmospheric transport

Receptors Puddles (formed on treated fields)

Ingestion Inhalation Air- 16 of 31

- 7.1. Stressors of Concern

The Agency does not routinely include, in its risk assessments, an evaluation of mixtures of active ingredients, either those mixtures of multiple active ingredients in product formulations or those in the applicator’s tank. In the case of the product formulations of multiple active ingredients (that is, a registered product containing more than one active ingredient), each active ingredient is subject to an individual risk assessment for regulatory decision regarding the active ingredient on a particular use site. The only two products registered for the furanones also contain the active ingredient d

- limonene. Registration Review for d

- limonene began in 2010.

Because the only effects data that are available are for the formulated product cont aining more than one active ingredient, they will be used qualitatively or quantitatively in accordance with the Agency’s Overview Document and the Services’ Evaluation Memorandum (U.S. EPA, 2004; USFWS/NMFS, 2004).

7.2. Measures of Exposure

In orde r to estimate risks of exposure to the furanones in aquatic and terrestrial environments, all exposure modeling and resulting risk conclusions will be based on registered labels including maximum application rates and methods cited in Table 3.2 for the one use that results in environmental exposure. Measures of exposure are based on aquatic and terrestrial models that predict estimated environmental concentrations (EECs) of the furanones. Several models are available to predict aquatic EECs, including FIR ST, GENEEC, Pesticide Root Zone Model coupled with the Exposure Analysis Model System (PRZM/ EXAMS) , and SCI

- GROW. The model used to predict terrestrial EECs on food items , or in the case of a granular application , the

LD 50 /square foot, is T

- REX (version 1. 4.1, October 2008) . The model used to derive EECs relevant to terrestrial and wetland plants is TerrPlant (version 1.2.2, December 2006) . These models are parameterized using relevant reviewed environmental fate data from registrant

submissions and the o pen literature when available; model input values will be consistent with the most recent version of the input parameter guidance (Version 2.1; EFED 2009). For more detailed descriptions, exposure models and their associated user guides can be located on t he Office of Pesticide Programs Models and Databases website. 5

The use of modeling to provide aquatic EECs depends on the submission of outstanding environmental fate and product chemistry data, which are currently considered data gaps. However, if data are not received, EFED will conservatively assume that the furanones are

stable.

In addition to modeling estimates, available monitoring data will be evaluated. Monitoring data will include those collected/reported by states and other federal department s/agencies. 6

5 http://www.epa.gov/pesticides/science/models_db.htm

6 USGS National Water Quality Assessment (NAQWA; http://wat er.usgs.gov/nawqa)- 17 of 31

- 7.3. Measures of Effect

Ecological effects data are used as measures of dir ect and indirect effects to biological receptors

. Data are obtained from registrant

- submitted studies or from literature studies identified by

ECOTOX. The ECOTOX database provide s more ecological effects data in an attempt to bridge existing data gaps. ECOTOX is a source for locating single chemical toxicity data and potential chemical mixture toxicity data for aquatic life, terrestrial plants, and wildlife. ECO TOX was

cre ated and is maintained by EPA, Office of Research and Development, and the National Health and Environmental Effects Research Laboratory's Mid

- Continent Ecology Division.

Information on the potential effects of the furanones on non

- target animals is also collected from the Ecological Incident Information System (EIIS; U.S. EPA, 2007 c ). The EIIS is a database containing adverse effect (typically mortality) reports on non

- target organisms where such

effects have been associated with the use of pesticides. Incidents reported in the aggregate incident reports and the Avian Incident Monitoring System (AIMS) will also be searched. 7
AIMS is a database administered by the American Bird Conservancy (partially funded by EPA). It contains publicly available data on reported avian incidents involving pesticides.

Where available, sub

- lethal effects observed in both registrant

- submitted and open literature studies will be evaluated qualitatively. Such effects may include behavioral changes ( e.g. , let hargy and changes in coloration). Quantitative assessments of risks, though, are limited to those endpoints that can be directly linked to the Agency’s assessment endpoints of impaired survival, growth and reproduction.

The assessme nt of risk for direct effects to non

- target organisms makes the assumption that toxicity of the furanones to terrestrial

- phase amphibians and reptiles is similar to birds . The same assumption is made for the toxicity to aquatic

- phase amphibians being simi lar to fish.

The acute measures of effect use d for animals in this assessment are the LD 50 , LC 50 and EC 50

. LD stands for "Lethal Dose", and LD 50 is the amount of a material, given all at once, that is estimated to cause the death of 50% of the test orga nisms. LC stands for “Lethal Concentration”

and LC 50 is the concentration of a chemical that is estimated to kill 50% of the test organisms.

EC stands for “Effective Concentration” and the EC 50 is the concentration of a chemical that is estimated to produce a specific effect in 50% of the test organisms. Endpoints for chronic measures of exposure for listed and non

- listed animals are the NOAEL/NOAEC and NOEC.

NOAEL stands for “No Observed

- Adve rse

- Effect

- Level” and refers to the highest tested dose of a substance that has been reported to have no harmful (adverse) effects on test organisms. The NOAEC ( i.e. , “No

- Observed

- Adverse

- Effect

- Concentration”) is the highest test concentration at

which n one of the observed effects were statistically different from the control. The NOEC is

the No

- Observed

- Effects

- Concentration. For non

- listed plants, only acute exposures are assessed ( i.e. , EC 25 for terrestrial plants and EC 50 for aquatic plants ); for li sted plants, either the

NOAEC or EC 05 is used

.

7 http://www.abcbirds.org/abcprograms/policy/pesticides/aims/aims/index.cfm- 18 of 31

- The evaluation of the measures of effects, as described above, and the following description of the integration of exposure and effects depend on the submission of several outstanding

environmental effects studies, which are currently considered data gaps. If acceptable data are not submitted, EFED will conservatively assume that all effects observed in the submitted data

are due to the furanones and that d

- limonene does not contribute to the toxicity of the formulation ( i.e., the acute freshwater LC 50 of 568 mg product/L will be interpreted as 0.28 mg a.i./L for dihydro

- heptyl

- 2(3H)

- furanone and 0.14 mg a.i./L for dihydro

- pentyl

- 2(3H)

- furanone, thus classifying both the furanones as highly toxic to freshwate r fish). Taxa for which data have not been submitted will result in the assumption of risk to listed species.

7.4. Integration of Exposure and Effects

Risk characterization is the integration of exposure and ecological effects characterization to

deter mine the potential ecological risk from the use of the furanones and the likelihood of direct

and indirect effects to non

- target organisms in aquatic and terrestrial habitats. For the

assessment of the risks of the furanones , the risk quotient (RQ) method is used to compare exposure and measured toxicity values. EECs are divided by acute and chronic toxicity values. The resulting RQs are then compared to the Agency’s L evels of Concern (LOC ) (U

. S

. EPA

, 2004). These criteria are used to indicate when use of the furanones , as directed on the label , has the potential to cause adverse direct or indirect effects to non

- target organisms

. In addition, incident data from EIIS, aggregate incident reports, and AIMS will be considered as part of the

risk characterization.

7.5. Deterministic and Probabilistic Assessment Methods

The quantitative assessment of risk will primarily depend on th e deterministic point

- estimate based approach described in the risk assessment. Depending on the risk manager’s need for additional information regarding risk, an effort will be made to further describe risk using probabilistic tools that the Agency has d eveloped. These tools have been reviewed by FIFRA Scientific Advisory Panels and have been deemed as appropriate means of refining assessments where deterministic approaches have identified risks. 8

7.6. Endangered Species Assessment

Consistent with the Agency’s responsibility under the Endangered Species Act (ESA), the Agency will evaluate risks to Federally

- listed threatened and/or endangered (listed) species from registered uses of the furanones. This assessment will be conducted i n accordance with t he

Overview Document (U.S. EPA, 2004) , provisions of the E SA , and the Services’ Endangered Species Consultation Handbook (USFWS/NMFS, 1998).

T he assessment of effects associated with the registration of the furanones is based on an action

area. The actio n area is considered to be the area directly or indirectly affected by the federal action, as indicated by the exceedance of Agency Levels of Concern (LOCs) used to evaluate direct or indirect effects. The Agency’s approach to defining the action area und er the provisions

8 http://www.epa.gov/scipoly/sap/index.htm- 19 of 31

- of the Overview Document (U.S. EPA, 2004) considers the results of the risk assessment process to establish boundaries for that action area with the understanding that exposures below the Agency’s defined LOCs constitute a no

- effect thres hold. F or the purposes of this assessment,

attention will be focused on the footprint of the action ( i.e ., the area where application occurs), plus all areas where offsite transport ( i.e ., runoff.) may result in potential exposure that exceeds the Agency’ s LOCs. Specific measure s of ecological effect that define the action area for listed species include any direct and indirect effect s and /or potential modification of its critical habitat, including reduction in survival, growth, and reproduction as well as the full suite of sub

- lethal

effects available in the effects literature. Therefore, the action area extends to a point where environmental exposures are below any measured lethal or sub

- lethal effect threshold for any biological entity at the whole organism, organ, tissue, and cellular level of organization. In situations where it is not possible to determine the threshold for an observed effect, the action area will be assumed to encompass the entire United States.

7.7. Drinking Water Asses sment

No prior drinking water assessments have been conducted. HED informed EFED that a drinking water assessment would not be required for registration review.

7.8. Preliminary Identification of Data Gaps

Use of the furanones is defined as having terrestrial residential uses. According to the Code of Federal Regulations 40 (CFR40 2007) Part 158 Subpart D (data requirements for pesticides)

environmental fate and non

- target organism effects data are required for the furanones based on

its terrestrial use. Available studies submitted to fulfill environmental fate and ecological effects guideline requirements, as well as outstanding data gaps for the furanones, are defined in

Sections 7.8.1 and 7.8.2

.

7.8.1. Fate Data Gaps

There is no submitted envi ronmental fate data. Data gaps for outdoor residential uses are identified in Table 7.1

. In addition, product chemistry data is required.

If data are not submitted, EFED will proceed as described in Section 3.3

.

Table 7.1. Environmental Fate Data Gaps for Outdoor Residential Uses

Guideline Description Data Gap? Comments

Not applicable Product Chemistry Data Yes These studies are required

for terrestrial residential

uses. Studies should be

conducted with each

furanone as the technical grade active ingredient. 835.2120

161

- 1 Hydrolysis Yes

835.4100

162

- 1 Aerobic Soil M etabolism Yes

835.1230

835.1240

163

- 1 Leaching

A dsorption/ D esorption Yes- 20 of 31

- Table 7.1. Environmental Fate Data Gaps for Outdoor Residential Uses

Guideline Description Data Gap? Comments

835.6100

164

- 1 Terrestrial Field Dissipation Yes

7.8.2. Effects Data Gaps

Although some submissions have bee n made to provide data on the effects of the furanones to aquatic and terrestrial organisms, data gaps still exist and are included in Tables 7.2 to 7.4

, below.

If acceptable data are not submitted, EFED will proceed as described in Section 4

.

STIR Analysis

Because the furanones are presumed to be volatile due to their presumed mode of action, the Screening Tool for Inhalation Risk (STIR v.1.0) 9

9 http://www.epa.gov/oppefed1/models/terrestrial/stir/stir_user_guide.html was used to determine whether an avian inhalation risk should be required. Because product chemist ry data was not submitted, EPISUITE was used to predict vapor pressures for both the furanones. For dihydro

- pentyl

2(3H)

- furanone, the vapor pressure was predicted to be 0.0119 mm Hg. For dihydro

- heptyl

2(3H)

- furanone, the vapor pressure was predicted to b e 0.00409 mm Hg. In the absence of toxicity data conducted with the TGAI, formulation data was converted and input into STIR. The

acute oral avian LD 50 of >2000 mg product/kg

- bw/day was converted to 0.98 mg a.i./kg

- bw, the

acute oral rat LD 50 of >5000 mg p roduct/kg was converted to 2.45 mg a.i./kg, and the

mammalian inhalation LC 50 of >5 mg product/L was converted to 0.00245 mg a.i./L. For dihydro

- pentyl

- 2(3H)

- furanone, 0.1045 lb a.i./acre was the selected application weight, and the molecular weight was 15 6.23 g/mole. For dihydro

- heptyl

- 2(3H)

- furanone, 0.2134 lb a.i./acre was the selected application weight, and the molecular weight was 184.28 g/mole. Although it is a conservative screen due to the use of predicted product chemistry data and extrapolated to xicity values, STIR indicated that inhalation risk may be possible and that refinements should be pursued. Therefore, an avian inhalation study is considered a data gap. See Appendix C for STIR inputs and outputs.- 21 of 31

- Table 7.2. Available Ecological Effects Data for Terrestrial Animals Exposed to the Furanones and Remaining Data Gaps for Outdoor Residential Uses

Guideline Description MRID/

Accession Classification Data Gap? Comments

850.2100 Avian oral toxicity 00109340 Supplemental Yes 1 1 The submitted studies were conducted with a formulated product that contained an additional active ingredient ( d

- limonene). Studies are required for each furanone using the technical grade active ingredient for either an upland game or waterfowl species and a passerine species.

2 The submitted studies were conducted with a formulated product that contained an additional active ingredient ( d

- limonene).

Stu dies are required for each furanone using the technical grade active ingredient for both an upland game and waterfowl species.

3 Studies were not submitted. Studies are required for each furanone using the technical grade active ingredient for both

for an upland game and waterfowl species.

4 Study was not submitted. Studies are required for each furanone using the technical grade active ingredient.

5 The submitted studies were conducted with a formulated product that contained an additional active ingredie nt ( d

- limonene). Studies are required for each furanone using the technical grade active ingredient.

6 The Screening Tool for Inhalation Risk (STIR v.1.0) suggested that refinements be pursued for addressing avian inhalation risk. Therefore, an avian inha lation study is considered a data gap. However, the model is based on conservatively predicted vapor pressures and extrapolated toxicity data; therefore, EFED would prefer to use a tiered approach in this situation

– acute oral and dietary avian studies co nducted with the

TGAI should be submitted first. When this data is input into STIR and if a need for refinement is still indicated, then an avian inhalation study should be submitted. 850.2200 Avian dietary toxicity 00103341 Supplemental

Yes 2

00109342 Supplemental

850.2300 Avian reproduction Not

submitted Not applicable

Yes 3

Not

submitted Not applicable

850.3020 Honeybee acute contact toxicity Not

submitted Not applicable Yes 4

870.1100 Mammalian

acute oral toxicity 1996 RED Not available Yes 5

870.3800 Mammalian 2

- generation reproduction Not

submitted Not applicable Yes 4

870.1300 Mammalian

inhalation

toxicity 1996 RED Not available Yes 5

Other Avian inhalation toxicity Not

submitted Not applicable Yes 6- 22 of 31

- Table 7.3. Available Ecological Effects Data for Aquatic Animals Exposed to the Furanones and Remaining Data Gaps

Guideline Description MRID/

Accession Classification Data Gap? C omments

850.1075 Freshwater fish

– Acute toxicity 00109343 Supplemental Yes 1 1 The submitted studies were conducted using a formulated product that contained another active ingredient ( d

- limonene). Studies are required for each furanone using the technical grade active ingredient.

2 Studies were not submitted. Studies are required for each

furanon e using the technical grade active ingredient.

3 In the absence of fate data, it is not possible to determine if sediment toxicity studies are required. These

studies remain reserved.

All other studies not currently classified as data gaps remain

reserved. 00109344 Supplemental

850.1075 Estuarine/marine fish

– Acute toxicity N ot
submitted Not applicable Yes 2

850.1010 Freshwater

invertebrates

– Acute toxicity 00109345 Supplemental Yes 1

850.1025

850.1035 Estuarine/marine

invertebrates

– Acute toxicity Not

submitted Not applicable

Yes 2
Not

submitted Not applicable

850.1400 Freshwater fish

– early life stage test Not

submitted Not applicable Yes 2

850.1400 Estuarine/marine fish

– early life stage test Not

submitted Not applicable No

850.1300 Freshwater

invertebrate

– life cycle test Not

submitted Not applicable Yes 2

850.1350 Estuarine/marine

invertebrates

– life cycle test Not

submitted Not applicable No

850.1735 Freshwater

invertebrate

– Acute

whole sediment Not

submitted Not applicable No 3

850.1740 Estuarine/marine

invertebrate

– Acute

whole sediment Not

submitted Not applicable No 3

Other Freshwater and

estuarine/marine

invertebrate

– Chronic

whole sediment Not

submitted Not applicable No 3

No plant studies were submitted. Data gaps are identified in Table 7.4

.- 23 of 31

- Table 7.4. Terrestrial and Aquatic Plant Data Gaps for the Furanones

Guideline Description Data Gap? C omments

850.4 100 Terrestrial Plant toxicity: Tier I seedling emergence Yes 1 1 Because the formulated product is a granule, only seedling emergence toxicity testing is required using the technical grade active ingredient (not TEP) for

each furanone.

2 Acceptable data are required for non

- vascular

and vascular plants using

the techni cal grade active ingredient for each

furanone

. 850.4 150 Terrestrial Plant toxicity: Tier I vegetative vigor No 1

850. 5 400 Aquatic Plant Growth: algae Yes 2

850.4 400 Aquatic Plant Growth: vascular plants Yes 2

8. References

Food and Agriculture Organization of the United Nations (FAO). 2000. Appendix 2. Parameters of pesticides that influence processes in the soil. In FAO Information Division Editorial Group (Ed.), Pesticide Disposal Series 8. Assessing Soil Cont amination: A Reference Manual. Rome: Food & Agriculture Organiza tion of

the United Nations. http://www.fao.org/DOCREP/003/X2570E/X2570E06.htm

Fletcher, J.S., J.E. Nellessen, and T.G. Pfleeg er. 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 Resid ues 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.

March, J. 1968. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure . McGraw

- Hill Company, New

York.

Morrison, R. and R. Boyd. 1973. Organic Chemistry . 3 rd edition. Allyn and Bacon, Inc. Boston.

U.S. Department of Agriculture (USDA). 2007. National Agricultural Statistics Service. United States Department of Agriculture. http://www.nass.usda.gov/

USEPA. 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

USEPA. 2002. Guidance for Selecting Input Parameters in Modeling the Environmental Fate and Transport of Pesticides, Version II. US Environmental Protection Agency, Washington DC. Online at: http://www.epa.gov/oppefed1/models water/input_guidance2_28_02.htm

.

USEPA. 2004. Overview of the Ecological Risk Assessment Process in the Office of Pesticide Programs. U.S.

Environmental Protection A gency, Office of Prevention, Pesticides and Toxic Substances, Office of Pesticide Programs, Washington DC. January 23, 2004.- 24 of 31

- USEPA. 2006 a . Standardized Soil Mobility Classification Guidance. U.S. Environmental Protection Agency, Office of Prevention, Pesticides and Toxic Substances, Office of Pesticide Programs, Environmental Fate and Effects Division, Memorandum. April 21, 2006.

USEPA. 2007 c . Ecological Incident Information System. http://www.epa.gov/espp/consultation/ecorisk

overview.pdf

USEPA. 2010 d . 40 CFR Part 158. Data Requirements for Pesticides. July 1, 2010.

USEPA. 2007 e . ECOTOXicology Database. Office of Research and Development National Health and

Environmen tal Effects Research Laboratory’s (NHEERL’s) Mid

- Continent Ecology Division (MED). http://cfpub.epa.gov/ecotox/

.

U.S. Fish and Wildlife Service (USFWS) and National Marine Fisheries Service (NMFS). 1998. Endangered Species Consultation Handbook: Procedures for Conducting Consultation and Conference Activities Under Section 7 of the Endangered Species Act. Final Draft. March 1998.

Williams, G. M. and J. H. Weisburger. 1991. Chemical Carcinogenesis in Casarett and Doul's Toxicology: The Basic Science of Poisons edited by Mary Amdur, Ph.D., John Doull, Ph.D., M.D., and Curtis D. Klaassen, Ph.D.

4 th edition. Pergamon Press, New York.

Worthing, C. R and R. J. Hance, editors. 1991. The Pesticide Manual: A World Compendium (9th edition). British Crop Protection Council , Surrey, UK. June, 1991.- 25 of 31

- Appendix A . Incidents

A search for ecological incidents related to use of the furanones , conducted on June 23, 2011

, yielded no incidents

.

Uncertainties Related to the Use of Incident Information from the Ecological Incident Information System

Incident data are used in risk assessments to provide evidence that the risk predictions from t he screening level assessment are supported by actual effects in the field. Incident reports submitted to EPA since approximately 1994 have been tracked by assignment of incident numbers in an Incident Data System (IDS), microfiched, and then entered to a second database, the Ecological Incident Information System (EIIS). Additionally, there is an on

- going effort to enter information to EIIS on incident reports received prior to establishment of current databases. Incident reports a re not received in a consistent format ( e.g ., states and various labs usually have their own formats), may involve multiple incidents involving multiple chemicals in one report, and may report on only part of a given incident investigation ( e.g ., residues)

.

Incidents entered into EIIS are categorized into one of several certainty levels regarding the likelihood that a particular pesticide is associated with the incident: highly probable, probable, possible, unlikely, or unrelated. In brief, “highly prob able” incidents usually require carcass residues and/or clear circumstances regarding the exposure. “Probable” incidents include those where residues were not available and/or circumstances were less clear than for “highly probable.” “Possible” incidents include those where multiple chemicals may have been involved and it is not clear what the contribution was of a given chemical. The “unlikely” category is used, for example, where a given chemical is practically nontoxic to the category of organism

kille d and/or the chemical was tested for but not detected in samples. “Unrelated” incidents are those that have been confirmed to be not pesticide

- related.

Incidents entered into the EIIS are also categorized as to use/misuse. Unless specifically confirmed by a state or federal agency to be misuse, or there was very clear misuse such as intentional baiting to kill wildlife, incidents are not typically consid ered misuse.

The number of documented kills in EIIS is believed to be a small fraction of total mortality caused by pesticides. Mortality incidents must be seen, reported, investigated, and have investigation reports submitted to EPA to have the potent ial for entry into the database. Incidents often are not seen, due to scavenger removal of carcasses, decay in the field, or simply because carcasses may be hard to see on many sites and/or few people are systematically looking. Poisoned animals may also move off

- site to less conspicuous areas before dying. Incidents may not get reported to appropriate authorities capable of investigating the incident for a variety of reasons including the finder may not know of the importance of reporting incidents,

may not know who to call, may not feel they have the time or desire to call, or may hesitate to call because of their own involvement in the kill. Incidents reported may not get investigated if resources are limited or may not get investigated thoroughly, wi th residue analyses, for example. Also, if kills are not reported and investigated promptly, there will be little chance of- 26 of 31

- documenting the cause, since tissues and residues may deteriorate quickly. Reports of investigated incidents often do not get subm itted to EPA, since reporting by states is voluntary.

Furthermore, the database relies heavily on registrant

- submitted incident reports, and registrants are currently only required to submit detailed information on ‘major’ ecological incidents, while

‘m inor’ incidents are reported aggregately. Based on the 40 CFR (§159.184 Toxic or adverse effect incident reports), an ecological incident is considered ‘major’ if any of the following criteria are met:

Fish or wildlife :

(A) Involves any incident caused b y a pesticide currently in Formal Review for ecological concerns.

(B) Fish: Affected 1,000 or more individuals of a schooling species or 50 or more

individuals of a non

- schooling species.

(C) Birds: Affected 200 or more individuals of a flocking species, or 50 or more individuals of a songbird species, or 5 or more individuals of a predatory species.

(D) Mammals, reptiles, amphibians: Affected 50 or more individuals of a relatively common or herding species or 5 or more individuals of a rare or solitary species.

(E) Involves effects to, or illegal pesticide treatment (misuse) of a substantial tract of habitat (greater than or equal to 10 acres, terrestrial or aquatic).

Plants :

(A) The effect is alleged to have occurred on more than 45 percent of the ac reage exposed to the pesticide.

All other ecological incidents are considered ‘minor’ and only need to be aggregately reported. ‘Minor’ incidents reported by the registrants are not included in the EIIS database. Therefore, for example, an incident coul d affect 900 fish, 150 birds, 45 mammals, and 40% of an exposed crop and not be included in the EIIS database [unless is it reported by a non

- registrant ( e.g ., an incident submitted by a state agency

– which are not systematically collected)]. Therefore,

because the number of documented kills in EIIS is believed to be a small fraction of total mortality caused by pesticides, absence of reports does not necessarily provide evidence of an

absence of incidents.- 27 of 31

- Appendix B . The Risk Quotient Method an d Levels of Concern

The Risk Quotient Method is the means used by EFED to integrate the results of exposure and ecotoxicity data. For this method, Risk Quotients (RQs) are calculated by dividing exposure estimates by the acute and chronic ecotoxicity values (i.e., RQ = EXPOSU RE/TOXICITY). These RQs are then compared to OPP's levels of concern (LOCs). These LOCs are criteria used by OPP to indicate potential risk to non

- target organisms and the need to consider regulatory action. EFED has defined LOCs for acute risk, potential restricted use classification, and for endangered species.

The criteria indicate that a pesticide used as directed has the potential to cause adverse effects

on non

- target organisms. LOCs currently address the following risk presumption categories:

(1) a cute

- there is a potential for acute risk; regulatory action may be warranted in addition to restricted use classification;

(2) acute restricted use

- the potential for acute risk is high, but this may be mitigated through restricted use classification;

(3) acute endangered species

- the potential for acute risk to endangered species is high, regulatory action may be warranted; and

(4) chronic risk

- the potential for chronic risk is high, regulatory action may be warranted.

Currently, EFED does no t perform assessments for chronic risk to plants, acute or chronic

risks to non

- target insects, or chronic risk from granular/bait formulations to mammalian or avian species.

The ecotoxicity test values (i.e., measurement endpoints) used in the acute and chronic RQs are derived from required studies. Examples of ecotoxicity values derived from short

- term laboratory studies that assess acute effects are: (1) LC50 (fish and birds), (2) LD50 (birds and mammals), (3) EC50 (aquatic plants and aquatic invertebra tes), and (4) EC25 (terrestrial plants). Examples of toxicity test effect levels derived from the results of long

- term laboratory studies that assess chronic effects are: (1) the Lowest Observed Adverse Effect Concentration (LOAEC) (birds, fish, and aquati c invertebrates), and (2) the No Observed Adverse Effect Concentration (NOAEC) (birds, fish and aquatic invertebrates). The NOAEC is generally used as the ecotoxicity test value in assessing chronic effects. Risk presumptions, along with the corresponding RQs and LOCs are summarized in Table B1.- 28 of 31

- Table B 1. Agency risk quotient (RQ) metrics and levels of concern (LOC) per risk class.

Risk Class Risk Description RQ LOC

Aquatic Animals (fish and invertebrates)

Acute Potential for effects to non

- listed animals from acute

exposures Peak EEC/LC 50 1 0.5

Acute

Restricted Use Potential for effects to animals from acute exposures

Risks may be mitigated through restricted use classification Peak EEC/LC 50 1 0.1

Acute Listed Species Listed species may be potentially affected by acute

exposures Peak EEC/LC 50 1 0.05

Chronic Potential for effects to non

- listed and listed animals from chronic exposures 60

- day EEC/NOEC (fish) 1

21

- day EEC/NOEC (invertebrates)

Terrestrial Animals (mammals and birds)

Acute Potential for effects to non

- listed animals from acute

exposures EEC 2 /LC 50 (Dietary) 0.5

EEC/LD 50 (Dose)

Acute

Restricted Use Potential for effects to animals from acute exposures

Risks may be mitigated through restricted use classification EEC 2 /LC 50 (Dietary) 0.2

EEC/LD 50 (Dose)

Acute Listed Species Listed species may be potentially affected by acute

exposures EEC 2 /LC 50 (Dietary) 0.1

EEC/LD 50 (Dose)

Chronic Potential for effects to non

- listed and listed animals from chronic exposures EEC 2 /NOAEC 1

Plants

Non

- Listed Potential for effects to non

- target, non

- listed plants from

exposures EEC/ EC 25 1

Listed Plant Potential for effects to non

- target, listed plants from

exposures EEC/ NOEC 1

EEC/ EC 05

1 LC 50 or EC 50

. 2 Based on upper bound Kenaga values.- 29 of 31

- Appendix C. STIR Input/Output



## 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 heptyl

Enter Chemical Use dog repellent Is the Application a Spray? (enter y or n) n
If Spray What Type (enter ground or air) ground Enter Chemical Molecular Weight (g/mole) 184.28 Enter Chemical Vapor Pressure (mmHg) 4.09E

- 03 Enter Application Rate (lb a.i./acre) 0.2134

Toxicity Properties

**Bird**

Enter Lowest Bird Oral LD 50 (mg/kg bw) 0.98 Enter Mineau Scaling Factor 1.15 Enter Tested Bird Weight (kg) 0.178

**Mammal**

Enter Lowest Rat Oral LD 50 (mg/kg bw) 2.45

Enter Lowest Rat Inhalation LC 50 (mg/L) 0.00245 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/m 3 ) 4.06E+01

Maximum 1

- hour Vapor Inhalation Dose (mg/kg) 5.10E+00

Adjusted Inhalation LD 50 5.46E

- 03

Ratio of Vapor Dose to Adjusted Inhalation LD 50 9.33E+02 Proceed to Refinements

Maximum Post

- treatment Spray Inhalation Dose (mg/kg) not applicable Ratio of Droplet Inhalation Dose to Adjusted

Inhalation LD 50 not applicable not applicable

Results Mammalian (0.015 kg )- 30 of 31

- Maximum Vapor Concentration in Air at Saturation (mg/m 3 ) 4.06E+01

Maximum 1

- hour Vapor Inhalation Dose (mg/kg) 6.41E+00

Adjusted Inhalation LD 50 1.46E

- 01

Ratio of Vapor Dose to Adjusted Inhalation LD 50 4.39E+01 Proceed to Refinements

Maximum Post

- treatment Spray Inhalation Dose (mg/kg) not applicable Ratio of Droplet Inhalation Dose to Adjusted

Inhalation LD 50 not applicable not applicable



## 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 pentyl

Enter Chemical Use dog repellent Is the Application a Spray? (enter y or n) n If Spray What Type (enter ground or air) ground Enter Chemical Molecular Weight (g/mole) 156.23 Enter Chemical Vapor Pressure (mmHg) 1.19E

- 02 Enter Application Rate (lb a.i./acre) 0.1045

Toxicity Properties

**Bird**

Enter Lowest Bird Oral LD 50 (mg/kg bw) 0.98 Enter Mineau Scaling Factor 1.15 Enter Tested Bird Weight (kg) 0.178

**Mammal**

Enter Lowest Rat Oral LD 50 (mg/kg bw) 2.45

Enter Lowest Rat Inhalation LC 50 (mg/L) 0.00245 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/m 3 ) 1.00E+02- 31 of 31

- Maximum 1

- hour Vapor Inhalation Dose (mg/kg) 1.26E+01

Adjusted Inhalation LD 50 5.46E

- 03

Ratio of Vapor Dose to Adjusted Inhalation LD 50 2.30E+03 Proceed to Refinements

Maximum Post

- treatment Spray Inhalation Dose (mg/kg) not applicable Ratio of Droplet Inhalation Dose to Adjusted

Inhalation LD 50 not applicable not applicable

Results Mammalian (0.015 kg )
Maximum Vapor Concentration in Air at Saturation (mg/m 3 ) 1.00E+02

Maximum 1

- hour Vapor Inhalation Dose (mg/kg) 1.58E+01

Adjusted Inhalation LD 50 1.46E

- 01

Ratio of Vapor Dose to Adjusted Inhalation LD 50 1.08E+02 Proceed to Refinements

Maximum Post

- treatment Spray Inhalation Dose (mg/kg) not applicable Ratio of Droplet Inhalation Dose to Adjusted

Inhalation LD 50 not applicable not applicable