Exposure Modeling Public Meeting

October 28, 2014

Greg Orrick, Cheryl Sutton, Katrina White, James Hetrick, 

R. David Jones, Mohammed Ruhman, Mah Shamim
Overview

 EFED Guidance to assist in evaluating unextracted 

residues (UR)

 i.e., residues that remain associated with the solid matrix

following extraction in submitted e-fate studies

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Extracted Unextracted (Weakly to Strongly Sorbed)

The amounts of extracted and unextracted 

residues depend on the chemical properties, 

soil properties, and the system of extraction.

Liquid Phase Solid Phase (Soil or Sediment)
Guidance Principles

 Foster consistency

 Especially in EFED’s evaluation and handling of the issues

 Clarify the issues

 Including some explanation of what EFED considers to be

an adequate extraction attempt

 Minimize requests for new data

 Using the available lines of evidence and, if necessary,

indicating the minimum data needed to reduce 

uncertainties

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Need for Guidance

 Some degradation studies with soil/sediment have high 

amounts of unextracted residues with little analytical 

method development

 It has been unclear what is an adequate extraction attempt

 There has been inconsistency in:

 Evaluating the adequacy of extractions

 Requesting data from registrants to address the issue

 Exposure modeling approaches in the absence of data

 Overall approaches to the issue

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Guidance Scope

 Clarify EFED’s current perspective on UR issues

 Provide an evaluation procedure for submitted studies

 Provide options for exposure assessment when

unextracted residues cannot readily be excluded from

the residues of concern

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The Bottom Line

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Dissolved

Extractable with Water

Extractable with Other Solvents

Non-extractable

 All residues available for degradation should be extracted

 When extractions are not adequate, it is not clear whether

the unextracted residues include only strongly sorbed 

non-extractables or some potentially extractable residues

that are available for degradation

Soil and sediment

studies have two 

general fractions: 

non-extractables and 

extractables.

Available for

degradation

Unavailable for

degradation
Issue: Use of Studies 

 Degradation studies are used for model inputs

 Need a half-life that reflects degradation, not a 

combination of degradation and partitioning to solids

 A sorption coefficient is used to model partitioning

 Need to reflect degradation in the total system

 Including dissolved and weakly sorbed residues that are 

available for degradation

 All residues available for degradation should be extracted

 Strongly sorbed (i.e., bound) residues not available for

degradation should not be extracted

 This double-counts their dissipation in exposure models

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Issue: Solvents Used

 Studies commonly involve extraction procedures with a 

limited selection of polar solvents

 Multiple polar and nonpolar mild extraction solvents

with varied chemical properties should be used to

 Speed up extraction

 Extract all residues available for degradation

 Solvent exploration is not intended to

 Remove bound residues

 Chemically alter the test compound or its products

 Estimate bioavailability

 Emulate actual environments

 The toxicity of solvents to aquatic organisms is irrelevant 8
Solvent Polarity

 Generally, one solvent from each of three groups should be

used when URs are >10%

 Example polar and nonpolar solvents with a range of 

dielectric constants are given

 Group 1: polar solvents with dielectric constants of 18-80

 E.g., water, formic acid, methanol, ethanol, isopropanol, acetone, 

acetonitrile, dimethyl sulfoxide

 Group 2: polar solvents with dielectric constants of 6.0-9.1

 E.g., acetic acid, ethyl acetate, tetrahydrofuran, dichloromethane

 Group 3: nonpolar solvents with dielectric constants of 1.9-4.8

 E.g., hexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether

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Solvent Selection

 Additional factors are considered, including

 Test compound chemical properties

 Solvent system pH

 If the extraction procedure can be considered 

adequate, the URs are considered strongly sorbed and 

not of concern from a regulatory perspective

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Flowchart for Addressing URs

YES

•Are unextracted residues <10% of the 

applied; and

•No minor transformation product of 

higher toxicity than the test compound 

is suspected to be unextracted?

YES

NO

Unextracted residues are 

considered likely to be 

irrelevant and not part of 

the residues of concern.

No further work 

on URs is needed.

Does the extraction method or its development 

include exploration of multiple solvents with varied 

chemical properties (e.g., varied dielectric constants)?

NO

Evaluating all lines of evidence, which may include 

the open literature, is there sufficient evidence that 

the extraction method is adequate?

•Compare the method efficiency and UR profiles with 

that of other e-fate data and studies.

YES

NO

Is exposure including URs <LOCs?

NO

Bound exposure estimates by 

including and excluding URs for at 

least the use site of highest exposure. 

Characterize the bounding estimates.

The risk manager has the option to contact the registrant, 

the latter of which has the option to provide additional 

data to reduce the uncertainty in the adequacy of the 

extraction method and/or to decrease and identify the URs.

No further work or data 

on URs is needed for the 

current assessment. 

Continue to treat URs as 

residues of concern. 

Revisit this issue in YES future assessments.

Is exposure including and excluding URs predicted 

(not modeled) to be similar (due to persistence)?

YES

NO

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Unextracted residues can 

be considered strongly 

sorbed and not part of 

the residues of concern.
Flowchart Off-ramps

 Don’t need to consider URs further when:

 <10% of applied, in general

 Extraction method uses multiple solvents with varied 

chemical properties (e.g., dielectric constants)

 Other data indicate extraction is adequate

 UR formation does not correlate with test compound 

decline and there are no degradates of concern

 Test compound is sufficiently persistent such that

exposure estimates with and without URs are similar

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Lines of Evidence

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 Discusses lines of evidence for evaluating URs

 Consider all submitted studies and data

 Evaluate formation and decline patterns

 Consider similar compounds with evidence of strong 

sorption to soil 

 For example, some chlorinated anilines

 Open literature may be useful

 Discusses evidence that is not useful

 For example, correlation of mineralization and UR levels

does not indicate URs are strongly sorbed
Example Cases

 Prometryn

 Soxhlet extraction did little to reduce levels of high URs

 Exploration of additional mild solvents was needed to 

reduce uncertainty in whether they extract URs

 Fenbutatin oxide

 Solvents explored: methanol substantially reduced URs

 Greater certainty in the exposure assessment

 Ethyl parathion

 URs increased for 90 days, then decreased over the next

270 days, indicating degradation of URs

 Solvent exploration was needed to reduce uncertainty 14
Registrant Contact

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 In many cases, UR issues are not communicated to

registrants through risk managers until the exposure 

assessment is completed

 Reduces the burden on industry if risk conclusions are

not affected by the issue

 However, the exposure assessment generally benefits

when the issues are resolved before it is conducted

 This may preclude the need to conservatively include the

URs in aquatic exposure estimates

 Early communication to resolve the issues may be

needed, especially when highly toxic transformation

products are involved
Exposure Assessment

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 URs are modeled only when off-ramps do not apply

 Same modeling approach for

 SW and GW

 DWAs and ERAs

 If exposure with URs < LOCs, no further work needed

 Exposure without URs may only be calculated for the

use pattern of maximum exposure

 Exposure estimates with URs should always be well 

characterized as an upper bound
PRIA Actions w/ New Studies

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 Studies should be screened for adequate extraction

methods if URs are ≥10% of the applied and additional 

evidence is not available to reduce uncertainty in 

whether the URs are available for degradation

 If the studies fail the screen, EFED should identify the

deficiency and request additional evidence to resolve 

the uncertainty in the 90-day Technical Screen

memorandum

 Should not be a reason to kick out the application
Registration Review

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 Old studies are not grandfathered in without review

 Data are not requested for every old study

 If there’s an uncertainty, registrant should be notified 

in Problem Formulation Data Gaps Section that data

are needed for one soil/sediment with high URs

 Solvent exploration is generally needed, rather than a 

new, GLP-compliant study

 Studies with UR issues are not automatically 

downgraded at the Problem Formulation phase
Additional Data in Reg. Review

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 If the additional data indicate that URs can be

considered strongly sorbed, this information can be

inferred to apply to other studies, in most cases

 If the additional data do not indicate that URs can be

considered strongly sorbed

 More data may be needed for any studies with high URs

 Exposure estimation may include URs
Questions?

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