The Dossier for New Insecticide Active Ingredientsuse patterns/pesticide label). 2. Formulate and...

The Dossier for New Insecticide Active Ingredients

Purpose

Clarify types of safety data to collect for vector control insecticides.

Stimulate ideas and dialogue to improve the efficiency and accuracy (more predictive) of the testing paradigm.

Risk Management Goal:

“Deliver important public health protection and access to

benefits with increased efficiency and accuracy.”

Disclaimer: This is not a formal

proposal from the WHO or IVCC.


Determining the Dossier Requirements

Framework and Guiding Concepts (Vicki Dellarco)

Toxicology Requirements: Human Health Effects (Werner Bomann) and

Ecological Effects (Patrick Rose)

Risk Modeling (Patrick Rose)

Group Discussion (suggested topics)

Practicality of Proposed Testing Strategy and Ideas to Improve or Clarify

Regulatory or Review Body Acceptance of Nontraditional Methods

Issues Concerning Risk Modeling

Framework and Guiding Concepts

Product Chemistry

Toxicology

Terrestrial and Aquatic Nontarget Organism

What would a dossier look like for vector control?

science to be more predictive.

Satisfying Requirements:

• Value of a decision framework to promote focus, consistency and

transparency in determining what information is needed.

• Importance of leveraging existing knowledge and best available

science to be more predictive.

[Code of Federal Regulations: http://www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=defff547e08d4c95b31ba9bd2d56aa93&mc=true&n=pt40.26.158&r=PART&ty=HTML]

Global focus on Improving Toxicity Testing and Assessment:

(More Predictive and Efficient)

Problem Formulation and Hypothesis-Based Approaches in

a Risk-Based Decision Framework with Tiered Analysis.

ILSI/HESI Agricultural Chemical

Assessment Project, 2006

OECD, Integrated Approaches to Testing

and Assessment informed by AOP, 2008/15

ILSI/HESI Risk21 Project, initiated

2014

EPA/OPP Guiding Principles for Data

Requirements; 21 Century Strategic Vision

Focus on the information that matters.

Determining the Toxicology Dossier

Cellular Organ IndividualExposure/PK Molecular

Combine data from different sources, Computational, in vitro, and in vivo methods.

Approach Informed by Adverse Outcome Pathway Knowledge

1. Start with problem formulation and define vector control

exposure scenario. (use patterns/pesticide label).

2. Formulate and evaluate risk hypotheses by integrating existing

exposure and effects data.

3. Target further data generation where required to assess a given exposure.

Problem Formulation and Hypothesis-Based Approach in a

Risk-Based Decision Framework

4. Use a tiered approach defined by acceptable risk levels (simple

to more refined, as necessary).

What information other

than that derived from test

guidelines may provide

sufficient knowledge to

inform a risk assessment

with sufficient certainty for

the regulatory decision?

1. Start with problem formulation

and define vector control exposure

scenario.

2. Formulate and evaluate risk

hypotheses by integrating existing


3. Target further data generation where required to inform regulatory decisions.

4. Use a tiered approach defined by

acceptable risk levels (simple to

more refined, as necessary).

Determining the Toxicology Dossier

Value of existing knowledge in addressing specific health effects.

Read-Across

Waiver

Alternative Ways to Satisfy Data (Information) Requirements

Improved Study

Designs

Note: Authorities should be consulted for alternative approaches.

Certain toxicology studies may be combined and/or

augmented to satisfy data requirements.

If a specified data requirement is not appropriate

for a particular product, a waiver can be requested.

Existing knowledge on the insecticide’s chemical class

may enable a chemical-to-chemical extrapolation.

Combination of the above

(weight-of-evidence)

EPA Guidance

• Acute Toxicity Studies.https://www.epa.gov/sites/production/files/docu

ments/acute-data-waiver-guidance.pdf.

• Neurotoxicity Battery, Subchronic

Inhalation, Subchronic Dermal and

Immunotoxicity Studies..https://www.epa.gov/sites/production/files/2014-

02/documents/part158-tox-data-requirement.pdf.

• A waiver could be requested for any

required data, e.g., developmental, reproductive, chronic/carcinogenicity

toxicity.

Waiver Rationales can be based on “Read-Across

Similarity Hypotheses” for the absence of an effect.

A data requirement could be waived, if based on strong scientific grounds.

A data requirement could be waived, if based on strong scientific grounds.

Waiver Rationale Based on Weight of Evidence

• Use/exposure, risk assessment impact.

• Physical-chemical properties.

• Toxicological data from existing

studies.

• Mode of action, toxicokinetics.

• Information on structurally similar chemicals.

Read-Across Assessment: Endpoint

information for a chemical(s) is used

to predict the same endpoint

(presence or absence) for another chemical that is considered to be

‘similar’ (structure, mode of action).

A data requirement could be satisfied by a “Read-Across Strategy”, if based on strong scientific grounds.

A data requirement could be satisfied by a “Read-Across Strategy”, if based on strong scientific grounds.

Reference Chemicals

Target Chemical

missing datareliable data

• Tools and guidance available

(ECHA, OECD, EPA), e.g., https://echa.europa.eu/support/registr

ation/how-to-avoid-unnecessary-testing-on-animals/grouping-of-

substances-and-read-across

• Pesticide regulatory examples,

including isomers, metabolites

and degradates; acute toxicity/formulations.

Using Biological Similarity to Strengthen Read-Across

Must be robust for regulatory acceptance

• Strengthen similarity rationale and increase confidence by

using concept of biological read-across.

• High quality data on structurally similar chemicals for endpoint of

interest.

• Supporting data on target chemical to bridge to reference

chemicals

• Data on toxicokinetics/metabolism, mode of action.

• Good coverage of chemical space.

Note: Authorities should be consulted for alternative approaches.

Cellular Organ IndividualExposure/PK Molecular

Combine data from different sources, Computational, in vitro, and in vivo methods.

Approach Informed by Adverse Outcome Pathway Knowledge

Framework for Determining the Toxicology Dossier

1. Start with problem formulation

and define vector control exposure

scenarios.

2. Formulate and evaluate risk

hypotheses by integrating existing


3. Target further data generation where required to inform regulatory decisions.

Define exposure

scenarios to identify

populations of concern,

timeframes (durations,

frequencies), routes,

and magnitudes of

exposure that must be

assessed.

4. Use a tiered approach defined by

acceptable risk levels (simple to

more refined, as necessary).

• Treated Nets

• Sleeping under insecticidal nets

• Handling and washing of nets

• Do-it-yourself net treatment (dipping)

• Spraying (indoor/outdoor)

• Indoor residual spraying (IRS) by operators, and post application exposure (residents, operators).

• Larvicide outdoor spraying by operators, and post application

exposure (residents and operators).

• Indoor and outdoor space spraying by operators and post-application exposure (residents and operators).

Vector Control Exposure Scenarios

Vector Scenario Population Route Duration

Sleeping under treated nets

All ages

Dermal, Incidental

oral (inhalation

likely negligible)

Long-term

Net washing Adults, ChildrenDermal, Incidental

oral

Acute

Long-term

(20 washes over 3 yrs)

IRS Application Operators Dermal, Inhalation

Acute

Long-term

(72 days/365 days)

IRS Post-Application

Operators and

residents (all

ages)

Dermal,

Incidental oral

(inhalation likely negligible)

Acute

Long-term

(6 months interval)

Short-term?(< 6 month interval)

Exposure Scenarios (Based on WHO Models)

Potential Environmental Exposure Scenarios Associated with Vector Control Insecticides

• Treated nets:

• washing nets (aquatic organisms),

• disposal of treatment solution (aquatic organisms),

• sweeping dead insects outdoor (secondary poisoning of

birds) - likely to be minimal.

• Indoor residual spraying:• sweeping residues outdoor (soil organisms, birds) - likely to

be minimal, but depends on frequency of use and

persistence of the insecticide.

Formulating and evaluating risk hypothesis based on

exposure (spatial and temporal) and effects characteristics.

Questions?

Determining the Dossier Requirements

Traditional Test Guideline Studies Needed for Assessing Vector Control Scenarios:

• Product chemistry

• Acute toxicity studies (oral, dermal, inhalation; skin and eye irritation; dermal sensitization)

• Genetic toxicity studies (in vitro, in vivo)• 28/90 day rat (oral)• 90 day dog (oral)• 28/90 day rat (dermal)• Rat and rabbit prenatal developmental studies (oral)• Reproductive/fertility study (oral)• Chronic/cancer rat; cancer mouse (oral) (if >6 month human exposure)• Special studies (if an issue arises, e.g., neurotoxicity, endocrine, mode of action)• Oral ADME• Dermal rat (in vivo) and/or in vitro rat/human dermal absorption (if dermal pathway

needs to be refined.)

Toxicology Information (Human Health)

While regulatory authorities have tables of data requirements, certain

‘required’ data may not be needed or can be addressed in other ways

based on exposure, chemical properties, existing knowledge, etc.

While regulatory authorities have tables of data requirements, certain

‘required’ data may not be needed or can be addressed in other ways

based on exposure, chemical properties, existing knowledge, etc.

Step 1: Define vector control exposure scenarios (population, route, duration), including spatial and temporal characteristics.

Step 2: Formulate risk hypotheses for each exposure scenario.

Step 3: Evaluate risk hypotheses based on available knowledge of exposure and effects, e.g.,

• physical-chemistry properties (e.g, vapor pressure, Log Kow, etc)• knowledge of insecticide’s class and mode of action (e.g., is there a common toxophore)

• findings on effects from mutagenicity battery, preliminary acute and short-term repeat toxicity oral rat studies (e.g.14/28-day, dev tox, fertility)

• ADME studies (biological half life, etc)

• Conduct preliminary risk assessments

Incidental oral exposure pathway

(acute, short-term or intermediate-term)

Inhalation exposure pathway

(repeated exposure)

If repeated inhalation exposure is

significant, conduct 28 or 90-day

inhalation rat toxicity study to

characterize port-of-entry and systemic effects.

Step 4. Conduct test guideline studies which may be used to derive reference values - 28 or 90-day oral

toxicity and prenatal studies - and assess vector control scenario with oral values.

Consider need to refine estimates and endpoints, and address special toxicities (e.g., neurotoxicity, immunotoxicity, endocrine toxicity).

If exposure is long-term (>6 months)

Conduct oral rat chronic and rat/mouse cancer

bioassays (consider use of an alternative approach to

address, e.g., read-across/SAR, modified protocol,

mechanism studies, rat only).

New Active Ingredient

Reproduction

Tiered and

Iterative

Process

Consider reproduction rat (potential use

of an alternative approach to address,

e.g., read-across/SAR, modified

protocol, mechanism studies, endocrine screening)

Dermal exposure pathway

(short-term or intermediate-term)

If risk threshold is exceeded, proceed to

refine by conducting in vitro rat/human and

if required in vivo rat dermal penetration

study.

If there is a likelihood of effects presenting after a single dose,

use data from repeat dose studies to assess acute exposure

scenarios. If risk threshold is exceeded, proceed to refine

exposure estimate or refine endpoint by conducting appropriate single dose study.

Acute exposure

Figure 1. Health Effects: Proposed Testing Strategy for Vector Control Insecticides

Figure 1. Health Effects: Propose Testing Strategy for Vector Control Insecticides





• findings on effects from mutagenicity battery, preliminary acute and short-term repeat toxicity oral rat studies (e.g.14/28-day, dev

tox, fertility)






(repeated exposure)





Step 4. Conduct test guideline studies which may be used to derive reference values - 28 or

90-day oral toxicity and prenatal studies - and assess vector control scenario with oral values.

Consider need to augment standard protocol or conduct separate studies to address special or target organ effects.



bioassays (consider use of an alternative

approach to address, e.g., read-across/SAR,

modified protocol, mechanism studies, rat only).


Reproduction

Tiered and

Iterative

Process

Consider reproduction rat (potential

use of an alternative approach to

address, e.g., read-across/SAR,

modified protocol, mechanism studies, endocrine screening)



If risk threshold is exceeded,

proceed to refine by conducting in

vitro rat/human and if required in vivo

rat dermal penetration study.

If there is a likelihood of effects presenting after a single

dose, use data from repeat dose studies to assess acute

exposure scenarios. If risk threshold is exceeded,

proceed to refine exposure estimate or refine endpoint by conducting appropriate single dose study.

Acute exposure

Step 1: Define vector control exposure scenarios (population, route, duration),

including spatial and temporal characteristics.


Step 3: Evaluate risk hypotheses based on available knowledge of exposure and

effects, e.g.,

• physical-chemistry properties (e.g, vapor pressure, Log Kow, etc)• knowledge of insecticide’s class and mode of action (e.g., is there a common

toxophore)

• findings on effects from mutagenicity battery, preliminary acute and short-term repeat toxicity oral rat studies (e.g.14/28-day, dev tox, fertility)

• ADME studies (biological half life, etc)• Conduct preliminary risk assessments

Product Chemistry is a basic requirement for all scenarios: Significance of human and

environmental exposure can be assessed based on physical-chemical properties, and data

can be used in a weight-of-evidence approach to justify a waiver for test guideline studies.

Figure 1. Health Effects: Propose Testing Strategy for Vector Control Insecticides






tox, fertility)






(repeated exposure)














Reproduction

Tiered and

Iterative

Process















Acute exposure

Step 1: Define vector control exposure scenarios (population, route, duration),

including spatial and temporal characteristics.


Step 3: Evaluate risk hypotheses based on available knowledge of exposure and

effects, e.g.,

• physical-chemistry properties (e.g, vapor pressure, Log Kow, etc)• knowledge of insecticide’s class and mode of action (e.g., is there a common

toxophore)

• findings on effects from mutagenicity battery, preliminary acute and oral rat short-term toxicity studies (e.g.14/28-day, dev tox, fertility)

• ADME studies (biological half life, etc)• Conduct preliminary risk assessments

Traditional: ADME studies are a basic requirement and should

be conducted prior to conducting repeated dose toxicity studies.

Nontraditional: To further refine the assessment consider

additional toxicokinetic data to guide dose selection, route-to-

route extrapolations (e.g., understanding first pass effects, oral absorption) and estimating internal or systemic dose for routes of

interest (versus administered dose).







tox, fertility)




(acute, repeat exposure)







Consider need to refine estimates and endpoints, and address special toxicities (e.g.,neurotoxicity, immunotoxicity, endocrine toxicity).







Reproduction

Tiered and

Iterative

Process













Acute exposure

Dermal exposure

pathway


Inhalation exposure

pathway

(acute, repeat exposure)Traditional: 28 or 90-day Dermal Toxicity Test

Guideline

If risk threshold is exceeded, proceed to refine by conducting in vitro rat/human and if required in

vivo rat dermal penetration study.

Nontraditional: In lieu of traditional dermal

toxicology study, conduct comparative oral and

dermal PK (understand systemic dose) and dermal penetration studies.


significant,

Traditional: 28 or 90-day inhalation rat toxicity study to







tox, fertility)






(repeated exposure)














Reproduction

Tiered and

Iterative

Process















Acute exposure

Step 4. Conduct test guideline studies which may be used to derive reference

values - 28 or 90-day oral toxicity and prenatal studies - and assess vector

control scenario with oral values.

Consider need to address special or target organ effects.

Special Toxicities


Special Toxicities

Neurotoxicity (EPA requirement) A number of insecticides target the nervous system, some do

not.

Immunotoxicity (EPA requirement)Studies of most pesticides showed no effects on the immune

system (retrospective analyses by EPA and CropLife).

Endocrine toxicity (OECD and EPA Test Guidelines) Much attention and ongoing debate.

Special Toxicities(Neurotoxicity, Immunotoxicity, Endocrine Toxicity)

Test guideline studies already incorporate a number of measures to help determine whether or not a specialized study is needed.

If there are no alerts, consider waiver weight-of-evidence rationale:

Data on structural analogs, mode of action, early testing results from 14, 28, or 90-day, developmental/reproductive screening studies.

Waiver rationale could be further strengthened by incorporating additional endpoints

(e.g., hormonal measures) into traditional sub-chronic test guidelines or with in

vitro mechanistic data.

If a concern is raised by existing data, address by:

Traditional – follow specific test guideline (neurotoxicity, immunotoxicity).

Further investigate endocrine with in vitro or short term in vivo specifically designed studies, or do extended F1 study.

Nontraditional (Alternative) - Read-across (must be robust to predict a conservative NOAEL).







tox, fertility)



















Reproduction

Tiered and

Iterative

Process















Acute exposure


Traditional: Multi-generation reproductive test guideline study.

Alternative: Extended F1 test guideline study, and if necessary add cohorts for

special toxicities (neurotoxicity, immunotoxicity)

Nontraditional: Read-across supplemented with early screening tests and mechanistic data (in vitro/in vivo). Must be robust.






tox, fertility)















Reproduction

Tiered and

Iterative

Process















Acute exposure


C read-across/SAR, modified protocol,

mechanism studies, rat only).

Cancer

Traditional Approach:

• Oral rat chronic and rat/mouse cancer bioassays


Nontraditional: • Read-across strategy supplemented with mechanistic data

(in vitro/ in vivo) and relevant in vivo organ weight and histopathology data.

• Rat bioassay only supplemented with relevant data from shorter-term studies and mechanistic information.






tox, fertility)




















Reproduction

Tiered and

Iterative

Process















Acute exposure


If there is a likelihood of effects occurring after a single


exposure scenarios. If risk threshold is exceeded, proceed to refine exposure

estimate or refine endpoint by conducting appropriate single dose study focusing on the endpoint of concern.

Questions?

Figure 2. Ecological Effects: Proposed Testing Strategy for Vector Control Insecticides

Step 1: Define exposure scenarios.


Step 3: Evaluate risk hypotheses based on available knowledge of the physical-chemical properties of the substance.

Step 4: For each intended use evaluate the potential for exposure. Develop a representative exposure scenario and determine if exposure

is likely to be negligible.

Exposure to birds

Is there potential for exposure to birds via contaminated insects? (Sweeping from house)

If exposure is likely to be negligible, further assessment not required.

But if exposure in a significant amount cannot be ruled out, assessment of toxicity to

birds is required:

Acute/chronic studies with birds (or surrogate data from mammalian data as screening).


Risk to soil organisms

If exposure to soil cannot be ruled out, assess:

Acute toxicity to earthworms (by studies or

screening step with equilibrium partition

calculation)

Toxicity to soil micro-organisms (carbon,

nitrogen transformation)

Chronic toxicity relevant?

Risk to aquatic organisms

If exposure to water cannot be ruled out, assess:

Acute toxicity to fish

Acute toxicity to aquatic invertebrates

Toxicity to algae

Chronic toxicity relevant?

Is substance likely to be persistent?

Assess DT50 in soil/water. If short (few

days), then unlikely to be persistent and

chronic exposure not relevant.

Consider frequency of intended uses, if

exceeds DT50 then prolonged exposure

cannot be ruled out and chronic toxicity is

relevant.

Bioaccumulative, Log Kow > 3?

If there is potential for bioaccumulation, secondary poisoning to

birds/mammals via fish and earthworms needs to be assessed.

Physical-chemical properties - Play a role in

assessing exposure potential.

• Degradation rate expressed as half-life (DT50)

• Octanol:water partition coefficient (log Kow)

• Soil-organic carbon:water partition coefficient (Koc)

Ecological Effects: Testing Strategy

Risk to soil organisms

If exposure to soil cannot be ruled out, assess:

• Acute toxicity to earthworms (by studies or screening step with equilibrium partition calculation)

• Toxicity to soil micro-organisms (carbon, nitrogen transformation)

• Chronic toxicity relevant?

Is substance likely to be persistent?

Assess DT50 in soil/water. If short (few days), then unlikely

to be persistent and chronic exposure is not relevant. Consider frequency of intended uses, if exceeds DT50

then prolonged exposure cannot be ruled out and chronic toxicity is relevant.



Step 3: Evaluate risk hypotheses based on available knowledge of the physical-

chemical properties of the substance.

Risk to aquatic organisms

If exposure to water cannot be ruled out, assess:

• Acute toxicity to fish

• Acute toxicity to aquatic invertebrates

Toxicity to algae

• Chronic toxicity relevant?

Step 4: For each intended, use evaluate the potential for exposure. Develop a

representative exposure scenario and determine if exposure is likely to be negligible.

Ecological Effects: Testing Strategy



Step 3: Evaluate risk hypotheses based on available knowledge of

the physical-chemical properties of the substance.

Step 4: For each intended use evaluate the potential for exposure.

Develop a representative exposure scenario and determine if

exposure is likely to be negligible.

Potential for exposure to birds via contaminated insects? (sweeping from

house etc)

➡If exposure is likely to be negligible, further assessment not required.

➡If exposure in a significant amount cannot be ruled out assessment of

toxicity to birds is required,

• Acute/chronic studies with birds (or surrogate data from mammalian

data as screening).

Bioaccumulative? (Log Kow > 3)

➡If there is potential for bioaccumulation, secondary

poisoning to birds/mammals via fish and earthworms

needs to be assessed.

Questions?

Risk Modeling

What models are available?

• Various guidance documents and models for estimating exposure to insecticides are available, mostly in the US and Europe.

• The WHO has developed generic guidance / models for public health insecticides used in vector control.•Aim to harmonise the risk assessments for each type of

application. •Derived from US EPA and EU models.

•The WHO models (conservative assumptions) are useful for initial risk analyses - commonly used for vector control dossiers submitted to WHOPES.

• If the risk threshold is exceeded, refined input parameters and improved risk assessment models should be considered, as appropriate.

WHO Generic Risk Assessment Models – Vector ControlAll models are to be updated for 2017 – proposed changes issued

September 2016

ITNs Human Health Risk Assessment Model. Revised Edition, 2012.

Sleeping under nets, washing nets, conventional treatment of

nets with insecticide (does not include risks associated with manufacturing nets in a factory environment)

IRS Human Health Risk Assessment Model. First Revision, 2011.

Operator mixing/loading and application; residents living in

treated houses, residents who are also operators

Indoor and outdoor space spraying

Human Health and Environmental Risk Assessment Model. First Revision, 2011.

Operator mixing/loading and application; residents who return to treated houses, bystanders present during outdoor application

Environment: air, soil, surface water and aquatic sediment

Larviciding Human Health and Environmental Risk Assessment Model. First Revision, 2011.

Operator mixing/loading and application; residents who may come into contact with or use the treated waters

Environment: air, soil, surface water and aquatic sediment

Key elements of the models

•Deterministic risk assessment models

•Consider both adults and children (all age groups), and acute

and long term exposures

•Exposure algorithms, default values and unit exposures mostly

derived from US EPA residential exposure guidance documents

and European guidance / models

•Need to understand the exposure scenarios and underlying assumptions

•Total exposure estimates calculated by summing up all relevant

exposure routes and pathways

•Outdoor environmental risk assessments based on established

methods for agricultural pesticides

Provide first tier exposure assessments – they can be

modified with data for higher tier refinement if needed

Higher tier refinementsProblem formulation

•Dermal route is usually the major pathway for exposure

• Default of 100% absorption can be greatly improved by conducting a study

•Oral ingestion is an important route for infants and toddlers

•Default of 100% - actual absorption usually available from rate ADME

•Chemical specific data can be generated to replace defaults

•Consider complexity and cost; eg. PBPK modelling or exposure monitoring

could be expensive options.

•Probabilistic exposure (and hazard?) assessment

• Presents a number of challenges, data rich or data poor environment?

•There may be options to modify the exposure algorithms based

on new guidance (e.g. EPA and EU) or scientific literature

Determine the key drivers for exposure – where do you get

most “bang for your buck” in refinement options?

Discussion of an example model

WHO ITN

The WHO models have a common framework

WHO ITN Model - Exposure estimation

Exposure

scenario

Population

groups

Exposure routes/pathways Refinement examples

Sleeping under

net

All Inhalation - v.p. >5x10-5 Pa Air monitoring

All Skin contact Dermal absorption,

translodgeable fraction

Infant and

toddler

Oral – hand to mouth

transfer and sucking nets

- breast milk (infants)2

Saliva extraction,

translodgeable fraction, oral

absorption

Washing of net Adult and child Dermal


transfer

Dermal absorption, fraction

released in wash, oral

absorption

“Do-it-yourself”

net treatment1Adult and child Dermal


transfer (lax scenario)Inhalation (poor ventilation

and v.p. as above)

Dermal absorption, transfer

fraction, oral absorption

1 Estimate of risks in optimal conditions (guideline scenario) or a lax standard scenario (some common deviations from use instructions)2 For insecticides with a long half life (e.g. >2 days): lipid soluble compounds (pKow ≥2) concentration = 5 x body burden; water soluble compounds = 1.4 x body burden

WHO ITN Model - Risk characterisation

Exposure scenario Population groups Risk characterisation1

Sleeping under net All Long term

Sleeping under net and net washing Adult and child Acute

“Do-it-yourself” net treatment (guideline

scenario), net washing and sleeping

under net

Adult and child Long term and acute

“Do-it-yourself” net treatment (lax

scenario), hand to mouth transfer, net

washing and sleeping under net

Adult and child Long term and acute

1 Ratio of the Estimated TWA systemic dose / long term TSD or Estimated maximal daily systemic intake / TSDAC Ratio <1 acceptableTWA = Time weighted average over 365 daysTSD = Tolerable systemic dose (NOAEL/Assessment Factor)

•Accidental swallowing of a concentrated insecticide formulation by a child (ITN “do-it-yourself”)

• Ingestion of liquid (20 mL), single tablet or single sachet compared with TSDAC

• Meaningless assessment as virtually every insecticide will fail

• Risk mitigation measures; eg. child resistant packaging, “bittering” agent

•Contaminated food stuffs from larviciding, space spraying or IRS

• Transfer from contaminated surfaces

• Crops grown in contaminated soil from irrigation with contaminated water or from sweeping the house (bioaccumulative / persistent insecticides) – measure actual levels

•Risk-benefit considerations

• Risk managers assess risks of potential toxicity vs. benefits of disease prevention; consider alternative insecticides or vector-borne disease control interventions

•Intentional misuses are not considered

• But possible re-use of empty insecticide packages for storing water is assessed

Other points from WHO models

Some key points

Human health risk assessment

• Exposure defaults use 75th percentiles rather than 95th percentiles or point estimates to reduce conservatism from multiplication of several estimated parameters.

• “Acute” exposure replaced by “short term” exposure (change in terminology) = maximal daily dose.

• Default adult body weight increased from 62 kg to 72 kg (US 16-21 yr female median).

• Dermal absorption defaults follow EFSA (EU) guidance (e.g. 25% concentrate, 75% dilution). Use concentrate value for nets and dried surface deposits.

Proposed changes Sept 16

Refinements of assumptions, parameters and algorithms Refinements of assumptions, parameters and algorithms – no fundamental changes to the risk assessment paradigms.

Human health risk assessment

• Default TSD assumes cumulative effect over repeated/continuous exposure, which is averaged over a year (TWA).

• Default UF of 100 modified where toxicity is related to Cmax rather than AUC. Assumes toxicokinetic variability is lower with Cmax effect and the TK components for interspecies and intraspecies variability are reduced by 50%.

• Risk assessment from exposure to a combination of a.i.s – synergy at low doses considered unlikely and default assumption is dose addition.

Environmental risk assessment – no change

Comments on proposed changes to WHO by 31st October !

Proposed Changes - Sept 16

Questions?


Group Discussion (suggested topics)

Practicality of Proposed Testing Strategy and Ideas to Improve or Clarify

Regulatory or Review Body Acceptance of Nontraditional Methods

Issues Concerning Risk Modeling

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