pyrethroid registration: review and updates€¦ · appropriate in-vitro (i.e., cell-based data) to...

Pyrethroid Registration:

Review and UpdatesDaniel Dawson, PhD

AMCA Legislative and Regulatory Committee

Chemical Control Subcommittee

Talk Outline

Pyrethroid Overview

Re-registration

Registration

Food Quality Protection Act Safety Factor

Pyrethroids

Synthetic pyrethrins

Natural pesticides derived from chrysanthemums

Neurotoxic

Mode of Action

Sodium channel blocker

Paralyzes effected organism

Toxic to arthropods

Generally of low toxicity to vertebrates

Can be toxic to fish

Pyrethroids

Pyrethrins degrade rapidly via solar radiation

Pyrethroids chemically altered

Be more resistant to solar degredation

Increase bio-activity

Useful for

Agricultural production

Pest control

Vector risk

Changes bring increased risks

Humans

Non-target species

Pyrethrin I

Cypermethrin: Class 2 Pyrethroid

Resmethrin: Class 1 Pyrethroid

Cyano-group

Pyrethroid Use

>3500 registered products

Pets

Treated Clothing

Agriculture

Mosquito Control

Permethrin

Resmethrin

D-Phenothrin

Re-registration

As part of the Federal Insecticide Fungicide, and Rodenticide Act (FIFRA):

Pesticides registered before 1984 had to be reviewed

Ensure compliance with scientific and regulatory standards

Authorized reregistration reviews 1988

Scientific studies

Input from stakeholders

Summarized in Reregistration Eligibility Decisions (REDs)

Completed some 384 “cases” of pesticides by 2008

Concurrently, the Food Quality Protection Act (FQPA) required the reassessment

tolerances of pesticides in food for human safety

Completed 99% of tolerance assessment in 2006

Re-registration

Process for implementing REDs

Ensure required risk mitigation determined in review is reflected on labels

Each product in a RED is individually considered

Data

Labeling

If meets standards, may be reregistered

If not, may be amended, suspected, or canceled.

Registration Review

Following registration and/or re-registration, EPA is mandated to review

pesticides at least every 15 years to determine if they continue to meet FIFRA

standards

For all pesticides registered as of 2007, they have until 2022 to review their

registration

10 pyrethrins, pyrethroids and synergists were registered before 1984, and

had re-registration reviews by 2008.

Pyrethroids, Pyrethrins and Synergists began registration review between

2010-2012

Registration Review Parts

Ecological Risk Assessment

Some pesticides reviewed as groups if they share

Structure

Chemical class

Mode of action

Human Health Risk Assessment

Conducted individually

Food Quality Protection Act Safety Factor Review

Registration review: Pyrethroids

Proposed interim decisions for 5 pyrethroids (As of Spring, 2020)

Cyphenothrin

Imiprothrin

Tetramethrin

Flumethrin

Momfluorothrin

Registration Review: Pyrethroids

Ecological Risk Mitigation Proposal

8 pyrethroids/pyrethrins in 2016

23 pyrethroids/pyrethrins in 2019

Assessed as a class to “increase efficiency and consistency”

Reduce spray drift

Reduce runoff

Promote soil conservation practices

Registration Review: Pyrethroids

Human Health Risk Assessments

Conducted individually

Risk assessments released in 2016-2018

Re-evaluated FQPA Safety Factor

2011

2019

Pyrethroids/Pyrethrins under Review

ChemicalDocket

NumberStatus

Special Docket for the Pyrethroids and

Pyrethrins

EPA-HQ-OPP-2008-0331 Accepting comments on the Pyrethroids and Pyrethrins

Ecological Risk Mitigation Proposal and the FQPA Safety Factor

until 1/13/20 (11/12/19)

Allethrins EPA-HQ-OPP-2010-0022 Interim decision (12/24/14)

Bifenthrin EPA-HQ-OPP-2010-0384 Draft ecological assessment (11/29/16)

Draft human health risk assessment (12/15/17)

Cyfluthrin and beta-cyfluthrin EPA-HQ-OPP-2010-0684 Draft ecological assessment (11/29/16)


Cypermethrin (alpha and zeta) EPA-HQ-OPP-2012-0167 Draft ecological assessment (11/29/16)


Cyphenothrin EPA-HQ-OPP-2009-0842 Accepting comments on the proposed interim decision until

1/13/20 (11/12/19)

Draft ecological assessment (11/29/16)

Draft human health risk assessment(5/25/17)

d-phenothrin EPA-HQ-OPP-2011-0539 Draft ecological assessment (11/29/16)

Draft human health assessment (11/29/16)

Deltamethrin EPA-HQ-OPP-2009-0637 Draft ecological assessment (11/29/16)


*Esfenvalerate EPA-HQ-OPP-2009-0301 Draft ecological assessment (11/29/16)


Etofenprox EPA-HQ-OPP-2007-0804 Draft ecological assessment (11/29/16)


Fenpropathrin EPA-HQ-OPP-2010-0422 Draft ecological assessment (11/29/16)


https://www.regulations.gov/docket?D=EPA-HQ-OPP-2008-0331











FlumethrinEPA-HQ-OPP-2016-0031 Accepting comments on the proposed interim decision until

1/13/20 (11/12/19)



Gamma-cyhalothrinEPA-HQ-OPP-2010-0479 Draft ecological assessment (11/29/16)


ImiprothrinEPA-HQ-OPP-2011-0692 Accepting comments on the proposed interim decision



Lambda-cyhalothrinEPA-HQ-OPP-2010-0480 Draft ecological assessment (11/29/16)


MomfluorothrinEPA-HQ-OPP-2015-0752 Accepting comments on the proposed interim decision until

1/13/20 (11/12/19)



PermethrinEPA-HQ-OPP-2011-0039 Draft ecological assessment (11/29/16)


PrallethrinEPA-HQ-OPP-2011-1009 Draft ecological assessment (11/29/16)


PyrethrinsEPA-HQ-OPP-2011-0885 Draft ecological assessment (11/29/16)


ResmethrinEPA-HQ-OPP-2010-0306 Ingredient canceled

Tau-fluvalinateEPA-HQ-OPP-2010-0915 Draft ecological assessment (11/29/16)


TefluthrinEPA-HQ-OPP-2012-0501 Draft ecological assessment (11/29/16)


TetramethrinEPA-HQ-OPP-2011-0907 Accepting comments on the proposed interim decision until

1/13/20 (11/12/19)



TralomethrinEPA-HQ-OPP-2012-0425 Registration review decision completed

Pyrethroids/Pyrethrins under Review














Evaluation of the FQPA Safety Factor

Food Quality Protection Act

Requires that default safety factors are applied to chemicals to account for

Interspecies differences (in-vivo toxicological assays are conducted on lab animals)

Intraspecies variation (children vs adults, female vs male, etc)

Also requires that an additional 10X interspecies safety factor to be protective of children and neo-natal toxicity

Typically broken up into two parts(on log scale), including

3.16 X for Toxicokinetics(TK)

3.16 X for Toxicodynamics(TD)

Can adjust safety factor if reliable data shows revised factor would be sufficiently protective

Data-derived Extrapolation factor (DDEF)

Quick aside: Toxicodynamics and

Toxicokinetics

Toxicodynamics: what the chemical does to the body

Pharmacological effects (i.e., intended therapy)

Toxicity (i.e., intended/unintended harm to body systems)

Toxicokinetics: What the body does to the chemical

Characterized by: Measured/modeled chemical concentration in tissue

Where does chemical end up and how fast after exposure?

Evaluation of the FQPA Safety Factor

Previous review (2011) had resulted in

3x reduced to 1X for TD (toxicological mechanism and affects sufficiently similar between adults and children)

Retention of 3x for TK(2011), based on higher modeled concentrations in tissues of juvenile rats, analogs for young children (<6 years old)

New analysis convinced EPA that

Infants/children are NOT more sensitive than adults

3X can be reduced to 1X for TK (2019)

How was this determined?

EPA white paper* says:

“Based on a review of the available guideline and literature studies as well as data from the Council for the Advancement of Pyrethroid Human Risk Assessment (CAPHRA) program, the Agency concludes that the PK contribution to the FQPA factor is also 1X for adults, including women of child-bearing age, and children. Therefore, the total FQPA safety factor for pyrethroids can be reduced to 1X for all populations.”

*USEPA Office of Pesticide Programs’ Re-Evaluation of the FQPA Safety Factor for Pyrethroids: Updated Literature and CAPHRA : Program Data Review (2019)

https://www.epa.gov/sites/production/files/2019-08/documents/2019-pyrethroid-fqpa-caphra.pdf

Council for the Advancement of Pyrethroid

Human Risk Assessment (CAPHRA)?

Following the reduction of the PD SF in 2011, EPA said:

Some evidence for “higher sensitivity” to pyrethroids to juveniles following high

doses

Not enough data for risk assessment purposes

Requested additional study designs/protocols to quantify differences in sensitivity

Pyrethroid registrants formed Council for the Advancement of Pyrethroid

Human Risk Assessment (CAPHRA)

Develop research program to fill in data gap

FQPA Safety Factor Evaluation

Systematic Review(2019): Intensive literature review to assess for informative studies

Found no new studies that could be used to inform guidelines

CAPHRA

TD: Conducted several rounds of studies; all found to be insufficiently informative to changeprevious ruling of 1x safety factor

TK: Developed generic human Physiologically-based Toxicokinetic Model (PBTK) that can be parameterized for all pyrethroids, and for adults and children

Goal: Use predicted concentrations in target tissues to calculate data-derived safety factor, instead of the generic 3.16 X

Wait, what is a PBTK model?

A mathematical model that predicts concentrations of chemical in different tissues in the body over time

Can be generic in form (i.e., equations), but requires experimental data to parameterize it for specific species/ages/chemicals.

Models are evaluated by comparing predictions against data (generally animal-based, in-vivo)

FQPA Safety Factor: TK modeling

Phase I: 2018

1. CAPHRA developed a PBTK model in rats for permethrin (type 1) and deltamethrin (type 2) as proxies for other pyrethroids; used available experimental data to parameterize

This process showed that a single PBPK model structure can simulate concentrations for both chemicals in animals of different ages if:

Parameterized with chemical-specific metabolism rates

Appropriate in-vitro (i.e., cell-based data) to in-vivo (i.e., animal-based data) extrapolation factors were applied

Age-specific metabolic enzyme information was incorporated

Based on findings, scaled up model to a human model

Performed simulations of exposure to different age classes of humans*

Submitted to EPA Review

*https://www.epa.gov/sites/production/files/2019-08/documents/stat-analysis-pbpk.pdf

FQPA Safety Factor: TK modeling

Phase II

Following EPA review, CAPHRA revised models and documentation

Applied model to 5 additional pyrethroids (esfenvalerate, bifenthrin, cyphenothrin, cyfluthrin and cyhalothrin)

Conducted comparisons between model predictions with in-vivo data from rats

Found that predictions and in-vivo data were generally within factor of 2 (i.e, pretty good)

Models then scaled up to humans

Used in-vitro measured data to parameterize

Calculated FQPA safety factors based on predicted concentrations

Calculated safety factor ranged from 0.66-1.16

After EPA Review, Office of Pesticide Programs concluded that a FQPA safety factor of 1X was sufficient for entire class of pyrethroids

Summary

Pyrethroid registration currently under review as mandated by FIFRA

Registration review requires ecological risk and human health assessments

Ecological risk assessments of most pyrethroids being conducted as a groups

Human health assessments completed individually

Current status

Some chemicals have interim decisions made (5)

Most are under review

EPA recently reduced the safety factor required by the Food Quality and Protection

Act to protect children to 1x

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