Pyrethroid Registration: Review and Updates Daniel 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 Pyrethrin I Pyrethroids
Pyrethrins degrade rapidly via solar radiation Pyrethroids chemically altered Be more resistant to solar degredation Resmethrin: Class 1 Pyrethroid Increase bio-activity Useful for
Agricultural production
Vector risk Changes bring increased risks
Humans Cypermethrin: Class 2 Pyrethroid
Non-target species
Cyano-group Pyrethroid Use
>3500 registered products
Pets
Treated Clothing
Agriculture
Mosquito Control
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)
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
Docket Chemical Status Number Special Docket for the Pyrethroids and EPA-HQ-OPP-2008-0331 Accepting comments on the Pyrethroids and Pyrethrins 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) Draft human health risk assessment (12/15/17) Cypermethrin (alpha and zeta) EPA-HQ-OPP-2012-0167 Draft ecological assessment (11/29/16) Draft human health risk assessment (2/28/18) 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) Draft human health risk assessment (8/03/17) *Esfenvalerate EPA-HQ-OPP-2009-0301 Draft ecological assessment (11/29/16) Draft human health risk assessment (8/03/17) Etofenprox EPA-HQ-OPP-2007-0804 Draft ecological assessment (11/29/16) Draft human health risk assessment (9/13/17) Fenpropathrin EPA-HQ-OPP-2010-0422 Draft ecological assessment (11/29/16) Draft human health assessment (11/29/16) Pyrethroids/Pyrethrins under Review
Flumethrin EPA-HQ-OPP-2016-0031 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 (5/24/18) Gamma-cyhalothrin EPA-HQ-OPP-2010-0479 Draft ecological assessment (11/29/16) Draft human health risk assessment (9/13/17) Imiprothrin EPA-HQ-OPP-2011-0692 Accepting comments on the proposed interim decision Draft ecological assessment (11/29/16) Draft human health assessment (11/29/16) Lambda-cyhalothrin EPA-HQ-OPP-2010-0480 Draft ecological assessment (11/29/16) Draft human health risk assessment (9/13/17) Momfluorothrin EPA-HQ-OPP-2015-0752 Accepting comments on the proposed interim decision until 1/13/20 (11/12/19) Draft ecological assessment (11/29/16) Draft human health assessment (11/29/16) Permethrin EPA-HQ-OPP-2011-0039 Draft ecological assessment (11/29/16) Draft human health risk assessment (9/13/17) Prallethrin EPA-HQ-OPP-2011-1009 Draft ecological assessment (11/29/16) Draft human health assessment (11/29/16) Pyrethrins EPA-HQ-OPP-2011-0885 Draft ecological assessment (11/29/16) Draft human health risk assessment (9/13/17) Resmethrin EPA-HQ-OPP-2010-0306 Ingredient canceled Tau-fluvalinate EPA-HQ-OPP-2010-0915 Draft ecological assessment (11/29/16) Draft human health assessment (11/29/16) Tefluthrin EPA-HQ-OPP-2012-0501 Draft ecological assessment (11/29/16) Draft human health assessment (11/29/16) Tetramethrin EPA-HQ-OPP-2011-0907 Accepting comments on the proposed interim decision until 1/13/20 (11/12/19) Draft ecological assessment (11/29/16) Draft human health assessment (11/29/16) Tralomethrin EPA-HQ-OPP-2012-0425 Registration review decision completed 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 change previous 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