US Environmental Protection Agency
Office of Pesticide Programs
Final Guidance for Waiving Sub-Acute Avian Dietary Tests
for Pesticide Registration and Supporting Retrospective
Analysis
February 2020
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1. Introduction
This document describes the results and implications of a retrospective study that the United
States Environmental Protection Agency (EPA) and stakeholders conducted to inform its
consideration of reduced animal testing in the form of waiver requests for sub-Acute Avian
Dietary Tests when registering conventional pesticides that would be used outdoors. The
document also provides additional points to consider when evaluating a waiver request based
available physical/chemical, mechanism of action, and other toxicological information for a
pesticide. This document is applicable to waiver requests for avian sub-acute lethal dietary
studies for waterfowl and upland gamebird species (Guideline 850.2200) as required under 40
CFR section 158.630 and does not apply to consideration of waivers for avian sub-acute dietary
studies for passerine species in lieu of a passerine acute single oral dose study (guideline
850.2100 as required under 40 CFR section 158.630).
EPA registers pesticides under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA).
Under 40 CFR part 158, EPA requires supporting studies to meet FIFRA safety standards.
There is flexibility, however, in implementing Part 158. Additional data can be required
(§§158.30, 158.75), alternative approaches can be accepted (§§158.30, 158.70), and studies can
be waived (§§158.30, 158.45). The 2007 National Academy of Sciences (NAS) report on
Toxicity Testing in the 21st Century1 describes a new vision for toxicity testing. EPA's Office of
Pesticide Programs (OPP) has developed a Strategic Direction for New Pesticide Testing and
Assessment Approaches2 which describes the EPA approach to implementing the NAS vision.
One component of this is improved approaches to traditional toxicity tests to minimize the
number of animals used while expanding the amount of information obtained. OPP's document
on Guiding Principles for Data Requirements3 emphasizes only requiring data that inform
regulatory decision making and avoiding unnecessary use of time and resources, data generation
costs, and animal testing. Waiving studies, when they offer little additional scientific
information or public health protection, is an important component of the guiding principles for
data requirements. This allows OPP staff to focus on the information most relevant to an
assessment and still ensure there is sufficient information for regulatory decisions that are
protective of public health and the environment.
For the registration of conventional pesticides used outdoors, OPP typically requires two avian
acute oral toxicity studies (one with an upland game or waterfowl species and one with a
passerine species) and two avian sub-acute dietary studies (one with an upland game species and
one with a waterfowl species). OPP's Pesticide Assessment Guidelines Subdivision E Hazard
Evaluation: Wildlife and Aquatic Organisms4 presents the rationale for both the acute oral and
1 National Research Council. 2007. Toxicity Testing in the 21st Century: A Vision and a Strategy. Washington DC:
The National Academies Press. https://www.nap.edU/read/11970/chapter/2.
2 https://www.epa.gov/pesticide-science-and-assessing-pesticide-risks/strategic-vision-adopting-21st-century-
science
3 https://www.epa.gov/pesticide-registration/guiding-principles-data-requirements
4 Pesticide Assessment Guidelines Subdivision E Hazard Evaluation: Wildlife and Aquatic Organisms
https://nepis.epa.gov/Exe/ZyNET.exe/P1007WF5.TXT7Zy Action D=ZyDocument&Client=EPA&lndex=1981+Thru+19
85&Docs=&Query=&Time=&EndTime=&SearchMethod=l&TocRestrict=n&Toc=&TocEntry=&QField=&QFieldYear=
&QFieldMonth=&QFieldDay=&lntQFieldOp=0&ExtQFieldOp=0&XmlQuery=&File=D%3A%5Czyfiles%5Clndex%20Da
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the sub-acute dietary tests. Among the rationale for requiring both tests was a stated concern that
reliance on a single test may be "misleading in evaluating a pesticide that exhibits cumulative
effects or one that is easily degraded" (note these characteristics are considered in this guidance
when making a decision on the need for a sub-acute dietary toxicity test). Furthermore,
Subdivision E maintains that the sub-acute dietary test is insufficient for characterizing the risks
of granular pesticide formulations. Finally, Subdivision E asserts that the single oral dose study
should be retained for hazard classification purposes. The Ecological Committee of FIFRA Risk
Assessment Methods, ECOFRAM 19995 provided further discussion of the relative strengths and
limitations for the studies. This discussion was from the perspective of incorporation of the
effects endpoint information into risk assessments that include refined methods beyond screening
work. ECOFRAM summarized several aspects of the avian dietary test that limits its utility in
refined assessments:
• The study cannot provide a dose estimate for the effects endpoint because test organism
consumption estimates are confounded by spillage, the lack of daily estimates of
consumption, and mortalities occurring before study termination.
• The five-day exposure window is arbitrary, having more to do with laboratory
expedience than any avian behavioral or toxicological factor.
• Toxicity is further confounded by the willingness of birds to consume food and the
methodology cannot account for such behaviors as enhanced feeding rate during
migration and the effect of assimilative energy differences between laboratory and field
dietary matrices.
• Dietary concentrations are held constant during the study, limiting the use of food item
degradation estimates in risk assessment.
Pesticide risk assessments evaluate potential risks to non-target bird species by calculating risk
quotients (RQs) using the most sensitive endpoint from each type of study (i.e., acute oral and
sub-acute dietary), the highest of which usually drives the risk conclusions and ultimately the
risk management decisions. Anecdotally, OPP risk assessors and risk managers have generally
found that the endpoints from acute oral studies normally give higher RQs than RQs from the
sub-acute dietary studies, suggesting that the acute oral RQ calculation usually represents a
protective approach. To explore this anecdotal position, a joint effort with People for the Ethical
Treatment of Animals (PETA) was undertaken to explore the quantitative and qualitative
contributions of risk assessment methods using the single oral dose and the sub-acute dietary
toxicity endpoints to the overall conclusions of acute avian risk.
EPA in collaboration with PETA retrospectively compared the conclusions of a series of publicly
available pesticide risk assessments, reached using the single oral dose and the dietary test
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d=h%7C-
&MaximumDocuments=l&FuzzyDegree=0&lmageQuality=r75g8/r75g8/xl50yl50gl6/i425&Display=hpfr&DefSeek
Page=x&SearchBack=Zy Action L&Back=ZyActionS&BackDesc=Results%20page&MaximumPages=l&ZyEntry=l&See
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5ECOFRAM Terrestrial Draft Report (ECOFRAM 1999) https://www.epa.gov/pesticide-science-and-assessing-
pesticide-risks/ecofram-terrestrial-draft-report
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endpoints (Hilton et al. 20196). This analysis focused on conventional pesticides that were
submitted to the Agency for registration between 1998 and 2017. The OPP/PETA analysis,
discussed in Section 2 below, addressed the question of whether OPP can confidently assess
acute risk for birds using the single oral dose protocol alone. This was done by considering how
often sub-acute dietary-based RQs have quantitatively and/or qualitatively driven risk assessment
conclusions. OPP used the results of this analysis to support a draft policy statement in Section 4
to accept waiver requests for avian sub-acute dietary studies that meet certain criteria. We
expect that most, but not all, conventional pesticides would meet these criteria.
2. Retrospective Analysis
2.1. A summary of the retrospective analysis conducted by OPP and PETA is provided
below.
2.1.1. Dataset for Analysis
The analysis focused on pesticides registered through OPP's Registration Division (RD) from
1998 through 2017. The rationale for selecting this date period was to provide a sampling of the
most recent chemical classes reasoning that these classes are the least mature in terms of addition
of new compounds within the class so likely represent classes for which new chemicals will be
encountered and which decisions of avian testing will be required. The chemical set was
comprised of 52 insecticides, 62 fungicides, 46 herbicides, and 22 compounds of other pesticidal
target (e.g. rodenticide). For the complete list of the chemicals considered, see Attachment A.
Attachment A also presents a list of the mechanism of action represented by the chemical set.
2.1.2. Selection of Documents and Data
EPA's Pesticide Chemical Search (ChemSearch) online database7 was searched for publicly
available documents inclusive of the 181 chemicals mentioned above. Information extraction
centered on documents logically assumed to contain reported effects endpoints for the avian
acute oral and sub-acute dietary tests. These documents included ecological risk assessments
(ERA), problem formulations (PF), preliminary risk assessments (PRA), and final work plans
(FWP). The available documents in these categories were downloaded and reviewed for relevant
toxicity and physicochemical information. The ERA and PRA documents typically contained
toxicity information for both acute and sub-acute endpoint values, as well as RQ values. If the PF
and FWP documents contained LD50 and LC50 values, but not RQ values, then additional
information from data evaluation records (DER), EPA reviews of studies submitted by
registrants, were examined for chemicals that were reported as a definitive test to ensure all
relevant information was collected for analysis. If the PF and FWP documents reported chemical
toxicity by limit test (i.e. one single high dose or concentration tested), and no additional studies
were requested for the chemical, then no quantitative estimate of acute avian risk was presumed.
6 Hilton, G.M. E. Odenkirchen, M. Panger, G. Waleko. A. Lowit, A.J. Clippinger. 2019. Evaluation of the avian acute
oral and sub-acute dietary toxicity test for pesticide registration. Regulatory Toxicology and Pharmacology, 105:30-
35
7 USEPA ChemSearch https://iaspub.epa.gov/apex/pesticides/f?p=chemicalsearch:l
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2.2. Overview of Dataset
Of the 181 pesticides searched on the ChemSearch website, 119 chemicals had available risk
assessment documents that could be used for the acute oral and sub-acute dietary RQ
comparative analysis. The remaining 62 pesticides were not included in comparative acute
versus sub-acute RQ analysis because documents containing information on acute oral and sub-
acute dietary studies were not available via ChemSearch. Additional evaluation was done on
these 62 excluded chemicals to determine if they represented unique or underrepresented modes
of action as described below.
For 87 of the 119 chemicals, both the oral and dietary reported effects endpoints were from limit
tests. Limit testing involves a study where the LD50 or the LC50 for the active ingredient was
reported as being greater than a single upper limit exposure level (5000mg/kg-bw for LD50 acute
oral and 2000 mg/kg-diet for dietary) or for a dose/exposure levels that is at or greater than
estimated environmental concentrations under labeled use). For 10 chemicals, the endpoints
were from a definitive test for both oral and dietary tests. Definitive tests are conducted over
multiple dose or exposure levels and return a defined LD50 or LC50. The endpoints for 17
chemicals were from a limit test for the sub-acute dietary study and from a definitive test for the
acute oral study. In 5 cases, the acute oral endpoint was from a limit test while the sub-acute
dietary endpoint was from a definitive test.
It is important to note that some chemical risk assessment documents reported definitive toxicity
test results but did not have reported RQ values. To ensure that the tests were reported accurately
in the downloaded risk assessment documents (e.g., an acute oral test with an LD50 reported as
2000 mg a.i./kg-bw instead of >2000 mg a.i./kg-bw) these sub-acute dietary and acute oral
toxicity studies were retrieved from problem formulation documents and study DERs to
eliminate spurious results from erroneous endpoint reporting in the available risk assessment
documents.
For 6 pesticides, the risk assessment documents failed to report toxicity information pertinent to
the avian effects characterization. In these cases, EPA reviewed DERs and earlier risk
assessments to determine the avian study outcome. These chemicals were found to have a new
use registration that did not require the acute avian test submission (e.g., indoor uses or were
found to have been conducted as a limit test), and therefore no acute avian risk is presumed.
2.3. Comparison of Risk Quotients from Avian Acute Oral and Sub-Acute Dietary
Studies
In 99% of cases (118 of 119 chemicals evaluated quantitatively) the RQ values for the sub-acute
dietary risk assessment approach were lower than the RQs calculated using the single oral dose
acute effects endpoint. Consequently, in 99% of cases evaluated, the conclusions of the risk
assessments were driven by the results of RQ calculations using the single oral dose data.
It is notable that the single exception for the comparisons was for a second-generation
anticoagulant rodenticide. This is a class of compounds for which repeat exposures can lead to
accumulation of the pesticide in target organs, and the clotting factor synthesis mode of action
would suggest that exposure persisting over time would also have cumulative effects concerns
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(continued inhibition of clotting factor synthesis results in depletion of existing clotting factor
pool over time).
2.4. Modes of Action and Analogue Considerations
Not all chemical risk assessment cases considered allowed for a quantifiable comparison of RQs
using the effects data from the sub-acute and acute studies. Of the 181 chemicals searched in the
ChemSearch website, 62 were not included in the above analysis because public documents
containing information on acute oral and sub-acute dietary studies were not available through the
ChemSearch database.
A review of the chemical modes of action (MOA) was conducted for all the chemicals to
determine whether the MO As for the 62 chemicals lacking public documents were covered by
one of the pesticides for which the comparison of RQs was completed {i.e., did they share a
chemical class with one of the chemicals included in the analysis?). Seven of the 62 chemicals in
six pesticide mode of action classes did not share a chemical class with a pesticide included in
the quantitative RQ comparison. The unrepresented pesticide mode of action codes, chemical
classes, and target sites are as follows:
IR A C7H R A C7F R A C putative
mechanism of action code
insecticide 2B
insecticide 24A
Insecticide
Unassigned
FungicideAl
Fungicide B2
Fungicide M
Chemical Class
Phenylpyrazole
Phosphide
Propenyl oxy ether
Acylalanine
N-phenyl carbamates
Sulfamides/quinone
Target site
GABA-gated chloride
channel blocker
Mitochondrial complex
IV electron transport
inhibitor
Insect cell growth inhibitor
RNA polymerase
B-tubulin assembly in mitosis
multi-site contact activity
Chemical
Name
ethiprole
phosphine gas
pyridalyl
benalaxyl-M
diethofencarb
dithianon,
tolylfluanid
Of these cases above, one (phosphine gas), because of its gaseous state would not be amenable to
a dietary residue-based risk assessment and so would not rely on subacute dietary toxicity
endpoints for the risk assessment. One, pyridalyl, represents a potentially bioaccumulative
compound which would trigger an exception to the waiver process as outlined later in this
document. The remaining compounds have not undergone ecological risk assessments to
support regulatory decision-making primarily because the regulatory decisions were import
tolerances.
Therefore, in most of the unevaluated cases (87%), the chemical class was represented by an
analogue in the RQ analysis, and the remaining cases are either immaterial to the analysis
because of a lack of dietary exposure pathway, the lack of any regulatory decisions requiring an
ecological risk assessment or are material to pesticide characteristics that would form criteria for
an exception to the waiver policy. Therefore, the available analyses lend confidence in the
results of the quantitative evaluation of RQs conducted to inform the expectations for risk
assessments going forward.
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3. Discussion: Implications of the Retrospective Analysis on the Utility of Avian Sub-
Acute Dietary Studies in Select Situations
This analysis is intended to address whether OPP can confidently assess acute risk for birds
using a reduced suite of effects studies focusing on the single oral dose protocol. As described
above, the retrospective analysis indicates that for almost all the pesticides in which the risk
conclusions across study types could be compared (>99%), the sub-acute dietary results had an
obvious lack of impact on the risk conclusions already reached using the acute oral data. The one
exception involved a chemical that impacts birds via accumulative damage and results in delayed
mortality {i.e., an anti-coagulant pesticide). For this chemical, the risk quotients using the sub-
acute dietary study risk quotients results were larger than those reached using the acute oral
study data. While in this particular case the conclusions of the risk assessment were not
impacted relative to exceedance of OPP levels of concern thresholds, in other cases such a larger
risk quotient observed for the dietary-based analysis might alter risk management decisions.
Encountering this nuanced exception in the analysis has led to include in section 4 of this
document a consideration of pesticide accumulation and toxicity properties that could likely
trigger a denial of a waiver.
Furthermore, a majority of pesticides that could not be evaluated because of a lack of avian risk
assessment information shared a MOA with a chemical included in the analysis {i.e., they had
analogs that were included in the analysis). There is a small subset of chemicals that had unique
MO As and did not share an analog with chemicals included in the analysis. Therefore, there is
uncertainty in how the risks based on avian acute oral and sub-acute dietary studies may compare
for this small subset of MO As chemicals and any chemical not sharing a MOA with a chemical
included in the analysis. EPA has included mechanism of action considerations in section 4 of
this document as an information area for consideration regarding a request to waive avian sub-
acute dietary testing.
A strength of existing sub-acute dietary toxicity tests is that the study can account for situations
where the properties of the chemical are such that there may be a rate-limiting step in the
absorption of the compound. The more protracted nature of the exposure period (the subject
animals receive a dose spread out across several days of dietary consumption) has the potential
to not reach absorption limits of the chemical as opposed to the intensive single oral exposure
study. In such cases of rate limited absorption, there is the potential for the single oral dose
study to underestimate effects under field conditions. Also, in cases where effects may be
cumulative over time or the chemical may accumulate in the body or selected sites of action over
time (e.g., the liver for second-generation anticoagulant rodenticides) to a point where a
biological effects threshold is reached, the sub-acute dietary study may provide a more relevant
short-term effects measure than the single oral dose study. The subsequent waiver
recommendation below includes points to consider from available data in this regard.
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4. Draft Waiver Guidance
OPP believes this retrospective analysis demonstrates that waivers may be granted for avian sub-
acute dietary testing unless one of the conditions described below is triggered. Possible
exceptions to the waiver could include:
Chemicals with unique/unspecified MO As or those chemicals with MO As not evaluated
in the retrospective analysis unless the waiver request presents evidence that the
chemical's MOA is not reasonably expected to result in accumulative damage. To the
extent that EPA receives studies on additional MO As that demonstrate such a showing,
EPA would likely waive the avian sub-acute dietary testing for pesticide with these
additional MO As without requiring additional information.
Chemicals with MOAs that suggest a mechanism for accumulative damage (i.e., where
pesticidal effects increase with repeated exposure over time)
Chemicals with a high potential for bioaccumulation or a saturable facilitated mechanism
of adsorption, as indicated by a weight of evidence evaluation of the following properties:
o High octanol-water partition coefficient (logKow>4) and high molecular weight
o High bioconcentration factor in fish (BCF>1000) (OCPPT850.17308) or
information suggesting limited metabolism and excretion
¦ Bioconcentration study showing low pesticide clearance rates following
cessation of exposure
o Mammalian toxicity and animal residue studies
¦ Results from a metabolism study (OPPTS 870.74859) that shows pesticide
absorption rates significantly lower at high doses than low doses or
clearance rates that are slow enough to suggest that repeated doses with
result in accumulated body burden
¦ The use of daily oral dose exposure in subchronic and chronic mammalian
studies when the usual exposure route is dietary
¦ Any data showing acute dietary endpoints that are lower than acute oral
endpoints in mammalian testing when adjusted for daily ingested dose.
¦ Results for residue studies (OPPTS 860.148010) showing:
• pesticide absorption rates significantly lower at high doses than
low doses suggestive of a saturable absorption mechanism and/or
• very low rates of metabolism and excretion (e.g. little to know
proportion of the parent found as metabolites, excretion rats on the
order of weeks)
Chemicals in which an avian acute oral study cannot be conducted (e.g., when the
chemical causes regurgitation via the acute oral route)
8 USEPA2016. Ecological Effects Test Guidelines. OCSPP 850.1730 Fish Bioconcentration Factor.
httpsi//www, regulations,gov/document?D=EPA-HQ-QPPT-2Q09-0154-0031
9 USEPA 1998. Health Effects Test Guideline OCSPP 870.7485 Metabolism and Pharmacokinetics
httpsi//www, regulations,gov/document?D=EPA-HQ-OPPT-2Q09~Q 156-0047
10 USEPA 1996. Residue Chemical Test Guidelines. 860.1480 Meat/Milk/Poultry/Eggs
httpsi//www, regulations,gov/document?D=EPA-HQ-OPPT-2Q09~Q 155-0012
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Applicants should submit requests to waive the data requirement for avian sub-acute dietary
toxicity studies as part of their registration application through existing processes. Waiver
requests should include all relevant information to support an EPA evaluation of the evidentiary
grounds for the waiver request to include the rationale for why the proposed chemical is not
subject to the criteria for waiver denial under Section 4 of this document.
This document and its finding do not necessarily preclude sub-acute dietary testing for birds.
Despite the protection nature of risk assessments relying on the single oral dose acute endpoint,
avian sub-acute dietary testing may bring perspective to a risk assessment and improve the
knowledge base supporting a regulatory decision. For example, avian sub-acute dietary studies
are a logical default study to arrive at a passerine lethal acute toxicity endpoint in cases where
test subject regurgitation has been demonstrated to be an insurmountable obstacle to establishing
a reliable single oral dose lethal endpoint. Similarly, the ability for the dietary study to account
for the potential for dietary matrix to be mitigatory for chemical absorption and thus toxicity may
also be a situation where additional information may be useful. The repeated and expected lower
episodic doses associated with the dietary study, if showing diminished effects relative to a
single oral challenge dose, may provide evidence of compensatory mechanisms in the test
organism nature of the subacute. Finally, inclusion of subacute dietary studies has the potential
to increase the number of testing avian species, theoretically affecting a distributional
consideration in the avian risk assessment, but only if the studies were rigorous enough to allow
for dose-based endpoints to be established.
5. Effect on Animal Testing Burden
Granting sub-acute dietary toxicity test waivers under the conditions described above has the
potential to reduce the number of animals tested by a total of 60 birds per test {i.e., 10 birds in
control and 10 birds in each of five tested dietary concentrations), based on the recommendation
outlined in OCSPP 850.2100. There are typically two species tested, bringing the reduction in
the number of birds up to 120 per chemical. With a typical average of 6 new chemicals
registered per year, the adoption of this guidance can reduce the number of animals tested by
approximately 720 animals per year. In cases where the avian dietary study is waived, fewer
species will be tested (i.e., two rather than three) thereby increasing uncertainty regarding species
sensitivity.
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Appendix A
Lists of Pesticide Active Ingredients for the Retrospective Analysis and the Mechanisms
of Pesticidal Action
10
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A
INSECTICIDE
B
HERBICIDE
Acequinocyl
Neonicotinoids
Acequinocyl
Thiamethoxam
Clothi ani din
Acetamiprid
Dinotefuran
Acetamlprid
Thiacloprid
Avermectins
~xadiazines
Emameciin Benzoate
Indoxacarb
Milbemectin
Phenylpyrazoles
Benzoylureas
Ethiprole
Novaluron
Noviflumuron
Phosphides
Flufenoxuron
Phosphine Gas
Lufenuron
Teflubenzuron
Pyrethroids/Pyrethrins
Etofenprox
Beta-
Imiprothrin
ketonitrilederivatives
Flumethrin
Cyflumetofen
Pyridalyl
Bifenazate
Pyridalyl
Bifenazate
Pyridine azomethine
Buprofezin
Pymetrozine
Buprofezin
Pyrifluquinazon
Butenolides
Semicarbaiones
Flupyradlfurone
Metafiumkone
Cypermethrin
Spinosyns
alpha-Cypermethrin
Spinetoram
Dlacylhydraziries
Sulfoximines
Methoxyfenozide
Sutfoxaftor
Diamides
Tetronic and Tetramic
Chlorantraniliprole
Spirotetramat
Cyantranili prole
Spirodiclofen
Flubendiamide
Spiromesifen
Etoxazole
NA
Etoxazole
Metofluthrin
Momfluorothrin
Flonicamid
Lithium (perfluorooctane)-
Flonicamid
Sulfonat©
METI acaricides and
Insecticides
Fenazaquin
Tolfenpyrad
Fenpyroximate
Tebufenpyrad
Alkylazines
Pyrimidinyl(thio)
Indaziflam
benzoate
Bispyribac Sodium
Aryloxyphenoxy-
propionate 'FOPs'
Sulfonylamino carbonyl-
Ctodinafop-propargy!
triazolinone
Cyhatofop-butyl
Flucarbazorie-sodium
Thiencarbazorie-methyl
Arylpicolinate
Propoxycarbazorie-Sodium
Halauxifen-methyl
Sulfonylurea
Cyclohexanedione
Flazasulfuron
'DIMs'
Foramsulfuron
Tralkoxydirri
Imazosulfurori
Mesosulfuron-methyl
Isoxazole
Orthosulfamuron
Isoxaflutole
Sulfosulfuron
Trifloxysulfuron-sodium
Long Chain Fatty
Ethametsulfuron Methyl
Acid Inhibitor
Pyroxasulfone
Thiadiazole
Fluthiacet-rnethyl
N-phenylphthalimide
Flumloxazln
Triazine
Propazine
Other (PPO)
Flufenpyr-ethyl
Triazolinone
Amicarbazone
Oxyacetamide
Carfentrazone-ethyl
Flufenacet
Azafenidin
Phenylpyrazole
Triazolopyrimidine
Pyraflufen-ethyl
Cloransulam-methyl
Florasulam
Phenyipyrazoline
Penoxsulam
Pinoxaden
Pyroxsulam
Diclosulam
Phthalamate
Semicarbazone
Triketone
Diflufenzopyr
Mesotriorie
Pyridine
NA
carboxylic acid
Aminocyclopyrachlor
Aminopyralid
Bicyclopyrone
Fluroxypyr
lodosulfuronmethyl Sodium
Pyrasulfatole
Pyrimidinediones
Tembotrione
Saflufenacil
Topramezone
Butafenacil
11
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c
FUNGICIDE
D
OTHER
2,6-dinitro-anilines
Methoxy-carbamates
Toluamides
Fiuazmarn
Pyraclostrobin
Zoxamide
Acyl alanines
Morpholines
Triazoles
Benalaxyl-M
Fenpropimorph
Flutriafo!
Ipconazole
Amino-pyrazoiinone
N-methoxy-pyrazole-
Meteor/azote
Fenpyrazamine
carboxamides
Bromuconazole
Pydiflumetofen
Epoxiconazole
Anilino-pyrlmidines
Tetraconazole
Cyprodinii
N-phenylcarbamates
Triticonazole
Mepanipyrim
Diethofencarb
Pyrimethanil
Triazolinthiones
Oxazolidine-diones
Prothioconazole
Aromatic hydrocarbons
Famoxadone
Tokiofos-rnethyl
Triazolo-
Oximino-acetates
pyrimidylamine
Aryloxyquinoline
Kresoxim-methyl
Ametoctradin
Quinoxyfen
T ri f ioxy strob i n
Valinamide carbamates
Benzophenone
Phenylacet amide
Benthiavalicarb-isopropyl
Metrafenone
Cyflufenamid
Iprovalicarb
Benzothiadiazole
Phenyl-oxo-
NA
Acibenzolar-s-methyl
ethylthlophene amide
Macleaya extract chloride
Isofetamid
Benzoylpyridine
Pyriofenone
Picoiinamides
Amiisulbrom
Cinnamic acid amides
Dimethomorph
Piperidines
Fenpropidin
Cyanoacetamideoxime
Spiroxamine
Cymoxanil
Piperidinyl-
Cyano-lmidazole
thiazoieisoxazolines
Cyazofamid
Oxathiapiprolin
Dihydro-dioxazines
Pyrazole-
Fluoxastrobin
4-carboxamides
Bsrrzovindiflupyr
Dinitrophenyl-crotonates
Fiuxapyroxati
Meptyldinocap
Penflufen
Penthiopyrad
Ethyl amino-
Sedaxane
thiazolecarboxamide
Isopyrazam
Ethaboxam
Pyridine carboxamides
Hexopyranosyl antibiotic
Nicobifen
Kasugamycin
Pyridinyl-
Hydroxy anilides
ethylbenzamides
Fenhexamid
Fluopyram
Imidazolinones
Pyridinylmethyl
Fenamidone
benzamides
Fluopicolide
Mandelic acid amides
Mandipropamid
Quinazolinone
Proquinazid
Methoxy-acetamide
Mandestrobin
Quinones
Dithianon
Methoxy-acrylates
Picoxystrobin
Sulfamides
Tolyltluariid
Prohexadione Calcium
Oxalic acid
Nicarbazin
lodornethane
n-methylneodecanami d e
Mammalian Gonadotropin Releasing Hormone
Ammonium Nitrate
Calcium Nitrate
Cuprous Chloride
EH-2001
Oxysilver Nitrate
Potassium tri-iodide
S-Dimethenamid
Sodium nitrite
Tepraloxydim
Zona-Stat
Fiuensuifone
Fosthiazate
Furfural
Demiditraz
Forchlorfenuron
PT807 (Ecolyst)-HCI
VCD and Triptotide
Difenacoum
alpha-Chlorohydrin
Acetaminophen
Dimethyl disulfide
12
-------
General Pest
IRAC/HRAC /
Chemical
MOA
Total Number of
Total Number of
Total
Target
FRAC
Class/AI
TARGET SITE
chemicals
chemicals
Number of
Putative
IRAC/HRAC/
IRAC/HRAC/
Chemicals
mechanism of
FRAC have
FRAC have
action
(includes all
assigned to the
MOA with a
assigned to the
MOA without a
MOAs for all
definitive and/or
definitive and/or
chemicals
limit test
limit test
1998-2017 set)
INSECTICIDES
IB
Organophosphates
Acetylcholineste
rase (AChE)
inhibitors. Nerve
action
1
0
1
2B
Phenylpyrazoles
GABA-gated
chloride channel
blockers. Nerve
action
0
1
1
3A
Cypermethrin;
Pyrethroids;
Pyrethrins
Sodium channel
modulators.
Nerve action
3
1
4
4A
Neonicotinoids
Nicotinic
acetylcholine
receptor
(nAChR)
competitive
modulators.
Nerve action
5
0
5
4C
Sulfoximines
Nicotinic
acetylcholine
receptor
(nAChR)
competitive
modulators.
Nerve action
1
0
1
13
-------
General Pest
Target
IRAC/HRAC /
FRAC
Putative
mechanism of
action
(includes all
MOAs for all
chemicals
1998-2017 set)
Chemical
Class/AI
MOA
TARGET SITE
Total Number of
chemicals
IRAC/HRAC/
FRAC have
assigned to the
MOA with a
definitive and/or
limit test
Total Number of
chemicals
IRAC/HRAC/
FRAC have
assigned to the
MOA without a
definitive and/or
limit test
Total
Number of
Chemicals
4D
Butenolides
Nicotinic
acetylcholine
receptor
(nAChR)
competitive
modulators.
Nerve action
1
0
1
5
Spinosyns
Nicotinic
acetylcholine
receptor
(nAChR)
allosteric
modulators.
Nerve action
1
0
1
6
Avermectins;
Milbemycins
Glutamate-gated
chloride channel
(GluCl)
allosteric
modulators.
Nerve and
muscle action
1
1
2
9B
Pyridine
azomethine
derivatives
Chordotonal
organ TRPV
channel
modulators.
Nerve action
2
0
2
14
-------
General Pest
Target
IRAC/HRAC /
FRAC
Putative
mechanism of
action
(includes all
MOAs for all
chemicals
1998-2017 set)
Chemical
Class/AI
MOA
TARGET SITE
Total Number of
chemicals
IRAC/HRAC/
FRAC have
assigned to the
MOA with a
definitive and/or
limit test
Total Number of
chemicals
IRAC/HRAC/
FRAC have
assigned to the
MOA without a
definitive and/or
limit test
Total
Number of
Chemicals
10B
Etoxazole
Mite growth
inhibitors.
Growth
regulation
1
0
1
15
Benzoylureas
Inhibitors of
chitin
biosynthesis,
type 0. Growth
regulation
2
3
5
16
Buprofezin
Inhibitors of
chitin
biosynthesis,
type 1. Growth
regulation
1
0
1
18
Diacylhydrazines
Ecdysone
receptor
agonists.
Growth
regulation
1
0
1
20B
Acequinocyl
Mitochondrial
complex TIT
electron
transport
inhibitors.
Energy
metabolism
1
0
1
15
-------
General Pest
Target
IRAC/HRAC /
FRAC
Putative
mechanism of
action
(includes all
MOAs for all
chemicals
1998-2017 set)
Chemical
Class/AI
MOA
TARGET SITE
Total Number of
chemicals
IRAC/HRAC/
FRAC have
assigned to the
MOA with a
definitive and/or
limit test
Total Number of
chemicals
IRAC/HRAC/
FRAC have
assigned to the
MOA without a
definitive and/or
limit test
Total
Number of
Chemicals
20D
Bifenazate
Mitochondrial
complex TIT
electron
transport
inhibitors.
Energy
metabolism
1
0
1
21A
METI acaricides
and
insecticides
Mitochondrial
complex I
electron
transport
inhibitors.
Energy
metabolism
3
1
4
22A
Oxadiazines
Voltage-
dependent
sodium channel
blockers. Nerve
action
1
0
1
22B
Semicarbazones
Voltage-
dependent
sodium channel
blockers. Nerve
action
1
0
1
16
-------
General Pest
Target
IRAC/HRAC /
FRAC
Putative
mechanism of
action
(includes all
MOAs for all
chemicals
1998-2017 set)
Chemical
Class/AI
MOA
TARGET SITE
Total Number of
chemicals
IRAC/HRAC/
FRAC have
assigned to the
MOA with a
definitive and/or
limit test
Total Number of
chemicals
IRAC/HRAC/
FRAC have
assigned to the
MOA without a
definitive and/or
limit test
Total
Number of
Chemicals
23
Tetronic and
Tetramic
acid derivatives
Inhibitors of
acetyl CoA
carboxylase
Lipid synthesis.
Growth
regulation
1
2
3
24A
Phosphides
Mitochondrial
complex IV
electron
transport
inhibitors.
Energy
metabolism
0
1
1
25A
Beta-ketonitrile
derivatives
Mitochondrial
complex II
electron
transport
inhibitors.
Energy
metabolism
1
0
1
28
Diamides
Ryanodine
receptor
modulators.
Nerve and
muscle action
3
0
3
17
-------
General Pest
Target
IRAC/HRAC /
FRAC
Putative
mechanism of
action
(includes all
MOAs for all
chemicals
1998-2017 set)
Chemical
Class/AI
MOA
TARGET SITE
Total Number of
chemicals
IRAC/HRAC/
FRAC have
assigned to the
MOA with a
definitive and/or
limit test
Total Number of
chemicals
IRAC/HRAC/
FRAC have
assigned to the
MOA without a
definitive and/or
limit test
Total
Number of
Chemicals
29
Flonicamid
Chordotonal
organ
Modulators -
undefined target
site. Nerve
action
1
0
1
UN
Unknown
Unknown,
pyridalyl
0
1
1
NA
NA
NA
7
NA
7
FUNGICIDES
A1
Acylalanines
RNA
polymerase I
0
1
1
B2
N-phenyl
carbamates
B-tubul in
assembly in
mitosis
0
1
1
B3
ethylamino-
thiazolecarboxami
de;toluamides
B-tubul in
assembly in
mitosis
2
0
2
B5
pyridinylmethyl
benzamides
delocalisation of
spectrin-like
proteins
1
0
1
18
-------
General Pest
IRAC/HRAC /
Chemical
MOA
Total Number of
Total Number of
Total
Target
FRAC
Class/AI
TARGET SITE
chemicals
chemicals
Number of
Putative
IRAC/HRAC/
IRAC/HRAC/
Chemicals
mechanism of
FRAC have
FRAC have
action
assigned to the
assigned to the
(includes all
MOA with a
MOA without a
MOAs for all
definitive and/or
definitive and/or
chemicals
limit test
limit test
1998-2017 set)
B6
benzoylpyridine;
benzophenone
actin/myosin/fi
mbrin function
1
1
2
C2
pyrazole-4-
carboxamides; N-
methoxy-
(phenylethyl)-
pyrazolecarboxam
ides; pyridinyl-
ethylbenzamides;
phenyl-oxo-ethyl
thiophene amide;
pyridine
carboxamides
Complex II:
succinate-
dehydrogenase
8
2
10
C3
oxazolidine-
diones;
Imidazolinones;
oximino-acetates;
methoxy-
acetamide;
methoxy-
acrylates;
methoxy-
carbamates;
oximino-acetates;
dihydro-
dioxazines
Complex TIT:
cytochrome bcl
(ubiquinol
oxidase) at Qo
site (cyt b gene).
6
2
8
19
-------
General Pest
Target
IRAC/HRAC /
FRAC
Putative
mechanism of
action
(includes all
MOAs for all
chemicals
1998-2017 set)
Chemical
Class/AI
MOA
TARGET SITE
Total Number of
chemicals
IRAC/HRAC/
FRAC have
assigned to the
MOA with a
definitive and/or
limit test
Total Number of
chemicals
IRAC/HRAC/
FRAC have
assigned to the
MOA without a
definitive and/or
limit test
Total
Number of
Chemicals
C4
picolinamides;
cyano-imidazole
Complex TIT:
cytochrome bcl
(ubiquinone
reductase) at Qi
site
1
1
2
C5
dinitrophenyl-
crotonates; 2,6-
dinitro-anilines
uncouplers of
oxidative
phosphorylation
1
1
2
C8
triazolo-
pyrimidylamine
Complex TIT:
cytochrome bcl
(ubiquinone
reductase) at Qo
site, stigmatellin
binding sub-site
1
0
1
D1
anilino-
pyrimidines
methionine
biosynthesis
(proposed) (cgs
gene)
1
2
3
D3
hexopyranosyl
antibiotic
protein synthesis
(ribosome,
initiation step)
1
0
1
El
quinazolinone;
aryloxyquinoline
signal
transduction
(mechanism
unknown)
1
1
2
20
-------
General Pest
Target
IRAC/HRAC /
FRAC
Putative
mechanism of
action
(includes all
MOAs for all
chemicals
1998-2017 set)
Chemical
Class/AI
MOA
TARGET SITE
Total Number of
chemicals
IRAC/HRAC/
FRAC have
assigned to the
MOA with a
definitive and/or
limit test
Total Number of
chemicals
IRAC/HRAC/
FRAC have
assigned to the
MOA without a
definitive and/or
limit test
Total
Number of
Chemicals
F3
aromatic
hydrocarbons
cell peroxidation
(proposed)
1
0
1
F9
piperidinyl-
thiazoleisoxazolin
es
lipid
homeostasis and
transfer/storage
1
0
1
G1
triazoles;
triazolinthiones
C14-
demethylase in
sterol
biosynthesis
(ergll/cyp51)
4
4
8
G2
piperidines;
morpholines
A14-reductase
and A8, A7-
isomerase in
sterol
biosynthesis
(erg24, erg2)
1
2
3
G3
hydroxyanilides;
amino-
pyrazolinone
3-keto
reductase, C4-
de-methylation
(erg27)
2
0
2
H5
valinamide
carbamates;
cinnamic acid
amides; mandelic
acid amides
cellulose
synthase
2
2
4
21
-------
General Pest
Target
IRAC/HRAC /
FRAC
Putative
mechanism of
action
(includes all
MOAs for all
chemicals
1998-2017 set)
Chemical
Class/AI
MOA
TARGET SITE
Total Number of
chemicals
IRAC/HRAC/
FRAC have
assigned to the
MOA with a
definitive and/or
limit test
Total Number of
chemicals
IRAC/HRAC/
FRAC have
assigned to the
MOA without a
definitive and/or
limit test
Total
Number of
Chemicals
M
sulfamides;
quinones
multi-site
contact activity
0
2
2
PI
benzothiadiazole
(BTH)
salicylate-
related
1
0
1
U
phenylacetamide;
cyanoacetamideox
ime
unknown
2
0
2
NA
NA
NA
2
0
2
HERBICIDES
A
Aryloxyphenoxy-
propionate 'FOPs'
Lipid synthesis
Inhiition
(inhibition of
ACCase)
1
0
1
A
Cyclohexanedione
'DIMs'
Lipid synthesis
Inhiition
(inhibition of
ACCase)
1
0
1
A
Phenylpyrazoline
'DEN'
Lipid synthesis
Inhiition
(inhibition of
ACCase)
1
1
2
B
Pyrimidinyl (thio)
benzoate
Inhibition of
ALS (branched
chain amino
acid synthesis)
1
0
1
22
-------
General Pest
Target
IRAC/HRAC /
FRAC
Putative
mechanism of
action
(includes all
MOAs for all
chemicals
1998-2017 set)
Chemical
Class/AI
MOA
TARGET SITE
Total Number of
chemicals
IRAC/HRAC/
FRAC have
assigned to the
MOA with a
definitive and/or
limit test
Total Number of
chemicals
IRAC/HRAC/
FRAC have
assigned to the
MOA without a
definitive and/or
limit test
Total
Number of
Chemicals
B
T riazolopyrimidin
e
Inhibition of
ALS (branched
chain amino
acid synthesis)
3
1
4
B
Sulfonylurea
Inhibition of
ALS (branched
chain amino
acid synthesis)
7
1
8
B
Sulfonylamino-
carbonyl-
triazolinone
Inhibition of
ALS (branched
chain amino
acid synthesis)
2
1
3
CI
Triazolinone
Inhibition of
photosynthesis
at photosystem
II
1
0
1
CI
Triazine
Inhibition of
photosynthesis
at photosystem
II
1
0
1
E
Triazolinone
Inhibition of
protoporphyrino
gen oxidase
1
1
2
E
Other (PPO)
Inhibition of
protoporphyrino
gen oxidase
1
0
1
23
-------
General Pest
IRAC/HRAC /
Chemical
MOA
Total Number of
Total Number of
Total
Target
FRAC
Class/AI
TARGET SITE
chemicals
chemicals
Number of
Putative
IRAC/HRAC/
IRAC/HRAC/
Chemicals
mechanism of
FRAC have
FRAC have
action
assigned to the
assigned to the
(includes all
MOA with a
MOA without a
MOAs for all
definitive and/or
definitive and/or
chemicals
limit test
limit test
1998-2017 set)
E
N-
phenylphthalimide
Inhibition of
protoporphyrino
gen oxidase
1
0
1
E
Thiadiazole
Inhibition of
protoporphyrino
gen oxidase
1
0
1
E
Phenylpyrazole
Inhibition of
protoporphyrino
gen oxidase
1
0
1
E
Pyrimidindione
Inhibition of
protoporphyrino
gen oxidase
1
1
2
F
NA
Inhibition of
pigment
synthesis
(bleaching)
1
0
1
F2
NA
Inhibition of 4-
HPPD
3
0
3
F2
Isoxazole
Inhibition of 4-
HPPD
1
0
1
F2
Triketone
Inhibition of 4-
HPPD
1
0
1
24
-------
General Pest
Target
IRAC/HRAC /
FRAC
Putative
mechanism of
action
(includes all
MOAs for all
chemicals
1998-2017 set)
Chemical
Class/AI
MOA
TARGET SITE
Total Number of
chemicals
IRAC/HRAC/
FRAC have
assigned to the
MOA with a
definitive and/or
limit test
Total Number of
chemicals
IRAC/HRAC/
FRAC have
assigned to the
MOA without a
definitive and/or
limit test
Total
Number of
Chemicals
K3
Oxyacetamide
Inhibition of cell
division
(inhibition of
VLCFAs)
1
0
1
K3
Other
Inhibition of cell
division
(inhibition of
VLCFAs)
1
0
1
L
Alkylazines
Inhibition of
cellulose
synthesis
1
0
1
0
Pyridine
carboxylic acid
Synthetic
Auxins
1
1
2
0
Arylpicolinate
NA
1
0
1
P
Phthalamate
Semicarbazone
Inhibition of
auxin transport
1
0
1
NA
NA
NA
3
0
3
25
-------
General Pest
IRAC/HRAC /
Chemical
MOA
Total Number of
Total Number of
Total
Target
FRAC
Class/AI
TARGET SITE
chemicals
chemicals
Number of
Putative
IRAC/HRAC/
IRAC/HRAC/
Chemicals
mechanism of
FRAC have
FRAC have
action
assigned to the
assigned to the
(includes all
MOA with a
MOA without a
MOAs for all
definitive and/or
definitive and/or
chemicals
limit test
limit test
1998-2017 set)
OTHER (NO
Oxalic acid
Antimicrobial
DATA)
Pesticide
Nicarbazin
Egg Hatch
Reduction in
Resident Canada
Geese
Macalayea
Extract,
Fungicide
Macleaya
extract chloride
n-
methylneodeca
namide
Insect Repellent
Lithium
Insecticide
(perfluorooctan
e) Sulfonate
Mammalian
Mammalian
Gonadotropin
Releasing
Hormone
Contraceptive
Ammonium
NA
Nitrate
Calcium Nitrate
NA
Cuprous
Chloride
NA
EH-2001
NA
26
-------
General Pest
IRAC/HRAC /
Chemical
MOA
Total Number of
Total Number of
Total
Target
FRAC
Class/AI
TARGET SITE
chemicals
chemicals
Number of
Putative
IRAC/HRAC/
IRAC/HRAC/
Chemicals
mechanism of
FRAC have
FRAC have
action
assigned to the
assigned to the
(includes all
MOA with a
MOA without a
MOAs for all
definitive and/or
definitive and/or
chemicals
limit test
limit test
1998-2017 set)
Oxysilver
NA
Nitrate
Potassium tri-
NA
iodide
S-
NA
Dimethenamid
Sodium nitrite
NA
Tepraloxydim
NA
Zona-Stat
NA
Demiditraz
Pesticide
Forchlorfenuro
Plant Growth
n
Regulator
PT807
plant growth
(Ecolyst)-HCl
regulator
VCD and
rodent
Triptolide
contraceptive
alpha-
Rodenticide
Chlorohydrin
Dimethyl
Soil Fumigant
disulfide
27
------- |