                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                             WASHINGTON, DC  20460

                         OFFICE OF CHEMICAL SAFETY AND
                             POLLUTION PREVENTION

MEMORANDUM

DATE:	25 February 2019

SUBJECT:	Clopyralid. Draft Human Health Risk Assessment for Registration Review of the Herbicide.

PC Code:  117401 (Monoethanolamine salt)
117403 (Acid)
117404 (Triethanolamine salt)
117423 (Potassium salt)
DP Barcode:   D442247
Decision Number:  532539
Registration Number:  See Table 3.3
Petition Number:  NA
Regulatory Action:  Registration Review
Risk Assessment Type:  Single Chemical Aggregate
Case Number:  7212
TXR Number:  NA
CAS Number:  1702-17-6 (Acid)
MRID Number:  NA
40 CFR:  §180.431

FROM:	William T. Drew, Chemist
		Linnea J. Hansen, PhD, Biologist
		Gerad Thornton, Environmental Protection Specialist
		Risk Assessment Branch II (RAB2)
		Health Effects Division (HED), 7509P

		Matthew Manupella, Chemical Review Manager
		Risk Management and Implementation Branch II (RMIB2)
		Pesticide Re-evaluation Division (PRD), 7508P

THROUGH:	Christina Swartz, Branch Chief
		RAB2/HED, 7509P

TO:		Veronica Dutch, Chemical Review Manager, RM Team 53
		Khue Nguyen, Team Leader, RM Team 53
		Risk Management and Implementation Branch V (RMIB5)
		PRD, 7508P

As part of Registration Review, the Pesticide Re-evaluation Division (PRD) of the Office of Pesticide Programs (OPP) has requested that the Health Effects Division (HED) evaluate the hazard and exposure data, and conduct dietary, residential, aggregate and occupational exposure assessments, as needed, to estimate the risk to human health associated with registered uses of pesticides.  This memorandum serves as HED's draft human health risk assessment of the dietary, occupational, and residential exposures, and aggregate risk from the registered uses of the herbicide clopyralid (and its salts).  The most recent quantitative human health risk assessment was completed in 2018 to support requested new uses (D437662; W.T. Drew; 4 April 2018).  Since then, the following risk assessment updates have been made:

 A screening-level occupational handler assessment using updated task force data and policy assumptions; and
 A non-occupational spray-drift exposure/risk assessment was completed.

A summary of the findings and an assessment of human health risk resulting from the registered uses of clopyralid are provided in this document.
                               Table of Contents
1.0	Executive Summary	4
2.0	Risk Assessment Conclusions	6
2.1	Data Deficiencies	6
2.2	Tolerance Considerations	7
2.2.1	Enforcement Analytical Method	7
2.2.2	Recommended & Established Tolerances	7
2.2.3	International Harmonization	7
2.3	Label Recommendations	7
3.0	Introduction	8
3.1	Chemical Identity	8
3.2	Physical/Chemical Characteristics	8
3.3	Pesticide Use Pattern	9
3.4	Anticipated Exposure Pathways	12
3.5	Consideration of Environmental Justice	12
4.0	Hazard Characterization and Dose-Response Assessment	13
4.1	Endocrine Disruptor Screening Program	16
5.0	Dietary Exposure and Risk Assessment	17
6.0	Residential Exposure/Risk Characterization	18
6.1	Residential Handler Exposure/Risk Estimates	18
6.2	Residential Post-Application Exposure and Risk Estimates	18
6.3	Residential Risk Estimates for Use in Aggregate Assessment	19
7.0	Aggregate Exposure/Risk Characterization	19
7.1	Acute Aggregate Risk	19
7.2	Short-Term Aggregate Risk	19
7.3	Chronic Aggregate Risk	20
8.0	Non-Occupational Bystander Post-Application Inhalation Exposure and Risk Estimates	20
9.0	Non-Occupational Spray Drift Exposure and Risk Estimates	20
10.0	Cumulative Exposure/Risk Characterization	21
11.0	Occupational Exposure/Risk Characterization	22
11.1	Short-/Intermediate-Term Occupational Handler Exposure and Risk Estimates	22
11.2	Short-/Intermediate-Term Post-Application Exposure and Risk Estimates	28
11.2.1	Dermal Post-Application Risk	28
11.2.2	Inhalation Post-Application Risk	28
12.0	Incident and Epidemiological Data Review	29
13.0	References	30
Appendix A. Toxicology Profile and Executive Summaries	31
A.1	Toxicology Data Requirements	31
A.2	Toxicity Profiles	32
A.3	Literature Search	35
Appendix B. Physical/Chemical Properties of Clopyralid	37
Appendix C. Review of Human Research	38

 Executive Summary

The Health Effects Division (HED) has conducted a human health draft risk assessment (DRA) to evaluate all existing registrations of the active ingredient (ai) clopyralid and its salts.  Clopyralid (with CAS name 3,6-dichloro-2-pyridinecarboxylic acid, and IUPAC name 3,6-dichloropicolinic acid) is a pyridine herbicide registered for use on a wide variety of food and feed crops for the postemergence control of broadleaf weeds, particularly thistles and clover.  This memorandum was conducted as part of Registration Review, and includes an updated screening level occupational handler assessment.  A dietary exposure assessment was conducted in support of the most recent human health risk assessment for clopyralid (D438299; W.T. Drew; 4 April 2018), and did not need to be updated for this DRA.

Use Profile
Clopyralid is registered for use on a variety of agricultural crops (including fruits, vegetables, and cereal grains), as well as on non-residential turf, golf courses, athletic and recreational fields, ornamentals, grasses, and landscapes.

Exposure Profile
Humans may be exposed to clopyralid in food and drinking water since it may be applied in agricultural areas, and application may result in clopyralid reaching surface and groundwater sources of drinking water.  Clopyralid labels require specific clothing and/or personal protective equipment (PPE).  In accordance with current guidance, HED has assumed that the registered clopyralid products are not intended for use by residential handlers, based on all labels requiring the use of PPE.  Non-occupational exposure may also result from spray drift during agricultural applications onto nearby residential areas.

In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application.  There is also potential for post-application exposure for workers re-entering treated fields.

Hazard Characterization & Dose Response Assessment
The toxicology database for clopyralid is complete for assessment of human health risk, and no additional studies are required.  Toxicity was observed in the rat, mouse and dog, but consistent target organs were not identified.  In dogs, reductions in red blood cell parameters, increased liver weight, and vacuolated adrenal cortical cells were observed, with skin lesions and clinical chemistry changes at the highest dose.  In rats, stomach lesions were observed at the lowest-observed-adverse-effects level (LOAEL), and decreased body weight was observed at the high dose.  In mice, the only observed effects were decreased body weight/body weight gain.  No systemic toxicity was seen in a rabbit 21-day dermal toxicity study.  The available toxicology studies did not indicate the potential for neurotoxicity, immunotoxicity or reproductive toxicity.  There was no evidence of increased pre- and/or postnatal qualitative or quantitative susceptibility.  Developmental effects in the rabbit (hydrocephalus, decreased fetal weight) were observed in the presence of maternal mortality.  Developmental effects were not seen in the rat.  Additionally, the exposure estimates were based on conservative assumptions.  Therefore, HED has reduced the required 10X Food Quality Protection Act (FQPA) Safety Factor (SF) to 1X.

Endpoints have been selected for assessing chronic dietary exposure, inhalation exposure, and incidental oral exposure.  An endpoint for assessing a single oral exposure was not identified; therefore, an acute point of departure (POD) was not selected.  In the absence of toxicity via the dermal route, an endpoint for dermal risk assessment was not identified, and there is no risk associated with dermal exposure.  Clopyralid is classified as "not likely to be carcinogenic to humans," based on the lack of evidence of carcinogenicity in the rat and mouse carcinogenicity studies, and negative results of the genotoxicity assays.

Dietary/Residential/Aggregate Exposures and Risk Assessments
The residue chemistry database is complete and supports the existing uses for clopyralid.  HED has estimated dietary, residential, and aggregate risks from exposure to clopyralid.  Dietary risk estimates were well below HED's level of concern (LOC) for all population subgroups, with the maximum risk estimate being 26% of the chronic population adjusted dose (cPAD) for children 1-2 years old.  The dietary risk estimates were based on conservative assumptions regarding residues in food commodities and drinking water, and actual exposure and risk are expected to be significantly lower.  All registered clopyralid products require specific clothing (such as long-sleeved shirt, long pants) and/or PPE (such as chemical resistant gloves).  Therefore, HED assumed that the registered clopyralid labels are not intended for use by residential handlers, and a quantitative residential handler assessment was not conducted.  Several clopyralid end-use products (EPs) are registered for weed control on lawns, turf and ornamentals in residential and public areas.  Therefore, HED conducted a residential post-application incidental oral exposure assessment for children to be protective of potential exposure to toddlers, and for the purpose of conducting an aggregate risk assessment.  The margin of exposure (MOE) for aggregate risk was 1,600 and is not of concern.

Non-Occupational Spray Drift Assessment
A quantitative spray drift assessment for clopyralid was not required because the turf assessment is protective of potential exposure from drift.  The maximum application rate to a crop/target site multiplied by the adjustment factor for drift of 0.26 is less than the maximum direct spray residential turf application rate of 0.499 pounds of acid equivalent per acre (lb ae/A).  The turf post-application MOEs previously assessed in 2012, and were based on the revised 2012 Residential SOPs, and indicate no risk estimates of concern.  Therefore, there are no risk estimates of concern associated with potential exposure from drift.

Occupational Exposure and Risk Assessment
Occupational handler exposure estimates indicated that the short- and intermediate-term inhalation risks for handlers are not of concern (MOEs >= 1,400; LOC < 100) assuming baseline attire (long-sleeved shirt, long pants, shoes, socks and no respirator).

Occupational post-application workers may be exposed to residues of clopyralid via dermal and inhalation routes if they enter treated fields to perform crop-related activities, such as thinning, irrigation, scouting, harvesting, etc.  Dermal post-application exposure was not evaluated, due to the lack of toxicity via the dermal route.  Based on the Agency's current practices, a quantitative non-cancer occupational post-application inhalation exposure assessment was not performed for clopyralid at this time.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for clopyralid.

Environmental Justice
Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with US Executive Order 12898, Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations (see the website, https://www.epa.gov/laws-regulations/summary-executive-order-12898-federal-actions-address-environmental-justice).

Human Studies
This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical (see Appendix C).  Those studies are subject to ethics review, have received that review, and are compliant with applicable ethics requirements.  Appendix C provides additional information on the review of human research used to complete this risk assessment.  There is no regulatory barrier to continued reliance on these studies, and all applicable requirements of EPA's Rule for the Protection of Human Subjects of Research (40CFR §26) have been satisfied.

 Risk Assessment Conclusions

There are no dietary (food and water), residential or occupational handler/post-application risk estimates of concern for the registered uses of clopyralid.  There are no aggregate (food + drinking water + residential) risk estimates of concern for the scenario included in the aggregate assessment.  A dietary assessment was previously updated in 2018, and is included in this memorandum, since no food or drinking water residue inputs have changed (D438299; W.T. Drew; 4 April 2018).  A screening-level occupational handler assessment was conducted for this memorandum using the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler Exposure Task Force (AHETF) database, the Outdoor Residential Exposure Task Force (ORETF) database, the Residential SOPs (Lawn/Turf), and proprietary data (MRID #44339801, an evaluation of potential exposures to herbicides for applicators during the mixing procedure and application via backpack sprayer at Christmas tree farms).

 Data Deficiencies

None.

 Tolerance Considerations

       Enforcement Analytical Method

The Pesticide Analytical Manual Volume II (PAM II) lists a method utilizing gas chromatography with electron capture detection (GC/ECD) for determination of clopyralid residues in plant commodities (Method I or Method ACR 75.6).

For this method, residues are extracted with dilute NaOH (0.25% or 0.1%) and filtered.  The extract is then acidified and salinized, and residues are partitioned into ethyl ether.  Residues are then methylated using diazomethane, and cleaned up on an activated alumina column.  Residues are then determined by GC/ECD using external standards.  The reported LOQs are 0.50 ppm in grains, and 2.0 ppm in green forage.

The FDA multiresidue methods are not likely to recover clopyralid.  However, it does appear to be adequately recovered by the Quick, Easy, Cheap, Effective, Rugged and Safe (QuEChERS) multiresidue method (http://www.quechers.com).

       Recommended & Established Tolerances

The residue definition for clopyralid currently established under 40CFR §180.431[a] complies with HED's Guidance on Tolerance Expressions (S. Knizner; 27 May 2009).  Therefore, no revision of the residue definition is necessary.  HED is not recommending any revisions to the currently established tolerances.

       International Harmonization

US tolerances are harmonized with the corresponding Codex Alimentarius and/or Canadian maximum residue limits (MRLs) wherever feasible.  Mexico has established MRLs based on US tolerances and, therefore, they are at the same levels.  As a result, there are no harmonization issues with clopyralid.

 Label Recommendations

Although the clopyralid ai in all of its EPs are in the form of one of its salts, when diluted with water in a tank mix, they are converted to the clopyralid acid.  The clopyralid acid is a severe eye irritant (Acute Toxicity Category I), and HED recommends that all tank-mixed clopyralid EP labels stipulate a restricted entry interval (REI) of 48-hours.

 Introduction

 Chemical Identity

Clopyralid is an herbicide belonging to both the picolinic acid and pyridine chemical groups.  It is used to control broadleaf weeds.  Clopyralid is structurally similar to plant auxins, and acts as an auxin imitator, disrupting plant growth by binding to auxin receptors.  It is registered for use on a variety of field, fruit and vegetable crops in agricultural settings.  For non-crop uses, clopyralid is registered for application to pastures and rangeland, rights-of-way, forestry sites, tree plantations, ornamental grasses in landscapes and nurseries, and nonresidential turf grass (including golf courses and recreational areas).  Several clopyralid EPs are registered for weed control on lawns, turf and ornamentals in residential areas.  Registered formulations containing clopyralid as an ai include liquids (L), granules (G), and water-dispersible granules (WDG).  In these formulations, clopyralid may be in the form of organic (monoethanolamine, triethanolamine) or inorganic (potassium) salts.  The chemical structure and nomenclature of clopyralid are presented in Table 3.1, below.

TABLE 3.1	Clopyralid Nomenclature.
Compound

Common name
Clopyralid (acid)
Company experimental name
Dowco 290
Molecular formula
C6H3Cl2NO2
Molecular weight
192.0 amu
IUPAC name
3,6-dichloropyridine-2-carboxylic acid
CAS name
3,6-dichloro-2-pyridinecarboxylic acid
CAS number
1702-17-6 (acid)
57754-85-5 (monoethanolamine salt)
End-use product (EP)
See Table 3.3

 Physical/Chemical Characteristics

THE RESIDUE CHEMISTRY DATABASE FOR clopyralid is complete and adequate to support the recommended tolerance levels, and to conduct human health risk assessments.  The available metabolism data and information regarding physicochemical properties (vapor pressure of 1.33 mPa at 25°C, and octanol/water partition coefficient of -2.63 at pH 7) do not indicate that there are any special concerns with this chemical in terms of bioaccumulation, exposure or other risk assessment considerations.  A table of physical and chemical properties for clopyralid is included in Appendix B.

 Pesticide Use Pattern

Clopyralid is registered for a variety of uses on food crops, non-food crops, and non-agricultural areas. The use pattern and REI/PHI requirements were compiled by using master use information provided by the Biological and Economic Analysis Division (BEAD), and by conducting a screening-level review of all the registered labels (HED did not capture every single label, but rather based its assessment on the highest application rates and scenarios, such that the risk assessment is protective of any potential occupational exposure to clopyralid). The representative selection of the registered uses is included in Table 3.3, below.

TABLE 3.3	Summary of Use Directions for Clopyralid.
                             Application Equipment
                     EPA Registration Number [Formulation]
                            Max Use Rate (lb ae/A)
                          Max Number of Uses per Year
                         Max Annual Use Rate (lb ae/A)
                                  PHI (Days)
                        Use Directions and Limitations
                               Orchard/Vineyard
                                  Groundboom
                                 62719-73 [EC]
                                     0.255
                                       2
                                      NS
                                      30
Disallowed in ● California ● Florida ● Nassau County, New York ● Suffolk County, New York
                Manually/ mechanically pressurized hand sprayer
                                 62719-73 [EC]
                              0.255 lb ae/acre[1]
                                       2
                                      NS
                                      30
Disallowed in ● California ● Florida ● Nassau County, New York ● Suffolk County, New York
                              Field Crop, Typical
                  Manually/ mechanically pressurized handgun
                                 62719-73 [EC]
                            0.255 lb ae/ gallon[2]
                                       2
                                      NS
                                      30
    Disallowed in ● Nassau County, New York ● Suffolk County, New York
                                  Groundboom
                                 62719-73 [EC]
                                     0.375
                                       2
                                      NS
                                      30
    Disallowed in ● Nassau County, New York ● Suffolk County, New York
                                  Groundboom
                                62719-278 [DF]
                                     0.22
                                      NS
                                      NS
                                      NS
                                      NS
                                    Aerial
                                 62719-73 [EC]
                                     0.261
                                       2
                                      NS
                                      30
    Disallowed in ● Nassau County, New York ● Suffolk County, New York
                           Field Crop, High Acreage
                                  Groundboom
                                 62719-73 [EC]
                                     0.261
                                       2
                                      NS
                                      30
    Disallowed in ● Nassau County, New York ● Suffolk County, New York
                                  Groundboom
                         62719-278 [DF] 62719-279 [WP]
                                     0.22
                                      NS
                                      NS
                                      NS
                                      NS
                                    Aerial
                                 62719-73 [EC]
                                     0.251
                                       2
                                      NS
                                      30
    Disallowed in ● Nassau County, New York ● Suffolk County, New York
                                Shank Injection
                               34704-1094 (SC/L)
                                     0.22
                                      NS
                                     0.28
                                      85
    Disallowed in ● Nassau County, New York ● Suffolk County, New York
                                  Grass/Turf
                                  Groundboom
                                62719-259 [EC]
                                     0.510
                                       2
                                      NS
                                      NA
Disallowed in ● Nassau County, New York ● Suffolk County, New York ● Not for use in landscaping, or on turfgrass or lawns (may be applied to parks and recreational areas).
                            Tractor-drawn spreader
                                 62719-262 [G]
                                     0.187
                                       2
                                      NS
                                      NA
    Disallowed in ● Nassau County, New York ● Suffolk County, New York
                Manually/ mechanically pressurized hand sprayer
                                62719-259 [EC]
                            0.510 lb ae/ gallon[3]
                                       2
                                      NS
                                      NA
    Disallowed in ● Nassau County, New York ● Suffolk County, New York
                                    Aerial
                                62719-259 [EC]
                                     0.499
                                      NS
                                      NS
                                      NA
    Disallowed in ● Nassau County, New York ● Suffolk County, New York
                                Rotary Spreader
                                 62719-262 [G]
                                     0.187
                                      NS
                                      NS
                                      NA
    Disallowed in ● Nassau County, New York ● Suffolk County, New York
                                    Nursery
                                  Groundboom
                                62719-305 [EC]
                                     0.51
                                      NS
                                      NS
                                      NA
                                      NA
         Backpack, or manually/ mechanically pressurized hand sprayer
                                62719-305 [EC]
                            0.0255 lb ae/ gallon[4]
                                      NS
                                      NS
                                      NA
                                      NA
                                   Forestry
                                  Groundboom
                         62719-73 [EC] 62719-259 [EC]
                                     0.499
                                      NS
                                      NS
                                      NA
Disallowed in ● Florida ● Nassau County, New York ● Suffolk County, New York
         Backpack, or manually/ mechanically pressurized hand sprayer
                                62719-259 [EC]
                            0.255 lb ae/ gallon[5]
                                      NS
                                      NS
                                      NA
Disallowed in ● Florida ● Nassau County, New York ● Suffolk County, New York
                           Hand injection equipment
                                62719-259 [EC]
                           0.000132 lb ae/ injection
                                      NS
                                      NS
                                      NA
                                      NS
                               Pasture/Rangeland
                                  Groundboom
                                62719-259 [EC]
                                     0.510
                                      NS
                                      NS
                                      NA
                                      NS
    Manually /mechanically pressurized hand sprayer, vehicle-drawn spreader
                                62719-259 [EC]
                            0.510 lb ae/ gallon[6]
                                      NS
                                      NS
                                      NA
                                      NS
                                    Aerial
                                62719-259 [EC]
                                     0.499
                                      NS
                                      NS
                                      NA
                                      NS
                               Premises/Areas[7]
                                  Groundboom
                         62719-73 [EC] 62719-259 [EC]
                                     0.499
                                      NS
                                      NS
                                      NA
                                      NS
                Manually/ mechanically pressurized hand sprayer
                         62719-73 [EC] 62719-259 [EC]
                                     0.499
                                      NS
                                      NS
                                      NA
                                      NS
                                    Aerial
                                62719-259 [EC]
                                     0.499
                                      NS
                                      NS
                                      NA
                                      NS
                                Hand Injection
                                62719-259 [EC]
                           0.000132 lb ae/ injection
                                      NS
                                      NS
                                      NA
                                      NS
                  Trigger spray bottle, brush rollers (frill)
                                62719-259 [EC]
                              0.000132 lb ae/cut
                                      NS
                                      NS
                                      NA
                                      NS
* See the PLUS reports for clopyralid for a full list of scenarios evaluated in this assessment.  NS = Not Specified.
1. Based on the maximum application rate for ground applications to orchard/vineyard scenarios assuming a 1-gallon dilution rate. See the minimum dilution quantity in the PLUS reports for clopyralid.
2. Based on the maximum application rate for ground applications to field crop typical scenarios assuming a 1-gallon dilution rate. See the minimum dilution quantity in the PLUS reports for clopyralid.
3. Based on the maximum application rate for ground applications to grass/turf (sod) scenarios assuming a 1-gallon dilution rate. See the minimum dilution quantity in the PLUS reports for clopyralid.
4. Based on the maximum application rate for ground applications to nursery scenarios assuming a 20-gallon dilution rate. See the minimum dilution quantity in the PLUS reports for clopyralid.
5. A quarter fluid ounce applied per 1000 square feet, the product concentration is 3 lb ae/gallon assuming 1 gallon of spray per acre.
6. Based on the maximum application rate for ground applications to pasture rangeland scenarios assuming a 1-gallon dilution rate. See the minimum dilution quantity in the PLUS reports for clopyralid.
7. Non-crop areas, such as airports, barrow ditches, communication transmission lines, electrical power and utility rights-of-way, fencerows, gravel pits, industrial sites, manufacturing and storage sites, military lands, mining and drilling areas, non-irrigation ditch banks, oil and gas pads, parking lots, petroleum tank farms, pipelines, railroads, roadsides, stormwater retention areas, substations, unimproved rough turf grasses, vacant lots and other non-crop residential areas, and around farm buildings.

 Anticipated Exposure Pathways

As a result of the registered and proposed uses of the herbicide clopyralid, humans may be exposed through food and drinking water, since the chemical may be applied directly to growing crops, and could reach surface and ground water sources of drinking water.  In an occupational setting, applicators may be exposed via dermal and inhalation routes while handling the pesticide prior to application (when mixing and loading), as well as during application.  There is also potential for post-application exposure for workers re-entering treated fields.

For non-crop uses, clopyralid is registered for application to pastures and rangeland, rights-of-way, forestry sites, tree plantations, ornamental grasses in landscapes and nurseries, and nonresidential turf grass (golf courses, rights-of-way, ornamentals, forest sites, industrial sites, natural areas, cemeteries, and sports fields). Thus, there is likely to be exposure in non-occupational settings.  Short-term post-application incidental oral and dermal exposures may occur for toddlers playing on treated turf.  Clopyralid is not registered for use on residential turf/lawns.

This risk assessment considers all relevant exposure pathways, and combines them as appropriate, to estimate overall exposure and risk.

 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with US Executive Order 12898, Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations, (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).  As a part of every pesticide risk assessment, the Office of Pesticide Programs (OPP) considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the US Department of Agriculture under the National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA).  These food consumption patterns are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups, and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products, and associated risks for adult applicators and for children, youths and adults entering or playing on treated areas post-application are evaluated.  Further considerations are currently in development, as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers, as well as lifestyle and traditional dietary patterns among specific subgroups.

 Hazard Characterization and Dose-Response Assessment

No new toxicity and/or metabolism data have been received since the most recent risk assessment, and therefore this DRA for registration review relies on toxicology information from the previous comprehensive assessment (D437662; W.T. Drew; 4 April 2018).

The toxicology database for clopyralid is complete and is sufficient for characterizing the hazard to human health.  No additional studies are required.  The HED HASPOC determined that the required rat acute and subchronic neurotoxicity and subchronic inhalation toxicity studies are not needed, based on weight-of-evidence considerations (TXR 0056270; K. Rickard and J. van Alstine; 29 March 2012), and recommended that the requirement for these studies be waived.  Additionally, rodent and non-rodent subchronic oral toxicity data requirements are satisfied by the chronic oral studies in the rat and dog.  The studies available for consideration in risk assessment are

 mouse subchronic oral toxicity,
 rabbit 21-day dermal toxicity,
 dog chronic, rat chronic/oncogenicity, mouse oncogenicity (all oral),
 rat and rabbit developmental toxicity,
 rat two-generation reproductive toxicity,
 genotoxicity battery,
 rat general metabolism, and
 rat immunotoxicity.

As part of the hazard characterization process for registration review, a search of the published scientific literature was conducted.  A total of 10 articles on clopyralid were identified, but no applicable studies were found that would impact the human health risk assessment (see Appendix A.3 for search criteria).  A published rabbit developmental toxicity study was the same study submitted to the Agency.

Clopyralid is an herbicide of the pyridinoxy acid chemical group that is structurally similar to plant auxins, and acts as an "auxin imitator," disrupting plant growth by binding to auxin receptors.  However, the mode of action for mammalian toxicity has not been characterized.  Toxicity was observed in the rat and dog following chronic exposure, but consistent target organs were not identified.  In the dog, reductions in red blood cell parameters, increased liver weight (males), and vacuolated adrenal cortical cells (females) were reported, along with skin lesions, and clinical chemistry changes (decreased serum glucose, protein and albumin).  In the rat, epithelial hyperplasia, thickening of the limiting ridge of the stomach, and decreased body weight were observed.  In the mouse, decreased body weight/weight gain and food efficiency were observed in the subchronic and carcinogenicity studies, but only at doses exceeding the limit dose.  No systemic toxicity was observed in rabbits following dermal exposure up to the limit dose for 21 days.  No clinical or histopathological indications of neurotoxicity were identified in the available studies at doses up to or exceeding the limit dose.

There was no evidence of increased qualitative or quantitative pre- and/or postnatal susceptibility.  No developmental toxicity was observed in the rat at doses that caused maternal mortality.  Decreased fetal body weight and hydrocephalus were observed in the rabbit, but only at a dose that caused significant maternal mortality, clinical signs of toxicity, and gastric mucosal lesions.  Reproductive toxicity was not observed in the rat, but mean pup weights were reduced by the end of lactation, and relative liver weights were increased at doses that caused parental toxicity (decreased body weight/weight gain and food consumption; gastric lesions).

Acceptable metabolism data in the rat showed that clopyralid was rapidly and almost completely absorbed regardless of the dose level.  Excretion was also rapid, primarily via the urine, with very low fecal excretion.  Radioactivity was not retained in tissues.  There was no evidence of metabolism; only parent compound was identified in the urine and feces.  There were no significant differences in metabolic disposition between males and females, or between dose groups.  A dermal absorption study was not available, but no toxicity was observed in the rabbit dermal study.

The acute toxicity of clopyralid is low (Toxicity Category III or IV) via oral, inhalation and dermal exposure, and it is not a dermal irritant or sensitizer.  However, in its acid form, clopyralid is a severe eye irritant (Category I).

After evaluation of the toxicological and exposure data for clopyralid, HED recommended that the required 10X FQPA SF be reduced to 1X, based on the completeness of the toxicology database; the lack of susceptibility in developmental and reproduction toxicity studies; the lack of neurotoxicity; and the conservative upper-bound estimates of exposure from food and drinking water, and in residential settings.

There has been no change in the cancer classification for clopyralid since the most recent risk assessment.  In accordance with EPA's Final Guidelines for Carcinogen Risk Assessment (March 2005), clopyralid is classified as "not likely to be carcinogenic to humans" under the Agency's 2005 Guidelines for Carcinogen Risk Assessment.

For combining routes of exposure for risk assessment, the same approach used in the April 2018 risk assessment has been used for this DRA.  HED has considered oral, dermal and inhalation routes of exposure in its assessment of clopyralid.  It is appropriate to combine routes of exposure when such exposures are expected to co-occur and result in the same toxicological effects.  For aggregate assessment, adults are exposed via the oral dietary (food + water) route, while for children, exposures consist of post-application oral exposure to residues on lawns, and oral dietary (food + water) exposure.  These exposures should be combined and compared to the short-term incidental oral endpoint and dose.  For occupational workers, only inhalation exposure and risk have been assessed.  The endpoint for chronic dietary exposure is stomach lesions observed in the rat chronic toxicity/carcinogenicity study.  Inhalation and incidental oral risk assessments are based on mortality (maternal) in the rat developmental toxicity study.

The endpoints and doses previously selected for risk assessment have not changed; for details regarding endpoint, dose and uncertainty factor selection and reduction of the FQPA factor, refer to the 2018 risk assessment.  The tables below summarize the doses and endpoints selected for risk assessment, as well as uncertainty factors and the FQPA safety factor.

TABLE 4.0.1	Summary of Toxicological Doses and Endpoints for Use in Clopyralid Dietary and Residential Human Health Risk Assessments.
                                   Exposure/
                                   Scenario
                           Point of Departure (POD)
                        Uncertainty/FQPA Safety Factors
                       RfD, PAD, LOC for Risk Assessment
                        Study and Toxicological Effects
Acute dietary (all populations)
An appropriate endpoint for a single exposure was not identified.
Chronic dietary (all populations)
NOAEL = 15 mg/kg/day
UFA = 10X
UFH = 10X
SFFQPA = 1X
cRfD = 0.15 mg/kg/day

cPAD = 0.15 mg/kg/day
2-Year Combined Chronic Toxicity/Carcinogenicity (oral)  -  rat

LOAEL = 150 mg/kg/day, based on increased epithelial hyperplasia and thickening of the limiting ridge of the stomach in both sexes.
Incidental oral, short-term (1-30 days)
NOAEL = 75 mg/kg/day
UFA = 10X
UFH = 10X
SFFQPA = 1X
Residential LOC for MOE <100

Developmental Toxicity (oral)  -  rat

Maternal LOAEL = 250 mg/kg/day, based on mortality.
Dermal, short-term
(1-30 days)
An appropriate endpoint for dermal exposure was not identified.  No dermal or systemic toxicity was observed at the limit dose (1000 mg/kg/day) in a rabbit 21-day dermal toxicity study, and there are no developmental or reproductive concerns.
Inhalation, short-term
(1-30 days)
Oral study
NOAEL = 75 mg/kg/day
(inhalation toxicity assumed to be equivalent to oral toxicity)
UFA = 10X
UFH = 10X
SFFQPA = 1X
Residential LOC for MOE <100
Developmental Toxicity (oral)  -  rat

Maternal LOAEL = 250 mg/kg/day, based on mortality.
Cancer (all routes)
"Not likely to be carcinogenic to humans."  Cancer risk is not of concern.
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data, and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no-observed-adverse-effect level.  LOAEL = lowest-observed-adverse-effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among human population members (intraspecies).  SFFQPA = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.

TABLE 4.0.2	Summary of Toxicological Doses and Endpoints for Use in Clopyralid Occupational Human Health Risk Assessments.
                                   Exposure/
                                   Scenario
                           Point of Departure (POD)
                              Uncertainty Factors
                            LOC for Risk Assessment
                        Study and Toxicological Effects
Dermal, short- and intermediate-term (1-30 days and 1-6 months, respectively)
No dermal or systemic toxicity was observed up to the limit dose (1000 mg/kg/day) in a 21-day dermal toxicity study.  Also, there are no developmental or reproductive concerns.
Inhalation, short-term
(1-30 days)
NOAEL = 75 mg/kg/day (inhalation toxicity assumed to be equivalent to toxicity via the oral route)
                                   UFA = 10X
                                   UFH = 10X

                           Occupational LOC for MOE
                                    <100
Developmental Toxicity (oral)  -  rat

Maternal LOAEL = 250 mg/kg/day, based on mortality.
Inhalation, intermediate- term (1-6 months)
NOAEL = 15 mg/kg/day (inhalation toxicity assumed to be equivalent to toxicity via the oral route)
                                   UFA = 10X
                                   UFH = 10X

                           Occupational LOC for MOE
                                    <100
2-Year Combined Chronic Toxicity/Carcinogenicity (oral)  -  rat

LOAEL = 150 mg/kg/day, based on increased epithelial hyperplasia and thickening of the limiting ridge of the stomach in both sexes.
Cancer (all routes)
"Not likely to be carcinogenic to humans."  Cancer risk is not of concern.
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data, and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no-observed-adverse-effect level.  LOAEL = lowest-observed-adverse-effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among human population members (intraspecies).  MOE = margin of exposure.  LOC = level of concern.

 Endocrine Disruptor Screening Program

As required by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal Food, Drug, and Cosmetic Act (FFDCA), EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals.  Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity.  These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring.  For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups.  As part of its most recent registration decision for clopyralid, EPA reviewed these data, and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database.  However, as required by FFDCA section 408(p), clopyralid is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a "naturally occurring estrogen, or other such endocrine effects as the Administrator may designate."  The EDSP employs a two-tiered approach to making the statutorily required determinations.  Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen or thyroid (E, A or T) hormonal systems.  Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A or T hormonal systems will proceed to the next stage of the EDSP, where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data.  Tier 2 testing is designed to identify any adverse endocrine-related effects caused by the substance and establish a dose-response relationship between the dose and the E, A or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals.  Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients.  A second list of chemicals identified for EDSP screening was published on 14 June 2013 (see the website, https://www.regulations.gov/document?D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of chemicals), and includes some pesticides scheduled for registration review, and chemicals found in water.  Neither of these lists should be construed as a list of known or likely endocrine disruptors.

For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines, and the Tier 1 screening battery, please visit our website (https://www.epa.gov/endocrine-disruption).

 Dietary Exposure and Risk Assessment
	Dietary Exposure Memorandum D438299; W.T. Drew; 4 April 2018

The residue chemistry database is complete; residues of concern for tolerance setting and risk assessment, as well as the residue data and estimated drinking water concentrations (EDWCs) used in the 2018 risk assessment have not changed.  Refer to the 2018 risk assessment and its supporting dietary assessment (D438299; W.T. Drew; 4 April 2018) for details.  The chronic dietary (food + drinking water) risk estimates are below HED's LOC for the US population and all population subgroups.  Chronic dietary exposure was 9.3% of the cPAD for the US population.  The chronic dietary exposure for the most highly exposed population subgroup, children 1-2 years old, was 26% of the cPAD.

TABLE 5.0	Summary of Dietary Exposure and Risk for Clopyralid.
                             Population Subgroup*
                                Chronic Dietary

                             Exposure (mg/kg/day)
                                    % cPAD
General US population
                                   0.013966
                                      9.3
All infants (<1 year old)
                                   0.016680
                                      11
Children 1-2 years old
                                   0.039381
                                      26
Children 3-5 years old
                                   0.033144
                                      22
Children 6-12 years old
                                   0.022587
                                      15
Youth 13-19 years old
                                   0.013237
                                      8.8
Adults 20-49 years old
                                   0.011448
                                      7.6
Adults 50-99 years old
                                   0.009899
                                      6.6
Females 13-49 years old
                                   0.010803
                                      7.2
 * The population subgroup with the highest chronic risk estimate is in shaded bold typeface.

 Residential Exposure/Risk Characterization
      ORE Memorandum D450041; M. Manupella and G. Thornton; 25 February 2019

Residential uses have been previously updated to reflect HED's 2012 Residential SOPs (available at http://www.epa.gov/pesticides/science/residential-exposure-sop.html) along with policy changes for body weight assumptions.  A summary of the residential handler, post-application, and scenarios for consideration in the aggregate are provided in this section.

       Residential Handler Exposure/Risk Estimates

HED uses the term "handlers" to describe those individuals who are involved in the pesticide application process.  HED believes that there are distinct tasks related to applications, and that exposures can vary depending on the specifics of each task.  Residential handlers are addressed somewhat differently by HED, because homeowners are assumed to complete all elements of an application without use of any protective equipment.

In a previous assessment (D391748; S. Oonnithan; 30 April 2012), residential handler exposures to clopyralid were evaluated based on EPA Registrations #62719-263 and #62719-305.  However, these and all registered clopyralid labels require specific clothing (such as long-sleeved shirt, long pants) and/or PPE (such as chemical resistant gloves and protective eyewear).  Therefore, HED has assumed that the registered clopyralid labels are not intended for use by residential handlers, and a quantitative residential handler assessment has not been conducted.

       Residential Post-Application Exposure and Risk Estimates

There is the potential for post-application exposure for individuals due to being in an environment that has been previously treated with clopyralid.  The quantitative exposure/risk assessment for residential post-application exposures can also be found in the most recent residential assessment (D391748; S. Oonnithan; 30 April 2012).  Note that for episodic granular ingestion, there was no endpoint attributable to a single dose, so no acute dietary POD was selected.  Therefore, a quantitative episodic granular ingestion assessment was not conducted.

Several formulations of clopyralid are registered for weed control on non-residential lawns, turf and ornamentals in a variety of locations that may result in residential exposures, including golf courses, rights-of-way, ornamentals, forest sites, industrial sites, natural areas, cemeteries, and sports fields.  No new residential uses of clopyralid are being proposed and none are pending before the Agency.  A previous assessment had indicated that the residential post-application exposures were not of concern when G and EC formulations are applied at 0.19 lb ae/A and 0.5 lb ae/A, respectively, on turf.  Exposures resulted in MOEs >= 10,000 (D391748; S. Oonnithan; 30 April 2012).  However, there are G-formulated EPs with an application rate of 0.5 lb ae/A on turf.  While this application rate is significantly higher than what was previous assessed in 2012, HED generally assumes residues from liquid formulations are 5X more available for transfer than residues from G formulations (HED assumes 1% of liquid formations are available for transfer, and 0.2% of granule formulations are available for transfer) using default TTR data in lieu of chemical specific data.  Therefore, the risk estimates determined for liquid formulation application on turf are protective for application of granular formulations on turf.

       Residential Risk Estimates for Use in Aggregate Assessment

Table 6.3 summarizes the residential risk estimate that is recommended for use in the aggregate assessment for clopyralid.  The recommended residential exposure for use in the aggregate assessment for children 1 to <2 years old reflects short-term hand-to-mouth exposure from post-application activity on treated turf.

TABLE 6.3	Recommendation for Residential Exposures for the Clopyralid Aggregate Assessment.[1]
                                   Lifestage
                               Exposure Scenario
                     Post-Application Exposure (mg/kg/day)
                  Post-Application Total Exposure (mg/kg/day)
                            Post-Application MOE[2]

                                    Dermal
                                  Inhalation
                                     Oral

                                   Child 1-2
                          Liquid (EC), hand to mouth
                                      NA
                                      NA
                                    0.00745
                                    0.00745
                                    10,000
1. Bolded risk estimate to be used in the residential exposure portion of the aggregate assessment.
2. Post-application MOE = the MOE associated with the highest residential exposure (children 1 to <2 years old, treated lawn post-application).
The scenario assessed was short-term post-application oral exposure for children playing on treated turf.  The residential post-application scenario resulted in an MOE of 10,000 which is greater than the LOC of 100 and not of concern.

 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources (food, drinking water, and residential exposures).  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (such as a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

       Acute Aggregate Risk

No toxicological endpoint attributable to a single exposure was identified in the available toxicology studies on clopyralid.  Therefore, acute aggregate exposure is not of concern.

       Short-Term Aggregate Risk

The short-term children's aggregate risk estimate is based on residential exposure plus the average exposure level from food and water (considered to be a background exposure level).  The aggregate risk estimate was an MOE of 1,600 for children 1 to <2 years old, which is considerably higher than the LOC of 100, and not of concern.  Table 7.2 summarizes the aggregate risk estimate.

TABLE 7.2	Aggregate Risk Calculation for Clopyralid.
                                  Population1
                                     NOAEL
                                  (mg/kg/day)
                                     LOC2
                               Maximum Allowable
                                   Exposure3
                                  (mg/kg/day)
                                    Average
                                 Food + Water
                                   Exposure
                                  (mg/kg/day)
                             Residential Exposure4
                                  (mg/kg/day)
                                 Aggregate MOE
                                   (Food and
                                 Residential)5
Children 1 to <2
                                      75
                                      100
                                     0.75
                                   0.039381
                                    0.00745
                                     1,600
1. Children 1-2 were selected for the aggregate risk evaluation as the sentinel children's population subgroup, that is, a subpopulation more likely to be exposed than any other.  Children 1-2 also had the highest background (chronic dietary) exposure.
2. The LOC includes the standard inter- and intra-species uncertainty factors, for a total of 100.
3. Maximum allowable exposure (mg/kg/day) = NOAEL / LOC.
4. Residential exposure (children 1-2) = incidental soil ingestion.
5. Aggregate MOE = [NOAEL / (average food and water exposure + residential exposure)].

       Chronic Aggregate Risk

Chronic aggregate risk is equivalent to chronic dietary exposure and risk, which is not of concern.  Refer to Section 5.0, above.

 Non-Occupational Bystander Post-Application Inhalation Exposure and Risk Estimates

Volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on 2 March 2010, which is available on the internet at the website http://archive.epa.gov/scipoly/sap/meetings/web/pdf/120309meetingminutes.pdf.  The Agency has evaluated the SAP report, and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis, which is available on the internet at the website (https://www.regulations.gov/contentStreamer?documentId=EPA-HQ-OPP-2014-0219-0003&disposition=attachment&contentType=pdf).  During Registration Review, the Agency will utilize this analysis to determine if additional data (such as flux studies, route-specific inhalation toxicological studies) or further analysis is required for clopyralid.

 Non-Occupational Spray Drift Exposure and Risk Estimates
      ORE Memorandum D450041; M. Manupella and G. Thornton; 25 February 2019

Off-target movement of pesticides can occur via many types of pathways and it is governed by a variety of factors.  Sprays that are released and do not deposit in the application area end up off-target and can lead to exposures to those it may directly contact. They can also deposit on surfaces where contact with residues can eventually lead to indirect exposures (such as for children playing on lawns where residues have deposited next to treated fields). The potential risk estimates from these residues can be calculated using drift modeling onto 50 feet wide lawns coupled with methods employed for residential risk assessments for turf products.

The approach to be used for quantitatively incorporating spray drift into risk assessment is based on a premise of compliant applications which, by definition, should not result in direct exposures to individuals because of existing label language and other regulatory requirements intended to prevent them.  (This approach is consistent with the requirements of the EPA's Worker Protection Standard which, when included on all labels, precludes direct exposure pathways.)  Direct exposures would include inhalation of the spray plume or being sprayed directly.  Rather, the exposures addressed here are thought to occur indirectly through contact with impacted areas, such as residential lawns, when compliant applications are conducted.  Given this premise, exposures for children (1 to <2 years old) and adults who have contact with turf where residues are assumed to have deposited via spray drift, thus resulting in an indirect exposure, are the focus of this analysis, analogous to how exposures to turf products are considered in risk assessment.

Several clopyralid products have existing labels for use on turf, thus it was considered whether the risk assessment for that use may be considered protective of any type of exposure that would be associated with spray drift.  If the maximum application rate on crops, adjusted by the amount of drift expected, is less than or equal to existing turf application rates, the existing turf assessment is considered protective of spray drift exposure.  Note that this assumes similar formulations are being applied to the agricultural crops and the residential turf (if a granular product is registered for use on residential turf, the scenarios assessed for that use may not be protective of liquid applications made to agricultural crops).  The currently registered maximum single application rate of clopyralid to pasture/rangeland, grass/turf, premise/areas and ornamentals, is 0.499 lb ae/A.  The highest degree of spray drift noted for any application method immediately adjacent to a treated field (Tier 1 output from the aerial application using fine to medium spray quality) results in a deposition fraction of 0.26 of the application rate.  A quantitative spray drift assessment for clopyralid is not required because the maximum application rate to a crop/target site multiplied by the adjustment factor for drift of 0.26 is less than the maximum direct spray residential turf application rate 0.499 lb ai/A for any clopyralid products (0.499 lb ae/A x 0.26 <= 0.499 lb ae/A).  The turf post-application MOEs have been previously assessed and are based on the revised SOPs for Residential Exposure Assessment.

 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to clopyralid and any other substances, and clopyralid does not appear to produce a toxic metabolite produced by other substances.  For the purposes of this tolerance action, therefore, EPA has not assumed that clopyralid has a common mechanism of toxicity with other substances.  In 2016, EPA's OPP released a guidance document titled Pesticide Cumulative Risk Assessment: Framework for Screening Analysis (https://www.epa.gov/pesticide-science-and-assessing-pesticide-risks/pesticide-cumulative-risk-assessment-framework).  This document provides guidance on how to screen groups of pesticides for cumulative evaluation using a two-step approach, beginning with the evaluation of available toxicological information and, if necessary, followed by a risk-based screening approach.  This framework supplements the existing guidance documents (Guidance for Identifying Pesticide Chemicals and Other Substances that have a Common Mechanism of Toxicity, USEPA, 1999; and Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Have a Common Mechanism of Toxicity, USEPA, 2002) for establishing common mechanism groups (CMGs), and conducting cumulative risk assessments (CRAs).  During Registration Review, the Agency will use this framework to determine if the available toxicological data for clopyralid suggests a candidate CMG may be established with other pesticides.  If a CMG is established, a screening-level toxicology and exposure analysis may be conducted to provide an initial screen for multiple pesticide exposure.

 Occupational Exposure/Risk Characterization

       Short-/Intermediate-Term Occupational Handler Exposure and Risk Estimates

HED uses the term handlers to describe those individuals who are involved in the pesticide application process.  HED believes that there are distinct job functions or tasks related to applications, and exposures can vary depending on the specifics of each task.  Job requirements (amount of chemical used in each application), the types of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.

The estimated exposures indicate that handlers' intermediate-term inhalation risks are not of concern (MOEs >= 1,400; LOC < 100) assuming no respirator.  The MOEs range from 1,400 (for aerial application in forestry settings) to 260,000,000 (for tree injection).

Based on the anticipated use patterns and current labeling, the types of equipment, and the techniques that can potentially be used, occupational handler exposure is expected from the registered uses.  The quantitative exposure/risk assessment developed for occupational handlers is based on a series of assumptions and exposure factors for completing the occupational handler risk assessments.  Each assumption and factor is detailed below on an individual basis.

Application Rate
See Section 3.3 for application rates and parameters.

Unit Exposures
It is the policy of HED to use the best available data to assess handler exposure.  Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, include PHED 1.1, the AHETF database, the ORETF database, or other registrant-submitted occupational exposure studies.  Some of these data are proprietary (such as AHETF data), and subject to the data protection provisions of FIFRA.  The standard values recommended for use in predicting handler exposure that are used in this assessment, known as "unit exposures", are outlined in the Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (available at https://www.epa.gov/sites/production/files/2016-11/documents/handler-exposure-table-2016.pdf), which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website (https://www.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupational-pesticide-handler-exposure-data).

Area Treated or Amount Handled
The area treated/amount handled are based on ExpoSAC Policy 9.1, and are summarized in Table 11.1, below.  However, there are scenarios that were not based on Policy 9.1:

 For hack and frill applications, HED assumes that 500 cuts could be made in an 8-hour work day.  HED believes this is a conservative estimate of handler exposure;
 for injections, the value used in the exposure calculation as the amount of ai handled in mixing/loading for tree injections is based on information that a professional applicator could perform up to 160 injections in an 8- hour workday.  This was estimated based on information from Arborjet's website (www.arborjet.com), a representative product for the tree injection scenario, indicating that one injection could take as little as 3 minutes (2-4 minutes to set up, and 1-2 minutes to inject).

Exposure Duration
HED classifies exposures from 1 to 30 days as short-term, and exposures 30 days to six months as intermediate-term.  Exposure duration is determined by many things, including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the cultural practices surrounding that use site.  For most agricultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for more than a one-month time frame.  However, there may be large agribusinesses and/or commercial applicators who may apply a product over a period of weeks (completing multiple applications for multiple clients within a region).  For clopyralid, short and intermediate exposures could be expected by occupational handlers.  However, while the endpoints for short- and intermediate-term exposures are different, the intermediate-term endpoint is protective for both durations, and has therefore been used to evaluate occupational handlers' risk from clopyralid exposures.

Mitigation/Personal Protective Equipment (PPE)
Results are presented for "baseline," defined as a single layer of clothing consisting of a long-sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator.  Engineering controls are assumed for aerial applicators.

TABLE 11.1	Occupational Handler Non-Cancer Exposure and Risk Estimates for Clopyralid.[1]
                               Exposure Scenario
                               Crop or Target[2]
                   Inhalation
Unit Exposure [3] (μg/lb ae)
                      Level of PPE or
Engineering Control
                         Maximum
Use Rate (lb ae/acre)
                Area Treated or
Amount Handled Daily[4] (Acres)
                            Inhalation (LOC = 100)

                              Dose[5] (mg/kg/day)
                                    MOE[6]
                                 Mixer/Loader
                      Dry flowable, groundboom, broadcast
                           Field crop, high-acreage
                                     8.96
                                     No-R
                                     0.22
                                      200
                                    0.00493
                                     3,000
                  Granule, tractor-drawn spreader, broadcast
                                      Sod
                                     0.825
                                     No-R
                                     0.499
                                      80
                                   0.000411
                                    36,000
                           Liquid, aerial, broadcast
                                      Sod
                                     0.219
                                     No-R
                                     0.51
                                      350
                                   0.000489
                                    31,000
                           Liquid, aerial, broadcast
                              Field crop, typical
                                     0.219
                                     No-R
                                     0.51
                                      350
                                   0.000489
                                    31,000
                           Liquid, aerial, broadcast
                           Field crop, high-acreage
                                     0.219
                                     No-R
                                     0.261
                                     1200
                                   0.000858
                                    17,000
                  Liquid, injection equipment, tree injection
                                   Forestry
                                     0.219
                                     No-R
                           0.000132 lb ae/injection
                                160 injections
                                   5.79E-08
                                  260,000,000
                         Liquid, aerial, ULV/wide-area
                                   Forestry
                                     0.219
                                     No-R
                                     0.51
                                     7500
                                    0.0105
                                     1,400
                          Liquid, airblast, broadcast
           Nursery (ornamentals, vegetables, trees, container stock)
                                     0.219
                                     No-R
                                     0.51
                                      20
                                   0.0000279
                                    540,000
                          Liquid, airblast, broadcast
                               Orchard/vineyard
                                     0.219
                                     No-R
                                     0.255
                                      40
                                   0.0000279
                                    540,000
                         Liquid, groundboom, broadcast
           Nursery (ornamentals, vegetables, trees, container stock)
                                     0.219
                                     No-R
                                     0.51
                                      60
                                   0.0000838
                                    180,000
                         Liquid, groundboom, broadcast
                                      Sod
                                     0.219
                                     No-R
                                     0.51
                                      80
                                   0.000112
                                    130,000
                         Liquid, groundboom, broadcast
                               Orchard/vineyard
                                     0.219
                                     No-R
                                     0.255
                                      40
                                   0.0000279
                                    540,000
                         Liquid, groundboom, broadcast
                              Field crop, typical
                                     0.219
                                     No-R
                                     0.375
                                      80
                                   0.0000821
                                    180,000
                         Liquid, groundboom, broadcast
                           Field crop, high-acreage
                                     0.219
                                     No-R
                                     0.261
                                      200
                                   0.000143
                                    100,000
                    Wettable powder, groundboom, broadcast
                           Field crop, high-acreage
                                     2.75
                                     No-R
                                     0.22
                                      200
                                    0.00151
                                     9,900
                           Liquid, aerial, broadcast
                             Pastureland/rangeland
                                     0.219
                                     No-R
                                     0.499
                                      350
                                   0.000489
                                    31,000
                         Liquid, groundboom, broadcast
                             Pastureland/rangeland
                                     0.219
                                     No-R
                                     0.51
                                      80
                                   0.000112
                                    130,000
                           Liquid, aerial, broadcast
                                Premises/areas
                                     0.219
                                     No-R
                                     0.499
                                      350
                                   0.000489
                                    31,000
                         Liquid, groundboom, broadcast
                                Premises/areas
                                     0.219
                                     No-R
                                     0.499
                                      80
                                   0.000109
                                    140,000
                  Liquid, injection equipment, tree injection
                                Premises/areas
                                     0.219
                                     No-R
                           0.000132 lb ae/injection
                                160 injections
                                   5.79E-08
                                  260,000,000
                                  Applicator
                  Spray (all formulations), aerial, broadcast
                              Field crop, typical
                                    0.0049
                                      EC
                                     0.51
                                      350
                                   0.0000109
                                   1,400,000
                Spray (all formulations), groundboom, broadcast
                              Field crop, typical
                                     0.34
                                     No-R
                                     0.51
                                      80
                                   0.000174
                                    86,000
                  Granule, tractor-drawn spreader, broadcast
                                      Sod
                                      1.2
                                     No-R
                                     0.499
                                      80
                                    0.00011
                                    360,000
                  Spray (all formulations), aerial, broadcast
                             Pastureland/rangeland
                                    0.0049
                                      EC
                                     0.499
                                      350
                                   0.0000109
                                   1,400,000
                Spray (all formulations), groundboom, broadcast
                             Pastureland/rangeland
                                     0.34
                                     No-R
                                     0.51
                                      80
                                   0.000174
                                    86,000
                  Spray (all formulations), aerial, broadcast
                                Premises/areas
                                    0.0049
                                      EC
                                     0.499
                                      350
                                   0.0000109
                                   1,400,000
                Spray (all formulations), groundboom, broadcast
                                Premises/areas
                                     0.34
                                     No-R
                                     0.499
                                      80
                                    0.00017
                                    88,000
                                    Flagger
                  Spray (all formulations), aerial, broadcast
                              Field crop, typical
                                     0.35
                                     No-R
                                     0.51
                                      350
                                   0.000781
                                    19,000
                  Spray (all formulations), aerial, broadcast
                             Pastureland/rangeland
                                     0.35
                                     No-R
                                     0.499
                                      350
                                   0.000764
                                    20,000
                  Spray (all formulations), aerial, broadcast
                                Premises/areas
                                     0.35
                                     No-R
                                     0.499
                                      350
                                   0.000764
                                    20,000
                            Mixer/Loader/Applicator
                    Liquid, backpack, ground-/soil-directed
                               Orchard/vineyard
                                     2.58
                                     No-R
                              0.255 lb ae/gallon
                              40 Gallons solution
                                   0.0000756
                                    46,000
             Liquid, trigger spray bottle, frill (hack and squirt)
                                   Forestry
                                     61.2
                                     No-R
                              0.000132 lb ae/cut
                                   500 Cuts
                                  0.00000404
                                    300,000
                    Liquid, backpack, ground-/soil-directed
                                   Forestry
                                     2.58
                                     No-R
                              0.255 lb ae/gallon
                              40 Gallons solution
                                   0.000151
                                    46,000
                          Liquid, backpack, broadcast
                                   Forestry
                                     69.1
                                     No-R
                              0.255 lb ae/acre[7]
                              40 Gallons solution
                                    0.00404
                                     1,700
                     Liquid, backpack, broadcast (foliar)
           Nursery (ornamentals, vegetables, trees, container stock)
                                     69.1
                                     No-R
                            0.0255 lb ae/gallon[8]
                              40 Gallons solution
                                   0.000404
                                    17,000
                    Liquid, backpack, ground-/soil-directed
           Nursery (ornamentals, vegetables, trees, container stock)
                                     2.58
                                     No-R
                            0.0255lb ae/gallon[1,5]
                              40 Gallons solution
                                   0.0000151
                                    460,000
           Liquid, manually-pressurized handwand, broadcast (foliar)
           Nursery (ornamentals, vegetables, trees, container stock)
                                      30
                                     No-R
                            0.0255lb ae/gallon[1,5]
                              40 Gallons solution
                                   0.000175
                                    39,000
         Liquid, mechanically-pressurized handgun, broadcast (foliar)
           Nursery (ornamentals, vegetables, trees, container stock)
                                     8.68
                                     No-R
                           0.0255 lb ae/gallon[1,5]
                             1000 Gallons solution
                                    0.00128
                                     5,400
    Liquid, mechanically-pressurized handgun, drench/soil-/ground-directed
           Nursery (ornamentals, vegetables, trees, container stock)
                                     8.68
                                     No-R
                           0.0255 lb ae/gallon[1,5]
                             1000 Gallons solution
                                    0.00128
                                     5,400
                               Loader/Applicator
                 Liquid, brush/roller, frill (hack and squirt)
                                Premises/areas
                                      280
                                     No-R
                              0.000132 lb ae/cut
                                   500 cuts
                                   0.000231
                                    65,000
                      Granule, rotary spreader, broadcast
                                      Sod
                                      10
                                     No-R
                                     0.187
                                       5
                                   0.000117
                                    130,000
1. Only intermediate-term exposure was assessed.  Intermediate-term endpoints are protective of short-term exposures.
2. See the clopyralid PLUS reports for a full list of scenarios evaluated in this assessment.
3. Based on the Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (June 2018) (https://www.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupational-pesticide-handler-exposure-data).  Levels of mitigation = baseline, PPE, engineering controls.
4. Exposure Science Advisory Council Policy #9.1.
5. Inhalation Dose = [Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gal/day)] / BW (80 kg).
6. Inhalation MOE = Inhalation HED (0.078 mg/kg/day) / Inhalation Dose (mg/kg/day).  Bolded values are risk estimates of concern (MOEs < 1000).
7. A quarter fluid ounce applied per 1000 square feet, the product concentration is 3 lb ae/gallon, assuming 1 gallon of spray per acre.
8. Based on the maximum application rate for ground applications to nursery scenarios, assuming a 20-gallon dilution rate.  See the minimum dilution quantity in the PLUS reports for clopyralid.

       Short-/Intermediate-Term Post-Application Exposure and Risk Estimates

HED uses the term post-application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re-entry exposure).  Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting.  Post-application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical's degradation properties.  In addition, the timing of pesticide applications relative to harvest activities, can greatly reduce the potential for post-application exposure at the time of harvest.

       Dermal Post-Application Risk

An occupational post-application dermal assessment was not completed for clopyralid because no dermal hazard was identified in the toxicity database.  Therefore, dislodgeable foliar residue (DFR) and turf transferable residue (TTR) studies are not required for clopyralid at this time (TXR 0056270; K. Rickard and J. van Alstine; 29 March 2012).

Restricted Entry Interval
Clopyralid salts are all classified as Toxicity Category IV via the dermal route, and as Toxicity Category III for skin irritation potential.  They are not skin sensitizers.  Under 40CFR §156.208[iii][2], ai's classified as Acute III or IV for acute dermal, eye irritation, and primary skin irritation are assigned a 12-hour REI.  Therefore, the 40CFR §156 subpart K Worker Protection Standard interim REI of 12 hours is adequate to protect agricultural workers from post-application exposures to clopyralid salts.  Although the clopyralid ai in all of its EPs are in the form of one of its salts, when diluted with water in a tank mix, they are converted to the clopyralid acid.  The clopyralid acid is a severe eye irritant (Acute Toxicity Category I), and under 40CFR §156.208[c][i], HED recommends that all tank-mixed clopyralid EP labels stipulate an REI of 48-hours.

       Inhalation Post-Application Risk

There are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields.  These potential sources include volatilization of pesticides, and resuspension of dusts and/or particulates that contain pesticides.  The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, FIFRA SAP in December 2009, and received the SAP's final report on 2 March 2010 (http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2009-0687-0037).  The agency has evaluated the SAP report, and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (https://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219).  During Registration Review, the agency will utilize this analysis to determine if data (flux studies, route-specific inhalation toxicological studies) or further analysis is required for clopyralid.

In addition, the Agency is continuing to evaluate the available post-application inhalation exposure data generated by the Agricultural Reentry Task Force.  Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the agency's risk assessments.

Although a quantitative occupational post-application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers.  Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post-application exposure.  Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post-application inhalation exposure scenarios.

Furthermore, inhalation exposure during dusty mechanical activities such as shaking and mechanical harvesting is another potential source of post-application inhalation exposure.  The non-cancer inhalation risk estimate for commercial airblast application was assessed as representative of these activities and was found to be not of concern (MOE >= 25,000)

 Incident and Epidemiological Data Review
	S. Recore et al; D442306; 31 October 2018

Clopyralid incidents were previously reviewed in 2013 (D416106; E. Evans and S. Recore; 20 November 2013).  At that time, based on the low frequency and generally low severity of cases reported to both Incident Data System (IDS) and NIOSH Sentinel Event Notification System for Occupational Risk (SENSOR)-Pesticides, there was no risk of concern that warranted further analysis.

In the current five-year IDS analysis from 1 January 2013 to 21 August 2018, 11 clopyralid incidents were reported to Main IDS involving multiple active ingredients.  There was one incident of major severity, 8 of moderate severity, and 2 of minor severity. However, because these were incidents with pesticides containing multiple actives, it is difficult to determine to which chemical the health effects should be attributed.  None of the incidents involved the single active ingredient clopyralid alone.  There were 44 clopyralid incidents reported to Aggregate IDS.  The current SENSOR-Pesticides analysis from 2010-2014 identified ten cases, all low in severity, involving clopyralid.  An updated query of SENSOR-Pesticides 1998-2015 identified no additional clopyralid case reports (per E. Evans, via personal Email from S. Recore of 12 February 2019).

Based on the continued low frequency of clopyralid incidents reported to both IDS and SENSOR-Pesticides, there does not appear to be a concern with incident exposures at this time.  In addition, the epidemiological evidence is considered inadequate at this time to conclude that a clear associative or causal relationship exists between clopyralid exposure and the health outcomes assessed in the studies reported.

 References

Clopyralid.  Aggregate Human Health Risk Assessment to Support Proposed New Uses on Pome Fruit Group 11-10 and Radish Roots, Along with Various Crop Group/Subgroup Conversions and Expansions.; D437662; W.T. Drew; 4 April 2018.

Clopyralid.  Occupational Exposure and Risk Assessment for a Proposed Use on Radish Grown for Seed, Pear, and Various Crop Group/Subgroup Conversions and Expansions.; D438300; D. Nadrchal; 18 August 2017.

Clopyralid.  Chronic Aggregate (Food and Drinking Water) Dietary Exposure and Risk Assessment for Proposed New Section 3 Uses of the Herbicide on Pome Fruits Group 11-10 and Radish Roots, Along with Various Crop Group/Subgroup Conversions and Expansions.; D438299; W.T. Drew; 4 April 2018.

Evaluation of Applicator Exposures to SURFLAN* A.S. During Mixing, Loading
and Application with Backpack Sprayers; MRID #44339801; K.K. Beard; 2 July 1997.

Clopyralid:  Summary of Hazard and Science Policy Council (HASPOC) Meeting of March 29, 2012:  Recommendation on the need for 28-day inhalation and acute/subchronic neurotoxicity studies in the rat and for a turf transferable residue study.; TXR 0056270; K. Rickard and J. van Alstine; 29 March 2012.

Clopyralid.  Occupational and Residential Exposure Assessment for Registration Review.; D450041; M. Manupella and G. Thornton; 25 February 2019.

Clopyralid: Occupational Exposure Assessment for a New Use on Apples; Expansion of Crop Group 5B; and Revised Residential Exposure Assessment for use on Turf.; D391748; S. Oonnithan; 30 April 2012.

Clopyralid: Tier I Update Review of Human Incidents and Epidemiology for Draft Risk Assessment; S. Recore et. al.; D442306; 31 October 2018.

Appendix A.	Toxicology Profile and Executive Summaries

A.1	Toxicology Data Requirements

The requirements (40CFR §158.340) for food use of clopyralid are in the table below.  Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.
TABLE A.1	Clopyralid Toxicology Data Requirements.
                                     Study
                             Clopyralid Technical

                                   Required
                                   Satisfied
870.1100    Acute Oral Toxicity
870.1200    Acute Dermal Toxicity
870.1300    Acute Inhalation Toxicity
870.2400    Primary Eye Irritation
870.2500    Primary Dermal Irritation
870.2600    Dermal Sensitization
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.3100    Oral Subchronic (rodent)
870.3150    Oral Subchronic (non-rodent)
870.3200    21-Day Dermal
870.3250    90-Day Dermal
870.3465    28-Day Inhalation
                                      yes
                                      yes
                                      yes
                                      no
                                     no[4]
                                      yes
                                    yes[1]
                                      yes
                                       -
                                       -
870.3700a  Developmental Toxicity (rodent)
870.3700b  Developmental Toxicity (non-rodent)
870.3800    Reproduction
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.4100a  Chronic Toxicity (rodent)
870.4100b  Chronic Toxicity (non-rodent)
870.4200a  Oncogenicity (rat)
870.4200b  Oncogenicity (mouse)
870.4300    Chronic/Oncogenicity
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                    yes[2]
                                      yes
                                    yes[2]
                                      yes
                                      yes
870.5100    Mutagenicity  -  Gene Mutation - bacterial
870.5300    Mutagenicity  -  Gene Mutation - mammalian
870.5375    Mutagenicity  -  Structural Chromosomal Aberrations
870.5550    Mutagenicity  -  Other Genotoxic Effects
                                      yes
                                      yes
                                      yes
                                      yes
                                    yes[3]
                                      yes
                                      yes
                                      yes
870.6100a  Acute Delayed Neurotoxicity (hen)
870.6100b  90-Day Neurotoxicity (hen)
870.6200a  Acute Neurotoxicity Screening Battery (rat)
870.6200b  90-Day Neurotoxicity Screening Battery (rat)
870.6300    Developmental Neurotoxicity
                                      no
                                      no
                                     no[4]
                                     no[4]
                                      no
                                       -
                                       -
                                       -
                                       -
                                       -
870.7485    General Metabolism
870.7600    Dermal Penetration
870.7800    Immunotoxicity
                                      yes
                                      no
                                      yes
                                      yes
                                       -
                                      yes
Special Studies for Ocular Effects
Acute Oral (rat)
Subchronic Oral (rat)
Six-month Oral (dog)

                                      no
                                      no
                                      no

                                       -
                                       -
                                       -
1. Satisfied by 870.4100b, chronic dog study.
2. Satisfied by 870.4300, rat combined chronic toxicity/carcinogenicity study.
3. Satisfied by negative genotoxicity database, including host-mediated assay of S. typhimurium and S. cerevisiae.
4. Requirement waived by HED's HASPOC, based on weight-of-evidence consideration of hazard, exposure, physicochemical properties, and structurally-related chemicals.
A.2	Toxicity Profiles

TABLE A.2.1	Acute Toxicity Profile for Clopyralid.
                               Guideline Number
                                  Study Type
                                     MRID
                                    Number
                                    Results
                               Toxicity Category
870.1100
Acute oral  -  rat
                                   41641301
LD50 (M/F) >5,000 mg/kg
                                      IV
870.1200
Acute dermal  -  rat
                                   41641302
LD50 (M/F) >5000 mg/kg
                                      IV
870.1300
Acute inhalation  -  rat
                                   41848301
LC50 (M/F) >1 mg/L
                                      III
870.2400
Acute eye irritation  -  rabbit
                                   41641304
Severe irritation at 7 days (corrosive)
                                       I
870.2500
Acute dermal irritation  -  rabbit
                                   41641305
Not an irritant
                                      IV
870.2600
Skin sensitization  -  guinea pig
                                   41641306
Not a sensitizer
                                       -

TABLE A.2.2	Subchronic, Chronic and Other Toxicity Profile for Clopyralid.
                               Guideline Number
                                  Study Type
                   MRID Number (Year), Classification, Doses
                                    Results
870.3100
90-Day oral toxicity (rat)
An acceptable study is not available.  Requirement satisfied by combined chronic oral toxicity/carcinogenicity study in the rat (870.4300).
870.3100

90-Day oral toxicity (mouse)

00127276 (2003)

Acceptable/guideline

0, 200, 750, 2000 or 5000 mg/kg/day
NOAEL = 2000 mg/kg/day
LOAEL = 5000 mg/kg/day, based on decreased body weight gain.
870.3150

90-Day oral toxicity (dog)
An acceptable study is not available.  Requirement satisfied by chronic oral study in the dog (870.4100).
870.3200

21-Day dermal toxicity (rabbit)
41790701 (1990)

Acceptable/guideline

0, 100, 500 or 1000 mg/kg/day
Systemic NOAEL = 1000 mg/kg/day (limit dose)

Systemic LOAEL = not established (>1000 mg/kg/day).

Local dermal NOAEL <100 mg/kg/day (LDT)

Local dermal LOAEL = 100 mg/kg/day, based on epithelial hyperplasia at application site.
870.3250

90-Day dermal toxicity
Study not required.
870.3465

28- Day inhalation toxicity (rat)
Study not required.
870.3700a

Prenatal developmental (rat)
00127279 (1981)

Acceptable/guideline

0, 15, 75 or 250 mg/kg/day

Maternal NOAEL = 75 mg/kg/day
LOAEL = 250 mg/kg/day, based on mortality, decreased body weight gains and reduced food consumption.

Developmental NOAEL = 250 mg/kg/day (HDT)
LOAEL = not established (>250 mg/kg/day).
870.3700b

Prenatal developmental (rabbit)
41649801, -02 (1990)

Acceptable/guideline

0, 50, 110 or 250 mg/kg/day by gavage
Maternal NOAEL = 110 mg/kg/day
LOAEL = 250 mg/kg/day, based on mortality, decreased body weight gains, reduced food consumption, and lesions in the gastric mucosa.

Developmental NOAEL = 110 mg/kg/day
LOAEL = 250 mg/kg/day, based on decreased fetal body weight and hydrocephalus.
870.3800

Reproductive and fertility effects
(rat)
00138155 (1983)

Acceptable/guideline

0, 150, 500 or 1500 mg/kg/day in diet

Parental NOAEL = 500 mg/kg/day (M/F)
LOAEL = 1500 mg/kg/day(M/F), based on decreased body weights and body weight gain in F0 and F1 males; body weights in F1 and F2 females.

Reproductive NOAEL >=1500 mg/kg/day
LOAEL = not attained, based on lack of effects on reproductive parameters (>1500 mg/kg/day).

Offspring NOAEL = 500 mg/kg/day (M/F)
LOAEL = 1500 mg/kg/day (M/F), based on decreased Day 28 body weights in F1 male pups and increased relative liver weights of F1a male and female pups and F1b male pups.
870.4100a

Chronic toxicity
(rat)
Requirement satisfied by 870.4300.
870.4100b

Chronic toxicity (dog)
00158256 (1984)

Acceptable/guideline

0, 100, 320 or 1000 mg/kg/day by capsule

NOAEL = 100 mg/kg/day
LOAEL = 320 mg/kg/day, based on decreases in RBC parameters, increased liver weight (males) and vacuolated adrenal cortical cells (females).  Clinical chemistry changes (decreased serum albumin, globulin and protein) and skin lesions were observed at high dose.
870.4200a
Carcinogenicity
(rat)
Requirement satisfied by 870.4300.
870.4200b

24-month Carcinogenicity
(mouse)
 00157783 (1984)

Acceptable/guideline

0, 100, 500 or 2000 mg/kg/day in the diet (24 months)
NOAEL = 500 mg/kg/day
LOAEL = 150 mg/kg/day, based on decreased body weight/weight gain and reduced food efficiency.

No evidence of carcinogenicity
870.4300

Chronic toxicity/carcinogenicity (rat)
00162393, 00162434 (1986)

Acceptable/guideline

0, 15, 150 or 1500 mg/kg/day in the diet (104 weeks)
NOAEL = 15 mg/kg/day
LOAEL = 150 mg/kg/day, based on gastric lesions (epithelial hyperplasia and thickening of the limiting ridge).  At 1500 mg/kg/day, decreased body weight gains and food consumption were also observed.

No evidence of carcinogenicity
Gene Mutation
870.5100
Study not submitted.  Not required due to lack of tumorigenicity in rat and mouse bioassays, and negative findings in all other genotoxicity assays, including host-mediated assays in Salmonella and Saccharomyces.
Gene Mutation
870.5300
In Vitro and In Vivo Host-Mediated Assay (Salmonella strains TA 1530, G-46 and Saccharomyces strain D-3) (1973)
In vivo assays were conducted using mice
00057086 (1973)

Acceptable/guideline

In vitro testing:  without S9 activation at 5% w/v
solution

In vivo testing:  0, 4, 40 or 400 mg/kg by gavage to 10 mice
Negative  -  no evidence of induced mutant colonies over background levels in Salmonella or Saccharomyces strains tested in either the in vitro or the in vivo assays.
Cytogenetics
870.5385
In Vivo micronucleus assay (rat)
00073638 (1973)

Acceptable/guideline

0, 4, 40 or 400 mg/kg for one day or for 5 days to male rats; sacrifice at 6, 24 or 48 hours post-dosing for all groups.
Negative  -  no evidence of an increase in the formation of chromosomal aberrations in bone marrow at any dose tested.
Other Effects
870.5450
Dominant lethal assay (rat)
00059053, 00099100 (1973)

Acceptable/guideline

4, 40 or 400 mg/kg/day for 5 days to male rats prior to mating
Negative  -  no evidence of treatment-related resorptions.
Other Effects
870.5550
Unscheduled DNA synthesis (rat hepatocytes)
00156387 (1985), 41790702 (1990)

Acceptable/guideline

5x10[-5], 1.56x10[-4], 5x10[-4], 1.56x10[-3], 5x10[-3], 1.56x10[-2], 5x10[-2] M, incubated for 18-20 hours
Negative  -  no evidence of increased unscheduled DNA synthesis in the initial or supplementary assays testing up to insoluble/toxic concentrations.
870.6200a

Acute neurotoxicity screening battery (rat)
Study not required.
870.6200b

Subchronic neurotoxicity screening battery (rat)
Study not required.
870.6300

Developmental neurotoxicity
Study not required.
870.7485

Metabolism and pharmacokinetics
(rat)
41790703 (1991)

Acceptable/guideline

5.0 and 50 mg/kg, single oral dose; 5.0 mg/kg, single IV dose; 5.0 mg/kg/day, repeated daily dose for 14 days
Clopyralid was rapidly and completely absorbed and eliminated with 95 to 115% of the AD recovered by 72 hours, most within 6-12 hours post-dosing.  Almost all radioactivity was eliminated via the urine, irrespective of dose or route of administration (91 to 113% of AD), with <4% excreted in the feces.  Tissue retention was negligible (<0.01% AD).  There was essentially no metabolism of clopyralid; only parent compound was identified.  No significant gender, dose or exposure-route differences were identified.
870.7600
Dermal penetration
Study not available.
870.7800
Immunotoxicity (rat)
48300001 (2010)

Acceptable/guideline

0, 158, 530, or 1062 mg/kg/day
Systemic NOAEL = 1062 mg/kg/day (limit dose)
Systemic LOAEL = not established (>1062 mg/kg/day)
Immunotoxicity NOAEL = 1062 mg/kg/day
Immunotoxicity LOAEL = not established (>1062 mg/kg/day)

A.3	Literature Search

Date and Time of Search:  10 May 2018; 10:04 am
Search Details:
((Clopyralid)) AND (rat OR mouse OR dog OR rabbit OR monkey OR mammal)
PubMed hits: 10
Number of Swift Articles: 6 for Animal
Number of Swift Articles: 6 for Human
Number of Swift Articles: 0 for No Tag

Searches below revealed no hits or articles:
(("Clopyralid monoethanolamine")) AND (rat OR mouse OR dog OR rabbit OR monkey OR mammal)
PubMed hits: 0

(("Clopyralid triethanolamine")) AND (rat OR mouse OR dog OR rabbit OR monkey OR mammal)
PubMed hits: 0

(("Clopyralid potassium")) AND (rat OR mouse OR dog OR rabbit OR monkey OR mammal)
PubMed hits: 0

Clopyralid - 117403
Clopyralid, monoethanolamine salt - 117401
Clopyralid, triethanolamine - 117404
Clopyralid, potassium - 117423

Appendix B.	Physical/Chemical Properties of Clopyralid

TABLE 3.2	Physicochemical Properties of the Technical Grade Clopyralid.
                                   Parameter
                                     Value
                                   Reference
Melting point/range (ºC)
151-152
The Pesticide Manual (14[th] Edition); C.D.S. Tomlin (Editor); 2006.
pH
Not reported

Density (g/cm[3] at 20C)
1.57

Water solubility (g/L at 20°C)
7.85

Solvent solubility (g/L at 20°C)
Acetone		250
Ethyl acetate	102
Xylene		4.6
Hexane		6.0

Vapor pressure (mm Hg [mPa] at 25°C)
1.0 x 10[-5] [1.33]

Dissociation constant (pKa)
2

Octanol/water partition coefficient (Log KOW)
-1.81 (pH 5)
-2.63 (pH 7)
-2.55 (pH 9)

Appendix C.	Review of Human Research

This clopyralid risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These data, which include studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler Exposure Task Force (AHETF) database, and other registrant-submitted exposure monitoring studies (MRID #44339801), are subject to ethics review pursuant to 40CFR §26, have received that review, and are compliant with applicable ethics requirements.  For certain studies, that review may have included review by the Human Studies Review Board.  Descriptions of data sources, as well as guidance on their use, can be found at https://www.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupational-pesticide-handler-exposure-data  and https://www.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupational-pesticide-post-application-exposure.