UN ITED STATES E VIRO ME TAL PROTECTIO AGE CY 

WASIJI GTO , D.C. '.W460 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

MEMORANDUM 

DATE: 9/9/2015 

SUBJECT: Amicarbazone. Scoping Document and Draft Human Health Risk Assessment 

for Registration Review 

PC Code: I 14004 

Decision No.: 503062 

DP Barcocl c: 0426602 

Registration No.: 66330-46, 66330-415, 

66330-416 

Petition No.: NA Regulatory Action: Reg Review Scoping/ORA 

Risk Assessment Type: Single Chemical Case No.: 7269 

TXR No.: 0054349 CAS No.: 129909-90-6 

MRID No.: NA 40CFR: §180.615 

FROM: 

T HROUGH: 

TO: 

Douglas A. Dotson, Ph.D., Chemist J. /).~ Jaime 

Zaida 

Risk Assessme

I. 

D' 

Figueroa, 

Agostino

nt Branch 

, 

DrPH, 

Ph.D., 

IT 

Indu

Toxicologist~ 

(RAB

strial 

2) 

Hygieni

/ 

s ~ 

- (j 

~ 

-- v-

~ 

Health Effects Division (7509P) 

Christina Swartz, Branch Chief 

Risk Assessment Branch TT 

Jess Rowland, Deputy Director ~c;G.:.~C?.---->.­ Health Effects Division (7509P) 

Office of Pesticide Programs 

Maria Piansay, Chemical Review Manager 

Linda Arrington, Branch Chief 

Risk Management and Implementation Branch V 

Pesticide Re-Evaluation Division (7508P) 

The Pesticide Reevaluation Division (PRD) requested the Health Effects Division (HED) to 

develop a scoping document to delineate the data requirements for conducting a human health 

risk assessment for the herbicide, amicarbazone, during the registration review process. As there 

are no data deficiencies (i.e., all data requirements are satisfi ed), HED has conducted a draft 

Page I of 53 
Amicarbazone Draft Risk Assessment DP Number 426602 

human health risk assessment (ORA). This ORA incorporates the most recent data and 

assumptions for conducting dietary, residential, occupational, and aggregate exposure and risk 

assessments. No risk estimates of concern were identified. 

Since the last human health risk assessment (20 11 for use on ornamentals), the following updates 

have been incorporated for amicarbazone: 

I) HED, based on weight-of-evidence considerations, has determined that an inhalation 

toxicity study is not required. 

2) Spray drift exposure/risk has been considered according to current science policies. 

3) The occupational risk assessment has been revised to incorporate updated scientific 

procedures and exposure assumptions. 

4) A dietary exposure assessment was performed using updated food consumption survey 

results. 

5) The registrant satisfied several residue chemistry conditional data deficiencies identified 

in the 2005 residue review and risk assessment. 

6) HED considered all the exposure and toxicity information for amicarbazone and 

determined that chemical-specific dislodgeable fo liar residue (DFR) or turf transferable 

residue (TTR) data are not required lo refine the exposure assessment. 

Page 2 of 53 
Amicarbazone Draft Risk Assessment DP Number 426602

Page 3 of 53

Table of Contents

1.0 Executive Summary............................................................................................................ 5

2.0 HED Recommendations...................................................................................................... 7

2.1 Data Deficiencies/Conditions of Registration................................................................ 7

2.2 Tolerance Considerations............................................................................................... 7

2.2.1 Enforcement Analytical Method ............................................................................... 8

2.2.2 Recommended Tolerances ........................................................................................ 8

2.3 Label Recommendations............................................................................................ 9

3.0 Introduction......................................................................................................................... 9

3.1 Chemical Identity ........................................................................................................... 9

3.2 Physical/Chemical Characteristics............................................................................... 10

3.3 Pesticide Use Pattern .................................................................................................... 10

3.4 Anticipated Exposure Pathways................................................................................... 11

3.5 Consideration of Environmental Justice....................................................................... 11

4.0 Hazard Characterization and Dose-Response Assessment............................................... 12

4.1 Toxicology Studies Available for Analysis.................................................................. 12

4.2 Absorption, Distribution, Metabolism, and Elimination (ADME) .............................. 12

4.2.1 Dermal Absorption .................................................................................................. 13

4.3 Toxicological Effects ................................................................................................... 13

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)..................................... 14

4.4.1 Completeness of the Toxicology Database ............................................................. 14

4.4.2 Evidence of Neurotoxicity....................................................................................... 14

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal.......... 14

4.4.4 Residual Uncertainty in the Exposure Database ..................................................... 15

4.5 Toxicity Endpoint and Point of Departure Selections.................................................. 15

4.5.1 Dose-Response Assessment .................................................................................... 15

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment.......... 17

4.5.3 Cancer Classification and Risk Assessment Recommendation .............................. 17

4.6 Endocrine Disruption ............................................................................................. 17

5.0 Dietary Exposure and Risk Assessment ........................................................................... 18

5.1 Residues of Concern Summary .................................................................................... 19

5.2 Food Residue Profile .................................................................................................... 19

5.3 Summary of Environmental Degradation..................................................................... 20

5.4 Water Residue Profile .................................................................................................. 21

5.5 Dietary Risk Assessment.............................................................................................. 21

5.5.1 Description of Residue Data Used in Dietary Assessments.................................... 21

5.5.2 Percent Crop Treated Data Used in Dietary Assessments ...................................... 22

5.5.3 Acute Dietary Risk Assessment .............................................................................. 22

5.5.4 Chronic Dietary Risk Assessment........................................................................... 22

5.5.5 Cancer Dietary Risk Assessment ............................................................................ 22

5.5.6 Dietary Summary Table .......................................................................................... 23

6.0 Residential (Non-Occupational) Exposure and Risk Assessment .................................... 24

6.1 Residential Handler Exposure/Risk Estimates............................................................. 24

6.2 Residential Post-Application Exposure/Risk Estimates............................................... 25

6.3 Residential Risk Estimates for Use in Aggregate Assessment..................................... 27
Amicarbazone Draft Risk Assessment DP Number 426602

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6.4 Spray Drift.................................................................................................................... 28

6.5 Residential Bystander Post-Application Inhalation Exposure ..................................... 29

7.0 Aggregate Exposure/Risk Characterization...................................................................... 29

7.1 Acute Aggregate Risk .................................................................................................. 29

7.2 Short-Term Aggregate Risk ......................................................................................... 29

7.3 Chronic Aggregate Risk ............................................................................................... 31

8.0 Cumulative Exposure/Risk Characterization.................................................................... 31

9.0 Occupational Exposure/Risk Characterization ................................................................. 31

9.1 Occupational Handler Exposure/Risk Estimates.......................................................... 31

9.2 Occupational Post-Application Exposure/Risk Estimates ........................................... 34

9.2.1 Occupational Post-Application Inhalation Exposure/Risk Estimates..................... 34

9.2.2 Occupational Post-Application Dermal Exposure/Risk Estimates ......................... 34

10.0 Public Health and Pesticide Epidemiology Data .............................................................. 35

11.0 References......................................................................................................................... 35

Appendix A. Toxicology Profile.................................................................................................. 37

A.1 Toxicology Data Requirements.................................................................................... 37

A.2 Toxicology Profile Tables............................................................................................ 38

Appendix B. Occupational and Residential Non-Cancer Handler Algorithms ........................... 45

Appendix C. Residential Non-Cancer Post-Application Algorithms.......................................... 46

Appendix D. Review of Human Research................................................................................... 50

Appendix E. Physical and Chemical Properties .......................................................................... 51

Appendix F. Amicarbazone International Maximum Residue Limits......................................... 52
Amicarbazone Draft Risk Assessment DP Number 426602

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1.0 Executive Summary

Amicarbazone, 4-amino-N-(1,1-dimethylethyl)-4,5-dihydro-3-(1-methylethyl)-5-oxo-1H-1,2,4-

triazole-1-carboxamide, is a selective herbicide that acts through the inhibition of photosynthesis. 

It is used for preplant, preemergence, or postemergence application to field corn for selective 

control of broadleaf weeds. It is also used for control of broadleaf weeds on turf, ornamental

plants including trees, Christmas tree farms, non-crop areas and on conifers in nurseries. 

Tolerances are established in 40CFR §180.615 for residues in or on field corn, livestock 

commodities, and rotational crops.

The three registered end-use products include water dispersible granule (WDG) and suspension

concentrate (SC) formulations of amicarbazone, all of which may be used for non-agricultural 

purposes. Only the WDG formulation is registered for use on corn. The single maximum 

application rates range from 0.044 lb ai/A up to 0.46 lb ai/A (which is the maximum seasonal 

application rate for some use sites). The most recent risk assessment that HED performed for 

amicarbazone was completed in 2011 (D386858, L. Hansen et al., 12/2/2011) to support 

proposed uses on turf, Christmas tree farms, non-crop areas, and on conifers in nurseries.

The toxicology database for amicarbazone is complete and adequate for risk assessment, with the 

exception of a subchronic inhalation toxicity study. This inhalation study was not available at 

the time of the previous risk assessment; however, HED’s Hazard and Science Policy Council 

(HASPOC), based on weight-of-evidence considerations, has determined that the subchronic 

inhalation study is not required (TXR No. 0054349). Since the 2011 risk assessment, no new 

toxicity and/or metabolism data have been received for amicarbazone. The toxicological 

endpoints and points of departure (PODs) have not been updated and remain the same as those 

used in the previous assessment.

In subchronic/chronic animal studies, amicarbazone primarily causes signs of general toxicity 

such as decreased body weight and liver effects. Changes in thyroid hormones and thyroid 

vacuolization were also seen, although mechanistic studies indicated that these changes were 

secondary to liver effects. Mice were more sensitive to the effects of amicarbazone than dogs 

and rats, which were equally sensitive. Minimal progression of toxicity was observed between 

subchronic and chronic exposure to amicarbazone, which is consistent with the rapid metabolism 

seen in the absorption, distribution, metabolism, and elimination (ADME) studies. Clinical signs 

of neurotoxicity (eyelid ptosis, decreased approach response, and red staining of the nasal area) 

were seen following acute exposure. Evidence of neurotoxicity was not seen in the subchronic 

or developmental neurotoxicity studies or any other study in the database. There was no 

evidence of quantitative or qualitative susceptibility in the rat and rabbit developmental, rat 

developmental neurotoxicity, and rat reproductive toxicity studies. There was no evidence of 

systemic toxicity following dermal exposure. Amicarbazone is classified as “not likely to be 

carcinogenic to humans” based on the lack of evidence for carcinogenicity in mice and rats and 

the lack of concern for mutagenicity. Evidence of immunotoxicity (decreased number of spleen 

cells per spleen, suppressed antibody response, and decreased spleen weight) was observed in the 

immunotoxicity study, but at doses higher than those that caused decreased body weight or liver 

effects in other studies.
Amicarbazone Draft Risk Assessment DP Number 426602

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Field corn is the only agricultural commodity for which amicarbazone is registered. However, 

humans can be exposed to amicarbazone residues in food through consumption of corn 

commodities, rotational crop commodities, or secondary residues in livestock commodities. In 

HED’s 2005 risk assessment for the proposed use on field corn, HED identified residue 

chemistry data deficiencies, which have been addressed by the registrants. As a result, there are 

no outstanding residue chemistry data requirements. However, HED notes that if the registrant 

would like root and tuber vegetables to remain on the label as rotational crops, extensive field 

rotational crop data for the leaves of root and tuber vegetables will be needed. HED can then 

determine the appropriate plant-back intervals and rotational crop tolerances.

HED conducted acute and chronic dietary exposure assessments that included residues in field 

corn, livestock commodities, rotational crops, and drinking water. The assessments were 

unrefined. Tolerance level residues and 100% crop treated assumptions were made for all 

commodities. Modeled estimated drinking water concentrations (EDWCs) were incorporated 

directly into the dietary assessments. The acute and chronic dietary risk estimates are not of 

concern for the U.S. population and all population subgroups. Drinking water is the most 

significant contributor to dietary risk for the U.S. population and all population subgroups.

For the residential exposure scenarios, an updated quantitative short-term residential exposure 

assessment (handler and post-application) has been completed in accordance with the 2012 

Residential Standard Operating Procedures (SOPs). All residential risk estimates are not of 

concern. In addition, all residential scenarios selected for the aggregate assessment are not of 

concern.

Amicarbazone can be applied via groundboom and airblast equipment and, therefore, there is 

the potential for indirect exposure to amicarbazone related to spray drift. A quantitative spray 

drift assessment 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 for the amicarbazone products. The turf post-application 

MOEs are protective for any potential exposures related to spray drift for amicarbazone. The 

risk estimates are not of concern. 

The residential handler exposure from applying amicarbazone using a manually-pressurized

handwand and children’s post-application incidental oral (hand-to-mouth) exposure were 

combined with the chronic dietary exposure from the most highly exposed adult and children’s 

subpopulations, respectively, to determine aggregate exposure and risk. For adults, the dietary 

exposure of the general U.S. population was used, and for children, the dietary exposure of all 

infants less than one year old was used. Despite the numerous conservative assumptions in 

developing the exposure estimates, the risk estimates are not of concern.

As the Environmental Fate and Effects Division (EFED) did not provide an updated drinking 

water assessment, HED also performed an aggregate risk assessment using the drinking water 

level of comparison (DWLOC) approach. In order to do this, HED performed the chronic 

dietary exposure analysis without drinking water. All assumptions with respect to residue levels 

and percent crop treated were the same as those used in the assessments that included drinking 

water. HED used these exposure estimates to calculate DWLOCs. The DWLOC is the 
Amicarbazone Draft Risk Assessment DP Number 426602

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maximum allowable drinking water concentration, given the estimated exposure through 

agricultural and residential sources, that could be present in order for HED not to have a concern 

for aggregate risk. In order for HED not to have a concern for short-term aggregate risk for any 

population subgroup, the chronic estimated drinking water concentration (EDWC) would need to 

be 590 ppb or less.

No chemical-specific handler exposure data were submitted in support of this draft risk 

assessment; therefore, HED relied on the best available data to assess handler exposure. Default 

assumptions established by HED’s Science Advisory Council for Exposure (ExpoSAC) were 

used for parameters such as body weight and amount handled. Dermal risks are not anticipated 

because of the lack of toxicity via the dermal route; therefore, the occupational handler 

assessment addresses inhalation exposures only. All occupational handler scenarios for the 

registered uses are not of concern (i.e., the MOEs are greater than 100). The lowest MOE of 610 

is associated with mixing/loading a dry flowable formulation being applied using groundboom 

equipment on up to 200 acres. All other MOEs were significantly higher, ranging from 3,900 to 

260,000. The personal protective equipment (PPE) statement on the registered labels requires 

applicators and other handlers to wear baseline clothing (i.e., long sleeved shirt, long pants,

shoes plus socks) chemical-resistant gloves, and no respirator. No additional PPE 

recommendations are needed based on the risk estimates for handlers. 

Based on the Agency’s current practices, a quantitative non-cancer occupational post-application 

inhalation exposure assessment was not performed for amicarbazone. 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 amicarbazone. Occupational dermal postapplication risks to agricultural workers following treatments to agricultural crops were not 

quantitatively assessed, since no dermal endpoint of concern was identified.

The restricted entry interval (REI) of 12 hours specified on the registered labels is based on the 

acute toxicity of amicarbazone and is adequate to protect agricultural workers from postapplication exposures.

Potential areas of environmental justice concerns were considered in this human health risk 

assessment to the extent possible. The assessment resulted in no risks of concern.

2.0 HED Recommendations

2.1 Data Deficiencies/Conditions of Registration

None

2.2 Tolerance Considerations

The current tolerances for residues of amicarbazone are listed in the international maximum 

residue limit (MRL) status sheet in Appendix F. HED is not recommending in favor of any 

changes to these tolerances, and there are no harmonization issues because there are no Codex or 

Canadian MRLs for amicarbazone.
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2.2.1 Enforcement Analytical Methods

Adequate analytical methods are available for enforcement of the plant and livestock commodity 

tolerances. The methods are based on liquid chromatography followed by tandem mass 

spectroscopy (LC-MS/MS). The plant method is titled “Analytical Residue Method for the 

Determination of MKH 3586 Residues in Plant Matrices” (Bayer Report Number 108340), and 

the livestock commodity method is titled “An Analytical Method for the Determination of MKH 

3586 Residues in Livestock Matrices.”

2.2.2 Recommended Tolerances

Tolerances are established for residues of amicarbazone in or on the commodities in 40 

CFR§180.615. While no changes are being recommended for the tolerance levels, HED is 

recommending a change in the tolerance expression.

40CFR §180.615(a) currently reads: “Tolerances are established for combined residues of the 

herbicide, amicarbazone [4-amino-4, 5-dihydro- N-(1,1-dimethylethyl)-3-(1-methylethyl)-5-oxo1H-1,2,4-triazole-1-carboxamide] and its metabolites DA amicarbazone [N-(1,1-dimethylethyl)-

4,5-dihydro-3-(1-methylethyl)-5-oxo-1H-1,2,4-triazole-1-carboxamide] and iPr-2-OH DA 

amicarbazone [N-(1,1-dimethylethyl)-4,5-dihydro-3-(1-hydroxy-1-methylethyl)-5-oxo-1H-1,2,4-

triazole-1-carboxamide], calculated as parent equivalents, in or on the following commodities.”

According to HED’s Interim Guidance on Tolerance Expressions (S. Knizner; 27 May 2009), 

the tolerance expression should be revised to state: “Tolerances are established for residues of 

amicarbazone, including its metabolites and degradates, in or on the commodities listed in the 

table below. Compliance with the tolerance levels specified below is to be determined by 

measuring amicarbazone [4-amino-4, 5-dihydro- N-(1,1-dimethylethyl)-3-(1-methylethyl)-5-

oxo-1H-1,2,4-triazole-1-carboxamide] and its metabolites DA amicarbazone [N-(1,1-

dimethylethyl)-4,5-dihydro-3-(1-methylethyl)-5-oxo-1H-1,2,4-triazole-1-carboxamide] and iPr2-OH DA amicarbazone [N-(1,1-dimethylethyl)-4,5-dihydro-3-(1-hydroxy-1-methylethyl)-5-

oxo-1H-1,2,4-triazole-1-carboxamide], calculated as parent equivalents, in or on the following 

commodities.”

In addition, 40CFR §180.615(d) currently reads: “Tolerances are established for the indirect or 

inadvertent residues of amicarbazone [4-amino-4, 5-dihydro- N-(1,1-dimethylethyl)-3-(1-

methylethyl)-5-oxo-1H-1,2,4-triazole-1-carboxamide] and its metabolites DA amicarbazone [N-

(1,1-dimethylethyl)-4,5-dihydro-3-(1-methylethyl)-5-oxo-1H-1,2,4-triazole-1-carboxamide] and 

iPr-2-OH DA amicarbazone [N-(1,1-dimethylethyl)-4,5-dihydro-3-(1-hydroxy-1-methylethyl)-5-

oxo-1H-1,2,4-triazole-1-carboxamide], calculated as parent equivalents, in or on the following 

commodities when present therein as a result of application of amicarbazone to the growing 

crops in paragraph (a) of this section.”

According to HED’s Interim Guidance on Tolerance Expressions (S. Knizner; 27 May 2009), 

the tolerance expression should be revised to state: “Tolerances are established for indirect or 

inadvertent residues of amicarbazone, including its metabolites and degradates, in or on the 

commodities listed in the table below. Compliance with the tolerance levels specified below is 
Amicarbazone Draft Risk Assessment DP Number 426602

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to be determined by measuring amicarbazone [4-amino-4, 5-dihydro- N-(1,1-dimethylethyl)-3-

(1-methylethyl)-5-oxo-1H-1,2,4-triazole-1-carboxamide] and its metabolites DA amicarbazone 

[N-(1,1-dimethylethyl)-4,5-dihydro-3-(1-methylethyl)-5-oxo-1H-1,2,4-triazole-1-carboxamide] 

and iPr-2-OH DA amicarbazone [N-(1,1-dimethylethyl)-4,5-dihydro-3-(1-hydroxy-1-

methylethyl)-5-oxo-1H-1,2,4-triazole-1-carboxamide], calculated as parent equivalents, in or on 

the following commodities when present therein as a result of application of amicarbazone to the 

growing crops in paragraph (a) of this section.”

2.3 Label Recommendations

Root and tuber vegetables are currently listed on amicarbazone product labels as rotational crops

with a 1-month plant-back interval. However, HED recommends that root and tuber vegetables 

be removed from the amicarbazone labels as rotational crops. If the registrant submits extensive 

field rotational crop data for the leaves of root and tuber vegetables, HED can determine the 

appropriate plant-back intervals and rotational crop tolerances.

3.0 Introduction

3.1 Chemical Identity

Table 3.1. Amicarbazone Nomenclature.

Chemical Structure

 

Empirical Formula C10H19N5O2

Common Name Amicarbazone

Company experimental name MKH 3586

IUPAC name 4-amino-N-tert-butyl-4,5-dihydro-3-isopropyl-5-oxo-1H-1,2,4-triazole-1-

carboxamide

CAS Name 4-amino-N-(1,1-dimethylethyl)-4,5-dihydro-3-(1-methylethyl)-5-oxo-1H1,2,4-triazole-1-carboxamide

CAS Registry Number 129909-90-6

End-use product/EP

Amicarbazone WDG Herbicide, 70% ai (also known as Dinamic 70WDG 

Herbicide and Xonerate Herbicide)(66330-46)

ARY 0452-110 Herbicide (66330-415)

ARY 0452-112 Herbicide (66330-416)

Chemical Class Triazolinone or Triazolone herbicide

Known Impurities of Concern N/A

N

N

N

O

NH2

CH3

H C3

N

H

H C3

CH3

H C3

O
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3.2 Physical/Chemical Characteristics

Amicarbazone is a solid that has a vapor pressure of 2.3x10-8 mmHg at 25°C. It is slightly water 

soluble (4.6 g/L) and partitions relatively equally between water and octanol. The octanol/water 

partition coefficient (log Kow) = 1.23 at pH 7. As a result, appreciable bioaccumulation is not 

likely. See Appendix E for a listing of additional physical and chemical properties.

3.3 Pesticide Use Pattern

At the present time, there is one technical product, Amicarbazone Technical Herbicide (EPA 

Registration Number 66330-45) and three end-use products. Amicarbazone WDG Herbicide 

(EPA Registration Number 66330-46) is registered for use on corn, a variety of turf areas (e.g., 

residential lawns, golf courses, sod farms, commercial turf sites, parks, recreation areas, school 

grounds, etc.), conifers in nurseries, and field plantings (including Christmas trees). The other 

two end-use products are registered for the same uses as the WDG Herbicide with the exception 

of the use on corn. These two products are ARY 0452-110 Herbicide (EPA Reg No. 66330-415) 

and ARY 0452-112 Herbicide (EPA Reg No. 66330-416). The use directions for these EPs are 

summarized in Table 3.3, below.

For the three end-use products (EPs), the single maximum application rates range from 0.044 lb 

ai/A up to 0.46 lb ai/A (which is the maximum seasonal application rate for some use sites). The 

EPs may be applied via handheld equipment, groundboom, or airblast, but may not be applied

aerially or through any type of irrigation system. The PPE statement on the registered labels

requires applicators and other handlers to wear long sleeved shirt, long pants, chemical-resistant 

gloves made of any waterproof material, and shoes plus socks. A restricted entry interval (REI)

of 12 hours appears on all registered product labels.

Table 3.3. Summary of Directions for End-Use Products of Amicarbazone.

Applic. Timing, 

Type, and Equip.

Formulation

[EPA Reg. No.]

Maximum 

Single 

Applic. Rate 

(lb ai/A)

Max. No. 

Applic. per 

Season

Max. 

Seasonal 

Applic. Rate 

(lb ai/A)

Use Directions and 

Limitations

Corn and Non-Agricultural Uses (including residential lawns, golf courses, sod farms, commercial turf sites, 

parks, recreation areas, school grounds), Conifers in Commercial Nurseries and Field Plantings (including 

Christmas trees)

Foliar spray

(directed) to 

containerized 

ornamental plants 

using handheld 

equipment. 

Applied using 

groundboom, 

airblast, and 

handheld 

equipment.

Amicarbazone 

WDG Herbicide

(WDG), 70% ai

[66330-46]

0.044-0.46 lb 

ai/A

(10.5 oz 

prod/A or 

0.023 lb 

ai/gal at 70% 

ai)

1-4 

(depending 

on rate)

0.46 lb ai/A

Do not apply with aerial 

equipment or through any 

type of irrigation system.

ARY 0452-110 

Herbicide (SC), 

46.2% ai

[66330-415]

ARY 0452-112 

Herbicide (SC), 

23.25% ai

[66330-416]
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3.4 Anticipated Exposure Pathways

Humans can be exposed to amicarbazone residues in their diets from both food and drinking 

water. 

There are residential uses for amicarbazone on turf and ornamental plants; therefore, there is 

likely to be exposure in residential and non-occupational settings. Although the product does not 

appear to be intended for homeowner use, there is the potential for homeowners to purchase and 

apply the product to their own lawns and ornamentals. While there is potential for dermal 

exposure, there is no expectation of dermal risk, based on the lack of dermal toxicity. 

Furthermore, the potential for post-application oral exposure to children is not expected from 

treated ornamentals because young children spend little time playing in areas where residential 

ornamentals are grown and, therefore, the extent to which they engage in oral-exposure activities 

is low. Residential post-application exposures to children are expected from treated turf. In 

addition, there is the potential for indirect exposure to amicarbazone related to spray drift. In an 

occupational setting, applicators might be exposed while handling the pesticide prior to 

application (i.e., mixing/loading) as well as during application. There is a potential for postapplication exposure for workers re-entering treated fields. 

3.5 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 U.S. 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, 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 U.S. 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. Exposure risk estimates were not of concern. 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.
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4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicology database is complete and adequate for risk assessment, with the exception of a 

subchronic inhalation toxicity study. This inhalation study is generally required in accordance 

with the current Part 158 Guidelines (40 CFR Part 158), but the HASPOC has determined that 

the subchronic inhalation study is not required at this time (TXR# 0054349). Toxicity studies 

available for analysis include:

 Subchronic oral toxicity studies in rat and dog

 A 21-day dermal toxicity study in rat

 Chronic toxicity studies in rat and dog

 Carcinogenicity studies in rat and mouse

 Developmental toxicity studies in rat and rabbit

 A reproductive toxicity study in rat

 Acute and subchronic neurotoxicity studies in rat

 A developmental neurotoxicity study in rat

 A battery of genotoxicity studies

 An immunotoxicity study in rat

 A metabolism study in rat

 Non-guideline mechanistic studies on thyroid hormones and neurotoxicity in rat and 

mouse

 A metabolism study on the soil metabolite 4-methyl MKH 3586 in rat

 Bacterial reverse gene mutation assays on oxadiazolinon and triazolinon, two 

intermediates of amicarbazone

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

Metabolism of amicarbazone was investigated in male rats only. Amicarbazone was wellabsorbed following oral dosing. Approximately 95% of the administered radioactive dose was 

recovered within 72 hours after dosing, with the majority being excreted within 24 hours via the 

urine (64%) and feces (27%). At 72 hours, the tissues and carcass contained <1% of the 

administered dose, with the highest concentrations remaining in the liver, kidney, and blood. 

Plasma levels of radioactivity were not determined in this study. Amicarbazone was extensively 

metabolized, with only 2% and <1% of the administered dose being excreted as unchanged 

parent in the urine and feces, respectively. The primary routes of metabolism were 

glucuronidation with excretion in the feces, and deamination and hydroxylation with excretion in 

the urine. The major metabolites that were identified were iPR-2-OH DA MKH 3586 (a 

hydroxylated, deaminated product of the parent compound excreted primarily in the urine, 32% 

out of 34% total excretion), tBu-OH DA MKH 3586 (11% in urine and 4% in feces), and iPR1,2-diOH DA MKH 3586 (6% in urine, <1% in feces). A glucuronidated metabolite, MKH 

3586GA, was excreted primarily in the feces (10% out of 11% total excretion). Five minor 

identified metabolites (<3% of dose) and seven unidentified metabolites (all <1% of dose) were 

isolated in the urine and the feces.
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4.2.1 Dermal Absorption

Dermal absorption data are not available for amicarbazone. However, an acceptable 21-day 

dermal toxicity study in the rat is available. There was no evidence of either systemic toxicity or 

local dermal irritation at doses up to and including the limit dose. Therefore, risks associated 

with the dermal route of exposure were not assessed.

4.3 Toxicological Effects

Amicarbazone is a triazolinone herbicide that controls broadleaf weeds by selective inhibition of 

acetolactate synthase (ALS), an enzyme involved in photosystem II in plants. While humans 

also have an ALS enzyme, it is of unknown function. Other ALS inhibiting pesticides, such as 

the sulfonyl ureas, primarily cause general toxicity indicated as decreased body weight and liver 

changes. Amicarbazone is similar in this regard. The most sensitive and consistent effects 

following repeat exposure were decreased body weight in rats and liver effects following 

subchronic and chronic exposure in rats and dogs (increased liver weights, cholesterol, 

triglycerides, and N- and O- demethylase). Changes in thyroid hormones and thyroid 

vacuolization were seen following subchronic exposure in rats and dogs, respectively; however, 

mechanistic studies indicated that there were no effects on thyroid hormone synthesis, and that 

changes were likely secondary to the liver effects observed. Chronic exposure to amicarbazone 

did not result in treatment-related increases in the incidence of tumors in the rat or mouse. 

Dogs and rats appeared to be similarly sensitive to the effects of amicarbazone based on 3⁄4 body 

weight scaling. In contrast, the mouse was much less sensitive. In rats and dogs, there appeared 

to be minimal progression of toxicity over time, as the liver and body weight effects were seen at 

similar or slightly lower doses following chronic exposure compared to subchronic exposure. In 

addition, the effects observed did not appear to be more severe following chronic exposure. The 

lack of progression is supported by the metabolism data that indicated that 91% of the dose was 

eliminated by 24 hours (combined urine and feces).

Clinical signs related to neurotoxicity were observed following acute, but not subchronic, 

exposure in rats. In the acute neurotoxicity study (ACN), rats exhibited eyelid ptosis, decreased 

approach response, and red staining of the nasal area. The acute neurotoxic effects of 

amicarbazone were further supported by two non-guideline acute neurotoxicity studies. In the 

first study, similar clinical signs were observed as in the guideline ACN study (sedation, ptosis, 

and salivation) at a similar dose. The second study showed that central nervous system (CNS)

functional impairment (increased reaction times, decreased traction focus, impaired motor 

coordination, sedation, partial ptosis) occurred following acute exposure, although at a higher 

dose. No evidence of neurotoxicity was observed in either adults or pups in the developmental 

neurotoxicity study.

There was no evidence of quantitative or qualitative susceptibility in the rat and rabbit 

developmental, rat developmental neurotoxicity, and rat reproductive toxicity studies. There was 

no evidence of systemic toxicity following dermal exposure. Evidence of immunotoxicity 

(decreased number of spleen cells per spleen, suppressed antibody response and decreased spleen 
Amicarbazone Draft Risk Assessment DP Number 426602

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weight) was observed in the immunotoxicity study, but at doses higher than those that caused 

decreased body weight or liver effects in other studies. 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

HED continues to recommend that the 10x FQPA Safety Factor (for the protection of infants and 

children) be reduced to 1x. This recommendation is supported by the following considerations: 

1) the toxicological database for amicarbazone is complete with regard to pre-and postnatal 

toxicity; 2) no evidence of increased quantitative and/or qualitative susceptibility was observed 

in the developmental toxicity studies in rats or rabbits, in the reproduction study in rats, or in the 

developmental neurotoxicity study in rats; 3) the endpoints and points of departure selected for 

risk assessment are protective of the effects observed in the developmental, reproduction, and 

acute neurotoxicity studies; and 4) the risk assessment does not underestimate exposure through 

food, water, and residential sources.

4.4.1 Completeness of the Toxicology Database

The toxicology database is considered complete and is adequate for assessing and characterizing 

potential pre- and/or post-natal susceptibility for infants and children. Acceptable/guideline 

developmental toxicity studies in rats and rabbits and a reproduction study in rats, as well as 

acute, subchronic, and developmental neurotoxicity studies in rats, are available for FQPA 

assessment.

4.4.2 Evidence of Neurotoxicity

Rats exhibited evidence of neurotoxicity following acute exposure. Clinical signs observed were 

eyelid ptosis, decreased approach response, and red staining of the nasal area. CNS functional 

impairment (increased reaction times, decreased traction focus, impaired motor coordination, 

sedation, partial ptosis) was also observed following acute exposure, although at a higher dose. 

No evidence of neurotoxicity was seen in the subchronic and developmental neurotoxicity 

studies or in other studies in the database. A clear NOAEL was established for the acute 

neurotoxic effects, and the endpoints and points of departure selected for risk assessment are 

protective of the clinical signs observed in the acute neurotoxicity study.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

No evidence of increased quantitative or qualitative susceptibility was seen in rat and rabbit 

developmental toxicity, rat reproduction, or rat developmental neurotoxicity studies. All effects 

in the young were observed in the presence of comparable maternal toxicity. Delayed skeletal 

development and incomplete ossification were observed in the rat and rabbit developmental 

studies, respectively, at doses where dams had decreased body weight. In the reproduction 

study, decreased pup weight was seen at the same doses as decreased body weight in the dams. 
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4.4.4 Residual Uncertainty in the Exposure Database

There is no residual uncertainty with respect to the exposure assessments conducted for 

amicarbazone. The dietary exposure estimates in this assessment rely on conservative estimates 

of all residues of concern from both the food and drinking water exposure pathways. The 

aggregate assessment, which includes children’s exposures to residues on treated turf, was based 

on turf residues on the day of application, even though the label indicates that the greatest 

herbicidal effectiveness of the product is achieved when it is watered-in.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

No new toxicity data have been received for amicarbazone since the previous risk assessment 

(D386858, L. Hansen et al., 12/2/2011). Upon review of the endpoints chosen for risk 

assessment, it was determined that for some studies, the toxicological effects reported at the 

LOAELs would not be considered adverse. However, these studies were not re-evaluated 

because the selected endpoints are protective of all the effects observed in the database and risks 

of concern that would require further refinement of the toxicity endpoints were not 

identified. Therefore, all endpoints/PODs selected for risk assessment remain the same as in 

previous assessments. A summary of toxicological doses and endpoints used in the 

amicarbazone human health risk assessments is presented below.

Table 4.5.1.a. Summary of Toxicological Doses and Endpoints for Amicarbazone for Use in Dietary and NonOccupational Human Health Risk Assessments.

Exposure/Scenario Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, 

LOC for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(General Population, 

including Infants and 

Children and 

Females 13-49 years 

of age)

NOAEL= 

10 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Acute RfD = 

0.10 

mg/kg/day

aPAD =0.10 

mg/kg/day

Acute Oral Neurotoxicity Screening Battery

LOAEL = 20 mg/kg/day based on eyelid ptosis 

and decreased approach response (both sexes) 

and red nasal staining in males

Chronic Dietary 

(General Population, 

including Infants and 

Children and 

Females 13-49 years 

of age)

NOAEL= 

2.3 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Chronic RfD 

= 0.023

mg/kg/day

cPAD = 

0.023 

mg/kg/day

Chronic Oral Rat and Chronic Oral Dog (cocritical)

Rat LOAEL = 25.3 mg/kg/day based on 

decreased body weight and weight gain

Dog LOAEL = 8.7 mg/kg/day based on liver 

effects, including increased absolute/relative 

liver weights, triglycerides and cholesterol. 
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Table 4.5.1.a. Summary of Toxicological Doses and Endpoints for Amicarbazone for Use in Dietary and NonOccupational Human Health Risk Assessments.

Exposure/Scenario Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, 

LOC for 

Risk 

Assessment

Study and Toxicological Effects

Incidental Oral 

Short- Term (1-30 

days)

NOAEL= 

6.28 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Residential 

LOC for 

MOE = 100

90-Day Oral Toxicity in Dogs

LOAEL = 25 mg/kg/day based on increased 

thyroid vacuolization and decreased food 

consumption and glucose in females; increased 

platelets, phosphate, bile acids, absolute and 

relative liver weights, and lymphoid hyperplasia 

of the gall bladder in males; and decreased 

albumin and increased triglycerides, Ndemethylase and O-demethylase in both sexes.

Dermal (all 

durations)

No systemic toxicity by the dermal route was seen at the limit dose tested of 1,000 mg/kg/day. 

Evidence of low dermal absorption was estimated by comparison of oral and dermal studies in the rat. 

This risk assessment was therefore not performed.

Inhalation Shortand IntermediateTerm (1-30 days and 

1-6 months, 

respectively)

NOAEL= 

6.28 

mg/kg/day

(inhalation 

toxicity 

considered 

equivalent 

to oral 

toxicity)

UFA= 10x

UFH=10x

FQPA SF= 1x

Residential 

LOC for 

MOE = 100

90-Day Oral Toxicity in Dogs

LOAEL = 25 mg/kg/day based on increased 

thyroid vacuolization and decreased food 

consumption and glucose in females; increased 

platelets, phosphate, bile acids, absolute and 

relative liver weights, and lymphoid hyperplasia 

of the gall bladder in males; and decreased 

albumin and increased triglycerides, Ndemethylase and O-demethylase in both sexes.

Cancer (oral, dermal, 

inhalation)

Classification: “not likely to be carcinogenic to humans.” There was no treatment-related increase in 

tumor incidence when compared to control

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 members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. RfD = 

reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.
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Table 4.5.1.b. Summary of Toxicological Doses and Endpoints for Amicarbazone for Use in Occupational 

Human Health Risk Assessments.

Exposure/ Scenario Point of 

Departure

Uncertainty Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Dermal (all 

durations)

No systemic toxicity by the dermal route was seen at the limit dose tested of 1,000 mg/kg/day. 

Evidence of low dermal absorption was estimated by comparison of oral and dermal studies in the rat. 

This risk assessment was therefore not performed.

Inhalation Short- and 

Intermediate-Term 

(1-30 days and 1-6 

months, respectively)

NOAEL= 

6.28 

mg/kg/day

(inhalation 

toxicity 

considered 

equivalent 

to oral 

toxicity)

UFA=10x

UFH=10x

Occupational LOC 

for MOE = 100

90-Day Oral Toxicity in Dogs

LOAEL = 25 mg/kg/day based on increased 

thyroid vacuolization and decreased food 

consumption and glucose in females; increased 

platelets, phosphate, bile acids, absolute and 

relative liver weights, and lymphoid hyperplasia 

of the gall bladder in males; and decreased 

albumin and increased triglycerides, Ndemethylase and O-demethylase in both sexes.

Cancer (oral, dermal, 

inhalation)

Classification: “not likely to be carcinogenic to humans.” There was no treatment-related increase in 

tumor incidence when compared to control. 

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 members of the human population (intraspecies). MOE = margin of exposure. LOC = level of 

concern. N/A = not applicable. 

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

When there are potential occupational and residential exposures to a pesticide, the risk 

assessment must address exposures from three major sources (oral, dermal, and inhalation) and 

determine whether the individual exposures from these routes can be combined based on the 

same toxicological effects. For amicarbazone, incidental oral and inhalation exposures can be 

combined because the risk assessments are based on studies with the same toxicological effects. 

Dermal exposure cannot be combined because of the lack of toxicity via the dermal route. 

4.5.3 Cancer Classification and Risk Assessment Recommendation

Amicarbazone is classified as “not likely to be carcinogenic to humans.” There were no 

treatment-related increases in the incidence of tumors in either the rat or mouse carcinogenicity 

studies, both of which were tested at adequate doses. There is no concern for mutagenicity.

4.6 Endocrine Disruption

As required by FIFRA and 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 
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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 amicarbazone, 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), 

amicarbazone 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 June 14, 20131and 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.

5.0 Dietary Exposure and Risk Assessment 

The only direct agricultural use for amicarbazone is field corn. The direct application to corn 

can result in inadvertent residues in the rotational crops alfalfa, cotton, soybeans, and wheat. As 

a result, tolerances have been established for residues in corn and rotational crops. Many of the 

agricultural commodities with tolerances are livestock feed items. As a result, tolerances have 

also been established for milk and livestock tissues at levels ranging from 0.01 ppm to 1.0 ppm.

 

1 See http://www.regulations.gov#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of 

chemicals.
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5.1 Residues of Concern Summary

The qualitative nature of the residues of amicarbazone in plants and livestock has been 

adequately characterized. No changes are being made to the residues of concern for tolerance 

enforcement and risk assessment. The residue of concern in plants and livestock for tolerance 

enforcement are the parent compound, desamino amicarbazone, and iPr-2-OH desamino 

amicarbazone.

In general, metabolites were included in risk assessment based on the presence of the 

triazolinone ring, and potential toxicity equivalent to that of the parent. The residues of concern 

in field corn consist of the parent amicarbazone, desamino amicarbazone, and iPr-2-OH 

desamino amicarbazone. The residues of concern in ruminants and poultry are listed in Table 

5.1, below. HED previously determined that the residues of concern in drinking water for 

dietary risk assessment are the parent amicarbazone, desamino amicarbazone, and N-methyldesamino amicarbazone. There is no expectation that the residues of concern will need to be 

revisited during registration review.

Table 5.1. Summary of Metabolites and Degradates to be included in the Risk Assessment 

and Tolerance Expression.

Matrix Residues included in Risk Assessment Residues included in Tolerance 

Expression

Plants

Primary Crop

amicarbazone,

desamino amicarbazone,

iPr-2-OH desamino amicarbazone

amicarbazone,

desamino amicarbazone,

iPr-2-OH desamino amicarbazone 

Rotational 

Crop

amicarbazone,

desamino amicarbazone,

iPr-2-OH desamino amicarbazone

amicarbazone,

desamino amicarbazone,

iPr-2-OH desamino amicarbazone 

Livestock

Ruminant

amicarbazone,

desamino MHK amicarbazone,

iPr-2-OH desamino amicarbazone, tBuOH 

amicarbazone

amicarbazone,

desamino amicarbazone,

iPr-2-OH desamino amicarbazone

Poultry

amicarbazone,

desamino amicarbazone,

iPr-2-OH desamino amicarbazone, iPrAcid desamino amicarbazone, iPr-1-OH 

desamino amicarbazone, iPr-Ene desamino 

amicarbazone

amicarbazone,

desamino amicarbazone,

iPr-2-OH desamino amicarbazone

Drinking Water

amicarbazone,

desamino amicarbazone,

N-methyl-desamino amicarbazone

Not Applicable

5.2 Food Residue Profile

Corn is the only agricultural commodity for which amicarbazone is registered. However, 

humans can be exposed to amicarbazone residues in food through consumption of corn 

commodities, rotational crop commodities, or secondary residues in livestock commodities. The 

residue chemistry database is adequate to support the current registration on field corn.
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In HED’s 2005 risk assessment for the proposed use on field corn, HED listed several 

conditional data deficiencies. The registrant, Arysta LifeScience, submitted responses to the data 

deficiencies. HED reviewed the submitted information and prepared responses to the individual 

deficiencies. HED concluded that all residue chemistry conditional data deficiencies listed in the 

2005 amicarbazone risk assessment were satisfied. However, HED recommended that the 

1-month plant back interval for root and tuber vegetables be removed from the amicarbazone 

label. If the registrant intends to retain root and tuber vegetables as rotational crops with a 1-

month PBI, then additional data are required to support crop group 2. The representative 

commodities for crop group 2, leaves of root and tuber vegetables, are turnip tops and either 

garden beet tops or sugar beet tops. The registrant will need to submit additional field rotational 

crop data for turnip tops and the tops of either garden beets or sugar beets. The OCSPP Series 

860.1500 Guidelines recommend that 5 trials be performed for turnip tops and 5 trials be 

performed for garden beets. As either garden beets or sugar beets are the representative 

commodities for crop group 2, the registrant may perform 5 field trials on either sugar beets or 

garden beets. If the registrant submits the data, HED can then determine the appropriate plantback intervals and rotational crop tolerances. For more information concerning the rotational 

crop issue or the other residue chemistry data deficiencies, see HED’s response to Arysta’s 

responses (D425340, D. Dotson, 6/10/2015).

5.3 Summary of Environmental Degradation

Amicarbazone is slightly soluble in water (4.6 g/L). Based on submitted environmental fate 

studies, the chemical is moderately persistent in aerobic soil. It appears to degrade slowly into a 

number of degradation products under different environmental conditions. Amicarbazone is 

stable to direct photolysis, hydrolysis, and anaerobic aquatic metabolism. With the exception of 

natural clear water bodies subjected to sunlight, the major route of dissipation of amicarbazone 

appears to be biotransformation. In clear water bodies subjected to sunlight, indirect photolysis 

can contribute to amicarbazone dissipation. Although photolysis might occur on soil surfaces 

(t1/2= 54 days), label-recommended incorporation of the pesticide just after application might

render this process unimportant. 

Laboratory and field studies identified only three major degradates for amicarbazone: desamino 

amicarbazone, N-methyl desamino amicarbazone, and the decarboxamide degradate. Available 

data suggest that amicarbazone is very highly mobile. Additionally, adsorption/desorption and 

aged leaching studies suggest that all of the three major degradates of amicarbazone are very 

highly mobile. The decarboxamide degradate would only be a major degradate in soils with a 

high pH; however, the product label prohibits application to soils with a pH higher than 7.4. As 

a result, it is not a major degradate, and is not included as a residue of concern for risk 

assessment. 

Given its moderate persistence, high mobility, and solubility, amicarbazone is expected to 

dissipate slowly and, at the same time, be vulnerable to leaching/run-off. The desamino and Nmethyl desamino degradates are expected to behave similarly to the parent and become the major 

terminal degradates of this chemical in surface and groundwater.
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5.4 Water Residue Profile

The Office of Pesticide Programs’ Environmental Fate and Effects Division (EFED) performed a 

drinking water assessment in support of the 2011 risk assessment (D384659, A. Shelby, 

9/7/2011). The EDWCs were incorporated directly into the dietary assessment into the food 

categories “water, direct, all sources” and “water, indirect, all sources.” The residues of concern 

in drinking water for risk assessment are parent amicarbazone and its desamino and N-methyl 

desamino degradates. The surface water and groundwater estimates were calculated using the 

PRZM/EXAMS and SCI-GROW Models, respectively. The EDWCs given in Table 5.4 are the 

total toxic residues of amicarbazone, which include the desamino and N-methyl desamino

degradates as well as unextracted residues. The EDWCs represent upper-bound estimates for

surface water and groundwater as a result of the application of amicarbazone on turf and conifers 

one time at the maximum yearly rate (worst case scenario). The groundwater estimate of 136 

ppb was used for both the acute and chronic assessments because it was higher than all of the 

surface water values.

Table 5.4. Amicarbazone EDWCs Determined Using the PRZM/EXAMS and SCI-GROW Models.

Chemical Surface water EDWCs (ppb) Groundwater

Acute/Chronic 

EDWC (ppb)

Peak 96 hour 

average

Peak annual 

average 30 Year Average

Total Toxic Residues 

of amicarbazone 33.3 25.8 11.1 136

The EDWCs would be reduced if degradates were not assumed to be of equal toxicity as parent 

amicarbazone or if unextracted residues were determined to be bound residues. Exclusion of 

bound residues results in reduction of EDWCs by as much as 20%. Exclusion of both degradates 

and bound residue results in reduction of EDWCs by as much as 70%. 

5.5 Dietary Risk Assessment

5.5.1. Description of Residue Data Used in Dietary Assessments

Acute and chronic dietary (food and drinking water) exposure assessments were conducted using 

the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database 

(DEEM-FCID) Version 3.16. This software uses 2003-2008 food consumption data from the 

U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What We 

Eat in America, (NHANES/WWEIA).

The acute and chronic dietary assessments are based on conservative estimates of residues in 

food and drinking water. For amicarbazone, drinking water is the greatest contributor to dietary 

exposure and risk. As noted above, EDWCs are based on a worst case scenario. Concentrations 

in food are based on high-end assumptions as well (tolerance-level residues for all food 

commodities). DEEM default processing factors were used for the only two processed 

commodities in the assessments, dried beef meat and field corn syrup. Because of these
Amicarbazone Draft Risk Assessment DP Number 426602

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conservative assumptions, the resulting exposure and risk estimates are considered to be 

conservative as well. HED is confident that the acute and chronic dietary exposure assessments 

do not underestimate risk to the general U.S. population or any population subgroup.

In order to determine the contribution that drinking water makes to dietary exposure, the acute 

and chronic assessments were also performed without the drinking water residue estimates. 

5.5.2 Percent Crop Treated Data Used in Dietary Assessments

In the acute and chronic assessments, the assumption was made that 100% of all commodities 

would have amicarbazone residues.

5.5.3 Acute Dietary Risk Assessment

When the EDWC of 136 ppb is included in the acute dietary exposure assessment, the risk 

estimates are not of concern for all population subgroups, including those comprised of infants 

and children. Generally, risk estimates are of concern when they exceed 100% of the 

population-adjusted dose (PAD). The amicarbazone acute risk estimate for the general U.S. 

population is 8.5% of the acute PAD (aPAD). The population subgroup with the highest acute 

dietary risk estimate is all infants less than one year old, which uses 26% of the aPAD. As 

percent crop treated estimates were not incorporated into the acute assessment, the risk estimates 

are being reported at the 95th percentile of exposure. When drinking water was eliminated from 

the assessment, the exposure estimates decreased significantly. The acute risk estimate for the 

general U.S. population decreased from 8.5% to 1.8% of the aPAD and that for All Infants 

decreased from 26% to 2.5% of the aPAD. Children 1-2 became the population subgroup with 

the highest acute dietary risk estimate at 3.5% of the aPAD.

5.5.4 Chronic Dietary Risk Assessment

When the EDWC of 136 ppb is included in the chronic dietary exposure assessment, the risk 

estimates for amicarbazone are not of concern for all population subgroups. The risk estimate 

for the general U.S. population is 15% of the chronic PAD (cPAD). The most highly exposed 

population subgroup is All Infants (<1 year old), which uses 37% of the cPAD. As with the 

acute assessment, when drinking water was eliminated from the assessment, the exposure 

estimates decreased significantly. The chronic risk estimate for the general U.S. population 

decreased from 15% to 2.8% of the cPAD and that for All Infants decreased from 37% to 5.3% 

of the cPAD. Children 1-2 became the population subgroup with the highest chronic dietary risk

estimate at 9.4% of the cPAD.

5.5.5 Cancer Dietary Risk Assessment

Amicarbazone has been classified as “not likely to be carcinogenic to humans.” As a result, 

cancer risk is not of concern.
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5.5.6 Dietary Summary Table 

The acute and chronic dietary exposure and risk estimates for amicarbazone are summarized in 

Table 5.5.6.a, below. The estimates include exposure to residues in both food and drinking 

water.

Table 5.5.6.a. Summary of Acute and Chronic Dietary (Food and Drinking Water) Exposure 

and Risk Estimates for Amicarbazone.

Population 

Subgroup

Acute Assessment (95th Percentile) Chronic Assessment

aPAD, 

mg/day

Exposure Estimate, 

mg/day

% aPad cPAD, 

mg/day

Exposure Estimate, 

mg/day

% cPad

U.S. Population 0.10 0.008521 8.5 0.023 0.003486 15

All infants* 0.10 0.025577 26 0.023 0.008571 37

Children 1-2 yrs 0.10 0.014560 15 0.023 0.006281 27

Children 3-5 yrs 0.10 0.011738 12 0.023 0.005127 22

Children 6-12 yrs 0.10 0.008531 8.5 0.023 0.003536 15

Youth 13-19 yrs 0.10 0.006924 6.9 0.023 0.002668 12

Adults 20-49 yrs 0.10 0.008049 8.1 0.023 0.003331 15

Adults 50+ yrs 0.10 0.007144 7.1 0.023 0.003232 14

Females 13-49 yrs 0.10 0.008111 8.1 0.023 0.003312 14

* Most highly exposed population subgroup

HED also performed the dietary exposure analyses without drinking water. All assumptions with 

respect to residue levels and percent crop treated were the same as those used in the assessments 

that included drinking water. The results are given in Table 5.5.6.b, below. As can be seen, 

drinking water makes a significant contribution to dietary exposure.

Table 5.5.6.b. Summary of the Acute and Chronic Exposure and Risk Estimates for 

Amicarbazone Excluding Drinking Water.

Population 

Subgroup

Acute Assessment (95th Percentile of 

Exposure)

Chronic Assessment

aPAD, 

mg/kg/day

Exposure Estimate, 

mg/kg/day

% aPAD

cPAD

Exposure 

Estimate, 

mg/kg/day

% cPAD

U.S. Population 0.10 0.001751 1.8 0.023 0.000638 2.8

All infants 0.10 0.002538 2.5 0.023 0.001229 5.3

Children 1-2 yrs* 0.10 0.003449 3.5 0.023 0.002173 9.4

Children 3-5 yrs 0.10 0.002887 2.9 0.023 0.001666 7.2

Children 6-12 yrs 0.10 0.002045 2.0 0.023 0.001040 4.5

Youth 13-19 yrs 0.10 0.001260 1.3 0.023 0.000591 2.6

Adults 20-49 yrs 0.10 0.001055 1.1 0.023 0.000490 2.1

Adults 50-99 yrs 0.10 0.000910 0.91 0.023 0.000423 1.8

Females 13-49 yrs 0.10 0.001049 1.1 0.023 0.000481 2.1

*Most highly exposed population subgroup

HED continues to conclude that there is a reasonable certainty that no harm will result to the 

general population, to infants and children, or any other population subgroup from dietary 

exposure to amicarbazone residues when the most recent EDWC of 136 ppb is used for drinking 

water.
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6.0 Residential (Non-Occupational) Exposure and Risk Assessment

Registered residential uses of amicarbazone have been reassessed in this document to reflect 

updates to HED’s 2012 Residential SOPs2along with policy changes for body weight 

assumptions. The revision of residential exposures will impact the human health aggregate risk 

assessment for amicarbazone.

6.1 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, as homeowners are assumed to complete all elements of an 

application without use of any protective equipment.

The quantitative exposure/risk assessment developed for residential handlers is based on the 

scenarios listed in Table 6.1.

Residential Handler Exposure Data and Assumptions

Application Rate: The maximum single application rates are listed in Table 3.3. Refer to 

Section 3.3 for a complete use pattern description.

Unit Exposures and Area Treated or Amount Handled: Unit exposure values and estimates for 

area treated or amount handled were taken from HED’s 2012 Residential SOPs. 

Exposure Duration: Residential handler exposure is expected to be short-term in duration. 

Intermediate-term exposures are not likely because of the intermittent nature of applications by 

homeowners. However, as the same endpoint and point of departure were selected for short- and 

intermediate-term durations, short-term exposure and risk estimates are considered to be 

protective of intermediate-term exposure and risk. 

Residential Handler Non-Cancer Exposure and Risk Estimates

The algorithms used to estimate exposure and dose for residential handlers can be found in 

Appendix B and/or the 2012 Residential SOPs.

The exposure and risk estimates for residential handlers are provided in Table 6.1. All estimated 

risks are above HED’s LOC for residential risk (MOE >100) and are not of concern.

 

2 Available at http://www.epa.gov/pesticides/science/residential-exposure-sop.html
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Table 6.1. Residential Handler Exposure and Risk Estimates for Amicarbazone.

Scenario Inhalation Unit 

Exposurea

(mg/lb ai)

Application 

Rateb

Acres Treated 

or Amount 

Handled

Inhalation 

Dosed 

(mg/kg/day)

Inhalation 

MOEe

Mixer/Loader/Applicator

Liquids for Backpack 

Sprayer Applications

0.14 (Baseline) 0.023 lb ai/gal 5 gal 0.00023 27,000

Dry Flowable for 

Backpack Sprayer 

Applications

1.1 (Baseline) 5 gal 0.00180 3,400

Liquids for Manuallypressurized Handwand

Applications

0.018 (Baseline) 5 gal 0.00003 210,000

Dry Flowable for 

Manually-pressurized 

Handwand 

Applications

1.1 (Baseline) 5 gal 0.00180 3,400

Dry Flowable for 

Hose-end Sprayer 

Applications

0.022 (Baseline) 0.46 lb ai/A 0.5 A 0.000073 86,000

a. Based on HED’s 2012 Residential SOPs.

b. Maximum single application rate based on the registered labels.

c. Based on HED’s 2012 Residential SOPs.

d. Inhalation Dose (mg/kg/day) = (Inhalation Unit Exposure (mg/lb ai)) x (Application Rate) x (Acres Treated or 

Amount Handled/Body Weight (80 kg)).

e Inhalation MOE = NOAEL (6.28 mg/kg/day)/Inhalation Dose (mg/kg/day). 

6.2 Residential Post-application Exposure/Risk Estimates

Post-application exposures are expected for adults and children following use of amicarbazone 

on residential sites. 

Dermal Post-application Exposure to Treated Turf

Because of the lack of dermal toxicity, HED did not perform a quantitative dermal postapplication exposure assessment. 

Post-application Exposure to Treated Ornamentals Purchased from Retail Stores

Although there is potential for post-application dermal exposure to adults and children (6 to < 11 

years old) as a result of the use on ornamentals or from treated ornamentals purchased at a retail 

location, a dermal endpoint was not selected; therefore, a dermal post-application exposure 

assessment was not conducted for this scenario. Furthermore, the potential for post-application 

oral exposure to children is not expected as a result of the use on ornamentals. 
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Incidental Oral Post-application Exposure to Treated Turf

Incidental oral (i.e., hand-to-mouth, object-to-mouth, and soil ingestion) post-application 

exposures are expected for children following use of amicarbazone on residential turf. The 

quantitative exposure/risk assessment for these exposures is based on the scenarios presented in 

Table 6.2.

In conjunction with the 2007 Part 158 Data Requirements, HED typically requires submission of 

a turf transferable residue (TTR) study to determine exposure and risk associated with 

individuals playing or conducting post-application activities on treated turf. Based on current 

HED guidance, if the estimated residential turf post-application exposure using default TTR 

values results in an MOE 10 times the level of concern, a chemical-specific TTR study will not 

be required. In the case of amicarbazone, the incidental oral exposure estimate associated with 

the use on turf is an MOE is 900, which is less than the LOC (10x the LOC of 100, or 1000). 

However, HED has concluded that a TTR study is not needed for amicarbazone due to the 

conservative dose and endpoint selected for incidental oral exposure and risk assessment.

The endpoint and dose used to calculate the MOE are based on effects on liver and body weight 

that would not be considered adverse in accordance with current guidance. Using the effects that 

are considered adverse in this study, which are protective of the other adverse effects observed in 

short- and intermediate-term studies, would result in an NOAEL that is approximately 4 times as 

high as the NOAEL currently being used for risk assessment, and the resulting MOE would be 

approximately 3600. Furthermore, although not required, labels indicate the herbicide is most 

effective for weed control if irrigation (watering in) or rainfall occur after application, which

would further reduce the residues available for transfer from treated turf. In this instance, it is 

unlikely that chemical-specific TTR data would be needed to further refine the exposure 

assessment or would add appreciably to our general understanding of the availability of turf 

transferable pesticide residues.

 

Residential Post-application Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the residential 

post-application risk assessment. Each assumption and factor is detailed in the 2012 Residential 

SOPs.

Lifestages: The lifestages selected for each post-application scenario are based on an analysis 

provided as an appendix in the 2012 Residential SOPs. While not the only lifestage potentially 

exposed for these post-application scenarios, the lifestage that is included in the quantitative 

assessment is health protective for the exposures and risk estimates for any other potentially 

exposed lifestage. The lifestage used for the residential post-application risk assessment is 

children 1 to <2 years old.

Application Rate: The maximum single application rates are listed in Table 3.3. Refer to 

Section 3.3 for a complete use pattern description.
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Exposure Duration: Residential post-application exposure is expected to be short-term in 

duration. Intermediate-term exposures are not likely because of the intermittent nature of 

applications by homeowners. 

Residential Post-application Non-Cancer Exposure and Risk Equations

The algorithms used to estimate residential post-application exposure and dose can be found in 

Appendix C and in the 2012 Residential SOPs.

Summary of Residential Post-application Non-Cancer Exposure and Risk Estimates

In the absence of dermal toxicity, the residential post-application assessment is based on 

incidental oral exposures only. The exposure and risk estimates for residential post-application 

exposure are provided in Table 6.2. All residential post-application MOEs are above the LOC of 

100 and are not of concern. 

Table 6.2. Residential Post-application Non-cancer Exposure and Risk Estimates for 

Amicarbazone.

Lifestage

Post-application Exposure 

Scenario Application Rate1 Dose 

(mg/kg/day)2 MOEs3

Use Site Route of Exposure4

Child 

(1<2 years 

old)

Turf

Oral (Hand-to-Mouth) 0.46 lb ai/A 0.0070 900

Oral (Object-to-Mouth) 0.46 lb ai/A 0.00021 30,000

Oral (Soil Ingestion) 0.46 lb ai/A 0.000016 400,000

1. Based on the registered maximum single application rate for turf (Table 3.3).

2. Dose (mg/kg/day) equations provided in Appendix C.

3. MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day).

4. Although incidental oral and inhalation exposure can be combined based on the same toxicological endpoints, 

based on the exposure scenario, only incidental oral exposures are applicable to children. Inhalation exposure

resulting from treated turf is not anticipated for this population subgroup.

6.3 Residential Risk Estimates for Use in Aggregate Assessment

Table 6.3 reflects the residential risk estimates used in the aggregate assessment for 

amicarbazone:

 The recommended residential exposure for use in the adult aggregate assessment reflects 

inhalation exposure from applications to turf via backpack sprayer.

 The recommended residential exposure for use in the children 1 to <2 years old aggregate 

assessment reflects hand-to-mouth exposures from post-application exposure resulting 

from outdoor (turf) applications.
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Table 6.3. Recommendations for the Residential Exposures for the Amicarbazone Aggregate Assessment.

Life-stage Exposure 

Scenario

Dose (mg/kg/day)1 MOE2

Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Adult

Turf 

(Backpack 

Sprayer)

N/A 0.00180 N/A 0.00175 N/A 3,400 N/A 3,400

Child (1 to <2 

years old) Turf N/A N/A 0.0070 0.00687 N/A N/A 900 900

1. Dose = the highest dose for each applicable lifestage of all residential scenarios assessed. Total = dermal + 

inhalation + incidental oral (where applicable). See tables 6.1 and 6.2 for detailed description. 

2. MOE = the MOEs associated with the highest residential doses. Total = 1 ÷ (1/Dermal MOE) + (1/Inhalation 

MOE) + (1/Incidental Oral MOE), where applicable. See tables 6.1 and 6.2 for detailed description.

6.4 Spray Drift

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 offtarget 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 (e.g., 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 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.3 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 amicarbazone 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. It should be noted that the registered residential uses 

on turf result in exposure greater than potential exposure from spray drift; therefore, no new 

residential assessment needs to be completed. 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. The currently registered

maximum single application rate of amicarbazone for agricultural crops is 0.46 lb ai/A. The 

 

3 This approach is consistent with the requirements of the EPA’s Worker Protection Standard which, 

when included on all labels, precludes direct exposure pathways.
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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 

amicarbazone 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 (0.12 lb ai/A) than the maximum 

direct spray residential turf application rate [(0.46 lb ai/A)]4for any amicarbazone product. The 

turf post-application MOEs were previously assessed and are based on the revised SOPs for 

Residential Exposure Assessment (see Section 6.2).

6.5 Residential Bystander Post-Application Inhalation Exposure

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 Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on 

March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

Agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). During Registration 

Review, the Agency will utilize this analysis to determine if data (i.e., flux studies, route-specific 

inhalation toxicological studies) or further analysis is required for amicarbazone.

7.0 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 (e.g., 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. In the case of amicarbazone, acute and chronic aggregate risks result from 

exposure through food and water only. For short-term risks, residential handlers’ inhalation 

exposure and children’s incidental oral exposures were combined with background exposure 

from food and water. 

7.1 Acute Aggregate Risk

Acute aggregate risk is equivalent to acute dietary exposure and risk, which is discussed in 

Section 5.5.3. There are no acute aggregate risks of concern.

7.2 Short-Term Aggregate Risk

The residential handler exposure from applying amicarbazone using a manually-pressurized

handwand (Table 6.1) and children’s post-application incidental oral (hand-to-mouth) exposure 

 

4 Maximum Application rate for Spray Drift Assessment = 0.46 lb ai/A x 0.26 = 0.12 lb ai/A ≤ 0.46 lb ai/A.
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(Table 6.2) were combined with the chronic dietary exposure from the mostly highly exposed 

adult (General U.S. population) and children’s (All Infants <1 year old) subpopulations (Table 

5.5.6.a), respectively, to determine aggregate exposure and risk. The aggregate MOEs are 

provided in Table 7.2.a. Despite the numerous conservative assumptions in developing these 

estimates, the MOEs are above the LOC of 100, and are not of concern.

Table 7.2.a. Short-Term Aggregate Risk Calculations for Amicarbazone.

Population

(Type of 

Exposure)

NOAEL 

(mg/kg/day)

LOC1

Max 

Allowable 

Exposure2

(mg/kg/day)

Average 

Food and 

Water 

Exposure 

(mg/kg/day)

Residential 

Exposure 

(mg/kg/day)

3

Total Exposure 

(mg/kg/day)

4

Aggregate 

MOE (food, 

water, and 

residential)5

Adult (Handler) 6.28 100 0.0628 0.003486 0.00175 0.005236 1,200

Child (Postapplication) 6.28 100 0.0628 0.008571 0.00687 0.015441 410

1 The LOC is based on the standard inter- and intra- species uncertainty factors totaling 100. The FQPA Safety Factor has been 

reduced to 1x.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL÷LOC

3 Residential Exposure (Adult Handler) = Inhalation Exposure (Table 6.1). Residential Exposure (Child Post-application) = 

Hand-to-Mouth Exposure (Table 6.2).

4 Total Exposure = (Avg. Food & Water Exposure + Residential Exposure)

5 Aggregate MOE = [NOAEL÷Total Exposure]

HED also performed the dietary exposure analyses without drinking water. All assumptions with 

respect to residue levels and percent crop treated were the same as those used in the assessments 

that included drinking water. The results are given in Table 5.5.6.b. HED used these exposure 

estimates to calculate drinking water levels of comparison (DWLOC). The DWLOC is the 

maximum allowable drinking water concentration. That is, it is the highest drinking water 

concentration that could be present in order for HED not to have a concern for aggregate risk. 

To determine the DWLOC, HED assumes that adults weigh 80 kilograms and drink 2 liters of 

water a day, and that children weigh 11 kilograms and drink 1 liter of water a day. HED 

determined the DWLOCs for the general U.S. population and the population subgroup, All 

Infants. The values are given in Table 7.2.b. 

Table 7.2.b. Short-Term Aggregate DWLOCs for Amicarbazone.

Population NOAEL 

(mg/kg/day)

LOC

Max 

Allowable 

Exposure 

(mg/kg/day)

Average Food 

Exposure 

(mg/kg/day)

Residential 

Exposure 

(mg/kg/day)

Food and 

Residential

Exposure 

(mg/kg/day)

DWLOC

(ppb)

Adult (Handler) 6.28 100 0.0628 0.000638 0.00175 0.005236 2,300

Child (Postapplication) 6.28 100 0.0628 0.002173 0.00687 0.009043 590

DWLOC = [[(NOAEL ÷ 100) – (food and residential exposure)] x (1,000 μg/mg) x (BW)] ÷ [(water consumption in 

L/day)]
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In order for HED not to have a concern for short-term aggregate risk for any population 

subgroup, the chronic EDWC would need to be 590 ppb or less.

7.3 Chronic Aggregate Risk

Chronic aggregate risk is equivalent to chronic dietary exposure and risk, which is discussed in 

Section 5.5.4. There are no chronic aggregate risks of concern.

8.0 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 amicarbazone and any other substances, and amicarbazone does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this risk assessment, therefore, 

EPA has not assumed that amicarbazone has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

9.1 Occupational Handler Exposure/Risk Estimates

Based on current labeling, types of equipment, and techniques that can potentially be used, 

occupational handler exposure is expected from the registered uses on corn and non-crop areas 

such as turf, ornamentals, and Christmas tree farms. The quantitative exposure/risk assessment 

developed for occupational handlers is based on the scenarios listed in Table 9.1. Based on the 

use pattern and agricultural practices, occupational exposure from the registered uses is expected 

to be short-term (1-30 days) and intermediate-term (1-6 months) in duration. As the same 

endpoint and point of departure were selected for short- and intermediate-term durations, shortterm exposure and risk estimates are considered to be protective of intermediate-term exposure 

and risk. Long-term exposures (longer than 6 months) are not anticipated.

Occupational Handler Exposure, Assumptions, and Risk Estimate Equations

Application Rate: The maximum single application rates are listed in Table 3.3. Refer to 

Section 3.3 for a complete use pattern description.

Body Weight & Absorption Factor: The standard adult body weight (80 kg) was used in this risk 

assessment because the endpoint selected was not developmental and/or based on fetal effects. 

As no inhalation absorption data are available, toxicity by the inhalation route is considered to be 

equivalent to the estimated toxicity by the oral route of exposure.
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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, and the AHETF database. Some of these data are proprietary (e.g., 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 Table5.” HED policy on use of surrogate data, including descriptions of the various 

sources, can be found at the Agency website6. 

Area Treated: The area treated inputs were based on the Science Advisory Council for Exposure 

Policy 9.1: Standard Values for Daily Acres Treated in Agriculture (listed in Table 9.1).

Risk Estimate Equations: The algorithms used to estimate non-cancer exposure and dose for 

occupational handlers can be found in Appendix B.

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimate

The occupational handler assessment is based on inhalation exposures only. All occupational 

handler scenarios for the registered uses resulted in MOEs greater than 100 at baseline level of 

risk mitigation (i.e., baseline attire with no gloves or respirator) and, therefore, are not of 

concern. The lowest MOE of 610 is associated with mixing/loading a dry flowable formulation 

applied using groundboom equipment over up to 200 acres. All other MOEs were significantly 

higher, ranging from 3,900 to 260,000. No additional PPE recommendations are needed on the 

registered labels.

 

5 Available: http://www.epa.gov/opp00001/science/handler-exposure-table.pdf

6 Available: http://www.epa.gov/pesticides/science/handler-exposure-data.html
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Table 9.1. Occupational Handler Exposures and Risks Estimates for Amicarbazone.

Exposure 

Scenario and 

Formulation

Use Site

Application 

Ratea

Area Treated 

or Amount 

Handled

Inhalation Unit 

Exposure b

(mg/lb)

Inhalation

Dose c

(mg/kg/day)

Inhalation 

MOE d

Mixer/Loader

Dry Flowable for 

Airblast Application

Christmas Tress 

(Nurseries) 0.46 lb ai/A

20 A 0.00896 (Baseline) 0.00103 6,100

Dry Flowable for 

Groundboom 

Application

Turf (Golf Course)

0.46 lb ai/A

40 A 0.00896 (Baseline) 0.00206 3,000

Sod Farms (Turf), 

Christmas Trees

80 A 0.00413 1,500

Corn 200 A 0.0103 610

Liquids for Airblast 

Application

Christmas Tress 

(Nurseries) 0.45 lb ai/A

20 A 0.000219 (Baseline) 0.0000246 260,000

Dry Liquids for 

Groundboom 

Application

Turf (Golf Course)

0.45 lb ai/A 40 A 0.000219 (Baseline) 0.0000493 130,000

Sod Farms (Turf), 

Christmas trees

80 A 0.0000985 64,000

Applicator

Sprays for Airblast 

Application

Christmas Tress 

(Nurseries) 0.46 lb ai/A

20 A 0.00471 (Baseline) 0.000541 12,000

Sprays for 

Groundboom 

Application

Turf (Golf Course)

0.46 lb ai/A

40 A 0.00034 (Baseline) 0.0000783 80,000

Sod Farms (Turf), 

Christmas Trees 80 A 0.000156 40,000

Corn 200 A 0.000391 16,000

Mixer/Loader/Applicator

Backpack Sprayer 

Christmas Trees; 

Turf, Golf Course, 

Sod Farms, Parks, 

Recreation and 

Athletic Fields 

(Foliar)

0.023 lb ai/gal 40 gals 0.14 (Baseline) 0.00161 3,900

Christmas Trees; 

Turf, Golf Course, 

Sod Farms, Parks, 

Recreation and 

Athletic Fields 

(Ground-Directed)

0.023 lb ai/gal 40 gals 0.00258 (Baseline) 0.0000296 210,000

Manually-pressurized 

Handwand

Christmas Trees; 

Turf, Golf Course, 

Parks, Recreation and 

Athletic Fields 

(Foliar)

0.023 lb ai/gal

40 gals

0.03 (Baseline) 0.000345 18,000

Mechanicallypressurized Handgun 

Sprayer (WDG)

Turf, Golf Course, 

Sod Farms, Parks, 

Recreation and 

Athletic Fields

0.46 lb ai/A 5 A 0.042 (Baseline) 0.00121 5,200

Christmas Trees 0.023 lb ai/gal 1,000 gal 0.0039 (Baseline) 0.00112 5,600

a. Based on maximum single application rates on registered labels (Table 3.2).

b. Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (Feb, 2015). Level of mitigation: 

Baseline (single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no 

respirator).

c. Inhalation Dose (mg/kg/day) = Inhalation Unit Exposure (mg/lb ai) * Application Rate * Acres Treated or Amount 

Handled/Body Weight (80 kg).

d. Inhalation MOE = NOAEL (6.28 mg/kg/day) / Inhalation Dose (mg/kg/day). LOC=100.
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9.2 Occupational Post-application Exposure/Risk Estimate

9.2.1 Occupational Post-application Inhalation Exposure/Risk Estimates

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, Fungicide, and Rodenticide Act Scientific Advisory Panel 

(SAP) in December 2009, and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency has 

evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent 

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQOPP-2014-0219). During registration review, the Agency will utilize this analysis to determine 

if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is 

required for amicarbazone.

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 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. No risks of concern were identified for any occupational handler inhalation 

exposure scenario.

9.2.2 Occupational Post-application Dermal Exposure/Risk Estimates

A quantitative dermal post-application exposure assessment is not required because of the 

absence of systemic and dermal toxicity in the dermal toxicity study.

There are no post-application dislodgeable foliar residue (DFR) or turf transferable residue 

(TTR) data available for amicarbazone. However, because of the lack of dermal toxicity, a 

quantitative post-application dermal risk assessment is not required. Therefore, HED has 

concluded that these data are not needed for amicarbazone. In this instance, it is unlikely that 

chemical-specific DFR and/or TTR data would be needed to further refine dermal postapplication exposure assessments or would add appreciably to our overall understanding of the 

availability of dislodgeable foliar or turf transferable pesticide residues for amicarbazone.
Amicarbazone Draft Risk Assessment DP Number 426602

Page 35 of 53

Restricted Entry Interval

The REI specified on the amicarbazone registered labels is based on the acute toxicity of active 

ingredient. Amicarbazone is classified as Toxicity Category IV via the dermal route and 

Toxicity Category IV for skin irritation potential. It is not a skin sensitizer. Under 40 CFR 

156.208 (c) (2) (iii), active ingredients classified as Acute III or IV for acute dermal, eye 

irritation, and primary skin irritation are assigned a 12-hour REI. Therefore, the [156 Subpart K] 

Worker Protection Statement REI of 12 hours is adequate to protect agricultural workers from 

post-application exposures to amicarbazone. 

10.0 Public Health and Pesticide Epidemiology Data

For this evaluation, HED consulted both the OPP Incident Data System (IDS) and the Centers for 

Disease Control and Prevention/National Institute for Occupational Safety and Health 

(CDC/NIOSH) Sentinel Event Notification System for Occupational Risk-Pesticides (SENSOR) 

databases for pesticide incident data on the active ingredient amicarbazone (D427159, S. Recore, 

5/6/2015). The purpose of the database search was to identify potential patterns in the frequency 

and severity of the health effects attributed to amicarbazone exposure. Amicarbazone is not 

included in the Agricultural Health Study (AHS) and, therefore, this study does not provide 

information for this report.

For both the Main IDS and Aggregate IDS, from January 1, 2010 to February 4, 2015, no 

incidents involving amicarbazone were reported. The SENSOR-Pesticides database covers 12 

states from 1998-2011, although reporting varies from state to state. A review of SENSORPesticides 1998-2011 identifies no cases involving amicarbazone. No incident cases were 

reported for amicarbazone to either IDS or SENSOR-Pesticides. There does not appear to be a 

concern at this time that would warrant further investigation.

11.0 References

D386858, Amicarbazone. Human Health Risk Assessment to Support Proposed Uses on Turf, 

Christmas Tree Farms, Non-Crop Areas and on Conifers in Nurseries, L. Hansen, et al., 

12/2/2011

D427159, Amicarbazone: Tier I (Scoping) Review of Human Incidents, S. Recore, 5/6/2015

D427771, Amicarbazone: Acute and Chronic Aggregate Dietary (Food and Drinking Water) 

Exposure and Risk Assessment for the Registration Review Draft Risk Assessment, D. Dotson, 

6/18/2015

D303867, Amicarbazone (MKH 3586). Petition for the Establishment of Permanent Tolerances 

for Use on Field Corn and Imported Sugarcane. Summary of Analytical Chemistry and Residue 

Data. PP#0F6131, M. Xue, 6/6/2005
Amicarbazone Draft Risk Assessment DP Number 426602

Page 36 of 53

D425340, Amicarbazone. HED’s Conclusions Concerning Registrant’s Responses to 

Conditional Data Cited in HED Risk Assessment for Use on Field Corn, D. Dotson, 6/10/2015

D394924, Amicarbazone: Occupational and Residential Exposure Assessment for Proposed 

Uses on Turf, Christmas Tree Farms, Non-Crop Areas and on Conifers in Nurseries, Z. Figueroa, 

11/30/2011

TXR No. 0054349, Amicarbazone: Summary of Hazard and Science Policy Council (HASPOC) 

Meeting of April 22, 2015: Recommendation on the Requirement for a Subchronic Inhalation

Study, U. Habiba, 6/15/2015
Amicarbazone Draft Risk Assessment DP Number 426602

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Appendix A: Toxicology Profile

A.1 Toxicology Data Requirements

The 40 CFR 158.340 requirements for food use for amicarbazone are in the table below.

Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study

Technical Amicarbazone

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 (nonrodent).........................................

870.3200 21-Day Dermal..............................................................

870.3250 90-Day Dermal..............................................................

870.3465 28-Day Inhalation..........................................................

yes

yes

yes

no

no

yes

yes

yes

--

no

870.3700a Developmental Toxicity (rodent) ..................................

870.3700b Developmental Toxicity (nonrodent) ............................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200a Oncogenicity (rat)..........................................................

870.4200b Oncogenicity (mouse) ...................................................

870.4300 Chronic/Oncogenicity ...................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.....................

870.5300 Mutagenicity—Gene Mutation - mammalian................

870.5xxx Mutagenicity—Structural Chromosomal Aberrations...

870.5xxx Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

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 Develop. Neurotoxicity .................................................

no

no 

yes

yes

yes

--

-- 

yes

yes

yes

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration........................................................

870.7800 Immunotoxicity .............................................................

yes

yes

yes

yes

yes

yes

Special Studies for Ocular Effects

Acute Oral (rat)...........................................................

Subchronic Oral (rat)..................................................

Six-month Oral (dog)..................................................

no

no

no

--

--

--
Amicarbazone Draft Risk Assessment DP Number 426602

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A.2 Toxicology Profile Tables

Table A.2.1 Acute Toxicity Profile – Amicarbazone Technical

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [rat] 45121504 Males LD50 > 2050 

mg/kg ;

Females LD50 = 1015 

mg/kg

III

870.1200 Acute dermal [rat] 45121503 LD50 > 5000 mg/kg IV

870.1300 Acute inhalation [rat] 45121506 LC50 = 2.030 mg/L IV

870.2400 Acute eye irritation [rabbit] 45121510 Eye irritation including 

corneal opacity at 24 

hr, cleared by Day 7

III

870.2500 Acute dermal irritation [rabbit] 45121509 No primary irritation 

observed

IV

870.2600 Skin sensitization [guinea pig] 45121505

45121628

Not a dermal sensitizer N/A

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral 

toxicity (Fischer -

344 rat)

45121523 (1997)

Acceptable/Guideline

0, 100, 250, 500, 1000, 

2500, 5000ppm

M: 0, 6.9, 18, 33, 67, 182, 

354 mg/kg/day

F: 0, 7.9, 21, 38, 78, 201, 

397mg/kg/day

NOAEL = 33/38 mg/kg/day [m/f]

LOAEL = 67/78 mg/kg/day [m/f] based on 

decreased body weight in females and 

cumulative body weight gain, decreased red 

cell indices, clinical chemistry alterations 

(increased cholesterol, T4, T3, N-demethylase 

in males and O-demethylase in females), 

increased relative liver weights in males and 

histopathology of the liver (minimal 

hepatocytomegaly) and spleen (minimal 

pigmentation) in males.

870.3150 90-Day oral 

toxicity (beagle 

dog)

45121524 (1998)

Acceptable/guideline

0, 200, 800, or 2000 ppm

M: 0, 6.74, 27.03, or 

57.40 mg/kg/day

F: 0, 6.28, 24.99 (25), or 

62.11mg/kg/day

NOAEL = 6.28 mg/kg/day

LOAEL = 24.99 mg/kg/day (25 mg/kg/day) 

based on increased thyroid vacuolization and 

decreased food consumption and glucose in 

females; increased platelets, phosphate, bile 

acids, absolute and relative liver weights, and 

lymphoid hyperplasia of the gall bladder in 

males; and decreased albumin and increased 

triglycerides, N-demethylase, and Odemethylase in both sexes.
Amicarbazone Draft Risk Assessment DP Number 426602

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3200 21/28-Day dermal 

toxicity (SpragueDawley rat)

45121525 (1998)

Acceptable/Guideline 

0, 200, 500, 1000 

mg/kg/day

NOAEL = 1000 mg/kg/day

LOAEL = Not Observed

870.3700a Prenatal 

developmental in 

(Sprague-Dawley 

rat)

45121530 (1999)

Acceptable/Guideline

0, 15, 100, 300 mg/kg/day

Maternal NOAEL = 15 mg/kg/day

LOAEL = 100 mg/kg/day based on decreased 

body weight/body weight gain and food 

consumption, and increased incidences of hard 

stools.

Developmental NOAEL = 15 mg/kg/day

LOAEL = 100 mg/kg/day based on multiple 

skeletal development retardations (incomplete 

ossification/unossification was observed in 

parietal bones, interparietal bones, 

supraoccipital bones, squamosal bones, 

zygoma, pubis, xiphoid, and fontanelle

870.3700b Prenatal 

developmental in 

(Himalayan 

rabbit)

45121627 (1999)

Acceptable/Guideline

0, 5, 20, 70 mg/kg/day

Maternal NOAEL = 5 mg/kg/day

LOAEL = 20 mg/kg/day based on decreased 

body weight gain during treatment.

Developmental NOAEL = 20 mg/kg/day

LOAEL = 70 mg/kg/day based on decreased 

fetal body weight, and increased incidences of 

incomplete ossification of the 5th medial 

phalanx (bilateral) and the 13th caudal vertebra, 

and slightly thick ribs.

870.3800 Reproduction and 

fertility effects

(Sprague-Dawley 

rat)

45121625 (1998)

Acceptable/Guideline

0, 100, 500, 1000 ppm

M: 0, 6.4, 33.9, 73.2 

mg/kg/day

F: 0, 7.3, 38.7, 84.0 

mg/kg/day

Parental/Systemic NOAEL = 6.4/7.3 

mg/kg/day

LOAEL = 33.9/38.7 mg/kg/day based on 

decreased body weight/body weight gain in 

both sexes.

Reproductive NOAEL = 73.2/84.0 mg/kg/day

LOAEL = Not Observed 

Offspring NOAEL = 6.4/7.3 mg/kg/day

LOAEL = 33.9/38.7 mg/kg/day based on 

decreased pup body weight and overall 

decreased body weight gain.

870.4100a Chronic toxicity

(Fischer-344 rat)

45121512 (1999)

Acceptable/Guideline

0, 50, 500, 1250/1000 

ppm

M: 0, 2.3, 25.3, 67 

mg/kg/day

F: 0, 2.7, 29.5, 65 

mg/kg/day

NOAEL = 2.3/2.7 mg/kg/day

LOAEL = 25.3/29.5 mg/kg/day based on 

decreased body weight in females and body 

weight gain in both sexes.

No evidence of carcinogenicity

At the doses tested there was not a treatment 

related increase in tumor incidence when 

compared to control. Dosing was considered 

adequate based on decreased body weight in 

females and body weight gain in both sexes.
Amicarbazone Draft Risk Assessment DP Number 426602

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.4100b Chronic toxicity 

(beagle dog)

45121529 (1999)

Acceptable/Guideline

0, 75, 100, 300, 1200 ppm

M: 0, 1.6, 2.5, 8.9, 31.5 

mg/kg/day

F: 0, 1.8, 2.3, 8.7 

34.6mg/kg/day

NOAEL =2.5/2.3 mg/kg/day

LOAEL = 8.9/8.7 mg/kg/day based on effects 

on the liver, including increased absolute and 

relative liver weights, and O-demethylase in 

males ; increased globulin and cytochrome P450 in females; and increased triglycerides and 

cholesterol in both sexes.

870.4300a Combined chronic 

toxicity/carcinoge

nicity

(Fischer-344 rat)

45121512 (1999)

Acceptable/Guideline

0, 50, 500, 1250/1000 

ppm

M: 0, 2.3, 25.3, 67 

mg/kg/day

F: 0, 2.7, 29.5, 65 

mg/kg/day

NOAEL = 2.3/2.7 mg/kg/day

LOAEL = 25.3/29.5 mg/kg/day based on 

decreased body weight in females and body 

weight gain in both sexes.

No evidence of carcinogenicity

At the doses tested there was not a treatment 

related increase in tumor incidence when 

compared to control. Dosing was considered 

adequate based on decreased body weight in 

females and body weight gain in both sexes.

870.4300b Carcinogenicity

(CD-1 mouse)

45121604 (1999)

Acceptable/Guideline

0, 100, 1500, 4000 ppm

M: 0, 15.7, 244.7, 709.0 

mg/kg/day

F: 0, 17.9, 275.0, 806.3 

mg/kg/day

NOAEL = 244.7/275.0 mg/kg/day

LOAEL = 709.0/806.3 mg/kg/day based on 

decreased body weight and body weight gain in 

both sexes, and subclinical anemia, and 

hemosiderin pigmentation of the spleen in 

males.

No evidence of carcinogenicity

At the doses tested there was not a treatment 

related increase in tumor incidence when 

compared to control. Dosing was considered 

adequate based on decreased body weight and 

body weight gain in both sexes, and subclinical 

anemia, and hemosiderin pigmentation of the 

spleen in males.

Gene 

Mutation

870.5100 

Bacterial reverse 

gene mutation (S. 

typhimurium)

45121617 (1999)

Acceptable/Guideline

0, 16, 50, 158, 500, 1581, 

or 5000 g/plate in the 

presence and absence of 

S9-activation

There was no evidence of induced mutant 

colonies over background in strains TA98, 

TA100, TA102, TA1535, TA1537.
Amicarbazone Draft Risk Assessment DP Number 426602

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

Gene 

Mutation

870.5100 

Bacterial reverse 

gene mutation (S. 

typhimurium)

45121616 (1996)

Acceptable/Guideline

0, 16, 50, 158, 500, 1581, 

or 5000 g/plate in the 

presence and absence of 

S9-activation

There was no evidence of induced mutant 

colonies over background in strains TA98, 

TA100, TA102, TA1535, TA1537.

Gene 

Mutation

870.5100 

Bacterial reverse 

gene mutation (S. 

typhimurium)

45121519 (1995)

Acceptable/Guideline

0, 16, 50, 158, 500, 1581, 

or 5000 g/plate in the 

presence and absence of 

S9-activation 

There was no evidence of induced mutant 

colonies over background in strains TA98, 

TA100, TA102, TA1535, TA1537.

Gene 

Mutation

870.5300 

Mammalian 

forward gene 

mutation (V79 

Chinese hamster 

lung fibroblast 

cells)

45121514 (1997)

Acceptable/Guideline

0, 250, 500, 1000, 2000, 

or 4000 g/mL in the 

presence and absence of 

S9 activation for 5 hours 

4000 g/mL was the limit 

of solubility

There was no evidence that MKH3586 induced 

mutant colonies over background in the 

presence or absence of S9-activation.

Cytogenetics 

870. 5375

In vitro

mammalian 

chromosome 

aberration test 

(V79 Chinese 

hamster lung 

fibroblast cells)

45121513 (1997)

Acceptable/Guideline

0, 1000. 2000, 4000, or 

5000 g/mL for 4 hours in 

the presence and absence 

of S9-activation

There was no evidence of chromosome 

aberration induced over background in the 

presence or absence of S9-activation.

Other 

Effects 

870.5395 

Mammalian in 

vivo erythrocyte 

micronucleus test 

(Hsd/Win NMRI 

mouse)

45121515 (1997)

Acceptable/Guideline

100 mg/kg

harvest times 16, 24, and 

48 hours post dosing

There was no significant increase in the 

frequency of micronucleated polychromatic 

erythrocytes in bone marrow at any treatment 

time.
Amicarbazone Draft Risk Assessment DP Number 426602

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.6200a Acute 

neurotoxicity 

screening battery 

(Fischer-344 rat)

45121528 (1996)

Acceptable/Guideline in 

conjunction with 

45121527

M: 0, 20, 150, 600 

mg/kg/day

F: 0, 20, 100, 400 

mg/kg/day

NOAEL = 10 mg/kg/day

LOAEL = 20 mg/kg/day based on eyelid ptosis, 

decreased approach response (both sexes), and 

red nasal staining in males.

A series of acute neurotoxicity studies were 

performed, the NOAEL for this study comes 

from 45121527.

870.6200b Subchronic 

neurotoxicity 

screening battery 

(Fischer-344 rat)

45121532 (1999)

Acceptable/Guideline

0, 100, 500, 1000 ppm

M: 0, 6.7, 33.4, 66.5 

mg/kg/day

F: 0, 7.8, 38.2, 75.8 

mg/kg/day

Female

NOAEL = 7.8 mg/kg/day

LOAEL = 38.2 mg/kg/day based on decreased 

body weight and overall body weight gain in 

females. 

Male

NOAEL = 66.5 mg/kg/day

LOAEL = Not observed for males.

870.6300 Developmental 

neurotoxicity 

(Wistar rat)

45441301 (2001)

0, 100, 500, 1000 ppm

(gest): 0, 8, 39, 91 

mg/kg/day

(lact): 0, 17, 84, 177 

mg/kg/day

Maternal NOAEL = 8 mg/kg/day

LOAEL = 39 mg/kg/day based primarily on 

decreased feed efficiency (combination of 

decreased body weight gain and increased food 

consumption) during lactation.

Offspring NOAEL = 39 mg/kg/day

LOAEL = 91 mg/kg/day based on decreased 

body weight gain.

870.7485 Metabolism and 

pharmacokinetics

(Fischer-344 rat)

45121701 (1997)

Acceptable/guideline

MKH 3586

(amicarbazone)

95% of the radioactive dose was recovered 

within 72 hours following dosing. The 

majority of the dose was recovered from the 

urine within 24 hours (64%), indicating 

substantial absorption. Fecal excretion 

accounted for 27% of the dose within 24 hours. 

Major metabolites were DA MKH, N-methyl 

DA MKH, and decarboxamide.

870.7485 Metabolism and 

pharmacokinetics

(Fischer-344 rat)

45121634 (1999)

Acceptable/Guideline

4-methyl MKH 3586

(soil metabolite)

91% of the radioactive dose was recovered 

within 96 hours. Urinary excretion accounted 

for 70% of the radioactive dose within 12 

hours, showing substantial absorption. Only 

8% of the radioactive dose was excreted via the 

feces within 24 hours.
Amicarbazone Draft Risk Assessment DP Number 426602

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.7800 Immunotoxicity

(Female Fischer344 rat)

48407504 (2011)

Acceptable/guideline

0, 250, 1000, 2500 ppm

0, 20, 81, 195 mg/kg/day

Immunotoxicity NOAEL = 81 mg/kg/day

Immunotoxicity LOAEL = 195 mg/kg/day, 

based on decreased spleen weight, total spleen 

cells/spleen and suppressed SRBC response.

Tentative systemic NOAEL = 81 mg/kg/day 

Tentative systemic LOAEL = 195 mg/kg/day, 

based on decreased body weight and body 

weight gain, food consumption and absolute 

spleen weight.

Special 

studies

Subchronic 

mechanistic 

feeding study 

(Fischer-344 rat)

45121603 (1999)

Acceptable/Nonguideline

0, 50, 1250, or 2500 ppm 

for 10 weeks

M:0, 0.8, 19.4, 40.0 

mg/kg/day

F: 0, 0.6, 19.4, 28.8 

mg/kg/day

Thyroid hormones were increased in the ≥19.4 

mg/kg/day females and 40.0 mg/kg/day males. 

However, thyroid to blood ratios of 125I in 

treated groups were comparable to negative 

controls, indicating there was no impairment of 

thyroid hormone synthesis. Thus, the 

differences in thyroid hormones are probably 

due to metabolism at an extra-thyroidal site. 

The liver was implicated as this site because 

liver weights and UDP-glucuronosyltransferase 

activity were increased.

Special 

studies

In vitro studies on 

enzymes of 

thyroid hormone 

regulation 

45121618 (1998)

Acceptable/Nonguideline

MKH 3586 does not affect the iodide 

organification step of thyroid hormone 

synthesis or the peripheral metabolism of 

thyroid hormones via Type I or Type II 

deiodinases in vivo. These findings support the 

subchronic mechanistic studies in rats which 

indicate that up-regulation of UDPglucuronosyl transferase in the liver may 

account for alterations in thyroid hormone 

profile.

Special 

studies

Nonguideline

behavioral study 

(HsdCbp WU rat)

45121511, 45121521, 

45121629 (1997)

Acceptable/Nonguideline

0, 1.0, 2.5, 5, 10, 20, or 

100 mg/kg

The following clinical signs were observed: 

sedation, ptosis, salivation (single animals 

affected except 2 for salivation) at 10 

mg/kg/day and above. Additionally at the 

HDT, piloerection, Straub phenomenon, and 

prone position were observed. The effects were 

observed at 30 minutes post dose, and no effect 

was observed at 150 minutes post dose, with 

the higher dose groups showing greater 

persistence of effects. A dose- and timedependent effect was demonstrated on motor 

activity - decreased travel distance, increased 

resting time, and decreased rearing. 
Amicarbazone Draft Risk Assessment DP Number 426602

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

Special 

studies

Nonguideline 

study of central 

nervous system 

safety 

pharmacology 

(HsdWin: NMRI 

mouse)

45121522 (1997)

Acceptable/Nonguideline

0, 1, 20, 100 mg/kg/day

The data indicate that a single dose of MKH 

3586 at 100 mg/kg causes minimal CNS 

functional impairment, characterized by 

increased reaction times to nociceptive stimuli, 

reduced traction force, impaired motor 

coordination, sedation, partial ptosis, and a 

mild anticonvulsive effect.
Amicarbazone Draft Risk Assessment DP Number 426602

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Appendix B. Occupational and Residential Non-cancer Handler Algorithms

Potential daily exposures for occupational handlers are calculated using the following formulas:

E=UE * AR * A * 0.001 mg/ug

where:

E = exposure (mg ai/day),

UE = unit exposure (μg ai/lb ai),

AR = maximum application rate according to registered labels (lb ai/A), and

A = area treated or amount handled (e.g., A/day).

The daily doses are calculated using the following formula:

ADD= 

E * AF

BW

4.0 where:

ADD = average daily dose absorbed in a given scenario (mg ai/kg/day),

E = exposure (mg ai/day),

AF = absorption factor (inhalation), and

BW = body weight (kg).

Margin of Exposure: Non-cancer risk estimates for each application handler scenario are 

calculated using a Margin of Exposure (MOE), which is a ratio of the toxicological endpoint to 

the daily dose of concern. The daily inhalation dose received by occupational handlers is

compared to the appropriate POD (i.e., NOAEL) to assess the risk to occupational handlers. All 

MOE values are calculated using the following formula:

MOE= 

POD

ADD

where:

MOE = margin of exposure: value used by HED to represent risk estimates (unitless),

POD = point of departure (mg/kg/day), and

ADD = average daily dose absorbed in a given scenario (mg ai/kg/day).
Amicarbazone Draft Risk Assessment DP Number 426602

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Appendix C: Residential Non-cancer Post-application Algorithms

Post-application Hand-to-Mouth Exposure Algorithm– Physical Activities on Turf

Exposure from hand-to-mouth activity is calculated as follows (based on the algorithm utilized in 

the SHEDS-Multimedia model):

E = [HR * (FM * SAH) * (ET * N_Replen) * (1- (1- SE)

(Freq_HtM/N-Replen))]

where:

E = exposure (mg/day);

HR = hand residue loading (mg/cm2);

FM = fraction hand surface area mouthed / event (fraction/event);

SAH = typical surface area of one hand (cm2);

ET = exposure time (hr/day);

N_Replen = number of replenishment intervals per hour (intervals/hour);

SE = saliva extraction factor (i.e., mouthing removal efficiency); and

Freq_HtM = number of hand-to-mouth contacts events per hour (events/hour).

and

SA * 2

Fai *DE

HR

H

hands



where:

HR = hand residue loading (mg/cm2);

Faihands = fraction ai on hands compared to total surface residue from dermal transfer coefficient 

study (unitless);

DE = dermal exposure (mg); and

SAH = typical surface area of one hand (cm2).

Dose, normalized to body weight, is calculated as:

BW

E

D 

where:

D = dose (mg/kg-day);

E = exposure (mg/day); and

BW = body weight (kg).
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Table C.1. Turf (Physical Activities) – Inputs for Residential Post-application Hand-to-Mouth 

Exposure 

Algorithm 

Notation

Exposure Factor

(units) Point Estimate(s)

Faihands

Fraction of ai on hands 

from dermal transfer 

coefficient study

(unitless)

Liquid formulations 0.06

Granular formulations 0.027

DE Dermal exposure (mg) Calculated

SAH

Typical surface area of one hand (cm2), children 1 < 

2 years old 150

AR Application rate

(mass active ingredient per unit area) 0.46 lb ai/A

HR Residue available on the hands (mg/cm2) Calculated via (DE * Faihands)/SAH

FM

Fraction hand surface area mouthed

(fraction/event) 0.127

N_Replen Replenishment intervals per hour

(intervals/hr) 4

ET Exposure time 

(hrs/day) 1.5

SE Saliva extraction factor

(unitless) 0.48

Freq_HtM Hand-to-mouth events per hour

(events/hr) 13.9

BW Body Weight

(kg)

Children 1 < 2 years 

old 11

Post-application Object-to-Mouth Exposure Algorithm– Physical Activities on Turf

Exposure from object-to-mouth activity is calculated as follows (based on the algorithm utilized 

in SHEDS-Multimedia):

E = [OR* CF1 * SAMO * (ET * N_Replen) * (1- (1- SEO)

(Freq_OtM/N_Replen))]

where:

E = exposure (mg/day);

OR = chemical residue loading on the object on day “t” (ug/cm2);

CF1 = weight unit conversion factor (0.001 mg/μg);

SAMO = area of the object surface that is mouthed (cm2/event);

ET = exposure time (hr/day);

N_Replen = number of replenishment intervals per hour (intervals/hour);

SEO = saliva extraction factor (i.e., mouthing removal efficiency); and

Freq_OtM = number of object-to-mouth contact events per hour (events/hour).

and

OR = AR * FO * CF2 * CF3
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where:

OR = chemical residue loading on the object (μg/cm2);

AR = application rate (lbs ai/ft2or lb ai/acre);

FO = fraction of residue available on the object (unitless);

CF2 = weight unit conversion factor (4.54 x 108 μg/lb); and

CF3 = area unit conversion factor (1.08 x 10-3ft2/cm2or 2.47 x 10-8acre/cm2).

Dose, normalized to body weight, is calculated as:

BW

E

D 

where:

D = dose (mg/kg-day);

E = exposure (mg/day); and

BW = body weight (kg).

Table C.2. Turf (Physical Activities) – Inputs for Residential Post-application Object-toMouth Exposure 

Algorithm 

Notation

Exposure Factor

(units) Point Estimate(s)

AR Application rate (to turf)

(mass active ingredient per unit area) 0.46 lb ai/A

FO Fraction of AR as OR following application 1 0.01

SAMO

Surface area of object mouthed 

(cm2/event) 10

N_Replen Replenishment intervals per hour (intervals/hour) 4

SEO

Saliva extraction factor

(fraction) 0.48

ET Exposure time 

(hours per day) 1.5

Freq_OtM Object-to-mouth events per hour (events/hr) 8.8

BW Body Weight (kg) Children 1 < 2 years old 11

1 This SOP assumes that all of the residue on the turf could be transferred to the object (e.g., object residue is 

equal to turf transferable residue).

Post-application Incidental Soil Ingestion Exposure Algorithm– Physical Activities on Turf

Exposure from incidental soil ingestion is calculated as follows:

E = SRt * SIgR * CF1

where:

E = exposure (mg/day);

SRt = soil residue on day "t" (μg/g);

SIgR = ingestion rate of soil (mg/day); and

CF1 = weight unit conversion factor (1 x 10-6g/μg).
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and

SRt = AR * FS * (1-FD)

t

* CF2 * CF3 * CF4

where:

SRt = soil residue on day "t" (μg/g);

AR = application rate (lbs ai/ft2or lb ai/acre);

FS = fraction of ai available in uppermost cm of soil (fraction/cm);

FD = fraction of residue that dissipates daily (unitless);

T = post-application day on which exposure is being assessed;

CF2 = weight unit conversion factor (4.54 x 108 μg/lb);

CF3 = area unit conversion factor (1.08 x 10-3ft2/cm2 or 2.47 x 10-8acre/cm2); and

CF4 = soil volume to weight unit conversion factor (0.67 cm3/g soil).

Dose, normalized to body weight, are calculated as:

BW

E

D 

where:

D = dose (mg/kg-day);

E = exposure (mg/day); and

BW = body weight (kg).

Table C.3. Turf (Physical Activities) – Inputs for Residential Post-application Incidental Soil 

Ingestion Exposure 

Algorithm 

Notation

Exposure Factor

(units) Point Estimate(s)

AR Application rate

(mass active ingredient per unit area) 0.46 lb ai/A

FS Fraction of AR available in uppermost 1 cm of soil

(unitless) 1

FD

Daily residue dissipation

(fraction) 0.1

SIgR Soil ingestion rate (mg/day) 50

BW Body weight (kg) Children 1 < 2 years old 11
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Appendix D. Review of Human Research

This 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 

PHED 1.1; the AHETF database; the ARTF database; and an exposure monitoring degradation 

study (MRID No. 49013500); are (1) subject to ethics review pursuant to 40 CFR 26, (2) have 

received that review, and (3) are compliant with applicable ethics requirements. For certain 

studies, the ethics 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 the Agency 

website.
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Appendix E. Physical and Chemical Properties

Table C.1 Amicarbazone Physical and Chemical Properties

Parameter Value Reference

Molecular Weight C10H19N5O2 = 241.29 g/mol N/A

pH 7.06 (2.5% slurry) MRID 45121501

Water solubility (20°C) 4.6 g/L MRID 45121501

Solvent solubility (ppm at 20°C to 25°C)

n-Heptane = 0.07, xylene = 9.2, 

1-octanol = 43, 2-propanol = 110,

ethyl acetate = 140, acetone >250,

polyethylene glycol = 79, 

acetonitrile >250, 

dimethylsulfoxide = 250, 

dichloromethane >250

MRID 45121502

Vapor pressure (25°C) 2.3x10-8 mmHg

(3.00 x 10-6Pa)

MRID 45121501

Dissociation constant, pKa Does not dissociate. No acidic or 

basic properties. MRID 45121501

Octanol/water partition coefficient (20°C) log Kow =1.23 @ pH 7 MRID 45121502

Soil Half-life (or other relevant information 

from EFED Drinking water assessment)

Aerobic Soil Metabolism

t1/2 = 87 days

DP Barcode No. D384516
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Appendix F. Amicarbazone International Maximum Residue Limits (114004; 5-12-2015)

Table F.1. Summary of US and International Tolerances and Maximum Residue Limits. 

Residue Definition:

US Canada Mexico1 Codex

40 CFR 180.615

Amicarbazone: [4-amino-4, 5-dihydro- N-(1,1-

dimethylethyl)-3-(1-methylethyl)-5-oxo-1H-1,2,4-

triazole-1-carboxamide] and its metabolites DA 

amicarbazone [N-(1,1-dimethylethyl)-4,5-dihydro3-(1-methylethyl)-5-oxo-1H-1,2,4-triazole-1-

carboxamide] and iPr-2-OH DA amicarbazone [N-

(1,1-dimethylethyl)-4,5-dihydro-3-(1-hydroxy-1-

methylethyl)-5-oxo-1H-1,2,4-triazole-1-

carboxamide], calculated as parent equivalents

None None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico1 Codex

Cattle, fat 0.01

Cattle, liver 1.0

Cattle, meat 0.01

Cattle, meat byproducts, 

except liver 0.10

Corn, field, forage 0.80

Corn, field, grain 0.05

Corn, field, stover 1.0

Goat, fat 0.01

Goat, liver 1.0

Goat, meat 0.01

Goat, meat byproducts, 

except liver 0.10

Hog, fat 0.01

Hog, liver 0.10

Hog, meat 0.01

Hog, meat byproducts, except 

liver 0.01

Horse, fat 0.01

Horse, liver 1.0

Horse, meat 0.01

Horse, meat byproducts, 

except liver 0.10

Milk 0.01

Sheep, fat 0.01

Sheep, liver 1.0

Sheep, meat 0.01
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Table F.1. Summary of US and International Tolerances and Maximum Residue Limits. 

Residue Definition:

US Canada Mexico1 Codex

Sheep, meat byproducts, 

except liver 0.10

Poultry, liver 0.10

Completed: M. Negussie; 05/11/15

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

(d) Indirect or inadvertent residues. Tolerances are established for the indirect or inadvertent residues of 

amicarbazone [4-amino-4, 5-dihydro-N-(1,1-dimethylethyl)-3-(1-methylethyl)-5-oxo-1H-1,2,4-triazole-1-

carboxamide] and its metabolites DA amicarbazone [N-(1,1-dimethylethyl)-4,5-dihydro-3-(1-methylethyl)-

5-oxo-1H-1,2,4-triazole-1-carboxamide] and iPr-2-OH DA amicarbazone [N-(1,1-dimethylethyl)-4,5-

dihydro-3-(1-hydroxy-1-methylethyl)-5-oxo-1H-1,2,4-triazole-1-carboxamide], calculated as parent 

equivalents, in or on the following commodities when present therein as a result of application of 

amicarbazone to the growing crops in paragraph (a) of this section:

Commodity Parts per million

Alfalfa, forage 0.05

Alfalfa, hay 0.10

Cotton, gin byproducts 0.30

Cotton, undelinted seed 0.07

Soybean, forage 1.50

Soybean, hay 5.0

Soybean, seed 0.80

Wheat, bran 0.15

Wheat, flour 0.15

Wheat, forage 0.50

Wheat, germ 0.15

Wheat, grain 0.10

Wheat, hay 1.0

Wheat, middlings, 0.15

Wheat, shorts 0.15

Wheat, straw 0.50