UN IT E D STATES E VIRO ME T A L PROT EC TIO AGE CY

W AS IJI GTO

, D. C. '.W 4

60

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

MEMORANDUM

DATE: 9/9/20 1 5

SUB J ECT: A micarba zo n e. Scoping Document and Draft Hum an H ea lth Risk Assessment fo r R eg i s trati o n Rev i ew

PC C ode: I 14004 Deci s ion No.: 503062 DP Barco cl c: 0426602 Registration No.: 66330-46

, 66330-415, 66330-416 Petit i on No.: NA Regulatory Action: Reg Review Scopi n g/ ORA Case No.: 7269 Ri s k Assess m e nt T y p e: Sing l e Chemical
TXR No.: 0054349 CAS No.: 129909-90-6 40CFR: § 180.615 MRID No .: NA

FROM:

T HR OUG H:

TO: Douglas A. D otso n , Ph.D.

, C h emis t 

# J.**/).~** Jaime D ' Agostino

, Ph .D.,

### Toxicologist~ /

### ~ Zaida I. Figueroa, DrPH, Indu str ial H yg i e ni s**~ ~**  Risk Assessme nt Branch IT ( RAB 2)

- 

## (j

- - 

# v-
H ea lth Effects D i vision (7509P)

C hri st i na Swa rtz
, Branch Chief Ri sk Assessment Branch TT

J ess R ow l and

, D e puty Dir ector

## ~c;G.:.~C?.--**--> .­**  H ea lth Effects Di vis i on (7509 P ) Office of Pesticide Pro grams

Maria Piansay

, Chemical R eview Manager Linda Arrington

, Branch Chief Ri s k Management a nd Implementation Br a n c h V Pe s ticide Re-Evaluation Di v i s i o n (7508 P )

The Pe s ticide Reevaluation Di v i s i o n ( PRD ) r equested th e H ea lth Effec t s Di v i s ion ( H E D ) to develop a scop in g document to delineate the data r eq uir e m e nt s fo r cond u c tin g a human health risk asse s s m e nt for th e h erb i c i de

, amicarbazone

, durin g the r eg i s trati o n r ev i ew proc ess. As th ere

a r e n o data deficiencies (i.e., all data requir e ment s a r e sa ti s fi e d)

, H ED ha s conducted a draft

Pa ge I of 53Amicarbazone Draft Ri s k Assess ment DP Number 426602

hum a n h ea lth ri sk assessment ( ORA ). T hi s ORA in corpora t es the m ost rec e nt data a nd assumptio n s for conducting d i etary
, resid e ntial

, occupat i o n a l

, a nd agg r ega t e exposure and risk
assessments. No r i sk estimates of concern we r e ident ifi e d.

Si n ce th e l as t hum a n h ea lth risk assessment (20 11 fo r use o n orna m e n tals), the fo ll owing updates ha ve been in corpora ted fo r am i carbazone:

I ) H ED, based o n weight-of -e v iden ce conside r atio n s , h as d e termin ed that an inhalation
t ox icit y st udy i s n ot r eq u i red

. 2) S pray drift ex posure / ri sk ha s been considered according t o c urr ent sc i ence policie s

. 3) Th e occ up at i o nal ri s k assessment h as been r ev i sed t o in co rp o r ate upd a t ed scie ntific procedure s and exposure assumptions. 4) A di e tary e xp os u r e assessment was per for med using upd a t e d food consumption s ur vey

r es u l t s

. 5) T h e r eg i stra n t sa ti sfied several residue c hemi s try co nditi o n al data d efic i e n c i es identified in the 2005 r esi du e review and ri s k assess m e nt. 6) H ED co n s id ered all the exposure a nd toxicit y inform a ti on fo r a micarba zo ne a nd d e termin ed that chemical

- specific dislod geab l e fo li a r r es idu e ( DFR ) or turf transferable

r es idue ( TTR ) data are not r equired lo refine th e ex p os ure assessme nt.



### Pa ge 2 of 53Amicarbazon e Draft Risk Assessment DP Number 426 602

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 C onsiderations

................................ ................................ ............................... 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

................................ ............... 1 2 4.1 Toxicology Studies Available for Analysis

................................ ................................ .. 1 2 4.2 Absorption, Distribution, Metabolism, and Elimination (ADME)

.............................. 1 2 4. 2.1 Dermal Absorption

................................ ................................ ................................ .. 1 3 4. 3 Toxicological Effect s

................................ ................................ ................................ ... 1 3 4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

................................ ..... 1 4 4.4.1 Completeness of the Toxicology Database

................................ ............................. 1 4 4.4.2 Evidence of Neurotoxicity

................................ ................................ ....................... 1 4 4.4.3 Evidence of Sensitivity/Susceptibility in the Developi ng or Young Animal

.......... 1 4 4.4.4 Residual Uncertainty in the Exposure Database

................................ ..................... 1 5 4.5 Toxicity Endpoint and Point of Departure Selections

................................ .................. 1 5 4.5.1 Dose

- Response Assessment

................................ ................................ .................... 1 5 4.5.2 Recommendation for Combining Rout es of Exposure for Risk Assessment

.......... 1 7 4.5.3 Cancer Classification and Risk Assessment Recommendation

.............................. 1 7 4. 6 Endocrine Disruption

................................ ................................ ............................. 1 7 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

................................ ................................ ..... 2 0 5.4 Water Residue Profile

................................ ................................ ................................ .. 2 1 5.5 Dietary Risk Assessment

................................ ................................ .............................. 21 5 .5.1 Description of Residue Data Used in Dietary Assessment s

................................ .... 2 1 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 C a nc er Dietary Risk Assessment

................................ ................................ ............ 22 5.5.6 Dietary Summary Table

................................ ................................ .......................... 2 3 6.0 Residential (Non

- Occupational) Exposure and Risk Assessment

................................ .... 24 6.1 Residential Handler Exposure /Risk Estimate s

................................ ............................. 24 6. 2 Residential Post

- Application Exposure /Risk Estimates

................................ ............... 25 6 .3 Residential Risk Estimates for Use in Aggregate Assessment

................................ ..... 2 7Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 4 of 53 6.4 Spray Drift

................................ ................................ ................................ .................... 2 8 6.5 Residential Bystander Post

- Application Inhalation Exposure

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

................................ ................................ ...... 2 9 7 .1 Acute Aggregate Risk

................................ ................................ ................................ .. 2 9 7.2 Short

- Term Aggregate Risk

................................ ................................ ......................... 2 9 7 .3 Chronic Aggregate Risk

................................ ................................ ............................... 3 1 8.0 Cumulative Exposure/Risk Characterization

................................ ................................ .... 3 1 9.0 Occupational Exposure/Risk Characterization

................................ ................................ . 31 9 .1 Occupational Handler Exposure/Risk Estimates

................................ .......................... 3 1 9

. 2 Occupational Post

- Application Exposure/Risk Estimates

................................ ........... 3 4 9

. 2 .1 Occupational Post

- Application Inhalation Exposure/Risk Estimates

..................... 3 4 9

. 2 .2 Occupational Post

- Application Dermal Exposure/Risk Estimates

......................... 3 4 10.0 Public Health and Pesticide Epidemiology Data

................................ .............................. 3 5 1 1 .0 References

................................ ................................ ................................ ......................... 3 5

Appendix A. Toxicology Profile

................................ ................................ ................................ .. 3 7 A.1 Toxicology Data Requirements

................................ ................................ .................... 3 7 A.2 Toxic olog y Profile Table s

................................ ................................ ............................ 3 8 Appendix B

. Occupational and Residential Non

- Cancer Handler Algorithms

........................... 4 5 Appendix C

. Residential Non

- Cancer Post

- Application Algorithms

................................ .......... 4 6 Appendix D

. Review of Human Research

................................ ................................ ................... 50 Appendix E

. Physical and Chemical Properties

................................ ................................ .......... 5 1 Appendix F

. Amicarbazone International Maximum Residue Limits

................................ ......... 5 2Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 5 of 53 1.0 Executive Summary

Amicarbazone, 4

- amino

- N

- (1,1

- dimethylethyl)

- 4,5

- dihydro

- 3

- (1

- methylethyl)

- 5

- oxo

- 1 H

- 1,2,4

- triazole

- 1

- carboxamide

, is a s elective herbicide that acts through the inhibition of p hotosynthesis. 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 tree s, Christmas tree farms, no n

- 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 granul e (WDG) and s uspension
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 ( whi ch 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 s upport proposed uses on turf, Christmas tree farms, non

- c rop areas , and on conifers in nurseries

.

T he toxicology database for amicarbazone is complete and adequate for risk assessment , with the exception of a subchronic inhalation toxicity study

. This i nhalation study was not available at the time of the previous risk assessment ; h owever, 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. T he 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 vacuol iz ation 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 b etween 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 resp onse, 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 qua litative 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

car cinogenic 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 w eight) was observed in the immunotoxicity study

, but at doses higher than those that caused decreased body weight or liver effects in other studies.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 6 of 53 Field c orn is the only agricultural commodity for which amicarbazone is registered. However, humans can be exposed to amicarba z one 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 chemis try data deficiencies , which have been addressed by the registrants . As a result , there are no outstanding residue chemistry data requirements. However, HED notes that i f the registrant would like root and tuber vegetables to remain on the label as rotat ional 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 a s sessments 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 assessment s

. The acute and chronic dietary risk estimates a re not of concern for the U.S. population and all population subgroups. Drinking water i s the most significant co ntributor to dietary risk for the U.S. population and all population subgroups.

For the r esidential exposure scenarios , an updated quantitative short

- term residential exposure assessment (handler and post

- application) has been complete d in accordance with the 2012 Residential Standard Operating Procedures (SOPs). All residential risk estimates are not of

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

concern.

A micarbazone 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 i s 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

. T he risk estimates are not of concern

.
The residential handler exposure from applying amicarbazone using a m anually

- pressurized handwand and children’s post

- application incidental oral (hand

- to

- mouth) exposure were combined with the chronic dietary e xposure 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 infan ts 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 assessm ent using the drinking water level of comparison (DWLOC) approach. In order to do this, HED performed the chronic dietary exposure analys i s without drinking water. All assumptions with respect to r esidue 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 theAmicarbazon e Draft Risk Assessment DP Number 426 602

Page 7 of 53 maximum allowable drinking water concentration , given the estimate d 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 estimat ed drinking water concentration ( EDWC ) would need to be 5 9 0 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. D ermal risks are not anticipated because of the lack of toxicity via the dermal route; the refore

, t he 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 flo wable 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 p ersonal p rotective e quipment (PPE) statement on the registered labels requires applicators and ot her 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 c urrent 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 post

application risks to agricultural workers follo wing 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

acu te toxicity of amicarbazone a nd is adequate to protect agricultural workers from post

application 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 an y changes to these tolerances , and there are no harmonization issues becaus e there are no Codex or Canadian MRLs for amicarbazone.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 8 of 53 2.2.1 Enforcement Analytical Method s

Adequate analytical methods are available for enf orcement 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

T olerances are established for residues of am icarbazone 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

- 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 f ollowing commodities.”

According to HED’s Interim Guidance o n 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

- dimethyle thyl)

- 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 f o llowing 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

- carboxamid e] 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

- carboxa mide], calculated as parent equivalents, in or on the f ollowing 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 isAmicarbazon e Draft Risk Assessment DP Number 426 602

Page 9 of 53 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 f ollowing 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 label s as rotational crops

. If the registrant submits extensive field rotational crop data for the leav es of root and tuber vegetables, HED can determine the appropriate plant

- back intervals and rotational crop tolerances.

3.0 In troduction

3.1 Chemical Identity

Table 3 .1. Amicarbazone Nomenclature

.

Chemical Structure

Empirical Formula C 10 H 19 N 5 O 2 Common Name Amicarbazone Company experimental name MKH 3586

IUPAC name 4

- amino

- N

- tert

- butyl

- 4,5

- dihydro

- 3

- isopropyl

- 5

- oxo

- 1 H

- 1,2,4

- triazole

- 1

- carboxamide

CAS Name 4

- amino

- N

- (1,1

- dimethylethyl)

- 4,5

- dihydro

- 3

- (1

- methylethyl)

- 5

- oxo

- 1 H

1,2,4

- triazole

- 1

- carboxamide CAS Registry Number 129909

- 90

- 6

End

- use product/EP Amicarbazone WDG Herbicide, 70% ai (also know n as Dinamic 70WDG Herbicide and Xonerate Herbicide) (66330

- 46) ARY 0452

- 110 Herbicide (66330

- 415) ARY 0452

- 112 Herbicide (66330

- 416)
Chemical Class T riazolinone or T riazolone herbicide Known Impurities of Concern N/AAmicarbazon e Draft Risk Assessment DP Number 426 602

Page 10 of 53 3.2 Physical/Chemical Characteristics

Amicarbazone is a solid that has a vapor pressure of 2.3x10

- 8 mmHg at 2 5 °C

. It is slightly water sol uble (4.6 g/L) and partitions relatively equally between water and octanol. The o ctanol/water partition coefficient ( log K ow ) = 1.23 at pH 7

. As a result, appreciable b ioaccumulation is not likely

. See Appendix E for a listing of additional p hysical and c hemical properties.

3.3 Pesticide Use Pattern

At the present time, t here is one te chnical product, Amicarbazone Technical Herbicide (EPA Reg istration Number 66330

- 45 ) and three end

- use products. Amicarbazone WD G 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 Her

bicide (EPA Reg No. 66330

- 416). The use directions for these EPs are summariz ed 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 label s require s applicators and ot her 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 a ll 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), C onifers in Commercial N urseries and F ield P lanti ngs (including Christmas trees)

F oliar spray (directed) to containerized ornamental plants using handheld equipment.

Applied u sing
g roundboom, airblast, and handheld equipment

. Amicarbazone

WDG Herbicide ( WDG ), 70 % ai [ 66330

- 46 ] 0.0 4 4

- 0. 4 6 lb

ai/ A

(10.5 oz prod/A or 0.023 lb ai/gal at 70% ai) 1

- 4

(depending on rate) 0.4 6 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]Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 11 of 53 3.4 Anticipated Exposure Pathways

H umans can be exposed to amicarbazone residues in their diets from both food and drinking
water.

T here are residential uses for amicarbazone on turf and ornamental plants ; therefore, there is likely to be exposure in residential and n on

- 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, the re is no expectation of dermal risk, based on the lack of dermal toxicity. Furthermore, t he potential for post

- application oral exposure to children is not expected from treated ornamentals because young children spend little time playing in areas where r esidential 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 expos ure 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 post

application 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. Executiv e 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 pa rt 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 o f 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 Heal th and Nutrition Examination Survey, “ What We E at 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
appropr iate, 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 co ncern. 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 dieta ry patterns among specific subgroups.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 12 of 53 4.0 Hazard Characteriz ation 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

s ubchronic 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 ) . T oxicity 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 an d 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, Di stribution, Metabolism, & Elimination (ADME)

Metabolism of amicarbazone was investigated in male rats only. Amicarbazone was well

absorbed 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 l evels 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 we re 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 primari ly in the urine

, 32% out of 34% total excretion), tBu

- OH DA MKH 3586 (11% in urine and 4% in feces), and iPR

1,2

- 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% tot al excretion). Five minor identified metabolites (<3% of dose) and seven unidentified metabolites (all <1% of dose) were isolated in the urine and the feces.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 13 of 53 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 . T he most sensitive and consistent effe cts following repeat exposure were decreased body weight in rat s 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 vacuol iz ation 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 th e effects of amicarbazone based on 3⁄4 body weight scaling. In contrast, the mouse was much less sensitive. I n rats and dogs

, t here appeared to be minimal progression of toxicity over time

, as the liver and body weight effects were seen at similar or sligh tly 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, decreas ed 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 A CN study (sedation, ptosis, and sal i vation) 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) occu rred 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 rabb it 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 r esponse and decreased spleenAmicarbazon e Draft Risk Assessment DP Number 426 602

Page 14 of 53 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 contin ues 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 pr e

- 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 ra ts; 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 exposur e through food, w ater
, 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. Accept able/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

assessme nt.

4.4.2 Evidence of Neurotoxicity

Rats ex hibited e vidence of neurotoxicity fol lowing 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 databa se. 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/Susce ptibility 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 reproductio n study, decreased pup weight was seen at the same doses as decreased body weight in the dams.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 15 of 53 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 exposur e pathways. The aggregate assessment , which includ es children’s exposure s 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 achie ved when it is water ed

- 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

, th e toxicological effects reported at the LOAEL s would not be considered adverse. However, these studies were not re

- evaluat ed 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, a ll 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 asses sments is presented below.

Table 4.5.1 .a. Summary of Toxicological Doses and Endpoints for Amicarbazone for Use in Dietary and Non

Occupational 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 UF A = 10x

UF H =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 na sal staining in males

Chronic Dietary (General Population, including Infants and Children and Females 13

- 49 years of age) NOAEL=

2.3 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x Chronic RfD

= 0.023 mg/kg/day

cPAD = 0.023 mg/kg/day Chronic Oral Rat and Chronic Oral Dog (co

critical)

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.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 16 of 53 Table 4.5.1 .a. Summary of Toxicological Doses and Endpoints for Amicarbazone for Use in Dietary and Non

Occupational 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 UF A = 10x

UF H =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, N

demethylase 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 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) UF A = 10x

UF H =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; an d decreased albumin and increased triglycerides, N

demethylase 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
expo sures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human popula tion (intraspecies). FQPA SF = FQPA Safety Factor. RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 17 of 53 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 Uncertain

ty 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) UF A =10x

UF H =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, N

demethylase and O

- demethylase i n 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 ad verse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = 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 becaus e the risk assessments are based on studies with the same toxicological effects. Dermal exposure can not be combined beca use 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 tum ors 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 includ e endpoints which may beAmicarbazon e Draft Risk Assessment DP Number 426 602

Page 18 of 53 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 ec ological 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 amicarbazon e, 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), amicarbazon e 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 suc h 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 in teract 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 i ngredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 1 and includes some pesticides scheduled for r egistration r eview and chemicals found in water

. Neither of these lists should be con strued 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 i s field co r n. The direct application to corn can result in inadvertent residues in the rotational crops alfalfa, cotton, soybeans, and wheat. As a result, t olerances have been established for residues in corn and rotational crops. Many of the agricultural commodities with tolerances are livestock feed items. As a result, t olerances have also been established for milk and livestock tis sues 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.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 19 of 53 5.1 Residue s of Concern Summary

The qu alitative nature of the residues of amicarbazon e in plants and livestock has been adequately ch aracterized. 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 presen ce of the triazolinone ring, and potential toxicity equ ivalent to that of the parent. The residues of concern in field corn consist of the parent amicarbazone, desamino amicarbazone, and i Pr

- 2

- OH desamino amicarbazone. The residues of concern in ruminant s 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 a micarbazone

, and N

- methyl

desamino amicarbazone . T here is no expecta tion 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 th e 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, iPr

Acid 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

Co rn is the only agricultural commodity for which amicarbazone is registered. However, humans can be exposed to amicarba z on e 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.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 20 of 53 In HED’s 200 5 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 vege tables 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 tria ls on either sugar beets or garden beets. If the registrant submits the data, HED can then determine the appropriate plant

back intervals and rotational crop tolerances. For more information concerning the rotational crop issue or the other residue chemi stry 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 photol ysis, 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, indir ect photolysis

can contribute to amicarbazone dissipation. Although photolysis might occur on soil surfaces (t 1/2 = 54 days), label

- recommended incorporation of the pesticide just after application m ight render this process unimportant.

Laboratory and fi eld 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/desorpti on 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 N

methyl desamino degradates are expected to behave similarly to the parent and become the major terminal degradates of this chemical in surface and g roundwater.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 21 of 53 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 ( D3 84659, A. Shelby, 9 / 7 /201 1). The EDWCs we re incorpora ted directly into th e 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 we re 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 gr oundwater 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 . A micarbazone 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 toxic ity as parent amicarbazone or if unextracted residues were determined to be bound residues. Exclusion of bound residue s 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 Assessment s

Acute and chronic dietary (food and drinking water) exposure assessments were conducted using the Dietary Exposure Evaluation Model software with the F ood 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 c hronic 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, EDWC s are based on a worst case scenario. C oncentrations 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 theseAmicarbazon e Draft Risk Assessment DP Number 426 602

Page 22 of 53 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. popula tion 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 Assessment s

In the acute and chronic assessments, the assumption was made that 100% of all commodities would have amicarbazon e residues.

5. 5 .3 Acute Dietary Risk Assessment

When the EDWC of 136 ppb is included in the acute dietary expos ure assessment, t he 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 95 th percentile of exposure. When drinking water was eliminated from the assessment, the exposure estimates decreased significantly. The acute risk estimate fo r 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 Chr onic 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 1 5 % 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 sign ificantly. The chronic risk estimate for the general U.S. population decreased from 1 5 % 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 carcinogen ic to humans .” As a result, cancer risk is not of concern.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 23 of 53 5. 5 .6 Dietary Summary Table

The acute and chronic dietary exposure and risk estimate s for amicarbazon e 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 A micarbazone

. Population Subgroup Acute Assessment (95 th Percentile) Chronic Assessment

aPAD, mg/day Exposure Estimate,

mg/day % aPad cPAD, mg/day Exposure Estimate,

mg/day % cPad

U.S. Population 0.10 0.008 521 8. 5 0.023 0.003 486 1 5 All infants * 0.10 0.02 5577 2 6 0.023 0.008571 37 Children 1

- 2 yrs 0.10 0.014 560 15 0.023 0.006281 27 Children 3

- 5 yrs 0.10 0.01 1738 1 2 0.023 0.00 5127 2 2 Children 6

- 12 yrs 0.10 0.00 8531 8.5 0.023 0.00 3536 1 5 Youth 13

- 19 yrs 0.10 0.0069 24 6.9 0.023 0.00 2668 1 2 Adults 20

- 49 yrs 0.10 0.00 8049 8.1 0.023 0.003 331 15 Adults 50+ yrs 0.10 0.00 7144 7.1 0.023 0.003 232 1 4 Females 13

- 49 yrs 0.10 0. 00 8111 8.1 0.023 0.003 312 1 4 * 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 (95 th 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 0.00 1751 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 0.00 2045 2.0 0.023 0.001040 4.5 Youth 13

- 19 yrs 0.10 0.00 1260 1.3 0.023 0.000591 2.6 Adults 20

- 49 yrs 0.10 0.0 01055 1.1 0.023 0.000490 2.1 Adults 50

- 99 yrs 0.10 0.00 0910 0.91 0.023 0.000423 1.8 Females 13

- 49 yrs 0.10 0.00 1049 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 amicarbazon e residues when the most recent EDWC of 136 ppb is used for drinking
water.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 24 of 53 6.0 Residential (Non

- Occupational) Exposure and Risk Assessment

R egistered r esidential uses of amicarbazone have been reassessed in this document to reflect updates to HED’s 2012 Residential SOPs 2 along with policy changes for body weight assumptions. The revision of residential exposures will impact the human health aggregate ri sk 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 appli cations

, 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.

T he quantitative exposure/risk assessment developed for residential handlers is based on the scenarios listed i n Table 6.1.

Residential Handler Exposure Data and Assumptions

Application Rate: The maximum single application rates are listed in Table 3. 3

. Refer to S ection 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: Resi dential 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, a s 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 Estimate s

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 handler s 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.htmlAmicarbazon e Draft Risk Assessment DP Number 426 602

Page 25 of 53 Table 6.1. Residential Handler Exposure and Risk Estimates for Amicarbazone.
Scenario Inhalation Unit

Exposure a (mg/lb ai) Application

Rate b Acres Treated

or Amount Handled Inhalation

Dose d (mg/kg/day) Inhalation

MOE e

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 Manually

pressurized 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 a pplication 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 expec t ed for adults and children following use of amicarbazone on residential sites.

Dermal Post

- application Exposure to Treated Turf

B ecause of the lack of dermal toxicity, HED did not perform a quantitative dermal post

application 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 derm al endpoint was not selected; therefore, a dermal post

- application exposure assessment was not conducted for this scenario. Furthermore, t he potential for post

- application oral exposure to children is not expected as a result of the use on ornamentals

.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 26 of 53 Incidental Oral Post

- application Exposure to Treated Turf

I ncidental oral (i.e., hand

- to

- mouth, object

- to

- mouth, and soil ingestion) p ost

- application exposures are expected for children following use of amicarbazone on residential turf

. The quantita tive 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 lev el 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 (10 x 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.

T he 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 inte rmediate

- 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 herbici de 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 a nd 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 a ppendix 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 S ection 3. 3 for a complete use pattern description.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 27 of 53 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

- ap plication 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 Rate 1 Dose (mg/kg/day) 2 MOEs 3 Use Site Route of Exposure 4

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 a re applicable to children. I nhalation 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 use d 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.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 28 of 53 Table 6.3. Recommendations for the Residential Exposures for the Amicarbazone Aggregate Assessment

.

Life

- stage Exposure

Scenario Dose (mg/kg/day) 1 MOE 2

Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Adult Turf

(Backpack Sprayer) N/A 0.00180 N/A 0.001 75 N/A 3,400 N/A 3,400

Child (1 to <2 years old) Turf N/A N/A 0.0070 0.00 687 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 off

target and can lead to exposures to those it may directly con tact. 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 whi ch, 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 wh o 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.

Se veral amicarbazone pro ducts 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 t he registe red 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 tha n 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.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 29 of 53 highest deg ree 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 spr ay drift assessment for amicarbazone is not required because the max imum application rate to a crop/ta rget site multiplied by the adjustment f actor for drift of 0.26 is less (0.12 lb ai/A) t han the maximum direct spray residential turf application rate [(0

. 46 lb ai/A)] 4 for any amicarbazone product . The turf post

- application MOEs were previously assessed and are based on the revised SOPs for Residential Exposure Assessme nt (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 A gency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, F ungicide, 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 A gency has evaluated the SAP report and has develop ed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219). D uring Registration Review, the A gency will utilize this analysis to determine if data (i.e., flux st udies, 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 ag gregated. 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 r isks, 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 m anually

- pressurized handwand (Table 6.1) and children’s post

- application incidenta l oral (hand

- to

- mouth) exposure

4 Maximum Application rate for Spray Drift Ass essment = 0.46 lb ai/A x 0.26 = 0.12 lb ai/A ≤ 0. 46 lb ai/A.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 30 of 53 (Table 6.2) were combined with the chronic dietary exposure from the mostly highly exposed adult (General U

. S

. population) and children’s ( A ll I nfants <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 ) LOC 1 Max Allowable Exposure 2 ( 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 0.003 486 0.00175 0.005 236 1

, 200 Child (Post

application) 6.28 100 0.0628 0.0 08571 0.00687 0.01 5441 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 1 x

. 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 Expo su re (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 treat ed 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 drinki ng 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 8 0 kilograms and drink 2 liters of
wate r a day , and that children weigh 1 1 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 DWLOC s 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 0.00 0638 0.00175 0.005 236 2, 3 00 Child (Post

application) 6.28 100 0.0628 0.0 02173 0.00687 0.0 09043 5 9 0

DWLOC = [[(NOAEL ÷ 100)

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

L/day)]Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 31 of 53 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 5 9 0 ppb or less.

7.3 Chronic Aggregate Risk

Chronic aggregate risk is equivalent to chronic dietary exposure and risk, wh ich is discussed in S ection 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 amicarbazon e and any other substances

, and amicarbazone d oes 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 deter mine 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 cumula ting 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, ty pes of equipment

, and techniques that can potentially be used, occupational handler exposure is expected from the registered use s on corn and non

- crop areas such as turf, ornamentals

, and Christmas tree farms . The quantitative exposure/risk assessment dev eloped 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 use s is expected to be short

- term (1

- 30 days) and i ntermediate

- term ( 1

- 6 months) in duration

. 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. L ong

- 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 S ection 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 w as not developmental and/or based on fetal effects. As no inhalation absorption data are available, toxicity by the in halation route is considered to be equivalent to the estimated toxicity by the oral route of exposure.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 32 of 53 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 d ata 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 Table 5

. ” HED policy on use of surrogate data, including descriptions of the various

sources , can be found at the Agency website 6

.
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 : Th e algorithms used to estimate non

- cancer exposure and dose for occupational handlers can be found in Appendix B.

Summary of Occupational Handler Non

- Ca ncer 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 asso ciated 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.htmlAmicarbazon e Draft Risk Assessment DP Number 426 602

Page 33 of 53 Table 9.1 . Occupational Handler Exposures and Risks Estimates for Amicarbazone. Exposure Scenario and Formulation Use Site Application Rate a 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 Co urse ) 0.46 lb ai/A 40 A 0.00896 (Baseline) 0.00206 3,000

Sod F arms (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 Co urse ) 0.45 lb ai/A 40 A 0.000219 (Baseline) 0.0000493 130,000

Sod F arms (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 Co urse )

0.46 lb ai/A 40 A 0.00034 (Baseline) 0.0000783 80,000

Sod F arms (Turf), Christmas Trees 80 A 0.000156 40,000

Corn 200 A 0.000391 16,000

Mixer/Loader/Applicator

Backpack Sprayer Christmas Trees; Turf, G olf C ourse, Sod F arms, P arks, Recreation and A thletic F ields (Foliar) 0.023 lb ai/gal 40 gals 0.14 (Baseline) 0.00161 3,900

Christmas Trees; Turf, G olf C ourse, Sod F arms, P arks, Recreation and A thletic F ields (Ground

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

Manually

- pressurized Handwand Christmas Trees; Turf, G olf C ourse, P arks, Recreation and A thletic F ields (Foliar) 0.023 lb ai/gal 40 gals 0.03 (Baseline) 0.000345 18,000

Mechanically

pressurized Handgun Sprayer (WDG) Turf, G olf C ourse, Sod F arms, P arks, Recreation and A thletic F ields 0.46 lb ai/A 5 A 0.042 (B a seline) 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 soc ks, 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.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 34 of 53 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 A gency 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 t he SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The A gency 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 r egistration r eview, the A gency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for am icarbazone

.
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 w ay to incorporate occupational post

- application inhalation exposure into the A gency ’ 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 prot ective of most occupational post

- application inhalation exposure scenarios. N o 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 avail able 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 post

application exposure assessments or would add appreciably to our overall understanding of the availability of dislodgeable foliar o r turf transferable pesticide residues for amicarbazone.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 35 of 53 Restricted Entry Interval

The REI specified on the amicarbazone registered label s 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), a ctive i ngredient s classified as Acute III or IV for acute dermal, eye irritation

, and primary skin irritation are assi gned a 12

- hour REI. Therefore, the [156 S ubpart 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

- Pestici des (SENSOR) databases for pesticide incident data on the active ingredient amicarbazone (D 42 7159 , S. Recore, 5 / 6 /2015 ) . The purpose of the database search wa s to identify potential patterns in the frequency and severity of the health effects attributed t o 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 M ain IDS and Aggregate IDS , from January 1, 2010 to February 4, 2015, no in cidents involving amicarbazone were reported

. The SENSOR

- Pesticides database covers 12 states from 1998

- 2011, although reporting varies from state to state. A revie w of SENSOR

Pesticides 1998

- 2011 identifies no cases involving amicarbazone. N o incident cases were reported for amicarbazone to either IDS or SENSOR

- Pesticides . T here does not appear to be a concern at this time that would warrant further investigation.

1 1 .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

D 42 7159

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

D 427771

, 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, 6/6/2005Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 36 of 53 D425340, Amicarbazone. H ED’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

TX R No. 0054349, Amicarbazone: Summary of Hazard and Science Policy Council (HASPOC) Meeting of April 22, 2015 : Recommendation on the R equirement f or a Subchronic I nhalation S tudy , U. Habiba, 6/15/2015Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 37 of 53 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 --

--

--Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 38 of 53 A.2 Toxic ology Profile Table s

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 LD 50 > 2050 mg/kg ;
Females LD 50 = 1015 mg/kg III

870.1200 Acute dermal [rat] 45121503 LD 50 > 5000 mg/kg IV

870.1300 Acute inhalation [rat] 45121506 LC 50 = 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), increa sed 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 O

demethylase in both sexes.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 39 of 53 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 (Sprague

Dawley 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 Materna l NOAEL = 5 mg/kg/day LOAEL = 20 mg/kg/day based on decreased body weight gain during treatment. Developmenta l NOAEL = 20 mg/kg/day LOAEL = 70 mg/kg/day based on decreased fetal body weight, and increased incidences of incomplete ossification of the 5 th medial phalanx (bilateral) and the 13 th 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.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 40 of 53 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, includin g increased absolute and relative liver weights, and O

- demethylase in males ; increased globulin and cytochrome P

450 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 sexe s.

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.

N o 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.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 41 of 53 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.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 42 of 53 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 appr oach 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 m g/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. Ma jor 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.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 43 of 53 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.7800 Immunotoxicity

(Female Fischer

344 rat) 48407504 (2011)

Acceptable/guideline 0, 250, 1000, 2500 ppm 0, 20, 81, 195 mg/kg/day I mmunotoxicity NOAEL = 81 mg/kg/day

I mmunotoxicity 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 (199 9)

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 125 I in treated groups were comparable to negative controls, indicating there was no impairment of thyroid hormone synthesis. Thu s, 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 deiodinas es in vivo . These findings support the subchronic mechanistic studies in rats which indicate that up

- regulation of UDP

glucuronosyl 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 time

dependent effect was demonstrated on motor activity

- decreased travel distanc e, increased resting time, and decreased rearing.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 44 of 53 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.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 45 of 53 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 = e xposure (mg ai/day), UE = u nit e xposure (μg ai/lb ai), AR = m aximum application rate according to registered label s (lb ai / A), and A = a rea 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 = e xposure (mg ai/day), AF = absorption fa ctor (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 a re 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 i n a given scenario (mg ai/kg/day).Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 46 of 53 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 * ( F

M * SA H ) * (ET * N_Replen) * (1

- (1

- SE ) (Freq_HtM/N

- Replen) )]

where:

E = exposure (mg/day); HR = hand residue load ing (mg/cm 2 ); FM = fraction hand surface area mouthed / event (fraction/event); SAH = typical surface area of one hand (cm 2 ); 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

where:

HR = hand residue loading (mg/cm 2 ); Fai hands = fraction ai on hands compared to total surface residue from dermal transfer coefficient study (unitless); DE = dermal exposure (mg); and SA H = typical surface area of one hand (cm 2 ).

Dose, normalized to body weight, is calculated as:

wher e: D = dose (mg/kg

- day); E = exposure (mg/day); and BW = body weight (kg).Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 47 of 53 Table C.1. Turf (Physical Activities)

– Inputs for Residential Post

- application Hand

- to

- Mouth

Exposure Algorithm Notation Exposure Factor (units) Point Estimate(s)

Fai hands Fraction of ai on hands

from dermal transfer coefficient study (unitless) Liquid formulations 0.06

Granular formulations 0.027

DE Dermal exposure (mg) Calculated

SA H Typical surface area of one hand (cm 2 ), 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/cm 2 ) Calculated via (DE * Fai hands )/SA H

F M 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 * SAM O * (ET * N_Replen) * (1

- (1

- SE O ) (Freq_OtM/N_Replen) )]

where:

E = exposure (mg/day); OR = chemical residue loading on the object on day “t” (ug/cm 2 ); CF1 = weight unit conversion factor (0.001 mg/μg); SAM O = area of the object surface that is mouthed (cm 2 /event); ET = exposure time (hr/day); N_Replen = number of replenishment intervals per hour (intervals/hour); SE O = 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 * F O * CF2 * CF3Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 48 of 53 where:

OR = chemical residue loading on the object (μg/cm 2 ); AR = application rate (lbs ai/ft 2 or lb ai/acre); F O = fraction of residue available on the object (unitless); CF2 = weight unit conversion factor (4.54 x 10 8 μg/lb); and CF3 = area unit conversion factor (1.08 x 10

- 3 ft 2 /cm 2 or 2.47 x 10

- 8 acre/ cm 2 ).

Dose, normalized to body weight, is calculated as:

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

- to

Mouth 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

F O Fraction of AR as OR following application 1 0.01

SAM O Surface area of object mouthed (cm 2 /event) 10
N_Replen Replenishment intervals per hour (intervals/hour) 4

SE O 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

- 6 g/μg).Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 49 of 53 and

SRt = AR * FS * (1

- F D ) t * CF2 * CF3 * CF4

where:

SR t = soil residue on day "t" (μg/g); AR = application rate (lbs ai/ft 2 or lb ai/acre); FS = fraction of ai available in uppermost cm of soil (fraction/cm); F D = fraction of residue that dissipates daily (unitless); T = post

- application day on which exposure is being assessed; CF2 = weight uni t conversion factor (4.54 x 10 8 μg/lb); CF3 = area unit conversion factor (1.08 x 10

- 3 ft 2 /cm 2 or 2.47 x 10

- 8 acre/cm 2 ); and CF4 = soil volume to weight unit conversion factor (0.67 cm 3 /g soil).

Dose, normalized to body weight, are calculated as:

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

F D Daily residue dissipation (fraction) 0.1

SIgR Soil ingestion rate (mg/day) 50

BW Body weight (kg) Children 1 < 2 years old 11Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 50 of 53 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 mon itoring degradation stud y (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 revie w by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website

.Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 51 of 53 Appendix E

. Physical and Chemical Properties

Table C.1 Amicarbazone Physic al and Chemical Properties

Parameter Value Reference Molecular Weight C 10 H 19 N 5 O 2 = 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

- 6 Pa ) MRID 45121501

Dissociation constant, pKa Does not dissociate. No acidic or basic properties. MRID 45121501
Octanol/water partition coefficient (20°C) log K ow =1.23 @ pH 7 MRID 45121502
Soil Half

- life (or other relevant information from EFED Drinking water assessment) Aerobic Soil Metabolism
t 1/2 = 87 da ys DP Barcode No. D384516Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 52 of 53 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 Mexico 1 Codex 40 CFR 180.6 1 5 A micarbazone : [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 None None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 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 0.01Amicarbazon e Draft Risk Assessment DP Number 426 602

Page 53 of 53 Table F.1

. Summary of US and International Tolerances and Maximum Residue Limits. Residue Definition :
US Canada Mexico 1 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 Code x 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 paren t 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