Linuron Human Health Risk Assessment DP No. D405828

Page 1 of 41 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA** **L SA FETY**  **AND POLLUTION PREVENTION**  **MEMORANDUM Date**  **:** September 18 , 2013 **SUBJECT: Linuron:**  Section 3 Human Health Risk Assessment for Proposed Use on

Coriander, Dill, Horseradish, Parsley , Celeriac, Rhubarb, and Pea (Dry). **PC Code:** 035506 **DP Barcode:** D405828 **Decision No.:** 4697 2 2 **Registration No. :**  61842
- 23 **Petition No .:**  2E8083 **Regulatory Action:** Section 3 Registration **Risk A**  **ss essment Typ**  **e :**  Single Chemical Aggregate **Case No.:** 0047 **T XR No.:**  NA **CAS No.:** 330
- 55
- 2 **MRID No.:** NA **40 CFR:** §180.184 **From:** Kristin Rury , Biologist

Whang Phang , Senior Toxicologist Nancy Tsaur, Chemist Risk Assessment Branch III Health Effects Division (7509P) **Through:** Christine Olinger , Branch Chief

Risk Assessment Branch III Health Effects Division (7509P) **To:** Laura Nollen , Risk Manager

Risk Integration Minor Use and Emergency Response Branch Division (7505P) This document provides an assessment of the human health risk resulting from the proposed and registered uses of linuron. The toxicology reevaluation was performed by Whang Phang, the drinking water assessment was conducted b y He Zh ong (EPA Environmental Fate and Effects Division (EFED)), the review of the residue chemistry data was conducted by

Nancy Tsaur, and the occupational, dietary , and human health risk assessments were cond ucted by Kristin Rury
.Linuron Human Health Risk Assessment DP No. D405828

Page 2 of 41 **Table of Contents 1.0**  **Executive Summary ................................**  **................................ ................................**  **........... 4**  **2.0 HED Recommendations**  **................................ ................................**  **................................ ....**  **6 2.1**  **Data Deficiencies**
................................ ................................ ................................ ............ 6 **2.2 Tolerance Considerations** 
................................ ................................ .............................. 7 **2.2.1 Enforcement Analytical Method** 
................................ ................................ ............... 7 **2.2.2 Recommended Tolerances** 
................................ ................................ ......................... 7 **2.2.3 Revisions to Petitioned**  **- For Tolerances** 
................................ ................................ .... 8 **2.2.4 International Harmonization** 
................................ ................................ ..................... 8 **2.3 Label Recommendations** 
................................ ................................ ................................ 8 **2.3.1 Recommendations from Residue Reviews** 
................................ ................................ 8 **2.3.2 Recommendations from Occupational Assessment** 
................................ ................. 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** 
................................ ................................ .... 12 **4.0 Hazard Characterization and Dose**  **- Response Assessment**  **................................ ..........**  **12 4.1**  **Toxicology Studies Available for Analysis**
................................ ................................ . 12 **4.2 Absorption, Distribution, Metabolism, % Elimination (ADME) Data** 
................... 13 **4.2.1 Dermal Absorption** 
................................ ................................ ................................ ... 13 **4.3 Toxicological Effects** 
................................ ................................ ................................ .... 13 **4.4 Safety Factor for Infants and Children (FQPA Safety Factor)** 
............................... 14 **4.4.1 Completeness of the Toxicology Database** 
................................ .............................. 14 **4.4.2 Evidence of Neurotoxicity** 
................................ ................................ ........................ 15 **4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young**  **Animal**
........ 15 **4.4.4 Residual Uncertainty in the Exposure Database** 
................................ ................... 15 **4.5 Toxicity Endpoint and Point of Departure Selections** 
................................ .............. 16 **4.6 Cancer Classification** 
................................ ................................ ................................ ... 17 **5.0 Dietary Exposure and Risk Assessment**  **................................ ................................**  **......... 18**  **5.1 Residues of Concern Summary and Rationale** 
................................ .......................... 18 **5.2 Food Residue Profile** 
................................ ................................ ................................ .... 19 **5.3 Water Residue Profile** 
................................ ................................ ................................ .. 20 **5. 4.1**  **Description of Residue Data Used in Dietary Assessment**
................................ .... 21 **5.4.2 Percent Crop Treated Used in Dietary Assessment** 
................................ .............. 21 **5.4.3 Acute Dietary Risk Assessment** 
................................ ................................ ............... 21 **5.4.4 Chronic Dietary Risk Assessment** 
................................ ................................ ........... 22 **5.4.5 Cancer Dietary Risk Assessment** 
................................ ................................ ............. 22 **5.4.6 Summary Table** 
................................ ................................ ................................ ......... 22 **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  **............................. 23**  **6.1 Residential Bystander Post**  **- application Inhalation Exposure** 
................................ . 23 **6.2 Spray Drift** 
................................ ................................ ................................ .................... 23 **7.0 Aggregate Exposure/Risk Characterization**  **................................ ................................**  **.. 24**  **8.0 Cumulative Exposure/Risk Characterization**  **................................ ...............................**  **24 9.0**  **Occupational Exposure/Risk Characterization ................................**  **............................ 24** Linuron Human Health Risk Assessment DP No. D405828

Page 3 of 41 **9.1 Short** **- Term Handler Risk** 
................................ ................................ ........................... 24 **9.2 Short** **- Term Post**  **- Application Risk** 
................................ ................................ ............. 30 **9.2.1 Dermal Post**  **- Application Risk** 
................................ ................................ ................. 30 **9.2.2 Inhalation Post** **- Application Risk** 
................................ ................................ ............ 31 **10.0 References**  **................................ ................................**  **................................ .........................**  **31 Appendix A. References for Published Toxicity Studies and Toxicology Profile**  **................ 33**  **Appendix B. Physical/Chemical Properties ................................**  **................................ .............**  **40 Appendix C. Review of Human Resea**  **rch ................................**  **................................ ...............**  **41**Linuron Human Health Risk Assessment DP No. D405828

Page 4 of 41 **1.0 Executive Summary**  Introduction Linuron is a selective phenylurea herbicide used to control broadleaf weeds and annual grasses by s ys temicall y inhibiting photos ynthesis. It may be applied pre
- plant, pre
- emergence, post emergence or post - transplant to various field crops and noncrop area s. The Interregional Research Project No. 4 (IR
- 4) submitted a petition (PP# 2E8083) to allow linuron use on coriander (fresh and seed), dill, horseradish, parsley , and dry pea. The proposed uses will be added to the technical product labels (Linuron Technical, EPA Reg. No. 61842
- 22; and Linuron Flake Technical, EPA Reg. No. 61842
- 24) and to the formulated end use product label (Lorox DF ® , EPA Reg. No. 61842
- 23). HED previously evaluated the occupational exposure risk from linuron use on rhubarb and celeriac during tolerance reassessment (S. Recore, D281845, 03/27/2002) and the se uses are also included in the currently proposed label. HED has reevaluated the exposure risk from linuron use on rhubarb and celeriac using current occupational exposure polici es and inputs. Concomitant with this IR
- 4 petition, additional analy tical method data have been submitted by Tessenderlo Kerley

to support the newl y proposed uses. A new enforcement method for plant and livestock commodities was previously required as conditional data ( K. Rury , DP 375451 , 04/01/2010 ). A high performance liquid chromatography /tandem mass spectrometry ( HPL C/MS/MS) method based on extraction of residues and identification of parent and specific metabolites has been submitted. A method was also submitted that hydrolyzes commodities with base to transform the total linuron residue to 3,4
- dichloroaniline ( 3,4
- DCA ) . Gas chromatography with mass spectrometry detection ( GC/MS) is used to quantitate the 3,4
- DCA. Independent laboratory

validati on of the latter method has been provided. In reviewing these data, HED has determined that the continued use of a common moiety definition ( 3,4
- DCA) is appropriate, and that the validated GC/MS method for 3,4
- DCA will be adequate for tolerance enforcement purposes. Thus, the requirement for additional enforcement analy tical methods is fulfilled. Use Profile Lorox DF ® is a water dispersible granular (WDG) formulation containing 50% linuron by weight. Lorox DF ® may

be applied both before and af ter weed emergence and usually earl y in the crop growing season. The maximum single application rates are as follows: 2.0 lb product/A (1.0 lb ai/A) for coriander and dill; 3.0 lb product/A (1.5 lb ai/A) for celeriac, rhubarb, horseradish, and parsley ; an d 2.0 lb product/A (1.0 lb ai/A) for dry peas and parsley

grown for seed in Oregon and Washington. The maximum seasonal application rates are as follows: 4.0 lb product/A for coriander and dill; 3.0 lb product/A for parsley, celeriac, rhubarb, and horseradish, and 2.0 lb product/A for dry pea and parsley

grown for seed in Oregon and Washington. Hazard Assessment With repeated dosing in test animals, linuron produces two primary effects: ( 1) changes in the hematopoetic s ys tem in rats, mice, and dogs; and (2) changes in the male reproductive s ys tem in developing rats. Linuron exhibits low acute toxicity via the oral (Toxicity

Category III), dermal (Toxicity Category III), and inhalation (Toxicity Category IV) routes of exposure. Li nuron is aLinuron Human Health Risk Assessment DP No. D405828

Page 5 of 41 minimal eye irritant (Toxicity Category I II), not a dermal irritant (Toxicity Category IV), and is not a dermal sensitizer. The HED Hazard and Science Policy Council (HASPOC) recentl y waived the requirement for a 28
- day inhalation toxicity

study , a 21
- day

dermal toxi city

study , and a subchronic neurotoxicity study (TXR#0056666 , TXR#0056436 and TXR#0056667). Based on the available hazard and exposure data, the Food Quality Protection Act (FQPA) safety factor is reduced to 1X for all population subgroups and exposure s cenarios. The level of concern (LOC) for non
- cancer occupational risk assessment is a margin of exposure ( MOE ) of 100 (i.e. an MOE < 100 is of concern). Linuron was classified as a Group C Carcinogen requiring no quantification of human cancer risk . Grou p C carcinogen classification is comparable to the current classification of “Suggestive Evidence of Carcinogenic Potential”. Residential Exposure There are no registered or proposed uses of linuron in residential settings
. Dietary Exposure The acute and chronic dietary (food and drinking water) exposure assessment for linuron assumed recommended tolerance
- level residues for all food commodities, assumed that all of the proposed and registered crops were treated in the acute assessment (100% crop treated; %CT), incorporated estimated percent crop treated (%CT) values in the chronic assessment , and used default processing factors. Estimated drinking water concentrations (EDWCs) from EFED were also included. The results of the acute anal ys is indicate that the acute dietary (food and drinking water) exposure and risk does not exceed HED’s LOC [i.e., <100% acute population adjusted dose (aPAD)] for the general U.S. population , and all population subgroups, including females 13
- 49 ye ars old. At the 95 th percentile of exposure, the resulting acute dietary (food and drinking water) risk estimates utilized 4.3% of the aPAD for the general U.S. population and 10% for all infants, the most highly

exposed population subgroup. At the 95 th percentile of exposure, the resulting acute dietary

(food and drinking water) risk estimate utilized 5.7% of the aPAD for females 13
- 49 years old
. The results of the chronic anal ys is indicate that chronic dietary (food and drinking water) exposure and risk does not e xceed HED’s LOC [i.e., <100% chronic population adjusted dose (cPAD)] for the U.S. population and all population subgroups. The resulting chronic dietary (food and drinking water) risk estimates utilized 22% of the cPAD for the general U.S. population and utilized 60 % of the cPAD for children 1
- 2 years old , the most highly exposed population subgroup. Aggregate Exposure There are no registered or proposed residential uses of linuron; therefore aggregate exposure is equivalent to dietary

(food + drinking water) exposure. Occupational Exposure There is potential for short
- term occupational exposure to linuron during handling activities (e.g. mixing, loading, application) and during post
- application activities
. There are some risk estimates of concern for the proposed uses of linuron at baseline (no personal protective equipment; PPE), and with the label
- specified PPE (coveralls/double layer and chemical resistant gloves). Mixing/loading for chemigation application to parsley , horseradish, celeriac, rhubarb,Linuron Human Health Risk Assessment DP No. D405828

Page 6 of 41 dry pea, coriander, and dill required engineering control mitigation to be not of concern to HED (MOEs >100). Based on the results of the occupational exposure assessment, HED recommends that engineering controls (e.g., a closed mixing/loading s ys tem) be required on the L orox DF ® label for mixing/loading for chemigation application to the proposed crops , or that the label restricts chemigation application
. Some occupational short
- term post - application risk estim ates were of concern on the day of application. In order for MOEs to be greater than the LOC at the maximum single application rate, hand
- set irrigation should occur 4 day s after application for parsley , dill, coriander and 8 day s after application for ce leriac. Since there were risk estimates of concern related to hand
- set irrigation both on day

0 after application and at the label
- specified restricted entry interval ( REI), HED recommends that the REI on the proposed label (12 hours) be revised to addres s those concerns. 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 data base; and the ARTF database; are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review b y the Human Studies Review Board. For citations of these data, see Appendix C. Environmental Justice Considerations Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U. S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pd f
. **2.0 HED**  **Recommendations** HED has examined the residue chemistry , toxicity , and exposure database s for linuron and concluded that, provided a revised label and a revised Section F are submitted , there are no deficiencies that would preclude granting Section 3 registration for the requested crop commodity

uses of linuron , or establishment of tolerances for residues of linuron
. The specific tolerance recommendations are discussed in Section 2.1.2. **2.1 Data Deficiencies**  Dislodgeable Foliar Residue (DFR) (158.1070) In accordance with the updated Part 158 data requirements (2007), one or more DF R studies are required when a pesticide has residential or occupational uses that could result in post
application dermal exposure. As part of the recent revision to the Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment, HED anal yz ed a number of DFR studies and selected a new default value for the frac tion of the application rate available to be dislodged after a foliar application (F AR). This default value is 25 % and is based on an anal ys is of 19 DFR studies where the F AR value ranged from 2% to 89%. This value isLinuron Human Health Risk Assessment DP No. D405828

Page 7 of 41 recommended for use in both residential and occupational post
- application assessments. Of the anal yz ed DF R studies, the maximum F AR value seen was 89% or 3.6 times higher than the default residue transfer value. Therefore, the HED has decided that a calculated MOE of approximately 4 times higher than the level of concern (e.g., an MOE > 400 if the LOC = 100) using the default dislodged residue values would provide an adequate margin of safety for any potentially

higher residues seen in a chemical
- specific DFR study ( Guidance for Req uiring/W

aiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) Studies
. 0 6/ 0 7/2012, Exposure Science Advisory Council). A DFR study is required for linuron at this time since some of the dermal MOEs are less than 4 times the L OC bas ed on default values for the fraction of application rate available for transfer after a foliar application. A previously

submitted study

evaluating residues on asparagus spears is not adequate to support the proposed and registered uses of linuron. **2.2 Tolerance Considerations**  **2.2.1 Enforcement Analytical Method**  Various adequatel y validated anal ytical methods are now available for linuron. For linuron residues of concern in plant commodities, Method ABC
- 68406
- M is available and suitable for residue co llection as well as enforcement of tolerances. This method involves reflux of c rop samples in strong base to hydrol yz e residues of linuron and its metabolites to 3,4
- DCA, which is anal yz ed using G C/MS . Based on the lowest level of method validation (LLMV) from the independent laboratory validation (ILV) study , the validated limit of quantification LOQ is 0.01 ppm for linuron and its metabolites hydrol yz able to 3,4
- DCA. In addition, Method ABC
65790 (L C/MS/MS) may be used as a confirmatory method . It is a multi
- residue method that is suitable for screening for enforcement of tolerances for linuron residues in plant commodities. This m ethod separatel y determines residues of linuron and metabolites 3
- (3,4
- dichlorophenyl )
- 1
- methylurea (DCPMU), N
- (3,4
- dichlorophenyl)urea (DCPU) , and desmethyl linuron in crop commodities. For linuron residues of concern in livestock commodities, Method ABC
- 67638
- M (GC/MS) is available and suitable for residue collection as well as enforcement of tolerances. Like the plant m ethod, linuron and its metabolites are hydrol yz ed to 3,4
- DCA using strong base and then anal yz ed by

GC/MS. **2.2. 2**  **Recommended Tolerances** In addition to the recommended tolerances listed below in Table 2.2.2, the tolerance with regional registration under 40 CFR §180.184(c) for parsley, leaves (0.25 ppm) should be deleted. **Table 2.2.2**  **. Tolerance Summary for Linuron**  **.** Commodity Established/Proposed

Tolerance (ppm) HED
- Recommended Tolerance (ppm) Comments

( correct commodity definition ) Cilantro, fresh leaves 3.0 1.5 Cilantro, dried leaves 27 10 Coriander, seed 0.01 0.05Linuron Human Health Risk Assessment DP No. D405828

Page 8 of 41 **Table 2.2.2**  **. Tolerance Summary for Linuron**  **.** Commodity Established/Proposed

Tolerance (ppm) HED
- Recommended Tolerance (ppm) Comments

( correct commodity definition ) Dillweed, fresh leaves 1.5 0.6 Dillweed, dried leaves 7.1 3.0 Dill, seed 0.3 0.5 Dill, oil 4.8 2.0 Horseradish 0.05 0.05 Parsley, leaves 3.0 4.0 Parsley, dried leaves 8.3 3.0 Pea, dry, seed 0.08 0.06 **Note to RD:** the tolerances of meat b yproducts of cattle, goat, pork, and sheep should be updated to 2.0 ppm, instead of the current tolerance of 0.1 ppm. **2.2. 3**  **Revisions to Petitioned -**  **For Tolerances** The revisions to the petitioned
- for tolerances are described below. The Organization for Economic Cooperation and Development (OECD) tolerance calculation procedures were used to calculate the tolerance levels for the following three commodities: cilantro , fresh leaves; dillweed, fresh leaves; and pea, dry , seed. Based on the OECD calculations, all three tolerance levels should be decreased. Instead of using the OECD calculator due to a limited number of field trials, the formula of 5X the mean was used to establish tolerance levels for the following three commodities: coriander, seed; dill, seed; and parsley , leaves. Based on this calculatio n method, all three proposed tolerance levels should be increased. For the dried herbs (cilantro, dillweed, and parsley) and the dill oil, the formula of the highest average field trial (HAFT) multiplied by the concentration factor was used to calculate the recommended tolerance levels (the concentration factors were derived from dividing the average dried/oil commodity

residue by

the average fresh commodity residue). Based on this calculation method, all four tolerance levels should be decreased. **2.2. 4**  **International Harmonization** There are no established maximum residue limits (MRL s) for linuron in Codex for any agricultural commodity . Furthermore, no Canadian or Mexican MRL s have been established for linuron. Therefore, there are no harmonization issues. **2.3 Label Recommendations**  **2.3.1 Recommendations from Residue Reviews**  Since there are livestock feed items associated with field pea, the following restriction should be added to the label: “Do not apply to field pea used for livestock feed.”Linuron Human Health Risk Assessment DP No. D405828

Page 9 of 41 **2.3. 2**  **Recommendations from Occupational Assessment**  HED recommends that engineering controls (e.g., a closed mixing loading sy stem) be required on the L orox DF ® label for mixing/loading for chemigation application to the proposed crops , or that chemigation is restricted from the proposed label . In addition, there were risk estimates of concern related to hand
- set irrigation both on day 0 after application and at the label
- specified REI ; therefore, HED is recommending that the REIbe revised on the label to address those concerns. In order for MOEs to be greater than the LOC at the maximum single application rate, the REIfor hand
- set irrigation should be 4 day s for parsley , dill, and coriander, and 8 day s for celeriac. **3.0 In**  **troduction 3.1**  **Chemical Identity Table 3.1. Linuron Nomenclature.** 

Com pound

Common name Linuron Com pany experimental name DPX
- Z0326 IUPAC name 3
- (3,4
- dichlorophenyl)
- 1
- me thoxy
- 1
- methylurea CAS name N‘
- (3,4
- dichlorophenyl)
-N
- methoxy
-N

- methylurea CAS # 330
- 55
- 2 End
- use product/EP Metabolite

Common name DCPMU Chemical name 3
- (3,4
- dichlorophenyl)
- 1
- me thylurea Metabolite

Common name DCPU Chemical name N
- (3,4
- dichlorophenyl)urea

N H Cl
Cl O N O C H3 C H3

N

H Cl
Cl O N H C H3

N H Cl
Cl O N H 2Linuron Human Health Risk Assessment DP No. D405828

Page 10 of 41 **Table 3.1. Linuron Nomenclature.** Metabolite

Common name Desmethyl linuron Chemical name N
- (3,4
- dichlorophenyl)
-N‘
- methoxyurea **3.2 Physical/Chemical Characteristics**  Linuron is an off

- white powder with a molecular weight of 249.1 g/mol , which indicates that the potential to cross biological barriers, such as the skin, is somewhat limited. Furthermore, the low log of the octanol/water partition coefficient (log P ow = 2.76 at 25  C ) suggests low potential for dermal absorption; the relatively low water solubility

and low lipophilic potential, indicate that linuron is not likely

to bioaccumulate. The vapor pressure for linuron is low (3.01× 10 - 7 mm Hg at 25  C ), and linuron is considered relatively insoluble in water. The Henry’s Law con stant was calculated to be 1.97× 10 - 9 atm· m 3 /mol
. Thus, linuron is unlikely to volatilize significantl y, and inhalation via chemical vaporization is unlikely
. Linuron is moderatel y persistent with an aerobic soil metabolism half
- life ranging from 57 to 100 day s. Because parent linuron is sufficiently persistent and may

be mobile under certain enviro nmental conditions, it has the potential to impact ground water quality. **3.3 Pesticide Use Pattern**  IR
- 4 is proposing new uses for the 50% DF formulation L orox® DF (EPA Reg. No. 61842
- 23). The use directions are summarized below in Table 3.3. **Table 3.3. Summ**  **ary of Proposed Directions for Use of Linuron (Lorox® DF, EPA Reg. No. 61842 -**  **23). Application,**  **Type, and Equipment**  **App Rate**

**(lb ai/A) Timing**  **Max No.**

**App per Season**  **Max.**

**Seasonal App Rate**  **(lb ai/A) PHI** 

**(days) Product Use Directions and**  **Limitations Coriander**  **(Cilantro)**
Broadcast Ground, Chemigation 0.5
- 1.0

preemergence 1 2.0 East of Rocky Mtns 1.5 West of Rocky Mtns 21 Do not apply by air. Do not apply to sand or loamy

sand soil types to avoid crop injury. Do not use on soils with less than 1% organic matter to avoid crop injury. Do not exceed 4 lbs. LOROX® DF per acre per year East of Rocky Mountains. Do not exceed 3 lbs. LOROX® DF per acre per year West of Rocky Mountains. Additional applications allowed, but do not exceed maximum rate. Do not apply within 155 days of harvest for seed. 0.5
- 1.0 postemergence 2
**Dill** N H Cl
Cl O N H O C H3Linuron Human Health Risk Assessment DP No. D405828

Page 11 of 41 **Table 3.3. Summ**  **ary of Proposed Directions for Use of Linuron (Lorox® DF, EPA Reg. No. 61842 -**  **23). Application,**  **Type, and Equipment**  **App Rate**

**(lb ai/A) Timing**  **Max No.**

**App per Season**  **Max.**

**Seasonal App Rate**  **(lb ai/A) PHI** 

**(days) Product Use Directions and**  **Limitations**

Broadcast Ground, Chemigation 1.0

preemergence 1 2.0 East of Rocky Mtns 1.5 West of Rocky Mtns 21 Do not apply by air. Do not apply to sand or loamy

sand soil types to avoid crop injury. Do not use on soils with less than 1% organic matter to avoid crop injury. Do not exceed 4 lbs. LOROX® DF per acre per year East of Rocky Mountains. Do not exceed 3 lbs. LOROX® DF per acre per year West of Rocky Mo untains. Additional applications allowed, but do not exceed maximum rate. 0.5
- 1.0 postemergence 2 **Parsley** Broadcast Ground, Chemigation 0.5
- 1.5

preemergence 1 1.5 30 Do not apply by air. Apply after planting, but before the crop emerges. Do not exceed a total of 3 lbs. of LOROX® DF per acre per season. Use lower rates on coarse soils and higher rates on heavier soils. 0.5 postemergence 1 0.5

**Parsley Grown for Seed (Oregon and Washington Only)** Broadcast Ground, Chemigation 0.5
- 1.0

preemergence 2 2.0 NA Do not apply by air. For best results apply preemergence to weeds or early postemergence while weeds are small. Wait at least 21 days between applications. Do not make more than two applications in the first growing season and do not make more than two applications in the second growing season. **Pea (Dry)** Broadcast Ground, Chemigation 1.0

preemergence 1 1.0 NA Do not apply by air. Do not apply to sand or loamy sand soil types. Do not u se on soils with less than 1% organic matter. Apply post planting but preemergence to the crop. Use lower rates on coarse soils and higher rates on heavier soils. **Horseradish** Broadcast Ground, Chemigation 1.5

preemergence 1 1.5 NA Do not apply by air. Apply after planting or during dormancy , but before the leaves emerge in spring. Use lower rates on lighter soils and higher rates on heavier soils. **3.4 Anticipated Exposure Pathways**  Humans may

be exposed to linuron in food and drinking water, since linuron may be applied as a spray over growing crops and these applications may result in linuron reaching surface and ground water. There are no registered residential uses of linuron , so exposure to residential handlers and those entering treated residential areas following application is not expected. In occupational settings, applicators may be exposed while handling linuron. There is also potential for post
- application exposure for workers re
- entering treated fields. Risk assessments have been completed for existing uses of linuron. This risk assessment considers all of the aforementioned exposure pathway s based on the proposed new uses of linuron, but also considers existing uses of linuron, particularl y in the dietary exposure assessment.Linuron Human Health Risk Assessment DP No. D405828

Page 12 of 41 **3.5 Consid**  **eration of Environmental Justice** Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf
. As a part of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well
- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the United States Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey (NHANES), What We Eat in America (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age and ethnic group. Additionally , OPP is able to assess dietary e xposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non
- dietary exposures based on home use of pesticide products and associated risks for adult applicators and f or toddlers, youths, and adults entering or playing on treated areas following application are evaluated. Further considerations are currentl y in development as OPP has committed resources and expertise to the development of specialized software and model s that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. **4.0 Hazard Characterization and Dose**  **- Response Assessment**  Since the last linuron risk assessment (D. Davis, D348519, 04 /17/2008) an acute neurotoxicity study and an immunotoxicity study have been submitted to the Agency
. Additionally, the HED HASPOC waived the requirement for the subchronic neurotoxicity, subchronic dermal toxicity, and subchronic inhalation toxicity studies (TXR#0056667, TXR#0056666, and TXR#0056436)
. With the submission of the acute neurotoxicity study , the toxicity

database of linuron has been reevaluated, and an acute dietary endpoint for the g eneral U.S. population has been established
. **4.1 Toxicol**  **ogy Studies Available for Analysis** The toxicological database for linuron is considered complete and the data requirements are satisfied
. The toxicology database includes a 14
- day inhalation study , 1
- ye ar and 2
- ye ar oral toxicity studies in dogs, chronic/carcinogenicity study in rats, a carcinogenicity study in mice, developmental toxicity

studies in rats and rabbits, 2
- generation and 3
- generation reproduction studies in rats, metabolism studies in rats, a dermal penetration study in rats, an acute neurotoxicity

study in rats, an immunotoxicity study in rats, a genotoxicity

battery , and many published studies, which evaluate the androgenic effects and L eydig cell tumorigenesis produced by linuron (see Appendix A for l i terature references and the linuron toxicology p rofile). Waivers were granted for the required subchronic dermal and inhalation studies and the subchronic neurotoxicity

study
.Linuron Human Health Risk Assessment DP No. D405828

Page 13 of 41 **4.2 Absorption, Distribution, Metabolism, % Elimination (ADME) Data**  With oral administration, linuron was extensively absorbed from the gastrointestinal ( GI) tract , metabolized, and eliminated. Total recovery was 96.1% of the administered dose in males and 97.3% in females. In males and females, radioactivity remaining in the ti ssues and carcass represented <1% of the administered dose. The liver had the highest level s of radioactivity
. The b iological half

- life (t 1/2 ) of linuron differed between the low and high dose s and between genders, ranging from 21 hours in low dose males to 56 hours in high dose females. The major route of elimination was via the urine (>80% of the radioactivity); fecal elimination accounted for approximately

15% of the administered dose. The major metabolites are hydroxy
- norlinuron and norlinuron. The data also demonstrated that linuron exposure resulted in the induction of mixed
- function oxidative enzy mes. **4.2.1 Dermal Absorption**  A dermal absorption factor (normalized over 8
- 10 hours) of 16% was applied to the dermal exposure assessments. **4.3 Toxicological Effects**  With repeated dosing in test animals, linuron produces two primary effects: (1) changes in the hematopoetic s ys tem in rats, mice, and dogs and; (2) changes in the male repro ductive s ys tem in developing rats. Lowest observed adverse effect levels (LOAEL s) for hematological effects produced b y linuron were substantially lower ( 40
- fold lower) than LOAELs for reproductive effects. D ogs were shown to be most sensitive to the he matological effects , including h emoly tic anemia characterized b y slightly reduced hemoglobin, hematocrit, and ery throcy te counts accompanied b y hemosiderin deposition in liver Kupffer cells. Secondary ery thropogenic activity (ery throid hy perplasia of bone marrow) was also found. Systemic toxicity observed in mice included increased methemoglobin formation, vacuolation and hemosiderosis of the spleen, and decreased ery

throcy te counts. In the c hronic rat study , microscopic observations consistent with hemo ly sis (hemosiderin in Kupffer cells and increased hemosiderosis in bone marrow, spleen, and/or mesenteric ly mph nodes) were found. The rat d evelopmental study showed increased post
- implantation loss, fetal resorptions, decreased litter size, and decreased fetal body weight. In the rabbit developmental toxicity study , an increased incidence of fetuses with skeletal skull variations was found. In the reproductive toxicity

study , rats exposed to linuron during both development and adulthood had gross lesion s of the testes (including reduction in size); abnormally soft and small epididy

mides; deformities of the epididy mides; decreased pup survival; decreased weanling body weights; decreased liver and kidney weights; and increased incidence of the liver atrophy in the offspring. The developmental effects on the reproductive sy stem seen in the guideline studies are consistent with those reported in the published literature. The available data indicate that linuron inhibits transcriptional activity of dihydrotestosterone (DHT), human androgen receptor (hAR) in vitro , and steroidogenic enzy

mes. Additional findings indicate linuron exposure decreases anogenital distance; may

increase retention of areole/nipples in male rat of fspring following in uteroLinuron Human Health Risk Assessment DP No. D405828

Page 14 of 41 exposure; increase luteinizing hormone ( LH ) levels in F 0 and F 1 male rats; reduces the size of androgen dependent tissues such as seminal vesicles, epididymis , and ventral prostate; and demonstrates a weak affinity for androgen receptors which may decrease fetal testosterone sy nthesis ( Gray , et al., 1999; Hotchkiss, et al., 2004; L ambright, et al., 2000; McIntyr e, et al, 2000). Itshould be noted that most of the literature studies employed dose level s of 100 mg/kg or greater . At this time, linuron has not been demonstrated to be an estrogen receptor antagonist (Vinggaard, et al., 1999). Itshould be emphasized that the toxicity endpoints based on the hematological effects for chronic exposure s were derived from the chronic ( 1
- year) dog oral toxicity study
. The point of departure (POD) for hematological effects was approximately 40
- fold lower than the LOAELthat caused the testicular e ffects seen in the rat reproduction toxicity study
. In rat and mouse carcinogenicity studie s, linuron induced interstitial cell adenomas in the testes of rats and hepatocellular adenomas in mice. In a special study with aged rats, linuron induced hy perplasia and adenomas of the testes within 6 to 12 months. However, linuron was not mutagenic in bacteria or in cultured mammalian cells. There was also no indication of a clastogenic effect up to toxic doses in vivo . Linuron was classified as a Group C carcinogen b y both the Cancer Assessment Review Committee (CARC) , the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA ) Science Advisory Panel (SAP) , and the Hazard Identification Assessment Review Committee ( HIARC Report, TXR#0050284, 11/20/2001) . This is equivalent to the current classification of “Suggestive Evidence of Carcinogenic Potential ”
. No quantification of human cancer is recommended. The acute neurotoxicity

study demonstrated that at 500 mg/kg, linuron produced many changes in the parameters of the field observation battery (FOB) ; these changes included rats holding their head s low, crusty

deposits on the nose, impaired mobility, ataxia, low arousal, decreased rearing, no reaction to tail pinch or startle, decreased righting reflex, reduced or no hindlimb extensor strength, decreased grip strength in both hindlimbs and fore limbs, reduced rotarod performance, decreased hindlimb footsplay, and increased cataleps y. At 100 mg/kg, linuron produced decreases in motor activity and rearing
. No effect s were seen at 20 mg/kg (no observed adverse effect level; NOAEL)
. However, no comp ound
- related changes in neurohistopathology

were observed at any of the tested dose levels
. In addition, linuron did not show any immunotoxicity in the submitted immunotoxicity study up to the highest dose tested (1000 ppm or 92 mg/kg/day)
. **4. 4**  **Safety F**  **actor for Infants and Children (FQPA Safety Factor)** HED has examined the currentl y available information on linuron and determined that the linuron database is adequate for assessing susceptibility of the young to linuron exposure. HED has determ in ed that the linuron FQPA factor is reduced to 1 X for the following reasons: **4. 4**  **.1 Completeness**  **o f**  **the Toxicology Database**  Linuron toxicity

database is robust and the study requirements are satisfied
. The toxicology database used to assess pre
- and po st - natal exposure to linuron is considered adequate. The following acceptable studies are available to support this determination: a rat developmentalLinuron Human Health Risk Assessment DP No. D405828

Page 15 of 41 toxicity study , a rabbit developmental toxicity study , a 3
- generation rat reproductive toxicity study , and a 2
- generation rat reproductive toxicity study . In addition, the database includes an acute neurotoxicity

study, and an immunotoxicity study
. **4. 4**  **.2 Evidence of N**  **eurotoxicity** In an acute oral toxicity

study , FOB findings of impaired mobility , alter ations in gait, lack of coordination, lowered body temperature, no reaction to stimuli, low arousal, and decreases in motor activity

were seen at the time of peak effect (7 hours post dosing) on study day 0. These observations were mostly seen in the 500 mg/kg group ; and no pathological changes were found in nervous sy stem tissues
. A clear NOAEL (20 mg/kg/day) was established, and this NOAEL was approximately

2
- 26X greater than most of the PODs selected for risk assessment. The nervous s ys tem was not a target organ for linuron. Therefore, the concern for neurotoxicity is low. **4. 4**  **.3 Evidence**  **o f Sensitivity/Su**  **sceptibility in the Developing o r Young Animal**  There is no qualitative/quantitative evidence of increased susceptibility of rabbit developmental study ; developmental effects wer e seen at a dose higher than those causing maternal toxicity . In the rat developmental study , increases in post
- implantation losses and increases in fetal resorptions/litter were seen at a dose that caused decreases in mate rnal body weight and food consumption. S ince increases in resorptions were marginal and there was no change in the number of live fetuses to corroborate the increases in post
- implantation losses , these effects were not indicative of qualitative evidence of susceptibility (HIARC report, 11/20/2001)
. There was no quantitative evidence of susceptibility either in the 2
- generation or the 3
- generation reproduction studies. In the 2
- generation study , reduced body weight gains of pups were seen at the same dos e that caused decreases in parental body weights. In the 3
- generation study , offspring effects (deceased pup survival and pup body weight) were seen a dose (44 mg/kg/day) higher than the dose that caused decreases in body weight gain in the parental animals (9 mg/kg/day). However, when the reproductive effects were examined, testicular atrophy was seen at the same dose (625 ppm, 45 mg/kg/day) in both studies. In both studies, while the F0 males were not affected, testicular lesions and reduced fertility were seen in the F1 males. This effect in the F1 males is an indication of qualitative evidence of susceptibility
. A clear NOAEL was established for the effects on the reproductive system. At this time, the PODs for risk assessment are protective of the effects seen on the male reproductive sy stem . Therefore, a FQPA safety factor could be reduced to 1X. **4. 4**  **.4 Residual**  **Uncertainty in the Exposure Datab ase**  There are no residual uncertainties in the linuron exposure database that would preclude granting the proposed uses of linuron. While some refinements were incorporated into the dietary exposure calculations, EPA is confident that the risk from exposure to linuron in food and drinking water will not be underestimated. The acute and chronic dietary (fo od) exposureLinuron Human Health Risk Assessment DP No. D405828

Page 16 of 41 assessment utilized conservative upper
- bound inputs including assuming tolerance
- level residues for all existing and proposed commodities and used %CT estimates when available (Screening Level Usage Anal ys is (SLUA), 04/10/2013). Although the acute and chronic assessments included minor refinements, the use of field trial and %CT estimates ensures that actual exposures/risks from residues in food will not be underestimated. The drinking water assessment utilized water concentration values gene rated b y m odels and associated modeling parameters which are designed to produce conservative, health protective, high
- end estimates of water concentrations which are not likely to be exceeded. The dietary (food and drinking water) exposure assessment doe s not underestimate the potential exposure for infants, children , or women of child bearing age. **4. 5**  **Toxicity Endpoint and Point of D**  **eparture Selections** The previousl y selected toxicity endpoints have been re
- evaluated in accordance with current policy
. The details for toxicity endpoint selection are presented in the HIARC report ( HIARC Report, TXR#0050284, 11/20/2001 ) and in the report : Summary of Toxicology Science Advisory Council Toxicology E
-R eview for Linuron (05/29/2013, internal memo)
. The toxicity endpoints and the PODs for risk assessment are presented below. Itshould be noted that since there were no guideline 28
- day

or 90
- day

oral toxicity

studies conducted with linuron , the HIARC evaluated all the effects in the available database seen over approximately 30 day s of treatment . The HIARC found that in the 2
- generation rat reproduction study, body weight was significantly decreased and considered adverse at 36 mg/kg/day (HIARC report, 11/20/2001) ; no effects were seen at dos es less than 5.8 mg/kg/day (NOAEL)
. Therefore, the body weight decrease around 30 day s at 36 mg/kg/day

could serve as the toxicity en dpoint for short
- term exposure. In addition at 36 mg/kg/day , testicular effects were also found in F1 test animals at the end of the study
. Therefore, 5.8 mg/kg/day was selected as the POD for short
- term dermal and inhalation risk assessment (LOAEL = 36 mg/kg/day). Furth ermore, the overall NOAEL/LOAEL for th e 2
- generation reproducti ve toxicity study as presented in App endix A is different from that seen 30 day s because the effect of body weight decrement was progressive with time; at the end of the study , this effect also occurred at the next lower dose level 5.8 mg/kg/day
. Therefore, the overall maternal and offsprin g NOAEL and LOAEL were 0.74 mg/kg/day and 5.8 mg/kg/day , respectivel y (see Toxicity Profile in Appendix A). **Table 4 .**  **5 .**  **Summ ary of Toxicological Doses and Endpoints for**  **Linuron for Use in Dietary and Occupational**  **Hum an Health Risk Assessments**  **. Exposure/**  **Scenario Point of** 

**Departure Uncertainty/FQPA** 

**Safety Factors RfD, PAD,** 

**Level of Concern for**  **Risk Assessment**  **Study and Toxicological Effects** Ac ute Dietary (General Population, including Infants and Children) NOAEL=

20 mg/kg/day UF A= 10 x

UF H= 10 x FQPA SF= 1 x Ac ute RfD =

0.2 mg/kg/day aPAD = 0.2 mg/kg/day Ac ute Neurotoxicity Study (Rat). LOAEL

= 100 mg/kg based on decreases in rearing and in motor activity.Linuron Human Health Risk Assessment DP No. D405828

Page 17 of 41 **Table 4 .**  **5 .**  **Summ ary of Toxicological Doses and Endpoints for**  **Linuron for Use in Dietary and Occupational**  **Hum an Health Risk Assessments**  **. Exposure/**  **Scenario Point of** 

**Departure Uncertainty/FQPA** 

**Safety Factors RfD, PAD,** 

**Level of Concern for**  **Risk Assessment**  **Study and Toxicological Effects** Ac ute Dietary (Females 13
- 49 years of age) NOAEL =

12 mg/kg/day UF A= 10 x

UF H= 10 x FQPA SF= 1 x Ac ute RfD =

0.12 mg/kg/day Rat Developmental Toxicity. LOAEL =

50 mg/kg/day based on increased post
im plantation loss and fetal/litter resorptions. Chronic Dietary (All Populations) NOAEL=

0.77 mg/kg/day UF A= 10 x

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

= 0.0077 mg/kg/day cPAD = 0.0077 mg/kg/day Chronic Oral Dog Study. LOAEL = 3.5

mg/kg/day based on hematological effects (increased met
- and sulf

- hemoglobin levels).

Dermal and Inhalation Short
- Term 1 ,2 (1
- 30 days) NOAEL=

5.8 mg/kg/day UF A= 10 x

UF H= 10 x FQPA SF= 1 x Occupational

LOC for MOE = 100 2
- Generation Rat Reproduction Study.

LOAEL = 36 mg/kg/day based on statistically and biologically significant decrease in premating body weights in F0 and F1 animals. Histopathological changes in the testes we re also seen at the end of the study in the F1 offspring. Cancer (oral, dermal, inhalation) Classification: Group C Carcinogen requiring no quantification of human cancer risk (HIARC

Report, TXR# 0050284, 11/20/2001). Group C carcinogen classification is equivalent to the current classification of “Suggestive Evidence of Carcinogenic Potential”. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose
- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (intraspecies). UF H = potential variation in sensitivity among members of the human population (interspecies). RfD = reference dose. 1 The dermal absorption factor of 16% (MRID No. 00163837) should be applied to extrapolate from the oral route to the dermal route. 2 Toxicity via the inhalation route is assumed to be equivalent to the oral route
. **4.6 Cancer Classification**  The linuron carcinogenicity data have been thoroughl y reviewed by the Agency
. There was a Sp ecial Review conducted by the Agency

Carcinogen Assessment Group (CAG), and subsequently , the decision of the CAG and carcinogenicity studies were reviewed by the SAP. The CAG and SAP both classified linuron as a Group C carcinogen ; the SAP recommended that no quantification of human cancer risk be conducted for linuron
. Later, the CARC re - evaluated the carcinogenicity data for linuron and concluded that linuron is classified as a Group C carcinogen (a possible human carcinogen for which there is limited animal evidence) and no quantification of human cancer risk is required (HIARC Report, TXR#0050284, 11/20/2001). A Group C carcinogen classification is equivalent to the current classification of “Suggestive Evidence of Carcinogenic Potential”.Linuron Human Health Risk Assessment DP No. D405828

Page 18 of 41 **5.0 Dietary Exposure and Risk Assessment**  **Reference s**  **:**

- Linuron
. Petition for the Establishment of Permanent Tolerances and Registration for Use on Coriander, Dill, Parsley, Pea (Dry), and Horseradish; and Submission of Residue Analytical Methods of Plants and Animal Matricies. Summary of Analytical Chemistry and Residue Data
. N
. Tsaur , D P#404359, DP#411652 , 08/ 14 /2013
.

- Linuron: Acute and Chronic Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section (3) Registration Action on Coriande r, Dill, Horseradish, Parsley, Celeriac, Rhubarb, and Dry Pea . K. Rury, DP#411650, 09 /04 /2013. **5.1 Residues of Concern Summary and Rationale**  The residue definitions for enforcement of tolerance and for risk assessment are identical, namely , linuron and metabolites convertible to 3,4
- DCA. The terminal residues of concern in plants and animals are linuron (parent) and metabolites convertible to 3,4
- DCA including DCPMU, DCPU, desmethyl linuron, and hydrox y- norlinuron. 3,4
- DCA is not of regulatory concern in connection with the registered use s of linuron due to the very low levels at which the chemical is detected in plants and animals (<0.01ppm). Metabolites convertible to 3,4
- DCA are not likely to be more toxic than the parent compound. Linuron can therefore , be regulated by using the enforcement anal ytical method in which known metabolites and unidentified polar components in plants and bound residues in animal tissues are hydrol yz ed to 3,4
- DCA. The total residue convertible to 3,4
- DCA will be compared to the reference dose for parent linuron for purposes of dietary risk assessment. The linuron drinking water exposure assessment is based upon review of environmental fate studies for parent linuron, modeling and monitoring results for parent linuron, and modeling results for the degradates of linuron based upon parent linuron model input parameters. Parent linuron appears to be moderatel y persistent and relatively immobile. Water degradates identified in the linuron aerobic soil metabolism study are desmethyl linuron, DCPMU, and DCPU. The degradate 3,4
- DCA was not included in the water assessment as it was not detected in the aerobic soil metabolism study (0.01 ppm detection limit). According to acceptable fate studies, 3,4
- DCA is formed under anaerobic aquatic conditions rarel y found in the environment and is not relevant to drinking water assessment. The environmental fate assessment for linuron is incomplete and tentative because information on the persistence, mobility and dissipation pathway s o f several degradates of linuron is not available. However, none of the linuron water degradates are present at levels greater than 10% of the applied parent, and therefore are not considered major water metabolites. As shown in Table 5.1, the degradates are included b y default (i.e. for risk assessment purposes, the residues included in the drinking water are linuron and metabolites convertible to 3,4
- DCA as the validated anal ytical method determin e s linuron and metabolites convertible to 3,4
- DCA).Linuron Human Health Risk Assessment DP No. D405828

Page 19 of 41 **5 .2**  **Food Residue**  **Profile** No n ew metabolism data were submitted to support this registration request. The qualitative nature of the residue in plants and animals is adequately understood. The residue data on coriander, dill, parsley , pea (dry), and horseradish are adequate for tolerance assessment and for use in dietary

risk assessment. Based on detectable residues found in forage/foliage of a few metabolism studies, linuron is assumed to have s ystemic activity in plants. Finite residues of linuron and/or its metabolites are anticipated on food and feed commodities, even from earl y season soil
- directed appli cations. Transfer to livestock commodities has been demonstrated, although the residue is primarily metabolites and unidentified polar components. Crop Field Trials All of the field trials were conducted according to the proposed label use directions in the appropriate representative geographical regions. Adjuvants were not used in any of the field trials. Residue decline studies were not conducted. The available residue data are acceptable and reflect the proposed use patterns provided in Section B. Furthermore, an acceptable method was used for residue quantitation and the data are supported by adequate storage stability data. The residue field trials are summarized in Table 5.2. **Table 5.2. Summ ary of Residues from Field Trials with Linuron.**  **Crop Matrix Analyte**  **b Applic. Rate**  **(lb ai/acre) PHI** 

**(days) n**  **Residues a,b**  **(ppm)**

**Min. Max.**  **HAFT Me**  **an SD**  **Coriander: Proposed Use = 2.0 lb ai/acre total application rate, 21 -**  **day PHI.** Fresh Leaves and Stems Linuron 1.997
- 2.118 19
- 21 8 0.08 1.14 1.055 0.65 0.4 Dried Leaves and Stems 19 1 8.5 NA NA NA Seed 155 2 <0.01 NA NA NA

**Dill: Proposed Use = 2.0 lb ai/acre total application rate, 21 -**  **day PHI.** Fresh Leaves and Stems Linuron 2.005
- 2.026 20
- 22 7 0.3 0.67 0.56 0.48 0.1 Dried Leaves and Stems 22 2 1.8 3.5 2.65 2.65 1.2 Seed 59
- 85 4 0.06 0.12 0.12 0.09 0.03 Oil 48 1 1.8 NA NA NA **Parsley: Proposed Use = 1.5 lb ai/acre total application rate, 30 -**  **day PHI.** Fresh Leaves and Stems Linuron 1.510 29
- 32 4 0.43 1.3 1.02 0.75 0.387 Dried Leaves and Stems 1.511 29 1 2.8 2.8 2.8 NA

**Pea (Dry): Proposed Use = 1.0 lb ai/acre total application rate, unspecified PHI.** Pea (Dry) 0.972
- 1.015 65
- 92 12 <0.01 0.052 0.051 0.014 0.018 **Horseradish: Proposed Use = 1.5 lb ai/acre total**  **application rate, unspecified PHI.** Roots Linuron 1.43

– 1.55 77
- 100 <0.05 NA NA NA aHAFT = highest average field trial. SD = Standard Deviation. For samples with no detectable residues (< 0.01 ppm) the LOQ value (0.01 ppm) was used to calculate the Mean and Standard Deviation. bResidues were converted to and measured as 3,4
- DCA. Values were converted to linuron equivalents. **T able**  **5.1 . Summ**  **ary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression**  **.** Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop linuron and metabolites convertible to 3,4
- DCA linuron and metabolites convertible to 3,4
- DCA Rotational Crop Livestock Ruminant

Poultry Drinking Water Not ApplicableLinuron Human Health Risk Assessment DP No. D405828

Page 20 of 41 Meat Milk Poultry and Eggs There are no feed items associated with this current petition. Cowpea commodities would affect the dietary

burden of cattle but since they are a bean rather than a pea, they are not included in the petition for dry

peas. Therefore , the previous livestock dietary intake calculations and resulting tolerance recommendations are not changed. However, since there are livestock feed items associated with field pea, the following restriction should be added to the label: “Do not apply to field pea used for live stock feed.” Processing Data Data on dill oil and dried coriander, dill, and parsley indicate that linuron residues concentrate after processing
. Storage Stability Data showed that linuron residues were stable in all matrices under frozen storage for the duration of the storage period. The storage stability data are adequate to support the storage intervals and conditions for the residue samples of coriander, dill, parsley , pea (dry), and horseradish from the field trials and processing studies
. **5.3 Water Residue Profile**  The drinking water residues used in the dietary risk assessment were provided by EFED in the following memorand

um : “ Revised Linuron Drinking Water Assessment for an IR
- 4 New Use on Coriander, Dill, Celeriac , Horseradish, Parsley , Dry Peas, and Rhubarb ” ( H. Zh ong , D 405829 , 06/25/2013 ) and incorporated directl y into this dietary assessment. Water residues were incorporated in the DEEM
- FCID into the food categories “water, direct, all sources” and “water, indirect, all sources.” EFED assumed a total toxic residue approach. EDWC s in surface water and in ground water (Table 5.3 ) were generated for the proposed agricultural uses of linuron. The calculated estimated drinking water concentrations (EDWCs) from Tier
- II Pesticide Root Zone Model/Exposure Analy sis Modeling S ys tem (PRZM
- EXAMS) and PRZM
- Ground Water (PRZM
- GW) supersede the previous upper bound EDWCs. The drinking water models and their descriptions are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/
.Linuron Human Health Risk Assessment DP No. D405828

Page 21 of 41 **Table 5.3**  **. Summary of Estimated Surface Water and Groundwater Concentrations**  **(EDWCs) for** 

**Linuron Used on**  **Coriander, Dill, Celeriac, Horseradish, Parsley, Dry Peas, and Rhubarb .**  Surface Water Conc., ppb a Groundwater Conc., ppb b Ac ute (non
- cancer, peak exposure) **89.05 48**  **. 8**  Chronic (non
- cancer, post -breakthrough average) 48.69 Chronic (cancer, long
- term mean) 30.81 a Pesticide Root Zone Model (PRZM v3.12.2, May 12, 2005) and Exposure Analysis Modeling System (EXAMS v2.98.04.06, April 25, 2005), simulation models, were coupled with the input PE5.pl.shell. The model does incorporate a degradation component
. b From the PRZM
- GW model. Bolded values are used in the dietary exposure assessment. **5.4 Dietary Risk Assessment**  **5.4.1 Description of Residue Data Used in Dietary Assessment**  HED used tolerance
- level residues for the proposed and registered crops and maximum or average %CT for the registered crops when available; therefore, this assessment is considered conservative
. D efault processing factors were used for dried potato, corn sy rup, and dried beef meat . Table 2.2.2 lists HED recommended tolerances for the prop o sed crops used in the dietary assessment. **5.4.2 Percent Crop Treated Used in Dietary Assessment**  A SLUA entitled, “Usage Report Package in Support of a Tolerance Petition for the Herbicide Linuron, BEAN DP# 410336” (J. Alsadek, 04/10/2013) was provided by the Biological and Economic Anal ys is Division ( BEAD )
. The acute dietary

anal ys is incorporated 100%CT for all registered and proposed commodities. The chronic dietary

analy sis incorporated average %CT data for asparagus (25%), carrots (85%), celery (25%), corn (1.0%), cotton (1.0%), potatoes (5.0%), sorghum (1.0%), soy beans (1.0%), sweet corn (1.0%), and wheat (1.0%) ; all other commodities were assumed to be 100%CT
. **5.4.3 Acute Dietary Risk Assessment**  The acute dietary

(food and drinking water) e xposure assessments for linuron were considered slightly refined; the assessments incorporated recommended and/or established tolerance level residues, and used d efault processing factors. Maximum %CT estimates for registered crops were also incorporated into the assessment. The EDWC from E FED (89.05 ppb) was also included. Because different toxicological PODs were selected for females 13
- 49 years old and for the general U.S. population, two separate dietary exposure anal ys es were conducted. The results of the acute anal ys e s indicate that the acute dietary (food and drinking water) exposure and risk estimates do not exceed HED’s LOC ( i.e., <100% aPAD ) for the general U.S. population , and all population subgroups, including females 13
- 49 ye ars old. At the 95 th percentile of exposure, the resulting acute dietary (food and drinking water) risk estimatesLinuron Human Health Risk Assessment DP No. D405828

Page 22 of 41 utilized 4.3% of the aPAD for the general U.S. population and 10% for all infants, the most highl y exposed population subgroup. At the 95 th percentile of exposure, the resulting acute dietary (food and drinking water) risk estimate utilized 5.7% of the aPAD for females 13
- 49 ye ars old
. **5.4.4 Chronic Dietary Risk Assessment**  The chronic dietary

(food and drinking water) exposure assessment for linuron was also considered slightly

refined; the assessment incorporated recommended and/or established tolerance
- level residues and used default processing factors. Average %CT estimates provided by BEAD were incorporated into the assessment for the existing uses , along with the EDWC from EFED (48.8 ppb). The results of the chronic anal ys is indicate that chronic dietary (food and drinking water) exposure and risk does not exceed HED’s LOC ( i.e., <100% cPAD) for the U.S. population and all population subgroups. The resulting chronic dietary (food and drinking water) risk estimates utilized 22% of the cPAD for the general U.S. population and utilized 60 % of the cPAD for children 1
- 2 years old , the most highl y exposed population subgroup. **5.4.5 Cancer Dietary Risk A**  **ssessment** Linuron is classified as a “Group C Carcinogen” and quantification of human cancer risk is not required. A Group C carcinogen classification is equivalent to the current classification of “Suggestive Evidence of Carcinogenic Potential”. **5.4.6 Summary Table**  **Table 5.4.6. Summary of Dietary (** **Food and Drinking Water) Exposure and Risk**  **Estimates for Linuron.** 
**Population Subgroup Acute Dietary**  **(9 5**  **th Percentile)**  **Chronic Dietary Dietary**  **Exposure (m**  **g/kg/day) % aPAD** * **Dietary Exposure**  **(m g/kg/day)**  **% cPAD** * General U.S. Population 0.008606 4.3 0.001690 22 All Infants (< 1 year old) **0.020671 10**  0.004298 56 Children 1
- 2 years old 0.016809 8.4 **0.004586 60**  Children 3
- 5 years old 0.013568 6.8 0.003114 40 Children 6
- 12 years old 0.008946 4.5 0.001981 26 Youth 13
- 19 years old 0.006172 3.1 0.001262 16 Adults 20
- 49 years old 0.006972 3.5 0.001466 19 Adults 50+ years old 0.006676 3.3 0.001463 19Linuron Human Health Risk Assessment DP No. D405828

Page 23 of 41 **Table 5.4.6. Summary of Dietary (** **Food and Drinking Water) Exposure and Risk**  **Estimates for Linuron.** 
**Population Subgroup Acute Dietary**  **(9 5**  **th Percentile)**  **Chronic Dietary Dietary**  **Exposure (m**  **g/kg/day) % aPAD** * **Dietary Exposure**  **(m g/kg/day)**  **% cPAD** * Females 13
- 49 years old 0.006864 5.7 0.001443 19 *T he values for the highest exposed population for each type of risk assessment are bolded
. **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  There are no existing or proposed residential uses of linuron. Therefore, residential handler and p ost - application assessments are not required. **6. 1**  **Residential Bystander Post**  **- application**  **Inhalation Exposure** Based on the Agency's current practices, a quantitative post
- application inhalation exposure assessment was not performed for linuron at this time primarily because of the low acute inhalation toxicity

(Toxicity Category IV). However, volatilization of pesticides may be a source of post
- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advic e and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 1 . The Agency is in the proces s of evaluating the SAP report and may , as appropriate, develop policies and procedures to identify the need for and, subsequently , the way to incorporate post
- application inhalation exposure into the Agency's risk assessments. If new policies or procedur es are developed, the Agency may revisit the need for a quantitative post
- application inhalation exposure assessment for linuron. **6. 2**  **Spray Drift** Spray drift is a potential source of exposure to those nearb y pesticide applications . This is particularl y the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application method s (e.g., groundboom and airblast) employed for linuron
. The Agency has been working with the Spray Drift Task Force ( a task force composed of various registrants which was developed as a result of a Data Call
- In issued by EPA) , EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency ’s Spray Drift website for more information)
. 2 The Agency is also taking means to qualitatively and qualitatively

address spray

drift as a potential source of exposure in risk assessments for pesticides through existing programs such as Ag Drift and chemical specific properties of

1 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html 2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmLinuron Human Health Risk Assessment DP No. D405828

Page 24 of 41 pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide wi ll be considered concurrently
. **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 a ggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED cons iders both the route and duration of exposure. Because linuron is not registered for use in residential areas, the dietary exposure assessments are equivalent to the aggregate exposure assessments. Refer to Section 5.0 for the dietary

exposure estimates. **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 linuron and any

other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that linuron has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released b y EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/
. **9.0 Occupational Exposure/Risk Characterization**  **Reference s**  **:**

- Linuron
. Occupational and Residential Exposure Assessment for Proposed Use on Coriander, Dill, Horseradish, Parsley, Celeriac, Rhubarb, and Pea (Dry). K. Rury, D P#405825 , 09 /04 /2013
. **9.1 Short** **- Term**  **Handler Risk** HED has evalu ated occupational exposure from the proposed uses of linuron. Application methods, maximum application rates, and use sites are summarized in Table 3.3. Aerial application is prohibited on the L orox DF ® label; however, linuron may be applied with chemigation, and ground equipment. Because linuron is an herbicide , and the proposed label specifies broadcast, banded, and over
- the
- row applications for the proposed crops , the use of handheld equipment is not expected and exposure from mixing/loading/applying using handheld equipment was not assessed. Based on the proposed and registered uses of linuron, only short
- term exposures are expected for the following reasons: ( 1) only up to 2 applications per season are allowed for the proposed uses of linuron; and ( 2) as an earl y season herbicide, applications occur for only a short period in the growing season, limiting the potential for continuous occupational exposure over a durationLinuron Human Health Risk Assessment DP No. D405828

Page 25 of 41 longer than 30 day s . The proposed label requires occupational mixer/loaders to wear long pants, long sleeved shirts, coveralls, chemical resistant gloves, shoes, socks, and a chemical resistant apron . Occupational applicators must wear coveralls, chemical resistant gloves, and chemical resistant footwear. HED’s LOC for the MOE is defined b y the uncertainty factors that are applied to the assessment. HED applies a 10X factor to account for variability among species and a 10X factor to account for variability within species. The total uncertainty factor that has been applied to the handler assessment of linuron is 100X for occupational exposure. Occupational exposure and risk resulting in MOEs greater than or equal to 100 will not be of concern to HED. Dermal and inhalation risk estim ates were combined in this assessment, since the toxicological effects for these exposure routes were similar. A summary

of the short
- term inhalation risks for occupational handlers applying linuron is provided in Table s 9. 1. 1 , 9.1.2, and 9.1.3
. There are some risk estimates of concern for the proposed uses of linuron at baseline (no PPE), and with the label
- specified PPE (coveralls/double layer and gloves). At baseline, all short
- term occupational handler combined (dermal + inhalation) MOEs ranged from 19 to 900. With coveralls and gloves, all short
- term occupational handler combined (dermal + inhalation) MOEs ranged from 56 to 4,900. Mixing/loading for chemigation application to parsley , horseradish, celeriac, rhubarb, dry pea, coriander, and dill required engineering control mitigation to be not of concern to HED (MOEs >100). With engineering controls for the specified crops, the occupational han dler MOEs ranged from 490 to 740.Linuron Human Health Risk Assessment DP No. D405828

Page 26 of 41 **Table 9.**  **1 .1**  **. Occupational Handler Short** **- Term**  **Exposure and Risk Estimates for Linuron**  **with Baseline Attire**
. **Exposure Scenario Crop or**  **Target Dermal Unit** 

**Exposure ( μ**  **g/lb ai)**  **1 Inhalation Unit** 

**Exposure ( μ**  **g/lb ai)**  **1 Ma** **xim um** 

**Application Rate**  **2 Area**  **Treated or Am**  **ount Handled**  **Daily 3**  **Dermal Inhalation**  **Total Baseline**  **Baseline Dose**  **(m g/k** **g/day) 4**  **MOE 5**  **Dose (m** **g/k g/day)**  **6 MOE**  **7 MOE**  **8** Mixer/Loader
Mixing/Loading for Chemigation Application Parsley, Horseradish, Celeriac, Rhubarb 227 8.96 1.5 lb ai/A 350 Acres 0.238 24 0.0588 99 **19** Dry Pea, Coriander, Dill 1.0 lb ai/A 0.159 36 0.0393 150 **29** Parsley Grown for Seed 0.5 lb ai/A 0.0794 73 0.0196 300 **59**

Mixing/Loading for Groundboom Application Dry Pea, Dill

227 8.96 1.0 lb ai/A 200 Acres 0.0908 64 0.0224 260 **51** Parsley, Horseradish, Celeriac, Rhubarb 1.5 lb ai/A
80 Acres 0.0544 110 0.0135 430 **88**
Coriander 1.0 lb ai/A 0.0364 160 0.00896 650 130 Parsley Grown for Seed 0.5 lb ai/A 0.0182 320 0.00448 1,300 260 Applicator
Applying with Groundboom Dry Pea,

Coriander, Dill 78.6 0.34 1.0 lb ai/A 200 Acres 0.0314 180 0.00085 6,800 180 Parsley, Horseradish, Celeriac, Rhubarb 1.5 lb ai/A 80 Acres 0.0189 310 0.00051 11,000 300 Coriander 1.0 lb ai/A 0.0126 460 0.00034 17,000 450Linuron Human Health Risk Assessment DP No. D405828

Page 27 of 41 **Table 9.**  **1 .1**  **. Occupational Handler Short** **- Term**  **Exposure and Risk Estimates for Linuron**  **with Baseline Attire**
. **Exposure Scenario Crop or**  **Target Dermal Unit** 

**Exposure ( μ**  **g/lb ai)**  **1 Inhalation Unit** 

**Exposure ( μ**  **g/lb ai)**  **1 Ma** **xim um** 

**Application Rate**  **2 Area**  **Treated or Am**  **ount Handled**  **Daily 3**  **Dermal Inhalation**  **Total Baseline**  **Baseline Dose**  **(m g/k** **g/day) 4**  **MOE 5**  **Dose (m** **g/k g/day)**  **6 MOE**  **7 MOE**  **8** Parsley Grown for Seed 0.5 lb ai/A 0.00628 920 0.00017 34,000 900 1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (May 2013) ; Level of mitigation: Baseline. 2 Based on registered or proposed label (Reg. No. 61842
- 23 ). 3 Exposure Science Advisory Council Policy #9.1. 4 Dermal Dose = Dermal Unit Exposure ( μg/lb ai) × Conversion Factor (0.001 mg/ μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) × DAF ( 16 %) ÷ BW ( 80 kg). 5 Dermal MOE = Dermal NOAEL ( 5.8 mg/kg/day) ÷ Dermal Dose (mg/kg/day). 6 Inhalation Dose = I

nhalation Unit Exposure ( μg/lb ai) × Conversion Factor (0.001 mg/ μg) × Application Rate (lb ai/acre or gal) × Ar ea Treated or Amount Handled (A or gal/day) ÷ BW ( 80 kg). 7 Inhalation MOE = I

nhalation NOAEL ( 5.8 mg/kg/day) ÷ Inhalation Dose (mg/kg/day). 8 Total MOE = NOAEL ( 5.8 mg/kg/day) ÷ Dermal Dose + I nhalation Dose. **Table 9**  **. 1.2**  **. Occupational Handler Short** **- Term**  **Exposure and Risk Estimates for Linuron with PPE Required on the Label (**  **Che mi**  **cal Resistant Gloves, Coveralls)** 
. **Exposure Scenario Crop or**  **Target Dermal Unit** 

**Exposure (**  **μ g/lb ai)**  **1 Inhalation Unit** 

**Exposure (**  **μ g/lb ai)**  **1 Ma** **xim um** 

**Application Rate**  **2 Area**  **Treated or Am**  **ount Handled**  **Daily 3**  **Dermal Inhalation**  **Total Gloves, Coveralls**  **Baseline Dose**  **(m g/k** **g/day) 4**  **MOE 5**  **Dose (m** **g/k g/day)**  **6 MOE**  **7 MOE**  **8** Mixer/Loader
Mixing/Loading for Chemigation Application Parsley, Horseradish, Celeriac, Rhubarb 41.2 8.96 1.5 lb ai/A 350 Acres 0.0432 130 0.0588 99 **56** Dry Pea, Coriander, Dill 1.0 lb ai/A 0.0288 200 0.0393 150 **86** Parsley Grown for Seed 0.5 lb ai/A 0.0144 400 0.0196 300 170
Mixing/Loading for Groundboom Application Dry Pea, Dill
41.2 8.96 1.0 lb ai/A 200 Acres 0.0165 350 0.0224 260 150 Parsley, Horseradish, Celeriac, Rhubarb 1.5 lb ai/A 80 Acres 0.00988 590 0.0135 430 250 Coriander 1.0 lb ai/A 0.0066 880 0.00896 650 370 Parsley Grown 0.5 lb ai/A 0.0033 1,800 0.00448 1,300 750Linuron Human Health Risk Assessment DP No. D405828

Page 28 of 41 **Table 9**  **. 1.2**  **. Occupational Handler Short** **- Term**  **Exposure and Risk Estimates for Linuron with PPE Required on the Label (**  **Che mi**  **cal Resistant Gloves, Coveralls)** 
. **Exposure Scenario Crop or**  **Target Dermal Unit** 

**Exposure (**  **μ g/lb ai)**  **1 Inhalation Unit** 

**Exposure (**  **μ g/lb ai)**  **1 Ma** **xim um** 

**Application Rate**  **2 Area**  **Treated or Am**  **ount Handled**  **Daily 3**  **Dermal Inhalation**  **Total Gloves, Coveralls**  **Baseline Dose**  **(m g/k** **g/day) 4**  **MOE 5**  **Dose (m** **g/k g/day)**  **6 MOE**  **7 MOE**  **8** for Seed Applicator

Applying with Groundboom Dry Pea, Dill

78.6 0.34 1.0 lb ai/A 200 Acres 0.00504 1,200 0.000425 6,800 1,000

Parsley, Horseradish, Celeriac, Rhubarb 1.5 lb ai/A 80 Acres 0.00302 1,900 0.00051 11,000 1,600
Coriander 1.0 lb ai/A 0.00202 2,900 0.00034 17,000 2,500 Parsley Grown for Seed 0.5 lb ai/A 0.00101 5,700 0.00448 1,300 4,900 1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (May 2013) ; Level of mitigation: Double Layer and Chemical Resistant Gloves
. 2 Based on registered or proposed label (Reg. No. 61842
- 23 ). 3 Exposure Science Advisory Council Policy #9.1. 4 Dermal Dose = Dermal Unit Exposure ( μg/lb ai) × Conversion Factor (0.001 mg/ μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) × DAF ( 16 %) ÷ BW ( 80 kg). 5 Dermal MOE = Dermal NOAEL ( 5.8 mg/kg/day) ÷ Dermal Dose (mg/kg/day). 6 Inhalation Dose = I

nhalation Unit Exposure ( μg/lb ai) × Conversion Fact or (0.001 mg/ μg) × Application Rate (lb ai/acre or gal) × Ar ea Treated or Amount Handled (A or gal/day) ÷ BW ( 80 kg). 7 Inhalation MOE = I

nhalation NOAEL ( 5.8 mg/kg/day) ÷ Inhalation Dose (mg/kg/day). 8 Total MOE = NOAEL ( 5.8 mg/kg/day) ÷ Dermal Dose + I nh alation Dose. **Table 9**  **. 1.3**  **. Occupational Handler Short** **- Term**  **Exposure and Risk Estimates for Linuron with Engineering Controls** 
. **Exposure Scenario Crop or**  **Target Dermal Unit** 

**Exposure ( μ**  **g/lb ai)**  **1 Inhalation Unit** 

**Exposure ( μ**  **g/lb ai)**  **1 Ma** **xim um** 

**Application Rate**  **2 Area**  **Treated or Am**  **ount Handled**  **Daily 3**  **Dermal Inhalation**  **Total Engineering**  **Controls Engineering** 

**Controls Dose**  **(m g/k** **g/day) 4**  **MOE 5**  **Dose (m** **g/k g/day)**  **6 MOE**  **7 MOE**  **8** Mixer/Loader Mixing/Loading for Chemigation Application Parsley, Horseradish, Celeriac, Rhubarb 9.8 0.24 1.5 lb ai/A 350 Acres 0.0103 560 0.00158 3,700 490 Dry Pea, Coriander, Dill 1.0 lb ai/A 0.00686 850 0.00105 5,500 740Linuron Human Health Risk Assessment DP No. D405828

Page 29 of 41 1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (May 2013) ; Level of mitigation: Engineering Controls
. 2 Based on registered or proposed label (Reg. No. 61842
- 23 ). 3 Exposure Science Advisory Council Policy #9.1. 4 Dermal Dose = Dermal Unit Exposure ( μg/lb ai) × Conversion Factor (0.001 mg/ μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) × DAF ( 16 %) ÷ BW ( 80 kg). 5 Dermal MOE = Dermal NOAEL ( 5.8 mg/kg/day) ÷ Dermal Dose (mg/kg/day). 6 Inhalation Dose = I

nhalation Unit Exposure ( μg/lb ai) × Conversion Factor (0.001 mg/ μg) × Application Rate (lb ai/acre or gal) × Ar ea Treated or Amount Handled (A or gal/day) ÷ BW ( 80 kg). 7 Inhalation MOE = I

nhalation NOAEL ( 5.8 mg/kg/day) ÷ Inhalation Dose (mg/kg/day). 8 Total MOE = NOAEL ( 5.8 mg/kg/day) ÷ D ermal Dose + I nhalation Dose.Linuron Human Health Risk Assessment DP No. D405828

Page 30 of 41 **9.2 Short** **- T**  **erm Post**  **- Application**  **Risk 9.2.1**  **Dermal Post -** **A pplication Risk**  Only short
- term post - application exposure is expected for linuron based on the prop osed use pattern , including that linuron is primarily applied in the earl y stages of the crop growth cycle and only once or twice per season. Because linuron is primarily applied in the earl y stages of the crop season, o nl y post - application exposure from application to plants with minimum foliage was assessed. Chemical
- specific DFR data have not been submitted for linuron . Therefore, this assessment uses HED’s default assumption that 25% of the application is available for transfer on day 0 following the application and the residues dissipate at a rate of 10% each following day
. The occupational short
- term dermal post - application risk estimate MOEs ranged from 45 to 3,700 on the day of application (Table 9.2.1 ) ; therefore, hand set irrig ation to parsley , dill, coriander, and celeriac was of concern on day 0
. The Lorox DF ® label recommends that chemigation or rainfall occur within two weeks (14 day s) after linuron application. However, in the Columbia River Basin, L orox ® DF is used only where the crop is sprinkler irrigated ; increasing the likelihood for exposure via hand
- set irrigation
. Inorder for MOEs to be greater than the LOC at the maximum single application rate, hand
- set irrigation should occur 4 days after application for parsl ey , dill, coriander and 8 day s after application for celeriac. **Table 9.2.1**  **. Occupational Post**  **- application**  **Short -**  **Term Derm**  **al Exposure and Risk Estimates**  **for Linuron**  **. Crop/Site**  **Activities Transfer Coefficient**  **(cm 2** **/hr) DFR**  **1 Dermal Dose**  **(m g/k** **g/day) 2**  **MOE 3**  **Days Needed Following Application to Reach**  **MOE > 100** Parsley, Dill, Coriander (1.0 lb ai/A) Hand
- Set

Irrigation 1900 2.80 0.085 68 4 Transplanting 230 0.010 560

N/A Scouting 210 0.0094 620 Thinning, Hand Weeding 70 0.0031 1,800 Parsley for Seed (0.5 lb ai/A) Hand
- Set

Irrigation 1900 1.40 0.043 140 Transplanting 230 0.0052 1,100 Scouting 210 0.0047 1,200 Thinning, Hand Weeding 70 0.0016 3,700 Celeriac (1.5 lb ai/A) Hand
- Set

Irrigation 1900 4.21 0.128 45 8 Scouting 210 0.014 410 N/A Thinning, Hand Weeding 70 0.0047 1,200 1 DFR = Application Rate × F × (1
- D) t × 4.54E8 μg/lb × 2.47E
- 8 acre/cm2 ; where F = 0.25 and D = 0.10 per day 2 Daily Dermal Dose = [DFR (μg/cm2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption ( 16 %)]  BW ( 80 kg). 3 MOE = POD ( 5.8 mg/kg/day) / Daily Dermal Dose. Daily Dermal Dose = [DFR (μg/cm2 ) × TC × 0.001 mg/μg × 8 hrs/day × dermal absorption factor (16%) ]  BW ( 80 kg)
.Linuron Human Health Risk Assessment DP No. D405828

Page 31 of 41 **9.2.2 Inhalation Post** **- A** **pplication Risk** Based on the Agency's current practices, a quantitative post
- application inhalation exposure assessment was not performed for linuron at this time primarily because of the low acute inhalation toxicity

(Toxicity Category III and IV). However, there are multiple potential sources of post
- application inhalation exposure to individuals performing post
- application activities in previously

treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 3 . The Agency is in the process of evaluating the SAP report as well as available post
- application inhalation exposure data generated b y the ARTF and may , as appropriate, develop policies and procedures, to identify the need for and, subsequently , the way

to incorporate occupational post
- application inhalation exposure into the Agency's risk assessments. 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 linuron. Although a quantitative occupational post
- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post
- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post
- application inhalation exposure scenarios. **10.0 References**  D. Davis, D348519, 04/17/2008. Linuron: Human Health Risk Assessment to Support a Section 18 Emergency

Exemption for Use on Lentils in Washington and Idaho. H. Zh ong, D405829, 06/25/2013. Second Revision of Linuron Drinking Water Assessment for IR
- 4 New Use on Coriander, Dill, Celeriac, Horseradish, Parsley , Dry Peas, and Rhubarb. Revisions on 6/19/2013, and 4/30/2013. J. Alsadek, D410336, 04/10/2013. Screening Level Usage Report In Support of a Tolerance Petition for the Herbicide Linuron. J. Van Alstine, TXR#0 0 56436, 10/26/2012. Linuron : Summary of Hazard and Science Policy Council (HASPOC) Meeting of August 9, 2012: Recommendations on the Requirement of a 28
- Day Inhalation S tudy , 21
- Day Dermal Toxicity

Study , and a Subchronic Neurotoxicity Study
. J. Van Alstine, TXR#0056667, 06/12/2013. Linuron: Revision to Summary of Hazard and Science Policy

Council (HASPOC) Meeting of August 9, 2013: Recommendation on the

3 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlLinuron Human Health Risk Assessment DP No. D405828

Page 32 of 41 Requirement of a 28
- Day Inhalation Study , 21
- Day Dermal Toxicity

Study , and a Subchronic Neurotoxicity

Study
. J. Van Alstine, TXR#0056666, 06/12/2013. Linuron: Summary of Hazard and Science Policy Council (HASPOC) E
- Review on the requirement of a subchronic neurotoxicity study
. K. Rury , D375451, 04/01 /2010. Linuron: Human Health Assessment Scoping Document in Support of Registration Review. Addendums: D378731, D380352. K. Rury , D405825, 09 / 04 /2013. Linuron: Occupational and Residential Exposure Assessment for the Proposed Use on Coriander, Dill, Ho rseradish, Parsley , Celeriac, Rhubarb, and Pea (Dry). K. Rury , D411650, 09 / 04 /2013. Linuron: Acute and Chronic Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section (3) Registration Action on Coriander, Dill, Horseradish, Parsl ey , Celeriac, Rhubarb, and Dry Pea. N. Tsaur, D404359 and D411652, 08/14/2013. Linuron. Petition for the Establishment of Permanent Tolerances and Registration for Use on Coriander, Dill, Parsley , Pea (Dry), and Horseradish; and Submission of Residue Anal ytical Methods of Plants and Animal Matrices. Summary of Anal ytical Chemistry

and Residue Data.Linuron Human Health Risk Assessment DP No. D405828

Page 33 of 41 **A ppendix**  **A .**  **References for Published Toxicity Studies and Toxicology Profile**  **References for Published Studies** Gray , L ; Wolf

, C ; Lambright , C ; Mann , P ; Price , M ; Cooper , R ; Ostby , J
. 1999. Administration of potentially

antiandrogenic pesticides (procy midone, linuron, iprodione, chlozolinate, p,p'
- DDE, and ketoconazole) and toxic substances (dibutyl
- and diethylhexyl phthalate, PCB 169, and ethan e dimethane sulphonate) during sexual differentiation produces diverse profiles of reproductive malformations in the male rat. Toxicol Ind Health, 15 (1
- 2) : 94
- 118. Hotchkiss, A; Parks
- Saldutti, L ; Ostby , J; L ambright, C; Furr, J; Vandenbergh, J; & Gray , L. 2004. A mixture of the “antiandro gens” linuron and butyl benzyl phthalate alters sexual differentiation of the male rats in a cumulative fashion. Biol. Of Reprod., 71 : 1852
- 1861. Lambright , C ; Ostby , J ; Bobseine , K ; Wilson , V ; Hotchkiss , A ; Mann , PC ; Gray , L
. 2000. Cellular and molecular mechanisms of action of linuron: an antiandrogenic herbicide that produces reproductive malformations in male rats. Toxicol Sci
. 56(2):389
- 99. McInty re , B ; Barlow , N ; Wallace , D ; Maness , S ; Gaido , K ; Foster , P
. 2000. Effects of in utero exposure to linuron on androgen
- dependent reproductive devel opment in the male Crl:CD(SD)BR rat. Toxicol Appl Pharmacol
. 167(2):87
- 9. Vinggaard, A ; Hnida, C ; Breinholt, V ; Larsen, J
. 2000. Screening of Selected Pesticidesfor Inhibition of CYP19 Aromatase Activity In vitro
. Toxicol in Vitro
. 14:227
- 234
. Vinggaard, A
. , Breinholt, V ., and Larsen, J
. 1999. Screening of selected pesticides for oestrogen receptor activation in vitro
. Food Addit Contam
. 16(12) : 533
- 542
. Wolf, C; L ambright, C; Mann, P; Price, M; Cooper, R; Ostby , J; Gray , D. 1999. Administration of potentially

antiandro genic pesticides (procy midone, linuron, iprodione, chlozolinate, p,p’
- DDE, and ketoconazole) and toxic substances (dibutylhex ylphthalate, PCB 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles or reproductive malformation in the male rats. Toxicol. Ind. Health 15:94
- 118. **Toxicological Profile for Linuron Acute Toxicity**  **for Linuron Guideline No.**  **Study Type MRID**  **Results Tox. Category**  870.1100 Ac ute Oral (Rat) 00027625 LD 50 = 2600 mg/kg III 870.1200 Ac ute Dermal (Rabbit) 00027625 LD 50 > 2000 mg/kg III 870.1300 Ac ute Inhalation (Rat) 00053769 LC 50 > 218 mg/L IV 870.2400 Primary Eye Irritation 42849001 Slight conjunctival redness at 24 hrs; clear at 72 hrs III 870.2500 Primary Skin Irritation 42849002 Not an irritant IV 870.2600 Dermal Sensitization 00146868 Not a sensitizer N/ALinuron Human Health Risk Assessment DP No. D405828

Page 34 of 41 **Repeated Dosing and Other Studies**  **on Linuron Guideline**  **No. Study**  **Type MRID No. (Year)/**  **Classification/Doses Results**  **Subchronic toxicity studies** 870.3100 90
- day oral
- rat Requirement fulfilled by Chronic rat study 870.3150 90
- Day oral toxicity
- dog Requirement fulfilled by Chronic dog study
- N/A 870.3200 21/28
- Day dermal

toxicity
- rabbit Waived (HASPOC, 10/26/20012; TXR: 0056436) 870.3250 90
- Day dermal toxicity Waived (HASPOC, 10/26/20012; TXR: 0056436) 870.3465 90
- Day inhalation toxicity Waived (HASPOC, 10/26/20012; TXR: 0056436) **Chronic toxicity studies**

1
- Year Feeding Study
- Dog 40952601 (1988) Acceptable/Guideline 0, 10, 25, 125, 625 ppm (M: 0, 0.29, 0.79, 4.17, 18.6 mg/kg/day; F: 0, 0.30, 0.77, 3.49, 16.1 mg/kg/day) **NOAEL** = 0.77 mg/kg/day **LOAEL =** 3.49 mg/kg/day, based on hematological effects in males and females (increased methemoglobin and sulfhemoglobin levels) 2
- Year Feeding Study
- Dog 00018374 (1963) Unacceptable/Guideline 0, 25, 125, 625 ppm (0, 0.6, 3.1, 16 mg/kg/day) (1 ppm=0.025 mg/kg/day) **NOAEL** = 3.1 mg/kg/day **LOAEL =** 16 mg/kg/day, based on mild hemolytic anemia, slightly deceased hemoglobin, hematocrit, and RBC counts 870.4200 Oncogenicity Study
-

Mouse 0124195 (1981) Acceptable/Guideline 0, 50, 150, and 1500 ppm (M:0, 8, 23, and 261 mg/kg/day; F: 0, 12, 35, and 455 mg/kg/day) **NOAEL** = 23 mg/kg/day **LOAEL =** 261 mg/kg/day, based on microscopic liver changes, methemoglobinemia, and deceased body weight gain throughout the study **Histopathology:** hepatocytomegaly, hepatocellular cytoplasmic alterations, vacuolation, and necrosis in liver, slightly increased incidence of hemosiderosis in spleens of both sexes; Significant increase in hepatocellular adenomas in females 870.4100 870.4200 Combined Chronic

Toxicity/ Carcinogenicity Study
- Rat 0029680, 00029679 (1980) 00167411 (1986) Acceptable/Guideline 0, 50, 125, 625 ppm (M: 0,2.09, 5.11, 27.1 mg/kg/day; F: 0, 3.13, 7.75, 48.3 mg/kg/day) **NOAEL** =2.09 mg/kg/day **LOAEL =** 5.11 mg/kg/day, based on hematological effects, decreased body weight gains in both sexes, microscopic observations consistent with hemolysis (hemosiderin in Kupffer cells and increased hemosiderosis in bone marrow, spleen, and/or mesenteric lymph nodes) **Histopathology:** Significant (p = 0.004) increase (27%, 5.7% control) in benign interstitial cell adenomas in testes incidences. **Developmental and reproductive toxicity studies** 870.3700 Developmental Toxicity

Study
- Rat 00018167 (1979) Acceptable/Guideline 0, 50, 125, 625 ppm (0, 5.0, 12, 50 mg/kg/day) **Maternal Systemic**  **NOAEL** = 12 mg/kg/day **LOAEL** = 50 mg/kg/day, based on decreased maternal body weight (9%) and food consumption (7
- 8%). **Developmental NOAEL**  = 12 mg/kg/day **LOAEL** = 50 mg/kg/day, based on increased post - implantation loss and litters with early resorptions. Developmental Toxicity
- Rabbit 00153867 (1985), 40437201(1985) **Maternal Systemic NOAEL**  = 5 mg/kg/day **LOAEL** = 25 mg/kg/day, based onLinuron Human Health Risk Assessment DP No. D405828

Page 35 of 41 **Guideline No.**  **Study Type**  **MRID No. (Year)/ Classification/Doses**  **Results** Acceptable/Guideline 0, 5, 25, 100 mg/kg/day decreased maternal body weight gain. **Developmental**

**NOAEL** = 25 mg/kg/day **LOAEL** = 100 mg/kg/day, based on alterations of the bones and skull (irregularly shaped fontanelle, hole in parietals, parietals contain intraparietals, and unossified). 870.3800 3
- Generation

Reproduction
- Rat 00146071 (1984) 00155168 (1985) Acceptab le/Guideline 0, 25, 125, 625 ppm (M: 0, 2, 10
- 11, 48
- 50 mg/kg/day F: 0, 2, 9, 44
- 50 mg/kg/day) **Parental NOAEL**  = 2 mg/kg/day **LOAEL** = 9 mg/kg/day, based on decreased body weight gains in males and females and anemia in females. **Reproductive NOAEL**  = 10 mg/kg/day **LOAEL** = 44 mg/kg/day based on reduced fertility, decreased pup survival, and lower pup body weights. **Offspring NOAEL**  = 9 mg/kg/day **LOAEL** = 44 mg/kg/day, based on decreased pup survival, and lower pup body weights. 2
- Generation Reproduction
- Rat 41463401 (1990) 41864701 (1991) Acceptable/Guideline 0, 12.5, 100, 625 ppm (M: 0, 0.74, 5.8, 36 mg/kg/day F: 0, 0.92, 7.3, 45 mg/kg/day) **Parental NOAEL** = 0.74 mg/kg/day; **Parental LOAEL** = 5.8 mg/kg/day, based on decreased body weight gains in males and females in both generations **Reproductive NOAEL**  = 36 mg/kg/day **LOAEL** = not established **Offspring NOAEL**  = 0.74 mg/kg/day **LOAEL** = 5.8 mg/kg/day, based on decreased pup body weights of F1 generation subsequent to 30days of treatment. **Metabolism and dermal absorption studies** 870.7485 Metabolism Study
- Rat 00146489 (1985), 40142401 (1985) 41960001 (1991 42006801 (1991) Linuron (single doses at 24 mg/kg and 400 mg/kg) was administered by gavage to male and female rats. The biological half
- lives ranged from 21 hr in the low dose males to 56 hr in the high dose females. Total recovery of radioactivity was 96% in males and 97% in females, the majority of the administered C
- linuron was eliminated in the urine (>80%) and, to a lesser extent, in the feces (~15%). Tissue and organ residues were very low (<l%) at both dose levels, and there was no indication of accumulation or retenti on of linuron or its metabolites. The major metabolites identified in the urine were hydroxy
- norlinuron, desmethoxy linuron and norlinuron, and in feces, hydroxy
- norlinuron, and norlinuron. Neither hydroxy
- 3,4
- dichloroanaline nor 3,4
- dichloroanaline were present in any of the samples. Exposure to linuron appeared to induce mixed
- function oxidative enzymes. 870.7600 Dermal Penetration
- Rat 00163837 (1984) Acceptable/Guideline Dermal absorption factor = 16% over 8 to 10 hr (2%/hr).Linuron Human Health Risk Assessment DP No. D405828

Page 36 of 41 **Guideline No.**  **Study Type**  **MRID No. (Year)/ Classification/Doses**  **Results**
14 C (2.35  Ci/mg) 0.12, 1.00, or 7.4 mg/2 in2 2.82, 23.5, or 17.4  Ci Dermal penetration studies (triple pack: in
- vivo and in
- vitro dermal penetration studies with rat and human skin) Afalon SC Formulation 48747806 ( in
- vivo rat) (2013) 48747807 ( in
- vitro rat & human skin) (2013) 48747807 ( in
- vitro rat & human skin) (2013) **In -**  **vivo study was unacceptable/non**  **** **guideline.** The in
- vivo study was unacceptable due to several deficiencies including exposure intervals, the recovery was too low for the low dose exposure (which was more relevant for establishing dermal absorption), the appropriate dermal absorption value was derived from only one animal, and insufficient reported data. **Genotoxicity battery** 870.5100 870.5100
- Bacterial

reverse gene mutation assay MRID 00131738 Acceptable/Guideline .5, 0.75, 1.0, 2.5, and 5.0  g/plate(S9
- mix) 1, 5, 10, 50, and 100 g/plate +S
9 mix. In a reverse gene mutation assay in bacteri, S. typhimurium strains TA98, TA100, TA1535, and TA1537 were exposed to Linuron (95
- 97%, lot number not given) in dimethylsulfoxide at concentrations of 0 There was no evidence of induced mutant colonies over background with or without S9 activation. 870.5300 CHO/HGPRT cell forward

gene mutation assay MRID 00137152 Acceptable/Guideline 0.05, 0 .25, 0.35, 0.40, 0.45, and 0.50 mM (S9
- mix) 0.25, 0.50, 0.75, 0.90, and 1.0 mM (+S9
- mix) In a mammalian cell gene mutation assay in vitro, triplicate (in the absence of activation) or duplicate (in the presence of activation) cultures of Chinese hamster ovary (CHO) CHO
- K1
- BH4 cells were exposed to Linuron (Lot No. 1N2
- 326
- 141, 94.5% a.i.) in F12 medium. The S9
- fraction was obtained from Aroclor 1254
- induced 8 to 9 week
- old male Charles River CD rats. Linuron was tested up to concentrations limited by cytotoxicity. Cy totoxicity was observed at 0.45 and 0.5 mM under nonactivated conditions and at 0.75 mM and above with 0.5 mg S9 protein/mL and at 1.0mM and above with 1.0 mg S9 protein/mL. (Percentage cell survival were not provided in the DER). There wa s no increase in mutant frequency in cells treated with linuron in either the presence or absence of metabolic activation. The positive (ethyl methane sulfonate (EMS) without S9
- mi x and dimethylbenzanthracene with S9
- mi x) and solvent (DMSO) controls respo nded appropriately. No evidence of an increased mutant frequency was observed in the presence or absence of metabolic activation. 870.5385 870.5395 In vivo bone marrow

chromosomal aberration assay MRID 00137153 Acceptable/Guideline 0, 100, 300, or 1000 mg/kg. In a mammalian cell cytogenetics chromosomal aberration assay in bone marrow cells of Sprague
- Dawley rats, 5 rats per sex per harvest time were administered Linuron (94.5%, lot number not given) by single gavage at doses. Bon e marrow cells were harvested 6
- , 12
- , 24
- , or 48
- hours after test compound administration and 48 hours after the positive control dose. The vehicle was corn oil (20 mL/kg) and the positive control was a single 40 mg/kg dose of cyclophosphamide.Linuron Human Health Risk Assessment DP No. D405828

Page 37 of 41 **Guideline No.**  **Study Type**  **MRID No. (Year)/ Classification/Doses**  **Results** One high
- dose rat in the 24
-hour group was found dead and 8 of 10 high
- dose rats in the 48
-hour group died prior to sacrifice on day 2. Low
- and mid
- dose animals exhibited slight depression, ataxia, and/or prostration. Treated animals also had decreased body wei ghts compared to controls. There was no significant increase in the frequency of aberrations in bone marrow cells of treated animals compared to controls at any sampling time. Values in treated animals ranged from 0.3
- 0.8% aberrant cells/group; the positive control group had 19.6% aberrant cells, indicating that this control responded appropriately. There was no change in mitotic index of dosed groups compared to controls. There is no evidence that Linuron induced chromosomal aberrations in bone marrow cells of rats over background levels. 870.5300 Unscheduled DNA

sy nthesis in mammalian cell culture MRID 00132583 Acceptable/Guideline 0.00001, 0.0001, 0.001, 0.01, 0.1, 1.0, 10, and 50.0 mM (trial 1) 0.01, 0.1, 1.0, 10, and 50.0 mM (trial 2) In an unscheduled DNA synthesis assay, primary rat hepatocyte cultures were exposed to Linuron (94.5% a.i. in dimethylsulfoxide; Lot No. T80311
- 81) in Williams’ Medium E (WME) for 18 hours. There is no evidence that Linuron induced chromosomal aberrations in bo ne marrow cells of rats over background levelS **Neurotoxicity battery** 870.6200a Acute Neurotoxcity study
rat (single gavage dose) 49096701 (2013) Acceptable/non
- guideline 0, 20. 100, 500 mg/kg NOAEL = 20 mg/kg LOAEL =100 mg/kg based on decreases in motor activity and rearing. At 500 mg/kg numerous changes in FOB parameters were found. 870.6200b Subchronic neurotoxicity

study The requirement of this study was waived by HASPOC, 6/12/2013 (TXR 0056666). 870.6300 Developmental

neurotoxicity study (DNT) A DNT study was not required because linuron affect testes and hematological parameters. but it did not produce increase susceptibility in young rats (TXR 0050429) **Immunotoxicity study** 870.7800 Immunotoxicity study
- rats 48840401 (2012) Acceptable/guideline 0, 150, 500, 1500/1000 ppm (1500 ppm was reduced to 1000 ppm day 10 due to excessive weight loss) M: 0, 13.3, 42.7, 132.1/92.1 mg/kg/day) F: 0, 13, 41.7, 130/92.8 mg/kg/day Systemic NOAEL = 41.7mg/kg/day Syst emic LOAEL = 92 based on decreases in body weight, body weight gains, and food consumption. NOAEL for Immunotoxicity = 92 mg/kg/day (highest dose tested) based on no effects seen in T
- cell dependent antibody response to antigen and natural killer cells **S pecial studies**  Special Study
- Leydig

cell tumorigenesis in rats 41630101 (1990) Acceptable/Nonguideline (0 or 200 mg/kg/day for 14 days to 32 to 33 and 93 day old rats) No treatment
- related clinical signs of toxicity were observed. Body weight and body weight change were significantly less than controls and decreased accessory sex organ weights for growing and adult rats. M: 0, 0.74, 5.8, 36 mg/kg/day; F: 0, 0.92, 7.3, 45 mg/kg/day Selected animals from the 2
- generation reproduction study were used to evaluate changes in serum hormone levels, accessoryLinuron Human Health Risk Assessment DP No. D405828

Page 38 of 4 1 **Guideline No.**  **Study Type**  **MRID No. (Year)/ Classification/Doses**  **Results** F0 and F1 animals from 2
- generation reproduction study (41463401), sex organ weights. Increased serum luteinizing hormone and estradiol levels were observed in F0 and F1 males. High
- dose F0 males had decreased absolute epididymides, dorsal lateral prostate, and levator ani muscle weights and increased relative testes, epididymides, and ventral prostate weights. Organ weights were unaffected in the two lower dose groups. These data suppo rt the hypothesis that rats exposed to linuron could develop interstitial hyperplasia and subsequent adenomas (Leydig cell tumors) via a mechanism of sustained hypersecretion of luteinizing hormone induced by the antiandrogenic potential of linuron. Special Study
- Cross Mating
- Rats 00159846 (1985) Acceptable/Nonguideline 0, 625 ppm (M: 0, 48 mg/kg/day F: 0, 44 mg/kg/day) The cross
- mating results suggest that linuron may cause paternally
- mediated effects based on decreased fertility and fecundity as well as maternally
- mediated effects based on decreased pup viability and litter survival. Special Study
- Aged male rats 45506501 (1986) Acceptable/Nonguideline 0, 625 ppm (0, 22 mg/kg/day) Linuron induced hyperplasia and adenomas of the testes in aged rats. In addition, life
time feeding was not necessary to induce oncogenic responses in this tissue. Exposure duration was 6 to 12 months. Special Study
- Biochemical and Histopathological effects 164093 (1986) Acceptable/Nonguideline 0, 12.5, 100, 625 ppm (M: 0, 0.75, 4.1, 22 mg/kg/day F: 0, 1.1, 6.1, 37 mg/kg/day) The biochemical and histopathological data presented in this report suggest that linuron may affect testosterone metabolism in horse testicular microsomes for a range of concentrations which overlap the dose levels given rats chronically. However, the net effect of these enzyme changes and the relevance to the rat in vivo are uncertain. Evidence in young and old rats exposed repeatedly (3
- 7x) or for 11 or 19 months suggests that Leydig cell incubates are differentially altered in their sensitivity to LH. Microscopic lesions in the testes and cervix have been confirmed in other studies.Linuron Human Health Risk Assessment DP No. D405828

Page 39 of 41 **Toxicology Data Requirements** The requirements (40 CFR 158.340) for food use for linuron are shown below in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline p rotocols were used. **Test Technical Linuron**  **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 21/28
- Day Dermal
................................ ......................... 870.3250 90
- Day

Dermal
................................ .............................. 870.3465 90
- Day

Inhalation
................................ .......................... yes yes yes CR CR +

+ waived a waived a waived a 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
................ 870.5375 Mutagenicity

— Structural Chromosomal Aberrations
... 870.5550 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 Developmental Neurotoxicity
................................ ........ no no yes yes no --

-- yes waived b

-- 870.7485 General Metabolism
................................ ...................... 870.7600 Dermal Penetration
................................ ........................ 870.7800 Immunotoxicity............................................... yes yes yes ye s

yes yes +: Satisfied by the availability of the chronic toxicity study. a : HASPOC, 10/26/12; TXR# 0056436 , 06/12/2013; TXR# 0056436 b : HASPOC, 6/12/13; TXR# 0056666Linuron Human Health Risk Assessment DP No. D405828

Page 40 of 41 **Appendix B**  **. Physical/Chemical**  **Properties Table**  **B . Physicochemical Properties of the Technical Grade Test Compound Linuron.**  Parameter Value Reference Molecular weight (g/mole) 249.1 MRID 42213301 Melting point/range 91
- 94±1°C MRID 42213301 pH 6.98, 7.09 for a 0.2% solution and 9.38, 9.41, for a 2.5% solution at 22.5±0.5  C MRID 42213301 Density 1.4963 g/mL at 22.3±0.5  C (air comparison pycnometer) MRID 42213301 Water solubility (20.5 ± 0.5  C) 5.88×10 - 3 g/100 mL MRID 42213301 Solvent solubility (20  C) dichloromethane 44.1 g/100 mL toluene 7.91 g/100 mL methanol 12.6 g/100 mL hexane 0.220 g/100 mL MRID 42213301 Vapor pressure at 25°C 4.015×10 - 5 Pa 3.01×10 - 7 mm Hg MRID 42213303 Henry’s Law Constant at 25°C 1.97×10 - 9 atm·m 3 /mol http://toxnet.nlm.nih.gov Dissociation constant (pKa) dissociation constant could not be determined; physical and chemical properties deemed all methods in OECD guidelines inappropriate MRID 42213302 Octanol/water partition coefficient Log(KOW) 8.2×10 2 at 23±1  C (GC method) log P ow = 2.76 MRID 42213301Linuron Human Health Risk Assessment DP No. D405828

Page 41 of 41 **Appendix C**  **. Review of Human Research**  The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Electronic Database. Task Force Members: Health Canada, U.S. EPA, and the National Agricultural Chemicals Associations, released February 1995. The Agricultural Handler Exposure Task Force (AHETF) , 2011. The Occupational Handler Unit Exposure Surrogate Reference Table. U.S. EPA. Released June 21, 2011.