                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
\* MERGEFORMAT
                                                           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.:  469722
Registration No.:  61842-23
Petition No.:  2E8083
Regulatory Action:  Section 3 Registration
Risk Assessment Type:  Single Chemical Aggregate
Case No.:  0047
TXR 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 by He Zhong (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 conducted by Kristin Rury.

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	12
3.5	Consideration of Environmental Justice	12
4.0	Hazard Characterization and Dose-Response Assessment	12
4.1	Toxicology Studies Available for Analysis	13
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)	15
4.4.1	Completeness of the Toxicology Database	15
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	16
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	22
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	24
7.0	Aggregate Exposure/Risk Characterization	24
8.0	Cumulative Exposure/Risk Characterization	24
9.0	Occupational Exposure/Risk Characterization	24
9.1	Short-Term Handler Risk	25
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 Research	41

1.0	Executive Summary

Introduction
Linuron is a selective phenylurea herbicide used to control broadleaf weeds and annual grasses by systemically inhibiting photosynthesis.  It may be applied pre-plant, pre-emergence, post-emergence or post-transplant to various field crops and noncrop areas.

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[(R)], 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 these 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 policies and inputs.

Concomitant with this IR-4 petition, additional analytical method data have been submitted by Tessenderlo Kerley to support the newly proposed uses.  A new enforcement method for plant and livestock commodities was previously required as conditional data (K. Rury, DP375451, 04/01/2010).  A high performance liquid chromatography/tandem mass spectrometry (HPLC/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 validation 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 analytical methods is fulfilled.

Use Profile
Lorox DF[(R)] is a water dispersible granular (WDG) formulation containing 50% linuron by weight.  Lorox DF[(R)] may be applied both before and after weed emergence and usually early 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; and 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 system in rats, mice, and dogs; and (2) changes in the male reproductive system 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.  Linuron is a minimal eye irritant (Toxicity Category III), not a dermal irritant (Toxicity Category IV), and is not a dermal sensitizer.  The HED Hazard and Science Policy Council (HASPOC) recently waived the requirement for a 28-day inhalation toxicity study, a 21-day dermal toxicity 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 scenarios.  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. Group 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 analysis 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 years 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 analysis indicate that chronic dietary (food and drinking water) exposure and risk does not exceed 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, 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 system) be required on the Lorox DF[(R)] 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 estimates 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 days after application for parsley, dill, coriander and 8 days after application for celeriac.  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 address 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 database; 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 by 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 Low-Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.

2.0	HED Recommendations

HED has examined the residue chemistry, toxicity, and exposure databases 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 DFR 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 analyzed a number of DFR studies and selected a new default value for the fraction of the application rate available to be dislodged after a foliar application (FAR).  This default value is 25% and is based on an analysis of 19 DFR studies where the FAR value ranged from 2% to 89%.  This value is recommended for use in both residential and occupational post-application assessments.  Of the analyzed DFR studies, the maximum FAR 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 Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) Studies. 06/07/2012, 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 LOC based 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 adequately validated analytical methods are now available for linuron.

For linuron residues of concern in plant commodities, Method ABC-68406-M is available and suitable for residue collection as well as enforcement of tolerances. This method involves reflux of crop samples in strong base to hydrolyze residues of linuron and its metabolites to 3,4-DCA, which is analyzed using GC/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 hydrolyzable to 3,4-DCA. In addition, Method ABC-65790 (LC/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 method separately 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 method, linuron and its metabolites are hydrolyzed to 3,4-DCA using strong base and then analyzed 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
                                     0.05

                            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 byproducts 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 calculation 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 (MRLs) for linuron in Codex for any agricultural commodity.  Furthermore, no Canadian or Mexican MRLs 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."

2.3.2	Recommendations from Occupational Assessment

HED recommends that engineering controls (e.g., a closed mixing loading system) be required on the Lorox DF[(R)] 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 REI be 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 REI for hand-set irrigation should be 4 days for parsley, dill, and coriander, and 8 days for celeriac.

3.0	Introduction

3.1	Chemical Identity

Table 3.1.  Linuron Nomenclature.
Compound

Common name
Linuron
Company experimental name
DPX-Z0326
IUPAC name
3-(3,4-dichlorophenyl)-1-methoxy-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-methylurea
Metabolite

Common name
DCPU
Chemical name
N-(3,4-dichlorophenyl)urea
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 Pow = 2.76 at 25C) 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 (3.01x10[-7] mm Hg at 25C), and linuron is considered relatively insoluble in water. The Henry's Law constant was calculated to be 1.97x10[-9] atm·m[3]/mol.  Thus, linuron is unlikely to volatilize significantly, and inhalation via chemical vaporization is unlikely.

Linuron is moderately persistent with an aerobic soil metabolism half-life ranging from 57 to 100 days.  Because parent linuron is sufficiently persistent and may be mobile under certain environmental 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 Lorox(R) DF (EPA Reg. No. 61842-23).  The use directions are summarized below in Table 3.3.

Table 3.3.  Summary of Proposed Directions for Use of Linuron (Lorox(R) 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(R) DF per acre per year East of Rocky Mountains.  Do not exceed 3 lbs. LOROX(R) 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
                                   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(R) DF per acre per year East of Rocky Mountains.  Do not exceed 3 lbs. LOROX(R) DF per acre per year West of Rocky Mountains.  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(R) 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 use 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 pathways based on the proposed new uses of linuron, but also considers existing uses of linuron, particularly in the dietary exposure assessment.

3.5	Consideration of Environmental Justice

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

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 general U.S. population has been established.

4.1	Toxicology 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-year and 2-year 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 Leydig cell tumorigenesis produced by linuron (see Appendix A for literature references and the linuron toxicology profile). Waivers were granted for the required subchronic dermal and inhalation studies and the subchronic neurotoxicity study.

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 tissues and carcass represented <1% of the administered dose.  The liver had the highest levels of radioactivity.  The biological half-life (t1/2) of linuron differed between the low and high doses 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 enzymes.

      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 system in rats, mice, and dogs and; (2) changes in the male reproductive system in developing rats.  Lowest observed adverse effect levels (LOAELs) for hematological effects produced by linuron were substantially lower (40-fold lower) than LOAELs for reproductive effects.   Dogs were shown to be most sensitive to the hematological effects, including hemolytic anemia characterized by slightly reduced hemoglobin, hematocrit, and erythrocyte counts accompanied by hemosiderin deposition in liver Kupffer cells.  Secondary erythropogenic activity (erythroid hyperplasia of bone marrow) was also found.  Systemic toxicity observed in mice included increased methemoglobin formation, vacuolation and hemosiderosis of the spleen, and decreased erythrocyte counts.  In the chronic rat study, microscopic observations consistent with hemolysis (hemosiderin in Kupffer cells and increased hemosiderosis in bone marrow, spleen, and/or mesenteric lymph nodes) were found.

The rat developmental 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 lesions of the testes (including reduction in size); abnormally soft and small epididymides; deformities of the epididymides; 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 system 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 enzymes.  Additional findings indicate linuron exposure decreases anogenital distance; may increase retention of areole/nipples in male rat offspring following in utero exposure; increase luteinizing hormone (LH) levels in F0 and F1 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 synthesis (Gray, et al., 1999; Hotchkiss, et al., 2004; Lambright, et al., 2000; McIntyre, et al, 2000).  It should be noted that most of the literature studies employed dose levels of 100 mg/kg or greater.  At this time, linuron has not been demonstrated to be an estrogen receptor antagonist (Vinggaard, et al., 1999).  It should be emphasized that the toxicity endpoints based on the hematological effects for chronic exposures 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 LOAEL that caused the testicular effects seen in the rat reproduction toxicity study.

In rat and mouse carcinogenicity studies, linuron induced interstitial cell adenomas in the testes of rats and hepatocellular adenomas in mice.  In a special study with aged rats, linuron induced hyperplasia 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 by 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 heads 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 forelimbs, reduced rotarod performance, decreased hindlimb footsplay, and increased catalepsy. At 100 mg/kg, linuron produced decreases in motor activity and rearing.  No effects were seen at 20 mg/kg (no observed adverse effect level; NOAEL). However, no compound-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 Factor for Infants and Children (FQPA Safety Factor)

HED has examined the currently available information on linuron and determined that the linuron database is adequate for assessing susceptibility of the young to linuron exposure.  HED has determined that the linuron FQPA factor is reduced to 1X for the following reasons:

4.4.1	Completeness of the Toxicology Database

Linuron toxicity database is robust and the study requirements are satisfied.  The toxicology database used to assess pre- and post-natal exposure to linuron is considered adequate.  The following acceptable studies are available to support this determination: a rat developmental 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 Neurotoxicity

In an acute oral toxicity study, FOB findings of impaired mobility, alterations 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 system 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 system was not a target organ for linuron.  Therefore, the concern for neurotoxicity is low.

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

There is no qualitative/quantitative evidence of increased susceptibility of rabbit developmental study; developmental effects were 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 maternal body weight and food consumption.  Since 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 dose 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 system. Therefore, a FQPA safety factor could be reduced to 1X.

4.4.4	Residual Uncertainty in the Exposure Database

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 (food) exposure 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 Analysis (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 generated by models 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 does not underestimate the potential exposure for infants, children, or women of child bearing age.

4.5	Toxicity Endpoint and Point of Departure Selections

The previously 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-Review for Linuron (05/29/2013, internal memo).  The toxicity endpoints and the PODs for risk assessment are presented below.  It should 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 days 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 doses less than 5.8 mg/kg/day (NOAEL).  Therefore, the body weight decrease around 30 days at 36 mg/kg/day could serve as the toxicity endpoint 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).

Furthermore, the overall NOAEL/LOAEL  for the 2-generation reproductive toxicity study as presented in Appendix A is different from that seen 30 days 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 offspring NOAEL and LOAEL were 0.74 mg/kg/day and 5.8 mg/kg/day, respectively (see Toxicity Profile in Appendix A).

Table 4.5.  Summary of Toxicological Doses and Endpoints for Linuron for Use in Dietary and Occupational Human Health Risk Assessments.
                              Exposure/ Scenario
                              Point of Departure
                        Uncertainty/FQPA Safety Factors
                RfD, PAD, Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Acute Dietary (General Population, including Infants and Children)
NOAEL= 20 mg/kg/day
UFA= 10x
UFH= 10x
FQPA SF= 1x
Acute RfD = 0.2 mg/kg/day

aPAD = 0.2 mg/kg/day
Acute Neurotoxicity Study (Rat).  LOAEL = 100 mg/kg based on decreases in rearing and in motor activity.
Acute Dietary
(Females 13-49 years of age)
NOAEL = 12 mg/kg/day
UFA= 10x
UFH= 10x
FQPA SF= 1x
Acute RfD = 0.12 mg/kg/day
Rat Developmental Toxicity.  LOAEL = 50 mg/kg/day based on increased post-implantation loss and fetal/litter resorptions.
Chronic Dietary (All Populations)
NOAEL= 0.77 mg/kg/day
UFA= 10x
UFH= 10x
FQPA SF= 1x
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
UFA= 10x
UFH= 10x
FQPA SF= 1x
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 were 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.  UFA = extrapolation from animal to human (intraspecies).  UFH = 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 thoroughly reviewed by the Agency.  There was a Special 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".

5.0	Dietary Exposure and Risk Assessment

References:
oo 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, DP#404359, DP#411652, 08/14/2013.
oo Linuron: Acute and Chronic Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section (3) Registration Action on Coriander, 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 hydroxy-norlinuron.  3,4-DCA is not of regulatory concern in connection with the registered uses 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 analytical method in which known metabolites and unidentified polar components in plants and bound residues in animal tissues are hydrolyzed 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 moderately 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 rarely 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 pathways of 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 by 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 analytical method determines linuron and metabolites convertible to 3,4-DCA).

Table 5.1.  Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression.
Matrix
Residues included in Risk Assessment
Residues included in Tolerance Expression
                                    Plants
                                 Primary Crop
                                  linuron and
                      metabolites convertible to 3,4-DCA
                linuron and metabolites convertible to 3,4-DCA

                                Rotational Crop

                                   Livestock
                                   Ruminant

                                    Poultry

                                Drinking Water

                                Not Applicable

5.2	Food Residue Profile

No new 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 systemic activity in plants.  Finite residues of linuron and/or its metabolites are anticipated on food and feed commodities, even from early season soil-directed applications.  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.  Summary 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
                                     Mean
                                      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
[a]HAFT = 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.
[b]Residues were converted to and measured as 3,4-DCA.  Values were converted to linuron equivalents.
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 livestock 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 memorandum: "Revised Linuron Drinking Water Assessment for an IR-4 New Use on Coriander, Dill, Celeriac, Horseradish, Parsley, Dry Peas, and Rhubarb" (H. Zhong, D405829, 06/25/2013) and incorporated directly 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.

EDWCs 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 Analysis Modeling System (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/.

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
Acute (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 v<IP_ADDRESS>, 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.  Default processing factors were used for dried potato, corn syrup, and dried beef meat.  Table 2.2.2 lists HED recommended tolerances for the proposed 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 Analysis Division (BEAD).

The acute dietary analysis incorporated 100%CT for all registered and proposed commodities.

The chronic dietary analysis incorporated average %CT data for asparagus (25%), carrots (85%), celery (25%), corn (1.0%), cotton (1.0%), potatoes (5.0%), sorghum (1.0%), soybeans (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) exposure assessments for linuron were considered slightly refined; the assessments incorporated recommended and/or established tolerance level residues, and used default processing factors.  Maximum %CT estimates for registered crops were also incorporated into the assessment. The EDWC from EFED (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 analyses were conducted.  The results of the acute analyses 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 years 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.

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 analysis 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 highly exposed population subgroup.

5.4.5	Cancer Dietary Risk Assessment

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
                               (95th Percentile)
                                Chronic Dietary

                          Dietary Exposure (mg/kg/day)
                                    % aPAD*
                                Dietary Exposure
                                  (mg/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
                                       19
 Females 13-49 years old
                                    0.006864
                                      5.7
                                    0.001443
                                       19
 *The 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 post-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 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.  The Agency is in the process 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 procedures 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 nearby pesticide applications.  This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (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).   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 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 will 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 aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.  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 by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

References:
oo Linuron. Occupational and Residential Exposure Assessment for Proposed Use on Coriander, Dill, Horseradish, Parsley, Celeriac, Rhubarb, and Pea (Dry).  K. Rury, DP#405825, 09/04/2013.

9.1	Short-Term Handler Risk

HED has evaluated 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 Lorox DF[(R)] 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 early season herbicide, applications occur for only a short period in the growing season, limiting the potential for continuous occupational exposure over a duration longer than 30 days.  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 by 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 estimates 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 Tables 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 handler MOEs ranged from 490 to 740.

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 (μg/lb ai)[1]
                    Inhalation Unit Exposure (μg/lb ai)[1]
                          Maximum Application Rate[2]
                    Area Treated or Amount Handled Daily[3]
                                    Dermal
                                  Inhalation
                                     Total

                                   Baseline
                                   Baseline

                              Dose (mg/kg/day)[4]
                                    MOE[5]
                              Dose (mg/kg/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
                                      450

                            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) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gal/day) x DAF (16%) / BW (80 kg).
5	Dermal MOE = Dermal NOAEL (5.8 mg/kg/day) / Dermal Dose (mg/kg/day).
6	Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gal/day) / BW (80 kg).
7	Inhalation MOE = Inhalation NOAEL (5.8 mg/kg/day) / Inhalation Dose (mg/kg/day).
8	Total MOE = NOAEL (5.8 mg/kg/day) / Dermal Dose + Inhalation Dose.

Table 9.1.2.  Occupational Handler Short-Term Exposure and Risk Estimates for Linuron with PPE Required on the Label (Chemical Resistant Gloves, Coveralls).
                               Exposure Scenario
                                Crop or Target
                             Dermal Unit Exposure
                                (μg/lb ai)[1]
                           Inhalation Unit Exposure
                                (μg/lb ai)[1]
                          Maximum Application Rate[2]
                    Area Treated or Amount Handled Daily[3]
                                    Dermal
                                  Inhalation
                                     Total

                               Gloves, Coveralls
                                   Baseline

                              Dose (mg/kg/day)[4]
                                    MOE[5]
                              Dose (mg/kg/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 for Seed

                                  0.5 lb ai/A

                                    0.0033
                                     1,800
                                    0.00448
                                     1,300
                                      750
                                  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) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gal/day) x DAF (16%) / BW (80 kg).
5	Dermal MOE = Dermal NOAEL (5.8 mg/kg/day) / Dermal Dose (mg/kg/day).
6	Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gal/day) / BW (80 kg).
7	Inhalation MOE = Inhalation NOAEL (5.8 mg/kg/day) / Inhalation Dose (mg/kg/day).
8	Total MOE = NOAEL (5.8 mg/kg/day) / Dermal Dose + Inhalation 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 (μg/lb ai)[1]
                    Inhalation Unit Exposure (μg/lb ai)[1]
                          Maximum Application Rate[2]
                    Area Treated or Amount Handled Daily[3]
                                    Dermal
                                  Inhalation
                                     Total

                             Engineering Controls
                             Engineering Controls

                              Dose (mg/kg/day)[4]
                                    MOE[5]
                              Dose (mg/kg/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
                                      740
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) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gal/day) x DAF (16%) / BW (80 kg).
5	Dermal MOE = Dermal NOAEL (5.8 mg/kg/day) / Dermal Dose (mg/kg/day).
6	Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gal/day) / BW (80 kg).
7	Inhalation MOE = Inhalation NOAEL (5.8 mg/kg/day) / Inhalation Dose (mg/kg/day).
8	Total MOE = NOAEL (5.8 mg/kg/day) / Dermal Dose + Inhalation Dose.

9.2	Short-Term Post-Application Risk

9.2.1	Dermal Post-Application Risk

Only short-term post-application exposure is expected for linuron based on the proposed use pattern, including that linuron is primarily applied in the early stages of the crop growth cycle and only once or twice per season.  Because linuron is primarily applied in the early stages of the crop season, only 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 irrigation to parsley, dill, coriander, and celeriac was of concern on day 0.  The Lorox DF[(R)] label recommends that chemigation or rainfall occur within two weeks (14 days) after linuron application.  However, in the Columbia River Basin, Lorox[(R)] DF is used only where the crop is sprinkler irrigated; increasing the likelihood for exposure via hand-set irrigation.  In order for MOEs to be greater than the LOC at the maximum single application rate, hand-set irrigation should occur 4 days after application for parsley, dill, coriander and 8 days after application for celeriac.

Table 9.2.1.  Occupational Post-application Short-Term Dermal Exposure and Risk Estimates for Linuron.
                                   Crop/Site
                                  Activities
                        Transfer Coefficient (cm[2]/hr)
                                    DFR[1]
                                  Dermal Dose
                                (mg/kg/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 x F x (1-D)t x 4.54E8 ug/lb x 2.47E-8 acre/cm[2]; where F = 0.25 and D = 0.10 per day
2	Daily Dermal Dose = [DFR (ug/cm[2]) x Transfer Coefficient x 0.001 mg/ug x 8 hrs/day x dermal absorption (16%)]  BW (80 kg).
3	MOE = POD (5.8 mg/kg/day) / Daily Dermal Dose.  Daily Dermal Dose = [DFR (ug/cm[2]) x TC x 0.001 mg/ug x 8 hrs/day x dermal absorption factor (16%)]  BW (80 kg).

9.2.2	Inhalation Post-Application 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. The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by 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. Zhong, 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#0056436, 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 Study, 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 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, Horseradish, 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, Parsley, 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 Analytical Methods of Plants and Animal Matrices.  Summary of Analytical Chemistry and Residue Data.

Appendix 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 (procymidone, linuron, iprodione, chlozolinate, p,p'-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane 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; Lambright, C; Furr, J; Vandenbergh, J; & Gray, L. 2004. A mixture of the "antiandrogens" 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.

McIntyre, B; Barlow, N; Wallace, D; Maness, S; Gaido, K; Foster, P. 2000.  Effects of in utero exposure to linuron on androgen-dependent reproductive development 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; Lambright, C; Mann, P; Price, M; Cooper, R; Ostby, J; Gray, D. 1999. Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p'-DDE, and ketoconazole) and toxic substances (dibutylhexyl phthalate, 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
Acute Oral (Rat)
                                   00027625
LD50 = 2600 mg/kg
III
870.1200
Acute Dermal (Rabbit)
                                   00027625
LD50> 2000 mg/kg
III
870.1300
Acute Inhalation (Rat)
                                   00053769
LC50 > 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/A

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)

Acceptable/Guideline

0, 5, 25, 100 mg/kg/day
Maternal Systemic
	NOAEL= 5 mg/kg/day
	LOAEL = 25 mg/kg/day, based on 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)

Acceptable/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 retention 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

[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 absorption factor = 16% over 8 to 10 hr (2%/hr).

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.  Cytotoxicity 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 was 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-mix and dimethylbenzanthracene with S9-mix) and solvent (DMSO) controls responded 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.   Bone 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.

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 weights 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 synthesis 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 bone 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
Systemic 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
Special 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

F0 and F1 animals from 2-generation reproduction study (41463401),

Selected animals from the 2-generation reproduction study were used to evaluate changes in serum hormone levels, accessory 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 support 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.

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 protocols 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
                                      yes
                                      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#0056666

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+-0.5C
MRID 42213301
Density
1.4963 g/mL at 22.3+-0.5C
(air comparison pycnometer)
MRID 42213301
Water solubility (20.5 +- 0.5 C)
5.88x10[-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
4.015x10[-5] Pa
3.01x10-7 mm Hg
MRID 42213303
Henry's Law Constant at 25°C
1.97x10[-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)
8.2x10[2] at 23+-1C (GC method)
log Pow = 2.76
MRID 42213301

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.