Page 1 of 48 UNITED STATES ENVIRONMENTA L PROTECTION AGENCY

WASHINGTON, D.C. 20460 OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION MEMORANDUM DATE: February 22 , 2011 SUBJECT: Mefenp yr - diethyl (HOE 107892) Safener: Revised Human Health Risk

Assessment to Support the New use Petition on Sorghum [grain, stover, and forage] and Grass Grown for Seed (including Conservation Reserve Program areas) ; D374653 PC Code: 811800 DP Barcode: 3 74653 Decision No.: 425581 Registration No. : NA Petition No.: NA Regulatory Action: Section 3 Risk Assessment Type: Single Chemical Aggregate Case No.: NA TXR No.: NA CAS No.: 135590
- 91
- 9 MRID No.: NA 40 CFR: NA FROM: Matthew Lloyd, CIH; ORE/Risk Assessor

Alexandra LaMay , Chemist Linda Taylor, Toxicologist Registration Action Branch 7 Health Effects Division (7509 P ) THROUGH: Michael S. Metzger, Chief

Registration Action Branch 7 Health Effects Division (7509 P ) TO: Bethany Benbow, RM 23

Registration Division (7505P) Mefenp yr - diethyl, also known as Diethyl
- 1
- (2,4
- Dichlorophenyl )
- 5
- Methyl
- 2
- Py razolin
- 3,5
- Dicarbox yl ate or HOE 107892, is a safener currently used with several herbicides on cereal grain. This action requests new uses on sorghum and grass grown for seed. Mefenp yr - diethyl is a component of HUSKIE TM herbicide; it is co
- formulated with the active ingredients p yrasulfotole and bromox ynil and is proposed for use on sorghum one application per season and two applications to grass grown for seed per season.Mefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 2 of 48 Table of Contents 1.0 Executive Summary
................................ ................................ ................................ ............ 4 Regulatory

Recommendations and Data Deficiencies
................................ ........................ 6 2.0 In gredient Profile
................................ ................................ ................................ ................ 6 2.1 Summary

of Registered/Proposed Uses
................................ ................................ .. 7 2.2 Structure and Nomenclature
................................ ................................ ................... 8 2.3 Phy sical and Chemical Properties
................................ ................................ ........... 9 3.0 Hazard Characterization/Assessment
................................ ................................ .................. 9 3.1 Hazard and Dose
- Response Characterization
................................ ......................... 9 3.1.1 Database Summary
................................ ................................ ..................... 9 3.1.2 Mode of Action, Metabolism, Toxicokinetic Data
................................ ... 10 3.1.3 Toxicological Effects
................................ ................................ ................ 10 3.1.4 FQPA Safety Factor
................................ ................................ .................. 12 3.2 Dose Response Assessment
................................ ................................ .................. 13 3.2. 1 Acute Reference Dose (aRfD)
- Females age 13
- 49
................................ . 13 3.2.2 Acute Reference Dose (aRfD)
- General Population
................................ 13 3.2.3 Chronic Reference Dose (cRfD)
................................ ............................... 14 3.2.4 Dermal Absorption
................................ ................................ .................... 14 3.2.5 Dermal Exposure (Short
- and Intermediate
- Term)
................................ ... 1 4 3.2.6 Dermal Exposure (Long
- Term)
................................ ................................ 15 3.2.7 Inhalation Exposure (Short
- and Intermediate
- Term)
............................... 15 3.2.8 Inhalation Exposure (Long
- Term)
................................ ............................ 15 3.2.9 Classification of Carcinogenic Potential
................................ ................... 15 3.2.10 Summary

of Toxicological Doses and Endpoints
................................ .. 16 3.3 Endocrine Disruption
................................ ................................ ............................ 17 4.0 Public Health and Pesticide Epidemiology Data
................................ .............................. 18 5.0 Dietary

Exposure/Risk Characterization
................................ ................................ ........... 18 5.1 Pesticide Metabolism and Environmental Degradation
................................ ........ 18 5.1.1 Metabolism in Plants, Animals and Rotational Crops
.............................. 18 5.1.2 Analy

tical Methodology
................................ ................................ ........... 19 5.1.3 Environmental Degradation
................................ ................................ ...... 19 5.1.4 Comparative Metabolic Profile
................................ ................................ . 19 5.1.5 Pesticide Metabolites and Degradates of Concern
................................ .... 20 5.1.6 Drinking Water Residue Profile
................................ ................................ 20 5.1.7 Food Residue Profile
................................ ................................ ................. 21 5.1.8 International Residue Limits
................................ ................................ ..... 21 5.2 Dietary

Exposure and Risk
................................ ................................ ................... 22 5.2.1 Acute Dietary

Exposure/Risk
................................ ................................ ... 22 5.2.2 Chronic Dietary

Exposure/Risk
................................ ................................ 22 5.2.3 Cancer Dietary

Risk
................................ ................................ .................. 22 6.0 Residential (Non
- Occupational) Exposure/Risk Characterization
................................ ... 23 7.0 Aggregate Risk Assessments and Risk Characterization
................................ .................. 24 8.0 Cumulative Risk Characterization/Assessment
................................ ................................ 24 9.0 Occupational Exposure/Risk Pathway
................................ ................................ .............. 25Mefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 3 of 48 9.1 Occupational Handler Risk
................................ ................................ ................... 25 9.2 Occupational Postapplication Risk
................................ ................................ ....... 27 10.0 Data Needs and Label Recommendations
................................ ................................ ........ 29 10.1 Toxicology
................................ ................................ ................................ ............ 29 10.2 Residue Chemistry
................................ ................................ ................................ 29 10.3 Occup ational and Residential Exposure
................................ ............................... 29 Appendix A: Toxicology Assessment
................................ ................................ ......................... 30 A.1 Toxicology

Data Requirements
................................ ................................ ............ 30 A.2 Toxicity

Profiles
................................ ................................ ................................ ........ 31 A.3 Executive Summaries
................................ ................................ ................................ 36 A.4 References ( in MRID order)
................................ ................................ ................ 42 A.5 Rationale for Requiring the Data
................................ ................................ .......... 45 Appendix B: Tolerance Summary and Table
................................ ................................ ............... 48 Appendix C: Review of Human Research
................................ ................................ ................... 48Mefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 4 of 48 1.0 Executive Summary Mefenp yr - diethyl, also known as Diethyl
- 1
- (2,4
- Dichlorophenyl )
- 5
- Methyl
- 2
- Py razolin
- 3,5
- Dicarbox yl ate or HOE 107892, is a safener currently used with several her bicides on cereal grain
. Tolerances for residues of m efenp yr- diethyl, and its 2,4
- dichlorophenyl
- py razoline metabolites resulti ng from application of the safener are listed in 40 CFR §180.509. This action requests new uses on sorghum and grass grown for seed
. Mefenpy r is a component of HUSKIE TM herbicide; it is proposed for use on sorghum one application per season and two applic ations to grass grown for seed per season. The toxicology

database on mefenpy

r- diethyl is considered adequate for selecting endpoints and uncertainty factors to support the proposed amended use of this safener. Metabolism studies indicate that mefenp yr - diethyl is rapidl y metabolized, widel y distributed, and primarily excreted via the urine. Repeated exposure via the dermal route did not induce any treatment - related effects at dose levels up to and including th e limit dose. Repeated exposure studies via the oral route demonstrate that the target organs are the liver and hematopoietic s ys tem in dogs, mice, and rats. Mefenp yr- diethyl was negative for carcinogenicity in rats and mice, and it did not show any geno toxic potential. Developmental toxicity was not observed in the rat but was observed in the rabbit (abortions). Mefenp yr - diethyl did not induce any signs of reproductive toxicity or neurotoxic potential. Additionally, mefenpy r - diethyl has low acute toxi city by the oral, dermal, and inhalation routes of exposure. It is not a dermal irritant but is a slight ocular irritant and dermal sensitizer and ocular irritant. There is no evidence of increased susceptibility in rats or rabbits following pre
- and/o r post - natal exposure to mefenp yr- diethyl, no evidence of neurotoxicity in any study, and exposure values are not expected to underestimate risk. Therefore, the FQPA factor has been reduced to 1X for this chemical. No effects were seen in the toxicity database that could be attributed to a single exposure of mefenp y r- diethyl. An endpoint and point of departure were selected from the dog chronic oral toxicity study for the chronic dietary

risk assessment. The chronic population adjusted dose (cPAD) of 0.51 mg/kg/day was based on the study NOAEL with a 100X uncertainty factor to account for inter
- and intra
- spec ies extrapolation . At the study L OAEL , liver effects were observed. There are currently no residential uses of mefenpy r - diethyl; therefore endpoints for non - dietary , non - occupational risk assessments were not selected. Based on the current use patterns chronic dermal and inhalation occupational exposures are not expected. The endpoints and doses used for the short
- and intermediate
- term dermal and inhalation exposures for occupational risk assessment were selected from the developmental toxicity study in the rabbit. For both durations and routes of exposure, the point of departure is the NOAELof 100. At th e study L OAEL , abortions were observed. The level of concern (LOC) for all four risk assessments is for margins of exposure (MOEs) that are less than 100. Absorption via the inhalation route was assumed to be equivalent to oral exposure for these assessments. A dermal absorption factor of 4 3 % was derived from available information andMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 5 of 48 used in the risk assessment. Mefenp yr - diethyl is classified as “not likel y to be carcinogenic to humans”. Adequate residue chemistry data have been submitted to support the proposed use and the necessary crop tolerances. An adequate GC/MSD anal ytical enforcement method for plants is available to enforce the newly p roposed tolerances. No Codex, Canadian, or Mexican maximum residue limits (MRL s) are established for residues of mefenp yr - diethyl and metabolites in crop or livestock commodities; therefore, there are no issues with international harmonization raised by this action. HED conducted a highly

conservative chronic dietary risk assessment for food and drinking water for mefenp yr- diethyl using tolerance level residues, assuming 100% crop treated, and incorporating modeled water numbers reflecting an exaggerate d application rate . Mefenpy rdiethyl dietary

exposure from food and drinking water based on the newly proposed use pattern results in an estimated risk equivalent to <1% of the cPAD for the general population and all regulated subpopulations. No toxic effects attributable to a single exposure of mefenp yr - diethyl were seen in the database; therefore, an acute dietary risk assessment was not conducted
. Mefenp yr - diethyl is not likely to be a human carcinogen; thus, a cancer dietary risk assessment is not required
. P roducts containing mefenpy r - diethyl are marketed and ty pically applied to agricultural crops, and are not used for residential pesticidal control based on the crops specified on the applicable labels. Therefore, a residential risk assessment w as not conducted. Since there are no residential uses for mefenp yr - diethyl, the aggregate risk assessments only include the contribution of risk from dietary (food and water) sources. HED has no concern for aggregate risks resulting from all uses for mef enpy r - diethyl
. HED conducted occupational handler and post application exposure and risk assessments to support the requested new use pattern. Mefenpy r is applied as a component of a mixed active ingredient herbicide, HUSKIE TM

. The risk assessment evaluated m efenp yr - diethyl applied b y aerial or ground application meth ods to sorghum and grass grown for seed. One application is proposed for sorghum and two applications are proposed on the product labels for the HUSKIE TM herbicide per growing season. C urrent labels require normal work clothing (WDGs) or double layer clothing (EC s ) with appropriate footwear, eye protection, and chemical resistant gloves. Respirators are not required. Restricted entry intervals (REI) are 24 hours on all labels. Risks f rom occupational exposures were calculated for handlers using aerial and ground
- based application equipment which would be ty pical for herbicide applications to large field crops. For all scenarios considered, risks were not of concern at current label re quirements for clothing and personal protective equipment use (i.e., calculated MOEs well exceeded the target of 100 ranging from ~ 170 up to ~200 ,000 at the baseline PPE). Post
- application worker risks were also evaluated for scouting activities which is the only likely hand labor activity which would occurMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 6 of 48 relative to the use of mefenpy r - diethyl in agriculture and risks were not of concern even on the day of application when individuals scout for an 8 hour workday (i.e., MOE s > 33 ,000 and target = 100). C urrent labels require a 24 hour REI so actual risks would be even of less concern because residues would dissipate some between application and the REI of 1 day
. Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L o w - Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide
. These studies, which comprise the Pesticide Handlers Exposure Database (PHED) and Agricultural Reentry Task Force (ARTF) , have been determined to require a review of their ethical conduct, and have received that review. Regulatory Recommendations and Data Deficiencies Provided the petitioner submits a revised Section F to correct the commodity definitions presented in Appendix B, Table B1, HED has no objection to the establishment of tolerances for the herbic ide safener mefenpy r - diethyl (1
- (2,4
- dichlorophenyl)
- 4,5
- dihydro
- 5
- methyl
- 1H
py razole
- 3,5
- dicarboxylic acid, diethyl ester) and its 2,4
- dichlorophenyl
- pyrazoline metabolites in/on the following crop commodities:

Grass, forage
................................ ................................ 1.6 ppm Grass, hay
................................ ................................ ..... 0.2 ppm S orghum, forage
................................ ........................... 0.4 ppm Sorghum, grain
................................ .......................... 0.04 ppm Sorghum, stover
................................ .......................... 0.2 ppm Data Gaps The following data should be required under 40 CFR Part 158 :  Subchronic (28
- day) Inhalation Study  Acute Neurotoxicity

Study (New requirement under the Revised Part 158 Toxicology Data Requirements (2007 edition)  Subchronic Neurotoxicity Study (New requirement under the Revised Part 158 Toxicology

Data Requirements (2007 edition)  Immunotoxicity

Study (New requirement under the Revised Part 158 Toxicology Data Requirement s (2007 edition) 2.0 Ingredient Profile Mefenp yr - diethyl is a safener used with several herbicides. Safeners are substances added to herbicidal active ingredients in formulations to protect crops from potential adverse effects of theMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 7 of 48 herbicides. Safen ers are often similar in molecular structure to active pesticides and may exhibit mammalian toxicity
. Thus, the Agency has established some tolerances for safener s. 2.1 Summary of Registered/Proposed Uses The proposed use pattern is for mefenp yr - diethyl on sorghum and grass grown for seed (including Conservation Reserve Program areas). Mefenp yr - diethyl is currently used as a safener with various herbicid es on cereal grain crops. HED considered the current product labels which contain mefenp yr- diethyl as part of the review to support the requested use revision. Mefenp yr - diethyl is formulated in HUSKIE TM Herbicide and is proposed at 0.010 lbs ai/A for sorghum, and 0.009 lbs ai/A for grass grown for seed and range conservation reserve land. Mefenp yr - diethyl has current registrations for cereal grains (wheat, barley , oats, rye). The maximum seasonal use rate is 0.053 lb safener/A in registered end
- use produc ts . The proposed uses include a maximum of two applications per season for grass grown for seed and sorghum. The submitted limited field rotational crop data for field corn and so yb ean are adequate for the proposed uses. The field rotational crop data fo r field corn will support a 90
- day plantback interval (PBI) with no need for rotational crop tolerances. The field rotational crop data for soy bean will support the established soy bean and canola tolerances and a 120
- day PBI.Mefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 8 of 48 2.2 Structure and Nomenclature Table 2.2. Mefenpyr - Diethyl Nomenclature
. Chemical structure

Common name Mefenpyr
- diethyl Com pany experimental name AE F107892, HOE 107892 IUPAC name Diethyl (RS )
- 1
- (2
- ,4
- dichlorophenyl)
- 5
- methyl
- 2
-py razoline
- 3,5
- dicarboxylic acid CAS name 1
- (2,4
- dichlorophenyl)
- 4,5
- dihydro
- 5
- me thyl
- 1 H
-pyrazole
- 3,5
- dicarboxylic acid, diethyl ester CAS registry number 135590
- 91
- 9 Chemical structure of AE F094270 (HOE 094270) metabolite

Chemical structure of AE F109453 (HOE 109453) metabolite

Chemical structure of AE F113225 (HOE 113225) metabolite O O C H 3 O O C H 3 N N Cl Cl

C H 3

N N Cl Cl

C H 3 C O 2 H

N N Cl Cl

C H 3 C O 2 H H O 2 C

N N Cl Cl

C H 3 C O 2 H H 3 CH 2 C O O CMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 9 of 48 2.3 Physical and Chemical Properties Table 2.3 Physicochemical Properties of Mefenpyr - Diethyl. Param eter Value Reference Melting point/range 50
- 52 oC 43
- 47 oC MRID 43984109 pH Was not determined , because mefenpyr
diethyl technical is practically insoluble and nondispersible in water. MRID 43984109 Density (20 oC) 1.31 g/cm3 at 20oC MRID 43984109 Water solubility (20 oC) 0.017 g/L at pH 0.9 0.020 g/L at pH 6.2 pH 10 solubility not determined due to compound hydrolysis MRID 43984109
Solvent solubility (20 oC) Methanol >400 g/L isopropanol 151 g/L n - hexane 35 g/L toluene >400 g/L dichloromethane >500 g/L acetone >500 g/L ethyl acetate >400 g/L dimethylsulfoxide >500 g/L polyethylene glycol 151 g/L sesame oil 56 g/L MRID 43984109

Vapor pressure (20 oC) 6.3 x 10 - 6 Pa MRID 44024001 Dissociation constant, pKa Neither acidic nor basic functional groups. Dissociation, if any, is expected to be neg ligible. MRID 43984109 Octanol/water partition coefficient, Log(KOW) 3.83 at pH 6.3 and 21 oC MRID 43984109 UV/visible absorption spectrum (nm) Primary λmax = <200 Secondary λmax = 305 MRID 43984109 3.0 Hazard Characterization/Assessment 3.1 Hazard and Dose - Response Characterization 3.1.1 Database Summary The toxicology

database on mefenpy

r- diethyl is considered adequate for risk assessment in support of the proposed amended use of this safener . An immunotoxicity study and acute and subchronic neurotoxicity

studies that are newl y required by the Part 158 Guidelines, and should be required as conditional data. A subchronic inhalation study is also required since inhalation exposure is likel y as a result of the proposed uses
. The following studies were available for consideration in this assessment. No additional information was found in a screening literatureMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 10 of 48 search relevant to the hazard assessment.

 Subchronic: 90
- day

oral toxicity

(rat); 13
- week oral toxicity (dog); 90
- day oral toxicity (mouse)  Developmental: rat (pre
- and postnatal) and rabbit studies  Reproduction: 2
- generation reproduction study (rat)  Chronic: combined oral chronic toxicity /carcinogenicity

(rat); carcinogenicity

(mouse); chronic oral toxicity

(dog)  Other: mutagenicity battery ; metabolism 3.1.2 Mode of Action, Metabolism, Toxicokinetic Data Metabolism studies in rats showed that mefenp yr - diethyl was rapidl y absorbed and metabolized, with the majority

of the radiolabel excreted via the urine and feces within the first 24 hours. Renal excretion was the predominant route of elimination in both sexes. Three metabolites were identified in both the urine and feces (HOE 113225, HOE 109453, HOE 094270), but the parent compound was found only in the feces. The metabolic pathway con sists of consecutive hydrol ys is (saponification) of the two carboxylic acid ester groups, resulting in an aromatization of the py razoline ring (Hoe 107892 → HOE 113225 → HOE 109453 → HOE 094270). Excretion is biphasic, and metabolism appears to be influenced b y s ex to a minor extent; i.e., males either have a lower intestinal absorption or a higher biliary excretion compared to females. 3.1.3 Toxicological Effects Mefenp yr - diethyl has low acute toxicity by the oral, dermal, and inhalation routes of exposure. It is not a dermal irritant but is a slight ocular irritant and dermal sensitizer
. Repeated exposure of rats via the dermal route did not induce any treatment - related effects at dose levels up to and including the limit dose. Repeated exposure studies via the oral route demonstrate that the target organs are the liver and hematopoietic sy stem in dogs, mice, and rats. Mefenpy r - diethyl was negative for carcinogenicity in rats and mice, and it did not show any genotoxic potential. Developmental toxicity

was not observed in the rat but was observed in the rabbit (abortions) at the same dose level producing maternal toxicity . Mefenpy r - diethyl did not induce any signs of reproductive toxicity . The developmental toxicity studies in rats and rabbits, as well as the reproductive toxicity

study in rats, did not demonstrate any pre - or post - natal sensitivity
. No neurotoxicity

studies are available on mefenpyr
- diethyl, but there was no evidence of neurotoxicity

in any of the submitted studies. The database for carcinogenicity is considered adequate, and mefenp yr - diethyl is classified “not likely to be carcinogenic to humans”. The mutagenicity /g enetic toxicity

database i s considered complete, and there is no concern for mutagenicity . The mouse carcinogenicity study was performed at adequate dose levels and was negative. There was no evidence of a carcinogenic response in the rat chronic toxicity /carcinogenicity study

foll owing dietary

exposure for 124 weeks at dose levels up to 250
- 300 mg/kg/day . Previously , the study was classified asMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 11 of 48 unacceptable because the doses employed were not considered adequate to test the carcinogenic potential of mefenp yr - diethyl. This was based on the determination that the increases in reticulocy te counts were not supported by changes in red blood cell parameters. Although this effect is observed across species, it was not considered to be biologicall y relevant previousl y because the effect was minimal, and no other effects were observed. During a re
- evaluation of the toxicology database on mefenp yr- diethyl, the issue of the adequacy of the dose levels used in this study was re - evaluated. The data considered in this re
- evaluation include the 1 24
- week study and the rat subchronic oral (90
- day) toxicity study that was used as the basis for dose selection for the chronic toxicity /carcinogenicity

study . No difference was observed in the hematologic response between the sexes in the subchronic study , which predicted that dose levels of 7500 ppm should be used in the chronic carcinogenicity/carcinogenicity study. In the chronic study, however, the response in the females at 5000 ppm was approaching an adverse level [all 3 red blood cell compartments a ffected ( ↓5%) with a regenerative anemia (32%
- 72% ↑ reticulocy

tes]. In the males, red blood cell parameters were not affected, but there was an increase in hematopoietic activity (13%
- 46% ↑reticulocy

tes). The 5000 ppm dose to the males was slightl y lower ( 252 mg/kg/day) than in the females (318 mg/kg/day), suggesting that had the high dose been closer to that in the females, a similar reduction in red blood cell parameters also would have also been seen in the males. The blood effects observed in the chroni c study at 5000 ppm in females are considered sufficient evidence that this dose level is approaching adverse toxicity . Therefore, the highest dose used in the rat carcinogenicity study is considered adequate to test the carcinogenic potential of mefenpy r - diethyl. There is no evidence that mefenp yr- diethyl interacts with the estrogen, androgen, or thy roid hormonal sy stems. The toxicology

database for mefenpy

r - diethyl is complete under Part 158 (1984 edition), with the exception of a subchronic inhalati on toxicity study . It is recommended that a 28
- day inhalation study

be required because the application of mefenpy r - diethyl will be by

either aerial application or spray

boom equipment leading to potential inhalation exposure , and there is no effective me asure of toxicity by the inhalation route. Under the Revised Part 158 Toxicology Data Requirements (2007 edition) for registration of a pesticide (food and non
- food uses), acute and subchronic neurotoxicity studies and an immunotoxicity

study are new data requirements and are not required for mefenp yr- diethyl
. There is no evidence of neurotoxicity in the toxicology

database on mefenpy

r - diethyl, which includes subchronic, chronic, developmental toxicity , and reproduction studies performed at doses of 250 m g/kg/day

and above. Therefore, based on the above considerations, HED does not believe that conducting acute and subchronic neurotoxicity studies will result in a NOAEL less than the NOAEL of 51 mg/kg/day already s et for mefenp yr- diethyl (see Section 3.2.2 below) , and an additional uncertainty factor (UF DB ) for database uncertainties does not need to be applied.Mefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 12 of 48 Mefenp yr - diethyl was assessed in a complete battery of subchronic, chronic, carcinogenicity, developmental and reproductive studies. HED considered the entire toxicity database for mefenp yr- diethyl for potential adverse effects on the thy mus and spleen as indications of potential immunotoxicity and noted enlarged spleens; more severe hematopoiesis and hemosiderin deposits and increased spleen weights were observed in mice at doses greater than the limit dose. However, these were determined to be non
- specific changes not indicative of immunotoxicity . Therefore, based on the above considerations, HED does not believe that conducting a special series 870.7800 immunotoxicity study will result in a NOAEL less than the NOAEL of 51 mg//kg/day already set for mefenpyr
- diethyl and an additional uncertainty factor (UF DB ) for database uncertainties does not need to be applied. 3.1.4 FQ PA Safety Factor The database for prenatal developmental and reproductive toxicity is considered adequate. Developmental toxicity

was not observed in the rat but was observed in the rabbit (abortions) at the same dose level producing maternal toxicity . Mefenpy r - diethyl is not considered a reproductive toxicant. The developmental and reproductive toxicity studies showed no evidence of increased sensitivity

or susceptibility

of young rats or rabbits following pre
- and/or postnatal exposure to mefenp yr- diethyl. There is a l ack of evidence of neurotoxicity in any study on mefenp yr- diethyl. There are no concerns and no residual uncertainties with regard to pre
- and/or postnatal toxicity, and estimates of exposure are not likel y to underestimate risk. The Food Quality Protec tion Act (FQPA) safety factor has been reduced to 1X for all population subgroups, including infants and children. 3.1.4.1 Evidence of Neurotoxicity There is no evidence of neurotoxicity resulting from exposure to mefenpy r - diethyl in the current database. An acute neurotoxicity study and a subchronic neurotoxicity study are new requirements under the Revised Part 158 Toxicology Data Requirements
. 3.1.4.2 Evidence of Developmental Toxicity In the two rat developmental toxicity studies conducted at 0 and 1000 mg/kg/day , minimal fetal body
- weight effects and decreased maternal body - weight gain were observed during the first week. There were no developmental effects. In the rabbit developmental toxicity study , d evelopmental toxicity

(abortion) was o bserved at the same dose level producing maternal toxicity . Executive summaries of the rat and rabbit developmental toxicity studies may

be found in Appendix A to this assessment. 3.1.4.3 Evidence of Reproductive Toxicity There was no evidence of reproductive toxicity following exposure via the diet at concentrationsMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 13 of 48 of 0, 200, 1000, and 5000 ppm [males: 16, 82, and 428 mg/kg/day ; females: 18, 94, and 482 mg/kg/day] for 2 generations. Parental toxicity consisted of decreased body weight and body
weight gain, and an increase in spleen weight and in the severity (not incidence) of splenic extramedullary

hematopoiesis in females. In the pups, decreased body weight and body
- weight gains were observed at the same dose levels as the parental animals. The NO AEL is 1000 ppm for both the parental animal and offspring. The executive summary of the reproductive toxicity study in rats may

be found in Appendix A to this document. 3.1.4.4 Additional Information from Literature Sources No additional information was found in the literature regarding pre
- or post - natal toxicity to mefenp yr- diethyl. 3.1.4.5 Determination of Susceptibility There is little concern for prenatal toxicity resulting from exposure to mefenpy r - diethyl. There is no evidence of increased s usceptibility [qualitative and quantitative] following in utero exposure to mefenp yr- diethyl in either the rat or rabbit developmental toxicity study , and there is no evidence of increased susceptibility [qualitative or quantitative] following in utero and /or pre
- /post
- natal exposure in the 2
- generation reproduction study in rats. Developmental toxicity was not observed in the rat at the limit dose (1000 mg/kg/day). The onl y effects observed in the rat developmental toxicity

study were decreased body
- weight gain and food efficiency during the first week of dosing and increased spleen weights in the maternal animal and a marginal decrease in fetal body

weight/body
- weight gain during lactation (postnatal study). Developmental toxicity (abortions) was observed in the rabbit at a dose level of 250 mg/kg/day . In the reproduction study , decreased body weight and body- weight gain (parental animal and offspring) and an increase in spleen weight and in the severity (not incidence) of splenic extramedullary hematopoie sis were observed in females. There is no evidence of neurotoxicity , and there are no residual concerns. 3.2 Dose Response Assessment 3.2.1 Acute Reference Dose (aRfD) - Females age 13 - 49 No appropriate endpoint attributable to a single exposure (dose) was identified from oral toxicity studies for females ages 13
- 49, including the developmental studies that would be appropriate for this population subgroup. HED’s current policy is that decreased body weight is not an effect likely to result from a single dose of a pesticide. Further, the abortions seen in the rabbit study did not occur within a timeframe suggesting a single dose effect. 3.2.2 Acute Reference Dose (aRfD) - General Population No appropriate endpoint attributable to a single exposure (dose) was identified from oral toxicity studies for the general population.Mefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 14 of 48 3.2.3 Chronic Reference Dose (cRfD) Study Selected : chronic oral toxicity

– dog (OPPTS 870.4100) MRID No. : 44316402 Executive Summary : See Appendix A, Guideline §870.4100 Dose and Endpoint for Risk Assessment : NOAEL = 51 mg/kg/day , based on increased liver weight in both sexes, cholestasis, and increased alkaline phosphatase at the sy stemic LOAEL of 260 mg/kg/day
. Uncertainty

Factor(s) : 100X [10 interspecies; 10X intraspecies] Comments about Study

/Endpoint/Uncertainty Factors : For the current risk assessment, a re
evaluation of the endpoints used was performed. Previously , the chronic dietary endpoint was sel ected b y H IARC from the 2
- generation reproduction study in rats. However, the endpoint associated with the NOAELof 1000 ppm (57 mg/kg/day) was based on the intake of test material b y the F1 males during the post
- mating phase, since this provided the lowe st dose. However, since it is more appropriate to use the intake from the premating phase of the study for the P0 generation, the NOAEL for the study wa s calculated to be 82 mg/kg/day for the 1000 ppm concentration. Since this change with the 2
- generatio n reproduction study no longer provides the lowest NOAEL, the mefenpy r - diethyl team re
- evaluated the other long
- term studies considered previously

by the HIARC. Based on this re
- assessment, the chronic dog study was selected. This study

is supported by

the chronic rat study , which shows a similar NOAEL(48 mg/kg/day). A comparison of the rat and dog subchronic oral toxicity studies shows that the dog is the more sensitive species (based on L OAEL for common effects). The route and duration of exposure ar e appropriate for selection of the chronic dietary endpoint. The executive summary of the chronic toxicity studies in dogs and rats may be found in Appendix A to this document. 3.2.4 Dermal Absorption A dermal absorption study was submitted (currently under review) for mefenpy r - diethyl, which shows that mefenp yr - diethyl is able to penetrate the skin and is found in the blood, internal organs, and excreta. A single dermal dose of 0.0052, 0.052, or 0.52 mg/cm 2 14 C
- mefenpy r diethyl was administered to male rats was rapidly absorbed, distributed and eliminated (MRID 47563901). The amount absorbed increased with duration of exposure. The average 14 C
mefenp yr- diethyl absorbed within 24 hours was 31%, 28%, and 6% of the applied dose for the low
- , mid
- , and high
- dose groups, respectivel y. Recovery of the applied dose was 77%
- 95% and most was recovered from the skin washes and urine. Following a preliminary review of the study , a dermal absorption factor of 43.1% was e stimated based on the sum of 36% absorbed after 10 hours in the low dose group (0.0052 mg/cm2 ), in addition to 7.1% of applied dose that was associated with the application site. There is a 21
- day dermal toxicity

study available for mefenp yr- diethyl ; the D ER is in process. 3.2.5 Dermal Exposure (Short- and Intermediate - Term) Study Selected : Developmental toxicity study

– rabbit (OPPTS 870.3700)Mefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 15 of 48 MRID No. : 44089202 Executive Summary : See Appendix A, Guideline §870.3700 Dose and Endpoint for Risk Assessment : NOAEL = 100 mg/kg/day , based on a higher rate of abortions at the LOAEL of 250 mg/kg/day
. Uncertainty

Factor(s) : 100X [10 interspecies; 10X intraspecies] Comments about Study

/Endpoint/Uncertainty Factors : Previously , no endpoints were select ed for short
- and intermediate
- term dermal risk assessment, based on the lack of effect following subchronic dermal exposure at limit dose in rats and the lack of developmental effects in the rat at the limit dose. The HIARC was silent regarding the aborti ons in the rabbit developmental toxicity study . For the current action, the rabbit developmental toxicity study was selected for this exposure assessment. The incidence of abortions at the highest dose tested is considered significant and treatment
- relat ed (occurred in over a third of the animals at this dose level; 6/15). The abortions first occurred following 10 day s of dosing (gestation day 16
- 23). Dermal absorption data are available that indicate a 43% absorption factor for mefenpy r - diethyl. 3.2. 6 Dermal Exposure (Long - Term) Based on the anticipated use pattern, long
- term exposure via the dermal route is not expected. 3.2.7 Inhalation Exposure (Short- and Intermediate - Term) Study Selected : developmental toxicity

– rabbit (OPPTS 870.3700) MRID No. : 44089202 Executive Summary : See Appendix A, Guideline §870.3700 Dose and Endpoint for Risk Assessment : NOAEL = 100 mg/kg/day , based on a higher rate of abortions at the LOAEL of 250 mg/kg/day
. Uncertainty

Factor(s) : 100X [10 interspecies; 10X intraspecies] Comments about Study

/Endpoint/Uncertainty Factors : Previously , no endpoint was selected for short
- term inhalation risk assessment, based on the low acute toxicity (Toxicity Category III) and the use pattern (1 application per growing season; either aerial application or spray boom equipment that is as low to the ground as possible). During the current assessment, it was determined that typical risk assessments routinely do inhalation exposures for these occupational scenarios. The same study and endpoint used for the dermal assessments have been selected for the short
- and intermediate
- term inhalation exposure assessments. Since no inhalation absorption data are available for mefenpy r - diethyl, toxicity

by the inhalation route was considered to be equivalent to toxicity

by the oral route of exposure. 3.2.8 Inhalation Exposure (Long - Term) Based on the current use pattern , a long
- term inhalation risk assessment is not required. 3.2.9 Classification of Carcinogenic Potential Mefenp yr - diethyl is classified as “not likel y to carcinogenic to humans” . Carcinogenicity studiesMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 16 of 48 showed no evidence of an increase in the incidence of tumors in either the rat or the mouse. 3.2.10 S ummary of Toxicological Doses and Endpoints There are no residential uses; therefore, dermal and inhalation exposure risk assessments not required. Table 3.4.1 Summary of Toxicological Doses and Endpoints for Mefenpyr - diethyl for Use in Dietary and Non - Occupational Human Health Risk Assessments Exposure/ Scenario Point of

Departure Uncertainty

Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects Ac ute Dietary (General Population, including Infants and Children) No hazard was identified in any toxicity study for this duration of exposure
Ac ute Dietary (Females 13
- 49 years of age) No haz ard was identified in any toxicity study for this duration of exposure

Chronic Dietary (All Populations) NOAEL = 51

mg/kg/day UF A= 10x

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

0. 51 mg/kg/day cPAD = 0. 51 mg/kg/day chronic oral toxicity study (dog)

LOAEL = 260 mg/kg/day, based on increased liver weight in both sexes, cholestasis, and increased alkaline phosphatase. chronic toxicity/carcinogenicity study (rat) LOAEL = 252 (males)/318 (females) mg/kg/day, based on statistically significant increases in reticulocyte counts in both sexes, and decreased RBC, hemoglobin, and hematocrit values in females. NOAEL = 48.5 (males)/60 (females) mg/kg/day. Cancer (oral) Classification: Not likely to be carcinogenic to humans 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 obs erved adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose
. N/A = not applicable.Mefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 17 of 48 Table 3.4.2 Summary of Toxicological Doses and Endpoi nts for Mefenpyr - diethyl for Use in Occupational Human Health Risk Assessments Exposure/ Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk Assessment Study and Toxicological Effects
Dermal Short
and Intermediate
Term oral a

NOAEL= 100 mg/kg/day (dermal absorption rate = 100%) UF A= 10x

UF H=10x Occupational LOC

for MOE = 100 Developmental toxicity study

– rabbit

LOAEL = 250 mg/kg/day based on abortions
Dermal Long
Term Based on the use pattern, chronic dermal exposure is not expected . Inhalation Short
- Term (1
- 30 days) and Intermediate
Term (1

– 6 mo nths) oral a

NOAEL= 100 mg/kg/day (inhalation absorption rate = 100%) UF A= 10x

UF H=10x Occupational LOC

for MOE = 100 Developmental toxicity study

– rabbit

LOAEL = 250 mg/kg/day based on abortions
Inhalation Long
- Term

(>6 mo nths) Based on the use pattern, chronic inhalation exposure is not expected . Cancer (oral, dermal, inhalation) Classification: Not likely to be carcinogenic to humans.

a Absorption via the dermal/inhalation route is assumed to be equivalent to oral absorption 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 associat edwith lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable. 3.3 Endocrine Disruption EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) “may have an effect in humans that is similar to an effect produced b y a naturall y occurring estrogen, or other such endocrine effects as the Administrator may d esignate.” Following recommendations of its Endocrine Disruptor and Testing Advisory Committee (EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thy roid hormone s ys tems, in addition to the e strogen hormone s ys tem. EPA also adopted EDSTAC’s recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a s ubstance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone sy stems may

be added to the Endocrine Disruptor Screening Program (EDSP).Mefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 18 of 48 4.0 Public Health and Pesticide Epidemiology Data Since mefenp yr - diethyl is used as a safener, and not as the active ingredient in pesticide formulations, incident data are not likel y to be available for mefenp yr- diethyl. Any incident reported for a formulation containing this safener, is likely to be attributed to the active ingredient in the formulation, not to this inert ingredient ; therefore a discussion of public health and epidemiology

data is not relevant to this action
. 5.0 Dietary Exposure/Risk Characteriz ation 5.1 Pesticide Metabolism and Environmental Degradation 5.1.1 Metabolism in Plants, Animals and Rotational Crops Residue Chemistry Memo DP#s 261566, 02/1/00, Y. Donovan (PP# 7F04850) Residue Chemistry Memo DP#s 238730, 271364, 264319, 276208, 11/22/02, Y. Donovan (PP# 7F04850) The metabolism of mefenpy r - diethyl is well understood in plants and animals. I dentified metabolic pathway s are substantially similar in plants and animals (goat, rat, and hen). EPA has determined that mefenp yr- diethyl parent and its three 2,4
- dichlorophenyl
- py razoline metabolites ( HOE 113225, HOE 109453, and HOE 094270) are the residues of concern for risk assessment and tolerance setting purposes in plant and animal commodities as well as in rotational crops.Mefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 19 of 48 5.1.2 Analytical Methodology Residue Chemistry Memo DP#D3 80768 , A
. LaM ay , 2/22/11 (PP# 7E7224) An enforcement method for plants entitled “An Analy tical Method for Determination of Residues of AE F107892 (mefenp yr - diethyl) and its Metabolites in Wheat and Barley by Gas Chromatography using Mass Selective Detection (Report Supplement to EPA MRID 45457 401)” is available. Radiovalidation and independent laboratory validation (ILV) data have been submitted for the plant method. The Agency determined that this method is suitable for food tolerance enforcement of mefenp yr- diethyl and the three metabolite s AE F094270, AE F113225, and/or AE F109453. No new livestock tolerances are required; therefore a discussion of an enforcement method for those commodities is not relevant to this risk assessment. 5.1.3 Environmental Degradation EFED Memoranda, D226076 , A. Clem, 3/18/97 and D262735, A. Clem, 11/26/01 Email communication from EFED to HED/PRD, 8/26/10 Laboratory

studies indicate the principal mode of dissipation of HOE
- 107892 to be aerobic metabolism in soil (microbially mediated hydrolysis), with second ary contribution by soil sensitized photolysis. Concentrations of HOE
- 107892 would decrease relatively rapidly in soil with a DT50 of approximately a few day s to one week. However, in the process, by
- products which are structurall y very similar to parent and longer
- lived are formed (HOE
- 094270, HOE
113225, and HOE
- 109453). 5.1.4 Comparative Metabolic Profile The metabolic profile for mefenp yr- diethyl appears to be substantially similar in plants, animals and the environment. The primary identified metabolites in rats, ruminants, poultry , cereal grains and after environmental degradation are the three 2,4
- dich lorophenyl
- py razoline metabolites, HOE 094720, HOE 113225 and HOE 109453, which are included in the risk assessment and for tolerance setting purposes. See Table 2
- 2 for further information.Mefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 20 of 48 5.1.5 Pesticide Metabolites and Degradates of Concern Table 5.1.5 Summary of Metabolites and Degradates to be included in th e Risk Assessment and Tolerance Expression for Mefenpyr - Diethyl Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop Parent and three 2,4
- dichlorophenyl
-py razoline metabolites ( HOE 113225, HOE 109453, and HOE 094270) Rotational Crop Parent and three 2,4
- dichlorophenyl
-py razoline metabolites ( HOE 113225, HOE 109453, and HOE 094270) Livestock Ruminant Parent and three 2,4
- dichlorophenyl
-py razoline metabolites ( HOE 113225, HOE 109453, and HOE 094270) Poultry Parent and three 2,4
- dichlorophenyl
-py razoline metabolites ( HOE 113225, HOE 109453, and HOE 094270) Drinking Water Parent and three 2,4
- dichlorophenyl
-py

razoline metabolites ( HOE 113225, HOE 109453, and HOE 094270) Not Applicable

5.1.6 Drinking Water Residue Profile EFED Memoranda, D226076, A. Clem, 3/18/97 and D262735, A. Clem, 11/26/01 Email communication from EFED to HED/PRD, 8/26/10 The drinking water residues used in the dietary risk assessment were provided by the Environmental Fate and Effects Division (EFED) in response to tolerance petitions for uses on wheat and barley . The assessment was based on use of the safener at an exaggerate d rate of 0.08 lb ai/A, which is higher than the currentl y requested use pattern; therefore, those estimated drinking water values remain valid and were incorporated directl y into this dietary assessment. Water residues were incorporated in the DEEM
- FCID into the food categories “water, direct, all sources” and “water, indirect, all sources.” Monitoring data for mefenpy r - diethyl and its metabolites are not available; therefore, surface and ground water estimated drinking water concentrations (EDWCs) were derived from models. The chronic surface water EDWC was calculated from the EFED FIRST (Tier 1) index reservoir simulation model for a single application of HOE
- 107892 at an exaggerated rate of 0.090 kg/ha (0.080 lb/acre). The tabulated concentrations are the summations (in p arent equivalent concentrations) of relatively short
- lived parent and several longer
- lived transformation products that are structurall y similar to the parent compound. The chronic concentration of combined parent and metabolites computed from FIRST in parent equivalents is 3 ppb. The chronic groundwater EDWC was calculated using the SCI
- GROW2 model. The database of pesticide chemicals used to develop and update the SCI
- GROW2 regression model shows thatMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 21 of 48 the highest pesticide concentration measured on a one pound per acre application basis for a certain mobile and persistent pesticide of similar molecular weight is roughly 55 μg/L (ppb). The current minimum value for Koc in the database used to develop SCI
- GROW2 is 11 mL/g , while maximum values for aerobic soil metabolism half
- life are roughl y 1000 day s. Since HOE
107892 has Koc and aerobic soil metabolism half
- lives well within the bounds covered b y the model, as do its structurally similar transformation products (from collateral laboratory evidence and reasonable inference), groundwater concentrations of HOE
- 107892 applied at exaggerated rate of 0.080 lb/acre/ye ar and any associated transformation products (in equivalent molar concentrations) are not likely to exceed individually , or in combination, a concentration of 4 μg/L (ppb). The higher value of the two, the chronic groundwater EDWC of 4 μg/L (ppb), was used for this dietary assessment. 5.1.7 Food Residue Profile Residue Chemistry Memo DP#D380768 , A. LaM ay , 2/22/11 (PP# 7E7224) New field trial data for mefenpy r were submitted for the primary crop commodities (grass, sorghum grain, forage and stover). Total mefenp yr - diethyl residues in grass forage ranged from below the LLMV (<0.40 ppm) to 1.59 ppm at a PHI of 0 day s. In grass hay , residues of mefenp yr- diethyl and its metabolites were all below 0.5 ppm. Following two applications of mefenp yr- diethyl to sorghum, total residues ranged from 0.4 ppm to 1.34 ppm at a PHI of 0 day s in sorghum forage. Total mefenp yr - diethyl residues were undetectable i n all sorghum grain and stover samples. There are livestock feedstuffs associated with the proposed crop tolerances. These feedstuffs include grass forage, grass hay , sorghum forage, sorghum grain and sorghum stover. While the addition of this grass forage livestock feed item has increased the dairy cattle livestock dietary burden slightl y , a review of the available metabolism studies indicates that no new or increased livestock tolerances are needed to support this action
. However, the petitioner is advised that any proposed future amendments which impact residues in feed items or any new uses on new feed items may

trigger the need for animal feeding studies. The livestock feeding study should include validation data for the parent compound and all m etabolites. 5.1.8 International Residue Limits HED has previously

determined that the residues of concern for tolerance setting purposes in plant and livestock commodities are mefenp yr - diethyl parent and its three 2,4
- dichlorophenyl
py razoline metabolit es ( HOE 113225, HOE 109453, and HOE 094270). Mefenp yr - diethyl tolerances for plant and animal commodities are listed in 40 CFR §180.509 (a) and are expressed in terms of the residues of the herbicide safener mefenp yr - diethyl (1
- (2,4
- dichlorophenyl)
- 4,5
- di hydro
- 5
- methyl
- 1H
- pyrazole
- 3,5
- dicarboxylic acid, diethyl ester) and its 2,4
- dichlorophenyl
py razoline metabolites.Mefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 22 of 48 No Codex, Canadian, or Mexican maximum residue limits (MRL s) are established for residues of mefenp yr - diethyl and metabolites in crop commodities; therefore, there are no issues with international harmonization raised b y this action. 5.2 Dietary Exposure and Risk Dietary Exposure and Risk Memorandum D3 80767 , A
. LaMay , 2/22/11 5.2.1 Acute Dietary Exposure/Risk No toxic effects attributable to a single exposure of mefenp yr - diethyl were seen in the database; therefore, an acute dietary endpoint was not selected and an acute dietary risk assessment was not conducted. 5.2.2 Chronic Dietary Exposure/Risk A highl y conservative chronic dietary risk assessment was conducted for food only and for food and drinking water for mefenp yr - diethyl using tolerance level residues and assuming 100% crop treated. Mefenp yr - diethyl dietary exposure from food alone results in an estimated risk equivalent to <1% of the chronic population adjusted dose (cPAD) for the general U.S. population and all regulated subpopulations. Additionally, exposure from food and drinking water results in an estimated risk equivalent to <1% of the cPAD for the general population and all regulated subpopulations. Exposure and risk estimates are shown in Table 5.2, below. 5.2.3 Cancer Dietary Ri sk Mefenp yr - diethyl is classified as a “not likel y to be carcinogenic to humans ”; a cancer dietary risk assessment is not required
.Mefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 23 of 48 Table 5.2. Summary of Dietary (Food Only and Food and Drinking Water)

Exposure and Risk for Mefenpyr - diethyl
Population Subgroup Chronic Dietary Food Only Chronic Dietary Food and Water Dietary Exposure (m g/kg/day) % cPAD* Dietary Exposure (m g/kg/day) % cPAD* General U.S. Population 0.000105 <1 0.000189 <1 All Infants (< 1 year old) 0.000067 <1 0.000343 <1 Children 1
- 2 years old 0.000235 <1 0.000360 <1 Children 3
- 5 years old 0.000239 <1 0.000356 <1 Children 6
- 12 years old 0.000167 <1 0.000248 <1 Youth 13
- 19 years old 0.000101 <1 0.000162 <1 Adults 20
- 49 years old 0.000089 <1 0.000167 <1 Adults 50+ years old 0.000070 <1 0.000153 <1 Females 13
- 49 years old 0.000080 <1 0.000158 <1 * The values for the highest exposed population for each type of risk assessment are bolded 6.0 Residential (Non - Occupational) Exposure/Risk Characterization No products containing mefenp yr- diethyl are available for sale in the residential market because of the crops specified on the applicable labels. Therefore , a residential risk assessment was not conducted. The proposed use pattern of this product is limited for use on grass grown for seed or hay onl y, not for sod to be used in residential setting.Mefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 24 of 48 Based on the Agency's current practices, a quantitative postapplication inhalation exposure assessment related to agricultural a

pplications was not performed for mefenp yr diethyl at this time. However, volatilization of pesticides may be a potential source of postapplication inhalation exposure to individuals nearb y to 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. The Agency received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipol y/ S AP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may , as appropriate, developing policies and procedures, to identifying the need for and, subsequentl y, the way to incorporate postapplication inhalation e xposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative postapplication inhalation exposure assessment for mefenp yrdiethyl. Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. This is particularly

the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for mefenp yr diethyl . The Ag ency

has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. On a chemical b y chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray

Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriatel y apply

the data and the AgDRIFT computer model to its risk assessments for pesticides applied b y air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency

may impose further ref

inements in spray

drift management practices to reduce off
- target drift with specific products with significant risks associated with drift. 7.0 Aggregate Risk Assessments and Risk Characterization There are no residential uses for mefenp yr- diethyl; therefore, the aggregate risk assessments include the contribution of risk from dietary (food and water) sources onl y. No toxic effects attributable to a single exposure of mefenp yr- diethyl were seen in the database; therefore, an acute aggregate risk assessment was not conducted. The chronic (long
- term) aggregate risk is equivalent to the chronic dietary risk from food and water detailed above. Mefenp yr - diethyl is classified as “not likel y to be carcin ogenic to humans ” ; thus, a cancer aggregate risk assessment was not conducted . H ED has no concern for aggregate risks resulting from the increased application of mefenp yr- diethyl requested in this petition. 8.0 Cumulative Risk Characterization/Assessme nt 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 mefenp yr- diethyl and any other substances and mefenpy r- diethyl does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that mefenp yr - diethyl has a common mechanism of toxicity withMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 25 of 48 other substances. For information regarding EPA’s ef forts 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 Pathway Occupational and Residential Exposure Memo DP#D379984, M. Lloyd, 10 / 07 /10 Occupational exposure risk estimates were calculated for products where mefenp yr - diethyl is used as a safener. The attached is a summary of the occupational risk assessment; the information for the complete assessment is referenced above. Mefenp yr - diethyl can be applied by aerial or ground application methods to sorghum and grass grown for seed
. It is applied as a component of HUSKIE TM herbicide, one earl y season application per season for sorghum and two applications per season for grass grown for seed
. The assessment considers the maximum proposed label rate for both sorghum and grass. The current product lab el require s normal work clothing (WDGs) or double layer clothing (EC) with appropriate footwear, eye protection, and chemical resistant gloves . The label required PPE is based on the active ingredients in the product and is not driven by the safener compon ent of the herbicide . Respiratory protection is not required. Risks from occupational exposures were calculated for handlers using aerial and ground
- based application equipment which would be ty pical for herbicide applications to large field crops. For all scenarios considered, risks were not of concern at current label requirements for clothing and personal protective equipment use (i.e., calculated MOEs well exceeded the target of 100 at baseline PPE ; the addition of the specified label PPE will increa se MOEs ). No dislodgeable foliar residue (DFR) data are available for the post
- application exposure assessment. Post
- application worker risks were also evaluated for scouting activities which is the only likel y hand labor activity which would occur relative to the use of mefenpy r - diethyl in agriculture and risks were not of concern even on the day of application when individuals scout for an 8 hour workday

(i.e., MOE s > 33 ,000 and target = 100). Current labels require a 24 hour Restricted Entry

Interval ( REI ) so actual risks would be even of less concern because residues would dissipate some between application and the REIof 1 day
. 9.1 Occupational Handler Risk The following occupational handler scenarios were assessed based on the proposed use dire ctions on the proposed products , and information on actual field practices: Mixer/L oader: (1) Mixing/L oading Liquids for Aerial Applications (PHED); (2) Mixing/L oading Liquids for Groundboom Applications (PHED); (3) Mixing/L oading Liquids for Chemigation Applications (PHED ) ; andMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 26 of 48 Applicators: (4) Applying Spray s via Aerial Equipment (PHED) (5) Applying Spray s via Groundboom Equipment (PHED) Flaggers: (6) Flagging for Aerial Application [Note: For exposure analysis water dispersible granules and dry flowable formulations are considered similar and as such, exposure data based on dry flowable formulations have been used in this assessment.] No chemical
- specific exposure monitoring data were submitted in support of this evaluation of mefenp yr- diethyl . The Pesticide Handlers Exposure Database V1.1 1 (Surrogate Guide of August 1998) was used for determining the unit exposure values. Additionally , standard Agency values for acres treated per day

for field crops (HED ExpoSAC policy 9.1) for the various s cenarios evaluated in this assessment. Application rates and the applicable product requirements were defined based on the labels referenced in Section 2 and Table 2.2 above. All applicable toxicological points of departure and associated uncertainty fac tors were defined based on the information presented above in Section 3.5. All calculated occupational handler risks are presented in Table 9.1 below. As indicated above, risk estimates based on current labels for the product that include mefenpy r - diethyl are not of concern (i.e., all MOEs exceed 100 for all scenarios). HED classifies exposures up to 30 day s as short
- term and exposures greater than 30 day s up to several months as intermediate
- term. Table 9.1 , below demonstrates occupational handler risks for both short
- and intermediate
- term exposures. HED expects the majority of occupational exposures will be short
- term in duration. The occupational risk estimates below are for baseline exposure (i.e., long sleeved shirt, long pants, socks, shoes). The proposed product label includes long
- sleeved shirt, long pants, socks, shoes, chemical resistant gloves, and protective eyewear. Mefenp yr - diethyl is a component of the herbicide HUSKIE TM (EPA Reg. No. 264
- 1023) and handler personal protective equipment is based on the active ingredients in the formulation (py rasulfotole and bromoxy

nil). Therefore, actual occupational handler exposures are lower (i.e., MOEs are higher) than in the risk estimates expressed below. Tabl e 9.1 . Mefenpyr Diethyl Occupational Noncancer Dermal and Inhalation Exposures and Risks from Application to Sorghum/Grass Application Rate (lb ai/acre) a Area

Treated Daily (acres) b Unit Exposures
--

Dermal and Inhalation (mg/lb ai) Doses (mg/kg/day) f MOEs g Combined MOEs h

Mixer/Loader for Aerial Applications

1 Available: http://www.epa.gov/pesticides/science/phedsur
- expo - guide.pdfMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 27 of 48 Tabl e 9.1 . Mefenpyr Diethyl Occupational Noncancer Dermal and Inhalation Exposures and Risks from Application to Sorghum/Grass Application Rate (lb ai/acre) a Area

Treated Daily (acres) b Unit Exposures
--

Dermal and Inhalation (mg/lb ai) Doses (mg/kg/day) f MOEs g Combined MOEs h

0.01 1200 Dermal Baseline c : 2.9 Dermal Baseline: 0.58 Dermal Baseline: 170 Baseline Dermal + Inhalation: 170 Inhalation Baseline d : 0.0012 Inhalation Baseline: 7E
- 5 Inhalation Baseline: 420,000 Mixer/Loader for Chemigation Applications (grasses)
0.009 350 Dermal Baseline c : 2.9 Dermal Baseline: 0.152 Dermal Baseline: 660 Baseline Dermal + Inhalation: 660 Inhalation Baseline d : 0.0012 Inhalation Baseline: 6E
- 5 Inhalation

Baseline: 1,600,000 Applicator for Aerial Equipment
0.01 1200 Dermal Enclosed Cockpit e : 0.0055 Dermal

Enclosed Cockpi t : 0.0011 Dermal Enclosed Cockpi t : 91 ,000 Engineering control

Dermal + Inhalation: 90 ,000 Inhalation Enclosed Cockpi t : 0.000467 Inhalation

Enclosed Cockpi t : 0.0000136 Inhalation

Enclosed Cockpi t : 7,400,000 Applicator for Groundboom Equipment
0.01 200 Dermal Baseline c : 0.014 Dermal Baseline: 0.000467 Dermal Baseline: 210 ,000 Baseline Dermal + Inhalation: 200 ,000 Inhalation Baseline d : 0.00148 Inhalation Baseline: 2.5E
- 5 Inhalation Baseline: 4,100,000 Flagger
0.01 350 Dermal Baseline: 0.011 Dermal Baseline: 0.000642 Dermal Baseline: 160 ,000 Baseline Dermal + Inhalation: 150 ,000 Inhalation Baseline: 0.0035 Inhalation Baseline: 2E
- 5 Inhalation

Baseline: 4,900,000 a Application rates are the maximum application rates determined from proposed labels for mefenpyr diethyl b Amount handled per day values are HED estimates of acres treated per day based on Exposure SAC SOP #9 “Standard Values for

Daily Acres Treated in Agriculture,” industry sources, and HED estimates. c Baseline Dermal: Long
- sleeve shirt, long pants, and no gloves. d Baseline I

nhalation: no respirator. e Enclosed Cockpit: enclosed cockpit and baseline attire (long
- sleeve shirt, long pants, shoes, and socks). f Dose (mg/kg/day) = Unit exposure(mg/lb ai) x App Rate (lb ai/acre) x Area Treated (acres/day) x %Absorption (100% dermal and

100% inhalation) / Body weight (60 kg). g MOE = NOAEL/Dose; where the short
- term dermal NOAEL = 100 mg/kg/day and the short
- term inhalation NOAEL = 100

mg/kg/day h Combined MOE = NOAEL / (dermal + inhalation daily dose (mg/kg/day)) 9.2 Occupational Postapplication Risk Hand labor activities for the crops considered in this assessment are very limited (essentially scouting and irrigation) which ty pically occurs only

sporadicall y after applications. Most other activities which would routinely occur such as harvest and, in some cases limited cultivationMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 28 of 48 activities, would be mechanized and result in occupational exposures lower than assessed below for scouting and irrigation. Dermal contact with treated foliage around cultivation is unlikely for s orghum and grass grown for seed. No chemical
- specific data (e.g., dislodgeable foliar residue or DFR) data were available for mefenp yr- diethyl with which to calculate risks so the Agency criterion for situations when no monitoring data are available was used (i.e., a DFR values calculated using a 20% transferability value and the nominal application rate)
. The maximum application rate for each crop was used. An 8 hour exposure duration was considered for the postapplication assessment. All other factors such as the point of departure , body weight, dermal absorption, and target uncertainty factors are similar to those described a bove in the occupational handler calculations. Based on the proposed application rates coupled with the dislodgeable foliar residue fraction the DFR concentration on the day of application , risk estimates are not of concern to HED (i.e., MOEs > 100 on D ay

0). For sorghum, the post
- application exposure assessment was conducted for crops at “low” and “medium” heights. The risk estimates for both scenarios are not of concern to HED (i.e., MOEs are above 100). Given the label directed use pattern, the post
a pplication risk estimate for sorghum at the “low” crop height is the more likely exposure scenario. As indicated above, the proposed product labels require a 24 hour REI so actual risks would be even of less concern because of residue dissipation between application and the REIof 1 day
. Table 9.2. Summary of Occupational Postapplication Risks for Mefenpyr- diethyl Crop Grouping Application

rate (lb ai/acre) Transfer Coefficient (cm 2 /hr) Day s after Application MOE at Day 0 (Level of Concern = 100) Sorghum 0.010 100 ( Scouting, irrigation crops at low

height) 1 0 (12 hours) 330 ,000 1,000 (Scouting, irrigation crops at medium

height) 1 0 (12 hours) 33 ,000 Grass grown for seed 0.009 500 (Scouting, fertilizing, irrigating,

aerating) 1 0 (12 hours) 74 ,000 1

– representative activities for mefenpyr
- diethyl post
- application exposuresMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 29 of 48 10.0 Data Needs and Label Recommendations 10.1 Toxicology The following toxicology study is required:  Subchronic (28
- day) Inhalation Study New requirement under the Revised Part 158 Toxicology Data Requirements (2007 edition):  Acute Neurotoxicity

S tudy (New requirement under the Revised Part 158 Toxicology Data Requirements (2007 edition)  Subchronic Neurotoxicity S tudy (New requirement under the Revised Part 158 Toxicology

Data Requirements (2007 edition)  Immunotoxicity

S tudy (New requirement under the Revised Part 158 Toxicology D ata Requirements (2007 edition) 10.2 Residue Chemistry 860.1480 Livestock Feeding Study The petitioner is advised that any pro posed future amendments which impact residues in feed items or any

new uses on new feed items may trigger the need for animal feeding studies. The livestock feeding study s hould include validation data for the parent compound and all metabolites. 860.155 0 Proposed Tolerances The petitioner is required to submit a revised Section F to reflect the commodity definitions. Note to RD: The 40 CFR §180.509(a) currentl y has the rotational crop tolerances for so ybean and canola listed under the general tolerances for residues as a direct application tolerance. The tolerances for canola seed, soy bean forage, so ybean hay, and so yb ean seed should be listed as indirect or inadvertent residues as they are rotational crop tolerances [180.509(d)]. 10.3 Occupational and Residential Exposure None required at this timeMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 30 of 48 Appendix A: Toxicology Assessment A.1 Toxicology Data Requirements The requirements (40 CFR 158.500; 2007 ) for a food use chemical for me fenpyr
- diethyl are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. Test Technical Required Satisfied 870.1100 Acute Oral Toxicity
................................ ....................... 870.1200 Acute Dermal Toxicity
................................ .................. 870.1300 Acute Inhalation Toxicity
................................ .............. 870.2400 Primary Eye Irritation
................................ .................... 870.2500 Primary Dermal Irritation
................................ .............. 870.2600 Dermal Sensitization
................................ ...................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent)
................................ ............... 870.3150 Oral Subchronic (nonrodent)
................................ ......... 870.3200 21
- Day

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

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

Inhalation
................................ .......................... yes yes yes no yes yes

yes yes no no 870.3700a Developmental Toxicity (rodent)
................................ ... 870.3700b Developmental Toxicity (nonrodent)
............................. 870.3800 Reproduction
................................ ................................ . yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent)
................................ .............. 870.4100b Chronic Toxicity (nonrodent)
................................ ........ 870.4200a Oncogenicity (rat)
................................ .......................... 870.4200b Oncogenicity (mouse)
................................ .................... 870.4300 Chronic/Oncogenicity
................................ .................... yes no yes yes yes yes

yes yes yes yes A 870.5100 Bacterial Reverse Mutation Assay
................................ . 870.5300 In Vivo Mammalian Cell Assay
................................ ..... 870.5xxx In Vitro Cy

togenetics Chromosomal Aberrations
.......... yes yes yes yes

yes yes 870.6100a Acute Delayed Neurotoxicity (hen)
............................... 870.6100b 90
- Day

Neurotoxicity (hen)
................................ ........... 870.6200a Acute Neurotox. Screening Battery (rat)
....................... 870.6200b 90
- Day

Neuro. Screening Battery (rat)
.......................... 870.6300 Developmental Neurotoxicity
................................ ........ no no yes yes CR no

no no no no 870.7200 Companion Animal Safety
................................ ............ 870.7485 Metabolism & Pharmacokinetics
................................ ... 870.7600 Dermal Penetration
................................ ........................ 870.7800 Immunotoxicity
................................ ............................. CR yes yes y es no

yes yes no Arat carcinogenicity study is not adequate to assess the carcinogenic potential of mefenpyr
- diethyl ; although not required for the current action, a new study will be required if new uses result in significantly higher residues in food and/or significantly higher occupational (or future residential) exposure; CR conditionally requiredMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 31 of 48 A.2 Toxicity Profiles Table A.2.1 Acute Toxicity Profile

– Mefenpyr - diethyl Guideline No. Study Type MRID(s) Results Toxicity Category 870.1100 Ac ute oral [rat] 43972211 ALD 50 = >5000 mg/kg IV 870.1200 Ac ute dermal [rat] 43972213 B LD 50 = >4000 mg/kg III 870.1300 Ac ute inhalation [rat] 43972214 C LC 50 = >1.32 mg/L III 870.2400 Ac ute eye irritation [rabbit] 43972215 slight ocular irritant PIS 12.8 III 870.2500 Ac ute dermal irritation [rabbit] 43972216 not a dermal irritant PII 0.17. IV 870.2600 Skin sensitization [guinea pig] 43972217 44280001 Slight dermal

sensitizer N/A

Table A.2.2. Subchronic, Chronic and Other Toxicity Profile

– Mefenpyr - diethyl Guideline No./ Study Type MRID No. (year) Classification /Doses Results 870.3100 90
- Day oral toxicity [Wistar rat IBM
- Han outbred, SPF] MRID 43972219 (1992)

(purity 94.5%) 0, 100, 500, 2500, 7500 ppm [males 0, 8.1, 42.1, 206.7, 660.6 mg/kg/day] [females 0, 8.6, 44 .3, 223, 708.9 mg/kg/day] (4
- week recovery phase) acceptable/guideline NOAEL = males 207/females 223 mg/kg/day (2500 ppm) LOAEL = males 661/female 709 mg/kg/day (7500 ppm), based on decreased body
- weight gains ( ≈10%), decreased erythrocyte counts, hemoglobin, and hematocrit values, increased reticulocyte counts (+29%
- 39%), mean corpuscular volume, and gamma glutamyl transfera se (GGT) activities (+55%).

870.3100 4
- week oral toxicity [Wistar rat IBM
Han outbred, SPF] MRID 44364401 (1992)

(purity 98.9%) 0, 100, 500, 1000, 2500, 5000, 7500 ppm [males: 0, 10.1, 52.3, 102, 258.3, 518.7, 773.6 mg/kg/day] [females: 0, 10, 52.3, 101.4, 249, 488.2, 744.3 mg/kg/day] acceptable/non
- guideline (study used to set dose levels for 90
- day study) NOAEL = 7500 ppm (744 mg/kg/day) assessment of several enzyme/biochemical parameters were performed (liver and kidney) Liver: induction of drug
- metabolizing enzymes: statistically
significant (n=5/sex/group) increases in GSH, DEM, PROD, TCCR, GGT in one or both sexes(mainly dose
- related)Mefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 32 of 48 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile

– Mefenpyr - diethyl Guideline No./ Study Type MRID No. (year) Classification /Doses Results
870.3150 13
- week oral toxicity in nonrodent (beagle dog) MRID 43972220 ( 1992 )

(purity 94.5% a.i.) 0, 400, 2000, 10000 ppm [males 0, 14.9, 80.5, 341 mg/kg/day] [females 0, 15.6, 81.2, 336.1 mg/kg/day] acceptable/guideline NOAEL = 2000 ppm (80.5 mg/kg/day) LOAEL = 10000 ppm (336 mg/kg/day), based on increased absolute and relative liver weight and alkaline phosphatase activity (both sexes); focal liver lesions (hemorrhage, necrosis, inflammation; females); slight anemia (both sexes); decreased mean body weight and body
- weight gain (females); and decreased food consumption (both sexes) other findings include decreases in RBC, hemoglobin, hematocrit, increased reticulocyte counts that are consistent with findings in other studies/species 870.3150 30 - day oral toxicity in nonrodent (beagle dog) MRID not assigned (1990)

(purity 98.9%) 0, 1250, 2500, 5000, 10000 ppm (males: 0, 48, 92, 174, 375 mg/kg/day) (females: 0, 53, 98, 184, 308 mg/kg/day) acceptable/non
- guideline NOAEL = 10000 ppm (375/308 mg/kg/day), HDT (increased alkaline phosphatase in females at HDT)

870.3100 90
- Day oral toxicity [Hanover
derived out
- bred NMRI mice] MRID 43972218 (1991)

0, 100, 500, 2500, 7500 ppm [males 0, 17.83, 89.27, 449.01, 1492.76 mg/kg/day] [females 0, 20.77, 105.39, 523.5, 1743.13 mg/kg/day]

acceptable/guideline NOAEL = 500 pp (89 mg/kg/day) LOAEL = 2500 ppm (449 mg/kg/day), based on decreased body weight, kidney weight, increased liver weight, and hepatocyte hy

pertrophy in males; decreased bilirubin and increased lactic acid dehydrogenase values in females At 7500 ppm , enlarged livers, increased liver weight (50% greater than control), hepatocyte hypertrophy, enlarged spleens; more severe hematopoiesis and hemosiderin deposits than controls, increased spleen weight (both sexes), decreased kidney weight (males), decreas ed bilirubin (females), increased lactic acid dehydrogenase values (both sexes), slightly elevated ALAT and ASAT (females) 870.3200 21/28
- Day dermal toxicity (Wistar rat) MRID 44089201 (1992)

(purity 94.3% a.i.) 0, 100, 300, 1000 mg/kg/day acceptable/guideline NOAEL = 1000 mg/kg/day

870.3250 90
- Day dermal toxicity no study located/not required
870.3465 90
- day inhalation toxicity DatagapMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 33 of 48 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile

– Mefenpyr - diethyl Guideline No./ Study Type MRID No. (year) Classification /Doses Results
870.3700a Prenatal developmental in rodent [Wistar rat] MRID 43972221(1992)

94.5% a.i. 0, 1000 mg/kg/day gestation days 7
- 16 acceptable/guideline Maternal NOAEL = <1000 mg/kg/day Maternal LOAEL = 1000 mg/kg/day, based on decreased body
- weight gain (76% of control) and food efficiency during first week of dosing; increases in absolute and r elative spleen weights Developmental NOAEL = 1000 mg/kg/day (HDT) Developmental LOAEL = no effects observed 870.3700a Prenatal developmental in rodent [Wistar rat] MRID 44654201 (1992)

94.3% a.i. 0, 1000 mg/kg/day gestation days 7
- 16 Includes post- natal development acceptable/guideline Maternal NOAEL = <1000 mg/kg/day Maternal LOAEL = 1000 mg/kg/day, based on decreased body
- weight gain and food efficiency during first week of dosing Developmental NOAEL <1000 mg/kg/day Developmental LOAEL = 1000 mg/kg/day, there was a marginal decrease in fetal body weight (95% of control at birth; 91% of control at PND 21) and body
- weight gain (90% of control overall) during lactation 870.3700b Prenatal developmental in nonrodent (Himalayan rabbit) MRID 44089202 (1992)

(purity 94.5% a.i.) 0, 40, 100, 250 mg/kg/day gestation days 6
- 18 acceptable/guideline Materna l toxicity NOAEL = 100 mg/kg/day Maternal toxicity LOAEL = 250 mg/kg/day, based on abortions (5 abortions between GD 16
- 23; premature delivery of 1 control (GD 28) and 1 HDT (GD 27) Developmenta l toxicity NOAEL = 100 mg/kg/day Developmental toxicity LOAEL = 250 mg//kg/day, based on abortions 870.3800 Reproduction and fertility effects (WIST Han Ibm:WIST ISPF rat) MRID 44661601/44654202

(1994/1995) (purity 94.3% a.i.) 0, 200, 1000, 5000 ppm [P0 males: 0, 16.4, 82.8, 428.3 mg/kg/day] [P0 females: 0, 18.6, 94.4, 482.7 mg/kg/day] NOTE: mg/kg/day changed to reflect P0 pre
- mating intake; doses of F1 males postmating used in original DER/HIARC

acceptable/guideline Parental toxicity NOAEL = 1000 ppm (82 mg/kg/day) Parental toxicity LOAEL = 5000 ppm (428 mg/kg/day), based on decreased mean body weight and body
- weight gain in parental animals and offspring and an increase in spleen weight and severity (but not incidence; all rats displayed this finding; both generations) of splenic extramedullary hematopoiesis in females (increased spleen weight in F1 females) Reproductive NOAEL = 5000 ppm (males 428/females 482 mg/kg/day), highest dose tested Reproductive LOAEL = > 5000 ppm Offspring NOAEL = 1000 ppm (82 mg/kg/day) Offspring LOAEL = 5000 ppm (428 mg/kg/day), based on decreased body weight [LD 14 (90% of control) and LD 21 (85% of control)]Mefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 34 of 48 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile

– Mefenpyr - diethyl Guideline No./ Study Type MRID No. (year) Classification /Doses Results
870.4100a Chronic toxicity rodents (Wistar rat) MRID 43972222/43972223 (1994)

(purity 94.3% a.i.) 0, 40, 200, 1000, 5000 ppm M 0, 1.92, 9.8, 48.5, 251.6 mg/kg/day F 0, 2.38, 12.1, 60, 318 mg/kg/day acceptable/guideline NOAEL = 1000 ppm ( males 48.5/females 60 mg/kg/day LOAEL = 5 000 ppm ( males 252/females 318 mg/kg/day, based on statistically significant increases in reticulocyte counts in both sexes, and decreased RBC, h emoglobin, and hematocrit values in females.

870.4100b Chronic toxicity nonrodent (beagle dog) MRID 44316402 (1992)

0, 60, 300, 1500, 7500 ppm (purity 94.3% a.i.) males 0, 2.3, 10.1, 51.4, 260.2 mg/kg/day females 0, 2.1, 11.1, 57.6, 282.2 mg/kg/day acceptable/guideline Systemic toxicity NOAEL = 1500 ppm (51 mg/kg/day) Systemic toxicity LOAEL = 7500 ppm (260 mg/kg/day, based on adverse findings in the liver (cholestasis, increased alkaline phosphatase, and increased liver weight in both sexes)

870.4200 Carcinogenicity (Wistar rat) MRID 43972222/43972223 (1994)

(purity 94.3%) 0, 40, 200, 1000, 5000 ppm M 0, 1.92, 9.8, 48.5, 251.6 mg/kg/day F 0, 2.38, 12.1, 60, 318 mg/kg/day acceptable/guideline see above under 870.4100a

re - evaluation of the database determined that the response in the female at 5000 ppm was approaching an adverse effect level, based on results of the 90
- day rat study; dose levels adequate to assess carcinogenic potential 870.4300 Carcinogenicity (Hanover
- derived out -bred NMRI mouse) MRID 43972224/43972225

(1994/1995) (purity 94.3% a.i.) 0, 20, 100, 500, 2500 ppm [males 0, 2.76, 14.1, 70.6, 350.8 mg/kg/day] [females 0, 3.78, 18.3, 92, 463 mg/kg/day] acceptable/guideline Systemic toxicity NOAEL = 2500 ppm (males 351 mg/kg/day /females 463 mg/kg/day Systemic toxicity LOAEL = not determined No treat me nt related tumors Doses considered adequate (based on subchronic study)

870.6200a Acute neurotoxicity screening battery No study available. Not required.
870.6200b Subchronic neurotoxicity screening battery No study available. Not requiredMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 35 of 48 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile

– Mefenpyr - diethyl Guideline No./ Study Type MRID No. (year) Classification /Doses Results
870.6300 Developmental neurotoxicity No study available. Not required.
870.7485 Metabolism and pharmacokinetics (Wistar Hoe WISKf, SPF 71 rat) MRID 44654203 (1996 )

(purity 99%) 1 mg/kg for 14 days + 1 mg/kg [phenyl
14 C ] labeled compound (gavage)

acceptable/guideline Urine primary elimination route; accounted for 83% (males)/ 92% (females) of administered dose; fecal excretion accounted for 22%/11%, respectively; most of [ 14 C] recovered during first 24 hours; tissue/organ residual activity at 168 hours ≤0.6%; biphasic elimination pattern was identified: initial rapid T 1/2: males 4.2/females 3. 7 hours (urine) and males 7.8/females 10.4 hours (feces); longer T 1/2: males 24.9/females 28.8 hours (urine); males 33.6/females 56.6 hours (feces); sex - specific differences in metabolic disposition found: males principal metabolite in urine was dicarboxylic acid HOE 109453 (89.3%) with only minor amounts of the pyrazolyl carboxylic acid HOE 094270 (7.5%) and the monocarboxylic acid HOE 113225 (3.2%); females excreted similar amounts of HOE 109453 (50.7%) and HOE 113225 (41.5%), with minor amounts of HOE 0 94270 (6.2%). Fecal excretion: HOE 113225 (males 54.1%/females 40.6%); HOE 109453 (males 34.1%/females 48.3%), HOE 094270 (<7%); no parent recovered in excreta; absorption and metabolic pathways did not become saturated at dose used (no accumulation in ti ssues/organs) 870.7485 Metabolism and pharmacokinetics (Wistar WISK SPF 71 rat) MRID 44654204 (1992)

(purity 99%) 1 or 100 mg/kg acceptable/guideline Renal excretion was predominant route of elimination (males 68% and 65%/females 72% and 65% by 48 hours) following 1 and 100 mg/kg, respectively; test material not found in urine; 3 metabolites identified: HOE 109453 (males 63% and 62%/females 42% and 48%); HOE 113225 (males 2% and 0.2%/females 28% and 14%); HOE 094270 (males 2.9$ and 2.4%/females 2.3% and 2.1%) following 1 and 100 mg/kg, respectively. Parent compound was found in the feces (males 7.9% and 8.1%/females 2.9% and 0.95%), respectively in addition to the 3 metabolites found in the urine; metabolic pathway: consecutive hydrolysis (saponific ation) of the 2 carboxylic acid ester groups and a decarboxylation of one of the carboxylic groups, resulting in an aromatization of the pyrazoline ring (Hoe 107892 → HOE 113225 → HOE 109453 → HOE 094270). HOE 109453 was found in the plasma. Metabolism appe ars to be influenced by sex to minor extent; males either have a lower intestinal absorption or a higher biliary excretion compared to females. 870.5265 Ames assay MRID 43972226

4
- 5000 ug/plate Classification: acceptable/guideline no indication that test material induced a mutagenic effect in any tester strain +/
- S9 activation; no clear evidence of cy totoxicity; compound insolubility seen at ≥2500 ug/plate
- S9, 10000 ug/plate +S9 870.5375 mammalian cell gene mutation assay MRID 43972230

10
- 100 ug/mL;
- S9; 25
- 100 ug/mL +S9 Classification: acceptable/guideline no evidence that test material was mutagenic under conditions of assay; cytotoxicity at 100 ug/mL
- S9 only.Mefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 36 of 48 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile

– Mefenpyr - diethyl Guideline No./ Study Type MRID No. (year) Classification /Doses Results 870.5375 in vitro mammalian cy togenetic assay (Chinese hamster lung fibroblasts) MRID 43972227

5
- 25 ug/mL (
- S9) and 5
- 100 ug/mL (+S9) Classification: acceptable/guideline no indication that test material induced a clastogenic response at any dose level or harvest time in either presence or absence of S9 activation

870.5385 in vivo mammalian cy togenetic assay (mouse) MRID 43972227

Classification: acceptable/guideline no evidence that test material induced a clastogenic or aneugenic effect in either sex at any s acrifice time at 5000 mg/kg.
Guideline 5550, unscheduled DNA sy nthesis in mammalian cells in culture MRID 439722229

doses up to 100 ug/mL (+/
- S9); cy totoxic/insoluble without S9; +S9 not cy totoxic at 100 ug/mL Classification: unacceptable/non
guideline no clear evidence that test material was genotoxic under assay conditions. overall assay sensitivity compromised because high levels of radioactive label, indicating that replicative DNA sy

nthesis was not successfully blocked in all experimental groups. 870.7485 Metabolism and pharmacokinetics (Wistar WISK SPF 71 rat) MRID 44661602/44661603

(1992/1993) 1 and 100 mg/kg main route of excretion is urine: males 76%/68%; females 88%/79% of administered dose (1 mg/kg and 100 mg/kg, respectively); feces: 30%/32%; females 14%/24%, respectively. most eliminated within first 24 hours; excretion biphasic: biological half

- life for excretion via urine for males and females at low and high dose were between 4 and 7 hrs (rapid phase I) and 23 and 31 hrs (terminal phase II); concentrations in organ/tissue and blood/plasma at study termination (7 days post dose) were 2
- 3 times higher in females than males (both doses); no [ 14 C] was detected in CNS; plasma showed highest concentrations in both sexes and dose levels (males 0.021 and 0.59 μg equivalents/g; females 0.063 and 1.96 μg equivalents/g), respectively; plasma levels ≈60%
- 80% higher than in blood (erythrocyte concentration of 7%
- 8% of plasma concentration at 1 mg/kg and 14%
- 22% at 100 mg/kg. 870.7600 Dermal penetration no study available
A.3 Executive Summaries (Note: see HIARC document TXR 012998 for all other Executive Summaries)Mefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 37 of 48 A.3.1 Prenatal Developmental Toxicity 870.3700a Prenatal Developmental Toxicity Study

– Rat EXECUTIVE SUMMARY: HOE 107892 (purity: 94.3% w/w) was administered by o ral gavage, once daily

f rom day 7 t o 16 of gravidity to a group of 20 mated female Wistar rats at a dose of 1000 mg/kg bw and a control group received the vehicle (2% w/v starch mucilag e) without the test substance (MRID 44654201). The animals delivered normally and reared their offspring for 21 day s. There were no maternal mortalities, no treatment related clinical signs of toxicity and no treatment - related gross pathological observatio ns. Mean maternal body

w eight was comparable between the control and treated group throughout gestation and lactation. Mean maternal body
- weight gain was significantl y lower (14%) during treatment (day s 7 to 17 of gestation) due to a significant difference (decreased 24%) during the first week of treatment (day s 7 to 14 of gestation) and was accompanied by

a s ignificant reduction in food efficiency and food consumption, therefore suggesting the decrease in maternal body
- weight gain was treatment - related. There was a possible treatment - related reduction in the absolute and relative spleen weights of the treated dams, but the biological and toxicological significance was uncertain. There was a marginal treatment
- related impairment in fetal body w eight (5
- 9% l ess than controls) and body
- weight gain (10% less than controls), and a treatment
- related decrease in the mean absolute spleen and heart weights of the pups in the treated group, which could be due to maternal stress and/or the toxicity o f the test substan ce. The biological and toxicological significance of the reduced absolute spleen and heart weights was uncertain. There were no treatment - related effects on the litter data parameters examined (with the exception of body w eight), and no impairment in the p hy sical, functional or behavioral development of the neonates which suggests that the test substance was not teratogenic under the conditions of the study
. Based on the results of the study, the NOAEL for maternal toxicity is < 1000 mg/kg/ bw/day and th e maternal LOAEL is 1000 mg/kg bw/day based on decreases in body weight gain and food efficiency during the first week of treatment. The NOAEL for developmental toxicity is < 1000 mg/kg bw/day and the developmental LOAEL is 1000 mg/kg bw/day based on margi nal decreases in fetal body weight and body weight gain during lactation. The post - natal development study i n the rat is classified as acceptable/nonguideline. There is no guideline requirement for a post
- natal developmental toxicity study
. EXECUTIVE SUMMARY: Ina d evelopmental toxicity

s tudy ( MRID 43972221) Hoe 107892 (94.5% a.i.) in starch mucilage was administered orally b y gavage to 20 Wistar rats at the limit dose (1,000 mg/kg/day) from day s 7 through 16 of gestation. At 1000 mg/kg/day , mean body weight gain for day s 7
- 14 was significantly l ower (24.2%) than the control group during the same time period. There was a slight, althoughMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 38 of 48 not statistically

significant increase in body weight gain during the latter part of treatment (day s 14
- 17) and during the post - treatment period. The food efficiency i ndex was also significantl y lower during the first week of treatment. In addition to the decrease in body weight gain during treatment, absolute and relative spleen weights were significantl y increased i n the treated animals when compared to the control group (anemia, enlarged spleens and increased hematopoiesis has been observed in other studies across species). The LOAEL for maternal toxicity is 1000 mg/kg/day and the NOAEL is < 1000 mg/kg/day based on decreases in body weight gain and food efficiency during the first week of treatment and on increases in absolute and relative spleen weights. There were no treatment- related effects in developmental parameters. A developmental LOAEL was not achieved. The developmental NOAEL is the limit dose, 1,000 mg/kg/day. The developmental toxicity s tudy i n the rat is classified Acceptable/Guideline and it satisfies the guideline requirement for a developmental toxicity s tudy [ OPPTS 870.3700; §83
- 3(a)] in rats. Although a maternal NOAELw as not defined, there was no developmental toxicity

at the limit dose. There are two rat developmental toxicity which were both performed at the limit dose only
. B oth show onl y minimal fetal body
- weight effects and decreased maternal body
weight gain during the first week. A lthough a NOAEL was not defines in either study , no developmental toxicity w as observed at the limit dose. Therefore, sensitivity t o infants and children as defined by FQPA can be addressed. 870.3700b Prenatal Developmental Toxicity Study - Rabbit EXECUTIVE SUMMARY: HOE 107892 (purity: 94.5% w/w) was administered by o ral gavage once dail y from day s 6 to 18 of gravidity to groups of 15 to 16 mated female Himalayan rabbits at a dose of 0 (vehi cle onl y), 40, 100 or 250 mg/kg bw (MRID 44089202). The test substance was suspended in 2% (w/v) starch mucilage. All surviving does were sacrificed and delivered by c aesarian section on day 2 9 of gravidity

a fter which the fetuses were kept for 24 horns in an incubator. There were no mortalities, no treatment - related adverse clinical observations and no treatment - related effects on gross pathology o r organ weights observed in the does. Mean maternal body w eight was comparable between the control group and the treated groups throughout the study
. At 100 mg/kg bw, there was a reduced mean absolute food consumption which was not considered adverse since there were no other treatment - related effects observed at this dose (8 1
- 85% of control during treatment peri od, p 0.05). At 250 mg/kg bw, there was a significant decrease (p 0.05) in body
- weight gain during the first week of treatment (day s 6 to 13) which was accompanied by a s ignificantly

reduced (p 0 .05) food efficiency index and food consumption. There was also a higher rate of abortions. There were noMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 39 of 48 other treatment - related effects at any dose level on delivery o r on litter data parameters examined, including those found dead due to abortions or premature delivery. The NOAEL for ma ternal toxicity is 100 mg/kg bw/day and the LOAEL is 250 mg/kg bw/day based on a higher rate of abortions. The decreases in body
- weight gain, food efficiency

i ndex and food consumption may also be an indication of maternal toxicity as well; however, due to the fact there was n o effect on mean body weights in the treated groups and that the percent increase in mean body weight over the entire gestation period, when compared to the total body weight is only

1 0% (11% for the control group and 9% for the high dose group), this effect is considered to be marginal. The NOAEL for developmental toxicity is 100 mg/kg bw and the LOAEL for developmental toxicity is 250 mg/kg bw based on a higher rate of abortions. Examination of the individual animal data does not indicate that the abortions were solel y due to maternal toxicity
. The developmental toxicity s tudy i n the rabbit is classified as Acceptable guideline and satisfies the guideline requirement for a developmental toxicity s tudy ( OPPTS 870.3700; §83
- 3(b)) in the rabbit. A.3.2 Repro ductive Toxicity 870.3800 Reproduction and Fertility Effects - Rat EXECUTIVE SUMMARY: A two - generation reproduction study w as conducted using WI ST Han Ibm: WI ST ISPF) rats, fed test diets containing CGA 107892, purity 9 4.3%, at dietary c oncentrations o f 0, 200, 1000 or 5000 ppm, continuously throughout the study period, 25 rats/sex/group (MRID 44661601/44654202). This is equivalent to ranges of 0, 11.2
- 16.4, 57.3
- 82.8 and 306
- 428 mg/kg/day f or males during the pre - and postmating periods for 2 generati ons and ranges of 0, 15.3
- 32.1, 76.0
- 161.2 and 392.0
- 779.6 mg/kg/day

f or females during the premating, gestation and lactation periods for 2 generations. The lowest dose levels were selected for the NOAELs and LOAELs. Each female in each generation was mat ed to produce one litter only . Parental sy stemic toxicity was observed at 5000 ppm (306 mg/kg/day) based on decreased mean body w eight and mean body

w eight gain in parents during the premating period (P generation, both sexes, and Fl generation, males only). There were no treatment - related effects on mean food consumption. Decreases in mean body w eight and body

w eight gain were also evident in the offspring at this dose level (Fl pups on day s 7, 14 and 21 postpartum, and F2 pups on day s 14 and 21 postpartum). The onl y other findings considered to be treatment - related were an increase in mean spleen weight and an increase in the severity (but not in the incidence) of splenic extramedullary h ematopoiesis in females in the 5000 ppm group. It was considered equi vocal whether a similar, but less pronounced, increase in the severity of splenic extramedullary h ematopoiesis noted for males in the 5000 ppm group was related to treatment.Mefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 40 of 48 The parental/offspring sy stemic toxicity N OAEL is set at 1000 ppm (82 mg/kg bw/day for males and 94 mg/kg bw/day f or females) and the LOAEL is set at 5000 ppm (428 mg/kg bw/day

f or males and 482 mg/kg bw/day f or females) based on decreased mean body w eight and mean body

w eight gain in parents and offspring and on an increase in me an spleen weight and an increase in the severity (but not in the incidence) of splenic extramedullary

h ematopoiesis in females. The reproductive NOAEL is set at 5000 ppm (428 mg/kg bw/day

f or males and 482 mg/kg bw/day f or females, the highest dose tested) , since there were no adverse, treatment - related effects on reproductive parameters evident at any dose level tested. The reproductive study

i n the rat is classified as Acceptable guideline and satisfies the guideline requirement for a 2
- generation repro ductive study ( OPPTS 870.3800, §83
- 4) in the rat. A.3.3 Chronic Toxicity 870.4100b Chronic Toxicity - Dog EXECUTIVE SUMMARY: HOE 107892, purity 9 4.3%, was evaluated for chronic oral toxicity i n pure bred beagle dogs (6 animals/sex/dose) (MMD 44316402)
. Animals were dosed in the diet for a period of 52 weeks and 4
- 6 day s at concentrations of 0, 60, 300, 1500 or 7500 ppm (equal to 0, 2.3, 10.1, 51.4 and 260.2 mg/kg bw/day , respectivel y, in males and 0,2.1, 11.1, 57.6 and 282.2 mg/kg bw/day , respectively , in females). There were no treatment - related mortalities, changes in body w eight or food consumption. Liver findings included high ALP enz ym e levels in males and females treated at 7500 ppm (13/14 and 52/53 weeks for males (178% (p <0.05), 213% (p <0.01)) and 13/14, 26/27 and 52/53 weeks for females (350
- 412%, p <0.01)); high absolute and relative liver weights in males (p <0.05) and females (p < 0.01) treated at 7500 ppm and a high liver/body

w eight ratio in females (p <0.05) treated at 1500 ppm; and grade 1 (minimal) intrahepatic cholestasis in the liver of 2 males and 2 females of the high
- dose group. Along with the other findings in the liver (high ALP and high liver weights), cholestasis is considered to be toxicologicall y significant. For this study, the NOAEL is 1500 ppm (51.4 mg/kg bw/day) and the LOAEL is 7500 ppm (260.2 mg/kg/day) based on adverse findings in the liver in the high
- dose group and treatment
- related, non
- adverse findings in animals treated at 1500 ppm (high liver/body w eight ratio i n females treated at 1500 ppm). This chronic toxicity

s tudy i n the dog is Acceptable guideline and satisfies the guideline requirement for a chronic oral study (870.4100) in dogs. A.3.4 Chronic Toxicity/Carcinogenicity 870.4100 Chronic Toxicity/Carcinogenicity - RatMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 41 of 48 EXECUTIVE SUMMARY : Ina c hronic toxicity

/carcinogenicity

s tudy [ MRIDs 43972222 and 43972223], HOE 107892 (94.3% a.i.; Lo t/Batch Op 1
- 8/91) was administered to 70 Wistar rats/sex/dose in the diet at dose levels of 0, 40, 200, 1000, or 5000 ppm (0, 1.92, 9.80, 48.47, and 251.60 mg/kg/day

f or males, and 2.38, 12.07, 59.98, and 317.96 mg/kg/day f or females) for 124 weeks. At otal of 10 rats/sex/group were terminated at 52 weeks, 20 rats/sex/group were terminated at 104 weeks, an d the remaining rats were sacrificed following 124 weeks of treatment. There were no treatment - related effects on survival, clinical signs, body w eights, body

w eight gains, feed and water consumption, the clinical chemistry and urinal ys is parameters monit ored, and no eye lesions or dose
- related differences in absolute or relative organ weights in either sex were observed. There were no treatment - related gross necrops y, non - neoplastic, or neoplastic findings detected during the course of the study in either sex. F emales at the 5000 ppm dose level displayed treatment - related changes in hematology p arameters that suggest slight anemia with an increase in hematopoietic activity , as indicated by an increase in reticulocy tes ( ↑32% to ↑72%). A slightl y lower RBC count (5% to 8 %) and a statisticall y significant, slightl y lower hemoglobin concentration ( ↓6% to ↓11%) were observed throughout the study i n females at 5000 ppm. Although the males at 5000 ppm also displayed lower RBC and hemoglobin values compared to th e control males, the magnitude of the deficit was small ( ↓2% to ↓4%). However, there was a treatment - related increase in reticulocy te counts ( ↑13% to ↑42%) in the males at this dose level. No difference was observed in the hematologic response between the sexes in the rat subchronic study used for dose selection, which predicted that dose levels of 7500 ppm should be used in the rat chronic carcinogenicity /carcinogenicity

study . The response in the females at 5000 ppm in the current study

w as approaching an adverse level (all 3 compartments affected ( ↓5%) with a regenerative anemia (32%
- 72% ↑ reticulocy tes). In the males, red blood parameters were not affected, but there was an increase in hematopoietic activity ( 13%
- 46% ↑reticulocy

tes). The 5000 ppm dose t o the males on a mg/kg/day basis was slightly

lower (252 mg/kg/day) than in the females (318 mg/kg/day), suggesting that had the high dose been closer to that in the females, a similar reduction in red blood cell parameters would have been seen in the male s. The blood effects observed in the rat chronic toxicity /carcinogenicity study

at 5000 ppm in females are considered sufficient evidence that this dose level is approaching adverse toxicity
. Therefore, the highest dose used in the rat carcinogenicity s tudy i s considered adequate to test the carcinogenic potential of mefenp yr diethyl
. The LOAEL is 5000 ppm (251.6 mg/kg/day f or males and 318.0 mg/kg/day f or females), based on statistically

s ignificant increases in reticulocy te counts in both sexes, and d ecreased RBC, hemoglobin, and hematocrit values in females. The NOAE L is 1000 ppm (48.5 mg/kg/day f or males and 60 mg/kg/day

for females).Mefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 42 of 48 A.4 References ( in MRID order) 43972211 Ehling, G.; Leist, K. (1990) (Inert ingredient): Testing for Acute Oral

Toxicity in the Male and Female Wistar Rat: Lab Project Number: 90.0420: A43614: 90.0608. Unpublished . 43972212 Ehling, G.; Leist, K. (1990) (Inert ingredient): Testing for Acute Oral Toxicity in the Male and Female NMRI Mouse: Lab Project Number: 90.0422: A43378: 90.0450. Unpublished. 43972213 Ehling, G.; Leist, K. (1990) (Inert ingredient): Testing for Acute Dermal Toxicity in the Male and Female Wistar Rat: Lab Project Number: 90.0427: A43325: 90.0451. Unpublished. 43972214 Hofmann, T. ; Jung, R. (1990) (Inert ingredient): Testing for Acute Aerosol Inhalation Toxicity

in the Male and Female Wistar Rat, 4
- Hour LC50: Lab Project Number: 90.0984: A44883: 90.1423. Unpublished 43972215 Leist, K.; Hack, R. (1990) (Inert ingredient): Testing for Primary Eye Irritation in the Rabbit: Lab Project Number: 90.0426: A43537: 90.0531. Unpublished. 43972216 Leist, K.; Hack, R. (1990) (Inert ingredient): Testing for Primary Dermal Irritation in the Rabbit: Lab Project Number: 90.0425: A43 416: 90.0510. Unpublished 43972217 Hack, R.; Leist, K. (1991) (Inert ingredient): Testing for Sensitizing Properties in the Pirbright
- White Guinea Pig in a Maximization Test: L ab Project Number: 90.0990: A45698: 91.0254. Unpublished 43972218 T ennekes, H.; Janiak, D.; Probst, H.; et al. (1991) (Inert ingredient): Substance Technical Sub
- Chronic Oral Toxicity : 13
- Week Feeding Study in Mice: Lab Project Number: 284894: A48481. Unpublished 43972219 Tennekes, H.; Janiak, T.; Probst, D. et al . (1990) (Inert ingredient): Substance Technical Sub
- Chronic Oral Toxicity : 13
- Week Feeding Study in Rats: RCC, Research and Consulting Co.; RCC Umweltchemie Ag; and EPS Ag Lab Project Number: 285028: A47873. Unpublished. 43972220 Allen, T.; B raunhofer, P.; Frei, T. et al. (1992) (Inert ingredient): 13
- Week Oral Toxicity

(Feeding) Study

with (inert ingredient) Substance Technical in the Dog: RCC, Research and Consulting Co.; RCC Umweltchemie Ag; and RCC L ab Project Number: 285120: A4775 3. Unpublished.Mefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 43 of 48 43972221 Albrecht, M.; Baeder, C. (1992) (Inert ingredient): Testing for Embryotoxicity

in the Wistar Rat After Oral Administration (Limit Test): Lab Project Number: RR0620: 90.0988: A48150. Unpublished. 43972222 Dotti, A.; Keller, B.; Luetkemeier, H. et al. (1994) (Inert ingredient): Combined Chronic Toxicity /Oncogenicity

(Feeding) Study

with (inert ingredient) Substance Technical in the Rat: RCC, Research and Consulting Co. AG. Lab Project Number: 29349 0: A53310. Unpublished. 43972223 Dotti, A. (1995) (Inert ingredient): Combined Chronic Toxicity /Oncogenicity

(Feeding) Study

with (inert ingredient) Substance Technical in the Rat
-- First Amendment to Report: RCC, Research and Consulting Co., Ltd., Lab Project Number: 293490: A56020. Unpublished. 43972224 Dotti, A.; Keller, B.; Luetkemeier, H.; et al. (1994) (Inert ingredient): Oncogenicity (Feeding) Study with (inert ingredient) Substance Technical in the Mouse: RCC, Research and Consulting Co. AG. Lab Project Number: 94101 JMA: 291137: A53241. Unpublished. 43972225 Dotti, A. (1995) (Inert ingredient): Oncogenicity (Feeding) Study with (inert ingredient) Substance Technical in the Mouse
-- First Amendment to Report: RCC, Research and Consulting Co., Ltd., Lab Project Number: A56021: 291137. Unpublished. 43972226 Mueller, W. (1990) (Inert ingredient): Study of the Mutagenic Potential in Strains of Salmonella ty

phimurium (Ames Test) and Escherichia coli: Lab Project Number: 90.0421: A44259: 90.0783. Unpublished. 43972227 Mueller, W. (1990) (Inert ingredient): Chromosome Aberrations in vitro in V79 Chinese Hamster Cells: Lab Project Number: 90.0430: A44267: 90.0884. Unpublished. 43972228 Mueller, W. (1990) (Inert ingredient): Micronucleus Test in Male and Female NMRI Mice after Oral Administration: Lab Project Number: 90.0419: A44264: 90.0808. Unpublished 43972229 Mueller, W. (1990) Evaluation of (inert ingredient)
-- Substance, Technical in the Unschedul ed DNA Sy nthesis Test in Mammalian Cells in Vitro: Lab Project Number: 90.0418: A44405: 90.0685. Unpublished 43972230 Mueller, W. (1990) (Inert ingredient): Detection of Gene Mutations in Somatic Cells in Culture HGPRT
- Test with V79 Cells: Lab Pro ject Number: 90.0429: A44823: 90.0611. UnpublishedMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 44 of 48 44089201 Ebert, E.; Leist, K. (1992) (Inert ingredient): Repeated
- Dose Dermal Toxicity (21 Treatments in 29 Day s) in the Wistar Rat: Hoechst Aktiengesellschaft . Lab Project Number: 91.0450: CR0103: A48666. Unpublished. 44089202 Horstmann, G.; Baeder, C. (1992) (Inert ingredient): Testing for Embryotoxicity

in the Himalayan Rabbit After Oral Administration: L ab Project Number: RK0621: 90.0989: A49620. Unpublished. 44280001 Stammberger, I.; Jung, R. (1991) Sensitivity Check of the Guinea Pig Strain (Pirbright
- White Guinea Pig) for Sensitization Tests on the Skin with Nickel
- II
- Sulphate in a Maximization Test: (Positive Control Test for MRID 43972217): Lab Project Number: 91. 0298: A47419: 92.0097. Unpublished 44316401 Allen, T.; Corney , S.; Frei, T.; et al. (1990) (Inert ingredient): 30
- Day Oral Toxicity (Feeding) Study with (inert ingredient) in the Dog: RCC Research and Consulting Co., Ltd; RCC Umweltchemie AG; and RCC (UK) Ltd. Lab Project Number: A45830: RCC 271754: 271754. Unpublished 44316402 Allen, T.; Braunhofer, P.; Frei, T.; et al. (1992) (Inert ingredient): 52
- Week Oral Toxicity

(Feeding) Study

with (inert ingredient) in the Dog: Lab Project Number: A49032: RCC 291115: 291115. RCC Research and Consulting Co., Ltd; RCC Umweltchemie AG; and BRL Biological Research Labs, Ltd. Unpublished 44316403 Ebert, E. (1992) (Inert ingredient) : Repeated Dose Oral Toxicity (4
- Week Feeding Study) in the NMRIMouse
-- Plus Addendum: Hoechst Aktiengesellschaft. Lab Project Number: A47423: A48480: 90.0424. Unpublished. 44364401 Ebert, E.; Leist, K. (1997) (Inert Ingredient): Repeated
-- Dose Oral Toxicity (4
- Week Feeding Study) in the Wister Rat
-- Plus Addendum: Hoechst Aktiengesellschaft Lab Project Number: A47872: A49720: 91
- 1152. Unpublished 44654201 Albrecht, M.; Baeder, C. (1992) (Inert Ingredient) Substance Technical: Testing for Embryotoxicity and Effects on Post
-Natal Development in Wistar Rats After Oral Administration (Limit Test): Lab Project Number: P2R0636/RR0636: A48786: 92.0559. UnpublishedMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 45 of 48 44654202 Dotti, A. (1995) (Inert Ingredient) Substance Technical: Two - Generation Reproduction Study

in Rat: Amendment to Report A52643: Lab Project Number: 293433: A56022. Unpublished 44654203 Burkle, W.; Maas, J. (1996) (Inert Ingredient
- (carbon 14): Investigation of the Kinetics and Metabolism in Male and Female Rats Following 14 Daily Non
- Labelled Doses and Radiolabelled Oral Dose of 1mg/kg/day : Lab Project Number: 172/4: H012/K114D: A56423. Unpublished 44654204 Burkle, W. (1992) (Inert Ingredient)
- (carbon 14): Metabolism in the Rat Following a Singl e Dose of 1 and 100mg/kg Body Weight p. o: Lab Project Number: CM92/113: 172/2: A49252. Unpublished 44661601 Dotti, A.; Springall, C.; Biedermann, K. (1994) (Inert Ingredient) Substance Technical (... ZC94 0001) Two
- Generation Reproduction Study in the Rat: L ab Project Number: 293433: A522643. Unpublished 44661602 Eckert, H.; Kellner, H.; Puttkamer, G. (1992) (Inert Ingredient)
- (carbon
14) Pharmacokinetics in the Rat After Oral Administration of 1 and 100 mg/kg Body Weight: Lab Project Number: 172/1: CM90/103. Unpublished 44661603 Eckert, H.; Kellner, H.; Puttkamer, G. (1993) (Inert Ingredient)
- (carbon
14) Pharmacokinetics in the Rat after Oral Administration of 1 and 100 mg/kg Body Weight: Amendment to Report Number A49005: La b Project Number: 172/1: CM90/103: A51777. Unpublished 47563901 Maas, J. (1994). Dermal Penetration in Male Rats Following Single Applications of Approximately 0.053, 0.53 and 5.3 mg/animal to the Surface of the Skin. L ab Projec t ID TEP: 172/3. Unpublished. A . 5 Rationale for Requiring the Data Guideline Number: 870.6200 Study Title : Neurotoxicity Battery (Acute and Subchronic Studies) Rationale for Requiring the Data This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non
- food uses). The Neurotoxicity

Screening Battery

(OPPTS 870.6200) is designed to evaluate the potential adverse effects o n the nervous s ys tem from exposure to pesticide chemicals. The Agency

believes that the guideline studies are inadequate in their assessment of behavioral effects and do not use optimal methods to evaluate the potential toxicity to the nervous tissue stru cture and function. To detect and characterize these potential effects more fully , a battery

of more sensitive testing is required. The objective of thisMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 46 of 48 neurotoxicity

battery testing is to evaluate the incidence and severity of the functional and/or behav ioral effects, the level of motor activity , and the histopathology of the nervous s ys tem. The acute neurotoxicity study is required to detect possible effects resulting from a single exposure. The subchronic neurotoxicity study is intended to detect possib le effects resulting from repeated or long
- term exposures. Practical Utility of the Data How will the data be used? The acute and subchronic neurotoxicity studies provide critical scientific information needed to characterize potential hazard to the human population on the nervous sy stem from pesticide exposure. These studies can provide data on a wide range of functional tests for evaluating neurotoxicity including sensory

effects, neuromuscular effects, learning and memory

and histopathology

of the nervous s ys tem For example, animal studies with organophosphorous chemicals have shown neurotoxicity to be the primary toxic endpoints (e.g., cholinesterase inhibition) of concern in rodents and non
- rodents. These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenarios and are considered a primary data source for reliable reference dose calculation. The Agency has established an oral reference dose (RfD) for assessing dietary risks for a number of c hemicals (e.g., organophoshates and carbamates) where neurotoxicity

was the most sensitive endpoint of concern. How could the data impact the Agency's future decision - making? If the acute or subchronic neurotoxicity studies show that mefenpy r - diethyl poses either a greater or a diminished risk than that given in the current decision’s conclusion, the risk assessment for mefenp yr - diethyl may need to be revised to reflect the magnitude of potential risk derived from the new data. If the Agency

does not have these data, a 10X database uncertainty factor may be applied when conducting a risk assessment using the currently available studies. Guideline Number: 870.7800 Study Title : Immunotoxicity Rationale for Requiring the Data This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non
- food uses). The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity testing and is designed to evaluate the potential of a repeated chemical exposure to produce adverse effects (i.e., suppression) on the immune system. Immunosuppression is a deficit in the ability of the immune system to respond to a challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired Respiratory Syndrome (SARS), or neoplasia. Because the immune system is highlyMefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 47 of 48 complex, studies not specifically conducted to assess immunotoxic endpoints are inadequate to characterize a pesticide’s potential i mmunotoxicity. While data from hematology, lymphoid organ weights, and histopathology in routine chronic or subchronic toxicity studies may offer useful information on potential immunotoxic effects, these endpoints alone are insufficient to predict immuno toxicity. Practical Utility of the Data How will the data be used? Immunotoxicity studies provide critical scientific information needed to characterize potential hazard to the human population on the immune system from pesticide exposure. Since epidemiologic data on the effects of chemical exposures on immune parameters are limited and are inadequate to characterize a pesticide’s potential immunotoxicity in humans, animal studies are used as the most sensitive endpoint for risk assessment. These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenarios and are considered a primary data source for reliable reference dose calculation. For example, animal studies have demonstrated that immunotoxicity in rodents is one of the more sensitive manifestations of TCDD (2,3,7,8
- tetrachlorodibenzo
-p - dioxin) among developmental, reproductive, and endocrinologic toxicities. Additionally, the EPA has established an oral reference dose (RfD) for tributyltin ox ide (TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997). How could the data impact the Agency's future decision - making? If the immunotoxicity study shows that the test material poses either a greater or a diminished risk than that given in the interim decision’s conclusion, the risk assessments for the test material may need to be revised to reflect the magnitude of potential risk derived from the new data. If the Agency does not have this data, a 10X database uncertainty factor may be applied for conducting a risk assessment from the available studies.Mefenp yr - DiethylHuman Health Risk Assessment D 374653

Page 48 of 48 Appendix B : Tolerance Summary and Table Appendix B 1 . Tolerance Summary for Mefenpyr - diethyl Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity

Definition Grass Forage 1.5 1.6 Grass, forage Grass Hay 0.05 0.2 Grass, hay Sorghum Forage 0.1 0.4 Sorghum, forage Sorghum Grain 0.01 0.04 Sorghum, grain Sorghum Stover 0.05 0.2 Sorghum, stover Appendix C : Review of Human Research Studies reviewed for ethical conduct: This assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide. These studies, listed below, have received the appropriate ethical review.

 The PHED Task Force, 1998. The Pesticide Handler Exposure Database (PHED), Version 1.1. Task Force members Health Canada, U.S. Environmental Protection Agency , the California Department of Pesticide regulation, and the American Crop Protection Associatio n, released August 1998.  ARTF Studies. Agricultural Reentry Task Force (ARTF). Reviewed b y HED, ExpoSAC SOP No. 003 (May 7th, 1998
- Revised August 7th, 2000).