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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

DATE: February 22, 2011

SUBJECT: Mefenpyr-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: 374653

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 (7509P)

THROUGH: Michael S. Metzger, Chief

Registration Action Branch 7

Health Effects Division (7509P)

TO: Bethany Benbow, RM 23

Registration Division (7505P)

Mefenpyr-diethyl, also known as Diethyl-1-(2,4-Dichlorophenyl)-5-Methyl-2-Pyrazolin-3,5-

Dicarboxylate 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. Mefenpyr-diethyl is a 

component of HUSKIETM herbicide; it is co-formulated with the active ingredients pyrasulfotole 

and bromoxynil and is proposed for use on sorghum one application per season and two 

applications to grass grown for seed per season. 
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Table of Contents

1.0 Executive Summary............................................................................................................ 4

Regulatory Recommendations and Data Deficiencies........................................................ 6

2.0 Ingredient Profile ................................................................................................................ 6

2.1 Summary of Registered/Proposed Uses.................................................................. 7

2.2 Structure and Nomenclature ................................................................................... 8

2.3 Physical 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)................................... 14

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 Analytical 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.............................................................................. 25
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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 Occupational 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................................................................................... 48
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1.0 Executive Summary

Mefenpyr-diethyl, also known as Diethyl-1-(2,4-Dichlorophenyl)-5-Methyl-2-Pyrazolin-3,5-

Dicarboxylate or HOE 107892, is a safener currently used with several herbicides on cereal 

grain. Tolerances for residues of mefenpyr-diethyl, and its 2,4-dichlorophenyl-pyrazoline 

metabolites resulting from application of the safener are listed in 40 CFR §180.509. This action 

requests new uses on sorghum and grass grown for seed. Mefenpyr is a component of 

HUSKIETM herbicide; it is proposed for use on sorghum one application per season and two 

applications to grass grown for seed per season. 

The toxicology database on mefenpyr-diethyl is considered adequate for selecting endpoints and 

uncertainty factors to support the proposed amended use of this safener. Metabolism studies 

indicate that mefenpyr-diethyl is rapidly metabolized, widely 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 the limit dose. Repeated exposure studies via the oral 

route demonstrate that the target organs are the liver and hematopoietic system in dogs, mice, 

and rats. Mefenpyr-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). Mefenpyr-diethyl did not induce any signs of reproductive toxicity or 

neurotoxic potential. Additionally, mefenpyr-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 and ocular irritant. 

There is no evidence of increased susceptibility in rats or rabbits following pre- and/or post-natal 

exposure to mefenpyr-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 

mefenpyr-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-species extrapolation. At the study LOAEL, liver effects were 

observed. There are currently no residential uses of mefenpyr-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 NOAEL of 100. At the 

study LOAEL, 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 43% was derived from available information and 
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used in the risk assessment.

Mefenpyr-diethyl is classified as “not likely 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 analytical enforcement method for plants is 

available to enforce the newly proposed tolerances. 

No Codex, Canadian, or Mexican maximum residue limits (MRLs) are established for residues 

of mefenpyr-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 mefenpyr-diethyl using tolerance level residues, assuming 100% crop treated, and 

incorporating modeled water numbers reflecting an exaggerated application rate. Mefenpyrdiethyl 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 mefenpyr-diethyl 

were seen in the database; therefore, an acute dietary risk assessment was not conducted. 

Mefenpyr-diethyl is not likely to be a human carcinogen; thus, a cancer dietary risk assessment is 

not required.

Products containing mefenpyr-diethyl are marketed and typically 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 was not conducted.

Since there are no residential uses for mefenpyr-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 mefenpyr-diethyl. 

HED conducted occupational handler and post application exposure and risk assessments to 

support the requested new use pattern. Mefenpyr is applied as a component of a mixed active 

ingredient herbicide, HUSKIE

TM

. The risk assessment evaluated mefenpyr-diethyl applied by 

aerial or ground application methods to sorghum and grass grown for seed. One application is 

proposed for sorghum and two applications are proposed on the product labels for the 

HUSKIETM herbicide per growing season. Current labels require normal work clothing (WDGs) 

or double layer clothing (ECs) with appropriate footwear, eye protection, and chemical resistant 

gloves. Respirators are not required. Restricted entry intervals (REI) are 24 hours on all labels. 

Risks from occupational exposures were calculated for handlers using aerial and ground-based 

application equipment which would be typical 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 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 occur 
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relative to the use of mefenpyr-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., MOEs >33,000 and target 

= 100). Current 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 Low-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 herbicide safener mefenpyr-diethyl (1-(2,4-dichlorophenyl)-4,5-dihydro-5-methyl-1Hpyrazole-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

Sorghum, 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 

Requirements (2007 edition)

2.0 Ingredient Profile

Mefenpyr-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 the 
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herbicides. Safeners are often similar in molecular structure to active pesticides and may exhibit 

mammalian toxicity. Thus, the Agency has established some tolerances for safeners. 

2.1 Summary of Registered/Proposed Uses

The proposed use pattern is for mefenpyr-diethyl on sorghum and grass grown for seed 

(including Conservation Reserve Program areas). Mefenpyr-diethyl is currently used as a 

safener with various herbicides on cereal grain crops. HED considered the current product labels 

which contain mefenpyr-diethyl as part of the review to support the requested use revision. 

Mefenpyr-diethyl is formulated in HUSKIETM 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.

Mefenpyr-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 products. 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 soybean are adequate for the 

proposed uses. The field rotational crop data for field corn will support a 90-day plantback 

interval (PBI) with no need for rotational crop tolerances. The field rotational crop data for 

soybean will support the established soybean and canola tolerances and a 120-day PBI. 
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2.2 Structure and Nomenclature

Table 2.2. Mefenpyr-Diethyl Nomenclature.

Chemical structure

Common name Mefenpyr-diethyl

Company experimental name AE F107892, HOE 107892

IUPAC name Diethyl (RS)-1-(2-,4-dichlorophenyl)-5-methyl-2-pyrazoline-3,5-dicarboxylic acid

CAS name 1-(2,4-dichlorophenyl)-4,5-dihydro-5-methyl-1H-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

H3C O

O

O

CH3

N N

Cl Cl

H C3

N N

Cl Cl

H C3 CO2H

N N

Cl Cl

H C3

CO2H

HO2C

N N

Cl Cl

H C3

CO2H

H3CH2COOC
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2.3 Physical and Chemical Properties

Table 2.3 Physicochemical Properties of Mefenpyr-Diethyl.

Parameter Value Reference

Melting point/range 50-52 oC

43-47 oC

MRID 43984109

pH Was not determined, because mefenpyrdiethyl technical is practically insoluble 

and nondispersible in water.

MRID 43984109

Density (20 oC) 1.31 g/cm3at 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 10-6Pa MRID 44024001

Dissociation constant, pKa Neither acidic nor basic functional groups. 

Dissociation, if any, is expected to be 

negligible.

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 mefenpyr-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 newly required by the Part 158 Guidelines, and should 

be required as conditional data. A subchronic inhalation study is also required since inhalation 

exposure is likely 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 literature 
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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 mefenpyr-diethyl was rapidly 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 consists of consecutive 

hydrolysis (saponification) of the two carboxylic acid ester groups, resulting in an aromatization 

of the pyrazoline ring (Hoe 107892→ HOE 113225 → HOE 109453 → HOE 094270).

Excretion is biphasic, and metabolism appears to be influenced by sex 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 

Mefenpyr-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 system in dogs, mice, and rats. Mefenpyr-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. Mefenpyr-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 mefenpyr-diethyl is classified “not 

likely to be carcinogenic to humans”. The mutagenicity/genetic toxicity database is 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 following dietary exposure for 124 

weeks at dose levels up to 250-300 mg/kg/day. Previously, the study was classified as 
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unacceptable because the doses employed were not considered adequate to test the carcinogenic 

potential of mefenpyr-diethyl. This was based on the determination that the increases in 

reticulocyte counts were not supported by changes in red blood cell parameters. Although this 

effect is observed across species, it was not considered to be biologically relevant previously 

because the effect was minimal, and no other effects were observed. 

During a re-evaluation of the toxicology database on mefenpyr-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 124-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 affected (↓5%) with a regenerative anemia 

(32%-72% ↑ reticulocytes]. In the males, red blood cell parameters were not affected, but there 

was an increase in hematopoietic activity (13%-46% ↑reticulocytes). The 5000 ppm dose to the 

males 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 also would have also been seen in the males. The blood effects observed in the 

chronic 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 mefenpyr- diethyl. 

There is no evidence that mefenpyr-diethyl interacts with the estrogen, androgen, or thyroid 

hormonal systems. 

The toxicology database for mefenpyr-diethyl is complete under Part 158 (1984 edition), with 

the exception of a subchronic inhalation toxicity study. It is recommended that a 28-day

inhalation study be required because the application of mefenpyr-diethyl will be by either aerial 

application or spray boom equipment leading to potential inhalation exposure, and there is no 

effective measure 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 mefenpyr-diethyl. 

There is no evidence of neurotoxicity in the toxicology database on mefenpyr-diethyl, which 

includes subchronic, chronic, developmental toxicity, and reproduction studies performed at 

doses of 250 mg/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 set for mefenpyr-diethyl (see Section 3.2.2 below), 

and an additional uncertainty factor (UFDB) for database uncertainties does not need to be 

applied.
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Mefenpyr-diethyl was assessed in a complete battery of subchronic, chronic, carcinogenicity, 

developmental and reproductive studies. HED considered the entire toxicity database for 

mefenpyr-diethyl for potential adverse effects on the thymus 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 

(UFDB) for database uncertainties does not need to be applied.

3.1.4 FQPA 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. Mefenpyr-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 mefenpyr-diethyl. There is a lack of evidence of neurotoxicity in any study on 

mefenpyr-diethyl. 

There are no concerns and no residual uncertainties with regard to pre- and/or postnatal toxicity, 

and estimates of exposure are not likely to underestimate risk. The Food Quality Protection 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 mefenpyr-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, 

developmental toxicity (abortion) was observed 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 concentrations 
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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 bodyweight 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 NOAEL 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 

mefenpyr-diethyl.

3.1.4.5 Determination of Susceptibility

There is little concern for prenatal toxicity resulting from exposure to mefenpyr-diethyl. There is 

no evidence of increased susceptibility [qualitative and quantitative] following in utero exposure 

to mefenpyr-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 only 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

hematopoiesis 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. 
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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 systemic 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 reevaluation of the endpoints used was performed. Previously, the chronic dietary endpoint was 

selected by HIARC from the 2-generation reproduction study in rats. However, the endpoint 

associated with the NOAEL of 1000 ppm (57 mg/kg/day) was based on the intake of test 

material by the F1 males during the post-mating phase, since this provided the lowest 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 was calculated to be 82 mg/kg/day for the 1000 ppm 

concentration. Since this change with the 2-generation reproduction study no longer provides the 

lowest NOAEL, the mefenpyr-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 LOAEL for common effects). The route and duration of exposure are 

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 mefenpyr-diethyl, which 

shows that mefenpyr-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/cm2 14C-mefenpyrdiethyl was administered to male rats was rapidly absorbed, distributed and eliminated (MRID 

47563901). The amount absorbed increased with duration of exposure. The average 14Cmefenpyr-diethyl absorbed within 24 hours was 31%, 28%, and 6% of the applied dose for the 

low-, mid-, and high- dose groups, respectively. 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 estimated 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 

mefenpyr-diethyl; the DER is in process. 

3.2.5 Dermal Exposure (Short- and Intermediate-Term)

Study Selected: Developmental toxicity study – rabbit (OPPTS 870.3700)
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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 selected 

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 abortions 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-related (occurred in over a third of the animals at this dose level; 6/15). 

The abortions first occurred following 10 days of dosing (gestation day 16-23). Dermal 

absorption data are available that indicate a 43% absorption factor for mefenpyr-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 mefenpyr-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

Mefenpyr-diethyl is classified as “not likely to carcinogenic to humans”. Carcinogenicity studies 
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showed no evidence of an increase in the incidence of tumors in either the rat or the mouse. 

3.2.10 Summary 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

Acute Dietary 

(General 

Population, 

including 

Infants and 

Children)

No hazard was identified in any toxicity study for this duration of exposure

Acute Dietary

(Females 13-49 

years of age)

No hazard was identified in any toxicity study for this duration of exposure

Chronic 

Dietary (All 

Populations)

NOAEL = 51 

mg/kg/day

UFA= 10x

UFH=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 observed adverse effect level. 

LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = 

potential variation in sensitivity among members of the human population (intraspecies). PAD = population adjusted dose (a = acute, c = 

chronic). RfD = reference dose. N/A = not applicable.
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Table 3.4.2 Summary of Toxicological Doses and Endpoints 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 Shortand 

IntermediateTerm

orala

NOAEL= 

100 

mg/kg/day

(dermal 

absorption 

rate = 100%)

UFA= 10x

UFH=10x

Occupational LOC 

for MOE = 100

Developmental toxicity study – rabbit 

LOAEL = 250 mg/kg/day based on abortions

Dermal LongTerm

Based on the use pattern, chronic dermal exposure is not expected.

Inhalation 

Short-Term

(1-30 days) and

IntermediateTerm (1 – 6 

months)

orala

NOAEL= 

100 

mg/kg/day

(inhalation 

absorption 

rate = 100%)

UFA= 10x

UFH=10x

Occupational LOC 

for MOE = 100

Developmental toxicity study – rabbit 

LOAEL = 250 mg/kg/day based on abortions

Inhalation 

Long-Term (>6 

months)

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 associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. 

LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = 

potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. 

N/A = not applicable.

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 by a naturally occurring estrogen, 

or other such endocrine effects as the Administrator may designate.” 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 thyroid hormone systems, in addition to the estrogen hormone system. 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 substance may have an effect in humans, FFDCA authority to require the 

wildlife evaluations. As the science develops and resources allow, screening of additional 

hormone systems may be added to the Endocrine Disruptor Screening Program (EDSP).
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4.0 Public Health and Pesticide Epidemiology Data

Since mefenpyr-diethyl is used as a safener, and not as the active ingredient in pesticide 

formulations, incident data are not likely to be available for mefenpyr-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 Characterization

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 mefenpyr-diethyl is well understood in plants and animals. Identified 

metabolic pathways are substantially similar in plants and animals (goat, rat, and hen). EPA has 

determined that mefenpyr-diethyl parent and its three 2,4-dichlorophenyl-pyrazoline 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.
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5.1.2 Analytical Methodology

Residue Chemistry Memo DP#D380768, A. LaMay, 2/22/11 (PP# 7E7224)

An enforcement method for plants entitled “An Analytical Method for Determination of 

Residues of AE F107892 (mefenpyr-diethyl) and its Metabolites in Wheat and Barley by Gas 

Chromatography using Mass Selective Detection (Report Supplement to EPA MRID 45457401)” 

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 mefenpyr-diethyl and the three metabolites 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 secondary contribution by soil 

sensitized photolysis. Concentrations of HOE-107892 would decrease relatively rapidly in soil 

with a DT50 of approximately a few days to one week. However, in the process, by-products 

which are structurally very similar to parent and longer-lived are formed (HOE-094270, HOE113225, and HOE-109453).

5.1.4 Comparative Metabolic Profile

The metabolic profile for mefenpyr-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-dichlorophenyl-pyrazoline 

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.
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5.1.5 Pesticide Metabolites and Degradates of Concern

Table 5.1.5 Summary of Metabolites and Degradates to be included in the 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-pyrazoline metabolites 

(HOE 113225, HOE 109453, and HOE 094270)

Rotational Crop Parent and three 2,4-dichlorophenyl-pyrazoline metabolites 

(HOE 113225, HOE 109453, and HOE 094270)

Livestock Ruminant Parent and three 2,4-dichlorophenyl-pyrazoline metabolites 

(HOE 113225, HOE 109453, and HOE 094270)

Poultry Parent and three 2,4-dichlorophenyl-pyrazoline metabolites 

(HOE 113225, HOE 109453, and HOE 094270)

Drinking Water Parent and three 2,4-

dichlorophenyl-pyrazoline 

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 exaggerated rate of 0.08 

lb ai/A, which is higher than the currently requested use pattern; therefore, those estimated 

drinking water values remain valid and were incorporated directly into this dietary assessment. 

Water residues were incorporated in the DEEM-FCID into the food categories “water, direct, all 

sources” and “water, indirect, all sources.” 

Monitoring data for mefenpyr-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 parent equivalent 

concentrations) of relatively short-lived parent and several longer-lived transformation products 

that are structurally 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 that 
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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 roughly 1000 days. Since HOE107892 has Koc and aerobic soil metabolism half-lives well within the bounds covered by 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/year 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. LaMay, 2/22/11 (PP# 7E7224)

New field trial data for mefenpyr were submitted for the primary crop commodities (grass, 

sorghum grain, forage and stover). Total mefenpyr-diethyl residues in grass forage ranged from 

below the LLMV (<0.40 ppm) to 1.59 ppm at a PHI of 0 days. In grass hay, residues of 

mefenpyr-diethyl and its metabolites were all below 0.5 ppm. Following two applications of 

mefenpyr-diethyl to sorghum, total residues ranged from 0.4 ppm to 1.34 ppm at a PHI of 0 days 

in sorghum forage. Total mefenpyr-diethyl residues were undetectable in 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 slightly, 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 metabolites.

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 mefenpyr-diethyl parent and its three 2,4-dichlorophenylpyrazoline metabolites (HOE 113225, HOE 109453, and HOE 094270). Mefenpyr-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 mefenpyr-diethyl (1-(2,4-dichlorophenyl)-4,5-

dihydro-5-methyl-1H-pyrazole-3,5-dicarboxylic acid, diethyl ester) and its 2,4-dichlorophenylpyrazoline metabolites.
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No Codex, Canadian, or Mexican maximum residue limits (MRLs) are established for residues 

of mefenpyr-diethyl and metabolites in crop commodities; therefore, there are no issues with 

international harmonization raised by this action. 

5.2 Dietary Exposure and Risk

Dietary Exposure and Risk Memorandum D380767, A. LaMay, 2/22/11

5.2.1 Acute Dietary Exposure/Risk

No toxic effects attributable to a single exposure of mefenpyr-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 highly conservative chronic dietary risk assessment was conducted for food only and for food 

and drinking water for mefenpyr-diethyl using tolerance level residues and assuming 100% crop 

treated. Mefenpyr-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 Risk

Mefenpyr-diethyl is classified as a “not likely to be carcinogenic to humans”; a cancer dietary

risk assessment is not required.
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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

(mg/kg/day)

% cPAD*

Dietary 

Exposure

(mg/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 mefenpyr-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 only, not for sod to be used in residential setting.
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Based on the Agency's current practices, a quantitative postapplication inhalation exposure assessment 

related to agricultural applications was not performed for mefenpyr diethyl at this time. However, 

volatilization of pesticides may be a potential source of postapplication inhalation exposure to 

individuals nearby 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/scipoly/SAP/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, subsequently, the way to incorporate postapplication inhalation exposure 

into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may 

revisit the need for a quantitative postapplication inhalation exposure assessment for mefenpyr diethyl.

Spray drift is always 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 mefenpyrdiethyl. The Agency 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 by 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 

appropriately apply the data and the AgDRIFT computer model to its risk assessments for 

pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in 

place, the Agency may impose further refinements 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 mefenpyr-diethyl; therefore, the aggregate risk assessments 

include the contribution of risk from dietary (food and water) sources only. No toxic effects 

attributable to a single exposure of mefenpyr-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. Mefenpyr-diethyl is 

classified as “not likely to be carcinogenic to humans”; thus, a cancer aggregate risk assessment 

was not conducted. HED has no concern for aggregate risks resulting from the increased 

application of mefenpyr-diethyl requested in this petition. 

8.0 Cumulative Risk Characterization/Assessment

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 mefenpyr-diethyl and any other substances and mefenpyr-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 mefenpyr-diethyl has a common mechanism of toxicity with 
Mefenpyr-Diethyl Human Health Risk Assessment D374653

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

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

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

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

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

9.0 Occupational Exposure/Risk Pathway

Occupational and Residential Exposure Memo DP#D379984, M. Lloyd, 10/07/10

Occupational exposure risk estimates were calculated for products where mefenpyr-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. 

Mefenpyr-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 early 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 label requires 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 component 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 

typical 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 increase 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 likely hand labor activity which would occur relative to the use of mefenpyr-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., MOEs > 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 REI of 1 day. 

9.1 Occupational Handler Risk

The following occupational handler scenarios were assessed based on the proposed use 

directions on the proposed products, and information on actual field practices: 

Mixer/Loader:

(1) Mixing/Loading Liquids for Aerial Applications (PHED);

(2) Mixing/Loading Liquids for Groundboom Applications (PHED);

(3) Mixing/Loading Liquids for Chemigation Applications (PHED); and
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Applicators:

(4) Applying Sprays via Aerial Equipment (PHED)

(5) Applying Sprays 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 

mefenpyr-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 scenarios 

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 factors 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 mefenpyr-diethyl are not of concern (i.e., all MOEs exceed 100 for all 

scenarios).

HED classifies exposures up to 30 days as short-term and exposures greater than 30 days 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. 

Mefenpyr-diethyl is a component of the herbicide HUSKIETM (EPA Reg. No. 264-1023) and 

handler personal protective equipment is based on the active ingredients in the formulation 

(pyrasulfotole and bromoxynil). Therefore, actual occupational handler exposures are lower (i.e., 

MOEs are higher) than in the risk estimates expressed below. 

Table 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 MOEsg Combined MOEsh

Mixer/Loader for Aerial Applications

 

1 Available: http://www.epa.gov/pesticides/science/phedsur-expo-guide.pdf
Mefenpyr-Diethyl Human Health Risk Assessment D374653

Page 27 of 48

Table 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 MOEsg Combined MOEsh

0.01 1200

Dermal

Baselinec: 2.9

Dermal

Baseline: 0.58

Dermal

Baseline: 170 Baseline Dermal + 

Inhalation: 170 Inhalation

Baselined: 0.0012

Inhalation

Baseline: 7E-5

Inhalation

Baseline: 420,000

Mixer/Loader for Chemigation Applications (grasses)

0.009 350

Dermal

Baselinec: 2.9

Dermal

Baseline: 0.152

Dermal

Baseline: 660 Baseline Dermal + 

Inhalation: 660 Inhalation

Baselined: 0.0012

Inhalation

Baseline: 6E-5

Inhalation

Baseline: 1,600,000

Applicator for Aerial Equipment

0.01 1200

Dermal

Enclosed Cockpite: 

0.0055 

Dermal

Enclosed Cockpit: 0.0011

Dermal

Enclosed Cockpit: 

91,000 Engineering control 

Dermal + Inhalation: 

90,000 Inhalation

Enclosed Cockpit: 

0.000467

Inhalation

Enclosed Cockpit: 

0.0000136

Inhalation

Enclosed Cockpit: 

7,400,000

Applicator for Groundboom Equipment

0.01 200

Dermal

Baselinec: 0.014

Dermal

Baseline: 0.000467

Dermal

Baseline: 210,000 Baseline Dermal + 

Inhalation Inhalation: 200,000

Baselined: 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 Inhalation: 150,000

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 Inhalation: 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 typically occurs only sporadically after applications. Most other 

activities which would routinely occur such as harvest and, in some cases limited cultivation 
Mefenpyr-Diethyl Human Health Risk Assessment D374653

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 

sorghum and grass grown for seed.

No chemical-specific data (e.g., dislodgeable foliar residue or DFR) data were available for 

mefenpyr-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 above 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 Day 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 postapplication 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 REI of 1 day. 

Table 9.2. Summary of Occupational Postapplication Risks for Mefenpyr-diethyl

Crop 

Grouping

Application 

rate

(lb ai/acre)

Transfer Coefficient (cm2/hr) Days 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 exposures 
Mefenpyr-Diethyl Human Health Risk Assessment D374653

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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 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 

Requirements (2007 edition)

10.2 Residue Chemistry

860.1480 Livestock Feeding Study

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 

metabolites.

860.1550 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) currently has the rotational crop tolerances for soybean 

and canola listed under the general tolerances for residues as a direct application tolerance. The 

tolerances for canola seed, soybean forage, soybean hay, and soybean 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 time
Mefenpyr-Diethyl Human Health Risk Assessment D374653

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Appendix A: Toxicology Assessment

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.500; 2007) for a food use chemical for mefenpyr-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

yesA

870.5100 Bacterial Reverse Mutation Assay.................................

870.5300 In Vivo Mammalian Cell Assay.....................................

870.5xxx In Vitro Cytogenetics 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

yes

no

yes

yes

no

A

rat 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 required
Mefenpyr-Diethyl Human Health Risk Assessment D374653

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A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile – Mefenpyr-diethyl 

Guideline 

No.

Study Type MRID(s) Results Toxicity 

Category

870.1100 Acute oral [rat] 43972211 ALD50 = >5000 mg/kg IV

870.1200 Acute dermal [rat] 43972213 BLD50 = >4000 mg/kg III

870.1300 Acute inhalation [rat] 43972214 CLC50 = >1.32 mg/L III

870.2400 Acute eye irritation [rabbit] 43972215 slight ocular irritant 

PIS 12.8

III

870.2500 Acute 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 transferase (GGT) activities 

(+55%). 

870.3100

4-week oral toxicity 

[Wistar rat IBMHan 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: statisticallysignificant (n=5/sex/group) increases in GSH, DEM, PROD, 

TCCR, GGT in one or both sexes(mainly dose-related)
Mefenpyr-Diethyl Human Health Risk Assessment D374653

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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 [Hanoverderived 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 hypertrophy 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), decreased 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

Datagap
Mefenpyr-Diethyl Human Health Risk Assessment D374653

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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 relative 

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

Maternal 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)

Developmental 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)]
Mefenpyr-Diethyl Human Health Risk Assessment D374653

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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 = 5000 ppm (males 252/females 318 mg/kg/day, 

based on statistically significant increases in reticulocyte 

counts in both sexes, and decreased RBC, hemoglobin, 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 treatment 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 required
Mefenpyr-Diethyl Human Health Risk Assessment D374653

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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 

[phenyl14C ] 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 [

14C] 

recovered during first 24 hours; tissue/organ residual activity 

at 168 hours ≤0.6%; biphasic elimination pattern was 

identified: initial rapid T1/2: males 4.2/females 3.7 hours 

(urine) and males 7.8/females 10.4 hours (feces); longer T1/2: 

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 

094270 (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 tissues/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 (saponification) 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 appears 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 

cytotoxicity; 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.
Mefenpyr-Diethyl Human Health Risk Assessment D374653

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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 

cytogenetic 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 

cytogenetic assay 

(mouse)

MRID 43972227

Classification: acceptable/guideline

no evidence that test material induced a clastogenic or 

aneugenic effect in either sex at any sacrifice time at 5000 

mg/kg. 

Guideline 5550, 

unscheduled DNA 

synthesis in 

mammalian cells in 

culture

MRID 439722229

doses up to 100 ug/mL (+/-S9); 

cytotoxic/insoluble without S9; +S9 not 

cytotoxic at 100 ug/mL

Classification: unacceptable/nonguideline

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 synthesis 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 [

14C] 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)
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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 oral 

gavage, once daily from day 7 to 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 

mucilage) without the test substance (MRID 44654201). The animals delivered normally

and reared their offspring for 21 days. There were no maternal mortalities, no treatmentrelated clinical signs of toxicity and no treatment-related gross pathological observations. 

Mean maternal body weight was comparable between the control and treated group 

throughout gestation and lactation. Mean maternal body-weight gain was significantly 

lower (14%) during treatment (days 7 to 17 of gestation) due to a significant difference

(decreased 24%) during the first week of treatment (days 7 to 14 of gestation) and was 

accompanied by a significant 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 weight (5-9% 

less 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 of the test substance. 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 weight), and no impairment in the physical, 

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 the 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 marginal decreases in fetal body weight and body 

weight gain during lactation.

The post-natal development study in the rat is classified as acceptable/nonguideline. 

There is no guideline requirement for a post-natal developmental toxicity study.

EXECUTIVE SUMMARY: In a developmental toxicity study (MRID 43972221) Hoe 

107892 (94.5% a.i.) in starch mucilage was administered orally by gavage to 20 Wistar 

rats at the limit dose (1,000 mg/kg/day) from days 7 through 16 of gestation.

At 1000 mg/kg/day, mean body weight gain for days 7-14 was significantly lower 

(24.2%) than the control group during the same time period. There was a slight, although 
Mefenpyr-Diethyl Human Health Risk Assessment D374653

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not statistically significant increase in body weight gain during the latter part of treatment 

(days 14- 17) and during the post-treatment period. The food efficiency index was also 

significantly lower during the first week of treatment. In addition to the decrease in body

weight gain during treatment, absolute and relative spleen weights were significantly 

increased in 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 study in the rat is classified Acceptable/Guideline and it 

satisfies the guideline requirement for a developmental toxicity study [OPPTS 870.3700; 

§83-3(a)] in rats. Although a maternal NOAEL was 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. Both show only minimal fetal body-weight effects and decreased maternal bodyweight gain during the first week. Although a NOAEL was not defines in either study, 

no developmental toxicity was observed at the limit dose. Therefore, sensitivity to 

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 oral 

gavage once daily from days 6 to 18 of gravidity to groups of 15 to 16 mated female 

Himalayan rabbits at a dose of 0 (vehicle only), 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 caesarian section on day 29 of gravidity after 

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 or organ weights observed in the does. Mean maternal body weight 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 period, 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 (days 

6 to 13) which was accompanied by a significantly reduced (p 0.05) food efficiency

index and food consumption. There was also a higher rate of abortions. There were no 
Mefenpyr-Diethyl Human Health Risk Assessment D374653

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other treatment-related effects at any dose level on delivery or on litter data parameters 

examined, including those found dead due to abortions or premature delivery. 

The NOAEL for maternal 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 index and food consumption may also be an indication of maternal 

toxicity as well; however, due to the fact there was no effect on mean body weights in the 

treated groups and that the percent increase in mean bodyweight over the entire gestation 

period, when compared to the total bodyweight is only 10% (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 solely due to maternal 

toxicity.

The developmental toxicity study in the rabbit is classified as Acceptable guideline and 

satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; 

§83-3(b)) in the rabbit. 

A.3.2 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects - Rat

EXECUTIVE SUMMARY: A two-generation reproduction study was conducted using 

WIST Han Ibm: WIST ISPF) rats, fed test diets containing CGA 107892, purity 94.3%, 

at dietary concentrations of 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 for males during the pre- and postmating 

periods for 2 generations and ranges of 0, 15.3-32.1, 76.0-161.2 and 392.0-779.6 

mg/kg/day for 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 mated to produce one litter only. Parental systemic toxicity 

was observed at 5000 ppm (306 mg/kg/day) based on decreased mean body weight and 

mean body weight 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 weight and body weight gain were also evident in 

the offspring at this dose level (Fl pups on days 7, 14 and 21 postpartum, and F2 pups on 

days 14 and 21 postpartum). The only 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 hematopoiesis in females in the 5000 ppm group. It 

was considered equivocal whether a similar, but less pronounced, increase in the severity 

of splenic extramedullary hematopoiesis noted for males in the 5000 ppm group was 

related to treatment. 
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The parental/offspring systemic toxicity NOAEL is set at 1000 ppm (82 mg/kg bw/day 

for males and 94 mg/kg bw/day for females) and the LOAEL is set at 5000 ppm (428 

mg/kg bw/day for males and 482 mg/kg bw/day for females) based on decreased mean 

body weight and mean body weight gain in parents and offspring and on an increase in 

mean spleen weight and an increase in the severity (but not in the incidence) of splenic 

extramedullary hematopoiesis in females. The reproductive NOAEL is set at 5000 ppm 

(428 mg/kg bw/day for males and 482 mg/kg bw/day for 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 in the rat is classified as Acceptable guideline and satisfies the 

guideline requirement for a 2-generation reproductive study (OPPTS 870.3800, §83-4) in 

the rat.

A.3.3 Chronic Toxicity

870.4100b Chronic Toxicity - Dog

EXECUTIVE SUMMARY: HOE 107892, purity 94.3%, was evaluated for chronic oral 

toxicity in 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 days 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, respectively, 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 weight or food consumption. 

Liver findings included high ALP enzyme 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 weight 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 toxicologically 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 weight ratio in females treated at 1500 

ppm).

This chronic toxicity study in 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 - Rat
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EXECUTIVE SUMMARY: In a chronic toxicity/carcinogenicity study [MRIDs 43972222 and 

43972223], HOE 107892 (94.3% a.i.; Lot/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 for males, and 2.38, 12.07, 59.98, and 317.96 mg/kg/day for females) for 124 

weeks. A total of 10 rats/sex/group were terminated at 52 weeks, 20 rats/sex/group were 

terminated at 104 weeks, and the remaining rats were sacrificed following 124 weeks of 

treatment.

There were no treatment-related effects on survival, clinical signs, body weights, body weight 

gains, feed and water consumption, the clinical chemistry and urinalysis parameters monitored, 

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 necropsy, non-neoplastic, or neoplastic 

findings detected during the course of the study in either sex. Females at the 5000 ppm dose 

level displayed treatment-related changes in hematology parameters that suggest slight anemia 

with an increase in hematopoietic activity, as indicated by an increase in reticulocytes (↑32% to 

↑72%). A slightly lower RBC count (5% to 8 %) and a statistically significant, slightly lower 

hemoglobin concentration (↓6% to ↓11%) were observed throughout the study in females at 

5000 ppm. Although the males at 5000 ppm also displayed lower RBC and hemoglobin values 

compared to the control males, the magnitude of the deficit was small (↓2% to ↓4%). However, 

there was a treatment-related increase in reticulocyte 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 was approaching an adverse level (all 3 compartments affected (↓5%) with a 

regenerative anemia (32%-72% ↑ reticulocytes). In the males, red blood parameters were not 

affected, but there was an increase in hematopoietic activity (13%-46% ↑reticulocytes). The 

5000 ppm dose to 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 males. 

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 study is considered adequate to test 

the carcinogenic potential of mefenpyr diethyl. 

The LOAEL is 5000 ppm (251.6 mg/kg/day for males and 318.0 mg/kg/day for females), based 

on statistically significant increases in reticulocyte counts in both sexes, and decreased RBC, 

hemoglobin, and hematocrit values in females. The NOAEL is 1000 ppm (48.5 mg/kg/day for 

males and 60 mg/kg/day for females).
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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: A43416: 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: Lab 

Project Number: 90.0990: A45698: 91.0254. Unpublished 

43972218 Tennekes, 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.; Braunhofer, 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 Lab Project Number: 285120: A47753. Unpublished. 
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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: 293490: 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 typhimurium (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 Unscheduled DNA Synthesis 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 Project 

Number: 90.0429: A44823: 90.0611. Unpublished 
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44089201 Ebert, E.; Leist, K. (1992) (Inert ingredient): Repeated-Dose Dermal 

Toxicity (21 Treatments in 29 Days) 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: Lab 

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 NMRI Mouse--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. Unpublished 
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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 Single 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: Lab Project Number: 293433: A522643. Unpublished 

44661602 Eckert, H.; Kellner, H.; Puttkamer, G. (1992) (Inert Ingredient)-(carbon14) 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)-(carbon14) Pharmacokinetics in the Rat after Oral Administration of 1 and 100 

mg/kg Body Weight: Amendment to Report Number A49005: Lab 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. Lab Project 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 on the nervous system 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 structure and function. To detect and characterize these potential effects 

more fully, a battery of more sensitive testing is required. The objective of this 
Mefenpyr-Diethyl Human Health Risk Assessment D374653

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neurotoxicity battery testing is to evaluate the incidence and severity of the functional 

and/or behavioral effects, the level of motor activity, and the histopathology of the 

nervous system. The acute neurotoxicity study is required to detect possible effects 

resulting from a single exposure. The subchronic neurotoxicity study is intended to 

detect possible 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 system 

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 system 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 chemicals (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 mefenpyr-diethyl poses either a 

greater or a diminished risk than that given in the current decision’s conclusion, the risk 

assessment for mefenpyr-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 highly 
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complex, studies not specifically conducted to assess immunotoxic endpoints are 

inadequate to characterize a pesticide’s potential immunotoxicity. 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 immunotoxicity. 

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 oxide (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.
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Appendix B: Tolerance Summary and Table

Appendix B1. 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 Association, released August 1998.

 ARTF Studies. Agricultural Reentry Task Force (ARTF). Reviewed by HED, 

 ExpoSAC SOP No. 003 (May 7th, 1998 - Revised August 7th, 2000).