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Background

Attached is the USEPA (―the Agency‖) Health Effects Division’s (HED) preliminary human 

health risk assessment for the pesticide chlorpyrifos. Chlorpyrifos is a currently being evaluated

under the FIFRA section 3(g) registration review program which requires the re-evaluation of 

pesticides on a 15 year cycle. This preliminary assessment is provided in support of the 

registration review process for chlorpyrifos.

Chlorpyrifos (O,O-diethyl O-(3,5,6-trichloro-2-pyridyl) phosphorothioate) is an 

organophosphate (OP) insecticide, acaricide and miticide used to control a variety of insects. 

Chlorpyrifos was first registered in 1965 for control of foliage and soil-borne insect pests on a 

variety of food and feed crops. Currently registered uses include food and feed crops, golf course 

turf, greenhouses, non-structural wood treatments such as utility poles and fence posts, ant bait 

stations, and as an adult mosquitocide.

In June 2000, during the reregistration process, the Agency released its revised human health risk 

assessment (D.Smegal, 6/8/00, Human Health Risk Assessment, Chlorpyrifos, U.S. EPA). 

Subsequently, the technical registrants voluntarily cancelled and phased out certain uses of 

chlorpyrifos. The voluntary cancellation/phase out expeditiously addressed the food, drinking 

water, residential and non-residential uses posing the greatest risks estimated for children. Risk 

mitigation measures include eliminating use on tomatoes, restricting use on apples, phasing out 

termiticide use, canceling all homeowner use product registrations (except insect bait stations), 

and canceling uses in schools and parks where children may be exposed.

An Interim Reregistration Eligibility Decision (IRED) was issued in February 2002. The IRED 

included additional mitigation measures addressing occupational and ecological risks not 

addressed by the 2000voluntary cancellation/phaseout. To mitigate worker risk estimates of 

concern, a combination of reduced application rates and seasonal maximum limits, increased 

retreatment intervals, increased PPE and/or use of engineering controls were required as well as 

increased REIs for a number of crops. Upon completion of EPA’s assessment of the cumulative 

risks from the organophosphate class of pesticides, the chlorpyrifos IRED became final (as a 

RED) in July 2006.

The June 8, 2000 HED human health risk assessment for chlorpyrifos was largely based on adult 

laboratory animal data for cholinesterase inhibition and the application of default uncertainty 

factors, including the retention of the 10x FQPA Safety Factor. Since 2000, there has been 

extensive and ongoing research on various aspects of chlorpyrifos including its neurological 

effects in in vitro and in animals and humans following gestational and post-natal exposures, and 

its pharmacokinetics. In 2008, the Agency developed a draft issue paper reviewing the science 

available for chlorpyrifos which was reviewed by the FIFRA Scientific Advisory Panel (SAP; 

September 2008). Since the SAP, new studies have been submitted to EPA including a special 

acute inhalation study, an immunotoxicity study, and acute and repeat dose comparative 

cholinesterase assays (CCA) in juvenile and adult rats. The CCA studies examined toxicity for 

both chlorpyrifos and chlorpyrifos oxon. This preliminary hazard characterization and risk 

assessment for chlorpyrifos includes existing data, findings of new studies made available since 

the 2000 assessment, and considers comments from the 2008 SAP reviews. This assessment is 
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considered preliminary and presents risk estimates from both the 2000 assessment (based on 

toxicity studies using adult animals) and risk estimates based on benchmark dose (BMD) 

analyses, where appropriate, from sensitive studies which use ages relevant to human exposure. 

For the final chlorpyrifos human health risk assessment, including determination of the most 

appropriate toxicological points of departure and FQPA factors, the Agency will consider the 

weight of the evidence of all available data and take into consideration any comments received. 
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Table of Contents

1.0 Executive Summary ........................................................................................................... 7

2.0 HED Recommendations .................................................................................................. 16

2.1 Data Deficiencies .......................................................................................................... 16

2.2 Tolerance Considerations............................................................................................ 18

2.2.1 Enforcement Analytical Method ......................................................................... 18

2.2.2 International Harmonization............................................................................... 18

2.2.3 Recommended/Reassessed Tolerances................................................................ 18

2.3 Recommendations from Residue Reviews ................................................................. 19

3.0 Introduction...................................................................................................................... 20

3.1 Chemical Identity ......................................................................................................... 20

3.2 Physical/Chemical Characteristics ............................................................................. 20

3.3 Anticipated Exposure Pathways................................................................................. 21

3.4 Consideration of Environmental Justice.................................................................... 21

4.0 Hazard Characterization and Dose-Response Assessment.......................................... 22

4.1 Toxicology Studies Available for Analysis................................................................. 22

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)............................. 22

4.3 Toxicological Effects .................................................................................................... 25

4.4 Epidemiology ................................................................................................................ 29

4.4.1 Three Major Epidemiological Prospective Studies in Mothers and Their 

Children................................................................................................................................ 29

4.4.2 Agricultural Health Study (AHS) ............................................................................ 34

4.5 New Developments since the 2008 SAP...................................................................... 34

4.6 Safety factor for Infants and Children (FQPA Safety Factor) ................................ 36

4.6.1 Completeness of the Toxicology Database.......................................................... 36

4.6.2 Key Scientific Information Available to Inform the Safety Factor.................. 37

4.6.3 Application of the FQPA Safety Factor for the Preliminary Risk Assessment39

4.7 Toxicity Endpoint and Point of Departure Selections .............................................. 42

4.7.1 Dose-Response Assessment .................................................................................. 42

4.8 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment............................................................................................................................... 47

4.9 Endocrine Disruption................................................................................................... 49

5.0 Dietary Exposure and Risk Assessment......................................................................... 50

5.1. Residues of Concern Summary and Rationale .......................................................... 50

5.2 Food Residue Profile .................................................................................................... 51

5.3 Water Residue Profile.................................................................................................. 52

5.4 Dietary Risk Assessment.............................................................................................. 58

5.4.1 Description of Residue Data Used in Dietary Assessment ................................ 58

5.4.2 Percent Crop Treated Used in Dietary Assessment........................................... 59

5.4.3 Acute Dietary Risk Assessment ........................................................................... 59

5.4.4 Chronic Dietary Risk Assessment ....................................................................... 61

5.4.5 Comparison of Dietary Results for Chlorpyrifos 2000 Risk Assessment and 

2011 Preliminary Risk Assessment .................................................................................... 65

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 68

6.1 Residential Handler Exposure .................................................................................... 68
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6.2 Residential Post-Application Exposure...................................................................... 68

6.3 Residential Bystander Post-application Inhalation Exposure ................................. 71

6.4 Spray Drift.................................................................................................................... 75

7.0 Aggregate Exposure/Risk Characterization.................................................................. 75

8.0 Cumulative Exposure/Risk Characterization ............................................................... 76

9.0 Occupational Exposure/Risk Characterization ............................................................ 77

9.1 Short-/Intermediate-Term Handler Risk................................................................... 77

9.2 Short-/Intermediate-Term Post-Application Risk .................................................... 88

9.2.1 Dermal Post-Application Risk ............................................................................. 88

9.2.2 Inhalation Post-application Risk ......................................................................... 96

9.2.3 ORE Evaluation of Chlorpyrifos-oxon ............................................................... 97

9.2.4 Comparison of the Chlorpyrifos 2000 Risk Assessment and 2011 Preliminary 

Risk Assessment................................................................................................................... 98

10.0 Incident Report .............................................................................................................. 101

11.0 References....................................................................................................................... 102

Appendices

Appendix A. Toxicology Profile and Executive Summaries ................................................ 110

A.1 Toxicology Data Requirements................................................................................. 110

A.2 Toxicity Profiles.......................................................................................................... 111

A.3 Hazard Identification and Endpoint Selection ........................................................ 124

A.3.1 Acute Population Adjusted Dose (aPAD) - Females age 13-49....................... 124

A.3.2 Acute Population Adjusted Dose (aPAD) - General Population .................... 124

A.3.3 Chronic PAD ....................................................................................................... 124

A.3.4 Incidental Oral Exposure (Short- and Intermediate-Term)........................... 124

A.3.5 Dermal Exposure (Short-, Intermediate- and Long-Term)............................ 124

A.3.6 Inhalation Exposure (Acute, Short- and, Intermediate-Term) ...................... 125

A.4 Executive Summaries................................................................................................. 125

A.4.1 Sub-chronic Toxicity........................................................................................... 125

A.4.2 Prenatal Developmental Toxicity ...................................................................... 129

A.4.3 Reproductive Toxicity ........................................................................................ 131

A.4.4 Chronic Toxicity.................................................................................................. 132

A.4.5 Carcinogenicity ................................................................................................... 133

A.4.6 Mutagenicity........................................................................................................ 135

A.4.7 Neurotoxicity ....................................................................................................... 137

A.4.8 Metabolism .......................................................................................................... 141

A.4.9 Immunotoxicity ................................................................................................... 142

A.4.10 Special/Other Studies.......................................................................................... 143

Appendix B. Physical/Chemical Properties........................................................................... 147

Appendix C. Current US Tolerances and International Residue Limits ............................ 148

Appendix D. Review of Human Research.............................................................................. 152

Appendix E. Summary Benchmark Dose Values.................................................................. 153
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List of Tables

Table 1 Recommended Tolerances for Chlorpyrifos..................................................................................................18

Table 2 Chlorpyrifos Degradate/ Residues of Concern Nomenclature.......................................................................20

Table 3 Comparison of Cholinesterase Inhibition for Adult Pregnant Female and Non-Pregnant Rats.......................25

Table 4 Summary of Tests and Outcomes in Adults (at least 5 weeks of age, males and/or females) Following 

Gestational and/or Postnatal Dosing of 1 mg/kg/day Chlorpyrifos....................................................................28

Table 5 Prenatal OPs and Mental Delays (Bayley Mental Development Index)........................................................31

Table 6 Application of FQPA SF Comparison of 2000 and 2011 Risk Assessment for Chlorpyrifos ........................41

Table 7 Application of FQPA SF in Risk Assessment for Chlorpyrifos Oxon...........................................................41

Table 8 Summary of Toxicological Doses and Endpoints and Points of Departure for Chlorpyrifos for Use in 

Preliminary Dietary, Non-Occupational (Residential), and Occupational Human Health Risk Assessments ...47

Table 9 Summary of Points of Departure, Toxicological Doses and Toxicity Endpoints for Chlorpyrifos oxon for 

Use in Dietary Exposure Risk Assessments.......................................................................................................49

Table 10 Acute and Chronic Relative Toxicity Factors for Chlorpyrifos Oxon (Compared to Chlorpyrifos) ...........49

Table 11 Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression

............................................................................................................................................................................51

Table 12 Estimated Drinking Water Concentrations of Chlorpyrifos and Chlorpyrifos-oxon Resulting From 

Chlorpyrifos Use on Grapes, Corn/Soybean and Sugar beets............................................................................54

Table 13 Summary of Preliminary Acute Dietary Food Only Exposure and Risk (Using Parent Chlorpyrifos PoD)

............................................................................................................................................................................60

Table 14 Summary of Preliminary Acute Drinking Water Only Exposure and Risk (at the 99.9th Percentile 

Exposure; Using the Chlorpyrifos-oxon PoD) ...................................................................................................61

Table 15 Summary of Preliminary Chronic Dietary Food Only Exposure and Risk (Using Parent Chlorpyrifos PoD)

............................................................................................................................................................................63

Table 16 Summary of Preliminary Chronic Drinking Water Only Exposure and Risk (Using the Chlorpyrifos-oxon 

PoD)...................................................................................................................................................................64

Table 17 Comparison of Chlorpyrifos Acute PoDs and Risk Estimates for 2000 Assessment and 2011 Preliminary 

Assessment.........................................................................................................................................................66

Table 18 Comparison of Chlorpyrifos Chronic PoDs and Risk Estimates for 2000 Assessment and 2011 Preliminary 

Assessment.........................................................................................................................................................67

Table 19 Adult and Child Short-term Risks (MOEs) from Residential Post-application Exposure to Turf Following 

Aerial ULV Mosquito Treatments At 300 Foot Spray Release Height (LOC is an MOE = 100)......................69

Table 20 Adult and Child Short-term Risks (MOEs) from Residential Post-application Exposure to Turf Following 

Ground-based ULV Mosquito Treatments At 300 Foot Spray Release Height (LOC is an MOE = 100) .........70

Table 21 Adult and Child Acute Risk (MOEs) from Residential Post-application Inhalation Exposure Following 

Aerial ULV Mosquito Treatments At 300 Foot Spray Release Height (LOC is an MOE = 300)......................70

Table 22 Adult and Child Acute Risk (MOEs) from Residential Post-application Inhalation Exposure Following 

Ground ULV Mosquito Treatments (LOC is an MOE = 300) ...........................................................................70

Table 23 Adult Estimated Short- and Intermediate-term Risk (MOEs) from Post-application Golfing Exposure to 

Chlorpyrifos Treated Golf Course Turf (MRID 44829601)...............................................................................70

Table 24 Chlorpyrifos Preliminary Volatilization MOE Analysis for Residential Bystanders ..................................72

Table 25 Summary of Maximum Application Rates for Chlorpyrifos Agricultural Uses ..........................................78

Table 26 Summary of Maximum Application Rates for Chlorpyrifos Non-Agricultural Uses..................................80

Table 27 Results of the post-application exposure and risk assessment .....................................................................90

Table 28 Comparative Analysis of Occupational Handler Exposure Estimates Considering 2000/2011 Dermal PoDs 

Using Low, Medium and High Level Representative Scenarios........................................................................99

Table 29 Comparative Analysis of Occupational Handler Exposure Estimates Considering 2000/2011 Inhalation 

PoDs Using Low, Medium and High Level Representative Scenarios............................................................100
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1.0 Executive Summary

Use Profile

Chlorpyrifos (0,0-diethyl-0-3,5,6-trichloro -2-pyridyl phosphorothioate) is a broad-spectrum, 

chlorinated organophosphate (OP) insecticide. Registered use sites include the following: food 

crops, including fruit and nut trees, many types of fruits and vegetables, and grain crops; and 

non-food crops such as forage, golf course turf, industrial sites, greenhouse and nursery 

production, sod farms, and wood products. Public health uses include aerial and ground-based 

fogger treatments to control mosquitoes. There are currently no homeowner uses except for 

roach bait products. Permanent tolerances are established (40 CFR§180.342) for the residues of 

chlorpyrifos in/on a variety of agricultural commodities (including meat, milk, poultry and eggs). 

There are also tolerances for use in food handling establishments. Chlorpyrifos is manufactured 

as granular, microencapsulated, soluble concentrate/liquids, water dispersible granular in water 

soluble packets (WSP) and wettable powder packaged in WSP formulations, as well as 

impregnated paints, cattle ear tags, insect bait stations and total release foggers. There is a wide 

range of application rates and methods.

Hazard Identification

The toxicology database for chlorpyrifos is substantially complete (40 CFR 158.340 guideline 

studies have been submitted) and has been used to characterize toxicity and for selecting points 

of departure for purposes of the current risk assessment. Chlorpyrifos, like other OPs, binds to 

and phosphorylates the enzyme, acetylcholinesterase (AChE), in both the central (brain) and 

peripheral nervous systems leading to accumulation of acetylcholine and, ultimately, to clinical 

signs of toxicity. In 2000, the Agency concluded for chlorpyrifos that inhibition of cholinesterase 

(ChE) was the most sensitive effect in all of the animal species evaluated (rats, mice, rabbits 

dogs) and in humans, regardless of exposure duration. The Agency is maintaining at this time, 

based on available data, that cholinesterase inhibition (ChEI) provides the most sensitive doseresponse information for deriving points of departure for chlorpyrifos. In animals, significant 

inhibition of plasma and red blood cell (RBC) ChE occur at doses below those that cause brain 

ChE inhibition. 

The toxicity database of laboratory animal studies spans multiple routes of exposure (oral, 

dermal, inhalation), animal species, lifestages and durations. The database consists of studies 

ranging from a single exposure (acute) to subchronic and chronic toxicity. Guideline studies on 

developmental toxicity and specifically developmental neurotoxicity toxicity, and reproductive 

toxicity. The metabolism and pharmacokinetics of chlorpyrifos is well-characterized due to a 

variety of studies in different species and lifestages. Recently, a comparative cholinesterase 

assay (CCA) was submitted which provides information on comparative sensitivity in adult and 

juvenile rats from acute and repeated exposures to both chlorpyrifos and its oxon. Special 

studies have been submitted including an acute neurotoxic esterase rat study, cognitive rat study, 

and recently an acute inhalation study. Chlorpyrifos is not likely to be carcinogenic to humans, 

based on the lack of evidence of carcinogenicity in studies in rats and mice and the absence of a 

mutagenicity concern. There was no sign of immunotoxicity in the guideline study at the highest 

dose tested.
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In addition to the extensive body of data on cholinesterase inhibition, there is a growing body of 

literature with laboratory animals (rats and mice) indicating that gestational and/or early 

postnatal exposure to chlorpyrifos may cause persistent behavioral effects into adulthood. There 

are supporting concurrent changes in brain neurochemistry based on both in vivo and in vitro

studies that may underlie these behavioral changes into adulthood. These behavioral effects are 

seen at doses that typically result in inhibition of ChE in vivo. Although there are several 

biological plausible hypotheses being investigated by researchers, the mode/mechanisms of 

action resulting in such effects are not known at this time.

In addition, there are three major epidemiology cohort studies evaluating pre- and post-natal 

pesticide (chlorpyrifos or OPs) exposure in mother-infant pairs with birth outcomes, and 

childhood neurobehavioral and neurodevelopment outcomes in neonates, infants, and young 

children. Although there are challenges in interpreting these studies in the context of human 

health risk assessment, there is consistency across the animal behavior and epidemiology studies, 

such as delays in cognitive achievement, motor control, social behavior, and intelligence 

measures. Because ChE inhibition provides the most sensitive dose-response data available, the 

Agency has focused the preliminary risk assessment on this effect. 

Chlorpyrifos has been issued an order to conduct Tier 1 screening phase of the Endocrine 

Disruption Screening Program. 

Points of Departure and FQPA Safety Factor

The focus of the 2011 preliminary risk assessment is on the cholinesterase inhibiting potential of 

chlorpyrifos. Consistent with this focus, EPA has evaluated the extensive database of ChE data 

for multiple lifestages and has selected the most sensitive studies which use ages relevant to 

human exposure. The toxicological points of departure (PoDs) are based on the results of 

benchmark dose (BMD) analyses where appropriate, and weight of the evidence (WOE) 

consideration of all reliable data. There are no residual uncertainties in the exposure database. 

The dietary risk assessment is conservative and is not expected to underestimate dietary exposure 

to chlorpyrifos and chlorpyrifos oxon.

Similar to risk assessments conducted for other ChE-inhibiting pesticides, juvenile pups aged 

PND11 provide the sensitive lifestage and endpoint (RBC ChE inhibition) for the acute dietary 

PoDs of both chlorpyrifos and the oxon. The chronic dietary PoD for chlorpyrifos is based on 

RBC ChE inhibition from a repeated dosing study in pregnant rats (developmental neurotoxicity, 

DNT). The cPOD for chlorpyrifos oxon is based on 11 day repeated exposures in adult female

rats (CCA study), which is protective of effects in juvenile pups. The acute and dietary PoDs for 

both chlorpyrifos and the oxon were derived from benchmark dose analyses.

For the dermal route (all durations) the PoD is based on RBC and plasma ChE inhibition in adult 

rats (NOAEL =5 mg/kg/day). For acute inhalation the PoD is based on lung ChE inhibition in 

rats. A NOAEL was not identified. For repeated inhalation, the PoD is based on RBC and 

plasma ChE inhibition (NOAEL = 287 ug/m3or 20 ppb from 2 inhalation studies in rats).
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A 1x FQPA safety factor (SF) is being proposed for this preliminary assessment for acute and 

chronic oral exposure for chlorpyrifos since the PoDs are selected from sensitive endpoints 

(RBC ChE inhibition) in sensitive lifestages/sexes (juveniles and/or pregnant rats). A 1X FQPA 

SF is also proposed for all dermal durations and repeated inhalation chlorpyrifos exposures. For 

acute inhalation exposure, a 10X FQPA database uncertainty factor (UF) is applied to account 

for LOAEL to NOAEL extrapolation (a NOAEL was not identified in the acute inhalation 

study). A 1X FQPA SF is also proposed for acute and chronic oral exposure for chlorpyrifos 

oxon because the PODs are based on the most sensitive age group in the CCA study. 

Due to the preliminary nature of this assessment the Agency is presenting assessments reflecting 

both the retention of the 10X FQPA Safety Factor as in the June 2000 chlorpyrifos risk 

assessment (USEPA 2000) which was largely based on adult animal data, and a preliminary 

proposal to reduce the FQPA SF to 1X based on more recently available ChE toxicity studies and 

analyses. Given the focus of this preliminary assessment on ChE inhibition, the Agency believes 

the ChE data support reduction of the FQPA SF to 1x for most exposure scenarios. EPA is 

conducting ongoing analyses of newly published literature studies on a variety of challenging 

scientific issues such as response relationships among different endpoints at lower exposures, 

animal to human extrapolation, lifestage dependent toxicities, evaluation of the non-cholinergic 

effects, inter-individual variation, and interpretation of epidemiology studies in the context of the 

entire database for assessing human health risk to chlorpyrifos. EPA will continue to evaluate all 

the data/studies to determine the most appropriate FQPA SF in the revised risk assessment and to 

determine if the new PoDs based on ChE inhibition are adequately protective of 

neurodevelopmental effects. This final determination will also consider the 2008 SAP comments 

and the public comments received on this preliminary risk assessment. 

Total Uncertainty Factors for Preliminary Assessment:

A total uncertainty factor of 100X was applied to the chlorpyrifos endpoints selected for the 

acute and chronic dietary, and incidental oral exposures [10X for interspecies extrapolation, 10X 

for intraspecies variation and a proposed 1X FQPA factor based on a sensitive lifestage and 

endpoint selected]. Similarly, a total uncertainty factor of 100X was applied to the chlorpyrifos 

oxon endpoints selected for the acute and chronic dietary exposures to the oxon.

For dermal exposures a total uncertainty factor of 100X was applied [10X for interspecies 

extrapolation, 10X for intraspecies variation and a proposed 1X FQPA factor]. 

For acute inhalation exposures, a total uncertainty factor of 300X was applied [3X for 

interspecies extrapolation, 10X for intraspecies variation and a 10X FQPA database uncertainty 

factor (for extrapolation from a LOAEL to a NOAEL). The interspecies extrapolation is reduced 

from 10X to 3X because the RfC methodology for inhalation is used to determine an HEC 

(human equivalent concentration) and takes into consideration the pharmacokinetic differences 

between animals and humans.

For short-term and intermediate- term inhalation exposures a total uncertainty factor of 30X was 

applied [3X for interspecies extrapolation (reduced from 10X because RfC/HEC methodology 
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used), 10X for intraspecies variation and a 1X FQPA. The repeated inhalation PoDs are 

considered protective of sensitive lifestages (LOAEL is based on DNT study with pregnant rats). 

Exposure/Risk Assessment and Risk Characterization

Dietary

Highly refined acute and chronic dietary (food and water) exposure and risk assessments were 

conducted for chlorpyrifos. USDA Pesticide Data Program (PDP) monitoring data and percent 

crop treated estimates were used for most foods. Processing factors from studies were 

incorporated when available.

The residues of concern for chlorpyrifos in food are for the parent only. Residues of concern in 

water include both parent chlorpyrifos and chlorpyrifos oxon, a known degradation product of 

chlorpyrifos. There are limited environmental fate data available for the oxon. The maximum 

amount of chlorpyrifos transformation to chlorpyrifos oxon (i.e.100%) was used as a 

conservative assumption based on empirical data that indicate chlorpyrifos quantitatively 

oxidizes to form chlorpyrifos oxon in a short period of time during water purification and 

minimal degradation of chlorpyrifos oxon is expected prior to consumption of the treated 

drinking water. It is possible that some drinking water treatment procedures such as granular 

activated carbon filtration and water softening may reduce the amount of chlorpyrifos oxon in 

drinking water; however, it is unlikely that these treatment processes significantly reduce the 

amount of chlorpyrifos oxon in drinking water. In addition, these treatment methods are not 

typical practices across the country for surface water. For these reasons, chlorpyrifos oxon is the

residue of concern for drinking water.

Environmental Fate and Effects Division (EFED) has provided chlorpyrifos oxon estimated 

drinking water concentrations (EDWCs) from PRZM-EXAMS modeling for chlorpyrifos use on 

grapes, corn/soybean and sugar beets in order to provide a range of possible EDWCs 

representing the many registered chlorpyrifos uses. In general, these grape, corn/soybean and 

sugar beet uses represent a broad range of higher end, middle, and lower end EDWCs, 

respectively, modeled for all chlorpyrifos uses. For each of these three crops, the Agency 

modeled both an average typical application rate, and a maximum application rate. These 

particular uses were selected as representative crops for this preliminary drinking water 

assessment because there is a large amount of chlorpyrifos applied to these crops per year, a 

large portion of these crops are treated with chlorpyrifos, and/or the use locations are distributed 

throughout the United States.

The EFED drinking water assessment also takes into account non-targeted water monitoring data 

from the USGS National Water-Quality Assessment Program (NAWQA), USEPA/USGS Pilot 

Reservoir Monitoring Program, and USDA Pesticide Data Program (PDP) and the California 

Department of Pesticide Regulation (CDPR). The reported monitoring data concentrations are 

less than the estimated concentrations derived from modeling recommended for use in the risk 

assessment. This result is attributed to 1) water monitoring sampling programs do not 

specifically target chlorpyrifos use areas and may not represent high use areas; therefore, peak 

concentrations of chlorpyrifos and chlorpyrifos oxon may not be detected, 2) sampling 
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frequencies in high chlorpyrifos use areas are not designed to capture peak concentrations and 3) 

there are limited sampling data available for some areas in the United States. Because currently 

available monitoring data likely underestimates chlorpyrifos and chlorpyrifos oxon

concentrations, monitoring data is not an appropriate estimation of the potential exposure 

resulting from chlorpyrifos use and are not used in this preliminary assessment. (See R. Bohaty, 

June 2011, D368388 and D389480, Preliminary Registration Review Chlorpyrifos Drinking 

Water Assessment for the complete drinking water characterization.)

For food alone, the preliminary acute dietary risk estimates for all populations assessed were 

below the level of concern. The most highly exposed subpopulation were children (1-2 years) at 

9.0% aPAD. 

For water alone (using the chlorpyrifos oxon PoD), the preliminary acute risk estimates using the 

lower end representative water scenario (sugar beet) were below the level of concern for all 

populations assessed at the maximum application rate except for infants at 210% aPAD. At the 

average typical rates for sugar beets, exposures were also of concern for infants (340% aPAD), 

and children (130-140% cPAD). Using the mid-range representative scenario (corn) the acute 

risk estimates for all populations assessed were above the level of concern for the maximum 

application rates; the risk estimate for the most highly exposed subpopulation, infants, was 770% 

aPAD. However, for typical application rates, the risk estimates were much lower (<120% 

aPAD) for all populations assessed. Using the higher end representative water scenario (grapes) 

the acute risk estimates were below the level of concern for all populations assessed at the typical 

application rates (<59% aPAD for infants), but were above the level of concern at the maximum 

application rates assessed (2700% aPAD for infants).

The preliminary chronic dietary risk estimates (food alone) for all populations assessed were 

below the level of concern. The most highly exposed group were children (1-2 years) at 8.4% 

cPAD [excluding food handling establishment (FHE) uses] and children (1-2 years) at 11% 

cPAD (including the FHE uses).

For water alone (using the chlorpyrifos oxon PoD), the preliminary chronic risk estimates span a 

large range, depending on the representative crop and application rate assessed. Using the lower 

end representative water scenario (sugar beets), risks were below the level of concern for all 

populations assessed based on the maximum application rates (<69% cPAD) however there were 

some risks of concern for typical rates assessed for infants and children (110-270% cPAD). 

Drinking water risk estimates for the mid-range and high end representative water scenarios

(corn and grapes), were below the level of concern at the typical application rates (<49% cPAD) 

for the highest exposed subpopulation, infants (<1 yr), but exceeded the level of concern at the 

maximum application rates (ranged from 280-890% cPAD) for infants (<1 yr). 

Comparison of the Chlorpyrifos Dietary Assessment (June 2000 Assessment and the 2011 

Preliminary Assessment)

The acute and chronic PoDs and resulting dietary risk estimates (for the most highly exposed 

subpopulations only: young children and/or infants) are compared for the June 2000 chlorpyrifos 

risk assessment and for the current 2011 preliminary assessment.
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In 2000 the acute and chronic dietary PoDs were based on NOAELs (plasma and/or RBC ChEI) 

from oral studies using adult laboratory animals (including pregnant females). The same PoD, 

based on toxicity of parent chlorpyrifos, was selected for both food and water. A 10x FQPA 

factor was retained. 

For the 2011 preliminary assessment, the acute and chronic PoDs for food exposures were based 

on the toxicity of parent chlorpyrifos (BMDs for RBC ChEI) to juvenile and pregnant animals, 

respectively. The acute and chronic PoDs for water exposures were based on the toxicity of the 

chlorpyrifos oxon (BMDs for RBC ChEI) from studies where juvenile and adult animals were 

directly dosed with the oxon. A 1x FQPA factor is proposed.

The acute dietary (food only) risk estimates for the most highly exposed subpopulation were 

82% of the aPAD (2000) and 9% of the aPAD (2011). 

In 2000 the acute EDWC was not included in the dietary analysis (water residues not 

incorporated directly into DEEM analysis) and a % aPAD result was not calculated. Instead a 

Drinking Water Level of Concern (DWLOC) method was used. An estimated ≤18% aPAD value 

for 2000 water was estimated herein for comparison purposes only and reflects the exposure 

amount allowed for water in the ‘risk cup’ after food exposures are subtracted. In the 2011 

preliminary water assessment, a range of representative scenarios was assessed (higher end, midrange, and lower end). The resulting acute drinking water risk estimates (for infants) ranged from 

59% to 2700% aPAD, depending on the crop and application rate.

The chronic dietary (food only) risk estimates for the most highly exposed subpopulation were 

51% of the cPAD (2000) and 11% of the cPAD (2011). 

As in the 2000 acute water assessment, the 2000 chronic water assessment used a DWLOC 

approach. A ≤ 49% cPAD value was estimated for 2000 water. In the 2011 preliminary water 

assessment, a range of representative scenarios was assessed (higher end, mid-range, and lower 

end). The resulting chronic drinking water risk estimates (for infants) ranged from 26% to 890% 

cPAD, depending on the crop and application rate.

It is important to note that, aside from differences in the PoDs and FQPA factors, there have 

been changes in the dietary input assumptions since 2000. For example, updated food monitoring 

data and percent crop treated data were used in the 2011 preliminary assessment. For water, in 

2000 EDWCs were based on parent chlorpyrifos and were derived from the SCI-GROW model 

for groundwater and monitoring data for surface water. It is now believed that the existing water 

monitoring data are not representative of the potential exposure in drinking water and is not 

recommended for use in quantitative risk assessment. Groundwater EDWCs are expected to be 

low relative to surface water based on environmental fate characteristics of chlorpyrifos. 

Therefore, the SCI-GROW modeling results used in 2000 likely underestimate the potential 

exposure. The 2011 preliminary risk assessment has used a range of surface water EDWCs 

derived using PRZM-EXAMS modeling. In 2000 the residue of concern in drinking water was 

assumed to be parent chlorpyrifos. Empirical data indicate the rapid conversion of chlorpyrifos to 

chlorpyrifos oxon during typical drinking water treatment; therefore, this preliminary assessment 
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considers the oxon as the residue of concern in treated drinking water and assumes 100% 

conversion of chlorpyrifos to oxon. The chlorpyrifos oxon is more toxic than parent 

chlorpyrifos.

Residential

To date, all homeowner use product registrations have been cancelled, except for roach bait 

station products, which are not expected to result in residential exposures. Also, applications of 

chlorpyrifos can be made professionally (not by homeowners) to ant mounds, but residential 

post-application contact is not anticipated from this use. Additionally, residential/recreational 

uses remain for aerial and ground-based fogger adult mosquitocide applications and for golf 

course turf applications, which could result in residential exposures.

Of the residential uses, only the roach bait products can be applied by a homeowner in a 

residential setting; however, a quantitative exposure/risk assessment for application of the roach 

bait products was not conducted because HED expects exposure to be negligible. With roach bait 

stations the active ingredient is completely contained within the bait station. Post-application 

homeowner exposure from residential ant mound treatment (applied by professionals only) was 

not quantitatively assessed because contact with the mound is not anticipated. Only residential 

exposures anticipated from the chlorpyrifos mosquitocide use and golf course use are 

quantitatively assessed. In addition, a residential bystander exposure has been quantitatively 

assessed which considers exposure from field volatilization of applied chlorpyrifos.

Estimated short-term adult and child dermal exposures, as well as child incidental oral exposure,

to turf following either aerial or ground mosquito treatments do not exceed the level of concern 

(i.e. calculated Margins of Exposure, or MOEs, are ≥ 100). Combined child exposure estimates 

(dermal and incidental oral) to turf following aerial mosquito treatment result in risk estimates of 

concern; however, combined risk estimates following ground treatment are not of concern. 

Acute adult and child inhalation (spray drift) exposure following aerial mosquito treatment 

results in risk estimates that are not of concern (i.e. MOEs are ≥ 30), but risk estimates are of 

concern following ground treatment. Inhalation exposure from ground based ULV treatment 

was assessed by assuming that the entire active ingredient applied to a 1 acre area is airborne and 

available to be inhaled by a child or adult.

Adult dermal exposure risk estimates from golfing do not exceed the level of concern (i.e. MOEs 

are ≥ 100) using any of the transferable residue (TTR) region-specific data for the emulsifiable 

concentrate formulation at the 0.25 and 1.0 lb ai/A application rates. 

The Agency has developed a preliminary bystander inhalation exposure assessment for 

chlorpyrifos using currently available inhalation toxicity and chlorpyrifos air monitoring data. 

EPA has assessed residential bystander exposure from field volatilization of applied chlorpyrifos 

based on the available ambient and application site air monitoring data. Of the 24 acute ambient 

air concentrations assessed, 4 result in risk estimates exceeding the level of concern (i.e. MOEs 

are < 300). No short-/intermediate-term ambient data assessed result in risk estimates of concern

(i.e. MOEs are > 30). Of the 5 acute application site air concentrations assessed, 3 resulted in a 

risk estimate of concern (i.e. MOEs are < 300). Of the 5 short- and intermediate-term 
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application site air concentrations assessed, 4 resulted in risk estimates of concern (i.e. MOEs 

are < 30).

The bystander exposure assessment is considered preliminary. Some of the limitations identified 

include the assumption that an individual is exposed to a constant chlorpyrifos concentration in a 

stationary outdoors location for 24 hours. As part of the December 2009 SAP, the Agency 

presented their analysis of several models that could be used as screening tools to predict the air 

concentration and volatilization flux based on intrinsic properties and transport behaviors of 

pesticides. The Agency is currently in the process of evaluating the SAP’s comments. As 

appropriate, the Agency may revise the modeling approach presented to the SAP may revisit the 

residential bystander exposure and risk assessment.

Aggregate

A quantitative aggregate (food, water and residential exposures combined) assessment was not 

performed for this preliminary chlorpyrifos assessment. The preliminary risk estimates for water 

alone exceed the level of concern and are the primary driver in this assessment. Combining food 

and/or residential exposures with the water exposures would not be expected to have a 

significant impact on the resulting risk estimates for water alone. A quantitative aggregate 

assessment for food, water, and residential exposures will be considered during the final 

chlorpyrifos risk assessment. 

With regard to potential aggregate exposures for workers, the Agency is carefully considering a 

number of complex science issues, and extensive public comments received on OPP’s proposed 

policy ―Revised Risk Assessment Methods for Workers, Children of Workers in Agricultural 

Fields and Pesticides with No Food Uses‖ (EPA-HQ-OPP-2009-0889-0002). 

Occupational

Short- and intermediate-term inhalation and dermal exposure and risk estimates were calculated 

for occupational handlers of chlorpyrifos for a variety of exposure scenarios at differing levels of 

personal protection (long-term exposures not expected). The assessments used surrogate data and 

non-chemical specific exposure studies. In total, 305 exposure scenarios which consist of unique 

combinations of product formulation, crop or target, application rate, and area treated were 

assessed.

Of the 305 exposure scenarios assessed 134 had risk estimates that did not exceed the level of 

concern at some level of personal protection (i.e. calculated Aggregate Risk Estimates, or ARIs, 

are > 1). Ninety-one (91) exposure scenarios had risk estimates not of concern when engineering 

controls were considered. The remaining 80 scenarios resulted in risk estimates of concern (i.e. 

ARIs are < 1) at all levels of personal protection and engineering controls considered.

In an effort to characterize occupational handler risk estimates calculated using both surrogate 

data and chemical specific biomonitoring (passive dosimetry) data, HED has presented a 

comparative analysis of these for applicable scenarios. Of the 4 exposure scenarios compared, 3 

(mixing/loading liquids for airblast application, airblast applications, and groundboom 
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applications) resulted in greater risk estimates using biomonitoring data than those estimated 

using surrogate data (i.e., the estimated MOEs are lower). The analysis of the exposure scenario 

mixing/loading liquids for aerial application resulted in reduced risk estimates using 

biomonitoring compared to surrogate data. Because a number of issues were identified which 

limit the utility of the available biomonitoring data, HED has determined that these data are best 

suited for characterization of the estimates calculated for representative exposure scenarios using 

the surrogate data.

Short- and intermediate-term exposure and risk estimates were calculated for occupational 

handlers performing seed treatment activities in commercial settings and for occupational 

secondary handlers from planting chlorpyrifos-treated seeds. No chemical-specific handler 

exposure data were submitted in support of this use pattern. 

The majority, 61 of 64, occupational handler seed treatment exposure scenarios assessed 

(combined dermal and inhalation) resulted in risk estimates which were not of concern (i.e. ARIs 

are > 1) at some level of personal protection. The remaining 3 exposure scenarios resulted in an 

ARI < 1 at all level of personal protection considered and, therefore, are of concern. All seed 

planter (secondary handler) combined short- and intermediate-term dermal and inhalation 

exposure scenarios assessed resulted in an ARI > 1 at some level of personal protection and, 

therefore, do not present risk estimates of concern.

EPA has assessed short- and intermediate term occupational post-application dermal exposure 

and risk for any crops which reentry into an area previously treated with chlorpyrifos is 

anticipated. The assessment was completed using 7 chemical-specific registrant submitted 

dislodgeable foliar residue (DFR) studies. 

The MOEs estimated for liquid spray and granular formulation reentry are not of concern (i.e., an 

MOE ≥ 100) in the range of 0 to 4 days for lower to medium exposure activities and 0 to 8 days 

for high exposure activities, with the greater majority falling between 0 to 4 days when all 

exposure activities are considered. HED also estimated the MOEs for reentry into 

microencapsulated and total release fogger formulation treated greenhouses. These estimates 

range from 0 to > 35 days after treatment (the completion of the monitoring period) for all 

exposure activities considered.

A quantitative occupational post-application inhalation exposure assessment was not performed 

for chlorpyrifos. An inhalation exposure assessment was performed for occupational/commercial 

handlers and handlers are expected to have greater exposures than workers involved in postapplication activities. The handler assessment is currently considered a worst-case assessment for 

post-application exposure.

Occupational/Residential Exposure to Chlorpyrifos Oxon

The Agency has considered the potential for occupational and residential exposure to 

chlorpyrifos oxon. Workers re-entering an environment previously treated with chlorpyrifos 

(occupational post-application) and the general population residing near chlorpyrifos application 

sites (bystanders) could potentially be exposed to the oxon as chlorpyrifos is degraded in the 
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environment. Dermal exposure to the oxon could occur through contact with chlorpyrifos treated 

surfaces and inhalation exposure through airborne oxon. However, the likelihood of exposure to 

the oxon is slight due to its rapid deactivation to TCP (3,5,6-trichloro-2-pyridinol). In an effort 

to further explore the potential for oxon exposure, EPA has researched and reviewed all available 

information sources. Based upon this review, EPA intends to require additional studies to 

address uncertainties regarding the formation of chlorpyrifos oxon in the air post-application and 

its formation and decay in greenhouses. 

Comparison of the Chlorpyrifos Occupational Assessment (June 2000 Assessment and the 

2011 Preliminary Assessment)

For comparison purpose, a range of resulting occupational handler risk estimates (MOEs) are 

presented for both the current preliminary (2011) chlorpyrifos assessment and the June 2000 

chlorpyrifos assessment. The range represents a low, medium, and high exposure scenario. Also 

presented is a range of personal protection (single layer/gloves, double layer/gloves, and 

engineering controls). [See Table 28(dermal) and Table 29 (inhalation).]

The dermal handler risk estimates remain virtually unchanged between the 2000 and 2011 

assessments since the dermal PoD is the same (NOAEL of 5 mg/kg/day from a dermal study). 

The 2008 SAP concurred with the selection of this PoD for assessing dermal scenarios. 

The inhalation PoD in 2000 was 0.1 mg/kg/day (LOAEL/NOAEL based on 90 day inhalation 

studies and DNT). That same PoD is used in the current assessment except that it has been 

converted to an HEC (human equivalent concentration). This resulted in the reduction of the 

default database uncertainty factor for interspecies extrapolation from a 10x to a 3x. Thus the 

level of concern MOE for this assessment is 30 (compared to 100 in 2000). In addition the 

NOAEL was corrected to account for an 8 hour workday because worker exposure is expected to 

occur during the course of an average workweek (8 hours/day and 5 days/week; animals were 

exposed 6 hours a day in the study). The inhalation handler risk estimates have changed since 

the 2000 assessment. This can be mainly attributed to the use of the HEC in the preliminary 

assessment.

Note that the actual dermal and inhalation MOEs presented in the 2000 assessment may differ 

somewhat than those presented here since some of the exposure assumptions used today may 

vary due to refinements made since 2000. The 2011 exposure assumptions were compared to the 

2000 PoD for illustrative purposes only.

2.0 HED Recommendations

2.1 Data Deficiencies

Toxicology

870.6300: Developmental Neurotoxicity (MRID 44556901). While the offspring NOAEL and 

LOAEL have not yet been identified for this developmental neurotoxicity study, it is recognized 
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that the study was well-conducted according to Agency guideline §83-6, and under GLP 

regulations. Remaining questions can be resolved with additional information and statistical 

analysis, but there are no outstanding concerns regarding the quality of the animal data. The 

study is currently classified as ―guideline-unacceptable, but upgradeable‖. The study may be 

upgraded to ―acceptable‖ pending submission and review of additional morphometric data for 

PND 66 low-dose females (parietal cortex and hippocampus measurements) (S. Makris, 3/3/00, 

TXR. 0014014, D254907).

Residue Chemistry

860.1500: Magnitude of the residue studies with lemon after application of Lorsban 4E and 75% 

WDG formulations separately to reassess the tolerance for the citrus fruit crop group; Magnitude 

of the residue studies to establish a tolerance for wheat hay.

860.1520: Processing studies for: cotton meal, hulls and refined oil and for soybean meal, hulls 

and refined oil.

Labels: Revise the corn and cotton use restrictions in the chlorpyrifos labels to eliminate feeding 

restrictions in treated areas. Maintain only dormant/delay dormant and trunk spray applications 

for tart cherries in the label of the 75% WDG end use product.

Tolerances: 

The following tolerances for chlorpyrifos are necessary to address residues found in field trails:

Cotton, gin byproducts........................... 15 ppm

Grain, aspirated fractions.........................22 ppm

Corn milled byproducts........................... 0.1 ppm

Wheat milled byproducts........................ 1.5 ppm

Revocation of the chlorpyrifos tolerance for lettuce (no registered uses; revocation pending).

Modification of the tolerance expression for chlorpyrifos in the 40 CFR 180.342 is needed to 

comply with the Interim Guidance for Writing Tolerance Expressions.

Occupational/Residential Exposure 

The Agency intends to require additional data to address uncertainties regarding the formation of 

chlorpyrifos oxon in the air post-application and its formation and decay in greenhouses. In 

addition, several data gaps were identified in the Registration Eligibility Decision (RED) for the 

occupational and residential assessment of chlorpyrifos (finalized 7/31/06; IRED issued 2/2002). 

The only one of these requirements that has not been satisfied is the requirement for a study 

confirming the area treated for sod farm chlorpyrifos treatment. This requirement remains 

outstanding.
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2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The methods in the PAM Volume II are adequate to analyze the residue of concern for tolerance 

enforcement purposes, chlorpyrifos only. The limit of detection of these methods is adequate to 

cover the lowest tolerance level included in the 40 CFR 180.342 for detection of chlorpyrifos 

only, 0.01 ppm. In addition, chlorpyrifos is completely recovered using FDA multiresidue 

protocols D and E (nonfatty matrices) and partially recovered using multiresidue method 

protocol E (fatty matrices).

2.2.2 International Harmonization

Current US permanent tolerances for chlorpyrifos are listed in 40 CFR§180.342 and are 

summarized in the residue chemistry chapter and in Appendix C of this document. The Codex 

Alimentarius Commission and Canada have established Maximum Residue Limits (MRLs) for 

chlorpyrifos. Mexico adopts US tolerances and/or Codex MRLs for its export purposes. US 

tolerances and Codex MRLs are based on the analysis of residues of chlorpyrifos. Canada MRLs 

are for chlorpyrifos for some commodities and for both parent chlorpyrifos and its metabolite 

TCP (3,5,6-trichloro-2-pyridinol; not a US residue of concern) for other commodities.

With the exception of apple commodities, harmonization with the Canada MRLs is not possible 

as the Canadian residue definition is for the combined residues of chlorpyrifos and TCP (in the 

US TCP is not considered a residue of concern for chlorpyrifos risk assessment or tolerance 

enforcement). Harmonization between the USA tolerances and Codex MRLs is only possible for 

corn, field, grain; cranberry; egg; sorghum, grain, grain; sorghum, grain, stover; and wheat, 

grain. In addition, two commodities of the Leafy Vegetable (CG 5) can be harmonized with the 

Codex, head cabbage, and Chinese cabbage (type petsai). A summary of the US and 

international tolerances and MRLs is included in Appendix C of this document.

2.2.3 Recommended/Reassessed Tolerances

The following tolerances would need to be established to address residues found on the 

following commodities in new crop field trial data received as part of the chlorpyrifos 2003 DCI:

Table 1 Recommended Tolerances for Chlorpyrifos

Commodity Established Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments

Correct Commodity Definition

Aspirated grain fractions NA 22

Cotton, gin by-products NA 15

On 5/27/09 HED established interim guidance on writing tolerance expressions for enforcement 

purposes. In order to add clarity to the language used to establish the coverage of the tolerance 

expression and measurement of the level of the residue in the RACs the text in the 40 CFR § 

180.342 should read: ―(a) General. (1) Tolerances are established for residues of chlorpyrifos, 

including its metabolites and degradates, in or on the commodities in the table below. 
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Compliance with the tolerance levels specified below is to be determined by measuring only 

chlorpyrifos.‖ The current tolerance expression reads ―chlorpyrifos per se (O,O -diethyl O -

(3,5,6-trichloro-2-pyridyl) phosphorothioate‖.

2.3 Recommendations from Residue Reviews

The following recommendations were made in I. Negrón-Encarnación, 5/24/11, D388164, 

Chlorpyrifos. Registration Review Action for Chlorpyrifos. Summary of Analytical Chemistry 

and Residue Data.

Revise the corn and cotton use restrictions in the chlorpyrifos labels to eliminate feeding 

restrictions in treated areas. 

The following tolerances for cotton gin byproducts and aspirated grain fractions are 

necessary to address residues found in field trails:

Cotton, gin byproducts ................................................. 15 ppm

Grain, aspirated fractions ..............................................22 ppm

Maintain only dormant/delay dormant and trunk spray applications for tart cherries in the 

label of the 75% WDG end use product.

Revocation of the tolerance for lettuce is in process as uses of chlorpyrifos in this crop 

are not included in the label for the registered products.

Magnitude of the residue studies are needed with lemon after application of Lorsban 4E 

and 75% WDG formulations separately to reassess the tolerance for the citrus fruit crop 

group.

Magnitude of the residue studies are needed to establish a tolerance for wheat hay.

Processing studies are needed for:

Cotton meal, hulls and refined oil

Soybean meal, hulls and refined oil

Tolerances are needed to address residues of chlorpyrifos on:

Corn milled byproducts as 0.1 ppm

Wheat milled byproducts as 1.5 ppm

Modification of the tolerance expression for chlorpyrifos in the 40 CFR 180.342 is 

needed to comply with the Interim Guidance for Writing Tolerance Expressions.
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3.0 Introduction

3.1 Chemical Identity

Table 2 Chlorpyrifos Degradate/ Residues of Concern Nomenclature.

Chlorpyrifos

O

P

S

N

Cl Cl

Cl OC2H5

OC2H5

IUPAC name O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphorothioate

CAS name O,O-diethyl O-(3,5,6-trichloro-2-pyridinyl) phosphorothioate

CAS registry number 2921-88-2

End-use product (EP) Lorsban 75% WDG and Lorsban 50% WP

TCP Metabolite/Degradate

(Residue of Concern for Canada)

IUPAC Name

3,5,6 Trichloro-2-pyridinol

Oxon Metabolite/Degradate

Common Name

Chlorpyrifos Oxon

IUPAC Name

O,O-diethyl. O-3,5,6-trichloro-2-

pyridyl

3.2 Physical/Chemical Characteristics

Technical chlorpyrifos is a white crystalline solid. Chlorpyrifos is stable in neutral and acidic 

aqueous solutions; however, stability decreases with increasing pH. Chlorpyrifos is practically 

insoluble in water, but is soluble in most organic solvents (i.e., acetone, xylene and methylene 

chloride). Chlorpyrifos is moderately volatile based on its vapor pressure of 1.87x10-5 mmHg at 

25oC.

In the environment, hydrolysis is not expected to play a significant role in chlorpyrifos 

dissipation; however, under alkaline conditions laboratory studies show chlorpyrifos is 

susceptible to hydrolysis. Laboratory studies suggest that volatilization and photodegradation 

are not likely to play a significant role in the dissipation of chlorpyrifos in the environment. 

Nonetheless, chlorpyrifos has been detected in air samples so volatilization may play more of a 

role in dissipation than laboratory studies indicate. The major route of dissipation appears to be 

aerobic and anaerobic metabolism. Based on available data, chlorpyrifos degrades slowly in soil 

under both aerobic and anaerobic conditions. Degradation begins with cleavage of the 

phosphorus ester bond to yield 3,5,6-trichloro-2-pyridinol (TCP). Field dissipation studies show 

that chlorpyrifos is moderately persistent under field conditions—dissipation half-life less than 

60 days. Chlorpyrifos is only slightly soluble in water but once it reaches aquatic environments 

N OH

Cl Cl

Cl
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the Log Kow (4.7) indicates that chlorpyrifos may bioaccumulate in fish and other aquatic 

organisms. A fish bioaccumulation study shows that chlorpyrifos is absorbed by fish; however, 

it rapidly depurates when exposure ceases.

Oxidation of chlorpyrifos to chlorpyrifos oxon could potentially occur through photolysis, 

aerobic metabolism, and chlorination as well as other oxidative processes. Chlorpyrifos oxon is 

expected to have similar fate characteristics as chlorpyrifos except chlorpyrifos oxon is more 

soluble in water and undergoes hydrolysis faster. The hydrolysis half-life of chlorpyrifos oxon is 

significantly shorter than that observed for chlorpyrifos. Chlorpyrifos oxon hydrolyses to form 

TCP. For chlorpyrifos, water purification (chlorination) has been shown to be a major route of 

chlorpyrifos oxon formation.

3.3 Anticipated Exposure Pathways

Humans may be exposed to chlorpyrifos in food and water since applications may be made 

directly to growing crops (food and feedstuffs) which could also result in chlorpyrifos reaching 

surface and ground water sources of drinking water. Registered uses that may result in residential 

(non occupational) exposures include aerial and ground-based fogger adult mosquitocide 

applications and golf course turf applications. There is also a potential for residential bystander 

exposure from field volatilization of applied chlorpyrifos. In occupational settings, exposure may 

occur while handling the pesticide prior to application, as well as during application. There is 

also a potential for post-application exposure for workers re-entering treated fields.

3.4 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the USDA under the Continuing 

Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to 

assess dietary exposure to smaller, specialized subgroups and exposure assessments are 

performed when conditions or circumstances warrant. Whenever appropriate, non-dietary 

exposures based on home use of pesticide products and associated risks for adult applicators and 

for toddlers, youths, and adults entering or playing on treated areas post-application are 

evaluated. In addition to the aforementioned exposure settings and population subgroups, the 

current chlorpyrifos risk assessment considered exposures to bystanders as a result of field 

volatilization of applied chlorpyrifos.
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4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicological database for chlorpyrifos is extensive and is adequate to support the 

registration review. Since the 2002 IRED/2006 RED, and in addition to many studies in the 

scientific literature, three new studies have been submitted to OPP: a special acute inhalation 

study (MRID 48139303), a comparative cholinesterase assay (MRID 48139301), and an 

immunotoxicity study (MRID 48139304). These submitted studies have been reviewed and 

found to be acceptable to support the chlorpyrifos risk assessment. The toxicity profiles and 

executive summaries of all submitted studies are listed in Appendix A.

The database spans multiple routes of exposure, animal species, and lifestages and consists of 

acute toxicity, subchronic oral, subchronic inhalation, immunotoxicity, developmental toxicity, 

multi generation reproduction, chronic feeding/carcinogenicity, dermal toxicity, metabolism, 

pharmacokinetic, acute and subchronic neurotoxicity, and developmental neurotoxicity studies. 

The genetic toxicity/mutagenicity database has been evaluated. In addition, special studies have 

been submitted including an acute neurotoxic esterase rat study, cognitive rat study, comparative 

cholinesterase assay where PND11 pups and adults were assessed (for both parent chlorpyrifos 

and its oxon metabolite) and an acute inhalation study.

In addition to the above submitted chlorpyrifos studies there are numerous literature studies 

available on various aspects of chlorpyrifos including inhibition of cholinesterase, neurological 

effects in animals and humans following gestational and post-natal exposures, pharmacokinetics, 

mechanism of action, as well as studies with adult human volunteers for ChE inhibition. Many of 

these studies were discussed at the 2008 SAP meeting and details are provided on the Science 

Advisory Panel website (http://www.epa.gov/scipoly/sap/meetings/2008/091608_mtg.htm). 

EPA plans to finalize the science documents reviewed by the SAP in the upcoming months. 

However, the advice received by the Agency at the 2008 SAP meeting has been used to inform 

the selection of toxicological points of departure for use in this preliminary chlorpyrifos risk 

assessment.

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

The metabolism and toxicokinetics (TK) of chlorpyrifos have been extensively studied in 

animals and humans as well as in vitro systems. Overall, rats and humans show similar patterns 

of metabolism for chlorpyrifos in adults.

Chlorpyrifos undergoes metabolic transformations mainly by the liver microsomal enzymes. 

Although, chlorpyrifos is lipophilic, its extensive metabolism into water soluble metabolites does 

not lead to accumulation of the parent material or its metabolites in the body tissues. The initial 

metabolic attack on the chlorpyrifos is its desulfuration, resulting in its bioactivation to the more 

toxic and potent ChE inhibitor, the oxon form. However, the oxon is unstable and is rapidly 

deactivated through hydrolytic cleavage by a process called dearylation releasing the 3,5,6-

trichloro-2-pyridinol (TCP). Simultaneously along the desulfuration process, dearylation will be 

acting on both the parent chlorpyrifos as well as on the oxon metabolite leading to the release of 
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TCP. TCP is further conjugated to form glycine or glucuronide conjugates and eliminated into 

the urine. TCP is the major excreted metabolite and used as the major biomarker in 

pharmacokinetic, biomonitoring, and epidemiology studies.

There are several enzymes that play a role in the metabolism and toxicity of chlorpyrifos. In 

addition to inhibition of ChE, the oxon also binds stoichometrically to butyrlcholinesterse 

(BuChE; abundant in blood and other tissues). In this regard BuChE is viewed as a scavenger of 

the oxon formed and may prevent it from entering the brain or peripheral targets for inhibition of 

ChE. The cytochrome P450 family of microsomal enzymes (CYPs) is responsible for its 

metabolic activation and deactivation. The oxon also binds irreversibly to carboxylesterases. 

Carboxylesterases are distributed among different issues (liver, blood, brain) with highest 

abundance in the liver. The glutathione dependent enzymes play an important role in the 

secondary metabolism of chlorpyrifos producing water soluble metabolites that are readily 

excreted into the urine. Finally, another group of important enzymes in the detoxification of

chlorpyrifos is the A-esterases; one such A-esterase is paraoxonase (i.e., PON1). These are 

calcium activated enzymes and are distributed in various tissues including the liver, brain and 

blood. These act on the oxon by hydrolyzing it before reaching its target AChE enzyme. Some 

have suggested that PON1 status is a determining factor in susceptibility to chlorpyrifos (Cole et 

al, 2005; Berkowitz et al, 2004; Wolff et al, 2007; Furlong et al, 2005; Brophy et al, 2001; 

Holland et al, et 2006; Chen et al, 2003). 

The increased sensitivity of the young from acute exposure is likely attributed to a reduced 

capacity to detoxify chlorpyrifos in juvenile animals (Gagne and Brodeur, 1972; Benke and 

Murphy, 1975; Pope et al., 1991; Chambers and Carr, 1993; Padilla et al., 2000; 2002; Karanth 

and Pope, 2000). Specifically, in rats, A-esterase activity is virtually nonexistent in the fetus 

(Lassiter et al., 1998) and increases from birth reaching adult levels around PND21 (Mortensen 

et al., 1996; Li et al., 1997). Mortensen et al (1996) showed that the plasma level of CPOase1in 

PND21 pups was 1/11 that of adult animals. The animal data regarding the role of 

carboxylesterase in mediating OP toxicity are also quite extensive (e.g., Clement, 1984; Fonnum 

et al., 1985; Maxwell, 1992 a, b). Fetal rats possess very little carboxylesterase activity (Lassiter 

et al., 1998) with increasing activity seen as the postnatal rat matures, reaching adult values after 

puberty (50 days-of-age; Morgan et al., 1994; Moser et al., 1998; Karanth and Pope, 2000). 

There are, however, very little data in human tissues which could evaluate age-related maturation 

of carboxylesterase expression. The available data come from Pope et al (2005) and Ecobichan 

and Stephens (1973). Ecobichan and Stephens (1973) showed a steady increase in AChE and 

ChE levels of infants beginning at birth up to adult levels. Pope et al (2005) evaluated 

maturational expression of liver carboxylesterases in human liver tissues from infants (2–24 

months) and adults (20–36 years). The authors report relatively small (and not statistically 

significant) differences in activities between children ages 2–24 months and adults (20–36 

years). The Agency notes, however, that youngest age evaluated in the study was 2 months old 

and this individual had the lowest level of carboxylesterase. 

There is a clear age-dependant sensitivity which diminishes as the pups mature; this pattern is 

likely reflective of the metabolic processes which rapidly mature in the rat pup. The SAP 

 

1 CPOase is A-esterase (PON1) activity specific to chlorpyrifos oxon
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concurred with the Agency that juveniles are more sensitive than adults to ChE inhibition 

following acute exposures, but not necessarily for repeated exposures. 

In 2008, the Agency solicited comments from the SAP on the use of information on PON1 to 

inform the intra-species extrapolation factor. The SAP panel agreed with EPA that PON1 status 

cannot be ruled out as a determinant of chlorpyrifos toxicity, and there appears to be a different 

susceptibility between fetuses and neonates compared to adults. The Panel did not support using 

such PON1 information alone to address population sensitivity, but instead suggested that PBPK 

modeling which accounts for all the metabolizing enzymes is a more supportive approach. 

In the rat, chlorpyrifos is excreted primarily in the urine (84%) with lesser amounts excreted in 

the feces (5%) within 72 hours. The metabolism of chlorpyrifos is extensive, and no unchanged 

parent compound is found in the urine. The major urinary metabolites were 3,5,6-TCP (TCP) and 

glucuronide and sulfate conjugates of TCP. In humans (adult males) approximately 70% of 

chlorpyrifos is excreted in the urine as conjugated TCP within 5 days following acute oral 

exposure, and the dermal absorption is 1 to 3% in this study (Nolan et al. 1982, Accession No. 

249203). The mean pharmacokinetic half-life for TCP in the urine is approximately 27 hours 

following both oral and dermal exposure.

There are some limited data that show that chlorpyrifos can be found in breast milk. 

Chlorpyrifos is lipophillic and has a Log Kow of 4.7, which would indicate a potential to 

accumulate in milk. Mattsson et al. (1998, 2000) provided data in rat milk which suggest that 

chlorpyrifos can reach milk at doses of 0.3 mg/kg/day. There is public literature that indicates 

that chlorpyrifos may be found in human breast milk in the U.S. (Casey 2005) and India 

(Srivastava et al., 2011). The degree to which the Indian data are relevant in the U.S. is 

unknown (and unlikely reflective of the general population exposed to chlorpyrifos in 

food/water).

Toxicokinetic (TK) studies from humans and rats show that chlorpyrifos and/or its metabolites 

may be available to the fetus, likely at levels similar to maternal tissues (Whyatt et al, 2003; 

Hunter al, 1999; Mattsson et al, 1998, 2000; Akhtar et al, 2006). In the 2008 draft issue paper, 

the Agency summarizes the studies which show that TK differences in young and adults play a 

key role in the age-dependant sensitivity with chlorpyrifos. Moreover, the 2008 document 

provides additional information in pregnant animals and humans which suggest that metabolic 

capacity to detoxify chlorpyrifos may be reduced during pregnancy, although the relevance of 

these changes is not known at low environmental levels. The Panel supported the Agency’s 

conclusions on the role of lifestage ontogeny in potential sensitivity to chlorpyrifos and the 

potential that pregnant females may be more sensitive to chlorpyrifos than males (FIFRA SAP, 

2008), Recent results of EPA’s analyses (see BMD Appendix E) for rat data suggest that 

pregnant females are approximately 2-12 fold more sensitive than non-pregnant adult females, 

as shown in Table 3 below.
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Table 3 Comparison of Cholinesterase Inhibition for Adult Pregnant Female and Non-Pregnant 

Rats

Endpoint Response Comments

Repeated Dose ChEI - male 

and female rats (Hoberman 

et al. 1998 a, b, MRID 

44556901; Mattsson et al. 

1998, MRID 44648101; 

Maurissen et al. 2000; 

Marty and Andrus (2010; 

DAS CCA MRID 

48139301; 4807001 ) 

Female rats, 11 days (CCA): 

BMD10/BMDL10:

 RBC ChEI: 0.45/0.35 

 brain ChEI: 1.03/0.95 mg/kg/day 

Female pregnant rats GD6-20; 15 days (DNT): 

BMD10/BMDL10:

 RBC ChEI: 0.06/0.03 mg/kg/day 

 brain ChEI: 0.65/0.54 mg/kg/day 

Pregnant female rats 

more sensitive than nonpregnant female rats for 

RBC and brain ChEI:

RBC ChEI: 7.5-12 fold 

more sensitive

Brain ChEI: 1.6-1.8 fold 

more sensitive

DNT= developmental neurotoxicity study

CCA= comparative cholinesterase study

4.3 Toxicological Effects

Cholinesterase (ChE) Inhibition. Chlorpyrifos, like other OPs, binds to and phosphorylates the 

enzyme, acetlycholinesterase (AChE), in both the central (brain) and peripheral nervous systems 

leading to accumulation of acetylcholine in critical neuronal junctions and, ultimately, to clinical 

signs of toxicity. This mode of action, in which ChE inhibition leads to neurotoxicity, has been 

well described (Mileson et al., 1998, Eaton et al., 2008; Gupta, 2011). In 2000, the Agency 

concluded for chlorpyrifos that inhibition of ChE provides the most sensitive dose response data

in all of the animal species evaluated (rats, mice, rabbits dogs) and in humans, regardless of 

exposure duration and route of exposure. The available data indicate that humans are more 

sensitive than animals to ChE following both oral and dermal exposure (Nolan et al. 1982, 

USEPA 2000a). Numerous ChE studies are available in different lifestages and ages in rats, 

which were included in the 2000 risk assessment and/or discussed at the 2008 FIFRA SAP 

(http://www.epa.gov/scipoly/sap/meetings/2008/091608_mtg.htm). These studies vary widely 

by the level and number of doses used, availability of time course information, and method of 

administration. The Agency has reviewed the studies submitted for registration as well as 

searched the public literature for studies in which adult animals and/or juvenile animals were 

exposed to chlorpyrifos. ChE inhibition is most commonly reported for the blood (plasma and 

RBC) and brain (whole or subsections). The chlorpyrifos database is unique since it includes 

evaluations of peripheral tissues such as the heart, diaphragm, or lung. In animals, significant 

inhibition of plasma and red blood cell (RBC) ChE occur at doses below those that cause brain 

ChE inhibition. Following inhalation exposure, inhibition of ChE in the lung was more sensitive 

than either RBC ChE or brain ChE inhibition.

With respect to considering the response of sensitive lifestages to ChE inhibition, the Agency has 

reviewed numerous repeated gestational exposure ChE studies for chlorpyrifos and other OPs. 

Overall, these gestational studies show that the fetus exhibits no more ChE inhibition than does 

the dam and in some studies fetus actually exhibits less inhibition (USEPA, 2008; USEPA, 
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2006). However, ChE data in fetuses from repeated dosing gestational studies may not 

accurately reflect potential fetal toxicity at a particular dose (USEPA 2008, draft chlorpyrifos 

hazard and dose-response characterization). The FIFRA SAP concurred with the Agency’s 

conclusion with respect to interpreting ChE data from in utero exposures. As part of the 

scientific analysis presented at the 2008 SAP meeting, the Agency showed acute brain post-natal 

ChE studies ranging from PND1 to PND33. There is a clear age-dependant sensitivity which 

diminishes as the pups mature; this pattern is likely reflective of the metabolic processes which 

rapidly mature as the rat pup matures. The SAP concurred with the Agency that juveniles are 

more sensitive than adults to ChE inhibition following acute exposures, but not necessarily for 

repeated exposures. 

The SAP also supported that pregnant animals and humans may be somewhat more sensitive to 

ChE inhibition from chlorpyrifos than non-pregnant adults based on a reduced capacity of key 

detoxification enzymes (e.g., paraoxonase, P450 isozymes) in modulating levels of chlorpyrifos 

in animal studies. It is unknown if the relatively small differences in enzyme levels is important 

at environmental exposure levels. As noted previously, pregnant rats were about 2-12 fold 

more sensitive than non pregnant rat females for ChE inhibition (See Table 3).

The Agency has recently reviewed an acute and repeat special non-guideline comparative 

cholinesterase (CCA) study, and an acute inhalation study. The CCA study was conducted to 

compare the relative toxicity of chlorpyrifos and chlorpyrifos oxon in both juvenile (PND11 

pups) and adult rats based on ChE inhibition (Marty and Andrus 2010, MRID No.: 48139301 

TXR No. 0055409). Both acute (single) dosing and a repeat 11-day exposure scenario were 

evaluated for chlorpyrifos and chlorpyrifos oxon. In the acute subpart, juvenile rats were dosed 

with chlorpyrifos via both gavage and milk. This study is considered high quality, and provides 

reliable measures of blood and brain ChE at the time of peak effect (6-8 hours post-dosing), use 

4-6 doses and use a wide range of doses. The Agency notes that the timing of ChE measurement 

in this study (8 hrs for milk) is later than other studies that report the peak at between 3-6 hours

but is supported by time course data collected as part of this study for 3-10 mg/kg dose levels

[see EPA 2008, draft appendix C, Mode of action, inhibition of acetylcholinesterase (AChE)]. 

The Agency used these data to conduct benchmark dose (BMD) analysis. Following acute 

exposure, based on BMD analysis, PND11 pups were more sensitive than adults at 10% RBC 

ChE inhibition (BMD10 are 0.5 mg/kg/day and 1.9 mg/kg/day, respectively), and 10% brain 

ChE inhibition (BMD10 are 1.4 and 4.1 mg/kg/day, respectively) for chlorpyrifos. For acute 

chlorpyrifos-oxon exposure, pups were also more sensitive for RBC ChE inhibition than adults 

(BMD10s are 0.08 and 0.21 mg/kg/day for pups and adults, respectively). Pups were more 

sensitive to ChE inhibition following milk exposure than from gavage dosing based on BMD10s. 

Following 11 days of repeated dosing, PND11 pups were slightly more sensitive than adults to 

chlorpyrifos based on BMD10s for RBC ChE inhibition (0.45 mg/kg/day for adults vs 0.11-0.17 

mg/kg/day for pups), but not for chlorpyrifos oxon. There was no inhibition of the brain ChE 

reported for the oxon at any dose up to 1 mg/kg for acute dosing and 0.5 mg/kg/day following 

repeat dosing in either pups or adults. The timing of measurement for the oxon was 4 hours 

post-dosing in this CCA. Other literature studies have reported the time of peak brain ChE 

inhibition was 1 hour post dosing (Betancourt and Carr 2004). 
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In a special acute inhalation study female rats were exposed by nose only to atmospheric 

concentrations of up to 53.9 mg/m3of particulate chlorpyrifos for six hours and allowed an 

additional 72 hours to recover (MRID No: 48139303 Hotchkiss et al. 2010, TXR # 0055409.). 

The peak inhibition for plasma and RBC ChE was at 2 hours post-dosing. Consistent and 

significant lung and plasma ChE inhibition were noted at the lowest concentration tested of 3.7 

mg/m3, which is a LOAEL. RBC and brain ChE inhibition were noted at ≥ 12.9 mg/m3and 53.9 

mg/m3, respectively, indicating they are less sensitive than lung and plasma ChE inhibition 

following acute inhalation exposures. It should be noted, however, that the lung may contain 

both butyrl and acetyl cholinesterase, which may partially explain the sensitivity of the lung 

ChE inhibition. No NOAEL was established. A BMD analysis was attempted but did not 

provide high confidence results due to the nature of the dose response data. The RBC ChE data 

had significant temporal variation and thus a reliable fit was not achieved. For the lung ChE 

data, no statistically reliable fit was obtained with exponential modeling using nonhomogeneous 

variance (suggested by BMD statistical results). However, a reliable fit was obtained with a 

homogeneous variance model. This analysis supports retention of a 10X LOAEL to NOAEL 

uncertainty factor for the single- day bystander inhalation risk assessment. Using the Agency’s 

Reference concentration (RfC) methodology, a human equivalent concentration (HEC) was 

calculated to be 0.62 mg/m3based on the LOAEL of 3.7 mg/m3.

Developmental Effects. There is a large body of literature on the effects of chlorpyrifos in the 

developing brain of laboratory animals (rats and mice) indicating that gestational and/or early 

postnatal exposure to chlorpyrifos may cause persistent behavioral effects into adulthood. These 

data provide support for the susceptibility of the developing rodent brain to chlorpyrifos 

exposure. Many of these studies were reviewed by EPA in the 2000 risk assessment and for the 

2008 SAP (USEPA 2000b, 2008). The SAP concurred with the Agency’s conclusion that in rats, 

chlorpyrifos causes alterations in brain development in offspring of exposed mothers. Studies in 

the peer reviewed literature and results of the guideline developmental neurotoxicity (DNT) 

study are supportive of the possibility that chlorpyrifos exposure may affect brain development 

(e.g., altered synaptic development, alterations in DNA, RNA, and protein synthesis, inhibition 

of mitosis and mitotic figures, disruption of the structural architecture of the brain). Studies from 

multiple laboratories in two rodent species provide evidence that adults may exhibit persistent 

behavioral changes following perinatal exposures. Since several laboratories included a dose of 

1 mg/kg/day, some comparisons in response may be made – these are summarized in Table 4

below. Chlorpyrifos studies in rats and/or mice have reported impaired cognition (spatial 

learning and working memory); changes in locomotor activity levels (exploration, rearing); and 

altered social interaction (aggression, maternal behavior). It is notable that the laboratory animal 

studies vary in experimental designs such as species, strain, gender, dosing regimens (age, 

routes, vehicle), and test parameters. However, in animals, the doses (1 and 5 mg/kg/day) most 

often used in the behavior studies are sufficient to elicit approximately ≥10% brain inhibition and 

≥30% in RBC inhibition, depending on the study design and the age of the animal. The results 

of these studies contribute to the overall hazard characterization of chlorpyrifos but are not useful 

in deriving PoD for risk assessment; the SAP concurred with the Agency’s proposed use of the 

behavioral studies.
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Table 4 Summary of Tests and Outcomes in Adults (at least 5 weeks of age, males and/or females) 

Following Gestational and/or Postnatal Dosing of 1 mg/kg/day Chlorpyrifos. 

Behavioral 

Domain Device/Task Outcomes Species Reference

Locomotor 

activity

Figure-8 maze Decreased 

habituation rate

Rat Levin et al., 2002

Open-field Increased activity Mouse Ricceri et al., 2003

Elevated plus 

maze 

Increased crossings

Decreased crossings

Rat

Mouse

Aldridgeet al., 2005c

Braquenier et al., 2010

T maze Decreased activity Rat Icenogle et al., 2004

Levin et al., 2001, 2002

Learning & 

Memory

Radial arm maze

Increased errors Rat Levin et al., 2002

Aldridge et al., 2005c

Johnson et al., 2009

Morris water 

maze

Slower learning Mouse Billauer-Haimovitch et 

al., 2009

Foraging in 

radial arm maze

Slower learning Mouse Haviland et al., 2010

Social 

Interactions 

(mice)

Agonistic 

behaviors (male)

Increased Mouse Ricceri et al., 2003, 

2006

Induced maternal 

behaviors 

(female)

Altered Mouse Ricceri et al., 2006

Anxiety/ 

Depression

Elevated plus 

maze 

Increased time in 

open arms

Decreased time in 

dark arms

Rat

Mouse

Aldridge et al., 2005c

Braquenier et al., 2010

Light/dark box Decreased time in 

light side

Mouse Braquenier et al., 2010

Over the last 15 years, biologically plausible hypotheses for chlorpyrifos have been proposed by 

researchers. These include effects on signaling pathways (Slotkin, 2006), a morphogenic role of 

AChE effect the structure of the brain (Brimijoin and Koenigsberger, 1999 and Bigbee et al, 

1999; Yang et al, 2008) and recently a reduction in axonal transport mediated through impaired 

tubulin polymerization (Prendergast et al, 2007; Grigoryan et al, 2008; Grigoryan et al 2009; 

Grigoryan and Lockridge, 2009; Jiang et al, 2010) Although multiple mechanisms have been 

proposed, a coherent mode of action with supportable key events, particularly with regard to 

dose-response and temporal concordance, has not yet been elucidated. The Agency continues to 

evaluate new studies on chlorpyrifos and if sufficient information becomes available to perform 

such an MOA analysis, the Agency may do so in the future. In 2008, the SAP supported the 

Agency’s conclusions that there were insufficient data to clearly identify a specific MOA for 

effects in the developing nervous system. Some panel members indicated that the data cited in 
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Eaton et al. (2008) could be useful in evaluating alternative (e.g., non-cholinergic) modes of 

action. 

Chlorpyrifos was evaluated for prenatal developmental toxicity in rats, mice and rabbits. In one 

rat study, developmental effects (increased postimplantation loss) were noted at 15 mg/kg/day 

(highest dose tested, HDT), that were also associated with maternal toxicity, while another rat 

study failed to observe similar developmental effects at 15 mg/kg/day. Developmental effects 

were also noted at higher doses in mice at 25 mg/kg/day (minor skeletal variations, delayed 

ossification and reduced fetal weight and length) and rabbits at 140 mg/kg/day (decreased fetal 

weights and crown rump lengths, and unossified xiphisternum and/or 5th sternebra). However, in 

both mice and rabbits, the developmental effects occurred at maternally toxic doses as indicated 

by reduced weight gain, and food consumption in both species, and increased mortality in mouse 

dams.

In the rat developmental neurotoxicity study, chlorpyrifos was associated with alterations in 

brain development in offspring of exposed mothers. Specifically, pups of the 1 mg/kg/day group 

exhibited significant decreases in measurements of the parietal cortex in female offspring at 

postnatal day 66. The only maternal effect at this dose was plasma and RBC ChE inhibition 

during the treatment period. At higher doses, pups of the 5 mg/kg/day group exhibited decreased 

body weight/body weight gain and food consumption in both sexes, reductions in pup viability, 

delays in development, decreased brain weight and morphometric alterations in the brain. 

However, these effects were observed in the presence of maternal toxicity as evidenced by 

fasciculations, hyperpnea and hyperactivity, in addition to reduced body weight gain.

Reproductive Effects. Chlorpyrifos induced reproductive toxicity in one generation of rats, but 

only at dose levels that induced parental toxicity. Reproductive effects in the F1 generation 

included reduced pup weights and increased pup mortality that corresponded to slightly but 

significantly reduced body weight gain in their parental F0 dams during lactation days 1-21. In 

addition, parental toxicity was characterized by inhibition of plasma, RBC and brain 

cholinesterase activities as well as histological lesions of the adrenal gland (vacuolation of cells 

of the zona fasciculata).

Carcinogenicity/Genotoxicity. Chlorpyrifos is not likely to be carcinogenic to humans, based 

on the lack of evidence of carcinogenicity in studies in rats and mice and the absence of a 

mutagenicity concern. Chlorpyrifos was not mutagenic in bacteria, or mammalian cells, but did 

cause slight genetic alterations in yeast and DNA damage to bacteria.

Immunotoxicity. There was no sign of immunotoxicity in the guideline study at the highest 

dose tested.

4.4 Epidemiology

4.4.1 Three Major Epidemiological Prospective Studies in Mothers and Their Children

There are three major prospective epidemiology cohort studies evaluating pre- and post-natal 

pesticide (chlorpyrifos and/or OPs) exposure in mother-infant pairs with birth outcomes, and 
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childhood neurobehavioral and neurodevelopment outcomes in neonates, infants, and young 

children. Two of the cohorts have also investigated the role of genetic susceptibility (PON1) in 

the association between pesticide exposure and adverse birth outcomes and neurodevelopmental 

effects. In 2008, EPA consulted the SAP on the use of these three cohort studies in mothers and 

their children. Details of this analysis and discussion are provided in the chlorpyrifos docket 

(draft Appendix D Epidemology at 

http://www.epa.gov/scipoly/sap/meetings/2008/091608_mtg.htm.) EPA plans to finalize the 

science documents reviewed by the SAP in the upcoming months.

Funded by multiple Federal Agencies, including US EPA, the three studies originate from: (1) 

Columbia University, NYC, (2) Mt Sinai, School of Medicine, NYC, and (3) University of 

California at Berkeley (Center for Health Assessment of Mothers and Children of Salinas, 

CHAMACOS). The first two study populations include multi-ethnic, urban low income motherinfant pairs, and the latter reflects a farm worker/agricultural worker study population2

. The 

Columbia study focuses on chlorpyrifos in cord blood and the latter two studies assess the nonspecific organophosphate (OP) metabolites diethyl phosphases (DEPs) and dialkyl phosphates 

(DAPs) in maternal urine, and link these biomarkers of exposure with associated health 

outcomes in children that were exposed in utero.

In EPA’s review of the epidemiologic evidence concerning potential neurodevelopmental effects 

of prenatal or early postnatal chlorpyrifos and/or OP exposure, EPA noted consistency across the 

studies, i.e. delays in cognitive achievement, motor control, social behavior, and intelligence 

measures that were reported in all three prospective cohorts (Columbia, Mt. Sinai and 

CHAMACOS) in children 2-3 years of age. However, EPA believes the degree to which 

chlorpyrifos is implicated in these outcomes varies. 

More recently, in April 2011, these same researchers published results indicating that in utero

chlorpyrifos and/or OP exposure may have persistent neurodevelopmental effects for school age 

children up to age 7 using the Weschsler Intelligence Scale for Children-IV. Since these studies 

were recently published, EPA has not conducted a full evaluation of these recent publications (of 

the same cohort) and integrated these data with the totality of the chlorpyrifos database, but will 

consider these human epidemiological studies along with the available empiricial data in a full 

weight of evidence analysis in the final assessment. The neurodevelopmental outcomes reported 

for children in these epidemiology studies are qualitatively similar to the behavioral outcomes in 

animal studies (following gestational and/or postnatal exposures to chlorpyrifos). Some initial 

aspects of these three cohort studies are as follows:

There appears to be consistency across the three children’s health cohorts in both the 

magnitude and direction of the association between prenatal chlorpyrifos and/or OP 

exposure and neurodevelopment effects measured in children at several different points 

in time (Rauh et al. 2006, 2011, Engel et al. 2011, Eskenazi et al. 2007, Bouchard et al. 

2011). The Columbia results are associated with high chlorpyrifos cord blood levels, 

while the CHAMACOS and Mt. Sinai teams correlated increasing levels of maternal 

 

2 The Mt Sinai study included inner city, black, Hispanic and white women, while the Columbia study evaluated 

inner city African American and Dominican. The Berkley study included homogenous Latino women from 

Agricultural communities.
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urinary DAPs with reported mental delays in children. Table 5 shows the results from the 

three cohorts on mental delays in children ages 2-3. 

Table 5 Prenatal OPs and Mental Delays (Bayley Mental Development Index)

Age of Child Berkeley (log10 

DAP maternal 

urine, Adj Beta)

Mt. Sinai (log10 

DAP maternal 

urine, Adj Beta)

Columbia Univ. 

(High v. Low 

chlorpyrifos cord 

blood , Adj Beta)

6 mo. -1.2 -- --

1 Year -1.3 -1.0 -0.3

2 Year -3.5* -2.08 -1.5

3 Year -- -- -3.3**

*p<0.05 **p<0.1

References: Eskenazi et al. 2007; Engel et al. 2011; Rauh et al. 2006

The Columbia cohort researchers reported that prenatal chlorpyrifos (as measured in 

umbilical cord blood) is associated with delays in motor development, cognitive function 

as well as social behavioral problems including symptoms of AttentionDeficit/Hyperactivity Disorder (ADHD) (Rauh et al. 2006). Recent study results indicate 

prenatal chlorpyrifos exposure may adversely influence intelligence measures at school 

age (Rauh et al. 2011).

The Columbia study overlapped with residential use cancellation in 2001. For children 

born before cancellation, high chlorpyrifos exposure in cord plasma was significantly 

associated with neurodevelopmental effects. In contrast, this relationship was no longer 

significant for newborns born after the cancellation because the blood levels dropped. 

Thus, this study identifies a natural experiment and indicates the effects upon 

neurodevelopment in children are not observed upon cessation of the exposure. As 

noted by the SAP in 2008, ―although the data on post-ban declines in exposure are 

compelling, limitations must be kept in mind when using these results in the weight of 

evidence. The study was not designed to assess the effect of the ban, so data are 

essentially cross-sectional (i.e., exposures among the same women were not measured 

over time).‖ 

Both Mt. Sinai and CHAMACOS cohorts report abnormal reflexes in neonates associated 

with urinary maternal DEP and DAP levels. Increases in pervasive developmental 

disorder were reported in both the Columbia and CHAMACOS cohorts (Rauh et al. 

2006, Engel et al. 2007, Young et al. 2005). It was acknowledged by the SAP that there 

are potential confounders and issues that reduce the utility of both the Mt. Sinai and 

Berkeley cohorts for risk assessment. For example, both studies measured non-specific

OP metabolites in urine but not chlorpyrifos. The Berkeley study has the least relevance 

to chlorpyrifos risk assessment because only a small percentage (10%) of the pesticides 

applied in Salinas Valley are chlorpyrifos therefore, chlorpyrifos would make only a 

small contribution to the non-specific metabolites measured in the study and study 
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outcomes, although this assumption has not been verified. As such, it is difficult to 

ascribe the effects seen to chlorpyrifos, in particular, rather than OPs in general. 

Nevertheless, the SAP advised that ―although Mt. Sinai and Berkely cohorts are less 

specific than the Columbia Study, they support the overall findings of the latter‖ (pg 43 

SAP report)

Although CHAMACOS and Mt. Sinai have focused on OP (i.e., DAPs) exposure and not 

chlorpyrifos, per se, the SAP encouraged the Agency to consider the results of all three 

cohorts together with an emphasis on Columbia University for the chlorpyrifos 

assessment since as there are ―more similarities than discrepancies across them‖ (p. 43, 

FIFRA SAP, 2008). But the SAP also noted that it cannot be stated that chlorpyrifos is 

the sole contributor to the observed outcomes; exposures to all three ACh-E inhibiting 

insecticides may act in combination to produce the observed effects. Although the 

authors of the Columbia studies have attempted to isolate the effects that would be 

associated with chlorpyrifos, the Panel noted it is difficult to quantify the contribution of 

other neurotoxic compounds in such simultaneous exposures. (See follow up analysis by 

Whyatt and Rauh (2010) that evaluated a joint effects model and concluded chlorpyrifos 

and not diazinon or propoxur were associated with the outcomes).

There are several strengths of the epidemiological database associating prenatal chlorpyrifos and 

other OP exposure with neurodevelopment effects in neonates, infants, young children and 

school aged children. Specifically, the measurement of the neurodevelopmental outcomes (e.g., 

Brazelton index, Bayley scale, and the Weschlar Intelligence Scale) are accepted valid and 

reliable measurement tools in clinical and epidemiologic research. In addition, the use of 

biological markers of exposure [i.e., cord blood concentration of chlorpyrifos or maternal urinary 

DEPs and DAPs], are more accurate and reliable measures of prenatal exposure than other forms 

of exposure assessment such as self-report questionnaire. Notably, the exposure measurements 

(biomonitoring and/or personal air monitoring) were well coordinated with the exposure period 

of interest (third trimester for birth outcomes)3. The Columbia study measured chlorpyrifos in 

umbilical cord blood at delivery, and maternal blood measurements during pregnancy and 

delivery. The researchers in each of these cohorts utilized robust and appropriate statistical 

analysis methods to model the exposure-response association including adjustment for 

potentially confounding variables.

All three cohort studies have limitations that include multiple chemical exposures and exposure 

to other organophosphates. The exposure classification is based on maternal spot urinary 

samples for the Mt. Sinai and CHAMACOS studies and maternal and cord blood samples in the 

Columbia Study that may not necessarily represent total chlorpyrifos or OP exposure throughout 

pregnancy because these pesticides have short half-lives. However, the prevalence of exposure 

among these cohorts based upon a one-time sample indicates the total exposure may be greater 

than measured (exposure measurement error likely exists), and results of meconium analyses in 

the Columbia cohort indicate chlorpyrifos exposure occurred throughout pregnancy. Meconium 

is considered to be an integrative measure of exposure throughout pregnancy. In addition, the 

Mt. Sinai and CHAMACOS studies associate increased maternal urinary DAP levels with 

increased mental delays in children. DAP metabolites are non-specific metabolites that result 

 

3 The third trimester is a critical window of exposure for brain development. 
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from several OP pesticides, so it is difficult to determine which OP compound may be 

contributing most to the adverse findings.

While neurodevelopment deficits may be multifactor in origins, these children are from low 

income multi-ethnic populations and urban neighborhoods and may experience other exposures 

that may also influence neurodevelopmental outcomes. These may include health disparities that 

compound pesticide exposure such as poor diet, low access to health care, socioeconomic issues 

associated with low income and low education, as well as exposure to urban air pollutants. In 

addition, a recent follow-up publication for the Columbia cohort reported that neighborhood 

context and chlorpyrifos exposure were independently associated with neurodevelopment 

(Lovasi et al. 2010). Additional analyses were performed to consider neighborhood 

characteristics, economic deprivation, neighborhood poverty, and maternal hardship to help 

explain the variation in early childhood psychomotor and mental development. Adjustment for 

these factors did not change the chlorpyrifos and child neurodevelopment association (Lovasi et 

al. 2010).

The SAP recommended that the epidemiology and direct dosing human studies should not be 

considered quantitatively for PoDs, but can be used for hazard characterization. The SAP

concluded that the results of the three cohort studies (Columbia University, Mt. Sinai Hospital, 

and the University of California at Berkeley) in concert with the animal studies indicate that 

―maternal chlorpyrifos exposure would likely be associated with adverse neurodevelopmental 

outcomes in humans‖. However, they indicated that exposure to multiple cholinesteraseinhibiting pesticides or other neurotoxicants might result in additive or interactive effects4

. The 

Columbia study was considered the most epidemiologically-sound and robust because it 

measured chlorpyrifos in maternal and cord blood (rather than non-specific metabolites). 

Challenges in the interpretation of the Mt. Sinai and Berkeley studies include use of non-specific 

measures of pesticide exposure, based on OP and carbamate metabolites, rather than 

chlorpyrifos, reduce their utility in a quantitative context for the chlorpyrifos risk assessment.

The Panel recommended that the Agency conduct a full weight of evidence evaluation for the

neurodevelopmental outcomes. Such an exercise requires explicit consideration of criteria such 

as strength, consistency, specificity related to chlorpyrifos or to its anticholinesterase effects 

common to OPs as a whole, dose-response, temporal concordance and biological plausibility in a 

framework analysis similar to that which is conducted currently for hypothesized modes of 

action. This allows comparative analysis across assessments of consistency of weight of 

evidence determinations. The weight of evidence analysis might increase confidence in this case 

and potentially identify additional relevant analyses to address uncertainties such as the role of 

other pesticides in the observed associations. 

The SAP recommended that the Columbia University cohort study could be used to determine 

bounding values for the levels of chlorpyrifos that might cause a measurable effect. In a similar 

way, data from the other epidemiological studies may also be used in risk assessment. The use 

of a PBPK model would enable estimation of an exposure dose metric for multiple sources of 

 

4

 Follow up analyses conducted by the Columbia Researchers (Whyatt and Rauh 2010) show that the adverse 

impact of chlorpyrifos on cognitive development is not due to other anticholinesterase pesticides (diazinon or 

propoxur exposure). 
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exposure, e.g., air, food, water. The panel agreed that the blood and urine data in the deliberate 

human dosing studies are important in interpreting the epidemiology and biomonitoring studies.

The Agency intends to carefully consider the strengths and limitations of the epidemiology 

studies along with the available empirical data in a full weight of evidence analysis in the final 

assessment.

4.4.2 Agricultural Health Study (AHS)

For chlorpyrifos, in addition to the guideline carcinogenicity studies, epidemiological data is 

available from an Agricultural Health Study (AHS). The Agency has reviewed the AHS report 

and concluded that while the AHS investigations currently published were hypothesis-generating 

in nature, initial strength and consistency in the findings for lung cancer and colorectal cancer are 

notable, and warrant further follow-up and additional research. Preliminary associations with 

breast and prostate cancer are weak, but also warrant monitoring the literature for additional 

publications on this association. There is no compelling evidence of an association with other 

cancer sites including pancreatic cancer, melanoma, brain, esophageal, kidney, all 

lymphohematopoietic cancers combined and NHL, leukemia, and multiple myeloma (C. 

Christensen, 6/16/11, D388167).

4.5 New Developments since the 2008 SAP

In 2008, the Agency held a SAP meeting (SAP 2008) to discuss the more recent and extensive 

research on various aspects of chlorpyrifos including its neurological effects in animals and 

humans following gestational and post-natal exposures, its pharmacokinetics, and mechanism of 

action. Details can be found in the Chlorpyrifos Final SAP Report at on the Scientific Advisory 

Panel website (http://www.epa.gov/scipoly/sap/meetings/2008/091608_mtg.htm). Many of the 

key recommendations have been incorporated into this preliminary risk assessment. 

Since the 2008 SAP the agency has reviewed new data and analyses, and held additional public 

meetings to discuss specific aspects of chlorpyrifos including:

• Evaluated new toxicity data

• Consulted the Human Studies Review Board (HSRB)

• Conducted follow up analysis on the Columbia Epidemiology Study

• Consulted the SAP in 2011 on PBPK modeling

New Toxicity Data: Since 2008, the Agency has reviewed an acute and repeat special nonguideline CCA study (Marty and Andrus 2010, MRID No.: 48139301, HED TXR No. 0055409), 

an acute inhalation study (2010, MRID 48139303), and immunotoxicity study. The CCA study 

was conducted to compare the relative toxicity of chlorpyrifos and chlorpyrifos oxon in both 

juvenile (PND11 pups) and adult rats based on ChE inhibition. Both acute (single) dosing and a 

repeat 11 day exposure scenario were evaluated for chlorpyrifos and chlorpyrifos oxon. 

Although the study identified both NOAELs and LOAELs for plasma, RBC and brain ChE

inhibition, the Agency used these data to conduct BMD analysis (see Appendix E for BMD 

results). An acute rat inhalation study was evaluated that identified lung and RBC ChE 
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inhibition as the most sensitive effect at the lowest dose tested of 3.7 mg/m3. A BMD analysis 

was attempted but did not provide high confidence results due to the nature of the dose response 

data. The Agency estimated a HEC of 0.62 mg/m3from this study for use in a preliminary 

assessment of bystander (field volatilization) exposures. In addition, the Agency also reviewed a 

guideline immunotoxicity study that did not identify adverse effects on the immune system at the 

highest dose tested. 

HSRB: In June 2009, the Agency consulted the Human Studies Review Board (HSRB) (June 

24-25, 2009; http://www.epa.gov/hsrb/jun-24-25-2009-public-meeting.htm) regarding deliberate 

dosing studies in adult (non-pregnant) humans that measure ChE activity and urinary and/or 

blood levels of chlorpyrifos and/or its metabolites. Nolan et al (1982; MRID 124144) was found 

to be scientifically and ethically conducted by HSRB and EPA also determined that the study 

was ethically acceptable. Kisicki et al (1999), (MRID 44811002) was found to be scientifically 

(and ethically) conducted by HSRB. However, EPA ethics review had determined that this study 

did not meet the Agency’s ethical standards and therefore concluded that ―EPA is forbidden by 

40 CFR §26.1704 to rely on the Kisicki et al. study, MRID 44811002, in actions taken under 

FIFRA or §408 of FFDCA....‖ (J.Carley memo dated 5/29/09; 

http://www.epa.gov/hsrb/files/1d6-ethics-rvw-kisicki-etal-060109.pdf). Thus, the Kisicki data 

have not been used in the preliminary chlorpyrifos human health risk assessment (Appendix D).

Epidemiology. The SAP recommended a number of follow up analyses for the Columbia 

cohort. Importantly, the panel advised that ―it would be useful to examine the results of a 

statistical analysis that includes all three ChE-inhibiting insecticides in the analysis model as 

dichotomous variables (above or below the LOD) in combination with continuous measurements 

for these variables.‖ Follow up analyses conducted by the Columbia Researchers (Whyatt and 

Rauh 2010) show that the adverse impact of chlorpyrifos on cognitive development is not due to 

other anticholinesterase pesticides (diazinon or propoxur exposure), and these analyses do not 

reduce the chlorpyrifos effect for any of the 3-year outcomes for mental or psychomotor delays. 

The Columbia researchers also addressed a number of other questions raised by the SAP, and 

they do not affect to conclusions of their publications.

PBPK Modeling. At the 2008 SAP, the panel recommended that the Agency consider the 

potential for using PBPK modeling in human health risk assessment for chlorpyrifos. PBPK 

models have been published for chlorpyrifos (Timchalk et al, 2002a, 2007; Rigas et al, 2001; 

Knaak, et al, 2004; Georgopoulos et al, 2008). The model(s) developed by Dr. Charles 

Timchalk and co-workers at of Pacific Northwest National Laboratory has been the most 

extensively developed. The Timchalk model was first published in 2002 as an adult rat and 

human model (Timchalk et al., 2002a) and has been updated as more data have become available 

(Poet et al. 2003; Poet et al. 2004; Slikker et al. 2005; Timchalk et al. 2002b; Timchalk et al. 

2003; Timchalk et al. 2005; Lowe et al., 2009). Timchalk et al. (2007) published a similar 

model for juvenile rats that incorporated age-dependent changes. Recently, Dow AgroSciences, 

Dow Chemical and Dr. Timchalk and co-workers have worked collaboratively to improve the 

chlorpyrifos PBPK model by considering more lifestages (6 month and 3 year olds) and 

evaluating population variability. The PBPK model has also been linked to a probabilistic 

exposure model as an approach to estimate population risk. The status of these efforts was 

considered by the FIFRA SAP in February 2011. At the 2011 meeting, the Panel was 
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supportive of the overall concepts of linking PBPK models to probabilistic exposure models and 

of estimating population risk; however, the Panel pointed out limitations to the current effort that 

precludes its use at the present time. For example, the PBPK models do not simulate pregnancy 

and thus do not estimate in utero exposure to the fetus. In addition, the model only considers 

oral exposure (with a particular focus on food exposure) but inhalation exposure can be an 

important route of exposure for chlorpyrifos for both bystanders from field volatilization and to 

pesticide applicators. 

In addition, the Agency is aware of another PBPK modeling effort led by Dr. Dale Hattis of 

Clark University in collaboration with the Columbia University epidemiology team. This PBPK 

model may, in the future, be useful in clarifying the exposure concentrations that correspond to 

the chlorpyrifos levels in umbilical cord blood associated with statistically significant adverse 

effects on fetal growth and child neurocognitive development. 

4.6 Safety factor for Infants and Children (FQPA Safety Factor)

Due to the preliminary nature of this assessment the Agency is presenting assessments reflecting 

both the retention of the 10X FQPA Safety Factor as in the June 2000 chlorpyrifos risk 

assessment (USEPA 2000), and a proposal to reduce the FQPA SF to 1X based on more recently 

available ChE toxicity studies and analyses. In those instances where the Agency has proposed 

to reduce the FQPA SF to 1x, the Agency believes data are supportive of this proposal. EPA is 

conducting on-going analyses of newly published literature studies on a variety of challenging 

scientific issues such as high to low dose extrapolation, animal to human extrapolation, 

evaluation of the non-cholinergic literature, and interpretation of epidemiology studies in the 

context of assessing human health risk to chlorpyrifos. EPA will continue to evaluate all the 

data/studies to determine the appropriate FQPA SF for future chlorpyrifos risk assessments.

4.6.1 Completeness of the Toxicology Database

The toxicological database for chlorpyrifos is extensive and is adequate to support the 

registration review (Section 4.1 above). The toxicity data base includes the standard battery of 

guideline studies as well as special studies conducted by the registrant. The scientific literature 

on chlorpyrifos includes data from many sources, in animals and humans, and some studies with 

atypical study designs and relatively new assessment techniques. Sources of human information 

include deliberate dosing studies, epidemiology studies, and metabolism studies (in vitro and in 

vivo). There are a variety of laboratory animal studies evaluating a broad range of doses for 

multiple sensitive lifestages. In addition, these studies consider different durations of exposure 

(acute, short-, intermediate-term and chronic) and relevant routes of exposure (oral, dermal, and 

inhalation), different laboratory animal species, reproductive and developmental toxicity, 

neurotoxicity, developmental neurotoxicity (DNT), new acute and repeat dose comparative 

cholinesterase assays (CCA) for both chlorpyrifos and chlorpyrifos oxon, a special acute 

inhalation toxicity study and a required immunotoxicity study.
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4.6.2 Key Scientific Information Available to Inform the Safety Factor

The mode of action (MOA) for organophosphate pesticides, like chlorpyrifos, leading to 

neurotoxicity is inhibition of ChE (See Section 4.3). Concerns regarding the potential hazards to 

children associated with post-natal exposure to chlorpyrifos and other organophosphate 

pesticides is derived from data showing that the young have increased sensitivity to ChE 

inhibition (i.e., the young will have more inhibition than the adult when given the same 

administered dose). Specific to chlorpyrifos, several toxicity studies with chlorpyrifos and its 

oxon, including the new CCA study, show that juvenile rat pups are more sensitive to acute 

chlorpyrifos exposure than adult rats for ChE inhibition. The increased sensitivity of the young 

from acute exposure is likely attributed to a reduced capacity to detoxify chlorpyrifos in juvenile 

animals. There is a clear age-dependant sensitivity which diminishes as the pups mature; this 

pattern is likely reflective of the metabolic processes which rapidly mature in the rat pup. The 

SAP concurred with the Agency that juveniles are more sensitive than adults to ChE inhibition 

following acute exposures, but not necessarily for repeated exposures. 

In addition to effects on ChE inhibition, there is concern that the young have a unique 

susceptibility to chlorpyrifos due to its effects on the developing brain. A number of animal 

toxicity studies examining the effects of chlorpyrifos in the developing brain indicate that 

gestational and/or early postnatal exposure to chlorpyrifos can lead to neurochemical and 

behavioral alterations that persist into adulthood (Gupta et al, 2011, USEPA 2008 draft hazard 

and dose response issue paper), including long-term neurobehavioral changes in motor and 

cognitive behaviors (Aldridge et al., 2005c; Levin et al., 2001, 2002, Ricceri et al., 2003, 2006 

Johnson et al 2009). However, these findings generally occurred at doses that are often 

associated with ChE inhibition (> 1 mg/kg/day; the 10% BMD for brain ChE inhibition is about 

1.4 mg/kg/day for acute and 0.6-0.8 mg/kg/day for repeated exposure to the PND11 pups in the 

CCA study) and thus at doses higher than the new oral PoDs being used in this preliminary 

assessment. In addition, most of the literature studies evaluating non-cholinergic mechanisms 

and behavioral outcomes provide insufficient information to establish a dose-response due to 

testing one or two treatment groups and or poor dose selection.

In addition, many in vitro literature studies and the guideline developmental neurotoxicity (DNT) 

study are supportive of the possibility that chlorpyrifos exposure may affect brain development

(e.g., altered synaptic development, alterations in DNA, RNA, and protein synthesis, inhibition 

of mitosis and mitotic figures, and disruption of the structural architecture of the brain) (USEPA 

2000b). Qualitative susceptibility between adult rats and their offspring was seen in the

guideline DNT study (cholinesterase inhibition in dams at ≥0.3 mg/kg/day versus structural 

effects on developing brain of the PND 66 offspring at ≥ 1 mg/kg/day) (Hoberman 1998a,b, 

HED Review D254907). Although an apparent increased qualitative susceptibility was 

observed in the DNT study, the SAP panel indicated that adult brain morphometric 

measurements of the cortical regions displayed about 10% variability, a level expected to be 

within normal variability for such crude measurements. The SAP also advised that histological 

assessment and morphometric measurements used in the DNT have significant limitations and 

cannot detect changes in the network organization of the brain or possible other changes. 

Unbiased stereology should be used for determining cell number and tissue volume. Thus, it is 
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possible that the Agency’s current interpretation of the PND 66 offspring morphometric data in 

the DNT study may be revisited pending additional information and analysis.

The mode(s) of action associated with the effects on the developing brain are still not known. 

However, over the last 15 years, biologically plausible hypotheses for chlorpyrifos have been 

proposed by researchers. These include effects on signaling pathways (Slotkin, 2006), a 

morphogenic role of ChE effect the structure of the brain (Brimijoin and Koenigsberger, 1999 

and Bigbee et al, 1999; Yang et al, 2008) and recently a reduction in axonal transport mediated 

through impaired tubulin polymerization (Prendergast et al, 2007; Grigoryan et al, 2008; 

Grigoryan et al 2009; Grigoryan and Lockridge, 2009; Jiang et al, 2010) Although multiple 

mechanisms have been proposed, a coherent mode of action with supportable key events, 

particularly with regard to dose-response and temporal concordance, has not yet been elucidated. 

The Agency may consider additional studies on possible non-cholinergic modes of action in the 

future, including those cited by Eaton et al. (2008), as well as studies reported since that time. 

The Agency is currently updating its evaluation of the non-cholinerigic literature.

The epidemiological data (Columbia University, Mt. Sinai, and CHAMACOS) do not provide 

sufficiently robust dose-response information for derivation of a quantitative measure of human 

risk at this time. The FIFRA SAP (2008) concurred with the proposal to use these studies for 

qualitatively supporting the risk assessment but not for use in quantitative extrapolation. The 

SAP pointed out some uncertainties remain the preclude the use of the epidemiology studies in 

quantitative risk assessment: 1) only measuring biomarkers (3rd trimester maternal, cord blood, 

meconium) at 1-point in time; 2) the studies do not information as to critical window of effect; 

and 3) they cannot exclude possibility that effect seen due to chlorpyrifos in combination with 

other pesticides (additive, multiplicative effect). Similar to many other epidemiology studies, 

these studies have not measured air exposures, urinary or blood metabolites at or near the timing 

of pesticide applications. However, the FIFRA SAP said these are high quality studies and 

supported their use as qualitative information to support the neurodevelopmental toxicity of 

chlorpyrifos following gestational and/or postnatal exposures since there are ―more similarities 

than discrepancies across them‖. The Columbia study was considered the most 

epidemiologically-sound and robust because it measured chlorpyrifos in maternal and cord blood 

(rather than non-specific metabolites). Qualitative similarities between the findings in animal 

behavioral studies and in the epidemiology studies include impaired cognition, abnormal motor 

development, and altered social development in children, possibly persisting into school-age (7 

years) (Rauh et al. 2006, 2011, Engel et al. 2011, Eskenazi et al. 2007, Bouchard et al. 2011).

Inhibition of ChE is the most sensitive endpoint measured in dose response studies in any animal 

species and in humans, regardless of route or duration of exposure. As such, ChE inhibition has 

been and continues to be the endpoint used for human health risk assessment for OPs, including 

chlorpyrifos. In the 2000 risk assessment (EPA 2000a), EPA used a weight of the evidence 

approach with ChE data from multiple adult laboratory animal studies and multiple species (rat, 

dog) as the basis of the PoD for all durations and routes of exposure. Since then, numerous new 

studies in juvenile animals have become available, notably acute and 11 day repeated dosing 

CCA studies for chlorpyrifos and its oxon. As shown in the draft EPA 2008 issue paper, and 

draft Appendix C (Mode of Action: Inhibition of Cholinesterase at 

http://www.epa.gov/scipoly/sap/meetings/2008/091608_mtg.htm), there are extensive ChE data 
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in juvenile rats ranging from PND1-PND33. EPA updated the oral PoDs based on the most 

sensitive lifestage(s) relevant to direct oral human exposures. Rat pups younger than 

approximately PND10 are more physiologically similar to human fetuses in utero. As such, the 

Agency has focused its quantitative dose response efforts on rats ages PND11 and older for oral 

exposures using BMD modeling for 10% RBC ChE inhibition. 

EPA is still evaluating the latest epidemiology (Rauh et al. 2011, Engel et al. 2011, Bouchard et 

al. 2011) and PBPK data and modeling efforts by Dow AgroSciences and Dr. Dale Hattis to be 

more explicit about uncertainty and variability, and to have a more accurate picture of the doses 

at which adverse effects might happen in humans and animals. Thus, the PoDs proposed in this 

preliminary assessment, and associated uncertainty/FQPA factors, could change. 

4.6.3 Application of the FQPA Safety Factor for the Preliminary Risk Assessment 

In this preliminary assessment, EPA is presenting the risk estimates using both the PoDs and the 

10X FQPA SF retained in 2000, and oral PoDs based on new CCA study providing a sensitive 

endpoint and lifestage with a 1X FQPA and updated quantitative tools (BMD modeling). EPA is 

continuing to conduct ongoing analysis to ensure a sound scientific basis for the appropriate

factor. 

2000 Risk Assessment. In the June 2000 chlorpyrifos risk assessment, the FQPA safety factor 

was retained at 10X for the protection of infants and children to exposure resulting from 

chlorpyrifos (USEPA 2000a, b, c). At that time, the Agency used PoDs based on NOAELs for 

plasma and/or RBC ChE inhibition from adult data in laboratory animals and recommended that 

a 10X safety factor be retained for chlorpyrifos due to: 

(1) Increased sensitivity and susceptibility was not only a high dose phenomenon since:

Increased sensitivity to ChE inhibition following a single oral exposure to 

neonates was seen at substantially lower doses in PND 7 pups compared to adults 

(i.e., < 1.5 mg/kg/day) (Zheng et al. 2000); and

A clear qualitative difference in response (i.e., susceptibility) between adult rats 

and their offspring was demonstrated in the developmental neurotoxicity (DNT) 

study (cholinesterase inhibition in dams versus structural effects on developing 

brain of the offspring) (Hoberman 1998a,b, HED Review D254907). 

(2) New data available in the literature at the time of the 2000 risk assessment also gave 

rise to uncertainties such as: 

The suggestion that the inhibition of cholinesterase may not be essential for 

adverse effects on brain development (see EPA literature review in USEPA 

2000b) 5; and 

 

5

The mechanism(s) of action for the chlorpyrifos-induced changes (e.g., macromolecular synthesis, cell signaling) 

is/are unclear. However, given that these effects can be found after intracisternal injection of chlorpyrifos, with in 
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The lack of an offspring NOAEL in the DNT based upon structural alterations in 

brain development as the toxicity endpoint of concern.

2011 Preliminary Risk Assessment: 

As noted previously, EPA solicited comment from the SAP in 2008 on extensive research on 

various toxicological aspects of chlorpyrifos, including its neurological effects in animals and 

humans following gestational and post-natal exposures, its pharmacokinetics, and mechanism of 

action. Details can be found in the Chlorpyrifos Final SAP Report at 

(http://www.epa.gov/scipoly/sap/meetings/2008/091608_mtg.htm ). The SAP made a number 

of recommendations on updating the PoDs which are incorporated into the current preliminary 

risk assessment. Key SAP recommendations included here are: take into account all sensitive

life stages; and use benchmark dose modeling instead of the NOAEL/ LOAEL approach when 

possible.

Since the 2008 SAP meeting, EPA has received and reviewed a new acute and repeat CCA study 

for both chlorpyrifos and chlorpyrifos oxon (Marty and Andrus 2010). This study is considered 

high quality, and provides reliable measures of blood and brain ChE at the time of peak effect (6-

8 hours post-dosing), uses 4-6 doses and use a wide range of doses. BMD analyses were 

conducted for both RBC and brain ChE inhibition for this CCA study, in addition to many other 

literature and registrant studies for both acute and repeat exposure (Betancourt and Carr 2004, 

Zheng et al. 2000, Moser et al. 2006, Timchalk et al. 2006, Mattsson et al 1998, Hoberman 

1998a,b) (see Appendix E for BMD analyses). These studies were all considered for endpoint 

selection. The RBC ChE inhibition BMD for acute chlorpyrifos exposure to PND11 pups 

administered via milk provides the lowest oral PoD in the entire database of the relevant studies6

and thus was selected as the new acute oral PoD (Marty and Andrus 2010). The chronic PoD

was based on data for pregnant rats in the DNT study (Hoberman 1998a,b), which resulted in the 

most sensitive PoD, and was also the basis of the 2000 cPoD, along with 4 other studies. For 

chlorpyrifos oxon, the CCA results were used to develop acute and chronic PoDs based on BMD 

analysis for RBC ChE inhibition. 

Like other OPs, ChE inhibition provides the most sensitive dose-response data for chlorpyrifos. 

As a result, the focus of the 2011 preliminary risk assessment is on the cholinesterase inhibiting 

potential of chlorpyrifos. Consistent with this focus, EPA has evaluated the extensive database of 

ChE data for multiple lifestages and has selected the most sensitive studies which use ages 

relevant to human exposure. There are no residual uncertainties in the exposure database. The 

dietary risk assessment is conservative and is not expected to underestimate dietary exposure to 

chlorpyrifos and chlorpyrifos oxon. Similar to risk assessments conducted for other ChEinhibiting pesticides where juvenile pups provide the PoDs for risk assessment, the FQPA SF is 

being reduced to 1X for this preliminary assessment for acute and chronic oral exposure, in 

addition to dermal and inhalation exposure to chlorpyrifos. The repeated inhalation PoDs are 

 

vitro TCP treatment, and in vitro PC12 cell cultures with limited capability to activate chlorpyrifos to its ChEinhibiting oxon, raised the issue of whether these effects can occur independent of cholinesterase inhibition.

6 Data for pups less than PND10 were not considered relevant for direct human exposure, since this represents the 

human fetal stage
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considered protective of sensitive lifestages (pregnant rats). For acute inhalation exposure, a

10X FQPA database uncertainty factor is retained to account for LOAEL to NOAEL 

extrapolation. 

For chlorpyrifos oxon, the Agency proposes to reduce the FQPA SF to a 1X for acute and 

chronic exposure because the acute PoD is based on a sensitive lifestage (juvenile pups) in the 

CCA study and the chronic is based on the lowest BMDL available in the CCA study. 

Table 6 Application of FQPA SF Comparison of 2000 and 2011 Risk Assessment for Chlorpyrifos

Point of Departure (mg/kg/day)

2000 10X FQPA SF (a) Proposed 1X FQPA SF (b)

Acute PoD 0.5 (mg/kg/day;NOAEL) 0.36 (BMDL10)

Chronic PoD 0.03 (NOAEL) 0.03 (BMDL10)

Incidental oral 0.5 (NOAEL) ST: 0.1 (BMDL10)

IT: 0.03 (BMDL10)

Dermal ST: 5 (NOAEL)

 IT: 0.03 (NOAEL) ST/IT: 5 (NOAEL) (c)

Inhalation

ST/IT: 0.1 (NOAEL)

Acute: 0.62 mg/m3 (HEC, LOAEL) (d)

ST/IT: 0.0057 mg/m3 (HEC, NOAEL 24 hr 

residential) (e)

BMDL10= benchmark dose lower confidence limit for 10% RBC ChE inhibition

HEC= human equivalent concentration; ST/IT= short and intermediate-term

ST= short –term; IT= intermediate- term

(a) A 10X FQPA SF is retained to the PoDs from the 2000 risk assessment because these are based on adult 

animal data. 

(b) Except where noted, 1X FQPA SF is proposed for 2011 PoDs because they are based on the most sensitive 

lifestage (i.e., PND 11 and pregnant animals). 

(c) For dermal exposure, a 1X FQPA SF is proposed because of the conservative nature of the PoD that is 

based rat data. Rats have more permeable skin than humans. 

(d) For acute inhalation exposure, a 10X FQPA database uncertainty factor is applied to account for LOAEL to 

NOAEL extrapolation.

(e) For repeated inhalation exposure, a 1X FQPA SF is applied because the PoD is based on route-specific 90 

day inhalation studies, and a LOAEL from the DNT study to protect pregnant females from RBC CHE 

inhibition (LOAEL of 0.3 mg/kg/day)

Table 7 Application of FQPA SF in Risk Assessment for Chlorpyrifos Oxon

Point of Departure (mg/kg/day)

Proposed 10X FQPA SF Proposed 1X FQPA SF 

Acute PoD -- 0.05 (BMDL10) (a)

Chronic PoD -- 0.011 (BMDL10) (b)

Dermal Not applicable

Inhalation Not applicable

(a) 1X FQPA SF proposed since the aPoD is based on sensitive lifestage (juvenile animals). 

(b) 1X FQPA database UF because the most sensitive PoD was selected (in 11 day CCA study using 

adults), that is protective of juvenile rats.
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Next Steps in the FQPA SF Analysis: 

Analyses are ongoing to fully examine recently proposed biologically plausible modes of action 

which could lead to effects on the developing brain and to consider these new data in light of the 

epidemiology studies in mothers and children. As such, the Agency continues to analyze and 

integrate the animal and human epidemiology data to ensure that a sound scientific analysis 

around key scientific areas such as high to low dose extrapolation, animal to human 

extrapolation, and interpretation of epidemiology studies in the context of assessing human 

health risk to chlorpyrifos. These ongoing analyses will ensure that the PoDs and UFs in this 

preliminary assessment are human health protective for neurodevelopmental toxicity that may 

arise from pre- or postnatal exposure. The Agency’s final FQPA determination will be based on 

a full scientific weight of evidence approach that considers the best available science and 

integrates all key lines of evidence, from empirical animal toxicology to observational human 

epidemiology studies, in an integrated framework analysis and will transparently address and 

clearly characterize the strength of the evidence and areas of remaining uncertainty and 

variability. The Agency plans to conduct a full weight of evidence evaluation integrating the 

epidemiology studies with the experimental toxicology studies for the neurodevelopmental 

outcomes using the Draft Framework for Incorporating Epidemiologic and Human Incidence 

Data in Human Health Risk Assessment7, which was reviewed favorably by the FIFRA SAP in 

February, 2010 (USEPA, 2010) Such a weight of evidence analysis requires explicit 

consideration of such criteria as strength, consistency, specificity, dose response, temporal 

concordance and biological plausibility.

This final determination will also consider the 2008 SAP comments and the public comments 

received on this preliminary risk assessment. Thus, the intra-, and inter-species UFs along with 

the FQPA SF could change with these additional analyses. The Agency is seeking comment on 

the proposed FQPA SF for the final chlorpyrifos risk assessment. 

4.7 Toxicity Endpoint and Point of Departure Selections

4.7.1 Dose-Response Assessment

Table 8 summarizes the chlorpyrifos toxicity endpoints and PoDs selected from a re-evaluation 

of the database (including data submitted since the 2002 IRED/2006 RED). Based on the results 

of benchmark dose (BMD) analyses and weight of the evidence (WOE) consideration of all 

quality and reliable data, the most sensitive compartment (i.e., RBC, lung or brain) from the most 

sensitive sex in both juvenile (> PND11) and adult rats were identified and used for endpoint 

selection and PoD determination for the following exposure scenarios. Descriptions of the 

primary toxicity studies used for selecting toxicity endpoints and points of departure for various 

exposure scenarios are presented in Appendix A of this document. The description and results of 

the BMD analyses can be found in Appendix E. The SAP recommended selecting PoDs based 

on BMD analysis for RBC ChE inhibition for the most sensitive lifestages (i.e., pup and pregnant 

females). The Panel supported the continued use of route-specific data for dermal and 

inhalation, but advised EPA to take into account sensitive lifestages since these studies are based 

 

7

http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2009-0851-0004
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on adult non-pregnant animals. Most of the panel believed that the PoDs based on ChE inhibition 

would be protective of the developing brain from low level in utero exposures, although there 

was no consensus. The Panel encouraged the Agency to address uncertainties including lack of 

information on an MOA for behavioral effects and in vivo and in vitro studies that indicate noncholinergic MOA are likely to be involved in neurodevelopment and behavioral effects. The 

Agency is conducting ongoing analyses to ensure that the PoDs and UFs in this preliminary 

assessment are human health protective for neurodevelopmental toxicity that may arise from preor postnatal exposure. 

Consistent with risk assessment on other OP and NMCs compounds, the Agency has used a 

benchmark response (BMR) level of 10% and has thus calculated BMD10s and BMDL10s. The 

BMD10 is the estimated dose where ChE is inhibited by 10% compared to background. The 

BMDL10 is the lower confidence bound on the BMD10. Extensive analyses conducted as part of 

the OP cumulative risk assessment (USEPA 2002) have demonstrated that 10% is a level that 

can be reliably measured in the majority of rat toxicity studies, and is generally at or near the 

limit of sensitivity for discerning a statistically significant decrease in ChE activity across the 

brain compartment and is a response level close to the background brain ChE level. The Agency 

uses the BMDL, not the BMD, for use as the PoD since the BMDL accounts for variability of the 

data.

The Agency has not performed BMD analysis on studies evaluating the effect of chlorpyrifos on 

the developing brain as these do not provide dose response data amenable to BMD modeling 

analysis. Specifically, these studies, in general, may include only a single dose at a particular 

age, do not report graded responses (i.e., all or nothing effect), and/or show non-monotonic dose 

response curves (e.g., response goes up then down). For these studies, the Agency simply 

considered the doses used. 

Acute Dietary (all populations) 

Two high quality studies were identified in the re-evaluation of the toxicological database; these 

include the new CCA rat study (MRID 48139301) and Moser et al. (2006) in male PND17 rats. 

Results of BMD analyses of these well-conducted studies revealed that male and female pup 

RBC ChE and male whole blood ChE inhibition were the most sensitive endpoints and 

appropriate as a PoD for the acute dietary (all populations) exposure scenario. A BMDL10 of 

0.36 mg/kg/day associated with RBC ChE inhibition in male and female rat pups exposed to 

chlorpyrifos in milk (new CCA study) was selected as a suitable PoD with support from the 

BMDL10 of 0.4 mg/kg from Moser et al. (2006). The published studies of Zheng et al. (2000) and 

Timchalk et al. (2006) provide additional support for the acute PoD. 

An uncertainty factor of 100X (10X to account for interspecies extrapolation and 10X for 

intraspecies variation) is applied to the BMDL10 to obtain an aRfD of 0.0036 mg/kg/day. Based 

on the proposed FQPA safety factor of 1, the acute population adjusted dose (aPAD) is 0.0036 

mg/kg/day.
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Chronic Dietary (all populations)

A chronic PoD of 0.03 mg/kg/day (BMDL10) was selected from pregnant (GD6-20) rats exposed 

to chlorpyrifos in the developmental neurotoxicity study (MRID 44556901, Hoberman et al. 

1998a,b) on the basis of inhibition of RBC ChE in pregnant dams. This PoD was supported by a 

WOE evaluation of other studies including an oral gavage study in pregnant (GD6-LD10) rats 

(MRID 44648101) and the new CCA study. An uncertainty factor of 100X (10X to account for 

interspecies extrapolation and 10X for intraspecies variation) was applied to the BMDL10 to 

obtain a cRfD of 0.0003 mg/kg/day. Based on the proposed FQPA safety factor of 1, the chronic 

population adjusted dose (cPAD) is 0.0003 mg/kg/day.

Incidental Oral

For short-term incidental oral exposure scenario, the results of the 11 day repeat phase of the 

new oral CCA study (MRID 48139301) indicated inhibition of RBC ChE in male PND11 rats as 

the most sensitive endpoint. A BMDL10 of 0.1 mg/kg/day was derived from a BMD analysis of 

the dose- response data. For intermediate-term incidental oral exposure scenarios a BMDL10 of 

0.03 mg/kg/day was identified (see chronic dietary PoD selection above).

A total uncertainty factor of 100X is appropriate for incidental oral exposures [10X for 

interspecies extrapolation, 10X for intraspecies variation and a 1X FQPA safety factor].

Dermal

A short-/intermediate-term dermal PoD was selected from a 21-day dermal toxicity study (MRID 

40972801) in rats based on plasma and red blood cell ChE inhibition (NOAEL = 5 mg/kg/day). 

The use of the 21-day dermal toxicity study is appropriate for durations up to 6 months as it is 

expected that steady state ChE inhibition would have been reached by approximately 21 days of 

dermal exposure. The Agency has previously shown (USEPA, 2001; preliminary 

organophosphate cumulative risk assessment) that at or near 3-4 weeks of exposure the degree 

of inhibition following repeated dosing with OPs does not change with increasing duration but 

instead remains approximately the same. 

For comparison to biomonitoring data in the risk assessment, which evaluates total exposure 

from oral, dermal and inhalation routes (in terms of absorbed dose), the 21-day rat dermal study 

is used with an adjustment for 3% dermal absorption to convert the NOAEL of 5 mg/kg/day 

resulting from topically applied chlorpyrifos to an internal absorbed NOAEL = 0.15 mg/kg/day. 

The dermal absorption factor of 3% was estimated based on the ratio of the oral LOAEL of 0.3 

mg/kg/day from the rat developmental neurotoxicity study (MRIDs 44556901, 44661001) to the 

dermal LOAEL of 10 mg/kg/day from the 21-day rat dermal study (MRID 40972801) for plasma 

and red blood cell cholinesterase inhibition. This absorption factor is comparable to the dermal 

absorption (minimum 1-3%) estimated from human data in Nolan et al. (1982, MRID 00249203) 

by back-calculating chlorpyrifos exposure based on urinary levels of TCP. Most of the absorbed 

dose in the worker biomonitoring study is the result of dermal exposure.
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A total uncertainty factor of 100X is appropriate for dermal exposures [10X for interspecies 

extrapolation, 10X for intraspecies variation and a 1X FQPA safety factor].

Inhalation

An acute inhalation PoD was selected from a recently submitted special acute inhalation study 

(2010, MRID 48139303) based on lung and plasma ChE inhibition (LOAEL = 3.7 mg/m3; 

NOAEL not established). In this special acute inhalation study, adult female rats (Crl:CD(SD)) 

were exposed nose only to atmospheric concentrations of 0, 3.7, 12.9, 22.1 or 53.5 mg/m3for six 

hours and allowed an additional 72 hours to recover. Using the Agency’s Reference 

concentration (RfC) methodology, a human equivalent concentration (HEC) was calculated and 

used to assess acute bystander exposure and risks. The HEC for acute bystander exposure is 0.62 

mg/m3.

Short- and intermediate-term inhalation risk assessments were based on two subchronic 

inhalation toxicity studies (MRID Nos.40013901, 40166501, 40908401) in the rat. Using the 

Agency’s Reference concentration (RfC) methodology, a human equivalent concentration (HEC) 

was calculated and used to assess both occupational and residential exposure/risks. The shortand intermediate-term inhalation HEC calculated for residential exposures was converted to a 

NOAEL of 0.56 mg/kg/day to allow for comparison to estimated occupational inhalation doses

(which are in units mg/kg). The HECs are based on no effects on plasma or RBC ChE inhibition 

identified from the two rat inhalation studies. For residential bystander exposure, the HEC for 

acute residential bystander exposure is 0.62 mg/m3, and is 0.0057 mg/m3for short- and 

intermediate-term exposure. Because the 90-day study was conducted 5 days per week at 6 

hours/day, the short- and intermediate-term residential HEC was adjusted to represent continual

(24 hr, 7 day/week) exposure. In contrast, the occupational inhalation exposure was only 

adjusted to account for an 8 hour workday because worker exposure is expected to occur during 

the course of an average workweek (8 hours/day and 5 days/week). 

For acute inhalation exposures, a total uncertainty factor of 300X was applied [3X for 

interspecies extrapolation (reduced from 10X because RfC methodology used which takes into 

consideration the pharmacokinetic differences between animals and humans), 10X for 

intraspecies variation, and a 10X FQPA database uncertainty factor (for extrapolation from a 

LOAEL to a NOAEL). 

For short-term and intermediate- term inhalation exposures, a total uncertainty factor of 30X was 

applied [3X for interspecies extrapolation (reduced from 10X because RfC methodology used), 

10X for intraspecies variation and a 1X FQPA SF (because the inhalation NOAEL is considered 

protective of pregnant females based on effects seen in the DNT at 0.3 mg/kg/day)].

Determination of Acute and Chronic Dietary PoDs for Chlorpyrifos Oxon

There is some potential for direct exposure to the oxon metabolite of chlorpyrifos, particularly 

from drinking water. BMD modeling of available oxon data for acute and repeated dosing 

studies was conducted (Appendix E, Tables 7 and 8). The purpose of this analysis is to 
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determine the toxicological PoDs for the oxon (Table 9) and to assess the relative potency of 

chlorpyrifos and its oxon metabolite.

A BMDL10 of 0.05 mg/kg/day associated with RBC ChE inhibition in male rat pups exposed to 

chlorpyrifos oxon (acute dosing CCA study using oxon) was selected for the acute dietary PoD

for the oxon. An uncertainty factor of 100X (10X to account for interspecies extrapolation and 

10X for intraspecies variation) is applied to the BMDL10 to obtain an aRfD of 0.0005 mg/kg/day. 

Based on the FQPA safety factor of 1, the acute population adjusted dose (aPAD) is 0.0005 

mg/kg/day.

The chronic dietary PoD for chlorpyrifos oxon is selected from a BMDL10 of 0.011 mg/kg/day 

from an 11 day repeat dosing CCA study using oxon and is based on inhibition of RBC ChE in 

adult female rats. A comparison of the resulting BMD10s for juvenile and for adult rats indicates

that juvenile rats are no more sensitive to the oxon than are adult rats. The BMDL10 for adult 

rats (0.011 mg/kg/day) was selected for the PoD because it was lower than that of the juvenile 

rats (0.025 mg/kg/day) and would be considered protective for juveniles. Uncertainty factors of 

10X to account for interspecies extrapolation and 10X for intraspecies variation is applied to the 

BMDL10 to obtain an aRfD of 0.00011 mg/kg/day. Based on the FQPA safety factor of 1, the 

chronic population adjusted dose (cPAD) is 0.000011 mg/kg/day.

Toxicity Factor for Chlorpyrifos Oxon. The Agency developed toxicity factors to estimate 

the potency of chlorpyrifos oxon relative to chlorpyrifos for the aggregate assessment. While the 

Agency uses the BMDL, not the BMD, for use as the PoD since the BMDL accounts for 

variability of the data, the BMD10 provides a point of comparison across studies and the BMD10

provides the basis for determining the relative toxicity of the chlorpyrifos oxon compared to 

chlorpyrifos. A toxicity factor for the oxon was calculated by dividing the chlorpyrifos BMD10 

for the endpoint associated with the most sensitive compartment from the most sensitive sex for 

the duration of interest by the corresponding BMD10 for the oxon. Table 10 summarizes the 

toxicity values for chlorpyrifos oxon. Acute (all populations) toxicity factors of 8.8 (males) and 

11.9 (females) were calculated from BMD analysis of inhibition of male and female pup RBC 

ChE (acute phase of the CCA study). The chronic toxicity factor of 18.0 was derived from BMD 

analysis of inhibition of RBC ChE in adult female rats (adult male rats not examined) observed 

in the repeated phase of the CCA study. The toxicity factors may be used in aggregate 

assessments where exposures to chlorpyrifos and the oxon are to be combined. Adjusting for 

relative toxicity will allow comparison of the combined exposures to a single PoD (since PoDs 

are different for chlorpyrifos and oxon). 
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4.8 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

Table 8 Summary of Toxicological Doses and Endpoints and Points of Departure for Chlorpyrifos 

for Use in Preliminary Dietary, Non-Occupational (Residential), and Occupational Human Health 

Risk Assessments

Exposure

Scenario

Point of Departure

(mg/kg/day)

Study and Toxicological

Effects

Acute Dietary (all 

populations)

BMDL10 = 0.36

UFA = 10x

UFH = 10x

FQPA SF = 1x

Acute PAD = 0.0036

Inhibition of RBC ChE in male and female rat pups.

Weight of evidence from several acute oral studies:

CCA Study (MRID 48139301) in the rat –

PND 11 male and female

Data on PND17 males , Moser et al.( 2006)

Qualitative support from Timchalk et al. 

(2006) and Zheng et al. (2000) studies

Chronic Dietary 

(all populations)

BMDL10 = 0.03

UFA = 10x

UFH = 10x

FQPA SF = 1x

Chronic PAD = 0.0003

Inhibition of RBC ChE in rat dams (GD 6 – 20).

Weight of evidence from studies including:

Developmental neurotoxicity study in 

pregnant (GD 6 - 20) rats (MRID 44556901)

Gavage study in pregnant (GD 6 – LD10) rats 

(MRID 44648101)

Short-Term 

Incidental Oral

(1 – 30 days)

BMDL10 = 0.1

UFA = 10x

UFH = 10x

FQPA SF = 1x

Residential LOC for MOE=100

Inhibition of RBC ChE in PND 11 male rats.

11 day repeat oral CCA study in the rat 

(MRID 48139301).

Intermediate –

term Incidental 

Oral 

BMDL10 = 0.03

UFA = 10x

UFH = 10x

FQPA SF = 1x

Residential LOC for MOE=100

See Chronic Dietary.

Dermal

Short-

(1 – 30 days) and 

IntermediateTerm (1-6 

months)

NOAEL = 5 mg/kg/day

[Absorbed dermal

NOAEL = 0.15

(for use in comparative 

assessment using biomonitoring

data)]

Plasma and RBC ChE inhibition.

21-day dermal study (NOAEL) and 4 day 

probe study (LOAEL) in adult rats (MRID 

40972801).
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Exposure

Scenario

Point of Departure

(mg/kg/day)

Study and Toxicological

Effects

UFA = 10x

UFH = 10x

FQPA SF = 1x (residential)

Residential LOC for MOE=100

Occupational LOC for MOE =100

Acute Inhalation Inhalation LOAEL = 3.7 mg/m3 

HEC = 0.62 mg/m3 (residential)

UFA = 3x

UFH = 10x

FQPA UFDB = 10x (LOAEL to 

NOAEL extrapolation 

(residential)

Residential LOC for MOE=300

Lung ChE inhibition.

Special 6 hour acute inhalation study (MRID 

48139303). (Aerosol)

Inhalation

Short- (1 – 30 

days) and 

Intermediate- (1 –

6 months)

NOAEL (calc from HEC) = 0.56 

mg/kg/day ( 8-hr occupational)

NOAELHEC = 0.0057 mg/m3

(24 hr residential)

UFA = 3x

UFH = 10x 

FQPA SF = 1x (residential)

Residential LOC for MOE=30

Occupational LOC for MOE =30

Lack of effects in 2 rat inhalation studies at the 

highest dose tested: LOAEL is based on 43% plasma 

and 41% RBC ChE inhibition following oral doses of 

0.3 mg/kg/day in the DNT study

Two 90-day inhalation studies and the rat 

DNT study (MRIDs 40908401; 40013901/ 

40166501). (Vapor study)

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). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFDB = to account for the absence of key data (i.e., lack of a critical study) or other residual uncertainties 

as evidenced by available data. FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = 

chronic). RfD = reference dose. RfC = reference concentration. HEC = human equivalent concentration. MOE = 

margin of exposure. LOC = level of concern. N/A = not applicable.
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Table 9 Summary of Points of Departure, Toxicological Doses and Toxicity Endpoints for 

Chlorpyrifos oxon for Use in Dietary Exposure Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, Level 

of Concern 

Study and Toxicological 

Effects

Acute 

Dietary 

(General 

Population, 

including 

Infants and 

Children)

BMDL10 = 

0.05

UFA= 10x

UFH=10x

FQPA SF = 1x

Acute RfD = 

0.0005 

aPAD =0.0005 

mg/kg/day 

CCA Study (oxon), acute 

dosing – Inhibition of RBC 

ChE in male rat pups

Chronic 

Dietary (All 

Populations)

BMDL10 = 

0.011

UFA= 10x

UFH=10x

FQPA SF= 1x

Chronic RfD = 

0.00011 mg/kg/day 

cPAD = 0.00011 

mg/kg/day 

CCA Study (oxon), 11 day 

repeat dosing – Inhibition of 

RBC ChE in adult female rats

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). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFDB = to account for the absence of key data (i.e., lack of a critical study) or other residual uncertainties 

as evidenced by available data. FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = 

chronic). RfD = reference dose. RfC = reference concentration. MOE = margin of exposure. LOC = level of 

concern. N/A = not applicable.

Table 10 Acute and Chronic Relative Toxicity Factors for Chlorpyrifos Oxon (Compared to 

Chlorpyrifos)

Dietary Scenario Toxicity Factor (based on BMD10 comparison)

Acute Dietary (all populations)

12 ♀

(8.8♂)

Chronic Dietary (all populations) 18

4.9 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and 

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 
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reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of its reregistration decision, EPA reviewed these data and selected 

the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard 

database. However, as required by FFDCA section 408(p), chlorpyrifos is subject to the 

endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a ―naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.‖ The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 

2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, 

which contains 58 pesticide active ingredients and 9 inert ingredients. Chlorpyrifos was included 

on that list and has been issued an order to conduct the Tier 1 testing. For further information on 

the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test 

guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/.

5.0 Dietary Exposure and Risk Assessment 

5.1. Residues of Concern Summary and Rationale

Plants - The qualitative nature of the residue in plants is adequately understood based on 

acceptable metabolism studies. The terminal residue of concern in/on plants is chlorpyrifos.

Livestock - The qualitative nature of residue in animals is adequately understood based on 

acceptable poultry and ruminant metabolism studies. The residue of concern in animals is 

chlorpyrifos. 

Drinking water- The cholinesterase inhibiting metabolite, chlorpyrifos oxon, which has been 

characterized as having higher toxicity than chlorpyrifos, has been detected in environmental 

samples including drinking water, surface water, precipitation, and air. The residues of concern 

for drinking water are chlorpyrifos and the chlorpyrifos oxon.
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NA = Not Applicable

The chlorpyrifos degradate TCP is not considered a residue of concern as it does not inhibit 

cholinesterase (separate human health risk assessments have been performed for TCP, which has 

its own toxicity database).

5.2 Food Residue Profile

Currently, no petitions for the establishment of new tolerances for chlorpyrifos are pending. The 

previously submitted petitions 7F7248 (alfalfa, alfalfa mixed stands, grass grown for hay or 

pasture), 3F4188 (barley grain and forage), and 3H5662 (barley, milling fractions) were 

withdrawn 05/07/2009. 

New crop field trial studies have been submitted for cotton gin byproducts (MRID 46651202), 

tart cherries (MRID 46651201), aspirated grain fractions for soybean, sorghum and wheat 

(MRID 46640901), and grass forage and hay as part of a data call in related to the 2002 

chlorpyrifos IRED. These studies were reviewed previously and regulatory conclusions are 

included here for all the commodities with the exception of grass forage and hay (original 

petition withdrawn). In addition, petitions for a PHI reduction for sweet potato and the 

registration of a microencapsulated formulation were submitted but the requests were cancelled 

and denied, respectively. 

Studies submitted to support the registration of a microencapsulated formulation of chlorpyrifos 

showed over tolerance residues after a foliar application of Lorsban 4E end use product to lemon 

with a rate of 6 lb ai/A. The maximum residue observed was 1.41 ppm while the tolerance for 

citrus fruit (CG 10) is 1.0 ppm. The label of the existing Lorsban 4E end use product (44.9% 

chlorpyrifos) allows a maximum application rate of 6.4 lb ai/A and addition of oil to the spray 

mixture. Under these conditions residues over tolerance may occur; therefore, HED 

recommends a reassessment of the tolerance for citrus fruit using lemon as the representative 

commodity. 

The crop field trial data requested in the IRED and submitted by the petitioner is considered 

adequate to conclude that tolerances of 15 ppm and 22 ppm would cover any residues of 

Table 11 Summary of Metabolites and Degradates to be included in the Risk Assessment and 

Tolerance Expression

Matrix Residues included in Risk 

Assessment

Residues included in 

Tolerance Expression

Plants

Primary Crop Chlorpyrifos parent only Chlorpyrifos parent only

Rotational Crop NA NA

Livestock

Ruminant Chlorpyrifos parent only Chlorpyrifos parent only

Poultry Chlorpyrifos parent only Chlorpyrifos parent only

Drinking Water Chlorpyrifos and Chlorpyrifos 

oxon 

NA
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chlorpyrifos on cotton gin by products and aspirated grain fractions, respectively, and would 

support the current tolerance level for tart cherries under the condition that only dormant/delayed 

dormant and trunk spray applications are allowed on the label of the 75% WDG end use product. 

Acceptable storage stability data (in cherry, alfalfa forage, alfalfa hay and corn grain matrices) is 

available to support the storage conditions and durations of the samples of tart cherries, cotton 

and aspirated grain fractions used in these studies. 

The dietary burden to livestock was recalculated to consider residues at tolerance level in the 

feedstock commodities (aspirated grain fractions and cotton gin byproducts) and to use the most 

current version of Table 1 of the OPPTS Test Guidelines 860.1000, released on June 2008. 

Based on the residues observed in the feeding study of cattle beef, dairy cow, swine and poultry 

at the 1x level or higher, HED concludes that the possible residues observed on livestock 

commodities (from animals fed with feedstock that may contain residues resulting from legal 

applications) are covered by the current tolerances established in the 40 CFR §180.342. 

According to the revised version of Table 1of the OPPTS 860.1000, several studies are required 

to establish a tolerance for feed items and/or processed commodities that correspond to RACs 

treated with chlorpyrifos. Tolerances are required for residues of chlorpyrifos on wheat, milled 

byproducts; wheat, hay; corn, milled byproducts; cotton, meal, hulls and refined oil; and 

soybean, meal, hulls and refined oil. A magnitude of the residue study to establish a tolerance for 

wheat hay was required in the previous RED and has not been received. A tolerance was 

previously established for wheat milling fractions excluding flour as 1.5 ppm. Also, for corn 

milled byproducts a tolerance of 0.1 ppm was previously recommended based on concentration 

factors from 1.25x in grits to 2x in flour (D188151, S. Knizner, 20/Aug/1993). Tolerances for 

residues of chlorpyrifos on wheat milled byproducts and corn milled byproducts should be 

included in the 40 CFR §180.342. For cotton, processing studies are required to establish 

tolerances in cotton meal, cotton hulls and refined oil. Similarly, for soybean, processing studies 

are required to establish tolerances in soybean meal, hulls and refined oil. 

 

[For details of the residue chemistry evaluations see I. Negrón-Encarnación, 5/24/11, D388164, 

Chlorpyrifos. Registration Review Action for Chlorpyrifos. Summary of Analytical Chemistry 

and Residue Data].

5.3 Water Residue Profile

EFED provided a drinking water assessment (DWA) which includes estimated drinking water 

concentrations (EDWCs) based on Tier II surface water and Tier I groundwater model 

simulations for currently registered uses of chlorpyrifos based on the most recent label data 

report provided by BEAD (R. Bohaty, 06/30/11, D368388 and D389480, Revised Preliminary 

Registration Review Chlorpyrifos Drinking Water Assessment). Tier II surface water EDWCs are 

more conservative than the Tier I groundwater EDWCs; therefore, only surface water EDWCs 

are discussed in the section below. This preliminary DWA also considers several sources of

monitoring data including datasets from state as well as national programs. Below is a very brief 

summary of the DWA; see D368388/D389480 for a comprehensive characterization of the 

drinking water assessment.
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EDWCs are provided for chlorpyrifos and chlorpyrifos oxon, a known transformation product of 

chlorpyrifos. EDWCs for chlorpyrifos oxon were derived from EDWCs calculated for 

chlorpyrifos because there are limited environmental fate data available for chlorpyrifos oxon 

and chlorpyrifos is expected to transform to chlorpyrifos oxon during drinking water treatment. 

Chlorpyrifos EDWCs were multiplied by 0.9541 (molecular weight correction factor) and 100% 

(maximum conversion during water purification) to generate chlorpyrifos oxon EDWCs. A 

100% conversion factor for the oxidation of chlorpyrifos to chlorpyrifos oxon was used as an

approximation based on bench scale laboratory data that indicate chlorpyrifos rapidly oxidizes to 

form chlorpyrifos-oxon almost quantitatively during typical water treatment.

8 Currently, there 

are no data available on the removal efficiency of chlorpyrifos prior to oxidation to chlorpyrifos 

oxon, or the removal efficiency of chlorpyrifos oxon. Stability studies indicate that once 

chlorpyrifos oxon forms during treatment little transformation is likely to occur before

consumption (drinking water distribution).

5,9,10 It is possible that some drinking water treatment 

procedures such as granular activated carbon filtration and water softening (increased rate of 

chlorpyrifos-oxon hydrolysis at pH > 9) may reduce the amount of chlorpyrifos oxon in drinking 

water. It is unlikely that these treatment processes significantly reduce the amount of 

chlorpyrifos-oxon in drinking water. In addition, these treatment methods are not typical 

practices across the country for surface water. For these reasons, chlorpyrifos-oxon is the residue 

of concern for drinking water. Additional discussion of the effects of drinking water treatment on 

chlorpyrifos and chlorpyrifos oxon are provided in the EFED Drinking Water Assessment. 

Another degradation product of chlorpyrifos, 3,5,6-trichloro-2-pyridinol (TCP) is not examined 

in this assessment as it is no longer considered to be of toxicological concern.

Tier II modeled (surface water) chlorpyrifos-oxon EDWCs for grapes, corn/soybean and sugar 

beets are provided in Table 12. These water scenarios are based on both the average typical and 

maximum label use rates unless otherwise noted in the drinking water assessment. Grape, 

corn/soybean and sugar beet were singled out for this preliminary drinking water assessment as 

representative crops because there is a large amount (>100,000 lb) of chlorpyrifos applied to 

these crops per year, a substantial portion (percent crop treated/percent crop planted) of these 

crops are treated with chlorpyrifos, and/or the use locations are distributed throughout the United 

States. In addition, the reported EDWCs for grapes, corn/soybean and sugar beets are generally 

representative of the other chlorpyrifos use scenarios modeled when EDWCs are compared. All 

EDWCs for all modeled chlorpyrifos use scenarios are provided in EFED’s DWA. Because 

chlorpyrifos is registered for use on turf (including sod farms, golf courses, road medians, and 

industrial areas) a percent cropped area (PCA) of 1 (considers 100% of the watershed is treated) 

was applied to modeling results a standard procedure in EFED. If chlorpyrifos were not used on 

turf, a PCA value of 0.87 (87% of the watershed is treated) would have been used based on the 

other crops chlorpyrifos is currently registered for use on; therefore, the EDWCs would be 

reduced by 13% if turf were not a registered use. This reduction is not expected to alter the 

conclusions of this risk assessment. 

 

8 Duirk, S. E.; Collette, T. W.; Degradation of Chlorpyrifos in Aqueous Chlorine Solutions: Pathways, Kinetics, and 

Modeling. Environ. Sci. Technol., 2006, 40(2), 546-550.

9 Wu, J.; Laird, D. A. Abiotic Transformation of Chlorpyrifos to Chlorpyrifos Oxon in Chlorinated Water. Environ. 

Toxcol.Chem., 2003, 22(2), 261-264.

10 Tierney, D. P.; Christensen, B. R.; Culpepper, V. C. Chlorine Degradation of Six Organophosphate Insecticides 

and Four Oxons in Drinking Water Matrix. Submitted by Syngenta Crop Protection, Inc. 2001.
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Table 12 Estimated Drinking Water Concentrations of Chlorpyrifos-oxon Resulting From 

Chlorpyrifos Use on Grapes, Corn/Soybean and Sugar beets

Crop Scenario Chlorpyrifos Oxon (ppb)

Average Typical Rate

Chlorpyrifos Oxon (ppb)

Maximum Rate

1-in-10 

Year Peak

1-in-10 

Year 

Annual 

Average

30 Year 

Annual 

Average

1-in-10 Year 

Peak

1-in-10 Year 

Annual 

Average

30 Year 

Annual 

Average

Grapes L.R. 2.76 0.41 0.25 107.05 14.06 9.38

Corn/soybean (a) 4.19 0.78 0.48 29.49 4.39 2.98

Sugar Beets 14.36 4.3 1.85 10.06 1.07 0.65

LR= lower rate of two grape application scenarios.

(a) Soybean was only evaluated at the maximum label rate for drinking water.

BEAD provided typical use information to EFED to help refine its assessment. In general, 

preliminary analysis suggest that typical single application rates correlate well with the modeled 

single application rates; however, in general the number of applications typically applied each 

year is less than the maximum allowed on the label. The results of this analysis can also be found 

in EFED’s DWA but are not currently consider in this assessment. Typical agronomic practices 

also vary from those modeled. In general, the farming methods used over the last five years 

result in EDWCs that are lower than the most vulnerable scenarios allowed on current labels. 

Submission of typical use rates and agronomic practices will assist EFED in further refine its 

final DWA for chlorpyrifos.

There are two modeled chlorpyrifos use scenarios that result in EDWCs that are substantially 

higher than the majority of the modeled chlorpyrifos use scenarios. These use scenarios are for 

grape (high rate; 33 lb ai/A) and turf. The EDWCs reported for Grape HR (high rate; 33 lbs 

a.i./acre) are the result of a high application rate trunk drench/soil application which is currently 

permitted on labels and may not represent actual or intended use of chlorpyrifos on grape. Some 

recently approved labels restrict the use of chlorpyrifos on grape to 6 lbs a.i./a. The EDWCs 

reported for Turf FA (frequent applications) is based on 26 applications (limit of PRZMEXAMS) and a 3 day application interval. This scenario was developed to highlight the 

uncertainty associated with the unrestricted use of chlorpyrifos on turf (turf labels do not 

currently restrict the number of chlorpyrifos applications per year or the maximum number of 

applications of chlorpyrifos per year) and may not may not represent actual or intended use of 

chlorpyrifos on turf. Because of the uncertainties with these labels, these modeled EDWCs were 

not used in the preliminary dietary (water) risk assessment for chlorpyrifos. 

Water monitoring data from the USGS National Water-Quality Assessment Program (NAWQA), 

USEPA/USGS Pilot Reservoir Monitoring Program, USDA Pesticide Data Program (PDP), 

California Department of Pesticide Regulation (CDPR), and National Center for Water Quality 

Research (NCWQR) at Heidelberg College were evaluated in reference to an acute exposure to 

chlorpyrifos and its degradation product chlorpyrifos oxon. The monitoring data show 

chlorpyrifos detections at low concentrations, generally not exceeding 0.5 μg/L. For example, 

USGS NAWQA, which contains an extensive monitoring dataset for chlorpyrifos and 

chlorpyrifos oxon, reports a peak chlorpyrifos detection of 0.57 μg/L in surface water with a 

detection frequency of approximately 15%. CDPR and NCWQR have detected chlorpyrifos 
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concentrations greater than 1 ppb in surface water on several occasions. Peak concentrations of 

chlorpyrifos observed for CDPA and NCWQR are 3.96 and 24 ug/L, respectively. Note the data 

from NCWQR have not been thoroughly reviewed at this time, but are supplemental. In 

addition, the NCWQR data are pre-RED and subsequent mitigation. Therefore, it is unclear if 

NCWQR monitoring data represent current chlorpyrifos uses. EFED is in the process of 

acquiring more recent data from NCWQR and conducting a more thorough review of the 

NCWQR data.

In general, the monitoring data include sampling sites that represent a wide range of aquatic 

environments including small and large water bodies, rivers reservoirs, and urban and 

agricultural locations. The sampling sites also vary by year and there are limited sampling data 

available for some areas in the United States where chlorpyrifos is used. None of the monitoring 

programs were specifically designed to target chlorpyrifos use; therefore, peak concentrations of 

chlorpyrifos and chlorpyrifos oxon likely went undetected in these programs. Sampling 

frequencies in high chlorpyrifos use areas are not be designed to capture peak concentrations. 

The sample frequencies vary from bimonthly to only once per year depending on the program 

and the sampling site with the exceptions of NCWQR. NCWQR sample frequencies range from 

daily to monthly. For atrazine (90 day exposure concern) CWS monitoring sampling frequency 

of 7 days was chosen to be appropriate; however, a recent SAP agreed that a duration of 

exposure concern that is less than 7 days, such is the case for chlorpyrifos or chlorpyrifos oxon,

would likely require even more frequent sampling to capture peaks. This is supported by the 

NCWQR data as well as PRZM-EXAMS model output time series data and underscores the need 

for frequent sampling in order to detect peak chlorpyrifos concentrations.

In summary, the monitoring programs analyzed in EFED’s DWA do not specifically target 

chlorpyrifos; consequently, detections cannot be directly associated with a particular use pattern 

or site nor are the detections expected to represent the potential peak exposure to chlorpyrifos or 

chlorpyrifos oxon. Additional discussion of the monitoring data can be found in the DWA and is 

not further discussed in this assessment as it is not considered an appropriate estimation of the 

potential exposure to chlorpyrifos and chlorpyrifos oxon. The monitoring data were only 

analyzed in reference to an acute exposure estimation and additional analysis is needed in order 

to determine if the data contained in the various datasets can be used for longer term exposure 

durations (i.e., chronic). 

DWA Uncertainties

EFED has noted several uncertainties associated with the use of chlorpyrifos. The uncertainties 

and assumptions are highlighted below.

While the predominate water treatment method used to disinfect drinking water 

throughout the United States is chlorination, there are other treatment methods that may 

reduce chlorpyrifos or chlorpyrifos-oxon exposure concentrations. For facilities that 

utilize alternative methods, the laboratory data showing 100% conversion of chlorpyrifos 

to chlorpyrifos-oxon during water purification may not be applicable. Therefore, the 

chlorpyrifos oxon exposure values presented here may be overestimated for those 

facilities. Additionally, the oxon may be partially removed with certain treatment 

processes. In order to reduce the uncertainty associated with the EDWCs reported in this 
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DWA, additional data including both targeted monitoring data as well as data on the 

removal efficiency of chlorpyrifos and chlorpyrifos-oxon during treatment is needed. 

This assessment does not take into account the potential loss of mass (either chlorpyrifos 

or chlorpyrifos-oxon) during treatment from methods such as activated carbon, 

sedimentation, water softening, etc., as these treatment methods as well as the sequence 

of these treatment methods vary considerably across the country. Therefore, for systems 

that do utilize such treatment methods, the EDWCs reported in this assessment may be 

higher than the likely exposure concentrations in drinking water. The amount of 

overestimation is unknown, as currently there are no data available on the removal 

efficiency of either chlorpyrifos or chlorpyrifos-oxon by these various treatment methods 

and sequences of treatments. The exception is for water softening where laboratory data 

can be used to calculate the rate of hydrolysis under water softening conditions (pH ≥ 11) 

for both chlorpyrifos and chlorpyrifos-oxon. Water softening, however, is not a common 

treatment process for surface water. 

Chlorpyrifos is registered for use on turf (including sod farms, golf courses, road 

medians, and industrial areas), therefore, a percent cropped area (PCA) of 1 (100% of the 

watershed is treated) was applied to the modeling results in order to cover the use on nonagricultural land. If chlorpyrifos was not registered on turf, the default PCA value of 0.87 

(87% of the watershed is treated) would have been used. EFED is currently working on 

developing crop specific PCAs. For the final DWA, a turf specific PCA may be available 

to help further refine this assessment. This assessment is national in scope covering 

multiple chlorpyrifos uses; therefore, it does not take into account regional PCA values 

(e.g., 0.87 for Missouri, 0.82 for Ohio, 0.07 for Upper Colorado, etc.) or PCA values that 

represent only a single or a few crops (e.g., 0.46 for corn, 0.83 for corn and soybean, 

etc.). 

The monitoring programs analyzed for this drinking water assessment do not specifically 

target chlorpyrifos. Consequently, detections cannot be directly associated with a 

particular use pattern or site, nor are the detections expected to represent the potential 

peak chlorpyrifos or chlorpyrifos-oxon exposures. In order to reduce uncertainties and 

help refine the current exposure assessment, EFED is seeking to incorporate targeted 

monitoring data in its drinking water assessment. 

Meteorological data and crop profiles, as well as best professional judgment, were used 

to establish an application date for modeling; however, the selected date may not 

represent the intended or actual application dates. The application date used for model 

runs can significantly alter the EDWCs; thus, EDWCs reported could over or under 

predict the potential exposure. For some chlorpyrifos use scenarios several application 

dates were evaluated. In general, the date that provided the most conservative EDWCs 

and corresponded to the appropriate pest pressure are reported. A brief examination of the 

variation in peak EDWCs for some of the multi-run scenarios ranged from 3-23% for 

peak EDWCs. Scenarios examined included those that resulted in high and low EDWCs. 

Based on this limited examination, the application date chosen for modeling can change 

the peak EDWCs by as much as 23%. This is only an estimate and may vary depending 
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on the scenario (soil and metrological data) and may not represent all chlorpyrifos use 

scenarios. 

Many chlorpyrifos labels include application restrictions on a per season basis; however, 

for some crops there can be multiple seasons per year. For modeling purposes one season 

was considered to be equal to one year unless otherwise noted. If multiple crop seasons 

are possible per year it is conceivable that the EDWCs reported in this document may 

underestimate the actual exposure. In general, this assessment makes conservative 

assumptions regarding re-cropping and rotations. EFED evaluated a number of labels for 

specific information regarding application methods and timing, and noted some 

application rates provided on the label are on a per season basis. The yearly application 

rates used in this assessment are primarily based on data from BEAD’s label data report. 

The typical use data provided by BEAD to date do not inform this uncertainty as the 

typical use rate information was not provided for crops that may have multiple seasons 

per year. 

Some of the labels do not provide maximum single or annual application rates for 

chlorpyrifos or application retreatment intervals. When this information is not specified 

on the label, a conservative application scenario was developed and modeled. For 

example, several labels permit trunk sprays (e.g., some orchard fruit and nut trees such as 

apples and almonds), at a dilution rate in lbs a.i./100 gallons of water; however, the 

amount of the dilution that can be applied is not stated on the label. The application rate 

was assumed to be lb a.i./a. It is unclear if this approach is representative of the intended 

or actual use scenarios. However, we did find that the average typical application rate 

provided by BEAD for apples was consistent with the assumed application rate for apples 

(trunk drench) made for modeling purposes. The extent to which actual use rates may be 

different is uncertain. 

Some labels restrict the amount of a specific chlorpyrifos formulation; however, the total 

amount of chlorpyrifos that can be applied per year is not provided. Therefore, the use of 

multiple chlorpyrifos-containing products is possible. This assessment does not consider 

the combined use of multiple chlorpyrifos containing products that contain such 

language, but if such use occurs the reported EDWCs in this assessment may not account 

for this event. 

Application rates (maximum single applications and yearly/seasonal) vary between 

labels. Recently approved labels better define chlorpyrifos use; however, there are still 

several older active labels that do not provide application restrictions or have higher 

maximum single and/or yearly applications rates than recently approved labels. The most 

conservative scenarios (highest applications rates) were modeled unless otherwise noted. 

In order to reduce the uncertainty associated with the EDWCs reported in this 

preliminary DWA, all chlorpyrifos labels should be updated to clearly state maximum 

yearly and single application rates, as well as minimum retreatment intervals. 
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The monitoring programs analyzed in EFED’s DWA do not specifically target 

chlorpyrifos; consequently, detections cannot be directly associated with a particular use 

pattern or site nor are the detections expected to represent the potential peak exposure to 

chlorpyrifos or chlorpyrifos oxon. In order to reduce the uncertainty associated with the 

interpretation of monitoring data EFED is seeking to incorporate targeted monitoring data 

in its DWA. Submission of such data would help refine the final risk assessment.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Highly refined acute and chronic dietary (food only, food and drinking water, and drinking water 

only) exposure and risk assessments of chlorpyrifos were conducted using the Dietary Exposure 

Evaluation Model DEEM-FCIDTM, Version 2.03. Risk estimates were determined for the general 

U.S. population and various population subgroups: all infants (<1 year old), children 1-2, 

children 3-5, children 6-12, youth 13-19, females 13-49, adults 20-49, and adults 50+ years.

Food residue data for the dietary assessment are almost entirely based upon PDP data. For crops 

not tested by PDP translations have been made from similar tested crops. Occasionally, older 

PDP data have been used where it represented the best estimate of real residues. Field trial data 

or tolerances have been used for a very few crops where translations from PDP data were not 

possible. The same data sources were used for both the acute and chronic assessments. Most 

input residues for the acute assessments were incorporated as residue distributions. Input 

residues for the chronic assessments were applied as a single point estimate (for detailed 

assumptions, inputs and results see D. Soderberg, 6/30/11, D388166, Chlorpyrifos Revised Acute 

(Probabilistic) and Chronic Dietary Exposure and Risk Assessments for Food Only (with and 

without Food Handling Use included) and for Water Only for the Registration Review Action: 

Typical Use Rates/Water Included.

Processing factors from cooking and processing studies were employed where available. 

From PDP (and BEAD) data it appears that chlorpyrifos is either applied to a variety of crops 

which lack the necessary tolerances for chlorpyrifos, or possibly that residues may have occurred

on several crops that are rotated in after use of chlorpyrifos on a registered crop. Residues in 

catfish (no tolerance) were also reported by PDP. Data on agricultural commodities without 

tolerances are not ordinarily included in HED assessments and were not included in this 

assessment. Omission of residues on these commodities may lead to underestimation of exposure 

in the current assessment. 

Environmental Fate and Effects Division (EFED) has provided chlorpyrifos and chlorpyrifosoxon estimated drinking water concentrations (EDWCs) for chlorpyrifos use on grapes, 

corn/soybean and sugar beets in order to provide a range of possible EDWCs representing the 

many registered chlorpyrifos uses. In general, these grape, corn/soybean and sugar beet uses 

represent a broad range of higher end, middle, and lower end EDWCs, respectively, modeled for 

all chlorpyrifos uses. These particular uses were selected as representative crops for this 
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preliminary drinking water assessment because there is a large amount of chlorpyrifos applied to 

these crops per year, a large portion of these crops are treated with chlorpyrifos, and/or the use 

locations are distributed throughout the United States. All estimated drinking water 

concentrations used in this assessment are based upon the PRZM-EXAMS model (Table 12

above). For the chronic assessment the 1-in-10 year annual means from PRZM-EXAMS were 

used. For acute, a distribution of the modeled EDWCs was incorporated into the assessment. 

The residues of concern for chlorpyrifos in food are for the parent chlorpyrifos only. Residues of 

concern in drinking water may include both parent and oxon. All drinking water residues were 

assumed to be in the form of the oxon as scientific literature suggests rapid and complete 

conversion of chlorpyrifos to chlorpyrifos-oxon during drinking water disinfection and also show 

that the oxon is relatively stable after drinking water disinfection. For the preliminary dietary 

assessment, residues in food are assumed to consist of parent chlorpyrifos only, while residues in 

water are assumed to consist of chlorpyrifos-oxon only. Therefore food exposures are assessed 

to toxicological points of departure (PoDs) based upon the toxicity of the parent and water 

exposures are assessed to PoDs based upon the toxicity of the oxon. 

5.4.2 Percent Crop Treated Used in Dietary Assessment

BEAD provided percent crop treated information for over 50 crops [Chlorpyrifos (059101)

Screening Level Usage Analysis (SLUA), dated 3/10/2010, and Addendum; see Attachment 3 of 

D388166]. Where supplied, maximum percent crop treated estimates were used in the acute 

dietary risk assessment and average percent crop treated estimates were used in the chronic 

dietary risk assessment. 100% crop treated values were assumed for the following: bananas, figs, 

radishes, rutabaga roots, turnip roots and greens, garlic, shallots, Brussels sprouts, kohlrabi, 

collards, kale, mustard and rapeseed greens, citron, citrus hybrids, limes, pommelos, and triticale.

BEAD also estimated that less than 2% (default value) of food handling establishments are treated 

with chlorpyrifos.

5.4.3 Acute Dietary Risk Assessment

The most highly exposed population subgroup for food only was children 1-2, at 9.0% aPAD. 

The exposure for the general U.S. population from food was 5.1%. Residues in peaches, 

peppers, apples, plums grapefruit juice, grape juice, soy milk, cranberry juice and orange juice 

were generally drivers of acute food exposure. (Residues on fresh peaches, plums and peppers in 

particular strongly tend to be on the imported crops rather than on domestically grown crops.) 

For water alone using the lower end representative water scenario (sugar beet) the acute exposure 

for the general U. S. population ranged from 61-99% of the aPAD based upon the chlorpyrifosoxon PoD for the maximum and typical application rates, respectively. For all infants, the most 

highly exposed subpopulation, the exposure ranged from 210-340% of the aPAD for the 

maximum and typical application rates, respectively. 

For water alone using the mid-range representative scenario (corn) the acute exposure for the 

general U. S. population ranged from 38-240% of the aPAD based upon the chlorpyrifos-oxon

PoD for the typical and maximum application rates, respectively. For all infants, the most highly 
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exposed subpopulation, the exposure ranged from 120-770% aPAD for the typical and maximum 

application rates, respectively. 

For water alone using the higher end representative scenario (grape) the acute exposure for the 

general U.S. population ranged from 19-810% of the aPAD based upon the chlorpyrifos oxon for 

the typical and maximum application rates, respectively. For all infants, the most highly exposed 

subpopulation, the exposure ranged from 59-2700% aPAD for the typical and maximum 

application rates, respectively. 

Table 13 Summary of Preliminary Acute Dietary Food Only Exposure and Risk (Using Parent 

Chlorpyrifos PoD)

Population Subgroup

Acute Food Only(99.9th percentile)

[Chlorpyrifos aPAD= 0.0036 (includes 1x FQPA Factor)]

Dietary Exposure (mg/kg/day) % aPAD

General U.S. Population 0.000182 5.1

All Infants (< 1 year old) 0.000190 5.3

Children 1-2 years old 0.000323 9.0

Children 3-5 years old 0.000275 7.6

Children 6-12 years old 0.000196 5.4

Youth 13-19 years old 0.000122 3.4

Adults 20-49 years old 0.000161 4.5

Adults 50+ years old 0.000170 4.7

Females 13-49 years old 0.000150 4.2
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Table 14 Summary of Preliminary Acute Drinking Water Only Exposure and Risk (at the 99.9th

Percentile Exposure; Using the Chlorpyrifos-oxon PoD)

Population 

Subgroup

Lower End 

Representative Water 

Scenario (a)

(Sugar Beet)

Mid-Range Representative 

Water Scenario (a)

(Corn)

Higher End 

Representative Water 

Scenario (a)

(Grape)

Exposure (μg/kg/day)

(% aPAD)

Exposure (μg/kg/day)

(% aPAD)

Exposure (μg/kg/day)

(% aPAD)

Average

Typical Rate

Maximum 

Rate

Average

Typical Rate

Maximum 

Rate

Average 

Typical

Rate

Maximum 

Rate

General U.S. 

Population

0.496

(99%)

0.304

(61%)

0.192

(38%)

1.192

(240%)

0.095

(19%)

4.090

(810%)

All Infants (< 1 

year old)

1.677

(340%)

1.029

(210%)

0.608

(120%)

3.840

(770%)

0.294

(59%)

13.415

(2700%)

Children 1-2 

years old

0.724

(140%)

0.445

(89%)

0.271

(54%)

1.689

(340%)

0.132

(26%)

5.856

(1200%)

Children 3-5 

years old

0.654

(130%)

0.404

(81%)

0.242

(48%)

1.526

(310%)

0.118

(24%)

5.259

(1100%)

Children 6-12 

years old

0.452

(90%)

0.281

(56%)

0.169

(34%)

1.055

(210%)

0.082

(16%)

3.683

(740%)

Youth 13-19 

years old

0.384

(77%)

0.238

(48%)

0.147 

(29%)

0.912

(180%)

0.072

(14%)

3.151

(630%)

Adults 20-49 

years old

0.442

(88%)

0.270

(54%)

0.164 

(33%)

1.026

(210%)

0.081

(16%)

3.538

(710%)

Adults 50+ years 

old

0.398

(80%)

0.248

(50%)

0.138

(28%)

0.882

(180%)

0.069

(14%)

3.059

(610%)

Females 13-49 

years old 

0.440 

(88%)

0.269

(54%)

0.162

(32%)

1.020

(200%)

0.081

(16%)

3.533

(710%)

Chlorpyrifos-oxon aPAD (includes 1x FQPA Factor) = 0.0005 mg/kg/day or 0.5 μg/kg/day

(a) Lower-end, Mid-range and Higher-end representative scenarios determined based on maximum application 

rate.

5.4.4 Chronic Dietary Risk Assessment

The chronic dietary exposure assessment was performed with and without food handling 

establishment (FHE) uses. FHE exposures are more appropriately performed as a chronic dietary 
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assessment. An acute assessment is more likely to overestimate the risk for FHE exposures since 

there are no detectable residues in the FHE studies and the percent establishments treated were 

below the threshold where BEAD is able to accurately quantify. 

The most highly exposed population subgroup for chronic food only (excluding FHE uses) were 

children 1-2, at 8.4 % cPAD, using a PoD based upon the toxicity of chlorpyrifos. The exposure 

for the general U.S. population from food without FHE use was 3.0 %cPAD. For food with FHE

use included the exposure for the general U. S. population was 3.7% cPAD, and for the most 

highly exposed subpopulation, children 1-2, was 11% cPAD. 

For water alone exposure to chlorpyrifos oxon, the risks span a large range, depending on the 

representative crop assessed (sugar beets, corn, grapes) and application rate. Using the lower 

end representative scenario (sugar beet) risk estimates did not exceed the level of concern based 

on the maximum application rates, however there were some risks of concern for average typical 

rates assessed for infants and children. The resulting risk estimates for the general U. S. 

population ranged from 21-82% cPAD using a PoD based upon the toxicity of chlorpyrifos-oxon

for the maximum and typical rates, respectively. For the most highly exposed subpopulation, all 

infants, exposure ranged from 69-270 % cPAD depending on the application rate assessed. 

Drinking water risk estimates for the mid-range and high end representative scenarios (corn and 

grapes) were not of risk concern at the typical application rates (<49% cPAD) for the highest 

exposed population, infants (<1 yr), but exceeded the level of concern at the maximum 

application rates (ranged from 280-890% cPAD) for infants (<1 yr). 

The results of the chronic dietary exposure analysis are reported in column 1 of Table 15 below. 

As can be seen, residues do not exceed the cPAD for any population subgroup. These food 

exposures are based only upon field use of chlorpyrifos and do not incorporate exposure from 

food handling establishment (FHE) uses. Estimated potential exposures from FHE uses were 

assessed separately from other food exposure as a matter of convenience and are provided in 

column 2 of Table 15, but are additive to the other food exposures. Therefore, column 3 of 

Table 15 shows the total chronic food plus FHE exposure. It should be noted that there is 

considerable uncertainty in the exposure estimates for FHE. There appear to be three currently 

registered FHE uses (labels), but BEAD has been unable to estimate a percent FHE treated and 

has defaulted to its minimum of 2%. In addition, the expected FHE residues are based upon an 

FHE residue study with no detectable residues (1/2 LOD is used for FHE anticipated residues). 
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Table 15 Summary of Preliminary Chronic Dietary Food Only Exposure and Risk (Using Parent 

Chlorpyrifos PoD) 

Population Subgroup

Chronic Food Only

[Chlorpyrifos cPAD= 

0.0003

(includes 1x FQPA 

Factor)]

Chronic Food 

Handling 

Establishment (FHE) 

Only

[Chlorpyrifos cPAD= 

0.0003

(includes 1x FQPA 

Factor)]

Chronic Food with 

FHE Only

[Chlorpyrifos cPAD= 

0.0003

(includes 1x FQPA 

Factor)]

Dietary 

Exposure 

(mg/kg/day)

% 

cPAD

Dietary 

Exposure

(mg/kg/day)

% 

cPAD

Dietary 

Exposure

(mg/kg/day)

% 

cPAD

General U.S. 

Population 0.000009 3.0 0.000002 0.7 0.000011 3.7

All Infants (< 1 year 

old) 0.000012 4.0 0.000004 1.3 0.000016 5.3

Children 1-2 years old 0.000025 8.4 0.000009 3.0 0.000034 11

Children 3-5 years old 0.000021 7.1 0.000006 2.1 0.000027 9.2

Children 6-12 years old 0.000013 4.3 0.000004 1.3 0.000017 5.6

Youth 13-19 years old 0.000007 2.5 0.000002 0.6 0.000009 3.1

Adults 20-49 years old 0.000007 2.3 0.000001 0.5 0.000008 2.8

Adults 50+ years old 0.000007 2.4 0.000001 0.5 0.000008 2.9

Females 13-49 years 

old 0.000007 2.2 0.000001 0.5 0.000008 2.7
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Table 16 Summary of Preliminary Chronic Drinking Water Only Exposure and Risk (Using the 

Chlorpyrifos-oxon PoD)

Population 

Subgroup

Lower End 

Representative Water 

Scenario (a)

(Sugar Beet)

Mid-Range 

Representative Water 

Scenario (a)

(Corn)

Higher End Representative 

Water Scenario (a)

(Grape)

Exposure (μg/kg/day)

(% cPAD)

Exposure (μg/kg/day)

(% cPAD)

Exposure (μg/kg/day)

(% cPAD)

Average 

Typical 

Rate

Maximum 

Rate

Average 

Typical Rate 

Maximum 

Rate

Average 

Typical Rate 

Maximum 

Rate

General U.S. 

Population

0.091

(82%)

0.023

(21%)

0.016 

(15%)

0.093

(84%)

0.009

(7.9%)

0.297

(270%)

All Infants (< 1 

year old)

0.297 

(270%)

0.076

(69%)

0.054

(49%)

0.304

(280%)

0.028

(26%)

0.974

(890%)

Children 1-2 

years old

0.135

(120%)

0.034

(31%)

0.024 

(22%)

0.138

(130%)

0.013

(12%)

0.441

(400%)

Children 3-5 

years old

0.126

(110%)

0.032

(29%)

0.023 

(21%)

0.129

(120%)

0.012

(11%)

0.513

(380%)

Children 6-12 

years old

0.087

(79%)

0.022

(20%)

0.016

(14%)

0.089

(80%)

0.008

(7.5%)

0.285

(260%)

Youth 13-19 

years old

0.066

(60%)

0.017

(15%)

0.012

(11%)

0.067

(61%)

0.006 

(5.7%)

0.215

(200%)

Adults 20-49 

years old

0.085

(77%)

0.022

(20%)

0.015

(14%)

0.087

(79%)

0.008

(7.3%)

0.277

(250%)

Adults 50+ 

years old

0.089

(81%)

0.023

(21%)

0.016 

(15%)

0.091

(83%)

0.008

(7.7%)

0.292

(270%)

Females 13-49 

years old 

0.084

(77%)

0.022

(20%)

0.015

(14%)

0.086

(78%)

0.008

(7.3%)

0.276

(250%)

Chlorpyrifos-oxon cPAD (includes 1x FQPA Factor) = 0.00011mg/kg/day or 0.11 μg/kg/day

(a) Lower-end, Mid-range and Higher-end representative scenarios determined based on maximum application 

rates.
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5.4.5 Comparison of Dietary Results for Chlorpyrifos 2000 Risk Assessment and 2011 

Preliminary Risk Assessment

For comparison purposes, Table 17 and Table 18 below present the acute and chronic PoDs and 

resulting dietary risk estimates (for the most highly exposed subpopulations only: young children 

and/or infants) for the June 2000 chlorpyrifos risk assessment and for the current 2011 

preliminary assessment.

The acute and chronic PoDs and resulting dietary risk estimates (for the most highly exposed 

subpopulations only: young children and/or infants) are compared for the June 2000 chlorpyrifos 

risk assessment and for the current 2011 preliminary assessment.

In 2000 the acute and chronic dietary PoDs were based on NOAELs (plasma and/or RBC ChEI) 

from oral studies using adult laboratory animals (including pregnant females). The same PoD, 

based on toxicity of parent chlorpyrifos, was selected for both food and water. A 10x FQPA 

factor was retained. 

For the 2011 preliminary assessment, the acute and chronic PoDs for food exposures were based 

on the toxicity of parent chlorpyrifos (BMDs for RBC ChEI) to juvenile and pregnant animals, 

respectively. The acute and chronic PoDs for water exposures were based on the toxicity of the 

chlorpyrifos oxon (BMDs for RBC ChEI) from studies where juvenile and adult animals were 

directly dosed with the oxon. A 1x FQPA factor is proposed. 

The acute dietary (food only) risk estimates for the most highly exposed subpopulation were 

82% of the aPAD (2000) and 9% of the aPAD (2011). 

In 2000 the acute EDWC was not included in the dietary analysis (water residues not 

incorporated directly into DEEM analysis) and a % aPAD result was not calculated. Instead a 

Drinking Water Level of Concern (DWLOC) method was used. An estimated ≤18% aPAD value 

for 2000 water was estimated herein for comparison purposes only and reflects the exposure 

amount allowed for water in the ‘risk cup’ after food exposures are subtracted. In the 2011 

preliminary water assessment, a range of representative scenarios was assessed (higher end, midrange, and lower end). The resulting acute drinking water risk estimates (for infants) ranged from 

59% to 340% aPAD for average typical application rates and from 210% to 2700% aPAD for the 

maximum application rates.

The chronic dietary (food only) risk estimates for the most highly exposed subpopulation were 

51% of the cPAD (2000) and 11% of the cPAD (2011). 

As in the 2000 acute water assessment, the 2000 chronic water assessment used a DWLOC 

approach. A ≤ 49% cPAD value was estimated for 2000 water. In the 2011 preliminary water 

assessment, a range of representative scenarios was assessed (higher end, mid-range, and lower 

end). The resulting chronic drinking water risk estimates (for infants) ranged from 26% to 270% 

cPAD for average typical application rates and from 69% to 890% cPAD for the maximum 

application rates.
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It is important to note that, aside from differences in the PoDs and FQPA factors, there have 

been changes in the dietary input assumptions since 2000. For example, updated food monitoring 

data and percent crop treated data were used in the 2011 preliminary assessment. For water, in 

2000 EDWCs were based on parent chlorpyrifos and were derived from the SCI-GROW model 

for groundwater and monitoring data for surface water. It is now believed that the existing water 

monitoring data are not representative of the potential exposure in drinking water and is not 

recommended for use in quantitative risk assessment. Groundwater EDWCs are expected to be 

low relative to surface water based on environmental fate characteristics of chlorpyrifos. 

Therefore, the SCI-GROW modeling results used in 2000 likely underestimate the potential 

exposure. The 2011 preliminary risk assessment has used a range of surface water EDWCs 

derived using PRZM-EXAMS modeling. In 2000 the residue of concern in drinking water was 

assumed to be parent chlorpyrifos. Empirical data indicate rapid conversion of chlorpyrifos to 

chlorpyrifos oxon during typical drinking water treatment; therefore, this preliminary assessment 

considers the oxon as the residue of concern in treated drinking water and assumes 100% 

conversion of chlorpyrifos to oxon. The chlorpyrifos oxon is more toxic than parent 

chlorpyrifos.

Table 17 Comparison of Chlorpyrifos Acute PoDs and Risk Estimates for 2000 Assessment and 

2011 Preliminary Assessment

Acute Dietary Risks

For highest exposed subpopulation

In 2000

Food and Water PoD 

(CPY): 0.5 mg/kg/day; 

total UF=1000 

(FQPA=10x)

In 2011

Food PoD (CPY): 0.36 mg/kg/day; total UF 

100 (FQPA=1x)

Water PoD (Oxon): 0.05 mg/kg/day; UF 100 

(FQPA=1)

% aPAD

% aPAD

Average Typical 

Application Rate

Maximum Application 

Rate

Food 82 9.0 (a)

Drinking Water

Lower 340 210

Mid-range 120 770

Higher Estimated ≤18* 59 2700

Aggregate DWLOC method; not of 

concern 

Not assessed in preliminary assessment

* not calculated in 2000 (DWLOC method used); this estimated value represents the difference between 

the aPAD and food exposures, i.e. what was left in the risk cup for water after taking into account food 

exposures. 

(a) Food estimates are highly refined and thus the average typical and maximum application rate 

scenarios are not applicable.
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Table 18 Comparison of Chlorpyrifos Chronic PoDs and Risk Estimates for 2000 Assessment and 

2011 Preliminary Assessment

Chronic Dietary Risks (includes FHE uses)

For highest exposed subpopulation

In 2000

Food and Water PoD (CPY): 0.03 

mg/kg/day; total UF=1000

(FQPA=10x)

In 2011

Food PoD (CPY): 0.03 mg/kg/day; 

total UF 100 (FQPA=1x)

Water PoD (Oxon): 0.011 mg/kg; 

UF 100 (FQPA=1x)

% cPAD

% cPAD

Average Typical 

Application Rate

Maximum 

Application Rate

Food 51 11 (a)

Drinking Water

Lower 270 69

Mid-range 49 280

Higher Estimated ≤49%* 26 890

Aggregate DWLOC method; not of concern Not assessed in preliminary 

assessment 

* not calculated in 2000 (DWLOC method used); this estimated value represents the difference between 

the cPAD and food exposures, i.e. what was left in the risk cup for water after taking into account food 

exposures. 

(a) Food estimates are highly refined and thus the average typical and maximum application rate 

scenarios are not applicable.
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6.0 Residential (Non-Occupational) Exposure/Risk Characterization

6.1 Residential Handler Exposure

Based upon review of all chlorpyrifos registered uses, only the roach bait products can be applied 

by a homeowner in a residential setting; however, exposure/risk from application of the roach 

bait products was not quantitatively assessed because HED expects handler exposure to be 

negligible. The roach bait product is designed such that the active ingredient is contained within 

the bait station, therefore, limiting contact with the active ingredient in the product. 

6.2 Residential Post-Application Exposure

Chlorpyrifos can be used in areas frequented by the general population including ant mounds on 

residential properties, golf courses and as an aerial and ground-based (thermal aerosol and fog 

machine) ULV mosquitocide applied by a public agency made in the vicinity of residential areas. 

As a result, individuals can be exposed by entering these areas if they have been previously 

treated. Short-term dermal (adults and children) and incidental oral (children only) exposures to 

turf following aerial and ground based ULV mosquito treatments have been assessed. Short- and 

intermediate-term dermal exposure/risk to adults resulting from playing golf has also been 

assessed. The assumptions and factors used in these risk calculations are consistent with current 

HED policy for completing residential exposure assessments (i.e., Draft SOPs for Residential 

Exposure Assessment). In addition to these factors, HED has used turf transferable residue (TTR) 

data from a chemical-specific turf study (MRID 44829601). Post-application exposure from 

residential ant mound treatment (applied by professional only) was not quantitatively assessed 

because contact with the mound is not anticipated. 

A quantitative residential post-application acute inhalation exposure (spray drift) assessment was 

also conducted for ground and aerial ULV mosquitocide application. The assessment of 

residential post-application inhalation was conducted under the assumption that people may be

present in the residential setting during the actual ULV application (ground and aerial). This

inhalation scenario is anticipated to be an acute event. In contrast, dermal and incidental oral 

exposures from ULV applications (due to the subsequent settling of airborne residues on turf) are 

anticipated to be short-term in duration because the potential for exposure extends beyond the 

application event. For these reasons, residential acute inhalation estimates from ULV application 

have been presented (Table 21and Table 22) but not aggregated with the other routes of exposure 

assessed. While the assessment of post-application inhalation from the mosquitocide use has 

been included under the residential post-application section, it may be more accurately 

characterized as a spray drift exposure.

Chemical-specific data for mosquito uses are not available. Therefore the equations and 

assumptions for these scenarios were taken from the Draft SOPs for Residential Exposure 

Assessment. In addition to the use of the Residential SOPs, the unique nature of the mosquito 

control uses requires additional information to determine the deposition rate of chlorpyrifos (i.e., 

the amount deposited on residential turf). Deposition rates for ground-based foggers were 

derived from non-chemical specific studies (Moore et al, 1993; Tietze et al, 1994). In order to 

calculate deposition and breathing level air concentration from aerial ULV applications, HED 
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used AgDRIFT (V 2.01) which is the model that was developed as a result of the efforts of the 

Spray Drift Task Force (SDTF). Inhalation exposure from ground based ULV treatment was 

assessed by assuming that the entire active ingredient applied to a 1 acre area is airborne and 

available to be inhaled by a child or adult. 

Risks were calculated using the Margin of Exposure (MOE) approach, which is a ratio of the 

body burden to the toxicological endpoint of concern. Exposures were calculated by considering 

the potential sources of exposure then calculating dermal, inhalation and non-dietary ingestion 

exposures. Short-term dermal (adults and children) and incidental oral (children only) exposures 

to turf following aerial and ground-based ULV mosquito treatments and adults golfing on treated 

turf were calculated. In addition, acute inhalation exposures to adults and children were 

estimated from aerial and ground ULV mosquitocide applications. Detailed assumptions and 

equations used to estimate exposure and risks can be found in W. Britton, 6/27/11, D388165, 

Chlorpyrifos: Occupational and Residential Exposure Assessment.

Estimated short-term adult and child dermal and child incidental oral exposure to turf following 

aerial and ground mosquito treatments do not exceed the level of concern (i.e. MOEs are ≥ 100). 

Combined child exposure estimates (dermal and incidental oral) to turf following aerial mosquito 

treatment result in risk estimates of concern; however, combined risk estimates following ground 

treatment are not of concern. Acute adult and child inhalation (spray drift) exposure following 

aerial mosquito treatment results in risk estimates that are not of concern (i.e. MOEs are ≥ 30), 

but risk estimates are of concern following ground treatment. 

Adult dermal exposure from golfing does not exceed the level of concern (i.e. MOEs are ≥ 100) 

using any of the transferable residue (TTR) region-specific data for the emulsifiable concentrate 

formulation at the 1.0 lb ai/A, or 0.25 application rates. 

Table 19 Adult and Child Short-term Risks (MOEs) from Residential Post-application Exposure 

to Turf Following Aerial ULV Mosquito Treatments At 300 Foot Spray Release Height (LOC is 

an MOE = 100)

Adult

Dermal 430

Children 3 to < 6

Dermal 260

Incidental Oral 130

Combined Exposure 88
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Table 20 Adult and Child Short-term Risks (MOEs) from Residential Post-application Exposure 

to Turf Following Ground-based ULV Mosquito Treatments At 300 Foot Spray Release Height 

(LOC is an MOE = 100)

Adult

Dermal 2,200

Children 3 to < 6

Dermal 1,300

Incidental Oral 670

Combined Exposure 440

Table 21 Adult and Child Acute Risk (MOEs) from Residential Post-application Inhalation 

Exposure Following Aerial ULV Mosquito Treatments At 300 Foot Spray Release Height (LOC 

is an MOE = 300)

Adult and Children 3 to < 6

Inhalation 1,600

Table 22 Adult and Child Acute Risk (MOEs) from Residential Post-application Inhalation 

Exposure Following Ground ULV Mosquito Treatments (LOC is an MOE = 300)

Adult and Children 3 to < 6

Inhalation 17

Table 23 Adult Estimated Short- and Intermediate-term Risk (MOEs) from Post-application 

Golfing Exposure to Chlorpyrifos Treated Golf Course Turf (MRID 44829601)

Application Rate - 1.0 lb ai/A

State Emulsifiable Concn. Granular

CA 830 960

IN 1,200 NA

MS 710 NA

Application Rate – 0.25 lb ai/A

State Emulsifiable Concn. Granular

CA 3,300 3,800

IN 4,600 NA

MS 2,800 NA

HED has relied upon the Draft SOPs for Residential Exposure Assessment for all residential 

scenarios assessed. The data used in the chlorpyrifos residential post-application exposure 

assessment represent the best exposure data and approaches that are currently available. To the 

extent possible, HED has used chlorpyrifos-specific data such as the TTR data used for 

assessment of exposure to treated golf course turf. Chemical-specific data for aerial and ground 

based ULV mosquito uses are not available. For ground based ULV application, HED used data 
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from studies conducted to measure off site deposition from these applications. Data similar to 

that for ground applications were not available to determine aerial deposition. In order to 

calculate chlorpyrifos deposition on turf and air concentration at breathing level from aerial ULV 

applications, HED used the AgDRIFT (V 2.01) model. Once the deposition input was identified, 

HED used the high-end equations and assumptions from the Draft SOPs for Residential 

Exposure Assessment to assess dermal exposure to turf and inhalation exposure from mosquito 

applications. Although the SOPs were initially developed for direct turf applications, the models 

are used in this assessment to determine if there is a potential concern using a conservative, 

screening level approach. 

HED believes that the values presented in this assessment represent the highest quality results 

that could be produced based on the currently available post-application exposure data. The 

quality of individual inputs should be considered when interpreting the risk results. It is difficult 

to ascertain where, on a distribution, the calculated values fall because the distributional data for 

exposure, residue dissipation and many other parameters are unrefined. HED does believe, 

however, that the risks represent conservative estimates of exposure because maximum 

application rates are used to define residue levels upon which the calculations are based. 

Additionally, estimates are thought to be conservative even when measures of central tendency 

(e.g., most transfer coefficients are thought to be central tendency) are used because values that 

would be considered to be in the lower percentile aspect of any input parameter have not been 

used in the calculations.

6.3 Residential Bystander Post-application Inhalation Exposure

Recently, the Agency has begun exploring the development of an approach for assessing 

inhalation exposure resulting from the field volatilization of conventional pesticides. The 

Agency has sought expert advice and input on these issues from its Federal Insecticide, 

Fungicide, and Rodenticide Act Scientific Advisory Panel in December 2009. More information 

on pesticide volatilization can be found on the Agency’s website at 

http://www.epa.gov/opp00001/about/intheworks/volatilization.htm. 

The Agency has developed a preliminary bystander volatilization inhalation exposure assessment 

for chlorpyrifos using currently available inhalation toxicity and air monitoring data. There are 

15 available chlorpyrifos air monitoring studies (brief study summaries available in W. Britton, 

6/27/11, D388165, Chlorpyrifos: Occupational and Residential Exposure Assessment). These 

include:

2 application site studies done in Tulare and Lompoc Counties, CA by the California Air 

Resource Board (CARB), and 

13 ambient air studies

o 2 conducted in North Central and Yakima Valley, OR by the University of 

Washington Department of Environmental and Occupational Health Sciences; and 

o 11 conducted by Pesticide Action Network North America (PANNA), two in 

Cowiche and Tieton, WA, and nine in Lindsay, CA.
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Application site air monitoring refers to the collection of air samples around the edges of a 

treated field during and after a pesticide application. Samples are generally collected for short 

intervals (e.g., < 8 hours), for at least the first day or two after application with subsequent 

samples increasing in duration. In this type of study, it is typically known when an application 

occurred, the equipment used for the application, and the application rate. Application site 

monitoring data represents an exposure to vapors at or near the field edge resulting from an 

application.

Ambient air monitoring typically is focused on characterizing the airborne pesticide levels within 

a localized airshed or community structure of some definition (e.g., city, township, or 

municipality). This type of monitoring effort also can be focused on capturing chronic 

background levels or other temporal characteristics of interest such as focusing on seasonal 

pesticide use patterns. Typically, samples are taken for 24 consecutive hours and collected at the 

same site over an extended period of time (e.g., several weeks or months). In contrast to 

application site air monitoring, information on the precise timing and location of pesticide 

applications are rarely collected in ambient air monitoring studies. However, this does not mean 

that an application did not occur near an ambient sampler during the monitoring period

HED has assessed residential bystander exposure to chlorpyrifos based on the available ambient 

and application site air monitoring data Table 24. The chlorpyrifos bystander volatilization 

inhalation exposure assessment includes acute and short-/intermediate-term exposure scenarios. 

The acute scenario compares the maximum air concentration detected in the monitoring studies 

to the acute HEC. The short-/intermediate-term scenario compares the arithmetic mean 

chlorpyrifos air concentration from several monitoring studies to the short -term HEC. 

EPA has assessed residential bystander exposure from field volatilization of applied chlorpyrifos 

based on the available ambient and application site air monitoring data. Of the 24 acute ambient

air concentrations assessed, 4 result in risk estimates exceeding the level of concern (i.e. MOEs 

are < 300). No short-/intermediate-term ambient data assessed result in risk estimates of concern

(i.e. MOEs are > 30). Of the 5 acute application site air concentrations assessed, 3 resulted in a 

risk estimate of concern (i.e. MOEs are < 300). Of the 5 short- and intermediate-term 

application site air concentrations assessed, 4 resulted in risk estimates of concern (i.e. MOEs 

are < 30).

Table 24 Chlorpyrifos Preliminary Volatilization MOE Analysis for Residential Bystanders

Study

Year 

of 

Study

Sampler/Site Location

Maximum 

Air 

Concentration 

(ng/m3)

Arithmetic 

Mean Air 

Concentration 

(ng/m3)

Acute 

MOEsa

(LOC is 

an MOE 

= 300)

Short- / 

Int.-term 

MOEsb

(LOC is 

an MOE 

= 30)

Ambient Air Data

Washington DOH 2008

North Central District 

Ambient 21 7 29,000 850

North Central District

Receptor 607 33 1,000 180
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Table 24 Chlorpyrifos Preliminary Volatilization MOE Analysis for Residential Bystanders

Study Year 

of 

Study

Sampler/Site Location Maximum 

Air 

Concentration 

(ng/m3)

Arithmetic 

Mean Air 

Concentration 

(ng/m3)

Acute 

MOEsa

(LOC is 

an MOE 

= 300)

Short- / 

Int.-term 

MOEsb

(LOC is 

an MOE 

= 30)

Yakima Valley Ambient 30 9 21,000 620

Yakima Valley Receptor 243 30 2,500 190

Lompoc County, 

CA (CARB) 2003

Central 8.3 1.5 19,000 3,800

Northwest 8.4 0.84 19,000 6,800

Southwest 6.8 0.78 24,000 7,400

West 17 2.3 9,400 2,500

Tulare, CA 

(CARB) 1996

Air Resource Board 39 10 16,000 590

Jefferson Elementary 

School 432 94 1,400 61

Kaweah School 412 70 1,500 82

Sunnyside Union 

Elementary School 815 52 760 110

University of CA, 

Lindcove Field Station 168 39 3,700 150

Cowiche, WA 

(PANNA) 2006 462 155 350 37

Tieton, WA

(PANNA) 2005 475 182 340 32

Lindsay, CA

(PANNA) 2004 Blue House 137 54 1,200 110

Lindsay, CA

(PANNA) 2004 Green House 720 120 220 50

Lindsay, CA

(PANNA) 2004 Orange House 1,340 190 120 30

Lindsay, CA

(PANNA) 2004 Purple House 180 48 900 120

Lindsay, CA

(PANNA) 2004 Red House 90 43 1,800 130

Lindsay, CA

(PANNA) 2005 Blue House 421 107 380 54

Lindsay, CA

(PANNA)

2005 Green House 1,119 177 140 32

Lindsay, CA

(PANNA)

2005 Orange House 561 188 290 31

Lindsay, CA

(PANNA)

2005

Purple House 515 123 310 47

Application Site Data

Washington DOH 2008

North Central District 

Perimeter Site 1145 153 540 37

Yakima Valley Perimeter 

Site 1,002 294 620 20

Tulare, CA 

(CARB) 1996

North 27,700 7,706 22 1

East 14,700 5,974 42 1

South 25,400 5,664 24 1

a. Acute MOE = Acute HEC (62,000 ng/m3) / Study maximum air concentration (ng/m3). 

b. Short-term MOE = Short-term HEC (5,700 ng/m3) / Study arithmetic mean air concentration (ng/m3). 
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Characterization of Bystander Risk Assessment/Uncertainties

Some of the limitations and considerations that have been identified that should be considered in 

the interpretation of these results include:

Most of the data utilized in this preliminary assessment are 24-hour air samples. When 

these data are used, an assumption is made that an individual is exposed to the same air 

concentration for 24-hours every day. However, this is not always the case as real world 

time-activity data indicate that many parts of the population move from site to site on a 

daily basis (e.g., go to work and back).

This assessment is only representative of outdoor concentrations (i.e., the exposure and 

risk estimates assume an individual is outdoors all the time). It does not take into account 

potential effects of air conditioning systems and similar air filtration systems which could 

potentially reduce air concentrations indoors. The Agency believes that indoor 

concentrations will be at worst equivalent to outdoor concentrations and may potentially 

be lower.

All of the data used for this analysis have been generated in California and Washington; 

however, chlorpyrifos is used in many regions throughout the country. Therefore, the 

results based on the limited available air monitoring data were used to represent the rest 

of the country due to a lack of adequate information for any other region. It is unclear 

what potential impacts this extrapolation might have on the risk assessment. Factors such 

as meteorology and cultural practices may impact the overall amounts of chlorpyrifos that 

volatilize from a treated field as well as the rate at which it volatilizes.

As part of the December 2009 SAP, the Agency presented their analysis of several 

models that could be used as screening tools to predict the air concentration and 

volatilization flux based on intrinsic properties and transport behaviors of pesticides. 

These models would allow the Agency to better represent the potential volatilization of 

semi-volatile pesticides across various regions of the country and thus would provide 

refinement to this assessment over using straight air monitoring data. The SAP provided 

a number of comments regarding the Agency’s model analysis, including the 

recommendation to evaluate some additional models. The Agency is currently in the 

process of evaluating the SAP’s comments. As appropriate, the Agency will revise the 

modeling approach presented to the SAP for determining the rate of volatilization (flux) 

for semi-volatile pesticides and for estimating air concentrations of applied pesticides in 

the atmosphere under varying environmental conditions. After any policies or procedures 

are put into place, the Agency may revisit the residential bystander exposure and risk 

assessment.
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6.4 Spray Drift

Spray drift is 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 chlorpyrifos. 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 (see the Agency’s Spray Drift website for more information at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the 

Agency evaluates the need for interim mitigation measures for aerial applications for placement 

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 seek further refinements in spray drift management 

practices to reduce off-target drift with specific products with significant risks associated with 

drift.

A quantitative residential post-application (acute) inhalation exposure (spray drift) assessment 

was conducted for ground and aerial ULV mosquitocide applied by a public agency made in the 

vicinity of residential areas (Section 6.2 above). Inhalation exposure from ground based ULV 

treatment was assessed by assuming that all of the active ingredient applied to a 1 acre area is 

airborne and available to be inhaled by a child or adult. HED used AgDRIFT (V 2.01), which is 

the model that was developed as a result of the efforts of the Spray Drift Task Force (SDTF), to 

determine residue deposition and the airborne concentration of chlorpyrifos anticipated from 

aerial product application. 

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate chlorpyrifos exposures and 

risks from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure.

A quantitative aggregate (food, water and residential exposures combined) assessment was not 

performed for this preliminary chlorpyrifos assessment. The preliminary risk estimates for water 

alone exceed the level of concern and are the primary driver in this assessment. Combining food 

and/or residential exposures with the water exposures would not be expected to have a 

significant impact on the resulting risk estimates for water alone. A quantitative aggregate 

assessment for food, water, and residential exposures will be considered during the final 

chlorpyrifos risk assessment.
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8.0 Cumulative Exposure/Risk Characterization

Section 408(b)(2)(D)(v) of the Federal Food, Drug, and Cosmetic Act (FFDCA), as amended by 

the Food Quality Protection Act (1996) stipulates that when determining the safety of a pesticide 

chemical, EPA shall base its assessment of the risk posed by the chemical on, among other 

things, available information concerning the cumulative effects to human health that may result 

from dietary, residential, or other non-occupational exposure to other substances that have a 

common mechanism of toxicity. The reason for consideration of other substances is due to the 

possibility that low-level exposures to multiple chemical substances that cause a common toxic 

effect by a common mechanism could lead to the same adverse health effect as would a higher 

level of exposure to any of the other substances individually. A person exposed to a pesticide at a 

level that is considered safe may in fact experience harm if that person is also exposed to other 

substances that cause a common toxic effect by a mechanism common with that of the subject 

pesticide, even if the individual exposure levels to the other substances are also considered safe.

Chlorpyrifos is a member of the organophosphate (OP) class of pesticides. Other members of 

this class of pesticides are numerous and include azinphos methyl, diazinon, chlorpyrifos-methyl, 

dichlorvos, dicrotophos, dimethoate, disulfoton, methamidophos, methidathion, monocrotophos, 

naled, oxydemeton-methyl, phorate, phosmet, pirimiphos-methyl, and trichlorfon to name a few. 

EPA considers organophosphates to express toxicity through a common biochemical interaction 

with cholinesterase which may lead to a myriad of cholinergic effects and, consequently the 

organophosphate pesticides should be considered as a group when performing cumulative risk

assessments. HED published the final guidance that it now uses for identifying substances that 

have a common mechanism of toxicity (FR 64(24) 5796-5799, February 5, 1999) ―Proposed 

Guidance of Cumulative Risk Assessment for Chemicals that have a Common Mechanism of 

Toxicity‖ was made available for public comment in the Federal Register (65 FR 40644, June 

30, 2000). The Agency presented this approach to the FIFRA Scientific Advisory Panel in late 

September, 2000. The SAP reviewed revised methods used to conduct a preliminary cumulative 

risk assessment for organophosphate pesticides in 2002 (US EPA, 2002), found at 

http://www.epa.gov/scipoly/sap/2002/index.htm. 

The Agency has completed a cumulative risk assessment for OPs, (US EPA, 2001), a revised 

cumulative risk assessment for OPs, (US EPA, 2002), and an updated OP cumulative risk 

assessment (US EPA, August 2006) which can be found on the Agency's web site 

http://www.epa.gov/pesticides/cumulative/rra-op/. The cumulative effects of exposure to 

multiple OPs, including chlorpyrifos, are evaluated in those documents. OPP is in the process of 

evaluating the most current methods and data for suitability of use in the next version of the OP 

cumulative risk assessment.
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9.0 Occupational Exposure/Risk Characterization

9.1 Short-/Intermediate-Term Handler Risk

Chlorpyrifos is an organophosphate insecticide currently registered for the control of various 

insects. Targeted pests include aphids, cockroaches, cutworms, fleas, grasshoppers, ticks, etc. 

Chlorpyrifos is manufactured as granular, microencapsulated, soluble concentrate/liquids, water 

dispersible granular in water soluble packets (WSP) and wettable powder packaged in WSP

formulations, as well as impregnated paints, cattle ear tags, insect bait stations and total release 

foggers. Registered use sites include the following uses: food crops, including fruit and nut 

trees, many types of fruits and vegetables, and grain crops; and non-food crops such as forage, 

golf course turf, industrial sites, greenhouse and nursery production, sod farms, and wood 

products. Public health uses include aerial and ground-based fogger treatments to control 

mosquitoes. There are a wide range of application rates. HED has conducted a review of all 

active product labels. Table 25 and Table 26 below summarize all agricultural and nonagricultural use sites identified for chlorpyrifos under this review, respectively. Maximum 

application rate (lb ai/A) and application equipment for each site are also identified. Various 

chlorpyrifos product formulations are represented by the application rates and methods presented 

in the tables. 
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Table 25 Summary of Maximum Application Rates for Chlorpyrifos Agricultural Uses

Crop or Target Maximum Application Rate (lb ai/A) Application Equipment

Alfalfa 1.0 Aerial, Chemigation, Groundboom, Tractor 

Drawn Spreader

Asparagus 1.0 Aerial, Groundboom

1.5 Tractor Drawn Spreader

Beets (Table and Sugar Grown for Seed) 1.9 Aerial

Brassica Vegetable (Bok Choy, Broccoli, Broccoli 

Raab, Brussel Sprout, Cabbage, Cauliflower, 

Chinese Broccoli, Collards, Kale, and Kohlrabi)

1.0 Aerial

2.3 Groundboom, Tractor Drawn Spreader

Carrot (Grown for Seed) 0.94 Aerial, Groundboom

Citrus Fruit 6.0 (AZ and CA), 3.5 (States other 

than AZ and CA)

Aerial, Airblast, Groundboom

1.0 Tractor Drawn Spreader

4.0 Backpack Sprayer, Handgun, Low Pressure 

Handwand

Clover (Grown for Seed) 1.0 Aerial, Groundboom

Corn (Field, Grown for Seed and Sweet) 1.5 Aerial, Chemigation

3.0 Groundboom

1.3 Tractor Drawn Spreader

Cotton 1.0 Aerial, Chemigation, Groundboom

Cranberry 1.5 Aerial, Chemigation, Groundboom

Fig (CA only) 2.0 Groundboom

Grapes 2.0 Airblast

1.0 Backpack Sprayer, Low Pressure Handwand

Legume Vegetables (Succulent or Dried, Except 

for Soybeans)

1.0 Groundboom

Mint (Peppermint and Spearmint) 2.0 Chemigation, Groundboom

Onion (Dry Bulb) 1.0 Groundboom, Tractor Drawn Spreader, Handgun

Peanut 2.0 Aerial, Groundboom, Tractor Drawn Spreader

Peppers 1.0 Groundboom
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Table 25 Summary of Maximum Application Rates for Chlorpyrifos Agricultural Uses

Crop or Target Maximum Application Rate (lb ai/A) Application Equipment

Pineapple (Non-bearing) 1.9 Groundboom, Airblast

Radish 2.8 Aerial, Groundboom, Tractor Drawn Speader, 

Handgun

Radish (Grown for Seed) 0.94 Aerial, Groundboom 

Rutabaga 2.3 Aerial, Groundboom, Tractor Drawn Spreader

Sorghum 1.0 Aerial, Chemigation, Groundboom

3.3 Tractor Drawn Spreader

Soybean 1.0 Aerial, Chemigation, Groundboom

Strawberry 1.0 Aerial

2.0 Groundboom

Sugarbeet 1.0 Aerial, Chemigation, Groundboom

2.0 Tractor Drawn Spreader

Sugarbeet (Grown for Seed) 1.9 Aerial, Chemigation, Groundboom

Sunflower 2.0 Aerial, Groundboom

Sweet Potato 2.0 Groundboom, Tractor Drawn Spreader

Tobacco 2.0 Groundboom, Tractor Drawn Spreader

Tree Nuts (Almonds, Filberts, Pecans, Walnuts) 4.0 Groundboom, Handgun

2.0 Aerial, Airblast

0.03 (lb ai/gallon) Low Pressure Handwand, Backpack Sprayer

Tree Fruit (Apples, Cherry, Nectarine, Peach, 

Pear, Plum, Prune, Sour Cherry)

2.0 Aerial, Airblast

0.03 (lb ai/gallon) Backpack Sprayer, Drench/Dip, Handgun, Low 

Pressure Handwand

Turnip 2.3 Groundboom, Tractor Drawn Spreader

Wheat 1.0 Aerial, Chemigation, Groundboom

2.0 Groundboom
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Table 26 Summary of Maximum Application Rates for Chlorpyrifos Non-Agricultural Uses

Crop or Target Maximum Application Rate

(lb ai/A) Application Equipment

Ants (Fire Ant Mound, Carpenter) 0.080 (lb ai/gallon) Backpack Sprayer, Handgun, Low Pressure 

Handwand

Cattle Ear Tags 0.0033 (lb ai/ ear tag) Hand

Christmas Trees (Nurseries and Plantations, 

Stumps)

1.0 Airblast

0.94 Aerial (Helicopter)

0.03 (lb ai/gallon) Backpack Sprayer, Handgun, Low Pressure 

Handwand

Golf Course Turf 1.0 Belly Grinder, Low Pressure Handwand, Push 

Type Spreader, Tractor Drawn Spreader, Turfgun

Grass Seed (Perennial Crops) 1.0 Groundboom

Greenhouse and Nursery Production (Bedding 

Plants, Containerized Ornamentals, Cut Flowers, 

Flowering Hanging Baskets, Pine Seedling 

Transplant, Potted Flowers, Ornamentals, Trees 

and Shrubs)

4.0 Aerial, Groundboom

1.1 Belly Grinder, Push Type Spreader, Tractor 

Drawn Spreader

1.0 Airblast

0.16 (lb ai/gallon) Backpack Sprayer, Handgun, Low Pressure 

Handwand

0.02 (lb ai/gallon) Soil Drench

0.01 (lb ai/can) Total Release Fogger

Mosquitocide (Outdoor Residential, Recreational, 

or Other Non-Cropland Areas)

0.010 Wide Area Aerial and Ground
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Table 26 Summary of Maximum Application Rates for Chlorpyrifos Non-Agricultural Uses

Crop or Target Maximum Application Rate

(lb ai/A) Application Equipment

Non-crop Areas (Commercial Indoor/Outdoor 

Industrial Sites, Commercial Livestock Holding 

and Housing, Dumpsters/ Trash Areas, Food 

Processing Plants, Grown for Seed, Industrial 

Plant Site Perimeter Treatments, Manufacturing 

Sites, Power Utilities, Railroad Box Cars, 

Railroad Equipment, Road Medians, Ship Holds, 

Sod Farms, Telecommunications, Warehouse 

Sites)

1.0 Aerial, Belly Grinder, Groundboom, Push Type 

Spreader, Tractor Drawn Spreader

0.11 (lb ai/gallon) Backpack Sprayer

0.080 (lb ai/gallon) Handgun, Low Pressure Handwand, Paint 

Brush/Roller

0.044 (lb ai/1,000 sq ft) Shaker Container

0.018 (lb ai/1,000 sq ft) Open Pour Bag

Ornamentals (Cut Flowers, Industrial 

Buildings/Plant Sites Perimeter Treatments and 

Road Medians, Evergreens, Field Grown Nursery 

Stock, Flowers, Greenhouses, Non-bearing Fruit 

Trees Shrubs, Nurseries, Trees, Vines, Woody) 

6.0 Belly Grinder, Push Type Spreader, Tractor 

Drawn Spreader

4.0 Groundboom

2.0 Aerial, Airblast

0.16 (lb ai/gallon) Backpack Sprayer, Handgun, High Pressure 

Handwand, Low Pressure Handwand

0.020 (lb ai/gallon) Drench/Dip

Roach Control Bait Stations 0.00040 (lb ai/gallon) Hand

Sewer Manhole Walls 0.080 (lb ai/gallon) Backpack Sprayer, Low Pressure Handwand, 

Paint Brush/Roller

Total Release Fogger (Greenhouse Bedding 

Plants, Cut Flowers, Flowering Hanging Baskets, 

Potted Flowers, Ornamentals)

0.010 (lb ai/container) Hand
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Table 26 Summary of Maximum Application Rates for Chlorpyrifos Non-Agricultural Uses

Crop or Target Maximum Application Rate

(lb ai/A) Application Equipment

Trees (Cottonwood and Poplar Trees Grown for 

Pulp, Conifer, Deciduous, Grown in Nurseries 

and Greenhouses) 

2.0 Airblast, Handgun, Low Pressure Handwand, 

Backpack Sprayer

1.9 Aerial

Turfgrass (Sod or Seed) 4.0 Aerial, Groundboom

1.0 Tractor Drawn Spreader

Wood Products (Fence Posts, Industrial Sites, 

Landscape Timbers, Logs, Manufacturing, 

Pallets, Processed Wood, Right of Way, Railroad 

Ties, Utility Poles, Wooden Containers) 

6.0 Belly Grinder, Push Type Spreader

0.17 (lb ai/gallon) Low Pressure Handwand

0.080 (lb ai/gallon) Backpack Sprayer, Handgun, Paint Brush/Roller
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Under current policy, both short- term (up to 30 days) and intermediate-term (30 days up to 6 

months) assessments are completed for occupational scenarios in essentially all cases, because 

these kinds of exposures are likely and acceptable use/usage data are not available to justify 

disregarding intermediate-term scenarios. Long-term exposure (essentially every working day 

over a year) is not anticipated based upon the use profile of chlorpyrifos. 

Short- (1 to 30 days) and intermediate-term (1 to 6 months) inhalation and dermal exposure and 

risks were calculated for occupational handlers of chlorpyrifos for a variety of exposure 

scenarios at differing levels of personal protection. Occupational handler exposure estimates 

used three major unit exposure data sources, PHED (Pesticide Handlers Exposure Database), the 

Outdoor Residential Exposure Task Force (ORETF), and recently completed exposure scenario 

monographs as conducted and submitted by the Agricultural Handlers Exposure Task Force

(AHETF). In addition to those surrogate data, two non-chemical specific exposure studies were 

used (MRID 44793301 and MRID 45250702).

In addition to the aforementioned studies, five chemical specific (chlorpyrifos) handler exposure 

(biomonitoring and passive dosimetry) studies were previously submitted in support of 

chlorpyrifos reregistration (MRID 42974501, Shurdut, B.A. et al. 1993; MRID 43138102;

Honeycutt, R.C. & Day, E.W. Jr. 1994; MRID 44483501 R. F. Bischoff 1998; MRID 44739302,

Knuteson et al. 1999; and MRID 43027901 Contardi et al. 1993). These studies have been 

reviewed and considered for use by the HED. Based on HED’s review of the five chemical 

specific studies, a number of issues were identified which limit the utility of the available data.

HED has determined that these data are most useful as a tool for comparison to the estimates 

generated for representative exposure scenarios using the surrogate data. That comparison is 

presented separately in this document. Citations and a full description of the study summaries 

and issues are presented in W. Britton, 6/27/11, D388165, Chlorpyrifos: Occupational and 

Residential Exposure Assessment.

Because the same adverse effect (i.e., ChEI) was seen following dermal, incidental oral and 

inhalation exposures, MOEs estimated for these routes of exposure can be combined. However, 

because the LOCs for dermal/incidental oral and inhalation routes of exposure are not the same 

(an MOE of 100 defines dermal/incidental oral while inhalation is defined by an MOE of 30) an 

aggregate risk index (ARI) was required to combine or aggregate estimated MOEs. EPA 

identifies as a level of concern ARIs that fail to reach or exceed the level of 1. ARIs below 1 

result in a risk estimate of concern. 

Of the 305 exposure scenarios assessed 134 had risk estimates that did not exceed the level of 

concern at some level of personal protection (i.e. ARIs are > 1). Ninety-one (91) exposure 

scenarios had risk estimates not of concern when engineering controls were considered. The 

remaining 80 scenarios resulted in risk estimates of concern (i.e. ARIs are < 1) at all levels of 

personal protection and engineering controls considered.
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Characterization of Occupational Handler Risk Assessment/Uncertainties

The occupational handler exposure and risk assessment for chlorpyrifos is based upon an array of 

calculations completed for all identified exposure scenarios using the short- and intermediateterm endpoints. HED completes both short- and intermediate-term assessments for occupational 

scenarios in essentially all cases, because exposures of these durations are likely and acceptable 

use/usage data are not available to justify deleting intermediate-term scenarios. HED identified 

49 different exposure scenarios which are defined based on the equipment used to make 

applications or the type of formulation used. Within each of these categories, different 

application rates and acres treated values were considered to evaluate the broad range of 

applications that may occur with each kind of equipment (e.g., a groundboom may be used for 

turf or agriculture). Finally, it should be noted that each calculation was completed at different 

levels of personal protection to allow for a more informed risk management decision. Even 

given the scope of the calculations that have already been completed, it is possible that some 

uses of chlorpyrifos that have not been quantitatively addressed in this document due to lack of 

exposure data or other information.

The data used in the chlorpyrifos occupational handler risk assessment represent the best data 

and approaches that are currently available. While some of the data which have been used may 

not be of optimal quality, they represent the best available data for the scenario in question. In 

many cases, the Pesticide Handlers Exposure Database (PHED) was used to develop the unit 

exposure values. PHED data quality varies widely from scenarios that meet guideline 

requirements for studies to others where a limited number of poor quality data points are 

available. The results for each scenario should be reviewed in the context of the quality of these 

data. PHED unit exposure values represent a central tendency of the data (i.e., geometric mean, 

median or arithmetic mean depending upon the distribution of the data). As such, the values 

based on the recent studies also are measures of central tendency (e.g., the geometric means were 

selected from each study for assessment purposes in most cases). HED used recently developed 

data from AHETF to assess the exposure scenarios mixing/loading liquid formulations and 

application of liquid sprays via open cab groundboom. HED has reviewed the data for the two 

studies and has confirmed that it meets study design benchmarks outlined in the AHETF 

Governing Document (AHETF, 2007) and is considered the most reliable data for assessing 

exposure and risk for these exposure scenarios. The efforts undertaken by AHETF represent a 

well-designed, concerted process to collect reliable, internally-consistent, and current exposure 

data in a way that takes advantage of and incorporates a more robust statistical design, better 

analytical methods, and improved data handling techniques. For the purpose of the assessment 

of the two exposure scenarios, HED has used the arithmetic mean unit exposure for short- and 

intermediate-term exposure durations as recommended in the study reviews (D373605). The 

AHETF scenarios were recently posted and are publically available on the EPA website as of 

4/8/2011 (http://www.epa.gov/pesticides/science/handler-exposure-data.html). This new data 

were included in the presentation of the most current data used to assess exposure and risk for 

occupational pesticide handlers.

Along with the unit exposure values used in the assessment, other inputs include application 

rates and daily acres treated values. The application rates selected for occupational handler risk 

assessment represent the maximum amounts that are allowed by the label for all uses. The 
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application rates that were selected for use in the risk assessment were defined based on a review 

of all current labels. The other key input for completing handler risk assessments used for 

defining how much chemical can be used in a day is how much can be treated in a day which is 

generally expressed as the number of acres treated per day. The values used for this parameter 

represent the HED’s most current thinking. 

In addition to the key sources of information considered above, there are many underlying 

factors that may impact the overall results of a risk assessment. For example, the protection 

factors used for adding additional levels of dermal and respiratory protection may impact the 

overall risk picture. The factors used in this assessment by HED have been in use for many 

years. There are exposures monitoring issues which must be considered. For example, in many 

cases the data included in PHED are based on the use of cotton gloves for hand exposure 

monitoring which is thought by many to have the potential to overestimate exposure because 

they potentially retain residue more than a bare hand would over the course of a work day. Such 

intangible elements of the risk assessment reflect many of the hidden uncertainties associated 

with exposure data. 

In summary, HED believes that the risk values presented in this occupational assessment 

represent the highest quality results that could be produced given the exposure, use, and 

toxicology data that are available. Risk managers and other interested parties should consider 

the quality of individual inputs when interpreting the results and make decisions accordingly. It 

is difficult to ascertain at what point on a distribution the values which have been calculated fall 

because the distributional data for exposure, application rates, acres treated and many other 

parameters are unrefined. HED does believe, however, that the risks represent conservative 

estimates of exposure because maximum application rates are coupled with high acreage 

estimates to define risk estimates that likely fall in the upper percentiles of the actual exposure 

distributions. Additionally, risk estimates are thought to be conservative even when measures of 

central tendency are combined because values that would be considered to be in the lower 

percentile aspect of any input parameter have not been used in the calculations. 

Occupational Handler Comparison Using Biomonitoring Data

Occupational handler exposure estimates were based on surrogate data from AHETF, ORETF 

and PHED, as well as two non-chemical specific studies. In addition to these data, five chemical 

specific handler exposure studies submitted in the past in support of chlorpyrifos re-registration 

were reviewed and considered for use by the HED. Risk estimates have been calculated using 

absorbed doses (mg/kg) measured from the biomonitoring studies determined to be acceptable 

for quantitative risk assessment purposes. In order to characterize occupational risk estimates 

calculated using surrogate, passive dosimetry exposure data, HED has presented a comparative 

analysis of these data and biomonitoring data available for applicable exposure scenarios. 

Comparative estimates using chemical specific handler exposure studies are limited to the level

of clothing and personal protection worn by the participants when the studies were conducted. 

Comparative short- and intermediate term occupational handler exposure/risk using 

biomonitoring and surrogate exposure data are presented in Appendix B which accompanies 

document D388165.
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All five chemical specific exposure studies (MRID 42974501, MRID 43138102, MRID 

44739302 and MRID 43027901 and MRID 44483501) were reviewed for ethical conduct. All 

but one (MRID 44483501) were determined to be ethically relevant to the standards of the time 

that the studies were conducted. In addition, all studies were reviewed as to their relevance in 

the current market in regard to product formulation. Based on this analysis, one study measured 

the mixing/loading of a wettable powder formulation which is no longer supported by the 

product registrant. Despite this limitation, the application of the mixed wettable powder 

formulation was considered for use because the formulation was mixed into a liquid form and is, 

therefore an acceptable surrogate. HED considered use of the four remaining handler exposure 

studies and weighed the strengths and weaknesses of each. A number of issues limit the utility 

of the studies, including: the sufficiency of sample size, PPE worn by study participants, 

sufficient risk mitigation is not provided (e.g., additional PPE or engineering controls), and the 

studies do not encompass all handler uses of the chemical. 

The number of monitored workers across the four studies range from 15 to 1. HED has typically 

relied on the criteria set forth by the Pesticide Assessment Guideline which recommend 15 

exposure measurements as a minimum for each exposure scenario. Only 1 of the 4 studies meets 

this criterion. For example, a mixer/loader/applicator greenhouse study (MRID 43027901)

attempted to monitor 6 different greenhouse handler scenarios and, as a result was only able to 

collect 5 measurements for 2 exposure scenarios, 3 for another, and only 1 for each of the 

remaining 3 scenarios. 

Workers participating in the four reviewed studies wore a wide range of clothing and personal 

protective equipment. All workers wore an inner dosimeter which included t-shirt and briefs 

used to measure the penetration of chlorpyrifos through the outer dosimeter. The outer 

dosimeter was typically represented either by coveralls, or long sleeved shirt and long pants. 

For example, in the mixing/loading for aerial applications study (MRID 44739302), participants 

wore chemical-resistant gloves, apron and knee high boots. In another study, 

mixing/loading/applying for ornamentals in greenhouses, the workers wore chemical-resistant 

gloves, socks, rubber boots, and protective eyewear. In this same study, participants who 

conducted overhead applications also wore neoprene rain paints and a rain jacket over the 

coveralls, a half face respirator equipped with two organic vapour cartridges and pre-filters, and 

a face shield. The study authors attempted to account for the additional PPE through means of 

assigned penetration factors. It is possible that the additional PPE, despite correction, affect 

passive and biomonitoring results by reducing worker exposure to chlorpyrifos that would have 

otherwise deposited on the inner or outer dosimeters in their absence and likewise, result in an 

assessment which potentially underestimates human health exposure/risk for the exposure 

scenario. This is of particular concern in the greenhouse study because the personal protective 

equipment worn by study participants making overhead applications exceeds current labelled 

requirements. 

Because the four available (ethically acceptable) studies were conducted with study participants 

wearing a specific combination of clothing and PPE, the utility of the data are limited to 

assessment of occupational handler exposure/risk which is represented by that level of clothing 

or personal protection. For example, in the mixing/loading for airblast application study (MRID 

43138102) workers wore inner dosimeters (t-shirts and briefs), short sleeved shirt, long pants and 
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outer dosimeters (coveralls), chemical resistant gloves and half-face respirator. Therefore, data 

from the study would be limited to the assessment of occupational handlers mixing/loading 

liquids with double layer clothing, gloves and PF10 respirator. Furthermore, since the available 

exposure studies are specific to particular handler activities and formulations (e.g., 

mixing/loading for liquid formulations) the utility of the data are limited to these parameters. 

In view of the issues outlined, HED has determined that of the four available studies reviewed, 

three should be considered for quantitative risk assessment purposes (MRIDs 42974501, 

43138102, and MRID 44739302). The mixing/loading liquids for aerial applications study 

(MRID 44739302) was used to present a comparative biomonitoring estimate for the 

mixing/loading liquids for aerial applications exposure scenario at double layer clothing, gloves 

and no respirator level of personal protection. The mixing/loading liquids for and airblast 

application study (MRID 43138102) was used to present a comparative estimate for the 

mixing/loading liquids for airblast application and airblast application exposure scenario at 

single layer clothing, gloves and PF10 respirator level of personal protection. Study MRID 

42974501 measured exposure from the mixing/loading and application of a wettable powder 

formulation and mixing/loading of a liquid formulation for ground boom application. Because 

the wettable powder formulation is no longer supported, only the subsequent liquid application 

by ground boom exposure data was used to present a comparative estimate at single layer, gloves 

and PF10 respirator level of personal protection. 

Appendix B, which accompany document D388165 present the comparative short- and 

intermediate-term occupational handler exposure/risk estimates, respectively. Risk estimates 

compare the level of personal protection measured in biomonitoring exposure studies and the 

corresponding level estimated using surrogate exposure data. 

In an effort to characterize occupational handler risk estimates calculated using both surrogate

data and passive dosimetry (chemical specific handler) exposure data, HED has presented a 

comparative analysis of these for applicable exposure scenarios. Comparative risk estimates 

were calculated using absorbed doses measured from chemical specific handler studies 

determined to be acceptable for quantitative risk assessment purposes. The comparison of 

handler risk estimates was limited based on the level of clothing and personal protection worn by 

the participants when the biomonitoring studies were conducted. 

Of the 4 exposure scenarios compared, 3 (mixing/loading liquids for airblast application, airblast 

applications, and groundboom applications) result in biomonitoring estimates of greater risk 

potential than those estimated using surrogate data (i.e., the estimated MOEs are lower). The 

analysis of the exposure scenario, mixing/loading liquids for aerial application, results in reduced 

risk potential (a 3.8X reduction in MOE estimate). Because a number of issues were identified 

which limit the utility of the available biomonitoring data, HED has determined that these data 

are best suited for characterization of the estimates calculated for representative exposure 

scenarios using the surrogate data.
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Commercial Seed Treatment

Occupational handlers may experience short- and intermediate-term (dermal and inhalation) 

exposure to chlorpyrifos while performing seed treatment activities in commercial settings. In 

addition, occupational secondary handlers may experience short- and intermediate-term exposure 

while planting chlorpyrifos-treated seeds. No chemical-specific handler exposure data were 

submitted in support of this use pattern. In order to assess commercial seed treatment and seed 

planting activities, unit exposure data were taken from HED ExpoSAC Policy 14: SOPs for Seed 

Treatment. The amount of active ingredient handled depends on the application rate (lb ai/lb 

seed) and the pounds of seed treated in a day (or the pounds of seed that can be planted in a day), 

all of which vary depending upon the seed type. Values for the amount of seed treated and 

planted per day were obtained from HED ExpoSAC Policy 15. 

Commercial seed treatment exposure and risk estimates were calculated using the formulas and 

MOE approach used for other occupational handler scenarios. It should be noted that for 

commercial seed treatment, the application rate is presented in units of lbs ai/lb seed and daily 

amount handled is presented in units of lbs seed/day. 

The majority, 61 of 64, occupational handler seed treatment exposure scenarios assessed 

(combined dermal and inhalation) resulted in risk estimates which were not of concern (i.e. ARIs 

are > 1) at some level of personal protection. The remaining 3 exposure scenarios resulted in an 

ARI < 1 at all level of personal protection considered and, therefore, are of concern. All seed 

planter (secondary handler) combined short- and intermediate-term dermal and inhalation 

exposure scenarios assessed resulted in an ARI > 1 at some level of personal protection and, 

therefore, do not present risk estimates of concern.

Complete results for short- and intermediate-term commercial seed treatment and secondary 

handler exposure is presented in Appendix C which accompanies document D388165. 

9.2 Short-/Intermediate-Term Post-Application Risk

9.2.1 Dermal Post-Application Risk

HED has assessed short- and intermediate term occupational post-application dermal exposure 

and risk for any crops which reentry into an area previously treated with chlorpyrifos is 

anticipated. The assessment was completed using 7 chemical-specific registrant submitted DFR 

studies. The studies, which encompass the use of five different formulations and twelve different 

crops, have been extrapolated to other groups based on the nature of the crop and application 

method and used to calculate risks for post-application workers in every region of the county. 

The results of the post-application exposure and risk assessment are summarized in Table 27

below. A full presentation of post-application exposure and risk including estimates calculated 

for low, medium and high contact activities and resulting REIs reference Appendix E which 

accompanies D388165.

The MOEs estimated for liquid spray and granular formulation reentry are not of concern (i.e., an 

MOE ≥ 100) in the range of 0 to 4 days for lower to medium exposure activities and 0 to 8 days 
Chlorpyrifos Preliminary Human Health Risk Assessment DP No. D388070

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for high exposure activities, with the greater majority falling between 0 to 4 days when all 

exposure activities are considered. HED also estimated the MOEs for reentry into 

microencapsulated and total release fogger formulation treated greenhouses. These estimates 

range from 0 to > 35 days after treatment (the completion of the monitoring period) for all 

exposure activities considered. 
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Table 27 Results of the post-application exposure and risk assessment

Crop Group Crop App. Rate 

(lbs ai/A)

DFR Data Source DFR 

Study 

Location

Growing 

Region

Estimated REI Range 

(days)

(Dermal LOC = 100)

Berry: Low Strawberry 1.0 MRID 42974501 

(cauliflower WP) AZ 3, 5, 10 and 12 0 - 2

Cranberry 1.5 1, 5, 10 and 12 0 - 4

Field and Row 

Crops: Low to 

Medium

Clover (Grown for Seed)

1.9 MRID 44748102 

(sugar beet EC)

MN 5 1

OR 11 1

Perennial Grass Seed Crops

1.0 MRID 44748102 

(sugar beet EC)

MN 5 1

OR 11 1

Alfalfa

1.0

MRID 44748102 

(cotton EC) TX 5 and 7 1

Cotton

1.0

MRID 44748102 

(cotton EC)

CA 10 0 – 3

MS 4 0 - 1

TX 6 and 8 0 - 1

Peppermint/

Spearmint 2.0 MRID 44748102 

(sugar beet EC)

MN 5 0 - 1

OR 11 0 - 1

Wheat

1.0 MRID 44748102 

(sugar beet EC)

CA 8 1

MN 5 and 7 1

Soybean 1.0 MRID 44748102 

(cotton EC) MS 4 and 5 0 - 1

Sugar Beet

1.0 MRID 44748102 

(sugar beet EC)

CA 10 0 - 1

MN 5 0 - 1

OR 11 0 - 1

Field and Row 

Crops: Tall

Corn: Sweet

1.5

MRID 44748102 

(sweet corn EC)

IL 1 and 5 0 - 3

MN 1 and 5 0 - 3

OR 11 0 - 2

Corn: Sweet

1.0

MRID 44748102 

(sweet corn EC)

IL 1 and 5 0 - 3

MN 1 and 5 0 - 3

OR 11 0 - 2

Corn: Field, Including Grown for 

Seed 1.5

MRID 44748102 

(sweet corn EC)

IL 5 0 - 3

MN 5 0 - 3
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Crop Group Crop App. Rate 

(lbs ai/A)

DFR Data Source DFR 

Study 

Location

Growing 

Region

Estimated REI Range 

(days)

(Dermal LOC = 100)

Corn: Field, Including Grown for 

Seed 1.0

MRID 44748102 

(sweet corn EC)

IL 5 0 - 3

MN 5 0 - 3

Sorghum

1.0

MRID 44748102 

(sweet corn EC)

IL 5, 6, 7 and 8 0 - 1

MN 5, 6, 7 and 8 0 - 1

Sunflowers

1.5 MRID 44748102 

(sweet corn EC)

IL 5 and 7 1

MN 5 and 7 1

Tree Fruit: 

Deciduous

Apple 

(Dormant and Delayed Dormant) 2.0

MRID 44748101 

(apple WP)

CA 10 0 - 1

WA 11 0 - 2

NY 1, 2, 5 0 - 2

Cherry (Sweet)

(Dormant and Delayed Dormant) 2.0 MRID 44748101 

(apple WP)

CA 10 0 - 1

WA 11 0 - 2

NY 5 0 - 2

Cherry (Sour)

(Dormant and Delayed Dormant) 2.0 MRID 44748101 

(apple WP)

NY 1 and 5 0 - 2

Peaches

(Dormant and Delayed Dormant) 2.0 MRID 44748101 

(apple WP)

CA 10 0 - 1

NY 2 0 - 2

Pears

(Dormant and Delayed Dormant) 2.0 MRID 44748101 

(apple WP)

CA 10 0 - 1

WA 11 0 - 2

Nectarines, Plums, Prunes

(Dormant and Delayed Dormant) 2.0 MRID 44748101 

(apple WP) CA 10 0 - 1

Apples

1.5

MRID 44748101 

(apple WP)

CA 10 0 - 1

WA 11 0 - 4

NY 1, 2, 5 0 - 4

Cherries (Sour) 1.5 MRID 44748101 

(apple WP) NY 1 and 5

Peaches 

(Post-harvest) 3.0 MRID 44748101 

(apple WP)

CA 10 0 - 1

NY 2 0 - 2

Pears

(Post-harvest) 2.0 MRID 44748101 

(apple WP)

CA 10 0 - 1

WA 11 0 - 2

Tree Fruit: 

Evergreen

Conifer Trees and Christmas Tree 

Plantations 1.0 MRID 43062701 

(citrus EC) CA Any 0 - 1

Citrus 6.0

(CA and 

AZ)

MRID 43062701 

(citrus EC) CA 3 and 10 0 - 2
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Crop Group Crop App. Rate 

(lbs ai/A)

DFR Data Source DFR 

Study 

Location

Growing 

Region

Estimated REI Range 

(days)

(Dermal LOC = 100)

3.5 MRID 43062701 

(citrus EC) CA 3 and 10 0 - 1

Forestry

Cottonwood/ Poplar Trees Grown 

for Pulp

(Dormant)

2.0 MRID 44748101 

(apple WP)

WA 11 2

NY 1 and 7 2

Deciduous Trees (Plantations and 

Seed Orchards) 1.0 MRID 44748101 

(apple WP)

CA 1

WA 1

NY 1

Tree Nuts

Almonds 2.0 MRID 44748101 

(almond WP)

CA

(arid) 10 1

Almonds

(Dormant and Delayed Dormant)

2.0 MRID 44748101 

(almond WP)

CA

(arid) 10 1

Filberts

2.0

MRID 44748101 

(pecan EC) GA 12 0

Pecans

MRID 44748101 

(pecan EC)

GA 2 0

LA 6 0

TX 8 0

Walnuts MRID 44748101 

(pecan EC) TX 10 0

Filberts (Dormant and Delayed 

Dormant) 

2.0

MRID 44748101 

(pecan EC) GA 12 0

Walnuts (Dormant and Delayed 

Dormant) MRID 44748101 

(pecan EC) TX 10 0

Ornamentals/ 

Nurseries 

(Outdoor Only)

Deciduous Trees in Nurseries and 

Orchards Except Apples 

(Dormant and Delayed Dormant)

Non-bearing Apple Trees 

2.0 MRID 44748101 

(apple WP)

CA 10 0

WA 11 1

NY 1, 2, 5 1

Ornamentals/ 

Nurseries 

(Outdoor Only)

Non-bearing Citrus, Tree Nut and 

Cherry 4.0 MRID 43062701 

(citrus EC) CA 2, 3, 6, 8, 10, 12 0

Non-bearing Peach and Nectarine 

Trees 3.0 MRID 44748101 

(apple WP)

CA 10 1

NY 2 1
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Crop Group Crop App. Rate 

(lbs ai/A)

DFR Data Source DFR 

Study 

Location

Growing 

Region

Estimated REI Range 

(days)

(Dermal LOC = 100)

Conifers in Nurseries 1.0 MRID 43062701 

(citrus EC) CA Any 0

Field and Row 

Crops: Low to 

Medium 

(Outdoor Only)

Ornamentals 2.0 MRID 44748102 

(sugar beet EC)

CA Any 0 - 5

MN Any 0 - 6

OR Any 0 - 2

Vegetable: Root 

and Tuber

Carrot (Grown for Seed)

0.94 MRID 44748102 

(sugar beet EC)

CA 10 0 – 1

MN 3 and 5 0 – 1

Radish (Grown for Seed) 0.94 MRID 44748102 

(sugar beet EC) MN 3 and 5 0 – 1

Vegetable: 

Fruiting Pepper 1.0 MRID 44748102 

(cotton EC)

CA 9 and 10 0 - 2

MS 2 and 3 0 - 1

TX 8 0 - 1

Vegetable: Head 

and Stem 

Brassica

Broccoli, Brussel Sprout and 

Cauliflower

1.0

MRID 42974501 

(cauliflower WP) AZ 10

0 - 8

Cabbage MRID 42974501 

(cauliflower WP) AZ 1, 2 and 5

Vegetable: 

Leafy

Bok Choy 1.0 MRID 42974501 

(cauliflower WP) AZ 3 and 10

0 - 4

Collards, Kale, Kohlrabi 1.0 MRID 42974501 

(cauliflower WP) AZ 2

Stalk and Stem: 

Vegetable

Asparagus

1.0

MRID 44748102 

(sugar beet EC)

CA 10 0 – 1

MN 5 0 - 1

OR 11 0 - 1

Non-bearing Pineapple

1.9

MRID 44748102 

(cotton EC) MS 13 0 - 1

Vine/ Trellis

Grapes (Dormant and Delayed 

Dormant)

Grapes (Post-harvest and Prior to 

Budbreak)

2.0 MRID 43062701 

(citrus EC) CA 10 0

Turf

Turf for Sod and Seed

4.0

MRID 448296-01 

(turf EC and WP)

CA 10 1

IN 5 1

MS 2 and 6 1

Turf for Golf Course

1.0 MRID 448296-01 

(turf EC and WP)

CA 10 0

IN 5 0
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Crop Group Crop App. Rate 

(lbs ai/A)

DFR Data Source DFR 

Study 

Location

Growing 

Region

Estimated REI Range 

(days)

(Dermal LOC = 100)

MS 2 and 6 0

Field and Row 

Crops: Low to 

Medium

Soybeans 1.0 MRID 44748102 

(sweet corn G) IL 4 and 5 0

Sugar Beet

2.0 MRID 44748102 

(sweet corn G)

IL 5 0

OR 10 and 11 0 - 1

Peanuts 4.0 MRID 44748102 

(sweet corn G) IL 2 and 6 0 - 1

Field and Row 

Crops: Tall

Corn: Sweet

1.0 MRID 44748102 

(sweet corn G)

IL 1 and 5 0

OR 11 0

Corn: Field and Grown for Seed 1.0 MRID 44748102 

(sweet corn G) IL 5 0

Nursery

Woody Ornamentals (In 

Container and Field Grown) 6.0 MRID 44748102 

(sweet corn G)

IL Any 0

OR

Turf

Turf for Sod or Seed

1.0

MRID 448296-01 

(turf G and fertilizer) CA Any

0

Golf Course

0

Greenhouse 

(Microencap. 

Formulations)

Commercial Ornamentals, 

Greenhouse Production: Bedding 

Plants, Cut Flowers, Flowering 

Hanging Baskets, Potted Flowers, 

Ornamentals, Trees and Shrubs 1.4

MRID 46722702 

(smooth ornamentals 

ME)

MO Any 0 to > 35

Greenhouse 

(Total Release 

Fogger and.

Liquid 

Concentrate 

Formulations)

Ornamentals 2

MRID 46722701 

(hairy ornamentals 

ME)

MO Any 18 to > 30

Commercial Ornamentals, 

Greenhouse Production: Bedding 

Plants, Cut Flowers, Flowering 

Hanging Baskets, Potted Flowers, 

Ornamentals, Trees and Shrubs 

0.01 lb ai/

fogger/

3,000 sq ft

0.15 lb ai/A

MRID 46722701 

(hairy ornamentals 

ME)

MO Any 2 - 22
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Characterization of Occupational Post-Application Risk Assessment

The occupational post-application exposure and risk assessment for chlorpyrifos is based upon 

an array of calculations completed for 15 different crop groups. These unique crop groupings are 

defined essentially based on the nature of the crop where a work activity would take place. 

Within each of these groupings, ranges of transfer coefficients were considered to reflect 

differences in exposures that would be associated with the variety of cultural practices required 

to produce the crop/product. Transfer coefficients are used ―generically‖ to allow for estimation 

of exposure for any pesticide active ingredient using estimates for exposure time and the 

concentration of residue the workers will contact that is specific to the pesticide of interest. The 

Agency has adopted a method of clustering groups, crop growth stages, and post-application 

activities into groups that are expected to result in comparable exposure. Chlorpyrifos postapplication exposures were estimated over subsequent days after application to reflect residue 

dissipation over time in the environment and to allow for a more informed risk management 

decision. 

The exposure data used in the chlorpyrifos post-application exposure and risk assessment 

represent the best data and approaches that are currently available. The latest HED transfer 

coefficients have been used to complete the assessment, as referenced from the Science Advisory 

Council for Exposure (ExpoSAC) Policy Number 3.2: Agricultural Transfer Coefficients 

(5/5/11). Most of the transfer coefficient values in Policy 3.2 are based on the work of the 

Agricultural Reentry Task Force (ARTF). The choice of post-application activities studied by the 

ARTF, as well as the subsequent assignment of transfer coefficients derived from these studies to 

non-monitored post-application activities was developed with input from both the ARTF and 

HED staff Agency and reviewed by the FIFRA SAP in 2008. It is possible that there are 

exposure scenarios not addressed by HED either due to the lack of appropriate exposure data or 

because the transfer coefficient model is not appropriate or little or no foliar contact is associated 

with a specific activity. Furthermore, unlike the vast majority of crop-activity combinations 

listed under the Transfer Coefficient Table in Policy 3.2, some common agricultural activities do 

not follow the standard ―foliar-based‖ transfer coefficient methodology. This should not be 

interpreted to mean that there is no potential exposure from these activities but rather that ―foliarbased‖ transfer coefficients are not applicable to evaluate worker exposure. For example, the 

crop-activity combinations of mechanical windrowing, mechanical sweeping and dormant hand 

pruning for the ―nut tree‖ crop grouping are standard cultural practices; however, do not follow 

the standard transfer coefficient methodology. 

HED completed the assessment of occupational post-application exposure and risk to 

chlorpyrifos using 7 chemical-specific DFR studies submitted by the registrant in support of the 

re-registration of chlorpyrifos. The studies, which encompass the use of five different 

formulations and twelve different crops, have been extrapolated to other groups based on the 

nature of the crop and application method and used to calculate risks for post-application 

workers in every region of the county. It is standard practice for the Agency to use these kinds 

of studies in this manner. Furthermore, it is possible that the use of the 7 chemical specific DFR 

studies to represent all crops and regions within the country could lead to results that do not 

reflect actual use practices and conditions in some parts of the country. Furthermore, the 

extrapolation of DFR data from one crop may not represent precisely the dissipation of another. 
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For example, DFR data which measured the dissipation of chlorpyrifos from cotton after 

application of an emulsifiable concentrate were used to represent dissipation of chlorpyrifos from 

soybeans which like cotton, are classified in the low/medium field row crop grouping. HED 

assumes that residue dissipation monitored in available studies approximates residues from like 

crops, but the extent that these residues might be an under- or over-estimate is unknown. 

Finally, DFR data for several crops were conducted in multiple states reflective of the regions of 

the country where the crops are typically grown and chlorpyrifos is used. HED has presented all 

state-specific DFR data for each crop under the assumption that these data accurately reflect 

dissipation anticipated in the different regions of the country (e.g., the subtropical Southeastern 

U.S. and the semi-arid climate of the Central Valley of California). HED has considered 

available use and usage information in development of the occupational post-application 

assessment and has refined the use of available region-specific DFR data to those areas of the 

U.S. where chlorpyrifos usage occurs. 

In summary, the Agency believes that the risk values presented in this post-application 

assessment represent the highest quality results that could be produced given the exposure, use, 

and toxicology data that are available. Risk managers and other interested parties should consider 

the quality of individual inputs when interpreting the results and make decisions accordingly. It 

is difficult to determine where on a distribution the values which have been calculated fall 

because the distributional data for exposure, residue dissipation and many other parameters are 

unrefined. The Agency does believe, however, that the risks represent conservative estimates of 

exposure because maximum application rates are used to define residue levels upon which the 

risk calculations are based and most maximum application rates exceed what is assumed to be 

typical.

9.2.2 Inhalation Post-application Risk

There are multiple potential sources of post-application inhalation exposure to individuals 

performing post-application activities in previously treated fields. These potential sources

include volatilization of pesticides and resuspension of dusts and/or particulates that contain 

pesticides. The Agency sought expert advice and input on issues related to volatilization of 

pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel 

(SAP) in December 2009, and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. 

However, based on the Agency's current practices, a quantitative post-application inhalation 

exposure assessment is not typically performed for a chemical when it is characterized by low 

acute inhalation toxicity (Toxicity Category III and IV) and low vapor pressure. Chlorpyrifos 

does not fit into these categories as it is classified as Toxicity Category II for inhalation toxicity 

and has a moderate vapor pressure of 1.9 x 10-5 mm Hg at 25o C. The inhalation exposure 

potential from occupational/commercial post-application activities may be elevated based upon 

these criteria. A quantitative occupational post-application inhalation exposure assessment was 
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not performed for chlorpyrifos; however, an inhalation exposure assessment was performed for 

occupational/commercial handlers. It is expected that while many of these handler inhalation 

exposure estimates are of concern to HED, exposure and risk from occupational post-application 

inhalation would be of no greater concern than occupational handler inhalation estimates. 

Chlorpyrifos can be used in indoor facilities as well as agricultural/commercial outdoor uses. 

Indoor use sites for chlorpyrifos include greenhouse use, indoor commercial uses (e.g., 

warehouses, indoor industrial sites) and commercial seed treatment facilities. HED has not 

assessed post-application inhalation exposure for greenhouses due to requirements for high air 

exchange rates and ventilation regulations. The Worker Protection Standard for Agricultural 

Pesticides contains requirements for protecting workers from inhalation exposures during and 

after greenhouse applications through the use of ventilation requirements [40 CFR 170.110, (3) 

(Restrictions associated with pesticide applications)]. Furthermore, HED assumes that 

commercial applicators do not typically return to the treated areas after an indoor use site 

pesticide application and thus an occupational post-application inhalation exposure assessment 

was not performed for commercial applicators. Seed treatment assessments provide quantitative 

inhalation exposure assessments for seed treaters and secondary handlers (i.e. planters). It is 

expected that these exposure estimates would be protective of most post-application inhalation

exposure scenarios.

9.2.3 ORE Evaluation of Chlorpyrifos-oxon

HED has considered the exposure potential for occupational and residential exposure to 

chlorpyrifos-oxon. Workers re-entering an environment previously treated with chlorpyrifos 

(occupational post-application) and the general population residing near chlorpyrifos application 

sites (bystanders) could potentially be exposed to the oxon as chlorpyrifos is metabolized in the 

environment. Dermal exposure to the oxon could occur through contact with chlorpyrifos 

treated surfaces and inhalation exposure through airborne oxon. However, the likelihood of 

exposure to the oxon is slight due to its rapid deactivation to TCP in the environment. In an 

effort to further explore the potential for oxon exposure, HED has researched and reviewed all 

available information sources. Chlorpyrifos and chlorpyrifos-oxon were measured in several air 

monitoring studies. A search of open literature resulted in 4 metabolism studies which measured 

whole fruit and leaf surface residue of chlorpyrifos and chlorpyrifos-oxon. [See W. Britton, 

6/27/11, D388165, Chlorpyrifos: Occupational and Residential Exposure Assessment, Section 4

for a full discussion of study results and conclusions.]

The Agency has considered the potential for occupational and residential exposure to 

chlorpyrifos-oxon. Workers re-entering an environment previously treated with chlorpyrifos 

(occupational post-application) and the general population residing near chlorpyrifos application 

sites (bystanders) could potentially be exposed to the oxon as chlorpyrifos is degraded in the 

environment. Dermal exposure to the oxon could occur through contact with chlorpyrifos treated 

surfaces and inhalation exposure through airborne oxon. However, the likelihood of exposure to 

the oxon is slight due to its rapid deactivation to TCP (3,5,6-trichloro-2-pyridinol). In an effort 

to further explore the potential for oxon exposure, EPA has researched and reviewed all available 

information sources. Based upon this review, EPA intends to require additional studies to 
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address uncertainties regarding the formation of chlorpyrifos-oxon in the air post-application and 

its formation and decay in greenhouses.

Dermal exposure to the oxon on foliar surfaces from reentry into an outdoor environment 

previously treated with chlorpyrifos is not anticipated and, therefore, has not been assessed. 

However, HED is concerned, based on study results, that the formation of the oxon may be 

greater and its deactivation slower in greenhouses when compared to the outdoor environment 

and that an assessment may be needed for exposure to the oxon in greenhouse settings. In order 

address these uncertainties and more accurately address the risk potential for exposure from 

occupational reentry into greenhouses treated with chlorpyrifos, HED requires a study to 

measure chlorpyrifos and oxon residues on leaf surfaces following treatment with a liquid 

formulation of chlorpyrifos in greenhouses. 

9.2.4 Comparison of the Chlorpyrifos 2000 Risk Assessment and 2011 Preliminary Risk 

Assessment

Table 28 and Table below present a range of resulting occupational handler risk estimates 

(MOEs) for both the current preliminary (2011) chlorpyrifos assessment and the June 2000 

chlorpyrifos assessment for comparison purposes. The range represents a low, medium, and high 

exposure scenario. Also presented is a range of personal protection (single layer/gloves, double 

layer/gloves, and engineering controls). Table 28 shows the short-term and intermediate –term 

dermal risk estimates and Table 29 shows the short-term and intermediate –term inhalation risk 

estimates.

The dermal handler risk estimates remain unchanged between the 2000 and 2011 assessments 

since the dermal PoD is the same (NOAEL of 5 mg/kg/day from a dermal study). The 2008 SAP 

concurred with the selection of this PoD for assessing dermal scenarios. 

The inhalation PoD in 2000 was 0.1 mg/kg/day (NOAEL based on inhalation studies). That 

same PoD is used in the current assessment except that it has been converted to an HEC (human 

equivalent concentration). This resulted in the reduction of the default database uncertainty 

factor for interspecies extrapolation from a 10x to a 3x. Thus the level of concern MOE for this 

assessment is 30 (compared to 100 in 2000). In addition the NOAEL was corrected to account 

for an 8 hour workday because worker exposure is expected to occur during the course of an 

average workweek (8 hours/day and 5 days/week; animals were exposed 6 hours a day in the 

study). The inhalation handler risk estimates have changed since the 2000 assessment. This can 

be mainly attributed to the use of the HEC in the preliminary assessment.

Note that the actual dermal and inhalation MOEs presented in the 2000 assessment may differ 

somewhat than those presented here since some of the exposure assumptions used today may 

vary due to refinements made since 2000. The 2011 exposure assumptions were compared to the 

2000 PoD for illustrative purposes only.
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Table 28 Comparative Analysis of Occupational Handler Exposure Estimates Considering 2000/2011 Dermal PoDs Using Low, Medium 

and High Level Representative Scenarios

Level Exposure Scenario Target

App. 

Ratea

(lb ai/A)

Level of Personal Protection – Risk Estimates (MOE)

Single Layer1, 

Gloves

Double Layer2, 

Gloves

Engineering 

Control

Risk Estimates with 2011 Assessment Dermal PoD (5 mg/kg/day)

Low Groundboom Applications Non-Crop Areas (Industrial Plant Sites, 

Road Medians, and Sod Farms), Turfgrass 0.25 1,100 1,400 3,400

Mediu

m

Mixing/Loading Liquids for 

Groundboom Application Asparagus, Brussel Sprouts, Sugarbeet 1.0 120 150 510

High Airblast Applications Citrus (CA and AZ) 6.0 6 11 77

Risk Estimates with 2000 Assessment Dermal PoD (5 mg/kg/day)

Low Groundboom Applications Non-Crop Areas (Industrial Plant Sites, 

Road Medians, and Sod Farms), Turfgrass 0.25 1,100 1,400 3,400

Mediu

m

Mixing/

Loading Liquids for 

Groundboom Application

Asparagus, Brussel Sprouts, Sugarbeet 1.0 120 150 510

High Airblast Applications Citrus (CA and AZ) 6.0 6 11 77

1. Single layer (long-sleeve shirt, long pants, shoes, socks), chemical resistant gloves

2. Double layer (single layer clothing with the addition of coverall), chemical resistant gloves
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Table 29 Comparative Analysis of Occupational Handler Exposure Estimates Considering 2000/2011 Inhalation PoDs Using Low, 

Medium and High Level Representative Scenarios

Level Exposure Scenario Target

App. 

Ratea

(lb ai/A)

Level of Personal Protection – Risk Estimates (MOE)

No 

Respirator

PF51

Respirator

PF102

Respirator

Engineering 

Control

Risk Estimates with 2011 Assessment Inhalation PoD (0.56 mg/kg/day) – LOC is an MOE = 30

Low Groundboom Applications

Non-Crop Areas (Industrial Plant Sites, 

Road Medians, and Sod Farms), 

Turfgrass 

0.25 5,800 29,000 58,000 46,000

Mediu

m

Mixing/

Loading Liquids for 

Groundboom Application

Asparagus, Brussel Sprouts, Sugarbeet 1.0 2,200 11,000 22,000 5,900

High Airblast Applications Citrus (CA and AZ) 6.0 36 180 360 1,800

Risk Estimates with 2000 Assessment Inhalation PoD (0.1 mg/kg/day) – LOC is an MOE =100

Low Groundboom Applications

Non-Crop Areas (Industrial Plant Sites, 

Road Medians, and Sod Farms), 

Turfgrass 

0.25 1,100 5,100 10,000 8,100

Mediu

m

Mixing/

Loading Liquids for 

Groundboom Application

Asparagus, Brussel Sprouts, Sugarbeet 1.0 400 2,000 4,000 1,100

High Airblast Applications Citrus (CA and AZ) 6.0 6 32 65 320

1. Single layer (long-sleeve shirt, long pants, shoes, socks), chemical resistant gloves

2. Double layer (single layer clothing with the addition of coverall), chemical resistant gloves
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10.0 Incident Report

One component of the Agency’s registration review program is consideration of human 

observational information including incident data, medical case reports, general medical 

information, biomonitoring data, and epidemiology studies. In conjunction with a human health 

risk assessment based on other data sources, such human incident and other human data can 

assist the Agency in better defining and characterizing the risk of pesticides/pesticide products. 

Based on the frequency and the effects noted in the Agency’s earlier scoping or Tier I incident 

assessment (Hawkins M. and Cordova J., 10/15/2008), the Agency determined that chlorpyrifos 

human incident data are an important source of information to consider in its updated

chlorpyrifos risk assessment.

HED has prepared a chlorpyrifos incident report review (S. Recore et al., 6/27/11, D388406, 

Chlorpyrifos: Tier II Incident Report). The review considers a variety of types and sources of 

human observational information including human incident data, medical data/case report 

information, and epidemiological information in an effort to inform the re-evaluation of 

chlorpyrifos in this phase of registration review. The human incident databases that were 

reviewed are:

the OPP Incident Data System (IDS); 

the National Pesticide Information Center (NPIC); 

NIOSH’s Sentinel Event Notification System for Occupational Risks (SENSOR); 

the California Pesticide Illness Surveillance Program Incident Data (CA PISP). 

Together, these databases indicate that the number of incidents associated with 

chlorpyrifos declined post-2002, correlating well with the phase out/cancellation of the almost all 

chlorpyrifos residential products in December 2001. In addition, the Agency's findings are 

consistent with other incident cases investigations of American Association of Poison Control 

Centers (AAPCC) data which have reported a decrease in the number of chlorpyrifos incidents 

that is temporally associated with the phase out/cancellation of most residential chlorpyrifos 

products. 

While the chlorpyrifos incidents are reported to have declined substantially (95%) among 

residential users from 2002 to 2010, it is unclear if occupational incidents have also decreased.

Specifically, chlorpyrifos occupational incidents, reported in CA PISP and SENSOR databases, 

appear to be constant over time, despite risk mitigation implemented including reduced 

application rates and seasonal maximum limits, increased retreatment intervals, increased PPE 

and/or use of engineering controls which were required as well as increased reentry intervals 

(REIs) for a number of crops. However, a number of these incidents appear to be due to 

accidents and misuse. Overall, the NIOSH SENSOR database indicated that the largest number 

of incidents are exposures due to actual application of chlorpyrifos, but California PISP data 

suggests that drift of chlorpyrifos to adjacent fields appears to be the largest contributor to 

occupational exposure. OPP will continue to monitor these incidents and remain alert for any 

changes in trend or patterns.
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In addition to the incident/poisoning data and medical case reports, epidemiological research can 

be an important source for human observational data and can potentially assist in identifying, 

characterizing, and (ideally) quantifying linkages between human exposures and resulting health 

effects. For chlorpyrifos, epidemiological data is available from both the Agricultural Health 

Study (AHS) and from a variety of university-based research groups. While the AHS 

investigations currently published were hypothesis-generating in nature, initial strength and 

consistency in the findings for lung cancer and colorectal cancer are notable, and warrant further 

follow-up and additional research. Preliminary associations with breast and prostate cancer are 

weak, but also warrant monitoring the literature for additional publications on this association. 

There is no compelling evidence of an association with other cancer sites including pancreatic 

cancer, melanoma, brain, esophageal, kidney, all lymphohematopoietic cancers combined and 

NHL, leukemia, and multiple myeloma (C. Christensen, 6/16/11, D388167).

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Holland NT. (2005). Association between in utero organophosphate pesticide exposure and 

abnormal reflexes in –neonates. NeuroToxicology 26 199–209 

Zheng, Q., Olivier, K., Won, Y. K., and Pope, C. N. (2000). Comparative cholinergic neurotoxicity of 

oral chlorpyrifos exposures in preweanling and adult rats. Toxicol Sci 55, 124-32. 
Chlorpyrifos Preliminary Human Health Risk Assessment DP No. D388070

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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) chlorpyrifos are in the table below. Use of the new guideline numbers does not 

imply that the new (1998) guideline protocols were used.

Study

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 Sub-chronic (rodent)..............................................

870.3150 Oral Sub-chronic (non-rodent) ......................................

870.3200 21-Day Dermal ..............................................................

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

870.3465 90-Day Inhalation..........................................................

yes

yes

yes

CR

CR

yes

yes

yes+

--

yes

870.3700a Developmental Toxicity (rodent)...................................

870.3700b Developmental Toxicity (non-rodent) ...........................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent) ..............................................

870.4100b Chronic Toxicity (non-rodent).......................................

870.4200a Oncogenicity (rat)..........................................................

870.4200b Oncogenicity (mouse)....................................................

870.4300 Chronic/Oncogenicity....................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.....................

870.5300 Mutagenicity—Gene Mutation - mammalian................

870.5375 Mutagenicity—Structural Chromosomal Aberrations...

870.5395 Mutagenicity—Other Genotoxic Effects (MN Assay) ..

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)...............................

870.6100b 90-Day Neurotoxicity (hen)...........................................

870.6200a Acute Neurotoxicity Screening Battery (rat) .................

870.6200b 90-Day Neurotoxicity Screening Battery (rat)...............

870.6300 Developmental Neurotoxicity........................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

no, but 

upgradeable*

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration ........................................................

870.7800 Immunotoxicity .............................................................

yes

CR

yes

yes

yes

yes

Special Studies Comparative Cholinesterase Assay yes yes

CR: Conditionally Required, *Performed, But Guideline-Unacceptable Rating, Upgradeable if additional 

morphometric data is submitted

+Satisfied Guideline 82-2, but not 870.3200 since N<10/sex
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A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile - Test Substance 

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute Oral LD50 - rat 44209101 223 mg/kg M&F II

870.1200

Acute Dermal LD50 - rat Acute 

Dermal LD50 - rabbit

Accession 

No. 

112115 

44209102 

202 mg/kg >5000 

mg/kg 

II, IV

870.1300

Acute Inhalation LC50; rat 

Supplementary

00146507 

and 

Accession 

No. 

257590 

LC50 > 0.2 mg/L 

(200 mg/m3) 

(nominal 

concentration) 

II

870.2400

Eye Irritation - rabbit 44209103 

slight irritation 

resolved within 24 

hours 

IV

870.2500

Dermal Irritation - rabbit 44209104 

mild irritant; 

(irritation resolved 

within 7 days) 

IV

870.2600 Dermal Sensitization - guinea pig 44209105 non-sensitizing NA
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Table A.2.2 Chlorpyrifos Sub-chronic, Chronic and Special Studies Toxicity Profile

Guideline No. Study Type MRID# / Classification /Doses Results

870.3100 90-Day Oral Toxicity 

(Rat)

MRID #: 40436406

Acceptable/guideline

0, 0.025, 0.5, or 10 mg/kg/day

(0, 0.5, 10 or 200 ppm)

95.5% a.i. chlorpyrifos

NOAEL ChEI: none for plasma ChEI due to reductions in male 

plasma enzymes at 0.025 mg/kg/day

LOAEL ChEI: 0.025 mg/kg/day (significant 22% in plasma ChE 

activity that was dose-related)

NOAEL (systemic): 0.5 mg/kg/day

LOAEL (systemic): 10 mg/kg/day

Effects: decreased weight gain and slight decreases in packed cell 

volume, red cells and hemoglobin

Note: Female ChEI data is unreliable due to a possible reporting 

error. RBC and brain ChE activity were not measured.

870.3100 90-Day Oral Toxicity 

(Rat)

MRID #: 40952801

Acceptable/guideline

0, 0.1, 1, 5 or 15 mg/kg/day

95.7 - 98.5% a.i. chlorpyrifos

NOAEL: 0.1 mg/kg/day (plasma and RBC ChEI)

LOAEL: 1 mg/kg/day (significant plasma and RBC ChEI in both 

sexes)

Effects: increased organ weights (brain and heart), and reduced 

weight gain at 15 mg/kg/day and increased adrenal gland 

vacuolation and significant brain ChEI in both sexes 5 and 15 

mg/kg/day. 

870.3150 Sub-chronic Oral 

(capsule) in Beagle Dogs

MRID #: 42172801

Acceptable/guideline

0, 0.01, 0.22, or 5 mg/kg/day

95.8% a.i. chlorpyrifos

NOAEL: 0.01 mg/kg/day

LOAEL: 0.22 mg/kg/day (significant 33-67% plasma and 24-

46% RBC ChEI)

Effects: Brain ChEI (46% ) occurred at 5 mg/kg/day.

Comments: At 0.01 mg/kg/day, plasma ChEI noted in females 

(significant 20-24% at week 6, and non-significant 24% at week 

12) and males (15% at week 13) that was not considered of 

sufficient magnitude and consistency to be biologically and 

toxicologically meaningful.
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Table A.2.2 Chlorpyrifos Sub-chronic, Chronic and Special Studies Toxicity Profile

Guideline No. Study Type MRID# / Classification /Doses Results

870.3200 21-Day Dermal Toxicity 

Study in Rats

MRID # 40972801

Satisfies Guideline 82-2, but has less 

than 10 animals/sex for 870.3200

0, 0.1, 0.5, 1 or 5 mg/kg/day (21 day 

study)

0, 1, 10, 100 or 500 mg/kg/day (4-

day dermal probe study)

100% pure chlorpyrifos

NOAEL: 5 mg/kg/day (plasma and RBC ChEI)

LOAEL: 10 mg/kg/day (45% plasma and 16% RBC ChEI 

following 4 days of exposure)

NOAEL (systemic): 5 mg/kg/day

LOAEL (systemic): Not Identified

Effects: Slight erythema in 2/4 females at 1 and 10 mg/kg/day, 

respectively.

4-day Dermal Probe Study as well

870.3465 90-Day, Sub-chronic 

Inhalation in Rats (nose 

only)

MRID # 40013901 & 40166501

Acceptable/guideline

0, 5.2, 10.3 or 20.6 ppb (0, 72, 143 or 

287 μg/m3) (maximum dose 

equivalent to 0.044-0.082 mg/kg/day)

100% pure chlorpyrifos

NOAEL: not identified (ChEI and systemic)

LOAEL: not identified at highest attainable vapor concentration 

(>20.6 ppb or >0.082 mg/kg/day or >287 μg/m3) (ChEI and 

systemic)

870.3465 90-Day, Sub-chronic 

Inhalation in Rats (nose 

only)

MRID # 40908401

Acceptable/guideline

0, 5, 10 or 20 ppb (0, 70, 143 or 287 

μg/m3) (equivalent to 0, 0.024, 0.048 

or 0.097 mg/kg/day, respectively)

95% a.i. chlorpyrifos

NOAEL: not identified (ChEI and systemic)

LOAEL: not identified at highest attainable vapor concentration 

(>20 ppb or 0.097 mg/kg/day) (ChEI and systemic)

870.3700a Developmental Study in 

CD rats (gavage) 

MRID# 40436407

Acceptable/guideline

0, 0.5, 2.5 or 15 mg/kg/day

(gestation day 6-15)

96.1% a.i. chlorpyrifos

Maternal NOAEL: none observed for plasma ChEI; 2.5 mg/kg/day 

for systemic

Maternal LOAEL: 0.5 mg/kg/day (decreased plasma ChEI); 15 

mg/kg/day (systemic) based on decreased food consumption (only 

the first few days of dosing) and body weight during dosing.

Developmental NOAEL: 2.5 mg/kg/day

Developmental LOAEL: 15 mg/kg/day (HDT) based on an 

increase in post-implantation loss.

Comments: RBC and brain ChE were not measured.
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Table A.2.2 Chlorpyrifos Sub-chronic, Chronic and Special Studies Toxicity Profile

Guideline No. Study Type MRID# / Classification /Doses Results

870.3700a Developmental Study in 

F344 rats (gavage)

MRID# 00130400

Acceptable/guideline

0, 0.1, 3, or 15 mg/kg/day (gestation 

day 6-15)

96.6% a.i. chlorpyrifos

Maternal NOAEL: 0.1 mg/kg/day (plasma and RBC ChEI)

Maternal LOAEL: 3 mg/kg/day (90.3% plasma and 74.3% RBC 

ChEI)

Developmental NOAEL: 15 mg/kg/day (HDT)

Developmental LOAEL: Not Identified 

870.3700a Developmental Study in 

CF-1 Mice (gavage)

MRID# 00095268

Unacceptable/Non-guideline

0, 0.1, 1, 10, or 25 mg/kg/day 

(gestation day 

6-15)

96.8% a.i. chlorpyrifos

Maternal NOAEL: 0.1 mg/kg/day (plasma and RBC ChEI); 10 

mg/kg/day (systemic toxicity)

Maternal LOAEL: 1 mg/kg/day (plasma and RBC ChEI);

25 mg/kg/day (systemic toxicity) based on decreased body weight, 

food and water consumption, and increased mortality.

Developmental NOAEL: 1 mg/kg/day (plasma and RBC ChEI); 10 

mg/kg/day for systemic toxicity

Developmental LOAEL: 10 mg/kg/day (plasma and RBC ChEI); 

25 mg/kg/day (systemic toxicity) based on minor skull variations, 

delayed ossification of skull bones and sternebrae and reduced 

fetal body length.

Comments: Brain ChE not measured.

870.3700b Developmental Study in 

New Zealand rabbits 

(gavage)

MRID# 40436408

Acceptable/guideline

0, 1, 9, 81, or 140 mg/kg/day 

(gestation day 

7-19)

96.1% a.i. chlorpyrifos

Maternal NOAEL: none observed for plasma ChEI; 81 for 

systemic toxicity

Maternal LOAEL: 1 mg/kg/day (plasma ChEI); 140 for systemic 

toxicity based on reduced food consumption, body weight loss, 

and apparent post-implantation loss. 

Developmental NOAEL (systemic): 81 mg/kg/day

Developmental LOAEL (systemic): 140 mg/kg/day based on 

slightly decreased fetal weights and crown-rump lengths, and an 

increased incidence of unossified xiphisternum and/or 5th

sternebra.
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Table A.2.2 Chlorpyrifos Sub-chronic, Chronic and Special Studies Toxicity Profile

Guideline No. Study Type MRID# / Classification /Doses Results

870.3800 2-Generation 

Reproduction Toxicity in 

SD Rats

MRID# 41930301 

Acceptable/guideline

0, 0.1, 1, or 5 for 10 mg/kg/day (F0) 

or 12 (F1) weeks prior to mating, 

through lactation and weaning

97.8-98.5% a.i. chlorpyrifos

Parental NOAEL: 0.1 mg/kg/day

Parental LOAEL: 1 mg/kg/day (significant 43-59% plasma, and 

65-69% RBC ChEI at 1 mg/kg/day; and 48-49% brain ChEI and 

histological lesions of the adrenal gland at 5 mg/kg/day). 

Reproductive NOAEL: 1 mg/kg/day

Reproductive LOAEL: 5 mg/kg/day (HDT) based on reduced pup 

weight and increased pup mortality in F1 generation only.

870.3800 3-Generation 

Reproduction Toxicity in 

SD Rats

MRID # 00029064, 00064934

Acceptable/guideline

0, 0.03, 0.1,or 0.3 mg/kg/day for first 

generation, and 0.1, 0.3 or 1 

mg/kg/day for second and third 

generation

Parental NOAEL: 0.1 mg/kg/day

Parental LOAEL: 0.3 mg/kg/day (plasma and RBC ChEI) 

Reproductive NOAEL: 1 mg/kg/day (HDT)

Reproductive LOAEL: Not Identified

870.3800 Reproduction Study in 

Rats

MRID# 00130401

Acceptable in combination with 

studies 00029064 & 00064934

0, 0.5, 0.8, 1.2 mg/kg/day in 

Sprague-Dawley Rats

NOAEL Neonatal Survival: 1.2 mg/kg/day

(Primary purpose of the study)

NOAEL Reproduction: 1.2 mg/kg/day

NOAEL General Toxicity: 0.8 mg/kg/day

LOAEL General Toxicity: 1.2 mg/kg/day based on decreased 

weight gain in males

870.4100a Chronic feeding study in 

CD-1 mice (2 yrs)

MRID # 00054352 & 00142902 

(Accession No. 242059)

Acceptable/guideline

0, 0.5, 5 or 15 ppm (highest dose 

tested is 2.25 mg/kg/day)

99.6% a.i. chlorpyrifos

LOAEL: 2.25 mg/kg/day (90% plasma, and 50% RBC ChE 

activity relative to controls after 1 week)

NOAEL(systemic) = 2.25 mg/kg/day

LOAEL (systemic): Not Determined

Effects: no systemic effects observed at highest dose tested (HDT). 

No treatment-related tumors. ChE only measured at 15 ppm (2.25 

mg/kg/day) after 1 and 4 weeks.
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Table A.2.2 Chlorpyrifos Sub-chronic, Chronic and Special Studies Toxicity Profile

Guideline No. Study Type MRID# / Classification /Doses Results

870.4100b Chronic feeding study in 

beagle dogs (2 yrs)

MRID # 00064933 & 00146519

Acceptable/guideline

0, 0.01, 0.03, 0.1, 1 or 3 mg/kg/day

97.2-98.8% a.i. chlorpyrifos

NOAEL: 0.01, 0.03, & 1 mg/kg/day for plasma, RBC and brain 

ChEI, respectively

LOAEL (plasma ChEI): 0.03 mg/kg/day (mostly significant mean 

of 23-29% at 1 year and 10-24% at 2 years)

LOAEL (RBC ChEI): cannot be established due to data quality 

issues

LOAEL (brain ChEI): 3 mg/kg/day (19.4-20.8% at 2 yr) 

NOAEL (systemic): 1 mg/kg/day

LOAEL (systemic): 3 mg/kg/day

Effects: increased absolute and relative liver weights that could be 

an adaptive response

870.4200a Carcinogenicity /chronic 

feeding study in F344 rats 

(2 yrs)

MRID # 42172802

Acceptable/guideline

Males: 0, 0.0132, 0.33 or 6.99 

mg/kg/day 

Females: 0, 0.0146, 0.365 or 7.78 

mg/kg/day

(0, 0.2, 5 or 100 ppm)

96.1% a.i. chlorpyrifos

NOAEL:0.0132 mg/kg/day

LOAEL: 0.33 mg/kg/day (significant 15-51% plasma ChEI in 

both sexes, 19-31% RBC ChEI at 104 weeks vs. controls and 11-

17% RBC ChEI vs. vehicle controls)

NOAEL (systemic):0.33 mg/kg/day

LOAEL (systemic): 6.99 mg/kg/day

Effects: decreased body weights in males and females, and 

cataracts, and diffuse retinal atrophy in females. No evidence of 

carcinogenicity.
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Table A.2.2 Chlorpyrifos Sub-chronic, Chronic and Special Studies Toxicity Profile

Guideline No. Study Type MRID# / Classification /Doses Results

870.4200a Carcinogenicity /chronic 

feeding study in F344 rats 

(2 yrs)

MRID # 40952802

Acceptable/guideline

0, 0.05, 0.1, 1 or 10 mg/kg/day

Lorsban 98.5% pure

NOAEL: 0.1 mg/kg/day (plasma and brain ChEI)

LOAEL: 1 mg/kg/day (significant 39-86% plasma, 14-34% RBC 

and 5-9% brain ChEI)

NOAEL (systemic): 1 mg/kg/day

LOAEL (systemic): 10 mg/kg/day

Effects: decreased body weight gain, red blood cells, hemoglobin, 

cholesterol, protein, and globulin, and increased platelets and 

specific gravity, increased adrenal gland weight, and fatty 

vacuolation of the zona fasciculata. No evidence of 

carcinogenicity.

870.4200b Carcinogenicity/ chronic 

feeding study in CD-1 

mice (78 weeks)

MRID # 42534201

Acceptable/guideline

Males: 0, 0.89, 8.84, 45.2 mg/kg/day

Females: 0, 0.938, 9.79, or 48.1 

mg/kg/day

(0, 5, 50 or 250 ppm)

95.5% a.i. chlorpyrifos

NOAEL: none for ChEI

LOAEL: 0.89 males; 0.938 females mg/kg/day (significant 45-

51% plasma ChEI in both sexes)

NOAEL (systemic): 8.84 males, 9.79 females mg/kg/day (50 ppm)

LOAEL (systemic): 48.1 females, 45.2 males mg/kg/day (HDT; 

250 ppm)

Effects: decreased body weight gain and food consumption in 

males, decreased water consumption in females, increased 

incidences of keratitis and hepatocyte fatty vacuolation, and 

increased incidence of gross clinical findings (ocular opacity and 

hair loss) in both sexes. Brain cholinesterase was inhibited at the 

high dose in both sexes. No evidence of carcinogenicity. Brain 

ChEI at high dose.

Note: The validity of the RBC ChE assay is questionable.
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Table A.2.2 Chlorpyrifos Sub-chronic, Chronic and Special Studies Toxicity Profile

Guideline No. Study Type MRID# / Classification /Doses Results

870.5100 Gene Mutation

Bacterial Cell (Ames 

Reversion)

MRID# 00157058 and 40436411

Acceptable/guideline

Tested in Salmonella strains TA 98, 

TA 100, TA 1535, TA 1537 and TA 

1538 in the presence and absence of 

S-9 at concentrations of 30, 100, 300, 

1000, 3000 and 10000 μg/plate

Negative for reverse mutations

Positive controls caused appropriate mutagenic responses.

870.5300 Gene Mutation 

Mammalian Cell

(CHO Cells/HGPRT)

MRID# 00152683 and 40436410

Acceptable/guideline

Tested for gene mutation potential at 

0, 10, 20, 25, 30, 40 & 50 μM in 

mammalian cells

Negative for reverse mutations

Cytotoxic at 10 μM and above without metabolic activation and no 

toxicity with activation. Precipitate formed at 30 μM and higher 

concentrations with or without activation. 

870.5375 In vitro Cytogenetics MRID# 40436409, 44533401

Acceptable/guideline

Concentrations assayed were as 

follows with non-activation in the 10 

hour assay at 1.56, 3.12, 5.2, 10.4, 

15.6, 31.2, 52, 104 & 156 μg/ml and 

in the 19-20 hour assay at 0.975, 

1.47, 2.93, 4.89, 9.75, 14.7, 29.3, 

48.9, 97.5 & 147 μg/ml. 

Concentrations tested with activation 

in the two 10 hour assays were 1, 1.5, 

3, 5, 10, 15, 30, 50 & 100 μg/ml and 

2.95, 4.95, 9.85, 14.8, 29.6, 49.4, 

98.5 & 296 μg/ml, plus 

concentrations for the 19-20 hour 

assay were 9.75, 14.7, 29.3, 48.9, 

97.5, 147 & 293 μg/ml.

Negative for chromosome aberrations

Cytotoxicity was shown in both non-activated as well as in 

activated assays. Positive controls mitomycin C (for nonactivation) and cyclophosphamide (for activation) caused the 

appropriate mutagenic responses.
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Table A.2.2 Chlorpyrifos Sub-chronic, Chronic and Special Studies Toxicity Profile

Guideline No. Study Type MRID# / Classification /Doses Results

870.5395 Micronucleus Assay in 

Mammalian Erythrocytes

MRID# 00152684

Acceptable/guideline

Tested at levels of 0, 7, 22, 70 mg/kg 

by gavage in corn oil in the mouse

Not clastogenic

870.5500 DNA Repair Assay in 

Bacteria

Accession# 256040

Acceptable/guideline

Increased damage to DNA was detected

870.5550 Unscheduled DNA 

Synthesis in Rat 

Hepatocytes

MRID# 00157057

Acceptable/guideline

Tested with concentrations from 

10E-06 M to 10E-04 M in isolated rat 

hepatocytes

Negative for induction of UDS

The high dose was cytotoxic and also formed a precipitate. 

870.5575 Mitotic Gene Conversion 

in Yeast

Accession# 256040

Acceptable/guideline

Increased recombination frequency detected

870.6100a Acute Delayed 

Neurotoxicity Study in 

Hens

MRID# 00097144 and 40510601

Acceptable/guideline

0, 50, 100 or 110 mg/kg

96.8% a.i. chlorpyrifos

NOAEL: 110 mg/kg (HDT) 

LOAEL: Not Determined

Not neurotoxic

870.6200a Acute Neurotoxicity Study 

in Rats

MRID 42669101 and 42943101

Acceptable/guideline

0, 10, 50 or 100 mg/kg

98.2% a.i. chlorpyrifos

NOAEL (systemic): 10 mg/kg

LOAEL (systemic): 50 mg/kg

Effects: Decreased body weight, and motor activity and increased 

incidence of adverse clinical signs
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Table A.2.2 Chlorpyrifos Sub-chronic, Chronic and Special Studies Toxicity Profile

Guideline No. Study Type MRID# / Classification /Doses Results

870.6200b 13-Week Rat 

Neurotoxicity Study in 

Rats

MRID 42929801

Acceptable/guideline

0, 0.1, 1, 5, or 15 mg/kg/day

98.2% a.i. chlorpyrifos

NOAEL (systemic): 15 mg/kg/day

LOAEL (systemic): none established

Effects: Decreased motor activity and an increased incidence of 

urine incontinence in females. 

Note: This study did not measure cholinesterase activity.

870.6300 Developmental 

Neurotoxicity in Rats

Cholinesterase and 

Metabolite Determination 

Study in Rats 

(Companion Study of the 

Developmental 

Neurotoxicity Study) 

MRID: 44556901 

Guideline-Unacceptable, But 

Upgradeable

0, 0.3, 1, or 5 mg/kg/day (gestation 

day 6 through lactation day 11)

MRID# 44648101

Acceptable/Non-Guideline

0, 0.3, 1, or 5 mg/kg/day (gestation 

day 6 through lactation day 11)

99.8% a.i. chlorpyrifos

Maternal NOAEL: none observed for plasma or RBC ChEI

Maternal LOAEL: 0.3 mg/kg/day (43% plasma and 41% % 

RBC ChE activity relative to controls)

Note: Submission of further morphometric data may upgrade the 

study.

99.8% a.i. chlorpyrifos

Maternal Effects: Dams in the 0.3 mg/kg/day group exhibited a 

33% plasma and 26 % RBC ChE activity relative to controls

Developmental Effects: Pups in the 5 mg/kg/day group exhibited 

an 85% plasma, 92 % RBC, 82% heart and 60% brain ChE 

activity relative to controls

Note: This is a pharmacokinetic study, and therefore, NOAELs 

and LOAELs were not identified. 

870.7485 Acute Pharmacokinetic 

Study in Rats

MRID 44648102

Acceptable/Non-Guideline

0.5, 1, 5, 10, 50, 100 mg/kg

89.4-99.8% a.i. chlorpyrifos

NOAEL: 0.5 mg/kg

LOAEL: 1 mg/kg (28-40% plasma ChEI at the peak time of 

inhibition, 3-6 hours post exposure)

Other: significant brain ChEI at doses 10 mg/kg

Note: red blood cell ChE measurements were not collected.
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Table A.2.2 Chlorpyrifos Sub-chronic, Chronic and Special Studies Toxicity Profile

Guideline No. Study Type MRID# / Classification /Doses Results

870.7485 Metabolism and 

Pharmacokinetics

In Fischer 344 Rats

MRID# 40458901

Acceptable/guideline

0.5 or 25 mg/kg of 14C labeled 

chlorpyrifos or 15 daily doses of 0.5 

mg/kg unlabeled chlorpyrifos 

followed by one dose of 0.5 mg/kg of 

14C labeled chlorpyrifos. 

During 72 hours, more than 84% of the radioactivity was 

recovered in the urine, about 5% was found in the feces and less 

than 0.2% was found in the tissues and carcass. The metabolism 

of chlorpyrifos was extensive, and no unchanged parent compound 

was found in the urine. The major urinary metabolites were TCP, 

as well as glucuronide and sulfate conjugates of TCP.

870.7485 Metabolism and 

Pharmacokinetics

In Fischer 344 Rats

MRID# 44648102

Acceptable, Non-guideline

0.5, 1, 5, 10, 50, or 100 mg/kg and 

followed vs time

Four male rats were given a single 

gavage dose of labeled chlorpyrifos 

at a concentration of 5 or 100 mg/kg 

and were sacrificed three hours later. 

Peak chlorpyrifos blood concentrations occurred within three 

hours of treatment. Plasma ChE activity decreased in a time- and 

dose-dependent manner. The plasma ChE activities of rats treated 

with 0.5, 1, 5 or 10 mg/kg were maximally decreased 3-6 hours 

after treatment, with both the decrease and recovery of activity 

being dose-dependent. In the 1 mg/kg dose group, plasma ChE 

activity was significantly inhibited approximately 28% and 40% 

relative to controls at 3 and 6 hours post exposure, respectively. 

By 12 hours post-exposure, plasma ChE activity was still 

significantly inhibited about 16% for the 1 mg/kg group. The 

decrease in plasma ChE activity of rats treated with 50 or 100 

mg/kg began within 10 minutes of treatment. By 12 hours after 

treatment, plasma ChE activity in both groups were approximately 

11% of the control group and had not shown signs of recovery.

Brain cholinesterase activity was not affected as dramatically by 

test material treatment as plasma activity with only the 10, 50, and 

100 mg/kg dose groups showing significant effects. The brain 

cholinesterase activity of rats treated with 10 mg/kg test material 

began to decline within three hours of treatment and was 

significantly decreased by six hours after treatment. The brain 

cholinesterase activity in the 50 or 100 mg/kg dose groups 

decreased significantly within one hour of treatments; and by 12 

hours, it was approximately 30% and 20%, respectively, of 

control. In none of the affected groups did brain cholinesterase 

show signs of recovery.
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Table A.2.2 Chlorpyrifos Sub-chronic, Chronic and Special Studies Toxicity Profile

Guideline No. Study Type MRID# / Classification /Doses Results

870.7600 Dermal Penetration 

(Human)

Accession No. 249203

Single doses of 0.5 mg/kg (N=1) and 

5.0 mg/kg (N=5) to male humans

Based on the urinary excretion of the 3,5,6-TCP metabolite, the 

minimum absorption was approximately 1-3% dermally. The 

proportion of the administered dose metabolized to this pyridinol 

is unknown, these estimates are considered minimum values (i.e.

absorption could be higher). 

870.7800 Immunotoxicity in 

Female Crl:CD(SD) Rats

MRID 48139304

Acceptable/guideline

0, 0.416, 2.13, or 10.7 mg/kg/day

NOAEL is 10 mg/kg/day

LOAEL not established

Special Study Special Acute Neurotoxic 

Esterase (NTE) Rat Study

MRID 44273901

Acceptable/Non-guideline

0, 1, 5, 10, 50 or 100 mg/kg

98.1% a.i. chlorpyrifos

NOAEL: 1 mg/kg [plasma ChE, and RBC and heart acetyl 

cholinesterase (AChE)]

LOAEL: 5 mg/kg (45% plasma ChEI; 17% RBC AChEI; and 19% 

heart AChEI). 

Effects: NTE was not inhibited at any dose. 

Note: cholinesterase measurements were made 24 hours post 

exposure.

Special Study Cognitive Rat Study MRID 44020901

Acceptable/Non-Guideline

0, 1, 3, or 10 mg/kg/day for 5 

days/week for 4 weeks

98.1% a.i. chlorpyrifos

NOAEL: none observed (plasma and RBC ChE), 

LOAEL: 1 mg/kg/day (68% plasma ChEI; 56% RBC ChEI and 8% 

brain ChEI). 

NOAEL (systemic): 1 mg/kg/day (miosis)

LOAEL (systemic): 3 mg/kg/day (miosis)
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Table A.2.2 Chlorpyrifos Sub-chronic, Chronic and Special Studies Toxicity Profile

Guideline No. Study Type MRID# / Classification /Doses Results

Special Study Comparative 

Cholinesterase Assay

MRID 48139301

Acceptable/Non-Guideline

Repeat Dosing Data 

Chlorpyrifos (CPY) & Oxon (CPO)

NOAEL/LOAEL in mg/kg/day (% Inhibition)

Plasma ChE: Pups & Adult 

CPY 0.1/0.5 (46%) & 0.1/0.5 (46%)

CPO 0.01/0.5 (62%) & 0.01/0.5 (76%)

RBC ChE: Pups & Adult 

CPY 0.1/0.5 (18%) & 0.1/0.5 (20%)

CPO 0.01/0.5 (84%) & 0.01/0.5 (87%)

Brain ChE: Pups & Adult 

CPY 0.5/1 (19%) & 0.5/1 (9%)

CPO Not inhibited & Not inhibited

Special Study Acute Inhalation Study MRID 48139303

Acceptable/Non-Guideline

NOAEL Not Identified

LOAEL 3.7 mg/m3based on lung cholinesterase activity
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A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Population Adjusted Dose (aPAD) - Females age 13-49

No endpoint selected for this category.

A.3.2 Acute Population Adjusted Dose (aPAD) - General Population

Study Selected: Comparative Cholinesterase Assay (CCA)

MRID No.: 48139301

Executive Summary: See Appendix A.4.9

Dose and Endpoint for Risk Assessment: BMDL10=0.36 mg/kg

Comments about Study/Endpoint/Uncertainty Factors: The CCA study is currently thought 

to be the most appropriate endpoint for chlorpyrifos. The UFA=10 and the UFH=10, with a

proposed FQPASF =1. The acute PAD=0.0036 mg/kg/day. 

A.3.3 Chronic PAD 

Study Selected: DNT Gavage Study in Pregnant Rats

MRID No.: 44648101 and 44556901

Executive Summary: See Appendix A.4.7, Guideline 870.6300

Dose and Endpoint for Risk Assessment: BMDL10=0.03 mg/kg/day

Comments about Study/Endpoint/Uncertainty Factors: The ChE data is currently thought to 

be the most appropriate endpoint for chlorpyrifos. The UFA=10 and the UFH=10, with a proposed

FQPA SF=1. The chronic PAD=0.0003 mg/kg/day.

A.3.4 Incidental Oral Exposure (Short- and Intermediate-Term)

Short Term Exposure

Study Selected: Repeat Oral CCA Study in Rat

MRID No.: 48139301

Executive Summary: See Appendix A.4.9 Special Studies

Dose and Endpoint for Risk Assessment: BMDL10=0.1 mg/kg/day

Comments about Study/Endpoint/Uncertainty Factors: The CCA study is currently thought 

to be the most appropriate endpoint for chlorpyrifos. The UFA=10 and the UFH=10, with a

proposed FQPA SF=1. 

Intermediate Term Exposure

See Chronic Dietary Endpoint

A.3.5 Dermal Exposure (Short-, Intermediate- and Long-Term)

Study Selected: 21-Day Dermal Study

MRID No.: 40972801

Executive Summary: See Appendix A.4.1, Guideline 870.3200
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Dose and Endpoint for Risk Assessment: NOAEL = 5 mg/kg/day based on plasma and RBC 

ChE inhibition seen at LOAEL = 10 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors: A repeated dose dermal study is the 

most appropriate study for this exposure and ChE inhibition is the most appropriate assay. The 

UFA=10, the UFH=10, the proposed FQPA SF =1 (residential exposures).

A.3.6 Inhalation Exposure (Acute, Short- and, Intermediate-Term) 

Acute Exposure

Study Selected: Acute Inhalation Study

MRID No.: 48139303

Executive Summary: See Appendix A.4.9, Special Study

Dose and Endpoint for Risk Assessment: LOAEL = 3.7 mg/m3and the HEC = 0.62 mg/m3 

(RfC=0.00021 mg/m3) based on ChE inhibition. A NOAEL was not identified.

Comments about Study/Endpoint/Uncertainty Factors: This study is appropriate since it is 

the correct exposure of inhalation and ChE activity is appropriate as an endpoint for chlorpyrifos. 

For residential: The UFA=3, UFH=10, FQPA UFDB =10 (extrapolation of LOAEL to NOAEL).

Short and Intermediate Term Exposure

Study Selected: 90-Day Inhalation Studies

MRID No.: 40908401, 40013901, 40166501, 44556901

Executive Summary: See Appendix A.4.1, Guideline 870.3465

Dose and Endpoint for Risk Assessment: NOAEL (calculated from an HEC) = 0.56 mg/kg/day 

(for occupational) and HEC = 0.0057 mg/m3) based on ChE inhibition seen at LOAEL = 0.3 

mg/kg/day in the DNT study.

Comments about Study/Endpoint/Uncertainty Factors: This study is appropriate since it is 

the correct exposure of inhalation and ChE activity is appropriate as an endpoint for chlorpyrifos. 

The HEC=0.0057 mg/m3. For residential: UFA=3, UFH=10, FQPA SF=1. For occupational: 

UFA=3, UFH=10. 

A.4 Executive Summaries

A.4.1 Sub-chronic Toxicity

870.3100 90-Day Oral Toxicity – Rat

In a sub-chronic oral toxicity study in rats (MRID 40436406), chlorpyrifos (95.5% a.i.) was fed 

to 20 rats/sex/dose at dose levels of 0, 0.5, 10 or 200 ppm (equivalent to 0, 0.025, 0.5 or 10 

mg/kg/day) for 13 weeks. 

There were no treatment related effects on mortality, clinical signs, histopathology or organ 

weights. A significant decrease in body weight gain was observed in high dose males during the 

first half of the study, and in high dose females during the first three weeks. However, body 

weight in exposed animals was similar to controls by week 13. Food consumption in the high-
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dose animals was also significantly increased during the time of increase body weight gain. 

Hematological effects were observed in both high-dose males and females, characterized by 

significantly reduced packed cell volume (PCV), hemoglobin (HB) and erythrocyte (RBC) group 

means relative to controls, which is suggestive of anemia. However, these parameters were 

within the normal range. Urinalysis revealed that males in the high dose group had a 

significantly reduced urine volume, increased urine pH, a higher specific gravity and a higher 

protein grading, which appear to be treatment-related. 

No biologically or significant or treatment-related differences were noted for clinical chemistry 

parameters, with the exception of cholinesterase (ChE) inhibition. Significant and dose-related 

plasma ChE inhibition of 22, 37 and 72% was observed in the 0.5, 10 and 200 ppm male groups, 

respectively. In females, plasma cholinesterase was also significantly inhibited at 91 and 57% 

for the 10 and 200 ppm groups, respectively, but was not inhibited in the low dose group (10% 

increase). However, the registrant acknowledged the possibility that the cholinesterase data for 

the 10 and 200 ppm female groups were accidently switched. Red blood cell and brain 

cholinesterase activity were not evaluated in this study. 

The LOAEL for plasma cholinesterase inhibition is 0.5 ppm (0.025 mg/kg/day) for males, 

which is the lowest dose tested. No NOAEL was observed for cholinesterase inhibition. 

The systemic NOAEL and LOAEL are 10 and 200 ppm, respectively (0.5 and 10 

mg/kg/day, respectively) based on decreased body weight gains and possible anemia. The 

study is classified as acceptable/guideline.

Chlorpyrifos was administered (0.1, 1, 5, and 15 mg/kg/day) in the diet for 90 days to CDF 

Fischer 344 rats (MRID 40952801). Body weight and body-weight gain were decreased in the 

high dose males (15 mg/kg) at the beginning (first 4 weeks) and near the end (day 70 on) of the 

study. Plasma and RBC cholinesterase activities were decreased in both sexes at the interim time 

point at 1, 5, and 15 mg/kg (dose-related) and in females at the 0.1 mg/kg dose level. At 

termination, brain cholinesterase was decreased (dose-related) at the 5 and 15 mg/kg dose levels 

in both sexes; plasma cholinesterase activity was decreased at 1, 5 and 15 mg/kg in both sexes; 

and erythrocyte cholinesterase activity was decreased in both sexes at 5 and 15 mg/kg and in 

females also at 1 mg/kg. The only other treatment-related effect was increased vacuolation in the 

adrenal gland in males of the 5 and 15 mg/kg dose groups. 

The NOAEL can be set at 0.1 mg/kg, the LOAEL at 1 mg/kg, based on decreased plasma 

and RBC cholinesterase activities. The study is classified as acceptable/guideline.

870.3150 90-Day Oral Toxicity – Dog

In a sub-chronic oral toxicity study in dogs (MRID 42172801), chlorpyrifos (95.8% a.i.) was 

administered by gelatin capsule to 4 beagle dogs/sex/dose at dose levels of 0, 0.01, 0.22, or 5 

mg/kg/day each day for 13 weeks. 

There were no treatment related effects on mortality, clinical signs, body weight, food 

consumption, ophthalmological examination, urinalysis, or organ weights. Although some 

statistically significant differences were noted in some hematological parameters, these findings 

were not considered biologically significant, or treatment related. No biologically significant 
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differences were noted for clinical chemistry parameters, with the exception of cholinesterase 

(ChE) inhibition. Significant and dose-related plasma and red blood cell ChE inhibition were 

observed in both sexes throughout the study. Plasma ChE was significantly inhibited in males 

(33-63%) and females (42-67%) exposed to 0.22 mg/kg/day and in males (69-85%) and females 

(64-87%) exposed to 5 mg/kg/day. Red blood cell ChE was also significantly inhibited in males 

(32-46%) and females (24-38%) exposed to 0.22 mg/kg/day during weeks 6 and 12 and in males 

(38-85%) and females (29-86%) exposed to 5 mg/kg/day during weeks 1, 6 and 12. Brain ChE 

activity was significantly reduced 46% at 5 mg/kg/day in both males and females. Although 

possible treatment-related gross and microscopic pathology changes were observed in the high

dose animals, these findings were not observed in the 2-year dog study, and only occurred in one 

male and one female. These include a thickened muscular wall of the duodenum and an area of 

papillomatous hyperplasia (pyloric). 

The NOAEL and LOAEL for plasma and red blood cell cholinesterase inhibition are 0.01 

and 0.22 mg/kg/day, respectively. The study is classified as guideline/acceptable.

870.3200 21/28-Day Dermal Toxicity – Rat

In a 21-day dermal toxicity study (MRID 40972801), 5 Fischer 344 rats/sex/dose were dermally 

exposed to 0, 0.1, 0.5, 1 or 5 mg/kg/day chlorpyrifos (100% a.i.) in corn oil on a 12 cm2area of 

the back once per day, 6 hours/application, 5 days/week for a total of 15 applications in 21 days. 

In a 4-day dermal probe study used to select the doses, 4 female Fischer 344 rats/dose were 

similarly treated via dermal application at dose levels of 0, 1, 10, 100 or 500 mg/kg/day 

chlorpyrifos in corn oil for four consecutive days.

In the 21-day study, there were no signs of treatment-related systemic or dermal toxicity at doses 

up to 5 mg/kg/day, including effects on cholinesterase inhibition, body weight, food 

consumption, ophthalmological examination, hematology, or clinical chemistry. In the 4-day 

probe study, 2 of 4 females in the 1 and 10 mg/kg/day groups developed slight erythema. Doserelated plasma (45, 92 and 98% ) and red blood cell (16, 49 and 75% ) cholinesterase inhibition 

were observed in the 10, 100 and 500 mg/kg/day groups. However, statistical analyses were not 

conducted. The cholinesterase activities of the 1 mg/kg/day females were slightly decreased, but 

within the historical control range. No other treatment-related effects were noted in the dermal 

probe study. 

The NOAEL and LOAEL for plasma and red blood cell cholinesterase inhibition are 5 and 

10 mg/kg/day, respectively, based on the results of both the 21-day and 4-day dermal probe 

studies. Satisfies the guideline requirement (82-2), but not guideline 870.3200, which 

requires 10 animals/sex/dose for dermal toxicity testing.

870.3465 90-Day Inhalation – Rat

In a sub-chronic nose-only inhalation study (MRID 40908401), Fischer 344 rats (10/ sex/ 

concentration) were exposed nose only to Chlorpyrifos (95% a.i.) at vapor concentrations of 0, 

5, 10, or 20.6 ppb (0, 72, 143 or 287 μg/m3, respectively) 6 hours/day, 5 days/week for 13 weeks. 

These concentrations resulted in estimated maximum exposures of 0, 0.024, 0.048 and 0.097 
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mg/kg/day, respectively based on the EPA default ventilation rate of 0.00715 m3/hr for rats 

(average of males and females), and average study specific body weights of 0.189 and 0.127 kg 

for male and female controls, respectively. The study author stated that the saturation or near 

saturation level was 20 ppb. 

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

ophthalmoscopy, hematology, gross pathology or histopathology. In females, food consumption 

was slightly depressed throughout the study in all dose groups without correlation to the dose 

level, although this observation was not considered of toxicological significance due to only 

slight decreases in corresponding body weights. There were some sporadic differences in 

clinical chemistry parameters, although these were not considered treatment-related due to a lack 

of dose-response and inconsistency between interim and terminal values. Sporadic differences in 

organ weights also were not considered treatment-related and appeared to be attributed to the 

increase mean body weights. 

Significant plasma cholinesterase (ChE) inhibition was observed in the high dose males (23%) 

and females (25%) at the terminal sacrifice. Significant plasma ChE inhibition was also noted in 

females of the 5 and 10 ppb groups (26 and 40%, respectively), although a dose-response 

relationship was not apparent. Interim (8 week) measurements were similar or slightly greater 

than controls. Red blood cell (RBC) (interim and terminal) and brain (terminal) ChE activities 

were not significantly inhibited at any dose level. It should be noted that the chlorpyrifos 

concentrations in the exposure chambers at 13 weeks were approximately 12, 16 and 24 ppb, 

which exceeds the 5, 10 and 20 ppb average exposure levels and this may partially explain the 

terminal results, while the 8 week concentrations were closer to the average levels. The plasma 

ChE inhibition was not considered of toxicological significance because of the minimal 

inhibition (23-25%) at the high dose, lack of dose-response, and an absence of inhibition in the 8 

week interval. 

No LOAEL was identified in this study. Therefore, the NOAEL for systemic effects and 

plasma cholinesterase inhibition exceeds 20 ppb or 0.097 mg/kg/day. This study is classified 

as acceptable/guideline.

In a sub-chronic, nose-only inhalation study (MRID 40013901 & 40166501), Fischer 344 rats 

(10/sex/concentration) were exposed nose only to Chlorpyrifos at vapor concentrations of 0, 5.2, 

10.3, or 20.6 ppb (0, 72, 143 or 287 μg/m3, respectively) 6 hours/day, 5 days/week for 13 weeks. 

Cholinesterase activity was measured at study termination. The maximum dose to rats in the 

20.6 ppb group was estimated to be 0.044-0.082 mg/kg/day based on average study specific body 

weights of 0.15 and 0.282 kg for female and male control animals, respectively and the EPA 

default rat ventilation rate of 0.00715 m3/hr (average for males and females). 

There were no treatment-related effects on body weight, clinical signs, urinalysis, hematology, 

clinical chemistry, organ weights, gross pathologic or histopathologic evaluations, or plasma, red 

blood cell or brain cholinesterase activities. Although female rats of all treatment groups had a 

slight (<4%) but significant decrease in red blood cell count, and males of all treatment groups 

had slightly elevated (approximately 13%) serum urea nitrogen, these observations were not 
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considered treatment-related due to a lack of dose-response, and all values were within the 

historical control range. 

No LOAEL was identified in this study. Therefore, the NOAEL for systemic toxicity and 

cholinesterase inhibition exceeds 20 ppb or 0.082 mg/kg/day. The studies are classified as 

acceptable/guideline. 

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study – Rat

Chlorpyrifos was dosed via gavage at 0, 0.5, 2.5 and 15 mg/kg/day in CD rats during gestation 

day 6-15 (MRID 40436407). 

Based on ChE inhibition, the maternal NOAEL is < 0.5 mg/kg/day (LDT) with the 

maternal systemic toxicity NOAEL =15 mg/kg/day. The maternal systemic toxicity LOAEL 

=15 mg/kg/day (decrease in food consumption only first few days of dosing) and decrease in 

body weight gain during dosing. The developmental toxicity NOAEL = 2.5 mg/kg with the 

LOAEL =15 mg/kg/day (increase in post implantation loss). This study is classified as 

acceptable/guideline.

In a developmental toxicity study (MRID 00130400) Chlorpyrifos, 96.6% a.i., was administered 

to Fischer 344 rats by gavage at dose levels of 0 (corn oil vehicle only), 0.1, 3.0, or 15 mg/kg/day 

from days 6 through 15 of gestation. There were 31 rats each in the control and the 0.1 

mg/kg/day (LDT) groups and 32 in the 3.0 mg/kg/day (MDT) group and 33 in the 15 mg/kg/day 

(HDT) group. 

Maternal toxicity - There were no deaths in any group. Food and water consumption were not 

altered by compound exposure and liver weights (the only organ for which weights were 

obtained) was not altered in dosed groups compared to controls. Mean group maternal body 

weight gain was not affected in the LDT or MDT compared to controls but was reduced 26% 

during the period of dosing (gestation days 6-15) in the HDT. This effect appeared to transient 

though, as the HDT group had weight gain similar to the other groups in the post-treatment 

period (gestation days 16-21).Clinical signs of toxicity were evident at the HDT only. Excessive 

salivation, perineal urine stains, peri-ocular porphyrin deposits, vaginal bleeding, and tremors 

were noted throughout the dosing period in the HDT. Most cesarean section parameters were not 

altered by compound exposure. The only parameter that was altered was the pre-implantation 

loss. Pre-implantation loss in the controls was 5.3% while it was 9.4, 7.2 and 17% in the LDT, 

MDT and HDT groups respectively. Inhibition of cholinesterase activity was seen in the MDT 

and HDT groups. Plasma cholinesterase activity was decreased from 44.73 μ/ml in the controls 

to 4.28 and 1.56 μ/ml in the MDT and HDT respectively (these represent inhibitions of 90.3% 

and 96.5%, respectively). Erythrocyte cholinesterase activity was reduced from 11.98 μ/ml in the 

controls to 3.07 and 2.51 μ/ml in the MDT and HDT respectively (this represents inhibitions of 

74.3% and 79%). The cholinesterase values for the LDT were similar to controls with plasma 

being 42.28 and erythrocyte being 11.85 μ/ml.
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The systemic maternal LOAEL is 15 mg/kg/day, based on clinical signs such as salivation, 

and tremors. The systemic maternal NOAEL is 3.0 mg/kg/day. The maternal 

cholinesterase LOAEL is 3.0 mg/kg/day based on statistically significant decreases in 

erythrocyte and plasma cholinesterase activity. The maternal cholinesterase NOAEL is 0.1 

mg/kg/day. 

External examinations, visceral examinations and skeletal examinations did not reveal an 

increase in variations or malformations. There were no treatment-related effects in 

developmental parameters seen at any dose. 

The developmental NOAEL is 15 mg/kg/day. The developmental LOAEL was not 

determined. This study is classified as acceptable/guideline.

In a developmental toxicity study (MRID 00095268), female CF-1 mice were administered 

chlorpyrifos by gavage on gestation days 6-15 at doses of 0, 1, 10, and 25 mg/kg/day 

(Experiment I). Because of severe maternal toxicity in the high dose group, additional groups of 

mice were exposed to 0, 0.1, 1.0, or 10 mg/kg/day on gestation days 6-15, inclusive (Experiment 

II). Maternal toxicity in the form of increased mortality (0/51, 1/40, 1/44, and 4/47 [p<0.05] at 0, 

1, 10, and 25 mg/kg/day) and an increase in the number of mice showing clinical signs (0/51, 

2/40, 9/44, and 32/47 at the above doses) were reported. Fetotoxicity was observed only at 25 

mg/kg/day (decreased fetal body measurements and an increased incidence of minor skeletal 

variants). To determine the degree of RBC and plasma cholinesterase depression, additional 

groups of 4-10 mice were given 0, 1, 10, or 25 mg/kg/day of chlorpyrifos on day 6, days 6 

through 10, or days 6 through 15 of gestation. Additionally, groups of 6-15 mice were given 0, 

0.1, 1.0 or 10.0 mg/kg/day of chlorpyrifos concurrently with the animals for the low dose study 

(Experiment II) on day 6, days 6-10, or days 6 through 15 of gestation. Five hours after the final

dosing (day 6, 10 or 15 of gestation, respectively), blood was obtained by cardiac puncture. A 

homogenate of fetuses from the mice sacrificed on day 15 of gestation was prepared to measure 

total fetal cholinesterase levels. Plasma cholinesterase levels decreased significantly in mice 

given 1, 10 or 25 mg/kg of chlorpyrifos on day 6, days 6 through 10, or days 6 through 15 of 

gestation. RBC cholinesterase levels also decreased significantly in mice given 10 or 25 mg/kg 

on day 6, days 6 through 10, or days 6 through 15 of gestation. Among mice given 1 mg/kg of 

chlorpyrifos on days 6 through 10 of gestation, a statistically significant decrease in RBC 

cholinesterase levels as compared to controls was observed. The fetal cholinesterase levels were 

decreased in fetuses from dams given 10 or 25 mg/kg of test material on days 6 through 15 of 

gestation.

The maternal LOAEL is 25 mg/kg/day, based on increased mortality and increased 

number of mice with clinical signs of cholinesterase inhibition. The maternal NOAEL is 10 

mg/kg/day. The developmental LOAEL is 25 mg/kg/day, based on decreased fetal body 

measurements and increased incidence of minor skeletal variants. The developmental 

NOAEL is 10 mg/kg/day. The NOAEL for plasma and red blood cells cholinesterase is 0.10 

mg/kg/day. This study is classified as unacceptable/non-guideline.
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870.3700b Prenatal Developmental Toxicity Study – Rabbit

Chlorpyrifos was dosed via gavage at 0, 1, 9, 81, and 140 mg/kg/day to New Zealand rabbits for 

gestation days 7-19 (MRID 40436408). 

Based on ChE inhibition the maternal NOAEL = 81 mg/kg with the maternal LOAEL = 

140 mg/kg (based on decreased food consumption on gestation days 15-19; body weight loss 

during the dosing period followed by a compensatory weight gain; suggestion of postimplantation loss). The developmental NOAEL = 81 mg/kg/day with the LOAEL = 140 

mg/kg/day (based on slight reduction fetal weights and crown-rump lengths; increased 

incidence of unmodified 5 th sternebra and/or xiphistrnum). The study is classified as 

acceptable/guideline.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat

In a two-generation reproduction study (MRID 41930301) chlorpyrifos (97.8-98.5% a.i.) was 

administered to 30 Sprague Dawley rats/sex/dose via the diet at dose levels of 0, 0.1, 1 and 5 

mg/kg/day during the pre-mating period of 10 or 12 weeks (F0 or F1 generation, respectively); 

with exposure continuing in dams through gestation, lactation and weaning. The F0-generation 

rats were mated once to produce F1 litters. Plasma, red blood and brain cholinesterase (ChE) 

activity were determined for the first 10 F0 and F1 adult rats/sex/dose at the scheduled necropsy. 

There were no treatment related effects on mortality, food consumption or clinical signs in either 

F0 or F1 animals. Parental toxicity was observed at 1 and 5 mg/kg/day as indicated by significant 

dose-related reductions in the ChE activities of the plasma (43-72% inhibition), and red blood 

cells (65-75% inhibition) in the F0 and F1 male and female adult rats. In addition, significant 

inhibition of brain ChE was noted in the high dose F0 adult male and females (48 and 49% 

inhibition, respectively) and high dose F1 males and females (53 and 58% inhibition, 

respectively). Parental F0 and F1 rats exposed to 5 mg/kg/day developed histopathological 

lesions of the adrenal gland that were confined to the cells of the zona fasciculata and were 

characterized as very slight to slight vacuolation. Also, histological changes in the adrenal gland 

were consistent with fatty changes in males and altered tinctorial properties in females. The 

body weights of the adult F1 males were slightly lower than controls throughout the study in the 

5 mg/kg/day dose group. 

Neonatal effects were observed only in the presence of maternal toxicity and consisted of 

reduced pup weights and increased mortality at 5 mg/kg/day. There were no treatment-related 

effects on other reproductive parameters such as fertility indices, length of gestation, time to 

mating, pup sex ratio, pup survival, or litter size in either generation.

The NOAEL and LOAEL for parental toxicity are 0.1 and 1 mg/kg/day, respectively based 

on significant plasma, and red blood cell cholinesterase inhibition. The NOAEL and 

LOAEL for neonatal effects are 1 and 5 mg/kg/day, respectively, based on decreased pup 

weight and increased pup mortality. This study is classified as acceptable/guideline.
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Chlorpyrifos was dosed to 10 males and 20 females per group at 58 days of age at levels of 0, 0, 

0.03, 0.1 and 0.3 mg/kg/day for 1st generation and 0, 0, 0.1, 0.3 and 1.0mg/kg/day for 

subsequent generations (MRID 00029064 & 00064934). For each mating, conducted at 118 days 

of age, the number of conceptions, litter size, still births, resorptions, number and size of pups 

weaned, pup weight and growth rate were examined., Necropsy was performed upon death and 

on 5 rats/sex/group of Fla, F2a and F3a pups. Histology was conducted on control and F3a pups. 

Maternal RBC and plasma cholinesterase activity was measured at the time of Cesarian delivery. 

Only the b litters were used for reproduction study.

No clinical signs of toxicity were observed in parents or offspring. No treatment related 

effect was found on mortality, body weight gain, food consumption, number of pups, mean 

litter size, sex ratios, mean litter weight, growth rate (to weaning), gross and histological 

examinations (on F3a pups). The parental NOAEL is 0.1 mg/kg/day and the LOAEL is 0.3 

mg/kg/day based on plasma and RBC ChE inhibition. The reproductive NOAEL not 

determined and the LOAEL is >1 mg/kg/day. The viability and lactation indices were 

decreased for F2a, F2b and F3a litters from the 1.0 mg/kg groups. Fetotoxicity may have 

arisen through the maternal milk. RBC and plasma ChE activity was depressed above 0.3 

mg/kg level for female and at 1.0 mg/kg for male. No maternal toxic sign to 1.0 mg/kg/day. 

Reproduction indices are all normal for dose up to 1.0 mg/kg. This study is classified as 

acceptable/guideline.

Chlorpyrifos was dosed at 0.5, 0.8, 1.2 mg/kg/day in Sprague-Dawley rats (MRID 00130401). 

Although not meeting core requirements for a reproduction study (primarily due to limited 

gross and no histological examination), the study is adequate to establish that the NOAEL 

for neonatal survival is 1.2 mg/kg/day (HDT), the primary purpose of the study. The 

NOAEL for other reproductive parameters is also 1.2 mg/kg/day and the NOAEL for 

general toxicity is 0.8 mg/kg/day based on decreased weight gain observed in the 1.2 

mg/kg/day male dose level. In combination with the previous reproduction study (MRID 

No. 00029064 & 00064934), this study is adequate to meet the requirement for a coreminimum study.

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity

Chlorpyrifos was dosed to CD-1 mice at 0, 0.5 and 15 ppm for 2 years (MRID 00054352). 

The systemic and oncogenic NOAEL was 2.25 mg/kg/day based on decreases in ChE 

activity of 90% in plasma and 50% in RBC. The study LOAEL values were not 

determined. The study is classified as acceptable and satisfies the requirement when taken 

together with MRID 00142902.
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870.4100b Chronic Toxicity – Dog

The chronic toxicity study (MRIDs 00064933, 00146519) in dogs consisted of two phases. In 

Phase A, chlorpyrifos (97.2-98.8% a.i) as Dowco® 179 was administered to 3 beagle 

dogs/sex/dose in diet at dose levels of 0, 0.01, 0.03, 0.1, 1 or 3 mg/kg/day for one year (Phase 

A). One dog/group was sacrificed at one year, and the remaining 2 dogs/group were sacrificed 

after a 3 month recovery period. In Phase B, chlorpyrifos was administered to 4 beagle 

dogs/sex/dose at the same dose levels for a total of two years (Phase B), at which time all dogs 

were sacrificed. 

The NOAEL and LOAEL for plasma ChE inhibition are 0.01 and 0.03 mg/kg/day based on 

consistent mean inhibition of 10% to 29% at 0.03 mg/kg/day compared to controls for both 

males and females in Phases A and B. HED did not identify a NOAEL and LOAEL for 

RBC ChE inhibition due to inconsistencies in the data and the large standard deviations 

that confounded the interpretation of the data at lower dose levels. The NOAEL and 

LOAEL for brain ChE were 1 and 3 mg/kg/day. The systemic NOAEL and LOAEL are 1 

and 3 mg/kg/day based on liver weight effects. The chronic toxicity study in dogs in 

conjunction with the addendum that contains supplemental information are classified as 

ACCEPTABLE-GUIDELINE.

A.4.5 Carcinogenicity

870.4200a Carcinogenicity Study – Rat

In a carcinogenicity toxicity study (MRID 42172802), chlorpyrifos (96.1% a.i) was administered 

to 55 Fisher F344 rats/sex/dose in diet at dose levels of 0, 0.2, 5 or 100 ppm (equivalent to 

approximately 0, 0.0132, 0.33, or 6.99 mg/kg/day for males and 0, 0.0146, 0.365 or 7.78 

mg/kg/day for females, respectively) for 104 weeks. Plasma cholinesterase (ChE) activity 

(10/animals/sex/group) was measured on weeks 14, 32, 45, 78 and 104, while red blood cell 

(RBC) ChE activity (10/animals/sex/group) was measured at weeks 45, 78 and 104. Plasma, 

RBC and brain ChE activities were measured on 5 animals/sex/group at week 50 and in 10 

animals/sex/group at terminal sacrifice.

Rats in the 100 ppm group exhibited significantly decreased body weights in both sexes, and a 

significant increased incidence of non-neoplastic lesions (cataracts and diffuse retinal atrophy) in 

females. Plasma ChE activity was significantly inhibited at 5 and 100 ppm in both sexes. 

Significant plasma cholinesterase inhibition in the 5 ppm group ranged from 15 to 51% 

throughout the study in both sexes. In females exposed to 0.2 ppm, red blood cell ChE was also 

significantly inhibited 42% at the 50 week sacrifice, but was elevated 14% at the terminal 

sacrifice. Red blood cell ChE was also significantly inhibited in the 50 week sacrifice for the 5 

and 100 ppm females (39 and 45% , respectively), but inhibition was less pronounced at the 

terminal sacrifice where inhibition was 11 and 18%, respectively. At the week 50 

measurements, the decrease in RBC ChE activity in the treated groups appeared to be seriously 

influenced by the high control value (3891 U/g tissue) compared to the other control values 

which ranged from 2092 to 2586 U/g tissue. Therefore, the RBC ChE inhibition in females at 50 

weeks is discounted because of the unusually high control value. Brain ChE was significantly 
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reduced in both high dose males and females at the 50 week and terminal sacrifices (57-80% ), 

but was not significantly decreased at the other doses. At terminal sacrifice, males in the high 

dose group had significantly lower absolute liver and kidney weights that were not significant 

after correction for body weight, and therefore were not considered treatment-related. There 

were no treatment related effects in mortality, clinical signs, food consumption, or hematology. 

At the doses tested, there was no treatment related increase in tumor incidence when compared to 

controls. Dosing was considered adequate based on decreased body weights and the increased 

incidence of non-neoplastic lesions. 

The LOAEL and NOAEL for plasma inhibition are 5 and 0.2 ppm, respectively (0.33 and 

0.0132 mg/kg/day, respectively). The LOAEL and NOAEL for systemic effects of 

decreased body weights in both sexes, and increased incidence of cataracts and diffuse 

retinal atrophy in females are 100 and 5 ppm, respectively (6.99 and 0.33 mg/kg/day, 

respectively). This carcinogenicity study in rats is classified as ACCEPTABLEGUIDELINE.

In a chronic toxicity/carcinogenicity study (MRID 40952802), chlorpyrifos (98.5% a.i) was 

administered to 50 Fisher F344 rats/sex/dose in diet at dose levels of 0, 0.05, 0.1, 1 or 10 

mg/kg/day for 104 weeks. Ten additional rats/sex/group were randomly allocated for the 12-

month sacrifice. Plasma and red blood cell (RBC) cholinesterase (ChE) activities 

(10/animals/sex/group) were measured at months 6, 12, 18 and 24. Brain ChE activities were 

also measured at the 12-month (10/rats/sex/dose) and 24 month (20 rats/sex/dose) scheduled 

sacrifices. 

Rats in the 10 mg/kg/day group exhibited a slight, but significant decrease in body weights (2-

9%) in both sexes. Body weight gain was approximately 90% of controls in males and 

comparable among females. Male rats in the high dose group had an increase in the size of the 

adrenal gland characterized microscopically by increased fatty vacuolation of the zonal 

fasciculata. In addition, males exhibited changes in clinical chemistry parameters (decreased 

serum cholesterol, total protein, and globulin), an increase in urine specific gravity, and a 

decrease in some common geriatric conditions (renal disease and biliary hyperplasia), which may 

be secondary changes and do not reflect any deleterious effect on a specific organ or the overall 

health of the animals. Similar, but less severe effects were noted in the high dose female rats. 

There were no significant differences in food consumption, or survival in either sex.

There was a dose-related (in most cases) decrease in ChE activity (plasma, red blood cell and 

brain) at each time point in both sexes. Plasma ChE was significantly inhibited in both sexes at 

the 1 mg/kg/day (39-86%) and 10 mg/kg/day (56-95%) dose levels throughout the study. Brain 

ChE was significantly decreased at both the 1 mg/kg/day (5-9%) and 10 mg/kg/day (58-61%) 

dose levels at the 12 month sacrifice, but was only statistically reduced in the 10 mg/kg/day dose 

group at termination (56-57%). In the 1 mg/kg/day dose group, brain ChE activities were 

increased 3% in males, and decreased 4% in females at the 24 month sacrifice. RBC ChE was 

significantly depressed at the 1 mg/kg/day (14-34%) and 10 mg/kg/day (24-37%) dose levels in 

males throughout the study, although statistical significance was not attained at 12-months, and 

the value in the 1 mg/kg/day males at termination was only 14% lower than the control value. In 
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females, mostly non significant RBC ChE inhibition ranged from 16-22% for the 1 mg/kg/day 

dose group and 18-40% for the 10 mg/kg/day dose group during the 12, 18 and 24 month 

sacrifices.

At the doses tested, there was no treatment related increase in tumor incidence when compared to 

controls. Dosing was considered adequate based on decreased body weights coupled with the 

significant inhibition of plasma, red blood cell and brain ChE.

The LOAEL and NOAEL for systemic effects are 10 and 1 mg/kg/day, respectively based 

on effects on the adrenal gland and clinical chemistry alterations in males. The LOAEL 

and NOAEL for significant plasma (39-86%) and brain (5-9%) cholinesterase inhibition 

are 1 and 0.1 mg/kg/day, respectively. This combined chronic toxicity/oncogenicity study in 

rats is classified as ACCEPTABLE-GUIDELINE.

870.4200b Carcinogenicity (Feeding) – Mouse

This study evaluated the oncogenic potential of test compound, at dietary concentrations of 0, 

5.0, 50 or 250 ppm chlorpyrifos (equivalent to approximately: 0, 0.89, 8.84, or 45.2 mg/kg/d 

(M); and 0, 0.938, 9.79, or 48.1 mg/kg/d (F), respectively) when administered to CD-1 mice for 

78 weeks (MRID 42534201).

Systemic toxicity was observed in high-dose animals and included decreased body weight and 

feed consumption in males, lower mean water consumption in females, increased incidence of 

gross clinical findings (ocular opacity, hair loss on head and around eyes) and non-neoplastic 

lesions (keratitis, hepatocytic fatty vacuolation) in high dose males & females. Neoplastic 

lesions were observed in both sexes, but were not considered to be treatment-related. Plasma 

cholinesterase activities were significantly reduced at all treatment levels; brain activities were 

significantly decreased only in the high-dose animals. 

The systemic NOAEL = 50 ppm (MDT). Systemic LOAEL = 250 ppm (HDT), based on 

decreased body weight in males, increase incidences of non-neoplastic lesions in males & 

females. Results of the study showed that the test compound does not have oncogenic 

potential. This study satisfies guideline requirements for an oncogenicity study in mice.

A.4.6 Mutagenicity

870.5100 Gene Mutation Bacterial Cell

Chlorpyrifos was tested in Salmonella strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538 

in the presence and absence of S-9 at concentrations of 30, 100, 300, 1000, 3000 and 10000 

μg/plate (MRID 00157058 and 40436410). DMSO was the solvent and negative control. The 

positive controls were sodium azide, 9-aminoacridine, 2-nitrofluorene and 2-anthramine. 

Chlorpyrifos was not toxic nor did it appear to increase over control values the number of 

revertant colonies/plate. Positive controls caused appropriate mutagenic responses. These 

studies were classified as Acceptable/Guideline.
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870.5300 Gene Mutation Mammalian Cell

Chlorpyrifos was tested for gene mutation potential at 0, 10, 20, 25, 30, 40 & 50 μM in 

mammalian cells (MRID 00152683). 

Chlorpyrifos was cytotoxic at 10 μM and above without metabolic activation and no 

toxicity with activation. Precipitate formed at 30 μM and higher concentrations with or 

without activation. Chlorpyrifos was negative for gene mutation. This study is classified as 

acceptable/guideline.

Chlorpyrifos was tested for gene mutation potential at the following concentrations: 

nonactivation from 5-75 μg/ml and with activation from 30-1000 μg/ml (MRID 40436410). 

Testing in the cytotoxicity assays at the following conditions: nonactivation from 1.5-3746 μg/ml 

and with activation from 1.5-500 μg/ml. Positive controls were ethyl-methane sulfonate 

(nonactivated) and dimethylnitrosamine (activated). 

Cytotoxicity was detected only in non-activated assays at 50 μg/ml. There was no evidence 

of mutation. This study is classified as acceptable/guideline.

870.5375 In Vitro Cytogenetics

Chlorpyrifos was tested in an in vitro chromosomal aberration assay with and without S-9 

activation (MRID 40436409). Concentrations assayed were as follows with non-activation in the 

10 hour assay at 1.56, 3.12, 5.2, 10.4, 15.6, 31.2, 52, 104 & 156 μg/ml and in the 19-20 hour 

assay at 0.975, 1.47, 2.93, 4.89, 9.75, 14.7, 29.3, 48.9, 97.5 & 147 μg/ml. Concentrations tested 

with activation in the two 10 hour assays were 1, 1.5, 3, 5, 10, 15, 30, 50 & 100 μg/ml and 2.95, 

4.95, 9.85, 14.8, 29.6, 49.4, 98.5 & 296 μg/ml, plus concentrations for the 19-20 hour assay were 

9.75, 14.7, 29.3, 48.9, 97.5, 147 & 293 μg/ml. Positive controls were mitomycin C (nonactivation) and cyclophosphamide (activation). 

Cytotoxicity was shown in both non-activated as well as in activated assays. Chlorpyrifos 

did not appear to cause chromosomal aberrations. Positive controls caused appropriate 

mutagenic response. This study was classified as Acceptable/guideline.

870.5395 Micronucleus Assay in Mammalian Erythrocytes

Chlorpyrifos was tested at levels of 0, 7, 22, 70 mg/kg by gavage in corn oil in the mouse (MRID 

00152684). 

Chlorpyrifos was negative for clastogenic effects. This study is classified as 

acceptable/guideline.
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870.5500 DNA Repair Assay in Bacteria

Increased damage to bacterial DNA was detected (Study 256040). This study is classified as 

acceptable/guideline. 

870.5550 Unscheduled DNA Synthesis in Hepatocytes

Chlorpyrifos was tested with concentrations from 10E-06 M to 10E-04 M in isolated rat 

hepatocytes (MRID 00157057). 

Chlorpyrifos was negative for UDS in isolated rat hepatocytes under the conditions of this 

study. The high dose was cytotoxic and also formed a precipitate. This study is classified 

as acceptable/guideline.

870.5575 Mitotic Gene Conversion in Yeast

Increased recombination frequency was detected in yeast (Study 256040). This study is 

classified as acceptable/guideline.

A.4.7 Neurotoxicity

870.6100 Delayed Neurotoxicity Study – Hen

Chlorpyrifos was dosed at 0, 50, 100 or 110 mg/kg in hens (MRID 00097144 and 40510601). 

There is no evidence of histopathologically observed neurotoxicity in hens. The NOAEL is 

110 mg/kg, negative for neurotoxicity at 110 mg/kg. The LOAEL was not determined. The 

LD50 in hens = 106 mg/kg. These studies are classified as acceptable/guideline.

870.6200a Acute Neurotoxicity Screening Battery

Male & female Fischer 344 rats were treated once, by oral gavage, with chlorpyrifos at doses of 

0, 10, 50 or 100 mg/kg and evaluated for neurotoxicity on days 1 (at the peak time of toxicity, 

approximately 6 hours after dosing), 8 and 15 (MRID 42669101 and 42943101). 

Systemic toxicity consisted of decreased body weights of animals in the 50 and 100 mg/kg 

groups. Neurotoxic effects consisted of decreased motor activity on day 1 through day 8 

(females only). Significant FOB changes were limited to high dose females, of which 6 out 

of 10 could not perform the landing hind leg splay on day 1 of the study. Grip performance 

on day 1 revealed a possible treatment-related decrease with increasing dose. 

Neuropathological examinations did not reveal any treatment-related effects. Systemic 

NOAEL (M&F) = 10 mg/kg (LDT) with the systemic LOAEL (M&F) = 50 mg/kg (MDT). 

LOAEL is based on decrease in both body weight and motor activity and increased 

incidence of adverse clinical signs consistent with organophosphorus intoxication. These 

studies are classified as guideline.
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870.6200b Sub-chronic Neurotoxicity Screening Battery

In this sub-chronic neurotoxicity study, male and female Fischer 344 rats were treated for 13 

weeks with diets containing sufficient chlorpyrifos to yield doses of 0, 0.1, 1.0, 5.0 or 15 

mg/kg/day (MRID 42929801). During the study, body weights, clinical signs, FOB, motor 

activity and neuropathology were examined. FOB, performed at pre-study and weeks 4, 8, 13 

consisted of hand-held and open field observations and measurement of grip performance and 

landing foot splay. 

The study indicated the treatment-related effects included decreased motor activity and an

increased incidence of urine incontinence on females. Although a statistically significant 

depression in motor activity was present in high-dose animals at week 4. The transitory nature 

of the effect suggests that the differences were not treatment-related. In addition, a low, and 

statistically non-significant, increase in the incidence of urine incontinence was observed in 

several 5 and 15 mg/kg/day females during the clinical examinations and FOB evaluations. One 

high-dose female showed urine incontinence at weeks 4, 8, and 13 and another, only at weeks 4 

and 8. None of the other animals showed urine incontinence in more than one FOB session. 

There was no clear dose- or time-relationships which would suggest that the incontinence was 

treatment-related. Body weights of treated animals were comparable to controls. 

Neuropathological examination did not reveal any differences which might be attributed to 

treatment. No neurotoxicity was noted at 15 mg/kg/day, a dose previously shown to markedly 

inhibit plasma (>80%), RBC (>45%) and brain (>62%) cholinesterase activities. 

The NOAEL for neurotoxicity was established at 15 mg/kg/day (high dose tested); the 

LOAEL was not established. This study is satisfies guideline requirements for a subchronic neurotoxicity screening battery in the rat.

870.6300 Developmental Neurotoxicity Study

In this developmental neurotoxicity study (MRID 44556901 and companion 44648101 

cholinesterase study), 25 pregnant Sprague-Dawley rats/group were administered chlorpyrifos 

(99.8% a.i.) by gavage from gestation day 6 (GD 6) through lactation day 11 at 0, 0.3, 1, or 5 

mg/kg/day. An additional 5 pregnant females/group were dosed at the same levels for the 

cholinesterase (ChE) phase of the study. Dams were examined for body weight, reproductive 

performance, number of viable pups, and postpartum behavior. During the dosing period, dams 

were observed daily for signs of autonomic function toxicity. Satellite dams were sacrificed four 

to five hours post-dosing on GD 20 for ChE analyses to be performed on brain, plasma, and 

erythrocytes. Offspring were examined for viability at birth, pup/litter survival, body weight, sex 

ratio, physical development landmarks (eye opening and pinna detachment), observed nursing 

behavior, and sexual maturation. F1 generation litters were randomly standardized on lactation 

day 5 and assigned to 4 subsets for continued observation. On postnatal day (PND) 12, fixed 

brain weight measurements (10 pups/sex/dose) and neuropathological evaluations including 

morphometrics (6 pups/sex/dose) were performed on Subset 1 pups, with the remaining 10 

pups/sex/dose necropsied for gross lesions. In Subset 2, 8 pups/sex/dose were selected for 

evaluation of learning and memory; evaluations were performed on PNDs 23-25 and 62-92. 

These Subset 2 animals were sacrificed on PNDs 97-101, following the last evaluation. The 

Subset 2 pups not selected for evaluation were necropsied for gross lesions on PND 22. The 
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Subset 3 pups were tested for motor activity on PNDs 14, 18, 22, and 61 and auditory startle 

habituation on PNDs 23 and 62; all Subset 3 animals were sacrificed on PNDs 63 or 64 

following the last evaluation. In Subset 4 pups, fixed brain weights were determined in 10 

pups/sex/dose, neuropathological examinations were performed on 6 pups/sex/dose, and all 

remaining Subset 4 animals (10/sex/dose) were necropsied for gross lesions upon sacrifice on 

PND 66-77.

Maternal toxicity in the high-dose (5 mg/kg/day) animals was manifested as increased signs of 

autonomic function toxicity, apparent at the end of gestation as fasciculations (6/25 treated vs 

0/25 controls), and during early lactation (days 1-5) as fasciculations (16/24 treated vs 0/25 

controls), hyperpnea (8/24 treated vs 0/25 controls), and hyperreactivity (17/24 treated vs 2/25 

controls). Dams with all pups dying were increased in the high-dose group (3/23 treated vs 0/25 

controls). There were no significant effects on bodyweight, food consumption, or pregnancy 

parameters. There were no unscheduled deaths in the maternal animals.

Brain ChE activity was decreased in the high-dose ( 90%) and mid-dose ( 18%) dams as 

compared to control. Erythrocyte ( 41-99%) and plasma ( 43-92%) ChE activities were 

decreased in a dose-dependent manner in all treated groups.

For the F1 generation pups, the high-dose group bodyweights were significantly reduced ( 8-

15%) at PND 1 and 5 (pre- and post-culling). Bodyweights were also reduced from birth to PND 

22 in Subset 4 high-dose animals ( 5-19%); bodyweight gains were reduced in these animals 

during the same period ( 5-30%). Additionally, compared to the controls, reduced terminal 

body weights were observed in the Subset 1 (PND 12) high-dose animals ( 17-19%) and the 

Subset 4 (PND 66) high-dose males ( 10%). For the F1 generation adults, body weights of the 

high-dose males were decreased at PND 22 through 66 ( 11-17% vs controls). High-dose F1

adult females also weighed less than controls at PND 22 ( 17% vs controls), but were of similar 

weight at PND 66. Bodyweight gains were also decreased in the high-dose males for the PND 

22-40 interval ( 13% vs controls) and PND 40-66 interval ( 7%). Food consumption was 

decreased immediately after weaning (PND 23-30) in high-dose males and females ( 13% vs 

controls).

Development as assessed by pinna unfolding was delayed (4.0 days in treated vs 3.5 days in 

controls) in the high-dose group. Sexual maturation was delayed as assessed by time to preputial 

separation (106% of controls) and vaginal patency (103% of controls).

Pup viability was reduced as assessed by the following parameters: surviving pups/ litter ( 27%) 

and live litter size at culling ( 16%), pup viability index ( 29%), and pups found dead or 

presumed cannibalized (day 1 - 7.2 % treated vs 0.0% controls; days 2 to 5 - 24.7% treated vs 

1.3% controls). 

There were no statistically significant differences between the groups in the average acquisition 

and delay training. Additionally, there were no differences among dose groups when comparing 

retention of information during PNDs 23-25 and 62-92. Motor activity was decreased in high 

dose male and female pups on PND 14 ( 56% in males and 37% in females), and increased in 
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high dose females on PNDs 18 and 22 ( 51% on both days). On PND 61, motor activity was 

increased for both sexes ( 16-17%). There was a statistically significant increase ( 16-25%) in 

the latency to peak response during the auditory startle habituation assessments on PND 23 in the 

high-dose animals compared to concurrent controls. At PND 62, the latency to peak response in 

the high-dose animals was 10-12% higher than in the controls. Additionally, the peak response 

amplitudes in the high-dose animals were decreased by 9 to 29% on PNDs 23 and 62 (not 

statistically significant) compared to the controls.

There were no gross or microscopic lesions of the nervous system in Subset 1 or 4 offspring. 

Subset 1 high-dose males at PND 12 had reduced absolute brain weights ( 9% vs controls), 

increased relative brain weights ( 13% vs controls), reduced anterior to posterior measurement 

of the cerebellum ( 24% vs controls), reduced height of the cerebellum ( 14% vs controls), 

decreased thickness of the parietal cortex ( 6% vs controls), and decreased thickness of the 

hippocampal gyrus ( 9% vs controls). High-dose female pups had reduced absolute brain 

weights ( 9% vs controls), increased relative brain weights ( 14% vs controls), decreased 

thickness of the parietal cortex ( 6% vs controls), decreased width of the caudate-putamen 

( 10% vs controls), and decreased thickness of the hippocampal gyrus ( 12% vs controls). In 

Subset 4 F1 animals, killed on PND 66, morphometric analysis revealed significantly decreased 

parietal cortex measurements in high-dose ( 5%) and mid-dose ( 4%) females, as compared to 

controls. Decreases in the thickness of the hippocampal gyrus in high-dose females ( 7%) 

resulted in contradictory statistical results when compared to controls; decreases in mid-dose 

( 4%) females as compared to control were not found to be statistically significant. There was 

no evaluation of the morphometric data for low dose females at PND 66. Brain weight in high 

dose females was similar to control brain weight at day 66 ( 0.3%).

It is not possible to definitively classify findings in the preweaning offspring as having originated 

with pre- or postnatal exposure, nor as resulting from developmental perturbation versus direct 

systemic- or neurotoxicity. However, adverse findings in the adult (~PND 66) offspring, i.e., 

alterations in motor activity, auditory startle response, and brain structure (decreased 

measurements of the parietal cortex and hippocampal gyrus, in the absence of brain weight 

deficits) can be interpreted to represent the long-term sequellae of developmental exposure to 

chlorpyrifos.

Adverse effects in the offspring have been identified at the MDT of 1.0 mg/kg/day; these include 

a significant treatment-related decrease in the measurement of the parietal cortex, supported by 

possible (although non-significant) alterations in the hippocampal gyrus, in the brain of female 

rats at postnatal day 66. 

The maternal toxicity NOAEL was not observed. The maternal LOAEL was < 0.3 

mg/kg/day, based on plasma and RBC cholinesterase inhibition. However, due to the lack 

of morphometric data for low-dose (0.3 mg/kg/day) female rats at postnatal day 66, the 

offspring NOAEL and LOAEL cannot be determined. This study has been classified as 

guideline/unacceptable (but upgradeable). 
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A.4.8 Metabolism

870.7485 Metabolism – Rat

This study (MRID 44648102) was done to help construct and validate a physiologically-based 

pharmacokinetic model for chlorpyrifos (Unlabeled - 99.8% a.i., Lot # MM930503-17; Labeled -

89.4% a.i., Lot # B930-51 [INV1134]) a weak inhibitor of acetylcholinesterase activity, and its 

metabolites, chlorpyrifos-oxon (OXON), a strong cholinesterase inhibitor and 3,5,6-

trichloropyridinol. Groups of 24 male rats were given a single gavage dose of 0.5, 1, 5, 10, 50, 

or 100 mg/kg chlorpyrifos in corn oil. Four rats from each group were killed 10 and 20 minutes 

and 1, 3, 6, and 12 hours after treatment. Cholinesterase activity was measured in the brain and 

plasma at each time point, as well as the plasma concentration of the test material and its OXON 

metabolite. In a separate portion of the study, four male rats were given a single gavage dose of 

labeled chlorpyrifos at a concentration of 5 or 100.0 mg/kg and were sacrificed three hours later. 

Blood was collected from the animals at sacrifice and the concentration of the test material and 

its metabolites 3,5,6-trichloropyridinol (TCP) and OXON determined.

Plasma cholinesterase activity decreased in a time- and dose-dependent manner. The plasma 

cholinesterase activities of rats treated with 0.5, 1, 5 or 10 mg/kg were maximally decreased 3-6 

hours after treatment, with both the decrease and recovery of activity being dose-dependent. The 

decrease in activity of rats treated with 50 or 100 mg/kg began within 10 minutes of treatment. 

By 12 hours after treatment, both groups were approximately 11% of the control group and had 

not shown signs of recovery.

Brain cholinesterase activity was not affected as dramatically by test material treatment as 

plasma activity with only the 10, 50, and 100 mg/kg dose groups showing significant effects. The 

brain cholinesterase activity in the 50 or 100 mg/kg dose groups decreased significantly within 

one hour of treatment; mirrored each other; and by 12 hours, were approximately 30% and 20%, 

respectively, of control. The brain cholinesterase activity of rats treated with 10 mg/kg test 

material began to decline within three hours of treatment and was significantly decreased by six 

hours after treatment. In none of the affected groups did brain cholinesterase show signs of 

recovery.

Peak chlorpyrifos blood concentrations occurred within three hours of treatment in all but the 

lowest dose group. The area under the curve (AUC) was calculated as 0.4, 1.1, 5.0, and 12.5 

μmole hr L-1 for the 5.0, 10.0, 50.0, and 100 mg/kg groups, respectively and yielded calculated 

blood half-lives of chlorpyrifos of 2.7,1.5, 2.1, and 7.3 hours for the 5.0, 10.0, 50.0, and 100.0 

mg/kg dose groups, respectively. Regardless of dose, the highest concentration of OXON 

detected was 2.5 ng/g found in the blood of rats treated with 50 mg/kg test material one hour 

post-treatment. Following treatment with 5 or 100 mg/kg labeled test material, >=98% of the 

activity detected in the blood was identified as TCP metabolite with the remaining attributed to 

the parent compound. Since OXON is an intermediate in the formation of TCP and none of the 

metabolite was detected, these studies support that the half-life of the OXON metabolite is short 

(reportedly 10 seconds) and that in vivo metabolism of chlorpyrifos is rapid. 

This study is considered acceptable (non-guideline). ). It may partially fulfill guideline 
Chlorpyrifos Preliminary Human Health Risk Assessment DP No. D388070

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requirements in other areas.

In another study of tissue distribution and metabolism (MRID 40458901), carbon-14 labelled 

chlorpyrifos was administered orally to Fischer 344 rats for 15 days (MRID 40458901). 

The majority of the radioactivity was recovered in the urine (>84%) and feces (>5%) within 72 

hours. Less than 0.2% of the radioactivity remained in tissues and carcass. No unchanged 

chlorpyrifos was found in the urine and the main urinary metabolites were identified as 3,5,6-

TCP and conjugates (glucuronide and possibly sulfate) of 3,5,6-TCP.

This study is classified as acceptable-guideline.

870.7600 Dermal Absorption

Single doses of 0.5 mg/kg (N=1) and 5.0 mg/kg (N=5) of chlorpyrifos were administered to male 

humans (accession No. 249203).

Based on the urinary excretion of the 3,5,6-TCP metabolite, the minimum absorption was 

approximately 1-3% dermally. The proportion of the administered dose metabolized to this 

pyridinol is unknown, these estimates are considered minimum values (i.e. absorption 

could be higher). 

A.4.9 Immunotoxicity

870.7800 Immunotoxicity

In an immunotoxicity study (MRID 48139304), chlorpyrifos technical (99.8% a.i., Lot No. 

KC28161419) was administered in the diet to 10 female Crl:CD(SD) rats/dose at nominal dose 

levels of 0, 0.4, 2, or 10 mg/kg/day (actual dose levels of 0, 0.416, 2.13, or 10.7 mg/kg/day) for 

28 days. The female rat was determined to be the appropriate test species/sex for this study.

Cyclophosphamide in sterile saline was intra-peritoneally administered to the positive control 

group on Days 24 to 28 at a rate of 20 mg/kg body weight/day. On Day 24, all animals received a 

0.5 mL intravenous injection of sheep red blood cells (SRBCs) in isotonic saline (2 x 108

SRBCs)/mL). T-cell dependent antibody response (TDAR) was evaluated at day 29. 

There were no statistically significant effects of treatment with chlorpyrifos on mean body 

weights, body weight gains, or food consumption. Statistically significant decreases in mean red 

blood cell (RBC) cholinesterase (ChE) activity were seen in all test substance treatment groups. 

Mean brain ChE activity was significantly decreased in the mid- and high-dose groups. There 

were no test substance treatment-related effects on clinical signs, gross anatomy, or 

hematological parameters. In the positive control group, mean body weights and body weight 

gains were lower than the control value throughout the study; these differences were attributed to 

normal body weight variability. No unscheduled mortalities occurred in any study group. For 

systemic toxicity related to treatment with chlorpyrifos, the NOAEL for female rats is 10 

mg/kg/day (highest dose tested) based on no effects were seen in clinical observations, body 
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weight, food consumption, and hematological parameters. The LOAEL for systemic toxicity was 

not established. For neurotoxic effects, the LOAEL for female rats is 0.4 mg/kg/day (lowest 

dose tested), based on decreased RBC cholinesterase activity. The NOAEL for neurotoxic 

effects was not established (i.e., less than 0.4 mg/kg/day).

For immunotoxicity, there were no treatment-related effects on mean absolute and relative spleen 

and thymus weights or hematological parameters at any dose level. The anti-SRBC IgM titers 

did not show statistically significant differences among treatment and the control groups. 

Decreased anti-SRBC titers for the 2 and 10 mg/kg/day treatment groups (64% and 41%, 

respectively) were observed when compared with the control. However, the decreased response 

in these dose groups may have been due, in part, to a high mean value for the control group. The 

biological significance of these observations also was confounded by the lack of a clear dose 

response (the decrease was greater for the mid-dose group than for the high-dose group). The 

positive control demonstrated the validity of the assay. Considered the trend and distribution of 

individual animal data in treatment and control groups, there was no significant suppression of 

the anti-SRBC titers with chlorpyrifos exposure. 

The NK cell activity was not evaluated. There were no treatment-related effects on spleen and 

thymus weights and histopathology parameters that would suggest the potential for 

immunotoxicity in repeat-dose studies (2-week, 28-day, 90-day, 2-year) studies in rats and mice. 

Under HED guidance, if the TDAR assay is negative and evaluation of observational endpoints 

from all available toxicology database provide no evidence of immunotoxicity, the test article is 

considered negative for immunotoxicity and evaluation of NK activity is not necessary.

Under conditions of this study, the NOAEL is 10 mg/kg/day (highest dose tested) based on 

the overall weight-of-evidence. A lack of dose-related response for anti-SRBC IgM titers at 

the mid- and high-dose levels, a lack of statistical significance at any dose level, and a lack 

of evidence of other immunological effects (absolute and relative spleen and thymus 

weights, hematological parameters). A LOAEL for immunotoxicity was not established.

This immunotoxicity study in the rat is considered as acceptable/guideline and satisfies the 

guideline requirement for an immunotoxicity study (OPPTS 870.7800) in rats. 

A.4.10 Special/Other Studies

Comparative Cholinesterase Assay

Comparison of cholinesterase (ChE) inhibition in young adult and preweanling CD rats after 

acute and repeated chlorpyrifos exposures were performed (MRID 48139301).
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The following table illustrates the NOAEL and LOAELs derived from the acute dosing aspects

of this study. Male pups had the same NOAELs and LOAELs as female pups. 

Enzyme

Source

Acute NOAEL/LOAEL mg/kg (% Inhibition at 

LOAEL)

 Pups (male/female %) Adults (females 

only)

Plasma ChE:

 CPY – gavage

 CPY – milk/diet

 CPO - gavage

0.5/2(51%/47%)

0.5/2(39%/44%) 

0.05/0.1(18%/21% but 

51% at 0.5 mg/kg) 

0.5/2(54%)

0.5/2(58%)

0.1/0.5(56%)

RBC AChE:

 CPY – gavage

 CPY – milk/diet

 CPO - gavage

0.5/2(35% /31%) 

0.5/2(29%/27%)/

0.1/0.5(46%/47%) 

0.5/2(19%)

0.5/2(52%) 

0.1/0.5(36%) 

Brain:

 CPY – gavage

 CPY – milk/diet

 CPO - gavage

2/5(51%/55%)

2/5(42%/56%) 

Not inhibited 

2/10(57%)

2/10(22%)

Not inhibited

Cpy = chlorpyrifos

CPO = chlorpyrifos oxon

The following table illustrates the NOAEL and LOAELs derived from the repeat dosing aspects 

of this study.

Enzyme

Source

NOAEL/LOAEL mg/kg (% Inhibition at LOAEL)

 Pups Adults

Plasma ChE:

 CPY 

 CPO 

0.1/0.5(46%) 

0.01/0.5 (62%) 

0.1/0.5 (46%)

0.01/0.5 (76%)

RBC AChE:

 CPY 

 CPO 

0.1/0.5 (18%)

0.01/0.5 (84%) 

0.1/0.5 (20%)

0.01/0.5 (87%)

Brain:

 CPY 

 CPO 

0.5/1 (19%) 

Not inhibited 

0.5/1 (9%)

Not inhibited 

The classification of this in vivo comparative cholinesterase inhibition study is 

Acceptable/Non-Guideline. 
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Special Acute Neurotoxic Esterase Study in Rat

In a special study designed primarily to assess for the potential of chlorpyrifos to inhibit 

neurotoxic esterase (NTE), chlorpyrifos was administered by gavage to six groups of Fischer 344 

strain female rats at dose levels of 0, 1, 5, 10, 50 or 100 mg/kg and sacrificed 24 hours later 

(MRID 44273901). NTE was assessed for by the method of Kayyali et al (J. Anal. Toxicol. 

15:86-89 (1991). Dosing was by gavage at a dosing volume of 10 ml/kg. The rats were also 

assessed for cholinesterase inhibition in the plasma, red blood cells (RBCs), heart and brain and 

there was an additional group dosed at 0.5 mg/kg included for assessment of cholinesterase only. 

The cholinesterase inhibition data indicated a NOAEL and LOAEL for plasma 

cholinesterase (ChE) and RBC and heart acetylcholinesterase (AChE) of 1 and 5 mg/kg, 

respectively. At 5 mg/kg, plasma ChE, RBC AChE and heart AChE were significantly inhibited 

approximately 45%, 17% and 19%, respectively. Brain AChE demonstrated a NOAEL and 

LOAEL of 10 and 50 mg/kg, respectively and at 50 mg/kg inhibition was approximately 53%. 

NTE was not inhibited at the highest dose level of 100 mg/kg and there was an apparent 9% 

increase in activity at this dose level. 

This study is classified as ACCEPTABLE (Non-Guideline). The study contains data useful 

for evaluating the potential for chlorpyrifos to inhibit neurotoxic esterase following 

systemic administration. 

Cognitive Rat Study

In this special study (MRID 44020901) the effects of repeated oral administration of chlorpyrifos 

technical (purity, 98.1%; lot no. #MM-890115-616) on the cognitive function of rats were 

evaluated with a delayed matching to position (DMTP) test. Groups of 10 female Long-Evans 

rats, pretrained in a DMTP apparatus were administered oral doses of chlorpyrifos in corn oil of 

0, 1, 3, or 10 mg/kg/day for 5 days/week for 4 weeks. DMTP testing was conducted 6 

days/week during treatment and continued post-dosing for 4 weeks. Testing for short-term 

memory (as evidenced by the retention rate) and attention/encoding deficits was based on the 

percent correct accuracy on several time delays. Slope over delay and intercept at time zero 

were calculated from these data for each rat and represented the "forgetting curve." 

A satellite group of 6 rats/dose was sacrificed after the 4-week dosing period and plasma, 

erythrocyte and brain cholinesterase (ChE) were determined. Neurotoxic esterase (NTE) activity 

was determined in satellite rats from the control and high-dose groups one day after the last dose 

administration. Plasma (68%), RBC (56%) and brain (8%) ChE were inhibited at 1 mg/kg/day. 

At 3 mg/kg/day, plasma (83%), RBC (65%) and brain (63%) ChE inhibition was increased. At 

10 mg/kg/day plasma (93%), RBC (65%) and brain (86%) ChE inhibition was further increased. 

NTE was minimally decreased (6%) in the high-dose group but this was not considered 

toxicologically significant. The clinical sign of miosis was observed in rats that received 3 and 

10 mg/kg/day particularly at weeks 3 and 4. Salivation and tremors were observed primarily at 

10 mg/kg/day with the tremors usually disappearing by the following morning.
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A statistical analysis of the actual percent correct data was provided (supplemental report dated 

February 10, 1999) and no statistical differences (i.e., p < 0.05) indicative of treatment related 

decreases in percent correct choices were established for any dose or delay time. Thus, 

cognitive function is not obviously impaired. No consistent pattern in the intercept of the 

retention gradient was noted since it was increased at week 2 and decreased at week 3 but 

equivalent to the control at weeks 1 and 4 at 10 mg/kg/day. The DMTP parameters of actual 

total delay (increased by as much as 2.5 sec in the 0 delay trial at week 2), void trials per session 

(increased from about 5 in the control to about 15) and nosepokes (decreased ~42% at week 1 for 

the 15 sec delay) were affected in the 10 mg/kg/day Chlorpyrifos dose at most or all intervals 

during dosing. Although these effects can be possibly related to a decrease in motor activity 

known to be associated with organophosphates, the increase in void trials may also indicate a 

motivational or attention deficit.

The LOAEL for ChE inhibition is 1 mg/kg/day, with no NOAEL was established. The 

LOAEL for overt cholinergic signs is 3 mg/kg/day based on miosis. The NOAEL is 1 

mg/kg/day. The LOAEL for DMTP performance (i.e. increase in void trials) is 10 

mg/kg/day with the NOAEL at 3 mg/kg/day. This study is classified ACCEPTABLE (Nonguideline).

Acute Inhalation Study

Acute inhalation exposure of adult Crl:CD(SD) rats to particulate chlorpyrifos aerosols was 

assessed (MRID 48139303). The kinetics of concentration dependent cholinesterase (ChE) 

inhibition in red blood cells, plasma, brain and lung was measured. In the special acute inhalation 

study female rats were exposed nose only to atmospheric concentrations of up to mg/m3of 

particulate chlorpyrifos for six hours and allowed an additional 72 hours to recover (MRID No: 

48139303 Hotchkiss et al. 2010). The peak inhibition for plasma and lung ChE was at 6 hours 

post-dosing. Significant lung (47%) and plasma (48%) ChE inhibition were noted at the lowest 

concentration tested of 3.7 mg/m3, which is a LOAEL. RBC and brain ChE inhibition were 

noted at 12.9 mg/m3and 53.9 mg/m3, respectively, indicating they are less sensitive than lung 

and plasma ChE inhibition following acute inhalation exposures. No NOAEL was established. 

EPA estimated a human equivalent concentration (HEC) of 0.62 mg/ m3based on the LOAEL of 

3.7 mg/m3. 

The LOAEL is 3.7 mg/m3 based on lung cholinesterase testing (HEC of 0.62 mg/ m3 

estimated by EPA). A NOAEL was not identified. The classification of this special 

inhibition study is Acceptable/Non-Guideline. 
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Appendix B. Physical/Chemical Properties

Physicochemical Properties of Chlorpyrifos.

Parameter Value Reference

Melting point/range 41.5-42.5 oC Chlorpyrifos IRED

pH NR

Density (21oC) 1.51 g/mL 

Water solubility (25°C) 1.05 mg/L

Solvent solubility (20°C) Acetone >400 g/L

Dichloromethane >400 g/L

Methanol 250 g/L

Ethyl acetate >400 g/L

Toluene >400 g/L

n-hexane >400 g/L

Vapor pressure, (25°C)

1.87x10-5 torr1

Dissociation constant, pKa NR

Octanol/water partition 

coefficient, Log(KOW)

4.7 

UV/visible absorption spectrum NR

NR – not reported.

1 R. Bohaty, June 2011, D368388 and D389480, Chlorpyrifos Drinking Water Assessment for Registration Review

(CRF assessment, Oct. 16, 2009 product chemistry BC 2062713)
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Appendix C. Current US Tolerances and International Residue Limits 

Chlorpyrifos (059101)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3

40CFR180.342

chlorpyrifos per se ( O,O -

diethyl O -(3,5,6-trichloro-2-

pyridyl) phosphorothioate

O,O-diethyl-O-(3,5,6-trichloro-2-

pyridyl) phosphorothioate (apples, 

grapes, tomatoes)

O,O-diethyl-O-(3,5,6- trichloro-2-

pyridyl) phosphorothioate, including 

the metabolite 3,5,6-trichloro-2-

pyridinol

(citrus fruits; fat, kidney, and liver of 

cattle; kiwifruit; peppers; rutabagas; 

meat and meat byproducts of cattle 

(calculated on the fat content)

Chlorpyrifos. The 

residue is fat 

soluble. 

Commodity1, Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex3

Alfalfa, forage 3.0

Alfalfa, hay 13 5 alfalfa fodder

Almond 0.2 0.05

Almond, hulls 12

Apple 0.01 0.01 1 pome fruits

Apple, wet pomace 0.02

Banana 0.1 2

Beet, sugar, dried pulp 5.0

Beet, sugar, molasses 15

Beet, sugar, roots 1.0 0.05

Beet, sugar, tops 8.0

Cattle, fat 0.3 1.0

Cattle, meat 0.05 1.0 1 (fat)

Cattle, meat byproducts 0.05 1.0 0.01 cattle, kidney 

and liver

Cherry, sweet 1.0

Cherry, tart 1.0

Citrus, dried pulp 5.0

Citrus, oil 20

Corn, field, forage 8.0

Corn, field, grain 0.05 0.05 0.05 maize

Corn, field, refined oil 0.25 0.2 maize oil, 

edible

Corn, field, stover 8.0 10 maize fodder 

(dry)

Corn, sweet, forage 8.0

Corn, sweet, kernel plus cob 

with husk removed

0.05 0.05 0.01 sweet corn 

(corn-on-the-cob)

Corn, sweet, stover 8.0

Cotton, undelinted seed 0.2 0.3 cotton seed

Cranberry 1.0 1

Cucumber 0.05 0.05

Egg 0.01 0.01 (*)

Fig 0.01
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Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3

Fruit, citrus, group 10 1.0 1.0 1

Goat, fat 0.2

Goat, meat 0.05

Goat, meat byproducts 0.05

Hazelnut 0.2

Hog, fat 0.2

Hog, meat 0.05 0.02 (fat)

Hog, meat byproducts 0.05 0.01 (*) pig, edible 

offal 

Horse, fat 0.25

Horse, meat 0.25

Horse, meat byproducts 0.25

Kiwifruit 2.0 2.0

Lettuce 1.0

Milk, fat (Reflecting 0.01 ppm 

in whole milk)

0.25 0.02 milk

Nectarine 0.05 0.05

Onion, bulb 0.5 0.2

Peach 0.05 0.05 0.5

Peanut 0.2

Peanut, refined oil 0.2

Pear 0.05 1 pome fruits

Pecan 0.2 0.05 (*)

Pepper 1.0

1.0

2 peppers sweet 

including pimento 

or pimiento); 20 

peppers chili, dried

Peppermint, tops 0.8

Peppermint, oil 8.0

Plum, prune, fresh 0.05 0.5 plums 

(including prunes)

Poultry, fat 0.1

Poultry, meat 0.1 0.01 (fat) 

Poultry, meat byproducts 0.1 0.01 (*) poultry, 

edible offal

Pumpkin 0.05

Radish 2.0

Rutabaga 0.5 0.5

Sheep, fat 0.2

Sheep, meat 0.05 1 (fat)

Sheep, meat byproducts 0.05 0.01 sheep, edible 

offal

Spearmint, tops 0.8

Spearmint, oil 8.0

Sorghum, grain, forage 0.5

Sorghum, grain, grain 0.5 0.5

Sorghum, grain, stover 2.0 2 sorghum straw 

and fodder, dry

Soybean, seed 0.3 0.1 soya bean (dry)

Strawberry 0.2 0.3
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Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3

Sunflower, seed 0.1 0.1

Sweet potato, roots 0.05

Turnip, roots 1.0

Turnip, tops 0.3

Vegetable, brassica, leafy, 

group 5

1.0 2 Broccoli 

1 Cabbages, head 

0.05 Cauliflower 

1 Chinese cabbage 

(type pe-tsai)

Vegetable, legume, group 6 

except soybean

0.05 0.05 lentils 0.01 common bean 

(pods and/or 

immature seeds); 

peas (pods and 

succulent=immatur

e seeds)

Walnut 0.2 0.05 (*)

Wheat, forage 3.0

Wheat, grain 0.5 0.5

Wheat, straw 6.0 5 wheat straw and 

fodder, dry

MRLs with No US Equivalents

Grapes 0.01 0.5

Tomatoes 0.01

Carrot 0.1

Coffee beans 0.05

Cotton seed oil, crude 0.05 (*)

Cotton seed oil, edible 0.05 (*)

Dried grapes (=currants, 

raisins and sultanas) 0.1

Potato 2

Rice 0.5

Soya bean oil, refined 0.03

Tea, green, black (black, 

fermented and dried) 2

Wheat flour 0.1

Completed: M. Negussie; 04/12/2011

1

Includes commodities listed in the CFR as of 4/12/11. The 40CFR 180.342 (a) (3) also stipulates that ―a tolerance 

of 0.1 part per million is established for residues of chlorpyrifos, per se, in or on food commodities (other than those 

already covered by a higher tolerance as a result of use on growing crops) in food service establishments where food 

and food products are prepared and served, as a result of the application of chlorpyrifos in microencapsulated form.‖

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = 

processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the 

fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.
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(c) Tolerances with regional registrations. Tolerances with regional registration, as defined in 180.1(m), are 

established for residues of the pesticide chlorpyrifos per se ( O,O -diethyl- O -(3,5,6-trichloro-2-pyridyl) 

phosphorothioate) in or on the following food commodities:

In addition, the following tolerances for chlorpyrifos are recommended under registration 

review:

Recommended/Reassessed Tolerances for Chlorpyrifos

Commodity Established Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments

Correct Commodity Definition

Grain, aspirated fractions NA 22

Cotton, gin by-products NA 15

Commodity Parts per million Canada Codex

Asparagus 5.0

Grape 0.01 0.01 0.5
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Appendix D. Review of Human Research

ORE:

The chlorpyrifos occupational residential exposure assessment relies in part on data from studies 

in which adult human subjects were intentionally exposed to a pesticide or other chemical. 

These studies, which comprise AHETF, ORETF and PHED, as well as the majority of chemicalspecific handler exposure data were determined to require a review of their ethical conduct, have 

received that review, and have been determined to be ethical. The chemical-specific handler 

exposure studies that were determined to be ethical and suitable for use in risk assessment are:

MRID 42974501, Shurdut, B.A. et al. (1993); MRID 43138102, Honeycutt, R.C. & Day, E.W. 

Jr. (1994); MRID 44739302, Knuteson et al. (1999); and MRID 43027901, Contardi et al. 

(1993). A single handler exposure study, ―Evaluation of Chlorpyrifos Exposure to Workers 

During Loading and Application of Lorsban 15 % Granular Insecticide During Corn Planting 

(MRID 44483501),‖ was determined to have been conducted in a manner which prohibits its use 

by the Agency. 

Toxicology:

Deliberate dosing studies in adult (non-pregnant) humans are available which measure AChE 

activity and urinary levels of chlorpyrifos and/or its metabolites. Results from Nolan et al (1982;

MRID 124144) have been used by the Agency in estimating (i.e. back-calculating) chlorpyrifos 

exposure based on urinary levels of TCP. This study has also been used to derive a dermal 

absorption factor in humans. The Nolan et al (1982)) study was reviewed by the Human Studies 

Review Board (June 24-25, 2009; http://www.epa.gov/hsrb/jun-24-25-2009-public-meeting.htm) 

and found to be scientifically and ethically conducted. EPA also determined that the study was 

ethically acceptable. Both the FIFRA SAP and HSRB supported the Agency’s proposal to use 

this study for purposes of characterizing biomonitoring studies but not for purposes of deriving 

points of departure or in directly estimating uncertainty factors. Another intentional human 

dosing study was reviewed by the June 2009 HSRB (Kisicki et al (1999), MRID 44811002) and 

the HSRB concluded that the study was scientifically (and ethically) conducted. However, EPA 

ethics review had determined that ―EPA is forbidden by 40 CFR §26.1704 to rely on the Kisicki et 

al. study, MRID 44811002, in actions taken under FIFRA or §408 of FFDCA. It is possible that the 

circumstances and purposes for which you propose to consider it may be such that the provisions of 

40 CFR §26.1706 for an exception to the prohibition in 40 CFR §26.1704 may be satisfied.‖ (J.

Carley memo dated 5/29/09; http://www.epa.gov/hsrb/files/1d6-ethics-rvw-kisicki-etal-060109.pdf). 

The Kisicki data has not been used in the preliminary chlorpyrifos human health risk assessment.
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Appendix E. Summary Benchmark Dose Values

As a preliminary analysis, the Agency has conducted BMD modeling on selected AChE 

studies. These studies were selected based on the availability of at least two treatment groups in 

addition to a control group. In addition, these studies were selected as they represented a variety 

of ages, lifestages, and durations. In the acute pup studies the Agency has focused on those 

studies representing rat ages (PND 10 and older) concordant with human post-natal exposure 

(i.e, birth and older) and durations of exposure.

BMD modeling was not performed on the 21-day dermal study or the subchronic 

inhalation studies in the rat since the highest doses tested were NOAELs. The recent acute 

inhalation CCA study (MRID 48139303) was not amenable to BMD analysis because of 

variability in the data (large standard deviations) and significant inconsistencies in baseline 

measurements over time. 

The Agency has used a decreasing exponential dose-response model similar to that used 

for the OP and N-methyl carbamate cumulative risk assessments and previously reviewed and 

supported by the FIFRA SAP on several occasions (FIFRA SAP 2001, 2002, 2005a, 2005b, 

2008). As shown below, the Agency has used two versions of the decreasing exponential 

model—R-based code similar to that used in the NMC cumulative risk assessment and the 

USEPA Benchmark Dose Software, version 2.1.1 (BMDS). The R-based program was derived 

from software written using version 1.2.1 of the open source statistical programming language R, 

and is based on methods utilized in the cumulative risk assessments. The Agency’s benchmark 

dose software (BMDS) exponential model includes a family of nested exponential models from 

which an optimal model (based on statistical and model criteria) can be determined. The 

flexibility of the nested exponential models is reflected by the number of parameters considered 

in the models. 

OPP has most often used R-based code to develop BMDs for risk assessment of 

cholinesterase inhibiting pesticides. However, recently, the Agency’s BMDS has implemented 

the decreasing exponential model. As OPP transitions to using BMDS primarily for single 

chemical assessments, both approaches may be used in some assessments. It is notable that the 

two approaches provide remarkably consistent results for the selected studies. 

Consistent with risk assessment on other OP and NMCs compounds, the Agency has used 

a benchmark response (BMR) level of 10% and has thus calculated BMD10s and BMDL10s. The 

BMD10 is the estimated dose where AChE is inhibited by 10% compared to background. The 

BMDL10 is the lower confidence bound on the BMD10. Extensive analyses conducted as part of 

the OP cumulative risk assessment (USEPA, 2002) have demonstrated that 10% is a level that 

can be reliably measured in the majority of rat toxicity studies, and is generally at or near the 

limit of sensitivity for discerning a statistically significant decrease in AChE activity across the 

brain compartment and is a response level close to the background AChE level. The Agency 

uses the BMDL, not the BMD, for use as the PoD since the BMDL accounts for variability of the 

data (USEPA, 2000). The BMD10 provides a point of comparison across studies and the BMD10

provides the basis for determining Toxicity Adjustment Factors (TAFs) for chlorpyrifos-oxon. 

Tables 1-4 provide the results of the BMD analysis of the parent, while Tables 5-8 provide the 
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results of BMD analysis of the oxon.

Typically, studies submitted for pesticide registration and most studies from the public 

literature only measure brain and/or blood ChEs. It is rare for data from peripheral tissues to be 

available for consideration. Chlorpyrifos is unique in that multiple studies are available which 

provide such peripheral data (Appendix B). Tables 10-13 do not include BMD results for plasma 

ChE measures. Consistent with OPP’s ChE policy, plasma ChE data from animals are used for 

risk assessment when RBC AChE data are not reliable and/or when peripheral AChE measures 

are not available. This is not the case for chlorpyrifos; reliable RBC and peripheral data are both 

available. Thus, the plasma data have not been considered for PoD determination. When 

conducting BMD analysis for RBC AChE inhibition, the Agency generally starts with the 

standard BMR of 10% but will consider 15% or 20% in some cases. However, in the case of 

chlorpyrifos, data from peripheral tissues (e.g., heart, lung, liver) show these tissues are similar 

in sensitivity to RBC AChE inhibition. As such, when using RBC AChE inhibition as a 

surrogate for such peripheral data, the BMR of 10% has been used.

For the re-evaluation of endpoint selection for the oral route, OPP considered the quality 

of the all available studies, both previous and new. 

The most robust studies for determining the acute oral PoD are from a new comparative 

cholinesterase (CCA) study (MRID 48139301) in the rat conducted by the registrant and the 

results of cholinesterase (ChE) analyses in male PND17 rats performed by EPA’s ORD (Moser 

et al, 2006). Both of these studies involved a wide range of doses and provided high quality 

AChE data. The results of published studies (e.g., Timchalk et al. 2006 and Zheng et al. 2000) 

add support the findings of the Dow CCA Study and Moser et al (2006). 
Chlorpyrifos Preliminary Human Health Risk Assessment DP No. D388070

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Table 1. Results of BMD Modeling of Male and Female Rat Pup Brain and RBC ChE 

Inhibition following a Single Oral Dose of Chlorpyrifos

aHigh dose dropped to improve fit. 

b High dose dropped to improve fit. 

c

P = 0.071.

d No computation (technical issues e.g., no convergence).

Dataset Sex/age Endpoint/Route

BMD Program/Software

R-based Program

EPA BMDS V2.1.1

BMD10 BMDL10 BMD10 BMDL10

Moser et al, 2006 Male PND 17

Brain ChE/

Acute Gavage 0.84 0.75 1.89a1.54a

Moser et al, 2006 Male PND 17

Whole Blood 

ChE/Acute Gavage 0.38 0.35 0.62b0.43b

CCA Study

MRID 48139301 Male PND 11 

Brain ChE/

Acute Gavage 2.13 1.51 2.13c1.53c

CCA Study

MRID 48139301 Male PND 11 

RBC ChE/

Acute Gavage 0.83 0.66 0.82 0.65

CCA Study

MRID 48139301 Male PND 11 

Brain ChE/

Acute Milk (no 

comput

ation)d

(no 

computat

ion)d

4.4 2.4

CCA Study

MRID 48139301 Male PND 11 

RBC ChE/

Acute Milk 0.5 0.35 0.47 0.36

CCA Study

MRID 48139301 Female PND 11 

Brain ChE/

Acute Gavage 2.17 1.53 2.18 1.56

CCA Study

MRID 48139301 Female PND 11 

RBC ChE/

Acute Gavage 0.97 0.76 0.96 0.75

CCA Study

MRID 48139301 Female PND 11 

Brain ChE/

Acute Milk 1.53 1.03 1.42 0.91

CCA Study

MRID 48139301 Female PND 11 

RBC ChE/

Acute Milk 0.5 0.35 0.5 0.36
Chlorpyrifos Preliminary Human Health Risk Assessment DP No. D388070

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Table 2. Results of BMD Modeling of Adult Female Rat Brain and RBC ChE Inhibition 

following a Single Oral Dose of Chlorpyrifos

Dataset Sex/route Endpoint/

Route

BMD Program 

R-based Single-Sex EPA BMDS V2.1

BMD10 BMDL10 BMD10 BMDL10

CCA 

MRID 

48139301

Adult 

Female

Acute 

Gavage

(8 hr)

Brain No convergence No convergence 4.11a2.26a

CCA 

MRID 

48139301

Adult 

Female

Acute 

Gavage

(8 hr)

RBC 1.5 1.13 1.9b1.2b

CCA 

MRID 

48139301

(a)

Adult 

Female

12 hr diet 

(6 pm-6 

am)

Brain

(no computation)c(no computation)c

4.47

(8 hr after 

feeding; 20 hr 

after food 

introduction)

3.30

(8 hr after 

feeding; 20 

hr after food 

introduction)

CCA 

MRID 

48139301 

Adult

Female

12 hr diet 

(6 pm-6 

am)

RBC 0.66 0.55

1.03

(8 hr after 

feeding; 20 hr 

after food 

introduction)

0.6

(8 hr after 

feeding; 20 

hr after food 

introduction)

a The homogeneous variance resulted in a lower BMDL than the model variance model and also provided an 

acceptable p value.. 

bAn acceptable p value was not achieved. 

c No computation (technical issues e.g., no convergence).

For exposure scenarios longer than acute duration, several high quality oral studies were 

available for BMD analyses and determination of oral PoDs for short- and intermediate-term 

incidental oral and chronic dietary scenarios. These included the new CCA study (MRID 

48139301) in the rat, a developmental neurotoxicity rat study (MRID 44556901) and a special 

ChE study in the rat (MRID 44648101). 
Chlorpyrifos Preliminary Human Health Risk Assessment DP No. D388070

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Table 3. Results of BMD Modeling of Pup Rat Brain and RBC ChE Inhibition following 

Repeat Oral Doses of Chlorpyrifos

Dataset Sex/time of dosing Endpoint/Route

BMD Program 

R-based Program EPA BMDS V2.1

BMD10 BMDL10 BMD10 BMDL10

CCA MRID 

48139301) 

PND 11-25 F

(11 days)

Gavage corn oil

Brain 0.60 0.48 0.80a

0.69a

CCA MRID 

48139301) 

PND 11-25 F

(11 days)

Gavage corn oil

RBC 0.17 0.15 0.17 0.15 

CCA MRID 

48139301) 

PND 11-25 M

(11 days)

Gavage corn oil

Brain 0.32 0.3 0.63 0.52

CCA MRID 

48139301) 

PND 11-25 M

(11 days)

Gavage corn oil

RBC 0.077 0.04 0.11 0.09 

a An acceptable p value was not achieved with BMDS program, however, there was good visual fit and value was 

similar to R-based program. 
Chlorpyrifos Preliminary Human Health Risk Assessment DP No. D388070

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Table 4. Results of BMD Modeling of Adult Rat Brain, RBC and Heart ChE Inhibition 

following Repeat Oral Doses of Chlorpyrifos

Dataset Sex/Time 

of Dosing

Endpoint/

Route

BMD Program/Software 

R-based Program EPA BMDS V2.1 

BMD10 BMDL10 BMD10 BMDL10

Dow (Hoberman 

et al. 1998a,b 

MRID 44556901); 

Maurissen, 2000

Dams, 

GD6-20

Brain 0.65 0.51 0.65a0.54a

Dow (Hoberman 

et al. 1998a,b 

MRID 44556901); 

Maurissen, 2000

Dams, 

GD6-20

RBC 0.06 0.04 0.06a0.03a

Dow (Mattsson et 

al. 1998 

44648101): 

Mattson, 2000

Dams, 

GD6-20

Brain

Hindbrain

1.1

Forebrain

(no computation)b

Hindbrain

0.8

Forebrain

(no computation)b

Hindbrain

1.1

Forebrain

1.2

Hindbrain

0.8

Forebrain

0.98

Dow (Mattsson et 

al. 1998 

44648101): 

Mattson, 2000

Dams, 

GD6-20

RBC/

Heart

RBC

0.14

Heart

0.30

RBC

0.08

Heart

0.26

RBC

0.14a

Heart

0.85c

RBC

0.08a

Heart

0.22c

Dow (Mattsson et 

al. 1998 

44648101): 

Mattson, 2000

Dams, 

LD1

Brain

Hindbrain

1.45

Forebrain

(no computation)

Hindbrain

0.54

Forebrain

(no computation)

Hindbrain

1.33

Forebrain

1.13

Hindbrain

0.65

Forebrain

0.89

Dow (Mattsson et 

al. 1998 

44648101): 

Mattson, 2000

Dams, 

LD1

RBC

RBC

0.055

Heart

0.23

RBC

0.045

Heart

0.21

RBC

0.050

Heart

0.21

RBC

0.044

Heart

0.18

CCA MRID 

48139301) 

Adult F

(11 days)

Gavage 

corn oil

Brain (no computation) (no computation) 1.03 (8 hr)

0.95 

(8 hr)

CCA MRID 

48139301) 

Adult F

(11 days)

Gavage 

corn oil

RBC 0.45 0.35 0.45d

0.35d

a The homogeneous variance provided a BMDL value and an acceptable p value.

b No computation (technical issues e.g., no convergence).

cAn acceptable p value was not achieved with BMDS program. Submodel 5 had best AIC and a BMDL10 value 

comparable to R-based program. Submodel 3 had BMD10 and BMDL10 values similar to R-based runs but not the 

best AIC value. 

dAn acceptable p value was not achieved with BMDS program, however visual fits were good and values same as Rbased program. 
Chlorpyrifos Preliminary Human Health Risk Assessment DP No. D388070

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Table 5. CCA Acute BMD10 /BMDL10 results for Chlorpyrifos Oxon: pup rats

Male Female

Chlorpyrifos oxon BMD10/BMDL10 Brain: 1.06/0.36

RBC: 0.093/0.050

Brain: No reliable fita

RBC: 0.081/0.063

aNo reliable fit with BMDS program and no convergence in R-based program. 

Table 6. CCA Acute BMD10 /BMDL10 results for Chlorpyrifos Oxon: adult rats

Male Female

Chlorpyrifos oxon BMD10/BMDL10 Brain and RBC:

Not examined 

Brain; 1.66/0.80a

RBC: 0.214/0.150

aBMD value from r-based program. Submodels 4 and 5 of the BMDS program failed to compute values

Table 7. CCA Chronic (11 day) BMD10 /BMDL10 results for Chlorpyrifos Oxon: pup rats

Male Female

Chlorpyrifos oxon BMD10/BMDL10 Brain: No reliable fita

RBC: 0.029/0.024

Brain: 0.60/0.13

RBC: 0.027/0.025

aNo convergence in r-based program. Bad completion or failure to compute BMD value in BMDS submodels 4 and 

5. 

bNo acceptable P value with BMDS but good visual fit and comparable to value obtained with R-based program. 

Table 8. CCA Chronic (11 day) BMD10/BMDL10 for Chlorpyrifos Oxon:adult rats

Male Female

Chlorpyrifos oxon BMD10/BMDL10 Brain and RBC: Not examined Brain: No reliable fit b

RBC: 0.025/0.011 (p=0.08)

aNo acceptable P value not achieved in BMDS but good visual fit and same value as R-based program. 

bNo convergence in r-based program. Failure to compute BMD value in BMDS submodels 4 and 5.