UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: September 15, 2015 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Chlorpyriphos-Methyl: Human Health Drc!ft Risk Assessment (ORA) for 

Registration Review 

PC Code: 059102 

Petition No.: NA 

Risk Assessment Type: Single Chemical 

Aggregate 

TXR No.: NA 

MRIDNo.: NA 

FROM: Danette Drew, Chemist/Risk Assessor 

Matthew Lloyd, CIH 

DP Barcode: 0426738 

Registration Nos.: NA 

Regulatory Action: Registration Review 

Case No.: NA 

CAS No.: 5598-13-0 

40 CFR: 180.419 

William Irwin, PhD, DABT, Toxicolog1st 

Ronnie Bever, PhD, OABT, Toxicologist 

Risk Assessment Branch V N II 

Health Effects Division (HED, 7509P) 

THROUGH: Michael Metzger, Branch Chief ~( /J jl I 

Risk Assessment Branch VNII Mtiv( / · 

Health Effects Division (HEO, 7509 ) 

And: 

TO: Joel Wolf, Chemical Review Manager 

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Risk Management and Implementation Branch II 

Pesticide Re-evaluation Division (7508P) 
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Attached is HED’s draft human health risk assessment in support of the registration review of the 

insecticide chlorpyrifos-methyl.

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

2.0 HED Recommendations...........................................................................................................8

2.1 Data Deficiencies.....................................................................................................................8

2.2 Tolerance Considerations.........................................................................................................8

2.2.1 Enforcement Analytical Method ..........................................................................................8

2.2.2 International Harmonization ................................................................................................9

2.2.3 Recommended Tolerances ...................................................................................................9

3.0 Introduction............................................................................................................................13

3.1 Chemical Identity...................................................................................................................13

3.2 Physical/Chemical Characteristics.........................................................................................13

3.3 Pesticide Use Pattern..............................................................................................................13

3.4 Anticipated Exposure Pathways ............................................................................................14

3.5 Consideration of Environmental Justice ................................................................................15

4.0 Hazard Characterization and Dose-Response Assessment....................................................15

4.1 Toxicology Studies Available for Analysis...........................................................................15

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME) ...........................................16

4.2.1 Dermal Absorption.............................................................................................................16

4.3 Toxicological Effects.............................................................................................................17

4.3.1 Critical Durations of Exposure...........................................................................................18

4.4 Literature Review on Neurodevelopment Effects..................................................................18

4.5 Safety Factor for Infants and Children (FQPA Safety Factor) ..............................................23

4.5.1 Completeness of the Toxicology Database ........................................................................24

4.5.2 Evidence of Neurotoxicity .................................................................................................24

4.5.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal.....................24

4.5.4 Residual Uncertainty in the Exposure Database ................................................................25

4.6 Toxicity Endpoint and Point of Departure Selections...........................................................25

4.6.1 Dose-Response Assessment ...............................................................................................25

4.6.2 Recommendation for Combining Routes of Exposures for Risk Assessment...................27

4.6.3 Cancer Classification and Risk Assessment Recommendation .........................................27

4.7 Endocrine Disruption.............................................................................................................30

5.0 Dietary Exposure and Risk Assessment ................................................................................31
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5.1 Metabolite Residue Profile ....................................................................................................31

5.1.1 Summary of Plant and Animal Metabolism Studies..........................................................31

5.1.2 Comparison of Metabolic Pathways ..................................................................................31

5.1.3 Residues of Concern Summary and Rationale...................................................................31

5.2 Residue Chemistry and Food Residue Profile .......................................................................32

5.3 Dietary Risk Assessment .......................................................................................................35

5.3.1 Description of Residue Data Used in Dietary Assessment ................................................35

5.3.2 Percent Crop Treated Used in Dietary Assessment ...........................................................36

5.3.3 Acute Dietary Risk Assessment.........................................................................................36

5.3.4 Steady State Dietary Risk Assessment...............................................................................37

5.3.5 Summary Table Dietary Risk Assessment.........................................................................38

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ........................................38

6.1 Spray Drift .............................................................................................................................38

6.2 Non-Occupational Bystander Post-Application Inhalation Exposure and Risk Estimates....38

7.0 Aggregate Exposure/Risk Characterization.............................................................................39

8.0 Occupational Exposure/Risk Characterization .....................................................................39

8.1 Occupational Handler Exposure/Risk Estimates (Steady State)............................................39

8.2 Occupational Post-application Exposure/Risk Estimates......................................................43

9.0 Public Health and Pesticide Epidemiology Data ...................................................................44

10.0 Cumulative Exposure/Risk Characterization.......................................................................45

11.0 References..............................................................................................................................45

12.0 Appendices.............................................................................................................................48

Appendix A. Toxicology Profile......................................................................................................48

Appendix B. Physical/Chemical Properties.....................................................................................51

Appendix C. International MRLs and U.S. Tolerances...................................................................51
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1.0 Executive Summary

The insecticide chlorpyrifos-methyl [O,O-dimethyl-O-(3,5,6-trichloro-2-pyridyl)phosphorothioate] 

is a member of the organophosphate (OP) class of pesticides and is registered as an emulsifiable 

concentrate (EC) for post-harvest use on stored grains and grain seeds (wheat, barley, oats, rice, 

and sorghum) and for use in grain storage facilities (bins and warehouses).

Humans may be exposed to residues in food since chlorpyrifos-methyl may be applied to stored 

grains or grain storage areas; or treated grain commodities may be fed to livestock, possibly 

resulting in secondary residues in animal commodities. Chlorpyrifos-methyl is not expected to 

reach drinking water sources based on the current post-harvest and enclosed container uses. 

Workers may be exposed (dermal and inhalation routes) to chlorpyrifos-methyl during mixing, 

loading, and/or applying activities associated with stored grains, bins and warehouses. In general, 

occupational post-application exposures are not expected as reentry activities are not anticipated 

for the registered chlorpyrifos-methyl uses. There are no residential uses of chlorpyrifos-methyl, so 

exposure in non-occupational settings is not expected. Exposure via spray drift is not anticipated 

based on the current use pattern. 

Hazard

The toxicology database for chlorpyrifos-methyl is incomplete. Data required include a 

comparative cholinesterase assay, a sub-chronic inhalation study, and an in vivo dermal penetration 

study. Appropriate database uncertainty factors are applied for the lack of these data. Acute and 

sub-chronic neurotoxicity, developmental neurotoxicity, and immunotoxicity studies are not 

required. It should be noted that in the past HED has relied on bridging of toxicity data from 

chlorpyrifos-ethyl to chlorpyrifos-methyl to satisfy the data requirements for the latter. However, 

because of the differences in potency of the two chemicals, and the potential differences in 

pharmacokinetic and pharmacodynamics properties, a recent decision was made that this was not 

scientifically defensible, and that chemical-specific data for chlorpyrifos-methyl is required. 

For chlorpyrifos-methyl, like other OPs, the initiating event in the mode of action/adverse outcome 

pathway (MOA/AOP) involves inhibition of the enzyme acetylcholinesterase (AChE) via

phosphorylation of the serine residue at the active site of the enzyme. This inhibition leads to 

accumulation of acetylcholine and ultimately to neurotoxicity in the central and/or peripheral 

nervous system. OPs also exhibit a phenomenon known as steady state AChE inhibition. After 

repeated dosing at the same dose level, the degree of inhibition comes into equilibrium with the 

production of new, uninhibited enzyme. OP AChE studies of 2-3 weeks generally show the same 

degree of inhibition as those of longer duration (i.e., up to 2 years of exposure). The steady state 

point of departure (POD) is typically less than the acute POD based on ChE inhibition. Therefore, 

a steady state assessment based on 21 days of exposure may be conducted in place of the 

traditional chronic or long-term assessments. 

AChE inhibition is the most sensitive endpoint in the chlorpyrifos-methyl toxicology database in 

multiple species, durations, and life stages and is the endpoint used for selection of toxicological 

points of departure (PODs). The PODs for all routes and durations of exposure for chlorpyrifosmethyl are based on red blood cell (RBC) ChEI from oral animal studies. A study measuring 
Page 5 of 52

cholinesterase inhibition resulting from a single dose or a single day’s dosing is not available for 

chlorpyrifos-methyl. However, since organophosphates are known to cause cholinesterase 

inhibition after only a single dose, an acute endpoint is required to assure that the risk assessment is 

protective. This endpoint was selected from a longer dosing-duration rat developmental study with 

a NOAEL = 1.0 mg/kg/day based on RBC cholinesterase inhibition observed at 12.5 mg/kg/day. 

While the cholinesterase inhibition observed in this study is expected to better reflect typical 

organophosphate steady state cholinesterase inhibition, it was selected as a protective endpoint for 

acute assessment in the absence of data more reflective of acute dosing since steady state PODs are 

typically lower than acute PODs. 

For steady state dietary, dermal, and inhalation exposures the NOAEL of 1.0 mg/kg/day is based 

on the co-critical rat chronic, sub-chronic, and developmental studies.

Prenatal developmental toxicity in rats and rabbits and the rat reproduction studies provided no 

evidence of increased susceptibility of the fetuses or offspring. However, there is no comparative 

cholinesterase study for chlorpyrifos-methyl, the study which best measures the potential for 

increased sensitivity to cholinesterase inhibition for organophosphates in developing young. An 

additional safety factor was applied in the absence of this study. 

The Food Quality Protection Act (FQPA) Safety Factor (SF) has been retained for infants, 

children, youths, and women of childbearing age for all exposure scenarios due to uncertainty in 

the human dose-response relationship for neurodevelopmental effects (see Section 4.4). For 

chlorpyrifos-methyl dietary exposures, a total FQPA Safety Factor (SF) of 30X (to account for the 

uncertainties in the human dose-response relationship for neurodevelopmental effects and for the 

lack of a comparative cholinesterase assay (CCA study)) is used for infants, children, youths, and

women of childbearing age. A total uncertainty factor (UF) of 3000X (10X to account for 

interspecies extrapolation, 10X for intra-species variation, and 30X for FQPA SF) is applicable to 

the dietary assessment of these life stages.

For chlorpyrifos-methyl occupational (inhalation and dermal) exposures (there are currently no 

scenarios that would result in non-occupational, residential exposures to chlorpyrifos-methyl), a 

total database uncertainty factor (UFDB) of 30X (to account for the uncertainty in the human doseresponse relationship for neurodevelopmental effects, the lack of a CCA study, and lack of a routespecific inhalation study) is applied. A total UF of 3000X (10X to account for interspecies 

extrapolation, 10X for intra-species variation, and 30X UFDB) is applicable to occupational 

scenarios. 

Residue Chemistry/ Tolerances

The residue chemistry database for chlorpyrifos-methyl is complete. Adequate storage stability, 

processed food, and nature and magnitude of the residue in plants and livestock data are available 

to support the registered uses. The nature of the residue in plants and livestock tissues is adequately 

identified; the residue of concern for tolerance enforcement and risk assessment is parent 

compound chlorpyrifos-methyl. U.S. tolerances for residues of chlorpyrifos-methyl in grain and 

livestock commodities are established under 40 CFR §180.419 for the combined residues of 

chlorpyrifos-methyl and its metabolite (3,5,6-trichloro-2-pyridinol) (TCP). The tolerance 
Page 6 of 52

expression should be amended to include only chlorpyrifos-methyl as TCP is not considered a 

residue of regulatory concern. There are adequate analytical methods for tolerance enforcement.

Data submitted for aspirated grain fractions were evaluated as part of the chlorpyrifos-methyl

registration review and were incorporated into a revised livestock dietary burden and secondary 

residue estimates. Those calculations indicate that many of tolerance levels for residues of 

chlorpyrifos-methyl (parent compound only) in livestock may be reduced, However, in order to 

harmonize with Codex (proposed or existing) maximum residue levels (MRLs) HED is 

recommending a reduction of tolerance levels for some commodities, and an increase or no change 

for others. There are no Canadian MRLs.

Dietary Risk Assessment

Acute and steady state (food only) exposure and risk assessments were conducted using the 

DEEM-FCID v3.18 model. The assessments included the consumption of cereal grain 

commodities (barley, oats, rice, sorghum and wheat) and livestock commodities. Drinking water 

was not included in the dietary assessments; exposure is not expected from drinking water as 

chlorpyrifos-methyl is not expected to enter drinking water sources based on the registered postharvest and enclosed container uses. The dietary exposure analyses are partially refined. All food

residues used were based upon U. S. Department of Agriculture’s Pesticide Data Program (USDA 

PDP) monitoring data. Where available, empirical processing and cooking factors were 

incorporated into the assessments. No adjustments for % crop treated (CT) are made when using 

PDP monitoring data for blended commodities such as grains.

The acute dietary exposure estimates are below HED’s level of concern (<100 % the acute 

population adjusted dose (aPAD)) for the U.S. population and the following population subgroups: 

all infants (<1 year old), youth 13-19, females 13-49, and adults 20-49 of age. However, at the 

99.9th percentile of exposure, acute dietary exposure estimates are above HED’s level of concern 

(>100 % aPAD) for children 1-2, children 3-5, and children 6-12 years of age; the highest exposed 

child subgroup was children 1-2 years at 170% of the aPAD.

The steady state dietary exposure estimates are below HED’s level of concern (<100 % the steady 

state population adjusted dose (ssPAD)) for the U.S. population and the following population 

subgroups: all infants (<1 year old), children 6-12, youth 13-19, females 13-49, and adults 20-49 

years of age. However, at the 99.9th percentile of exposure, steady state dietary exposure 

estimates are above HED’s level of concern (>100 % ssPAD) for children 1-2 and 3-5 years of age; 

the highest exposed child subgroup was children 1-2 years at 140% of the ssPAD.

Acute and steady state dietary exposures were below the level of concern for the children 

subgroups (and all other population subgroups) at the 99th and 95th percentile of exposures.

Consumption of wheat products was the greatest contributor to the acute and steady state dietary 

exposure and risk estimates for children. 

Residential Exposure and Risk 

There are no registered residential uses, or commercial/professional uses at residential sites 

associated with chlorpyrifos-methyl at this time. Residential exposures are not expected from the 
Page 7 of 52

current uses; therefore, a quantitative residential handler and post-application assessment was not 

conducted. 

Spray Drift

Based on the current use-pattern, HED has determined that chlorpyrifos-methyl is not registered on 

use sites that would result in spray drift. Therefore, a quantitative spray drift assessment was not 

conducted for chlorpyrifos-methyl.

Aggregate Risk Assessment

The registered uses of chlorpyrifos-methyl are not anticipated to result in residential or drinking 

water exposure; only exposure from food is anticipated. The acute and steady state dietary (food 

only) risk estimates are of concern for children.

Occupational Exposure and Risk

Handler:

Steady state dermal and inhalation exposures and risks were calculated for occupational handlers 

of chlorpyrifos-methyl for the registered use on grain or in grain storage containers. Chlorpyrifosmethyl may be applied to grain with automated equipment as it moves in or out of storage. It may 

be applied via handheld equipment to grain bins and warehouses. Generic, surrogate handler data 

were used in the assessment. A female body weight of 69 kg was assumed to account for 

potentially pregnant workers.

Dermal and inhalation risk estimates were combined since the toxicological effects (RBC AChE) 

for these exposure routes are the same. These routes of exposure are combined using the 

Combined MOE approach. The level of concern (LOC) is the same (3000) for inhalation and 

dermal exposures. 

Risk concerns were identified for all handler scenarios (combined MOEs <3,000) with labelspecified PPE (single layer plus gloves and PF5 respirator); the automated equipment MOE was 

350, and the handheld equipment MOEs range from 12 to 28. Risks for these scenarios remain of 

concern despite consideration of additional PPE. 

The existing label is unclear and sometimes contradictory on the equipment per use scenario, 

particularly for the treatment of grain bins and warehouses. The product label does note that “This 

product may only be applied to empty grain bins using high-pressure hand held or automated 

equipment” although warehouse applications using other handheld equipment appear to be allowed 

in the Directions for Use section. This assessment quantitatively calculates risk estimates using 

handheld equipment. 

Bystander/Post-application:

In the case of chlorpyrifos-methyl, bystander exposure may be possible to dusts generated by 

treated grain being conveyed into, out of or within storage containers, and dermal exposure when 

sampling treated grain. Personnel rarely have direct contact with the stored grain and therefore 

dermal exposure is expected the negligible during testing of grain, maintenance, or other 
Page 8 of 52

intermittent activities. Commercial applicators do not typically return to the treated areas after an 

indoor commercial pesticide application (sites such as warehouses, etc.) and thus a quantitative 

occupational post-application inhalation exposure assessment was not performed for commercial 

applicators.

Occupational bystander inhalation exposure through dust may be possible for either the employee 

of a grain elevator or farmer/operator who operates a portable auger to load treated grain into a bin 

but there are no data available to quantify these exposures. However, bystander exposure in these 

cases are anticipated to be negligible because of dust management practices for grain dust at onfarm storage sites. Additionally, the available Storicide II product label directs users to avoid 

application at extremely dusty sites.

No REI is listed on the available product label as the label-defined use sites are not subject to the 

Worker Protection Standard (WPS).

Human Studies Review

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

PHED 1.1; the AHETF database; these studies are: (1) subject to ethics review pursuant to 40 CFR 

26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For 

certain studies, the ethics review may have included review by the Human Studies Review Board. 

Descriptions of data sources, as well as guidance on their use, can be found at the Agency 

website1

. 

2.0 HED Recommendations

2.1 Data Deficiencies

Toxicology data required include a comparative cholinesterase assay (non-guideline study), a 

subchronic inhalation study (GLN 870.3465) and an in vivo dermal penetration study 

(GLN.870.7600).

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The Pesticide Analytical Manual (PAM) Vol. II lists a GC/ECD method (Method I) that 

determines the combined residues of chlorpyrifos-methyl and TCP in grain commodities following 

conversion of chlorpyrifos-methyl to TCP via hydrolysis; residues of TCP are then derivatized 

prior to GC analysis. This method is not ideal for enforcement purposes because it measures the 

combined residues of chlorpyrifos-methyl and TCP. The residue of concern for tolerance 

enforcement in grains is chlorpyrifos-methyl only. 

 1 http://www.epa.gov/pesticides/science/handler-exposure-data.html and http://www.epa.gov/pesticides/science/postapp-exposure-data.html
Page 9 of 52

However, there is adequate methodology available to enforce tolerances for residues of parent 

compound chlorpyrifos-methyl in plant commodities: The FDA PESTDATA database (PAM Vol. 

I, January 1994) indicates that chlorpyrifos-methyl is completely recovered using FDA 

Multiresidue Protocols D and E (PAM I Sections 232.4 and 211.1). In addition, residue data on 

stored grains and grain processed commodities were collected for field trials using adequate 

analytical methods (Methods ACR 78.18 and ACR 77.6(3), respectively) capable of determining 

chlorpyrifos-methyl only. While not necessary, if the registrant would like to propose a single 

analyte method for enforcement, the registrant should conduct an independent laboratory validation 

(ILV) for one of these methods and submit results to the Agency for consideration as a single 

analyte enforcement method.

The GC/FPD method listed in PAM Vol. II (Method II) is capable of determining residues of 

parent compound chlorpyrifos-methyl in meat, milk, and eggs and is adequate for tolerance 

enforcement for chlorpyrifos-methyl in livestock commodities.

2.2.2 International Harmonization

The Codex Alimentarius Commission has established, or has proposed, maximum residue limits 

(MRLs) for chlorpyrifos-methyl residues in various plant and livestock commodities. The U.S. 

tolerance expression currently includes both the parent compound chlorpyrifos-methyl and its 

metabolite TCP, whereas the Codex definition includes parent compound chlorpyrifos-methyl

only. However, HED has previously recommended that the U.S. tolerance expression be amended 

to include only chlorpyrifos-methyl (E. Doyle, 4/1/91 and S. Levy, 11/1/99, D259808) as TCP is 

not considered a residue of concern. Once the U.S. tolerance definition is changed to include only 

chlorpyrifos-methyl, and the U.S. tolerance levels are revised to include the levels recommended in 

this document (Section 2.2.3 below), and assuming Codex adopts their currently proposed 

chlorpyrifos-methyl MRLs, U.S. tolerances and Codex MRLs would be harmonized for the 

following commodities: barley, grain; oat, grain; rice, grain; sorghum, grain; wheat, grain; the meat 

and meat byproducts of livestock; milk (whole) and eggs. The level for milk fat would not be 

harmonized as residue data indicate a potential for a higher level of chlorpyrifos-methyl than the 

Codex MRL.

Canada has no MRLs established or proposed for residues of chlorpyrifos-methyl. A summary of 

U.S. tolerances and Codex MRLs is presented in Appendix C.

2.2.3 Recommended Tolerances

Tolerances for residues of chlorpyrifos-methyl in grain and livestock commodities are established 

under 40 CFR §180.419 (a) section (1) general and section (2) which includes in the definition that 

the tolerance is for “application to stored grains.” The current tolerance expression is for the 

combined residues of chlorpyrifos-methyl and its metabolite (3,5,6-trichloro-2-pyridinol) (TCP). 

The residue of concern is chlorpyrifos-methyl only. HED has previously recommended that the 

U.S. tolerance expression be amended to include only chlorpyrifos-methyl as TCP is not 

considered a residue of regulatory concern (E. Doyle, 4/1/91). HED also is now recommending

that the commodities under 40 CFR §180.419 (a) (2) be moved to 40 CFR §180.419 (a) (1) and 

that the section 180.419 (a) (2) be deleted. The tolerance definition does not need to specify “as a 

result of application to stored grains” as is specified under section (a) (2). The tolerance definition 
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should be modified as follows, to be consistent with the Tolerance Expression Guidance issued 

5/27/09 (S. Knizner):

Tolerances are established for residues of chlorpyrifos-methyl including its metabolites 

and degradates, in or on the commodities in the table below. Compliance with the 

tolerance levels specified below is to be determined by measuring only chlorpyrifos 

methyl [O,O-dimethyl-O-(3,5,6-trichloro-2-pyridyl)phosphorothioate], in or on the 

commodity. 

The tolerance levels for residues of chlorpyrifos-methyl have been reassessed under registration 

review in light of the recent residue data submission for wheat aspirated grain fraction (AGF). A 

tolerance level is now being recommended for aspirated grain fractions (330 ppm). The livestock 

dietary burden calculation was updated incorporating the AGF data and resulting secondary 

residues in livestock tissue were also updated. Those calculations indicate that the tolerance level 

for residues of chlorpyrifos-methyl in livestock (including poultry) meat and meat byproducts may 

be reduced from 0.5 ppm to 0.01 ppm; however, since the Codex MRL for meat and meat 

byproducts is 0.1 ppm, HED is recommending a reduction only to the MRL level of 0.1 ppm for 

those commodities. The current tolerance of 0.5 ppm for livestock (including poultry) fat is 

appropriate. The tolerance for eggs may be reduced to 0.01 ppm, which is harmonized with Codex. 

The tolerance for “Milk, fat (0.05 ppm (N) in whole milk” should be revoked and separate 

tolerances should be established for “milk” and “milk, fat”. The recommended tolerance of 0.01 

ppm for milk is harmonized with Codex. The recommended milk, fat tolerance of 0.05 ppm cannot 

be harmonized as data indicate a potential for higher chlorpyrifos-methyl residues than the Codex 

MRL. (See all recommended tolerances in Table 2.2.3 below.)

The established tolerances for the grain of barley, oat, rice, sorghum and wheat may be increased 

from 6.0 ppm to 10 ppm in order to harmonize with the proposed Codex levels. The tolerance 

levels for the processed commodities of barley, rice and wheat may be also be reduced (see Table 

2.2.3 for individual values) except for rice, hulls and rice, polished rice; those tolerances should be 

revoked as rice, hulls is no longer considered a significant livestock feed item and rice, polished 

rice does not need a separate tolerance from rice, grain as residues of chlorpyrifos-methyl do not 

concentrate in polished/milled rice. The tolerance for sorghum, grain, bran should also be revoked 

as sorghum bran is not a sorghum processed commodity.

Tolerances for residues of chlorpyrifos-methyl in milled fractions (excluding flour) of barley, oats, 

rice, sorghum, and wheat should be revoked concomitant with establishing separate tolerances for 

residues in the appropriate processed commodities under 40 CFR §180.419 (see Table 2.2.3). 
Page 11 of 52

Table 2.2.3. Tolerance Summary for Chlorpyrifos-Methyl

Commodity Established

Tolerance (ppm)

HEDRecommended 

Tolerance (ppm)

Comments 

(correct commodity definition)

Tolerances listed under 40 CFR §180.419:

Barley, grain 6.0 10

Increase tolerance level to 

harmonize with CODEX proposed 

MRL

Cattle, fat 0.5 0.5

Cattle, meat 0.5 0.1

Decrease tolerance level to 

harmonize with CODEX MRL 

Cattle, meat byproducts 0.5 0.01

Decrease tolerance level to 

harmonize with CODEX MRL

Egg 0.1 0.01

Decrease tolerance level to 

harmonize with CODEX MRL

Goat, fat 0.5 0.5

Goat, meat 0.5 0.1

Decrease tolerance level to 

harmonize with CODEX MRL

Goat, meat byproducts 0.5 0.01

Decrease tolerance level to 

harmonize with CODEX MRL

Hog, fat 0.5 0.5

Hog, meat 0.5 0.1

Decrease tolerance level to 

harmonize with CODEX MRL

Hog, meat byproducts 0.5 0.01

Decrease tolerance level to 

harmonize with CODEX MRL

Horse, fat 0.5 0.5

Horse, meat 0.5 0.1

Decrease tolerance level to 

harmonize with CODEX MRL

Horse, meat byproducts 0.5 0.01

Decrease tolerance level to 

harmonize with CODEX MRL

Milk, fat (0.05 ppm (N) in 

whole milk 1.25

Revoke

Revoke concomitant to 

establishing tolerances for milk

and milk, fat

Milk -- 0.01 Establish tolerance at CODEX 

MRL

Milk, fat -- 0.05

Oat, grain 6.0 10

Increase tolerance level to 

harmonize with CODEX proposed 

MRL

Poultry, fat 0.5 0.5

Poultry, meat 0.5 0.1

Decrease tolerance level to 

harmonize with CODEX MRL

Poultry, meat byproducts 0.5 0.01

Decrease tolerance level to 

harmonize with CODEX MRL

Rice, grain 6.0 10

Increase tolerance level to 

harmonize with CODEX proposed 

MRL

Sheep, fat 0.5 0.5

Sheep, meat 0.5 0.1

Decrease tolerance level to 

harmonize with CODEX MRL

Sheep, meat byproducts 0.5 0.01

Decrease tolerance level to 

harmonize with CODEX MRL
Page 12 of 52

Table 2.2.3. Tolerance Summary for Chlorpyrifos-Methyl

Commodity Established

Tolerance (ppm)

HEDRecommended 

Tolerance (ppm)

Comments 

(correct commodity definition)

Sorghum, grain 6.0 10

Increase tolerance level to 

harmonize with CODEX proposed 

MRL

Wheat, grain 6.0 10

Increase tolerance level to 

harmonize with CODEX proposed 

MRL

Barley, bran 90 20

1999 tolerance recommendation 

(residue and processing data) *

Barley, pearled barley 90 20

1999 tolerance recommendation 

(residue and processing data)*

Rice, bran 30 13

1999 tolerance recommendation 

(residue and processing data)*

Rice, hulls 30 Revoke No longer considered a significant 

feedstuff

Rice, polished rice 30

Revoke

Residue data indicate a separate 

tolerance for this rice processed 

commodity is not required. 

Residues of chlorpyrifos-methyl

do not concentrate in 

polished/milled rice.

Sorghum, grain, bran 90 Revoke Sorghum bran is not a sorghum 

processed commodity

Wheat, bran 30

20

1999 tolerance recommendation 

(residue and processing data)*

(CODEX currently at 20 ppm with 

proposed MRL of 6 ppm)

Wheat, germ 30 20

1999 tolerance recommendation 

(residue and processing data)*

Wheat, middlings 30 20

1999 tolerance recommendation 

(residue and processing data)*

Wheat, shorts 30 20

1999 tolerance recommendation 

(residue and processing data)*

Aspirated grain fractions

---

330

Based on residue and processing 

data, a tolerance should be 

established on aspirated grain 

fractions.

Tolerances listed under 40 CFR §185 and §186.1050:

Barley milling fractions

(except flour)

90.0

Revoke

Tolerance should be revoked 

concomitant with establishing a 20 

ppm tolerance on barley, bran.

Oats milling fractions

(except flour)

130.0 Tolerance should be revoked 

concomitant with establishing a 10

ppm tolerance for oat, grain.

Rice milling fractions

(except flour) 

30.0 Tolerance should be revoked 

concomitant with establishing a 13 

ppm tolerance on rice, bran.

Sorghum milling fractions

(except flour) 

90.0 Tolerance should be revoked. 

There are no longer any processed 

commodities of grain sorghum 
Page 13 of 52

Table 2.2.3. Tolerance Summary for Chlorpyrifos-Methyl

Commodity Established

Tolerance (ppm)

HEDRecommended 

Tolerance (ppm)

Comments 

(correct commodity definition)

considered as food for humans or 

feed for livestock. 

Wheat milling fractions

(except flour)

30.0 Tolerance should be revoked 

concomitant with establishing a 

tolerance at 20 ppm on wheat,

bran; wheat, germ; wheat,

middlings and wheat, shorts.

*D259808, 11/1/99, S. Levy.

3.0 Introduction

3.1 Chemical Identity

TABLE 3.1.1 Chlorpyrifos-Methyl Nomenclature. 

Chemical structure

Common name Chlorpyrifos-methyl

Company experimental name NA

IUPAC name O,O-dimethyl-O-(3,5,6-trichloro-2-pyridyl)phosphorothioate

CAS name O,O-dimethyl-O-(3,5,6-trichloro-2-pyridyl)phosphorothioate

CAS registry number 5598-13-0

End-use product (EP) 1.80 lb ai/gal emulsifiable concentrate (EC) formulation of chlorpyrifos-methyl (StorcideTM 

II Grain, Bin, and Warehouse Insecticide); EPA Reg. No. 264-992)

3.2 Physical/Chemical Characteristics

Chlorpyrifos-methyl is a clear to white crystalline solid with a melting point around 46 °C. 

Chlorpyrifos-methyl is not expected to volatilize significantly due to a fairly low vapor pressure of 

2.2 x 10-5 torr (25°C). The solubility of chlorpyrifos-methyl in water is low (4 mg/L at 25°C). 

Chlorpyrifos-methyl is hydrophobic, with an octanol-water partition coefficient (Log Kow) of 4.3.

See Appendix B for a table of the physiochemical properties.

3.3 Pesticide Use Pattern

Chlorpyrifos-methyl is registered for post-harvest use on stored grains and grain seeds (wheat, 

barley, oats, rice, and sorghum) and for use on grain storage facilities (bins and warehouses).
Page 14 of 52

The only currently registered formulation is a 21.6 % EC formulation (Storicide II). The EC may 

be applied to stored grains at 0.18 lb a.i/1000 bushels to provide a maximum concentration of 3 

ppm of chlorpyrifos-methyl on stored grains.

The use directions of the chlorpyrifos-methyl product are summarized in Table 3.3.1.

Table 3.3.1 Summary of Directions for Use of Chlorpyrifos-Methyl.

Applic. Timing, 

Type, and Equip.

Formulation 

[EPA Reg. No.]

Max. Single 

Applic. Rate 

Max. No. 

Applic. per 

Season

Max. 

Seasonal 

Applic. 

Rate 

(lb ai/A)

PHI 

(days)

Use Directions and 

Limitations

Automated Grain Application (wheat, barley, rice, sorghum, oats) 

Automated spray 

equipment

StoricideTM II

264-992

0.18 lbs ai/1,000 

bushels

[all grains except 

oats]

N/A N/A N/A

• For protection against 

grain insect 

pests/empty grain bins

• Do not make more 

than one application 

to stored grain or seed

Handheld Equipment 

to treat empty grain 

bins [mechanically 

pressurized 

handwand, manually 

pressurized 

handwand, backpack] StoricideTM II

264-992

0.03 lbs ai/gallon

[all grains except 

oats]2

N/A N/A N/A

• Fumigate as necessary 

to control existing 

populations 

• Apply for residual 

control as a course 

spray to deposit 3 

ppm chlorpyrifosmethyl and 0.5 ppm 

deltamethrin on grain

• Clean and treat 

storage areas prior to 

storage of seed

0.02 lbs ai/gallon

[oats]

StoricideTM II 264-992 is co-formulated with deltamethrin (3.7%) 

3.4 Anticipated Exposure Pathways

Humans may be exposed to residues in food since chlorpyrifos-methyl may be applied to stored 

grains or grain storage areas; or treated grain commodities may be fed to livestock, possibly 

resulting in secondary residues in animal commodities. Chlorpyrifos-methyl is not expected to 

reach drinking water sources based on the current post-harvest uses. Workers may be exposed to 

chlorpyrifos-methyl during mixing, loading, and/or applying activities associated with stored 

grains, bins and warehouses. Occupational post-application exposures are not expected as reentry 

activities are not anticipated for the registered chlorpyrifos-methyl uses. There are no residential 

uses of chlorpyrifos-methyl, so exposure in non-occupational settings is not expected. Exposure 

via spray drift is not anticipated based on the current use pattern.

 2 500 gallons of spray solution/day for mechanically pressurized equipment; 20 gallons of spray solution assumed/day for 

manually pressurized and backpack sprayers
Page 15 of 52

3.5 Consideration of Environmental Justice

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

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

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

(http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf) As a part of every pesticide 

risk assessment, OPP considers a large variety of consumer subgroups according to wellestablished 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 National Health and Nutrition 

Survey/What We Eat in America (NHANES/WWEIA) and are used in pesticide risk assessments 

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

based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, 

specialized subgroups and exposure assessments are performed when conditions or circumstances 

warrant. Whenever appropriate, non-dietary exposures based on home use of pesticide products 

and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on 

treated areas post-application are evaluated. Further considerations are currently in development as 

OPP has committed resources and expertise to the development of specialized software and models 

that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 

patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

Chlorpyrifos-methyl is a member of the OP class of pesticides. Like other OPs, the initiating event 

in the AOP/MOA for chlorpyrifos-methyl involves inhibition of the enzyme acetylcholinesterase 

(AChE) via phosphorylation of the serine residue at the active site of the enzyme. This inhibition 

leads to accumulation of acetylcholine and ultimately to neurotoxicity in the central and/or 

peripheral nervous system (see Figure 1). For chlorpyrifos-methyl, AChE inhibition (ChEI) is 

typically the most sensitive endpoint in the toxicology database in multiple species, durations, life 

stages, and routes, thus ChEI is the focus of this hazard characterization. The availability of 

reliable ChEI dose response data is one of the key determinants in evaluating the toxicology 

database. 

Figure 1. AOP for OPs.

4.1 Toxicology Studies Available for Analysis

It should be noted that in the past HED has relied on bridging of toxicity data from chlorpyrifosethyl to chlorpyrifos-methyl to satisfy the data requirements for the latter. However, because of 

the differences in potency of the two chemicals, and the potential differences in pharmacokinetic 

Target 

Tissue 

Dose

Phosphorylation 

of the active site 

of AChE

Neurotoxicity

Accumulation 

of 

acetylcholine
Page 16 of 52

and pharmacodynamics properties, a recent decision was made that this was not scientifically 

defensible, and that chemical-specific data for chlorpyrifos-methyl is required (HASPOC meeting 

September 2, 2015; TXR# 0057247).

The toxicology database for chlorpyrifos-methyl is incomplete. Data required include a 

comparative cholinesterase assay (a non-guideline study) to address the potential susceptibility to 

the young, a sub-chronic inhalation study (GLN 870.3465) to assess the route-specific effects via 

inhalation exposure and an in vivo dermal penetration study (GLN 870.7600) so that a chemical 

specific dermal absorption value can be utilized with an oral chlorpyrifos methyl study POD for 

dermal scenarios. Database uncertainty factors will be applied, until the data are received and 

evaluated. Only orally administered toxicology studies were available for chlorpyrifos-methyl.

Toxicology data requirements and the status of each requirement are presented in Appendix A.1. 

The database includes the following toxicity studies: 

• Sub-chronic oral studies in rat and dog

• Developmental study in rat

• 2-Generation reproduction study in rat

• Combined chronic toxicity/ carcinogenicity studies in rat and mouse

• Other studies, such as mutagenicity battery, acute 6-pack, and metabolism study

The HASPOC recommended waiving all outstanding toxicity data requirements except the 

comparative cholinesterase study, a 90-day inhalation study, and a dermal penetration study. 

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

Chlorpyrifos-methyl requires metabolic activation to the oxon metabolite to inhibit AChE activity. 

Generally, absorption and distribution are rapid with extensive metabolism and no accumulation in 

the tissues for OPs. 

Chlorpyrifos-methyl is metabolized (MRID 00029484) to produce 3,5,6-trichloro-2-pyridinol 

(TCP) which is conjugated and excreted in the urine. Following oral administration to rats in corn 

oil, 83-85% radiolabel originating from chlorpyrifos-methyl was recovered in the urine, only 7-9% 

in the feces with < 0.5% in the respiratory air at 72 hours. The carcass retained 0.65 to 1.3% with 

label found in the fat, muscle, bone and liver). Peak blood levels occurred at 5 hours after dosing.

4.2.1 Dermal Absorption

There are no dermal absorption studies available for chlorpyrifos-methyl.
Page 17 of 52

4.3 Toxicological Effects

Chlorpyrifos-methyl is an OP with a neurotoxic AOP and OP neurotoxicity is typically the most 

sensitive effect in all species, and life stages and is being used in deriving point of departures. The 

toxicity profile of chlorpyrifos-methyl shows that the principal toxic effect is ChEI. There were 

microscopic lesions in the adrenal glands in the rat reproduction study at 3 mg/kg/day, however, 

these results were not replicated in any other study at this dose and findings were mild in severity.

The rat sub-chronic study had adrenal gland effects, however, at a higher dose where 25.5% RBC 

ChE inhibition also occurred (i.e. 10 mg/kg/day). The red blood cell (RBC) AChE was generally 

more sensitive than the brain AChE to chlorpyrifos-methyl-induced inhibition. There was 

inadequate information to allow definitive judgment on sensitivity due to life stage. Only six 

toxicity studies were available for evaluation. Furthermore, the doses in each study were often 

separated by an order of magnitude or more, resulting in a dose-spread not conducive to 

benchmark dose (BMD) modeling or accurate estimation of a NOAEL. Evaluation of the hazard 

for the oxygen analog of chlorpyrifos-methyl was not necessary; the oxon is not expected to occur

on food or in the environment based on the current chlorpyrifos-methyl use pattern 

In the rat sub-chronic dietary study (MRIDs 44906902 and 45048301), the NOAEL for RBC and 

brain cholinesterase inhibition was 1.0 mg/kg/day, and the LOAEL was 10 mg/kg/day in both 

sexes. The NOAEL for systemic toxicity was 1.0 mg/kg/day, and the LOAEL was 10 mg/kg/day 

based on histopathology (hypertrophy, vacuolation and necrosis) of the adrenal gland. There are no 

acceptable sub-chronic dermal or inhalation studies with chlorpyrifos-methyl.

In the rat prenatal developmental toxicity (MRID 44680603) and the rat reproduction study (MRID 

45826201), no evidence of increased susceptibility of the fetuses or offspring were observed. 

Cholinesterase inhibition was evaluated in the chlorpyrifos-methyl developmental and 

reproduction studies. There is no developmental neurotoxicity study for chlorpyrifos-methyl (and 

the study is not required). In the chlorpyrifos-methyl rat developmental study, there were no 

treatment-related effects on survival, maternal body weight, or food consumption. RBC ChEI was 

seen in dams at the 12.5 mg/kg/day (33%) and at 50 mg/kg/day (47%) dose groups. Brain ChEI 

was seen only at the high dose. For maternal toxicity, the NOAEL was 1.0 mg/kg/day, and the 

LOAEL was 12.5 mg/kg/day based on RBC ChEI. No developmental toxicity was seen, and there 

were no treatment-related increases in external, visceral or skeletal malformations or anomalies. 

For developmental toxicity, the NOAEL was 50 mg/kg/day, the highest dose tested (HDT). In the 

chlorpyrifos-methyl reproduction study, microscopic lesions in the adrenal glands of the parents 

were noted at 3 mg/kg/day (NOAEL = 1 mg/kg/day), and no systemic effects were observed in the 

offspring or on reproduction at the HDT. RBC ChEI was noted at 10 mg/kg/day or more in adults 

and pups. The reproduction study adult females had an apparent RBC ChEI LOAEL of 1.0 

mg/kg/day (the lowest dose tested [LDT]); however, the number of animals tested were only 

5/group. Furthermore, based on RBC ChEI, the female offspring and the male adults and offspring 

all had a LOAEL of 10.0 mg/kg/day and a NOAEL of 3.0 mg/kg/day in the same study. In the 

PND22 offspring groups, the ChE activity increased at 10.0 mg/kg/day in both males and female 

pups. The apparent LOAEL of 1 mg/kg/day in parental females is inconsistent with the ChE 

inhibition findings in other groups within the same study and with the entire rat data base for 

chlorpyrifos methyl, with consistent findings of a true NOAEL of 1 mg/kg/day in the rat studies. 

Again, no increased susceptibility was noted in PND 1, PND 4, or PND 22 male and female pups, 

where ChEI was evaluated as well as systemic effects.
Page 18 of 52

In the rat combined chronic toxicity/ carcinogenicity study (MRID 42269001), the NOAEL and 

LOAEL for RBC ChEI were established at 1.0 and 50.0 mg/kg/day, respectively, but there were no 

indications of clinical signs. At 50 mg/kg/day in the rat, body weight decreases, alterations in the 

adrenals (increased weight, slight to moderate vacuolation with lipid accumulation in the zona 

fasciculata) were observed. In the mouse combined chronic toxicity/ carcinogenicity study (MRID 

44680602), the LOAEL for systemic effects is 44.0 mg/kg/day for males and 41.5 mg/kg/day for 

females based on histopathologic lesions in the liver, kidney, and adrenal glands (NOAEL is 4.40 

mg/kg/day for males and 3.94 mg/kg/day for females). There was no evidence of carcinogenicity 

following oral exposure to chlorpyrifos-methyl in chronic studies in rats and mice.

Steady-state cholinesterase inhibition appears to be reached quickly, because in the rat a NOAEL 

of 1.0 mg/kg/day was seen after 10 days of exposure (developmental study) through 2 years of 

exposure (chronic).

Chlorpyrifos-methyl is classified as slightly toxic via the oral (Toxicity Category III), dermal, and 

inhalation routes (Toxicity Category IV). It was found to be a slight dermal irritant and did not 

cause eye irritation (Toxicity Category IV). The skin sensitization study for chlorpyrifos-methyl

was unacceptable.

4.3.1 Critical Durations of Exposure

One of the key elements in risk assessment is the appropriate integration of temporality between 

the exposure and hazard assessments. One advantage of an AOP understanding is that human 

health risk assessments can be refined to focus on the most relevant durations of exposure. 

However, limited data exist for the temporal effects of chlorpyrifos-methyl versus dose for 

inhibition of cholinesterase. For OPs, the steady state period is typically 2-3 weeks. 

Although there are data at a shorter time period than 21 days, exposure assessments of 21 days and 

longer will be conducted for all routes of exposure (i.e., oral, dermal and inhalation) for all single 

chemical OP assessments. Although the durations of the toxicity and exposure assessments may 

differ, an exact match is not necessary and would suggest a level of precision that the toxicity data 

do not support. Given this, the 21-day and longer exposure assessment is scientifically supportable 

and also provides consistency with the OP cumulative risk assessment (OP CRA; 2002, 2006) and 

across the single chemical risk assessment for the OPs. 

4.4 Literature Review on Neurodevelopment Effects

For the OPs, historically the Agency has used inhibition of AChE as the POD for human health 

risk assessment; at present time, this policy continues. This science policy is based on decades of 

work which shows that AChE inhibition is the initial event in the pathway to acute cholinergic 

neurotoxicity. The use of AChE inhibition data for deriving PODs was supported by the FIFRA 

SAP (2008, 2012) for chlorpyrifos as the most robust source of dose-response data for 

extrapolating risk and is the source of data for PODs for chlorpyrifos methyl. A detailed review of 

the epidemiological studies used in this review can be found either in the 2014 chlorpyrifos revised 

draft human health risk assessment (D424485, D. Drew et al, 12/29/2014) or in the 2015 literature 

review for other organophosphates (OPP/USEPA; D331251; 9/15/15). 
Page 19 of 52

Newer lines of research on OPs in the areas of potential AOPs, in vivo animal studies, and notably 

epidemiological studies in mothers and children, have raised some uncertainty about the agency’s 

risk assessment approach with regard to the potential for neurodevelopmental effects in fetuses and 

children. Many of these studies have been the subject of review by the agency over the last several 

years as part of efforts to develop a risk assessment for chlorpyrifos (D424485, D. Drew et al, 

12/29/2014). Initially, the agency focused on studies from three US cohorts: 1) The Mothers and 

Newborn Study of North Manhattan and South Bronx performed by the Columbia Children’s 

Center for Environmental Health (CCCEH) at Columbia University; 2) the Mt. Sinai Inner-City 

Toxicants, Child Growth and Development Study or the “Mt. Sinai Child Growth and 

Development Study;” and 3) the Center for Health Assessment of Mothers and Children of Salinas 

Valley (CHAMACOS) conducted by researchers at University of California Berkeley. The agency 

has evaluated these studies and sought external peer review (FIFRA SAP reviews in 2008 and 

2012; federal panel, 20133

) and concludes they are of high quality. In the three US epidemiology 

cohort studies, mother-infant pairs were recruited for the purpose of studying the potential health 

effects of environmental exposures during pregnancy on subsequent child development. Each of 

these cohorts evaluated the association between prenatal chlorpyrifos and/or OP exposure (with 

adverse neurodevelopmental outcomes in children through age 7 years). For the 2014 chlorpyrifos 

revised human health risk assessment (D424485, D. Drew et al, 12/29/2014), EPA included 

epidemiologic research results from these three US prospective birth cohort studies but primarily 

focused on the results of CCCEH since this cohort has published studies on the association 

between cord blood levels of chlorpyrifos and neurodevelopmental outcomes. The agency retained 

the FQPA 10X Safety Factor (SF) in the 2014 chlorpyrifos revised risk assessment, in large part, 

based on the findings of these studies.

In the 2015 updated literature review (OPP/USEPA; D331251; 9/15/15), the agency conducted a 

systematic review expanding the scope of the 2012/2014 review focused on US cohort studies with 

particular emphasis on chlorpyrifos. The expanded 2015 review includes consideration of the 

epidemiological data on any OP pesticide, study designs beyond prospective cohort studies, and 

non-U.S. based studies. The updated literature review identified seven studies which were relevant 

(Bouchard et al., 2010; Fortenberry et al., 2014;Furlong et al., 2014; Guodong et al., 2012; Oulhote 

and Bouchard, 2013; Zhang et al., 2014; Shelton et al., 2014). These seven studies have been 

evaluated in context with studies from the 2012/2014 review (D424485, D. Drew et al, 

12/29/2014). Only a brief summary is provided below.

The OP exposure being assessed in many of these studies used concentrations of urinary dialkyl 

phosphate metabolites (DAPs) as the urinary biomarker. Total DAPs is a non-specific measure of 

OP exposure and is the sum of six separate molecules - three dimethyl alkylphosphate (DMAP) 

molecules of DMP, DMTP, DMDTP, and three diethyl alkylphosphate (DEAP) molecules of DEP, 

DETP, and DEDTP. Each metabolite is a breakdown product from multiple OPs (Table 4.4.1; 

CDC, 2008)4

. Specifically, DMP, DMTP, and DMDTP are associated with 18, 13, and 5 OPs, 

whereas DEP, DETP, and DEDTP are associated with 10, 10, and 4 OPs, respectively. Thus, using 

urinary DAPs alone as an exposure measure, it is not possible to separate the exposure and 

associated effects for single, specific OPs. 

 3 http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2008-0850-0170 4 http://www.cdc.gov/nchs/data/nhanes/nhanes_03_04/l26opd_c_met_organophosphorus_pesticides.pdf
Page 20 of 52

Table 4.4.1.CDC Table of organophosphate pesticides and their dialkyl phosphate metabolites (2008). 

Pesticide DMP DMTP DMDTP DEP DETP DEDTP

Azinphos methyl X X X

Chlorethoxyphos X X

Chlorpyrifos X X

Chlorpyrifos methyl X X

Coumaphos X X

Dichlorvos (DDVP) X

Diazinon X X

Dicrotophos X

Dimethoate X X X

Disulfoton X X X

Ethion X X X

Fenitrothion X X

Fenthion X X

Isazaphos-methyl X X

Malathion X X X

Methidathion X X X

Methyl parathion X X

Naled X

Oxydemeton-methyl X X

Parathion X X

Phorate X X X

Phosmet X X X

Pirimiphos-methyl X X

Sulfotepp X X

Temephos X X

Terbufos X X X

Tetrachlorviphos X

Trichlorfon X

DMP = dimethylphosphate; DEP = diethylphosphate; DMTP = dimethylthiophosphate; DMDTP = 

dimethyldithiophosphate; DETP = diethylthiophosphate; DEDTP = diethyldithiophosphate.

For studies which measured urinary 3,5,6-trichloro-2-pyridinol (TCPy) (e.g., Fortenberry et al, 

2014; Eskenazi et al, 2007; Whyatt et al, 2009), this metabolite can be derived from chlorpyrifos, 

chlorpyrifos-methyl, and the herbicide triclopyr. TCPy is also the primary environmental 

degradate of chlorpyrifos, chlorpyrifos-methyl, and triclopyr; thus exposure can be found directly 

on food treated with these pesticides. CCCEH studies have largely used chlorpyrifos measured in 

cord blood as the specific biomarker (e.g., Lovasi et al, 2010; Whyatt et al, 2004; Rauh et al, 

2011). The CHARGE study (Shelton et al, 2015) did not measure biomarkers but instead used 

geospatial analysis to focus on the residential proximity to OP exposure using data from the 

California Department of Pesticide Regulation, with five OPs accounting for a total of 73% of the 

pesticide applied near residential settings (chlorpyrifos, acephate, diazinon, bensulide, and 

dimethoate). 

Similarly, DAPs can be found directly on food following OP applications (Zhang et al, 2008; Chen 

et al, 2012). Specifically, studies have shown that DAPs may form as environmental degradates 
Page 21 of 52

from abiotic hydrolysis, photolysis, and plant metabolism (Zhang et al, 2008; Chen et al, 2012; 

Racke et al, 1994). Furthermore, since these DAPs are excreted more rapidly and extensively than 

the parent OPs (Zhang et al, 2008; Forsberg et al, 2008), direct exposure to DAPs may lead to an 

overestimate of OP exposure when using urinary DAPs as a biomarker of OP exposure. The 

agency recognizes that this is a source of uncertainty when using DAPs for assessing OP exposure 

and will continue to monitor this issue in future assessments. 

With respect to neurological effects near birth, the CHAMACOS and Mt. Sinai cohorts measured 

neurological effects at birth, and observed a putative association with total DEAP, total DMAP, 

and total DAP exposure (Engel et al., 2007; Young et al., 2005). Similarly, a Chinese study 

(Zhang et al., 2014) reported statistically significant associations between for total DEAPs, total 

DMAPs, and total DAPs from prenatal OP pesticide exposure and neonatal neurodevelopment 

assessed 3 days after birth. However, another cross-sectional Chinese study, Guodong et al (2012), 

observed no association with urinary DAPs and a developmental quotient score for 23-25 month 

old children.

The 3 US cohorts (CCCEH, Mt. Sinai, CHAMACOS) each reported evidence of impaired mental 

and psychomotor development, albeit not consistent by age at time of testing (ranging from 6 

month to 36 months across the three cohorts). Attentional problems and ADHD were reported by 

three prospective cohorts [Rauh et al, 2006; Eskenazi et al., 2007; Marks et al, 2010; and 

Fortenberry et al (2014)] investigators with additional support from a case control study, Bouchard 

et al. (2010). The exposure metric varied among these studies. Specifically, Fortenberry et al 

(2014) found suggestive evidence of an association with TCPy and ADHD in boys whereas 

statistically significant associations were observed by Rauh et al (2006) with chlorpyrifos exposure 

and ADHD. Eskenazi et al (2007) reported associations with total DMAPs and total DAPs and 

ADHD; Marks et al (2010) reported associations with total DEAP, DMAP, and total DAP 

exposure and ADHD. In a national cross-sectional study of Canadian children, using 2007-2009 

data for children age 6-11 years (Oulhote and Bouchard, 2013), there were no overall statistically 

significant associations observed between child urinary DEAP, DMAP, or total DAP metabolite 

levels and parentally reported behavioral problems. In contrast, Bouchard et al. (2010), looking at 

U.S. children age 8-15 years in the 2000-2004 National Health and Nutrition Examination Survey 

(NHANES), observed a positive association between attention and behavior problems and total 

DAPs and DMAPs, but not DEAPs. As part of their analysis, Oulhote and Bouchard (2013) noted 

that their outcome assessment for behavioral problems may not have been as sensitive as Bouchard 

et al (2010), which may in part account for the difference in the observed results from these 

studies. 

In addition, the three US cohorts and the CHARGE study have reported suggestive or positive 

associations between OP exposure and autism spectrum disorders (Rauh et al., 2006; Shelton et al., 

2014; Eskenazi et al, 2007; Furlong et al., 2014). Specifically, Furlong et al (2014) documented 

suggestive evidence of an association between total DEAP exposure and reciprocal social 

responsiveness among blacks and boys. Eskenazi et al (2007) reported a statistically significant 

association between pervasive developmental disorder (PDD) and total DAP exposure, whereas 

Eskenazi et al (2010) reported non-significant, but suggestive, increased odds of PDD of 2.0 (0.8 to 

5.1; p=0.14). Rauh et al (2006) documented a significant association between PDD and 

specifically chlorpyrifos exposure. Both PDD and reciprocal social responsiveness are related to 

the autism spectrum disorder. Using a different exposure assessment method (geospatial analysis 
Page 22 of 52

and residential proximity to total OP exposure), Shelton et al (2014) also showed statistically 

significant associations between total OP exposure and ASD. While these studies vary in the 

magnitude of the overall strength of association, they have consistently observed a positive 

association between OP exposure and ASD. Finally, CCCEH, Mt. Sinai, CHAMACOS have 

reported an inverse relation between the respective prenatal measures of chlorpyrifos and 

intelligence measures at age 7 years (Rauh et al. ,2011; Engel et al., 2011; Bouchard et al., 2011). 

Across the epidemiology database of studies, the maternal urine, cord blood, and other (meconium) 

measures provide evidence that exposure did occur to the fetus during gestation but the actual level 

of such exposure during the critical window(s) of susceptibility is not known. While significant 

uncertainties remain about the actual exposure levels experienced by mothers and infant 

participants in the children’s health cohorts, it is unlikely that these exposures resulted in AChE 

inhibition. As part of the CHAMACOS study, Eskenazi et al. (2004) measured AChE activity and 

showed that no differences in AChE activity were observed. The biomarker data (chlorpyrifos) 

from the Columbia University studies are supported by the agency’s dose reconstruction analysis 

using the PBPK-PD model (D424485, D. Drew et al, 12/29/2014). Following the recommendation 

of the FIFRA SAP (2012), the agency conducted a dose reconstruction analysis of residential uses 

available prior to 2000 for pregnant women and young children inside the home. The PBPK-PD 

model results indicate for the highest exposure considered (i.e., indoor broadcast use of a 1% 

chlorpyrifos formulation) <1% RBC AChE inhibition was produced in pregnant women. While 

uncertainty exists as to actual OP exposure at (unknown) critical windows of exposure, EPA 

believes it is unlikely individuals in the epidemiology studies experienced RBC AChE inhibition.

A review of the scientific literature on potential modes of action/adverse outcome pathways 

(MOA/AOP)5 leading to effects on the developing brain was conducted for the 2012 FIFRA SAP 

meeting (USEPA, 2012) and updated for the December 2014 chlorpyrifos revised risk assessment 

(D424485, D. Drew et al, 12/29/2014). In short, multiple biologically plausible hypotheses and 

pathways are being pursued by researchers that include targets other than AChE inhibition, 

including cholinergic and non-cholinergic systems, signaling pathways, proteins, and others. 

However, no one pathway has sufficient data to be considered more credible than the others. The 

fact that there are, however, sparse AOP data to support the in vitro to in vivo extrapolation, or the 

extrapolation from biological perturbation to adverse consequence significantly limits their 

quantitative use in risk assessment. The SAP concurred with the agency in 2008 and 2012 about 

the lack of definable key events in a MOA/AOP leading to developmental neurobehavioral effects. 

However, since the 2014 literature review, there are no substantive changes in the ability to define 

and quantitate steps in an MOA/AOP leading from exposure to effects on the developing brain. 

Published and submitted guideline DNT laboratory animal studies have been reviewed for OPs as 

part of the 2012/2014 review (D424485, D. Drew et al, 12/29/2014) and the updated 2015 review 

(OPP/USEPA; D331251; 9/15/15). Neurobehavioral alterations in laboratory animals were often 

reported, albeit at AChE inhibiting doses, but there was generally a lack of consistency in terms of 

pattern, timing, or dose-response for these effects, and a number of studies were of lower 

quality. However, this information does provide evidence of long-lasting neurodevelopmental 

disorders in rats and mice following gestational exposure.

 5 Mode of action (MOA) and adverse outcome pathways (AOPs) describe a set of measureable key events that make 

up the biological processes leading to an adverse outcome and the causal linkages between such events. 
Page 23 of 52

At this time, a MOA(s)/AOP(s) has/have not been established for neurodevelopmental outcomes. 

This growing body of literature does demonstrate, however, that OPs are biologically active on a 

number of processes that affect the developing brain. Moreover, there is a large body of in vivo

laboratory studies which show long-term behavioral effects from early life exposure, albeit at doses 

which cause AChE inhibition. EPA considers the results of the toxicological studies relevant to the 

human population, as qualitatively supported by the results of epidemiology studies. The agency 

acknowledges the lack of established MOA/AOP pathway and uncertainties associated lack of 

ability to make strong causal linkages and unknown window(s) of susceptibility. These 

uncertainties do not undermine or reduce the confidence in the findings of the epidemiology 

studies. The epidemiology studies reviewed in the 2012/2014 and 2015 literature reviews 

represent different investigators, locations, points in time, exposure assessment procedures, and 

outcome measurements. Despite all these differences in study design, with the exception of two 

negative studies in the 2015 literature review (Guodong et al, 2012; Oulhote and Bouchard, 2013), 

authors have identified associations with neurodevelopmental outcomes associated with OP 

exposure across four cohorts and twelve study citations. Specifically, there is evidence of delays in 

mental development in infants (24-36 months), attention problems and autism spectrum disorder in 

early childhood, and intelligence decrements in school age children who were exposed to OPs 

during gestation. Investigators reported strong measures of statistical association across several of 

these evaluations (odds ratios 2-4 fold increased in some instances), and observed evidence of 

exposures-response trends in some instances, e.g., intelligence measures.

As section 408(b)(2)(C) of the FFDCA instructs EPA, in making its “reasonable certainty of no 

harm” finding, that in “the case of threshold effects, an additional tenfold margin of safety for the 

pesticide chemical residue and other sources of exposure shall be applied for infants and children 

to take into account potential pre- and postnatal toxicity and completeness of data with respect to 

exposure and toxicity to infants and children.” Section 408 (b)(2)(C) further states that “the 

Administrator may use a different margin of safety for the pesticide chemical residue only if, on 

the basis of reliable data, such margin will be safe for infants and children.” Given the totality of 

the evidence, there is sufficient uncertainty in the human dose-response relationship for 

neurodevelopmental effects which prevents the agency from reducing or removing the statutory 

10X FQPA Safety Factor. For the chlorpyrifos methyl DRA, a value of 10X has been applied. 

Similarly, a database uncertainty factor of 10X will be retained for occupational risk assessments. 

The agency will continue to evaluate the epidemiology studies and pursue approaches for 

quantitative or semi-quantitative comparisons between doses which elicit AChE inhibition and 

those which are associated with neurodevelopmental outcomes prior to a revised human health risk 

assessment. 

4.5 Safety Factor for Infants and Children (FQPA Safety Factor)

As noted above, the lack of an established MOA/AOP makes quantitative use of the epidemiology 

studies in risk assessment challenging, particularly with respect to determining dose-response, 

critical duration of exposure, and window(s) of susceptibility. However, exposure levels in the 

range measured in the epidemiology studies are likely low enough that they are unlikely to result in 

AChE inhibition. Epidemiology studies consistently identified associations with 

neurodevelopmental outcomes associated with OP exposure such as delays in mental development 

in infants (24-36 months), attention problems and autism spectrum disorder in early childhood, and 

intelligence decrements in school age children. Therefore, there is a need to protect children from 
Page 24 of 52

exposures that may cause these effects; this need prevents the agency from reducing or removing 

the statutory FQPA Safety Factor. Additionally, there is a data gap for chlorpyrifos-methyl for the 

CCA. Therefore, a total FQPA Safety Factor of 30X, to account for the uncertainty in the 

human dose-response relationship for neurodevelopmental effects and the lack of a CCA 

study, will be used for chlorpyrifos-methyl for the population subgroups that include infants, 

children, youths, and women of childbearing age for all exposure scenarios. 

4.5.1 Completeness of the Toxicology Database

The toxicity database for chlorpyrifos-methyl is incomplete. The following studies are available: 

rat sub-chronic, developmental, reproduction, and combined chronic/carcinogenicity studies; a dog 

sub-chronic study; a mouse chronic/carcinogenicity study; and several mutagenicity studies. 

Among studies not available are the following: a developmental study in non-rodents; a CCA; a

neurotoxicity screening battery (acute and sub-chronic neurotoxicity studies); a delayed 

neurotoxicity study; an immunotoxicity study; an inhalation toxicity study; and dermal absorption

and toxicity studies. 

The database was presented to a combined ToxSAC/HASPOC on 9/2/15 and again to the 

HASPOC on 9/3/15. These committees recommended the following:

• Not translating toxicity data from chlorpyrifos ethyl to chlorpyrifos methyl because of the 

differences in potency, and potential differences in absorption, distribution, metabolism, 

and excretion which may lead to significantly differing toxicity profiles; 

• Waiving all outstanding toxicity studies except for the following which are expected to be 

the most pertinent in deriving protective risk assessment points of departure: a CCA; a 90-

day inhalation study; and a dermal penetration study. 

As discussed in Section 4.4, there is uncertainty in the human dose-response relationship for 

neurodevelopmental effects and this warrants retention of the FQPA Safety Factor for the 

population subgroups that include infants, children, youths, and women of childbearing age for all 

exposure scenarios.

4.5.2 Evidence of Neurotoxicity

Chlorpyrifos methyl is an OP with an established neurotoxic AOP. Neurotoxicity is typically the 

most sensitive effect in all species, routes, and life stages and is being used in deriving the PODs. 

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

There is no evidence of increased quantitative or qualitative sensitivity/susceptibility to offspring 

following exposure to chlorpyrifos-methyl in submitted studies (including studies evaluating 

ChEI). However, there is no comparative cholinesterase study available, the study typically used 

for organophosphate pesticides to determine increased sensitivity to ChEI.

As discussed in Section 4.4, there is uncertainty in the human dose-response relationship for 

neurodevelopmental effects and this warrants retention of the FQPA Safety Factor for the 
Page 25 of 52

population subgroups that include infants, children, youths, and women of childbearing age for all 

exposure scenarios.

4.5.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties with regard to the acute and steady state dietary (food) exposure 

assessments. Monitoring data and anticipated residues were used. For stored cereal grains 100% 

were assumed to be treated. Although data were used to partially refine the dietary exposure 

assessments, the assessments are not expected to underestimate dietary exposures. There are no 

expected exposures from drinking water or in residential settings.

4.6 Toxicity Endpoint and Point of Departure Selections

4.6.1 Dose-Response Assessment

Tables 4.6.4.1 and 4.6.4.2 summarize the chlorpyrifos-methyl toxicity endpoints and PODs 

selected from an evaluation of the database. This endpoint selection was based on a weight-ofevidence evaluation using the following considerations:

• Relative sensitivity of the brain and RBC compartments: For chlorpyrifos-methyl, across 

most studies, RBC cholinesterase is more sensitive than in the brain. As such, OPP has 

utilized the RBC data in POD derivation.

• Potentially susceptible populations (fetuses, juveniles, pregnancy): The available AChE 

data across multiple life stages (adults, pregnant adults, fetuses, juveniles) show no 

quantitative life stage sensitivity for chlorpyrifos-methyl. However, results of CCA studies 

are typically used to determine increased susceptibility for organophosphate compounds, a 

data gap for chlorpyrifos-methyl. 

• Route of exposure: It is preferred to match, to the degree possible, the route of exposure in 

the toxicity study with that of the exposure scenario(s) of interest. However, route-specific 

dermal and inhalation studies are not available for chlorpyrifos-methyl.

• Duration of exposure: It is preferred to match, to the degree possible, the duration of 

toxicity study with that of the exposure duration of interest. However, there are only 

steady-state oral toxicity studies (except acute lethality studies) available for chlorpyrifosmethyl. 

• Consistency across studies: In cases where multiple datasets are available for a single 

duration, it is important to evaluate the extent to which data are consistent (or not) across 

studies. The chlorpyrifos-methyl rat developmental study NOAEL, the rat 90-day oral 

study NOAEL and the rat reproduction NOAEL are identical to the rat chronic study 

NOAEL at 1.0 mg/kg/day, thereby increasing the confidence in such values in the steadystate period. 

For chlorpyrifos-methyl, NOAELs rather than benchmark doses were utilized for points of 

departure because the doses in each study were often separated by an order of magnitude or more, 

resulting in a dose-spread not conducive to benchmark dose (BMD) modeling. Inhibition of ChE 

was typically the most sensitive effect in all animal species evaluated. The same studies were 

utilized for regulation as in the previous assessment (G. Bangs, D265055); however, the NOAELs 
Page 26 of 52

and LOAELs were updated to reflect the current HED policy of using RBC cholinesterase 

inhibition for PODs instead of plasma cholinesterase inhibition. 

Acute Dietary (all populations) 

No chlorpyrifos-methyl study is available which measures cholinesterase inhibition following a 

single dose or a single day’s dosing.

A POD for the acute dietary (all populations) exposure scenario was derived from the results in the 

rat developmental study (MRID 44680603) based on RBC ChE inhibition at the LOAEL of 12.5 

mg/kg/day (NOAEL is 1.0 mg/kg/day). For OPs, the steady state period is typically 2-3 weeks and 

the POD drops with exposure duration until the steady state period is reached. The rat 

developmental study has the same NOAEL as the 90-day sub-chronic rat study, thus chlorpyrifosmethyl seems to have reached steady state kinetics by the end of the rat developmental study. 

Therefore, using the rat developmental study in pregnant female rats for regulating acute durations 

is conservative and protective. 

For acute dietary exposures a total uncertainty factor (UF) of 3000X (10X to account for 

interspecies extrapolation, 10X for intra-species variation, and a 30X for FQPA SF incorporating 

uncertainty in the human dose-response relationship for neurodevelopmental effects (see Section 

4.4) and the lack of a CCA study is applied to the NOAEL to obtain an acute population adjusted 

dose (aPAD) of 0.00033 mg/kg/day for exposure scenarios with infants, children, youths, and 

women of childbearing age. 

Steady State Dietary (all populations)

Of the repeated dosing studies, data from the rat combined chronic/carcinogenicity study (MRID 

42269001) was found to be the most robust for the steady-state period duration. The NOAEL is 1.0 

mg/kg/day, and the LOAEL (50.0 mg/kg/day) is based on RBC ChEI. The rat developmental study 

and 90-day rat oral toxicity study also had a NOAEL of 1.0 mg/kg/day (LOAEL of 10 and 12.5 

mg/kg/day, respectively, both based on RBC ChEI) and are considered co-critical studies. The

reproduction study systemic effects are supportive with a NOAEL of 1.0 mg/kg/day and a LOAEL 

for parental toxicity of 3.0 mg/kg/day based on microscopic lesions in the adrenal glands of F0

females and F1 animals of both sexes. The reproduction study adult females had an apparent RBC 

ChEI LOAEL of 1.0 mg/kg/day (the lowest dose tested [LDT]); however, the number of animals 

tested were only 5/group. Furthermore, based on RBC ChEI, the female offspring and the male 

adults and offspring all had a LOAEL of 10.0 mg/kg/day and a NOAEL of 3.0 mg/kg/day in the 

same study. In the PND22 offspring groups, the ChE activity increased at 10.0 mg/kg/day in both 

males and female pups. The developmental rat study had a much higher LOAEL of 12.5 

mg/kg/day and a NOAEL of 1.0 mg/kg/day. The chlorpyrifos methyl rat toxicology data base 

supports that the NOAEL for chlorpyrifos methyl is 1.0 mg/kg/day based on RBC ChE inhibition. 

The chronic mouse study had an RBC ChE LOAEL of 3.9 mg/kg/day in females and a NOAEL of 

0.4 mg/kg/day. Considering the reproducibility of rat studies, the similarity in magnitude of the 

NOAELs of 0.4 mg/kg/day in mice compared to 1.0 mg/kg/day in rats, the NOAEL of 1.0 

mg/kg/day from the rat studies is considered protective for steady state RBC cholinesterase 

inhibition and was chosen as the POD for this assessment.
Page 27 of 52

For steady-state dietary exposures a total uncertainty factor (UF) of 3000X (10X to account for 

interspecies extrapolation, 10X for intra-species variation, and a 30X FQPA SF incorporating 

uncertainty in the human dose-response relationship for neurodevelopmental effects (see Section 

4.4) and the lack of a CCA study) is applied to the NOAEL (1.0 mg/kg/day) to obtain a steadystate population adjusted dose (ssPAD) of 0.00033 mg/kg/day for exposure scenarios with infants, 

children, youths, and women of childbearing age. 

Dermal, Steady State

A dermal toxicity study was unavailable for chlorpyrifos-methyl; therefore, the POD for the 

steady-state oral exposure was used. The chronic rat study was selected with a NOAEL of 1.0 

mg/kg/day. The rat developmental and sub-chronic studies were considered co-critical (NOAEL of 

1.0 mg/kg/day) and the rat reproduction study supportive (systemic NOAEL of 1.0 mg/kg/day). 

A dermal absorption study is not available for chlorpyrifos-methyl. In the absence of dermal 

toxicity or absorption data, 100% dermal absorption will be assumed. 

For dermal exposures (occupational only; there are currently no scenarios that would result in nonoccupational, residential exposures to chlorpyrifos-methyl), a total uncertainty factor of 3000X is

appropriate [10X for interspecies extrapolation, 10X for intra-species variation and 30X database 

uncertainty factor incorporating the uncertainty in the human dose-response relationship for 

neurodevelopmental effects (see Section 4.4) and the lack of a CCA study] to protect the fetuses of 

pregnant workers.

Inhalation, Steady State

An inhalation toxicity study was unavailable for chlorpyrifos-methyl; therefore, the POD for the 

steady-state oral exposure was used. The chronic rat study was selected with a NOAEL of 1.0 

mg/kg/day. The rat developmental and subchronic studies were considered co-critical (NOAEL of 

1.0 mg/kg/day) and the rat reproduction study supportive (systemic NOAEL of 1.0 mg/kg/day). 

For inhalation exposures (occupational only; there are currently no scenarios that would result in 

non-occupational, residential exposures to chlorpyrifos-methyl), a total uncertainty factor of 3000X 

is appropriate [10X for interspecies extrapolation, 10X for intra-species variation and a 30X 

database uncertainty factor incorporating uncertainty in the human dose-response relationship for 

neurodevelopmental effects (see Section 4.4), the lack of a CCA study, and the lack of an 

inhalation study to elucidate possible route-specific effects] to protect the fetuses of pregnant 

workers.

4.6.2 Recommendation for Combining Routes of Exposures for Risk Assessment

PODs for the oral, dermal, and inhalation routes of exposure are all derived from the same studies, 

and based on the same toxicological effect, RBC cholinesterase inhibition; therefore, all routes may

be combined.

4.6.3 Cancer Classification and Risk Assessment Recommendation
Page 28 of 52

Acceptable carcinogenicity studies in both rats and mice produced no treatment-related increase in 

tumor incidence; furthermore, no genotoxicity was noted in the mutagenicity battery. 

Consequently, in accordance with the Agency’s 2005 Guideline for Carcinogen Risk Assessment, 

chlorpyrifos-methyl is classified as “Not Likely to be Carcinogenic to Humans”. A quantitative 

cancer risk assessment is not required for chlorpyrifos-methyl.

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

Assessment 

Table 4.6.4.1 Summary of Toxicological Doses and Endpoints for Chlorpyrifos-Methyl for Use in 

Dietary and Non-Occupational Human Health Risk Assessment

Exposure

Scenario

Point of Departure

(mg/kg/day)

Study and Toxicological

Effects

Acute Dietary

(all populations)

NOAEL = 1.0 mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 30x*

acute PAD = 0.00033 mg/kg/day

Rat Developmental Study

NOAEL = 1.0 mg/kg/day

LOAEL = 12.5 mg/kg/day, based on inhibition of 

RBC cholinesterase

Steady-State 

Dietary

(all populations)

NOAEL = 1.0 mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 30x*

Steady State PAD = 0.00033

mg/kg/day

Rat Chronic Study

NOAEL = 1.0 mg/kg/day

LOAEL = 50 mg/kg/day, based on RBC ChE Inhibition

Co-Critical Study 

Rat Developmental Study

Rat Sub-chronic Study

NOAEL = 1.0 mg/kg/day in both studies

LOAEL = 10.0- 12.5 mg/kg/day, based on inhibition of 

RBC cholinesterase

Cancer (oral, 

dermal, inhalation) Chlorpyrifos-methyl is not likely to be carcinogenic to humans.

Point of departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no-observed adverse-effect level. LOAEL = lowest-observed adverse-effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity 

among members of the human population (intra-species). FQPA SF = FQPA Safety Factor. PAD = population 

adjusted dose (a = acute, ss = steady-state). RfD = reference dose (a = acute, ss = steady-state). MOE = margin of 

exposure. LOC = level of concern.

*30x FQPA safety factor (SF) for females of child-bearing age, infants, children, and youths to account for uncertainty 

in the human dose-response relationship for neurodevelopmental effects (see Section 4.4), as well as the lack of a 

comparative cholinesterase study. The 30x FQPA SF would not apply to other population subgroups (e.g. all adults 50+ 

years of age).
Page 29 of 52

Table 4.6.4.2. Summary of Toxicological Doses and Endpoints for Chlorpyrifos-Methyl for Use in 

Occupational Human Health Risk Assessment

Exposure

Scenario

Point of Departure

(mg/kg/day)

Study and Toxicological

Effects

Dermal

Steady-State

NOAEL = 1.0 mg/kg/day

UFA = 10x

UFH = 10x

UFDB = 30x*

Occupational LOC for MOE =3000

100% dermal absorption assumed

Rat Chronic Study

NOAEL = 1.0 mg/kg/day

LOAEL = 50 mg/kg/day, based on RBC ChE Inhibition

Co-Critical Study 

Rat Developmental Study

Rat Sub-chronic Study

NOAEL = 1.0 mg/kg/day in both studies

LOAEL = 10.0-12.5 mg/kg/day, based on inhibition of 

RBC cholinesterase

Inhalation

Steady-State

NOAEL = 1.0 mg/kg/day

UFA = 10x

UFH = 10x 

UFDB = 30x**

Occupational LOC for MOE =3000

Rat Chronic Study

NOAEL = 1.0 mg/kg/day

LOAEL = 50 mg/kg/day, based on RBC ChE Inhibition

Co-Critical Study 

Rat Developmental Study

Rat Sub-chronic Study

NOAEL = 1.0 mg/kg/day in both studies

LOAEL = 10.0-12.5 mg/kg/day, based on inhibition of 

RBC cholinesterase

Cancer (oral, 

dermal, inhalation) Chlorpyrifos-methyl is not likely to be carcinogenic to humans.

Point of departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no-observed adverse-effect level. LOAEL = lowest-observed adverse-effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity 

among members of the human population (intra-species). FQPA SF = FQPA Safety Factor. PAD = population 

adjusted dose (a = acute, ss = steady-state). RfD = reference dose (a = acute, ss = steady-state). MOE = margin of 

exposure. LOC = level of concern.

*30x database uncertainty factor (UFDB) to account for the uncertainty in the human dose-response relationship for 

neurodevelopmental effects (see Section 4.4) and lack of a comparative cholinesterase study. 

**30x database uncertainty factor (UFDB) to account for the uncertainty in the human dose-response relationship for 

neurodevelopmental effects (see Section 4.4), lack of a comparative cholinesterase study, and lack of an inhalation study 

to elucidate possible route-specific effects.
Page 30 of 52

4.7 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, sub-chronic and

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental 

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 most recent reregistration decision for chlorpyrifos-methyl, 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-methyl 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. A second list of chemicals identified for EDSP screening was 

published on June 14, 20136 and includes some pesticides scheduled for registration review and 

chemicals found in water. Neither of these lists should be construed as a list of known or likely 

endocrine disruptors.

For further information on the status of the EDSP, the policies and procedures, the lists of 

chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our 

website.7

 6 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of

chemicals.

7 http://www.epa.gov/endo/
Page 31 of 52

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

Toxicology/chemistry Memo: PP6F3429, 4/29/91, M. Flood

Residue Chemistry Memo: DP# 259808, 11/1/99, S. Levy

The qualitative nature of the residue in plants and livestock is adequately understood based on 

metabolism studies conducted on stored corn and wheat grain, and in goats and poultry. Across 

the studies, the major metabolites are TCP and chlorpyrifos-methyl monoacid. Unchanged parent 

compound chlorpyrifos-methyl was also found but parent decreased with time with a 

corresponding increase in the major metabolites. The oxygen analog of chlorpyrifos-methyl was 

not identified in the metabolism studies.

5.1.2 Comparison of Metabolic Pathways

The metabolism of chlorpyrifos-methyl is similar in the plant and animal metabolism studies: in 

general the phosphate ester undergoes extensive hydrolysis yielding products that are expected to 

have little or no cholinesterase inhibiting activity, primarily TCP and the chlorpyrifos-methyl

monoacid. Unchanged parent chlorpyrifos-methyl was also found but parent decreased with time 

with a corresponding increase in the major metabolites.

5.1.3 Residues of Concern Summary and Rationale

HED had previously determined that the major metabolite TCP is no longer a residue of concern 

because of its inactivity as a cholinesterase inhibitor (E. Doyle, 4/1/91). Therefore, HED 

concluded that tolerances are to be expressed in terms of chlorpyrifos-methyl only and that TCP 

need not appear in the tolerance expression (M. Flood, 4/29/91). The residue of concern for risk 

assessment is also parent compound chlorpyrifos-methyl only. 

A potential metabolite of concern, the oxygen analog of chlorpyrifos-methyl, is not expected to 

occur on food or in the environment based on the current use pattern for stored grains and grain 

storage facilities. In addition, from 2000 to 2010, PDP tested 7,344 food samples (including rice, 

oats, milk, butter, cream, and beef and chicken commodities) specifically for the oxygen analog. 

None of the samples had detectable residues of the oxygen analog. The chlorpyrifos-methyl

oxon was not found in livestock tissues in the metabolism studies at exaggerated feeding rates. 

All residues in food are assumed to be parent compound chlorpyrifos-methyl only. Based on the 

post-harvest use pattern of chlorpyrifos-methyl, residues are not expected to occur in drinking 

water sources.
Page 32 of 52

Table 5.1.3 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-methyl Chlorpyrifos-methyl

Rotational Crop N/A N/A

Livestock Ruminant Chlorpyrifos-methyl Chlorpyrifos-methyl

Poultry Chlorpyrifos-methyl Chlorpyrifos-methyl

Drinking Water N/A N/A

N/A=not applicable based on current use pattern.

5.2 Residue Chemistry and Food Residue Profile

Residue Chemistry Memo: DP# 259808, 11/1/99, S. Levy

Dietary Assessment Memo: draft DP# 426988, 7/15/15, D. Drew

Tolerances are established for residues of chlorpyrifos-methyl in grain commodities and also in 

livestock commodities since residues may occur in milk, eggs, meat, fat, or meat byproducts as a 

result of livestock consuming treated grain commodities. This section provides the background 

and current status of residue chemistry requirements for chlorpyrifos-methyl and includes 

residue data submitted and reviewed since the 1999 Residue Chemistry Chapter of the 

chlorpyrifos-methyl RED and U.S.EPA’s December 30, 2000 Tolerance Reassessment 

Eligibility Decision (TRED) which was made final in 2006 as part of the organophosphate (OP) 

cumulative risk assessment. 

In the 1999 residue Chemistry Chapter and the 2000 TRED, additional magnitude of the residue 

data (Guideline 860.1500) for aspirated grain fractions (AGF) of sorghum and wheat were

identified as outstanding.

Subsequent to the chlorpyrifos-methyl TRED, a 2013 residue study was submitted for the 

aspirated grain fractions of sorghum and wheat (MRID 49215801). That study was reviewed 

under D415697 (D. Drew, 8/24/2015) and was determined to be adequate. The AGF data 

(860.1500) deficiencies for chlorpyrifos-methyl are now fulfilled and no further data is being 

required. The data indicate that residues of chlorpyrifos-methyl may concentrate in wheat and 

grain sorghum AGF generated from grain bearing quantifiable residues. The processing factors 

for chlorpyrifos-methyl were 55x for wheat AGF and 6.0x for grain sorghum AGF. It was 

determined that a tolerance for residues of chlorpyrifos-methyl on “aspirated grain fractions” be 

established at 330 ppm [55 x 6 ppm (current tolerance for wheat grain; tolerances for cereal 

grains were established based on hypothetical maximum residue that could result from direct 

treatment of grains with chlorpyrifos-methyl at the maximum labeled rate. A HAFT value is not 

available for grains)].

The livestock dietary burden calculation was revised incorporating the AGF data and the updated 

Revisions of Table 1 Feedstuffs (OPPTS Test Guideline 860.1000) (Table 5.2.1) and resulting 

secondary residues in livestock tissue were estimated (Tables 5.2.2 and 5.2.3). Those 

calculations indicate that the tolerance level for residues of chlorpyrifos-methyl in livestock 

(including poultry) meat and meat byproducts may be reduced from 0.5 ppm to 0.01 ppm (LOQ 
Page 33 of 52

for livestock commodities); however, since the Codex MRL for meat and meat byproducts is 0.1 

ppm, HED is recommending a reduction only to the MRL level of 0.1 ppm for those 

commodities. The current tolerance of 0.5 ppm for livestock (including poultry) fat is 

appropriate. The tolerance for eggs may be reduced to 0.01 ppm, which is harmonized with 

Codex. The tolerance for “Milk, fat (0.05 ppm (N) in whole milk” should be revoked and 

separate tolerances should be established for “milk” and “milk, fat”. The recommended 

tolerance of 0.01 ppm for milk is harmonized with Codex. The recommended milk, fat tolerance 

of 0.05 ppm cannot be harmonized as data indicate a potential for higher chlorpyrifos-methyl

residues than the Codex MRL. (See all recommended tolerances in Section 2.2, Table 2.2.3.)
Page 34 of 52

Table 5.2.1. Livestock Dietary Burden for Chlorpyrifos-Methyl (Maximum Reasonably Based Diet)

Feedstuff Type1 % Dry 

Matter1 % Diet1 Residue(ppm)

Dietary Contribution 

(ppm)2

Beef Cattle: 15% R, 80% CC, 5% PC

Corn silage 

(untreated)3

R 40 15 NA 0

Aspirated grain 

fractions

CC 85 5 3304 19

Wheat milled 

byproducts

CC 88 40 20 9

Sorghum grain CC 86 35 6 2.4

Soybean meal 

(untreated)3

PC 92 5 NA 0

TOTAL BURDEN -- -- 100 -- 30

Dairy Cattle: 45% R, 45% CC, 10% PC

Corn silage 

(untreated)3

R 40 45 NA 0

Wheat milled 

byproducts

CC 88 30 20 6.8

Sorghum grain CC 86 15 6 1.0

Soybean meal 

(untreated)3

PC 92 10 NA 0

TOTAL BURDEN -- -- 100 -- 7.8

Poultry: 75% CC, 25% PC

Wheat milled 

byproducts

CC 88 50 20 10

Sorghum grain CC 86 25 6 1.5

Soybean meal 

(untreated)3

PC 92 25 NA 0

TOTAL BURDEN -- -- 100 -- 12

Swine: 85% CC, 15% PC

Wheat milled 

byproducts

CC 88 50 20 10

Sorghum grain CC 86 35 6 2.1

Soybean meal 

(untreated)3

PC 92 15 NA 0

TOTAL BURDEN -- -- 100 -- 12 1 Revisions of Table 1 Feedstuffs (OPPTS Test Guideline 860.1000).

2 Contribution = ([Tolerance/% DM] X % diet) for beef and dairy cattle; contribution = (Tolerance X % diet) for poultry and 

swine. 3 There are no registered uses of chlorpyrifos-methyl that would result in residues on R (roughage) or PC (protein concentrate) 

feedstuffs. Untreated R and PC feedstuffs are included in the dietary burden calculation as they are important components of 

livestock diets.

4 Recommended tolerance level for aspirated grain fractions (based on wheat AGF data) = 330 ppm [55 (concentration factor) x 6 

ppm (current tolerance for wheat grain; tolerances for cereal grains were established based on hypothetical maximum residue that 

could result from direct treatment of grains with chlorpyrifos-methyl at the maximum labeled rate. A HAFT value is not available 

for grains)]. 
Page 35 of 52

Table 5.2.2. Summary of Livestock Feeding Studies1 with 

Chlorpyrifos-Methyl.

Commodity Feeding Level, 

ppm1

Residue in 

Tissue, ppm1

Tissue-to-Feed 

Ratio

Milk 100 0.03 0.0003

Milk, fat 100 0.40 0.004

Muscle (cattle) 100 < 0.01 0.0001

Fat (cattle)2 100 0.61 0.0061

Liver (cattle) 100 < 0.01 0.0001

Kidney (cattle) 100 0.03 0.0003

Eggs 10 < 0.01 --

30 < 0.01 --

100 0.02 0.0002

Muscle (poultry) 10 < 0.01 --

30 < 0.01 --

100 0.01 0.0001

Fat (poultry) 10 < 0.01 --

30 0.01 0.0003

100 0.08 --

Liver (poultry) 10 < 0.01 --

30 < 0.01 --

100 < 0.01 0.0001

1 MRIDs 00042600-00042603

Table 5.2.3. Estimation of Secondary Residues from Use of Chlorpyrifos-Methyl

Commodity Tissue-to-Feed Ratio Dietary Burden (ppm) Expected Residue

Milk 0.0003 7.8 0.0023

Milk, fat 0.004 7.8 0.031

Muscle (cattle) 0.0001 30 0.0030

Fat (cattle) 0.0061 30 0.18

Liver (cattle) 0.0001 30 0.0030

Kidney (cattle) 0.0003 30 0.0090

Eggs 0.0002 12 0.0024

Muscle (poultry) 0.0001 12 0.0012

Fat (poultry) 0.0003 12 0.0036

Liver (poultry) 0.0001 12 0.0012

5.3 Dietary Risk Assessment

5.3.1 Description of Residue Data Used in Dietary Assessment

HED has conducted acute and steady state dietary (food) exposure and risk assessments using 

DEEM version 3.18 for chlorpyrifos-methyl. The assessment included the consumption of cereal 

grain commodities (barley, oats, rice, sorghum and wheat) and livestock commodities. Drinking 

water was not included in the dietary assessments; exposure is not expected from drinking water 
Page 36 of 52

as chlorpyrifos-methyl is not expected to enter drinking water sources based on the registered 

post-harvest and enclosed container uses. 

OPs exhibit a phenomenon known as steady state AChE inhibition. After repeated dosing at the 

same dose level, the degree of inhibition comes into equilibrium with the production of new, 

uninhibited enzyme. OP AChE studies of 2-3 weeks generally show the same degree of 

inhibition as those of longer duration (i.e., up to 2 years of exposure). Therefore, a steady state 

assessment based on 21 days of exposure may be conducted in place of the traditional chronic 

assessment.

For steady state dietary assessments for OP pesticides, the DEEM acute module may be used to 

conduct two-day average assessments which uses two-day average food and water consumptions 

along with the steady state POD. These two-day average assessments provide an estimate of 21-

day (steady state) average daily food and drinking water exposures. Since the DEEM two-day 

average assessment does not capture day to day variation in food residues, it will generally result 

in higher food-only exposure estimates than a model that calculates 21-day rolling averages for 

food. Although the DEEM two-day average assessment for chlorpyrifos-methyl may result in 

higher exposure estimates for food than would a 21-day average model, the assessment provides

an acceptable estimate of steady state exposure for use in risk assessment and will not 

underestimate the risk. 

Chlorpyrifos-methyl dietary risk assessments were performed for the following population 

groups: the general U.S. population, all infants <1 year, children 1-2, children 3-5., children 6-

12, youth 13-19, adults 20-49, and females 13-49.

The dietary exposure analyses are partially refined. All food residues used were based upon U. S. 

Department of Agriculture’s Pesticide Data Program (USDA PDP) monitoring data. Where 

available, empirical processing and cooking factors were incorporated into the assessments. 

5.3.2 Percent Crop Treated Used in Dietary Assessment

The acute and steady state dietary risk assessments for chlorpyrifos-methyl assumed 100% crop 

treated (no adjustments for % crop treated (CT) are made when using PDP monitoring data for 

blended commodities).

5.3.3 Acute Dietary Risk Assessment

The acute dietary exposure estimates are below HED’s level of concern (<100 % the acute 

population adjusted dose (aPAD)) for the U.S. population and the following population 

subgroups: all infants (<1 year old), youth 13-19, females 13-49, and adults 20-49years of age. 

However, at the 99.9th percentile of exposure, acute dietary exposure estimates are above HED’s 

level of concern (>100 % aPAD) for children 1-2, children 3-5, and children 6-12 years of age; 

the highest exposed child subgroup was children 1-2 years at 170% of the aPAD.
Page 37 of 52

Acute dietary exposures were below the level of concern for the children subgroups (and all 

other population subgroups) at the 99th and 95th percentile of exposures. Wheat commodities 

were the greatest contributor to child dietary exposures.

Consumption of wheat products was the greatest contributor to dietary risk estimates for 

children. 

Table 5.3.3 Results of Acute Dietary (Food) Exposure and Risk Analysis for Chlorpyrifos-Methyl.

Population Subgroup1 aPAD2

(mg/kg/day)

95th Percentile 99th Percentile 99.9th Percentile

Exposure 

(mg/kg/day)

% 

aPAD

Exposure 

(mg/kg/day)

% 

aPAD

Exposure 

(mg/kg/day)

% 

aPAD

General U.S. Population 0.00033 0.000071 22 0.000131 40 0.000282 85

All Infants (<1 year old) 0.00033 0.000104 32 0.000163 49 0.000281 85

Children 1-2 years old 0.00033 0.000166 50 0.000244 74 0.000555 170

Children 3-5 years old 0.00033 0.000128 39 0.000200 61 0.000501 150

Children 6-12 years old 0.00033 0.000093 28 0.000155 47 0.000381 120

Youth 13-19 years old 0.00033 0.000057 17 0.000098 30 0.000257 78

Adults 20-49 years old 0.00033 0.000043 13 0.000077 23 0.000202 61

Females 13-49 years old 0.00033 0.000042 13 0.000073 22 0.000190 58

1 Population with the greatest exposure is in bold.

2 aPAD = acute population-adjusted dose.

5.3.4 Steady State Dietary Risk Assessment

The steady state dietary exposure estimates are below HED’s level of concern (<100 % the 

steady state population adjusted dose (ssPAD)) for the U.S. population and the following 

population subgroups: all infants (<1 year old), children 6-12, youth 13-19, females 13-49, and 

adults 20-49 years of age. However, at the 99.9th percentile of exposure, steady state dietary 

exposure estimates are above HED’s level of concern (>100 % ssPAD) for children 1-2 and 3-5 

years of age; the highest exposed child subgroup was children 1-2 years at 140% of the ssPAD.

Steady state dietary exposures are below the level of concern for the children subgroups (and all 

other population subgroups) at the 99th and 95th percentile of exposures. Wheat commodities 

were the greatest contributor to child dietary exposures.

5.3.4. Results of Steady State Dietary (Food) Exposure and Risk Analysis for Chlorpyrifos-Methyl.

Population Subgroup1 ssPAD2

(mg/kg/day)

95th Percentile 99th Percentile 99.9th Percentile

Exposure

(mg/kg/day)

% 

aPAD

Exposure 

(mg/kg/day)

% 

aPAD

Exposure 

(mg/kg/day)

% 

aPAD

General U.S. Population 0.00033 0.000068 20 0.000118 36 0.000226 68

All Infants (<1 year old) 0.00033 0.000105 32 0.000152 46 0.000264 80

Children 1-2 years old 0.00033 0.000155 47 0.000207 63 0.000446 140

Children 3-5 years old 0.00033 0.000114 34 0.000167 51 0.000395 120

Children 6-12 years old 0.00033 0.000084 26 0.000130 39 0.000297 90

Youth 13-19 years old 0.00033 0.000051 15 0.000082 25 0.000191 58

Adults 20-49 years old 0.00033 0.000039 12 0.000065 20 0.000163 50

Females 13-49 years old 0.00033 0.000038 12 0.000060 18 0.000143 43
Page 38 of 52

1 Population with the greatest exposure is in bold.

2 ssPAD = steady state population-adjusted dose.

5.3.5 Summary Table Dietary Risk Assessment

.

Table 5.3.5. Summary of Dietary (Food) Exposure and Risk for Chlorpyrifos-Methyl.

Population Subgroup1

Acute Dietary

(99.9th Percentile)

Steady State

(99.9th Percentile) Cancer

Dietary 

Exposure 

(mg/kg/day)

% aPAD

Dietary 

Exposure

(mg/kg/day)

% ssPAD

Dietary 

Exposure

(mg/kg/day)

Risk

General U.S. Population 0.000282 85 0.000226 68

NA

All Infants (<1 year old) 0.000281 85 0.000264 80

Children 1-2 years old 0.000555 170 0.000446 140

Children 3-5 years old 0.000501 150 0.000395 120

Children 6-12 years old 0.000381 120 0.000297 90

Youth 13-19 years old 0.000257 78 0.000191 58

Adults 20-49 years old 0.000202 61 0.000163 50

Females 13-49 years old 0.000190 58 0.000143 43

1 Population with the greatest exposure is in bold.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no registered residential uses, or commercial/professional uses at residential sites 

associated with chlorpyrifos-methyl at this time. Residential exposures are not expected from 

the current uses and a quantitative assessment is not required. 

6.1 Spray Drift

Based on the current use-pattern, HED has determined that chlorpyrifos-methyl is not registered 

on use sites that would result in spray drift. Therefore, a quantitative spray drift assessment was 

not conducted for chlorpyrifos-methyl.

6.2 Non-Occupational Bystander Post-Application Inhalation Exposure and Risk 

Estimates

Volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby pesticide applications. The agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on 

March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). 
Page 39 of 52

During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux 

studies, route-specific inhalation toxicological studies) or further analysis is required for 

chlorpyrifos-methyl.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure. The registered uses of chlorpyrifos-methyl are not anticipated to result in 

residential or drinking water exposure; only exposure from food is anticipated. The acute and 

steady state dietary risk estimates (provided in Section 5.3.3 and 5.3.4) are of concern for 

children.

8.0 Occupational Exposure/Risk Characterization

8.1 Occupational Handler Exposure/Risk Estimates (Steady State)

HED uses the term handlers to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct job functions or tasks related to 

applications and exposures can vary depending on the specifics of each task. Job requirements 

(amount of chemical used in each application), the kinds of equipment used, the target being 

treated, and the level of protection used by a handler can cause exposure levels to differ in a 

manner specific to each application event. 

Based on the anticipated use patterns and current labeling, types of equipment and techniques 

that can potentially be used, occupational handler exposure (dermal and inhalation) is expected 

from the proposed uses. The steady state endpoint selection for chlorpyrifos-methyl overlaps 

HED’s traditional short-term exposure duration endpoint selection and is considered health 

protective for occupational handlers that apply commercially over longer periods of time (i.e., 

intermediate-term exposures).

Grain elevator workers apply this product in liquid form to a moving stream of grain (i.e., 

conveyor or auger) using automated equipment. Only mixing and loading are expected to 

contribute significantly to worker exposure when using an automated process. Grain storage 

workers and farm workers also may apply liquid chlorpyrifos-methyl to the walls of empty grain 

storage containers using hand sprayers such as backpack and manually-pressurized hand wand 

equipment.

The quantitative steady state exposure/risk assessment developed for occupational handlers is 

based on the following scenarios: 

(1) mixing/loading liquid formulation for automated equipment (admixture) [open loading 

systems]; 
Page 40 of 52

(2) mixing/loading/applying liquid formulation using hand-held equipment (grain bin 

treatments):

• Mechanically pressurized hand wand (grain bin treatments)

• Manually pressurized hand wand (warehouse treatments)

• Backpack sprayer (warehouse treatments)

Occupational Handler Exposure Data and Assumptions 

The detailed exposure data and assumptions (e.g., unit exposure, area treated or amount handled, 

duration) used in the occupational handler assessment can be found in D426987 (M. Lloyd).

Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, 

include PHED 1.1 and the AHETF database.

For adults, when an endpoint is not sex-specific (i.e., the endpoints are based on developmental 

or fetal effects) a body weight of 80 kg is typically used in risk assessment; however, in this case, 

a female-specific body weight of 69 kg was used. While the endpoint of concern, RBC AChE 

inhibition, is not sex-specific, the female body weight was used to protect for pregnant women 

due to uncertainty in the human dose-response relationship for neurodevelopmental effects (see 

Section 4.4).

The maximum single application rates on the registered label were used to assess the handler 

exposure scenarios. The amount handled is based on the specifications on the registered label 

and a citation from a previous handler assessment (M. Collantes, D268643, 12/21/00).

For the automated treatment scenarios (open loading), it is assumed that 26,000 bushels of stored 

grain are treated per day. The product label provides an application rate of 12.4 fluid oz per 

1,000 bushels of grain treated. HED assessed the label maximum rate (for treating wheat; 12.4 fl. 

oz / 1,000 bushels of grain).

For the handheld application scenarios, the following is assumed: 20 gallons per day for 

backpack sprayer and manually pressurized hand wand and 500 gallons per day for 

mechanically pressurized hand wand. 

Estimates of dermal and inhalation exposure were calculated for various levels of personal 

protective equipment (PPE) depending on the scenario. The chlorpyrifos-methyl product label 

directs mixers, loaders, applicators and other handlers to wear long-sleeved shirt and long pants, 

chemical resistant gloves, and protective eyewear. Empty grain bin applications require handlers 

to wear “a NIOSH-approved respirator with any N, R, P or HE filter.” Handlers applying 

directly to grain or seed must use an automated admixture system. Those systems must both 

apply the pesticide directly to the grain or seed and transfer into stationary storage facilities.

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates

Table 8.1 presents the steady state dermal and inhalation risk estimates for occupational 

handlers. Since the dermal and inhalation PODs are both based on RBC AChE inhibition, these 
Page 41 of 52

routes of exposure can be combined (using the combined MOE approach) for risk assessment 

purposes. The level of concern (LOC) for both dermal and inhalation exposure is 3000.

Steady state risk estimates for occupational/commercial handlers based on both 1) label-specified 

PPE and 2) maximum feasible PPE for handheld scenarios are presented in Table 8.1. 

• Risk concerns were identified for all scenarios (combined MOEs <3,000 based on a LOC 

of 3,000) with both label-specified PPE (single layer plus gloves and PF5 respirator):

o Mix/load/apply (M/L/A) for Mechanically-pressurized hand wand equipment 

(Combined MOE of 12)

o M/L/A for Manually-pressurized hand wand equipment (Combined MOE of 14)

o M/L/A Backpack Sprayer scenario (Combined MOE of 14)

o M/L for automated application (combined MOE of 350)

Risk estimates for these scenarios remain of concern despite considerations of additional PPE. 

Specifically, the addition of additional dermal protection (e.g., coveralls) or a PF10 respirator (in 

the case of the manually-pressurized hand wand scenario) does not increase the combined MOE 

over the LOC of 3000.

The existing label is unclear and sometimes contradictory on the equipment per use scenario, 

particularly the grain bin and warehouse uses. The product label does note that “This product 

may only be applied to empty grain bins using high-pressure hand held or automated equipment” 

although warehouse applications using other handheld equipment appear to be allowed in the 

Directions for Use section. This assessment quantitatively calculates risk estimates using 

handheld equipment. If the label language is clarified to clearly restrict handheld equipment 

scenarios for a specific use site, those scenarios would not be applicable. Also, the label allows 

for open pour mixer/loader scenarios for automated spray equipment application. 
 

Page 42 of 52

Table 8.1. Occupational Handler Exposure and Risk Estimates for Chlorpyrifos-methyl. 

Exposure 

Scenario and 

Product

Crops

Application 

Ratea

Amount 

Handled

Dermal Unit 

Exposureb,h

(ug/lb ai)

[Mitigation 

Level]

Inhalation 

Unit 

Exposureb

(mg/lb ai)

[Mitigation 

Level]

Dermal 

Dosec

(mg/kg/day)

Dermal 

MOEd

LOC = 

3,000

Inhalation 

Dosee

(mg/kg/day)

Inhalation 

MOEf

LOC = 

3,000

Total MOEg

LOC = 

3,000

Mixer/Loader

M/L for 

automated 

application 

[open loading]

Stored 

Grain/Stored 

Seed

(wheat, 

barley, rice, 

sorghum)

0.18 

lbs ai/1000 

bushels

26,000 

bushels

37.6

[Baseline; 

Gloves]

0.219

[No respirator] 0.00281 360 0.0000165 61,000 350

Mixer/Loader/Applicator

Sprays using 

Mechanicallypressurized 

Hand wand

Empty grain 

bins 0.03 lb ai/gal 500 gal

390

[Baseline; 

Gloves]

0.78

[PF5 

Respirator]

0.0838 12 0.00017 5,900 12

390

[Double layer +

gloves]

0.78

[PF5 

Respirator]

0.0624 16 0.00017 5,900 16

Sprays using 

Manuallypressurized 

Hand wand

Warehouse 0.03 lb ai/gal 20 gal

8600

[Baseline; 

Gloves]

220

[PF5 

Respirator]

0.0739 14 0.00191 520 14

6200

[Double layer; 

Gloves]

110

[PF10 

Respirator]

0.0535 19 0.000957 1,000 18

Backpack 

Sprayer Warehouse 0.03 lb ai/gal 20 gal

8260

[Baseline; 

Gloves]

0.516

[PF5 

Respirator]

0.0726 14 0.00000449 220,000 14

8260

[Double layer; 

Gloves]

0.516

[PF5 

Respirator]

0.0353 28 0.00000449 220,000 28

a. Maximum single application rates are based on registered labels (see Table 4.0).

b. Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (March, 2014).

c. Dermal Dose (mg/kg/day) = [Dermal Unit Exposure (mg/lb ai) * Application Rate * Amount Handled]/Body Weight (69 kg).

d. Dermal MOE = NOAEL (1 mg/kg/day)/Dermal Dose (mg/kg/day); LOC= 3,000.

e. Inhalation Dose (mg/kg/day) = [Inhalation Unit Exposure (mg/lb ai) * Application Rate * Amount Handled]/Body Weight (69 kg).

f. Inhalation MOE = NOAEL (1 mg/kg/day)/Inhalation Dose (mg/kg/day); LOC = 3,000.

g. Total MOE = NOAEL (mg/kg/day) ÷ (Dermal Dose + Inhalation Dose) OR Total MOE = 1 ÷ [(1 / Dermal MOE) + (1 /Inhalation MOE)].

h. 100% Dermal absorption assumed
 

Page 43 of 52

8.2 Occupational Post-application Exposure/Risk Estimates

There are multiple potential sources of post-application inhalation exposure to individuals 

performing post-application activities in previously treated fields or other treated areas. These 

potential sources include volatilization of pesticides and re-suspension 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 has evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). During Registration 

Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route-specific 

inhalation toxicological studies) or further analysis is required for chlorpyrifos-methyl.

In addition, the Agency is continuing to evaluate the available post-application inhalation 

exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the 

Agency will continue to identify the need for and, subsequently, the way to incorporate 

occupational post-application inhalation exposure into the agency's risk assessments.

In the case of chlorpyrifos-methyl, bystander exposure may be possible to dusts generated by 

treated grain being conveyed into, out of or within storage containers, and dermal exposure when 

sampling treated grain. Personnel rarely have direct contact with the stored grain and therefore 

dermal exposure is expected the negligible during testing of grain, maintenance, or other 

intermittent activities. Commercial applicators do not typically return to the treated areas after 

an indoor commercial pesticide application (sites such as warehouses, etc.) and thus an 

occupational post-application inhalation exposure assessment was not performed for commercial 

applicators.

Occupational bystander inhalation exposure through dust may be possible for either the 

employee of a grain elevator or farmer/operator who operates a portable auger to load treated 

grain into a bin but there are no data available to quantify these exposures. However, bystander 

exposure in these cases are anticipated to be negligible because of dust management practices for 

grain dust at on-farm storage sites. Additionally, the available Storicide II product label directs 

users to avoid application at extremely dusty sites.

No REI is listed on the available product label as the label-defined use sites are not subject to the 

Worker Protection Standard (WPS).
 

Page 44 of 52

9.0 Public Health and Pesticide Epidemiology Data

Incident Report Memo: DP#426989, 6/2/15, E. Evans

HED has prepared a Tier I review of human incidents report. For this evaluation, both OPP 

Incident Data System (IDS) and the Centers for Disease Control and Prevention/National 

Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System 

for Occupational Risk-Pesticides (SENSOR) databases were consulted for pesticide incident data 

on the active ingredient chlorpyrifos-methyl. The purpose of the database search is to identify 

potential patterns in the frequency and severity of the health effects attributed to chlorpyrifosmethyl exposure. 

The Agricultural Health Study (AHS) is a high quality, prospective epidemiology study 

evaluating the link between pesticide use and various health outcomes including cancer. 

Chlorpyrifos-methyl is not included in the AHS, and therefore this study does not provide 

information for this report.

From January 1, 2010 to May 21, 2015, there were no incidents reported to Main IDS involving 

the single active ingredient, chlorpyrifos-methyl. There was one incident reported to Main IDS, 

involving multiple active ingredients including chlorpyrifos-methyl and deltamethrin that is 

classified as moderate severity. From January 1, 2010 to March 18, 2015, there were 13 

incidents reported to Aggregate IDS involving chlorpyrifos-methyl. These incidents were 

classified as minor severity. Overall there were few incidents reported to IDS involving 

chlorpyrifos-methyl.

A query of SENSOR-Pesticides 1998-2011 identifies a total of nine cases, stemming from nine 

events, involving chlorpyrifos-methyl. Of these, seven cases involved the single active ingredient 

chlorpyrifos-methyl. Four of the seven single ai cases involved chlorpyrifos-methyl applications 

to grain storage facilities (the remaining three cases provide no discernable case information). 

Of the seven cases single ai chlorpyrifos-methyl cases, two cases were high in severity, one case 

was moderate in severity, and four cases were low in severity. In one high severity case, a truck 

driver was near an application made to a wheat storage facility. He developed neurological 

symptoms including confusion, headache, and blurred vision, gastrointestinal symptoms and 

rapid heartbeat. He was transported later that evening by his wife to the local ER. He was given 

atropine, stabilized, and admitted for two days. The second high severity case appears to have 

been a residential exposure; however this case was lost to follow-up and no descriptive case 

information is provided. The moderate severity case involved a worker mixing/loading the 

pesticide at a grain manufacturing facility. Of the remaining four low severity cases, two 

involved grain facility exposures and two provided no case details. Of the seven single ai cases: 

six cases experienced neurological symptoms (chiefly headache) and five cases had 

gastrointestinal symptoms (nausea and vomiting), three cases had ocular symptoms, two cases 

had dermal symptoms, two cases had respiratory symptoms and one case experienced 

cardiovascular symptoms. Although two cases were high in severity, there is a low frequency of 

cases and there have been no case reported to SENSOR-Pesticides since 2004.
 

Page 45 of 52

Based on the low frequency of incidents reported to both IDS and SENSOR-Pesticides, there 

does not appear to be a concern at this time. The Agency will continue to monitor the incident 

information and if a concern is triggered, additional analysis will be conducted.

10.0 Cumulative Exposure/Risk Characterization

OPs, like chlorpyrifos methyl share the ability to inhibit AChE through phosphorylation of the 

serine residue on the enzyme leading to accumulation of acetylcholine and ultimately cholinergic 

neurotoxicity. This shared MOA/AOP is the basis for the OP common mechanism grouping per 

OPP’s Guidance For Identifying Pesticide Chemicals and Other Substances that have a Common 

Mechanism of Toxicity (USEPA, 1999). The 2002 and 2006 CRAs used brain AChE inhibition 

in female rats as the source of dose response data for the relative potency factors and PODs for 

each OP, including chlorpyrifos methyl Prior to the completion of Registration Review, OPP 

will update the OP CRA on AChE inhibition to incorporate new toxicity and exposure 

information available since 2006. 

As described in Section 4.4, OPP has retained the FQPA Safety Factor for OPs, including 

chlorpyrifos methyl due to uncertainties associated with neurodevelopmental effects in children 

and exposure to OPs. There is a lack of an established MOA/AOP for the neurodevelopment 

outcomes which precludes the agency from formally establishing a common mechanism group 

per the Guidance For Identifying Pesticide Chemicals and Other Substances that have a 

Common Mechanism of Toxicity (USEPA, 1999) based on that outcome. Moreover, the lack of a 

recognized MOA/AOP and other uncertainties with exposure assessment in the epidemiology 

studies prevent the agency from establishing a causal relationship between OP exposure and 

neurodevelopmental outcomes. The agency will continue to evaluate the epidemiology studies 

associated with neurodevelopmental outcomes and OP exposure prior to the release of the 

revised DRA. During this period, the agency will determine whether or not it is appropriate to 

apply the draft guidance document entitled, Pesticide Cumulative Risk Assessment: Framework 

for Screening Analysis for the neurodevelopment outcomes. 

11.0 References

Chlorpyrifos-Methyl HASPOC MEMO (September 2, 2015; TXR# 0057247)

M. Flood, 4/29/1991, PP#6F3429/FAP#6H5506. Chlorpyrifos-Methyl on Stored Corn. Amendment to 

Remove TCP from Tolerance Expression. 

S. Levy, 11/1/1999, D259808, CHLORPYRIFOS-METHYL. Product and Residue Chemistry Chapters of 

RED. 

M. Collantes, 12/21/2000, D268643, Occupational Exposure and Risk Assessment for Section 18 Use of 

Chlorpyrifos-methyl on Stored Grains, Bins and Warehouses.

USEPA, 12/30/2000, Chlorpyrifos Methyl. Tolerance Reassessment Eligibility Decision (TRED).

J. Doherty, 6/12/2012, D400210, Chlorpyrifos methyl. Bridging the Comparative Cholinesterase, 

Subchronic Inhalation and Immunotoxicity Studies from the Chlorpyrifos (ethyl) Data Base to Meet the 

Requirements for Chlorpyrifos Methyl.
 

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D. Davis, 7/8/2003, D291405.

E. Evans, 6/2/2015, D426989, Chlorpyrifos Methyl: Tier I Review of Human Incidents for Draft Risk.

D. Drew, 9/15/2015, D426988, Chlorpyriphos Methyl: Acute and Steady State Dietary (Food Only) 

Exposure and Risk Assessments for the Registration Review Human Health Risk Assessment

M. Lloyd, 9/15/2015, D426987, Chlorpyrifos-methyl. Occupational and Residential Exposure/Risk 

Assessment for Registration Review.

D. Drew, 8/24/2015, D415697, Chlorpyriphos-Methyl (chlorpyrifos-methyl): Review of Residue Data for 

Aspirated Grain Fractions of Wheat and Sorghum (Generic Data Call-In).

FIFRA Scientific Advisory Panel. (2008). “The Agency's Evaluation of the Toxicity Profile of 

Chlorpyrifos.” Report from the FIFRA Scientific Advisory Panel Meeting of September 16-19, 

2008. FIFRA Scientific Advisory Panel, Office of Science Coordination and Policy, Office of 

Prevention, Pesticides and Toxic Substances, U.S. Environmental Protection Agency. 

Washington, DC. Available: http://www.epa.gov/scipoly/sap/meetings/2008/091608_mtg.htm.

FIFRA Scientific Advisory Panel. (2012). “Scientific Issues Associated with Chlorpyrifos”. FIFRA 

Scientific Advisory Panel, Office of Science Coordination and Policy, Office of Prevention, 

Pesticides and Toxic Substances, U.S. Environmental Protection Agency. Washington, DC. 

Available at: http://www.epa.gov/scipoly/sap/meetings/2012/041012meeting.html.

U.S. Environmental Protection Agency. 2006a. Revised Organophosphorous Pesticide Cumulative Risk 

Assessment, July 31, 2006. Office of Pesticide Programs, U.S. Environmental Protection Agency. 

Washington, D.C. Available http://www.epa.gov/pesticides/cumulative/rra-op/ 

Bouchard MF, Chevrier J, Harley KG, Kogut K, Vedar M, Calderon N, et al. Prenatal Exposure to

Organophosphate Pesticides and IQ in 7-Year-Old Children. Environ Health Perspectives. 

2011;119:1189-1195.

Bouchard M.F., Bellinger D.C., Wright R.O., Weisskopf M.G., (2010). Attention-Deficit/Hyperactivity

Disorder and Urinary Metabolites of Organophosphate Pesticides. PEDIATRICS

DOI:10.1542/peds.2009- 3058.

Chen L, Zhao T, Pan C, Ross JH, Krieger RI. (2012) Preformed biomarkers including dialkylphosphates 

(DAPs) in produce may confound biomonitoring in pesticide exposure and risk assessment. J 

Agric Food Chem. 2012 Sep 12;60(36):9342-51. doi: 10.1021/jf303116p. Epub 2012 Sep 4.

Engel SM, Berkowitz GS, Barr DB, Teitelbaum SL, Siskind J, Meisel SJ, Wetmur JG, Wolff MS. 

Prenatal Organophosphate Metabolite and Organochlorine Levels and Performance on the 

Brazelton Neonatal Behavioral Assessment Scale in a Multiethnic Pregnancy Cohort. American 

Journal of Epidemiology. 2007;165:1397-1404.

Engel SM, Wetmur J, Chen J, Zhu C, Barr DB, Canfield RL, Wolff MS. Prenatal Exposure to 

Organophosphates, Paraoxonase 1, and Cognitive Development in Childhood. Environmental 

Health Perspectives. 2011;119:1182-1188. 

Eskenazi B, Harley K, Bradman A, Weltzien E, Jewell NP, Barr DB, Furlong CE, Holland NT. 

Association of in Utero Organophosphate Pesticide Exposure and Fetal Growth and Length of 

Gestation in an Agricultural Population. Environmental Health Perspectives. 2004;115:792–798.

Eskenazi B, Marks AR, Bradman A, Harley K, Barr DB, Johnson C, Morga N, Jewell NP. 

Organophosphate Pesticide Exposure and Neurodevelopment in Young Mexican-American 

Children. Environmental Health Perspectives. 2007;115:792–798.
 

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Fortenberry, GZ, Meeker, JD, Sánchez, BN, Barr, DB, Panuwet, P, Bellinger, D, Schnaas, L, SolanoGonzález, M, Ettingera, AS, Hernandez-Avila, M, Hu, H, Tellez-Rojoj, MM. Urinary 3,5,6-

trichloro-2-pyridinol (TCPY) in pregnant women from Mexico City: Distribution, temporal 

variability, and relationship with child attention and hyperactivity. International Journal of 

Hygiene and Environmental Health 217 (2014): 405–412.

Forsberg ND, Rodriguez-Proteau R, Mab L, Morréc J, Christensen JM, Maierc CS, Jenkins JJ, Anderson

KA. Organophosphorus pesticide degradation product in vitro metabolic stability and timecourse uptake and elimination in rats following oral and intravenous dosing. Xenobiotica, 2011; 

41(5): 422–429. 

Furlong, Melissa A., Engel, Stephanie M., Boyd Barr, Dana, Wolff, Mary S. Prenatal exposure to 

organophosphate pesticides and reciprocal social behavior in childhood. 2014. Environment 

International 70:125-131.

Guodong, Ding, Pei, Wang, Ying, Tian, Jun, Zhang, Yu, Gao, Xiaojin, Wang, Rong, Shi, Guoquan, 

Wang, and Xiaoming, Shen. Organophosphate Pesticide Exposure and Neurodevelopment in 

Young Shanghai Children. Environmental Science and Technology 46:2911-2917, 2012.

Marks AR, Harley K, Bradman A, Kogut K, Barr DB, Johnson C, et al. Organophosphate Pesticide 

Exposure and Attention in Young Mexican-American Children: The CHAMACOS Study. 

Environmental Health Perspectives. 2010;118:1768-1774.

Oulhote, Youssef and Bouchard, Maryse F. Urinary Metabolites of Organophosphate and Pyrethroid 

Pesticides and Behavioral Problems in Canadian Children. Environmental Health Perspectives. 

121:1378-1384 (2013) 

Racke J.D. Degradation of organophosphorous insecticidesin environmental matrices. In: 

Organophosphates Chemistry, Fate and Effects. Academic Press, Inc., San Diego, CA, 1992, pp 

47–72.

Rauh VA, Garfinkel R, Perera FP, Andrews HF, Hoepner L, Barr DB, Whitehead R, Tang D, Whyatt 

RW. Impact of Prenatal Chlorpyrifos Exposure on Neurodevelopment in the First 3 Years of Life 

Among Inner-City Children. Pediatrics. 2006;18(6): 1835-1859.

Rauh V, Arunajadai S, Horton M, Perera F, Hoepner L, Barr DB, et al. 2011. Seven-Year 

Neurodevelopmental Scores and Prenatal Exposure to Chlorpyrifos, a Common Agricultural 

Pesticide. Environmental Health Perspectives. 2011;119:1196-1201.

Shelton, Janie F., Geraghty, Estella M., Tancredi, Daniel J., Delwiche, Lora D., Schmidt, Rebecca J., 

Ritz, Beate, Hansen, Robin L., and Hertz-Picciotto, Irva. Neurodevelopmental disorders and 

prenatal residential proximity to agricultural pesticides: The CHARGE Study. Environmental 

Health Perspectives 122:1103–1109, 2014.

Young JG, Eskenazi B, Gladstone EA, Bradman A, Pedersen L, Johnson C, Barr DB, Furlong CE, 

Holland NT. Association Between In Utero Organophosphate Pesticide Exposure and Abnormal 

Reflexes in Neonates. NeuroToxicology. 2005;26:199–209.

Zhang, Ying, Han, Song, Liang, Duohong, Shi, Xinzhu, Wang, Fengzhi, Wei Liu, Zhang, Li, Chen, Lixin, 

Gu, Yingzi, Tian, Ying. Prenatal exposure to organophosphate pesticides and neurobehavioral 

development of neonates: A birth cohort study in Shenyang, China. PlosOne 47:80–85, 2014.

Zhang X, Driver JH, Li Y, Ross JH, Krieger RI. (2008) Dialkylphosphates (DAPs) in fruits and 

vegetables may confound biomonitoring in organophosphorus insecticide exposure and risk 

assessment. J Agric Food Chem. 2008 Nov 26;56(22):10638-45. doi: 10.1021/jf8018084. 
 

Page 48 of 52

12.0 Appendices

Appendix A. Toxicology Profile 

Appendix B. Physical/Chemical Properties 

Appendix C. International MRLs and U.S. Tolerances

Appendix A. Toxicology Profile

A.1 Toxicology Data Requirements

Use of the new guideline numbers does not imply that 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

no

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

no

yes

yes

yes

yesc

--

no b

870.3700a Developmental Toxicity (rodent) ..................................

870.3700b Developmental Toxicity (non-rodent)...........................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yesc

yes

870.4100a Chronic Toxicity (rodent)..............................................

870.4100b Chronic Toxicity (non-rodent) ......................................

870.4200a Oncogenicity (rat)..........................................................

870.4200b Oncogenicity (mouse) ...................................................

870.4300 Chronic toxicity/Carcinogenicity (rat) ..........................

870.4300 Chronic toxicity/Carcinogenicity (mouse) ....................

yes

yes

yes

yes

yes

yes

yes a

yes a

yes a

yes a

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

no

yes c

yes

yes c

yes c

-

870.7485 General Metabolism......................................................

870.7600 Dermal Penetration........................................................

870.7800 Immunotoxicity .............................................................

yes

yes

yes

yes

no b

yes c

Special Studies Comparative Cholinesterase Assay yes no b
 

Page 49 of 52

a Requirements met by 870.4300.

b HASPOC recommends against waiving (TXR# 0057247)) c HASPOC recommends waiving (TXR# 0057247)

A.2. Toxicity Profiles

Table A.2.1 Acute Toxicity Profile – Chlorpyrifos-methyl

Guideline No. and Study Type MRID1 Results

Toxicity 

Category

81-1 (870.1100) 

Acute Oral Toxicity

48868101 LD50 > 2000 mg/kg III

81.2 (870.1200)

Acute Dermal Toxicity

48868102 LD50 > 5000 mg/kg IV

81.3 (870.1300)

Acute Inhalation Toxicity

48868103 LC50 > 2.48 mg/L IV

81.4 (870.2400)

Acute Eye Irritation

48868104 No irritation IV

81.5 (870.2500)

Acute Dermal Irritation 

48868105 Slight erythema. Resolved in 3/3 rabbits

on days 2-3 after exposure 

IV

81.6 (870.2600)

Skin Sensitization 2

44906901 

44989001

Delayed Contact Hyper-sensitization Study in 

the Guinea Pig [Unacceptable/ not upgradable]

NA

1 MRIDs reviewed 8/13/2012, B. Yurchak, PRD, D403821. 2 The skin sensitization study may be waived according to M. Lewis, 12/4/09 email communication to J. Doherty

NA = Not applicable due to lack of data.

A.3. Sub-chronic, Chronic and Other Toxicity Table for Chlorpyrifos-methyl.

Guideline 

No.

Study Type MRID No./(year)

Classification/Doses

Results

870.3100 90-Day Oral Toxicity, 

rats

44906902,45048301 (1990)

0, 0.1, 1.0, 10.0, 250 

mg/kg/day

NOAEL = 1.0 mg/kg/day

LOAEL = 10.0 mg/kg/day based on inhibition of 

RBC ChE

870.3150 90-Day Oral Toxicity in 

Dogs

44680601 (1990)

0, 0.1, 10.0, 50.0 mg/kg/day

NOAEL = 0.1 mg/kg/day

LOAEL = 10.0 mg/kg/day based on inhibition of 

RBC ChE

870.3700 Prenatal developmental 

toxicity, rats

44680603 (1992)

0, 1, 12.5, 50 mg/kg/day

Maternal 

NOAEL=1.0 mg/kg/day 

LOAEL=12.5 mg/kg/day based on inhibition of 

RBC ChE

Developmental 
 

Page 50 of 52

A.3. Sub-chronic, Chronic and Other Toxicity Table for Chlorpyrifos-methyl.

Guideline 

No.

Study Type MRID No./(year)

Classification/Doses

Results

NOAEL=12.5 mg/kg/day

LOAEL>12.5 mg/kg/day, no effects seen at the 

HDT.

870.3800 Reproductive Toxicity 

and Fertility Effects

45826201 (2002)

0, 1, 3, or 10 mg/kg bw/day

Parental

NOAEL=1.0 mg/kg/day

LOAEL=3.0 mg/kg/day based on microscopic 

lesions in the adrenal glands of F0 females and F1

animals of both sexes

Cholinesterase Inhibition

NOAEL=1.0 mg/kg/day

LOAEL=10.0 mg/kg/day based on RBC ChE 

inhibition (parental males; male and female 

offspring)

Offspring

NOAEL=10 mg/kg/day

LOAEL ≥10 mg/kg bw/day

Reproductive

NOAEL=10 mg/kg/day

LOAEL≥10 mg/kg bw/day

870.4300 Combined chronic 

toxicity/carcinogenicity 

in Rats

42269001 (1991)

0, 0.05, 0.1, 1.0, 50.0 

mg/kg/day

NOAEL=1.0 mg/kg/day

LOAEL=50.0 mg/kg/day based on RBC ChE 

inhibition

870.4300 Chronic 

toxicity/carcinogenicity 

in Mice

44680602 (1988)

0, 1, 5, 50, 500 ppm

NOAEL=0.418/0.403 mg/kg/day (M/F)

LOAEL=4.40/3.94 mg/kg/day (M/F) based on 

RBC ChE inhibition

870.5100 Bacterial reverse 

mutation test

41887601 (1985)

0.1- 10000 microgram/mL

Negative +/- S9 fraction

870.5300 In vitro mammalian cell 

mutation test

00146053

0-32.3 microgram/mL

No evidence of mutagenic effects +/- S9 fraction

870.5375 Chromosomal 

Aberration Assay

00154130 (1985) No evidence of a clastogenic effect in the absence 

of metabolic activation 4 to 40 μg/mL.

In the presence of metabolic activation (S9) and 

at 15 and 50 μg/mL chlorpyrifos-methyl was 

determined to be positive clastogenic in vitro. 

870.5395 In vivo Mouse

Micronucleus Assay

00145108 (1985) No evidence of clastogenic effects at dose levels 

up to 1460 mg/kg

870.5550 Unscheduled DNA 

synthesis in mammalian 

cells in culture

00145107 (1985) Negative

870.7485 Metabolism in rat 00029484 (1971) Following oral administration to rats in corn oil, 

83-85% radiolabel originating from chlorpyrifosmethyl was recovered in the urine, only 7-9% in 

the feces with < 0.5% in the respiratory air at 72 

hours. Produces 3,5,6-trichloro-2-pyridinol (TCP) 

which is conjugated and excreted in the urine.

Peak blood levels were reached in 5 hours after 

dosing.
 

Page 51 of 52

Appendix B. Physical/Chemical Properties 

TABLE B.1. Physicochemical Properties of Chlorpyrifos-methyl. 

Parameter Value Reference

Melting point/range 45.5-46.5 oC

http://pubchem.ncbi.nlm.

nih.gov/ pH NR

Density (23 °C) 1.64 g/mL 

Water solubility (at 25 °C) 4.0 mg/L 

Solvent solubility (20 °C) acetone > 400; methanol 190; hexane 120 (g/kg )

Vapor pressure, mPa (25 °C) 3 mPa (2.25X10-5 mm Hg) 

Dissociation constant, pKa NR

Octanol/water partition coefficient, 

Log(KOW)

4.31

UV/visible absorption spectrum NR

Appendix C. International MRLs and U.S. Tolerances

Chlorpyrifos-methyl (059102):Summary of US and International Tolerances and Maximum Residue Limits 

US Canada Mexico Codex

Residue Definition:

40CFR180.419.

combined residues of the insecticide 

chlorpyrifos-methyl [ O,-O,- dimethyl O -

(3,5,6-trichloro-2-pyridyl)] phosphorothioate 

and its metabolite (3,5,6-trichloro-2-pyridinol)

None None Chlorpyrifos-methyl (fat-soluble). 

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

Commodity US1 Canada Mexico Codex2, 3

Barley, grain 6.0 10 Po3 (proposed)

3 Po (withdrawal recommended)

Cattle, fat 0.5

Cattle, meat 0.5 0.1 (fat) meat (from mammals 

other than marine mammals)

Cattle, meat byproducts 0.5 0.01 edible offal (mammalian)

Egg 0.1 0.01 (*) 

Goat, fat 0.5

Goat, meat 0.5 0.1 (fat) meat (from mammals 

other than marine mammals)

Goat, meat byproducts 0.5 0.01 edible offal (mammalian)

Hog, fat 0.5

Hog, meat 0.5 0.1 (fat) meat (from mammals 

other than marine mammals)

Hog, meat byproducts 0.5 0.01 edible offal (mammalian)

Horse, fat 0.5

Horse, meat 0.5 0.1 (fat) meat (from mammals 

other than marine mammals)

Horse, meat byproducts 0.5 0.01 edible offal (mammalian)
 

Page 52 of 52

Chlorpyrifos-methyl (059102):Summary of US and International Tolerances and Maximum Residue Limits 

US Canada Mexico Codex

Milk, fat (0.05 ppm (N) in 

whole milk 1.25 0.01 (*) milks0.01(*) milk fats

Oat, grain 6.0 10 Po3 (proposed)

Poultry, fat 0.5

Poultry, meat 0.5 0.01 (fat) poultry meat

Poultry, meat byproducts 0.5 0.01 (*) poultry, edible offal of

Rice, grain 6.0

10 Po3 (proposed) 

0.1 rice (withdrawal 

recommended)

Sheep, fat 0.5

Sheep, meat 0.5 0.1 (fat) meat (from mammals 

other than marine mammals)

Sheep, meat byproducts 0.5 0.01 edible offal (mammalian)

Sorghum, grain 6.0 10 Po3

Wheat, grain 6.0 10 Po3 (proposed)

3 Po (withdrawal recommended)

(2) Tolerances are established for the combined 

residues of the insecticide chlorpyrifos-methyl 

(O,-O- dimethyl-O-(3,5,6-trichloro-2-pyridyl) 

phosphorothioate and its metabolite (3,5,6-

trichloro-2-pyridinol) in or on the following 

food commodities when present therein as a 

result of application to stored grains

None Chlorpyrifos-methyl (fat-soluble).

Barley, bran 90

Barley, pearled barley 90

Rice, bran 30

Rice, hulls 30

Rice, polished rice 30

Sorghum, grain, bran 90

Wheat, bran 30 6 PoP3 (proposed)

20 PoP

Wheat, germ 30 5 PoP3 (proposed)

Wheat, middlings 30

Wheat, shorts 30 1 Includes commodities with tolerances currently established in the CFR. 

2 * = 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. 3Commodities with Codex MRLs but without corresponding US tolerances have been excluded. For example, there is a Codex 

MRL of 0.5 mg/kg for apple.