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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

PREVENTION, PESTICIDES AND

TOXIC SUBSTANCES

MEMORANDUM

Date: January 12, 2010

SUBJECT: Chlorpyrifos Methyl. Human Health Assessment Scoping Document in Support of 

Registration Review.

PC Code: 059102 DP Barcode: D370119

Decision No.: 421187 Registration No.: NA

Petition No.: NA Regulatory Action: Registration Review 

Scoping Document

Risk Assessment Type: NA Case No.: 8011

TXR No.: NA CAS No.: 5598-13-0

MRID No.: NA 40 CFR: 40 CFR §180.419

FROM: Danette Drew, Chemist

Seyed Tadayon, Chemist

John Doherty, Toxicologist

Risk Assessment Branch V

Health Effects Division (7509P)

Office of Pesticide Programs

THROUGH: Jack Arthur, Acting Branch Chief

Risk Assessment Branch V

Health Effects Division (7509P)

Office of Pesticide Programs

TO: Katie Weyrauch

Tom Myers

Pesticide Re-evaluation Division (7508P)

 Office of Pesticide Programs

Executive Summary

Chlorpyrifos methyl (CPM) is an organophosphate insecticide limited to post-harvest 

treatment of stored grains or grain storage facilities. Tolerances are established for the 

combined residues of chlorpyrifos methyl and its metabolite 3,5,6-thrichloro-2-pyridinol 

(TCP) on grains (wheat, barley, oats, rice, and sorghum) and livestock commodities. 

Food and feed additive tolerances for grain milled fractions are also established.
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Currently there are no registered uses of CPM that could result in residential exposure or 

exposure from drinking water. Exposure to CPM may occur via food. Occupational 

activities may result in dermal and inhalation exposures.

EPA’s Health Effects Division (HED) has evaluated the available data and the most 

recent human health risk assessments for CPM to determine the scope of work necessary

to support the registration review process. HED considered the current use patterns as 

well as the available toxicity and exposure information for CPM. The primary source for 

the status update was the most recent HED Human Health Risk Assessment conducted 

April 19, 2000 and the Tolerance Reassessment and Risk Management Decision (TRED) 

for CPM issued 12/30/2000 and made final in 2006 as part of the organophosphate (OP)

cumulative risk assessment. 

The purpose of this scoping process is to determine whether sufficient data are available 

to assess the safety of this pesticide, as well as to determine whether any new data have 

been submitted since the last assessment that would necessitate conducting a new human 

health risk assessment to support registration review.

CPM, like other organophosphate pesticides, affects the nervous system by inhibiting the 

activity of cholinesterase (ChE), an enzyme necessary for the proper functioning of the 

nervous system. Inhibition of ChE was the most sensitive effect in all animal species 

evaluated. For all exposure routes and durations, the most recent risk assessments for 

CPM were based on ChE inhibition. In the 2000 assessment, a 10x FQPA factor was

retained for the protection of infants and children to CPM exposures (HED was unable to 

rule out or establish the potential for susceptibility to young based on existing data). In 

2003 HED determined that because CPM is likely to be less toxic than chlorpyrifos 

(CPY), many of the CPY toxicology studies may be bridged to CPM, including the 

results of a CPY DNT study. However, it was determined that the 10x FQPA factor was 

still applicable to CPM in the absence of chemical specific DNT data because it was not 

possible to either establish or rule out the potential for susceptibility from CPM exposure 

based on the weight of the evidence findings for CPY. The requirement for a DNT study 

for CPM has since been waived. Comparative cholinesterase assays (CCAs) with post-natal 

exposures have been shown to provide more sensitive results than DNT studies or from 

studies using in utero only exposures. In lieu of a DNT study, a CCA is required for CPM.

The scoping team has concluded that the only new toxicology data needed at this time to 

support the registration review of CPM are acute toxicity studies [acute oral, acute 

dermal, acute inhalation, primary eye irritation, primary skin irritation; the dermal 

sensitization study may be waived. The technical has been classified as a skin sensitizer 

(TB/HED 1/20/82)], a subchronic inhalation study, an immunotoxicity study, and a nonguideline acute and repeated dose comparative cholinesterase assay (CCA) (see

Appendix 1, DCI rationale tables). The toxicological points of departure (PoDs) may be 

revised after receipt and review of additional toxicity data. A 10x FQPA factor is still 

appropriate at this time and will cover uncertainties remaining because of the lack of a 

CPM CCA study. If the registrant desires to submit the results of a pending CCA study

for CPY (and any other relevant toxicology data for CPY) for bridging to CPM, EPA will 
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examine those data for suitability for bridging and for possible toxicological PoD

selection for CPM.

In the 2000 TRED, additional magnitude of the residue data (aspirated grain fractions)

were identified as outstanding. Those data remain outstanding. The results of these 

studies would not be expected to have a significant impact on the dietary (food) risk 

assessment. However, if the tolerances for livestock commodities increase because of 

higher residues on feedstuffs, the dietary assessment may be revised to reflect those 

residues. 

Refined acute and chronic dietary exposure and risk estimates associated with the 

supported uses of CPM did not exceed HED's level of concern for any population 

subgroup. Because of the use pattern for CPM (on stored grains and inside grain storage 

facilities), residues in water are not anticipated. Therefore, a drinking water exposure 

analysis was not conducted and will not be required under registration review. If acute 

and chronic PoDs are revised, a food only dietary assessment will be performed under 

registration review.

To date, there are no residential uses of CPM; therefore, aggregate risk estimates are 

equivalent to the dietary risk estimates.

The 2000 CPM occupational assessment was based on Reldan 2% and 3% dust products 

and the liquid product Reldan 4E (43% EC) and. Handler exposure estimates were of 

concern for all but one scenario- mixing and loading liquids for direct grain treatment 

using an automated system. In response to those concerns, the registrant requested 

voluntary cancellation of all dust products and agreed to mitigation measures to address 

risks to liquid handlers. Post-application exposures from liquid applications were 

expected to be minimal. A 22% EC replaced the 43%EC and is the only currently 

registered product. The 22% EC has a lower maximum application rate than the 43%EC 

and it was determined that occupational risks would be lower than those for the 43% EC 

(MOEs were not calculated for the 22% EC). The number of bushels treated per day was 

assumed to be 80,000 for the 43% formulation and was assumed to be 26,000 for the 

22%. Under registration review, an occupational assessment should be performed for the 

22% EC (Storcide II) assuming the default 80,000 bushels treated a day along with the 

maximum application rate currently supported. Any changes to the toxicity PoDs will

also be incorporated.

Hazard Identification/Toxicology

At the time of the 2000 HED risk assessment, the toxicity and exposure databases, while 

incomplete, were considered adequate to perform CPM human health risk assessments. 

CPM, like other organophosphate pesticides, affects the nervous system by inhibiting the 

activity of cholinesterase (ChE), an enzyme necessary for the proper functioning of the 

nervous system. Inhibition of ChE was the most sensitive effect in all animal species 

evaluated. All exposure routes and durations in the 2000 HED risk assessment were

based on ChE inhibition.
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The 2000 TRED identified a number of gaps in the CPM database. The Data Call-In

toxicology requirements included acute, subchronic, and developmental neurotoxicity

studies. In lieu of developing data to address the neurotoxicity and other data gaps, the 

registrant decided at that time to voluntarily cancel registered uses (but maintain 

tolerances for import purposes). To address some of the data gaps and allow EPA to 

better characterize the risks associated with CPM during a proposed product phase out 

period, the registrant agreed to provide EPA with an acute delayed neurotoxicity study

and a two-generation rat reproduction study. A two-generation rat study was 

subsequently submitted and reviewed (MRID 45048301; TXR 0051811; 6/04).The study

LOAEL is not expected to have an impact on the current CPM risk assessment. An acute 

delayed neurotoxicity study was not submitted.

In 2003, HED examined the existing toxicity database for the closely related structural 

analog, chlorpyrifos (CPY), and determined that CPM was likely to be less toxic than 

CPY and that toxicity data generated using CPY could be used to address data gaps for 

CPM (memos dated 7/8/2003: D291405 and D289974, TXR 0051734). At that time it 

was determined that the only remaining data gaps for CPM were those gaps for CPY with 

the exception of the acute toxicity test requirements which were required to be performed 

for CPM (acute studies review is under the purview of OPPs Registration Division). The 

current outstanding data for CPY are a comparative ChE assay (CCA) study on both CPY 

and its oxygen analog and an immunotoxicity study (new data requirement under 40 CFR 

Part 158) (memo dated 2/9/09, D361144). An acute delayed neurotoxicity study with 

CPM is no longer a requirement. Additionally, the inhalation studies for CPY did not 

demonstrate a NOAEL and cannot be bridged to CPM. Therefore, a subchronic inhalation 

study should be performed for CPM. HED also concluded in the 2003 memos that CPM 

continue to be regulated using CPM specific endpoints and that the 10x FQPA factor be 

retained in the absence of chemical specific DNT data because it was not possible to 

either establish or rule out the potential for susceptibility from CPM exposure based on 

the weight of the evidence findings for CPY. The endpoint selection table for previous 

risk assessments can be seen in Appendix 2.

For the 2006 cumulative risk assessment, registrants of the organophosphates had the 

option of retaining the 10x FQPA safety factor or provide a comparative cholinesterase 

study. Comparative cholinesterase data were not available for CPM at that time, 

therefore, the 10x FQPA safety factor was retained. This study has not yet been submitted 

for CPM and is now being requested (see Appendix 1, DCI rationale tables). The CCA 

study would provide information on whether juvenile animals are more susceptible to the 

toxicity of CPM than adult animals. Because there is no expected exposure to 

chlorpyrifos methyl oxon in drinking water, on food or to workers, a CCA study with 

chlorpyrifos methyl oxon is not being required at this time. If the registrant desires to 

submit the results of a pending CCA study for CPY for bridging to CPM, EPA will 

examine those data for suitability for bridging and for possible point of departure 

selection for CPM. A developmental neurotoxicity (DNT, OPPTS 870.3700) study is 

waived for CPM. 
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An immunotoxicity study is required as a part of new data requirements in the 40 CFR 

Part 158 (870.7800) for conventional pesticide registration. Because the immune system 

is highly complex, studies not specifically conducted to assess immunotoxic endpoints 

are considered inadequate to characterize a pesticide’s potential immunotoxicity. While 

data from hematology, lymphoid organ weights, and histopathology in routine chronic or 

subchronic toxicity studies may offer useful information on potential immunotoxic 

effects, these endpoints alone are insufficient to predict immunotoxicity. In the absence 

of the required immunotoxicity studies, EPA may use a database uncertainty factor of up 

to10x. An immunotoxicity study on CPM should be conducted (see Appendix 1). Once 

all data have been received and reviewed, the HED Registration Review Team 

recommends that the points of departure and safety factors used for CPM risk 

assessment purposes be reexamined and a new risk assessment performed, if necessary. 

In support of the need for an immunotoxicity study for CPM, although no reports of 

immunotoxicity with this chemical itself were found, there are reports in the open 

literature associating the closely related organophosphate chlorpyrifos (CPY) with 

alterations in the immune system. For example, immunologic abnormalities due to CPY

exposure have been reported in workers (Thrasher, 1993 and Gotoh et al, 2001). In 

laboratory rats, when dosed orally for 28 days, CPY induced immune alterations 

associated with lymphocyte subpopulations (Blakely et al, 1999). Dosing rat pups on 

post-natal days 1-4 or on post-natal days 11-14 subcutaneously in DMSO and testing the 

pups when they became 60 day old adults demonstrated that T-cell responses were 

significantly impaired in a manner implicating an effect on mitogenic activation 

(Navarro et al, 2001). According to one review of the issue of immunotoxicity

associated with the chemical class of organophosphates, immunotoxicity is a concern for 

this class of chemicals in general (Galloway and Handy, 2002). A more recent paper 

Oostingh, et al. 2009) determined that in vitro the immunomodulatory effects of CPY

(and diazinon) were similar for most cytokine promoters and that induction of cellular 

stress enhanced the effect of CPY. Yet another recent paper (Li et al, 2009) 

demonstrated that CPY induces apoptosis in human T cells in vitro. 

Developmental and reproductive toxicity. Prenatal developmental toxicity in rats and 

rabbits and the rat reproduction studies provided no evidence of increased susceptibility

of the fetuses or offspring. There is no developmental neurotoxicity study with CPM. 

The developmental neurotoxicity study with the closely related CPY did not provide clear 

indications of increased quantitative susceptibility in the offspring, although there were 

concerns for qualitative susceptibility in offspring. However, the DNT study together 

with a growing body of studies in the open literature suggest that gestational and early 

postnatal exposure to CPY to pups may result in persistent alterations as indicated by

various assessments of the laboratory animals when they reach adulthood. A summary of 

these studies with CPY from the open literature was prepared for consideration by the 

September 16-18, 2008 Science Advisory Panel (SAP). The SAP (final report dated 

December 17, 2008) did not conclude that there was a non-cholinergic effect responsible 

for any adverse effects and that regulating CPY based on NOAELs for ChE inhibition 

would be protective against developmental effects. Since CPM is so closely related to 

CPY and because HED already recognizes the similarity between CPY and CPM (memos 

dated 7/8/2003: D291405 and D289974, TXR 0051734), HED considers that the 
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conclusions of the SAP regarding possible adverse developmental effects for CPY may

also apply to CPM. 

Subchronic Toxicity. The subchronic feeding study in rats demonstrated a NOAEL and 

LOAEL of 0.1 and 1 mg/kg/day, respectively, based on ChE inhibition. There was slight 

plasma ChE inhibition at 0.1 mg/kg in males. At higher doses, the rats demonstrated 

decreased body weight and gain and urine staining, decreased hair coat condition and 

lacrimation. Adrenal weights were increased along with histological changes 

(hypertrophy, vacuolation and necrosis). Liver weight was also increased with 

indications of hypertrophy. A NOAEL of > 0.1 mg/kg/day (highest dose tested) was 

demonstrated in dogs. There are no acceptable subchronic dermal or inhalation studies 

with CPM although a subchronic dermal study with CPY may be bridged to CPM.

Chronic Toxicity. CPM was evaluated for chronic toxicity in rats and dogs. In all animal 

species, the most sensitive effect is inhibition of plasma, RBC and brain ChE. In the rat, 

the NOAEL and LOAEL for inhibition were established at 0.1 and 1 mg/kg/day,

respectively, but there were no indications of clinical signs. At higher doses in the rat, 

body weight deceases, alterations in the adrenals (increased weight, slight to moderate 

vacuolation with lipid accumulation in the zona fasciculata). The dog chronic feeding 

study demonstrated a NOAEL and LOAEL of 0.1 and 1 mg/kg/day for ChE inhibition. At 

higher doses, there was increased liver weight and indications of increased SGPT and 

SAP). 

Carcinogenicity/Genotoxicity. CPM was evaluated for carcinogenic potential in both rats 

and mice. There was no evidence of carcinogenicity following oral exposure. CPM is not 

mutagenic in in vitro in bacteria (Ames test) or in a CHO/HGPRT mammalian cells tests. 

No evidence of a clastogenic effect was found in either an in vitro cytogenetics test or in 

an in vivo mouse micronucleus test. There was also no evidence of unscheduled DNS 

synthesis. 

Metabolism/Pharmacokinetic Studies. Available studies indicate that CPM is 

metabolized to produce 3,5,6-trichloro-2-pyridinol (TCP) which is conjugated and 

excreted in the urine. Seventy two hours following oral administration in corn oil, 83-

85% radiolabeled originating from CPM was recovered in the urine, only 7-9% in the 

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

found in the fat, muscle, bone and liver). In another study, three hours after 

administration in olive oil, labeled material was found in fat, liver, kidney with a 

“moderate” amount in the adrenal cortex, brain and nerve tissue with low levels in the 

spleen. 

FQPA Considerations. HED recommended that the FQPA factor should be retained at 

10x for the protection of infants and children to exposure resulting from CPM. The 

Hazard Identification Assessment Review Committee (HIARC) could not make a 

determination on the increased susceptibility to infants and children (as required by

FQPA) to CPM due to the inadequate toxicology database (HIARC Document 013377, 

5/17/99). Based on the hazard and exposure data, the HED FQPA Safety Factor 
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Assessment Review Committee determined that the additional 10x factor should be 

retained for acute and chronic dietary risk assessments (FQPA Safety Factor 

Recommendations for the organophosphates, 8/6/98). HED also concluded in 2003 that 

although CPY toxicology data could be bridged to CPM, the 10x FQPA factor be 

retained in the absence of chemical specific (DNT) data for CPM. A DNT study

requirement is waived. A 10x FQPA will cover the uncertainties remaining because of 

the lack of a CPM CCA study. The default 10x interspecies factor and 10x intraspecies

factor are also appropriate for CPM (total UF=1000).

The scoping team has concluded that the only new toxicology data needed at this time to 

support the registration review of CPM are the acute toxicity studies [oral, dermal, 

inhalation, ocular and dermal irritation; the dermal sensitization study may be waived 

according to M. Lewis, email communication 12/4/09.The technical has been classified 

as a skin sensitizer (TB/HED 1/20/82)], a subchronic inhalation study, an immunotoxicity

study, and a non-guideline acute and repeated dose comparative cholinesterase assay

(CCA) (see Appendix 1, DCI rationale tables). The toxicological points of departure 

(PoDs) may be revised after receipt and review of additional toxicity data.

Residue Chemistry and Dietary Assessment

Tolerances are currently established (40 CFR §180.419) for residues of CPM and its 

metabolite TCP in/on barley, oats, rice, sorghum, wheat grain at 6.0 ppm, and in milk, 

eggs, meat and meat-by-products (mbyp) and fat of cattle, goats, hogs, horses, poultry 

and sheep at levels ranging from 0.1 ppm to 1.25 ppm; tolerances for milled grain

fractions (excluding flour) are established at levels ranging from 30 ppm to 130 ppm. 

During the reregistration of CPY, the Agency determined that the metabolite TCP, 

common to both CPY and CPM, is no longer considered to be of toxicological concern; 

HED recommended the removal of TCP from the tolerance expression for CPM (M. 

Flood, 4/29/91 and S.Levy, 11/1/99; D259808). Therefore, tolerances for residues in/on 

plant and animal commodities should be changed to be expressed in terms of parent CPM 

only. Additional previously recommended changes to the tolerances as listed in 40 CFR 

§180.419 are summarized in the Tolerance Assessment and International Harmonization

section of this document and in Appendix 3B.

In the 2000 TRED, additional magnitude of the residue data were required for aspirated 

grain fractions. Those data do not appear to have been submitted to date. The results of 

these studies would not be expected to have a significant impact on the dietary (food) risk 

assessment. However, if the tolerances for livestock commodities increase because of 

higher residues on feedstuffs, the dietary assessment may be revised to reflect those 

residues.

Refined acute and chronic dietary (food only) exposure and risk estimates associated with 

the supported uses of CPM did not exceed HED's level of concern (100% aPAD or 

cPAD) for any population subgroup. Dietary assessments included USDA Pesticide Data 

Program (PDP; 1995-1997) monitoring data for wheat (translated to other grains) and 

milk, as well as processing factors and cooking factors. More recent PDP data (2005-
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2006) for CPM on wheat are available and indicate similar average residue levels on 

wheat grain, but a much lower percentage of samples with detectable residues, compared 

to the values used in the 2000 assessment. For the years 1995 to 1997, average detectable 

residues in wheat were 0.09 ppm to 0.11 ppm and percentage of samples with detects 

were 54% to 73%. For the 2005-2006 data, average detectable residues were 0.11 ppm to 

0.12 ppm and the percentage of samples with detects were 23% and 17%. More recent 

milk and cream data (PDP; 2004-2005, 2007), like the older data, show no detectable 

residues of CPM. If acute and chronic toxicological PoDs are revised, a food only dietary

assessment will be performed under registration review.

Because of the use pattern for CPM (on stored grains and inside grain storage facilities), 

residues in water are not anticipated. Therefore, a drinking water exposure analysis was 

not conducted and will not be required under registration review.

Residential/Aggregate Assessment

To date, there are no residential uses of chlorpyrifos methyl; therefore, aggregate risk 

estimates are equivalent to the dietary estimates and are not of concern.

Occupational Assessment

Chlorpyrifos methyl is an organophosphate insecticide used to protect stored grain, 

including wheat, barley, oats, rice, and sorghum. The current end-use product 

formulation (Storcide II) is a liquid containing 22% CPM. Deltamethrin is also an active 

ingredient in Storcide II. Workers may be exposed to CPM during mixing, loading, and 

applying activities associated with stored grains, bins and warehouses. Based on the 

proposed use patterns, short- and intermediate-term dermal and inhalation exposure are 

expected to occur. The following exposure scenarios were identified for CPM: (1) 

mixing/loading liquid formulation for automated equipment (admixture); (2) 

mixing/loading liquid formulation for hand-held equipment; (3) applying liquid 

formulation by hand wand to grain bins in warehouses. Grain elevator workers are 

known to 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 apply liquid CPM to the walls of empty grain storage 

containers using hand sprayers such as high or low pressure hand wands. 

The 2000 occupational assessment was based on the CPM product Reldan 4E (43% EC) 

and Reldan 2% and 3% dust products. Handler exposure estimates were of concern for all 

but one scenario- mixing and loading liquids for direct grain treatment using an 

automated system. In response to those concerns, the registrant requested voluntary

cancellation of all dust products and agreed to mitigation measures to address risks to 

liquid handlers. Post-application exposures from liquid applications were expected to be 

minimal. The only liquid uses to remain were empty bin treatment with downward spray

from outside bins and direct grain treatment with automated systems.
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Reldan dust formulations were cancelled in 2002. Reldan 4E (43% EC) was cancelled in 

2007. A 22% EC formulation (Storcide) was registered in 2002 and cancelled in 2005. 

The only currently registered formulation is a 22% EC (Storcide II) formulation. The 

22% EC may be applied to stored grains at 0.18 lb a.i/1000 bushels to provide a 

concentration of 3 ppm of CPM on stored grains whereas the 43% EC could be applied at 

0.42 lb ai/1000 bushels to provide 6 ppm CPM on grain.

Wheat is the highest treated commodity, so the rate at which Reldan 4E is applied to 

wheat was used for the 2000 assessment (0.42 lb ai/1000 bushels). The default 

assumption was made that 80,000 bushels are treated in an 8 hour work day. In 2001 for 

the purposes of a Section 18 exemption to use Storcide 22% EC on stored grains, a memo

(D268142; 1/2/2001) compared the handler assumptions between the 43% EC and the 

22% EC. For the 22%EC it was assumed the product is mixed and loaded and 

automatically applied as a spray on grain (0.18 lb ai/1000 bushels) as it travels along a 

conveyer belt. Empty bin wall and floor applications with hand wands assumed 0.0254 

lbs ai/1000ft2and 20 gallons (0.51 lb ai) handled per day. That memo, while it did not 

provide exposure estimates or MOEs, concluded that occupational exposures from 

Storcide 22% would be no higher than exposures from Reldan 43% EC. That memo also 

concluded that the established tolerances for CPM are adequate to support the Storcide 

22% use.

Under registration review, an occupational handler assessment should be performed for 

the 22%EC (Storcide II) assuming the default 80,000 bushels treated a day along with the 

maximum application rate currently supported. Any changes to the toxicity PoDs will 

also be incorporated.

Post-application exposures may include bystander exposure 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 skin exposure is only likely during short exposures for testing of grain, 

maintenance, or other intermittent activities. Bystander dust exposure may be significant 

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.

Public Health and Pesticide Epidemiology Data 

A summary report for incidents of CPM has been provided in the memorandum, 

“Updated Review of Chlorpyrifos Methyl Incident Reports” (D370451, M. Hawkins, 

11/24/09). According to the review, no incidents occurred (were reported) in the United 

States from 2002 to the present for the single chemical CPM. 

Tolerance Assessment and International Harmonization

Tolerances for CPM residues are currently expressed as the combined residues of CPM 

and TCP (3,5,6-trichloro-2-pyridinol) in or on plant and animal commodities [40 CFR 
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§180.419; Appendix 3A]. HED has previously concluded that the U.S. tolerance 

expression should be amended to include only CPM (M. Flood, 4/29/91 and D259808, 

Chlorpyrifos Methyl Residue Chemistry Chapter of the RED, 11/1/99). Accordingly, the

tolerance definition for CPM should be amended to include only parent CPM. 

Several commodity tolerances were reassessed in the 11/1/99 chemistry chapter of the 

RED and a full discussion of those recommendations can be found in that document. In 

summary, tolerances for aspirated grain fractions should be established based on the 

results of the outstanding residue data for aspirated grain fractions. Once those data are 

received, the tolerances for livestock commodities (meat, meat byproducts and milk) 

should also be reassessed. In addition, available data support lowering the tolerances for 

poultry commodities. The tolerances for grain milled fractions (exc. flour) listed 

separately under 40 CFR §185.419 (b) should be revoked concomitant to establishing the 

appropriate tolerances for residues of CPM in processed commodities under 40 CFR 

§180.419. A summary of the CPM tolerance reassessment for the above commodities as 

well as recommended modifications in commodity definitions are presented in Appendix 

3B.

Summary tables of U.S. tolerances (40§CFR180.419) and Codex Maximum Residue 

Limits (MRLs) are provided in Appendix 3C. U.S. tolerances are not harmonized with 

Codex MRLs. [Note: that there have been recent (2009) changes to the Codex MRLs that 

have not yet been finalized and some older Codex recommendations remain pending. 

These items are marked as ‘proposed’ in the Appendix 3C table. Where there have been 

multiple proposals for the same commodity only the most recent proposal has been 

included]. There are no Canadian or Mexican MRLs. Any CPM tolerances reassessed 

during registration review will be considered for possible harmonization with 

international MRLs.

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, will be

considered in the chlorpyrifos methyl human health risk assessment, in accordance with 

U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in 

Minority Populations and Low-Income Populations," 

http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf. The Office 

of Pesticide Programs (OPP) typically considers the highest potential exposures from the 

legal use of a pesticide when conducting human health risk assessments, including, but 

not limited to, people who obtain drinking water from sources near agricultural areas, the 

variability of diets within the U.S., and people who may be exposed when harvesting 

crops. Should these highest exposures indicate potential risks of concern, OPP further 

refines the risk assessments to ensure that the risk estimates are based on the best 

available information.
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Cumulative 

The Food Quality Protection Act (FQPA) requires the Agency to consider the cumulative 

risks of chemicals sharing a common mechanism of toxicity. Chlorpyrifos methyl is a 

member of the organophosphate common mechanism group. The most recent cumulative 

risk assessment for the organophosphates was published on in 2006 and is available at 

http://www.epa.gov/pesticides/cumulative/2006-op/op_cra_main.pdf. No cumulative 

risks of concern for chlorpyrifos methyl were identified in that assessment.

Prior to a final registration review decision for chlorpyrifos methyl, the Agency will 

determine if there is any new information, such as new hazard or exposure data or 

information on changes to the use pattern, which would affect the cumulative risk 

assessment. Should the Agency determine that new information on chlorpyrifos methyl is 

available that could potentially impact the cumulative risk assessment and result in a risk 

of concern, the Agency will revisit the cumulative risk assessment.

Human Studies

The occupational assessments were completed based on the use of the Pesticide Handlers 

Exposure Database (PHED). The PHED has been reviewed from an ethics perspective 

and no issues were found that would preclude its use in the risk assessment process. Two 

toxicity human studies with CPM were considered by the HED (MRID 00030754, 

00043238 and MRID 00030755, 00043239) but were classified as unacceptable for 

technical reasons and were not relied on in the risk assessment.

A human study using CPY was used as part of a weight of the evidence approach for 

determining a dermal absorption factor for CPM (MRID 00124144 and 47918801). This 

study was reviewed by the Human Study Review Board (HSRB June 2009 meeting; final 

report dated 10/26/09) and it was concluded that the data were reliable. The HSRB did 

not find the study to be unethical. If OPP determines any other human studies have 

potential use for future risk assessments, they will need to undergo HSRB review.

Endocrine Disruptor Screening Program

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor 

Screening Program (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.
Page 12 of 21

Between October 2009 and February 2010, EPA is issuing test orders/data call-ins for the 

first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert 

ingredients. This list of chemicals was selected based on the potential for human 

exposure through pathways such as food and water, residential activity, and certain postapplication agricultural scenarios. This list should not be construed as a list of known or 

likely endocrine disruptors.

Chlorpyrifos methyl is not among the group of 58 pesticide active ingredients on the 

initial list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must 

screen all pesticide chemicals. Accordingly, EPA anticipates issuing future EDSP test 

orders/data call-ins for all pesticide active ingredients. 

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

67 chemicals, the test guidelines and the Tier 1 screening battery, please visit the website: 

http://www.epa.gov/endo/.

Data Requirements

Toxicology 

• 870 Series acute toxicity studies (acute oral, acute dermal, acute inhalation, primary eye 

irritation, primary skin irritation). The dermal sensitization study may be waived 

according to M. Lewis, 12/4/09 email communication to J. Doherty.

• 870.3250 Subchronic inhalation study.

• 870.7800 Immunotoxicity (This is a new data requirement under 40 CFR Part 158; see 

Appendix 1)

• Comparative cholinesterase assay (CCA): required for organophosphates including 

chlorpyrifos methyl. This study has not been submitted for chlorpyrifos methyl (see 

Appendix 1).

Residue Chemistry

• 860.1500 Magnitude of the residue data were identified as outstanding in the 2000 

TRED for aspirated grain fractions. Those data remain outstanding. 

Occupational – no data gaps currently identified
Page 13 of 21

Appendix 1

Data Call In Tables

Guideline Number: 870.7800

Study Title: Immunotoxicity

Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the data requirements 

for registration of a pesticide (food and non-food uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional 

immunotoxicity testing and is designed to evaluate the potential of a repeated chemical 

exposure to produce adverse effects (i.e., suppression) on the immune system. 

Immunosuppression is a deficit in the ability of the immune system to respond to a 

challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired 

Respiratory Syndrome (SARS), or neoplasia. Because the immune system is highly 

complex, studies not specifically conducted to assess immunotoxic endpoints are 

inadequate to characterize a pesticide’s potential immunotoxicity. While data from 

hematology, lymphoid organ weights, and histopathology in routine chronic or subchronic 

toxicity studies may offer useful information on potential immunotoxic effects, these 

endpoints alone are insufficient to predict immunotoxicity. 

Practical Utility of the Data

How will the data be used?

Immunotoxicity studies provide critical scientific information needed to characterize 

potential hazard to the human population on the immune system from pesticide exposure. 

Since epidemiologic data on the effects of chemical exposures on immune parameters are 

limited and are inadequate to characterize a pesticide’s potential immunotoxicity in 

humans, animal studies are used as the most sensitive endpoint for risk assessment. These 

animal studies can be used to select endpoints and doses for use in risk assessment of all 

exposure scenarios and are considered a primary data source for reliable reference dose 

calculation. For example, animal studies have demonstrated that immunotoxicity in rodents 

is one of the more sensitive manifestations of TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) 

among developmental, reproductive, and endocrinologic toxicities. Additionally, the EPA 

has established an oral reference dose (RfD) for tributyltin oxide (TBTO) based on 

observed immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Agency's future decision-making?

If the immunotoxicity study shows that the test material poses either a greater or a 

diminished risk than that given in the interim decision’s conclusion, the risk assessments 

for the test material may need to be revised to reflect the magnitude of potential risk 

derived from the new data.

If the Agency does not have these data, a 10X database uncertainty factor may be applied 

for conducting a risk assessment from the available studies.
Page 14 of 21

Guideline Number: Special Study

Study Title: Comparative Cholinesterase Assay (CCA)

Rationale for Requiring the Data

Chlorpyrifos methyl is an organophosphate pesticide (OP) whose mode of toxic action is 

inhibition of the enzyme, acetylcholinesterase (AChE) via phosphorylation of the active 

site leading to accumulation of acetylcholine and to clinical signs of neurotoxicity. The 

detoxifying systems for destroying both the parent and active forms of OPs are less 

developed in the neonatal animals and humans. 

The Agency does not have comparative AChE inhibition studies conducted using 

chlorpyrifos methyl to compare the relative sensitivity of juvenile to adult animals. Thus, 

EPA is seeking a comparative cholinesterase assay for chlorpyrifos methyl. Specifically, 

this study should include both acute (1 day) and repeated (11 days) exposures to pups and 

young adult rats. The acute exposures should be administered to post-natal day 11 (PND 

11) rats and young adults. The repeated exposures should be given for 11 consecutive 

days beginning at PND 11. The chlorpyrifos methyl should be administered directly (e.g., 

gavage). 

Practical Utility of the Data

How will the data be used? 

The new data generated in the CCA study with chlorpyrifos methyl will be used in the 

dietary assessment for chlorpyrifos methyl to account for any additional risks arising from 

exposure to neonatal subjects to chlorpyrifos methyl. 

How could the data impact the Agency’s future decision-making?

The newly generated CCA data could potentially impact the FQPA safety factor in both 

the single chemical and cumulative risk assessments. If the FQPA safety factor changes, 

then this impacts the calculation of the acute and chronic Population Adjusted Doses, and 

therefore may either reduce or increase risk estimates in the dietary assessments for the 

chlorpyrifos methyl and cumulative risk assessments. If the dietary risk is increased 

based on information in the new CCA study, then additional mitigation may be needed to 

address potential risks of concern. If the dietary risk is decreased, then the registrants may 

be able to expand uses.
Page 15 of 21

Appendix 2 

Toxicology Endpoint and Dose Selection

The doses and toxicological endpoints previously selected for use in chlorpyrifos methyl 

assessment:
Page 16 of 21

Appendix 3A

Chlorpyrifos Methyl: U.S. Tolerances (currently)

[Code of Federal Regulations]

[Title 40, Volume 23]

[Revised as of July 1, 2008]

From the U.S. Government Printing Office via GPO Access

[CITE: 40CFR180.419]

 TITLE 40--PROTECTION OF ENVIRONMENT

 CHAPTER I--ENVIRONMENTAL PROTECTION AGENCY (CONTINUED)

PART 180_TOLERANCES AND EXEMPTIONS FROM TOLERANCES FOR PESTICIDE CHEMICALS IN 

 Subpart C_Specific Tolerances

Sec. 180.419 Chlorpyrifos-methyl; tolerances for residues.

 (a) General. (1) 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:

------------------------------------------------------------------------

 Parts per

 Commodity million

------------------------------------------------------------------------

Barley, grain............................................... 6.0

Cattle, fat................................................. 0.5

Cattle, meat................................................ 0.5

Cattle, meat byproducts..................................... 0.5

Egg......................................................... 0.1

Goat, fat................................................... 0.5

Goat, meat.................................................. 0.5

Goat, meat byproducts....................................... 0.5

Hog, fat.................................................... 0.5

Hog, meat................................................... 0.5

Hog, meat byproducts........................................ 0.5

Horse, fat.................................................. 0.5

Horse, meat................................................. 0.5

Horse, meat byproducts...................................... 0.5

Milk, fat (0.05 ppm (N) in whole milk....................... 1.25

Oat, grain.................................................. 6.0

Poultry, fat................................................ 0.5

Poultry, meat............................................... .5

Poultry, meat byproducts.................................... .5

Rice, grain................................................. 6.0

Sheep, fat.................................................. 0.5

Sheep, meat................................................. 0.5

Sheep, meat byproducts...................................... 0.5

Sorghum, grain.............................................. 6.0

Wheat, grain................................................ 6.0

------------------------------------------------------------------------

 (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:
Page 17 of 21

------------------------------------------------------------------------

 Parts per

 Food million

------------------------------------------------------------------------

Barley milling fractions (except flour)...................... 90

Oat milling fractions (except flour)......................... 130

Rice milling fractions (except flour)........................ 30

Sorghum, grain, bran......................................... 90

Wheat milling fractions (except flour)....................... 30

------------------------------------------------------------------------

 (b) Section 18 emergency exemptions. [Reserved]

 (c) Tolerances with regional registrations. [Reserved]

 (d) Indirect or inadvertent residues. [Reserved]

[65 FR 33715, May 24, 2000]
Page 18 of 21

Appendix 3B

Chlorpyrifos Methyl: Reassessed U.S. Tolerances

(11/1/99 HED memo:Chlorpyrifos Methyl Residue Chemistry Chapter of the RED; 

D259808)

Commodity

Current 

Tolerance

(ppm)

Tolerance 

Reassessment 

(ppm)

Comment/Correct Commodity Definition

Tolerances listed under 40 CFR §180.419:

Barley, grain 6.0 6.0

Oats, grain 6.0 6.0

Rice, grain 6.0 6.0

Sorghum, grain 6.0 6.0 Sorghum, grain, grain

Wheat, grain 6.0 6.0

Fat of cattle, goats, hogs, horses, & 

sheep

0.5 TBD1 Residue data on aspirated grain fractions 

derived from treated wheat and sorghum are 

required. Aspirated grain fractions 

contribute significantly to the dietary burden 

for cattle and swine. If significantly higher 

residues are found in wheat or sorghum 

aspirated grain fractions, then a new 

ruminant feeding study may be required. 

Meat and meat byproducts of cattle, 

goats, horses, & sheep

0.5

Hogs, muscle 0.5

Hogs, meat byproducts 0.5

Milk 0.05

Milk, fat 1.25

Poultry, fat 0.5 0.05 Residue data support lowering the tolerances 

established on poultry commodities. Poultry, meat byproducts 0.5 0.01

Poultry, meat 0.5 0.01

Eggs 0.1 0.01

Tolerances listed under 40 CFR §185 and §186.1050:

Barley, milled fractions

(excluding flour)

90.0 Revoke Tolerance should be revoked concomitant 

with establishing a 20 ppm tolerance on 

barley bran.

Oats, milled fractions 130.0 Tolerance should be revoked concomitant 

with establishing a ppm tolerance for oat 

bran.

Rice, milled fractions

(excluding flour)

30.0 Tolerance should be revoked concomitant

with establishing tolerances on rice bran

(12.5 ppm).

Sorghum, milled fractions

(excluding flour)

90.0 Tolerance should be revoked. There are no 

longer any processed commodities of grain 

sorghum considered as food for humans or 

feed for livestock. 

Wheat, milled fractions

(excluding flour)

30.0 Tolerance should be revoked concomitant 

with establishing a tolerance on wheat bran, 

wheat germ and germ oil at 20 ppm.
Page 19 of 21

Commodity

Current 

Tolerance

(ppm)

Tolerance 

Reassessment 

(ppm)

Comment/Correct Commodity Definition

Tolerances needed under 40 CFR §180.419

Aspirated Grain Fractions None TBD1 The available data on corn support a 

tolerance of at least 400 ppm. Additional 

data are required for sorghum and wheat

Barley, bran 90.0 20.0 Concomitant with revoking the tolerance for 

barley milled fractions, a tolerance on barley 

bran should be established

Rice, bran 30.0 12.5 Concomitant with revoking the tolerance for 

rice milled fractions, a tolerance on rice bran

should be established.

Rice, hulls None 25.0 Concomitant with revoking the tolerance for 

rice milled fractions, a tolerance on rice bran

should be established.

Oat, bran None 17.0 Concomitant with revoking the tolerance for 

oat milled fractions, a tolerance on oat,bran 

should be established.

Wheat, bran 30.0 20.0 Concomitant with revoking the food/feed 

additive tolerance for wheat milled fractions, 

a tolerance on wheat,bran should be 

established.

Wheat, germ 30.0 20.0 Concomitant with revoking the food/feed 

additive tolerance for wheat milled fractions, 

a tolerance on wheat,germ should be 

established.

1 TBD = To be determined; i.e., the Agency considers the existing tolerance to be reassessed at 

the current level; however, adequate confirmatory data are warranted and if found lacking, the 

Agency intends to modify or revoke the tolerance.
Page 20 of 21

Appendix 3C

Chlorpyrifos Methyl: Codex Maximum Residue Limits (MRLs)

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 Chlorpyrifosmethyl (fatsoluble). 

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

Commodity US Canada Mexico Codex2, 3

Barley, grain 6.0 None None 3 Po proposed

Cattle, fat 0.5

0.05

(withdrawal 

proposed)

Cattle, meat 0.5 0.05

(0.1 proposed)

Cattle, meat byproducts 0.5 0.05

(0.01 proposed)

Egg 0.1

0.05

(0.01 (*) 

proposed)

Goat, fat 0.5

Goat, meat 0.5

Goat, meat byproducts 0.5

Hog, fat 0.5

Hog, meat 0.5

Hog, meat byproducts 0.5

Horse, fat 0.5

Horse, meat 0.5

Horse, meat byproducts 0.5

Milk, fat (0.05 ppm (N) 

in whole milk 1.25 0.01 (*)

Oat, grain 6.0 10 Po proposed

Poultry, fat 0.5 0.05

Poultry, meat 0.5 0.05

(0.01 proposed)

Poultry, meat 

byproducts 0.5

0.05

(0.01 (*) 

proposed)
Page 21 of 21

Summary of US and International Tolerances and Maximum Residue Limits 

US Canada Mexico Codex

Rice, grain 6.0

0.1

(withdrawal 

proposed)

Sheep, fat 0.5

Sheep, meat 0.5

Sheep, meat byproducts 0.5

Sorghum, grain 6.0 10 Po

Wheat, grain 6.0 10 Po

(3 proposed)

Barley, bran190

Barley, pearled barley190

Rice, bran130

Rice, hulls130

Rice, polished rice130

Sorghum, grain, bran190

Wheat, bran130 20 PoP

(6 proposed)

Wheat, germ130 5 PoP proposed

Wheat, middlings130

Wheat, shorts130

1As a result of application to stored grains.

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.