UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON

, D

. C

. 20460

M EM ORA N D UM

Dat e: September 15

, 2015 OFFICE OF
CHE M ICAL SAFETY AND
POL L UTIO N P REVE N TIO N

SU B JECT : C hl o rp y ripho s

- Meth y l: Human H ealth Dr c!ft R i sk Assessme n t (ORA) for

Re g i s tration Revie w

P C Co d e : 059102

P e titi o n No.: NA

Ri s k Asses sm e nt Ty p e : Single C h e mical Aggregate

TX R No .: NA

MRIDNo.: NA

F RO M: Dan e tte Drew, Chemist/Risk Assessor

Matthew Ll oyd, C I H DP Barcode : 0426738 Regi s tration Nos.: NA

R eg ul at o ry A cti o n : Re g i stra tio n R ev iew

Case No.: NA

C AS No

. : 5598-13-0

40 CFR:**180.419**

William I rwin

, PhD

, DABT

, Toxicolog 1 st

Ronn i e Bever

, PhD

, OABT

, Toxicologist

Risk Assess ment Branch V N II

H ea lth Effects Di v i sion (HED, 7509 P )

TH RO UG H : M i chael Metzger

, Branch Chief

# ~( /J 

# jl I

Risk Assessme nt Branch VNII 

# Mtiv( / ·

H ea lth Effects Divi s i o n ( H EO, 7509 )

And:

T O : Joel Wolf, Chemical Review Manager

Pag e 1 of 52 Risk Management and Impl e m en tation Branch II

P esticide Re- e va l uation Divi s ion ( 7508P )Page 2 of 52 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 Anim al

..................... 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

................................ ................................ ................ 31Page 3 of 52 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

................................ ................................ ......................... 3 6

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

- Occu pational 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 Pesti cide 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

................................ ................................ ... 51Page 4 of 52 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

resul ting 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

- methy l during mixing, loading, and/or applying activities associated with stored grains, bins and warehouses. In general,

o ccupational post

- application exposures are not expected as reentry activities are not anticipated for the registered chlorpyrifos

- methyl u ses

. 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 th e 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

- spec ific 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 assessment s

.

AChE inhibition is the most sensitive endpoint in the chlorpyrifos

- methyl toxicology database in multiple species, dura tions, 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 chlorpyrifos

methyl are based on red blood cell (RBC) Ch EI from oral animal studies. A study measuringPage 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 as sessment 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 l ower than acute PODs

.

F or 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, t here is no comparative

cholinesterase study for chlorpyrifos

- methyl , the study which best measures the potential for increased sensitivity to cho linesterase 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 a pplicable 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 (UF DB ) of 30X (to account for the uncertainty in the human dose

response relationship for neurodeve lopmental effects

, the lack of a CCA study , and lack of a route

specific inhalation stud y ) is applied

. A total UF of 3000X (10X to account for interspecies extrapolation, 10X for intra

- species variation, and 30X UF DB ) 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. t olerances 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 t olerancePage 6 of 52 expression should be amende d to i nclude 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 level s for residues of chlorpyrifos

- methyl (parent compound only) in livestock may be re duced, 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 R isk Assessment

Acute and steady state ( food only ) exp osure and risk assessments were con ducted using the

DEEM

- FCID v3.18 model. The assessment s included the consumption of cereal grain commodities (barley, oats, rice, sorghum and wheat) and livestock comm odities. Drinking water was not included in the dietary assessments; e xposure is not expected from drinking water as chlorpyrifos

- methyl is not expected to enter drinking water sources based on the registered post

harvest and enclosed container uses. The d ietary 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 incorpor ated 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)) f or 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 % ss PAD) for children 1

- 2 and 3

- 5 years of age; the highest expos ed 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 99 th and 95 th percentile of exposures. Consumpti on 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 thePage 7 of 52 current uses; therefore , a quantitative residential handler an d post

- application assessment was not

conducted.

Spray Drift

Based on the current use

- pattern, HED has determined that c hlorpyrifos

- 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 resu lt 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. Chlorpyrifos

methyl 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.

Derm al and inhalation risk estimates were combined since the toxicological effects (RBC AChE) for these exposure routes are the same. T hese routes of exposure are combined using the Combined MOE approach. The level of concern (LOC) is the same (3000) for inha lation and dermal exposures.

Risk concerns were identified for all handler scenarios (combined MOEs <3,000) with label

specified 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

- pre ssure 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/ P ost

- application:

In the case of c hlorpyrifos

- 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 negligi ble during testing of grain, maintenance, or otherPage 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

occup ational 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 por table 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 sit es. 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. Descript ions of data sources, as well as guidance on their use, can be found at the Agency

website 1

.

2.0 HED Recommendations

2.1 Data Deficiencies

Toxicology data required include a comparative cholinesterase assay (non

- guideline study), a

subchronic inhalati on 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 id eal 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/pestici des/science/post

app

- exposure

- data.htmlPage 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

Multir esidue Protocols D and E (PAM I Sections 232.4 and 211.1). In addition, r esidue 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) capab le of determining chlorpyrifos

- methyl only

. While not necessary, i f 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 a nd 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 toler ance 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 recom mended 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 chlorpyr ifos

- 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 pot ential for a higher level of chlorpyrifos

- methyl than the

C odex 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

T olerances 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 fo r “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 expres sion 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 t he 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 definitionPage 10 of 52 should be modified as follows, to be consistent with the Tolerance Expression Guidance issu ed 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 spe cified 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 calcu lation 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 by products may

be re duced 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 p rocessed commodities of barley, rice and wheat may be also be reduced (see T able

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 r esidues of chlorpyrifos

- methyl do not concentrate in polished/milled rice. The tolerance for sorghum, grain, bran should also be revoked

as s orghum bran is not a sorg hum 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 pro cessed commodities under 40 CFR §180.419 (see Table 2.2.3).Page 11 of 52 Table 2.2.3 . Tolerance Summary for Chlorpyrifos

- M ethyl Commodity Established Tolerance (ppm) HED

Recommended 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 MRLPage 12 of 52 Table 2.2.3 . Tolerance Summary for Chlorpyrifos

- M ethyl Commodity Established Tolerance (ppm) HED

Recommended 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

2 0 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 sorghumPage 13 of 52 Table 2.2.3 . Tolerance Summary for Chlorpyrifos

- M ethyl Commodity Established Tolerance (ppm) HED

Recommended 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.

*D 259808, 11/1/99, S. Levy.

3.0 Introduction

3.1 Chemical Identity

TABLE 3.1.1 Chlorpyrifo s

- M ethyl 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 crystallin e 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 K
ow ) 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 s eeds (wheat, barley, oats, rice, and sorghum) and for use on grain storage facilities (bins and warehouses)

.Page 14 of 52 The only currently registered formulatio n is a 21.6 % EC formulation (Stor i cide 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

- M ethyl

.

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

Storicide TM 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] Storicide TM 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 chlorpyrifos

methyl and 0.5 ppm deltamethrin on grain

• Clean and treat storage areas prior to storage of seed 0.02 lbs ai/gallon
[oats]

Storicide TM 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

chl orpyrifos

- methyl during mixing, loading, and /or applying activities associated with stored grains, bins and warehouses

. O ccupational 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 sprayersPage 15 of 52 3.5 Consideration of Environmental Ju stice

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 variet y of consumer subgroups according to well

established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and

activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the National Health and Nutrition Survey/What We Eat in America (NHANES/WWEIA) and are used in pesticide risk as sessments 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 p erformed 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 an d 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 periphe ral 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 ChE I 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 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 

### Target
Tissue

Dose Phosphorylation
of the active site
of AChE Neurotoxicity Accumulation
of acetylcholinePage 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. D ata required include a comparative cholinesterase assay ( a non

- guideline study) t o 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 absorp tion value can be utilized with an oral chlorpyrifos methyl study POD for

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

evaluated

. Only oral ly 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:

• S ub

- chronic oral studies in rat and dog

• Developmental study in rat

• 2

- Generation reproduction stu dy in rat

• Combined chronic toxicity/ carcinogenicity studies in rat and mouse

• Other studies, such as m utagenicity battery, acute 6

- pack, and metabolism stud y

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)

C hlorpyrifos

- 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

.

C hlorpyrifos

- methyl is metabo lized (MRID 0002948 4 ) to produce 3,5,6

- trichloro

- 2

- pyridinol (TCP) which is conjuga ted 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 t he 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 st udies 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,

thes e 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 evalua tion. 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 histopath ology (hypertrophy, vacuolation and necrosis) of the adrenal gland. There are no acceptable sub

- chronic dermal or inhalation studies with chlorpyrifos

- methyl

.

In the rat p renatal developmental toxicity (MRID 44680603) and the rat reproduction stud y (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 develo pmental 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 appar ent 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 NOA EL 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 othe r 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 pu ps, 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/ ca rcinogenicity 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 f or females). There was no evidence of carcinogenic ity 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).

C hlorpyrifos

- 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 ex posure 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, l imited data exist for the temporal effects of chlorpyrifos

- methyl versus dose for

inhibition of cholinesterase. For OPs, the steady state per iod is typically 2

- 3 weeks.

Although there are data at a shorter time per iod 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 scientific ally 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 Agenc y 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

ne urotoxicity. 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 wi th 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, t he 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 Univer sity; 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, 2013 3 ) and concludes they are of high quality. In the three US epidemiology

cohort studies, mothe r

- 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 expo sure (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 Fac tor (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 inclu des consideration of the epidemiological data on any OP pesticide, stud y 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 e t 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, 200 8) 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 exp osure 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.pdfPage 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 degrad ate 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; Wh yatt 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 Regulat ion, 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 degradatesPage 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 exc reted 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 exposu re 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 cohort s (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 studie s. 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 associat ions 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

- 200 9

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 contras t, 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

stu dies.

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). Spec ifically, 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 pervasiv e 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 specif ically chlorpyrifos exposure. Both PDD and reciprocal social responsiveness are related to the autism spectrum disorder. Using a different exposure assessment method (geospatial analysisPage 22 of 52 and residential proximity to total OP exposure), Shelton et al (201 4) 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, an d 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 r ecommendation 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 consi dered (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 individual s 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 AC hE 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 s upport 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

a nd 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 5 2 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

unce rtainties 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 assessme nt 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 n eurodevelopmental 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 child hood, 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 additio nal 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 toxicit y 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.” Gi ven 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

- quantit ative 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, expos ure 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 fromPage 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 S afety 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 stud ies; 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 ne urotoxicity 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 Tox SAC /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;

• Wa iving 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; a nd 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

fol lowing expos ure 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 d iscussed 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 thePage 25 of 52 population subgroups that include infants, children, youths, and women of chi ldbearing age for all exposure scenarios.

4.5.4 Residual Uncertainty in the Exposure Database

T here 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. A lthough 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

Table s 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

- of

evidence 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 susceptibi lity 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

- s pecific 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, t here are onl y steady

- state oral toxicity studies (except acute lethality studies) available for chlorpyrifos

methyl

.

• Consistency across studies: In cases where multiple datasets are available for a single duration, it is important to evaluate the extent to which da ta 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 confiden ce in such values in the steady

state period.

For chlorpyrifos

- methyl , NOAEL s rather than benchmark doses w ere utilized for points of departure because t he 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 NOAELsPage 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 s tate period is reached. The rat developmental study has the same NOAEL as the 90

- day sub

- chronic rat study, thus chlorpyrifos

methyl 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 p rotective

.

For acute dietary exposures a total uncertainty factor (UF) of 3 000X (10X to account for interspecies extrapolation, 10X for intra

- species variation, and a 3 0X for FQPA SF incorporating uncertainty in the human dose

- response relationship for neurodevelopmental effects (see Section 4.4) and the lack of a CCA stud y is applied to the NOAEL to obtain an acute population adjusted dose (aPAD) of 0.00 03 3 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 ChE I . 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 F 0 females and F 1 animals of both sexes

. The reproduction study adul t 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. T he 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 RB C 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 3 000X (10X to account for interspecies extrapolation, 10X for intra

- species variation, and a 30X FQPA SF inco rporating 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 N OAEL (1. 0 mg/kg/day) to obtain a steady

state population adjusted dose (s sPAD ) of 0.0003 3 mg/kg/day for exposure scenarios with infants, children, youth s, 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 ch ronic 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 absorptio n 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 non

occupatio nal, residential exposures to chlorpyrifos

- methyl ) , a total uncertainty factor of 3 000X is

app ropriate [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 s tudy 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 3 000X

is app ropriate [10X for interspecies extrapolation, 10X for intra

- species variation and a 30X database uncertainty factor incorporating uncertainty in the human dose

- response relationship for neurodevelop mental effects (see Section 4.4)

, the lack of a CCA stu dy, 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 Asse ssment RecommendationPage 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 200 5 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 En dpoints 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 Assessmen t

Exposure

Scenario Point of Departure (mg/kg/day) Study and Toxicological

Effects

Acute Dietary

(all populations) NOAEL = 1.0 mg/kg/day

UF A = 10x

UF H = 10x FQPA SF = 30x *

acute PAD = 0.0003 3 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

UF A = 10x

UF H = 10x FQPA SF = 30x *

Steady State PAD = 0.0003 3 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) C hlorpyrifos

- 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. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human po pulation (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) f or 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

- M ethyl 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

UF A = 10x

UF H = 10x

UF DB = 3 0x *

Occupational LOC for MOE =3 000

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

UF A = 10x

UF H = 10x

UF DB = 3 0x * *

Occupational LOC for MOE = 3 000 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

- ob served adverse

- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (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 (UF DB ) 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 (UF DB ) 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 FF DCA, 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 carcinogenicit y, neurotoxicity, developmental reproduct ive, 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 rat es, 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 reregi stration 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 sectio n 408(p), chlorpyrifos

- methyl is subj ect 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 o r wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocri ne effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making t he statutorily required determinations. Tier 1 consists of a battery of 11 scr eening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, o r 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 ho rmonal systems will proceed to the n ext stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify any

adverse endocrine

- related effec ts 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/da ta 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, 2013 6 and includes some pesticides scheduled for reg istration 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 lis ts, 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 M emo: PP 6F3429

, 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 chlorpyrifo s

- 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 cho linesterase 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 Summa ry 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 ter ms of chlorpyrifos

- methyl only and that TCP need not appe ar 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 analo g 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, f rom 2000 to 2010, PDP tested 7,344 food samples (including rice, oats, milk, but ter, 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 f eeding rates. All residues in food are assumed to be parent compound chlorpyrifos

- methyl only. B ased on the

post

- harvest use pattern of chlorpyri f os

- 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: D P# 259808, 11/1/99, S. Levy Dietary Assessment Memo : draft DP# 4269 88, 7/ 15 /15, D. Drew

Tolerances are established for residues of chlorpyrifos

- methyl in grain commodities and also in

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

result of li vestock consuming treated grain commodities

. This section provides the background and current status of residue chemistry requirements for chlorpyrifos

- methyl and includes

residue data submi t ted 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 D 415697 (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 generat ed 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

est ablished 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 l ivestock 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 (LOQPage 33 of 52 for liv estock 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 recom mended 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 i n Section 2.2, Table 2.2.3.)Page 34 of 52 Table 5.2.1. Livestock Dietary Burden for Chlorpyrifos

- M ethyl ( M aximum Reasonably Based Diet)

Feedstuff Type 1 % Dry

Matter 1 % Diet 1 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 5 330 4 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 frac tions (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 t hat

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 Studies 1 with Chlorpyrifos

- M ethyl

. Commodity Feeding Level,

ppm 1 Residue in Tissue, ppm 1 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

- M ethyl 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; e xposure is not expected from drinking waterPage 36 of 52 as chlorpyrifos

- methyl is not expected to enter drinking water sources based on the registered

post

- harve st 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 studi es 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 p rovide an estimate of 21

- day (steady state) average daily food and drinking water exposures. Si nce 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 t han 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 provide s an acceptable est imate of steady state exposure for use in risk assessment and will not

underestimate the risk.

C hlorpyrifos

- methyl dietary risk assessments were performed for the following population

g roups : 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 da ta. 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 a ssumed 100% crop

tr eated (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 diet ary 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 le vel of concern for the children subgroups (and all other population subgroups) at the 99 th and 95 th percentile of exposures. Wheat commodities were the greatest contributor to child dietary exposures.

Consumption of wheat products was the greatest contrib utor to dietary risk estimates for

children.

Table 5.3.3 Results of Acute Dietary (Food) Exposure and Risk Analysis for Chlorpyrifos

- M ethyl

.

Population Subgroup 1 aPAD 2 (mg/kg/day) 95 th Percentile 99 th Percentile 99.9 th 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, yo uth 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 % ss PAD) 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 99 th and 95 th 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

- M ethyl

.

Population Subgroup 1 ssPAD 2 (mg/kg/day) 95 th Percentile 99 th Percentile 99.9 th 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 43Page 38 of 52 1 Population with the greatest exposure is in bold.

2 ss PAD = 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

- M ethyl

.

Population Subgroup 1 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 t his 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 c hlorpyrifos

- 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

Volatili zation 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 Vola tilization 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, r oute

- 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 a ggregated. 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 o f 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 selec tion 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 c hlorpyrifos

- 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 detail ed 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 chem ical

- sp ecific 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 c ase, 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 ne urodevelopmental effects (see Section 4.4)

.

The maximum single application rates on the registered label w ere used to assess the handler exposure scenarios. The amount handled is based on the specific ations 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.

E stimates of dermal and inhalation exposure were calculated for various levels of personal protective equipment ( PPE ) depending on the scenario. The c hlorpyrifos

- methyl product label

direct s mixers, loaders, applicators and other handlers to wear long

- slee ved 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 autom ated 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. Si nce the dermal and inhalation PO Ds are both based on RBC AChE inhibition, thesePage 41 of 52 routes of exposure can be combined (using the combined MOE approach ) for risk as sessment

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 pre sented 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 3 000.

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

- pre ssure 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

Rate a Amount

Handled Dermal Unit Exposure b ,h
( u g/lb ai ) [Mitigation Level] Inhalation

Unit Exposure b (mg/lb ai ) [Mitigation Level] D ermal

Dose c (mg/kg/day) Dermal

MOE d

LOC = 3,000 Inhalation

Dose e (mg/kg/day) Inhalation

MOE f

LOC = 3,000 Total MOE g
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] 0.00 281 360 0.0000165 61

, 000 350

Mixer/Loader/Applicator

Sprays using

M echanically

pressurized

Hand wand Empty grain

bins 0.03 lb ai/gal 500 gal 390 [Baseline ; Gloves] 0.78 [PF5 Respirator] 0.0 838 12 0.00017 5,900 12

390 [Double layer +

g loves] 0.78 [PF5 Respirator] 0.0 624 16 0.00017 5,900 16

Sprays using Manually

pressurized

Hand wand Warehouse 0.03 lb ai/gal 20 gal 8600 [Baseline ; Gloves] 220 [PF5 Respirator] 0.0 739 14 0.00191 520 14

6200 [Double layer ; Gloves] 110 [PF10 Respirator] 0.0 535 19 0.000957 1,000 18

Backpack Sprayer Warehouse 0.03 lb ai/gal 20 gal 8260 [Baseline ; Gloves] 0.516 [PF5 Respirator] 0.0 726 14 0.00000449 220,000 14

8260 [Double layer ; Gloves] 0.516 [PF5 Respirator] 0.0 353 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 assumedPage 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 Advis ory 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

subse quent 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

- a pplication inhalation exposure into the agency's risk assessments.

In the case of c hlorpyrifos

- methyl, bystander exposure may be possible to dusts generated by treated grain being conveyed into, out of or within storage containers, and dermal exposure whe n 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 inh alation 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

expo sure 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 i s 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#42698 9

, 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 Notifi cation 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 o f the health effects attributed to chlorpyrifos

methyl 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.

F rom January 1, 20 10 to May 21, 2015, there were no incidents reported to Main IDS involving the single active ingredient, chlorpyrifos

- methyl

. T her e was one incident reported to Main IDS, involving multiple active ingredients including chlorpyrifos

- methyl and deltamethrin that is classified as moderate severity. F rom January 1, 20 10 to March 18, 2015, there were 13 incidents reported to Aggregate ID S 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 ni ne 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 f acility. 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 admitt ed 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 ca ses 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 i s 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 conti nue 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 comm on 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 cont inue 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 docum ent 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, D 259808

, CHLORPYRIFOS

- METHYL. Pr oduct and Residue Chemistry Chapters of

RED.

M. C ollantes, 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, D40021 0 , Chlorpyrifos methyl. Bridging the Comparativ e Cholinesterase,

Subchronic Inhalation and Immunotoxicity Studies from the Chl orpyrifos (ethyl) Data Base to M eet the Requirements for Chlorpyrifos Methyl.Page 46 of 52 D. Davis, 7/8/20 0 3, D291405.

E. Evans, 6/2/2015, D426989, Chlorpyrifos Methyl : Tier I Revi ew 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 Asses sment

M. Lloyd, 9 / 15 / 2015, D426987, Chlorpyrifos

- methyl. Occupational and Residential Exposure/Risk Assessment for Registration Review.

D. Drew, 8/ 24 /2015, D 415697, 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 Evalua tion of the Toxicity Profile of

C hlorpyrifos.” 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.

FIFR A 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 C hildren. 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/j f303116p. 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 M ultiethnic 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. Environmenta l 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 Popu lation. 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.Page 47 of 52 Fortenberry, GZ, Meeker, JD, Sánchez, BN, Barr, DB, Panuwet, P, Bellinger, D, Schnaas, L, Solano

González, M, Ettingera, AS, Hernandez

- Avila, M, Hu, H, Tellez

- Rojoj, MM. Urinary 3,5,6

- trichloro

- 2

- pyridinol (TCPY) in pregnan t 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, Christe nsen JM, Maierc CS, Jenkins JJ, Anderson KA. Organophosphorus pesticide degradation product in vitro metabolic stability and time

course 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 Organophosphat e 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 E ffects. 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 In ner

- 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 Heal th 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 proxi mity 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 Pe sticide 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 pesticid es 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 organopho sphorus 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

yes c

--

no b

870.3700a Developmental Toxicity (rodent)

................................ .. 870.3700b Developmental Toxicity (non

- rodent)

........................... 870.3800 Reproduction

................................ ................................ . yes

yes

yes yes

yes c

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 bPage 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 MRID 1 Results Toxicity Category

81

- 1 (870.1100)

Acute Oral Toxicity 48868101 LD 50 > 2000 mg/kg III

81.2 (870.1200)

Acute Dermal Toxicity 48868102 LD 50 > 5000 mg/kg IV

81.3 (870.1300)

Acute Inhalation Toxicity 48868103 LC 50 > 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, D 403821.

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

DevelopmentalPage 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 F 0 females and F 1 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)

O ffspring 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 chlorpyrifos

methyl was recovered in the urine, only 7

- 9% in the feces with < 0.5% in the respiratory air at 72

hours. Pr oduces 3,5,6

- trichloro

- 2

- pyridinol (TCP)

which i s 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

h ttp://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 (2 0 °C) acetone > 400; methanol 190; hexane 120 (g/kg )

Vapor pressure , mPa (25 °C) 3 mPa (2.25X10

- 5 mm Hg)

Dissociation constant, pK a NR

Octanol/water partition coefficient, Log(K OW ) 4.31

UV/visible absorption spectrum NR

Appe ndix 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 US 1 Canada Mexico Codex 2

, 3

Barley, grain 6.0 10 Po 3 (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 (*) milks

0.01 (*) milk fats Oat, grain 6.0 10 Po 3 (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 Po 3 (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 Po 3

Wheat, grain 6.0 10 Po 3 (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 PoP 3 (proposed)

20 PoP Wheat, germ 30 5 PoP 3 (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.

3 Commodities 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.