Page 1 of 21 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES

MEMORANDUM Date: January 12 , 2010
SUBJECT: Chlorpyrifos Methyl. Human Health Assessment Scop ing Document in Support of

Registration Review

. PC Code: 059102 DP Barcode: D370119 Decision No.: 421187 Re gistration No. : NA Petition No
. : NA Regulatory Action: Registration Review Scoping Document Risk A ss essment Type : NA Case No.: 8011 T XR No.: NA CAS No.: 5598

- 13

- 0 MRID No . : NA 40 CFR: 40 CFR §180.419

FROM: Danette Drew, Chemist

Seyed Tadayon, Chemist John Doherty , Toxicologist Risk Assessment Branch V Health Effects Division (7509P) Office of Pesticide Programs THROUGH: Jack Arthur , Acting Branch Chief

Risk Assessment Branch V Health Effects Division (7509P) Office of Pesticide Programs
TO: Katie Wey

rauch Tom Myers Pesticide Re

- evaluation Division (7508P) Office of Pesticide Programs Executive Summary Chlorpy rifo s methyl (CPM) is an organophosphate insecticide limited to post

- harvest treatment of stored grains or grain storage facilities

. Tolerances are established for the combined residues of chlorpy rifos methyl and its metabolite 3,5,6

- thrichloro

- 2

- py ridinol ( TC P ) on grains (wheat, barley , oats, rice, and sorghum) and livestock commodities

. Food and feed additive tolerances for grain milled fractions are also established.Page 2 of 21

Currently there are no registered uses of CPM that could result in residential exposure or e xposure from drinking water. Exposure to CPM may occur via food. Occupational activities may

result in dermal and inhalation exposures. EPA’s Health Effects Division (HED) has evaluated the available data and the most recent human health risk assessments for CPM to determine the scope of work necessary to support the registration review process. HED considered the current use patterns as well as the available toxicity and exposure information for CPM . The primary source for the status update was the most recent HED Human Health Risk Assessment conducted April 19, 2000 and the Tolerance Reassessment and Risk Management Decision ( T RED) for CPM issued 12 / 30/200 0 and made final in 2006 as part of the organophosphate (OP) cumulative risk assessment

. The pur pose of this scoping process is to determine whether sufficient data are available to assess the safety of this pesticide, as well as to determine whether any new data have been submitted since the last assessment that would necessitate conducting a new hu man health risk assessment to support registration review.
CPM , like other organophosphate pesticides, affects the nervous s ys tem by inhibiting the activity of cholinesterase (ChE), an enz ym e necessary for the proper functioning of the nervous s ys tem. Inh ibition of ChE was the most sensitive effect in all animal species evaluated. For all exposure routes and durations, the most recent risk assessments for CPM were based on ChE inhibition

. Inthe 2000 assessment, a 10x FQPA factor was retained for the prote ction of infants and children to CPM exposures ( HED was unable to rule out or establish the potential for susceptibility to young based on existing data). In 2003 HED determined that because CPM is likely to be less toxic than chlorpy rifos (CPY), many

of the CPY toxicology

studies may be bridged to CPM , including the results of a CPY DNT study . However, it was determined that the 10x FQPA factor was still applicable to CPM in the absence of chemical specific DNT data because it was not possible to either establish or rule out the potential for susceptibility from CPM exposure based on the weight of the evidence findings for CPY. The requirement for a DNT study for CPM has since been waived. Comparative cholinesterase assays (CCAs) with post

- natal exposures have been shown to provide more sensitive results than DNT studies or from studies using in utero only exposures. In lieu of a DNT study, a CCA is required for CPM. The scoping team has concluded that the onl y new toxicology data needed at this time to s upport the registration review of CPM are acute toxicity studies [ acute oral, acute dermal, acute inhalation, primary eye irritation, primary

skin irritation ; the dermal sensitization study may

be waived. T he technical has been classified as a skin sensiti zer (TB/HED 1/20/82 ) ] , a subchronic inhalation study, an immunotoxicity study , and a non

guideline acute and repeated dose comparative cholinesterase assay (CCA) (see Appendix 1, DCIrationale tables). The toxicological points of departure (PoDs) may be re vised after receipt and review of additional toxicity data. A 10x FQPA factor is still appropriate at this time and will cover uncertainties remaining because of the lack of a CPM CCA study

. If the registrant desires to submit the results of a pending CCA study for CPY (and an y other relevant toxicology data for CPY) for bridging to CPM, EPA willPage 3 of 21

examine those data for suitability for bridging and for possible toxicological PoD selection for CPM. In the 2000 TRED, additional magnitude of the residue data ( aspirated grain fractions) were identified as outstanding . Those data remain outstanding. The results of these studies would not be expected to have a significant impact on the dietary (food) risk assessment. However, if the tolerances for livestock commodities increase because of higher residues on feedstuffs, the dietary assessment may

be revised to reflect those residues. Refined acute and chronic dietary exposure and risk estimates associated with the supported uses of CPM did not exceed HED's level o f concern for any population subgroup. Because of the use pattern for CPM (on stored grains and inside grain storage facilities), residues in water are not anticipated. Therefore, a drinking water exposure anal ys is was not conducted and will not be require d under registration review. If acute and chronic PoDs are revised, a food onl y dietary assessment will be performed under registration review. To date, there are no residential uses of CPM ; therefore, aggregate risk estimates are equivalent to the dietary risk estimates

. The 2000 CPM occupational assessment was based on Reldan 2% and 3% dust products and the liquid product Reldan 4E (43% EC) and. Handler exposure estimates were of concern for all but one scenario

- mixing and loading liquids for direct grain treatment using an automated s ys tem. In response to those concerns, the registrant requested voluntary cancellation of all dust products and agreed to mitigation measures to address risks to liquid handlers. Post

- application exposures from liquid appli cations were expected to be minimal. A 22% EC replaced the 43%EC and is the only currentl y registered product. The 22% EC has a lower maximum application rate than the 43%EC and it was determined that occupational risks would be lower than those for the 43 % EC (MOEs were not calculated for the 22% EC ). The number of bushels treated per day was assumed to be 80,000 for the 43% formulation and was assumed to be 26,000 for the 22%. Un d er registration review, an occupational assessment should be performed for the 22% EC (Storcide II) assuming the default 80,000 bushels treated a day along with the maximum application rate currently supported. Any changes to the toxicity PoDs w ill also be incorporated.
H azard Identification/Toxicology At the time of the 2000 HE D risk assessment, the toxicity and exposure databases , while incomplete, were considered adequate to perform CPM human health risk assessments. CPM , like other organophosphate pesticides, affects the nervous s ys tem by inhibiting the activity of cholineste rase (ChE), an enz ym e necessary for the proper functioning of the nervous s ys tem. Inhibition of ChE was the most sensitive effect in all animal species evaluated. A ll exposure routes and durations in the 2000 HED risk assessment were based on ChE inhibitio n
.Page 4 of 21

The 2000 TRED identified a number of gaps in the CPM database. The Data Call

- In toxicology requirements included acute, subchronic, and developmental neurotoxicity studies

. Inlieu of developing data to address the neurotoxicity and other data gaps, th e registrant decided at that time to voluntarily cancel registered uses (but maintain tolerances for import purposes) . To address some of the data gaps and allow EPA to better characterize the risks associated with CPM during a proposed product phase out p eriod, the registrant agreed to provide EPA with an acute delayed neurotoxicity study and a two

- generation rat reproduction study. A two

- generation rat study was subsequently submitted and reviewed (MRID 45048301; TXR 0051811 ; 6/04 ).The study LOAE L is not expected to have an impact on the current CPM risk assessment. An acute delayed neurotoxicity

study was not submitted. In 2003, HED examined the existing toxicity database for the closel y related structural analog, chlorp yrifos (CPY) , and determined that C PM was likely to be less toxic than CPY and that toxicity

data generated using CPY could be used to address data gaps for CPM (memos dated 7/8/2003: D291405 and D289974, TXR 0051734) . At that time it was determined that the only remaining data gaps for CPM were those gaps for CPY with the exception of the acute toxicity test requirements which were required to be performed for CPM ( acute studies review is under the purview of OPPs Registration Division). The current outstanding data for CPY are a comparativ e ChE assay (CCA) study

on both CPY and its oxygen analog and an immunotoxicity study (new data requirement under 40 CFR Part 158) (memo dated 2/9/09, D361144). An acute delayed neurotoxicity study with CPM is no longer a requirement. Additionally , the inhalation studies for CPY did not demonstrate a NOAEL and cannot be bridged to CPM. Therefore, a subchronic inhalation study should be performed for CPM. HED also concluded in the 2003 memos that CPM continue to be regulated using CPM specific endpoints and that the 10x FQPA factor be retained in the absence of chemical specific DNT data because it was not possible to either establish or rule out the potential for susceptibility from CPM exposure based on the weight of the evidence findings for CPY. The endp oint selection table for previous risk assessments can be seen in Appendix 2

. For the 2006 cumulative risk assessment, registrants of the organophosphates had the option of retaining the 10x FQPA safety factor or provide a comparative cholinesterase study

. Comparative cholinesterase data were not available for CPM at that time, therefore, the 10x FQPA safety factor was retained. This study has not yet been submitted for CPM and is now being requested (see Appendix 1, DCI rationale tables). The CCA study w ou ld provide information on whether juvenile animals are more susceptible to the toxicity o f CPM than adult animals. Because there is no expected exposure to chlorpy rifos methyl oxon in drinking water , on food or to workers, a CCA study w ith chlorpy rifos me thyl oxon is not being required at this time. If the registrant desires to submit the results of a pending CCA study f or CPY for bridging to CPM, EPA will examine those data for suitability f or bridging and for possible point of departure selection for CPM

. A developmental neurotoxicity ( DNT, OPPTS 870.3700) study i s waived for CPM.Page 5 of 21

An immunotoxicity

study is required as a part of new data requirements in the 40 CFR Part 158 (870.7800) for conventional pesticide registration

. Because the immune sy stem is highly complex, studies not specificall y conducted to assess immunotoxic endpoints are considered i nadequate to characterize a pesticide’s potential immunotoxicity . While data from hematology , l ymphoid organ weights, and histopathology in routine chronic or subchronic toxicity

studies may

offer useful information on potential immunotoxic effects, these endpoints alone are insufficient to predict immunotoxicity . In the absence of the required immunotoxicity studies, EPA may use a database uncertainty fac tor of up to10 x . An immunotoxicity study on CPM should be conducted (see Appendix 1 )

. Once all data have been received and reviewed, the HED Registration Review Team recommends that the points of departure and safety factors used for CPM risk assessment p urposes be reexamined and a new risk assessment performed , if necessary

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

with this chemical itself were found, there are reports in the open literature associ ating the closely related organophosphate chlorp yrifos ( CPY ) with alterations in the immune sy stem. For example, immunologic abnormalities due to CPY exposure have been reported in workers (Thrasher, 1993 and Gotoh et al, 2001). In laboratory

rats, when d osed orall y for 28 days, CPY induced immune alterations associated with l ymphocy te subpopulations (Blakely et al, 1999). Dosing rat pups on post

- natal day s 1

- 4 or on post

- natal day s 11

- 14 subcutaneousl y in DMSO and testing the pups when they

became 60 day old adults demonstrated that T

- cell responses were significantl y impaired in a manner implicating an effect on mitogenic activation (Navarro et al, 2001). According to one review of the issue of immunotoxicity associated with the chemical class of organophosphates, immunotoxicity is a concern for this class of chemicals in general (Galloway and Handy , 2002). A more recent paper Oostingh, et al. 2009) determined that in vitro the immunomodulatory effects of CPY (and diazinon) were similar for most cy tokin e promoters and that induction of cellular stress enhanced the effect of CPY . Yet another recent paper (Li et al, 2009) demonstrated that CPY induces apoptosis in human T cells in vitro. Developmental and reproductive toxicity. Prenatal developmental to xicity in rats and rabbits and the rat reproduction studies provided no evidence of increased susceptibility of the fetuses or offspring. There is no developmental neurotoxicity study with CPM

. The developmental neurotoxicity study with the closely

relate d CPY did not provide clear indications of increased quantitative susceptibility in the offspring, although there were concerns for qualitative susceptibility in offspring. However, the DNT study together with a growing body of studies in the open literature suggest that gestational and earl y postnatal exposure to CPY to pups may result in persistent alterations as indicated by various assessments of the laboratory animals when they reach adulthood. A summary of these studies with CPY from the open literature was prepared for consideration by the September 16

- 18 , 2008 S cience A dvisory P anel (SAP)

. The SAP (final report dated December 17, 2008) did not conclude that there was a non

- cholinergic effect responsible for an y adverse effects and that regulating CPY based on NOAE Ls for ChE inhibition would be protective against developmental effects. Since CPM is so closely related to CPY and because HED already recognizes the similarity between CPY and CPM (memos dated 7/8/2003: D291405 and D289974, TXR 0051734) , HED considers that thePage 6 of 21

conclusions of the SAP regarding possible adverse developmental effects for CPY may also apply

to CPM

. Subchronic Toxicity

. The subchronic feeding study in rats demonstrated a NOAEL and LOAEL of 0.1 and 1 mg/kg/day , respectively , based on ChE inhibition. There was slight plasma ChE inhibition at 0.1 mg/kg in males. At higher doses, the rats demonstrated decreased body weight and gain and urine staining, decreased hair coat condition and lacrimation. Adrenal weights were increa sed along with histological changes (hy pertrophy , vacuolation and necrosis). L iver weight was also increased with indications of hy

pertrophy . A NOAEL of > 0.1 mg/kg/day (highest dose tested) was demonstrated in dogs. There are no acceptable subchronic d ermal or inhalation studies with CPM although a subchronic dermal study with CPY may

be bridged to CPM. Chronic Toxicity. CPM was evaluated for chronic toxicity in rats and dogs. Inall animal species, the most sensitive effect is inhibition of plasma, RBC and brain ChE . In the rat, the NOAEL and LOAEL for inhibition were established at 0.1 and 1 mg/kg/day , respectivel y, but there were no indications of clinical signs. At higher doses in the rat, body weight deceases, alterations in the adrenals (incre ased weight, slight to moderate vacuolation with lipid accumulation in the zona fasciculata). The dog chronic feeding study demonstrated a NOAELand LOAEL of 0.1 and 1 mg/kg/day for ChE inhibition. At higher doses, there was increased liver weight and indications of increased SGPT and SAP). Carcinogenicity/Genotoxicity. CPM was evaluated for carcinogenic potential in both rats and mice. There was no evidence of carcinogenicity following oral exposure. CPM is not mutagenic in in vitro in bacteria (Ames test) or in a CHO/HGPRT mammalian cells tests. No evidence of a clastogenic effect was found in either an in vitro cy togenetics test or in an in vivo mouse micronucleus test. There was also no evidence of unscheduled DNS sy nthesis. Metabolism/Pharmac okinetic Studies
. Available studies indicate that CPM is metabolized to produce 3,5,6

- trichloro

- 2

- py ridinol (TCP) which is conjugated and excreted in the urine. Seventy two hours following oral administration in corn oil, 83

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

- 9% in the feces with < 0.5% in the respiratory air. The carcass retained 0.65 to 1.3% with label found in the fat, muscle, bone and liver). In another study , three hours after administration in olive oil, labe led material was found in fat, liver, kidney with a “moderate” amount in the adrenal cortex, brain and nerve tissue with low levels in the spleen. FQPA Considerations. HED recommended that the FQPA factor should be retained at 10 x for the protection of infants and children to exposure resulting from CPM

. The Hazard Identification Assessment Review Committee (HIARC) could not make a determination on the increased susceptibility to infants and children (as required by FQPA) to CPM due to the inadequate to xicology database (HIARC Document 013377, 5/17/99). Based on the hazard and exposure data, the HED FQPA Safety FactorPage 7 of 21

Assessment Review Committee determined that the additional 10x factor should be retained for acute and chronic dietary risk assessments (F QPA Safety Factor Recommendations for the organophosphates, 8/6/98). HED also concluded in 2003 that although CPY toxicology data could be bridged to CPM, the 10x FQPA factor be retained in the absence of chemical specific (DNT) data for CPM. A DNT study requirement is waived. A 10 x FQPA will cover the uncertainties remaining because of the lack of a CPM CCA study

. The default 10x interspecies factor and 10x intraspecies factor are also appropriate for CPM (total UF=1000). The scoping team has concluded that the onl y new toxicology data needed at this time to support the registration review of CPM are the acute toxicity studies [ oral, dermal, inhalation, ocular and dermal irritation ; the dermal sensitization study may be waived according to M . Lewis, email communication 1 2/4/ 09.T he technical has been classified as a skin sensitizer (TB/HED 1/20/82 ) ] , a subchronic inhalation study , an immunotoxicity study , and a non

- guideline acute and repeated dose comparative cholinesterase assay (CCA) (see Appendix 1, DCI rationale tables). The toxicological points of departure (PoDs) may

be revised after receipt and review of additional toxicity data. Residue Chemistry and Dietary Assessment
T olerances are currentl y established (40 CFR §180.419) for residues of CPM and its metabolite TCP in/on barley , oats, rice, sorghum, wheat grain at 6.0 ppm, and in milk, eggs, meat and meat

- by

- products (mb yp) and fat of cattle, goats, hogs, horses, poultry and sheep at levels ranging from 0.1 ppm to 1.25 ppm; tolerances for milled gr ain fractions (excluding flour) are established at levels ranging from 30 ppm to 130 ppm. During the reregistration of CPY, the Agency determined that the metabolite TCP, common to both CPY and CPM, is no longer considered to be of toxicological concern; H ED recommended the removal of TCP from the tolerance expression for CPM (M. Flood, 4/29/91 and S.Levy , 11/1/99; D259808). Therefore, tolerances for residues in/on plant and animal commodities should be changed to be expressed in terms of parent CPM only

. Additional previously recommended changes to the tolerances as listed in 40 CFR §180.419 are summarized in the Tolerance Assessment and International Harmonization section of this document and in Appendix 3B. In the 2000 TRED, additional magnitude of the residue data were required for aspirated grain fractions. Those data do not appear to have been submitted to date. The results of these studies would not be expected to have a significant impact on the dietary (food) risk assessment. However, if the tolerances for livestock commodities increase because of higher residues on feedstuffs, the dietary assessment may

be revised to reflect those residues. Refined acute and chronic dietary (food only) exposure and risk estimates associated with the supported uses of CPM did not exceed HED's level of concern (100% aPAD or cPAD) for any

population subgroup. Dietary assessments included USDA Pesticide Data Program (PDP ; 1995

- 1997 ) monitoring data for wheat (translated to other grains) and milk, as well as processing factors and cooking factors. More recent PDP data ( 2005

-Page 8 of 21

2006) for CPM on wheat are available and indicate similar average r esidue levels on wheat grain , but a much lower percentage of samples with detectable residues, compared to the values used in the 200 0 assessment . For the years 1995 to 1997, average detectable residues in wheat were 0.09 ppm to 0.11 ppm and percentage of samples with detects were 54% to 73%

. For the 2005

- 2006 data, average detectable residues were 0.11 ppm to 0.12 ppm and the percentage of samples with detects were 23% and 17%. More recent milk and cream data (PDP; 2004

- 2005, 2007) , like the older data, show no detectable residues of CPM

. If acute and chronic toxicological PoDs are revised, a food only dietary assessment will be performed under registration review. Because of the use pattern for CPM (on stored grains and inside grain storage facilities), residues in water are not anticipated. Therefore, a drinking water exposure anal ys is was not conducted and will not be required under registration review. Residential/Aggregate Assessment To date, there are no residential uses of chlorp yri fos methyl ; therefore, aggregate risk estimates are equivalent to the dietary estimates and are not of concern. Occupational Assessment Chlorpy rif os methyl is an organophosphate insecticide used to protect stored grain, including wheat, barley , oats, rice, and sorghum. The current end

- use product formulation (Storcide II) is a liquid containing 2 2 % CPM . Deltamethrin is also an active ingredient in Storcide II. Workers may be exposed to CPM during mixing, loading, and applying activities associated with stored grains, bins and warehouses. Based on the proposed use patterns, short

- and intermediate

- term dermal and inhalation exposure are expected to occur. The following exposure scenarios were identified for CPM : (1) mixing/loading liquid formulation for automated equipment (admixture); (2) mixing/loading liquid formulation for hand

- held equipment; (3) applying liquid formulation by

hand wand to grain bins in warehouses. Grain elevator workers are known to apply

this product in liquid form to a moving stream of grain (i.e., conveyor or auger) using automated equipment. Only mixing and loading are expected to contribute significantl y to worker expos ure when using an automated process. Grain storage workers and farm workers also apply liquid CPM to the walls of empty grain storage containers using hand sprayers such as high or low pressure hand wands. The 2000 occupational assessment was based on the CPM product Reldan 4E ( 43% EC) and Reldan 2% and 3% dust products. Handler exposure estimates were of concern for all but one scenario

- mixing and loading liquids for direct grain treatment using an automated sy stem. In response to those concerns, the registrant requested voluntary cancellation of all dust products and agreed to mitigation measures to address risks to liquid handlers. Post

- application exposures from liquid applications were expected to be minimal. The only

liquid uses to remain were emp ty bin treatment with downward spray from outside bins and direct grain treatment with automated sy stems.Page 9 of 21

Reldan dust formulations were cancelled in 2002. Reldan 4E (43% EC) was cancelled in 2007. A 22% EC formulation (Storcide) was registered in 2002 an d cancelled in 2005. The only currently registered formulation is a 22% EC (Storcide II) formulation . The 22% EC may

be applied to stored grains at 0.18 lb a.i/1000 bushels to provide a concentration of 3 ppm of CPM on stored grains whereas the 43% EC coul d be applied at 0.42 lb ai/1000 bushels to provide 6 ppm CPM on grain. Wheat is the highest treated commodity , so the rate at which Reldan 4E is applied to wheat was used for the 2000 assessment (0.42 lb ai/1000 bushels). The default assumption was made that 80,000 bushels are treated in an 8 hour work day . In 2001 for the purposes of a Section 18 exemption to use Storcide 22% EC on stored grains, a memo (D268142; 1/2/2001) compared the handler assumptions between the 43% EC and the 22% EC. For the 22%EC it was assumed the product is mixed and loaded and automatically

applied as a spray

on grain (0.18 lb ai/1000 bushels) as it travels along a conveyer belt. Empty

b in wall and floor applications with hand wands assumed 0.0254 lbs ai/1000ft2 and 20 gallons (0.51 lb ai) handled per day

. That memo, while it did not provide exposure estimates or MOEs, concluded that occupational exposures from Storcide 22% would be no higher than exposures from Reldan 43% EC

. That memo also concluded that the established tolerances for CPM are adequate to support the Storcide 22% use. Under registration review, an occupational handler assessment should be performed for the 22%EC (Storcide II) assuming the default 80,000 bushels treated a day along with the maximum application rate currently supported. Any changes to the toxicity PoDs will also be incorporated.
Post

- application exposures may include by stander exposure to dusts generated by treated grain being conveyed into, out of or within storage containers, and dermal exposure when sampling treated grain. Personnel rarel y have direct contact with the stored grain and therefore skin exposure is only likely during short exposures for testing of grain, maintenance, or other intermittent activities. By stander dust exposure may be significant for either the employee of a grain elevator or farmer/operator who operates a portable auger to load treated grain into a bin but there are no data available to quantify these exposures. Public Health and Pesticide Epidemiology Data A summary

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

“Updated Review of Chlorpy rifos Methyl Incident Reports ” ( D370451, M. Hawkins, 11/24/09). According to the review, no incidents occurred (were reported) in the United States from 2002 t o the present for the single chemical CPM.
Tolerance Assessment and International Harmonization Tolerances for CPM residues are currently expressed as the combined residues of CPM and TCP ( 3,5,6

- trichloro

- 2

- py ridinol) in or on plant and animal commoditi es [40 CFRPage 10 of 21

§180.419; Appendix 3A]. HED has previously concluded that the U.S. tolerance expression should be amended to include onl y CPM (M. Flood, 4/29/91 and D259808, Chlorpy rifos Meth ylResidue Chemistry Chapter of the RED, 11/1/99). Accordingl y, the tolerance definition for CPM should be amended to include only parent CPM. Several commodity

tolerances were reassessed in the 11/1/99 chemistry chapter of the RED and a full discussion of those recommendations can be found in that document. In summary , tolerances for aspirated grain fractions should be established based on the results of the outstanding residue data for aspirated grain fractions. Once those data are received, the tolerances for livestock commodities (meat, meat b yproducts and milk) sho uld also be reassessed. In addition, available data support lowering the tolerances for poultry commodities. T he tolerances for grain milled fractions (exc. flour) listed separately under 40 CFR §185.419 (b) should be revoked concomitant to establishing the appropriate tolerances for residues of CPM in processed commodities under 40 CFR §180.419. A summary

of the CPM tolerance reassessment for the above commodities as well as recommended modifications in commodity definitions are presented in Appendix 3 B

. Summary tables of U

. S

. tolerances ( 40 § CFR180.419) and Codex Maximum Residue Limits (MRL s ) are provided in Appendix 3 C

. U

. S

. tolerances are not harmonized with Codex MRL s
. [Note: that there have been recent (2009) changes to the Codex MRL s that have not yet been finalized and some older Codex recommendations remain pending. These items are marked as ‘proposed’ in the Appendix 3C table. Where there have been multiple proposals for the same commodity onl y the most recent proposal has been included]. There are no Canadian or Mexican MRL s
. An y CPM tolerances reassessed during registration review will be considered for possible harmonization with international MRL s. Environmental Justice Potential areas of environmental justice concerns, to the extent possib le, w ill be considered in the chlorpyrifos methyl human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf . The Office of Pesticide Programs (OPP) ty pically considers the highest potential exposures from the legal use of a pe sticide when conducting human health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability

of diets within the U.S., and people who may be exposed when harvesting crops. Sho uld these highest exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure that the risk estimates are based on the best available information.Page 11 of 21

Cumulative The Food Quality

Protection Act (FQPA) requires the Agen cy to consider the cumulative risks of chemicals sharing a common mechanism of toxicity . Chlorpy rifos methyl is a member of the organophosphate common mechanism group. The most recent cumulative risk assessment for the organophosphates was published on in 2006 and is available at http://www.epa.gov/pesticides/cumulative/2006

- op/op_cra_main.pdf. No cumulative risks of concern for chlorpy rifos methyl were identified in that assessment. Prior to a final registration review decision for chlorpy rifos methyl, th e Agency

will determine if there is any new information, such as new hazard or exposure data or information on changes to the use pattern, which would affect the cumulative risk assessment. Should the Agency determine that new information on chlorpy rifos m eth ylis available that could potentially impact the cumulative risk assessment and result in a risk of concern, the Agency

will revisit the cumulative risk assessment.
Human Studies The occupational assessments were completed based on the use of the Pes ticide Handlers Exposure Database (PHED). The PHED has been reviewed from an ethics perspective and no issues were found that would preclude its use in the risk assessment process. Two toxicity human studies with CPM were considered by the HED (MRID 00030 754, 00043238 and MRID 00030755, 00043239) but were classified as unacceptable for technical reasons and were not relied on in the risk assessment

. A human study

using CPY was used as part of a weight of the evidence approach for determining a dermal absor ption factor for CPM (MRID 00124144 and 47918801). This study was reviewed by

the Human Study

Review Board (HSRB June 2009 meeting; final report dated 10/26/09) and it was concluded that the data were reliable. The HSRB did not find the study

to be unethic al. If OPP determines any other human studies have potential use for future risk assessments, they will need to undergo HSRB review. Endocrine Disruptor Screening Program As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor S creening Program (EDSP) to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced b y a “naturally occurring estrogen, or other such endocrine effects as the Administrator may

designate.” The EDSP employ s a two

- tiered approach to making the statutorily

required determinations. Tier 1 consists of a battery of 11 screening assay s to identify the potential of a chemical substance to interact with the estrogen, androgen, or thy roid (E, A, or T) hormonal sy stems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal s ys tems will proceed to the next stage of the EDSP where EPA will determine which, i f any , of the Tier 2 tests are necessary

based on the available data. Tier 2 testing is designed to identify any adverse endocrine related effects caused b y the substance, and establish a dose

- response relationship between the dose and the E, A, or T effec t.Page 12 of 21

Between October 2009 and February 2010, EPA is issuing test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. This list of chemicals was selected based on the potential fo r human exposure through pathway s such as food and water, residential activity , and certain post

application agricultural scenarios. This list should not be construed as a list of known or likely endocrine disruptors. Chlorpy rifos meth yl is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingl y, EPA anticipates issuing future EDSP test orders/data call

- ins for all pestic ide active ingredients

. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery , please visit the website: http://www.epa.gov/endo/. Data Requirement s Toxicology

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

skin irritation). The dermal sensitization study may be waived according to M. Lewis, 1 2/4/09 email communication to J. Dohe rty

. • 870.3250 Subchronic i nhalation study

. • 870.780 0 Immunotoxicity ( This is a new data requirement under 40 CFR Part 158 ; see Appendix 1 )

• Comparative cholinesterase assay (CCA): required for organophosphates including chlorpy rifos methyl. This study has not been submitted for chlorp yrifos methyl (see Appendix 1 ). Residue Chemistry

• 860.1500 Magnitude of the residue data were identified as outstanding in the 2000 TRED for aspirated grain fractions. Those data remain outstanding. Occupational

– no data gaps currently identifiedPage 13 of 21

Appendix 1
Data Call In Tables Guideline Number : 870.7800 Study Title : Immunotoxicity Rationale for Requiring the Data This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non

- food uses). The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity testing and is designed to evaluate the potential of a repeated chemical exposure to produce adverse effects (i. e., suppression) on the immune system. Immunosuppression is a deficit in the ability of the immune system to respond to a challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired Respiratory Syndrome (SARS), or neoplasia. Because the immune system is highly complex, studies not specifically conducted to assess immunotoxic endpoints are inadequate to characterize a pesticide’s potential immunotoxicity. While data from hematology, lymphoid organ weights, and histopathology in ro utine chronic or subchronic toxicity studies may offer useful information on potential immunotoxic effects, these endpoints alone are insufficient to predict immunotoxicity. Practical Utility of the Data How will the data be used? Immunotoxicity studies provide critical scientific information needed to characterize potential hazard to the human population on the immune system from pesticide exposure. Since epidemiologic data on the effects of chemical exposures on immune parameters are limited and are inadequate to characterize a pesticide’s potential immunotoxicity in humans, animal studies are used as the most sensitive endpoint for risk assessment. These animal studies can be used to select endpoints and doses for use in risk assessment of all expo sure scenarios and are considered a primary data source for reliable reference dose calculation. For example, animal studies have demonstrated that immunotoxicity in rodents is one of the more sensitive manifestations of TCDD (2,3,7,8

- tetrachlorodibenzo

- p - dioxin) among developmental, reproductive, and endocrinologic toxicities. Additionally, the EPA has established an oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997).
How could the data impact the Agency's future decision
- making? If the immunotoxicity study shows that the test material poses either a greater or a diminished risk than that given in the interim decision’s conclusion, the risk assessments for the test material may need to be revised to reflect the magnitude of potential risk derived from the new data. If the Agency does not have th ese data, a 10X database uncertainty factor may be applied for conducting a risk assessment from the available studies.Page 14 of 21 Guideline Number : Special Study Study Title : Comparative Cholinesterase Assay (CCA) Rationale for Requiring the Data Chlorpyrifos methyl is an organophosphate pesticide (OP) whose mode of toxic action is inhibition of the enzyme, acetylcholinesterase (AChE) via phosphoryl ation of the active site leading to accumulation of acetylcholine and to clinical signs of neurotoxicity. The detoxifying systems for destroying both the parent and active forms of OPs are less developed in the neonatal animals and humans. The Agency d oes not have comparative AChE inhibition studies conducted using chlorpyrifos methyl to compare the relative sensitivity of juvenile to adult animals. Thus, EPA is seeking a comparative cholinesterase assay for chlorpyrifos methyl . Specifically, this stu dy should include both acute (1 day) and repeated (11 days) exposures to pups and young adult rats. The acute exposures should be administered to post

-natal day 11 (PND 11) rats and young adults. The repeated exposures should be given for 11 consecutive days beginning at PND 11. The chlorpyrifos methyl should be administered directly (e.g., gavage). Practical Utility of the Data
How will the data be used? The new data generated in the CCA study with chlorpyrifos methyl will be used in the dietary a ssessment for chlorpyrifos methyl to account for any additional risks arising from exposure to neonatal subjects to chlorpyrifos methyl. How could the data impact the Agency’s future decision
- making? The newly generated CCA data could potentially impact the FQPA safety factor in both the single chemical and cumulative risk assessments. If the FQPA safety factor changes, then this impacts the calculation of the acute and chronic Population Adjusted Doses, and therefore may either reduce or increase risk e stimates in the dietary assessments for the chlorpyrifos methyl and cumulative risk assessments. If the dietary risk is increased based on information in the new CCA study, then additional mitigation may be needed to address potential risks of concern. I f the dietary risk is decreased, then the registrants may be able to expand uses.Page 15 of 21

Appendix 2
T oxicology Endpoint and Dose S election The doses and toxicological endpoints previousl y selected for use in chlorpyrifos methyl assessment:Page 16 of 21

Appendix 3 A Chlorpyrifos Methyl: U.S. Tolerances (currently)
[Code of Federal Regulations] [Title 40, Volume 23] [Revised as of July 1, 2008] From the U.S. Government Printing Office via GPO Access [CITE: 40CFR180.419]
TI TLE 40

-- PROTECTION OF ENVIRONMENT
CHAPTER I

-- ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PART 180_TOLERANCES AND EXEMPTIONS FROM TOLERANCES FOR PESTICIDE CHEMICALS IN Subpart C_Specific Tolerances
Sec. 180.419 Chlor pyrifos

- methyl; tolerances for residues. (a) General. (1) Tolerances are established for the combined residues of the insecticide chlorpyrifos

- methyl [O,

- O,

- dimethyl O

- (3,5,6

- trichloro

- 2

- pyridyl)] phosphorothioate and its metabolite (3,5,6

- trichlor o - 2

- pyridinol) in or on the following food commodities:

------------------------------------------------------------------------ Parts per Commodity million

------------------------------------------------------------------------ Barley, grain............................................... 6.0 Cattle, fat................................................. 0.5 Cattle, meat........ ........................................ 0.5 Cattle, meat byproducts..................................... 0.5 Egg......................................................... 0.1 Goat, fat................................................... 0.5 Goat, meat.................................................. 0.5 Goat, meat byproducts....................................... 0.5 Hog, fat.................................................... 0.5 Hog, meat................... ................................ 0.5 Hog, meat byproducts........................................ 0.5 Horse, fat.................................................. 0.5 Horse, meat................................................. 0.5 Horse, meat byproducts...................................... 0.5 Milk, fat (0.05 ppm (N) in whole milk....................... 1.25 Oat, grain.................................................. 6.0 Poultry, fat....................... ......................... 0.5 Poultry, meat............................................... .5 Poultry, meat byproducts.................................... .5 Rice, grain................................................. 6.0 She ep, fat.................................................. 0.5 Sheep, meat................................................. 0.5 Sheep, meat byproducts...................................... 0.5 Sorghum, grain............................. ................. 6.0 Wheat, grain................................................ 6.0

------------------------------------------------------------------------ (2) Tolerances are established for the combined residues of the insecticide chlorpyrifos

- methyl (O,

- O

- dimethyl

- O

- (3,5,6

- trichloro

- 2

- pyridyl) phosphorothioate and its metabolite (3,5,6

- trichloro

- 2

- pyridinol) in or on the following food commodities when present therein as a result of application to stored grains:Page 17 of 21 -------------- ---------------------------------------------------------- Parts per Food million

---------------------------------------------------- -------------------- Barley milling fractions (except flour)...................... 90 Oat milling fractions (except flour)......................... 130 Rice milling fractions (except flour)........................ 30 Sorghum, grain, bran......................................... 90 Wheat milling fractions (except flour)....................... 30

------------------------------------------------------------------------ (b) Section 18 emergency exemptions. [Reserved] (c) Tolerances with regional registrations. [Reserved] (d) Indirect or inadvertent residues. [Reserved] [65 FR 33715, May 24, 2000]Page 18 of 21

Appendix 3 B Chlorpyrifos Methyl: Reassessed U.S. Tolerances (11/1/99 HED memo: Chlorpyrifos Methyl Residue Chemistry Chapter of the RED; D259808)

Commodity Current Tolerance (ppm) Tolerance

Reassessment (ppm) Comment/ Correct Commodity Definition
Tolerances listed under 40 CFR §180.419: Barley, grain 6.0 6.0 Oats, gra in 6.0 6.0 Rice, grain 6.0 6.0 Sorghum, grain 6.0 6.0 Sorghum, grain, grain Wheat, grain 6.0 6.0 Fat of cattle, goats, hogs, horses, & sheep 0.5 TBD 1 Residue data on aspirated grain fractions derived from treated wheat and sorghum are required. Aspirated grain fractions contribute significantly to the dietary burden for cattle and swine. If significantly higher residues are found in wheat or sorghum aspirated grain fractions, then a new ruminant feeding study may be required. Meat and meat byproducts of cattle, goats, horses, & sheep 0.5 Hogs, muscle 0.5 Hogs, meat byproducts 0.5 Milk 0.05 Milk, fat 1.25 Poultry, fat 0.5 0.05 Residue data support lowering the tolerances established on poultry commodi ties. Poultry, meat byproducts 0.5 0.01 Poultry, meat 0.5 0.01 Eggs 0.1 0.01 Tolerances listed under 40 CFR §185 and §186.1050: Barley, milled fractions (excluding flour) 90.0 Revoke Tolerance should be revoked concomitant with estab lishing a 20 ppm tolerance on barley bran

. Oats, milled fractions 130.0 Tolerance should be revoked concomitant with establishing a ppm tolerance for oat bran

. Rice, milled fractions (excluding flour) 30.0 Tolerance should be revoked concomitant with establishing tolerances on rice bran (12.5 ppm). Sorghum, milled fractions (excluding flour) 90.0 Tolerance should be revoked. There are no longer any processed commodities of grain sorghum considered as food for humans or feed for livestock. Wheat, milled fractions (excluding flour) 30.0 Tolerance should be revoked concomitant with establishing a tolerance on wheat bran, wheat germ and germ oil at 20 ppm.Page 19 of 21 Commodity Current Tolerance (ppm) Tolerance

Reassessment (ppm) Comment/ Correct Commodity Definition Tolerances needed under 40 CFR §180.419 Aspirated Grain Fractions None TBD 1 The available data on corn support a tolerance of at least 400 ppm . Additional data are required for sorghum and wheat Barley, bran 90.0 20.0 Concomitant with revoking the tolerance for barley milled fractions, a tolerance on barley bran should be es tablished Rice, bran 30.0 12.5 Concomitant with revoking the tolerance for rice milled fractions, a tolerance on rice bran should be established. Rice, hulls None 25.0 Concomitant with revoking the tolerance for rice milled fractions, a tolerance on rice bran should be established. Oat, bran None 17.0 Concomitant with revoking the tolerance for oat milled fractions, a tolerance on oat,bran should be established. Wheat, bran 30.0 20.0 Concomitant with revoking the food/feed additive toler ance for wheat milled fractions, a tolerance on wheat,bran should be established. Wheat, germ 30.0 20.0 Concomitant with revoking the food/feed additive tolerance for wheat milled fractions, a tolerance on wheat,germ should be established. 1 TBD = To be determined; i.e., the Agency considers the existing tolerance to be reassessed at the current level; however, adequate confirmatory data are warranted and if found lacking, the Agency intends to modify or revoke the tolerance.Page 20 of 21

Appendi x 3 C Chlorpyrifos Methyl: Codex Maximum Residue Limits (MRLs) Summary of US and International Tolerances and Maximum Residue Limits US Canada Mexico Codex Residue Definition: 40CFR180.419. combined residues of the insecticide chlorpyrifos

- methyl [ O

, - O,

- dimethyl O

- (3,5,6

- trichloro

- 2

- py

ridyl)] phosphorothioate and its metabolite (3,5,6

- trichloro

- 2

- py ridinol) None None Chlorpyrifos

methyl (fat

soluble). Commodity

Tolerance (ppm) /Maximum Residue Limit (mg/kg) Commodity US Canada Mexico Codex 2, 3 Barley , grain 6.0 None None 3 Po proposed Cattle, fat 0.5 0.05 (withdrawal proposed) Cattle, meat 0.5 0.05 (0.1 proposed) Cattle, meat by

products 0.5 0.05 (0.01 proposed) Egg 0.1 0.05 (0.01 (*) proposed) Goat, fat 0.5 Goat, meat 0.5 Go at, meat b yproducts 0.5 Hog, fat 0.5 Hog, meat 0.5 Hog, meat b yproducts 0.5 Horse, fat 0.5 Horse, meat 0.5 Horse, meat b yp roducts 0.5 Milk, fat (0.05 ppm (N) in whole milk 1.25 0.01 (*) Oat, grain 6.0 10 Po proposed Poultry, fat 0.5 0.05 Poultry , meat 0.5 0.05 (0.01 proposed) Poultry , meat by products 0.5 0.05 (0.01 (*) proposed)Page 21 of 21

Summary of US and International Tolerances and Maximum Residue Limits US Canada Mexico Codex Rice, grain 6.0 0.1 (w ithdrawal proposed) Sheep, fat 0.5 Sheep, meat 0.5 Sheep, meat b yproducts 0.5 Sorghum, grain 6.0 10 Po Wheat, grain 6.0 10 Po (3 proposed) Barley , bran 1 90 Barley , pearled barley 1 90 Rice, bran 1 30 Rice, hulls 1 30 Rice, polished rice 1 30 Sorghum, grain, bran 1 90 Wheat, bran 1 30 20 PoP (6 proposed) Wheat, germ 1 30 5 PoP p roposed Wheat, middlings 1 30 Wheat, shorts 1 30 1 As a result of application to stored grains.

2 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity , such as processing of treated stored wheat.

3 Commodities with Codex MRL s but without corresponding US tolerances have been excluded. For example, there is a Codex MRLof 0.5 mg/kg for apple.