TITLE Briefings on Epidemiology Studies Pertaining to Chlorpyrifos Exposures and New Research on the Potential Hazard and Risk for Chlorpyrifos-Oxon TEST GIDDELINE (NIA) AUTHOR Oliver, G.R., Juberg, D.R., Burns, C.J., Bartels, M.J., Marty, M.S., Velovich, JJ., Poletika, N.N. STUDY COMPLETION DATE (September 2014) SPONSOR (Dow Agro Sciences LLC) 9330 Zionsville Rd. Indianapolis, IN 46268) USA PERFOMINGLABORTORY (Dow Agro Sciences LLC) 9330 Zionsville Rd. Indianapolis, IN 46268) USA PAGE COUNT (1of10) EPA-HQ-2017-004961_PANNA v EPA_0002098 Dow AgroSciences LLC Study ID: GR02014 Page2 STATEMENT OF NO DATA CONFIDENTIALITY CLAIMS Compound: Chlorpyrifos Study Title: Epidemiology Studies Pertaining to Chlorpyrifos Exposures New Research on the Potential Hazard and Risk for Chlorpyrifos-Oxon No claim of confidentiality, on any basis whatsoever, is made for any information contained in this document. I acknowledge that information not designated as within the scope of FIFRA sec. lO(d)(l)(A), (B), or (C) and which pertains to a registered or previously registered pesticide is not entitled to confidential treatment and may be released to the public, subject to the provisions regarding disclosure to multinational entities under FIFRA sec. lO(g). Company: _ _ _ _ _ _D_o_w_A~g~r_oS_c_ie_n_ce_s_L_L_C_ _ _ __ Company Agent: _ _ _ _ _ _ _G_e_o_,,rg"-e_O_li_ve_r_ _ _ _ _ __ Title: _ _ _ _ _ _ _R_e""""cru_la_to_r...._y_L_ea_d_er_ _ _ _ __ Signature: ~4-~/~ .!(_~---~-+-~-/_ . ~-~_VY _ __ Date: _ _ THIS DATA MAY BE CONSIDERED CONFIDENTIAL IN COUNTRIES OUTSIDE THE UNITED STATES EPA-HQ-2017-004961_PANNA v EPA_0002099 Dow AgroSciences LLC Study ID: GR02014 Page3 STATEMENT OF COMPLIANCE WITH GOOD LABORATORY PRACTICE STANDARDS Title: Epidemiology Studies Pertaining to Chlorpyrifos Exposures New Research on the Potential Hazard and Risk for Chlorpyrifos-Oxon Compound: Chlorpyrifos This report does not meet the definition of a OLP study as it appears in: United States Environmental Protection Agency Title 40 Code of Federal Regulations Part 160 Federal Register, 17 August 1989 Organization for Economic Cooperation and Development ENV/LMC/CHEM(98) 17, Paris - January 26, 1998 NON-GLP STUDY /6-Sv/-...eo/f' Date Sponsor Company Ge~db, /ta ... -'~ -,.<:'d/jV Date Submitter Company ~~~ /6 -S~ - ;?O/Y" Date Study Director Company EPA-HQ-2017-004961_PANNA v EPA_0002100 Dow AgroSciences LLC Study ID: GR02014 Page4 Introduction Extensive research has been conducted on potential epidemiological effects of chlorpyrifos and recent extensive new testing has been conducted on the potential hazard of the chlorpyrifosoxon. Included in this report are two separate briefs, one on epidemiology studies pertaining to chlorpyrifos and the other on the new research on toxicity and hazard of the chlorpyrifos-oxon. These briefs are intended to help bring together the large number of studies and reports on each of these important topics, and then for each, to hopefully provide a road map of the research and positions and connect-the-dots to highlight key points. EPA-HQ-2017-004961_PANNA v EPA_0002101 Dow AgroSciences LLC Study ID: GR020l4 Page5 Epidemiology Studies Pertaining to Chlorpyrifos Exposures Overview of available data & considerations of reliability and utilit of the Columbia stud Introduction Review of Relevant Studies For chlorpyrifos, in addition to a robust data base of animal studies, there is range of varied epidemiology research. A few studies, including most notably a study from Columbia University, have raised questions about neurodevelopment effects in infants and children. The purpose of this issue brief is to help put the available epidemiology data in context relative to the applicability to risk assessment Animal studies show clear no effect levels This brief is based largely on reports by Edwards et al. (2013) and (Racke et al. 2011) which contain references to additional studies that support the positions. Edwards et al. (2013) concluded that in extensive animal experimentation, neurodevelopmental and/or behavioral effects have only been reported at exposures higher than 1.0 mg/kg body weight per day (bw/day). The LO mg/kg bw/day would therefore be considered the threshold level of exposure. This is 30-fotd higher than the RBC ChE metric (USEPA, 2011) of 0.03 mg/kg bw/day used by EPA This threshold of 1 mg/kg/day is also at least 5,000 times higher than estimated exposures from the Columbia study (Lowe et al. 2009). Summary and Conclusions Epidemiology - Review of available studies 1. The chlorpyrifos toxicological database required and used for global registrations is complete. Multiple reviews have looked across studies and concluded that at the measured levels of exposure, the evidence from these studies is insufficient to show causality between chlorpyrifos and adverse neurodevelopment effects in infants and children (Burns et al. 2013; Eaton et al. 2008; Li et al. 2012a; Li et al. 2012b; Mink et al. 2012) Effects and endpoints are well defined. 2. Extensive animal experimentation has shown that neurodevelopmental and/or behavioral effects only occur at doses far exceeding human exposure and regulatory endpoints. 3. Looking across the epidemiology studies, the data are not sufficiently robust to support a causal relationship between chlorpyrifos exposures and neurodevelopment effects. 4. The Columbia Children's Center for Environmental Health (Columbia) study has warranted significant consideration, however: • It has significant limitations in methodology, many confounding factors, and no public accessibility of the data for examination and validation • The neurodevelopment effects postulated lack biological plausibility and are not consistently reproduced in other studies. University researchers (Ntzani et al. 2013), under contract from the EU' s European Food Safety Authority (EFSA), reviewed the epidemiology studies published since 2006. They concluded there is no evidence to suggest an association between pesticide exposure, including chlorpyrifos, and neurodevelopmental effects. In a separate publication, EFSA (2014) also supported the use of RBC ChE as the most appropriate endpoint for assessing health risks from chlorpyrifos, and concluded the epidemiology data are not sufficiently robust to support a causal relationship with neurodevelopment effects. Epidemiology - Columbia cohort study Regulatory Endpoints While inhibition of brain acetylcholinesterase (AChE) is the most toxicologically-relevant adverse effect in mammals, red blood cell cholinesterase (RBC ChE) inhibition is a sensitive marker of exposure to chlorpyrifos and used by EPA as the basis for regulation of chlorpyrifos. Of the studies that have claimed possible neurodevelopment effects on infants and children from exposures to chlorpyrifos, the Columbia Children's Center for Environmental Health (Columbia) has gained the most attention. The EPA has given weight to this particular study since it measured chlorpyrifos, not the metabolite, in maternal and cord blood. EPA-HQ-2017-004961_PANNA v EPA_0002102 Dow AgroSciences LLC Study ID: GR02014 Page6 Epidemiology Studies Pertaining to Chlorpyrifos Exposures Overview of available data & considerations of reliabilit and utility of the Columbia stud Challenges to claims from the study from both a ( 1) hypothesis-based weight of analysis (Racke et al. 2011) and (2) critical analysis of the reliability of the data, as reported by Edwards et al. (2013) and Racke et al. (2011), render the study inappropriate for risk assessment. 1. Hypothesis-based weight of evidence analysis c) Credible, alternative explanations for effects There are credible alternative hypotheses for the health problems observed in the study children. These include exposures to other chemicals, including known neurotoxicants; and importantly, living in low income situations, d) Inability for further, independent analysis of the study The Columbia study reported unique and statistically significant adverse health effects. If there were true causal relationships between these effects and chlorpyrifos exposures, these relationships should be repeated in other independent studies. Using a hypothesis-based weight of evidence analysis, the effects reported in the Columbia study were not supported by 4 other independent studies (Racke et al., 2011). This lack of support raises valid questions as to whether these results are actually false positives. 2. Consideration of reliability o[data In addition to highlighting the lack of consistency from other studies, Edwards et al. (2013) also identified other significant limitations of the Columbia cohort: Transparency and documentation of the decision process are at the core of a credible risk assessment. Despite repeated requests through the Freedom of Information Act to EPA to obtain the Columbia data, there remains a restriction on data access by the authors. Thus independent evaluation and verification of the analyses is not possible. Accessibility to the data would also allow further evaluation of the exposure and health groupings which have an important impact on reported findings. In addition, this would facilitate comparisons against other, independent studies. Considering the issues raised for this study, making the data available to the broader scientific community is necessary for enhanced analysis and confirmation of the validity of the claims. a) The analytical method used has not been validated at the low concentrations reported in the study subjects. A basic foundation of the scientific process is that exposure measurements be accurate, precise, and reproducible. But in the Columbia study, the only validation was for detection levels 15-30 times higher than the limit of detection used. Since more than 80% of the Columbia subjects were below the validated level, any decisions based on the use of such methodology should be highly scrutinized. b) No biological plausibility for effects There is no established biological mode of action which would link the neurodevelopmental effects in the study to chlorpyrifos exposures. As discussed earlier, no effect levels for chlorpyrifos have been clearly defined at 1.0 mg/kg bw/day' below which neurodevelopmental effects have not been found. This is 5,000 times higher than the estimated dose of 0.15 ug/kg bw/day in the Columbia study (Lowe et al.2009). EPA-HQ-2017-004961_PANNA v EPA_0002103 Dow AgroSciences LLC Study ID: GR02014 Page7 Epidemiology Studies Pertaining to Chlorpyrifos Exposures Overview of available data & considerations of reliability and utility of the Columbia study Listing of key references to support the analysis in this brief (list is not intended to be all Broader reviews of the epidemiology studies related to chlorpyri[os inclusive on the subject and each contain additional references of value) • Burns CJ, Mcintosh LJ, Mink PI, Jurek, Li AA. (2013). Pesticide exposure and neurodevelopmental outcomes: review of the epidemiologic and animal studies. J Toxicol Environ Health B Crit Rev. 16 (34): 127-283. doi: 10.1080/10937404.2013/783383. Review Erratum in: J Toxicol Environ Health B Crit Rev. 2013: 16(6): 395-8 • Eaton DL, Daroff RB, Autrup H, Bridges J, Buffler P, Costa LG, Coyle J, Mc.Khann G, Mobley, WC, Nadel L, Neubert D, Schulte_Hermann R, Spencer PS. (2008). Review of the Toxicology of Chlorpyrifos with an Emphasis on Human Exposure and Neurodevelopment. Crit Rev Toxicol 38 Suppl 2: 1125. • Li AA, Levine TE, Burns CJ, Anger WK. (2012a). Integration of Epidemiology and Animal Neurotoxicity Data for Risk Assessment. Neurotox 1347. • Li AA, Lowe KA, Mcintosh, LJ, Mink PJ. (2012b). Overall review of the understanding of e(lidemiology findings for chlorpyrifos • Racke, K.D., Juberg, D.R., Cleveland, C.B., Poletika, N.N., Loy, C.A., Selman, F.B., Burns, CJ., Bartels, M.J., Price, P.S., Shaw, M.C., Tiu, C.C. (201 l). Dow AgroSciences' Response to EPA' s Preliminary Human Health Assessment for Chlorpyrifos EPA-HA-OPP-2008-0850Registration Review 0025. Dow AgroSciences, Indianapolis, IN. Critical review o[the Columbia study • • Edwards, D., Juberg, D. Burns, C., Goodman, J., Li, A., Bartels, M., Lickfeldt, D. (2013). Epidemiology Studies Pertaining to Chlorpyrifos Exposures: Consideration of Reliability and Utility. Report submitted by Dow AgroSciences, Indianapolis, IN. MRID 49371401. Lowe, E.R., T.S. Poet, D.L. Rick, M.S. Marty, J.L. Mattsson, et al. (2009). The Effect of Plasma Lipids on the Pharmacokinetics of Chlorpyrifos and the Impact on Interpretation of Blood Biomonitoring Data. Toxicol Sci 108:258-272. EPA 's Preliminary Health Assessment epidemiology data and the Columbia Study • Evaluation of Epidemiology and Animal Data for Risk Assessment: Chlorpyrifos Developmental Neurobehavioral Outcomes. J. Toxicol Environ Health B 15:109-184. • Mink PJ, Kimmel CA, Li AA. (2012). Potential Effects of Chlorpyrifos on Fetal Growth Outcomes: Implications for Risk Assessment. J Toxicol Environ Health B 15:281-316. • Ntzani EE, Chondrogiorgi M, Ntritsos G, Evangelou (2013). Literature review on E,Tzoulaki,I. epidemiology studies linking exposure to pesticides and health effects. EFSA supporting publication 2013: EN-497. 159 pp. including US EPA Office of Pesticide Program. (2011). Chlorpyrifos: Preliminary Human Health Risk Assessment for Registration Review. DP No. D388070. EPA-HA-OPP-2008-0850-0025. EU's European Food Safety Authority review • EFSA. (2014). Final addendum to the Art. 21 Review on chlorpyrifos - public version - Initial risk assessment provided by the Rapporteur Member State Spain for the existing substance CHLORPYRIFOS as referred to in Article 21 of regulation (EC) No. 1107/2009. February, 2014. Chapter: Addendum III to Vol 3 to DAR. Pg. 53. EPA-HQ-2017-004961_PANNA v EPA_0002104 Dow AgroSciences LLC Study ID: GR02014 Page8 New Research on the Potential Hazard and Risk for Chlorpyrifos-Oxon Neiver research makes the data base essentially complete f(Jr the oxon and indicates no hazard and therefore no risk at potential real-world exposures Introduction At the time of the Chlorpyrifos Preliminary Human Health Assessment (EPA, 2011), EPA identified concerns about residues in drinking water of both parent chlorpyrifos and the metabolite chlorpyrifos-oxon. The only source of the oxon is degradation of chlorpyrifos during water purification for finished drinking water and this is the only route for possible human exposure. Assuming all of the chlorpyrifos converts to the oxon and no further degradation of the oxon, worst-case modeled runoff scenarios resulted in estimated exposure levels up to 2700% of the acute Population Adjusted Dose (aPAD). Regulatory endpoints While inhibition of brain acetylcholinesterase (AChE) is the most toxicologically-relevant adverse effect in mammals, Red Blood Cell cholinesterase (RBC ChE) inhibition is a sensitive marker of exposure to chlorpyrifos and used by EPA as the basis for regulation of chlorpyrifos and the oxon Summary and Conclusions New studies yield a more thorough understanding of the potential hazard and risk from the oxon Since the earlier Chlorpyrifos Preliminary Human Health Assessment, research has been conducted so the toxicity data base for the oxon is now essentially complete. The purpose of this brief is to incorporate new, additional research which indicates: 1. The oxon is metabolically unstable and therefore, even at the highest estimated drinking water exposures, it is not systemically bioavailable so no effect is seen in systemic tissue. 2. No RBC ChE inhibition was found when oxon was given by both drinking water and the more extreme dosing by gavage at levels based on the maximum potential levels in drinking water and far in excess of even those estimated in worst-case modeling. These routes simulate both normal human drinking water consumption and bottle-feeding routes for infants. 3. No difference in sensitivity to the oxon was seen due to age differences based on RBC or brain ChE inhibition. The combination of these three factors indicates no hazard from the oxon in drinking water. With no hazard there would be no risk. This is aligned with the principles of the EPA's four-stage paradigm for assessing human health risks in that if it can be concluded there is no hazard; there is no risk (EPA, 2014) Further supporting the concept of no risk, new research shows: 4. Real-world water monitoring data can be used to estimate exposures for even the highest percentile of exposed population. 5. Based on (4), the aggregate assessment for the oxon, including both food and water consumption, is well below the levels of concern and protective of even the highest exposed populations. Review of Newer Research The metabolic pathways and resulting toxicity of the oxon are well understood First-pass metabolism of the oxon Marty and Andrus (2010) found inhibition of the brain AChE did not occur at oxon doses up to and including 10 mg/kg-bw/day. Chambers et al. (2013) found no difference in sensitivity to the oxon in other systemic tissues compared to brain so this trigger-level applies to other tissues. This is due to first-pass metabolism of the oxon in the GItract, portal vein blood, and liver which then limits the bioavailability of the axon to central nervous system (CNS) and peripheral (skeletal, muscle, lung and heart) EPA-HQ-2017-004961_PANNA v EPA_0002105 Dow AgroSciences LLC Study ID: GR02014 Page9 New Research on the Potential Hazard and Risk for Chlorpyrifos-Oxon Nei-i.:er research makes the data base essentially complete j(Jr the oxon and indicates no hazard and therefore no risk at potential real-world exposures tissues. The relatively slow absorption of the oxon into the blood combined with rapid hydrolysis and enzymatic degradation of oxon in the portal blood and liver, are the mechanisms for this first past metabolism. Only when the dose exceeds lO mg/kg-bw/day is the capacity of these metabolic processes exceeded and the oxon becomes available to interact with the other tissues. The maximum acute exposure levels in the EPA's modeling estimates were 0.013 mg/kg-bw/day (Reiss et al., 2014) which is 750X below the exposure level that would exceed this first-pass metabolism. Oxon only forms from the degradation of chlorpyrifos during the water purification process, so the highest potential exposure to oxon would be limited to the water solubility of chlorpyrifos. Marty and Bartels (2014) evaluated the biological effects from the oxon in drinking water at a concentration based on the solubility limit for chlorpyrifos. No inhibition of RBC ChE, was found at a mean dose level of 0.098 mg/kg-bw/day. Even at this dose, which is 7X the level of oxon that could be found in water based on the solubility of chlorpyrifos, and about 77X greater than maximum acute exposure levels in the EPA's modeling estimates, no hazard was found Lack of effects in the GI-tract J2rior to complete first-pass metabolism In a review of studies that included clinical signs of GI-tract function, Llckfeldt et al (2012) reported a possible slight portal of entry effect on the GI tract from the axon only at doses as high as 5 mg/kg which far exceeds maximum detected and even maximum estimated drinking water exposures. No differences in sensitivity due to age Using the regulatory endpoint of inhibition of RBC ChE, Marty and Andrus found no difference in sensitivity between young animals and adults with both showing the same effect/no significant effect at the same doses. Following acute exposures both showed significant inhibition at 0.5 mg/kg but neither showed significant inhibition at the next lower dose (0.1 mg/kg).). The lack of age-related differences in RBC ChE inhibition also is supported by benchmark dose modeling (Reiss et al., 2012). Water monitoring supports lack of risk While the new toxicity studies indicate no hazard from levels of oxon that could be found in drinking water, the second half of any risk equation is the exposure levels. Reiss et al. (2014) reviewed available water monitoring surveys of community water systems on both large to small rivers and streams,from various time periods between 1991and2013. Of the more than 14,000 samples where the oxon was specifically looked for, it was only found in 27 samples. Even if it is assumed that any chlorpyrifos residue would convert to the oxon, the occurrence would be low. In over 47000 samples, chlorpyrifos was detected in less than 5000 and the maximum level ever reported of 0.57 ppb. While survey data are challenged for potentially missing a peak concentration event, Reiss et al. concluded that the data set is sufficient to use statistical methods to characterize the distribution of exposures at the higher percentiles of exposure. The estimated central estimate for oxon concentration was 0.08 ppb with an upper bound of 0.15 ppb.The maximum detected value for chlorpyrifos 0.57 ppb can then be used as the lOOtli percentile for oxon. When Reiss et al. based exposure estimates on actual monitoring data, levels dropped significantly. The total aggregate risk from food plus drinking water fell from the earlier estimated high of 2700% to only about 12% and 13% of the acute and chronic levels of concern (aPAD & cPAD), respectively. CDC biomonitoring data showed close agreement with exposures that could be accounted for solely through food, again supporting that drinking water exposures would be low. EPA-HQ-2017-004961_PANNA v EPA_0002106 Dow AgroSciences LLC Study ID: GR02014 Page 10 New Research on the Potential Hazard and Risk for Chlorpyrifos-Oxon Nei.ver research makes the data base essentially complete f(1r the oxon and indicates no hazard and therefore no risk at potential real-world exposures • listing of key references to supp01·t the analysis in this brief (list is not intended to be all inclusive and many include additional references of value) EPA 's Preliminary Health Assessment • US EPA Office of Pesticide Program. (2011). Chlorpyrifos: Preliminary Human Health Risk Assessment for Registration Review. DP No. D388070. EPA-HA-OPP-2008-0850-0025. Overall review of the toxicity data, exposure levels and aggregate assessment for the oxon • Racke, K.D., Juberg, D.R., Cleveland, C.B., Poletika, N.N., Loy, C.A., Selman, F.B., Bums, CJ., Bartels, M.J., Price, P.S., Shaw, M.C., Tiu, C.C. (2011). Dow AgroSciences' Response to EPA's Preliminary Human Health Assessment for Chlorpyrifos Registration Review - EPA-HA-OPP-2008-08500025. Dow AgroSciences, Indianapolis, IN. Aggregate assessment including estimation of chlorpyrifos oxon in drinking water based on distributions of data from monitoring surveys Cholinesterase inhibition in various rat tissues from chlorpyrifos-oxon: • Chambers, J.E., Meek, E.C., Chambers, H.W. 2013. In vitro Sensitivity of Cholinesterase to inhibition by Chlorpyrifos-oxon in Several Tissues of the Rat. MRID 49221901. • Chandra, S.M., Mortensen, S.R., Moser, V.C., Padilla, S. 1997. Tissue-specific effects of chlorpyrifos on carboxylesterase and cholinesterase activity in rats: an in vitro and in vivo comparison. Fundam. Appl. Toxicol. 38, 148-157. Cholinesterase inhibition from oxon via drinking water • Reiss, R., Tucker, K., Weidling, R. 2014 (June 4). Refined Aggregate Exposure and Risk Assessment for Chlorpyrifos. Exponent, 1800 Diagonal Road, Suite 500. Alexandria, VA 22314 (MRID 49405101) Marty, M.S., Bartels, M.J. 2014. Characterization of Cholinesterase (ChE) Inhibition Following Exposures to Chlorpyrifos-Oxon in Drinking Water. Dow AgroSciences LLC, Indianapolis, IN. Additional EPA references related to risk • • Marty, M.S., Andrus, A.K. 2010. Comparison of Cholinesterase (ChE) inhibition in young adult and preweaning CD Rats after Acute and Repeated Chlorpyrifos or Chlorpyrifos-Oxon Exposures. Dow AgroSciences LLC, Indianapolis, IN. MRID 48139301. US EPA Office of Chemical Safety and Pollution Prevention. 2014. Chlorpyrifos: Reevaluation of the Potential Risks from Volatilization in Consideration of Chlorpyrifos Parent and Oxon Vapor Inhalation Toxicity Studies. Memorandum dated 6/25/14. Washington, DC. A broad review of the oxon data base: • Lickfeldt, D.W, Bartels, M.J., Marty, M.S., Chambers, J., Galligan, J. 2012 (Aug 17). White Paper Discussion of Toxicity Adjustment Factors used for the Risk Assessment of Chlorpyrifos Oxon in Drinking Water. Dow AgroSciences, Indianapolis, IN Comparative cholinesterase assay following exposure to oxon EPA-HQ-2017-004961_PANNA v EPA_0002107 List of use groups that Dow AgroSciences had previously indicated are not supported on current Dow AgroSciences labels for chlorpyrifos products (Dow AgroSciences comments to EPA on the Master Label April, 2014 through July 2014) Submitted by: G. Oliver, Dow AgroSciences, LLC. Indianapolis, IN Date: June 1, 2015 AGRICULTURAL FARM PREMISES: Livestock housing and holding areas (such as hog barns, empty chicken houses, dairy areas, milkrooms, calf hutches, calving pens and parlors). APPLE (DORMANT) SLN: 83222-2. (3.0 lb a.i./A) BEEF/RANGE/ FEEDER CATTLE (MEAT)/ DAIRY CATTLE (NON-LACTATING) COMMERCIAL/INSTITUTION-AL/ INDUSTRIAL PREMISES/ EQUIP. (INDOOR) Non-food areas of manufacturing industrial, and food processing plants; warehouses; ship holds; railroad boxcars. COMMERCIAL/INSTITUTIONAL /INDUSTRIAL PREMISES/EQUIP. (OUTDOOR) Outdoor commercial use around non-food areas of manufacturing, industrial, and food processing plants; warehouses; ship holds; railroad boxcars PROCESSING PLANT PREMISES (NONFOOD CONTACT) COTTON: SLN NM 040003 for use on cotton in NM (2 lbs /A foliar up to 6 applications/crop cycle FOREST PLANTINGS (REFORESTATION PROGRAMS) (TREE FARMS, TREE PLANTATION, ETC.): foliar and stump FOREST TREES (SOFTWOODS, CONIFERS): foliar and stump GOLF COURSE TURF GREENHOUSE - fogger HOUSEHOLD/DOMESTIC DWELLING INDOOR PREMISES MOSQUITO CONTROL: HOUSEHOLD/DOMESTIC DWELLINGS OUTDOOR PREMISES; RECREATIONAL AREAS NONAGRICULTURAL OUTDOOR BUILDINGS/STRUCTURES to and around outside surfaces of nonresidential buildings and structures. Permitted areas of use include fences, pre-construction foundations, refuse dumps, outside of walls, and other areas where pests congregate or have been seen ORNAMENTAL LAWNS AND TURF, SOD FARMS (GROWN FOR RESALE) ORNAMENTAL WOODY SHRUBS AND VINES - EXCEPT FOR NURSERY PRODUCTION USES POUL TRY LITTER RIGHTS OF WAY, ROAD MEDIANS SEWER MANHOLE COVERS AND WALLS UTILITIES :For use in and around telecommunications, power, utilities and railroad systems I EPA-HQ-2017-004961_PANNA v EPA_0002108 equipment: Buried cables, cable television pedestals, cables, pad-mounted electric power transformers, telephone cables, underground vaults, telecommunications equipment, power and utilities equipment WIDE AREA/ GENERAL OUTDOOR TREATMENT For ants and other misc. pests. WOOD PROTECTION TREATMENT TO BUILDINGS/ PRODUCTS OUTDOOR 2 EPA-HQ-2017-004961_PANNA v EPA_0002109 Revised Dow AgroSciences' List of Proposed Current Chlorpyrifos Uses to Discuss Further with EPA Regarding No Longer Supporting Submitted: G. Oliver, Dow AgroSciences LLC, Indianapolis, IN Date: June 1, 2015 1. All uses with the following application methods: Push type spreader Belly grinder Spoon Sprinkling can 2. All backpack and handgun (excluding tractor mounted 1 applications for the following uses: ) Almonds Nectarines Ornamental non-flowering plants Ornamental trees (except nursery stock) Ornamental vines and shrubs Plums I prunes Shade trees (excluding nursery stock) 1 Growers ask to retain hand wand and the assessments do have an MOE> 100. Often growers will employ a tractor mounted handgun which would be similar then to a hand wand. 1 EPA-HQ-2017-004961_PANNA v EPA_0002110 3. All aerial and chemigation uses to the following crops: Apples Citrus Corn (preplant) - excluding sweet corn Figs Nectarines Nursery stock (pre-plant) Peaches Peanut Pear Plums/Prunes Sod Farms (turf) Strawberries Sunflower (preplant only) Tobacco 2 EPA-HQ-2017-004961_PANNA v EPA_0002111 4. All Water Dispersible Granular I Dispersible Granular formulation applications to the following crops Almonds Apple (foliar only) Asparagus Corn - excluding sweet corn Figs Peanut Peppermint Rutabaga Sorghum grain Soybean Spearmint Sugar beets Sunflower Sweet potato Tobacco Tree nut orchard floors (pecans) Turnip Walnut 3 EPA-HQ-2017-004961_PANNA v EPA_0002112 COMMITTEE ON TOXICITY OF CHEMICALS IN FOOD, CONSUMER PRODUCTS AND THE ENVIRONMENT Statement on I ong-term neurological, neuropsychological and psychiatric effects of low -level exposure to organophosphates in adults Executive summary This statement considers whether adverse neurological, neuropsychological or neuropsychiatric effects can result from exposure of adults to cholinesteraseinhibiting organophosphates at levels insufficient to cause overt acute poisoning. When the question was last considered by COT as part of a report published in 1999, the evidence was judged to be inconclusive. i. ii. The statement was drafted by a working group, comprising the chairman and another member of the COT, along with four external scientists, who were invited to contribute because they provided complementary expertise in relevant scientific areas. Potentially relevant papers were identified through a computerised literature search covering the period up to September 2013, and those that provided useful information were appraised and abstracted. Where reports referenced further publications that might be relevant, these too were retrieved and evaluated. Preliminary consideration indicated that the most pertinent evidence would come from epidemiological investigations, and that toxicological studies in animals and in vitro would be less telling. The search was therefore limited to studies in humans, and reports of other types of research were not reviewed systematically. iii. iv. Since 1999, 13 new papers have been published on the relation of low-level exposure to organophosphates to peripheral neuropathy, adding to 13 studies that were already available at the time of the last COT report. The current balance of evidence suggests that there is no long-term risk of clearly demonstrable peripheral neuropathy from exposure to organophosphates that does not cause overt acute poisoning, a conclusion that has strengthened with the passage of time. v. There is uncertainty as to whether long-term low level exposure to organophosphates causes detectable impairment of sensory thresholds, but if there is an effect then it is likely to be small. 1 EPA-HQ-2017-004961_PANNA v EPA_0002113