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Chlorpyrifos CI CI CI N O O O C 2H5 C 2H5 P Chlorpyrifos is an organophosphorus insecticide used for the control of various crop pests in soil and on foliage, household pests and aquatic larvae. C N S 2 Physiochemical Properties Vapour pressure 2.49 x 103 Pa at 250C Water Solubility 2 mgL at 250C Log octanolwater 4.82 5.11 (high) partition coefficient tightly absorbed by soil and is not expected to leach sig ynificantly persists in soil for 60 to 120 days rate of hydrolysis in water with pH and temperature, and is enhanced by the presence of copper between 30 and 60% of the total amount of chlorpyrifos in an aqueous phase may disappear within 24 hours, through adsorption, degradation and vaporization5 General Toxicology of Chlorpyrifos chlorpyrifos is a cholinesterase inhibitor it is readily absorbed from the gastrointestinal tract and is rapidly metabolized metabolites are excreted in the urine and to a l i h fesser extent in the feces the main metabolites are 3,5,6trichloro2 pyridylphosphate and 3,5,6trichloropyridinol small amounts of unmetabolized chlorpyrifos have been detected in the blood, brain, and liver after accidental human ing
12/9/2010 1 Chlorpyrifos CI C I CI N O O OC 2 H 5 C 2 H 5 P Chlorpyrifos is an organophosphorus insecticide used for the control of various crop pests in soil and on foliage, household pests and aquatic larvae. C N S 2 5 Physiochemical Properties Vapour pressure 2.49 x 10 -3 Pa at 25 0 C Water Solubility 2 mg/L at 25 0 C Log octanol-water 4.82 - 5.11 (high) partition coefficient tightly absorbed by soil and is not expected to leach si g nificantl y gy persists in soil for 60 to 120 days rate of hydrolysis in water with pH and temperature, and is enhanced by the presence of copper between 30 and 60% of the total amount of chlorpyrifos in an aqueous phase may disappear within 24 hours, through adsorption, degradation and vaporization Residue limits have been set for exposure to chlorpyrifos through both food and water by a Chlorpyrifos Exposure series of laboratory exposure studies General Toxicology of Chlorpyrifos chlorpyrifos is a cholinesterase inhibitor it is readily absorbed from the gastrointestinal tract and is rapidly metabolized metabolites are excreted in the urine and to a lihf l esser extent i n t h e f eces the main metabolites are 3,5,6-trichloro-2- pyridylphosphate and 3,5,6-trichloro-pyridinol small amounts of unmetabolized chlorpyrifos have been detected in the blood, brain, and liver after accidental human ingestion 12/9/2010 2 Toxicological Studies Teratogenicity/Reproduction chlorpyrifos was not teratogenic to mice at doses up to and including 25 mg/kg bw/day, although severe maternal toxicity and fetotoxicity were evident at that dose some malformations were observed among litters of mice given 1 mg/kg chlorpyrifos; however, a dose- related teratogenic response was not observed, nor repeated in additional mice given the same dose no evidence of a teratogenic response was observed in mice given 0.1, 1, 10 or 25 mg/kg of chlorpyrifos during the critical period of organogenesis From Deacon et al 1979 Teratogenicity/Reproduction reproduction performance was not affected by chlorpyrifos at any dose level administered to mice fetotoxicity, as evidenced by increased occurrence of minor skeletal variants, and decreased fetal body weight measurements was noted at a dose level of 25 /k d i i mg /k g d ose i n m i ce Neurotoxicity groups of rats were administered chlorpyrifos orally at dosage levels of 0, 0.5, 1, 5, 10, 50 or 100 mg/kg/day 28- 40% plasma cholinesterase inhibition (ChEI) was observed 3-6 hours post exposure with chlorpyrifos doses of 1 mg/kg/day or higher Significant brain ChEI was observed with doses of Significant brain ChEI was observed with doses of greater than 10 mg/kg/day The NOAEL was determined to be 0.5 mg/kg/day Neurotoxicity groups of adult hens were administered chlorpyrifos orally at dosage levels of 0, 25, 50, 100, 200 or 400 mg/kg bw/day, with atropine (30 mg/kg) being given to all birds prior to dosing there were dose-dependent, acute cholinergic effects observed for the chlorpyrifos treated groups. Symptoms ildd i nc l u d e d : - transient signs of ataxia - CNS depression and paralysis (reversible) histologic evaluation revealed no evidence of neurotoxic effects in chlorpyrifos treated hens the acute dose of 100 mg/kg bw/day of chlorpyrifos did not induce a delayed neurotoxic response in hens 12/9/2010 3 Carcinogenicity groups of CD-1 mice were fed chlorpyrifos in the diet at dosage levels of 0, 0.05, 0.5 and 1.5 mg/kg/day for a period of 105 weeks histological examination revealed a significant difference between control and mid-dose males for the incidence of hyperplastic nodules of the liver there was a significant increase in the incidence of spindle cell hyperplasia of the adrenal gland for male mice at low and mid-dose levels, and in female mice at low dose there were no other significant lesions or increased hyperplastic and/or nodular lesions the results of this study demonstrate that chlorpyrifos is not oncogenic in mice at a dietary level up to and including 1.5 mg/kg/day human volunteers were administered oral doses of 0.014 mg/kg bw/day of chlorpyrifos for 27 days, 0.03 mg/kg bw/day for 20 days or 0.10 mg/kg bw/day for nine days red blood cell cholinesterase activity was not affected at any level Short-Term Toxicity affected at any level in a more recent study, human volunteers were administered a single 0.5 mg/kg oral dose of chlorpyrifos, followed two or more weeks later by a 0.5 or 5.0 mg/kg dermal dose of chlorpyrifos no signs or symptoms of toxicity or changes in erythrocyte cholinesterase were observed plasma cholinesterase was depressed to 15% of predose levels by Short-Term Toxicity plasma cholinesterase was depressed to 15% of predose levels by the 0.5 mg/kg oral dose, but was essentially unchanged following the 5.0 mg/kg dermal dose 0.5 mg/kg was considered a NOE(A)L for cholinergic signs in humans, because all studies in laboratory animals indicate that extensive inhibition of both RBC and plasma cholinesterase occur before there are any actual expressions of cholinergic signs Beagle dogs were fed diets containing chlorpyrofos at dose levels of 0, 0.01, 0.03, 0.1, 1, or 3 mg/kg bw/day for two years red blood cell cholinesterase was inhibited in males and females at 0.1, 1.0 and 3.0 mg/kg bw/day in a similar study, rats were fed diets containing Chronic Toxicity in a similar study, rats were fed diets containing chlorpyrifos at concentrations of 0, 0.01, 0.03, 0.1, 1 and 3 mg/kg bw/day for two years brain cholinesterase activity was inhibited at 3.0 mg/kg bw/day, and slightly depressed at 1.0 mg/kg bw/day based on these results, the no-observed-adverse- effect level (NOAEL) for red blood cell and brain cholinesterase inhibition is considered to be 0.1 mg/kg bw/day 12/9/2010 4 Chlorpyrifos Study NOAEL Endpoint mg/kg/day Short-term toxicity (human) 0.1 AChE depr. (human) 0.5 Chol. Symp. (monkey) 0.1 AChE depr. Chronic toxicity (dog) 0.03 AChE depr. (rat) 0.1 AChE depr. Reproduction (mouse) 1.0 Implantation, resorption sites and live young Teratology (mouse) 25 Malformations Neurotoxicity (rats) 0.5 AChE depr. Carcinogenicity (mouse) 1.5 Tumorgenicity aRfD = NO(A)EL Uncertainty Factor The aRfD for methidathion has been derived by the U.S. EPA as follows: Acute Reference Dose for Chlorpyrifos aRfD = 0.5 mg/kg/day 100 where: 0.5 mg/kg/day is the NOAEL derived from the neurotoxicity study in rats 100 is the uncertainty factor = 0.005 mg/kg/day Acute Population Adjusted Dose for Chlorpyrifos The EPA found that in the case of chlorpyrifos the default FQPA Safety Factor of 10 was required Therefore, the acute Population Adjusted Dose (aPAD)is: aPAD = aRfD 10 = 0.005 mg/kg/day = 0.0005 mg/kg/day 10 cRfD = NO(A)EL Uncertainty Factor The cRfD for chlorpyriofs has been derived by the U.S. EPA as follows: Chronic Reference Dose for Chlorpyrifos cRfD = 0.03 mg/kg/day 100 where: 0.03 mg/kg/day is the NOAEL derived from the chronic toxicity study in dogs 100 is the uncertainty factor = 0.0003 mg/kg/day 12/9/2010 5 Chronic Population Adjusted Dose for Chlorpyrifos Once again the FQPA Safety Factor of 10 has been applied in calculating the chronic Population Adjusted Dose (cPAD) cPAD = aRfD 10 = 0.0003 mg/kg/day = 0.00003 mg/kg/day 10 Acute Dietary Risk Assessment A revised acute dietary risk analysis was conducted with the DEEM The exposure at a maximum was to children (1-6 years old) - 0.00041 mg/kg/day (99.9 th percentile of exposure) aPAD = 0.0005 mg/kg/day and the Maximum 99.9 th percentile of exposure (acute food exposure) = 0.00041 mg/kg/day aPAD > Acute food exposure, therefore the use is considered safe. Chronic Dietary Risk Assessment A chronic dietary risk analysis was conducted using the DRES analysis Using DRES, the Theoretical Maximum Daily Intake (TMDI) was calculated, however it did incorporate data from % treated crop, anticipated residue data and market basket surve y data cPAD = 0.00003 mg/kg/day and the TMDI = 0.0000153mg/kg/day PAD > TMDI, therefore the use is considered safe. y Dietary Risk from Drinking Water • The EPA determines the dietary risk based on modeling or from monitoring data from both surface and ground water • To determine the maximum allowable contribution of water - containing pesticide residues permitted in of water containing pesticide residues permitted in the diet, EPA first looks at the risk from food and then determines a “drinking water level of comparison” (DWLOC) to determine whether modeled or monitoring levels exceed this level • The DWLOC is the maximum concentration in drinking water which, when considered together with food exposure, does not exceed the PAD 12/9/2010 6 • For acute risk, the potential drinking water exposure derived from either ground or surface water was modeled resulting in an Estimated Environmental Concentration (EEC) of 0.4 ppb for surface water • Actual concentrations of chlorpyrifos in surface water and finished drinkin g water are likel y to be less Acute Risk from Drinking Water gy Acute Risk from Drinking Water Calculating the DWLOC DWLOC = aPAD – acute food exposure = 0 0005 – 0 00041 (child 1 - 6yrs) 0 . 0005 0 . 00041 (child , 1 6 yrs) = 0.00009 mg/kg/day or 0.9 ppb In comparing the DWLOC (0.9 ppb) with the EEC (0.4 ppb): DWLOC > EEC, therefore the use is considered to be safe Chronic Risk from Drinking Water • For chronic risk, the potential drinking water exposure derived from either ground or surface water was modeled resulting in an Estimated Environmental Concentration ( EEC ) of 0.026 pp b for surface wate r () pp Chronic Risk from Drinking Water Calculating the DWLOC DWLOC = cPAD – chronic food exposure = 0 00003 – 0 0000153 (child 1 - 6yrs) 0 . 00003 0 . 0000153 (child , 1 6 yrs) = 0.0000147 mg/kg/day or 14.7 ppb In comparing the DWLOC (14.7 ppb) with the EEC (0.026 ppb): DWLOC > EEC, therefore the use is considered to be safe . (cPAD) cPAD = aRfD 10 = 0.0003 mg/kg/day = 0.00003 mg/kg/day 10 Acute Dietary Risk Assessment A revised acute dietary risk analysis was conducted with the DEEM The exposure at a maximum. > Acute food exposure, therefore the use is considered safe. Chronic Dietary Risk Assessment A chronic dietary risk analysis was conducted using the DRES analysis Using DRES, the Theoretical. 0.0000153mg/kg/day PAD > TMDI, therefore the use is considered safe. y Dietary Risk from Drinking Water • The EPA determines the dietary risk based on modeling or from monitoring data from both surface and