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ClILORPYRIFOS BACKGROUND INFORMAT ION Chlorpyrifos, an organophosphate pesticide, is a white, crystalline solid marketed as Duroban and Loroban. It has a wide variety of uses, including control of f ire ants, turf and ornamental plant insects, mosquitoes, cockroaches, and termites; as a soil insecticide; seed treatment; and application to dormant and foliar plants. In August 1980, EPA granted a conditional registration for use of chlorpyrifos as a subsurface termiticide. Physical and chemical properties of chlorpyrifos are shown in Table 1. SUbMARY OF TOXICITY INFORMATION EFFECTS IN [lUMANS Some studies have investigated the effects of airborne chlorpyrifos on humans. Ludwig _ al. (1970) exposed volunteers to a fog containing varying concentrations of chlorpyrifos and examined ehe effects on plasma cholinesterase and red-cell cholinesterase activity. Decreases in plasma cholinesterase (peeudocholinesterase) activity of 84-85 percent were observed in volunteers 24 h after exposure at 132.6 mgJm3 for 2 min and at 80.4 mg/m3 for 4 min. Recovery to preexposure values occurred within 96 h. There was no effect on red-cell cuolinesterase activity. No changes in the activity of either cholinesterase were detected 24 h after exposure at 79.1 mg/~ for 1 min or at 1.1 mg/m3 for ~ min. The authors did not state whether any ocher changes were observed after exposure to chlorpyrifos. Eliason et al. (1969) examined the effects on plasma cholinesterase activity in workers who had sprayed chlorpyrifos for mosquito control. One group of five men had used ~ 0.5 percent emulsion of chlorpyrifos for 9 d; ~ second group of four men had sprayed a total of 177 gal of a 0.25 percent suspension and 145 gal of a 0.5 percent emulsion for 5 d; and a third group of seven men had applied 8 0.5 percent emulsion or suspension of chlorpyrifo. for 2 wk. In the first group, three of the men had decreases in plasma cholinesterese activity of 65-62 percent, compared with preexposure values; the other two had-decreases of up to 52 percent and 56 percent during the 9-d spraying period, but no preexposure values were recorded. In the second group, no significant changes in plasma cholinesterase were observed during exposure to chlorpyrifos. In the shirt group, plasma cholinesterase activity was determined before, during, and after exposure to chlorpyrifos and compared with preexposure values and with values measured in four men not exposed to chlorpyrifos. After 1.5 wk of spraying, four of the workers had decreases in plasma cholinesterase activity of 41-91 percent, two 37

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other workers bad much smaller decreases (7 percent and 15 percent), and cholinesterase activity was not measured in the seventh worker. Continued exposure for an additional 4 d did not result in further decrease in plasma cholinestera8e activity. Inhibition of the enzyme was reversible: 37 d after exposure ended, the activity was similar to or greater than the preexposure activity in six of the seven workers. The four men who served as unexposed controls exhibited little change in plasma cholinesterase activity during the 2-wk observation period concomitant with the exposure period of the exposed workers. From the data supplied on the number of gallons of chlo~pyrifos that each worker sprayed, it was evident that the decrease in plasma cholinesterase activity was generally related to the amount of material to which a worker was exposed. No clinical manifestations of toxicity were observed in any of the workers in the three groups exposes to chlorpyrifos. Coulston et al. (1972) gave groups of four men chlorpyrifos orally at 0.014 mg/kg of body weight per day for 28 d, 0.03 mg/kg per day for 21 d, or 0. 10 mg/kg per day f or 9 d . Cb 1 orpyri foe a t 0. 014 or 0 .03 mg/kg per day had no ~ ignif icant ef fee ~ on plasma and Medical 1 cholinesterase activity; nor were any other effects observed. A dosage of 0.10 mg/kg resulted in a decrease in plasma cholinesterase activity of 34 percent of baseline in 9 d, ant treatment was stopped. Cholinesterase activity returned to preexposure values within 4 wk. Chlorpyrifoe can be absorbed through the skin to produce toxic effects; however, prolonged exposure appears necessary for appreciable absorption to take place. When chlorpyrifos in a xylene solution was applied to the akin of volunteers for 12 h at 50, 7.5, 5.0, 3.0, t.5, and 1.0 mg/kg, no effects on plasma or red-cell cholinesterase activity were obeervet (Kilian et al., 1970; Pennington and Edwards, 1971~. Some changes were noticed when chlorpyrifos was given for several 12-h periods with 12-h intervals between exposures. A woman given three dermal applications of chlorpyrifos at 25 mg/kg of body weight hat decreases in plasma cholinesterase activity of 67 percent and 47.5 percent (compared with preexposure activity) 12 and 60 h, respectively, after the final application. Another WOm;lQ was given 20 dental applications at 5 mg/kg; she exhibited no decrease in plasma cholinesterase activity during the exposure period, but a decrease of 64.3 percent 12 h after the last exposure. No effects on red-cell cholinesterase were detected in either subject; by 7.5 d after the exposures ended, plasma cholinesterase activity had returned to normal EFFECTS IN ANIMALS Acute Exposure LD,o values for rats indicate that chlorpyrifo. is absorbed through the akin An appreciable amounts. The dental LDs<) for male rats, 202 mg/kg, is in the range of the oral LDso, 135-245 mg/kg (Gaines, 1969; Gray, 1965; McCollister et al; 1974~. Studies in other animals have choirs a wide range of sensitivity. me oral Ll~,o for chickens - 38 -

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is 32-34.8 mg/kg (Gray, 1965; Miyazaki and Hodgoon, 1972); for guinea pigs, 500 mg/kg (Gray, 1965); and for rabbits, 1,000-2,000 mg/kg (Gray, 1965). Information on the denmal effects of chlorpyrifos, although minimal, 8ugge8t8 that precautions should be taken to prevent skin contact. Prolonged dermal exposure of rabbits to chlorpyrifos resulted in burning, hardening of the skin, swelling, and hyperemia (~10, 1973~. Inhalation studies in animals have examined the effects of chlorpyrifos on cholinesterase activity. Dogs, rats, sheep, and pigs exposed to a "thermal to'" or "wet-mist f og" spray c ontaining culorpyrifos at 145 mg/m:, for an unspecif fed period showed no inhibition of cholinesterase (Gray, 1965~. Rat!. that received chlorpyrifos at 0.007 mg/m3 for ~ Sixteen 7-h exposures over a 21-d period exhibited no decrease in blood cholinesterase activity (Tor~elson, 1965~. ~~ s~~e A_ _~_~iCitY Although no data were fount on the effects of long-term inhalation of chlorpyrifos, long-term feeding studies in animals have determined no-adverse-effec t level ~ with regard to chat inesterase inhibition. Groups of rats and dogs received chlorpyr~fos in the diet for 2 yr at 0-3 mg/kg of body weight per day, ant plasma and ret~cell cholinesterase activity was measured at various intervals (McCollzater et al; 1974~. Dosages of 0.1 mg/kg per day or less had no effect on asma and red-cell cholinesterase activity in rats, whereas 0.03 mg/kg per day was the largest dose tested that had no measurable ef feet in dogs. Higher dietary concentrations of chlorpyrifos caused significant decreases in cholinesterase activity. No signs of toxicity were observed za any of the animals during the experiment. In another long-Berm study (Warner et al., 1980), CD-1 mice were given chlorpyrifos in the diet at 0.85, b.7;!, and 15.8 ppm (approximately 0.05, 0.5, and 1.5 mg/l~g of body weight per day, respectively) for 105 wk. There was no significant effect on behavior, mortality, food consumption, body weight, or organ weight in treated animals, compared with controls. A variety of square (such as lung, liver, and lymphoreticular) and other lesion. (such as inflammation and t~yperplasia) were observed in control and treated mice. There appeared to be co tumors directly related to admiD-istration of chlorpyrifos. Teratogenicity and Reproductive Effects Pregnant CE-1 mice were given chlorpyrifos by garage at 0, 1, 10, or 25 mg/kg on days 6-15 of gestation (Deacon et al., 1980~. Severe maternal toxicity was observed at 25 mg/kg, and there was a decrease in plasma ant red-cell cholinesterase activity at all dosages, compared with controls. Fetotoxicity was also reported at 25 mg/kg, ant there was an increase in exencepaly at 1 mg/kg, but not at 10 or 25 mg/kg. The authors repeated the experiment with dosages of 0, 0.1, 1, ant 10 mg/kg. There was a decrease in cholinesterase activity at 1 - 39 -

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or 10 mg/kg; however, no teratogenic effects were observed at any of these dosages. Mutagenicity The mutagenic potential of chlorpyrifos was investigated in several strains of Salmonella typhimurium and Escherichia cold with a rat liver meeabolic-activation system (Poole et al., 1977; Shirasu et al., 1976~. The results were negative in each of the tests. Toxicokinet ice Chlorpyrifos metabolism has been investigated in a few species. When rats were given a single 5-mg dose of chlorpyrifos labeled with carbon-14 by stomach tube, 88.4 percent of the total dose was recovered in the urine within 48 h (Bakke et al., 1976~. Compounds identified in the urine Included the glucuron~de of 3,5,6-trichloro-2-pyridinol (80 percent), 3,5,6-trichloro-2-pyridinol (13 percent), and 3,5,6-trichloro-2-pyritinol glucoside (4 percent). Smith et al. (1967) found that 90 percent of the radioactivity from a 10-mg dose of chlorpyrifos labeled with chlorine-36 administered to rats by stomach tube was recoverable in 24 h--90 percent of it in the urine and 10 percent in the feces. Isolated metabolites included 3, 5, 6- trichl oro-2~pyridyl pho ~ phase ~ 7 5-80 percent ), 3,5,6-trichloro-2-pyridinol (15-20 percent), and chlorpyrifos (traces). The authors fount little accumulation of chlorpyrifos in any tissue except fat. The biologic half-1 ives were 10 h in the liver, 12 h in the kidney, 16 h in skeletal muscle, and 62 h in fee. The principal urinary metabolites of chlorpyrifo. in COWS were fount to differ from those in rate. When a lactating cow was fed chlorpyrifo. in the diet at 5 ppm per day for 4 d, desethylated chlorpyrifos derivatives were not fount (Gutenmann et al., 1968). Instead, diethylmethyl thiopbosphate (35.9 percent of total dose) and diethylmethyl phosphate (26.8 percent) were recovered in the urine, and chlorpyrifo. (1. 7 percent) was found in the feces. No traces of chlorpyrifo. were found in the milk. In another study on lactating c owe (McKellar et al., 1976), chlorpyrifo. was given in the diet at 0.3, 1, 3, 10, and 30 ppe consecutively, each for 14 d. Milk ant cream samples were collected throughout the experiment. Chlorpyrifos was Resected in the milk at 0.01 ppm for the 30-ppm concentration and Higher the at lees than 0.01 ppm for the other dietary concentrations. concentratione of chlorpyrifoe were found in the crease, and residues increased with increasing dietary content. The concentratione of chlorpyrifos in the cream were less than 0.01 ppm at a dietary concentration of 3 ppm or lower, 0.03 ppm at 10 ppm, and 0.10 ppm at 30 ppm. The residues of 3,5,6-trichloro-2-pyridinol in the milk were lees than 0.01 ppm at a dietary concentration of 10 ppm or less and 0.01 ppm at 30 ppm, and all cream samples hat pyridinol at less than 1).025 ppm. The oxygen analogue of chlorpyrifos, which is a more potent chol inesterase inhibitor than the parent compound, was detected at less than 0.01 ppm in all milk and cream samples. 40

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Tranformation of chlorpy2-ifos to 3,5,6-trichloro-2-pyridinol, one of the major metabolizes in rats, results in a far less toxic product that is readily removes in the urine. me oral LDsos of this Hydrolysis product are 794 mg/kg for rats and over 1,000 mg/kg for chickens, compared with oral LD,o. of chlorpyrifos of 138-245 mg/kg for rats and 3S mg/kg for chickens (Miyazaki and Hodgeon, 1972; WilO, 1 9 73) . EXIST ING GUIDELINES AND STANDARDS ACGIH ( 1981 ) has recommended a TLV-TWA of 0.2 mg/m3 and a TLV-STEL of t). 6 mg/m3 for chlorpyrifos. It was noted that chlorpyrifos is absorbed through the skin and that dermal exposure should therefore be avoided. ACGIl1 ( 1980) cited data from lon8-te~ feeling studies in dogs and rats and short-term feeding studies in humans that del ineated the effects on cholinesterase activity and concluded that 0.2 mg/m3 "provides a very wide margin of safety in preventing cholinergic symptoms or organic in jury . " The NRC Committee on Toxicology (1978), in a review of chlorpyrifos, used an extrapolation from ingestion to inhalation exposure to suggest an appropriate airborne concentration in submarines. If it is ase~et that a given amount of chlorpyrifos has the same effect by inhalation as by ingestion and if average values for minute volume and body weight are used, the approximate no~adveree-effect level from airborne exposure can be calculated. If one assumes a minute volume of 25 L/min as the average for a man doing light to medium work for 12 h and 7 L/min while he is at rest (Altman and Dittmer, 1974) and a no~adverse-effect level for plasma and red-cell cholinesterase activity for humans of 0.03 mg/kg, the approximate no-adverse-effect airborne concentration for a 70-kg man would be O. 1 mg/m3. The value of an extrapolation of this nature is obviously limited by the vat idity of its assumptions. However, with the 1 imited amount of inhalation data available, it provided the best approximation of the exposure-effec t relationship for chlorpyrifos; and there is a built-in safety factor, in that it assumes that 10~) percent of the inhaled chl orpyrifos is absorbed . To prevent significant decreases in cholinesterase activity, which court cause functional alterations, a 90-d continuous exposure limit for chlorpyrifo. of 0.10 mg/~3, derived from the no-adveree~effect level for ingestion, was recommended by the NRC Committee on Toxicology ( 1978~ . Ibe recommendation assumed that exposure to chlorpyrifo. would be only by inhalation. 41

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