820K88120 DRAFT August, 1987 DISULFOTON Health Advisory Office of Drinking Water U.S. Environmental Protection Agency I. INTRODUCTION The Health Advisory (HA) Program, sponsored by the Office of Drinking Water (ODW), provides information on the health effects, analytical method- ology and treatment technology that would be useful in dealing with the contamination of drinking water. Health Advisories describe nonregulatory concentrations of drinking water contaminants at which adverse health effects would not be anticipated to occur over specific exposure durations. Health Advisories contain a margin of safety to protect sensitive members of the population. Health Advisories serve as informal technical guidance to assist Federal, State and local officials responsible for protecting public health when emergency spills or contamination situations occur. They are not to be construed as legally enforceable Federal standards. The HAs are subject to change as new information becomes available. Health Advisories are developed for one-day, ten-day, longer-term (approximately 7 years, or 10% of an individual's lifetime) and lifetime exposures based on data describing noncarcinogenic end points of toxicity. Health Advisories do not quantitatively incorporate any potential carcinogenic risk from such exposure. For those substances that are known or probable human carcinogens, according to the Agency classification scheme (Group A or B), Lifetime HAs are not recommended. The chemical concentration values for Group A or B carcinogens are correlated with carcinogenic risk estimates by employing a cancer potency (unit risk) value together with assumptions for lifetime exposure and the consumption of drinking water. The cancer unit risk is usually derived from the linear multistage model with 95% upper confidence limits. This provides a low-dose estimate of cancer risk to humans that is considered unlikely to pose a carcinogenic risk in excess of the stated values. Excess cancer risk estimates may also be calculated using the One-hit, Weibull, Logit or Probit models. There is no current understanding of the biological mechanisms involved in cancer to suggest that any one of these models is able to predict risk more accurately than another. Because each model is based on differing assumptions, the estimates that are derived can differ by several orders of magnitude. ------- Disulfoton August, 1987 -2- II. GENERAL INFORMATION AMD PROPERTIES CAS No. 298-04-4 Structural Formula - S-C,H5 0,0-Diethyl-S-[2-(ethylthio)-ethyl], phosphorodithioate Synonyms • Disulfoton; Disyston; Disystox; Dithiodemeton; Bayer 19639; Di-syston; Ethyl thiometon; Frumin AL; M-74 (Meister, 1983). Uses 0 Systemic insecticide-acaricide (Meister, 1983). Properties (Meister, 1983; Windholz et al., 1983) Chemical Formula Molecular Weight 274.38 Physical State (at 25°C) Pale yellow liquid Boiling Point 108eC (0.01 mm Hg); 132 to 133°C (1.5 mm Hg) Melting Point Density (20«C) 1.144 Vapor Pressure (at 20°C) 1.8 x 10-4 mn Hg Water Solubility (at 23°C) 25 mg/L Log Octanol/Water Partition Coefficient Taste Threshold Odor Threshold Conversion Factor ~ Occurrence * Disulfoton has been found in only 1 of the surface water samples and none of the ground water samples analyzed from 835 samples taken at 764 locations. (STORET, 1987). ------- Disulfoton August, 1987 -3- Environmental Fate 0 Disulfoton has a low mobility in Hugo sandy loam soil; 28% of the pesticide applied to a 6-inch-high soil column was eluted with a total of 110 feet of dilute buffer (McCarty and King, 1966). In another study, disulfoton sulfoxide and disulfoton sulfone were more mobile in sandy loam, clay loam and silty clay loam soils than the parent compound. Aging 32p- ------- Disulfoton August, 1987 —4— III. PHARMACOKINETICS Absorption 0 Puhl and Fredrickson (1975) administered by gavage single oral doses of disulfoton-o-ethyl-1-14c (99% purity) to Sprague-Dawley rats (12/sex/dose). Males received 1.2 mg/kg and females received 0.2 mg/kg. In the 10 days following dosing, an average of 81.6, 7.0 and 9.2% of the dose was recovered in the urine, feces and expired air, respectively. Males excreted 50% of the administered dose in the urine in the first 4 to 6 hours; females required 30 to 32 hours. These data indicate that disulfoton is absorbed readily from the gastrointestinal tract. Distribution 0 In the study by Puhl and Fredrickson (1975), described above, 4.1 and 16.1% of the administered dose was detected in the livers of males and females, respectively, and 0.4 and 1.2% of the dose was detected in the kidneys of males and females, respectively, 48 hours postdosing. Metabolism 0 March et al. (1957) studied the metabolism of disulfoton in vivo and in vitro in mice (strain not specified). In the in vivo portion of the study, mice received radiolabeled disulfoton intraperitoneally (dose not specified). Results indicated that unspecified urinary metabolites consisted mainly of hydrolysis products. In vitro metabolism data indicated the presence of dithio-systox sulfoxide and sulfone, and the thiol analog sulfoxide and sulfone. The dithio- systox sulfoxide was present in the greatest quantity followed by thiol analog sulfoxide, dithio-systox sulfone and thiol analog sulfone. Based on a review of these data (U.S. EPA, 1984a), it was concluded that the metabolism of disulfoton in mice involves at least two reactions: (1) the sequential oxidation of the thioether sulfur and/or oxidative desulfuration; and (2) hydrolytic cleavage of the ester, producing phosphoric acid, thiophosphoric acid and dithio- phosphoric acid. 0 In the above study by Puhl and Fredrickson (1975), the major urinary metabolites detected in both sexes were diethylphosphate (DEP) and diethylphosphorothioate (DEPT). These products were formed from hydrolysis of disulfoton and/or its oxidation products. Minor urinary metabolites included the oxygen analog sulfoxide, oxygen analog sulfone and disulfoton sulfoxide. Excretion In the above study by Puhl and Fredrickson (1975), 96 to 99% of the administered dose was recovered (81.6% in urine, 7.0% in feces and 9.2% as expired carbon dioxide during a 10-day postdosing period. Excretory pathways were similar for males and females, but the rate of excretion was slower for females. ------- Disulfoton August, 1987 -5- IV. HEALTH EFFECTS Humans Short-term Exposure 0 No significant anticholinesterase effects were observed in human subjects (five test subjects, two controls) who received disulfoton in doses of 0.75 mg/day (orally) for 30 days (Rider et al., 1972). 0 Quinby (1977) reported that three carpenters were sprayed accidentally with disulfoton while the compound was being applied by airplane to a wheat field adjacent to their work site. The individuals were reexposed as they handled contaminated building materials in the days following spraying. Exposure levels were not identified. The older two carpenters experienced coronary attacks and one had at least two severe cerebral vascular effects subsequent to exposure. The author postulated that the effects may have been due to disturbances of clotting mechanisms. Long-term Exposure 0 No Long-term human studies were identified for disulfoton. Animals Short-term Exposure 0 Reported acute oral LD50 values for adult rats administered disulfoton (approximately 94 to 96% purity when identified) ranged from 1.9 to 2.6 mg/kg for females and 6.2 to 12.5 mg/kg for males (Crawford and Anderson, 1973b; Bombinski and DuBois, 1957); a value of 5.4 mg/kg was reported for weanling male rats (Brodeur and Dubois, 1963). In guinea pigs, acute oral LD^g values ranged from 8.9 to 12.7 mg/kg (Bombinski and Dubois, 1957; Crawford and Anderson, 1973a). Mihail (1978) reported acute oral LD50 values of 7.0 mg/kg and 8.2 mg/kg in male and female NMRI mice, respectively. Hixson (1982) reported that the acute oral LD5Q of disulfoton (98% pure) in white Leghorn hens was 27.5 mg/kg. Hixson (1983) reported the results of an acute delayed neurotoxicity study in which 20 white Leghorn hens were administered technical disulfoton (97.8% pure) by gavage at a dose level of 30 mg/kg on two occasions, 21 days apart. The study also employed live animals for each of the negative controls, antidote controls and positive controls. Disulfoton did not produce acute delayed neurotoxicity under the conditions of this study. Based on this information, a No-Observed-Adverse-Effect-Level (NOAEL) of 30 mg/kg (the only dose tested) was identified in this study. Taylor (1965) reported the results of a demyelination study in which white Leghorn hens (six/dose) were administered disulfoton in the diet ------- Disulfoton August, 1987 -6- for 30 days at concentrations of 0, 2, 10 or 25 ppm. Assuming that 1 ppm in the diet of hens is equivalent to 0.06 mg/kg/day (Lehman, 1959), these dietary levels correspond to doses of about 0, 0.1, 0.6 and 1.5 mg/kg/day. The author indicated that no evidence of demyelina- tion was observed in any of the tissues examined. Based on this information, a NOAEL of 1.5 mg/kg/day (the highest dose tested) was identified. Dermal/Ocular Effects 0 DuBois (1957) reported that the acute dermal LD5Q of technical disulfoton in male Sprague-Dawley rats was 20 mg/kg. Mihail (1976) reported acute dermal 1.050 values of 15.9 mg/kg and 3.6 mg/kg in male and female Wistar rats, respectively. 0 No information was found in the available literature on the effects of ocular exposure to disulfoton. Long-term Exposure 6 Hayes (1983) presented the results of a 23-month feeding study in which CD-1 mice (50/sex/dose) were administered disulfoton (98.2% pure) at dietary concentrations of 0, 1, 4 or 16 ppm. Assuming that 1 ppm in the diet of mice is equivalent to 0.15 mg/kg/day (Lehman, 1959), these dietary levels correspond to doses of about 0, 0.15, 0.6 and 2.4 mg/kg/day. No treatment-related effects were observed in terms of body weight, food consumption or hematology. A statistically significant increase in mean kidney weight and kidney-to-body weight ratio was noted in high-dose females; this increase may have been associated with a nonsignificant increase in the incidence of malignant lymphomas of kidneys in this group. Plasma, red blood cell and brain cholinesterase (ChE) activity was decreased significantly in both sexes at the highest dose tested (16 ppm). However, since ChE activity was measured only in the control and high-dose groups, a NOAEL for this effect could not be determined. 0 In a study by Hoffman et al. (1975), beagle dogs (four/sex/dose) were administered disulfoton (95.7% pure) at dietary concentrations of 0, 0.5 or 1.0 ppm for 2 years. Assuming that 1 ppm in the diet of dogs is equivalent to 0.025 mg/kg/day (Lehman, 1959), these dietary levels correspond to doses of about 0, 0.0125 and 0.025 mg/kg/day. A fourth group of animals received disulfoton in the diet at 2 ppm for 69 weeks, then 5 ppm for weeks 70 to 72, and finally 8 ppm from week 73 until termination (104 weeks); these doses correpond to 0.05, 0.125 and 0.2 mg/kg/day, respectively. No treatment-related effects were observed in terms of general appearance, behavior, ophthalmoscopic examinations, food consumption, body weight, organ weight, hematology, clinical chemistry or histopathology. Additionally, no effects on ChE activity were observed in animals that received 0.5 or 1.0 ppm (0.0125 or 0.025 mg/kg/day). However, exposure at 2.0 ppm (0.05 mg/kg/day) for 69 weeks caused ChE inhibition in plasma and red blood cells in both sexes. Maximum inhibition occurred at week 40, when males exhibited 50% and 33% inhibition of Che in red blood cells and plasma; ------- Disulfoton August, 1987 -7- respectively; females exhibited 22 and 36% inhibition of ChE in red blood cells and plasma, respectively. At a dose level of 8 ppm (0.2 mg/kg/day), males exhibited 56 to 66% and 63 to 70% inhibition of red blood cell and plasma ChE, respectively; females exhibited 46 to 53% and 54 to 64% inhibition of red blood cell and plasma ChE, respectively. Based on these data, a NOAEL of U0 ppm (0.025 mg/kg/day) was identified. 0 Carpy et al. (1975) presented the results of a 2-year feeding study in which Sprague-Dawley rats (60/sex/dose) were administered disulfoton (95.7% pure) at dietary concentrations of 0, 0.5, 1.0 or 2.0 ppm. Based on data presented by the authors, these dietary levels correspond to doses of about 0, 0.02, 0.05 and 0.1 mg/kg/day for males and 0, 0.03, 0.04 and 0.1 mg/kg/day for females. At week 81 of the study, the 0.5-ppm dose was increased to 5.0 ppm (0.2 and 0.3 mg/kg/day for males and females, respectively) since no adverse effects were observed in the 1.0-ppm dose group. No treatment-related effects were observed in terms of food consumption, body weight, hematology, clinical chemistry, urinalysis and histopathology. A trend was observed at all dose levels toward increased absolute and relative spleen, liver, kidney and pituitary weights in males and toward decreased weights of these organs in females. In males receiving 5 ppm, the increases were statistically significant (p <0.05) for absolute spleen and liver weights. In females receiving 5 ppm, the decrease in absolute and relative kidney weights was statistically significant (p <0.05). At all levels tested, the brain showed a trend toward decreased absolute and relative weights in males and increased weights in females. Additionally, statistically significant inhibition of plasma, red blood cell and brain ChE was observed in both sexes at 2.0 and 5.0 ppm. At 1.0 ppm brain ChE in females was inhibited 11% (p <0.01). Based on this information, a Lowest-Observed-Adverse- Effect-Level (LOAEL) of 1.0 ppm (0.04 ing/kg/day for females) was identified for ChE inhibition. It was concluded (U.S. EPA, 1984a) that a NOAEL for systemic toxicity could not be identified due to the inadequacy of histopathology and necropsy data. 0 Hayes (1985) presented the results of a 2-year feeding study in which Fischer 344 rats (60/sex/dose) were administered disulfoton (98.1% pure) at dietary concentrations of 0, 0.8, 3.3 or 13 ppm. Assuming that 1 ppm in the diet of rats is equivalent to 0.05 mg/kg/day (Lehman, 1959), these dietary levels correspond to doses of about 0, 0.04, 0.17 and 0.65 mg/kg/day. Mortality was generally low for all groups with the exception of increased mortality in high-dose females during the last week of the study. No compound-rela ted effects were observed in terms of clinical chemistry, hematology or urinalysis. A dose-related trend in ChE inhibition was observed in both sexes at all dose levels. Statistically significant inhibition of plasma, red blood cell and brain ChE occurred in all dose groups throughout the study. Histopathologically, a statistically significant increase (p <0.05) in corneal neovascularization was observed in both sexes at 13 ppm (0.65 mg/kg/day). A dose-related increase in the incidence of optic nerve degeneration was also observed. This effect was statistically significant (p <0.05) in mid-dose males and in mid- and high-dose females. Additionally, a significantly (p <0.05) ------- Disulfoton August, 1987 -8- higher incidence of cystic degeneration of the Harderian gland was observed in females at all doses and in mid-dose males. A significantly (p <0.05) increased incidence of atrophy of the pancreas also was observed in high-dose males. On the basis of ChE inhibition, this study identified a LOAEL of 0.8 ppm (0.04 mg/kg/day) (lowest dose tested). Reproductive Effects 0 Taylor (1966) conducted a three-generation reproduction study in which albino Holtzman rats (20 females and 10 males) were administered disulfoton (98.5% pure) at dietary concentrations of 0, 2, 5 or 10 ppnu Assuming that 1 ppm in the diet of rats is equivalent to 0.05 mg/kg/day (Lehman, 1959), these dietary levels correspond to doses of about 0, 0.1, 0.25 and 0.5 mg/kg/day. At 10 ppm (0.5 mg/kg/day), litter size was reduced by 21% in the Pa and 33% in the Fb in both the first and third generations. Also in these generations, a 10 to 25% lower pregnancy rate was noted for Fa matings. Histopathologically, ?3b litters at 10 ppm (0.5 mg/kg/day) exhibited cloudy swelling and fatty infiltration of the liver (both sexes), mild nephropathy in kidneys (females) and juvenile hypoplasia of the testes. No histopathological examinations were conducted on the 2- and 5-ppm dose groups. Cholinesterase determinations revealed a 60 to 70% inhibition of red blood cell ChE in F^b litters and their parents at 5 and 10 ppm (0.25 and 0.5 mg/kg/day). At 2 ppm (0.1 mg/kg/day), the inhibition was insignificant in males and moderate (30 to 40%) in females. Based on these data, a LOAEL of 2 ppm (0.1 mg/kg/day) was identified for ChE inhibition. It was concluded (U.S. EPA, 1984a) that a reproductive NOAEL could not be determined due to deficiencies in data reporting (e.g., insufficient data on reproductive parameters, no statistical analyses, incomplete necropsy report and insufficient histopathology data). Developmental Effects 0 Lamb and Hixson (1983) conducted a study in which CD rats (25/dose) were administered disulfoton (98.2% pure) by gavage at levels of 0, 0.1, 0.3 or 1 mg/kg/day on days 6 through 15 of gestation. Mean plasma and red blood cell ChE activities were decreased significantly in dams receiving 0.3 and 1 mg/kg/day. Examination of the fetuses after Cesarean section reflected no increases in the incidence of soft tissue, external or skeletal abnormalities. However, at the 1.0-mg/kg/day dose level, increased incidences of incompletely ossified parietal bones and sternebrae were observed. This is considered a fetotoxic effect, since it is indicative of retarded development. Based on the information presented in this study, a developmental NOAEL of 0.3 mg/kg/day was identified based on fetotoxic effects. A NOAEL of 0.1 mg/kg/day was identified for ChE inhibition in treated dams, 0 Tesh et al. (1982) conducted a teratogenicity study in which New Zealand White rabbits were administered disulfoton (97.3% pure) at initial doses of 0, 0.3, 1.0 or 3.0 mg/kg on days 6 through 18 of ------- Disulfoton August, 1987 -9- gestation. Due to mortality and signs of toxicity, the high dose was reduced to 2.0 mg/kg/day and finally to 1.5 mg/kg/day. The control group consisted of 15 animals, the low- and mid-dose groups consisted of 14 does each and the high-dose group contained 22 animals. No signs of maternal toxicity were observed in the low- or mid-dose groups. In the high-dose group, signs of maternal toxicity included , muscular tremors, unsteadiness and incoordination, increased respiratory rate and increased mortality. No compound-related effects on maternal body weight or fetal survival, growth and development were observed. Based on this information, a NOAEL of 1.0 mg/kg/day was identified for maternal toxicity. The NOAEL for teratogenic and fetotoxic effects was 1.5 mg/kg/day (the highest dose tested). Mutagenicity 0 Hanna and Dyer (1975) reported that disulfoton (99.3% pure) was mutagenic in Salmonella typhimurium strains C 117, G 46, TA 1530 and TA 1535, and in Escherichia coli strains WP 2, WP 2uvrA, CM 571, CM 611, WP 67 and WP 12. These tests were performed without metabolic activation; however, demeton, the major metabolite of disulfoton, was also mutagenic in these microbial tests (U.S. EPA, 1984a). 0 Simmon (1979) presented the results of an unscheduled DNA synthesis assay using human fibroblasts (W 138). Disulfoton (purity not specified) was positive in this assay only in the absence of metabolic activation. Carcinogenic!ty 8 Carpy et al. (1975) presented the results of a 2-year feeding study in which Sprague-Dawley rats (60/sex/dose) were administered disulfoton (95.7% pure) at dietary concentrations of 0, 0.5, 1.0 or 2.0 ppm. Based on data presented by the authors, these dietary levels correspond to doses of about 0, 0.02, 0.05 and 0.1 mg/kg/day for males and 0, 0.03, 0.04 and 0.1 mg/kg/day for females. At week 81 of the study, the 0.5-ppm dose was increased to 5.0 ppm (reported to be equivalent to 0.2 and 0.3 mg/kg/day for males and females, respectively) since no adverse effects were observed in the 1.0-ppm dose group. The number of tumor-bearing animals at all dose levels was comparable to that of controls suggesting that, under the conditions of this study, disulfoton is not oncogenic. However, a review of this study (U.S. EPA, 1984a) concluded that due to numerous deficiencies (e.g., invalid high dose, insufficient necropsy data, insufficient histology data), the data presented were inadequate for an oncogenic evaluation. 0 Hayes (1983) presented the results of a 23-month feeding study in which CD-1 mice (50/sex/dose) were administered disulfoton (98.2% pure) at dietary concentrations of 0,- 1, 4 or 16 ppm. Assuming that 1 ppm in the diet of mice is equivalent to 0.15 mg/kg/day (Lehman, 1959), these dietary levels correspond.to doses of about 0, 0.15, 0.6 and 2.4 mg/kg/day. The incidence of specific neoplasms was similar among treated and control animals. There, was an increased incidence of malignant lymphoma (the most frequently observed neoplastic lesion) in both males and females at 16 ppm (2.4 mg/kg/day) when compared with ------- Disulfoton August, 1987 -10- controls, but this change was not statistically significant. Therefore, under the conditions of this study, disulfoton was not oncogenic in mice at dietary concentrations up to 16 ppm (2.4 mg/kg/day). 0 Hayes (1985) presented the results of a 2-year feeding study in which Fischer 344 rats (60/sex/dose) were administered disulfoton (98.1% pure) at dietary concentrations of 0, 0.8, 3.3 or 13 ppm, corresponding doses of about 0, 0.04, 0.17 and 0.65 mg/kg/day (Lehman, 1959). The most commonly occurring neoplastic lesions included leukemia, adenoma of the adrenal cortex, pheochromocytoma, fibroadenoma of the mammary glands, adenoma and carcinoma of the pituitary glands, interstitial cell adenoma of the testes, and uterine stromal polyps. The incidences of these lesions showed no dose-related trend and were not significantly different in treated versus control animals. Therefore, under the conditions of this assay, disulfoton was not oncogenic in male or female Fischer 344 rats at dietary concentrations up to 13 ppm (0.65 mg/kg/day). V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS Health Advisories (HAs) are generally determined for one-day, ten-day, longer-term (approximately 7 years) and lifetime exposures if adequate data are available that identify a sensitive noncarcinogenic end point of toxicity. The HAs for noncarcinogenic toxicants are derived using the following formula: HA = (NOAEL or LOAEL) x (BW) , /L ( /L) (UF) x ( L/day) where: NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level in mg/kg bw/day. BW = assumed body weight of a child (10 kg) or an adult (70 kg). UF = uncertainty factor (10, 100 or 1,000), in accordance with NAS/ODW guidelines. ^^_^ L/day = assumed daily water consumption of a child (1 L/day) or an adult (2 L/day). One-day Health Advisory No suitable information was found in the available literature for the determination of a One-day HA value for disulfoton. It is, therefore, recommended that the Ten-day HA value for a 10-kg child of 0.01 mg/L (10 ug/L), calulated below, be used at this time as a conservative estimate of the One-day HA value. ------- Disulfoton August, 1987 Ten-day Health Advisory The developmental toxicity study by Lamb and Hixson (1983) has been selected to serve as the basis for the Ten-day HA value for disulfoton. In this study, CD rats were administered disulfoton (98.2% pure) by gavage at doses of 0, 0.1, 0.3 or 1 mg/kg/day on days 6 through 1 5 of gestation. Mean plasma and red blood cell ChE activities were decreased significantly in dams receiving 0.3 and 1 mg/kg/day. Based on this information, a NOAEL of 0.1 mg/kg/day was identified. The only other study of comparable duration was a rabbit teratology study (Tesh et al., 1982). This study identified NOAELs of 1.0 mg/kg/day for maternal toxicity and 1.5 mg/kg/day (the highest dose tested) for developmental toxicity. The rabbit appeared to be less sensitive to disulfoton than the rat, therefore the rat study was selected for this calculation. Using a NOAEL of 0.1 mg/kg/day, the Ten-day HA for a 1 0-kg child is calculated as follows: Ten-day HA = (0-1 mg/kq/day) (10 kg) . 0.01 mg/L (10 ug/L) (100) (1 L/day) where: 0.1 mg/kg/day « NOAEL, based on the absence of ChE effects in female rats administered disulfoton by gavage on days 6 through 1 5 of gestation. 1 0 kg * assumed body weight of a child. 1 00 = uncertainty factor chosen in accordance with NAS/ODW guidelines for use with a NOAEL from an animal study. 1 L/day = assumed daily water consumption by a child. Longer-term Health Advisory The 2-year dog feeding study by Hoffman et al. (1975) has been selected to serve as the basis for the Longer-term HA values for disulfoton. In this study, beagle dogs were administered disulfoton (95.7% pure) at dietary concentrations of 0, 0.5 or 1.0 ppm (0, 0.0125 and 0.025 mg/kg/day). A fourth group of dogs received disulfoton at 2.0 ppm (0.05 mg/kg/day) for 69 weeks, then 5.0 ppm (0.125 mg/kg/day) for weeks 70 to 72, and finally 8.0 ppm (0.2 mg/kg/day) from weeks 73 to 104. Exposure to 2.0 ppm (0.05 mg/kg/day) for 69 weeks caused plasma and red blood cell ChE inhibition in both sexes. Brain ChE inhibition was also noted at termination in this group. Based on this information, a NOAEL of 1.0 ppm (0.025 mg/kg/day) was identified. No other suitable studies were available for consideration for the Longer-term HA. Since the effects in the study by Hoffman et al. (1975) were observed following 69 weeks of exposure, the study is considered to be of appropriate duration for derivation of a Longer-term HA. Using a NOAEL of 0.025 mg/kg/day, the Longer-term HA for a 1 0-kg child is calculated as follows: ------- Disulfoton August, 1987 -12- Longer-term HA - (0.025 mg/kg/day) (10 kg) „ 0.0025 mg/L (3 ug/L) (100) (1 L/day) where: 0.025 ing/kg/day = NOAEL, based on the absence of ChE effects in dogs administered disulfoton in the diet; ChE effects were noted at the higher dose during the first 40 to 69 weeks of exposure and thereafter. 10 kg - assumed body weight of a child. 100 « uncertainty factor, chosen in accordance with NAS/ODW guidelines for use with a NOAEL from an animal study. 1 L/day * assumed daily water consumption of a child. Using a NOAEL of 0.025 mg/kg/days, the Longer-term HA for a 70-kg adult is calculated as follows: Longer-term HA = (0-025 mg/kg/day) (70 kg) = 0.0088 mg/L (9 ug/L) (100) (2 L/day) where: 0.025 mg/kg/day » NOAEL, based on the absence of ChE effects in dogs administered disulfoton in the diet; ChE effects were noted at the higher dose during the first 40 to 69 weeks of exposure and thereafter. 70 kg = assumed body weight of an adult. 100 = uncertainty factor, chosen in accordance with NAS/ODW guidelines for use with a NOAEL from an animal study. 2 L/day = assumed daily water consumption of an adult. Lifetime Health Advisory The Lifetime HA represents that portion of an individual's total exposure that is attributed to drinking water and is considered protective of noncar- cinogenic adverse health effects over a lifetime exposure. The Lifetime HA is derived in a three-step process. Step 1 determines the Reference Dose (RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti- mate of a daily exposure to the human population that is likely to be without appreciable risk of deleterious effects over a lifetime, and is derived from the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided by an uncertainty factor. From the RfD, a Drinking Water Equivalent Level (DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking^ water) lifetime exposure level, assuming 100% exposure from that medium, at which adverse, noncarcinogenic health effects would not be expected to occur. ------- Disulfoton August, 1987 -13- The DWEL is derived from the multiplication of the RfD by the assumed body weight of an adult and divided by the assumed daily water consumption of an adult. The Lifetime HA is determined in Step 3 by factoring in other sources of exposure, the relative source contribution (RSC). The RSC from drinking water is based on actual exposure data or, if data are not available, a value of 20% is assumed for synthetic organic chemicals and a value of 10% is assumed for inorganic chemicals. If the contaminant is classified as a Group A or B carcinogen, according to the Agency's classification scheme of carcinogenic potential (U.S. EPA, 1986a), then caution should be exercised in assessing the risks associated with lifetime exposure to this chemical. The studies by Hayes (1985) and Carpy et al. (1975) have been selected to serve as the bases for the Lifetime HA values for disulfoton. Each of these studies identifies a LOAEL of 0.04 mg/kg/day. In the Hayes (1985) study, Fischer 344 rats were administered disulfoton (98.1% pure) at dietary concentrations of 0, 0.8, 3.3 or 13 ppm (0, 0.04, 0.17 and 0.65 mg/kg/day) for 2 years. Dose-related, statistically significant inhibition of ChE in plasma, red blood cell and brain was observed in both sexes at all doses; also, a dose-related optic nerve degeneration was observed in females. Based on this information, a LOAEL of 0.04 mg/kg/day was identified. In the Carpy et al. (1975) 2-year study, Sprague-Dawley rats were administered disulfoton (95.7% pure) at dietary concentrations of 0, 0.5, 1.0 or 2.0 ppm (0, 0.02, 0.05 and 0.1 mg/kg/day for males and 0, 0.03, 0.04 and 0.1 mg/kg/day for females). At week 81 of the study, the 0.5 ppm dose was increased to 5.0 ppm (equivalent to 0.2 and 0.3 mg/kg/day for males and females, respectively). Statistically significant inhibition of plasma and red blood cell ChE was observed in both sexes at 2.0 and 5.0 ppm. Additionally, at 1 ppm (0.04 mg/kg/day), brain ChE was inhibited significantly (p <0.01) in females. Since the initial low dose used in the study (0.5 ppm) was raised to 5.0 ppm, the 1.0-ppm dose is the lowest dose tested and represents the study LOAEL. Using a LOAEL of 0.04 mg/kg/day, the Lifetime HA is calculated as follows: Step 1: Determination of the Reference Dose (RfD) RfD = (0.04 mg/kg/day) = 0.00004 mg/kg/day (1,000) where: 0.04 mg/kg/day = LOAEL, based on ChE inhibition anf optic nerve degeneration in rats exposed to disulfoton in the diet for 2 years. 1,000 = uncertainty factor, chosen in accordance with NAS/ODW guidelines for use with a LOAEL from an animal study. Step 2: Determination of the Drinking Water Equivalent Level (DWEL) DWEL = (0.00004 mg/kg/day) (70 kg) = Q.0014 mg/L (1 ug/L) (2 L/day) ------- Disulfoton August, 1987 -14- where: 0.00004 mg/kg/day * RfD. 70 kg = assumed body weight of an adult. 2 L/day - assumed daily water consumption of an adult. Step 3: Determination of the Lifetime Health Advisory (HA) Lifetime HA - (0.0014 mg/L)(20%) = 0.0003 mg/L (0.3 ug/L) where: 0.0014 mg/L * DWEL. 20% = assumed relative source contribution from water. Evaluation of Carcinogenic Potential 0 Three studies were available on the carcinogenicity of disulfoton. The chronic study in rats by Carpy et al. (1975) was inadequate for an oncogenic evaluation. The remaining two studies presented results indicating that disulfoton was not carcinogenic in mice (Hayes, 1983) or in rats (Hayes, 1985). e The International Agency for Research on Cancer has not evaluated the carcinogenicity of disulfoton. * Applying the criteria described in EPA's guidelines for assessment of carcinogenic risk (U.S. EPA, 1986a), disulfoton may be classified in Group E: no evidence of carcinogenicity in humans. This category is used for substances that show no evidence of carcinogenicity in at least two adequate animal tests or in both epidemiologic and animal studies. However, disulfoton and its metabolites are mutagenic compounds (see section on Mutagenicity). VI. OTHER CRITERIA, GUIDANCE AND STANDARDS 0 The National Academy of Sciences (NAS, 1977) has calculated an ADI of 0.0001 mg/kg/day, based on a NOAEL of 0.01 mg/kg/day from a subchronic dog feeding study on phorate (a closely related organophosphorus insecticide) and an uncertainty factor of 100, with a Suggested-No- Adverse-Response-Level (SNARL) of 0.0007 mg/L. • The World Health Organization (WHO, 1976) has identified an ADI of 0.002 mg/kg/day based on chronic data from a 2-year chronic feeding study in dogs (Hoffman et al., 1975) with a NOAEL of 0.025 mg/kg/day. 0 U.S. EPA Office of Pesticide Programs (OPP) has established residue tolerances for disulfoton at 0.1 to 0.75 ppm in or on a variety of raw agricultural commodities (U.S. EPA, 1985). At the present time, these tolerances are based on a Provisional ADI (PADI) of 0.00004 ------- Disulfoton August, 1987 -15- mg/kg/day. As for the RfD calculation, this PADI is calculated based on a LOAEL of 0.8 ppm (0.04 mg/kg/day) for both ChE inhibition and optic nerve degeneration that were identified in the 2-year rat feeding study by Hayes (1985) and using a safety factor of 1,000. VII. ANALYTICAL METHODS 0 Analysis of disulfoton is by a gas chromatographic (GC) method appli- cable to the determination of certain nitrogen-phosphorus-containing pesticides in water samples (U.S. EPA, 1986b). In this method, approximately 1 L of sample is extracted with methylene chloride. The extract is concentrated and the compounds are separated using capillary column GC. Measurement is made using a nitrogen-phosphorus detector. The method detection limit has not been determined for disulfoton, but it is estimated that the detection limits for analytes included in this method are in the range of 0.1 to 2 ug/L. VIII. TREATMENT TECHNOLOGIES 0 No information was found in the available literature regarding treat- ment technologies used to remove disulfoton from contaminated water. ------- Disulfoton August, 1987 -16- IX. REFERENCES Bombinski, T.J., and K.P. Dubois.* 1957. Itie acute mammalian toxicity and pharmacological actions of Di-Syston. Report No. 1732. Unpublished study received Nov. 20, 1957 under 3125-58; prepared by Univ. of Chicago, Dept. of Pharmacology, submitted by Mobay Chemical Corp., Kansas City, MO. CDL:100153-B. MRID 00069347. Brodeur, J., and K.P. Dubois.* 1963. Comparison of acute toxicity of anticholinesterase insecticides to weanling and adult male rats. jCn Proceedings of the Society for Experimental Biology and Medicine. Vol. 114. New York: Academic Press, pp. 509-511. MRID 05004291. Carpy, S., C. Klotzsche and A. Cerioli.* 1975. Disulfoton: 2-year feeding study in rats: AGRO DOK CBK 1854/74. Report No. 47069. Unpublished study received December 15, 1976 under 3125-58; prepared by Sandoz, Ltd., Switzerland, submitted by Mobay Chemical Corp., Kansas City, MO. CDL:095641-C. MRID 00069966. Chemagro Corporation. 1969. Di-Syston soil persistence studies. Unpublished study. Crawford, C.R., and R.H. Anderson.* 1973a. The acute oral toxicity of Di-Syston technical to guinea pigs. Report No. 39113. Unpublished study received December 15, 1976 under 3125-58; submitted by Mobay Chemical Corp., Kansas City, MO. CDL:095640-F. MRID 00071872. Crawford, C.R., and R.H. Anderson.* 1973b. The acute oral toxicity of several Di-Syston metabolites to female and male rats. Report No. 39687. Unpublished study received December 15, 1976 under 3125-58; submitted by Mobay Chemical Corp., Kansas City, MO. CDL:095640-G. MRID 00071873. Doull, J.* 1957. The acute inhalation toxicity of Di-Syston to rats and mice. Report No. 1802. Unpublished study received November 20, 1957 under 3125-58; prepared by Univ. of Chicago, Dept. of Pharmacology, submitted by Mobay Chemical Corp., Kansas City, MO. CDL:1001 53-D. Fiche Master ID 00069349. DuBois, K.P.* 1957. The dermal toxicity of Di-Syston to rats. Report No. 2063. Unpublished study received January 23, 1958 under unknown admin. no.; prepared by Univ. of Chicago, Dept. of Pharmacology, submitted by Mobay Chemical Corp., Kansas City, MO. CDL:109216-8. MRID 00043213. DuBois, K.P., and F.K. Kinoshita.* 1971. Effect of repeated inhalation exposure of female rats to Di-Syston. Submitted 30571. Unpublished study received November 30, 1971 under 3125-119; prepared by Univ. of Chicago, Toxicity Laboratory, submitted by Mobay Chemical Corp., Kansas City, MO. CDL:10059-A. MRID 00087935. Flint, D.R., D.D. Church, H.R. Shaw and J. Armour II. 1970. Soil runoff, leaching and adsorption, and water stability studies with Di-Syston: Report No. 2899. Unpublished study submitted by Mobay Chemical Kansas City, MO. ------- Disulfoton August, 1987 « -17- Hanna, P.J., and K.F. Dyer. 1975. Mutagenicity of organophosphorus compounds in bacteria and Drosophila. Mutat. Res. 28:405-420. Hayes, R.H.* 1983. Oncogenicity study of disulfoton technical on mice. An unpublished report of study No. 80-271-04 prepared by the Corporate Toxicology Department, Mobay Chemical Corp., Stilwell, KS. Dated Aug. 10, 1983. MRID 0000000. Hayes, R.H.* 1985. Chronic feeding/oncogenicity study of technical disulfoton (Di-Syston) with rats. Unpublished study no. 82-271-01. Prepared by Mobay Chemical Corp. Accession No. 258557. Hixson, E.J.* 1982. Acute oral toxicity of Di-Syston technical in hens. An unpublished report (No. 341) prepared by the Environmental Health Research Institute of Mobay Chemical Corp., Stilwell, KS. Study No. 82-018-01, dated Oct. 25, 1982. MRID 00000000. Hixson, E.J.* 1983. Acute delayed neurotoxicity study on disulfoton. 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Persistence and degradation of chlorfenvinphos, chlormephos, disulfoton, phorate and primiphos-ethyl following spring and late-summer soil application. Unpublished study submitted by ICI Americas, Inc., Wilmington, DE. ------- Disulfoton August, 1987 -19- Taylor, R.E.* 1965. Letter sent to Chemagro Corporation dated Jan. 5, 1965: Report on demyelination studies on hens. Report No. 15107. Unpublished study received March 24, 1965 under 6F0478; prepared by Harris Labora- tories, Inc., submitted by Mobay Chemical Corp., Kansas City, MO. CDL.-090534-C. MRID 00057265. Taylor, R.E.* 1966. Letter sent to D. MacDougall dated May 5, 1966: Di-Syston, three generation rat breeding studies: Submitter 18154. Unpublished study received March 7, 1977 under 3125-252; prepared by Harris Labora- tories, Inc., submitted by Mobay Chemical Corp., Kansas City, MO. CDL:096021-L. MRID 00091104. Tesh, J.M. et al.* 1982. S 276: Effects of oral administration upon pregnancy in the rabbit. An unpublished report (Bayer No. R 2351) prepared by Life Science Research, Essex, England and submitted to A.G. Bayer, Wuppertal, Germany. Dated Dec. 22, 1982. MRID 00000000. Thornton, J.S., J.B. Hurley, and J.J. Obrist. 1976. Soil thin-layer mobility of twenty-four pesticide chemicals: Report No. 51016. Unpublished study submitted by Mobay Chemical Corporation, Kansas City, MO. U.S. EPA.* 1984a. U.S. Environmental Protection Agency. Disulfoton (Di-Syston) Registration Standard. Washington, DC: Office of Pesticide Programs. U.S. EPA. 1985. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 180.183. July 1, 1985. U.S. EPA. 1986a. U.S. Environmental Protection Agency. Guidelines for carcinogen risk assessment. Fed. Reg. 51(185):33992-34003. September 24. U.S. EPA. 1986b. U.S. Environmental Protection Agency. U.S. EPA Method #1 - Determination of nitrogen and phosphorus containing pesticides in ground water by GC/NPD, January 1986 draft. 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