820K88003 August, 1987 DRAFT FONOFOS 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 thes^ 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. ------- Fonofos August, 1987 II. GENERAL INFORMATION AND PROPERTIES CAS No. 944-22-9 Structural Formula 0-Ethyl-s-phenylethylphosphonodithioate Synonyms 0 Difonate; Difonatal; Dyfonate; Dyfonate®; Dyphonate*; ENT 25, 796; Fonophos; Stauffer N2790 (Meister, 1983). Uses 0 Soil insecticide (Meister, 1983). Properties (Windholz et al.( 1983; TDB, 1985) Chemical Formula C10H15OS2P Molecular Weight 246.32 Physical State (25°C) Light yellow liquid Boiling Point 130°C Melting Point — Vapor Pressure (25°C) 2.1 x 10~4 mm Hg Specific Gravity (20°C) 1.154 Water Solubility (25°C) Practically insoluble Octanol/Water Partition Coefficient Taste Threshold —- Odor Threshold -- Conversion Factor — Occurrence 0 Fonofos has been detected in ground waters in California at 0.01 to 0.03 ppb (U.S.G.S. Regional Assessment Project, C. Eiden, 1985). 0 Fonofos has been found in tailwater pit sediment and water samples. Monitoring studies conducted in 1973 and 1974 in Haskell County, Kansas, showed that the highest concentrations found were 770 ppb for sediment and 5.9 ppb for water during 1974. Mean peak concen- trations were highest in June and July (Kadoum and Mock, 1978). 0 Fonofos (Dyfonate) has been found in Iowa ground water; a typical positive sample found was 0.1 ppb (Cohen et al«, 1986). ------- Fonofos August, 1987 -3- Environmental Fate 0 Under aerobic conditions, fonofos at 10 ppm was degraded at a moderate rate with a half-life ranging from 3 to more than 16 weeks in soils varying in texture from loamy sand to clay loam to peat (McBain and Menn, 1966; Hoffman et al., 1973; Hoffman and Ross, 1971; Miles et al., 1979). The major degradate identified was 0-ethylethane phosphonothioic acid; other degradates identified included fonofos oxon, O-ethylethane phosphonic acid, O-ethyl O-methylethyl phosphonate, diphenyl disulfide, methylphenyl sulfoxide, and methylphenyl sulfone (Hoffman et al., 1973; Hoffman and Ross, 1971). The soil fungus, Rhizopus japonicus rapidly degraded !4C-fonofos to yield dyfoxon, thiophenol, ethylethoxy phosphonic acid and methylphenyl sulfoxide (Lichtenstein et al., 1977). 0 Fonofos is relatively immobile in a silt loam and sandy loam soil but relatively mobile in quartz sand. After 7 to 12 inches of water were added to 7-inch soil columns, 2 to 9% of the applied l^C-fonofos leached from the treated soil layer in Piano silt loam and Fox fine sandy loam columns. When a quartz sand was leached with 7 inches of water, 50% of the applied radioactivity was detected in the leachate. Dyfoxon, a fonofos degradate, and two unidentified compounds were found in the leachate of the silt loam soil (Lichtenstein et al., 1972). 0 Fonofos is relatively mobile in runoff water from loam sand. After 30 days, only 0.54 to 1.2% of the applied l^C-fonofos was recovered in runoff water from drenching a Sorrento loam soil on an inclined plane at a 15-degree slope. Fonofos accounted for most of the recovered radioactivity, which was primarily adsorbed to the silt fraction (Hoffman et al., 1973). 0 Fonofos is not volatile from soil but is fairly volatile from water. Within 24 hours after .application, 15 to 16% of the 14C-fonofos applied volatilized from soil water (a suspension of fine sand in tapwater or tapwater alone; 1% volatilized from a silt loam soil alone). !4C-Fonofos volatilized from soil water with a half-life of 5 days; 80% of the applied radioactivity was volatilized at the end of 10 days (Lichtenstein and Schulz, 1970). 0 In the field, fonofos dissipated with a half-life of 28 to 40 days when either a 10% G or a 4 ilb/gal EC formulation was applied at 4.8 to 10 Ib ai/A to a sandy loam and two silt loam soils (Kiigemagi and Terriere, 1971; Schulz and Lichtenstein, 1971; Talekar et al., 1977). Using a root maggot bioassay, toxic fonofos residues in a sandy loam field soil were detected up to 17 weeks after the 10% G formulation was applied at 2 to 5 Ib ai/A. Residues were detected up to 28 weeks after treatment when the same soil was maintained in a greenhouse (Ahmed and Morrison, 1972). ------- Fonofos August, 1987 -4- III. PHARMACOKINETICS Absorption 0 McBain et al. (1971) administered 14c-phenyl-labeled fonofos (99% purity, dissolved in corn oil) orally to albino rats (two/dose) at doses of 2, 4 or 8 mg/kg. Only 7% of the label was recovered in feces, indicating that absorption was nearly complete (about 93%). Hoffman, et al. (1971) reported essentially identical results in rats dosed with 0.8 mg/kg fonofos. Measurements of urinary, fecal and biliary excretion indicated that about 80 to 90% of the dose was absorbed from the gastrointestinal tract. 0 Hoffman et al. (1971) administered single oral doses of 35s-labeled fonofos (2.0 mg/kg; 99% purity) to rats. About 32% of the label was excreted in feces. Measurement of biliary excretion indicated that 15% of the label in the feces came from the bile. The authors concluded that about 17% had not been absorbed. Distribution 0 Hoffman et al. (1971) administered 35s_iabeied fonofos (2.0 mg/kg, 13.4 mCi/mmol; 99% purity) to rats by gavage (in safflower oil); the levels of label in blood and tissues were measured for 16 days. Higher levels of radioactivity were found in the kidneys, blood, liver and intestines, and lower levels were found in bone, brain, fat, gonads and muscle. Concentration values at 2 days ranged from about 400 ppb in the kidneys to about 70 ppb in other tissues. All values were 10 ppb or lower by day 8. Tissue levels declined in first-order fashion, with near total (99.3%) elimination during 2 to 16 days after dosing. Metabolism 0 McBain et al. (1971) administered single oral doses of 2, 4 or 8 mg/kg of ethyl or phenyl-14C-labeled fonofos (97.5% or 99% purity) to male albino rats (two/dose). Only 2.6 to 7.1% was recovered as unchanged fonofos in the urine. The remainder was converted to a variety of terminal metabolites, including: 0-ethylethane phosphonothioic acid, 0-ethylethane phosphonic acid, and 0-conjugates of 3- and 4-(hydrox- phenyDmethyl sulfone. McBain et al. (1971) reported that fonofos was converted by rat liver microsomes in vitro to the more toxic fonofos oxon, but only traces of this compound were excreted by the intact animal. Excretion McBain et al. (1971) administered single oral doses of 2, 4 or 8 mg/kg of 14C-labeled fonofos (97.5% or 99% purity) orally to male albino rats (two rats/dose). When the label was on the phenyl ring, recovery of was 90.7% in urine and 7.4% in feces. When the label was on the ethyl group, recovery of label was 62.8% in urine and 31.8% in feces. Of this fecal label, 15.3% was found to be excreted in the bile. ------- Fonofos August, 1987 -5- Hoffman et al. (1971) dosed rats orally with 14C-ethyl-labeled fonofos (0.8 mg/kg; 98% purity). After 15 days, average recovery of label was 91% in urine, 7.4% in feces and 0.35% in expired air. Essentially all of the excretion occurred within 4 days. In rats dosed with 35s-labeled fonofos (2 mg/kg; 99% purity), average recovery of label after 4 days was 62.5% in the urine, 31.8% in feces and 0.1% in expired air. Bile duct cannulation studies indicated that about 15% of the label in feces arose from biliary excretion. IV. HEALTH EFFECTS Humans j5hort-term Exposure 0 The Pesticide Incident Monitoring System (PIMS) database reported 21 cases between 1966 and 1979 of human toxicity resulting from exposure to fonofos. Fourteen of the cases involved fonofos only, and seven involved mixtures. Two fatalities occurred, and four individuals required medical treatment. No quantitative exposure data and no description of adverse effects were provided (U.S. EPA, 1979). 0 One reported case of accidental ingestion involved a woman who ate pancakes prepared with a formulation containing fonofos. No quanti- tative estimate of the dose level was provided. The individual developed nausea, vomiting, salivation, sweating and suffered cardio-respiratory arrest. She was treated at a hospital and was found to have muscle fasciculation, blood pressure of 64/0 mm Hg, a pulse rate of 46, pinpoint pupils, and profuse salivary and bronchial secretions. The patient also developed a pancreatic pseudocyst. The woman was discharged after 2 months of treatment. A second individual who also ate the contaminated pancakes died (Hayes, 1982). Long-term Exposure 0 No information on the long-term exposure effects of fonofos on humans was found in the available literature. Animals ghort-term Exposure 0 Fonofos is an organophosphorus compound. Acute toxic effects of such compounds are due largely, if not entirely, to inhibition of cholinesterase (ChE) and acetylcholine accumulation in the body (Derache, 1977). 0 Reported values for the oral LD50 of fonofos for female rats range from 3.2 to 7.9 mg/kg, and values for male rats range from 6.8 to 18.5 mg/kg (Horton, 1966a,b; Dean, 1977). ------- Fonofos August, 1987 -6- 0 Horton (1966a) administered single oral doses of fonofos (purity not specified) to rats (strain not specified). Doses of 1.0 or 2.15 rag/kg did not produce visible symptoms. Doses of 4.6 to 46 mg/kg elicited rapid appearance of fasciculations and tremors, salivation, exophthalmia and labored respiration, with females being somewhat more sensitive than males. Gross autopsy of animals that died revealed congested liver, kidneys and adrenals and lung erythema. Autopsy of survivors showed no effects. Based on gross changes, a No-Observed-Adverse-Effect- Level (NOAEL) of 2.15 mg/kg was identified by this study. 0 Cockrell et al. (1966) fed fonofos in the diet to dogs at levels of 0 or 8 ppm for 5 weeks. Based on the assumption that 1 ppm in the diet of dogs is equivalent to 0.025 mg/kg/day (Lehman, 1959), these doses correspond to 0 or 0.2 mg/kg/day. Plasma and red blood cell cholinesterase were measured at 2 and 4 weeks; organ weights, brain cholinesterase and changes in gross pathology were measured at termination (5 weeks). Following treatment, no systemic toxicity was observed; brain and plasma or red blood cell cholinesterase levels were unaffected. No other details were provided. This study identified a NOAEL of 8 ppm (0.2 mg/kg/day). 0 In a demyelination study, groups of 10 adult hens each received fonofos in the diet for 46 days (Woodard and Woodard, 1966). Levels fed were equivalent to 0, 2, 6.32 or 20 mg/kg/day. Only hens at 20 mg/kg showed impairment of locomotion and equilibrium, and one showed histological evidence of possible demyelination of the peripheral nerves. A NOAEL for demyelination of 6.32 mg/kg/day was indicated by the study. Dermal/Ocular Effects 0 Reported dermal LD$Q values of fonofos for the rabbit (both sexes) ranged from 121 to 147 mg/kg (Horton, 1966a,b). However, Dean (1977) determined a different LD5Q in rabbits: 25 mg/kg for females and 100 mg/kg for males. 0 Instillation of 0.1 mL undiluted fonofos (about 23 mg/kg/day) in one eye of each of three rabbits caused negligible local irritation, but was lethal to all within 24 hours (Horton, 1966a,b; Dean, 1977). 0 Dean (1977) applied 0.5 mL undiluted fonofos to closely -lipped intact skin of rabbits; no dermal irritation was reported but all animals died within 24 hours. 0 Horn et al. (1966) applied fonofos (10% granular) to intact or abraded skin of New Zealand rabbits (five/sex/dose; the five animals included both normal and abraded skin animals) 5 days per week for 3 weeks at doses of 0, 35 or 70 mg/kg. Following treatment, dermal effects, general appearance and behavior, hematology, organ weights, cholinesteras^ levels, gross pathology and histopathology were evaluated. No difference was observed in any of the responses between the intact or abraded skin animals. One normal and one abraded skin males and one ------- Fonofos August, 1987 -7- normal skin female died in the 70 mg/kg group; and one intact skin male died in the 35 mg/kg group. No irritation of the skin was observed at any dose tested for either intact or abraded skin. In males, adrenal weights were increased by about 50% at 35 mg/kg, and by 70% at 70 mg/kg (p value not given). Similar but smaller (15 to 20%) increases in adrenal weights were seen in females. No hematological effects were observed at any dose tested. No histopathological changes occurred except slight to moderate liver glycogen depletion at 70 mg/kg. Reductions were observed in red blood cell, plasma and brain cholinesterase activity for both sexes of the treated groups. At 35 mg/kg, ChE in red blood cells was inhibited 70% (for both sexes), while plasma ChE levels were inhibited 74% (males) and 91% (females), and brain ChE was inhibited 66% (males) and 89% (females). At 70 mg/kg, ChE in red blood cells was inhibited 36% (males) and 45% (females). ChE in plasma was inhibited 67% inhibited for both sexes. ChE in brain was inhibited 59% (males) and 57% (females). Long-term Exposure 0 Daily oral doses of fonofos in corn oil (at 0, 2, 4 or 8 mg/kg/day) for 90 days failed to elicit delayed neurotoxicity in adult hens (Miller et al., 1979, abstract only). A minimum NOAEL of 8 mg/kg/day for delayed neurotoxicity was indicated by these reported results. 0 In a similar experiment (Cockrell et al., 1966), rats were fed diets containing 0, 10, 31.6 or 100 ppm for 13 weeks. Based on the assumption that 1 ppm in the diet is equivalent to 0.05 mg/kg/day, these doses correspond to 0, 0.5, 1.58 or 5 mg/kg/day (Lehman, 1959). Cholinesterase was measured in serum and red blood cells before and after exposure, and brain ChE was measured at termination. At 100 ppm, there was significant inhibition of ChE in serum (70%, females only), red blood cells (85%, females only) and brain (51% to 60%, both sexes). Decreases of over 50% in red blood cell ChE in both males and females were reported at the 31.6-ppm level. At 10 ppm, the largest difference detected was a 23% decrease in red blood cell ChE in females; the authors did not consider this to be significant. All other ChE measurements at this dose were comparable between exposed and control animals. Other observations were negative for compound effect, and there were no histopathological findings. Based on ChE inhibition, the NOAEL in rats was identified as 10 ppm (0.5 mg/kg/day). 0 Cockrell et al. (1966) fed fonofos in the diet to dogs at levels of 0, 16, 60 or 240 ppm for 14 weeks. Based on the assumption that 1 ppm in the diet is equivalent to 0.025 mg/kg/day, these doses correspond to 0, 0.4, 1.5 or 6 mg/kg/day (Lehman, 1959). Dogs showed increased lacrimation and salivation plus convulsions (at 16 ppm), bloody diarrhea (at 60 ppm) or tremors and anxiety and increased liver weight (at 240 ppm). At 16 ppm, there was about 60% ChE inhibi- tion in erythrocytes and slight ChE inhibition in brain (female only). At 60 ppm, ChE in red blood cells was inhibited 60% or more, and plasma ChE was decreased about 20% (in males only) at week 13. At the high dose (240 ppm), ChE was nearly totally inhibited in red ------- Fonofos August, 1987 -8- blood cells; about 50% inhibited in plasma; and moderately inhibited in brain. Based on cholinesterase inhibition and systemic toxicity, a Lowest-Observed-Adverse-Effect-Level (LOAEL) of 16 ppm (0.4 mg/kg/day), the lowest dose tested, was identified. 0 Pure-bred beagle dogs were fed fonofos in the diet for 2 years (Woodard et al., 1969). Groups of four males and four females each received 0, 16, 60 or 240 ppm fonofos. Based on the assumption that 1 ppm in the diet is equivalent to 0.025 mg/kg/day, these doses correspond to 0, 0.4, 1.5 or 6 mg/kg/day (Lehman, 1959). After 14 weeks, the low dose (16 ppm) was reduced to 8 ppm (0.2 mg/kg/day), and this dose level was maintained for the duration of the study. Cholinesterase levels in plasma were inhibited about 50% at 240 ppm, about 25% to 50% at 60 ppm, and were not different from controls at the low dose (16 or 8 ppm). In red blood cells, ChE levels were inhibited almost completely at the 240-ppm level and about 65% at 60 ppm. In animals receiving 16 ppm for 14 weeks, ChE in red blood cells was inhibited about 30%. After reduction of the dose to 8 ppm, ChE levels returned to values comparable to controls. At sacrifice, no inhibition of ChE in brain was detected at any dose level. At 240 ppm, nervous, apprehensive behavior and tremors were seen, and three dogs died, each with marked acute congestion of tissues and hemorrhage of the small intestinal mucosa. At this dose level, also, serum alkaline phosphatase was increased, as were liver weights. Histopathological examination of animals receiving 240 ppm revealed a marked increase in basophilic granulation of the myofibril of the inner layer of the muscularis of the small intestine, and there were slight changes in the liver. At 60 ppm, increased liver weight was observed. At the low dose (16/8 ppm), the only effect was a single brief episode of fasciculation in one male dog at 5 months. The author judged that this could not be ascribed with certainty to fonofos exposure. For this study, the NOAEL for ChE inhibition and for systemic toxicity was 8 ppm (0.2 mg/kg/day). 0 Albino rats received fonofos in the diet for 2 years at 0, 10, 31.6 or 100 ppm (0, 0.5, 1.58 or 5 mg/kg/day, Lehman, 1959) (Bannerjee et al., 1968). Fonofos was judged not to have affected survival, food intake, body weight gain, organ weights or gross and histopatho- logical findings. At 100 ppm, females showed tremors and nervous behavior, and males had reduced hemoglobin and packed-cell volume. At 100 ppm, ChE was markedly decreased in plasma (50 to 75%), red blood cells (close to 100%) and brain (about 40%, in females only). At 31.6 ppra, there was moderate (about 50%) inhibition of ChE in red blood cells and plasma (at weeks 26 and 52 only). At 10 ppm, no decrease in ChE was seen in brain or red blood cells, and no effect was seen in plasma, except for a moderate decrease (40 to 56%) in males at weeks 19 and 26 only. Based on cholinesterase inhibition, a NOAEL of 10 ppm (0.5 mg/kg/day) is identified. Reproductive Effects 0 Woodard et al. (1968) exposed three generations of rats to dietary fonofos at 0, 10 or 31.6 ppm. Based on the assumption that 1 ppm in ------- Fonofos August, 1987 -9- the diet is equivalent to 0.05 mg/kg/day (Lehman, 1959), this corre- sponds to doses of 0, 0.5 or 1.58 mg/kg/day. No differences were detected in exposed dams with respect to mortality, body weight or uterine implantation sites. No effects were seen in offspring on conception ratio, litter size, number of live-born and still-born, litter weight and weanling survival. Skeletal and visceral examina- tion of offspring revealed no evidence of developmental defects. A minimum NOAEL of 31.6 ppm (1.58 mg/kg/day, the highest dose tested) was identified. Developmental Effects 0 Groups of pregnant mice each received 10 daily doses of fonofos by gavage (0, 2, 4, 6 or 8 mg/kg/day) on gestational days 6 through 15 (Minor et al., 1982). At 8 mg/kg/day, maternal food intake and body weight gain were decreased. At 6 mg/kg/day, two dams experienced tremors and died. Increased incidences of variant ossifications of the sternebrae (8 mg/kg/day) and a slight dilatation of the fourth ventricle of the brain (4 and 8 mg/kg/day) were observed, but the authors did not interpret this as evidence of teratogenicity. The NOAEL for fetotoxicity identified in this study was 2 mg/kg/day. Mutagenicity 0 Fonofos, with or without metabolic activation, was not mutagenic in each of five microbial assay systems (the Ames (Salmonella) test; reverse mutation in an Escherichia coli strain; mitotic recombination in the yeast, Saccharomyces cerevisiae D3; and differential toxicity assays in strains of _E. coli and Bacillus subtilis) and in a test for unscheduled DNA synthesis in human fibroblast cells (Simmon, 1979). Carcinogenicity 0 Groups of 30 male and 30 female CD albino rats (Charles River) each received 0, 10, 31.6 or 100 ppm fonofos in the diet (0, 0.5, 1.58 or 5 mg/kg/day) for 2 years (Bannerjee et al., 1968). Based on gross and histological examination, the authors detected no carcinogenic effects. 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. ------- Fonofos August, 1987 -10- 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 by a child (1 L/day) or an adult (2 L/day). One-day Health Advisory No information was found in the available literature that was suitable for determination of the One-day HA value for fonofos. It is therefore recommended that the Longer-term HA value for a 10-kg child of 0.02 mg/L (20 ug/L, calculated below) be used at this time as a conservative estimate of the One-day HA value. j*en-day Health Advisory No information was found in the available literature that was suitable for determination of the Ten-day HA value for fonofos. It is therefore recommended that the Longer-term HA value for a 10-kg child (0.02 mg/L, calculated below) be used at this time as a conservative estimate of the Ten-day HA value. Longer-term Health Advisory The 2-year feeding study in dogs by Woodard et al. (1969) has been selected to serve as the basis for the Longer-term HA for fonofos. In this study, dogs received dietary fonofos at 0, 16, 60 or 240 ppm (0, 0.4, 1.5 or 6 mg/kg/day). After 14 weeks, marginal (about 30%) inhibition of ChE was noted in red blood cells at the 16-ppm level; this dose was reduced to 8 ppm (0.2 mg/kg/day) for the remainder of the study. Following dose reduction, ChE levels returned to those of controls. At 60 ppm, dogs showed increased liver weights and significant inhibition (25 to 65%) of ChE activity in plasma and erythrocytes. At 240 ppm, there was increased ChE inhibition and increased mortality. There were no toxic effects in dogs at 8 ppm (0.2 mg/kg/day), with the possible exception of one brief episode of fasciculation in one dog at 5 months. This was not judged to be significant, and a NOAEL of 8 ppm (0.2 mg/kg/day) was identified. The 13-week feeding study in rats by Cockrell et al. (1966) has not been selected, since the rat appears to be less sensitive than the dog. The 14-week feeding study in dogs by Cockrell et al. (1966) has not been selected since frank toxic responses were noted at the lowest dose tested in this study (0.4 mg/kg/day). Using a NOAEL of 0.2 mg/kg/day, the Longer-term HA for a 10-kg child is calculated as follows: Longer-term HA = (0»2 mg/kg/day) (10 kg) = 0.02 mg/L (20 ug/L) (100) (1 L/day) ------- Fonofos August, 1987 -11- where: 0.2 mg/kg/day = NOAEL, based on absence of systemic toxicity or ChE inhibition in dogs exposed to fonofos in the diet for 2 years. 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 by a child. The Longer-term HA for a 70-kg adult is calculated as follows: Longer-term HA = (0-2 mg/kg/day) (70 kg) = 0.070 mg/L (70 ug/L) (100) (2 L/day) where: 0.2 mg/kg/day = NOAEL, based on absence of systemic toxicity or ChE inhibition in dogs exposed to fonofos in the diet for 1 month. 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 by 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. 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, 1986), then caution should be exercised in assessing the risks associated with lifetime exposure to this chemical. ------- Fonofos August, 1987 -12- The 2-year feeding study in dogs by Woodard et al. (1969) has been selected to serve as the basis for the Lifetime HA for fonofos. Dogs received dietary fonofos at 0, 16, 60 or 240 ppm (0, 0.4, 1.5 or 6 mg/kg/day) for 14 weeks. Marginal (about 30%) inhibition of ChE was noted in red blood cells at the 16-ppm level; this dose was reduced to 8 ppm (0.2 mg/kg/day). Following dose reduction, ChE levels returned to control. At 60 ppm, dogs showed increased liver weights and significant inhibition (25 to 65%) of ChE activity in plasma and erythrocytes. At 240 ppm, there was increased ChE inhibition and increased mortality. There were no toxic effects in dogs at 8 ppm (0,2 mg/kg/day), with the possible exception of one brief episode of fasciculation in one dog at 5 months. This was not judged to be significant, and a NOAEL of 8 ppm (0.2 mg/kg/day) was identified. The 2-year feeding study in rats by Bannerjee et al. (1968) has not been selected, since rats appear to be less sensitive than dogs when doses are calculated on a body weight (mg/kg) basis. Step 1: Determination of the Reference Dose (RfD) RfD = -(-°*2 mg/kg/day) = Q.002 mg/kg/day (100) where: 0.2 mg/kg/day = NOAEL, based on absence of systemic toxicity or ChE inhibition in dogs exposed to fonofos in the diet for 2 years. 100 = uncertainty factor, chosen in accordance with NAS/ODW guideline for use with a NOAEL from an animal study. Step 2: Determination of the Drinking Water Equivalent Level (DWEL) DWEL = (0.002 mg/kg/day) (70 kg) , 0>07 mg/lj (70 /L) (2 L/day) where: 0.002 mg/kg/day = RfD. 70 kg = assumed body weight of an adult. 2 L/day = assumed daily water consumption by an adult. Step 3: Determination of the Lifetime Health Advisory Lifetime HA = (0.07 mg/L) (20%) = 0.014 mg/L (14 ug/L) where: 0.07 mg/L = DWEL. 20% = assumed relative source contribution from water. ------- Fonofos August, 1987 -13- Evaluation of Carcinogenic Potential 0 Groups of 30 male and 30 female albino rats (Charles River, Cesarean- derived) each received 0, 10, 31.6 or 100 ppm fonofos in the diet (0, 0.5, 1.58 or 5 mg/kg/day) for 2 years (Bannerjee et al., 1968). Based on gross and histological examination, the authors detected no carcinogenic effect. 0 IARC (1982) has not evaluated the carcinogenic potential of fonofos. e Applying the criteria described in EPA's guidelines for assessment of carcinogenic risk (U.S. EPA, 1986), fonofos may be classified in Group D: not classified. This category is for substances with inadequate animal evidence of carcinogenicity. VI. OTHER CRITERIA, GUIDANCE AND STANDARDS No existing criteria, guidelines or standards for oral exposure to fonofos were located. 0 The U.S. EPA Office of Pesticide Programs (OPP) has calculated an ADI of 0.002 mg/kg/day for fonofos. This was based on a NQAEL of 0.2 mg/kg/day (8 ppm) for both ChE inhibition and systemic effects, in a 2-year feeding study in dogs (Woodard et al., 1969), and an uncertainty factor of 100. 0 The Threshold Limit Value (TLV) for fonofos is 100 ug/m3 (ACGIH, 1984). The U.S. EPA (1985) has established tolerances for fonofos in or on raw agricultural commodities that range from 0.1 to 0.5 ppm. VII. ANALYTICAL METHODS Analysis of fonofos is by a gas chromatographic (GC) method applicable to the determination of certain nitrogen-phosphorus-containing pesticides in water samples (U.S. EPA, 1986b). In this method, approximately 1 liter 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 fonofos, 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 No information on treatment technologies used to remove fonofos from contaminated water was found in the available literature. ------- Fonofos August, 1987 -14- IX. REFERENCES ACGIH. 1984. American Conference of Governmental Industrial Hygienists. Documentation of the threshold limit values for substances in workroom air, 3rd ed. Cincinnati, OH: ACGIH. Ahmed, J. and P.O. Morrison. 1972. Longevity of residues of four organo- phosphate insecticides in soil. Phytoprotection. 53(2-3}:71-74. Bannerjee, B.M., D. Howard and M.W. Woodard.* 1968. Dyfonate (N-2790) safety evaluation by dietary administration to rats for 105 weeks. Woodard Research Corporation. Unpublished study. MRID 00082232. Cockrell, K.O., M.W. Woodard and G. Woodard.* 1966. N-2790 Safety evaluation by repeated oral administration to dogs for 14 weeks and to rats for 13 weeks. Woodard Research Corporation. Unpublished study. MRID 0090818. Cohen, S.Z., C. Eiden and M.N. Lorber. 1986. Monitoring ground water for pesticides in the U.S.A. American Chemical Society Symposium Series titled: Evaluation of Pesticides in Ground Water (in press). Dean, W.P.* 1977. Acute oral and dermal toxicity (LD5o> in male and female albino rats. Study No. 153-047. International Research and Development Corporation. Unpublished study. MRIDS 00059860, 00059856 and 00059857. Derache, R. 1977. Organophosphorus pesticides. Criteria (dose/response effect relationships) for organophosphorus pesticides). Published for the Commission of the European Conmunities. Oxford, England: Pergamon Press. Hayes, W.J. 1982. Pesticides studied in man. Baltimore, MD: Williams and Wilkins. Hoffman, L.J., J.M. Ford and J.J. Menn. 1971. Dyfonate metabolism studies. I. Absorption, distribution, and excretion of O-ethyl S-phenyl ethyl- phosphonodithioate in rats. Pesticide Biochemistry and Physiology. 1:349-355. Hoffman, L.J., J.B. McBain and J.J. Menn. 1973. Environmental behavior of O-ethyl S-phenyl ethylphosphonodithioate (Dyfonate): ARC-B-35. Unpublished study submitted by Stauffer Chemical Company, Richmond, CA. Hoffman, L.J. and J.H. Ross. 1971. Dyfonate soil metabolism: Project 038022. Unpublished study submitted by Stauffer Chemical Company, Richmond, CA. Horn, H.J., G. Woodard and M.T. Cronin.* 1966. N-2790 10% granular: Subacute dermal toxicity: 21-day experiment in rabbits. Unpublished study. MRID 00092438. Horton, R.J.* 1966a. N-2790: Acute oral LD5Q - rats; acute dermal toxicity - rabbits; acute eye irritation - rabbits. Technical Report T-986. Stauffer Chemical Company. Unpublished study. MRID 00090806. ------- Fonofos August, 1987 -15- Horton, R.J.* 1966b. N-2790: Acute oral LD50 - rats; acute dermal toxicity - rabbits; acute eye irritation - rabbits. Technical Report T-985. Stauffer Chemical Company. Unpublished study. MRID 00090807. IARC. 1982. International Agency for Research on Cancer, World Health Organization. IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans. Chemicals, industrial processes and industries associated with cancer in humans. International Agency for Research on Cancer Monographs. Vols. 1 to 29, Supplement 4. Geneva: World Health Organization. Kadoum, A.M. and D.E. Mock. 1978. Herbicide and insecticide residues in tailwater pits: water and pit bottom soil from irrigated corn and sorghum fields. J. Agric. Food Chem. 26(1)-.45-50. Kiigemagi, U. and L.C. Terriere. 1971. The persistence of Zinophos and Dyfonate in soil. Bull. Environ. Contam. Toxicol. 6(4):355-361. Lehman, A.J. 1959. Appraisal of the safety of chemicals in foods, drugs and cosmetics. Assoc. Food Drug Off. U.S. Lichtenstein, E.P., H. Parlar, F. Korte and A. Suss. 1977. Identification of fonofos metabolites isolated from insecticide-treated culture media of the soil fungus Rhizopus japonicus. J. Agric. Food Chem. 25(4):845-848. Lichtenstein, E.P., and K.R. Schulz. 1970. Volatilization of insecticides from various substrates. J. Agric. Food Chem. 18(5):814-818. Lichtenstein, E.P., K.R. Schulz and T.W. Fuhremann. 1972. Movement and fate of Dyfonate in soils under leaching and nonleaching conditions. J. Agric. Food Chem. 20(4):831-838. McBain, J.B. and J.J. Menn. 1966. Persistence of £-Ethyl-S-phenyl ethylphosphonodithioate (Dyfonate) in soils: ARC-B-10. Unpublished study submitted by Stauffer Chemical Company, Richmond, CA. McBain, J.B., L.J. Hoffman and J.J. Menn. 1971. Dyfonate metabolism studies II. Metabolic pathway of 0-ethyl S-phenyl ethylphosphonodithioate in rats. Pesticide Biochem. Physiol. 1:356-365. Meister, R., ed. 1983. Farm chemicals handbook. Willoughby, OH: Meister Publishing Company. Miles, J.R.W., C.M. Tu and C.R. Harris. 1979. Persistence of eight organophosphorus insecticides in sterile and non-sterile mineral and organic soils. Bull. Environ. Contam. Toxicol. 22:312-318. Miller, J.L., L. Sandvik, G.L. Sprague, A.A. Bickford and T.R. Castles. 1979. Evaluation of delayed neurotoxic potential of chronically administered Dyfonate in adult hens. Toxic. Appl. Pharmacol. 48.-A199. Minor, J., J. Downs, G. Zwicker et al.* 1982. A teratology study in CD-1 mice with Dyfonate technical T-10192. Final report. Stauffer Chemical Company. Unpublished study. MRID 00118423. ------- Fonofos August, 1987 -16- Schulz, K.R. and E.P. Lichtenstein. 1971. Field studies on the persistence and movement of Dyfonate in soil. J. Econ. Entonol. 64(1):283-287. Simmon, V.F. 1979. In vitro microbiological mutagenicity and unscheduled DNA synthesis studies of eighteen pesticides. National Technical Infor- mation Service, Springfield, Virginia, publication EPA-600/1-79-041, Research Triangle Park, North Carolina, p. 164. TDB. 1985. Toxicology Data Bank. MEDLARS II. National Library of Medicine's National Interactive Retrieval Service. Talekar, N.S., L.T. Sun, E.M. Lee and J.S. Chen. 1977. Persistence of some insecticides in subtropical soil. J. Agric. Food Chem. 25(2):348-352. U.S. EPA. 1979. U.S. Environmental Protection Agency, Office of Pesticide Programs. Summary of reported incidents involving fonofos. Pesticide Incident Monitoring Systems. Report No. 220. Washington, DC: U.S. Environmental Protection Agency. U.S. EPA. 1985. United States Environmental Protection Agency. Code of Federal Regulations. 40 CFR 180.221, p. 290. U.S. EPA. 1986. 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. Available from U.S. EPA's Environmental Monitoring and Support Laboratory, Cincinnati, Ohio. Windholz, M., S. Budavari, R.F. Blumetti and E.S. Otterbein, eds. 1983. The Merck index—an encyclopedia of chemicals and drugs, loth ed. Rahway, NJ: Merck and Company, Inc. Woodard, M.W., J. Donoso, J.P. Gray et al.* 1969. Dyfonate (N-2790) safety evaluation by dietary administration to dogs for 106 weeks. Woodard Research Corporation. Unpublished study. MRID 00082223. Woodard, M.W., C.L. Leigh and G. Woodard.* 1968. Dyfonate (N-2790) three- generation reproduction study in rats. Woodard Research Corporation. Unpublished study. MRID 00082234. Woodard, M.W. and G. Woodard.* 1966. N-2790 {Dyfonate): Demyelination study in chickens. Woodard Research Corporation. Unpublished study. MRID 00090819. •Confidential Business Information submitted to the Office of Pesticide Programs. ------- |