x August, 1987 t PRONAMIDE 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. ------- Pronamide August, 1987 -2- II. GENERAL INFORMATION AND PROPERTIES CAS No. 23950-58-5 Structural Formula 0 H CH3 C-N-C-CsCH I CH3 3,5-Dichloro(N-1,1-dimethyl-2-propynyl)benzamide Synonyms 8 Kerb*; Kerb* SOW; Propyzamide; RH315 (Meister, 1983). Uses 0 Pronamide is used as an herbicide for pre- or postemergence weed and grass control in small, seeded legumes grown for forage or seed, southern turf, direct seeded or transplanted lettuce, endive, escarole, woody ornamentals, nursery stock and Christmas trees (Meister, 1983). C12HnCl2ON 256.14 White crystals 154 to 156°C 8o5 x 10-5 mm Hg 0.48 gm/cc 0.015 mg/L 3.05 to 3.27 Properties (NIOSH, 1985; TDB, 1985) Chemical Formula Molecular Weight Physical State (25°C) Boiling Point Melting Point Vapor Pressure (25°C) Specific Gravity Water Solubility Log Octanol/Water Partition Coefficient Taste Threshold Odor Threshold Conversion Factor Occurrence 0 Pronamide has been found in 18 of 258 ground water samples analyzed (STORET, 1987). No surface water samples were collected, and samples were collected from 252 ground water locations. Pronamide was found only in California. The 85th percentile of all nonzero samples was 1 ug/L, and the maximum concentration found was 1 ug/L. Environmental Fate • 14c-Pronamide (100% radiopurity) at 1.5 ppm hydrolyzes very slowly (10% of applied material) in sterile, deionized water buffered to ------- Pronamide August, 1987 -3- pH 5, ~l, and 9 and incubated at 20°C for 28 days in the dark (Rohm and Haas Bristol Research Laboratories, 1973). The following minor hydrolysis products were identified: RH-24,644 (2-(3,5-dichlorophenyl)- 4,4-dimethyl-5methyleneoxazoline); RH-24,580 (3,5-dichloro-N-(l,l- dimethylacetonyl) benzamide); and RH-25,891 (2-(3,5-dichlorophenyl)- 4,4-dimethyl-5-hydroxymethyl-oxazoline). Similar results were obtained in other hydrolysis studies (Rohm and Haas Bristol Research Laboratories, 1970). 0 Pronamide has a half-life of 10 to 120 days in aerobic soils (Fisher, 1971; Walker, 1976; Walker and Thompson, 1977; Walker, 1978; Hance, 1979;). Complete experimental conditions and purity were not specified, and/or a formulated product was applied. The degradation rate does not appear to depend upon soil texture. However, increasing soil temperature, and to a lesser extent, soil moisture and pH enhance pronamide degradation. The major degradates are RH-24,580 and RH-24,644. Soil sterilization greatly reduced the degradation rate of pronamide. Pronamide (at a recommended application rate of 0.5 to 2 Ib/A) does not inhibit the growth or CC>2 evolution of bacteria and fungi (Lashen, 1970). 0 Pronamide is moderately mobile in soils ranging in texture from loamy sand to clay based on preliminary soil column and adsorption/desorption tests (Walker and Thompson, 1977; Rohm and Haas Company, 1971; Fisher and Satterthwaitte, 1971). The two major degradates of pronamide (RH-24,580 and RH-24,644) are mobile in sand and clay soils (Fisher, 1973). The mobility of pronamide and its two major degradates tends to decrease as the organic matter content, clay content and cation exchange capacity of the soil increases. 0 The dissipation rate of pronamide from terrestrial field sites is quite variable, with half-lives ranging from 10 to 90 days (Benson, 1973; Walker, 1976; Hance et al., 1978a; Hance et al., 1978b; Kostowska et al., 1978; Walker, 1978; Zandvoort et al., 1979). Data are insuf- ficient to determine the effect, if any, of meteorological conditions or the role leaching may play in pronamide dissipation. 0 The environmental fate of pronamide is the subject of several unpub- lished, undated reports (Cummings and Yin; Fisher and Cummings; Rohm and Haas; Satterthwaite and Fisher; Yin). III. PHARMACOKIN ETICS Absorption 0 No information on the absorption of pronamide was found ir. the available literature. Distribution 0 No information on the distribution of pronamide was found in the available literature. ------- Pronamide August, 1987 -4- Metabolism 0 About 54 and 0.6% of the radioactivity was recovered as unmetabolized Kerb* in the feces and urine, respectively, of rats treated orally with (14c-carbonyl)-pronamide (dose not specified) (Yin and Swithenbank, undated). The major metabolite in the feces was 2-(3,5-dichlorophenyl)- 4,4-dimethyl-5-hydroxymethyloxazoline (15%), and the major metabolites in the urine were <*-(3, 5-dichlorobenzamido) isobutyric acid (22.4%), B-(3,5-dichlorobenzamido)-a-hydroxy-8 methyl-butyric acid (19.2%), and two unknown metabolites (24.1 and 16.7%). • Unmetabolized Kerb* did not appear in the urine of cows treated orally with (14C-carbonyl) Kerb*; the major metabolite was 6-(3,5-dichloro- benzamido)-o-hydroxy-B-methyl-butyric acid (71.4%)(Yin and Swithenbank, undated). Excretion After oral ingestion of radiolabeled Kerb* by rats, unmetabolized Kerb* accounted for 54 and 0.6% of the radioactivity recovered in feces and urine, respectively. In the cow, oral ingestion of Kerb® produced no unmetabolized Kerb* in the urine (Yih and Swithenbank, undated). IV. HEALTH EFFECTS Humans No information on the health effects of pronamide in humans was found in the available literature. Animals Short-term Exposure 0 The acute oral LD50 in rats for pronamide (technical) is in the range of 8,350 mg/kg bw (Meister, 1984) to 16,000 mg/kg bw (Powers, 1970a). Dermal/Ocular Effects 0 Pronamide is not a primary dermal irritant to albino rabbits. In two separate studies, an aqueous paste of 500 mg pronamide [50% active ingredient (a.i.)] was applied to the skin of six rabbits for 24 hours (Powers, 1970c; Regel, 1972). No signs of irritation were observed by Powers (1970c). Twenty-four hours after exposure, Regel (1972) observed erythema, which subsided at 72 hours. 0 Powers (1970b) administered 100 mg of Kerb* (50% a.i.) in the con- junctival sac of 12 rabbits. Eye irritation and chemosis were noted at 24 hours but disappeared by day 7, as confirmed by fluorescein examination. ------- Pronamide August, 1987 -5- Long-term Exposure 8 Rats (10/sex/dose) were fed a diet containing 0, 50, 150, 450, 1,350 or 4,050 ppm pronamide (100% a.i.) for 3 months (Larson and Borzelleca, 1967a). This corresponds to 0, 2.5, 7.5, 22.5, 67.5 or 202.5 nig/kg/day, assuming 1 ppm in feed is equivalent to 0.05 mg/Jcg/day (Lehman, 1959). Significant body weight depression was observed at the 4,050 ppm dose level. Initial significant body weight depression also occurred in the rats fed 1,350 ppm, but disappeared on continued feeding. At the 150 ppm dose, absolute and relative liver weights in females were-significantly higher than in controls; no histological lesions were seen, and no dose-related trend was observed for this increase in relative liver weight. Individual data were not presented for organ weights and several other parameters, clinical observations were not presented and analytical determination of the test compound was not reported. The No-Observed-Adverse-Effect-Level (NOAEL) identified in this study was 2.5 mg/kg/day. 0 Beagle dogs (10 months old; one/sex/dose) were fed a diet containing 0, 450, 1350 or 4050 ppm pronamide (100% a.i.) for 3 months (Larson and Borzelleca, 1967b). This corresponds to approximate doses of 0, 10, 30 or 90 mg/kg/day, assuming 1 ppm in feed is equivalent to 0.025 mg/kg/day (Lehman, 1959). A decrease in weight gain and food consumption and an increase in serum alkaline phosphatase, liver weight and liver-to-body weight ratios, as compared to controls, were seen in the animals dosed at 4,050 ppm. No histological changes were seen in the livers. The hematological and urinalysis findings were within normal ranges. The NOAEL identified in this study was 30 mg/kg/day. 0 In a 2-year feeding study in beagle dogs (four/sex/dose) the addition of pronamide (97% a.i.) to the diet at dose levels of 0, 30, 100 or 300 ppm (0, 0.75, 2.5 or 7.5 mg/kg/day, assuming 1 ppm in feed is equivalent to 0.025 mg/kg/day; Lehman, 1959) caused no adverse effects at any of the doses tested (Larson and Borzelleca, 1970b). A NOAEL of 7.5 mg/kg/day (the highest dose tested) was identified in this study. 0 Smith (1974) administered Kerb* (97% a.i.) to 6-week-old (C57 BL16 x C3H Anf)Fi male and female mice (100/sex/dose), for 78 weeks at dietary concentrations of 0, 1000 or 2000 ppm (0, 150 or 300 mg/kg/day, assuming 1 ppm in feed is equivalent to 0.15 mg/kg/day; Lehman, 1959) pronamide. Male and female mice that ingested 2000 ppm gained sig- nificantly less weight (p <0.05); males also exhibited adenomatous hyperplasia, degeneration, hyperplasia, intrahepatic cholestasis, necrosis and/or fatty changes of the liver. Liver weights were significantly increased over controls for males and females in both treatment groups. Based on this information, a Lowest-Observed-Adverse- Effect-Level (LOAEL) of 1,000 ppm (150 mg/kg/day) was identified. 0 Newberne et al. (1982) administered pronamide (94% a.i.) to male B6C3F1 mice at dose levels of 0, 20, 100, 500 or 2,500 ppm (0, 3, 15, 75 or 375 mg/kg/day, assuming 1 ppm in feed is equivalent to ------- Pronamide August, 1987 -6- 0.15 mg/kg/day: Lehman, 1959) for up to 24 months. Another group was fed 2,500 ppm (375 mg/kg/day) pronamide for 6 months. The mean body weight of the mice fed 2,500 ppm was significantly depressed at 14 days and thereafter throughout the study. At the 24-month sacrifice, the mean body weight of this group was approximately 70% of the control group. Survival of the mice was unaffected. The highest dose level (2,500 ppm) resulted in liver lesions including bile duct hyperplasia, parenchymal cell hypertrophy, parenchymal cell necrosis, hyperplasia and cholestasis at all time periods examined. Based on this infor- mation, a NOAEL of 500 ppm (75 mg/kg/day) was identified. Reproductive Effects 0 In a teratogenicity study in New Zealand White rabbits (18/dose), pronamide was administered at levels of 0, 5, 20 or 80 mg/kg/day (technical, 97% pure) during gestation days 7 to 19 (Costlow and Kane, 1985). Five abortions were observed in the 80 mg/kg/day group. There were no compound-related effects on the incidence of implantations, resorptions, fetal deaths or on fetal body weight at any dose tested. Maternal toxicity (anorexia, vacuolation of hepatocytes) was observed in the 20-mg/kg/day group. A NOAEL of 20 mg/kg/day was identified based upon the absence of developmental/reproductive effects and a NOAEL of 5 mg/kg/day was identified based upon the absence of maternal toxicity. 0 In a three-generation reproduction study, 20 to 25 albino CD rats were fed a diet containing pronamide (RH-315; purity not stated) at dose levels of 0, 30, 100 or 300 ppm (Larson and Borzelleca, 1970c). Assuming 1 ppm in the diet is equivalent to 0.05 mg/kg/day, this corresponds to doses of 0, 1.5, 5 or 15 mg/kg/day (Lehman, 1959). The authors reported no adverse reproductive effects in parents or pups, but individual animal data were not available to validate the above conclusions. Based on this information a NOAEL of 300 ppm (15 ing/kg/day, the highest dose tested) was identified. Developmental Effects 0 In a teratogenicity study in New Zealand White rabbits (18/dose), pronamide was administered at levels of 0, 5, 20 or 80 mg/kg/day (technical, 97% pure) during gestation days 7 to 19 (Costlow and Kane, 1985). An increased incidence of gross and microscopic liver lesions, one materna^. death, five abortions and a significant (p <0.05) decrease in the maternal body weight gain were observed at the 80-mg/kg/day dose. At the 20-mg/kg/day dose, rabbits exhibited anorexia, vacuolation of hepatocytes and a slight decrease in body weight gain. There were no compound-related effects on the incidence of implantations, resorptions, fetal deaths or on fetal body weight at any dose tested. The NOAEL in this study was 5 mg/kg/day based on maternal effects, and 80 mg/kg/day based on developmental effects. 0 In a study designed to evaluate fetal development, adult female rats (FDRL) were administered 0, 7.5 or 15 mg/kg/day pronamide by gavage in corn oil from days 6 through 16 of gestation (Vogin, 1972). No ------- Pronamide August, 1987 -7- adverse effects were reported for the mean number of implantation sites, the number of live or dead fetuses or the mean fetal weight. The authors concluded that pronamide administered orally to rats at doses up to 15 mg/kg/day was not teratogenic, but individual animal data were not available to validate these conclusions. Based on this information a NOAEL of 15 mg/kg/day (the highest dose tested) was identified. Mutagenicity 0 In a cytogenetic study, pronamide (Kerb®, analytical) administered by intragastric intubation at dose levels of 5, 50 or 500 mg/kg to rats did not produce any aberrations of the bone marrow chromosomes (Fabrizio, 1973). Carcinogenicity 0 In a study evaluating the carcinogenic potential of Kerb®, 6-week-old (C57 BL16 x C3H Anf)F1 male and female mice (100/sex/dose) were fed pronamide (97% a.i.) in the diet at doses of 0, 1,000 or 2,000 ppm (0, 150 or 300 mg/kg/day, assuming 1 ppm in feed is equivalent to 0.15 mg/kg/day; Lehman, 1959) for 78 weeks (Smith, 1974). Male and female mice that ingested 2,000 ppm gained significantly less weight (p <0.05); the animals also gained slightly less weight at the 1,000-ppm level, but the change was not significant. No increase in tumors was observed for female mice treated with pronamide over controls. For male mice, a total of 35 of the 99 animals in the high-dose group, 21 of the 100 animals in the low-dose group and 7 of the 100 animals in the control group developed hepatic neoplasms, of which 24, 18 and 7 were carcinomas in the high-dose, low-dose and control groups, respectively. A total of 28 of 99 male mice that ingested 2,000 ppm exhibited intrahepatic cholestasis, but did not have carcinomas of the liver. 0 In a 2-year study in male B6C3F-J mice (Newberne et al., 1982), pronamide was fed to the animals (63 animals/dose) at dose levels of 0, 20, 100, 500 or 2,500 ppm (0, 3, 15, 75 or 375 mg/kg/day, assuming 1 ppm in feed is equivalent to 0.15 mg/kg/day; Lehman, 1959). Another group was fed 2,500 ppm ('375 mg/kg/day) pronaaide for 6 months. The mean body weight of mice fed 2,500 ppm was significantly depressed at 14 days and thereafter throughout the study. At the 24-month sacrifice, the mean body weight of this group was approximately 70% of the con- trol group. Survival of the mice was unaffected. The highest dose (2,500 ppm) resulted in liver lesions, including bile duct hyperplasia, parenchymal cell hypertrophy, parenchymal cell necrosis, hyperplasia and cholestasis at all time periods examined. At 18 months, the 2,500-ppm dose group had increased parenchymal cell neoplasms, but this was not statistically different from the controls. At 24 months, there was a statistically significant increased incidence of hepatic adenomas and carcinomas in the 500- and 2,500-ppm dose groups. The incidence of hepatic carcinomas was 5/63, 9/63, 12/63, 18/63 and 14/61 in the control, 20-ppm, 100-ppm, 500-ppm and 2,500-ppm groups, respectively. Thus, the liver appears to be the target organ for ------- Pronamide August, 1987 -8- neoplasia. According to the authors, hypertrophy and hyperplasia are not uncommon in untreated older mice of this strain. However, pronamide tended to shift the onset of these lesions to an earlier age. 0 Pronamide in the diet at dose levels of 0, 30, 100 or 300 ppm (0, 1.5, 5 or 15 mg/kg/day, assuming 1 ppm in feed is equivalent to 0.05 mg/kg/day; Lehman, 1959) fed to rats (30/sex/group) for 2 years did not produce any carcinogenic effects (Larson and Borzelleca, 1970a). However, doses used in this study were too low to assess the carcinogenic potential of pronamide. 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) = mg/L (__ ug/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 information was found in the available literature that was suitable for determination of the One—day HA value for pronamide. It is therefore recommended that the Lifetime HA value of 0.052 mg/L (52 ug/L) be used at this time as a conservative estimate of the One-day HA value for pronamide. Ten-day Health Advisory Little information is available on the acute toxicity of pronamide. Toxicity from acute exposure to pronamide has been assessed in three reproduction/teratology studies, but it is not possible to evaluate the most sensitive end point for acute toxicity from these studies. No effects were observed in rats exposed to pronamide via gavage (Vogin, 1972) or in feed (Larson and Borzelleca, 1967b) at doses as high as 15 mg/kg/day. No higher doses were tested in the rat, but higher doses have been tested in the rabbit (Costlow and Kane, 1985). In this study, New Zealand White rabbits ------- Pronamide August, 1987 -9- were administered pronamide during gestation days 7 through 19 at dose levels of 0, 5, 20 or 80 mg/kg/day. Toxic effects observed at the highest dose include a statistically significant decrease in maternal body weight gain and an increased incidence of gross and microscopic liver lesions. Less significant effects on body weight and liver toxicity were observed at the 20-mg/kg/day dose, and a NOAEL of 5 mg/kg/day was identified. This value is similar to the NOAEL identified from a 2-year feeding study in dogs (7.5 mg/kg/day; Larson and Borzelleca, 1970b), which is used as the basis for the Lifetime HA. Considering the limitations of the database on pronamide, it is therefore recommended that the Lifetime HA value of 0.052~mg/L (52 ug/L), calculated below, be used at this time as a conservative estimate of the Ten-day HA value for pronamide. Longer-term Health Advisory Liver toxicity has been observed after acute, subchronic and chronic administration of pronamide to experimental animals. Adverse effects on the liver have been observed after acute exposure of rabbits to 80 mg/kg/day via gavage (Costlow and Kane, 1985), subchronic exposure of rats and dogs to 7.5 mg/kg/day and 90 mg/kg/day, respectively (Larson and Borzelleca, 1967a,b), and chronic feeding of 300 and 375 mg/kg/day to mice (Smith, 1974; Newberne et al, 1982). In contrast to the subchronic rat feeding study, a NOAEL of 15 mg/kg/day was identified in a 2-year rat feeding study (Larson and- Borzelleca, 1970a); however, this study was invalidated (U.S. EPA, 1985). Both rat studies suffer similar deficiencies, which make them unsuitable to serve as the basis for HA values (U.S. EPA, 1985a). Considering the limita- tions of the database on pronamide and the potential for this compound to cause liver damage, it is therefore recommended that the Lifetime HA value of 0.052 mg/L (52 ug/L) be used at this time as a conservative estimate of the Longer-term HA value for pronamide. 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(s). 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 ------- Pronamide August, 1987 -10- carcinogenic potential (U.S. EPA, 1986a), then caution should be exercised in assessing the risks associated with lifetime exposure to this chemical. Two-year chronic pronamide feeding studies have been performed in three species: the rat (Larson and Borzelleca, 1970a), dog (Larson and Borzelleca, 1970b), and mouse (Newberne et al., 1982). For the rat and dog studies, only low doses were used and no toxic effects were observed. The highest doses tested, 15 mg/kg/day (rat) and 7.5 mg/kg/day (dog), were identified as NOAELs for these studies. Because of various deficiencies in the rat study, this study was not validated (U.S. EPA, 1985), and is therefore not acceptable as the basis for the Lifetime HA value. The 2-year study performed on mice (Newberne et al., 1982) was rejected as the basis for the Lifetime HA because of the relative insensitivity of mice to pronamide compared to other species. The NOAEL of 75 mg/kg/day identified in this study was higher than doses causing liver toxicity in subchronic feeding studies in both the rat and dog (Larson and Borzelleca, 1967a,b). Taking all of these studies into consid- eration, the 2-year feeding study in dogs (Larson and Borzelleca, 1970b) was selected as the basis for determination of the Lifetime HA for pronamide. In this study, beagle dogs fed a diet containing pronamide at dose levels of 0, 30, 100 or 300 ppm (0, 0.75, 2.5 or 7.5 mg/kg/day) for 2 years showed no adverse effects at any of the doses tested. A NOAEL of 7.5 mg/kg/day (the highest dose tested) was identified in this study. Using a NOAEL of 7.5 mg/kg/day, the Lifetime HA is calculated as follows: Step 1: Determination of the Reference Dose (RfD) RfD = (7'5 mg/kg/day) = 0.075 mg/kg/day (100) where: 7.5 mg/kg/day » NOAEL, based on the absence of adverse effects in dogs administered pronamide in the diet for 2 years. 100 = uncertainty factor, chosen in accordance with NAS/ODW guidelines for use with a NOAEL from an animal study. Step 2: Determination of the Drinking Water Equivalent Level (DWEL) DWEL = (0.075 mg/kg/day) (70 kg) , 2.6 mg/L (2,600 ug/L) 2 L/day where: 0.075 mg/kg/day = RfD. 70 kg = assumed body weight of an adult. 2 L/day = assumed daily water consumption of an adult. ------- Pronamide August, 1987 -11- Step 3: Determination of the Lifetime Health Advisory Lifetime HA = (2'6 mg/D (20%) = 0.052 mg/L (52 ug/L) (10) where: 2.6 mg/L = DWEL. 20% = assumed relative source contribution from water. 10 = additional uncertainty factor per ODW policy to account for possible carcinogenicity. Evaluation of Carcinogenic Potential 0 Applying the criteria described in EPA's final guidelines for assess- ment of carcinogenic risk (U.S. EPA, 1986a), pronamide has tentatively been classified in Group C: possible human carcinogen. This category is for substances with limited evidence of carcinogenicity in animals in the absence of human data. VI. OTHER CRITERIA, GUIDANCE AND STANDARDS 0 A Provisional Acceptable Daily Intake (PADI) of 0.0750 mg/kg/day and a calculated Theoretical Maximum Residue Concentration (TMRC) of 0.0409 mg/day that utilizes 0.91% of the PADI has been established (U.S. EPA, 1985a). 8 Residue tolerances have been established for pronamide and its metabo- lites in or on raw agricultural commodities that range from 0.02 ppm to 10.0 ppm (U.S. EPA, 1985b). VII. ANALYTICAL METHODS 0 Analysis of pronamide 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 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 pronamide, 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 Reverse osmosis (RO) is a promising treatment method for pesticide- contaminated water. As a general rule, organic compounds with molecular weights greater than 100 are candidates for removal by RO. ------- Pronamide August, 1987 -12- Larson et al. (1982) report 99% removal efficiency of chlorinated pesticides by a thin-film composite polyamide membrane operating at a maximum pressure of 1,000 psi and at a maximum temperature of 113°F. More operational data are required, however, to specifically determine the effectiveness and feasibility of applying RO for the removal of pronamide from water. Also, membrane adsorption must be considered when evaluating RO performance in the treatment of pronamide-contami- nated drinking water supplies. ------- Pronamide August, 1987 -13- IX. REFERENCES Benson, N.R. 1973. Efficacy, leaching and persistence of herbicides in apple orchards. Bulletin 863. Washington State University, College of Agriculture Research Center. Costlow, R.D., and W.W. Kane.* 1985. Teratology study with Kerb technical (no clay) in rabbits. Unpublished study no. 83R-026 prepared and submitted by Rohm and Haas Company, Spring House, PA. Accession no. 256590. Cummings, T.L., and R.Y. Yih. Undated. Metabolism of Kerb (3,5-dichloro-N- (l,l-dimethyl-2-propynyl)benzamide) in different types of soil. Unpublished report prepared by Rohm and Haas Co., Philadelphia, PA. Memorandum Report No. 52. Fabrizio, P.O.A.* 1973. Final report: Cytogenetic study: Kerb analytical. Unpublished report no. CDL:093756-D prepared by Litton Bionetics, Inc., Kensington, MD for Rohm and Haas Company, Philadelphia, PA. April 16. MRID 00038031. Fisher, J.D. 1971. Dissipation and metabolism study of Kerb in soil and its effects on microbial activity. Unpublished report prepared by Rohm and Haas Co., Philadelphia, PA. Lab. 11 Research Report No. 11-229. Fisher J.D. 1973. Soil leaching study with Kerb degradation products RH-24, 580 and RH-24,644. Unpublished report prepared by Rohm and Haas Co., Philadelphia, PA. Tech. Report No. 3923-73-4. Fisher, J.D., and T.L. Cummings. Undated. Biodegradation study of carbonyl- !4C-Kerb and ring-!4C-3,5-dichlorobenzoate in a semicontinuous activated sludge test. Unpublished study prepared by Rohm and Haas Co, Philadelphia, PA. Report No. 16. Fisher, J.D., and S.T. Satterthwaite. 1971. Leaching and metabolism studies of !4C-Kerb in soils. Unpublished report prepared by Rohm and Haas Co., Philadelphia, PA. Lab. 11 Research Report No. 11-228. Hance, R.J. 1979. Effect of pH on the degradation of atrazine, dichlorprop, linuron and propyzamide in soil. Pestic. Sci. 10(1):83-36. Hance, R.J., P.O. Smith, T.H. Byast and E.G. Cotterill. 1978a. Effects of cultivation on the persistence and phytotoxicity of atrazine and propy- zamide. Proc. Br. Crop Prot. Conf. Weeds. 14(2):541-547. Hance, R.J., P.O. Smith, E.G. Cotterill and D.C. Reid. 1978b. Herbicide persistence: Effects of plant cover, previous history of the soil and cultivation. Med. Fac. Landbouww. Rijksuniv. Gent. 43(2):1127-1134. Kostowska, B., J. Rola and H. Slawinska. 1978. Decomposition dynamics of propyzamide in experiments with winter rape. Pamiet. Pulawski. 70:199-205. ------- Pronamide August, 1987 -14- Larson, P.S., and J.F. Borzelleca.* 1967a. Toxicologic study on the effect of adding RH-315 to the diet of rats for a period of three months. Unpub- lished study no. CDL:091422-D prepared by the Medical College of Virginia, Dept. of Pharmacology, for Rohm and Haas Company, Philadelphia, PA. November 27. MRID 00085506. Larson, P.S., and J.F. Borzelleca.* 1967b. Toxicologic study on the effect of adding RH-315 to the diet of beagle dogs for a period of three months. Unpublished study no. CDL:091422-E prepared by the Medical College of Virginia, Dept. of Pharmacology, for Rohm and Haas Company, Philadelphia, PA. November 22. MRID 00085507. Larson, P.S., and J.F. Borzelleca.* 1970a. Toxicologic study on the effect of adding RH-315 to the diet of rats for a period of two years. Unpub- lished study no. CDL-.004357-A prepared by the Medical College of Virginia, Dept. of Pharmacology, for Rohm and Haas Company, Philadelphia, PA. June 11. MRID 00133111. Larson, P.S., and J.F. Borzelleca.* 1970b. Toxicologic study on the effect of adding RH-315 to the diet of beagle dogs for a period of two years. Unpublished study no. CDL:090918-A prepared by the Medical College of Virginia, Dept. of Pharmacology, for Rohm and Haas Company, Philadelphia, PA. June 12. MRID 00107949. Larson, P.S., and J.F. Borzelleca.* 1970c. Three-generation reproduction studyt on rats receiving RH-315 in their diets. Unpublished study prepared by the Medical College of Virginia, Dept. of Pharmacology, for Rohm and Haas Company, Philadelphia, PA. April 11. MRID 00107950. Larson, R.E., P.S. Cartwright, P.K. Eriksson and R.J. Petersen. 1982. Applications of the FT-30 reverse osmosis membrane in metal finishing operations. Paper presented at Tokohama, Japan. Lashen, E.S. 1970. Inhibitory effects of Kerb and Kerb transformation products on typical soil microorganisms. Unpublished report prepared by Rohm and Haas Co., Philadelphia, PA. Memorandum Report No. 22. Lehman, A.J. 1959. Appraisal of the safety of chemicals in foods, drugs and cosmetics. Assoc. Food Drug Off. U.S., Q. Bull. Meister, R., ed. 1983. Farm chemicals handbook. Willoughby, OH: Meister Publishing Co. Newberne, P.M., R.G. McConnell and E.A. Essigmann.* 1982. Chronic study in the mouse. Final report no. 81RC-157 prepared by the MIT Animal Pathology Laboratory. Submitted by Rohm and Haas Company. August 10. EPA Accession No. 248233. NIOSH. 1985. National Institute for Occupational Safety and Health. Registry of Toxic Effects Chemical Substances. ------- Pronamide August, 1987 ? -15- Powers, M.B.* 1970a. Final Report (Study 1) - Acute Oral - Rats. Unpublished study. Project No. 417-337, prepared by TRW, Inc., Vienna, VA for Rohm and Haas Co., Philadelpia, PA, dated October 6, 1970. Powers, M.B.* 1970b. Final Report (Study 2) - Draize Eye - Rabbits. Unpub- lished study, Project No. 417-337, prepared by TRW, Inc., Vienna, VA for Rohm and Haas Co., Philadelpia, PA, dated October 6, 1970. MRID 00083663. Powers, M.B.* 1970c. Final Report (Study 4) - Primary Skin - Rabbits. Unpublished study, Project No. 417-337, prepared by TRW, Inc., Vienna, VA for Rohm and Haas Co., Philadelpia, PA, dated October 6, 1970. Regel, L.* 1972. Primary skin irritation study in albino rabbits. Unpublished study no. 2060619, prepared by WARF Institute, Inc., Madison, WI for O.M. Scott & Sons, Marysville, OH, dated June 28, 1972. MRID 0001265. Rohm and Haas Bristol Research Laboratories. 1970. Fate and persistence of Kerb (3,5-dichloro-N-(l,l-dimethyl-2-propynyl)-benzamide) in aqueous systems. Unpublished report prepared by Rohm and Haas Co., Philadelphia, PA. RAR Report No. 597. Rohm and Haas Bristol Research Laboratories. 1973. A study of the hydrolysis of the herbicide Kerb in water. Unpublished report prepared by Rohm and Haas Co., Philadelphia, PA. Lab. 23. Technical Report No. 23-73-8. Rohm and Haas Company. Undated. Research Report No. XXXXVI. Field dissipation studies. Unpublished report prepared by Rohm and Haas Co., Philadelphia, PA, Rohm and Haas Company. 1971. Soil adsorption studies with Kerb. Unpublished report prepared by Rohm and Haas Co., Philaldelphia, PA. Lab. 23 Tech. Report No. 23-71-12. Satterthwaite, S.T., and J.D. Fisher. Undated. Photodecomposition of Kerb in water. Unpublished report prepared by Rohm and Haas Co., Philadelphia, PA. Lab. 11 Memorandum Report No. 7. Satterthwaite, S.T.* 1977. 14C-Kerb mouse feeding study. Unpublished study no. 34H-77-3 prepared and submitted by Rohm and Haas Company, Philadelphia, PA. February 19. MRID 0062604. Smith, J.* 1974. Eighteen month study on the carcinogenic potential of Kerb (RH-315: pronamide) in mice. Unpublished study received September 16 under 3F1317; prepared in cooperation with the Medical College of Virginia, submitted by Rohm and Haas Company, Philadelphia, PA; CDL:094304-A. MRID 008201601. STORET. 1987. TDB. 1985. Toxicology Data Book. MEDLARS II. National Library of Medicine's National Interactive Retrieval Sevice. U.S. EPA. 1985a. U.S. Environmental Protection Agency, Office of Pesticide Programs. Pronamide registration standard. ------- Pronamide August, 1987 -16- U.S. EPA. 1985b. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 180.106. p. 252. July 1, 1985. U.S. EPA. 1986a. U.S. Environmental Protection Agency. Guidelines for carcinogen risk assessment. Fed. Reg. 51(185)s33992-34003. 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, OH. Vogin, E.E.* 1972. Effects of RH-315 on the development of fetal rats. Unpublished study no. 0512 by Food and Drug Research Laboratories, Inc., Maspeth, NY for Rohm and Haas Company, Spring House, PA. October 22. MRID 00125789. Walker, A. 1976. Simulation of herbicide persistence in soil. III. Propy- zamide in different soil types. Pestic. Sci. 7:59-64. Walker, A. 1978. Simulation of the persistence of eight soil-applied herbi- cides. Weed Res. 18:305-313. Walker, A., and J.A. Thompson. 1977. The degradation of simazine, linuron and propyzamide in different soils. Weed Res. 17(6):399-405. Yin, R.Y., and C. Swithenbank.* Undated. Identification of metabolites of N-(1,1-dimethylpropynyl)-3,5-dichlorobenzamide in rat and cow urine and rat feces. Unpublished report prepared by Rohm and Haas Company, Spring House, PA. MRID 00107954. Yih, R.Y. Undated. Metabolism of N-(l,l-dimethylpropynyl)-3,5-dichlorobenzamide (Rh-315) in soil, plants and mammals. Unpublished report prepared by Rohm and Haas Co., Philadelphia, PA. Lab. 11 Research Report No. 11-210. Zandvoort, R., D.C. van Dord, M. Leistra and J.G. Verlaat. 1979. The decline of propyzamide in soil under field conditions in the Netherlands. Weed Res. 19:157-164. Confidential Business Information submitted to the Office of Pesticide Programs. ------- |