820K88009 DRAFT August, 1987 BAYGON (Propoxur) 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. ------- Baygon August, 1987 -2- II. GENERAL INFORMATION AND PROPERTIES CAS No. 114-26-1 Structural Formula 2-( 1 -Me thylethoxy) -phenol methylcarbamate Synonyms 0 Propoxur (proposed common name); Aprocarb; Blattenex; BAY 39007; Bayer 39007; Pillargon; Propyon; Suncide; Tugon; QMS 33; Unden (Meister, 1984). Uses 0 A nonfood insecticide used on humans, animals and turf grass (Meister, 1984). Properties (ACGIH, 1984; Meister, 1984; and CHEMLAB, 1985) Chemical Formula C Molecular Weight 209.24 Physical State (at 258C) White to tan crystalline solid Boiling Point Melting Point 91 8C Density (°C) Vapor Pressure (120°C) 0.1 mmHg Water Solubility (20°C) 2000 mg/L Log Octanol/Water Partition 0.14 Coefficient Taste Threshold Odor Threshold Conversion Factor Occurrence Baygon has been found in none of the 58 ground water samples analyzed from 55 locations. No surface water samples were analyzed (STORET, 1987). Environmental Fate (Forthcoming from OPP) ------- Baygon August, 1987 -3- III. PHARMACOKINETICS Absorption 0 Vandekar et al. (1971) administered a single oral dose of 1.5 mg/kg of propoxur, 95% active ingredient (a.i.), to a 42-year-old male volunteer. About 45% of the dose was recovered in urine within 24 hours as o-isopropoxyphenol. Since vomiting occurred 23 minutes after ingestion, the authors assumed that much of the dose was expelled by this route, so the percent actually absorbed could not be calculated. 0 Chemagro Corp. (no date) investigated the dermal absorption of 1^c- labeled Baygon in human subjects. Baygon (4 ug/cm2, total dose less than 1 mg) was applied to the forearm of the subjects(s) in four tests: (1) application to the skin without preparation, (2) application after stripping of the skin with an adhesive tape, (3) application followed by occlusion and (4) application followed by induction of sweating. The amounts excreted (route not specified, but presumably in urine) after these treatments were 20, 51, 64 and 18%, respectively, indicating that Baygon is well absorbed through the skin. 0 Krishna and Casida (1965) administered single oral doses of 14C-labeled Baygon (50 mg/kg) to Sprague-Dawley rats. After 48 hours, about 4% of the dose had been excreted in feces, and the remainder was detected in urine (64 to 72%), expired air'(26%) or the body (4.2 to 7.9%). This indicated that Baygon had been well absorbed (at least 96%) from the gastrointestinal tract. Similar findings were reported by Foss and Krechniak (1980). Distribution 0 Foss and Krechniak (1980) investigated the fate of Baygon after oral administration of 50 mg/kg to male albino rats. Analysis of tissues indicated that Baygon levels were greatest in the kidneys, with somewhat lower levels in the liver, blood and brain. Metabolism 0 Dawson et al. (1964) administered single oral doses of 92.2 mg of Baygon (purity not specified) to six male volunteers, and single oral doses of 50 mg to three subjects. Urine samples were collected and analyzed for metabolites. A material identified as 2-isopropoxyphenol was observed in the urine of both groups. Similar results were reported by Vandekar et al. (1971). 0 Foss and Krechniak (1980) investigated the metabolism of Baygon after both oral and intravenous administration of 50 mg/kg to male albino rats. Isopropoxyphenol was detected in tissues 10 minutes following administration, and the highest concentrations were attained between 30 and 60 minutes after dosing. This metabolite prevailed in the blood and liver, but in the kidney only unchanged Baygon could be detected. Eight hours postdosing, only traces of Baygon and its metabolites were detected in these tissues. ------- Baygon August, 1987 -4- * Everett and Gronberg (1971) studied the metabolism of Baygon in Holtzman rats. Animals were dosed by gavage with Baygon (5 to 10 mg/kg) labeled with 1 4c Or ^H in the carbonyl or the isopropyl groups. Pooled urine from eight rats (four/sex) dosed with 20 mg/kg/day of unlabeled Baygon for 4 days was used to isolate sufficient quantities of metabolites for identification of structure. Results indicated that the major pathway of Baygon metabolism involved depropylation to 2-hydroxyphenol-N-methyl carbamate and hydrolysis of the carbamate to isopropoxyphenol. Minor pathways involved ring hydroxylation at the five- or six-position, secondary hydroxylation of the 2'-carbon of the isopropoxy group and N-methyl hydroxylation. Metabolites that contained the 6-hydroxy group formed N-conjugates, while those that contained the 5-hydroxy group formed 0-glucuronides. Excretion Dawson et al. (1964) reported that in humans given a single oral doses of 92.2 mg Baygon (purity not specified), 38% of the dose was excreted as phenols in urine over the next 24 hours; most was excreted in the first 8 to 10 hours. Krishna and Casida (1965) administered single oral doses of 50 mg/kg of 14c-carbonyl-labeled Baygon to Sprague-Dawley rats. After 48 hours, recovery of label in excretory products was as follows: 64% (males) and 72% (females)'in urine; 4% in feces (males and females); and 26% in expired carbon dioxide (males and females). Residual label in the body was 4.2% (males) and 7.9% (females). One-third of the excreted dose was hydrolyzed, with most of the remainder being intact. Everett and Gronberg (1971) reported that 85% of orally administered 14c-carbonyl-labeled Baygon (5 to 8 mg/kg) was recovered from Holtzman rats within 16 hours of dosing; 20 to 25% of the radioactivity appeared in the expired air, and 60% of the radioactivity appeared in the urine as conjugates. Also, Foss and Krechniak (1980) indicated that 85 to 95% of an oral dose (50 mg/kg) administered to male albino rats was excreted in urine with a half-life of 0.18 to 0.26 hour. IV. HEALTH EFFECTS Humans Short-term Exposure 0 Vandekar et al. (1971) studied the acute oral toxicity of Baygon in human volunteers. A 42-year-old man ingested a single oral dose of 1.5 mg/kg of propoxur (Baygon) (95% a.i., recrystallized). Cholinergic symptoms, including blurred vision, nausea, sweating, tachycardia and vomiting, began about 15 to 20 minutes after exposure. Effects were transient and disappeared within 2 hours. Cholinesterase (ChE) activity (measured spectrophotometrically) in red blood cells decreased to 27% of control values by 15 minutes after exposure, and returned ------- Baygon August, 1987 -5- to control levels by 2 hours. No effect was detected in plasma ChE activity. In a second test, a single dose of 0.36 mg/kg caused short-lasting stomach discomfort, blurred vision and moderate facial redness and sweating. Red blood cell ChE activity fell to 57% of control values within 10 minutes, then returned to control levels within 3 hours. 0 Vandekar et al. (1971) administered five oral doses of 0.15 or 0.20 mg/kg to male volunteers at half-hour intervals (total dose of 0.75 or 1.0 mg/kg). In each subject, a symptomless depression of red blood cell ChE was observed; the lowest level, about 60% of control values, was reached between 1 and 2 hours following doses 3, 4 and 5. After the final dose, red blood cell ChE activity rose to control levels within about 2 hours. The authors noted that a dose of Baygon was tolerated better if it was divided into portions and given over time than if it was given as a single dose. Long-term Exposure 0 Davies et al. (1967) described the effects of a large-scale spraying operation in El Salvador in which Baygon (OMS-33, 100% a.i.) was used. The trial was planned so that medical assistance would be available, and appropriate clinical support could be provided to those affected by the spraying. The total amount of OMS-33 sprayed was 345 kg. Among the spraymen, exposure (expressed in person-days) was 70.5; 19 experienced symptoms (26% incidence). In the general population, the exposure was 3,340 person-days, and 35 experienced symptoms (1% incidence). The primary symptoms were headache, vomiting and nausea. In the spraymen, the symptoms occurred mostly in the first days, with no visible symptoms after this time. In severe cases, atropine was administered as antidote. It was concluded that the acute toxicity symptoms were observed in a low incidence, and they were, in general, mild, evanescent, reversible, responsive to small doses of atropine, and tended to occur at the beginning of the spray program. 0 Montazemi (1969) reported on the toxic effects of Baygon on the population of 26 villages in Iran that were sprayed with Baygon at the rate of 2 g/m2 daily for 18 days. Selected inhabitants from six villages and sprayers were examined on days 2, 8 and 18 and after the completion of the spraying. Depression of ChE activity was found in the inhabitants and in the sprayers, but the sprayers generally had more severe symptoms. Atropine or belladonna was adequate to treat those exhibiting symptoms. Animals Short-term Exposure 0 The acute oral LD5Q value for technical Baygon (purity not spedified) in male and female Sherman rats was reported to be 83 and 86 mg/kg, respectively (Gaines, 1969). The oral LD5Q was reported to be 32 mg/kg in mice and 40 mg/kg in guinea pigs (NIOSH, 1983). ------- Baygon August, 1987 -6- 8 Farbenfabriken Bayer (1961) determined an oral LD5Q of 100 to 150 mg/kg (purity not specified) in male albino rats. Severe muscle spasms were observed, but no dose-response information was provided. 0 Eben and Kimmerle (1973) studied the acute toxicity of Baygon in SPF-Wistar rats. Single oral doses of propoxur (98.7% a.i.), diluted with propylene glycol, were given by gavage to groups of three male rats at levels of 15, 20, 40 or 60 mg/kg; female rats were given doses of 10, 20, 40 or 60 mg/kg. Cholinesterase levels were measured in plasma, erythrocytes and brain at 10, 20 and 180 minutes after dosing. Maximum ChE depression was observed at 10 and 20 minutes in the plasma and erythrocytes, and at 180 minutes in the brain. The inhibition was dose-dependent and a no-effect level was not observed. In plasma, ChE was inhibited from 19% (low dose) to 63% (high dose) in males and from 0 to 32% in females. In erythrocytes, ChE was inhibited from 27 (low dose) to 63% (high dose) in males and from 15 to 45% in females. Based on ChE inhibition, this study identified a Lowest-Observed-Adverse-Effect-Level (LOAEL) of 10 mg/kg/day. 0 Farbenfabriken Bayer (1966) conducted a 9-week feeding study with Bay 39007 (purity not specified) in male and female rats (Elberfeld FB), Baygon was included in the diets of the male animals at dose levels of 0, 1,000, 2,000, 4,000 or 8,000 ppm. Based on the assumption that 1 ppm in the diet of rats is equivalent to 0.05 mg/kg/day (Lehman, 1959), this corresponds to doses of 0, 50, 100, 200 or 400 mg/kg/day, respectively. Females were given only one dose (4,000 ppm). The study was begun when the animals (15/dose level) were 4 weeks of age and weighed about 48 g. In males, food consumption and body weight were depressed in a dose-dependent manner. At the 4,000 and 8,000-ppm levels, the males were less lively and exhibited slightly shaggy coats. Gross pathologic examinations of all animals were conducted. Two males exposed to 4,000 ppm died during the study, one at 11 days (evidence of myocarditis) and one at 23 days. Two males also died at the 8,000-ppm level (at 23 and 25 days); one showed necrotic inflammation of the mucosa of the small intestine. Females (exposed to 4,000 ppm only) displayed decreased food consumption and reduced weight gain similar to that seen in exposed males. One of 15 female controls died at day 12 (death attributed to pneumonia), and two of 15 exposed females died, one at 7 days and one at 45 days (in this rat there was suppuration of the cerebellar bottom). There were apparently no measurements of ChE activity or other clinical tests performed during this study. It was concluded by the authors that the observed pathology could not be directly attributed to the presence of Baygon in the diet. Based on gross observations, the No-Observed- Adverse-Effect-Level (NOAEL) for male animals was identified as 2,000 ppm (100 mg/kg/day) and the LOAEL as 4,000 ppm (200 mg/kg/day). In females, 4,000 ppm (200 mg/kg/day, the only dose tested) was a toxic level. 0 Eben and Kimmerle (1973) exposed SPF-Wistar rats (four/sex/dose) by gavage to doses of 3, 10 or 30 mg/kg/day of Baygon for 4 weeks. The high-dose animals (30 mg/kg/day) displayed cholinergic symptoms. Cholinesterase activity in plasma and red blood cells, measured 15 ------- Baygon August, 1987 -7- minutes after dosing on days 3, 8, 14, 21 and 28, was generally depressed in a dose-related manner at 10 and 30 mg/kg, but not at the 3-mg/kg dose. For example, on day 28, ChE activity in plasma was reduced by 0, 21 or 27% in males and by 14, 27 or 41% in females. In erythrocytes, ChE was inhibited by 9, 24 or 32% in males and by 11, 32 or 43% in females. No cumulative toxic effects were observed. Based on ChE inhibition, the NOAEL for this study was 3 mg/kg/day, and the LOAEL was 10 mg/kg/day. Dermal/Ocular Effects 0 The acute dermal LD50 of technical Baygon (purity not specified) was reported to be greater than 2,400 mg/kg for both male and female Sherman rats (Gaines, 1969). 0 Crawford and Anderson (1971) indicated that 500 mg of technical Baygon (purity not specified, dissolved in acetone) did not cause any skin irritation within 72 hours of its application to the abraded or unabraded skin of mature New Zealand White rabbits (six/group). 0 Heimann (1982) demonstrated that Baygon (98.8% pure) is not a skin sensitizer when tested in guinea pigs. 0 Crawford and Anderson (1971) instilled 100 mg of technical Baygon (purity not specified) in the left eye of six rabbits. Examination at 48 and 72 hours revealed no evidence of ocular irritation or corneal damage. Long-term Exposure 0 Eben and Kimmerle (1973) fed propoxur (98.7% a.i.) to male rats in the diet for 15 weeks. Doses were 0, 250, 750 or 2,000 ppm. Assuming that 1 ppm in the diet is equivalent to 0.05 mg/kg/day (Lehman, 1959), this corresponds to doses of about 0, 12.5, 37.5 or 100 mg/kg/day. Assays for ChE activity in plasma, erythrocytes and brain showed no . constancy of inhibition and no dependence on the administered dose. No other details were given. 0 Root et al. (1963) studied the effect of Bayer 39007 added to the diet of Sprague-Dawley rats for 16 weeks. The rats (12/sex/dose, weighing 72 to 145 g at the start of the feeding trial) were fed Baygon (technical, 95.1% pure) at dose levels of 0, 100, 200, 400 or 800 ppm. Assuming that 1 ppm in the diet of rats is equivalent to 0.05 mg/kg/day (Lehman, 1959), this corresponds to doses of 0, 5, 10, 20 or 40 mg/kg/day. Biweekly measurements revealed no changes in growth or food consump- tion. Cholinesterase was assayed in blood, brain and submaxillary glands of five animals of each sex at each dose level, and no inhi- bition was detected. Necropies were performed on five animals of each sex at the termination of the study, and no significant pathology was found. It was concluded that the NOAEL for the rats was greater than 800 ppm (40 mg/kg/day, the highest dose tested). ------- Baygon August, 1987 -8- 0 Suberg and Loeser (1984) conducted a chronic (106-week) feeding study of Baygon (99.4% a.i.) in rats (Elberfeld strain) at dose levels of 0, 200, 1,000 or 5,000 ppm. Based on the assumption that 1 ppm in the diet of rats is equivalent to 0.05 mg/kg/day (Lehman, 1959), this corresponds to doses of about 0, 10, 50 or 250 mg/kg/day. There were 50 rats of each sex per dose level, plus an additional 10 of each sex for interim autopsies at the end of the first year. At the 200-ppm dose, there was no effect on food consumption or body weight, there were no cholinergic signs, and clinical chemistry, gross pathology, histopathology and organ weights showed no changes from control values. At 1,000 ppm, retarded weight gain was observed in males during the first 20 weeks. At 1,000 and 5,000 ppm, there were significant hyperplasia of urinary bladder epithelium (described in more detail in the Carcinogenicity section) and increased incidence of neuropathy. At the 5,000-ppm dose, both weight gain and food consumption were significantly retarded throughout the study; males showed increased thromboplastin time, and females had consistently lower mean plasma ChE activity than did controls or other test groups. Both sexes showed some degree of splenic atrophy, but there were no other significant changes in other organs. Based on body weight gain, the NOAEL for this study was identified as 200 ppm (10 mg/kg/day), and the LOAEL as 1,000 ppm (50 mg/kg/day). 0 Loser (1968a) conducted a 2-year feeding study of Baygon in male and female SPF-Wistar rats. Starting at 1 month of age, the test material, BAY 39007 (99.8% a.i., technical), was included in the diet at levels of 0, 250, 750, 2,000 or 6,000 ppm. Based on the assumption that 1 ppm in the diet of rats is equivalent to 0.05 mg/kg/day (Lehman, 1959), this corresponds to doses of 0, 12.5, 37.5, 100 or 300 mg/kg/day. The control group consisted of 50 animals of each sex, while test groups contained 25 animals of each sex. Growth and behavior were observed, liver function and ChE activity were tested, and blood and urine were analyzed periodically. Necropsies on five animals of each sex were conducted at the termination of the experiment. The major adverse effects noted were low food consumption and low body weight in all animals at the 6,000-ppm dose level, and low body weight in the female (but not male) animals at the 2,000-ppm dose level. Cholinesterase determinations on blood (measured at the high dose only) revealed no changes; ChE activity was 9.8 and 9.9 units in control males and females, respectively, compared with 9.9 and 10,0 in exposed males and females. The author indicated that the methodology may have been too insensitive to detect small changes that may have occurred. No spasms or other symptoms of ChE inhibition were observed. No impairment of liver or kidney function was detected by clinical tests, but necropsy revealed increased liver weight at all doses greater than 250 ppm. Results of blood analysis were normal at all dose levels except at 6,000 ppm. Apart from increased liver weights, necropsy findings were unremarkable. Based on increased liver weights, this study identified a NOAEL of 250 ppm (12.5 mg/kg/day) and a LOAEL of 750 ppm (37.5 mg/kg/day). 0 Loser (1968b) conducted a 2-year study of Baygon toxicity in beagle dogs. The product, BAY 39007 (technical, 99.8% pure), was included in ------- Baygon August, 1987 -9- the diet at levels of 0, 100, 250, 750 or 2,000 ppm. Assuming that 1 ppm in the diet of dogs is equivalent to 0.025 mg/kg/day (Lehman, 1959), this corresponds to doses of about 0, 2.5, 6.25, 18.7 or 50 mg/kg/day. The study was begun when the dogs (four/sex/dose) were 4 to 5 months old. Observations on the animals included weight and food consumption at periodic intervals, ChE determinations in blood at 16 weeks, clinical evaluations of blood and urine, and tests for liver and kidney function. Necropsies were performed on animals that died during the study and at termination of the study. The appearance, behavior, and food consumption of dogs at the 100, 250 or 750 ppm levels were comparable to those of the controls. At the 2,000-ppm level, dogs of both sexes appeared to be weak and sick. One of the males and all four females at this dose died before completion of the study. During the first 6 months, dogs at this dose level exhibited quivering and spasms, particularly in the abdominal region, and food consumption was less than for the controls (especially in females); as expected, the dogs showed statistically significant depression in weight gain compared with the controls. Males, but not females, showed lower weights than did controls at the 750-ppm dose level, but the decrease was not statistically significant. Clinical analyses did not reveal any aberrations in the blood or any changes in liver or kidney function. However, increased liver weights were observed at necropsy, and serum electrophoresis performed at the time of sacrifice revealed decreased levels of some serum proteins, inter- preted by the author as reflecting impaired protein synthesis. Cholinesterase determinations in whole blood at 16 weeks did not reveal any significant inhibition of activity. In males, ChE inhibi- tion at 100, 250, 750 and 2,000 ppm was 0, 11, 1 and 13%, respectively, and in females ChE inhibition was 0, 10, 7 and 0%, respectively. The author indicated that the assay method may have been too insensitive to detect small changes that may have occurred. Emaciation was the principal finding in dogs that died during the study; one female had abnormal liver parenchyma. The NOAEL for this study was 250 ppm (6.25 mg/kg/day), and the LOAEL (based on increased liver weight, decreased body weight and altered blood proteins) was 750 ppm (18.7 mg/kg/day). Bomhard and Loeser (1981) conducted a 2-year feeding study of propoxur (99.5% a.i.) in SPF CFI/W71 mice at dose levels of 0, 700, 2,000 or 6,000 ppm. Assuming that 1 ppm in the diet of mice is equivalent to 0.15 mg/kg/day (Lehman, 1959), this corresponds to doses of about 0, 105, 300 or 900 mg/kg/day. Mice were 5 to 6 weeks of age, weighing 22 to 25 g at the beginning of the study; each group consisted of 50 animals of each sex, plus an additional 10/sex/group included for interim autopsy at 1 year. Body weight gain was slightly depressed in male mice at the 6,000-ppm level. Apart from this observation, all aspects of behavior, appearance, food intake, weight and mortality were comparable to control values. Clinical chemistry and blood studies, including glucose and cholesterol levels, were within the normal range for all groups, and there were no significant gross pathological or histopathological findings that could be attributed to the ingestion of Baygon. It was concluded that the male mice tolerated the pesticide at levels up to and including 2,000 ppm, ------- Baygon August, 1987 -10- while the female mice tolerated doses up to and including 6,000 ppm without adverse effects. Based on these conclusions, the NOAEL for this study was 2,000 ppm (300 mg/kg/day), and the LOAEL (based on depressed weight gain in males) was 6,000 ppm (900 mg/kg/day). Reproductive Effects 0 No multigeneration studies of the effects of Baygon on reproductive function of animals were found in the available literature. 0 In a developmental toxicity study in rabbits, Schlueter and Lorke (1981) observed no adverse effects on several reproductive end points. This study is described below. Developmental Effects 0 Schlueter and Lorke (1981) studied the effect of propoxur (99.6% a.i.) on Himalayan CHBBsHM rabbits during gestation. Propoxur was admini- stered by gavage (in 0.5% cremophor) to 15 animals/dose at 0, 1, 3 or 10 mg/kg. No adverse effects were observed in the dams, and no changes were detected in implantation index, mean placental weight, resorption index or litter size. Embryos were examined for visceral and skeletal defects grossly, then were stained with Alizarin, and transverse sections were prepared using the Wilson technique. No adverse fetal effects were found at any dose level with respect to mean fetal weight, the percent of stunting, the percent of slight skeletal deviations, or the malformation index. These results indicate that the NOAEL for maternal toxicity, teratogenicity and fetotoxicity is greater than 10 mg/kg/day (the highest dose tested). 0 Lorke (1971) fed Baygon (technical, 98.4% a.i., 0.82% isopropoxyphenol) in the diet to female FB-30 rats on days 1 to 20 of gestation, at levels of 0, 1,000, 3,000 or 10,000 ppm (10/dose). Assuming that 1 ppm in the diet of rats is equivalent to 0.05 mg/kg/day, (Lehman, 1959), this corresponds to doses of about 50, 150 or 500 mg/kg/day. The rats were 2.5 to 3.5 months of age, weighing 200 to 250 g at the time of the experiment. Cesarean sections were performed on day 20. External and internal examinations on fetuses were performed, and fetuses were subjected to skeletal staining. At the 3,000- and 10,000-ppm dose levels, average fetal weights were significantly lower than control values, but ether fetal measurements were in the control range. No terata were observed at a higher incidence than in the control group. Data on fetal ossification were not adequately described for an adequate evaluation. Although this study appears to reflect a NOAEL of 1,000 ppm (50 mg/kg/day) based on fetotoxic effects, information obtained from this study is limited due to the small number of animals tested and an apparent dose-related decrease in maternal weight gain and fetal weight at the lowest dose tested (although these effects were not statistically significant). ------- Baygon August, 1987 -11- Mutagenicity 0 DeLorenzo et al. (1978) evaluated the mutagenic properties of Baygon and other carbamate pesticides by use of the Salmonella mutagenicity test of Ames. In assays using five strains of Salmonella typhimurium, no mutagenic activity was obtained with Baygon (with microsomal activation). 0 Moriya et al. (1983) tested Baygon in five strains of £. typhimurium and one strain of Escherichia coli using the Ames technique (without metabolic activation) and observed no evidence of mutagenic activity. 0 Blevins et al. (1977) used five mutants of _S. typhimurium LT2 to examine the mutagenic properties of Baygon and other methyl carbamates and their nitroso derivatives. No mutagenic activity was observed with Baygon in this experiment using the Ames technique. Carcinogenicity 0 Suberg and Loeser (1984) conducted a chronic (106-week) feeding study of Baygon (99.4% a.i.) in rats (Elberfeld strain) at dose levels of 0, 200, 1,000 or 5,000 ppm. Assuming that 1 ppm in the diet of rats is equivalent to 0.05 mg/kg/day (Lehman, 1959), this corresponds to doses of about 0, 10, 50 or 250 mg/kg/day. The study utilized 50 rats/sex/dose, plus an additional 10 of each sex included for interim necropsies at the end of the first year. At 5,000 ppm there was significant hyperplasia of the urinary bladder epithelium was noted. The incidence at this dose level after 2 years was 44/49 in males and 48/48 in females, as compared with 1/49 and 0/49 in control males and females, respectively. At 1,000 ppm, there was a smaller increased incidence (10/50 and 5/49 in males and females), respectively. No significant effect occurred at 200 ppm (1/50 and 0/49, males and females, respectively). Bladder papillomas were observed in both males (26/57) and females (28/48) at the highest dose after 2 years. In addition, at the 5,000-ppm level, carcinoma of the bladder was found in 8/57 males and 5/48 females, and carcinoma of the uterus was seen in 8/49 females, as compared with 3/49 for the control group. At the mid-dose level (1,000 ppm) only papillomas were noted in one male. The tumors of significance in this study are the uncommon bladder tumors (carcinoma and papillomas) with high incidences at the high dose level. The combined tumor incidences were 34/57 males and 33/48 females at 5,000 ppm; 1/59 males and 0/48 females at 1,000 ppm. and none in the 200-ppm or control groups. 0 Bomhard and Loeser (1981) conducted a 2-year feeding study of propoxur (99.5% a.i.) in SPF CFI/W71 mice at dose levels of 0, 700, 2,000 or 6,000 ppm. Assuming that 1 ppm in the diet is equivalent to 0.15 mg/kg/day (Lehman, 1959), this corresponds to doses of about 0, 105, 300 or 900 mg/kg/day. Mice were 5 to 6 weeks of age, weighing 22 to 25 g at the beginning of the study; each group consisted of 50 animals of each sex, plus an additional 10/sex/group included for interim necropsy at 1 year. Gross and histological examination of tissues revealed no evidence of increased tumor frequency. ------- Baygon August, 1987 -12- 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 ( /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 The study by Vandekar et al. (1971) has been selected to serve as the basis for determination of the One-day HA for Baygon. In this study, human volunteers who ingested single oral doses of 0.36 or 1.5 mg/kg displayed transient cholinergic signs accompanied by marked (43 and 75%, respectively) inhibition of red blood cell ChE (measured 10 to 15 minutes after exposure). Total doses of 0.75 or 1.0 mg/kg administered in five equal portions over 2 hours did not cause clinical signs, but inhibited red blood cell ChE by about 40%, A NOAEL was not identified; 0.36 mg/kg is taken as the LOAEL for bolus exposure, and 0.45 mg/kg (three-fifths of a 0.75-mg/kg/day total dose, administered in the first 3/5 doses) is the LOAEL when exposure to this dose is spread over several hours. It should be noted that both values are considerably lower than the NOAEL values for Baygon identified in subchronic and chronic feeding studies in animals, especially rodents. Possible reasons for this disparity are that humans may be more sensitive to this chemical than animals are; furthermore, single oral doses probably produce higher peak inhibitions than if the same total dose is ingested over a longer period of time. It is also likely that measurement of ChE activity 10 to 15 minutes after exposure (as in the case of human studies) detects peak inhibition, while sampling later reveals smaller effects (due to the reversible nature of ChE inhibition with carbamates). Since a child's exposure is more likely to occur in a manner similar to Vandekar's test, where doses were administered in five equal portions over time, the LOAEL of 0.45 mg/kg (three-fifths of a 0.75 mg/kg total dose) is used for the calculation below: The One-day HA for a 10-kg child is calculated as follows: One-day HA = (0-45 mg/kg/day) (10 kg) = 0>045 /L (4Q /L) (100) (1 L/day) ------- Baygon August, 1987 -13- where: 0.45 mg/kg/day = LOAEL, based on an inhibition of 40% in red blood cell ChE activity in humans as determined 10 minutes after oral exposure to three-fifths of a 0.75-mg/kg dose, each fifth given at half-hour intervals, and based on the fact that complete recovery of the ChE activity occurred within 2 hours after administration of the last fifth of the total dose. 1 0 kg = assumed body weight of a child. 100 = uncertainty factor, chosen in accordance with NAS/ODW guidelines for use with a LOAEL from a human study. 1 L/day = assumed daily water consumption of a child. Ten-day Health Advisory In addition to human studies by Vandekar et al. (1971) discussed above, two studies were considered for determination of the Ten-day HA. In a tera- tology study in rabbits by Schlueter and Lorke (1981), the NOAEL appeared to be higher than 10 mg/kg/day, the highest dose tested. In a teratology study in rats by Lorke (1971), the dietary administration of Baygon to animals during gestation was designed to assess both maternal and fetal effects. While sufficient data were obtained to derive a NOAEL of 50 mg/kg/day and a LOAEL of 150 mg/kg/day in rats, it is important to note that a dosage of 50 mg/kg/day was sufficient to kill all female animals in a chronic study in dogs by Loser (1968b); all deaths occurred before the end of the 2-year study period. Because humans appear to be more sensitive to Baygon than animals, the human study by Vandekar et al. (1971), used in the determination of the One-day HA value, is also the most suitable study for calculation of the Ten-day HA. The two LOAELs identified in this study, 0.36 mg/kg (bolus exposure) and 0.45 mg/kg/day (exposure to three-fifths of a 0.75-mg/kg total dose spread out over the day) can be approximated to 0.40 mg/kg; this value is used below for calculation of the Ten-day HA. The Ten-day HA for a 10-kg child is calculated as follows: Ten-day HA = (0.40 mg/kg/day) (10 kg) = 0>040 /L (40 /L) (100) (1 L/day) where: 0.40 mg/kg/day = LOAEL, based on mild cholinergic signs and 40% inhibition of red blood cell ChE in humans 10 minutes after a single oral dose. 10 kg = assumed body weight of a child. 100 = uncertainty factor, chosen in accordance NAS/ODW guidelines for use with a LOAEL from a human study. 1 L/day = assumed daily water consumption of a child. ------- Baygon f August, 1987 -14- Longer-tenn Health Advisory No suitable information was found in the available literature for the determination of the Longer-term HA value for Baygon. It is, therefore, recommended that the modified Drinking Water Equivalent Level (DWEL) of 40 ug/L for a 10-kg child be used as a conservative estimate for a Longer-term exposure. The DWEL of 100 ug/L, calculated below, should be used for the Longer-term value for a 70-kg 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, 1986a), then caution should be exercised in assessing the risks associated with lifetime exposure to this chemical. The 2-year feeding study in dogs by Loser (1968b) and the human study by Vandekar et al. (1971) have been considered for determination of the Lifetime HA. In the 2-year dog study by Loser (1968b), the chronic NOAEL was identified as 6.25 mg/kg/day and the LOAEL as 18.7 mg/kg/day. The dog NOAEL value is supported by the data of Loser (1968a) and of Suberg and Loeser (1984), which identified NOAEL values of 12.5 and 10 mg/kg/day, respectively, in chronic studies in rats. However, t^e dog appears to be far more sensitive at the higher doses than are rodents; all female dogs and some of the males in the high-dose group, 50 mg/kg/day, died before the end of the study period, while mild systemic toxicity was noted at this dose level in rats. Cholinesterase determinations were not performed in the dog study for use in comparison with human data. Due to the reversible nature of ChE inhibition by carbamates, a large difference is noted between the dosages that can cause biologically significant levels of ChE inhibition and the dosages that can produce cholinergic symptoms of toxicity (including death). Hence, in the absence of ChE data in the dog study, and because of the sensitivity of this end point in the determination of the toxicity of this chemical, the study by Vandekar et al. (1971) in humans has been selected to serve as the basis for the Lifetime HA for Baygon. This study was discussed in the previous sections ------- Baygon August, 1987 -15- on the One-day and Ten-day HAs. The 2-year mouse study by Bomhard and Loeser (1981) was not considered, since the data suggest that the mouse is even less sensitive than the rat. Using a human ChE LOAEL of 0.36 mg/kg/day, the Lifetime HA is calculated as follows: Step 1: Determination of the Reference Dose (RfD) RfD = (0*36 mg/kg/day) = 0.004 mg/kg/day (100) where: 0.36 mg/kg/day = LOAEL, based on mild cholinergic signs and 43% inhibition of red blood cell ChE in a human 10 minutes after a single oral dose. 100 = uncertainty factor, chosen in accordance with NAS/ODW guidelines for use with a LOAEL from a human study. Step 2: Determination of the Drinking Water Equivalent Level (DWEL) DWEL = (0-004 mg/kg/day) (70 kg) = 0.140 mg/L (140 ug/L) (2 L/day) where: 0.004 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 Lifetime HA = (0-140 mg/L) (20%) = Q.003 ng/L (3 ug/L) (10) where: 0.140 mg/L = DWEL. 20% = assumed relative source contribution from water. 10 = additional uncertainty factor in accordance with ODW policy* to account for possible carcinogenicity. *This policy is used only for group C oncogen. However, since there is a •potential that this chemical may be a more potent oncogen, its oncogenic potency (qi*) was calculated using the multistage model (U.S. EPA, 1987a). The q1* was estimated to be 7.9 x 10~3 (mg/kg/day)~1; if the oncogenic risk . level associated with the above determined Lifetime HA value is computed using this q,*, the risk level would be 7 x 10~7 (7 in 10,000,000). ------- Baygon August, 1987 -16- Evaluation of Carcinogenic Potential 0 Suberg and Loeser (1984) detected an increased frequency of urinary bladder epithelium hyperplasia, bladder papillomas and carcinomas, and carcinoma of the uterus in rats fed Baygon (250 mg/kg/day) for 2 years. 0 Bomhard and Loeser (1981) did not detect an increased incidence of tumors in mice fed Baygon at doses up to 90 mg/kg/day for 2 years. e The International Agency for Research on Cancer (IARC) has not evalu- ated the carcinogenic potential of Baygon. 0 Applying the criteria described in EPA's guidelines for assessment of carcinogenic risk (U.S. EPA, 1986a), Baygon may be 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. However, this classification group may be considered preliminary at the present (U.S. EPA, 1987b) since the U.S. EPA Office of Pesticide Programs (OPP) has classified this chemical in Group 82: probable human carcinogen (U.S. EPA, 1987a). A resolution will be reached between OPP and the Cancer Assessment Group (CAG) in the near future. VI. OTHER CRITERIA, GUIDANCE AND STANDARDS 0 Residue tolerances have not been established for Baygon by the OPP. • The American Conference of Governmental Industrial Hygienists (ACGIH, 1984) has proposed a threshold limit value of 0.5 mg/m3. 0 The World Health Organization (WHO) calculated an ADI of 0.02 mg/kg/day for Baygon (Vettorazzi and Van den Hurk, 1985). VII. ANALYTICAL METHODS 8 Analysis of Baygon is by a high-performance liquid chromatographic (HPLC) procedure used for the determination of N-methyl carbamoyloximes and N-methylcarbamates in water samples (U.S. EPA, 1986b). In this method, the water sample is filtered and a 400-uL aliquot is injected into a reverse-phase HPLC column. Separation of compounds is achieved using gradient elution chromatography. After elution from the HPLC column, the compounds are hydrolyzed with sodium hydroxide. The methyl amine formed during hydrolysis is reacted with o-phthalaldehyde (OPA) to form a fluorescent derivative that is detected with a fluorescence detector. The method detection limit has not been determined for Baygon, but it is estimated that the detection limits for analytes included in this method are in the range of 0.5 to 3 ug/L. ------- Baygon August, 1987 -17- VIII. TREATMENT TECHNOLOGIES 0 Available data indicate granular activated carbon (GAC) adsorption to be a possible Baygon removal technique. 0 Adsorption of Baygon on GAC proceeds in accordance with both Freundlich and Langmuir isotherms (El-Dib et al., 1974; Whittaker et al., 1982). 0 One full-scale laboratory test was carried out on a commercially available system (Dennis et al., 1983; Kobylinski et al., 1984). Different levels of Baygon (20 mg/L, 60 mg/L and 100 mg/L) were added to tap water. At a flow rate of 67.4 gpm, the column removed 99% of the Baygon in 3.5, 8.5, and 21 hours, respectively, using only 45 Ib of granular carbon. ------- Baygon August, 1987 -18- 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. Blevins, R.D., M. Lee and J.D Regan. 1977. Mutagenicity screening of five methyl carbamate insecticides and their nitroso derivatives using mutants of Salmonella typhimurium LT2. Mutat. Res. 56:1-6. Bomhard, E., and E. Loeser,* 1981. Propoxur, the active ingredient of Baygon: Chronic toxicity study on mice (two-year feeding experiment). Bayer Report No. 9954;69686. Bayer A.G, Institut fur Toxicologie. Unpublished study. MRID 00100546. Chemagro Corporation.* (no date). Toxicity study on humans. Report No. 28374. Unpublished study. MRID 00045091. CHEMLAB. 1985. The Chemical Information System, CIS, Inc., Bethesda, MD. Crawford, C.R., and R.H. Anderson.* 1971. The skin and eye irritating properties of (R) Baygon technical and Baygon 70% WP to rabbits. Report No. 29706. Unpublished study. MRID 00045097. Davies, J.E., J.J. Freal and R.W. Babione. 1967. Toxicity studies: Field trial of OMS-33 insecticide in El Salvador. Report No. 23933. World Health Organization. CDL:091768-F. Unpublished Study. MRID 00052281. Dawson, J.A., D.F. Heath, J.A. Rose, E.M. Thain and J.B. Word. 1964. The excretion by humans of the phenol derived from 2-isopropoxyphenyl N-methylcarbamate. Bull. WHO. 30:127-134. DeLorenzo, F., N. Staiano, L. Silengo and R. Cortese. 1978. Mutagenicity of Diallate, Sulfallate and Triallate and relationship between structure and mutagenic effects of carbamates used widely in agriculture. Cancer Res. 38:13-15. Dennis, W.H., A.B. Rosencrance, T.M. Trybus, C.W.R. Wade and E.A. Kobylinski. 1983. Treatment of pesticide-laden wastewaters from Army pest control facilities by activated carbon filtration using the carbolator treatment system. U.S. Army Bioengineering Research and Development Laboratory, Ft. Detrick, Frederick, MD. Eben, A., and G. Kimmerle.* 1973. Propoxur: Effect of acute and subacute oral doses on acetylcholinesterase activity in plasma, erythrocytes, and brain of rats. Report No. 4262. Report No. 39114. Unpublished study. MRID 00055148. El-Dib, M.A., F.M. Ramadan and M. Ismail. 1974. Adsorption of sevin and baygon on granular activated carbon. Water Res. 9:795-798. ------- Baygon August, 1987 f -19- Everett, L.J., and R.R. Gronberg.* 1971. The metabolic fate of Baygon (o-isopropoxyphenylmethyl carbamate) in the rat. Chemagro Corp. Research and Development Department Report No. 28797. Unpublished study. MRID 00057737. Farbenfabriken Bayer.* 1961. Toxicity of Bayer 39007 (Dr. Bocker 5812315): Report No. 6686. Farbenfabriken Bayer Aktiengesellschaft. Unpublished study. MRID 00040433. Farbenfabriken Bayer.* 1966. Two-month feeding test with Bayer 39007. Report No. 17466. Institut fur Toxicologie. Unpublished study. MRID 00035412. Foss, W., and J. Krechniak. 1980. The fate of propoxur in rat. Arch. Toxicol. 4:346-349. Gaines, T.B. 1969. Acute toxicity of pesticides. Toxicol. Appl. Pharmacol. 14:515-534. Heimann, K. 1982. Propoxur (the active ingredient of Baygon and Unden): study of sensitization effects on guinea pigs: Bayer Report No. 11218. (Mobay Report 82567, prepared by Bayer AG, Institute fuer Toxikologie). Unpublished study. MRID 00141139. Kobylinski, E.A., W.H. Dennis and A.B. Rosencrance. 1984. Treatment of pesticide-laden wastewater by recirculation through activated carbon. American Chemical Society. Krishna, J.G., and J.E. Casida.* 1965. Fate of the variously labeled methyl- and dimethyl-carbamate-14C insecticide chemicals in rats. Report No. 16440. Unpublished study. MRID 00049234. Lehman, A. J. 1959. Appraisal of the safety of chemicals in foods, drugs and cosmetics. Assoc. Food Drug Off. U. S. Lorke, D.* 1971. BAY 39007: Examination for embryotoxic effects among rats. Report No. 2388. Report No. 29035. MRID 00045094. Loser, E. * 1968a. BAY 39007: Chronic toxicological studies on rats. Report No. 726. Report No. 22991. Unpublished study. MRID 00035425. Loser, E. * 1968b. BAY 39007: Chronic toxicological studies on dogs. Report No. 669. Report No. 22814. Unpublished study. MRID 00035423. Meister, R., ed. 1984. Farm chemicals handbook. Willoughby, OH: Meister Publishing Company. Montazemi, K. 1969. Toxicological studies of Baygon insecticide in Shabankareh area, Iran. Trop. Geogr. Med. 21:186-190. Moriya, M., T. Ohta, K. Wantanabe, T. Miyazawa, K. Kato and Y. Shirasu. 1983. Further mutagenicity studies on pesticides in bacterial reversion assay systems. Mutat. Res. 116:185-216. ------- Baygon August, 1987 -20- NIOSH. 1983. National Institute for Occupational Safety and Health. Registry of toxic effects of chemical substances. Tatken, R.L., and R.J. Lewis, eds. Cincinnati, OH: National Institute for Occupational Safety and Health. DHHS (NIOSH) Publication No. 83-107. Root, M., J. Cowan and J. Doull.* 1963. Subacute oral toxicity of Bayer 39007 to male and female female (sic) rats: Report No. 10685. Unpublished Study. MRID 00040447. Schlueter, G., and D. Lorke.* 1981. Propoxur, the active ingredient of Baygon: Study of embryotoxic and teratogenic effects on rabbits after oral administration. Bayer Report No. 10183; MOBAY ACD Report No. 80034r Bayer AG Institut fur Toxicologie. Unpublished study. MRID 00100547. STORET. 1987. Suberg, H., and H. Loeser.* 1984. Chronic toxicological study with rats (feeding study over 106 weeks): Report 12870. Unpublished MOBAY study No. 88501 prepared by Bayer Institute of Toxicology. Unpublished study. MRID 00142725. 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. Method #5. Measure- ment of N-methyl carbamoyloximes and N-methylcarbamates in ground water by direct aqueous injection HPLC with post column derivatization. January 1986 draft. Cincinnati, OH: U.S. EPA Environmental Monitoring and Support Laboratory. U.S. EPA. 1987a. U.S. Environmental Protection Agency. Qualitative and quantitative risk assessment for Baygon. Office of Pesticide Programs. A memo from Bernice Fisher to Dennis Edwards, 4/3/87. U.S. EPA. 1987b. U.S. Environmental Protection Agency. Supplemental discussion of Baygon classification. Cancer Assessment Group. A memo from Arthur Chiu to William H. Farland, 4/6/87. Vandekar, M., R. Plestina and K. Wilhelm. 1971. Toxicity of carbamates for mammals. Bull. WHO. 44:241-249. Vettorazzi, G. and G.W. Van den Hurk. 1985. Pesticides Reference Index, Joint Meeting on Pesticide Residues (JMPR) 1961-1984. Whittaker, K.F., J.C. Nye, R.F. Wukash, R.J. Squires, A.C. York and H.A. Razimier. 1982. Collection and treatment of wastewater generated by pesticide application. U.S. Environmental Protection Agency, Cincinnati, OH. EPA-600/2-82-028. 'Confidential Business Information submitted to the Office of Pesticide Programs ------- |