820K88128 August' 1987 DRAFT MCPA (4-Chloro-2-Methylphenoxy)-Acetic Acid 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 ^hat 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. ------- MCPA August, 1987 -2- II. GENERAL INFORMATION AND PROPERTIES CAS Mo. 94-74-6 Structural Formula OCH2COOH (4-Chloro-2-methyl phenoxy) -acetic acid Synonyms 0 MCPA; MCP; Agroxone; Hormotuho; Metaxon. Uses 0 MCPA is a hormone-type herbicide used to control annual and perennial weeds in cereals, grassland and turf (Hayes, 1982). Properties (CHEMLAB, 1985; Meister, 1983) Chemical Formula CgHgC^Cl Molecular Weight 200.63 Physical State (25°C) Light brown solid Boiling Point Melting Point 118 to 119°C Vapor Pressure (25°C) Density (25°C) 1.56 Water Solubility 825 mg/L (room temperature) Log Octanol/Water Partition 2.07 (calculated) Coefficient Taste Threshold Odor Threshold Conversion Factor Occurrence 0 MCPA has been found in 4 of 12 surface water samples analyzed and in none of 99 ground water samples (STORET, 1987). Samples were collected at 8 surface water locations and 97 ground water locations. MCPA was found only in California. The 85th parcentile of all nonzero samples was 0.54 ug/L in surface water, and the maximum concentration found was 0.54 ug/L. Environmental Fate 0 MCPA is not hydrolyzed at pH 7 and 34 to 35°C (Soderquist and Crosby, 1974, 1975). MCPA in aqueous solution (pH 8.3) has a photolytic half-life of 20 to 24 days in sunlight. With fluorescent light, MCPA ------- MCPA August, 1987 -3- in aqueous solution (pH 9.8) produced three minor (less than 10%) photolysis products: 4-chloro-2-methyl-phenol, 4-chloro-2-formylphenol and ^-cresol in 71 hours (Soderquist and Crosby, 1974, 1975). MCPA is degraded more rapidly (1 day) in soils containing less than 10% organic matter than in soil containing higher levels (3 to 9 days) (Torstensson, 1975). This may be due to adsorption to the soil organic matter. MCPA, when applied a second time to soil, is degraded twice as fast (6 to 12 days) as it is after one application (15 to 28 days). Persistence does not depend greatly upon the soil type (Loos et al., 1979). Unlabeled MCPA in rice paddy water under dark conditions is totally degraded by aquatic microorganisms in 13 days (Soderquist and Crosby, 1974, 1975). MCPA would be expected to leach readily in most soils. Phytotoxic levels of MCPA leached 30 cm in a sandy soil column eluted with 50 cm of water (Herzel and Schmidt, 1979). Using soil thin-layer chromato- graphic techniques, MCPA was mobile (Rf 0.6 to 1.0) in calcium montmorillonite clay (Helling, 1971) and in sandy loam, silt loam, and silty clay loam soils (Helling and Turner, 1968). Mobility increases as organic matter content decreases, possibly due to adsorption of MCPA to this soil component. MCPA does not volatilize from aqueous solution (pH 7.0) heated for 13 days at 34 to 35°C (Soderquist and Crosby, 1974, 1975). Using bioassays, MCPA appears to dissipate fairly rapidly (3 to 7 weeks) from soil treated with levels of 0.75 to 1.5 ppm for 6 to 19 previous years (DeRose, 1946; Fryer and Kirkland, 1970; Torstensson et al., 1975). An initial application of MCPA may require up to 20 weeks for complete dissipation. In another study, MCPA dissipated to nondetectable levels from sandy and silt loam soils in 30 to 60 days (Suzuki, 1977). In the aquatic environment, MCPA disipates rapidly (14 to 32 days) in water, but residue levels in the flooded soil remain unchanged (Soderquist and Crosby, 1974, 1975; Sokolov et al., 1974, 1975). A common metabolite, 5-chloro^o-cresol, is formed at low levels (1.3% or less) within 1 day of treatment. Frank et al. (1979) detected MCPA residues (1.1 to 1000 ppb) in 2 of 237 wells in Ontario, Canada, between 1969 and 1978. In the forest ecosystem, MCPA remains in soil (0 to 3 cm) and leaf litter at 0.7 and 32 ppm, respectively, 10 months after application at 2.5 kg active ingredient per hectare (ai/ha) (Eronen et al., 1979). MCPA residues in moss decline to 7% of the initial level within 40 days. Residues in soil (3 to 15 cm deep) are not detectable after 40 days. MCPA has not been found in U.S. ground water. ------- MCPA August, 1987 -4- III. PHARMACOKINETICS Absorption 0 No information on the absorption of MCPA was found in the available literature. Distribution 0 Elo and Yltalo (1979) treated rats with 8 mg of 14c-MCPA [98% active ingredient (a.i.)] intravenously and measured the distribution of radioactivity in nine tissues 1.5 hours after treatment. Highest levels were found in plasma, kidney, lung, liver and heart with lesser amounts found in brain/cerebrospinal fluid (CSF), testis and muscle. Prior treatment of rats with MCPA (intravenous injections of 25 to 500 mg/kg 3 hours before administration of radiolabeled compound or chronic exposure to 500 or 2,500 mg/L in drinking water) lead to decreased levels of 14C-MCPA in the plasma and kidney and increased levels in brain/CSF. 0 Elo and Yltalo (1977) treated rats with 8 mg of 14C-MCPA (purity not specified) intravenously and measured the distribution of radioactivity in brain, CSF, muscle, liver and kidney 1.5 to 120 hours after treat- ment. Prior treatment of rats with MCPA (subcutaneous injections of 250 or 500 mg/kg) caused a decrease in the amount of radioactivity found in the plasma. Increased levels were found in other tissues with the largest increases found in the CSF (39- to 67-fold) and brain (11- to 18-fold). Metabolism e MCPA is metabolized by the liver. Stimulation of microsomal oxidation by phenobarbital increases the rate of MCPA breakdown (Buslovich et al., 1979). Gaunt and Evans (1961) found that 5-chloro-methyl-catechol is one of the metabolites of MCPA (Hattula et al., 1979). Excretion In studies by Fjeldstad and Wannag (1977), four healthy human volun- teers each ingested a dose of 5 mg of MCPA (purity not specified). Approximately 50% (2.5 mg) of the dose was detected in the urine within several days. Urinary levels were not detectable on the fifth day following exposure. Rats treated orally with MCPA (purity not specified) excreted nearly all of the MCPA during the first 24 hours after intake (90% in urine and 7% in feces) (Elo, 1976). ------- MCPA August, 1987 -5- IV. HEALTH EFFECTS Humans Short-term Exposure 0 Palva et al. (1975) reported- one case of MCPA (purity not specified) exposure (dose and duration not specified) in a farmworker involved in spraying operations. Exposure resulted in reversible aplastic anemia as well as muscular weakness, hemorrhagic gastritis and slight signs of liver damage that were later followed by pancytopenia of all of the myeloid cell lines. In a followup study in the exposed farmer, Timonen and Palva (1980) reported the occurrence of acute myelomono- cytic leukemia. Long-term Exposure 0 No information on the human health effects of chronic exposure to MCPA was found in the available literature. Animals Short-term Exposure 0 Reported acute oral LD50 values for MCPA (purity not specified) in mice and rats are 550 mg/kg and 700 mg/kg, respectively (RTECS, 1985). 0 Gurd et al. (1965) reported an acute oral LD50 value for MCPA (purity not specified) of 560 mg/kg in mice. 0 Elo et al. (1982) showed that MCPA (sodium salt; 99% a.i.) causes a selective damage of the blood-brain barrier. These authors observed that the penetration of intravenous tracer molecules such as 14c-MCPA, 14C-PABA, 14C-sucrose, 14C-antipyrine and iodinated human albumin (125i_HA) in the brain and CSF of MCPA-intoxicated rats (200 to 500 mg/kg, sc) was increased compared to controls. The tissue-plasma ratios of 14C-sucrose, 14C-antipyrine and 125I-HA treated rats were also increased in the brain and CSF of intoxicated animals, but the increases were less pronounced than those of 14C-MCPA or 14C-PABA. 0 In oral studies by Vainio et al. (1983), Wistar rats administered an ester of MCPA (purity not specified) (0, 100, 150 or 200 mg/kg/day), 5 days per week for 2 weeks, showed hypolipidemia and peroxisome proliferation in the liver. A Lowest-Observed-Adverse-Effect-Level (LOAEL) of 100 mg/kg was identified. Dermal/Ocular Effects 0 Raltech (1979) reported acute dermal LDso values for MCPA (purity not specified) in rabbits of 4.8 g/kg for males and 3.4 g/kg for females. 0 In acute dermal studies conducted by Verschuuren et al. (1975), an aqueous paste of MCPA (80.6% a.i.) (0.5 g) was applied to the abraded ------- MCPA August, 1987 -6- skin of five chinchilla rabbits. Slight erythema resulted; the skin became sclerotic after 5 to 6 days and healed by 12 days. 0 In subacute dermal studies, Verschuuren et al. (1975) applied an aqueous paste of MCPA (80.6% active ingredient; 0, 0.5, 1.0 or 2.0 g) five times weekly for 3 weeks to the shaved skin of rabbits. Slight to moderate erythema occurred at all dose levels, and elasticity of the skin was decreased. The effects subsided at 2 weeks post-treatment. Weight loss was observed at all dose levels. High mortality and histopathological alterations were observed in the liver, kidneys, spleen and thymus at the 1.0- and 2.0-g dose levels. Long-term Exposure 0 Verschuuren et al. (1975) administered MCPA (80.6% a.i.) in the diet for 90 days to SPF weanling rats (10/sex/dose) at levels of 0, 50, 400 or 3,200 ppm. Assuming that 1 ppm in the diet of rats is equiva- lent to 0.05 mg/kg/day (Lehman, 1959), this corresponds to doses of about 0, 2.5, 20 or 160 mg/kg/day. Following treatment, growth, food intake, mortality, hematology, blood and liver chemistry, organ weights and histopathology were measured. No compound-related effects were reported for any of these parameters except for growth retard- ation and elevated relative kidney weights at 400 ppm (20 mg/kg/day) or more. A No-Observed-Adverse-Effect-Level (NOAEL) of 50 ppm (2.5 mg/kg/day) and a LOAEL of 400 ppm (20 mg/kg/day) were identified. * Holsing and Kundzin (1970) administered MCPA (considered to be 100% a.i.) in the diet of rats (10/sex/dose) for 3 months. Doses were reported as 0, 4, 8 or 16 mg/kg/day; the concentration in the diet was not specified. Following treatment, no compound-related effects were observed in the physical appearance, behavior, growth, food consumption, survival, clinical chemistry, organ weights, organ-to- body weight ratios, gross pathology or histopathology at any dose tested, except for increases in kidney weight in males at 16 mg/kg/day. A NOAEL of 8 mg/kg/day and a LOAEL of 16 mg/kg/day were identified by this study. 0 Holsing and Kundzin (1968) administered oral doses of MCPA to rats at dose levels of 0, 25, 50, and 100 mg/kg/day for 13 weeks. Cytopatho- logical changes in the liver and kidneys were observed at all doses. Kidney effects included focal hyperplasia of tht< eptithelial lining, interstitial nephritis, tubular dilation and/or hypertrophy. A LOAEL of 25 mg/kg/day (the lowest dose tested) is identified by this study. 0 Reuzel and Hendriksen (1980) administered MCPA (94% a.i.) in feed to dogs in two separate 13-week studies. Dosing regimens of 0, 3, 12 or 48 mg/kg/day, and 0, 0.3, 1 or 12 mg/kg/day, respectively, were employed. Decreased kidney and liver function, characterized by increases in blood urea, SGPT and creatinine were observed at doses as low as 3 mg/kg/day. Low prostatic weight and mucopurulent conjunc- tivitis were observed at higher doses. A NOAEL of 1 mg/kg/day and a LOAEL of 3 mg/kg/day were identified by these studies. ------- MCPA August, 1987 -7- 0 Hellwig (1986) administered oral doses of MCPA (95% a.i.) to dogs at doses of 0, 6, 30, or 150 ppm for 1 year. Assuming that 1 ppro in the diet of dogs is equivalent to 0.025 mg/kg (Lehman, 1959), this corre- sponds to doses of 0, 0.15, 0.75 or 1.5 mg/kg/day. Renal toxicity was observed at the two highest doses and was characterized by elevated serum levels of creatinine, urea and potassium, coloration of the kidneys and increased storage of pigment in the renal tubules. A NOAEL of 0.15 mg/kg/day and a LOAEL of 0.75 mg/kg/day were identified by this study. 0 Holsing (1968) administered oral doses of MCPA (considered to be 100% a.i.) (0, 25, 50 or 75 mg/kg/day) to beagle dogs (three/sex/dose) for 13 weeks. Histopathological changes and alterations in various hematologic and biochemical parameters indicative of bone marrow, liver and kidney damage were observed at all dose levels. The hematological findings included decreased hematocrit, hemoglobin and erythrocyte counts. Several dogs had elevated blood urea nitrogen, serum glutamic-pyruvic transaminase, serum-oxaloacetic transaminase, alkaline phosphatase and serum bilirubin. Histopathological alterations were seen in the liver, kidney, lymph nodes, testes, prostate and bone marrow. All dogs of all three groups had various degrees of hepatic, renal and bone marrow injury. A LOAEL of 25 mg/kg/day (the lowest dose tested) was identified. 0 Gurd et al. (1965) administered technical MCPA (purity not specified) in the feed to rats (five/sex/dose) for 7 months at dose levels of 0, 100, 400, 1,000 or 2,500 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, 20, 50 or 125 mg/kg/day. Following treatment, there was a marked decrease in body weight gain at 1,000 ppm (50 mg/kg/day) or 2,500 ppm (125 mg/kg/day), and some deaths occurred at 2,500 ppm (125 mg/kg/day). At 400 ppm (20 mg/kg/day) or greater, there was a reduction in numbers of red blood cells, hemoglobin content and hematocrit. Relative kidney weights were increased at 100 ppm (5 mg/kg/day), but no effects on body weight were evident. No histopathological changes were reported at any dose level tested. A LOAEL of 5 mg/kg/day (the lowest dose tested) was identified. Reproductive Effects 0 No effects on reproduction were found in rats exposed to doses of 0, 50, 150, or 450 ppm MCPA (95% a.i.) in the diet over a period of two generations (MacKenzie, 1986). Assuming that 1 ppm in the diet of rats corresponds to 0.05 mg/kg/day (Lehman, 1959), this corresponds to doses of 0, 2.5, 7.5 or 15 mg/kg/day. Body weight depression was observed in the F-\ and F2 generations at the two highest doses. A NOAEL of 15 mg/kg/day was identified for reproductive function, and a NOAEL of 2.5 mg/kg/day was identified for fetoxtoxicity (depressed weight gain). Developmental Effects 0 Irvine et al. (1980) administered MCPA (purity not specified) (0, 5, 12, 30 or 75 mg/kg/day) by gavage to rabbits (15 to 18/dose) on days ------- MCPA August, 1987 -8- 6 to 18 of gestation. No fetotoxicity or teratogenicity was observed at any dose level tested. Body weights of the does were markedly reduced in the 75 mg/kg/day dosage group. A fetal NOAEL of 75 mg/kg/day and a maternal NOAEL of 30 mg/kg/day were identified. 0 Irvine (1980) administered MCPA (purity not specified) (0, 20, 50 or 125 mg/kg/day) by gavage to pregnant CD rats (16 to 38/dose) on days 6 to 15 of gestation. No maternal or fetal toxicity or teratogenic effects were observed. A NOAEL of 125 mg/kg/day (the highest dose tested) was identified. 0 Palmer and Lovell (1971) administered oral doses of MCPA (75% a.i.; 0, 5, 25 or 100 mg/kg/day of the active ingredient) to mice (20/dose) on days 6 to 15 of gestation. Dams were monitored for pregnancy rate, body weight, and gross toxicity; no significant effects were observed. At 100 mg/kg/day, fetal weights were significantly reduced and there was delayed skeletal ossification. A NOAEL of 25 mg/kg/day and a LOAEL of 100 mg/kg/day based on fetal weights were identified. Mutagenicity 0 Moriya et al. (1983) reported that MCPA (purity not specified) (5,000 ug/plate) did not produce mutagenic activity in Salmonella typhimurium (TA 100, TA 98, TA 1535, TA 1537, TA 1538) and in Escherichia coli (WP2 her) either with or without metabolic activation. 0 In studies conducted by Magnusson et al. (1977), there were no effects on chromosome disjunction, loss or exchange in Drosophila fed MCPA (250 or 500 ppm). 0 In studies by Linnainmaa (1984), no increases were observed in the frequency of sister chromatid exchange (SCE) in blood lymphocytes from rats intragastrically administered MCPA (purity not specified) at 100 mg/kg/day for 2 weeks. A slight increase in SCE was observed in bone marrow cells from Chinese hamsters given daily oral doses of 100 mg/kg for 2 weeks. In Chinese hamster ovarian cell cultures, SCE was slightly increased following treatment with MCPA (10~5, 10~4, 10-3^ 1 hour) with and without activation. Carcinogenicity 0 No information on the potential carcinogenicity of MCPA was found in the available literature. However, MCPA stimulates liver peroxisomal proliferation, which has been implicated in carcinogenicity (Vainio et al., 1983). 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; ------- MCPA August, 1987 -9- HA = (NOAEL or LOAEL) x (BW) = mg/L ( ug/L) (UF) x ( L/day) where: NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effeet-Level in mg/kj bw/day. BW = assumed body weight of a child (10 kj) 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 MCPA. It is therefore recom- mended that the Longer-term HA value for a 10-kj child (0.1 mg/L, calculated below) be used at this time as a conservative estimate of the One-day HA value. Ten-day Health Advisory No information was found in the available literature that was suitable to serve as the basis for determining the Ten-day HA value for MCPA. Several reproductive/teratology studies have been performed in which rats or rabbits have been given oral doses of MCPA for acute duration (Irvine, 1980; Irvine et al., 1980; Palmer and Lovell, 1971; MacKenzie, 1986). The only signs of maternal toxicity observed in these studies was a reduction in body weight in rats exposed to 75 mg/kj (Irvine, 1980). Estimates of maternal NOAELs range from 30 to 125 mg/kj/day (Irvine, 1980; Irvine et al, 1980). Fetotoxicity has been observed at dose levels as low as 7.5 mg/kj/day (MacKenzie, 1986). The toxicity of MCPA from acute exposure has not been well characterized. It is therefore recommended that the Longer-term HA value for a 10-kg child of (0.1 mg/L, calculated below) be used at this time as a conservative estimate of the Ten-day HA value. Longer-term Health Advisory Evidence of renal dysfunction has been observed in both 13-week (Reuzel and Hendriteen, 1980; Holsing, 1968) and 1-year (Hellwig, 1986) feeding studies in beagle dogs and serves as the basis for the Longer-term HA. In subchronic studies changes in blood urea and creatinine levels have been observed at doses of 25 mg/kj/day (Holsing, 1968) and 3 mg/kj/day (Reuzel and Hendriteen, 1986). Renal toxicity is not unique to dogs and has been observed in rats after 90-day exposure at dose levels of 20 mg/kj/day (Verschuuren et al., 1975) and 25 mg/kj/day (Holsing, 1968), The rat and dog may have similar sensitivities; a conservative estimate of the NOAEL was obtained from the studies described by Reuzel and Hendriteen (1980). In these studies, oral doses of 0, 3, 12 or 48 mg/kj/day, and 0, 0.3, 1 or 12 mg/kj/day, respectively, were administered to ------- MCPA August, 1987 -10- dogs for 13 weeks. Increases in blood urea, SGPT and creatinine levels were observed at dose levels as low as 3 mg/Jq/day; low prostatic weight and mucopurulent conjunctivitis were observed at higher dose levels. A NOAEL of 1 mg/kg/day was identified by these studies. Using a NOA^L of 1 mg/Jq/day, the Longer-term HA for a 10-Jq child is calculated as follows: Longer-term HA = (1.0 mg/Jq/day) (10 Jq) = Q.10 mg/L (100 ug/L) (100) (1 L/day) where: 1.0 mg/Jq/day = NOAEL, based on the absence of renal effects in dogs exposed to MCPA in the diet for 90 days. 1 0 Jq = assumed body weight of a child. 100 = uncertainty factor, chosen in accordance with NAS/ODW guidelines for use with a NOAEL from an animal study. 1 L/day = assumed daily water consumption of a child. The Longer-term HA for a 70-Jq adult is calculated as follows: Longer-term HA = (1'° mg/Jq/day) (70 Jq) = Q%35 /L (350 ug/L) (100) (2 L/day) where: 1.0 mg/Jq/day = NOAEL, based on the absence of renal effects in dogs exposed to MCPA in the diet for 90 days. 70 Jq = assumed body weight of an adult. 100 = uncertainty factor, chosen in accordance with NAS/ODW guidelines for use with a NOAEL from an animal study. 2 L/day = assumed daily water consumption of an adult. Lifetime Health Advisory The Lifetime HA represents that portion of an individual's total exposure that is attributed to drinJdng 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 IntaJe (ADI). The RfD is an esti- mate of a daily exposure to the human population that is liJely to be without appreciable ris k 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 Drin JcLng Water Equivalent Level (DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinJdng water) lifetime exposure level, assuming 100% exposure from that medium, at ------- MCPA August, 1987 -11- 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. The chronic toxicity study in dogs (Hellwig, 1986) has been selected to serve as the basis for the determination of the Lifetime HA. Beagle ,dogs were exposed to 0, 6, 30 and 150 ppm (0.15, 0.75, or 3.75 mg/kg/day) for 1 year. Renal toxicity was observed at the two highest doses and was characterized by elevated serum levels of creatinine, urea and potassium, coloration of the kidneys and increased storage of pigment in the renal tubules. A NOAEL of 0.15 mg/kg/day was identified, which is supported by the findings from subchronic feeding studies. From 90-day feeding studies, NOAELs of 1 mg/kg/day and 2.5 mg/kg/day have been identified for dogs (Reuzel and Hendriksen, 1980) and rats (Verschuuren et al., 1975), based on the absence of effects on the kidney seen at higher doses. In a 7-month feeding study, Gurd (1965) observed increased kidney weight in rats exposed to doses as low as 5.0 mg/kg/day, the lowest dose tested. Using a NOAEL of 0.15 mg/kg/day, the Lifetime HA is calculated as follows: Step 1: Determination of the Reference Dose (RfD) RfD = (0.15 mg/kg/day) = 0.0005 mg/kg/day (100) (3) where: 0.15 mg/kg/day = NOAEL, based on the absence of kidney effects in dogs exposed to MCPA in the diet for 1 year. 100 = uncertainty factor, chosen in accordance with NAS/ODW guidelines for use with a NOAEL from an animal study. 3 = additional uncertainty factor, chosen in accordance with U.S. EPA Office of Pesticide Programs (OPP) policy to account for the incomplete database on chronic toxicity. Step 2: Determination of the Drinking Water Equivalent Level (DWEL) DWEL = (0.0005 mg/kg/day) (70 kg) = 0>018 mg/L (18 ug/L) (2 L/day) ------- MCPA August, 1987 -12- where: 0.0005 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 = (0.018 mg/L) (20%) = 0.0036 mg/L (3.6 ug/L) where: 0.018 = DWEL. 20% = assumed relative source contribution from water. Evaluation of Carcinogenic Potential 0 No studies on the carcinogenic potential of MCPA were found in the available literature. 0 The International Agency for Research on Cancer (IARC, T983) concluded that the potential carcinogenicity of MCPA in both humans and laboratory! animals was indeterminate. 0 Applying the criteria described in EPA's guidelines for assessment of carcinogenic risk (U.S. EPA, 1986), MCPA may be classified in Group D: not classified. This category is used for substances with inadequate animal evidence of carcinogenicity. VI. OTHER CRITERIA, GUIDANCE AND STANDARDS 0 The National Academy of Sciences has recommended an ADI of 0.00125 mg/kg/day and a Suggested-No-Adverse-Response-Level (SNARL) of 0.009 mg/L, based on a LOAEL of 1.25 mg/kg/day in a 90-day study in rats (NAS, 1977). 0 Residue tolerances have been established for MCPA at 0.1 ppm in milk and meat. Peed and forage residue tolerances range from 0.1 to 300 ppm (U.S. EPA, 1985a). VII. ANALYTICAL METHODS 0 Analysis of MCPA is by a gas chromatographic (GC) method applicable to the determination of certain chlorinated acid pesticides in water samples (U.S. EPA, 1985b). In this method, approximately 1 liter of sample is acidified. The compounds are extracted with ethyl ether using a separatory funnel. The derivatives are hydrolized with potassium hydroxide, and extraneous organic material is removed by ------- MCPA August, 1987 -13- a solvent wash. After acidification, the acids are extracted and converted to their methyl esters using diazomethane as the derivatizing agent. Excess reagent is removed, and the esters are determined by electron-capture GC. The method detection limit has been estimated at 249 ug/L for MCPA. VIII. TREATMENT TECHNOLOGIES 0 Oxidation by ozone of 500 mg/L MCPA, after 50 to 80% disappearance of initial compound, produced no identifiable degradation products (Legube et al., 1981). This indicates that oxidation by ozone may be a possible MCPA removal technique. ------- MCPA August, 1987 -14- IX. REFERENCES Buslovich, S.Y.i Z.A. Aleksashina and V.M. Kolosovskaya. 1979. Effect of phenobarbital on the embryotoxic action of 2-methyl-4-chlorophenoxyacetic acid (a herbicide). Russ. Pharmacol. Toxicol. 24(2):57-61. CHEMLAB. 1985. The Chemical Information System, CIS, Inc., Bethesda, MD. DeRose, H.R. 1946. Persistence of some plant growth-regulators when applied to the soil in herbicidal treatments. Botanical Gazette. 107:583-589. Elo, H.A. 1976. Distribution and elimination of 2-methyl-4-chlorophenoxy- acetic acid (MCPA) in male rats. Scand. J. Work Environ. Health. 3:100-103. Elo, H.A., and P. Ylitalo. 1977. Substantial increase in the levels of chlorophenoxyacetic acids in the CNS of rats as a result of severe intoxication. Acta Pharmacol. Toxicol. 41:280. Elo, H.A., and P. Ylitalo. 1979. Distribution of 2-methyl-4-chlorophenoxyacetic acid and 2,4-dichlorophenoxyacetic acid in male rats: Evidence for the involvement of the central nervous system in their toxicity. Toxicol. Appl. Pharm. 51:439-446. Elo, H.A., P. Ylitalo, J. Kyottila and H. Herronen. 1982. Increase in the penetration of tracer compounds into the rat brain during 2-methyl-4- chlorophenoxyacetic acid (MCPA) intoxication. Acta Pharmacol. Toxicol. 50:104-107. Eronen, L., R. Julkunen and A. Saarelainen. 1979. MCPA residues in developing forest ecosystem after aerial spraying. Bull. Environ. Contain. Toxicol. 21:791-798. Fjeldstad, P., and A. Wannag. 1977. Human urinary excretion of the herbicide 2-methyl-4-chlorophenoxyacetic acid. Scand. J. Work Environ. Health. 3:100-103. Frank, R., G.J. Siron and B.D. Ripley. 1979. Herbicide contamination of well waters in Ontario, Canada, 1969-78. Pestic. Monitor. J. 13:120-127. Fryer, J.D., and K. Kirkland. 1970. Field experiments to investigate long term effects of repeated applications of MCPA, tri-allate, simazine and linuron: report after 6 years. Weed Res. 10(2): 1 33-1 58. Gurd, M.R., G.L.M. Harmer and B. Lessel. 1965. Summary of toxicological data: Acute toxicity and 7-month feeding studies with mecoprop and MCPA. Food Cosmet. Toxicol. 3:883-885. Hattula, M.L., H. Reunanen, R. Krees, A. V. Arstila and J. Knuutinen. 1979. Toxicity of 5-chloro-3-methyl-catechol to rat: Chemical observations and light microscopy of the tissue. Bull. Environ. Contain. Toxicol. 22:457-461. ------- MCPA August, 1987 -15- Hayes, W.J. 1982. Pesticides studied in man. Baltimore, MD: Williams and Wilkins. Helling, C.S. 1971. Pesticide mobility in soils. II. Application of soil thin-layer chromatography. Proc. Soil Sci. Soc. Am. 35(5):737-743. Helling, C.S., and B.C. Turner. 1968. Pesticide mobility: Determination by soil thin-layer chromatography. Science. 162(3853):562-563. Hellwig, J. 1986. Report on the study of the toxicity of MCPA in beagle dogs after 12-month administration in the diet. Project No. 33D0046/8341. Unpublished study. MRID 164352. Herzel, F., and G. Schmidt. 1979. Testing the leaching behavior of herbicides on lysimeters and small columns. WaBoLu-Berichte. (3):1-16. Holsing, G.C.* 1968. Thirteen-week dietary/oral administration in dogs. Final Report. Project No. 517-101. Unpublished study. MRID 00004756. Holsing, G.C., and M. Kundzin.* 1968. Three-month dietary administration study in rats. Project No. 517-100. Unpublished study. MRID 00004775. Holsing, G.C., and M. Kundzin.* 1970. Three-month dietary administration study in rats. Final Report. Project No. 517-106. Unpublished study. MRID 00004776. IARC. 1983. International Agency for Research on Cancer. IARC monograph on the evaluation of carcinogenic risk to chemicals to man. Lyon, France: IARC. Irvine, L.F.H., D. Whittaker, J. Hunter et al.* 1980. MCPA/oral teratogenicity study in the Dutch belted rabbit. Report No. 1737R-277/5. Unpublished study. MRID 00041637. Irvine, L.F.H.* 1980. MCPA oral teratogenicity study in the rat. Report No. 1996-277/76. Unpublished study. MRID 00066317. Legube, B., B. Langlaia, B. Sohm and M. Dore. 1981. Identification of ozonation products of aromatic hydrocarbon micropollutants: Effect on chlorination and biological filtration. Ozone: Sci. Eng. 3(1):33-48. Lehman, A.J. 1959. Appraisal of the safety of chemicals in foods, drugs and cosmetics. Assoc. Food Drug Off. U.S., Q. Bull. Linnainmaa, K. 1984. Induction of sister chromatid exchanges by the peroxisome prolif era tors 2,4-D, MCPA and clofibrate in vivo and in vitro. Carcino- genesis. 5(6):703-707. Loos, M.A., I.F. Schlosser and W.R. Mapham. 1979. Phenoxy herbicide degrada- tion in soils: quantitative studies of 2,4-D- and MCPA-degrading microbial populations. Soil Biol. and Biochem. 11 (4): 377-385. ------- MCPA August, 1987 -16- MacKenzie, K.M. 1986. Two-generation study with MCPA in rats. Final report. Study No. 6148-100. Unpublished study. Magnusson, J. et al. 1977. Mutagenic effects of chlorinated phenoxyacetic acids in Drosophila melanogaster. Hereditas. 87:121-123. Meister, R., ed. 1983. Farm chemicals handbook. Willoughby, OH: Meister Publishing Company. Moriya, M., T. Ohta, T. Watanabek, T. Miyazawa, K. Kato and Y. Shirasu. 1983. Further mutagenicity studies on pesticides in bacterial reversion assay systems. Mutat. Res. 116:185-216. HAS. 1977. National Academy of Sciences. Drinking water and health, Vol. 1. Washington, DC: National Academy Press. Palmer, A.K., and M.R. Lovell.* 1971. Effect of MCPA on pregnancy of the mouse. Unpublished study. MRID 00004447. Palva, H.L.A., 0. Koivisto and I.P. Palva. 1975. Aplastic anemia after exposure to a weed killer, 2-methyl-4-chlorophenoxyacetic acid. Acta. Haemat. 53:105-108. Raltech.* 1979. Raltech Scientific Services, Inc. Dermal LD50. Unpublished Study. MRID 00021973. Reuzel, P., and Hendriksen, C.* 1980. Subchronic (13-week) oral toxicity study of MCPA in Beagle dogs: Final report: Project No. B77/1867: Report Nos. R6478 and R6337. Unpublished study prepared by Central Institute for Nutrition and Food Research. RTECS. 1985. Registry of Toxic Effects of Chemical Substances. NIOSH, National Library of Medicine On-Line File. Soderquist, C.J., and D.G. Crosby. 1974. The dissipation of 4-chloro-2- methylphenoxyacetic acid (MCPA) in a rice field. Unpublished study prepared by Univ. of California, Davis, Department of Environmental Toxicology, submitted by Dow Chemical Company, Midland, MI. Soderquist, C.J., and D.G. Crosby. 1975. Dissipation of 4-chloro-2-methyl- phenoxyacetic ac^d (MCPA) in a rice field. Pestic. Sci. 6(1):17-33. Sokolov, M.S., L.L. Knyr, B.P. Strekozov, V.D. Agarkov, A.P. Chubenko, and B.A. Kryzhko. 1974. The behavior of some herbicides under the conditions of a rice irrigation system. Khimiya v Sel'skom Khozyaistve (Chemistry in Agriculture). 13:224-234. Sokolov, M.S., L.L. Knyr, B.P. Strekozov, and V.D. Agarkov. 1975. Behavior of proanide, yalan, MCPA and 2,4-D in rice irrigation systems of the Kuban River. Agrokhimiya (Agricultural Chemistry). 3:95-106. Suzuki, H.K.* 1977. Dissipation of Banvel, bromozynil or MCPA or combination thereof in two soil types: Report No. 181. Unpublished study submitted by Velsicol Chemical Corporation, Chicago, IL. ------- MCPA August, T987 -17- STORET. 1987. Timonen, T.T., and I. P. Palva. 1980. Acute leukemia after exposure to a weed killer, 2-raethyl-4-chlorophenoxyacetic acid. Acta Haemat. 63:170-171 Torstensson, N.T.L. 1975. Degradation of 2,4-D and MCPA in soils of low pH. In: Pesticides: IUPAC Third International Congress; July 3-9, 1974, Helsinki, Finland. Coulston, P., and F. Korte, eds. Stuttgart, West Germany: George Thieme. (Environmental Quality and Safety, Supplement, Vol. 3). pp. 262-265. Torstensson, N.T.L., J. Stark and B. Goransson. 1975. The effect of repeated applications of 2,4-D and MCPA on their breakdown in soil. Weed Res. 15(3):159-164. U.S. EPA. 1985a. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 180.339. U.S. EPA. 1985b. U.S. Environmental Protection Agency. U.S. EPA Method 615 - Chlorinated phenoxy acids. Fed. Reg. 50:40701. October 4. U.S. EPA. 1986. U.S. Environmental Protection Agency. Guidelines for car- cinogen risk assessment. Fed. Reg. 51(185):33992-34002. September 24. Vainio, H., K. Linnainmaa, M. Kahonen, J. Nickels, E. Hietanen, J. Marniemi and P. Peltoneu. 1983. Hypolipidemia and peroxisome proliferation induced by phenoxyacetic acid herbicide in rats. Biochem. Pharmacol. 32(18):2775-2779. Verschuuren, H.G., R. Kroes and E.N. denTonkecaar. 1975. Short-term oral and dermal toxicity of MCPA and MCPP. Toxicology. 3:349-359. Confidential Business Information submitted to the Office of Pesticide Programs. ------- |