August, 1988 MCPA (4-Chloro-2-Methylph6noxy)-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 enforceaole Federal standards. The HAs are subject to cnange as new information becomes available. Healtn Advisories are developed for one-day, ten-day, longer-term (approximately 7 years, or 10% of an individual's lifetime) and lifetime exposjres based on data describing noncarcinogenic end points of toxicity. 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. ------- MCPA August, 1988 -2- GENERAL INFORMATION AND PROPERTIES CAS NO. 94-74-6 Structural Formula CH, c,0 OCHtCOOH ( 4-Chloro-2-Tnethylphenoxy) -acetic acid Synonyms MCPA; MCP; Agroxone; Hormotuho; Metaxon. Uses ° MCPA is a hornone-type herbicide used to control annual and perennial weeds in cereals, grassland and turf (Hayes, 1982). Properties (CHEMLAB, 1985, 'feistsr, 1983) Chemical Formula Molecular Weignt Physical State C25°C) Boiling Point. Melting Point Vapor Pressure (25°C) Density (25°C) Water Solubility Log Octanol/Water Partition Coefficient Taste Threshold Odor Threshold Conversion Factor C9H903C1 200.63 Light brown solid 118 to 119°C 1.56 825 mg/L (20° C) 2.07 (calculated) Occurrence 0 MCPA nas been found in 4 of 18 surface water samples analyzed and in none of 118 ground water samples (STORET, 1988). Samples were collected at 13 surface water locations and 117 ground water locations. MCPA was found only in California. The 85th percentile of all nonzero samples was 0.54 ug/L in surface water, and the range of concentrations was 0.04 to 0.54 ug/L. This information is provided to give a general impression of the occurrence of tnis chemical in ground and surface waters as reported in the STORET database. The individual data points retrieved were, used as they came !rom STORET and have not been confirmed as to their validity. STORET data is often not valid when individual numbers are used out of the context of the entire sampling regime, as they are here. Therefore, this information can only be used to form an impression of tne intensity and location of sampling for a particular chemical. ------- MCPA August, 1988 -3- ° MCPA has been detected in groundwater in Montana. The highest level found was 5.5 ppb (5.5 ug/L). Frank et al. (1979) detected MCPA residues (1.1 to 1000 ppb) in 2 of 237 wells in Ontario, Canada, between 1969 and 1978. Environmental Fate ° 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 in aqueous solution (pH 9.8) produced three minor (less than 10%) photolysis products: 4-chloro-2-methyl-phenol, 4-chloro-2-formylphenol and o-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 m rice paddy water under dark conditions is totally degraded by aquatic microorganisms in 13 days (Soderquist and Crosby, 1974, 1975). 0 MCPA would d€ 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). ° 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. ° In tne 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 August, 1988 -4- III. PHARMACOKINETICS Absorption ° No information on the absorption of MCPA was found in the available literature. Distribution 0 Elo and Ylitalo (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 infections 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. ° Elo and Ylitalo ( 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-toid). Metabolism ° 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 tnat 5-chloro-methyl-catechol is one of the metabolites of MCPA (Hattula et al., 1979). Excretion ° In studies by F^eldstad 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, 1988 -5- HEALTH EFFECTS Humans Short-term Exposure 0 Case reports of attempted suicide by ingestion of MCPA have been published (Jones et al., 1967; Johnson et al, 1965; Geldmacher et al., 1966). Symptoms included pinpoint pupils, diminished/absent reflexes, low blood pressure, spasms, unconsciousness, and death. Dose estimates were not reported. ° 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. The farmer exhibited reversible aplastic anemia, muscular weakness, hemorrhagic gastritis and signs of slight liver damage that were later followed by pancytopenia of all of the myeloid cell lines. In a followup study of the exposed farmer, Timonen and Palva (1930) reported the occurrence of acute myelomonocytic leukemia. Long-term Exposure ° No information on the human healtn effects of chronic exposure to MCPA was found in the available literature. Animals Short-term Exposure ° Gura et al. (1965) reported an acute oral LD50 value for MCPA (purity not specified) of 560 mg/kg in mice. Oral LDjq's f°r MCPA in mice of 550 mg/kg and 700 mg/kg/day m rats were reported in RTECS (1985). 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, 1 4C-antipynne and lodinated human albumin (12^I-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, 1 4C-antipynne and 125j-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 the iso-octyl ester of MCPA (purity not specified) at doses of 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 aerial values for MCPA (purity not specified) in rabbits of 4.8 g/kg for males and 3.4 g/kg for females. ------- MCPA -6- August, 1988 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 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), these levels correspond to doses of about Oj 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 retardation and elevated relative kidney weights at 400 ppm (20 mg/kg/day) or more. A No-Observed-Adverse-Effect Level (NOAEL) of 50 ppn (2.5 mg/kg/day) and a L0AEL of 400 ppm (20 mg/kg/day) were identified. ° Holsing and Kundzin (1970) administered MCPA technical (considered to be 100% a.i.) in the diet of Charles-River CD rats (10/sex/dose) for 3 montns. Doses were reported as 0, 4, 8 or 16 mg/kg/day; the concen- tration 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 weignts, organ-tobody 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 technical to Charles-River CD rats at dose levels of 0, 25, 50, and 100 mg/kg/day for 13 weeks. Cytopathological changes in the liver and kidneys were observed at all doses. Kidney effects included focal hyperplasia of the epithelial lining, interstitial nephritis, tubular dilation and/or hypertrophy. A LOAEL of 25 mg/kg/day (the lowest dose tested) is identified by this study. ° Reuzel and Hendnksen (1980) administered MCPA (94% a.i.) in feed to beagle 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 m 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, 1988 -7- ° 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 ppm in the diet of dogs is equivalent to 0.025 mg/kg (Lehman, 1959), these levels correspond to doses of 0, 0.15, 0.75 or 3.75 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. ° Holsing (1968) administered oral doses of MCPA (considered to be 100% a.i.) by capsule at 0, 25, 50 or 75 mg/kg/day to beagle dogs (three/sex/dose) for 13 weeks. Histopathological changes and altera- tions 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 tne 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), these levels correspond 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, hemo- globin 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 ° 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), these levels correspond to doses of 0, 2.5, 7.5 or 22.5 mg/kg/day. Body weight depression was observed in the F1 and F2 generations at the two highest doses. A NOAEL of 22.5 mg/kg/day was identified for reproductive function, and a NOAEL of 2.5 mg/kg/day was identified for fetoxtoxicity (depressed weight gain). ------- MCPA August, 1988 -8- 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 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 mgAg/day were identified. ° 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. ° 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 ° Moriya et al. M98i) reported that MCPA (purity not specified) (5,000 ug/plate) dia not produce mutagenic activity in Salmonella typhimurium (TA 100, TA 9b, TA 1535, TA 1537, TA 1538) or in Escherichia coll (WP2 her) either with ur witnout metabolic activation. ° In studies conducted by Magnusson et al. (1977), there were no effects on chromosome disjunction, loss or exchange in Droaophila fed MCPA at 250 or 500 ppm. ° 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"^, 10"^, 10~^M, 1 hour) with and without activation. Carcinogenicity ° 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 a 1., 1983). ------- MCPA August, 1988 -9- V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS Healtn Advisories (HAs) are generally determined for one-day, ten-day, longer-term (up to 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, 1,000 or 10,000), in accordance with EPA or 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 tne available literature that was suitable for determination of the One-day HA value for MCPA. It is therefore recom- mended tnat the Longer-term HA value for a 10-kg 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 Several reproductive/developmental toxicity studies have been performed in which rats or rabDits 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 m these studies was a reduction in body weight in rats exposed to 75 mg/kg (Irvine, 1980). Estimates of mater- nal NOAELs range from 30 to 125 mg/kg/day (Irvine, 1980; Irvine et al, 1980). In contrast, fetotoxicity has been observed at dose levels as low as 7.5 mg/kg/day (MacKenzie, 1986). These studies were judged to be inadequate for evaluating the toxicity of MCPA from acute oral exposure, especially with respect to kidney toxicity observed after longer durations of exposure. 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 Hendriksen, 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 ------- MCPA August, 1988 -10- 25 mg/kg/day (Holsmg, 1968) and 3 mg/kg/day (Reuzel and Hendriksen, 1986). Renal toxicity is not unique to dogs and has been observed in rats after 90-day exposure at dose levels of 20 mg/kg/day (Verschuuren et al., 1975) and 25 mg/kg/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 Hendriksen (1980). In these studies, oral doses of 0, 3, 12 or 48 mg/kg/day, and 0, 0.3, 1 or 12 mg/kg/day, respectively, were administered to dogs for 13 weeks. Increases in blood urea, SGPT and creatinine levels were observed at dose levels as low as 3 mg/kg/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 NOAEL of 1 mg/kg/day, the Longer-term HA for a 10-kg child is calculated as follows: Longer-term HA = (1.0 mg/kg/day) (10 kg) _ g.i mg/L (100 ug/L) (100) (1 L/day) where: 1.0 mg/kg/day = NOAEL, oased on tne absence of renal effects in dogs exposed to MCPA in the diet for 90 days. 10 kg = assumed body weight of a child. 100 = uncertainty factor, chosen in accordance with EPA of NAS/ODW guidelines for use with a NOAEL from an anmal study. 1 L/day = assumed daily water consumption of a child. The Longer-term HA for a 70-kg adult is calculated as follows: Longer-term HA = (1«0 mg/kg/day) (70 kg) = o.4 mg/L (400 ug/L) (100) (2 L/day) where: 1.0 mg/kg/day = NOAEL, based on the absence of renal effects in dogs exposed to MCPA in the diet for 90 days. 70 kg = assumed body weight of an adult. 100 = uncertainty factor, chosen in accordance with EPA or NAS/ODW guidelines for use with a NOAEL from an animal study. 2 L/day = assumed daily water consumption of an adult. Lifetime Health Advisory The Lifetime HA represents that portion of an individual's total exposure that is attributed to drinking wat«?r and is considered protective of noncar- ------- MCPA August, 1988 -1 1- 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. 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 tne 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 a$ follows: Step 1: Determination of the Reference Dose (RfD) RfD = (O'TS 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 EPA or NAS/ODW guidelines for use with a NOAEL from an animal study. 3 = additional uncertainty factor, used to account for the incomplete database on chronic toxicity. ------- MCPA where: August, 1988 -1 2- Step 2: Determination of the Drinking Water Equivalent Level (DWEL) DWEL = (0«0005 mg/kg/day) (70 kg) _ 0.02 mg/L (20 ug/L) (2 L/day) 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 = (0.02 mg/L) (20%) = 0.004 mg/L (4 ug/L) where: 0.02 = DWEL. 20% = assumed relative source contribution from water. Evaluation of Carcinogenic Potential ° No studies on tne carcinogenic potential of MCPA were found in the available literature. ° The International Agency for Research on Cancer (IARC, 1983) classified the potential carcinogenicity of MCPA in both humans and laboratory animals as indeterminate. 0 Applying tne criteria described in EPA's guidelines for assessment of carcinogenic risk (U.S. EPA, 1986), MCPA may be classified in Group D: not classified. Tnis category is used for substances with inadequate animal evidence of carcinogenicity. VI. OTHER CRITERIA, GUIDANCE AND STANDARDS ° 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. Feed and forage residue tolerances range from 0.1 to 300 ppm (U.S. EPA, 1985a). VII. ANALYTICAL METHODS ° Analysis of MCPA is by a gas chromatographic (GC) method applicable ------- MCPA -1 3- August, 1988 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 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 ° 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, 1988 -14- REFERENCES Buslovich, S.Y., 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. 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. , 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. Hervonen. 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 h. Saarelainen. 1979. MCPA residues in developing forest ecosystem after aerial spraying. Bull. Environ. Contam. Toxicol. 21:791-798. Fjeldstai, 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. Geldmacher, M., V. Mallinckrodt and L. Lautenbach. 1966. Zwei todliche Vergiftungen (Suicid) mit chlorierten Phenoxyessigauren (2,4-D und MCPA. Archiv fur Toxikologie 21:261-278. 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 ot 5-cnloro-3-methyl-catecnol to rat: Chemical observations and light microscopy of tne tissue. bull. Environ. Contam. Toxicol. 22:457-461. Hayes, W.J. 1982. Pesticides studieJ in nan. Baltimore, MD: Williams and Wilkins. ------- MCPA -15- August, 1988 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 - dogs. Final Report. Project No. 517-101. Unpublished study. MRID 00004756. Holsing, G.C., and M. Kundzin.* 1968. Three-month dietary administration - rats. Project No. 517-100. Unpublished study. MRID 00004775. Holsing, G.C., and M. Kundzin.* 1970. Final Report: three-month dietary administration - 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. Irvihe, L.F.H., D. Wnittaker, J. Hunter et al.* 1980. MCPA oral teratogenicity study in the Dutch belted raboit. Report No. 1737R-277/5. Unpublished study. MRID 00041637. Irvine, L.F.H.* 1980. MCPA oral teratogenicity study in the rat. Report No. 1996-277/7b. Unpublished study. MRID 00066317. Johnson, H.R.M., and 0. Koumides. 1965. A further case of M.C.P.A. poisoning. Brit. Med. J. 2:629—630. Jones, D.I.R., A.G. Knight and A.J. Smith. 1967. Attempted suicide with herbicide containing MCPA. Arch. Environ. Health 14:363-366. 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 proliferators 2,4-D, MCPA, and clofibrate in vivo and in vitro. Carcino- genesis. 5(6):703-707. Loos, M.A., I.F. Scnlosser and W.R. Maphaa. 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 -16- August, 1988 MacKenzie, K.M. 1986. Two-generation reproductive study with MCPA in rats« Final report. Study No. 6148-100. Unpublished study. Magnusson, J., C. Ramel and A. Eriksson. 1977. Mutagenic effects of chlorinated phenoxyacetic acids in Drosophila melanoqaster. Hereditas. • 87:121-123. Meister, R., ed. 1983. Farm chemicals handbook. Willoughby, OH: Meister Publishing Company. Monya, M., T. Ohta, K. Watanabe, T. Miyazawa, K. Kato and Y. Shirasu. 1983* Further mutagenicity studies on pesticides in bacterial reversion assay systems. Mutat. Res. 116:185-216. NAS. 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. 53:105-109. Raltech.* 1979. Raltech Scientific Services, Inc. Defined dermal LD5Q* Unpublished study. MR1D 00021973. Reuzel, P.G.J., and HendriKsen, C.F.M.* 1930. 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 acid (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. STORET. 1988. STORET Water Quality File. Office of Water. U.S. Environ- mental Protection Agency (data file search conducted in May, 1988). ------- MCPA August, 1988 -17- Timonen, T.T., and I.p. Palva. 1980. Acute leukemia after exposure to a weed killer, 2-methyl-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, F., 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. Linnammaa, M. Kahonen, J. Nickels, E. Hietanen, J. Marniemi and P. Peltonen. 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.M. den Tonkelaar. 1975. Short-term oral and dermal toxicity of MCPA and MCPP. Toxicology. 3:349-359. ~Confidential Business Information submitted to the Office of Pesticide ------- |