7.4 Hazard Characterization 7.4.1 Synthesis and Evaluation of Major Non Cancer Effects While the studies relating to the metribuzin exposure on human health effects are lacking, the hazard characterization is performed from the available animal studies. Studies conducted in animals suggest that metribuzin exposure causes low acute toxicity as evidenced by the reported high LD 50 values ( Kimmerle et al., 1969; Morgan, 1982; Hartley and Kidd, 1987). Also, acute exposure studies suggest that metribuzin, at the doses tested, does not result in eye or dermal irritations ( Kimmerle et al., 1969). Subchronic studies suggest that metribuzin could cause adverse effects in body weight gain, organ weight, and hematological parameters. For example, a significant reduction in body weight gain and an increase in liver and thyroid weights were reported in Wistar rats exposed to metribuzin at 1,500 ppm ( Loser et al., 1969). Three weeks of dermal exposure to metribuzin ( 1,000 mg/ kg) in rabbits also resulted in an increase in liver enzymes such as N demethylase and cytochrome P450 ( Flucke and Hartmann, 1989). These effects are not pronounced when the studies were conducted at lower doses in dogs. Threemonth metribuzin exposure to Beagle dogs did not affect body weight gain or food consumption, but altered the clinical parameters such as SGOT and SGPT levels ( Chaisson and Cueto, 1970).

Chronic effects of metribuzin exposure may include changes in body weight gain, mortality, liver enzyme activities and histopathological changes. Two year feeding studies were performed on rats ( Loser and Mohr, 1974; Christenson and Wahle, 1993), mice ( Hayes, 1981) and Beagle dogs ( Loser and Mirea, 1974). In general, there were no significant differences in body weight gain, food consumption or mortality after two years of exposure to metribuzin to rats ( Loser and Mohr, 1974) and mice ( Hayes, 1981). However, Christenson and Wahle ( 1993) observed a decrease in body weight gain in rats after metribuzin treatment. The differences in body weight gain observed in rats could possibly be attributed to the higher dose ( 900 ppm) administered by Christenson and Wahle ( 1993) as compared to a maximum dose of 100 ppm given by Loser and Mohr ( 1974).

Major histopathological changes reported by one study after chronic feeding of metribuzin include a significant increase in corneal neovascularization, the incidence of a discolored zone in the liver, an enlarged abdomen, enlarged adrenal and thyroid glands, ocular opacity, and enlarged epididymal mass in male rats and the presence of ovarian cysts in female rats ( Christenson and Wahle 1993). 7 10 Metribuzin   February 2003 Chronic exposure to metribuzin ( 1,500 ppm) could cause a significant increase in the mortality rate in Beagle dogs. Liver dysfunction was also observed as evidenced by elevation in the activities of liver enzymes such as SGOT, SGPT and OCT. In addition, an increase in thyroid weight was observed in the high dose group of both males and females ( Loser and Mirea, 1974). However, inconsistent hematological results were observed in mice following chronic exposure to metribuzin ( Hayes, 1981).

There are a few studies available on metribuzin treatment and developmental and reproductive effects. These studies were performed using rats ( Kowaski et al., 1986; Machemer, 1972) and rabbits ( Unger and Shellenberger, 1981; Clemens and Hartnagel, 1989). In general, the maternal toxic effects are accompanied by little toxic effect to the fetus. These maternal toxic effects are characterized by a reduction in body weight gain and food consumption. In a twogeneration reproduction study, Porter et al. ( 1988) reported that F 0 and F 1 generations consumed less food and gained less body weight. Necropsy findings in both the F 0 and F 1 generations were not affected by metribuzin exposure. Also, no treatment related effects were reported in a 3 generation reproduction study in rats ( Loser and Siegmund, 1974).

There are no animal studies available which have examined neurotoxic or immunotoxic effects of metribuzin. However, metribuzin exposure could produce some endocrine effects in vivo. For example, evidence suggests that metribuzin could elevate plasma thyroxine ( T4) levels in rats ( Porter et al., 1993; Christenson and Wahle, 1993) and decrease triiodothyronine ( T3) levels in rats ( Christenson and Wahle, 1993) and rabbits ( Flucke and Hartmann, 1989).

A few inhalation studies are available on metribuzin exposure and the effects are comparable to the existing oral exposure studies. An increase in thyroid and liver weights as well as liver enzyme activities such as N demethylase, O demethylase and cytochrome P450 was reported in Wistar rats exposed to metribuzin at 720 mg/ m3 ( Thyssen, 1981).

7.4.2 Synthesis and Evaluation of Carcinogenic Effects There are no human studies available which have examined the relationship between exposure to metribuzin and cancer. Metribuzin exposure did not increase the incidence of tumors in a lifetime dietary study using CD 1 mice when compared to both concurrent and historic controls ( Hayes, 1981). In a 2 year feeding study utilizing Wistar rats, there were no significant differences in neoplastic findings between the test and control groups ( Loser and Mohr, 1974; Christenson and Wahle, 1993). Short term studies in bacteria and mammalian systems suggest that metribuzin is not mutagenic. Recent in vitro studies suggest, however, that metribuzin can induce adduct formation ( Shah et al., 1997).

7.4.3 Mode of Action and Implications in Cancer Assessment The available evidence from animal studies suggest that there is little data to support metribuzin induced carcinogenicity and therefore no studies are reported which examine the mode of action of metribuzin for cancer effects. 7 11 Metribuzin   February 2003 7.4.4 Weight of Evidence Evaluation for Carcinogenicity There are no studies identified that examine the carcinogenic effects of metribuzin on humans. There are three lifetime studies which have been reported, one in mice and two in rats, that examine the relationship between metribuzin exposure and tumor incidence. Evidence from these animal studies is inadequate and therefore, metribuzin is classified as a class D carcinogen, applying the criteria described in the EPA's guidelines for the assessment of carcinogenic risk ( U. S. EPA, 1986).

7.4.5 Sensitive Populations There are no human studies available which examine the toxic effects of metribuzin and its effect on sensitive populations. 8 1 Metribuzin   February 2003 8.0 DOSE RESPONSE ASSESSMENT 8.1 Dose Response for Non Cancer Effects 8.1.1 RfD Determination Choice of Principal Study The oral Reference Dose ( RfD) is based on the assumption that thresholds exist for certain toxic effects. The RfD is expressed in units of mg/ kg day. In general, the RfD is an estimate ( with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population ( including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime.

The principal study utilized for RfD derivation, as recommended by the OPP/ HED RfD Committee, was the chronic study in rats conducted by Christenson and Wahle ( 1993) in rats described in section 7.2.6. A 2 year feeding study was conducted in which Fischer 344 rats received 0, 30, 300 or 900 ppm ( 0, 1.3, 13.8, 42.2 mg/ kg day in males; 0, 1.6, 17.7, 53.6 mg/ kgday females) metribuzin ( 93.0% active ingredient) for 104 weeks. At 30 ppm ( 1.3 mg/ kg day for males and 1.6 mg/ kg day for females), both sexes exhibited increased absolute and relative thyroid weights, statistically significant increases in blood levels of thyroxine ( T4), and statistically significant decreases in blood levels of triiodothyronine ( T3). Females also exhibited decreased lung weight. However, these effects were considered to be of marginal biological significance. Therefore, the RfD Committee determined that the 30 ppm dose ( 1.3 mg/ kg day in males) should be considered the NOAEL.

RfD Derivation RfD = 1.3 mg/ kg day = 0.013 mg/ kg day 100 Based on a chronic exposure study, an uncertainty factor of 100 was used to account for inter species extrapolation ( 10) and intra species variability ( 10).

8.1.2 RfC Determination There is insufficient data available from which to derive the RfC at this time. 8 2 Metribuzin   February 2003 8.2 Dose Response for Cancer Effects In a study by Hayes ( 1981), metribuzin was orally administered via the diet to mice ( 50/ sex/ dose) at dose levels of 200, 800 or 3,200 ppm ( 30, 120 or 480 mg/ kg day) for 24 months. Following treatment, the incidence of tumor formation was analyzed in a variety of tissues. Neoplasms of various tissues and organs were similar in type, location, time of occurrence, and incidence in control and treated animals. The mice study is supported by the tumor incidence data observed in 2 year feeding cancer studies in rats ( Loser and Mohr, 1974; Christenson and Wahle, 1993).

Applying the criteria described in EPA's guidelines for assessment of carcinogenic risk ( U. S. EPA, 1986), metribuzin should be classified in Group D: not classifiable as to human carcinogenicity. This category is used for substances with inadequate animal evidence of carcinogenicity. 9 1 Metribuzin   February 2003 9.0 REGULATORY DETERMINATION AND CHARACTERIZATION OF RISK FROM DRINKING WATER 9.1 Regulatory Determination for Chemicals on the CCL The Safe Drinking Water Act ( SDWA), as amended in 1996, required the U. S. Environmental Protection Agency ( EPA) to establish a list of contaminants to aid the agency in regulatory priority setting for the drinking water program. EPA published a draft of the first Contaminant Candidate List ( CCL) on October 6, 1997 ( 62 FR 52193, U. S. EPA, 1997a). After review of and response to comments, the final CCL was published on March 2, 1998 ( 63FR 10273, U. S. EPA, 1998). The CCL grouped contaminants into three major categories as follows:

Regulatory Determination Priorities  Chemicals or microbes with adequate data to support a regulatory determination.

Research Priorities  Chemicals or microbes requiring research for health effects, analytical methods, and/ or treatment technologies.

Occurrence Priorities  Chemicals or microbes requiring additional data on occurrence in drinking water.

The March 2, 1998 CCL included one microbe and 19 chemicals in the regulatory determination priority category. More detailed assessments of the completeness of the health, treatment, occurrence and analytical method data led to a subsequent reduction of the regulatory determination priority chemicals to a list of 12 ( one microbe and 11 chemicals) which was distributed to stakeholders in November 1999.

SDWA requires EPA to make regulatory determinations for no fewer than five contaminants in the regulatory determination priority category by August, 2001. In cases where the Agency determines that a regulation is necessary, the Agency has two years to propose an NPDWR and one and a half years to finalize the rule. The Agency is given the freedom to also determine that there is no need for a regulation if a chemical on the CCL fails to meet the statutory criteria established by SDWA and described in section 9.1.1.

9.1.1 Criteria for Regulatory Determination These are the three criteria used to determine whether or not to regulate a chemical on the CCL:

The contaminant may have an adverse effect on the health of persons The contaminant is known to occur or there is a substantial likelihood that the contaminant will occur in public water systems with a frequency and at levels of public health concern 9 2 Metribuzin   February 2003 In the sole judgment of the administrator, regulation of such contaminant presents a meaningful opportunity for health risk reduction for persons served by public water systems.

The findings for all three criteria are used in making a determination to regulate a contaminant. As required by SDWA, a decision to regulate commits the EPA to publication of a Maximum Contaminant Level Goal ( MCLG) and promulgation of a National Primary Drinking Water Regulation ( NPDWR) for that contaminant. The Agency may determine that there is no need for a regulation when a contaminant fails to meet one of the criteria. A decision not to regulate is considered a final Agency action and is subject to judicial review. The Agency can choose to publish a Health Advisory ( a nonregulatory action) or other guidance for any contaminant on the CCL, independent of the regulatory determination.

9.1.2 National Drinking Water Advisory Council Recommendations In March 2000, the U. S EPA convened a Working Group under the National Drinking Water Advisory Council ( NDWAC) to help develop an approach for making regulatory determinations. The Working Group developed a protocol for analyzing and presenting the available scientific data and recommended methods to identify and document the rationale supporting a regulatory determination decision. The NDWAC Working Group report was presented to and accepted by the entire NDWAC in July 2000.

Because of the intrinsic difference between microbial and chemical contaminants, the Working Group developed separate but similar protocols for microorganisms and chemicals. The approach for chemicals was based on an assessment of the impact of acute, chronic, and lifetime exposures, as well as a risk assessment that includes evaluation of occurrence, fate, and dose response. The NDWAC Protocol for chemicals is a semi quantitative tool for addressing each of the three CCL criteria. The NDWAC requested that the Agency use good judgement in balancing the many factors that need to be considered in making a regulatory determination. The U. S. EPA modified the semi quantitative NDWAC suggestions for evaluating chemicals against the regulatory determination criteria and applied them in decision making. The quantitative and qualitative factors for metribuzin that were considered for each of the three criteria are presented in the sections that follow.

9.2 Health Effects The first criterion asks if the contaminant may have an adverse effect on the health of persons. Because all chemicals have adverse effects at some level of exposure, the challenge is to define the dose at which adverse health effects are likely to occur, and to estimate a dose at which adverse health effects are either not likely to occur ( threshold toxicant), or have a low probability for occurrence ( non threshold toxicant). The key elements that must be considered in evaluating the first criterion are the mode of action, the critical effect( s), the dose response for critical effect( s), the RfD for threshold effects, and the slope factor for non threshold effects. 9 3 Metribuzin   February 2003 A full description of the health effects associated with exposure to metribuzin is presented in Chapter 7 of this document and summarized below in Section 9.2.2. Chapter 8 and Section 9.2.3 present dose response information.

9.2.1 Health Criterion Conclusion Although there are no studies reporting the adverse effects of metribuzin on human health, animal studies indicate that metribuzin has the potential to cause adverse health effects at high doses. Exposure to metribuzin may occur primarily in an occupational setting, particularly in the agriculture industry where it is used as an herbicide. The RfD of 0.013 mg/ kg day was derived from a study reporting the adverse health effects of metribuzin in rats.

9.2.2 Hazard Characterization and Mode of Action Implications There are no epidemiology studies that have assessed adverse human health effects caused by exposure to metribuzin. Acute toxicity animal studies indicate that metribuzin induces low toxicity as evidenced by the relatively high LD 50 values ( Kimmerle et al., 1969; Morgan, 1982; Hartley and Kidd, 1987). In addition, metribuzin has not been found to cause eye irritation in rabbits, and causes only slight dermal irritation in rabbits ( Kimmerle et al., 1969).

Subchronic studies in animals suggest that metribuzin may cause adverse effects on body weight gain, organ weight and hematological parameters. Wistar rats exposed to metribuzin in the diet at 1500 ppm for three months exhibited a significant reduction in body weight gain, and increased liver and thyroid weights ( Loser et al., 1969). However a 3 month dietary exposure in Beagle dogs did not affect body weight gain or food consumption, and only altered clinical parameters such as SGOT and SGPT levels ( Chaisson and Cueto, 1970).

Chronic studies of metribuzin report effects on body weight gain, mortality, liver enzyme activities and histopathological changes. Two year feeding studies conducted in rats ( 0, 25, 35, 100 or 300 ppm) and mice ( 0, 200, 800 or 3200 ppm) indicated no significant differences in body weight gain, food consumption, or mortality ( Loser and Mohr, 1974; Hayes, 1981). Another two year feeding study in rats using a higher dose ( 900 ppm) of metribuzin did report a decrease in body weight gain ( Christenson and Wahle, 1993). This study also reported histopathological changes such as significant increases in corneal neovascularization, discolored zones in the liver, an enlarged abdomen, enlarged adrenal and thyroid glands, ocular opacity, an enlarged epididymal mass in males, and the presence of ovarian cysts in female rats ( Christenson and Wahle, 1993). In Beagle dogs, chronic exposure to the highest dose of 1,500 ppm caused a significant increase in the mortality rate and liver dysfunction as evidenced by increases in the activity of liver enzymes such as SGOT, SGPT and OCT ( Loser and Mirea, 1974). Thyroid weight was also increased in the highest dose group. Histopathologic findings included liver and kidney damage at the highest dose. The liver and kidney effects, decreased body weight gain, and mortality at the highest dose are considered the critical effects of metribuzin exposure. 9 4 Metribuzin   February 2003 There are few studies that have assessed the developmental and reproductive effects of metribuzin exposure. In general, maternal toxicity effects observed in rats and rabbits include reduced body weight gain and food consumption, and are accompanied by slight toxicity to the fetus ( Kowaski et al., 1986; Machemer, 1972; Unger and Shellenberger, 1981; Clemens and Hartnagel, 1989). A two generation study in rats reported that both F 0 and F 1 generations consumed less food and gained less body weight ( Porter et al., 1988). Necropsy findings in both generations were not affected by exposure to metribuzin. Another 3 generation reproduction study in rats found no treatment related effects ( Loser and Siegmund, 1974).

No animal studies have addressed the neurologic or immunotoxic effects of metribuzin. There is evidence of endocrine effects induced by metribuzin, including elevated plasma thyroxine levels in rats and decreased triiodothyronine levels in rats and rabbits ( Porter et al. 1993; Christenson and Wahle, 1993; Flucke and Hartmann, 1989).

The EPA has classified metribuzin as a class D carcinogen due to inadequate carcinogenicity data in humans and animals. A lifetime dietary study in CD 1 mice and 2 year feeding studies in Wistar rats were negative for the induction of tumors compared to control incidences ( Hayes, 1981; Loser and Mohr, 1974; Christenson and Wahle, 1993).

9.2.3 Dose Response Characterization and Implications in Risk Assessment The principal study utilized for RfD derivation, as recommended by the OPP/ HED RfD Committee, was the chronic study in rats conducted by Christenson and Wahle ( 1993) in rats described in section 7.2.6. A 2 year feeding study was conducted in which Fischer 344 rats received 0, 30, 300 or 900 ppm ( 0, 1.3, 13.8, 42.2 mg/ kg day in males; 0, 1.6, 17.7, 53.6 mg/ kgday females) metribuzin ( 93.0% active ingredient) for 104 weeks. At 30 ppm ( 1.3 mg/ kg day for males and 1.6 mg/ kg day for females), both sexes exhibited increased absolute and relative thyroid weights, statistically significant increases in blood levels of thyroxine ( T4), and statistically significant decreases in blood levels of triiodothyronine ( T3). Females also exhibited decreased lung weight. However, these effects were considered to be of marginal biological significance. Therefore, the RfD Committee determined that the 30 ppm dose ( 1.3 mg/ kg day in males) should be considered the NOAEL. The RfD of 0.013 mg/ kg day was derived by dividing the NOAEL by an uncertainty factor of 100, which was used to account for inter and intraspecies variability.

9.3 Occurrence in Public Water Systems The second criterion asks if the contaminant is known to occur or if there is a substantial likelihood that the contaminant will occur in public water systems with a frequency and at levels of public health concern. In order to address this question, the following information was considered: 9 5 Metribuzin   February 2003 ° Monitoring data from public water systems ° Ambient water concentrations and releases to the environment ° Environmental Fate Data on the occurrence of metribuzin in public drinking water systems were the most important determinants in evaluating the second criterion. EPA looked at the total number of systems that reported detections of metribuzin, as well as those that reported concentrations of metribuzin above an estimated drinking water health reference level ( HRL). For noncarcinogens the estimated HRL risk level was calculated from the RfD assuming that 20% of the total exposure would come from drinking water. For carcinogens, the HRL was the 10 6 risk level. The HRLs are benchmark values that were used in evaluating the occurrence data while the risk assessments for the contaminants were being developed.

The available monitoring data, including indications of whether or not the contamination is a national or a regional problem, are included in Chapter 4 of this document and are summarized below. Additional information on production, use, and environmental fate are found in Chapters 2 and 3.

9.3.1 Occurrence Criterion Conclusion The available data on metribuzin production and use indicate a modestly declining trend. Although detection of metribuzin is found in both surface and ground waters of urban and agricultural regions, concentrations are extremely low and well below the HRL or half the HRL. In regards to drinking water, metribuzin detection frequencies and concentrations are extremely low to undetectable, with the exception of detections in Pennsylvania, Indiana, Illinois and Washington. These data indicate that although metribuzin is found in ambient waters, little to no metribuzin is detected in drinking water systems.

9.3.2 Monitoring Data Drinking Water A national cross section of 20 states reported metribuzin detection data in the SDWIS/ FED database. This cross section provides a good representation of the nation's varied climatic and hydrogeologic regions, and the breadth of pollution potential. In addition, occurrence data is presented from all the states participating under the Unregulated Contaminant Monitoring ( UCM) program begun in 1991. Metribuzin was not included in this program until Round 2, which began in 1993.

In the cross section of 20 states, approximately 0.007% of Public Water Systems ( PWS) reported detections of metribuzin above the minimum reporting level ( MRL), affecting about 0.0003% of the population. Only the state of Washington reported a metribuzin detection above the MRL, at a level of 0.10 : g/ L, which is far below the Health Reference Level ( HRL) of 91 9 6 Metribuzin   February 2003 : g/ L. A national extrapolation of this data indicates that approximately 5 PWSs would experience detections of metribuzin above the MRL, and that approximately 1,000 people would be affected. When all the states participating in Round 2 of the UCM program were considered, 0.28% of PWSs experienced detections above the MRL. This indicates that approximately 1.61% of the population, or 3.4 million people nationally, is affected by concentrations of metribuzin above the MRL. No PWSs experienced detections > ½ HRL or > HRL. Therefore, 0% of the population is affected by metribuzin concentrations > ½ HRL or > HRL. The median and 99th percentile concentrations of detections are 1.0 µ g/ L and 3 µ g/ L, respectively.

Ambient Water The USGS began the National Ambient Water Quality Assessment ( NAWQA) program in 1991 to monitor water quality status and trends in the U. S. This program consists of 59 watersheds and aquifers referred to as " study units" and represents approximately two thirds of the overall water usage and a similar proportion of the population served by public water systems. The Method Detection Limit ( MDL) for metribuzin is 0.004 : g/ L.

Detection frequencies and concentrations of metribuzin in ambient surface and ground waters are low. Surface waters exhibited the highest maximum concentration of metribuzin at 0.530 : g/ L, with a reported frequency of 13.82% of samples with concentrations greater than the MDL. Although the occurrence in ground water is lower than in surface water, detection in 1.95% of ground water samples at a maximum concentration of 0.300 : g/ L make metribuzin one of the 21 most commonly detected pesticides in intensive NAWQA monitoring. In both surface and ground waters, metribuzin was more frequently detected in agricultural regions as compared to urban areas.

9.3.3 Use and Fate Data Metribuzin, a synthetic organic compound, is a selective triazinone herbicide used to discourage growth of broadleaf weeds and annual grasses among vegetable crops and turf grass. Using data from the USDA and NCFAP, the EPA estimates that the average annual use for the years 1990 94 at 2.8 million pounds of active ingredient with 8.5 million acres treated. The USGS estimates that 2.7 million pounds of metribuzin treating 8.4 million acres were used in 1992. The non agricultural use of metribuzin is minimal. Table 3 1 of Chapter 3 indicates a modest decline of metribuzin use from 1990 1999.

Data from the Toxic Release Inventory ( TRI) indicate a general decline in environmental releases of metribuzin between 1995 and 1998 ( Table 3 2). Air emissions are reported to have declined although surface water discharges have increased.

Metribuzin is a solid at ambient temperatures and has a low vapor pressure. Therefore, it is unlikely to readily partition to air. Since metribuzin is not labeled for residential use, it is not anticipated to be found in residential soils. The Organic Carbon Partition Coefficient ( K oc) is 95, 9 7 Metribuzin   February 2003 and indicates that metribuzin is highly mobile in soil. It is also moderately adsorbed on soils with high clay or organic content and leaches more readily from sandy soils. In soil, biodegradation is the primary fate process ( HSDB, 2000). In the aquatic environment, volatilization from water and bioconcentration in fish are not anticipated to be relevant ( HSDB, 2000). No data are available for the biodegradation of metribuzin in water.

9.4 Risk Reduction The third criterion asks if, in the sole judgement of the Administrator, regulation presents a meaningful opportunity for health risk reduction for persons served by public water systems. In evaluating this criterion, EPA looked at the total exposed population, as well as the population exposed above the estimated HRL. Estimates of the populations exposed and the levels to which they were exposed were derived from the monitoring results. These estimates are included in Chapter 4 of this document and summarized in Section 9.4.2 below.

In order to evaluate risk from exposure through drinking water, EPA considered the net environmental exposure in comparison to the exposure through drinking water. For example, if exposure to a contaminant occurs primarily through ambient air, regulation of emissions to air provides a more meaningful opportunity for EPA to reduce risk than regulation of the contaminant in drinking water. In making the regulatory determination, the available information on exposure through drinking water ( Chapter 4) and information on exposure through other media ( Chapter 5) were used to estimate the fraction that drinking water contributes to the total exposure. The EPA also evaluated effects on potentially sensitive populations, including fetuses, infants and children. The sensitive population considerations are included in Section 9.4.4.

9.4.1 Risk Criterion Conclusion Based on the data from the cross section analysis of 20 states, metribuzin exposure from drinking water would be very low with only 1,000 people exposed nationally. When all the Round 2 data are considered, including data from the state of Pennsylvania, approximately 3.4 million people nationally are exposed to any concentration of metribuzin. Aside from the potential of occupational exposure, no other source of exposure would lead to significant doses of metribuzin. These observations indicate that regulation of metribuzin in drinking water would have little impact on human risk reduction.

9.4.2 Exposed Population Estimates As described in 9.3.1, a cross section survey of 20 states reported that 0.007% of Public Water Systems had detections of metribuzin above the minimum reporting level ( MRL), affecting less than 0.0003% of the population. A national extrapolation of this data indicates that approximately 1,000 people would be exposed to metribuzin through the drinking water. Of the 20 states in this cross section survey, only the state of Washington reported a detection of metribuzin. Since Washington is the only state to report a metribuzin detection at 0.10 : g/ L, this value is both the median and 99th percentile concentrations. 9 8 Metribuzin   February 2003 However, when all of the participating states in Round 2 of the UCM program were considered, 0.28% of PWSs reported detections above the MRL. National extrapolation of this data indicates that approximately 1.6% of the population, or 3.4 million people, are exposed to concentrations above the MRL.

9.4.3 Relative Source Contribution Relative source contribution analysis compared the magnitude of exposure to metribuzin expected via drinking water and the magnitude of exposure from other media, such as food, air and soil. The intake of metribuzin from drinking water can be calculated from the median concentrations described above for both the cross section study and the study of all the Round 2 states. Using the median metribuzin level from the 20 state cross section study of 0.10 : g/ L, an average daily intake of 2 L/ day for an adult, and an average weight of 70 kg for an adult, the corresponding dose would be 2.8 × 10 3 mg/ kg day for adults. For children, assuming an intake of 1 L/ day and an average weight of 10 kg, the dose would be 1.0 × 10 2 mg/ kg day.

As part of the FDA's Regulatory Monitoring Program, 9,438 domestic and imported food samples were analyzed for pesticides, including metribuzin. Metribuzin was not detected in any samples of grains, milk products, fruits or vegetables. In addition, no detections were found in 218 domestic and 298 imported fish and shellfish samples. The daily intake of metribuzin from food is anticipated to be close to zero.

No data are available for the ambient levels of metribuzin in air. However, metribuzin is a solid at ambient temperatures and has a low vapor pressure; partitioning of metribuzin into air is highly unlikely. Therefore, the average daily intake for the general population is anticipated to be close to zero. However, inhalation of metribuzin may be potentially significant for occupational exposure. The occupational subgroup may include workers involved in the mixing, loading, handling and application of metribuzin. The EPA has estimated that inhalation exposures of this subgroup range from 0.006 to 91.14 mg/ day. Calculations of doses based on this range of exposure and 70 kg body weight are 8.6 × 10 5 to 1.3 mg/ kg day.

Metribuzin is not labeled for residential use and so it is not anticipated to be found in residential soils. General population exposures are anticipated to be close to zero. In agricultural regions where metribuzin is applied, metribuzin may be found in soils in concentrations as high as 0.78 mg/ kg. Based on an average body weight of 70 kg and a daily soil intake of 480 mg/ day, the maximum daily intake for a contact intensive worker would be 5.3 × 10 3 mg/ kg day, which is below the RfD.

For estimating the HRL from the RfD, the default value of 20% was used for the relative source contribution assuming that the total exposure to metribuzin is not from drinking water.

9.4.4 Sensitive Populations No sensitive populations to metribuzin have been identified. 9 9 Metribuzin   February 2003 9.5 Regulatory Determination Summary Although there is evidence from animal studies that metribuzin may cause adverse health effects at high doses, its occurrence in public water systems and the numbers of people potentially exposed through drinking water are low. In addition, there are no available studies, either epidemiological or case studies of accidentally exposed agricultural workers, assessing adverse health effects in humans due to metribuzin. Overall, metribuzin is not anticipated to cause adverse health effects in humans at the concentrations detected in public water systems and is unlikely to expose a large number of people outside of an occupational setting. For these reasons, EPA may not propose to regulate metribuzin with NPDWR. All final determinations and future analysis will be presented in the Federal Register Notice covering CCL proposals. 10 1 Metribuzin   February 2003 10.0 REFERENCES ACGIH. 1986. Documentation of the threshold limit values and biological exposure indices, 5th ed, Cincinnati, OH. American Conference of Governmental Industrial Hygienists, Inc. 6: 1042, 1991. ( as cited in RTECS, 2000; HSDB, 2000).

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Bouchard, D. C., T. L. Lavy, and D. B. Marx. 1982. Fate of metribuzin, metolachlor and fluometuron in soil. Weed Science 30: 629 632.

Brown, D. F., D. K. McCool, R. I. Papendick, et al. 1985. Herbicide residues from winter wheat triticum aestivum plots effect of tillage and crop management. Journal of Environmental Quality. 14 ( 4): 521 532.

Burgard, D. J., R. H. Dowdy, W. C. Koskinen, et al. 1994. Movement of metribuzin in a loamy sand soil under irrigated potato production. Weed Science 42 ( 3): 446 452.

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Cain, K., C. Hanlon and J. Lane. 1987. The excretion and metabolism of Sencor by rats. Unpublished study. Submitted by Mobay Chemical Corp. Kansas City, MO ( MRID 40255503) ( as cited in U. S. EPA 1998).

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Chaisson, C. F. and C. Cueto. 1970. 90 day subacute oral toxicity study of BAY 94337 in Beagle dogs. Submitted by Mobay Chemical Corp. Kansas City, MO ( MRID 00106162)

Christenson, W. R. and B. S. Wahle. 1993. Technical Grade Metribuzin ( Sencor ® ) : A combined chronic toxicity/ oncogenicity feeding toxicity study in the rat. Unpublished study. Prepared by Miles Inc. ( MRID 42672501)

Clemens, G., and R. Hartnagel Jr. 1989. Teratology study in the rabbit with Sencor Technical ( Metribuzin). A Unpublished study. Prepared by Miles Inc. ( MRID 41249201) 10 2 Metribuzin   February 2003 Cohen, B., R. Wiles, and E. Bondoc. 1995. Weed Killers by the Glass: a citizen's tap water monitoring project in 29 cities. Washington, D. C.: Environmental Working Group. 83 pp.

Crawford, C. and R. Anderson. 1972. The acute dermal toxicity of Sencor Technical and Sencor 50% wettable powder to rats and rabbits: Report No. 33123. Unpublished study. Submitted by Mobay Chemical Corp., Kansas City, MO ( MRID 00106149) ( as cited in U. S. EPA, 1998a)

Crawford, C. R. and R. H. Anderson*. 1974. The acute oral toxicity of Sencor technical, several Sencor metabolites and impurities to rats and guinea pigs. Report no. 38927. Rev. unpublished study. MRID 00045270 ( as cited in U. S. EPA1988)

Dao, T. H. 1995. Subsurface mobility of metribuzin as affected by crop residue placement and tillage method. Journal of Environmental Quality 24: 1193 1198.

EXTOXNET. 1998. Pesticide Information Profile: Metribuzin. Ithaca, NY: Extension Toxicology Network, Pesticide Management Education Program. Available on the Internet at http:// pmep. cce. cornell. edu/ profiles/ extoxnet/ metiram propoxur/ metribuzin ext. html# top Last modified 03/ 11/ 1998.

Flucke, W. and E. Hartmann. 1989. DIC 1468. Technical grade: ( Common Name: Metribuzin): Subacute dermal toxicity study in rabbits. Unpublished study. Prepared by Bayer. ( MRID 43970701) ( as cited in U. S. EPA 1998)

Gallaher, K. and T. C. Mueller. 1996. Effect of crop presence on persistence of atrazine, metribuzin, and clomazone in surface soil. Weed Science 44 ( 3): 698 703.

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Loser, E. and D. Mirea*. 1974. Bay 94337: Chronic toxicity studies on dogs ( Two year feeding experiment): Report No. 4887; Report No. 41814. Unpublished study. submitted by Mobay Chemical Corp., Kansas City, MO. ( MRID 00061260)

Loser, E. and U. Mohr*. 1974. Bay 94337: Chronic toxicity studies on rats ( Two year feeding experiment): Report No. 4888; Report No. 41816. Unpublished study. submitted by Mobay Chemical Corp., Kansas City, MO. ( MRID 00061261)

Loser, E., L. E. Mawdesley Thomas and D. Lorke*. 1969. Bay 94337. Subchronic toxicological studies on rats ( three month feeding experiment). Submitted by Mobay Chemical Corp., Kansas City, MO ( MRID 00106161).

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Mobay Chemical Corporation. 1974b. MRID No. 00086765 ( as cited in U. S. EPA, 1993)

Mobay Chemical Corporation. 1975. MRID No. 00086767 ( as cited in U. S. EPA, 1993)

Mobay Chemical Corporation*. 1976. MRID No. 00086768 ( as cited in U. S. EPA, 1993)

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U. S. EPA. 1996b. Guidelines for Reproductive Toxicity Risk Assessment. U. S. Environmental Protection Agency, Office of Research and Development, Washington, D. C. EPA/ 630/ R 96/ 009.

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* Confidential Business Information submitted to the Office of Pesticide Programs. A 1 Metribuzin   February 2003 APPENDIX A: Abbreviations and Acronyms AA  Atomic Absorption ACGIH  American Conference of Governmental Industrial Hygienists a. i.  active ingredient ANPRM  Advanced Notice of Proposed Rule Making APHA  American Public Health Association ARMS  Agricultural Resources Management Study ATSDR  Agency for Toxic Substances and Disease Registry CA  Census of Agriculture CAS  Chemical Abstract Service CASRN  Chemical Abstract Service Registry Number CCL  Contaminant Candidate List CEC  cation exchange capacity CERCLA  Comprehensive Environmental Response, Compensation & Liability Act CMR  Chemical Monitoring Reform CPS  Cropping Practices Survey CWS  Community Water System DBCP  dibromochloropropane DCIs  Data Call Ins DEA  deethyl atrazine DWEL  Drinking Water Equivalent Level ECD  Electron Capture Detectors EDB  ethylene dibromide EDL  Estimated Detection Limit Eh  oxidation reduction potential EHS  Extremely Hazardous Substance EPA  Environmental Protection Agency EPCRA  Emergency Planning and Community Right to Know Act ESA  ethanesulfonic acid FCRS  Farm Costs and Returns Survey FDA  Food and Drug Administration FIFRA  Federal Insecticide, Fungicide, and Rodenticide Act FQPA  Food Quality Protection Act GAC  granular activated carbon ( treatment technology for organic compounds) GC  gas chromatography ( a laboratory method) GW  ground water A 2 Metribuzin   February 2003 GWP  ground water  purchased GUDI  Ground Water Under the Direct Influence ( of surface water) GUP  Ground Water Under Direct Influence  Purchased HA  Health Advisory HAL  Health Advisory Level HRL  Health Reference Level IDL  Instrument Detection Level IGWM  Iowa Ground Water Monitoring Program IOC  inorganic compound IRIS  Integrated Risk Information System MCL  Maximum Contaminant Level MDL  Method Detection Limit MMT  methylcyclopentadienyl manganese tricarbonyl MRL  Minimum Reporting Level MS  mass spectrometry ( a laboratory method)

NAWQA  National Water Quality Assessment Program NCFAP  National Center for Food and Agricultural Policy NCOD  National Drinking Water Contaminant Occurrence Database NDWAC  National Drinking Water Advisory Council NERL  National Environmental Research Laboratory NIOSH  National Institute for Occupational Safety and Health NPD  nitrogen/ phosphorus detector NPDES  National Pollution Discharge Elimination System NPDWR  National Primary Drinking Water Regulation NPS  National Pesticide Survey NRMRL  National Risk Management Research Laboratory NTIS  National Technical Information Service NTNCWS  Non Transient Non Community Water System NTTAA  National Technology Transfer and Advancement Act OA  oxanilic acid OCT  ornithine carbamyl transferase OGWDW  Office of Ground Water and Drinking Water OMB  Office of Management and Budget ORD  Office of Research and Development OSHA  Occupational Safety and Health Administration PAH  polycyclic aromatic hydrocarbon PB  particle beam PBMS  performance based measurement system A 3 Metribuzin   February 2003 PCE  tetrachloroethylene PEL  permissible exposure limit PGWD  Pesticides in Ground Water Database ppm  part per million PWS  Public Water System PWSF  Public Water System Facility PWSID  Public Water System Identifier QA  quality assurance QC  quality control RCRA  Resource Conservation and Recovery Act RFA  Regulatory Flexibility Act RFF  Resources for the Future RO  reverse osmosis RPD  relative percent difference RSD  relative standard deviation SARA Title III  Superfund Amendments and Reauthorization Act SBREFA  Small Business Regulatory Enforcement Fairness Act SD  standard deviation SDWA  Safe Drinking Water Act SDWIS  Safe Drinking Water Information System SDWIS FED  the Federal Safe Drinking Water Information System SGOT  serum glutamate oxaloacetate transaminase SGPT  serum glutamate pyruvate transaminase SM  standard methods SMCL  Secondary Maximum Contaminant Level SMF  Standard Compliance Monitoring Framework SOC  synthetic organic compound SPE  solid phase extraction ( a laboratory method) SRF  State Revolving Fund STORET  Storage and Retrieval System SW  surface water SWP  surface water  purchased TBD  to be determined TCE  trichloroethylene TDS  total dissolved solids THM  trihalomethane TNCWS  Transient Non Community Water System TPQ  Threshold Planning Quantity TRI  Toxic Release Inventory A 4 Metribuzin   February 2003 UCM  Unregulated Contaminant Monitoring UCMR  Unregulated Contaminant Monitoring Regulation/ Rule UMRA  Unfunded Mandates Reform Act of 1995 URCIS  Unregulated Contaminant Monitoring Information System USDA  United States Department of Agriculture U. S. EPA  United States Environmental Protection Agency USGS  United States Geological Survey VOC  volatile organic compound µ g/ L  micrograms per liter mg/ L  milligrams per liter > MCL  percentage of systems with exceedances > MRL  percentage of systems with detections B 1 Metribuzin   February 2003 APPENDIX B: Round 2 Metribuzin Occurrence Metribuzin Occurrence in Public Water Systems in Round 2, UCM ( 1993) results State Total Unique PWS # GW PWS # SW PWS % PWS > MRL % GW PWS > MRL % SW PWS > MRL % PWS > HRL % GW PWS > HRL % SW PWS > HRL 99% Value (: g/ L)

Tribes ( 06) 1 1 0 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% < 0.00 AK 20 17 3 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% < 0.00 AL AR 536 431 105 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% < 0.00 AZ CA CO 750 538 212 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% < 0.00 CT 69 35 34 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% < 0.00 IN KY 418 204 214 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% < 10.00 LA MA 56 29 27 14.29% 13.79% 14.81% 0.00% 0.00% 0.00% 2.00 MD 684 627 57 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% < 0.30 ME M I 2,650 2,570 80 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% < 0.00 M N 1,264 1,234 30 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% < 0.00 M O 638 437 101 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% < 0.60 MS NC 623 567 56 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% < 0.00 ND 296 258 38 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% < 0.02 NH 557 524 33 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% < 0.00 NJ NM 715 686 29 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% < 0.60 OH 2,178 2,017 161 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% < 2.00 OK 107 82 25 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% < 0.00 OR 1,135 984 151 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% < 0.00 PA 358 231 127 9.50% 5.63% 16.54% 0.00% 0.00% 0.00% 3.00 RI 15 6 9 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% < 0.53 Appendix B ( continued)

State Total Unique PWS # GW PWS # SW PWS % PWS > MRL % GW PWS > MRL % SW PWS > MRL % PWS > HRL % GW PWS > HRL % SW PWS > HRL 99% Value (: g/ L)

B 2 Metribuzin   February 2003 SC 940 842 98 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% < 0.00 SD TN 7 2 5 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% < 0.00 TX 426 121 305 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% < 0.20 VT 390 338 52 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% < 0.00 WA 600 530 70 0.17% 0.19% 0.00% 0.00% 0.00% 0.00% < 0.00 WI Total 15,333 13,311 2,022 0.28% 0.14% 1.24% 0.00% 0.00% 0.00% < 2.00 20 States 13,568 11,862 1,706 0.07% 0.04% 0.23% 0.00% 0.00% 0.00% < 2.00 19 States 13,512 11,833 1,697 0.01% 0.01% 0.00% 0.00% 0.00% 0.00% < 2.00 1. Massachusetts data not included in " 19 States" summary for metribuzin. PWS = Public Water System; GW = Ground Water ( PWS Source Water Type); SW = Surface Water ( PWS Source Water Type); MRL = Minimum Reporting Limit ( for laboratory analyses) The Health Reference Level ( HRL) is the estimated health effect level as provided by EPA for preliminary assessment for this work assignment. "% > HRL" indicates the proportion of systems with any analytical results exceeding the concentration value of the HRL. The Health Reference Level ( HRL) used for Metribuzin is 91 : g/ L. This is a draft value for working review only. The highlighted States are part of the SDWI/ FED 20 State Cross Section.