### Page 2 of 29

The toxicity database for metribuzin is nearly complete at the present time with the exception of an immunotoxicity study whic h is required in accordance with new data requirements for conventional pesticide registration (40 CFR Part 158)

. T he Agency has

determined that metribuzin is “not classifiable as to human carcinogenicity” based on conflicting evidence for carcinogenicity in rats and evidence of non

- carcinogenicity in

mice. M etribuzin did not induce a mutagenic response in a battery of mutagenicity testing. Metribuzin has a low to moderate acute toxicity via the oral, dermal and inhalation routes of exposure and it is not classified as a skin sensitizer or ocular irritant

. No reproductive or developmental effects were observed in metribuzin toxicity studies using rats and rabbits. During the registration review process , HED will reevaluate the points of departure (PODs) and uncertainty factors for the dietary

, occupational and

residential exposure assessments.

The existing residue chemistry database for metribuzin is adequate for risk assessment purposes. No additional data are required at this time ; however

, there are multiple residue chemistry studies that need to be reviewed during the registration review process

. The qualitative nature of the residue(s) of metribuzin in plants and animals has been adequately identified/characterized and is understood. The residues of concern in plants

and animals for tolerance enforcement and risk assessment are metribuzin and its triazinone metabolites (DADK, DK, and DA)

. 

### The current tolerance expression as listed

in the 40 CFR §180. 332 (a) has not been updated to reflect current HE D policies and thus will need to be revised during the registration review process.

The dietary exposure database is adequate to support the existing registrations. Based on the fact that monitoring data were used previously, n ew dietary exposure and ris k

assessments may be requi red during registration review process. These exposure

assessments would incorporate current consumption informat ion, updated residue values, updated percent crop treated information

, and any revised PoDs or uncertainty factors.

The residential exposure database is in adequate to support the registration review process

for metribuzin due to lack of a Turf Transferrable Residue (TTR) study . A residential exposure assessment will be required under registration review. This assess ment should incorporate, as necessary, the additional toxicology studies that have been submitted to

HED as well as the recently updated Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment

.

Previous a ggregate assessments in the 1998 RED evaluated only dietary and drinking water routes, since significant non

- occupational exposures were considered unlikely

based on then

- current policies. However, metribuzin can now be used on residential

lawns as well a s turf in public areas such as parks, athletic fields, and golf courses. Based on the updated Residential SO Ps, the Agency will now be evaluating potential post

application exposures from these uses of metribuzin. Therefore, u pdated aggregate

exposure an d risk assessments will be required under registration review based on the

need to combine exposure estimates from residential uses with dietary exposure estimates

The occupational exposure database is in adequate to support the registration review

process for metribuzin due to lack of Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) studies. Updated occu pational handler exposure assessments may

### Page 3 of 29

be required under registration review based upon revisions to the Agency’s s cenario

specif ic surrogate handler exposure data ( http://www.epa.gov/pesticides/science/handler

exposure

- table.pdf

). An occupational post

- application assessment will also be required

under r egistration review

.

Introduction Metribuzin is a systemic triazinone herbicide which selectively controls certain broadleaf weeds and grassy weed spec ies

. HED has reviewed the most recent exposure and risk

assessments for metribuzin , as well as toxicity data, exposure and usage databases, and the latest Agency science policy and risk assessment methodologies to determine if sufficient data are available and if updates are needed to support registration review. Additionally, the team conducted a screening

- level literature search for any information that would aid in assessing human health risks to metribuzin

.

Chemical Identity Metribuzin [4

- amino

- 6

- (1,1

- dimethylethyl)

- 3

- (methylthio)

- 1,2,4

- triazin

- 5(4 H )

- one] is a systemic triazinone herbicide which selecti vely controls certain broadleaf weeds and grassy weed specie s in vegetable and field crops as well as in non

- crop areas including residential turfgrass

. Metribuzin is currently registered for use on a variety of food and

feed cro ps including alfalfa, aspar agus, barley, carrot, corn (field, sweet, and pop), grass (grown for seed only), lentil, pea (including chick pea/garbanzo bean), potato, sainfoin, soybean, sugarcane, tomato, and wheat. The chemical structure and nomenclature of

metribuzin and its triazi none metabolites, and the physicochemical properties of the technical grade of metribuzin are presented in Tables 1 and 2.

Hazard Identification/Toxicology The toxicological data requirements for metribuzin are listed in Table 3. Since the RED was comple ted in 199 8 , additional toxicology studies have been submitted to HED. These include: a set of six acute toxicity studies on metribuzin technical; a battery of nine mutagenicity assays on metribuzin metabolites; a subchronic oral toxicity study in dogs

an d acute and subchronic neurotoxicity studies in rats

. HED has completed the

e valuation and preparation of Data Evaluation Records (DERs) for the six acute studies, the nine mutagenicity assays and the subchronic oral dog study . These studies have been

in corporated into the updated subchronic, chronic and other toxicity profile for metribuzin. When the remaining acute and subchronic studies are evaluated, HED will

revisit the Po D s and uncertainty factors for the dietary

, occupational and residential

expos ure assessments.

Toxicology Studies Available for Analysis With these evaluated new data, the toxicity database for metribuzin is nearly complete. The only exception is an immunotoxicity study, which is required in accordance with new data requirements f

or conventional pesticide registration (40 CFR Part 158)

.

Toxicology Profile

As shown in Table 4, metribuzin generally has low to moderate toxicity by the oral, dermal and inhalation routes of exposure. It is neither a dermal nor an ocular irritant; it was also found not to be a dermal sensitizer in guinea pigs.

### Page 4 of 29

The updated subchronic, chronic and other toxicity profile for metribuzin is presented in

Table 5. In the available subchronic toxicity studies, metribuzin produced decreases in body weight, changes in clinical chemistry associated with liver damage and anemia in orally exposed dogs, increased liver enzyme activity in dermally exposed rabbits, and increased liver enzymes accompanied by increased liver weights in rats exposed via

inhalation. I ncreased thyroid weights were also noted in the inhalation study. Further evidence that the liver and thyroid are target organs for metribuzin comes from effects observed in a developmental study (increased thyroid weights and increased T 4 

### levels in

rat pups) , the reproductive study (hepatocyte hypertrophy in adult rats) , and liver and/or thyroid effects in the chronic rat, mouse and dog studies . In the chronic studies, toxicity

was characterized as increased liver and thyroid weights in rats; increased liver weights and alterations in hematological parameters in mice; and death, increased liver weights and changes in clinical chemistry associated with liver damage in dogs

. M etribuzin did not demonstrate increased sensitivity to fetuses and offspring and there were no indications of impaired reproductive performance in rats. In 1995, the RfD/peer review committee listed metribuzin as a “Group D”, not classifiable as to human carcinogenicity. This decision was based on a significant increase in the incid ence of pituitary adenomas (both pairwise comparison and positive trend) but with no progression to malignancy (MRID 00061261, 00065136, 00147942) only in female rats at the top dose (40%↑ vs. 16% in control) reported in a 1974 carcinogenicity study. Howe ver, the top dose (300 ppm) was not considered sufficiently high to address carcinogenicity. Despite the negative findings from more recently conducted Fischer 344 rat and a CD

- 1 mouse cancer studies, the RfD Committee expressed concerns regarding the di sturbance of the T4 and T3 levels and the increased incidence of thyroid hyperplasia in the 1974 study. It was stated that these disturbances may have had “underlying or contributing factors in alteration of other components of the endocrine system.” The test material was largely negative for mutagenicity. Nevertheless, the data do suggest that metribuzin has the potential to interact with the thyroid hormone system.

In metabolism studies, radiolabeled metribuzin was excreted rapidly in the urine and feces of rats (within 8 hours) and reached a plateau at 48 hours. The prevalent metabolite

that was found is DA

- N

- Ac

- Cys. Mutagenicity data for metabolites are presented in

Table 6. As shown, the three metabolites, (metribuzin

- 4

- methyl DADK, DIC 1468 an d

BCS

- AA 1003) did not induce gene mutations in bacteria or mammalian cells. Similarly,

DIC 1468

- Dk was not clastogenic in mammalian cells. However, metribuzin

- 4

- methyl

DADK and BCS

- AA 1003 were clastogenic in the in vitro Chinese hamster lung

fibroblasts (V79) assay. The former test material induced a significant, confirmed, and

dose

- related increase in structural chromosome aberrations in the presence of S9 activation following a 4

- hour exposure and either a 14

- or 26

- hour cell harvest. By contrast, th e clastogenic effects observed with BCS

- AA were only seen in the absence of S9 activation and only after a prolonged, 18

- hour exposure. It is of note that while the parent compound induced a clastogenic effect, this response was scored at an S9

-

ac tivated concentration that was severely cytotoxic. Furthermore, there is no evidence

that metribuzin is clastogenic in the germinal cells of whole animals or causes DNA damage in cultured hepatocytes. No in vivo data have been submitted on the

metabolites.

### Page 5 of 29

P oints of Departure Risk assessment for acute dietary exposure is based on an oral developmental study in rabbits (NOAEL 15 mg/kg/day) and is based on reduced body weight gain and reduced feed and water consumpti on in dams and decreased fetal body weight, increased number of runts, and increased incidence of extra and partial ribs at 45 mg/kg/day (LOAEL). Risk assessment for chronic dietary exposure is based on a combined chronic toxicity/carcinogenicity study in rats (NOAEL 1.3 mg/kg/day) based on decreas ed body weight gains (F), increased thyroid (M) and increased liver weights (M&F) at 13.8 mg/kg/day (LOAEL) . No short

- or intermediate

- term incidental oral exposure endpoints have been previously selected; however this will be revisited during registratio n review

since exposure may occur from residential post

- application activities.

No appropriate study was previously identified for the dermal exposure (short

- term or
intermediate

- term). The Agency will need to re

- evaluate this, as systemic toxicity was

s een in the 21

- day dermal study (NOAEL 200 mg/kg/day) . It should be noted that no acceptable dermal absorption data are available; therefore a default assumption of 100% may be used in future assessments.

For all durations of the inhalation exposure, the previous 1996 risk assessment used a route specific 21

- day inhalation study ( NOAEL of 219 mg/m 3 

### air, which was converted to 58.5 mg/kg/day )

.

The Agency has previously concluded that the FQPA Safety Factor should be reduced to

1X based on a conclusion of no increased susceptibility and no residual uncertainty. The FQPA Safety Factor will be reevaluated during registration review based on the results of

all available data.

A summary of the metribuzin toxicological points of departure for use in risk asses sment
is shown in Table 7.

Endocrine Disruption Screening Program As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute,

subchronic and chro nic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target org an histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, develop mental and reproductive effects in different taxonomic groups. As part of its reregistration decision, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), metribuzin is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed EDSP to determine whether certain substances (including pesticide active and other ingredients ) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the

### Page 6 of 29

Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required det erminations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and

are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify an y adverse endocrine related effects caused by the substance, and establish a dose

- response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between
October 2009 and Februa ry 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients.

Metribuzin was included on that list and has been issued an order to conduct the Tier 1 testing. On ce all required Tier 1 and Tier 2 data have been received and reviewed, the endpoints and safety factors used for metribuzin risk assessment purposes will be examined and a new risk assessment performed if necessary. For further information on

the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.

Conclusion s for Hazard Identification/Toxicology The toxicity database for metribuzin is complete except for an immunotoxicity study, which is required under the 2007 revised 40CFR Part 158 Toxicology Data Requirements. Considerable amounts of new data have been received and aw ait

evaluation , all of which will be reviewed during the registration review process

. T he endpoints, PODs , and the uncertainty factors for metribuzin will be reevaluated during registration review based on the review of this outstanding data as well as al l of the currently available data.

Residue Chemistry The existing residue chemistry database for metribuzin is adequate f or risk assessment

purposes. H owever
, multiple studies (crop field trials, processed commodities, and limited field rotational crop d ata) have been recei ved by the Agency since the 1998 RED and subsequent 1998 GDCI that need to be reviewed

.

The qualitative nature of the residue(s) of metribuzin in plants and animals has been adequately identified/characterized and is understood. The residues of concern for

tolerance enforcement and risk assessment are metribuzin and its triazinone metabolites (DADK, DK, and DA). Tolerances have been established for the combined residues of metribuzin and its triazinone metabolites in/on various crop and livestock c ommodities in 40 CFR §180.332 . No rotational crop tolerances have been established

. Adequate

a nalytical methods exist for data collection and tolerance enforcement. Adequate storage stability data exist. Adequate magnitude of the residu e data exist for most commodities with the exception of those data still yet to be reviewed as noted above.

The current tolerance expression as listed in the 40 CFR §180. 332 has not been updated to reflect current HED polices. The tolerance expression wi ll need to be revised during

### Page 7 of 29

the registration review process (see the Tolerance Assessment and International Harmonization section)

.

C onclusions for Residue Chemistry The residue chemistry database for metribuzin is adequate for risk assessment purposes.

T here are multiple outstanding residue chemistry studies that have been submitted to the Agency s ince the 1998 GDCI that will need to be reviewed during the registration review

process. Any impacts that these reviews have on existing tolerances and/or ri sk estimates will be incorporated into any revised assessments that may be performed during registration review

.

Dietary Exposure and Risks Partially refined acute and chronic dietary exposure assessment s were conducted ( D. Dotson, D328338, 04/17/2006 ) u sing the Dietary Exposu re Evaluation Model (DEEM

FCIDTM, Version 2.03 ), which use d food consumption data from the USDA’s Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994

- 1996 and 1998. The analysis was based on tolerance level residues for most commodities, Pe sticide Data Program (PDP) monitoring data for potatoes and certain animal commodities, an anticipated residue (AR) value for milk, and default processing factors. The U.S. population and all population subgroups have dietary exposure and risk estimates t hat are below HED’s level of concern for both acute and chronic exposure scenarios (<100% Population Adjusted Dose (PAD)). Therefore, H ED concluded that there is a reasonable certainty that no harm will result to the general population, infants and childr en from chronic dietary exposure to metribuzin

.

Drinking Water For both the acute and chronic dietary exposure analyses, residues in water were included directly incorporated into the DEEM program. The values used were those that were

used for the metr ibuzin RED (Case 0181, February 1998). For the acute analysis, a drinking water residue value of 21 ppb was used for water, all sources. The metribuzin RED states the following: “A metribuzin concentration appropriate for use in an acute drinking water a ssessment is 21 ppb. This concentration was the highest value detected in drinking water wells in the Central Sands area of Wisconsin.” For the chronic analysis, six monitoring values were available. The highest of these values, 5.37 ppb,

was used for w ater (all sources).

Acute Dietary Exposure and Risk 

### A partially refined acute dietary exposure analysis was performed for the herbicide

metribuzin. T he acute dietary analysis for metribuzin is a conservative estimate of dietary exposure even though it u ses some ARs

. One hundred percent of all crops were

assumed to be treated and to contain residues

. At the 95 th 

### percentile of exposure, the exposure estimate for the general U.S. population was 40% of the acute PAD ( aPAD )

. The most highly exposed populat ion subgroup was Children 1

- 2 Years, which was 75%

of the aPAD.

Chronic Non

- Cancer Dietary Exposure and Risk 

### A partially refined chronic non

- cancer dietary exposure analysis was performed for

metribuzin. This exposure assessment used the same parameters as mentioned above,

### Page 8 of 29

except that average percent crop treated estimates from The Biological and Economic Analysis Division (BEAD) were used where appropriate. The general U.S. population utilizes 26% of the chronic PAD (cPAD). The most highly exposed sub group, Children

1

- 2 years, utilizes 69% of the cPAD

.

Conclusions for Dietary Exposure and Risks The dietary exposure database is adequate to support the existing registrations. However, since monitoring data were used, i t may be necessary for HED to condu ct new dietary
exposure assessment s ( acute and chronic ) for metribuzin . These new exposure

assessments sh ould include incorporating new and updated inform ation and policies and any revised points of departure (PoDs) or uncertainty factors . Also, since th e drinking water estimates are from 1996, these will likely need to be updated

. Th e revised

assessment should also include updated c onsumption information and utilize the newest

version of DEEM

- FCID. Additionally, should a review of the PD P, estimated pe rcent crop treated, and other relevant information show that exposure may be increasing, new anticipated residues may need to be generated and incorporated into the dietary risk

assessments.

Residential Exposure and Risks Metribuzin is registered for ho meowner us e on residential lawns. Metribuzin containing products are also marketed for use on residential turf, on golf courses, and other turf such as recreational fields. Based on these uses, adult residential homeowners may experience
exposure to metr ibuzin during application of the chemical (i.e., residential handler exposures). Adults and children may experience exposure to metribuzin when contacting

metribuzin

- treated areas (i.e., residential post

- application exposure).

The 1998 RED did not addres s residential handler or post

- application exposures

. Since the 1998 RED, additional toxicology studies have been submitted to HED , registered use sites have changed, and the Health Effects Division’s 2012 Standard Operating Procedures for Residential Pest icide Exposure Assessment have recently been updated

.

Conclusions for Resident ial Exposure and Risks The residential exposure database is in adequate to support the registration review process

for metribuzin due to lack of a Turf Transferrable Residue (T TR) study

. In accordance with the updated Part 158 data requirements (2007), a TTR study is required for all occupational (e.g., sod farms, golf courses, parks, and recreational ar eas) or residential

turf uses. Since metribuzin is regist ered for use at t hese sites, this study is required. A residential exposure assessment will be required under registration review . This assessment should incorporate, as necessary, the additional toxicology studies that have

been submitted to HED and the 2012 Revised Res idential SOPs.

Aggregate Exposure and Risk Assessment The aggregate risk assessment evaluates the combined risk from dietary exposure (food and water) and any non

- oc cupational (residential) uses. Previous aggregate assessments
in the 1998 RED evaluated o nly dietary and drinking water routes, since significant non

occupational exposures were considered unlikely based on then

- current policies. However, metribuzin can be used on residential lawns as well as turf in public areas suc h

### Page 9 of 29

as parks, athletic field s, and golf courses. As described above, a residential exposure assessment will be required under registration review.

Conclusions for Aggregate Exposure and Risk Assessment

U pdated aggregate exposure and risk assessment s will be required under registrat ion

review based on the need to combine exposure estimates from residential uses with dietary exposure estimates

. These r evised aggregate exposure and risk assessments will also reflect any toxicological endpoint change s or other new data are received by the Agency that may impact exposure estimates.

Occupational Exposure and Risks Metribuzin is registered for the control of annual broadleaf and grass weeds in vegetable, forage

- grass and crop sites such as alfalfa, asparagus, barley, carrots, chick peas, corn, grass (grown for seed), lentils, pasture and rangeland, peas, potatoes, sainfoin, soybeans, sugarcane, tomatoes, turfgrass grown for sod, and wheat. The Agency has determined that there is a potential for occupational handler and post

- application ex posures resulting from the registered uses of metribuzin.

Occupational Handlers Due to the scope of the various metribuzin occupational uses, the 199 8 RED evaluated 10 occupational handler scenarios to represent the major metribuzin occupational handler

s cenarios based on application equipment and formulation. Th is assessment indicated that occupational handler scenarios resulted in inhalation risk estimates that do not exceed HED’s level of concern (MOEs ≥ 100) except for mixing/loading wettable powders for aerial application at the highest label rate (6 lb ai/A ). Risk mitigation measures that were mentioned in the RED were to reduce the label application rate of

metribuzi n that is applied to sugarcane from 6.0 lb ai/A to 2.0 lb ai/A to reduce the
potent ial risks to workers.

Occupational Post

- application The 1998 RED did not quantitatively address occupational post

- application exposures. A default Restricted Entry Interval of 12 hours was set based on the low to moderate acute toxicity of metribuzin via the oral, dermal, and inhalation routes of exposure.

Conclusions for Occupational Exposure and Risks The occupational exposure database is in adequate to support the registration review process for metribuzin due to lack of Turf Transferrable Residue (T TR) and Dislodgeable Foliar Residue (DFR) studies. In accordance with the updated Part 158 data requirements (2007

– GDLN 875.2100 ), a TTR study is required for all occupational (e.g., sod farms, golf courses, parks, and recreational ar eas) or residential turf uses. Pa rt 158 data requirements ( 2007

– GDLN 875.2100 ) also state that one or more DFR studies are required when a pesticide has residential or occupational uses that could result in post

application dermal exposure. Since metribuzin is registered for use at these sites, the se studies are required. Updated occu pational handler exposure assessments may be required under registration review based upon revisions to the Agency’s s cenario

- specific surrogate handler exposure data ( http://www.epa.gov/pesticides/science/handler

exposure

- table.pdf

). A n occupational post

- application assessment will also be required

under registration review

.

### Page 10 of 29

Human Studies

Metribuzin risk assessme nts rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. Studies such as the

Pesti cide Handlers Exposure Database

, Outdoor Residential Exposure Task Force , and Agricultural Handler Ex posure Task Force have been reviewed by the Agency and found on the basis of available evidence to have been neither fundamentally unethical nor significantly deficient relative to standards of ethical research conduct prevailing when they were conducted. There is no barrier in EPA's "Protection of Human Subjects"

R egulation to reliance on these studies.

P ublic Health and Pesticide Epidemiology Data An updat ed review of metribuzin incident reports was rec ently prepared by HED (S.

Recore , D 401093

, 05/08/2 012 )

. For this evaluation, the OPP Incident Data System (IDS) was consulted for pesticide incident data on the active ingredient metribuzin

. There are

also two relevant studies from the Agricultural Health Study (AHS) evaluating the

association between li fetime use of metribuzin and adverse health outcomes.

The IDS includes reports of alleged human health incidents from various sources, including mandatory Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6 (a) (2) reports from registrant s, other federal and state health and environmental agencies and individual consumers. IDS contain s reports from across the U.S. and most incidents have all relevant product information recorded. Reports submitted to the IDS represent anecdotal cases or allegations only, unless otherwise stated. IDS records incidents resulting in high er severity outcomes in more detail, in a module called the

Main IDS module. This system stores incident data for death, major and moderate incidents, and it includes more details about the location, date and nature of the incident.

For the M ain IDS, from January 1, 200 7 to February 22, 2012, there were no incidents reported for the single chemical only in the database and 1 incident reported that involved

more than one che mical. In A ggregate IDS , from January 1, 200 7 to February 22, 2012,

there were six reported incident s involving metribuzin

. Overall, there are few incidents involving metribuzin reported to IDS.

There are two relevant studies evaluating the associatio n between lifetime use of metribuzin and adverse health outcomes within the AHS: a cohort study of metribuzin use in relation to all cancers, and a study of risk factors for fatal injuries among AHS participants. These investigations are briefly summarized here.

Delancey et al. (2009) performed a prospective cohort investigation of metribuzin use in relation to all cancers combined, as well as specific anatomical cancer sites. Among 23,072 participants in the AHS who provided information regarding lifetime metribuzin use (take home questionnaire only), there were 554 cases of cancer identified at the time of this study. Using pesticide exposure information ascertained through applicator self

report questionnaire collected at enrollment ( i.e. , the enrollment questionnaire), authors performed Poisson regression to model the association with both lifetime days of use and intensity

- weighted lifetime days of use in connection with specific cancer sites. Overall,

authors identified limited evidence of an associati on with all

- cancers combined or most anatomical cancer sites for which authors had enough exposed cases to perform a robust

### Page 11 of 29

statistical analysis. However, researchers did report non

- statistically significant 2

- fold elevated risks of lymphohematopoietic can cers including non

- Hodgkin lymphoma (NHL) and leukemia among those who reported the highest levels of metribuzin use, as well as statistical evidence of an exposure

- response trend (p for trend<0.05 lymphohematopoetic cancers combined). Authors observed sim ilar associations using both the cumulative and weighted exposure metric.

Authors note that while associations are elevated and trends statistically significant, this association was not previously hypothesized nor has it been previously observed in othe r investigations, and therefore, caution is needed in the interpretation of these results. Strengths of the AHS include the prospective nature of the study, high

- quality exposure assessment tools which have been validated and illustrated to be reliable, an d the large sample size, among other things. Limitations include the relatively small number of metribuzin exposed cases for specific sub

- types of these blood cancers which have been shown to have different etiologies. Other nested case

- control studies wit h the AHS cohort did not illustrate associations between specific anatomical cancer sites and metribuzin use including cancers of the prostate, breast, colorectal, lung, pancreatic, and cutaneous melanoma. Additional research including an assessment of lym phohemotopoeitic cancers in a nested case control study within the AHS are needed to further understand and

characterize these results.

In an investigation of risk factors of fatal injury in the farm environment (Waggoner et al. 2012), authors in the AHS reported non

- significantly elevated risks of fatal injury among users of metribuzin (odds ratio 1.56 (95% confidence interval (95% CI) 0.71, 3.34), adjusted for age and state of residence. However, the trend by quartile of metribuzin

lifetime use was not s tatistically significant. This study reflects over 750,000 person

years of follow

- up in the AHS. However, it is unclear what aspect of herbicide and possibly metribuzin use may contribute to an increased risk of fatal injury, i.e. , total use,
use pattern o r equipment, or other related factor. This is the first investigation of its type reported in the literature.

Based on the low frequency and severity of incident cases reported for metribuzin

, there does not appear to be a concern at this time that would warrant further investigation based upon acute poisoning incident data . The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in

the risk assessment.

Tolerance Assessment and Inter national Harmonization

Tolerances are established under 40 CFR §180. 332 for residues of metribuzin , including its metabolites and degradates, in or on a variety of food and feed crops as shown in

Table 8

. The Codex Alimentarius Commission and Mexico have not established maximum residue limits (MRLs) for metribuzin ; while PMRA only has one MRL for
potato. Any metribuzin tolerances reassessed during the registration review process will be considered for possible harmonization with international MRLs should they be

established.

The current tolerance expression as listed in the 40 CFR §180.332 has not been updated to reflect current HED polic i es. The revised tolerance expression should be as follows:

### Page 12 of 29

Tolerances are established for residues of metribuzin , i ncludin g its metabolites and degradate s , in or on th e commodities listed in Table 8 . Compliance with the tolerance levels specified below is to be determined by measuring only the sum of m etribuzin [4

- amino

- 6

- (1,1

- dimethylethyl)

- 3

- (methylthio)

- 1,2,4

- triaz in

- 5(4 H )

- one] and its triazinone metabolites (DADK, DK, and DA) , calculated as the stoichiometric equivalent of

metribuzin , in or on the commodity.

Environmental Justice Potential areas of environmental justice concerns, to the extent possible, were consi dered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

Income Populations," http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf . The Office of Pesticide Programs (OPP) typically considers the highest potential exposures from the legal use of a pesticide when conducting human health ri sk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diets within the U.S., and people who may be exposed when harvesting crops. Should these high exposures indicate poten tial risks of concern, OPP will further

refine the risk assessments to ensure that the risk estimates are based on the best available

information.

Cumulative Risk Assessment At this time, EPA does not have available data to determine whether metribuzin ha s a common mechanism of toxicity with other substances. EPA has not made a common mechanism of toxicity finding as to metribuzin and any other substances, and metribuzin does not appear to produce a toxic metabolite produced by other substances which have tolerances in the U.S. Therefore, EPA has not assumed that metribuzin has a common mechanism of toxicity with other substances.

Data Requirements HED does not anticipate that additional residue chemistry, toxicology or occupational/residential exposure data will be required for the metribuzin registration review process, with the exception of the following studies listed below:

Immunotoxicity Study ( GDLN 870.7800) Dislodgeable Foliar Residue Studies ( GDLN 875.2100) Turf Transferrable Residue Study ( GDL N 875.2100)

### Page 13 of 29

Table 1. Metribuzin Nomenclature

. Chemical structure

Common name Metribuzin
Company experimental name N/A

IUPAC name 4

- amino

- 6

- tert

- butyl

- 3

- (methylsulfanyl)

- 1,2,4

- triazin

- 5(4 H )

- one

CAS name 4

- amino

- 6

- (1,1

- dimethylethyl)

- 3

- (methylthi o)

- 1,2,4

- triazin

- 5(4H)

- one CAS registry number 21087

- 64

- 9

End

- use product (EP) Canopy® Herbicide (75% WDG; EPA Reg. No. 352

- 444)

Chemical structure of DADK

metabolite

6

- (1,1

- dimethylethyl)

- 1,2,4

- triazine

- 3,5(2H,4H)

- dione

Chemical structure of DK

met abolite

4

- amino

- 6

- (1,1

- dimethylethyl)

- 1,2,4

- triazine

- 3,5(2H,4H)

- dione

Chemical structure of DA

metabolite

6

- (1,1

- dimethylethyl)

- 3

- (methylthio)

- 1,2,4

- triazin

- 5(4H)

- one

### Page 14 of 29

Table 2. Physicochemical Properties of Metribuzin.

Pa rameter Value Re ference

Melting point/range 125

- 126.5 °C Metribuzin Product Chemistry RED Chapter Density 1.28 g/cm 3

Water solubility 1.2 g/L (20 °C)
Solvent solubility g/100 g at 20 oC

acetone 82

chloroform 85 dimethylformamide 178

ethanol 19 ethyl acetate 47

meth anol 35

n

- hexane 0.2

toluene 12 xylene 9

Vapor pressure 0.017 mPa (20 oC)
Dissociation constant, pK

a 1.0 USDA Pesticide Properties

Database Octanol/water partition coefficient, Log(K OW ) 1.60 (20 oC)

### Page 15 of 29

Table 3. Metribuzi n Toxicology Data Requirements

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ...................... 870.1200 Acute Dermal Toxicity

................................ ................. 870.1300 Acute Inhalation Toxicity

................................ ............. 870.2400 Primary Eye Irritation

................................ ................... 870.2500 Primary Dermal Irritation

................................ ............. 870.2600 Derma l Sensitization

................................ .................... Yes
Yes
Yes
Yes
Yes
Yes Yes

Yes
Yes
Yes
Yes
Yes

870.3100 Oral Subchronic (rodent)

................................ .............. 870.3150 Oral Subchronic (nonrodent)

................................ ........ 870.3200 21

- Day Dermal

................................ ............................. 870.3250 90

- Day Dermal

................................ ............................. 870.3465 90

- Day Inhalation

................................ ......................... Yes
Yes
Yes
No
No No a

Yes
Yes
No
N o

870.3700a Developmental Toxicity (rodent)

................................ . 870.3700b Developmental Toxicity (nonrodent)

........................... 870.3800 Reproduction

................................ ................................ Yes
Yes
Yes Yes

Yes
Yes

870.4100a Chronic Toxicity (rodent)

................................ ............. 870.4100b Chronic Toxicity (nonrodent)

................................ ....... 870.4200a Oncogenicity (rat)

................................ ........................ 870 .4200b Oncogenicity (mouse)

................................ .................. 870.4300 Chronic/Oncogenicity

................................ .................. No
Yes
No
Yes
Yes Yes

Yes
Yes
Yes
Yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

.................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

.............. 870.5xxx Mutagenicity

— Structural Chromosomal Aber rations

.. 870.5xxx Mutagenicity

— Other Genotoxic Effects

...................... Yes
Yes
Yes
Yes Yes

Yes
Yes
Yes

870.6100a Acute Delayed Neurotox. (hen)

................................ .... 870.6100b 90

- Day Neurotoxicity (hen)

................................ ........ 870.6200a Acute Neurotox. Screening Battery (rat)

...................... 870.6200b 90 Day Neuro. Screening Battery (rat)

........................

870.6300 Develop. Neuro

................................ ............................ No
No
Yes
Yes

No ---

--- b

b

---

870.7485 General Metabolism

................................ ..................... 870.7600 Dermal Penetration

................................ ....................... 870.7800 Immunotoxicity.............................................. Yes
No

Yes Yes

No

No

Special Studies

a 

### At this time, an accepta ble study is not available for this requirement but it has been satisfied by Guideline 870.4100.
b 

### In review.

### Page 16 of 29

Table 4. Acute Toxicity Profile

- Metribuzin

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral (Wistar rats) 00106158

(1969) LD 50 = 2300 mg/kg

(M) 2.2 mg/kg (F) III

44652401

(1998) LD 50 = 510 mg/kg (M)

322 mg/kg (F);

>322 mg/kg Combined) II

46105406

(2003) LD 50 = >2200 mg/kg

(M/F) III

870.1200 Acute dermal (New Zealand

White rab bits) 00106149

(1972) LD 50 = > 20,000

mg/kg IV

Acute dermal (Wistar rats) 44713907

(1998) LD 50 = > 5000 mg/kg

46105407

(2003) LD 50 = > 5000 mg/kg

870.1300 Acute inhalation [Rat] 00157524

(1986) LC 50 = >0.648 mg/L a III

Acute inhalation (Wistar rats) 46105408

(2003) LC 50 = >0.709 mg/L

(Combined) (gravimetric)

870.2400 Acute eye irritation [Rabbit] 00106158

(1969) Not an eye irritant IV

Acute eye (New Zealand White rabbits) 44738101

(1998) Mild conjunctival

irritation in all animals

46105 409

(2003) No ocular irritation

870.2500 Acute dermal irritation

[Rabbit] 00106158

(1969) PIS = 0.33/8.0

Not a dermal irritant IV

Acute dermal irritation (New Zealand White rabbits) 44713904

(1998) 2 F with very slight

erythema at 48 hrs.

4610541 0

(2003) No dermal irritation

870.2600 Skin sensitization [Guinea

pig] 41555101

(1989) Not a dermal sensitizer NA

46105411

(2003) Not a dermal sensitizer

### Page 17 of 29

Table 5. Subchronic, Chronic and Other Toxicity Profile for Metribuzin

Guideline No. S tudy Type MRID No. (year)/

Classification /Doses Results

870.3100 90

- Day oral

toxicity An acceptable study is not available for this requirement but it has been satisfied by

Guideline 870.4100

870.3150 90

- Day oral

toxicity (Beagle dog) 45621001 (2002 )

Acceptable/guideline 0, 75, 300, 1200 ppm M: 0, 2.0, 8.4, 26.2 mg/kg/d

F: 0, 1.9, 8.6, 30.2 mg/kg/d NOAEL = 8.4/8.6 mg/kg/day (M/F) LOAEL = 26.2/30.2 mg/kg/day (M/F) based on findings in the moribund sacrificed animals [clinical signs, decreased body

we ight, body weight gain and food consumption and changes in blood chemistry, anemia, and microscopic findings. No adverse effects were seen during neurological examinations and no pathological evidence of an adverse effect on endocrine organs was observed.

870.3200 21/28

- Day

dermal toxicity (New Zealand White rabbits) 43970701 (1989 )

Acceptable/guideline

0, 40, 200, 1000 mg/kg/d Systemic NOAEL =200 mg/kg/day LOAEL =1000 mg/kg/day based on increased plasma cholesterol and liver enzyme activities.

Dermal NOAEL =≥1000 mg/kg/day (HDT)

870. 3465 21

- Day

inhalation toxicity (Wistar rats) 00153706 (1981 )

Acceptable/guideline

Study 1 : 0, 300, 1000, 3000 mg/m 3 /d [0, 93, 219, 720 mg/m 3 /d (Analytical)].

Study 2 : 0, 100, 300, mg/m 3 /d [(0, 32, 90 mg/m 3 /d (Analytica l)]. NOAEL = 219 mg/m 3
LOAEL = 720 mg/m 3 based on clinical signs [disturbed behavior (apathetic with ungroomed coats)], increased liver enzymes (N

- demethylase, O

- demethylase, cytochrome P

- 450), increased liver weights

and increased absolute and relative th yroid weights.

870.3700a Prenatal

developmental in (Charles

River Crl:CD BR rats) 00163802/41881801

(1986 ) Acceptable/guideline

0, 25, 70, 200 mg/kg/d on gestation days (GDs) 6

- 18 Maternal NOAEL =<25 mg/kg/day LOAEL = ≥25 mg/kg/day based on reduced body weight gain and mean gravid uterine weights, and decreased food consumption at

all doses. Developmental NOAEL = 70 mg/kg/day LOAEL = 200 mg/kg/day based on decreased fetal weight and reduced

ossification or unoss ified skull bones, vertebrae, sternebrae, pelvic bones, and appendages.
Note: Thyroid effects seen: Increased thyroid weight & increased T 4 levels in maternal animals at 200 mg/kg/d.

### Page 18 of 29

Table 5. Subchronic, Chronic and Other Toxicity Profile for Metribuzin

Guideline No. S tudy Type MRID No. (year)/

Classification /Doses Results

870.3700b Prenatal

developmental in (New

Zealand White Rabbits) 0008 7796 (1981 )

Acceptable/guideline

0, 15, 45, 135 mg/kg/d

on GDs 6

- 18 Materna l NOAEL = 15 mg/kg/day LOAEL = 45 mg/kg/day based on reduced body weight gain and reduced feed and water consumption. Developmenta l NOAEL = 15 mg/kg/day mg/kg/day LOAEL = 45 mg/k g/day based on decreased fetal body weights, increased number of runts, and increased incidence of extra and partial ribs.

870.3700b Prenatal

developmental in (American Dutch Rabbits) 41249201/41835501

(1989 ) Acceptable/guideline

0, 10, 30, 85 mg/kg/d

on GDs 18

- 28 Materna l NOAEL = 10 mg/kg/day LOAEL = 30 mg/kg/day based on decreased body weight gain on days 18

- 28. Developmenta l NOAEL = 30 mg/kg/day

LOAEL = 85 mg/kg/day based on increased incidence of irregular spinous processes

870.3800 Reproducti on

and fertility

effects (Rat Charles

River Crl:CD BR) 40838401

(1988) Acceptable/guideline 0, 30, 150, 750 ppm (~0, 1.5, 7.5, 37.5 mg/kg/d) Parental/Systemic NOAEL = 1.5 mg/kg/day LOAEL = 7.5 mg/kg/day based on decreased body weight gain and hypertrophy of the hepatocytes. Reproductive NOAEL = <37.5 mg/kg/day

LOAEL = Not established Offspring NOAEL = 1.5 mg/kg/day LOAEL = 7.5 mg/kg/day based on decreased body weight gain for F 2 pups.

870.4100a Chronic toxicity

(Fischer 344 Rat) 42672501 (1993)

Accepta ble

0, 30, 300, 900 ppm

[0, 1.3, 13.8, 42.2 mg/kg/d (M); 0, 1.6, 17.7, 53.6 mg/kg/d (F)] NOAEL = 30 ppm mg/kg/day (<1.3/1.6 mg/kg/day M/F) LOAEL = 300 ppm mg/kg/day (13.8/17.7 mg/kg/day M/F) based on decreased body weight gains (F), increased thyroid weig hts in males and increased liver weights (M &F). Thyroid considered a target organ for metribuzin in this study.

870.4100b Chronic toxicity

(Beagle dog) 00061260 (1974)

Acceptable

0, 25, 100, 1500 ppm

[0, 0.82, 3.44, 55.65 mg/kg/d (M); 0, 0.84, 3.56, 55.3 mg/kg/d (F)] NOAEL = 100 ppm (3.44/3.56 mg/kg/day M/F) LOAEL = 1500 ppm (55.65/55.3 mg/kg/day M/F) based on mortality, decreased body weight, increased liver weights and changes in clinical chemistry parameters.

870.4200 Carcinogenicity

(Fischer 344 Rat) 42672501 (1993)

Acceptable 0, 30, 300, 900 ppm

[0, 1.3, 13.8, 42.2 mg/kg/d (M); 0, 1.6, 17.7, 53.6 mg/kg/d (F)] See 870.4100a
No evidence of carcinogenicity

### Page 19 of 29

Table 5. Subchronic, Chronic and Other Toxicity Profile for Metribuzin

Guideline No. S tudy Type MRID No. (year)/

Classification /Doses Results

870.4200 Chronic/

Carcinogenicity

(Wistar Rat) 00061261/00065136/0

0147942 (1974)

Acceptable 0, 25, 35, 100, 300 ppm

[0, 1.3, 1.87, 5.27 14.36 mg/kg/d (M); 0, 1.68, 2.28, 6.53, 20.38 mg/kg/d (F)] Systemic NOAEL = 100 ppm (5.27/6.53 mg/kg/d (M/F)

LOAEL = 300 ppm (14.36/20.38 mg/kg/d (M/F) based on decreased body weight gain and pathological chang es in the liver, kidneys, uterus, and mammary glands.

870.4200 Chronic/

Carcinogenicity

(Wistar Rat) 00061261/00065136/0

0147942 (1974)

Unacceptable (not adequate high dose) 0, 25, 35, 100, 300 ppm

[0, 1.3, 1.87, 5.27 14.36 mg/kg/d (M); 0, 1.68, 2.28, 6 .53, 20.38 mg/kg/d (F)] Incidence of pituitary adenomas in high dose females (40% vs. 16% in control) significantly increased (pairwise comparison % positive trend). No tumors in males & no significant increase in

carcinomas.

870.4300 Carcinogenicity

( CD

- 1 mice) 00087795 (1981)

Acceptable/guideline

0, 200, 800, 3200 ppm

[0, 25, 111, 438 mg/kg/d (M); 0, 35, 139, 567 mg/kg/d (F)] NOAEL = 800 ppm (111/139 mg/kg/day M/F)

LOAEL = 3200 ppm (438/567 mg/kg/day M/F) based on increased liver weights &

decreased hematological parameters. No evidence of carcinogenicity

870.5100

Gene Mutation

- bacterial Salmonella

typhimurium TA1535, TA1537, TA98, TA100;

Escherichia coli

WP2

mammalian

microsome

reverse gene mutation assay 00086770 & 00109254

(1977 & 1978)

Ac ceptable

0, 500 μg/plate

– S9 & 0, 2, 20, 500 μg/plate

+S9 derived from rats

or mice Negative for reverse gene mutations in

bacteria when these studies are considered together.

870.5300

In vitro

mammalian cells gene

mutation test Chinese hamster

ovary (C HO)

cells /HGPRT forward gene mutation assay 00157527 (1986)

Acceptable/Guideline 0, 600, 700, 800, 900 & 1000 μg/mL

– S9 0, 50, 100, 150, 175 & 200 μg/mL +S9 Negative up to the highest dose tested

- /+S9.

### Page 20 of 29

Table 5. Subchronic, Chronic and Other Toxicity Profile for Metribuzin

Guideline No. S tudy Type MRID No. (year)/

Classification /Doses Results

870.5375

In vitro

mammalian

cell

chromosome

aber ration test CHO

Cytogenetics in

vitro 42555102 (1990)

Acceptable/Guideline 0, 99.7, 199, 299, 399, 499, 598 μg/mL

– S9 (20

- hr harvest) 0, 25.0, 37.5, 50.0 μg/mL +S9 (10

- harvest); 0, 50.1, 100, 150, 200 μg/mL +S9 (20

- hr harvest) Negative up to a cytot oxic concentration (499 μg/mL

– S9).

Positive evidence of chromosome aberrations at severely cytotoxic dose (150 μg/mL +S9) but suggestive evidence of clastogenicity at 50 and 100 μg/mL +S9.

870.5380

Mammalian spermatogonial

chromosome

aberration test C hinese

hamsters (male) 00086765 (1964)

Acceptable 0, 100 mg/kg oral gavage 2X Negative for chromosome aberrations in germinal cells of male Chinese hamsters

870.5450

Rodent

dominant lethal assay NMRI male &

female mice (50 F/group; 8 mating periods) 000 86767 (1975)

Acceptable 0, 300 mg/kg Negative for dominant lethal effects at a mildly toxic dose.

870.5450

Rodent

dominant lethal assay NMRI male &

female mice (37

- 38 F/group; 1 mating at gestation day 14) 00086768 (1976)

Acceptable 0, 300 mg/kg Negative for dominant lethal effects at a mildly toxic dose.

870.5550

Bacterial DNA damage or repair tests Bacillus subtilis

H17 (rec + ) & M45 (rec - ) 00086770 & 00109254

(1977 & 1978) Acceptable 0, 3, 30 , 300 μg/disc

– S9 Negative for preferential inhibition of

r epair

- deficient strain M45, compared to

H17.

Other Effects

870.5550 Unscheduled

DNA synthesis

in mammalian

cells in culture

(Primary rat hepatocytes) 00157526 (1986)

Acceptable 0.007, 0.07, 0.7, 6.7, 20, 10, 200 μg/mL Negative up to a cytotoxic concen tration (200 μg/mL).

870.6200a Acute

neurotoxicity screening battery 44804101

In review

870.6200b Subchronic

neurotoxicity screening battery 44804102

In review

### Page 21 of 29

Table 5. Subchronic, Chronic and Other Toxicity Profile for Metribuzin

Guideline No. S tudy Type MRID No. (year)/

Classification /Doses Results

870.7485 Metabolism

study (Wistar rats) 40255503 (1987)

Acceptable

High dose = 500 mg/kg Low dose = 5 mg/kg

unlabeled &

radiolabeled with 14 C (Specific activity =

20.8 mCi/mmol Excretion data indicate that radiolabeled metribuzin was rapidly excreted in the urine and feces (observed at 8 hrs) and reached a plateau at 48 hrs for the sin gle dose groups (low and high), except the high dose female feces which reached a plateau at 72 hrs. The investigator found 27.3 to 43.4% of the
label in the urine and 55.8 to 71.5% of the
label in the feces at 96 hrs. Pilot studies determined that negli gible amounts of label were found in the expired air; therefore, it was not collected in this primary study. The high dose group excreted the greatest

amount of the label in the feces and the least amount of label, of all 3 test groups, in the

urine. Blo od levels at various time points were not determined; however, very small

amounts were found at 96 hrs. in the low dose and slightly higher levels in the high dose at sacrifice. No specific differences in

tissue levels were noted in the low dose group. T he high dose group had higher tissue levels, which would be expected, with the G.I. tract having considerable higher levels. The investigators identified

metabolites in both the urine and feces with the most prevalent metabolite being DA

- N

Ac

- Cys.

870.7600 Dermal

penetration No acceptable study

available

870.7800 Immunotoxicity No study available

NOAEL = no observed adverse effect level; LOAEL = lowest observed adverse effect level; FQPA SF = FQPA Safety Factor; PAD = population adjusted dos e (c = chronic); LOC = level of concern; MOE = Margin of exposure.

### Page 22 of 29

Table 6

. Studies for Metribuzin Metabolites

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

Metribuzin

- 4

- methyl DADK

870.5100

Gene Mutation

- bac terial Salmonella

typhimurium TA1535, TA1537, TA98,

TA100

mammalian

microsome

reverse gene mutation assay (Plate incorporation and pre

incubation methods) 47099702 (2006)

Acceptable/guideline

0, 16, 50, 158, 500, 1581, & 5000 μg /

plate +/

– S9 Negative f or reverse gene mutations in bacteria up to the limit dose ( 5000

μg / plate +/

– S9)

.

870.5300

In vitro

mammalian cell gene mutation assay Chinese hamster

Lung V79 cells

at the HPRT

locus 47099705 (2006)

Acceptable/guideline

0, 30, 60, 120, 240, 480, 960, & 1920 μg/mL +/

– S9 Negative for forward gene mutations in mammalian cells up insoluble concentrations (≥960 μg/mL +/

– S9); moderate cytotoxicity seen at 1920 μg/mL +/

– S9

870.5375

In vitro

mammalian

cell cytogenetics

assay Chinese hamster

Lung V79 cells 47099708 (2007 )

Acceptable/guideline

0, 150, 300, 600, 800, &

1000 μg/mL + S9 (4

- hr exposure, 14

- hr harvest)

0, 600, 800, & 1000 μg/mL

- S9 (4

- hr exposure, 26

- hr harvest) Positive; significant & dose

- related

increases in structural chromosome aberrations at 300, 600 & 1 000 μg/mL

+ S9 ( 4

- hr exposure, 14

- hr harvest). The most frequently observed types of

aberrations were chromatid and chromosome breaks and exchanges.

Similar increases seen after the 4

- hr exposure, 26

- hr harvest.

DIC 1468

- DK

### Page 23 of 29

Table 6

. Studies for Metribuzin Metabolites

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.5100

Gene Mutation

- ba cterial Salmonella

typhimurium TA1535, TA1537, TA98,

TA100

mammalian

microsome

reverse gene mutation assay (Plate incorporation and pre

incubation methods) 47099703 (2006)

Acceptable/guideline

0, 16, 50, 158, 500, 1581, & 5000 μg /

plate +/

– S9 Negative f or reverse gene mutations in bacteria up to the limit dose ( 5000

μg / plate +/

– S9) ; cytotoxicity was

seen at this level.

870.5300

In vitro

mammalian cell gene mutation assay Chinese hamster

Lung V79 cells

at the HPRT

locus 47099705 (2006)

Acceptable/guid eline

0, 29, 58, 116, 232, 464, 928, & 1856 μg/mL +/

– S9 Negative for forward gene mutations in mammalian cells up to an insoluble concentration (1856 μg/mL +/

– S9)

870.5375

In vitro

mammalian

cell cytogenetics

assay Chinese hamster

Lung V79 cells 4 7099707 (2007 )

Acceptable/guideline

0, 462, 693, 924, 1386, &

1848 μg/mL +/

- S9 (4

- hr exposure, 14

- hr harvest)

0, 924, 1386 & 1848 μg/mL +/

- S9 (4

- hr exposure, 26

- hr harvest)

0, 75, 150, 300, 500, &

700 μg/mL

- S9 (18

- hr continuous exposure) Negative for chromosome aberrations up to cytotoxic concentrations (1848 g/mL +/

- S9 all harvest times. Note:

1848 g/mL = 10 mM.

BSC

- AA10033

870.5100

Gene Mutation

- bacterial Salmonella

typhimurium TA1535, TA1537, TA98,

TA100

mammalian

microsome

reverse gene

mu tation assay (Plate incorporation and pre

incubation methods) 47099704 (2006)

Acceptable/guideline

0, 16, 50, 158, 500, 1581, & 5000 μg /

plate +/

– S9 Negative up to the limit dose ( 5000

μg / plate +/

– S9) ; cytotoxicity seen at

this level.

### Page 24 of 29

Table 6

. Studies for Metribuzin Metabolites

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.5300

In vit ro mammalian cell gene mutation assay Chinese hamster

Lung V79 cells

at the HPRT

locus 47099706 (2006)

Acceptable/guideline

0, 53, 106, 212, 424, 848, & 1696 μg/mL +/

– S9 Negative for forward gene mutations in mammalian cells up to the limit dose (1696 μ g/mL +/

– S9).

Note: 1696 g/mL = 10 mM.

870.5375

In vitro

mammalian

cell cytogenetics

assay Chinese hamster

Lung V79 cells 47099709 (2007 )

Acceptable/guideline

0, 425, 850 &1700 μg/mL +/

- S9 (4

- hr exposure, 14

- hr harvest)

0 & 1700 μg/mL +/

- S9 (4

- hr exp osure, 26

- hr harvest)

0, 300, 600, 1200, 1450,

& 1700 μg/mL

- S9 (18

- hr continuous exposure) Weakly positive at 1450 μg/mL (10.0%↑frequency of structural chromosome aberrations) and 1700 μg/mL (10.5%↑) but only in the

absence of S9 activation & a prolonged exposure (18

- hour continuous exposure). The most frequently observed types of

aberrations were chromatid breaks and chromosome isofragments and isodeletions and exchanges.

### Page 25 of 29

Table 7. Summary of Toxicological Points of De parture and Endpoints for Metribuzin 1

Exposure/
Scenario Point of

Departure (POD) Uncertainty/

FQPA Safety

Factors RfD, PAD, Level of

Concern for Risk

Assessment Study and Toxicological
Effects

Acute Dietary (General Population, Including Infants and Children) NOAEL =

15 mg/kg/day UF A =10x

UF H =10x FQPA SF=1x 15 mg/kg/day

NOAEL 100 (UF)

aRfD = 0.15 mg/kg/day Prenatal Developmental Study in New Zealand

Rabbits

MRID 00087796

Maternal LOA EL = 45 mg/kg/day, based on reduced body weight gain

and reduced feed and water consumption Developmental LOAEL = 45 mg/kg/day, based on decreased fetal body weight, increased number of runts, and increased

incidence of extra and partial ribs.

Chronic Dietary NOAEL =

1.3 mg/kg/day UF A =10x

UF H =10x FQPA SF=1x 1.3mg/kg/day

NOAEL 100 (UF)

cRfD = 0.013 mg/kg/day Chronic (2

- Year Fischer

- 344 Rat) Feeding Toxicity

MRID 42672501

LOAEL = 13.8 mg/kg/day, based on decreased body weight gains (F), increased thyroid (M) and increased liver weights (M&F)

Incidental Oral

Short

- Term (1

- 30 days)

No points of departure were previously chosen. This will be revisited during registration review. Inci dental Oral

Intermediate

- Term (1

- 6 months)

Dermal

Short

- Term (1

- 30 days)

Dermal Intermediate

Term (1

- 6 months)

Dermal Long

- Term (>6 months)

1 Explanation of Abbreviations: Point of Departure (PoD) = A data point or an estimated point that is deriv ed from

observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed

adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF D = database un certainty, lack of neurotoxicity (acute and subchronic) and immunotoxicity studies. FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic).

RfD = reference dose. MOE = margin of exposure. LOC = level of concern.

### Page 26 of 29 Tab le 7. Summary of Toxicological Points of Departure and Endpoints for Metribuzin 1

Exposure/
Scenario Point of

Departure Uncertainty

Factors Level of Concern for

Risk Assessment Study and Toxicological Effects

Inhalation Short

- Term (1

- 30 days)
NOAEL = 21 9

mg/mL 3 air (0.219 mg/L) UF A =10x

UF H =10x Residential/ Occupational

LOC for MOE = 100 21

- Day Rat Inhalation Toxicity Study

MRID 00153706 LOAEL for this study is 720 mg/mL 3 air
, (0.720 mg/L) based on clinical signs [disturbed behavior (apathetic with ungroomed coats)], increased liver enzymes (N

demethylase, O

- demethylase, and cytochrome P

- 450), increased liver weights and increased absolute and relative thyroid weights. Inhalation Intermediate

term (1

- 6 months)

Inhalation Long

- term (>6 months)

Cancer (oral, dermal, inhalation) Classification: Group D (Not classifiable as to human carcinogenicity) 2

1 Explanation of Abbreviations: Point of Departure (PoD) = A data point or an estimated point that is derived from

observed dose

- response data and u sed to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapol ation from animal to human (interspecies). UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF D = database uncertainty, lack of neurotoxicity (acute a nd subchronic) and immunotoxicity studies. MOE = margin of exposure. LOC = level of concern.

2 Extracted from Toxicology Endpoint Selection Document (TES) (Dapson, Ioannou, Irene, dated July 16, 1996).

### Page 27 of 29



## Table 8

. International Re sidue Limits Metribuzin ( 101101, 04/18/2012 )
Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 1 

### Codex 2



### 40 CFR 180.332:

Plant s / Livestock: c ombined

residues of the herbicide metribuzin (4

- amino

- 6

- ( 1,1

- dimethyl

- ethyl)

- 3

- (methylthio)

- ;1,2,4

- triazin

- 5(4 H )

- one) and

its triazinone metabolites 4

- amino

- 6

- tert

- butyl

- 3

- methylthio

4,5

- dihydro

- 1,2,4

- triazin

- 5

- one, including the

metabolites 6

- tert

- butyl

- 3

- methylthio

- 4,5

- dihydro

- 1,2,4

- triazin

5

- one, 4

- amin o

- 6

- tert

- butyl

- 2,3,4,5

- tetrahydro

- 1,2,4

- triazin

- 3,5

- dione

and 6

- tert

- butyl

- 2,3,4,5

- tetrahydro

1,2,4

- triazin

- 3,5

- dione None



### Commodit

y Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 1 Codex 2
Alfalfa, forage 2.0 Alfalfa, hay 7.0 Asparagus 0.1 Barley, grain 0.75 Barley, hay 7.0 Barley, pearled barley 3.0 Barley, straw 1.0
Carrot, roots 0.3 Cattle, fat 0.7 Cattle, meat 0.7 Cattle, meat byproducts 0.7 Corn, field, forage 0.1 Corn, field, grain 0.05 Corn, field, stover 0.1 Corn, pop, grain 0.05 Corn, sweet, forage 0.1 Corn, sweet, kernel plus

cob with husks removed 0.05

Corn, sweet, stover 0.1 Egg 0.01 Goat, fat 0.7
Goat, meat 0.7 Goat, meat byproducts 0.7 Grass, forage 2.0 Grass, hay 7.0 Hog, fat 0.7 Hog, meat 0.7 Hog, meat byproducts 0.7 Horse, fat 0.7
Horse, meat 0.7 Horse, meat byproducts 0.7

Lentil 0.05

Milk 0.05 Pea, dry, seed 0.05 Pea, field, hay 4.0

Pe a, field, vines 0.5 Pea, succulent 0.1

### Page 28 of 29

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 1 

### Codex 2

Potato 0.6 0.5 potatoes Potato, chips 3.0 Potato, processed potato

waste 3.0

Poultry, fat 0.7 Poultry, meat 0.7 Poultry, meat byproducts 0.7 Sainfoin, forage 2.0 Sainfoin, hay 7.0 Sheep, fat 0.7 Sheep, meat 0.7 Sheep, meat byproducts 0.7 Soybean, seed 0.3 Soybean, forage 4.0 Soybean, hay 4.0 Sugarcane, cane 0.1 Sugarcane, molasses 2.0

Tomato 0.1 Wheat, bran 3.0 Wheat, forage 2.0 Wheat, g erm 3.0 Wheat, grain 0.75 Wheat, hay 7.0 Wheat, middlings 3.0 Wheat, shorts 3.0 Wheat, straw 1.0



### Completed by: M. Negussie; 04/ 24 /2012

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

2 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated a s proposed have not been finalized by the

CCPR and the CAC.

### Page 29 of 29

Table 9 : HED Memoranda Relevant to Registration Review

Author Barcode/TXR # Date Title K. Boyle NA 08/06/1996 Metribuzin; the Revised HED Chapter of the Reregistration Eligibil ity Decision Document (RED)

S. Dapson NA 07/16/1996 Toxicology Endpoint Selection

Document: Revised Metribuzin

D. Dotson D328338 04/17/2006 Metribuzin Acute and Chronic Dietary Exposure Assessments

G. Ghali TX011554 05/16/1995 RfD/Peer Review Report o f Metribuzin (Sencor) [4

- amino

- 6

- (1,

1

- dimethyl)

- 3

- (methylthio)

- 1,2,4

triazin

- 5(4H)

- one]

J. Leahy D201872 05/31/1995 Metribuzin. The Revised HED Chapter of the Reregistration Eligibility Document