Page 2 of 29

The toxicity database for metribuzin is nearly complete at the present time with the 

exception of an immunotoxicity study which is required in accordance with new data 

requirements for conventional pesticide registration (40 CFR Part 158). The 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. Metribuzin 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 HED 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, new dietary exposure and risk 

assessments may be required during registration review process. These exposure 

assessments would incorporate current consumption information, updated residue values, 

updated percent crop treated information, and any revised PoDs or uncertainty factors. 

The residential exposure database is inadequate 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 assessment 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 aggregate 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 as turf in public areas such as parks, athletic fields, and golf courses. Based 

on the updated Residential SOPs, the Agency will now be evaluating potential postapplication exposures from these uses of metribuzin. Therefore, updated aggregate 

exposure and 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 inadequate to support the registration review 

process for metribuzin due to lack of Turf Transferrable Residue (TTR) and Dislodgeable 

Foliar Residue (DFR) studies. Updated occupational handler exposure assessments may 
Page 3 of 29

be required under registration review based upon revisions to the Agency’s scenariospecific surrogate handler exposure data (http://www.epa.gov/pesticides/science/handlerexposure-table.pdf). An occupational post-application assessment will also be required 

under registration review.

Introduction

Metribuzin is a systemic triazinone herbicide which selectively controls certain broadleaf 

weeds and grassy weed species. 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(4H)-one] is a 

systemic triazinone herbicide which selectively controls certain broadleaf weeds and 

grassy weed species 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 crops including alfalfa, asparagus, 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 triazinone 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 completed in 1998, 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 

and acute and subchronic neurotoxicity studies in rats. HED has completed the 

evaluation 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 

incorporated into the updated subchronic, chronic and other toxicity profile for 

metribuzin. When the remaining acute and subchronic studies are evaluated, HED will 

revisit the PoDs and uncertainty factors for the dietary, occupational and residential

exposure 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 for 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. Increased 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 T4 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. Metribuzin 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 incidence 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. However, 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 disturbance 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 and 

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, the 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-

activated 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

Points 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 consumption 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 decreased 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 registration 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 

seen 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/m3air, 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 assessment 

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 chronic 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 organ 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, 

developmental 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 determinations. 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 any 

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 February 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. Once 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/. 

Conclusions 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 await 

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

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 all of the 

currently available data.

Residue Chemistry

The existing residue chemistry database for metribuzin is adequate for risk assessment 

purposes. However, multiple studies (crop field trials, processed commodities, and 

limited field rotational crop data) have been received 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 commodities in 

40 CFR §180.332. No rotational crop tolerances have been established. Adequate

analytical methods exist for data collection and tolerance enforcement. Adequate storage 

stability data exist. Adequate magnitude of the residue 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 will need to be revised during 
Page 7 of 29

the registration review process (see the Tolerance Assessment and International 

Harmonization section).

Conclusions for Residue Chemistry

The residue chemistry database for metribuzin is adequate for risk assessment purposes.

There are multiple outstanding residue chemistry studies that have been submitted to the 

Agency since 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 risk 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 assessments were conducted (D. 

Dotson, D328338, 04/17/2006) using the Dietary Exposure Evaluation Model (DEEMFCIDTM, Version 2.03), which used 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, Pesticide 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 that are below HED’s 

level of concern for both acute and chronic exposure scenarios (<100% Population 

Adjusted Dose (PAD)). Therefore, HED concluded that there is a reasonable certainty 

that no harm will result to the general population, infants and children 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 metribuzin 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 assessment 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 water (all sources).

Acute Dietary Exposure and Risk 

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

metribuzin. The acute dietary analysis for metribuzin is a conservative estimate of 

dietary exposure even though it uses some ARs. One hundred percent of all crops were 

assumed to be treated and to contain residues. At the 95th percentile of exposure, the 

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

The most highly exposed population 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 subgroup, 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, it may be necessary for HED to conduct new dietary 

exposure assessments (acute and chronic) for metribuzin. These new exposure 

assessments should include incorporating new and updated information and policies and

any revised points of departure (PoDs) or uncertainty factors. Also, since the drinking 

water estimates are from 1996, these will likely need to be updated. The revised 

assessment should also include updated consumption information and utilize the newest 

version of DEEM-FCID. Additionally, should a review of the PDP, estimated percent 

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 homeowner use 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 metribuzin 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 address 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 Pesticide Exposure Assessment have recently been updated. 

Conclusions for Residential Exposure and Risks

The residential exposure database is inadequate to support the registration review process 

for metribuzin due to lack of a Turf Transferrable Residue (TTR) 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 areas) or residential 

turf uses. Since metribuzin is registered for use at these 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 Residential SOPs.

Aggregate Exposure and Risk Assessment

The aggregate risk assessment evaluates the combined risk from dietary exposure (food 

and water) and any non-occupational (residential) uses. Previous aggregate assessments 

in the 1998 RED evaluated only dietary and drinking water routes, since significant nonoccupational exposures were considered unlikely based on then-current policies. 

However, metribuzin can be used on residential lawns as well as turf in public areas such 
Page 9 of 29

as parks, athletic fields, and golf courses. As described above, a residential exposure 

assessment will be required under registration review.

Conclusions for Aggregate Exposure and Risk Assessment

Updated aggregate exposure and risk assessments will be required under registration 

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

dietary exposure estimates. These revised aggregate exposure and risk assessments will 

also reflect any toxicological endpoint changes 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 exposures resulting 

from the registered uses of metribuzin.

Occupational Handlers

Due to the scope of the various metribuzin occupational uses, the 1998 RED evaluated 10 

occupational handler scenarios to represent the major metribuzin occupational handler 

scenarios based on application equipment and formulation. This 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 

metribuzin that is applied to sugarcane from 6.0 lb ai/A to 2.0 lb ai/A to reduce the 

potential 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 inadequate to support the registration review 

process for metribuzin due to lack of Turf Transferrable Residue (TTR) 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 areas) or residential turf uses. Part 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 postapplication dermal exposure. Since metribuzin is registered for use at these sites, these 

studies are required. Updated occupational handler exposure assessments may be 

required under registration review based upon revisions to the Agency’s scenario-specific 

surrogate handler exposure data (http://www.epa.gov/pesticides/science/handlerexposure-table.pdf). An occupational post-application assessment will also be required 

under registration review.
Page 10 of 29

Human Studies

Metribuzin risk assessments 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 

Pesticide Handlers Exposure Database, Outdoor Residential Exposure Task Force, and 

Agricultural Handler Exposure 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" 

Regulation to reliance on these studies.

Public Health and Pesticide Epidemiology Data

An updated review of metribuzin incident reports was recently prepared by HED (S. 

Recore, D401093, 05/08/2012). 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 lifetime 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 registrants, other federal and state health and environmental 

agencies and individual consumers. IDS contains 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 higher 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 Main IDS, from January 1, 2007 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 chemical. In Aggregate IDS, from January 1, 2007 to February 22, 2012, 

there were six reported incidents involving metribuzin. Overall, there are few incidents 

involving metribuzin reported to IDS. 

There are two relevant studies evaluating the association 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 selfreport 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 association 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 cancers 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 similar 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 other 

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, and 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 with 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 lymphohemotopoeitic 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 statistically significant. This study reflects over 750,000 personyears 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 or 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 International 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 policies. The revised tolerance expression should be as follows: 
Page 12 of 29

Tolerances are established for residues of metribuzin, including its metabolites and 

degradates, in or on the commodities listed in Table 8. Compliance with the tolerance 

levels specified below is to be determined by measuring only the sum of metribuzin [4-

amino-6-(1,1-dimethylethyl)-3-(methylthio)-1,2,4-triazin-5(4H)-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 considered 

in this human health risk assessment, in accordance with U.S. Executive Order 12898, 

"Federal Actions to Address Environmental Justice in Minority Populations and LowIncome 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 risk 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 potential 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 has 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 (GDLN 875.2100)
Page 13 of 29

Table 1. Metribuzin Nomenclature.

Chemical structure

N

N

N

O

NH2

S

CH3

H3C

H3C

CH3

Common name Metribuzin

Company experimental name N/A

IUPAC name 4-amino-6-tert-butyl-3-(methylsulfanyl)-1,2,4-triazin-5(4H)-one

CAS name 4-amino-6-(1,1-dimethylethyl)-3-(methylthio)-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

N

N

H

NH

O

O

H3C

CH3

H3C

6-(1,1-dimethylethyl)-1,2,4-triazine-3,5(2H,4H)-dione

Chemical structure of DK 

metabolite

N

N

H

N

O

O

NH2

CH3

H3C

H3C

4-amino-6-(1,1-dimethylethyl)-1,2,4-triazine-3,5(2H,4H)-dione

Chemical structure of DA 

metabolite

N

N

NH

O

S

CH3

H3C

CH3

H3C

6-(1,1-dimethylethyl)-3-(methylthio)-1,2,4-triazin-5(4H)-one
Page 14 of 29

Table 2. Physicochemical Properties of Metribuzin.

Parameter Value Reference

Melting point/range 125-126.5 °C Metribuzin Product 

Density Chemistry RED Chapter 1.28 g/cm3

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

methanol 35

n-hexane 0.2

toluene 12

xylene 9

Vapor pressure 0.017 mPa (20 oC)

Dissociation constant, pKa 1.0 USDA Pesticide Properties 

Octanol/water partition coefficient, Database

Log(KOW)

1.60 (20 oC)
Page 15 of 29

Table 3. Metribuzin 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 Dermal 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

Noa

Yes 

Yes 

No

No

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 Aberrations..

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 acceptable 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)

LD50 = 2300 mg/kg 

(M) 2.2 mg/kg 

(F)

III

44652401

(1998)

LD50 = 510 mg/kg (M) 

322 mg/kg (F); 

>322 mg/kg 

Combined)

II

46105406

(2003)

LD50 = >2200 mg/kg 

(M/F) 

III

870.1200 Acute dermal (New Zealand 

White rabbits)

00106149

(1972) 

LD50 = > 20,000 

mg/kg

IV

Acute dermal (Wistar rats) 44713907

(1998)

LD50 = > 5000 mg/kg

46105407

(2003)

LD50 = > 5000 mg/kg

870.1300 Acute inhalation [Rat] 00157524

(1986)

LC50 = >0.648 mg/LaIII

Acute inhalation (Wistar rats) 46105408

(2003)

LC50 = >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

46105409

(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.

46105410

(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. Study 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 

weight, 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/m3/d [0, 93, 

219, 720 mg/m3/d 

(Analytical)].

Study 2: 0, 100, 300, 

mg/m3/d [(0, 32, 90 

mg/m3/d (Analytical)].

NOAEL = 219 mg/m3

LOAEL = 720 mg/m3based 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 thyroid 

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 unossified skull bones, 

vertebrae, sternebrae, pelvic bones, and 

appendages. 

Note: Thyroid effects seen: Increased 

thyroid weight & increased T4 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. Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3700b Prenatal 

developmental 

in (New 

Zealand White 

Rabbits)

00087796 (1981)

Acceptable/guideline

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

on GDs 6-18

Maternal NOAEL = 15 mg/kg/day

LOAEL = 45 mg/kg/day based on reduced 

body weight gain and reduced feed and 

water consumption.

Developmental NOAEL = 15 mg/kg/day 

mg/kg/day

LOAEL = 45 mg/kg/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

Maternal NOAEL = 10 mg/kg/day

LOAEL = 30 mg/kg/day based on decreased 

body weight gain on days 18-28.

Developmental NOAEL = 30 mg/kg/day 

LOAEL = 85 mg/kg/day based on increased 

incidence of irregular spinous processes

870.3800 Reproduction 

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 F2 pups.

870.4100a Chronic toxicity

(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)]

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 weights 

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. Study 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 changes 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)

Acceptable

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 (CHO) 

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. Study Type MRID No. (year)/ 

Classification /Doses

Results

870.5375

In vitro 

mammalian 

cell 

chromosome 

aberration 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 cytotoxic 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

Chinese 

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)

00086767 (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 

repair-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 concentration 

(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. Study 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 14C 

(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 single 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 negligible 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. Blood 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. The 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-NAc-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 dose (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 

- bacterial 

Salmonella 

typhimurium

TA1535, 

TA1537, TA98, 

TA100 

mammalian 

microsome 

reverse gene 

mutation assay 

(Plate 

incorporation 

and preincubation 

methods)

47099702 (2006)

Acceptable/guideline

0, 16, 50, 158, 500, 1581, 

& 5000 μg/plate +/ – S9

Negative for 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 & 1000 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 

- bacterial 

Salmonella 

typhimurium

TA1535, 

TA1537, TA98, 

TA100 

mammalian 

microsome 

reverse gene 

mutation assay 

(Plate 

incorporation 

and preincubation 

methods)

47099703 (2006)

Acceptable/guideline

0, 16, 50, 158, 500, 1581, 

& 5000 μg/plate +/ – S9

Negative for 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/guideline

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

47099707 (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 

mutation assay 

(Plate 

incorporation 

and preincubation 

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 vitro 

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 μg/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 exposure, 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 Departure 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

UFA=10x

UFH=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 LOAEL = 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

UFA=10x

UFH=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.

Incidental Oral 

Intermediate-Term (1-6 

months)

Dermal

Short-Term (1-30 days)

Dermal IntermediateTerm (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 derived 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. UFA = extrapolation from animal to human (interspecies). UFA = 

extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the 

human population (intraspecies). UFD = database uncertainty, 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

Table 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 = 219 

mg/mL3air

(0.219 mg/L)

UFA=10x

UFH=10x Residential/ Occupational 

LOC for MOE = 100

21-Day Rat Inhalation Toxicity Study 

MRID 00153706 

LOAEL for this study is 720 

mg/mL3air , (0.720 mg/L)

based on clinical signs [disturbed 

behavior (apathetic with ungroomed 

coats)], increased liver enzymes (Ndemethylase, O-demethylase, and 

cytochrome P-450), increased liver 

weights and increased absolute and 

relative thyroid weights.

Inhalation Intermediateterm (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 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. UFA = extrapolation from animal to human (interspecies). UFA = 

extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the 

human population (intraspecies). UFD = database uncertainty, lack of neurotoxicity (acute and 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 Residue Limits Metribuzin (101101, 04/18/2012)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex2

40 CFR 180.332:

Plants/Livestock: combined 

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-methylthio4,5-dihydro-1,2,4-

triazin-5-one, including the 

metabolites 6-tert-butyl-3-

methylthio-4,5-dihydro-1,2,4-triazin5-one, 4-amino-6

-tert-butyl-2,3,4,5-tetrahydro-1,2,4-

triazin-3,5-dione

and 6-tert-butyl-2,3,4,5-tetrahydro1,2,4-triazin-3,5-

dione

None

Commodity

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

US Canada Mexico1 Codex2

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

Pea, 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 Mexico1 Codex2

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, germ 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 as 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

Eligibility 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 of

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