UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

DA TE: November 24, 20 I 5 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: Metconazole. Human Hea lth Scoping Document in Support of Registration Review. 

PC Code: 125619 

Decision No.: 505195 

Petition No.: NA 

Risk Assessment Type: NA 

TXR No.: NA 

MRID No.: NA 

DP Barcode: D428304 

Registration No.: NA 

Regulatory Action: Registration Review 

Scoping Document 

Case No.: 7049 

CAS No.: 1251 16-23-6 

40 CFR: I 80.617 

FROM: Barry O ' Keefe, Sc. nior Bio.logist /3, ~< . 

Nancy Dodd, Chemist ~. 

Myron Ottley, Senior Biologist /U0Jp-l 

Risk Assessment Branch Ill (RAB3) 

Health Effects Division (7509P) 

THROUG H: Christine Olinger, Branch Chief 

Risk Assessment Branch rII (RAB 

Health Effects Division (7509P) 

TO: Jordan Page, Chemical Review Manager 

Jill Bloom, Team Leader 

Linda An-ington, Branch Chief 

Risk Management and Implementation Branch 5 (RMIB5) 

Pesticide Re-Evaluation Division (PRO) (7508P) 

Executive Summa ry 

Following is the Health Effects Division's (HED's) human health scoping document for the 

fungicide metconazole to support Registration Review. To evaluate the scope of work necessary 

to support Registration Review, HED has considered previous risk assessments for metconazole; 

updates to its toxicity, exposure, and usage databases; and the latest Agency science policy and 

risk assessment methodologies. The most recent HED risk assessment for metconazole was 

completed in 2014 (D418671, B. O'Keefe, 12/15/2014). 

Page 1 of27 
The toxicological database for metconazole is complete, except for a subchronic inhalation 

toxicity study required in accordance with the 2007 40 CFR Part 158 toxicology data 

requirements. HED will consider the existing toxicity database as well as any additional toxicity 

studies received during registration review and will reevaluate points of departure (PO Os) and 

safety factors (SFs) used for risk assessment purposes. 

The liver is the primary target organ (with observed adverse effects such as increased liver 

weight and enzyme activity, increased incidence of hypertrophy and vacuolization) in the mouse. 

rat and dog. Other adverse effects observed included decreased body weight, blood effects 

(reductions in erythrocyte and/or platelet parameters), splenic effects (including increased spleen 

weight and hyperplasia), lenticular degeneration (cataracts), and gastrointestinal irritation in the 

mouse, rat, dog and/or rabbit. Metconazole is classified as "not likely to be carcinogenic to 

humans" at levels that do not cause mitogenesis. The FQPA Safety Factor has been reduced to 

lX, since there are no residual uncertainties for pre- and/or post-natal toxicity. 

The residue chemistry database for metconazole is adequate to support cuITent Registration 

Review data requirements. Adequate metabolism studies (crops, livestock, and rotational crops), 

storage stability, magnitude of the residue, and processing data are available to support the 

registered uses. Adequate methods are available for enforcement of the currently established 

tolerances. 

New dietary risk assessments are not anticipated during Registration Review, unl ess there are 

changes to the drinking water exposure estimates that need to be incorporated. 

The residential and occupational exposure databases are adequate to support the Registration 

Review process for metconazole. Residential and occupational handler and post-application 

exposure assessments are reflective of maximum application rates and current exposure policies 

and data, and did not identify risks of concern. However,·at the time of Registration Review, 

HED will reevaluate the points of departure and uncertainty factors currently used for risk 

assessment purposes regarding inhalation exposures. Based upon that reevaluation, HED will 

determine if updated residential and occupational handler inhalation exposure risk assessments 

are needed. 

HED will examine the need for a volatilization assessment, as well as evaluate the potential for 

exposure from spray drift during Registration Review. However, for metconazole, several enduse products are labeled for use on residential turf. Thus, the risk assessment for residential turf 

may be considered protective of any type of exposure that would be associated with spray drift. 

Residential bystander exposures resulting from off-site transport (i.e., volati lization) may occur 

as a result of occupational applications of metconazole. The need for a bystander risk 

assessment for metconazole will also be considered during Registration Review. 

At the time of Registration Review, HED will reevaluate the points of departure and uncertainty 

factors currently used for risk assessment purposes regarding inhalation exposures. Based upon 

that reevaluation, HED will determine if updated aggregate exposure risk assessments are 

needed. 

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Introduction 

Metconazole is a broad-spectrum triazole fungicide active ingredient that works systemica ll y by 

preventing spore formation and infobiting mycelial growth. Metconazole acts primarily as an 

inhibitor of ergosterol biosynthesis, thereby interfering with synthesis of fungal cell membranes 

and providing systemic seed and seedling protection. 

The most recent human health risk assessment for metconazole was completed in 20 I 4 for new 

uses on dry shelled pea and beans (except soybean) crop subgroup 6C and sunflower crop 

subgroup 20B, crop group expansion to rapeseed subgroup 20A, crop group conversions to fruit, 

stone, group 12-12 and tree nut crop group 14-12 (041 8671 , B. O'Keefe, I 2/15/20 14). 

Metconazole is currently registered for use on numerous agricultural crops, including barley, 

bushberries, corn, cotton, dry shelled pea and beans, oats, peanut, rapeseed, rye, soybeans, stone 

fruits, sugar beets, sunflower, sugarcane, tree nuts, triticale, tuberous and corm vegetables, and 

wheat. It is also registered for use as a seed treatment for barley, canola, corn, cotton, oats, sugar 

beets, triticale and wheat seeds. Additionally, it is registered for use on turf and ornamentals in 

residential settings. Homeowners may apply metconazole to residential turf and ornamentals. 

Metconazole end use products are formulated as the following formulation types: emulsifiable 

concentrates, fl owabl e concentrates, soluble concentrates, water dispersible granules, granulars 

and ready-to-use solutions. Metconazole is also formulated into products with other fungicides. 

Applications can be made with ground, aerial, airblast, chemigation, hand he ld, or seed treatment 

equipment. Refer to Attachment I (Table I) for the chemical identity of metconazole. 

Hazard ldentificationff oxicology 

The toxicological database for metconazole is complete, except for a subchronic inhalation study 

which is required in accordance with the revised toxicology data requirements (TXR0057053, J. 

Lesh in, 10/09/20 I 4). The toxicity database also does not include an acute neurotoxicity study, 

but a waiver has been granted for the requirement of this study (TXR0056405, K. Rury, 

08/09/20 I 2). 

Metconazole is a member of the triazole class of systemic fungicides which acts primarily as an 

inhibitor of ergosterol biosynthesis. The proposed mode of action for metconazole is via 

inhibition of sterol (ergosterol) biosynthesis in fungi which is consistent with altered cholesterol 

levels observed in mice and rats. 

Overall , metconazole appears to affect the liver, kidney, spleen, and various blood parameters in 

all the species tested. Dose levels at which these effects occur are similar across species. Like 

other tri azoles, a primary target organ in mammalian toxic ity studies is the liver. Liver toxicity 

was seen in the mouse, rat and dog fo llowing oral exposure to metconazole via subchronic or 

chronic exposure durations. While liver effects have been reported consistently across multiple 

exposure durations and species, these effects were considered slight or minimal in some studies 

and appeared to be adaptive responses. However, based on the weight of evidence from the 

consistency of these reported effects and evidence that these effects increase in severity with 

exposure duration, leading to liver tumors in the chronic mouse study, they were considered 

adverse and fo rmed the basis of the study LOAELs. Metconazole induced liver tumors in mal e 

Page 3of27 
and female CD-I mice. It is classified as "Not likely to be carcinogenic to humans" based on 

acceptable mode of action studies which established a mitogenic mode of action for the liver 

tumors. There is no concern for mutagenicity/genotoxicity. The chronic RID would be 

protective of liver tumor induction via mitogenesis. Other major critical effects observed in oral 

studies were decreased body weight and blood effects (reductions in erythrocyte and/or platelet 

parameters) in the mouse, rat, dog and/or rabbit. Splenic effects including increased spleen 

weight and hyperplasia were observed in the mouse, rat and dog at dose levels where liver 

effects were also observed. In dogs, lenticular degeneration (cataracts) was observed at the 

highest dose tested (114 mg/kg/day). Furthermore, at high dietary levels, there is evidence that 

metconazole is a gastrointestinal irritant in the dog. Metconazole was not immunotoxic or 

neurotoxic in the appropriate studies conducted. 

There was no quantitative susceptibility to the fetuses of rabbits following in utero exposure to 

metconazole. In the prenatal developmental toxicity study in rabbits, developmental effects 

(increased post-implantation loss and reduced fetal body weights) were observed at the same 

dose that caused maternal toxicity (reduced food consumption and alterations in hematology 

parameters). ln the two-generation reproduction study in rats, offspring toxicity (reduced fetal 

body weights F2 offspring and decreased viability in F l and F2 offspring) was observed only at 

the highest tested dose, a dose which also resulted in parental toxicity as evidenced by reduced 

parental body weight, increased incidence of fatty hepatocyte changes in male parental animals 

and increased incidence of spleen congestion in FI parental females. ln the developmental 

toxicity study in rats, an increased incidence of post-implantation loss, hydrocephaly and visceral 

anomalies (cranial hemorrhage, dilated renal pelvis, dilated ureters, and displaced testis) were 

reported, in the presence of material toxicity. Skeletal variations (predominantly lumbar ribs) 

occurred in the absence of maternal toxicity. However, there is lov.r concern for quantitative 

susceptibility (skeletal variation in the absence of maternal toxicity) because the endpoint and 

point of departure for risk assessment are based on the effects in the fetus, for which there is a 

clear no-observed effect level (NOAEL). Therefore, it is concluded that there is no residual 

uncertainty for pre- and/or post-natal toxicity. The FQPA Safety Factor has been reduced to IX. 

Acute oral and dermal toxicities are Category Ill, while acute inhalation is Category IV. 

Metconazole is a moderate eye irritant (Category lll) and a mild skin irritant (Category fV). rt is 

not a skin sensitizer. 

Please refer to Attachment 3 for a summary of the toxicity endpoints and points of departure 

(PODs) for metconazole, and to Attachment 4 for the complete toxicity profile tables for 

metconazole. 

Conclusions: The toxicology database for metconazole is not complete for risk assessment of the 

current uses, in that a subchronic inhalation toxicity study is required and remains a data gap. As 

a result, a database uncertainty factor (UFoa) of 1 OX has been applied to the risk assessments of 

inhalation exposures. At the time of Registration Review, or when the required subchronic 

inhalation toxicity study is submitted, HED will reevaluate the points of departure and 

uncertainty factors cmTently used for risk assessment purposes regarding inhalation exposures. 

Page 4 of27 
Residue Chemistry and Dietary Exposure 

The nature of the residue in primary/rotational crops and livestock has been adequately defined . 

Metconazole (parent) is the residue of concern for the tolerance expression for primary/rotational 

crops and livestock. Metconazole is the residue of concern for risk assessment purposes in 

primary and rotational crops, except for cereal grains; the residues of concern for risk assessment 

in cereal grains (as both primary and rotational crops) are metconazole and the metabolite M 11. 

The residues of concern in livestock for purposes of the risk assessment are metconazole and 

metabolites M I (free/unconjugated and its glucuronic acid conjugate), M 12, and M3 l (free and 

its glucuronic ac id conjugate). For drinking water, the residue of concern for metconazole is the 

parent only. HED also has concern for residues of 1,2,4-triazole, 1riazolylalanine (TA) and 

triazolylacetic acid (T AA) in plants and I ivestock as a result of the use of metconazole. 

However, because endpoints for these separate compounds have been established, exposure and 

risks from free triazole and its conjugates will be addressed separately. 

The existing residue chemistry database for metconazole is adequate to support current 

Registration Review data requirements. Adequate metabolism, enforcement methods, 

multircsidue methods, storage stability, field tri als, processing and rotational crop data are 

available to support the registered uses. 

Analytical reference standards for metconazole are currently available in the EPA National 

Pesticide Standards Repository (e-mail from Theresa Cole, ACB, 7/31/15). 

Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments 

were conducted in 2014. 

The acute and chronic assessments were conservative, using tolerance-level residues except for 

cereal grains and livestock commodities, DEEM default or empirical processing factors, and 

I 00% crop treated. Since cereal grains and livestock commodities include metabolites as 

residues of concern in the risk assessment, maximum residue values for the metabolites from 

field trials were added to the mctconazole tolerance levels. The estimated drinking water 

concentration (EDWC) of 51.8 ug/L (ppb) used in the acute assessment was generated by the 

PRZM-Ground Water (PRZM-GW) model. The EDWC used in the chronic dietary assessment 

of 43.9 ug/L (ppb) was generated by the Surface Water Concentration Calculator (SWCC) 

model. 

The acute dietary (food and drinking water) exposure to metconazole is below HED's level of 

concern for females 13-49 years old, the only population subgroup of concern. For the general 

U.S. population, including infants and children, an appropriate dose/endpoint attributable to a 

single dose was not observed in the available oral toxicity studies. The acute dietary exposure 

estimate at the 95th percentile is 4.6% of the acute population adjusted dose (aPAD) for females 

13-49 years old, the only population subgroup of concern. 

The chronic dietary (food and drinking water) exposure to metconazole is below HED's level of 

concern for the general U.S. population and all population subgroups. The chronic dietary 

Page 5of27 
exposure estimates are 6.6% of the chronic population adjusted dose ( cPAO) for the general U.S. 

population and 14% of the cPAO for children l-2 years old, the most highly exposed population 

subgroup. 

Metconazole was classified as " not likely to be carcinogenic to humans;" therefore, a cancer 

dietary assessment was not performed. 

Conclusions: A new dietary exposure assessment is not anticipated to be needed during 

Registration Review unless there are increases to the drinking water exposure estimates that need 

to be incorporated. 

Residential Exposure 

There are existing uses of metconazole on turf and ornamentals in residential settings that were 

reassessed in the most recent HED risk assessment (0418671 , B. O' Keefe, 12/ 15/2014) to reflect 

HED's 2012 Residential SOPs1 along with policy changes for body weight assumptions. 

Because dermal toxicity endpoints for the appropriate duration of exposure (short-term) were not 

identified up to the limit dose, only residential handler inhalation exposures/risks for adults, and 

residential post-application incidental oral exposures/risks for children were assessed. For 

residential handler exposures to adults, all inhalation risk estimates were greater than the level of 

concern (LOC) of 1,000, and therefore are not of concern (MO Es range from 6,300 to 

23,000,000). For post-application exposures to small children ( l to <2 years old), all incidental 

oral risk estimates are greater than the LOC of 100, and therefore are not of concern (MO Es 

range from 1,000 to 450,000). 

In accordance with 40CFR§158, turf transferrablc residue (TTR) data are required for all 

occupational (e.g., sod farms, golf courses, parks, and recreational areas) or residential turf uses 

that could result in post-application exposure to turf. In the absence of chemical-specific TTR 

data, EPA uses default values. As mentioned above, an assessment of incidental oral exposures 

to small children, using these default values, was completed as part of the most recent HED risk 

assessment (041867 1, B. O'Keefe, 12115/20 14). Since the estimated residential turf postapplication exposure for residential turf using default TTR values for metconazole is minimal in 

comparison to the level of concern (i.e., the calculated MOE is greater than 10 times higher than 

the level of concern, MOE= I ,000 compared to the LOC of 100), EPA has waived the 40 CFR 

TTR data requirement. In this instance, it is unlikely that chemical-specific TTR data would be 

needed to further refine exposure assessments. 

In accordance with 40 CFR §I 58, dislodgeable foliar residue (Of-R) data are required for all 

occupational (e.g., crop, nursery, greenhouse use sites) or residential (e.g., ornamental and 

vegetable gardens, pick your own farms, retail tree farms) uses that could result in postapplication exposure to foliage. Since metconazole does not result in adverse systemic toxicity 

via the dermal route of exposure, EPA has waived the 40 CFR OFR data requirement at this 

time. 

1 Available: http : I / www2 . epa. gov / pesticide -scien ce - a nd-ass ess ing-pe sticide -

r i sks/ stan dard-operating - procedu res- r e siden t i al- p esticide 

Page 6of27 
Sprav Drift and Volatilization: Residential bystander exposures resulting from off-site transport 

(e.g., spray drift or volatilization) may occur as a result of applications ofmetconazole. The 

potential for spray drift will be quantitatively evaluated for each pesti cide during the Registration 

Review process that ensures that all uses for that pesticide will be considered concmTentl y. 

However, for metconazole, several end-use products are labeled for use on residential turf. Thus, 

the risk assessment for that use may be considered protective of any type of exposure that would 

be associated with spray drift. Jn terms of volatili zation, the agency has developed a 

Volatilization Screening Tool and a subsequent Volatilization Screening Ana lysis 

(http://www.regulations.gov/#!docketDetail:D=EPA-HQ-OPP-2014-0219). During Registration 

Review, the agency will utili ze this analysis to determine if data (i.e., flux studies, route-specific 

inhalation toxicological studies) or further analyses are required for specific chemicals. 

Conclusions: Short-term residential exposures are expected from existing uses on turf and 

ornamentals. Since these exposures have been recently reassessed to reflect HED's 2012 

Residential SOPs2 a long with policy changes for body weight assumptions, HED does not 

anticipate the need to reassess these exposures during Registration Review. However, at the time 

of Registration Review, HED will reevaluate the points of departure and uncertainty factors 

currently used for risk assessment purposes regarding inhalation exposures. Based upon that 

reevaluation, I-IED will determine if updated residential handler inhalation exposure risk 

assessments are needed. 

The Agency will examine the need for a volatilization assessment, as well as evaluate the 

potential for exposure from spray drift during Registration Review. However, for metconazole, 

several end-use products are labeled for use on residential turf. Thus, the risk assessment for 

residential turf may be considered protecti ve of any type of exposure that would be associated 

with spray drift. Residential bystander exposures resulting from off-site transport (i.e., 

volatilization) may occur as a result of occupational applications of metconazole. The need for a 

bystander risk assessment for metconazole will also be considered during Registration Review. 

Aggregate Risk Assessment 

In accordance with the rood Qua lity Protection Act (FQPA), HED must consider and aggregate 

pesticide exposures and risks from three major sources: food, drinking water, and residential 

exposures. The acute and chronic aggregate risk assessments included food and drinking water. 

The short-term aggregate risk assessment included food, drinking warer, and residenti al 

exposures. No intermediate-term aggregate risk assessment was conducted since all residential 

exposures are anticipated to be short-tenn in duration. 

Acute and Chroni c: The 20 14 acute and chronic aggregate risk assessments included exposure to 

metconazole residues in food and drinking water. Acute and chronic dietary risk estimates for 

food and drinking water exposure are below HED's level of concern (<100% of the aPAD and 

cPAD). 

2 Available: http : / /www2 . epa . gov /pest.icide-science - and-assessing-pesticiderisks/standard-operating-procedures-residential-pesticide 

Page 7of27 
Short-term: In 2014, a short-term aggregate risk assessment was completed for metconazole. 

For adults, the short-term aggregate assessment combined the average food and drinking water 

exposures with handler inhalation exposures on treated turf. For small children (1 to <2 years 

old), the short-term aggregate assessment combined the average food and drinking water 

exposures with post-application incidental oral (hand-to-mouth) exposures from contact with 

treated turf. The assessments resulted in risk estimates that are below the I-IED's level of 

concern (MOE <100 for children, aggregate risk index (ARI) <1 ). The short-term aggregate 

MOE for children was 630 and the ARI for adults was 5.3. 

Conclusions: Aggregate exposure to metconazole is currently not of concern to HED. A new 

aggregate assessment is not anticipated to be needed during Registration Review. However, at 

the time of Registration Review, HED will reevaluate the points of departure and uncertainty 

factors currently used for risk assessment purposes regarding inhalation exposures. Based upon 

that reevaluation, HED will determine if updated residential handler inhalation exposure risk 

assessments are needed; and thus, whether an updated aggregate assessment is needed. 

Occupational Exposure 

All occupational exposure scenari os for all currently registered uses were previously assessed in 

several risk assessments (see References). Occupational handlers and post-application workers 

can become exposed to metconazole at short- or intermediate-term durations ttu-ough its use. 

Because dermal toxicity endpoints for the appropriate durations of exposure (short- and 

intermediate-term) were not identified up to the limit dose, only occupational handler inhalation 

exposures/risks were assessed. 

Occupational Handlers 

Previous occupational handler exposure and risk assessments for metconazole were conducted at 

the maximum application rates and assumed the maximum area treated per day for all the 

registered use sites. Applications can be made with ground, aerial, airblast, chemigation, hand 

held, or seed treatment equipment. Occupational exposure assessments have been updated in 

accordance with current HED policies and standard operating procedures. Risk estimates for all 

scenarios are not of concern with labeled personal protective equipment (PPE), and therefore, 

HED does not anticipate the need to reassess these exposures during Registration Review. 

However, at the time of Registration Review, HED will reevaluate the points of departure and 

uncertainty factors currently used for risk assessment purposes regarding inhalation exposures. 

Based upon that reevaluation HED will determine if updated occupational handler inhalation 

exposure risk assessments are needed. 

Occupational Post-Application 

Since metconazole does not result in adverse systemic toxicity via the dermal route of exposure, 

a quantitative dermal assessment is not required for metconazole or needed during Registration 

Review. Based on the Agency's current practices, a quantitative occupational post-application 

inhalation exposure assessment was not performed for metconazole at this time. If new policies 

or procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for metconazole. 

Page 8of27 
In accordance with 40Cf'R § 158, TIR data are required for all occupational (e.g., sod farms, 

golf courses, parks, and recreational areas) or residential turf uses that could result in postapplication exposure to turf. Additionally, in accordance with 40CFR § 158, DFR data are 

required for all occupational (e.g., crop, nursery, greenhouse use sites) or residentia l (e.g., 

ornamenta l and vegetable gardens. pick your own fanns, retail tree farms) uses that could result 

in post-application exposure to foliage. However, as mentioned above, metconazole does not 

result in adverse systemic toxicity via the dermal route of exposure, and therefore. EPA has 

waived the 40 CFR TTR and DFR data requirements at this time . 

Conclusions: The occupational exposure database is adequate to support the Registration 

Review process for metconazole. The occupational handler and post-application exposure 

assessments are re flective of current exposure policies and data, and therefore, there is sufficient 

information available to assess occupational handl er and post-application exposures. Updated 

occupational handler and post-application exposure assessments are not anticipated to be needed 

duri ng Registration Review. However, at the time of Registration Review, H"ED will reevaluate 

the points of departure and uncertainty factors currently used for risk assessment purposes 

regarding inhalation exposures. Based upon that reevaluation, HED will determine if updated 

occupational handler inhalation exposure risk assessments are needed. 

Public Health and Pesticide Epidemiology Data 

In the Main OPP Incident Data System (IDS), from January I, 20 I 0 to May 27, 2015, there were 

no incidents reported for the single chemical metconazole only in the database. There were three 

incidents reported involving metconazole and pyraclostrobin. These incidents were classified as 

moderate severity. 

In the Aggregate IDS, from January I, 2010 to May 27, 2015, there were 17 incidents reported 

involving metconazole. These incidents were classified as minor severity. Overall, there are few 

incidents reported to IDS involving metconazole. 

I\ query of the Centers for Disease Control and Prevention/National Institute for Occupational 

Safety and Health (CDC/NTOSH) Sentinel Event Notification System for Occupational RiskPesticides (SENSOR)-Pesticides database for 1998-2011 identifies no cases involving 

metconazole. 

The Agricultural Health Study (AHS) is a high quality, prospective epidemiology study 

evaluating the link between pesticide use and various health outcomes, including cancer. The 

AHS includes private and commercial pesticide applicators and their spouses. Metconazole-is 

not included in the AHS, and therefore, this study does not provide information for this report. 

Conclusion: Based on the low frequency and severity of incident cases reported for metconazolc 

in both IDS and SENSOR-Pesticides, there does not appear to be a concern at this time that 

would warrant further investigation. The Agency will continue to monitor the incident 

information and, if a concern is triggered, additional analysis wi ll be included in the risk 

assessment. 

Page 9 of27 
Toler ance Assessment and International Ha rmonization 

Tolerances are established for plant and livestock commodities under 40 CFR § l 80.6 l 7(a) for 

residues of metconazole, including its metabolites and degradates. Compliance with the 

tolerance levels is to be determined by measuring only metconazole [5-[(4-

chlorophenyl)methyl]-2,2-dimethyl-1-(lH-1 ,2,4-triazol-l-ylmethyl)cyclopentanol) as the sum of 

its cis- and trans-isomers. No tolerances are established for Section 18s, regional registrations, 

or indirect/inadvertent residues. 

As shown in Attaclunent 6, there are no Codex maximum residue limits (MRLs) established for 

metconazole; therefore, there is no harmonization issue with Codex at this time. Residue 

definitions are harmonized with Canada (D4 18671 , B. O'Keefe, 12/ 15/2014). For commodities 

with both U.S. and Canadian tolerances/MRLs, most of the tolerance/MRL levels are the same. 

Cumulative 

Metconazole is a member of the triazole-containing class of pesticides. Although conazoles act 

similarly in plants (fongi) by inhibiting ergosterol biosynthesis, there is not necessarily a 

rel ationship between their pesticidal activity and their mechanism of toxicity in mammals. 

Structural similarities do not constitute a common mechanism of toxicity. Evidence is needed to 

establish that the chemicals operate by the same, or essentially the same, sequence of major 

biochemical events. In conazoles, however, a variable pattern of toxicological responses is 

found; some are hepatotoxic and hepatocarcinogenic in mice. Some induce thyroid tumors in 

rats. Some induce developmental, reproductive, and neurological effects in rodents. 

Furthennore, the conazoles produce a diverse range of biochemical events including altered 

cholesterol levels, stress responses, and altered DNA methylation. It is not clearly understood 

whether these biochemical events are directly connected to their toxicological outcomes. Thus, 

there is currently no evidence to indicate that conazoles share common mechanisms of toxicity 

and EPA is not following a cumulative risk approach based on a common mechanism of toxicity 

for the conazoles. For information regarding EPA's procedures for cumulating effects from 

substances found to have a common mechanism of toxicity, see EPA's website at 

http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/cumulative-assessmentrisk-pesticides 

Human Studies 

The risk assessments which have been previously conducted for metconazole relied in pa11 on 

data from studies in which adult human subjects were intentionally exposed to a pesticide to 

determine their dermal and inhalation exposure. Many such studies, involving exposure to many 

different pesticides, comprise generic pesticide exposure databases such as the Pesticide 

Handlers Exposure Database (PHED), the Agricultural Handler Exposure Task Force (AHETF) 

database, the Outdoor Residential Exposure Task Force (ORETF), and the Agricultural Reentry 

Task Force (ARTF) Database. EPA has reviewed all the studies supporting these multi-pesticide 

generic exposure databases, and has found no clear and convincing evidence that the conduct of 

any of them was either fundamentally unethical or significantly deficient relative to the ethical 

standards prevailing at the time the research was conducted. All applicable requirements of 

Page 10 of27 
EPA's Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been 

satisfied, and there is no regulatory barrier to continued reliance on these studies. 

Data Deficiencies 

The following toxicology data are needed to support the registered uses of metconazole: 

870.3465 Subchronic Inhalation Study 

A subchronic inhalation study is required because the use of an oral point of departure 

(POD) for inhalation exposure results in MOEs as low as 380 for occupational exposure, 

which does not meet the target of I 000 for a waiver (TXR0057053, J. Lesh in, 

I 0109120 14). Therefore, a l OX database uncertainty factor has been added for inhalation 

exposures in the absence of the required inhalation toxicity study. 

References 

Recent Memoranda Relevant to Rel!istration Review of Mctconazolc 

Author DPffXR # Date Title 

Human Health Risk Assessments 

B. O'Keefe D308794 07106106 Metconazole: Human Health Risk Assessment for Proposed Tolerance on 

Imported Bananas. 

B. O' Kee fc D328676 09106107 Metconazole: Human Health Risk Assessment for Proposed New Uses on 

Turf and Ornamentals. 

Yan 0 33 1926 03/ 12/08 Mctconazole: FQPA Human Health Risk Assessment for Proposed New 

Donovan Uses on Small Grains, Stone Fruits, Tree Nuts, Peanuts, Soybeans, and 

Sugar Beets. 

B. O' Keefe 0 341748 08115108 Metconazole. FQPA Human Health Risk Assessment for Proposed New 

Section 3 Uses on Corn and Cotton and Section 18 Use on Sugarcane. 

B. O' Keefe D350369 10/20/08 Mctconazole. Human Health Risk Assessment for Proposed Section 3 

Use on Canola. 

B. O'Keefe D362044 02/ 19/09 Metconazole: Addendum to the Human Health Risk Assessment (DP 

#s34 l 748 & 351382) for Proposed New Section 3 Uses on Corn and 

Cotton and Section 18 Use on Sugarcane. 

B. O'Keefc 0375762 02/28/ 11 Metconazole. Human Health Risk Assessment for Seed Treatment Use 

on Barley, Canola, Cotton, Oats, Triticale, Wheat, Com (Field, Sweet, 

and Popcorn), and Sugar Beets. 

B. O'Keefe D380512 05/24/ 11 Metconazole: Human Health Risk Assessment for Proposed Uses on 

Tuberous and Corm Vegetables Subgroup IC and Bush berry Subgroup 

13-078. 

B. O'Keefe 0386421 09/30/ 11 Metconazole: Human Health Risk Assessment for Proposed Uses on 

Sugarcane. 

J. Dawson 0399532 08/09/ 12 Metconazole. Summary of Risk Issues Associated With Increase In 

Tolerance For Corn Stover. 

B. O'Keefe 0418671 12/ 15/ 14 Metconazole - Human Health Risk Assessment for a Section 3 

Registration of New Uses on Dry Shelled Pea and Beans (Except 

Soybean) Crop Subgroup 6C and SunOower Crop Subgroup 208 ; Crop 

Group Expansion to Rapeseed Subgroup 20A; and Crop Group 

Conversions to Fruit, Stone, Group 12-12; and Nut, Tree, Group 14-12. 

Residue Chemistry 

N. Dodd 0309499 11/23/04 Metconazole Residue Chemistry Database Scope. 

Page 11 of 27 
Recent Memoranda Relevant to Re1ristration Review of Metconazole 

Author DP/TXR # Date Title 

N. Dodd D32454 1 12/ 14/05 Metconazole. Request for a Tolerance on Imported Bananas. Summary 

of Analytical Chemistry and Residue Data. Petition Number 9E05052. 

N. Dodd D348168 02/20/08 Metconazole. Petition for Establishment of Tolerances for Use on Small 

Grains, Stone l'ruits, Tree Nuts, Peanuts, Soybeans, and Sugar Beets. 

Summary of Analytical Chemistry and Residue Data. 

N. Dodd D34 I 746 05/0 1/08 Metconazole. Petition for Establishment of Tolerances for Use on Corn 

and Cotton. Summary of Analytical Chemistry and Residue Data. 

N. Dodd D350367 09/ 18/08 Metconazole. Petition for the Establishment of a Tolerance for Use on 

Cano la. Summary of Analytical Chemistry and Residue Data. 

D. D36 1I1 0 02/26/ 10 Metconazole. Response to Data Gaps fo r Conditional Registration on 

Soderberg Small Grains, Stone Fruits, Tree Nuts, Peanuts, Soybeans, and Sugar 

Beets. Summary of Analytical Chemistry and Residue Data. 

A. Acierto D371571 08/20110 Metconazole. Response to Data Gaps for Conditional Registration in/on 

Canola. Summary of Analytical Chemistry and Residue Data. 

D. Drew D363016 0 1/ 12112 Storage Stability of 1,2,4-Triazole. Triazolylalanine and Triazolylacetic 

Acid in Various Crop Matrices and Processed Commodities (up to four 

years under frozen storage). 

N. Dodd 0399057 07119/12 Metconazole. Additional Residue Data on Corn Stover. Summary of 

Residue Data. 

S. Funk D380050 02/13113 Metconazole: Response to Condition of Registration - Storage Stability 

Data for Triazole Metabolites in Plant Samples. 

S. Funk D403859 02114/13 Metconazole: Amendment to Add Dry Bean, Sorghum and Sunflower as 

Rotated Crops with a 0-day Plant-back Interval (PB!) after Application 

ofCaramba, Multiva, or BAS 556 End-Use Products to Any of the 

Primary Crops Listed on the Label. Summary of Analytical Chemistry 

and Residue Data. 

N. Dodd D4 19223 10/23/14 Metconazole. Petition for the Establishment of Permanent Tolerances 

and Registration for Use on the Pea and Bean, Dried Shelled, except 

Soybean, Subgroup 6C and the Sunflower Subgroup 20B; Expansion of 

the Canola Tolerance to the Rapeseed Subgroup 20A; and Conversion of 

the Established Stone Fruit and Tree Nut Crop Groups to the Stone Fruit 

Group 12-1 2 and the Tree Nut Group 14-12. Summary of Analytical 

Chemistry and Residue Data. 

Dietary Exposure Assessment 

N. Dodd D423622 1117/14 Metconazole Acute and Chronic Aggregate Dietary (Food and Drinking 

Water) Exposure and Risk Assessment for the Section 3 Registration 

Actions on Pea and Bean. Dried Shelled, except Soybean, Subgroup 6C 

and the Sunflower Subgroup 208; Expansion of the Canola Tolerance to 

the Rapeseed Subgroup 20A; and Conversion of the Established Stone 

Fruit and Tree Nut Crop Groups to the Stone Fruit Group 12- 12 and the 

Tree Nut Group 14-1 2. 

Occupational and Residential Exposure Assessments 

K. Rury D423992 1211 1/ 14 METCONAZOLE. Occupational and Residential Exposure Assessment 

fo r Proposed Uses on Dry Shelled Pea and Beans (Except Soybean) Crop 

Subgroup 6C and Sunflower Crop Subgroup 208 : Crop Group Expansion 

to Rapeseed Subgroup 20A; and Crop Group Conversions to Fruit, Stone, 

Group 12-12; and Nut, Tree, Group 14-12. Also a Re-Eval uation of all 

existing Residential Uses of Metconazole. 

N. Tsaur D386786 06/08/11 Metconazole. Occupational and Residential Exposure Assessment for a 

Proposed New Foliar Use on Sugarcane. 

Page I 2of27 
Recent Memoranda Relevant to Re1?istration Review of Metconazole 

Auth or DPffXR # Date Title 

N. Tsaur 0380989 02/03111 Metconazole. Occupational and Residential Exposure Assessment for 

Proposed IR-4 Foliar Uses on Oushberrics (Crop Subgroup 3-078 ) and 

Tuberous and Com1 Vegetables (Crop Subgroup IC). 

N. Tsaur 0 375763 02/03/ 11 Metconazole. Occupational and Residential Exposure Assessment for 

Seed Treatment Use on Barley. Canola, Cotton, Oats, Triticale. Wheat, 

Com (Field, Sweet, and Popcorn), and Sugar Beets. 

N. Tsaur 0 350368 09/22/08 Metconazole. Occupational and Residential Exposure/Risk Assessment 

for Section 3 Use on Canola. 

B. O' Kecfe 0343433 08/20/08 Metconazole. Occupational and Residential Exposure/Risk Assessment 

for Section 3 Use on Corn and Cotton, and Section 18 Use on Sugarcane. 

J. Arthur 0 331932 10/ 18/07 Metconazole: Occupational and Residential Exposure/Risk Assessment 

for Use on Peanut, Stone Fruit, Tree Nuts, Barley, Oats, Rye, Soybeans, 

Sugar Beets, Triticale and Wheat. 

J. Arthur 0 341832 08.03/07 Metconazole: Occupational and Residential Exposure/Risk Assessment 

for Use on Ornamentals and Turf. 

Incident Report 

S. Recore 0428900 09/01 / 15 Metconazole: Tier I Review of Human Incidents 

Toxicology 

J. Leshin TXR0057053 10/09/ 14 Metconazolc: Summary of Hazard and Science Policy Council 

(HASPOC) Meeting of September 1 I th, 2014: Revisit for the 

Requirement ofa Subchronic Inhalation Study from the June 19'h meeting 

K. Rury TXR0056405 08/09/12 Metconazole: Summary of Hazard and Science Policy Council 

(HASPOC) Meeting of July 19, 20 12: Recommendations on the 

Requirement or a Subchronic Inhalation Study and an Acute 

Ncurotoxicity Study. 

M. Copley 0329170 09103109 Mctcom1zolc: Corrected Appendix 3. Subchronic, Chronic and Other 

Toxicity Profile Table for use in future Risk Assessments for 

Metconazole. 

J. Kidwell TXR005421 I 04114106 METCONAZOLE: Report or the Cancer Assessment Review Comminee 

Attachments 

I. Chemical Identity Table 

2. Physicochemical Properties of Technical Grade Metconazole Table 

3. Endpoint Selection Table 

4. Toxicity Profile Tables 

5. Toxicology Data Requirements Table 

6. Tolerance/MRL Table 

Page 13 of27 
Attachment 1 

Chemical Identity Table 

Table 1. Metconazole Nomenclature. 

Chemical Structure 

Common name 

CAS name 

CAS ff 

Cl Cl 

cis-isomer trans-isomer 

Metconazole 

KNF-S-474m (Kureha); BAS 555 F (BASF); V- 10 11 6 (Va lent) 

( 1RS,5RS;1RS,5SR)-5-(4-chlorobenzyl)-2,2-dimethyl-1-(1 H-1,2,4-triazol- lilmeth l)c clo entanol 

5-(( 4-ch lorophenyl)methyl)-2,2-dimethyl-1-( l /-/-1,2,4-triazol-1-

ylmethyl)c clo entanol 

1251 16-23-6 (cis- and trans-isomers) 

11 5850-27-6 (cis-isomer) 

115850-28-7 (trans-isomer 

Page 14of27 
Attachment 2 

Table 2. Physicocbemical Properties of Mctconazole 

Parameter Value References• 

(MRID) 

Melting poinl/range I 00.0-108.4°C (using Electrothermal Digital Melting Point 44721505 

Apparatus) (AC900,768 technical grade) 

pH 5.8 1 at 25°C ( I% aqueous suspension) 46808402 

Relative density (20°C) 1.14 (relative density to water at 4°C, using capillary- 4472 1505 

stoppered, density-specific gravity bottle) (Lot No. AC 8879-

1408) 

Water solubility (20°C) Using shake-nask method: 44721505 

18.7 ± 1.0 mg/L (cis-isomer, WL 14827 1, KNF-S-474m) 

I 3.6 ± 1.7 mg/L (1rans-isomer, WL 14827 1, KNF-S-474m) 

Solvent solubility (g/L) at So lvent Metconazole cis trans 44721505 

20°c 

acetone 363 251 117 

methanol 403 294 117 

dichloromethane 481 343 141 

ethyl acetate 260 173 90.0 

propanol 132 86.6 46.7 

toluene 103 66.2 38.0 

Hexane 1.40 0.929 0.483 

Vapor pressure (20°C) Using gas-saturation method: 44721505 

< I .23x I 0.5 Pa or 9.23 x I o·8 mm Hg (metconazole) 

< 1.04x I o·5 Pa or 7 .80 x I o·8 mm Hg (cis-isomer) 

< I .96x I o-6 Pa or 1.47 x l o·8 mm Hg (1rt1ns-isomer) 

Dissociation constant (pK.) 11.38±0.03 and 1.06±0.03 (in water at 29. 1°C using 44721505 

spectrophotometric method; Lot No. AC 8879-1408) 

Octanol/water partition At 20 °C (using flask shaking method}: 44721505 

coefficient, Log(Kow) Knw (log Kow) = 7090±989 (3.85) (Lot No. AC 8879-1408) 

(TGAI) 

Kow (log Kow) = 7150±803 (3.85) (cis-isomer, CL 354,80 I) 

Kow (log Ko,.) = 6800± 1700 (3.8) (/rans-isomer, CL 354,802) 

UY/visible absorption pH A. A log E 46808403 

spectrum cis-isomer 

2.0 22 1.4 0.828 4.03 

6.8 0.8452 4.04 

7.0 0.9126 4.08 

10.3 0.7226 3.98 

/rans-isomer 

2.0 22 1.4 0.9053 4.07 

7.0 0.9547 4. 10 

10.1 0.9893 4.1 1 

* Product Chemistry Reviews: DP f/256877, Shyam Mathur, Ph.D. , 9/ 12/2000 and DP #329168, Shyam Mathur, 

Ph.D., 7/ 13/07. 

Page 15of27 
Attachment 3 

Summary of Toxicity Endpoints and Points of Departure of Mctconazole 

Table 3.1. Summary of Toxicological Doses and Endpoints for Metconazole for Use in Dietary and NonOccupational Human Health Risk Assessments 

Exposure/ Point of Uncertainty/FQPA RID, PAO, Level Study and Tox icological Effects 

Scenario Departure Safety Factors of Concern for 

Risk Assessment 

Acute Dietary An appropriate dose/endpoint attributable to a single dose was not observed in the available oral 

(General toxicity studies reviewed. 

Population, 

including 

Infants and 

Children) 

Acute Dietary NOAEL= 12 UFA= IOX Acute RID = 0.12 Developmental toxicity in rats: 

(Females 13-49 mg/kg/day UFH= IOX mg/kg/day LOA EL= 30 mg/kg/day based on 

years of age) FQPA SF= IX increases in skeleta l variations. At 75 

aPAD= 0. 12 mg/kg/day (the next higher dose 

mg/kg/day level) increased incidence of postimplantation loss. hydrocephaly and 

visceral anomalie'.?a (cranial 

hemorrhage, dilated renal pe lvis, 

dilated ureters, and displaced testis) 

were reported. 

Chronic NOAEL= 4.3 UFA= I OX Chronic RID = Chronic oral toxicity study in rats: 

Dietary (All mg/kg/day UF11= IOX 0.04 mg/kg/day LOA EL = 13.1 mg/kg/day based on 

Populations) FQPA SF= IX increased liver (M) weights and 

cPAD = 0.04 associated hepatocellular lipid 

mg/kg/day vacuolation (M) and centrilobular 

hypertrophy(M). Similar effects were 

observed in fema les at 54 mg/kg/day. 

plus increased spleen weight. 

Incidental Oral NOAEL= 9.I UFA= IOX Residential LOC 28-Day oral toxicity study in rats: 

Short-Term (I- mg/kg/day UF11=IOX for MOE = 100 LOA EL = 90.5 mg/kg/day based on 

30 days) FQPA SF= IX decreased body weight (M), increased 

liver and kidney weight and 

hepatocellular hypertrophy and 

vacuolation (M/F). 

Incidental Oral NOAEL= 6.4 UFA= IOX Residential LOC 90-Day oral tox icity study in rats: 

Intermediate- mg/kg/day UFH= IOX for MOE = 100 LOAEL = 19.2 based on increased 

Tenn (1-6 FQPA SF= IX spleen wt (F) and hepatic vacuolation 

months) (M). 

Dermal Short- Quantification of dermal risk is not required due to lack of systemic or dermal toxicity at the Limit 

( 1-30 days) & Dose in a 21 -day dermal toxicity study in the rat, the lack of neurotoxicity, and the lack of concern 

Intermediate- for developmental, reproductive or neurotoxicity. 

Tenn (1 -6 

months) 

Inhalation NOAEL= 9.1 UFA= IOX Residential LOC 28-Day oral tox icity study in rats: 

Short- Term mg/kg/day UFH= IOX for MOE = I 000 LOA EL = 90.5 mg/kg/day based on 

(1-30 days) UFoo=IOX decreased body weight (M), increased 

FQPA SF= IX liver and kidney weight and 

hepatocellular hypertrophy and 

vacuolation (M/F). 

Page 16of27 
Table 3. 1. Summary of Toxicological Doses and End points fo r Metconazolc for Use in Dietary and NonOccuoational Huma n Health Risk Assessments 

Exposure/ Point of Uncertainty/FQPA RID, PAD, Level Study and Toxicologica l Effects 

Scenario Departure Safety Factors of Concern fo r 

Risk Assessment 

Inhalation NOAEL= 6.4 UFA= !OX Residential LOC 90-Day ora l tox icity study in ra ts: 

Intermediate- mg/kg/day UFtt=IOX for MOE = I 000 LOAEL = 19.2 mg/kg/day based on 

Term (1-6 UFoo= IOX increased spleen wt (F) and hepatic 

months) FQPA SF= IX vacuolation (M). 

Cancer (oral, Classification: "Not likely to be Carcinogenic to Humans" 

demrnl, 

inhalation) 

Point of Dcpanurc (POD)= A da1a po1111 or an cs111na1ed point that 1s derived from observed dose-response data and used to mark the bcgmnmg 

of cx1rapola11 011 10 dctcnninc risk associated wi1h lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. 

LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF,. = extrapolation from animal 10 human (interspecies). UFu = 

potential variation in sensitivity among members of the human populmion (intraspccics). UFoo = to account for the absence of key data (i.e .. lnck 

of a critical study). FQP/\ SF = FQPA Safety Factor. PAD = populmion adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE= 

margin of exposure. l.OC = level of concern. NIA = not applicable. 

Ta ble 3.2. Summary of Toxicological Doses and Endpoints for Metconazole for Use in Occupationa l Huma n 

Hea lth Risk Assessments 

Exposure/ Poin t of Uncerta inty Level of Concern Study and Toxicological Effects 

Scenario Departure Factors for Risk 

Assessment 

Dermal Short- Quantification of dermal risk is not required due to lack of systemic or dermal toxicity at the Limit 

( 1-30 days) & Dose in a 2 1-day dermal toxicity study in the rat, the lack of concern for developmental, reproductive 

Intermediate- or neurotoxicity. 

Tcm1 (1-6 

months) 

Inhalation NOAEL=9. I UFA= !OX Occupational LOC 28-Day ora l tox icity study in rats: 

Short-Term ( 1- mg/kg/day UFtt= IOX for MOE = I 000 LOAEL = 90.5 mg/kg/day based on 

30 days) UFoe= IOX decreased body weight (M), increased 

liver and kidney weight and 

hepatocellular hypertrophy and 

vacuolation (M/f.'). 

Inhalation NOAEL=6.4 UFA= IOX Occupational LOC 90-Day oral toxicity study in rats: 

Intermediate- mg/kg/day UF11=IOX for MOE = l 000 LOAEL = 19.2 mg/kg/day based on 

term ( 1-6 UFoe= IOX increased spleen wt (F) and hepatic 

months) vacuolation (M). 

Cancer (oral, Classification: "Not Likely to be Carcinogenic to Humans" 

dennal, 

inhalation) 

Point ol Dcpnrturc (POD)= A data pomt or an csumatcd po111 t lhat 1s derived from observed dose-response darn and used to mark the bcg1nn111g 

of extrapolation to determine risk associalcd with lower cnviro11111c111<1lly re levant human exposures. NOAEL = no observed adverse cfTcct level. 

LOAEL = lowest observed adverse effect level. UF = uncenainty factor. UFA= extrapolation from animal to human (interspecies). UF11 = 

potential variation in sensitivity among members of the humru1 population (intraspecies). Ul700 = to account for the absence of key date (i.e .. lack 

of a cri11cal study) MOE= margin of exposure. LOC = level of concern. NIA= not applicable. 

Page 17of27 
Attachment 4 

Toxicity Profile for Metconazole 

Table A.2.1. Acute Toxicity Profile - Metconazole Technical 

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

870. I 100 Acute oral [mouse] 44721512 LDso = >566 mg/kg III 

870.1100 Acute oral [rat) 44721512 LDso = >566 mg/kg Ill 

870. l JOO Acute oral [rat] 44721513 LDso = > 14 59 mg/kg Ill 

870.1100 Acute oral [rat) 44721514 LDso = >5000 rng/kg IV 

870.1200 Acute dennal [rat] 44721512 Dermal LDso > 2000 111 

870.1200 Acute dermal [rnbbit] 44721512 Dermal LDso > 2000 Ill 

870. 1200 Acute inhalation [rat] 4472 15 12 LDso = >5.6 mg/L IV 

870.2400 Acute eye irritation [rat] 44721513 moderate irritant III 

870.2500 Acute dermal irritation [rabbit] 44721513 mild irritant IV 

870.2600 Skin sensitization [guinea pig] 44721513 neg. -

Table A.2.2. Non-acute Toxicity Profile for Metconazole 

Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Metconazole Technical' 

Guideline Study Type MRJO No. (year)/ Results 

No. Classification /Doses 

870.3100 28-Day oral toxicity 44721515 (1990) NOA EL (M/F) = 9.1 / 10.1 mg/kg/day 

rodents (rat) MlF: 0, 30, I 00, I 000. LOA EL (M/F) = 90.5/97 mg/kg/day based 

3000 ppm on depression of body weight in M, liver 

M: 0, 2.7, 9. 1, 90.5, 26 1.1 and kidney weight increases with 

mg/kg/day associated histopathological effects 

F: 0, 3. 1, IO.I. 97, 287.4 (hypenrophy and fatty vacuolation) in liver 

mg/kg/day only. 

Acceptable/guideline 

870.3 100 90-Day oral toxicity 44 721517 ( 1991) NOAEL (M/F) = 6.4/7.2 mg/kg/day 

rodents (rat) M/F: 0, 30. I 00. 300, I 000, LOAEL (M/F) = 19.2/22.1 mg/kg/day 

3000 ppm based on increased spleen weight in 

M: 0, 1.94. 6.4, 19.2, 64.3, females and hepatic vacuolation in ma les. 

192. 7 mg/kg/day 

F: 0, 2.1 , 7.2, 22.1 , 71.4. 

208.0 rng/kg/day 

Acceptable/guideline 

870.3100 90-Day oral toxicity 44721519 (199 1) NOAEL (M/F) = 9.58/6.94 mg/kg/day 

rodents (mouse) MlF: 0, 30, 300, 3000 (wk LOAEL (MlF) = 50.5/60.7 mg/kg/day 

l)/2000(wk 2-13) ppm based on increase in absolute and relative 

M: 0, 9.58, 50.5, 34 1. I liver weights, hepatocellular hypenrophy 

mg/kg/day and vacuolation, and increase in relative 

F: 0, 6.94. 60.7, 438.5 spleen weight (F), elevated AST and ALT 

mg/kg/day activity. 

Acceptable/guideline 

Page 18 of27 
Table A.2.2. Subchronic, Chronic and Other Toxicity Profile fo r Metconazole Technical 1 

Guideline Study Type MRID No. (year)/ Results 

No. Classification /Doses 

870.3150 28-Day oral toxicity 44721520 (1991) NOAEL (M/F) = I 00 ppm in diet 

non-rodents (dog) M/F: 0, I 00, I 000, and LOA EL (M/F) = I 000 ppm in diet (increase 

7000-10000 ppm in diet in relative and absolute thyroid wt. in 

Unacceptable/non- one/rwo fema les) 

guideline (some Deficiencies: low n (2M/2F per dose); 

preliminary test data decrease in food consumption means low 

provided) exposure to test compound; actual dose 

rece ived per dose group not provided. 

870.3150 90-Day oral 44721521 ( 1991) NOA EL (M/F) = 2.5/2.6 mg/kg/day 

toxicity non-rodents M/F: 0, 60, 600, 6000 ppm LOA EL (M/F) = 24.4/24.3 mg/kg/day 

(dog) in diet based on decreased food consumption in 

M: 0, 2.5, 24.4, 225.2 females and elevated platelets and 

mg/kg/day reticulocytes in males. 

F: 0, 2.6, 24.3, 206.6 

mg/kg/day 

Acceptable/guideline 

870.3200 21-day Dermal 46808439 (2006) NOA EL: I 000 mg/kg 

Toxicity 0,250,500, 1000 

mg/kg/day LOA EL: > I 000 mg/kg Acceptable/guideline 

No evidence of dermal toxicity. 

870.6200 Subchronic ( 13- 46808440 (2002) Systemic NOAEL (M/F) = 4.84/5.10 

week) Oral 0, 50, 170, 500 ppm mg/kg/ 

Neurotoxicity- rat M: 0, 4.84, 15.69, 47.08 Systemic LOAEL (M/F) = 15.69/ 17.62 

mg/kg/day mg/kg/ based on decreases in body weight F:0,5.10, 17.62,49.82 and food consumption. 

mg/kg/day 

Acceptable/Non-guideline 

Ncurotoxicity NOA EL (M/F) ~ 

47.08/49.82 mg/kg/day 

870.3700 Prenatal 4472 1522 (1991) Maternal NOAEL = 75 mg/kg/day 

development in 0, 12, 30, 75 mg/kg/day LOA EL > 75 mg/kg/day, not established. 

rodents (rat) Gavage Decreased body weight gain was observed 

Acceptable/Guideline at 30 mg/kg/day and higher, upon which the 

maternal LOAEL was based in previous 

risk assessments. However, body weight 

gain changes without changes in absolute 

body weight are not currently considered an 

adverse effect, so there is currently no 

maternal LOAEL. 

Developmental NOAEL = 12 mg/kg/day 

LOA EL = 30 mg/kg/day based on 

increased incidence of skeletal variations 

(predominantly lumbar ribs). At 75 

mg/kg/day increased incidence of postimplantation loss, hyclrocephaly and 

visceral anomalies (cranial hemorrhage, 

dilated renal pelvis, dilated ureters, and 

displaced testis) were reported. 

Page 19of27 
Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Metconazole Technical

1 

Guideline Study Type MRID No. (year)/ Results 

No. Classification /Doses 

870.3700 Prenatal 46808443 (2002) Maternal NOAEL- 16 mg/kg/day 

development in 0, I, 4, 16, 64 mg/kg/day LOAEL= 64 mg/kg/day based on decreased 

rodents (rat) Gavage body weight and food consumption. Acceptable/Guideline increased placental weight and increased 

incidence of swollen placenta. 

Developmental NOAEL= 16 mg/kg/day 

LOAEL= 64 mg/kg/day based on based on 

an increase in early and late resorptions, 

decreased fetal body weight and increased 

incidence of incomplete ossification of 

stemebrae. 

870.3700 Prenatal 44721602 ( 1997) Maternal NOA EL= 20 mg/kg/day 

developmental in 0, 5, I 0, 20, 40 mg/kg/day LOAEL = 40 mg/kg/day based on 

non-rodents (rabbit) gavage reduction in food consumption, and 

Acceptable/Guideline changes in various hematology parameters 

Definitive Study (reductions in hematocrit, hemoglobin, 

mean corpuscular volume and increases in 

platelet counts and alkaline phosphatase 

activity). 

Developmental NOAEL = 20 mg/kg/day 

LOA EL = 40 mg/kg/day based on increases 

in post-implantation losses. 

870.3700 Prenatal 44721603 (1991) Materna l NOAEL = 25 mg/kg/day 

developmental in 0, 4, I 0, 25, 62.5 LOA EL = 62.5 mg/kg/day based on body 

non-rodents (rabbit) mg/kg/day (Exp. ff I) weight changes and slight clinical signs 

0, 2, 4, I 0 mg/kg/day (Exp. (anorexia/reduced or altered fecal output, 

#2) cold cars). 

Acceptable/Guideline 

Developmental NOAEL = 4 mg/kg/day 

LOA EL = I 0 mg/kg/day based on 

examining data from the two experiments. 

Effects at 62.5 mg/kg/day show total litter 

loss, decreased live fetuses. increased early 

and late resorptions. Effects at 25 

mg/kg/day show some malformations: 

hydrocephaly (4 fetuses from 4 different 

litters, but NOT seen at 62.5 mg/kg/day) 

and limb effects (2 fetuses from 2 different 

litters, with one fetus with same effect at 

62.5 mg/kg/d). Hydrocephaly and limb 

effects were observed at I 0 mg/kg/day in 

Experiment #2. but not at that same dose in 

Experiment ff I . 

Page 20of27 
Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Metconazole Technical

1 

Guideline Study Type MRID No. (year)/ Results 

No. Classification /Doses 

870.3800 Reproduction and 46808447 (2002) Parental/Systemic NOA EL (M/F) = fertility effects 0, 30, 150 and 750 ppm 9.8/ 10.8 mg/kg/day 

2-generation- rat M/F: 010, 2/2. I 0.8/10.6, LOAEL (M/F) = 49.4/53.2 mg/kg/day 

53.2/53.0 mg/kg/day based on: decreased body weight and 

Acceptable/Guideline decreased weight gain in male and female 

parental animals, increased incidence of 

fatty hepatocyte change in male parental 

animals, and increased incidence of spleen 

congestion in FI parental females. 

Reproductive NOAEL (M/F) = ~49.4/ 

I 0.8 mg/kg/day 

LOAEL (M/F) = 53.2 mg/kg/day based on 

increased gestation length and decreased 

gestation index driven by dystocia (d ifficult 

labor). 

Offspring NOAEL (M/F) = 9.8/10.8 

mg/kg/day 

LOAEL (M/F) = 49.4/53.2 mg/kg/day 

based decreased viability on lactation day 0 

and decreased body weight in F2 offspring. 

870.4 IOOa Chronic toxicity 4472109 (1992) NOA EL = (M/F) = 4.3/16.0 mg/kg/day 

rodents (rat) 0, I 0, I 00, JOO, I 000 ppm LOAEL = (M/F) = 13.1/ 53.8 mg/kg/day 

M:0,0.44, 4.3, 13.1,43.9 based on an increase in mean adjusted liver 

mg/kg/day weights at 12 months (M) and 24 months 

F: 0, 0.52, 5.3, 16.0, 53.8 (F), increase in spleen weights at 24 months 

mg/kg/day (F), and increased hepatocellular lipid 

Acceptable/Guideline vacuolation (M/F) and centrilobular 

hypertrophy (M/F). 

870.41 OOb Chron ic toxicity- 4472 161 0 NOAEL (M/F) = 12.0/10.3 mg/kg/day 

dog 0, 30, 300, I 000, 3000 ppm LOAEL (M/F) = 38.5/36.8 mg/kg/day 

in diet based on increased alkaline phosphatase 

M: 0, I.I , 12.0, 38.5, 110.0 activity (both sexes) and increased 

mg/kg/day incidence of Kupffer cell pigmentation 

F: 0, I.I , 10.3, 36.8, 113.7 (females). 

mg/kg/day 

Acceptable/Guideline 

870.4200a Carcinogenicity - 44721611 (1992) NOAEL (M/F) = 4.6/ 16.6 mg/kg/day 

rat 0, I 00, 300, I 000 ppm LOA EL (M/F) = 13.8/56.2 mg/kg/day 

M: 0, 4.6, 13.8, 46.5 based on non-neoplastic findings of 

mg/kg/day increased incidence of hepatocellular lipid F: 0, 5.5, 16.6, 56.2 vacuolation (M/F), centrilobular 

mg/kg/day hypertrophy (M/F), liver pigment Acceptable/Guideline deposition (M), histiocytic foci in the 

spleen (M/F),and increase in severity of 

chronic renal nephropathy (M). Evidence of 

mononuclear cell leukemia (17). 

Page 21 of27 
Table A.2.2. Subchronic, Chronic and Other Toxicity Profile fo r Metconazole Technical

1 

Guideline Study Type MRID No. (year)/ Results 

No. Classification /Doses 

870.4200b Carcinogenicity- 44721612 ( 1992) NOAEL (M/F) = 39.5/ 5.9 mg/kg/day 

mouse 0, 30, 300, 1000 ppm LOAEL (M/F) = 166.9/58.1 mg/kg/day M: 0, 4.5, 39.5, 166.9 based on non-neoplastic findings of an 

mg/kg/day increase in corticomedullary pigmentation, F: 0, 5.9, 58. 1, 195.5 sinusoidal hypercellularity/single cell 

mg/kg/day necrosis. Neoplastic findings: increase in 

Acceptable/Guide! ine liver cell tumors at high dose (M/F): 

Increased incidence of hepatocellular 

adenomas in males and hcpatocellular 

carcinomas in females. 

870.5 100 Salmonella 44 72 161 3 ( 1990) Test material was not cytotoxic with or 

typhi11111ri11111 and Up to limit dose of 5000 without S9 activation in fi ve S. 

Escherichia coli ~1 g/ plate (S. typhi11111ri11111) typhi11111ri11111 strains and one strain of£. 

Reverse Mutation and (£. coli) in the coli, and did not induce a genotoxic 

Assay presence and absence of response in any strain. 

metabolic activation 

(± S9) 

Acceptable/Guideline 

870.5300 In vitro Mouse 44721615 ( 1991 ) There was no evidence of biologically 

Lymphoma Six doses up to 125 μg/ml significant induction of mutant colonies. 

Mutagenesis Assay (toxicity was observed 

WLl36184• above that dose) in the 

presence and absence of 

•cis only isomer metabolic activation (± S9) 

Acceptable/Guideline 

870.5375 In vitro Cytogenetics 447216 16 ( 1991 ) Weakly positi ve (induced chromosome 

Test From 6.25 to 400 ~1g/ml, aberrations in Chinese hamster ovary cells) 

with and without metabolic in the presence ofS9 activation, negative 

activation (± S9) without S9 activation. 

Acceptable/Guideline 

870.5395 In vivo Mammalian 447216 18 ( 1995) There was no statistically significant 

Erythrocyte Up to the limit dose of increase in the frequency of micronucleated 

Micronucleus Test: 2000 mg/kg polychromatic erythrocytes in mouse bone 

Mouse Acceptable/Guideline marrow at any dose or collection time. 

870.5550 In vivo/in vitro 44721620 (1995) Negative for unscheduled DNA synthesis. 

Mammalian UDS Up to the limit dose of 

test 2000 mg/kg 

Rat Acceptable/Guideline 

870.6200b Subchronic 46808440 (2002) Systemic NOAEL (M/F) = 4.84/5. 10 

Neurotoxicity- rat 0, 50, 170. 500 ppm mg/kg/ 

M: 0, 4.84, 15.69, 47.08 Systemic LOAEL (M/F) = 15.691 17.62 

mg/kg/day mg/kg/ based on decreases in body weight 

F: 0, 5. 10, 17.62, 49.82 and food consumption. 

mg/kg/day 

Acceptable/Non-guideline 

Neurotoxicity NOAEL (M/F) ;o: 

47.08/49.82 mg/kg/day 

(Acute neurotoxicity study has been 

waived) 

Page 22 of27 
Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Mctconazole Technica l' 

Guideline Study Type MRTD No. (year)/ Results 

No. Classification /Doses 

870.7485 Metabolism and 4472 1622 ( 1992) Approximately 94% of radioactivity in 

pharmacokinetics: single high dose: 164 excreta afler five days: feces (males -

rat mg/kg 81.3%, females - 65.5%) and urine (males -

Radiolabel: 13.6%, females - 28.4%) 

(cyclopentyl14C) 

Acceptable/Guideline 

870.7485 Metabolism and 4472 1623 (1991) Approximately 94% of radioactivity in 

pharmacokinetics: single low dose: 2 mg/kg excreta after 72 hrs: feces (males - 80%, 

rat Radiolabel: females - 67%) and urine (males - 14.8%, 

(cyclopentyl-'~C) females - 26%). Metabolite information 

Acceptable/Guideline presented. 

870.7485 Metabolism and 44721624 ( 1991) Approximately 96% of radioactivity in 

pharmacokinetics: single high dose: 200 excreta after seven days: feces (76%) and 

rat mg/kg (males only) urine (20%). Metabo lite information 

WL136184• Radiolabel: presented. 

•cis only isomer (Triazole - HC) 

Acceptable/Guideline 

870.7485 Metabolism and 44721625 ( 1991 ) Excretion/retention in bile-duct cannulated 

pharmacokinetics: single low dose: 2 mg/kg rats. Approximately 80% of radioactivity 

rat Radiolabel: was excreted in the bile after 48 hrs: males 

WL136184* (Cyc lopentyl - 14C) (78.7%) and females (83.3%). 

*cis only isomer Acceptable/Guideline 

870.7485 Metabolism and 46808449 (2002) Low potential for bioaccumulation 

pharmacokinetics: male/fema le rat following single or multiple dosing 

rat single low dose: 2 mg/kg regimen. The time to maximum plasma 

single high dose: 200 concentration for male and female rats 

mg/kg treated with either 2 mg/kg or 200 mg/kg 

repeated dose: 2 mg/kg was the earliest sampling interval, 0.25 

Acceptable/Non-guideline hours and 4 hours, respectively The plasma 

half-life of low- and high-close rats was 

slightly shorter in males than females, - 20-

25 hours and - 34 hours, respectively. 

870.7600 In Vivo Dermal 46808450 ( 1990) Dermal absorption= 16% (72 hrs) 

Penetration Study Acceptab lc/N on-guide I inc 

870.7800 lmmunotoxicity 48107301 (2010) Systemic 

Study: male rat NOAEL: 52 mg/kg/day. 

0, 70, 2 10. 6300 ppm LOAEL: > 52 mg/kg/day 

0, 5.4, 17, 52 mg/kg/day 

lmmunotoxicity 

Acceptable/Guideline NOAEL: 52 mg/kg/day. 

LOAEL: > 52 mg/kg/day 

Page 23of27 
Table A.2.2. Subchronic, Chronic and Other Toxicity Profile fo r Metconazole Technical

1 

Guideline Study Type MRID No. (year)/ Results 

No. Classification /Doses 

Non- Effects on rat/mice 44 72 1626 ( 199 1) Increased liver weight, cytochrome P450, 

guideline liver enzymes 0, 300 ppm in diet (mice) ethoxycoumarin 0 -deethylase. 

WLl 36 184* and 0, I 000 ppm in diet ethylmorph ine N-demethylase, and lauric 

(rats) for seven or 28 days acid 11 -hydroxylase in both rats and mice. 

*cis only isomer Acceptable/Non-guideline No effect on ethoxyrcsoru fi n 0 -dcethylase. 

palmitoyl-CoA oxidation, or peroxisome 

proliferation (in terms ofperoxisome 

number or morphology). 

Non- 14-day Mechanistic 46665403 (2004) Increased liver weight (300 and I 000 ppm); 

guideline Study 0, 30, 300, I 000 ppm in increased hepatic drug metabolizing 

diet (mice) for 14 days. enzymes (300 and I 000 ppm) after 7 days; 

F: 4.5, 48, 151 mg/kg/day enlarged livers (I 000 ppm) at days 3. 7 and 

Acce ptable/No11-gz1ideline 14; hepatic hypertrophy and vacuolation 

(300 and 1000 ppm) at day 14; increased 

ALT and AST activities at I 000 ppm (day 

14); increased lipid peroxide (300 and 

1000) at day 14; increased PCNA labeling 

at 1000 ppm at day 3 and 7. 

1 cis/trans ratio is 85: 15. All stud ies used cis/rrans mixture unless otherwise noted. 

Page 24 of27 
Attachment 5 

Toxicology Data Requirements 

The requirements ( 40 CFR 158.500) for food uses of metconazole are in the table below. Use of 

the new guideline numbers does not imply that the new ( 1998) guideline protocols were used. 

Test Technical 

Required Satisfi ed 

870. 11 00 Acute Ora l Toxicity ...................................................... yes yes 

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

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

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

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

870.2600 Dermal Sensitization ..................................................... yes yes 

870.3100 Oral Subchronic (rodent) .............................................. yes yes 

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

870.3200 21 -Day Dermal. ............................................................. yes yes 

870.3250 90-Day Dermal .............................................................. no -- 870.3465 90-Day Inhalation ......................................................... yes no* 

870.3700a Developmental Toxicity (rodent) .................................. yes yes 

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

870.3800 Re product ion ................................................................. yes yes 

870.4 1 OOa Chronic Toxicity (rodent) .............................................. yes yes 

870.4 1 OOb Chronic Toxicity (nonrodent) ................................... .... yes yes 

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

870.4200b Oncogenicity (mouse) ................................................... yes yes 

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

870.5100 Mutagenicity- Gene Mutation - bacterial .................... yes yes 

870.5300 Mutagenicity- Gene Mutation - mammalian ............... yes yes 

870.Sxxx Mutagenicity-Structural Chromosomal Aberrations .. yes yes 

870.5xxx Mutagenicity- Other Genotoxic Effects ...................... yes yes 

870.61 OOa Acute De layed Neurotox. (hen) ..................................... 11 0 no 

870.6100b 90-Day Neurotoxicity (hen) .......................................... no no 

870.6200a Acute Neurotox. Screening Banery (rat) ....................... yes waived** 

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

870.6300 Develop. Neuro ............................................................. no no 

870.7485 General Metabolism ...................................................... yes yes 

870.7600 Dermal Penetration ....................................................... no yes 

870.7800 lmmunotoxicity ............................................................. yes yes 

Special Studies for Ocular Effects 

Acute Oral (rat) .......................................................... no no 

Subchronic Oral (rat) .................................................. no no 

Six-month Oral (dog) ................................................. no no 

* TXR0057053, J. Lesh in, I 0109120 14 waiver not granted 

** TXR0056405, K. Rury, 08/09/2012 waiver granted 

Page 25of27 
Attachment 6 

Tolcrancc/MRL Table 

Metconazolc (125619; Date of Request 8/3/15) 

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition: 

us Canada Mexico' Codex 

40 CFR § I 80.6 I 7(a) General. 5-[( 4-chlorophenyl)methyl]-2.2- None 

Metconazole [5-[(4-chlorophenyl)methyl)- dimethyl- I -(I H-1 ,2,4-triazol- I2,2-dimethyl-I -( 1 H-1 ,2,4-triazol-I- ylmethyl) cyclopentanol 

ylmethyl)cyclopentanol] as the sum of its 

cis- and trans-isomers 

Commodity Tolerance (ppm) !Maximum Residue limit (111$!/kf.{) 

us Canada Mexico' Codex 

Almond, hulls 4.0 

Banana2 0.1 0. 1 

Barley, grain 2.5 2.5 

Barley, hay 7.0 

Barley, straw 7.0 

Beet, sugar, dried pulp 0.70 

Beet. sugar. molasses 0.08 

Beet, sugar, roots 0.07 0.15 

Bushberry subgroup 13-07B 0.40 0.4 

Catt le, meat byproducts 0.04 0.04 

Corn, field, forage 3.0 

Corn, field, grain 0.02 0.04 

Corn, fie ld, stover 30 

Corn, pop, grain 0.02 0.04 

Corn. pop, stover 30 

Corn, sweet, forage 3.0 

Corn, sweet, kernel plus cob 0.01 0.04 

with husks removed 

Corn, sweet, stover 30.0 

Cotton, gin byproducts 8.0 

Cotton, undelinted seed 0.25 

fa.£!. 0.04 0.04 

Fruit, stone, group 12-1 2 0.2 0.2 

Goat, meat byproducts 0.04 0.04 

Grain, aspirated grain fractions 7.0 

Horse, meat byproducts 0.04 0.04 

Nut, tree, group 14-1 2 0.04 0.04 

Oat, grain 1.0 I 

Oat, hay 17 

Oat, straw 6.0 

Pea and bean, dried shelled, 0.15 0. 15 

except soybean, subgroup 6C 

Peanut 0.04 0.04 

Peanut, refined oil 0.05 0.05 

Rapeseed subgroup 20A 0.08 0.08 

Rye, grain 0.25 0.25 

Rye, straw 14 

Page 26 of27 
Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definitio11: 

us Canada 

Sheep, meat byproducts 0.04 0.04 

Soybean, forage 3.0 

Soybean, hay 6.0 

Soybean, hulls 0.08 

Soybean, seed 0.05 0.05 

Sugarcane, cane 0.06 

Sunflower subgroup 208 0.7 

Vegetable, tuberous and corm, 0.04 0.04 

subgroup IC 

Wheat, grain 0.1 5 0.15 

Wheat, hay 16 

Wheat, milled byproducts 0.20 

Wheat straw 18 

MRls with NO US Equivalent 

Fat of cattle 0.04 

Fat of l).oats 0.04 

Fat of hogs 0.04 

Fat of horses 0.04 

Fat of poultry 0.04 

Fat of sheep 0.04 

Meat of can le 0.04 

Meat of goats 0.04 

Meat of hogs 0.04 

Meat of horses 0.04 

Meat of poultry 0.04 

Meat of sheep 0.04 

Milk 0.04 

Completed: M. Negussie; 8/ 12/ 15 1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes. 2 No U.S. registration as of August 30, 2006. 

Page 27of27 

Mexico• Codex