UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

 

 OFFICE OF 

 PREVENTION, PESTICIDES 

 AND TOXIC SUBSTANCES 

June 14, 2007 

MEMORANDUM

SUBJECT: Metiram: Human Health Risk Assessment for PP#9E6006. Petition for 

the Establishment of Import Tolerances on Grapes and Bananas. 

 PC Code : 014601, DP Barcode: D267866. 

 Regulatory Action: Registration Action

 Risk Assessment Type: Single Chemical Aggregate 

 

FROM: Toiya Goodlow, Risk Assessor 

 Reregistration Branch 1 

 Health Effects Division (7509P) 

THROUGH: Michael S. Metzger, Branch Chief 

 Linda Taylor, Ph. D., Senior Scientist 

 Deborah Smegal, MPH, Senior Scientist 

 Reregistration Branch 1 

 Health Effects Division (7509P) 

TO: Cynthia Giles-Parker, Branch Chief 

 Fungicide-Herbicide Branch 

 Registration Division (7505P) 

BASF Corporation has proposed to establish import tolerances for residues of the 

fungicide metiram in/on banana, banana pulp and grape. The Registration Division of 

Office of Pesticide Programs (OPP) has requested that the Health Effects Division (HED) 

evaluate hazard and exposure data and conduct dietary and aggregate exposure 

assessments, as needed, to estimate the risk to human health that will result from all 

registered and proposed uses of metiram. A summary of these findings is provided in this 

document. This risk assessment is an update of the most recent metiram risk assessment 

conducted in support of the metiram reregistration eligibility decision document (RED) 

(D291661, 6/13/05, K. Farwell) and supersedes all previous assessments. The residue 

chemistry review and dietary exposure assessment were provided by Christine Olinger of 

RRB1; support for the hazard characterization was provided by Linda Taylor of RRB1; 

and the drinking water assessment was provided by Ron Parker and Mohammed Ruhman 

of the Environmental Fate and Effects Division (EFED). 

Page 1 of 45 
Table of Contents

1.0 Executive Summary.............................................................................................. 4 

2.0 Ingredient Profile................................................................................................ 11 

2.1 Summary of Registered/Proposed Uses................................................ 12 

2.2 Structure and Nomenclature ................................................................. 14 

2.3 Physical and Chemical Properties......................................................... 15 

3.0 Hazard Characterization/Assessment............................................................... 15 

3.1 Hazard and Dose-Response Characterization...................................... 15 

3.1.1 Database Summary..................................................................... 15 

3.1.2 Toxicological Effects................................................................... 15 

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)................ 22 

3.3 FQPA Considerations............................................................................. 22 

3.3.1 Recommendation for a Developmental Neurotoxicity Study.. 22 

3.3.2 Safety Factor for Infants and Children .................................... 23 

3.4 Hazard Identification and Toxicity Endpoint Selection...................... 23 

3.4.1 Acute Reference Dose (aRfD) - Females age 13-49.................. 23 

3.4.2 Acute Reference Dose (aRfD) - General Population................ 23 

3.4.3 Chronic Reference Dose (cRfD)................................................. 24 

3.4.4 Recommendation for Aggregate Exposure Risk Assessments 25 

3.4.5 Classification of Carcinogenic Potential ................................... 25 

3.4.6 Summary of Toxicological Doses and Endpoints for Metiram 

for Use in Human Risk Assessments..................................................... 26 

3.5 Hazard Characterization of ETU.......................................................... 26 

3.6 Endocrine Disruption ............................................................................. 28 

4.0 Public Health and Pesticide Epidemiology Data.............................................. 28 

5.0 Dietary Exposure/Risk Characterization ......................................................... 28 

5.1 Pesticide Metabolism and Environmental Degradation...................... 28 

5.1.1 Metabolism in Plants and Animals............................................ 28 

5.1.2 Metabolism in Rotational Crops................................................ 29 

5.1.3 Analytical Methodology.............................................................. 29 

5.1.4 Environmental Degradation ...................................................... 29 

5.1.4.1 Surface Water............................................................... 30 

5.1.4.2 Ground Water .............................................................. 31 

5.1.5 Food Residue Profile................................................................... 32 

5.1.6 International Residue Limits..................................................... 37 

5.2 Dietary Exposure and Risk .................................................................... 37 

5.2.1 Acute Dietary Exposure/Risk..................................................... 37 

5.2.2 Chronic Dietary Exposure/Risk................................................. 38 

5.2.3 Cancer Dietary Risk ................................................................... 39 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ................ 39 

7.0 Aggregate Risk Assessments and Risk Characterization................................ 40 

7.1 Acute Aggregate Risk ............................................................................. 40 

7.2 Chronic Aggregate Risk ......................................................................... 40 

7.3 Cancer Aggregate Risk........................................................................... 40 

7.4 ETU Aggregate Exposure from All Sources (Metiram, Mancozeb and 

Maneb) ................................................................................................................. 41 

Page 2 of 45 
8.0 Cumulative Risk Characterization/Assessment............................................... 42 

9.0 Occupational Exposure/Risk Pathway.............................................................. 42 

10.0 Data Needs and Label Recommendations ........................................................ 42 

References........................................................................................................................ 44 

Page 3 of 45 
1.0 Executive Summary

The Health Effects Division of EPA's Office of Pesticide Programs has evaluated the 

toxicity and exposure databases for the pesticide active ingredient metiram, and has 

conducted a human health risk assessment to support the proposed establishment of 

import tolerances on bananas and grapes. Metiram is a member of the ethylene 

bisdithiocarbamate (EBDC) group of fungicides, which includes the related active 

ingredients mancozeb and maneb. Metiram [a mixture of 5.2 parts by weight of 

ammoniates of {(ethylenebis(dithiocarbamato)} zinc with 1 part by weight ethylenebis 

{dithiocarbamic acid} bimolecular and tri molecular cyclic anhydrosulfides and 

disulfides] is the common name of the fungicide. The RED for metiram was completed 

on August 29, 2005. 

Use Profile 

Metiram is a broad spectrum contact fungicide used for the prevention of downy 

mildews, anthracnose, rusts, leaf spots and seedling damping off. Metiram end-use 

products with registered food/feed uses are available as dry flowable (DF) formulations. 

Approximately 600,000 pounds of metiram are used in agricultural settings on an annual 

basis, with a greater portion of the market allocated to apples (70%) than to potatoes 

(30%). Agricultural uses are concentrated in, but not limited to, the following states: ID, 

MI, MN, NY, NC, SC, PA and WA. 

In support of the proposed import tolerances, the petitioner has submitted specimen labels 

for bananas and grapes. For bananas, a specimen label was submitted for Polyram® 80 

WG (wettable granular formulation) for use on banana crops grown in Central and South 

America. For grapes, labels for Polyram® DF and Polyram® WG were submitted for 

use on grape orchards in Italy, France and Germany. The registrant has also submitted a 

proposed label that will harmonize grape use patterns in Europe. 

There are no residential labels and no agricultural uses that could result in exposure to 

metiram in residential settings. However, residential exposure is considered for the 

common EBDC metabolite ethylenethiourea (ETU) aggregate assessment, since 

mancozeb and maneb are both used in residential settings and therefore result in 

exposures of ETU. Separate risk assessment documents were conducted for mancozeb 

and ETU. No new uses for maneb have been proposed; therefore, an updated risk 

assessment for maneb is not necessary at this time. The ETU aggregate risk assessment 

document discusses potential exposure to ETU from all sources (metiram, mancozeb and 

maneb), and characterizes such exposures in a broader sense. The aggregate assessment 

also contains more detailed discussions of the ETU hazard characterization, FQPA (Food 

Quality Protection Act) considerations, endpoint selection and dose-response assessment. 

Relevant information excerpted from the ETU risk assessment is presented in Section 3.5 

of this assessment, in order to appropriately address potential exposure to ETU resulting 

from metiram uses. 

Page 4 of 45 
Hazard Assessment 

The hazard database for metiram is incomplete; the missing studies include acute 

neurotoxicity and reproduction studies in rats, a developmental study in rabbits, and a 

developmental neurotoxicity study in rats. However, the available toxicity data have 

been used to select endpoints for risk assessment from dietary and non-dietary routes of 

exposure and for a variety of durations of exposure. Refinements to the current risk 

estimates may be possible with the submission of missing toxicity data. 

Metiram is not acutely toxic via the oral, dermal, or inhalation routes of exposure, nor is 

it a skin or eye irritant. It is, however, a strong-to-severe skin sensitizer. The thyroid is a 

target organ for metiram. Thyroid effects observed in subchronic studies in rats include 

increased thyroid weights, increased thyroid stimulating hormone (TSH) and decreased 

T4 (serum thyroxin) values. There were changes observed in T3 (triiodothyronine) 

values, but they were inconsistent and showed no dose-response. Levels of TSH, T4 and 

T3 are analyzed when there are potential impacts on thyroid function and hormone 

homeostasis, but they are not routinely measured in all guideline studies. Thyroid effects 

were not measured in the rat developmental (acceptable), rabbit developmental 

(unacceptable) or the rat reproduction (unacceptable) studies. In metiram chronic studies 

in rats, thyroid effects were measured, but they were inconsistent. 

Metiram degrades and/or is metabolized to ETU. In oral rat metabolism studies with 

radiolabelled metiram and other EBDCs, an average 7.5% in vivo metabolic conversion 

of EBDC to ETU occurred, on a weight-to-weight basis. Metabolism data indicate 

metiram does not bio-accumulate. 

The nervous system is a target for metiram. Neurotoxic signs and neuropathology have 

been observed in subchronic studies in rats following oral dosing with metiram. Signs of 

neurotoxicity occurred after 2 weeks of dosing, including reduced forelimb grip strength, 

hindlimb paralysis, muscle wasting and ataxia. Neuropathology findings in theses studies 

indicated decreased areas of myelinated axons in the sciatic, sural and tibial nerves. 

Metiram has been tested in a series of in vitro and in vivo genotoxicity assays. Metiram 

did not cause bacterial gene mutation, but there was evidence of mammalian gene 

mutation in two studies. The genotoxic effect was not considered to be related to the 

metabolism of metiram to ETU. 

There are no adequate carcinogenicity studies for metiram in either the rat or the mouse. 

In the absence of adequate data for metiram, the potential for carcinogenicity has been 

based on ETU, which is classified as a probable human carcinogen, with a Q1* of 0.0601 

(mg/kg/day)-1 for risk assessment. Because metiram is known to be converted to ETU, it 

has also been classified as a probable human carcinogen. 

Developmental toxicity was observed in the rat (increased incidence of post-implantation 

loss; hydrocephaly and related lesions, skeletal system defects and other gross defects) at 

a dose level where minimal maternal toxicity (decreased body-weight gains) was 

Page 5 of 45 
observed. However, there is low concern for the qualitative susceptibility observed in the 

rat study since the dose-response was well characterized; there was a clear NOAEL (no 

observed adverse effect level)/LOAEL (lowest observed adverse effect level) for 

maternal and developmental toxicity; and the doses selected for risk assessment were 

based on neurotoxicity and address concerns for developmental toxicity and thyroid 

toxicity, which occurred at higher doses. Additionally, in a rabbit developmental study, 

in which the maternal animals were adequately assessed, maternal toxicity observed 

included abortions and decreased body-weight gains. 

The submitted data do not support the reduction or removal of the 10X FQPA safety 

factor (SF) due to the absence of required toxicological studies. HED has retained the 

10X FQPA SF for metiram dietary and aggregate risk assessments. 

The rabbit developmental toxicity study was used to establish an acute reference dose for 

females 13-49 years old, based on abortions observed at the maternal LOAEL of 40 

mg/kg/day. Application of the combined uncertainty factors (UFs) for interspecies 

extrapolation and intraspecies variability, as well as the FQPA 10X database uncertainty 

factor (UFDB) to the maternal NOAEL of 10 mg/kg/day results in an acute reference dose 

of 0.01 mg/kg/day. The acute population adjusted dose (aPAD) is equal to the acute RfD, 

0.01 mg/kg/day. 

The chronic reference dose (cRfD) for the general population was selected from a 

subchronic oral toxicity study in rats. The endpoint selected was reduced forelimb grip 

strength in females, observed at the LOAEL of 6.7 mg/kg/day. After application of the 

combined UFs and the FQPA 10X UFDB to the study NOAEL of 0.4 mg/kg/day, the 

cRfD is 0.0004 mg/kg/day. The chronic population adjusted dose (cPAD) of 0.0004 

mg/kg/day is equivalent to the chronic RfD. 

The database for ETU is limited based on guideline studies, and HED has relied on a 

combination of guideline data and studies in the open literature to assess hazard for ETU. 

The thyroid is a target organ for ETU; thyroid toxicity in subchronic and chronic rat, 

mouse and dog studies included decreased levels of T4, increases or decreases in T3, 

compensatory increases in levels of TSH, increased thyroid weight and microscopic 

thyroid changes, chiefly hyperplasia. Overt liver toxicity was observed in one chronic 

dog study. 

Developmental defects in the ETU rat developmental study included hydrocephaly and 

related lesions, skeletal system defects and other gross defects. These defects showed 

increased susceptibility to fetuses because they occurred at a dose which only caused 

decreased maternal food consumption and body-weight gain. Although the data provided 

evidence for increased susceptibility to fetuses following dosing with ETU, 

developmental effects were well characterized in numerous studies in the published 

literature. In addition, the dose-response relationship was well characterized, and doses 

selected for overall risk assessments addressed concerns for developmental and thyroid 

toxicity. However, due to the lack of several guideline studies, HED retained the 10X 

Page 6 of 45 
FQPA safety factor due to database uncertainties for dietary, residential and aggregate 

risk assessments for ETU. 

The ETU acute dietary endpoint for females 13-49 years old was selected from a nonguideline developmental toxicity study in rats. The LOAEL was 10 mg/kg/day based on 

developmental effects of the brain, and the NOAEL for the study was 5 mg/kg/day. 

Application of the combined 10X UFs and the FQPA 10X UFDB results in an acute 

reference dose of 0.005 mg/kg/day. The acute population adjusted dose is equal to the 

acute RfD. 

The ETU chronic reference dose for the general population was selected from a chronic 

toxicity study in dogs. The study NOAEL was 0.18 mg/kg/day based on thyroid toxicity. 

The combined 10X UFs and the FQPA 10X UFDB results in a chronic reference dose, 

RfD, of 0.0002 mg/kg/day. The cPAD is equivalent to the chronic RfD. 

Exposure Assessment 

The use pattern for metiram is expected to result in exposure to the general population 

through food and drinking water. There are no residential uses or agricultural uses that 

would result in residential exposure to the general population. No occupational exposure 

to metiram is expected to occur in the U.S. as a result of metiram use on imported grapes 

and bananas (i.e. proposed uses are for the application of metiram in Europe, Central 

America and South America). 

Applications of metiram result in exposures to both metiram and ETU in the diet. To 

assess the total exposure to ETU, exposure from the 7.5% metabolic conversion of 

metiram to ETU was added to ETU residues measured in/on food and water. 

Metiram and ETU Dietary (Food) Exposure and Risk 

The residue chemistry database for metiram is incomplete. Residue chemistry 

deficiencies exist for the proposed and existing uses of metiram. However, the available 

data are adequate to evaluate the dietary exposure and risk attributed to existing and 

proposed metiram uses. The nature of metiram residues is adequately understood, both 

for tolerance enforcement and risk assessment purposes. 

Dietary exposure from metiram (and ETU resulting from metiram) is limited to apples, 

potatoes, grapes and bananas. Refined acute and chronic dietary exposure and risk 

assessments were conducted for metiram and metiram-derived ETU, based on field trial 

residue data and monitoring data from the EBDC/ETU Market Basket Survey; processing 

factors derived from extensive processing and cooking and consumer practices studies; 

and estimated percent crop treated (% CT) data for both acute and chronic assessments. 

Percent crop treated information is not available for the proposed import tolerances; 

however, percent imported factors were incorporated for bananas and grapes. 

Anticipated residue estimates for ETU include the 7.5% metabolic conversion of metiram 

to ETU residues. 

Page 7 of 45 
Acute dietary exposure and risk from metiram and ETU are below HED’s level of 

concern. For females 13-49 years old, estimated dietary exposure (food only) to metiram 

per se was 0.002215 mg/kg/day, which utilized 22% of the acute population adjusted 

dose at the 99.9th percentile. For metiram-derived ETU, the acute dietary exposure was 

0.000299 mg/kg/day which utilized 6.0% of the aPAD. 

Chronic dietary exposure and risk from metiram and metiram-derived ETU are below 

HED’s level of concern for the general U.S. population and various population 

subgroups. For metiram, the most highly exposed population subgroup is children 1-2 

years old, estimated at 0.000281 mg/kg/day representing 70% of the chronic population 

adjusted dose. For metiram-derived ETU, children 1-2 years old were the most highly 

exposed population subgroup, at 0.000100 mg/kg/day representing 50% of the cPAD. 

The cancer risk estimate for metiram-derived ETU was based on the same anticipated 

residues derived for the chronic dietary exposure assessment. The estimated chronic 

dietary exposure for the general U.S. population corresponds to a cancer risk of 1 x 10-6, 

which is not of concern. 

Drinking Water Assessment 

The OPP Environmental Fate and Effects Division (EFED) prepared the drinking water 

assessment. The parent EBDC fungicides are very short-lived in soil and water, and 

would not reach water used for human consumption whether from surface water or 

ground water. However, ETU is highly water soluble, and may reach both surface and 

ground water under some conditions. The drinking water exposure assessment for 

metiram, and each of the parent EBDCs, addresses concentrations of ETU alone, as 

residues of the parent EBDC compounds are not expected in drinking water. 

Estimated drinking water concentrations (EDWCs) for surface water were derived using 

a combined modeling/monitoring approach. The monitoring data were from a targeted 

surface water monitoring study conducted by the ETU Task Force, in which none of the 

tested water samples had concentrations above the limit of detection of 0.1 ppb. A 

ground water EDWC was selected from a targeted ground water monitoring study 

conducted in Florida in a known EBDC use area. Acute surface water estimates were 

reported as a range of 0.1 ppb (monitoring) to 25.2 ppb (modeling) and chronic/cancer 

surface water estimates were 0.1 ppb (monitoring). Acute/chronic/cancer ground water 

estimates were 0.21 ppb (monitoring). 

Combined (Aggregate) Exposure from Food and Drinking Water 

There are no residential exposure concerns for metiram, so aggregate exposure and risk 

assessments consider only food and drinking water. Since residues of metiram per se are 

not expected in drinking water, aggregate risks for metiram consist of aggregate ETU 

exposures for acute and chronic (cancer and non-cancer) durations. For estimating 

Page 8 of 45 
aggregate ETU exposure, the ETU surface and ground water EDWCs provided by EFED 

were incorporated into the dietary assessment. 

For the metiram-derived ETU aggregate acute risk assessment, a surface water EDWC 

value of 25.4 ppb was used, which resulted in dietary exposure and risk below HED’s 

level of concern. For females 13-49 years old, estimated dietary exposure for food and 

water was 0.003511 mg/kg/day, which utilized 70% of the aPAD at the 99.9th percentile. 

For the metiram-derived ETU aggregate chronic (non-cancer and cancer) dietary 

assessment, a ground water EDWC value of 0.21 ppb was used. Aggregate ETU chronic 

non-cancer risks are below HED's level of concern for the general U.S. population and all 

other population subgroups. The most highly exposed population subgroup, children 1-2 

years old, had a chronic aggregate exposure of 0.000107 mg/kg/day which utilized 54% 

of the cPAD. Aggregate ETU cancer risk for the general U.S. population is not of 

concern, with an estimated risk of 1 x 10-6 including existing and proposed uses. 

ETU Aggregate Exposure from All Sources (Metiram, Mancozeb and Maneb) 

The acute, chronic and cancer aggregate assessments for ETU considered food, water and 

residential exposures resulting from current and proposed uses of metiram, mancozeb and 

maneb; only mancozeb and maneb are used in residential settings. Acute and chronic 

risks from all sources of ETU were not of concern; however, the ETU aggregate cancer 

risk exceeds HED’s level of concern (3.8 x 10-6). HED conducted sensitivity analyses 

and determined the greatest contributors to ETU exposure are bananas, leaf lettuce, 

water, turnip greens, grape juice and mangoes. If the proposed import tolerance in/on 

bananas (from metiram applications) is removed from the aggregate assessment, then the 

aggregate cancer risk does not exceed HED’s level of concern (3.2 x 10-6). Note that the 

metiram-derived ETU residue values from crop field trials used in the aggregate 

assessment are considered to be overestimates. Projected percent crop treated 

information was not available, so percent imported information was used and it is highly 

unlikely that all bananas will be treated. In general, monitoring data available for other 

commodities show much lower residues than field trial data, so the actual exposure is 

likely to be lower. For these reasons, HED is requiring the submission of monitoring 

data for metiram and ETU on bananas. 

Environmental Justice Considerations 

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.eh.doe.gov/oepa/guidance/justice/eo12898.pdf). 

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED 

estimates risks to population subgroups from pesticide exposures that are based on 

patterns of that subgroup’s food and water consumption, and activities in and around the 

Page 9 of 45 
home that involve pesticide use in a residential setting. Extensive data on food 

consumption patterns are compiled by the United States Department of Agriculture 

(USDA) under the Continuing Survey of Food Intake by Individuals (CSFII) and are used 

in pesticide risk assessments for all registered food uses of a pesticide. These data are 

analyzed and categorized by subgroups based on age, season of the year, ethnic group 

and region of the country. Additionally, OPP is able to assess dietary exposure to 

smaller, specialized subgroups and exposure assessments are performed when conditions 

or circumstances warrant. Whenever appropriate, non-dietary exposures based on home 

use of pesticide products and associated risks for adult applicators and for toddlers, 

youths and adults entering or playing on treated areas postapplication are evaluated. 

Further considerations are currently in development as OPP has committed resources and 

expertise to the development of specialized software and models that consider exposure 

to bystanders and farm workers as well as lifestyle and traditional dietary patterns among 

specific subgroups. 

Review of Human Research 

This risk assessment does not rely on any data from studies in which human subjects 

were intentionally exposed to a pesticide or other chemical. 

Data Gaps 

Residue chemistry deficiencies for the current metiram import tolerance petition include 

the following: 

• Guideline 860.1200 Directions for use (label submission) 

• Guideline 860.1380 Storage stability data 

• Guideline 860.1520 Processed food/feed 

• Guideline 860.1550 Proposed tolerances 

• Guideline 860.1560 Reasonable grounds in support of the petition (banana 

monitoring data) 

Deficiencies or data gaps previously identified in the RED exist for the following 

guideline studies: 

Toxicology

• Guideline 870.3700 Developmental toxicity, rabbit (only the maternal animal 

was adequately assessed in the available rabbit study) 

• Guideline 870.3800 2-generation reproduction, rat 

• Guideline 870.6200 Acute neurotoxicity, rat 

• Guideline 870.6300 Developmental neurotoxicity, rat 

* Comparative study for thyroid toxicity in adults and offspring is required for ETU only 

Residue Chemistry

• Guideline 860.1200 Directions for use (label revision) 

• Guideline 860.1850 Confined accumulation in rotational crops 

Page 10 of 45 
Product Chemistry

• Guideline 830.1700 Preliminary analysis 

• Guideline 830.7050 UV/visible absorption 

Occupational Exposure

The registrant should submit a DFR study on apples; the submitted study is inadequate, 

and leads to lower confidence in estimated postapplication risks. 

Regulatory Recommendations 

Although several deficiencies were identified within the residue chemistry database, 

HED does not object to establishing import tolerances for grapes at 5 ppm and raisins at 

10 ppm, provided a revised Section F and product labels are submitted. Confirmatory 

storage stability and processing data are also required. 

HED does not object to granting a temporary import tolerance for bananas at 3.0 ppm 

provided banana monitoring data for metiram and ETU are submitted, and all residue 

chemistry deficiencies are resolved. A full resolution of these deficiencies is required 

before HED can recommend the establishment of permanent import tolerances. 

2.0 Ingredient Profile

Metiram is the common name of a pesticide which is a mixture of 5.2 parts by weight of 

ammoniates of [ethylenebis(dithiocarbamato)]zinc with 1 part by weight ethylenebis 

[dithiocarbamic acid] bimolecular and trimolecular cyclic anhydrosulfides and disulfides. 

It is a broad spectrum contact fungicide registered on apples, potatoes and ornamental 

plants (greenhouse-grown ferns) for the prevention of downy mildews, anthracnose, 

rusts, leaf spots and seedling damping off. 

ETU is a metabolite, environmental degradate, and cooking byproduct of metiram and 

the other EBDC fungicides, maneb and mancozeb. 

Page 11 of 45 
2.1 Summary of Registered/Proposed Uses 

Table 2.1. Summary of Currently Registered Uses of Metiram 

Label Application Rates (lb ai/acre) Average Application Rates 

 (lb ai/acre)

Crop

Maximum 

Per 

Application

Minimum Per 

Application

Maximum 

Per Season

Per Application Per Year

Apples: Prebloom1 4.8 NA 19.2 

Apples: Extended1 2.4 NA 16.8 

2.22 8.32

Leatherleaf Ferns3 1.6 0.8 No Limit 1.34 ND5

Potatoes 1.6 1.2 11.2 1.52 4.12

1

 The prebloom schedule consists of no more than 4 applications, 7 to 10 days apart; no applications are 

permitted after bloom. The prebloom schedule may not be combined with the extended schedule. The 

extended schedule consists of no more than 7 applications 7 to 10 days apart. For both prebloom and 

extended schedules, applications can be made starting at the 0.25 -0.5 green tip stage. 

2

 NASS data (1993 to 2001) were used for apples and potatoes. 

3

 Rates for ornamentals are given in lbs ai/100 gallons and were converted to lb ai/acre by assuming that 

100 gallons of spray would be applied per acre as stated on the label. 

4

 NASS 2003 Nursery and Floriculture Summary, September 2004. 

5

 ND - No data available 

Table 2.2. Summary of Proposed Uses for Metiram on Bananas and Grapes 1

Application 

Timing; 

Equipment 

Type 2

Formulation Applic. 

Rate 3

Max. No. 

Applic/ 

Season 

Max. 

Seasonal 

Applic. Rate 

(lb ai/A) 

PHI 

(days) 

Use Directions and 

Limitations 

Bananas (For Use in Central and South America) 

Broadcast spray 

to established 

banana crops 

Polyram® 80 

WG 

2.0-2.5 

kg/ha 

Not 

specified 

(NS) 

NS 7 Spray mix is to be prepared 

by adding 0.4 L/ha of Nu 

Film (surfactant) to water 

(spray volume not 

specified) and Polyram® 

80 WG. Initial application 

may be made when disease 

symptoms first appear and 

repeated at 8-15 day 

intervals. 

Grapes (For Use in Italy)

Broadcast spray 

to established 

grape orchards 

Polyram® DF 

Fungicide 

150-400 

g/100 L 

water 

NS NS 28 When mixed with other 

formulations, the longest 

waiting period must be 

observed. The following 

varieties may be sensitive 

to Polyram® DF: Butirra 

d’Estate, Conference, 

Coscia, Gentil Bianca, S. 

Maria and Spadona. 

Grapes (For Use in France)

Page 12 of 45 
Table 2.2. Summary of Proposed Uses for Metiram on Bananas and Grapes 1

Application 

Timing; 

Equipment 

Type 2

Formulation Applic. 

Rate 3

Max. No. 

Applic/ 

Season 

Max. 

Seasonal 

Applic. Rate 

(lb ai/A) 

PHI 

(days) 

Use Directions and 

Limitations 

Broadcast spray 

to established 

grape orchards 

Polyram® DF 

Fungicide 

2.0-3.5 

kg/ha 

NS NS NS 

Grapes (For Use in Germany)

Broadcast spray 

to established 

grape orchards 

Polyram® 

WG 

0.8-3.2 

kg/ha 

8 NS 56 Do not apply more than 8 

applications in producing 

plantings, of which 

maximally 4 with decaying 

flowers until start of 

maturing (vine stages 68-

81, BBCH Code) 

1 Information included in table excerpted directly from proposed label. 

2 Type of application equipment is not specified on the labels. 

3

 It could not be determined if the application rates were in terms of product or the active ingredient. 

Table 2.3. Label Directions for the Use of Metiram on Grapes Grown in Europe1

Country Product 

Name 

Growth 

Stage & 

Season 

BBCH 

No. 

Applic. 

per 

Season2

Single Applic. 

Rate 

Implied Max. 

Seasonal Rate 

PHI 

(days) 

Germany3 Polyram® DF 15-79 6 2.24 kg ai/ha 

(2.0 lb ai/A) 

13.44 kg ai/ha 

(12.0 lb ai/A) 

56 

EU (N+S-EU)4 Polyram® DF 15-79 3 1.1 kg ai/ha 

(1.0 lb ai/A) 

3.3 kg ai/ha 

(2.9 lb ai/A) 

56 

EU (N+ S-EU)5 Polyram® DF 15-79 3 1.8 kg ai/ha 

(1.6 lb ai/A) 

5.4 kg ai/ha 

(4.8 lb ai/A) 

56 

France (N + SEU) 518 01F 60-80 3 1.1 kg ai/ha 

(1.0 lb ai/A) 

3.3 kg ai/ha 

(2.9 lb ai/A) 

35 

1

 Information included in table excerpted directly from proposed label. 

2

 Minimum retreatment interval is 12 days 

3

 Exemplarily listed for a national label direction. 

4

 Minimum use rate for metiram in grapes (supports also use of mix formulations) 

5

 Future EU harmonized GAP. 

Page 13 of 45 
2.2 Structure and Nomenclature 

Table 2.4. Test Compound Nomenclature- Metiram

Compound 

NH S

NH

Zn

S

S

S

NH S

NH

S

S

S

3 x

Empirical Formula (C16H33N11S16Zn3)x

Common name Metiram 

Company experimental name BAS 222 F 

IUPAC name zinc ammoniate ethylenebis(dithiocarbamate)-poly(ethylenethiuram disulfide) 

CAS name mixture of 5.2 parts by weight of ammoniates of 

[ethylenebis(dithiocarbamato)]zinc with 1 part by weight ethylenebis 

[dithiocarbamic acid] bimolecular and trimolecular cyclic anhydrosulfides and 

disulfides 

CAS registry number 9006-42-2 

End-use products (EPs) used 

in residue field studies 

70% WG (BAS 222 28 F; Polyram DF Fungicide) 

55% WG (BAS 518 00 F) 

Table 2.5. Test Compound Nomenclature-ETU

Compound 

Empirical Formula C3H6N2S 

Common name Ethylenethiourea (ETU) 

CAS registry number 96-45-7 

Page 14 of 45 
2.3 Physical and Chemical Properties 

Table 2.6. Physicochemical Properties of the Technical Grade of Metiram

Parameter Value Reference 

Melting point/range Decomposes at ~140 oC 

pH Not applicable because of low water 

solubility; titrations with acid/base will 

not yield reliable pH values. 

Density 0.33 (loose), 0.49 (packed) kg/L 

Water solubility Practically insoluble (2 mg/L at 20 oC) 

Solvent solubility 8 x 10-3 g/100g ethanol at 20 oC; 

insoluble in acetone, benzene and ethyl 

alcohol 

Vapor pressure <1 x 10-7 mbar at 20 °C 

Dissociation constant, pKa Not applicable; titrations with acid/base 

will not yield reliable pKa values. 

Octanol/water partition coefficient, 

Log(KOW) 

1.76-2.48 at pH 7 and 21 oC 

Product Chemistry 

Chapter of the Metiram 

Update, 8/11/1992 

UV/visible absorption spectrum Not available 

3.0 Hazard Characterization/Assessment 

3.1 Hazard and Dose-Response Characterization

3.1.1 Database Summary

The metiram toxicology database is incomplete. Toxicological data gaps include acute 

neurotoxicity and reproduction studies in rats, a developmental study in rabbits and a 

developmental neurotoxicity study in rats. However, HED has used the currently 

available data for hazard characterization and endpoint selection, for both dietary (food 

and water) and non-dietary (dermal, inhalation, incidental oral) routes of exposure, and 

for various durations of exposure. 

3.1.2 Toxicological Effects

Acute toxicity: Metiram is not acutely toxic via the oral, dermal, or inhalation routes of 

exposure, nor is it a skin or eye irritant. It is, however, a strong-to-severe skin sensitizer. 

The acute toxicity profile for metiram is shown in Table 3.1 below. 

Page 15 of 45 
Table 3.1. Acute Toxicity of Metiram

Guideline No. Study Type MRIDs # Results Toxicity 

Category

870.1100 Acute Oral – rat 40497002 

40497005 

LD50 = >5000 mg/kg IV 

870.1200 Acute Dermal – rabbit 40497007 

40497008 

LD50 = >2000 mg/kg III 

870.1300 Acute Inhalation – rat 40497010 LC50 = 5.7 mg/L IV 

870.2400 Primary Eye Irritation 40497012 not an eye irritant III 

870.2500 Primary Skin Irritation 40497004 not a skin irritant IV 

870.2600 Dermal Sensitization 40497006 strong-to-severe dermal 

sensitizer 

N/A 

870.6100 Acute Delayed 

Neurotoxicity – hen 

- - N/A 

870.6200 Acute Neurotoxicity - DATA GAP - Study Required N/A 

Subchronic toxicity: The thyroid is a target organ for metiram. In a subchronic (90-

day) oral toxicity study in Wistar rats, an increase in thyroid stimulating hormone (TSH, 

also known as thyrotropin) was observed at all dose levels at study termination, but there 

was no apparent dose response. The triiodothyronine (T3) values were comparable 

among the females, but the males displayed an increase, not dose-related, in T3 at study 

termination. Serum thyroxin (T4) values were decreased at study termination at the highdose level in both sexes. In another 90-day study in Sprague-Dawley CFY rats, both 

sexes displayed lower mean T4 values than the control at termination. Comparable T4

values were observed among the groups following the withdrawal period. No consistent 

effect was observed on mean T3 values in either sex. Following 13 weeks of exposure, 

there was a dose-related decrease in [131I] uptake, and the decrease is considered 

treatment-related at all dose levels in both sexes. 

 

Chronic toxicity: There were no consistent effects on the thyroid hormones monitored 

in the chronic toxicity study in Charles River CD Sprague-Dawley rats, and no definitive 

conclusion could be made with respect to thyroid weight. However, this may be 

attributed to the fact that the highest dose tested in the chronic study was considerably 

lower than the dose levels in the subchronic studies where thyroid effects were 

demonstrated. No effects on the thyroid were observed in the CFLP mouse 

carcinogenicity study, and there were no histopathological findings in the mouse thyroid, 

but thyroid weight, T3, T4, TSH and/or 131I data were not measured in this study. In the 

2-generation reproduction study in Crl:COBS CD(SD)BR rats and in the Crl:COBS 

CD(SD)BR rat or rabbit developmental toxicity studies, thyroid endpoints were not 

monitored. Slight, non-significant, decreases were observed in T4 values at week 13 in 

the subchronic inhalation study in Sprague-Dawley CD rats at the high-dose level in both 

sexes, and TSH values were decreased in both sexes at the high-dose level compared to 

the controls. A comparative thyroid study is required for the ETU metabolite only. 

Carcinogenicity: There are no adequate carcinogenicity studies for metiram in either the 

rat or the mouse. However, it is expected that metiram’s potential for carcinogenicity (as 

well as that of the other EBDCs, maneb and mancozeb) is due to the formation of the 

metabolite ETU, so additional carcinogenicity studies for metiram are not required. ETU 

Page 16 of 45 
is classified as a probable human carcinogen (B2), with a cancer potency factor (Q1

*

) of 

0.0601 (mg/kg/day)-1 for risk assessment. On this basis, metiram cancer risk has been 

calculated by estimating exposure to metiram-derived ETU (including the 7.5% in vivo

metabolic conversion) and using the ETU cancer potency factor to provide a quantitative 

estimate of risk. 

Developmental/Reproductive toxicity: There is increased qualitative fetal 

susceptibility in rats as demonstrated in the rat developmental toxicity study. 

Developmental toxicity was observed in the rat (increased incidence of post-implantation 

loss; hydrocephaly and related lesions, skeletal system defects and other gross defects) at 

a dose level where minimal maternal toxicity (decreased body-weight gains) was 

observed. There is no acceptable rabbit developmental toxicity study due to an 

inadequate assessment of the fetal animal; the maternal animal was adequately assessed. 

There is no acceptable rat two-generation reproduction study. Both of these studies are 

required, and have been cited as data gaps. 

Genotoxicity: Metiram has been tested in a series of in vitro and in vivo genotoxicity 

assays. Metiram is negative for (1) gene mutation in both the bacterial/Ames assay with 

and without S9 and in the CHO/HGPRT assay with metabolic activation; (2) structural 

chromosomal alterations including rat bone marrow cytogenetics and in vivo

chromosomal aberrations; and (3) other genotoxic effects (UDS/rat hepatocytes). In the 

assay for sister chromatid exchange (SCE) in Chinese hamster ovary cells (CHO), 

metiram induced weak but concentration-related increases in SCEs over controls with 

and without mouse S9 and without rat S9. Metiram was clearly positive in the gene 

mutation assay (CHO/HGPRT) without metabolic activation. There was a reproducible 

and strong response in this latter assay without S9 at doses 10-fold lower than the doses 

used for the assay with S9 where the results were negative. Therefore, it cannot be 

concluded that the positive response is the result of metabolism of metiram to ETU. No 

studies in the open literature were found to support the positive response. The negative 

Ames assay is supported by studies in the open literature confirming that metiram is not 

mutagenic in bacteria. Nevertheless, the two positive mammalian cell assays cannot be 

ignored; hence, a potential for genotoxic effects cannot be ruled out for metiram. 

Neurotoxicity: The nervous system is a target for metiram. There is evidence of 

neurotoxicity and neuropathology following oral exposure. In a range-finding rat 

developmental toxicity study in non-pregnant females, increased activity and slight 

impairment of grasping and hindlimb support reflexes were reported, along with paralysis 

and death. In a rat subchronic oral toxicity study, hindlimb paralysis [stilted and rolling 

hindlimb gait, impaired reflexes (grip, righting and flexor) and muscle wasting] was 

observed in the majority of the females at the high-dose (76 mg/kg) level after 2 weeks of 

exposure. In another subchronic oral toxicity study in rats, reduced general state and 

ataxia were observed in females at the high-dose (89 mg/kg) level. There was a doserelated decrease in forelimb grip strength in females from day 15 on, with the three 

highest dose levels displaying significant decreases at day 90. High-dose (74-89 mg/kg) 

rats of both sexes displayed significant decreases in hindlimb grip strength. In the highdose females that displayed ataxia, there was a decrease in the areas of myelinated axons 

Page 17 of 45 
in the sciatic, sural and tibial nerves compared to the control. In the chronic 

toxicity/carcinogenicity study in rats, the incidence of muscle atrophy (thigh muscle) was 

significantly increased in the high-dose (12-15 mg/kg) rats of both sexes compared to the 

control and other dose groups. The lesion was characterized by a narrowing of muscle 

fibers with reduced sarcoplasm and/or the presence of adipose cells in muscle bundles. 

Neurotoxic effects were not assessed in the dermal or inhalation toxicity studies. 

Table 3.2. Toxicity Profile of Metiram Technical

Study Type 

[Guideline No.] 

MRID No./ 

Classification 

Results 

Subchronic feeding – rat 

(Sprague-Dawley CFY) 

[870.3100] 

00126738 

Acceptable 

NOAEL (Thyroid effects) = Not determined, based 

on decreased [ 131I] uptake in males at all dose levels. 

LOAEL (Thyroid effects) = 50 ppm (males 

3/females 4 mg/kg/day), the lowest dose tested 

(LDT). 

Systemic NOAEL =100 ppm (8 mg/kg/day) 

Systemic LOAEL =300 ppm (24 mg/kg/day), based 

on muscle lesions in females. 

At the highest dose, 900 ppm (males 61, females 76 

mg/kg/day), muscle lesions were seen in both sexes, 

and females also had hindlimb paralysis. 

Subchronic feeding - Wistar 

rat 

[870.3100] 

40290601 

42539101/ 

Acceptable 

NOAEL = 5 ppm (0.4 mg/kg/day) 

LOAEL = 80 ppm (6.7 mg/kg/day), based on 

reduced forelimb grip strength in females. 

At the highest dose (males 74, females 89 

mg/kg/day) both sexes had ↑ thyroid weight and ↓ T4

values. At all doses, both sexes, ↑ TSH was seen, 

but with no dose-response. 

Subchronic feeding – mouse 

(B6C3F1) 

[870.3100] 

42595001/ 

Acceptable 

NOAEL = 300 ppm (males 84/females 133 

mg/kg/day); 

LOAEL = 1000 ppm (males 302/females 465 

mg/kg/day), based on the decrease in total serum T4

concentrations in both sexes and decreased bodyweight gain in females. 

Thyroid lesions were observed in both sexes at the 

two highest doses. 

Subchronic feeding - monkey 

[870.3150] 

00031591 

Acceptable 

NOAEL = not established; 

LOAEL = 5 mg/kg/day, based on decreased levels of 

iodine in the thyroid at weeks 1 and 8. 

At the two highest doses, the following were 

observed: ↑ thyroid weight; minimal thyroid 

follicular hyperplasia; ↓ T3 and T4 levels, ↓ total 

plasma iodine; ↑ protein-bound plasma iodine levels; 

↑ iodine in the thyroid; and ↓ body-weight gain. 

Subchronic feeding - dog 

[870.3150] 

None N/A 

21-day dermal – rabbit 404797001 Systemic NOAEL = not established; however, an 

Page 18 of 45 
Table 3.2. Toxicity Profile of Metiram Technical

Study Type 

[Guideline No.] 

MRID No./ 

Classification 

Results 

[870.3200] Acceptable assessment of effects on the thyroid, the target organ 

was not performed 

Dermal NOAEL = 50 mg/kg/day; 

Dermal LOAEL = 250 mg/kg/day, based on local 

dermal irritation. 

90-day inhalation – rat (nose 

only) 

(Sprague Dawley CD) 

[870.3465] 

00164083, 40044701 

Acceptable 

NOAEL = 2.1 mg/m3; (0.5 mg/kg/day) 

LOAEL = 20 mg/m3; (5.1 mg/kg/day) based on ↓

body-weight gain in both sexes & the occurrence of 

alveolitis in the lungs of both sexes. 

Slight, non-significant, decreases were observed in 

T4 values at the high-dose level in both sexes. TSH 

values were decreased in both sexes at the high-dose 

level compared to the controls, and T3 values were 

comparable to the control values in both sexes at the 

high-dose level. 

Subchronic neurotox. - rat 

[870.6100] 

None DATA GAP - Study Required 

Chronic toxicity – rat 

(CD/Sprague-Dawley) 

[870.4100] 

00098449, 00098450 

41163101 

Acceptable 

NOAEL* = 5 ppm (0.4 mg/kg/day); 

LOAEL* = 80 ppm (6.7 mg/kg/day), based on 

reduced forelimb grip strength in females. 

*Endpoint and dose from subchronic bridging study 

in Wistar rats. 

In SD rats at the highest dose tested in the chronic 

study (320 ppm; 12.3/15.5 mg/kg/day for 

males/females), increased thigh muscle atrophy was 

observed in both sexes. The Wistar rat endpoint is 

consistent with this finding. 

Carcinogenicity - 

CD/Sprague-Dawley rat 

[870.4100] 

00098449, 41163101 

Unacceptable 

Lack of any significant effect on survival, bodyweight, or body-weight gain, indicates the rats could 

have tolerated higher dose levels. HED concluded 

the dose levels were inadequate for assessing 

carcinogenic potential. 

Chronic toxicity - dog 

[870.4100] 

42133101, 42491401 

Acceptable 

NOAEL = 80 ppm (males 2.49, females 2.69 mg/kg) 

LOAEL = 1000 ppm (males 29.8, females 29.9 

mg/kg), based on decreased body-weight gain/food 

consumption, changes in hematology/clinical 

chemistry parameters indicative of thyroid 

toxicity/anemia, increased thyroid weight and 

follicular (thyroid) hyperplasia. 

Carcinogenicity – mouse 

(CFLP) 

[870.4200] 

00030245 

Unacceptable 

No significant, treatment-related, findings in either 

sex. Dose levels were inadequate for determining 

the carcinogenic potential of metiram, and there was 

an inadequate microscopic examination of tissues. 

There was no assessment of thyroid function, i.e., T3, 

T4, and TSH values and [131I] uptake were not 

determined. Organ-weight data were not provided. 

No microscopic lesions were reported in the thyroid, 

and no treatment-related thyroid tumors were 

observed. The CARC concluded this study is 

Unacceptable. 

Page 19 of 45 
Table 3.2. Toxicity Profile of Metiram Technical

Study Type 

[Guideline No.] 

MRID No./ 

Classification 

Results 

Developmental tox. – rat 

Sprague-Dawley (Crl:COBS 

CD SD BR) 

[870.3700] 

00030565 

Acceptable 

Maternal NOAEL = 80 mg/kg/day; 

Maternal LOAEL = 160 mg/kg/day, based on 

decreased body-weight gain. 

Developmental NOAEL = 80 mg/kg/day 

Developmental LOAEL = 160 mg/kg/day, based on 

increased pre- and post-implantation losses, 

decreased litter size, decreased litter weight

hydrocephaly and related lesions, skeletal system 

defects and other gross defects. 

Developmental tox. – rabbit 

Himalayan Chbb:HM 

[870.3700] 

40711401 

Unacceptable 

Maternal NOAEL = 10 mg/kg/day, 

Maternal LOAEL = 40 mg/kg/day, based on 

abortions. 

There was excessive maternal toxicity at the highest 

dose (8 abortions and negative body-weight gain), 

and the mid-dose does displayed a similar, but less 

severe, toxicity (2 abortions and negative bodyweight gain during the dosing period). 

Developmental NOAEL = not established 

Developmental LOAEL = not established 

(The heads of the fetuses were not examined) 

DATA GAP - Study is Required (Unacceptable 

because the heads of the fetuses were not examined. 

The maternal animal was adequately assessed in this 

study.) 

2-Generation Reproduction - 

Crl:COBS CD (SD) BR rat 

[870.3800] 

00098431 

Unacceptable 

Maternal NOAEL = 40 ppm (2.2 mg/kg/day); 

Maternal LOAEL = 320 ppm (19.8 mg/kg/day), 

based on decreased body-weight during gestation 

and lactation. 

Reproductive NOAEL = 40 ppm (males 1.8/females 

2.2 mg/kg/day); 

Reproductive LOAEL = 320 ppm (males 

14.2/females 19.9 mg/kg/day), based on decreased 

mating performance in the F2 generation. 

Offspring NOAEL = 320 ppm (males 14.2/females 

19.8 mg/kg/day), the highest dose tested. 

DATA GAP - Study is Required (Unacceptable 

because of the lack of one-to-one pairing and lack of 

histopathological examination of reproductive and 

target organs.) 

Developmental neurotox - rat 

[870.6300] 

None DATA GAP- Study is Required 

Gene mutation 

[870.5100] 

[870.5300] 

0148682 

HGPRT 

Acceptable 

00148680 

Dose range from 0.681-100 μg/mL with SD-rat S9 - 

positive without S9, marginally positive with S9. 

Negative; TA 1530 as indicator strain and CD-1 

Page 20 of 45 
Table 3.2. Toxicity Profile of Metiram Technical

Study Type 

[Guideline No.] 

MRID No./ 

Classification 

Results 

(mouse host-mediated) 

Acceptable 

mice as host (dose levels of 0, 500, 670 and 5000 

mg/kg) 

Cytogenetics/Structural 

Chromosomal Aberrations 

[870.5900] 

[870.5385] 

00148681

in vitro sister chromatid 

exchange assay 

(SCE/CHO) 

Acceptable 

00163786 

in vivo bone marrow 

cytogenetics 

Acceptable 

Positive for SCE induction both with and without 

mouse S9; dose levels up to 100 μg/mL without S9 

and up to 200 μg/mL with S9; negative up to 

cytotoxic doses with rat S9 

Negative; single 2.4 gm/kg or 5 x 0.2 gm/kg/day in 

male rats - no significant increases in chromosomal 

aberrations in bone marrow cells sampled over 

complete mitotic cycle 

Other Genotoxic Effects 

[870.5550] 

00149528 

Unscheduled DNA 

Synthesis 

Acceptable 

Negative - did not induce unscheduled DNA 

synthesis (dose range of 0.492-49.2 μg/mL) 

Metabolism – CD rat 

[870.7485] 

00155160 

Acceptable 

Metiram is rapidly metabolized and excreted via the 

feces and urine following single and repeated doses. 

For both sexes, a greater percentage of the dose was 

excreted via the feces than the urine, i.e., the major 

portion of the administered dose was unabsorbed. In 

both sexes, residues in the plasma peaked at 4 hours 

following a single low dose and at 6 hours following 

the single high-dose. 

The highest concentrations of radiolabel were found 

in the thyroids, gastrointestinal tract and kidneys of 

both sexes. 

Biliary excretion of 14C-labelled metiram accounted 

for 14.3% and 7.1% of a single 5 mg/kg bw dose in 

males and females, and 4.3% and 3.7% of a single 50 

mg/kg bw dose in males and females, respectively. 

ETU and numerous low molecular weight 

metabolites were found in the urine and bile. 

Dermal penetration CD rat 

[870.7600] 

155161 

Acceptable 

Dermal absorption of metiram is relatively low. For 

risk assessment, a dermal absorption value of 1% 

was selected, based on absorption at a dose of 0.24 

mg/kg/day. 

Domestic animal safety 

870.7200 

N/A 

Page 21 of 45 
3.2 Absorption, Distribution, Metabolism, Excretion (ADME)

Metiram degrades and/or is metabolized to ETU. In oral rat metabolism studies with 

radiolabelled metiram and other EBDCs, an average 7.5% in vivo metabolic conversion 

of EBDC to ETU occurred, on a weight-to-weight basis. This metabolic conversion has 

been taken into consideration in the human health risk assessment, including the dietary 

exposure assessment as well as previously conducted dermal and inhalation assessments. 

There is inherent uncertainty in assuming the metabolic conversion occurs following 

dermal and inhalation dosing, since dermal and inhalation exposure do not involve the GI 

tract. In addition to ETU, other identified decomposition products are ethylenethiuram, 

ethylene-bis-isothiocyanate sulfide (EBIS), carbon disulfide (CS2) and elemental sulphur 

(the latter 3 being known inhibitors of mono-oxygenases). Metabolism data indicate 

metiram does not bioaccumulate. 

3.3 FQPA Considerations 

HED has reviewed the potential for increased susceptibility of infants and children from 

exposure to metiram according to the February 2002 OPP FQPA 10X Safety Factor 

guidance document. It was concluded that the toxicity database for metiram is 

incomplete. Studies available for FQPA consideration include an acceptable 

developmental toxicity study in rats, an unacceptable two-generation reproduction study 

in rats and an unacceptable developmental toxicity study in rabbits. 

There is qualitative indication of increased sensitivity based on the results of the rat 

developmental toxicity study in which pre- and post-implantation losses were observed at 

a dose level that produced less severe maternal toxicity (decreased body-weight gain). 

HED considered the degree of concern for susceptibility within the context of all 

available toxicity data, and concluded there is low concern for the observed qualitative 

susceptibility based on the following: 

• The dose-response in the rat developmental study was well-characterized; 

• There was a clear NOAEL/LOAEL for maternal and developmental toxicity; 

• Developmental effects were seen in the presence of maternal toxicity; and 

• The doses selected for overall risk assessment are protective for effects seen in the 

prenatal developmental toxicity study. 

• The doses selected for risk assessment also address concerns for thyroid toxicity, 

although a comparative assessment of the thyroid between young and adult rats is 

required for ETU. The thyroid effects identified in the available studies occurred at 

higher dose levels than the dose levels where neurotoxicity was observed. 

3.3.1 Recommendation for a Developmental Neurotoxicity Study 

HED concluded there is a concern for developmental neurotoxicity following exposure to 

metiram. Evidence of neurotoxicity, neuropathology and thyroid toxicity has been seen 

in rats following oral exposure to metiram in both subchronic and chronic studies. The 

metiram metabolite/degradate ETU has been shown to be a developmental toxicant in 

Page 22 of 45 
rats, with effects seen in the central nervous system, urogenital and skeletal systems. In 

addition, neurotoxic effects have been observed in studies with another EBDC, maneb. 

Therefore, a developmental neurotoxicity study (DNT) is required for metiram. 

3.3.2 Safety Factor for Infants and Children 

Although there are no residual uncertainties for pre- and/or post-natal toxicity, the FQPA 

Safety Factor of 10X was retained due to database uncertainties for metiram. In addition 

to the required DNT study, HED noted data gaps for an acute neurotoxicity study, a 

developmental toxicity study in the rabbit and a 2-generation reproduction study in the 

rat. HED determined that the FQPA SF must be retained to account for the lack of these 

studies, since the available data provide no basis to support reduction or removal of the 

factor. 

3.4 Hazard Identification and Toxicity Endpoint Selection 

HED evaluated the toxicology database of metiram and selected the doses and endpoints 

for risk assessment based on a variety of exposure pathways. These doses and endpoints 

are summarized in Table 3.4. Since exposure to the metabolite and degradate ETU 

occurs in conjunction with the use of metiram, endpoints and doses for ETU are included 

in Section 3.5. 

3.4.1 Acute Reference Dose (aRfD) - Females age 13-49 

The rabbit developmental toxicity study was used to establish an acute reference dose for 

females 13-49 years old, based on abortions observed at the maternal LOAEL of 40 

mg/kg/day. Application of the standard 100X combined uncertainty factors for 

interspecies extrapolation and intraspecies variability, as well as the FQPA 10X database 

uncertainty factor to the maternal NOAEL of 10 mg/kg/day results in an acute reference 

dose of 0.01 mg/kg/day. The acute population adjusted dose is equal to the acute RfD, 

0.01 mg/kg/day. The endpoint is relevant for acute dietary risk assessment as defined in 

OPP, since it is assumed that the toxic effect, abortions, could occur following one 

exposure. The study was considered unacceptable due to a lack of examination of the 

heads of the fetuses; a developmental LOAEL/NOAEL could not be established. 

However, since this deficiency does not interfere with the determination of maternal 

toxicity, the basis for acute dietary endpoint selection, the study can be used for this risk 

assessment. 

3.4.2 Acute Reference Dose (aRfD) - General Population 

HED concluded that an aRfD/aPAD for the general population is not needed, since there 

was no appropriate endpoint attributable to a single dose in the available toxicity studies. 

Page 23 of 45 
3.4.3 Chronic Reference Dose (cRfD) 

The chronic reference dose for the general population was selected from a subchronic 

oral toxicity study in rats. The endpoint selected was reduced forelimb grip strength in 

females, observed at the LOAEL of 6.7 mg/kg/day. After application of the standard 

100X combined UFs and the FQPA 10X UFDB to the study NOAEL of 0.4 mg/kg/day, 

the cRfD is 0.0004 mg/kg/day. The cPAD of 0.0004 mg/kg/day is equivalent to the 

chronic RfD. 

A comparison of the results of two rat subchronic studies and the rat chronic study 

support the use of the endpoint and dose from the subchronic study for the purpose of 

chronic exposure and risk assessment, see Table 3.3 below. 

Table 3.3. Comparison of NOAEL/LOAEL for Non-Thyroid Effects in Oral Rat Studies for 

Metiram 

Subchronic rat 

(Wistar) 

Subchronic rat 

(Sprague-Dawley) 

Chronic rat 

(Sprague-Dawley) 

Doses (ppm) 5, 80, 320, 960 50, 100, 300, 900 5, 20, 80, 320 

Doses (mg/kg/day) males: 0.4, 5.8, 23.5, 73.9 

females: 0.4, 6.7, 27.3, 88.8 

males: 3, 6, 20, 61 

females: 4, 8, 24, 76 

males: 0.2, 0.8, 3.1, 12.3 

females: 0.2, 1.0, 3.8, 15.5 

Effects at HDT ataxia w/decrease in areas of 

myelinated axons in sciatic, 

sural tibial nerves (females); 

reduced forelimb (females) 

and hindlimb (both sexes) 

grip strength 

73.9/88.8 mg/kg/day 

hindlimb paralysis, stilted 

and rolling gait, impaired 

reflexes (grip, righting and 

flexor) in females and 

muscle wasting (both 

sexes) 

61/76 mg/kg/day 

muscle atrophy 

12.3/15.5 mg/kg/day 

NOAEL 0.4 mg/kg/day 8 mg/kg/day 3.1/3.8 mg/kg/day 

Endpoint (LOAEL) reduced forelimb grip 

strength (females) 

6.7 mg/kg/day 

muscle lesions in females 

24 mg/kg/day 

muscle atrophy (both sexes) 

12.3/15.5 mg/kg/day 

Muscle atrophy was observed at the high-dose (LOAEL 12.3/15.5 mg/kg/day) level in the 

Sprague-Dawley (SD) rat chronic study, and the NOAEL was set at 3.8 mg/kg/day. In a 

subchronic oral toxicity study in Sprague-Dawley rats, muscle lesions were observed in 

females at the LOAEL of 24 mg/kg/day; the NOAEL is 8 mg/kg/day. In a subchronic 

oral toxicity study in Wistar rats, which included a neuromuscular/functional test (not 

included in either SD), a LOAEL of 6.7 mg/kg/day was determined, based on reduced 

forelimb grip strength in Wistar females; a NOAEL of 0.4 mg/kg/day was established. 

The effects seen at the LOAELs in these three studies were neuromuscular effects. The 

different values of NOAEL and LOAEL found in these studies could be the result of 

study design and parameters used to assess neuromuscular effects. The findings in the 

Wistar rat study (reduced forelimb grip strength) are consistent with the muscle lesion 

observations in the chronic and subchronic SD rat studies. The neurofunctional test 

performed in the Wistar rat study provides a sensitive measure of the endpoint of 

concern. The three studies, considered together, show consistent neuromuscular effects, 

with the Wistar rat study providing a more sensitive measure of the endpoint of concern. 

Since the NOAEL from the subchronic Wistar rat study (0.4 mg/kg/day) would be more 

protective, it was selected for the chronic risk assessment. 

Page 24 of 45 
Although there are apparent differences between the SD and Wistar rat studies, all three 

studies show consistent neuromuscular effects at approximately similar doses, with the 

Wistar rat study providing a more sensitive measure of the endpoint of concern. This may 

be due to the fact that the Wistar rat study employed a neurofunctional test while the SD 

studies did not. As stated above, consistent neuromuscular effects were observed in the 

three studies and together they provide adequate data for chronic risk assessment. There 

are major data gaps in the metiram database, and the required studies may provide a 

lower dose/different endpoint for risk assessment. Based on the weight of evidence, a 

chronic toxicity study in Wistar rats is not required. Although some of the endpoints of 

concern (neuromuscular effects) may be observed during the clinical observations in a 

chronic toxicity study, the evaluations conducted during the neurotoxicity testing battery 

in the required neurotoxicity studies will provide a more sensitive evaluation of the 

endpoint of concern identified in the subchronic and chronic studies. 

3.4.4 Recommendation for Aggregate Exposure Risk Assessments 

Since there are no residential uses for metiram, the aggregate exposure assessment 

considered exposures from food and drinking water estimates for ETU only (residues of 

metiram per se are not expected in drinking water). 

3.4.5 Classification of Carcinogenic Potential 

The HED Cancer Peer Review Committee (CPRC) classified ETU as a group B2 

probable human carcinogen (Bill Sette, Ph.D. memo, 4/16/90 and Albin Kocialski, Ph.D. 

memo, 9/26/91). The cancer potency factor (Q1*) for ETU, using a 3⁄4 scaling factor, was 

determined to be 0.0601 (mg/kg/day)-1 based on female mouse liver tumors in the NTP 

(National Toxicology Program) study (Bernice Fisher and Hugh Pettigrew memo, 

2/24/95). Due to the lack of adequate studies on metiram for assessing the carcinogenic 

potential and the fact that ETU is a metabolite/degradate of metiram and the other 

EBDCs, the Q1* for ETU is also used for to account for ETU derived from metiram 

(HED Document No. 013554, 7/7/99). Cancer risk assessments for metiram and the 

other EBDCs are based on exposure to the ETU degradate and metabolite estimated from 

the EBDC agricultural use patterns and residue information. 

Page 25 of 45 
3.4.6 Summary of Toxicological Doses and Endpoints for Metiram for Use in 

Human Risk Assessments 

Table 3.4. Summary of Toxicological Doses and Endpoints for Metiram for Use in Human Health 

Risk Assessments 

Exposure/ 

Scenario 

Point of 

Departure 

Uncertainty/FQPA 

Safety Factors 

RfD, PAD, Level of 

Concern for Risk 

Assessment 

Study and Toxicological 

Effects 

Acute Dietary 

(General 

Population, 

including Infants 

and Children) 

There was no appropriate endpoint attributable to a single dose in the available toxicity 

studies. 

Acute Dietary 

(Females 13-49 

years of age) 

NOAEL= 10 

mg/kg/day 

UFA= 10x 

UFH=10x 

FQPA SF= 10x,UFDB

Acute RfD = 

0.01mg/kg/day 

aPAD = 

0.01mg/kg/day 

Developmental Toxicity 

(Rabbit) 

LOAEL = 40 mg/kg/day, 

based on abortions 

Chronic Dietary 

(All Populations) 

NOAEL= 0.4 

mg/kg/day 

UFA= 10x 

UFH=10x 

FQPA SF= 10x,UFDB

Chronic RfD = 

0.0004 

mg/kg/day 

cPAD = 0.0004 

mg/kg/day 

Subchronic Oral Toxicity 

(Rat, bridging study) 

LOAEL= 6.7 mg/kg/day 

based on decreased 

forelimb grip strength 

Cancer (oral, 

dermal, 

inhalation) 

Q1* = 6.01x10-2 (mg/kg/day)-1 Metiram is classified as Group B2 carcinogen 

(probable human carcinogen); use low-dose 

extrapolation for human risk assessment, based on 

ETU. Quantitative cancer risk assessments for 

metiram and other EBDCs are based on exposure 

to the ETU degradate. 

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). UFH = potential variation in sensitivity among members of the human population 

(intraspecies). UFS = use of a short-term study for long-term risk assessment (not required for metiram). 

UFDB = to account for the absence of key data (i.e., lack of a critical study). FQPA SF = FQPA Safety 

Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. 

3.5 Hazard Characterization of ETU 

The toxicology database for ETU is limited based on guideline studies, and HED has 

relied on a combination of guideline data and several studies in the open literature to 

assess hazard for ETU. The thyroid and the nervous system are the targets for ETU. 

Thyroid toxicity in subchronic and chronic rat, mouse, and dog studies included 

decreased levels of T4, increases or decreases in T3, compensatory increases in levels of 

the thyroid stimulating hormone, increased thyroid weight, and microscopic thyroid 

changes, chiefly hyperplasia. Overt liver toxicity was observed in one chronic dog study. 

Developmental defects in the rat developmental study included hydrocephaly and related 

lesions, skeletal system defects, and other gross defects. These defects showed increased 

susceptibility to fetuses because they occurred at a dose that only caused decreased 

Page 26 of 45 
maternal food consumption and body weight gain. 

Although the data provided evidence for increased susceptibility to fetuses following 

dosing with ETU, HED determined that the degree of concern for the qualitative 

susceptibility is low because the developmental effects were well characterized in 

numerous studies in the published literature, as well as in a guideline study submitted by 

the registrant. In addition, the dose-response relationship was well characterized, and 

doses selected for overall risk assessments addressed concerns for developmental and 

thyroid toxicity. 

The submitted data do not support the reduction or removal of the 10X FQPA SF due to 

the absence of required toxicological studies. HED has retained a 10X FQPA safety 

factor for dietary and aggregate risk assessments for ETU. 

The doses and endpoints used for ETU are listed Table 3.5 below. See the ETU 

Aggregate Risk Assessment document (D337241, T. Goodlow) for further details. 

Table 3.5 ETU Toxicological Doses and Endpoints for Use in Human Health Risk Assessment 

Exposure/ 

Scenario 

Point of 

Departure 

Uncertainty/FQPA 

Safety Factors 

RfD, PAD, Level of 

Concern for Risk 

Assessment 

Study and Toxicological 

Effects 

Acute Dietary 

(General 

Population, 

including Infants 

and Children) 

There was no appropriate endpoint attributable to a single dose in the available toxicity 

studies. 

Acute Dietary 

(Females 13-49 

years of age) 

NOAEL= 5 

mg/kg/day 

UFA= 10x 

UFH=10x 

FQPA SF= 10x,UFDB

Acute RfD = 0.005 

mg/kg/day 

aPAD = 0.005 

mg/kg/day 

Developmental Rat 

Toxicity 

(Khera Study, MRID No. 

45937601) 

LOAEL = 10 mg/kg/day, 

based on developmental 

defects of brain 

Chronic Dietary 

(All Populations) 

NOAEL= 0.18 

mg/kg/day 

UFA= 10x 

UFH=10x 

FQPA SF= 10x,UFDB

Chronic RfD = 

0.0002 

mg/kg/day 

cPAD = 0.0002 

mg/kg/day 

Dog Chronic Oral 

Toxicity 

LOAEL= 1.99 mg/kg/day 

based on thyroid toxicity 

Cancer (oral, 

dermal, 

inhalation) 

Q1* = 6.01x10-2 (mg/kg/day)-1 ETU is classified as a Group B2 carcinogen with 

a low-dose extrapolation approach for human risk 

assessment, based on liver tumors in female mice. 

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 

(intraspecies). UFH = potential variation in sensitivity among members of the human population 

(interspecies). UFDB = to account for the absence of key data (i.e., lack of a critical study). FQPA SF = 

FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. 

Page 27 of 45 
3.6 Endocrine Disruption 

EPA is required under the Federal Food, Drug and Cosmetic Act (FFDCA), as amended 

by FQPA, to develop a screening program to determine whether certain substances 

(including all pesticide active and other ingredients) “may have an effect in humans that 

is similar to an effect produced by a naturally occurring estrogen, or other such endocrine 

effects as the Administrator may designate.” Following recommendations of its 

Endocrine Disruptor and Testing Advisory Committee (EDSTAC), EPA determined that 

there was a scientific basis for including, as part of the program, the androgen and thyroid 

hormone systems, in addition to the estrogen hormone system. EPA also adopted 

EDSTAC’s recommendation that the Program include evaluations of potential effects in 

wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in 

wildlife may help determine whether a substance may have an effect in humans, FFDCA 

authority to require the wildlife evaluations. As the science develops and resources 

allow, screening of additional hormone systems may be added to the Endocrine Disruptor 

Screening Program (EDSP). 

When additional appropriate screening and/or testing protocols being considered under 

the Agency’s EDSP have been developed, metiram may be subjected to further screening 

and/or testing to better characterize effects related to endocrine disruption. 

4.0 Public Health and Pesticide Epidemiology Data 

Reference: 

Review of Metiram Incident Reports. D286186. Jerry Blondell. 

The most recent assessment of metiram incident reports was completed in 2002. 

Information sources consulted included the OPP Incident Data System (IDS); the Poison 

Control Centers (1993-1998); the California Department of Pesticide Regulation survey 

information collected from 1982 to present; and the National Pesticide 

Telecommunications Network (NPTN). In all, only one occupational incident was 

reported for metiram, through the Poison Control Centers; the incident involved exposure 

to the eye for one adult, and only minor effects were noted. 

5.0 Dietary Exposure/Risk Characterization 

5.1 Pesticide Metabolism and Environmental Degradation 

5.1.1 Metabolism in Plants and Animals 

The nature of metiram residues in plants is adequately understood based on acceptable 

studies conducted on apples and potatoes; these studies indicate that the bulk of total 

radioactive residues represent the incorporation of carbon fragments into natural 

products. The nature of metiram residues in livestock is also adequately understood 

Page 28 of 45 
based on acceptable goat and poultry metabolism studies. The Agency has determined 

that the terminal residues of concern in plants and livestock are metiram and its 

metabolite ETU. 

5.1.2 Metabolism in Rotational Crops 

No data pertaining to rotational crops are required for an imported crop (HED SOP 98.6, 

Data Requirements for Import Tolerances, Table 3, 12/3/98). 

5.1.3 Analytical Methodology 

The available analytical methodology is considered adequate for tolerance enforcement. 

The Pesticide Analytical Manual (PAM) Vol. II lists Methods I, II, III, IV and A for the 

determination of dithiocarbamate residues in/on plant commodities. These methods are 

based on the decomposition of dithiocarbamates with release of carbon disulfide (CS2). 

Using these methods, the CS2 is swept through a trap to remove any H2S and into a 

reaction tube containing a solution of copper acetate and an amine. A colored copper 

dithiocarbamate complex is formed, and its absorbance is read as a measure of the 

original dithiocarbamate. The stated limit of detection (LOD) for Method I is 0.5-4.0 

ppm. 

Although enforcement methods which are specific to metiram and ETU are not available, 

no additional analytical methodologies are required. It was concluded in the 10/13/2004 

Residue Chemistry Chapter that analytical methods converting all EBDCs and some 

metabolites to carbon disulfide will be considered adequate for enforcement, along with a 

specific method for ETU. The colorimetric method of Keppel (Method III in PAM Vol. 

II) is currently the preferred enforcement method for residues of metiram per se. For 

determination of ETU residues, the Agency recommends the GC method of Onley 

(AOAC 14th Edition 29.119:554) which provides acceptable results when properly 

validated with recovery and control data. In conjunction with the reregistration of other 

EBDCs (maneb and mancozeb), the Agency has recommended use of the Onley method 

as the official, final action method for determination of ETU residues in/on potatoes, 

spinach, apple sauce and milk. 

5.1.4 Environmental Degradation 

Reference: 

Estimated Drinking Water Concentrations of ETU (Ethylene-thio-urea, degradate of mancozeb, and 

common degradate of EBDCs “Ethene-bis-dithio-carbamates”) for Use in Human Health Risk Assessment. 

D323143 and D323141. M.A. Ruhman and Ronald Parker. 

Since no applications will be made in the U.S. for the proposed uses on imported grapes 

and bananas, the previously assessed drinking water estimates are appropriate for this risk 

assessment. Conclusions from the EFED drinking water assessment are presented below. 

The EFED drinking water assessment evaluated ETU alone because residues of metiram 

per se are not expected in drinking water. The EBDC metabolite/degradate ETU has an 

Page 29 of 45 
aerobic soil half-life of about 3 days; in the absence of data, the aquatic aerobic 

metabolism half-life was assumed to be about 6 days, or double the soil half life. The 

measured anaerobic aquatic metabolism half-life, however, is substantially longer (149 

days) possibly leading to the periodic detections in ground water. ETU is soluble in 

water (20,000 ppm); highly vulnerable to indirect photolysis (half-life= 1 day), and 

moderately mobile (288 L/kg). It also has a relatively high vapor pressure, but high 

solubility reduces the possibility of losses from surface water due to volatilization. 

5.1.4.1 Surface Water 

Water Monitoring: The EBDC/ETU Task Force conducted a national surface water 

monitoring survey from 2001-2003. A total of 22 sites were chosen to represent 

vulnerable and high EBDC-use sites. Surface water sites were sampled twice monthly 

for three months during each application season and quarterly for the three remaining 

quarters of each year for a period of 2 years. There were no detections of ETU in surface 

water during this period. The limit of quantitation for the study was 0.1 ppb. 

The Agency has been unable to locate any other surface water monitoring data for the 

EBDC fungicides or for ETU. The EBDCs and ETU were not included in the U.S. 

Geological Survey (USGS) National Water Quality Assessment (NAWQA) sampling 

program because EBDC/ETU test methods were incompatible with NAWQA test 

methods. The USGS is currently planning to begin method development and limited 

EBDC/ETU monitoring. 

Water Modeling: The ETU surface water estimates were calculated using the linked U.S. 

EPA PRZM (Pesticide Root Zone Model) and EXAMS (Exposure Analysis Model 

System) simulation models. This type of modeling provides high-end estimates for 

surface water pesticide concentrations. Calculation includes pesticide-specific properties, 

multiple years of actual weather variations, and crop-specific information. In addition to 

runoff from the field, the model takes into account surface water residues resulting from 

spray drift (aerial or ground). Conservative assumptions included the use of a vulnerable 

drinking water reservoir surrounded by a runoff-prone watershed, maximum use rate, 

lowest application intervals, and no buffer zone. Modeling was done for 22 crop 

scenarios. 

The highest one-in-ten year acute surface water EDWC was 25.2 ppb and the lowest 

value was 4.5 ppb. These values were calculated using the default national percent 

cropped area (PCA) value of 0.87. If the maximum regional PCA value (0.56 California 

PCA) is used, then the highest acute surface water EDWC was 13.9 ppb and the lowest is 

1.4 ppb. 

The highest chronic concentration value was 1.9 ppb and the lowest value was 0.2 ppb. 

This was calculated using the national maximum PCA. 

Acute Surface Water EDWCs: The ETU surface water estimated drinking water 

concentrations were generated using a combined monitoring/modeling approach. The 

Page 30 of 45 
targeted ETU monitoring found no surface water concentrations above the detection limit 

of 0.1 ppb. Because samples were taken every 14 days during the application season and 

acute values may have been missed, a range of acute surface EDWCs was established 

with a lower limit based on monitoring and an upper limit based on PRZM/EXAMS 

modeling. 

The range of acute EDWCs was 0.1 ppb (monitoring) and the upper limit was 25.2 ppb 

(modeling). The values were adjusted by the national maximum default percent cropped 

area (PCA) value of 0.87. 

Chronic Surface Water EDWC: The chronic EDWC is 0.1 ppb from the targeted ETU 

monitoring program mentioned above. No surface water concentrations were found 

above the detection limit of 0.1 ppb and the Agency believes that monitoring 

demonstrates that long-term average chronic values would not exceed the detection limit. 

5.1.4.2 Ground Water 

Water Monitoring: A monitoring program of community ground water systems was 

conducted by the EBDC Task Force from 2001-2003. Untreated and associated treated 

ground water was sampled for a period of two years in 84 sites chosen to represent high 

EBDC-use sites. ETU was detected above the detection limit intermittently in untreated 

water from two ground water sites. The highest concentration was 0.21 ppb in untreated 

water in Florida. There were no detections in treated water in any of the 84 community 

water sites, including those two sites where ETU was detected in the untreated water. 

A monitoring program of private wells was conducted by the EBDC Task Force from 

2001-2003. Raw ground water was sampled monthly for a period of two years in 125 

sites chosen to represent high EBDC-use sites. ETU was detected in the range of 0.10 to 

0.25 ppb continuously at 2 sites in Florida and intermittently at six sites: three in Florida 

and one each in New York, Illinois and Maine . The highest detected ETU concentration 

measured for a private well near an EBDC treated field was 0.57 ppb in an apple growing 

region of New York. No detection of ETU was observed in all the other 117 sites. Such 

higher groundwater concentration values, found in private areas in rural areas, are very 

rare and are unlikely to represent ground water ETU concentrations expected in drinking 

water relevant for use in a national assessment. 

In 25 years of monitoring in California, there has been only one ETU detection (0.75 

ppb). Additionally, ground water monitoring in Holland, resulted in only 8 positive 

samples with a maximum concentration of 1.5 ppb. 

Water Modeling: The ETU EDWCs in ground water, derived from the industry's 

targeted ground water monitoring study, were evaluated by comparing them to 

concentrations predicted by the SCI-GROW model. This is a screening model used to 

estimate pesticide concentrations in vulnerable ground water. The SCI-GROW estimate 

is based on environmental fate properties of the pesticide, maximum application rate and 

existing data from small-scale prospective ground water monitoring studies at sites with 

Page 31 of 45 
sandy soils and shallow ground water (i.e., exceptionally vulnerable ground water). 

Pesticide concentrations estimated by SCI-GROW represent conservative or high-end 

exposure values and in most cases, use areas will have groundwater that is less vulnerable 

to contamination than the areas used to derive the SCIGROW estimate. The SCI-GROW 

modeling indicates that the upper level ETU concentrations from the targeted monitoring 

study are unlikely to be exceeded even under the most vulnerable conditions. 

Ground Water EDWCs (acute and chronic): For ETU, the EDWC value for both acute 

and chronic exposure is 0.21 ppb. This value is from monitoring untreated water in 

Florida. 

Table 5.1. Summary of Estimated Surface Water and Groundwater Concentrations for ETU

Exposure Duration Surface Water Conc. 1 

 (ppb)

Groundwater Conc. 1

(ppb)

Acute 0.1-25.2 0.21 

Chronic (non-cancer) 0.1 0.21

Chronic (cancer) 0.1 0.21

1 Bolded values represent drinking water estimates included in the aggregate dietary assessment. 

5.1.5 Food Residue Profile 

Reference: 

Metiram. Petition for the Establishment of Import Tolerances on Grape and Banana. Summary of 

Analytical Chemistry and Residue Data. PP# 9E6006. D267866 and D322230. Christine Olinger. 

In support of the requested import tolerances, BASF has submitted several volumes of 

residue chemistry studies. These studies were evaluated according to the draft NAFTA 

Guidance Document on Data Requirements for Tolerances on Imported Commodities 

jointly issued in April 2003 by the U.S. Environmental Protection Agency, Canada’s Pest 

Management Regulatory Agency (PMRA) and Mexico’s Comision Intersecretarial para 

el Control del Proceso y Uso de Plaguicidas y Sustancias Toxicas (CICOPLAFEST). 

For bananas grown in Central and South America, the Polyram® 80 WG formulation is 

proposed for multiple spray applications; HED could not determine from the specimen 

label if the application rates were in terms of product or active ingredient. The proposed 

preharvest interval (PHI) is 7 days. The submitted label for bananas is inadequate to 

allow evaluation of the residue data relative to the proposed foreign use pattern because 

the label does not specify the maximum number of applications (or total application rate) 

that may be made on banana crops grown in Central and South America per growing 

season. In addition ̧ the label does not provide information pertaining to the type of 

equipment which may be used for applications. Although the use information provided 

to the Agency is unclear, HED assumed the use pattern employed in the residue trials 

were representative of the uses in Central and South America. The petitioner may rely on 

the submitted field trial data for bananas provided the product labels are revised for 

consistency with the application methods used in the field trials; details of suggested 

label revisions are presented in the Section 10.0 of this document. Note that if the 

Page 32 of 45 
petitioner significantly changes the use pattern in the future, this could potentially impact 

the residue levels in/on bananas. 

For grapes grown in Europe, the Polyram® DF Fungicide and Polyram® WG 

formulations are proposed for multiple spray applications; HED could not determine 

from the specimen labels if the application rates were in terms of product or active 

ingredient. The proposed PHIs are 28 days in Italy, 35 days in France and 56 days in 

Germany. The submitted labels for grapes are inadequate to allow evaluation of the 

residue data relative to the proposed foreign use pattern because not all labels specify the 

maximum single and seasonal rates as well as the preharvest intervals for each European 

country where uses are proposed. However, the petitioner has indicated that during the 

past few years, the European Union (EU) is attempting to harmonize label uses of 

metiram for grapes grown all over Europe. The proposed harmonized grape use pattern in 

EU specifies: a maximum single application rate of 1.8 kg ai/ha (1.6 lb ai/A), a 

maximum of 3 applications per growing season for an implied seasonal rate of 5.4 kg 

ai/ha (4.8 lb ai/A), and a 56-day PHI. 

When EU has completed the harmonization of all metiram labels intended for use on 

grapes, EPA requires the submission of revised labels to verify whether the available 

residue data can support the harmonized use patterns. In the interim, the Agency will 

assess the adequacy of the submitted residue data for grape data relative to the maximum 

use patterns for each European country (where labels are provided) as well as the 

proposed harmonized use pattern. Note that if the petitioner significantly changes the use 

pattern in the future, this could potentially impact the residue levels in/on grapes. 

The data-collection methods used for the analysis of samples, taken from field and 

processing studies, are adequate based on acceptable method recoveries which were, 

overall, within the acceptable range of 70-120%. Samples of grapes and its processed 

commodities were analyzed for residues of metiram, determined as CS2, using a 

spectrophotometry method (BASF Methods 135, 135/4, or Institut Fresenius Method No. 

IF-95/22962-00); the reported limits of quantitation (LOQ) for CS2 ranged from 0.03 to 

0.05 ppm. Grapes and its processed commodities were analyzed for ETU using an HPLC 

method (BASF Method 373/2, 373/1, or 373/0) with pulsed amperometric detection or an 

HPLC/UV method (Institut Fresenius No. IF-95/24090-00) based on BASF Method No. 

373; the reported LOQ for ETU ranged from 0.01 to 0.05 ppm. The ETU method (BASF 

Method 373/2) was subjected to successful independent laboratory validation (ILV). The 

EBDC and ETU methods need not be further validated by Agency chemists at 

ACB/BEAD since there are adequate enforcement methodologies for metiram and ETU. 

Samples of banana were analyzed for residues of metiram, determined as CS2, using a 

GC/MSD method (LAARL SOP PA.0244) and for ETU using an LC/UV method 

(LAARL SOP PA.0247); the validated LOQ was 0.05 ppm for metiram and ETU in 

whole banana, pulp and peel (0.03 ppm for CS2). 

Adequate storage stability data for metiram are available to support the storage conditions 

and intervals of RAC samples collected from the grape and banana field studies as well 

as samples from the grape processing studies. The 10/13/04 Residue Chemistry Chapter 

Page 33 of 45 
of the Metiram RED reported that metiram is relatively stable in/on diverse crop matrices 

such as apple, peanut, potato, sugar beet and tomato and in apple processed commodities 

when stored frozen for up to one year; these data for metiram may be translated to 

bananas, grapes and grape processed commodities. There are also adequate storage 

stability data for ETU on grapes. Weathered residues of ETU were found to be 

reasonably stable for up to 8.5 months in/on grapes under frozen storage conditions. The 

maximum freezer storage intervals of grape samples, from harvest to analysis, were ≤8.3 

months for metiram and ≤7.9 months for ETU. The maximum storage interval of whole 

banana samples, from harvest to analysis, was 4.0 months for metiram and ETU; 

maximum storage interval for banana pulp and peel was 4.5 months. 

There are, however, inadequate storage stability data for ETU in/on bananas and in grape 

processed commodities (raisins and juice); these data are required for risk assessment. 

Because of the instability of ETU in some plant commodities, the Agency has taken the 

approach that storage stability data for metiram residues of concern (including ETU) are 

not translatable to data collected by other laboratories. Therefore, HED requests the 

petitioner to use the same analytical laboratories, which performed the analysis of 

samples collected from the submitted banana field study and grape processing study, in 

the generation of the requested storage stability data for ETU. 

The magnitude of the residue data for bananas were generated from a total of 12 field 

trials conducted between the 2004 and 2005 growing seasons in Costa Rica (2 trials), 

Colombia (2 trials), Ecuador (2 trials), Honduras (2 trials), Martinique (2 trials) and 

Mexico (2 trials). The number and locations of field trials are adequate for the purpose of 

establishing an import tolerance on bananas. The maximum residues of metiram, 

determined as CS2, in/on samples harvested 0 days following the last of 10 or 11 

broadcast foliar applications of the 70% WG formulation for a total seasonal rate of 12.5-

13.9 lb ai/A were: (i) 0.13 ppm in/on bagged whole bananas, (ii) 2.8 ppm in/on unbagged 

whole bananas, (iii) below the method LOQ (<0.03 ppm) in/on pulp from bagged 

bananas, (iv) 0.11 ppm in/on pulp from unbagged bananas; (v) 0.16 ppm in/on peel from 

bagged bananas and; (vi) 1.5 ppm in/on peel from unbagged bananas. Residues of ETU 

were: (i) below the method LOQ (<0.05 ppm) in/on all treated bagged/unbagged samples 

of whole bananas and banana pulp; (ii) below the method LOQ (<0.05 ppm) in/on peel 

from bagged bananas and; (iii) at or below the method LOQ (≤0.05 ppm) in/on peel from 

unbagged bananas. 

Because quantifiable residues of metiram were observed in/on all samples of bananas, the 

tolerance spreadsheet was used to determine the appropriate tolerance level; residues 

were first converted from metiram equivalents to CS2 equivalents. Based on the 

calculations in the tolerance spreadsheet, the appropriate tolerance level for bananas is 

3.0 ppm. The petitioner is required to submit a revised Section F to delete the tolerance 

proposal for banana pulp since the Agency does not set tolerances on banana pulp and 

peel separately; however, data for banana pulp and peel are useful for dietary risk 

assessment. 

Page 34 of 45 
The magnitude of the residue data for grapes were generated from a total of 34 field trials 

conducted between the 1999 and 2003 growing seasons in France (13 trials), Germany (9 

trials), Italy (2 trials) and Spain (10 trials). The number and locations of field trials are 

adequate for the purpose of establishing an import tolerance on grapes. Varieties tested 

included wine and table varieties of grapes. 

Data bracketing a 27/28/29-day PHI indicate that the maximum residues of metiram, 

determined as CS2, in/on mature grapes were: (i) 1.5 ppm following eight applications of 

the 55% WG formulation for a total rate of 7.4-7.7 lb ai/A; (ii) 2.6 ppm following eight 

applications of the 70% WG formulation for a total rate of 9.5-9.8 lb ai/A; (iii) 2.05 ppm 

following six applications of the 70% WG formulation for a total rate of 8.2-8.5 lb ai/A; 

and (iv) 1.96 ppm following three applications of the 55% WG formulation for a total 

rate of 2.9 lb ai/A. Residues of ETU in/on the respective treated samples ranged from 

below the method LOQ (<0.01 or <0.05 ppm) to 0.032 ppm. These data may be used to 

support the label PHI of 28 days in Italy pending submission of additional use pattern 

information. The residue data summarized above reflect a total application rate range of 

2.9-9.8 lb ai/A. 

Data bracketing a 35/36-day PHI indicate that the maximum residues of metiram, 

determined as CS2, in/on mature grapes were: (i) 1.7 ppm following eight applications of 

the 55% WG formulation for a total rate of 7.4-7.7 lb ai/A; (ii) 2.2 ppm following eight 

applications of the 70% WG formulation for a total rate of 9.5-9.8 lb ai/A; (iii) 1.49 ppm 

following three applications of the 55% WG formulation for a total rate of 2.9 lb ai/A; 

and (iv) 2.3 ppm following three applications of the 70% WG formulation for a total rate 

of 2.9-3.0 lb ai/A. Residues of ETU in/on the respective treated samples ranged from 

below the method LOQ (<0.01 or <0.05 ppm) to 0.015 ppm. These data may be used to 

support the label use pattern in France which specifies a 35-day PHI and an implied 

maximum seasonal rate of 2.9 lb ai/A. The residue data summarized above reflect a total 

application rate range of 2.9-9.8 lb ai/A (1.0-3.4x the maximum seasonal label rate in 

France). 

Data bracketing a 54/55/56-day PHI indicate that the maximum residues of metiram, 

determined as CS2, in/on mature grapes were: (i) 1.2 ppm following eight applications of 

the 55% WG formulation for a total rate of 7.4-7.7 lb ai/A; (ii) 1.8 ppm following eight 

applications of the 70% WG formulation for a total rate of 9.5-9.8 lb ai/A; (iii) 1.81 ppm 

following six applications of the 70% WG formulation for a total rate of 8.2-8.5 lb ai/A; 

(iv) 1.69 ppm following three applications of the 70% WG formulation for a total rate of 

2.9-3.0 lb ai/A. Residues of ETU in/on the respective treated samples ranged from below 

the method LOQ (<0.01 or <0.05 ppm) to 0.012 ppm. These data may be used to support 

the proposed harmonized use pattern in EU which specifies a 56-day PHI and an implied 

maximum seasonal rate of 4.8 lb ai/A. The residue data summarized above reflect a total 

application rate range of 2.9-9.8 lb ai/A (0.6-2.0x the maximum harmonized seasonal rate 

in EU). 

Quantifiable residues of metiram were observed in/on all samples of grapes. Current 

product labels vary considerably among the regions of Europe, but the registrant has 

Page 35 of 45 
stated that it is their intention to develop a harmonized label. HED has concluded that a 

tolerance level of 5 ppm would be appropriate considering the current use patterns and 

the registrant’s proposal, and would harmonize with the Codex Maximum Residue Limit 

for grapes. The petitioner is required to submit a revised Section F reflecting a tolerance 

of 5 ppm. 

The submitted grape processing studies are incomplete to satisfy guideline requirements 

because these studies did not include residue data for grape juice. According to Table 1 

of OPPTS 860.1000, the regulated processed commodities of grapes are juice and raisins. 

Although incomplete, the grape processing data indicate that residues of metiram 

(determined as CS2) and ETU concentrated by average processing factors of 3.3x and 

1.7x, respectively, in raisins following processing of the RAC (grapes) with detectable 

residues and using procedures simulating commercial practices. The maximum expected 

residues of metiram in imported raisins can be calculated by multiplying the processing 

factor (3.3x) by the highest RAC residue value expressed as CS2 (2.6 ppm) obtained from 

a trial reflecting 28-day PHI which may have been conducted at an exaggerated rate 

pending use clarification. The product of 8.58 ppm is greater than the recommended 

tolerance of 5 ppm. The registrant should submit a revised Section F proposing a 

tolerance in/on raisins of 10 ppm. 

HED will make a definitive determination regarding the need for import tolerances on 

grape processed commodities when the requested bridging data for grape juice become 

available. 

The submitted grape processing studies included residue data for various matrices 

following processing of wine varieties of grapes using procedures for commercial wine 

production. Average processing factors were reported for metiram (determined as CS2) 

in: Rosé must (0.1x and 0.6x), Rosé young wine (<0.02x), Rosé mature wine (<0.02x 

and <0.1x), Red must (0.1x and 0.5x), Red young wine (<0.02x) and Red mature wine 

(<0.03x and <0.1x). Average processing factors were reported for ETU in: Rosé must 

(<0.3x and 0.8x), Rosé young wine (>3.0x), Rosé mature wine (0.6x and >2.9x), Red 

must (>2.5x and 10.4x), Red young wine (>3.7x) and Red mature wine (>3.5x and 

10.7x). Average wine processing factors reported for ETU are likely to be the result of 

the conversion of metiram to ETU, not the concentration of actual residues. The Agency 

does not set pesticide tolerances in wine because wine is under the purview of the Bureau 

of Alcohol, Tobacco and Firearms. 

Although several deficiencies were identified within the residue chemistry database, 

HED does not object to granting import tolerances for grapes at 5 ppm and raisins at 10 

ppm, provided a revised Section F and product labels are submitted. Confirmatory 

storage stability and processing data are also required. 

HED does not object to granting a temporary import tolerance for bananas at 3.0 ppm 

provided banana monitoring data for metiram and ETU are submitted, and all residue 

chemistry deficiencies are resolved. A full resolution of these deficiencies is required 

Page 36 of 45 
before HED can recommend the establishment of permanent import tolerances; see 

Section 10.0 of this document for further detail. 

5.1.6 International Residue Limits 

There are no established or proposed Codex MRLs for metiram residues per se; however, 

Codex limits for dimethyldithiocarbamate fungicides are grouped under 

dithiocarbamates. Maximum residue limits (MRLs) for the dithiocarbamates are 

established for several commodities resulting from the use of mancozeb, maneb, 

metiram, propineb, thiram and ziram and are currently expressed as ppm carbon 

disulfide. The residue definition has been harmonized with Codex. The recommended 

tolerance for banana, 3 ppm, cannot be harmonized with Codex because residues 

exceeded the Codex MRL of 2 ppm. HED has recommended harmonizing the proposed 

grape tolerance with the Codex MRL of 5 ppm. 

5.2 Dietary Exposure and Risk 

Reference: 

Metiram Acute, Chronic, and Cancer Dietary Exposure Assessments for New Tolerances on Imported 

Grapes and Bananas. PP# 9E6006. D326753. April 17, 2007. Christine Olinger.

Metiram and ETU acute, chronic and cancer dietary risk assessments were conducted 

using the Dietary Exposure Evaluation Model (DEEM-FCIDTM), Version 2.03, which 

used food consumption data from the United States Department of Agriculture’s 

(USDA’s) Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 

and 1998. 

Dietary risk assessment incorporates both exposure and toxicity of a given pesticide. For 

acute and chronic assessments, the risk is expressed as a percentage of the aPAD or 

cPAD, respectively. For acute and non-cancer chronic exposures, HED is concerned 

when estimated dietary risk exceeds 100% of the PAD. HED is generally concerned 

when estimated cancer risk exceeds one in one million. 

5.2.1 Acute Dietary Exposure/Risk

Metiram per se Data Sources and Assumptions 

To estimate metiram acute dietary exposure and risk, a refined probabilistic assessment 

was conducted using a distribution of either field trial or monitoring data for commodities 

considered to be either nonblended or partially blended. Average field trial or monitoring 

residues were used for blended commodities. Maximum % CT and relevant processing 

factors were also included in the assessment. Percent crop treated information is not 

available for the proposed import tolerances; however, percent imported factors were 

incorporated for bananas and grapes. 

Page 37 of 45 
ETU (from Metiram) Data Sources and Assumptions 

To estimate metiram-derived ETU acute dietary exposure and risk, the full distribution of 

field trial or monitoring residues was used for nonblended and partially blended 

commodities; for blended commodities, the average field trial or monitoring residue 

value was used. For all included commodities, relevant processing and cooking factors, 

conversion of EBDC to ETU for certain cooked commodities, and the 7.5% metabolic 

conversion of EBDC residues to ETU were incorporated into the anticipated residues. 

Acute Dietary Results

Acute dietary exposure and risk from metiram and metiram-derived ETU are below 

HED’s level of concern. For females 13-49 years old, estimated dietary exposure (food 

only) to metiram per se was 0.002215 mg/kg/day, which utilized 22% of the aPAD at the 

99.9th percentile. For ETU, the acute dietary exposure was 0.000299 mg/kg/day which 

utilized 6.0% of the ETU aPAD. The results of the acute dietary exposure assessments 

for metiram per se and ETU are shown in Summary Table 5.2. 

5.2.2 Chronic Dietary Exposure/Risk

Metiram per se Data Sources and Assumptions 

To estimate chronic dietary exposure and risk to metiram per se, a refined assessment 

was conducted using average field trial or average monitoring residues. In addition, 

average % CT and relevant processing factors were included. Percent crop treated 

information is not available for the proposed import tolerances; however, percent 

imported factors were incorporated for bananas and grapes. 

ETU (from Metiram) Data Sources and Assumptions 

The metiram-derived ETU chronic dietary exposure (for both non-cancer and cancer risk 

assessments) was estimated using average ETU residues. Average ETU residues derived 

from field trials or monitoring were used, along with the average % CT, percent import 

information, relevant processing and cooking factors, potential conversion of EBDC to 

ETU in certain cooked commodities and the 7.5% metabolic conversion of metiram per 

se to ETU. 

Chronic Dietary Results

Chronic dietary exposure and risk from metiram and metiram-derived ETU are below 

HED’s level of concern for the general U.S. population and various population 

subgroups. For metiram, the most highly exposed population subgroup is children 1-2 

years old, estimated at 0.000281 mg/kg/day representing 70% of the cPAD. For ETU, 

children 1-2 years old were the most highly exposed population subgroup, at 0.000100 

mg/kg/day representing 50% cPAD. The results of the chronic dietary exposure 

assessments for metiram per se and ETU are shown in Summary Table 5.2. 

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5.2.3 Cancer Dietary Risk

The cancer dietary assessment for ETU was based on the same anticipated residues 

derived for the chronic dietary exposure assessment. The estimated chronic dietary 

exposure for the general U.S. population corresponds to a cancer risk of 1 x 10-6 which is 

not of concern. The results of the cancer dietary exposure assessments for ETU are 

shown in Summary Table 5.2. 

Table 5.2. Result of Acute and Chronic Dietary Exposure and Risk Estimates for Metiram Using 

DEEM-FCIDTM

Population Subgroup Metiram per se ETU (from metiram) 

Exposure, 

mg/kg/day 

% PAD Exposure, 

mg/kg/day 

%PAD 

Acute Dietary Estimates (99.9th Percentile of Exposure) 

Females 13-49 yrs 0.002215 22 0.000299 6.0 

Chronic Dietary Estimates 

U.S. Population 0.000048 12 0.000018 9.0 

All infants (< 1 yr) 0.000052 13 0.000051 25 

Children 1-2 yrs 0.000281 70 0.000100 50 

Children 3-5 yrs 0.000163 41 0.000056 28 

Children 6-12 yrs 0.000063 16 0.000022 11 

Youth 13-19 yrs 0.000022 5.4 0.000008 3.8 

Adults 20-49 yrs 0.000028 6.9 0.000010 5.1 

Adults 50+ yrs 0.000039 9.7 0.000015 7.6 

Females 13-49 yrs 0.000030 7.4 0.000011 5.3 

Cancer Dietary Estimate 

U.S. Population NA1 NA 0.000018 1 x 10-6

1 Potential for carcinogenicity attributed to the ETU metabolite only.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization 

There are no residential uses or agricultural uses that would result in residential exposure 

to the general population for metiram. 

Spray drift is a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for metiram. 

The Agency has been working with the Spray Drift Task Force, EPA Regional Offices 

and State Lead Agencies for pesticide regulation and other parties to develop the best 

spray drift management practices. On a chemical by chemical basis, the Agency is now 

requiring interim mitigation measures for aerial applications that must be placed on 

product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and 

is developing a policy on how to appropriately apply the data and the AgDRIFT 

Page 39 of 45 
computer model to its risk assessments for pesticides applied by air, orchard airblast and 

ground hydraulic methods. After the policy is in place, the Agency may impose further 

refinements in spray drift management practices to reduce off-target drift with specific 

products with significant risks associated with drift. 

7.0 Aggregate Risk Assessments and Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide 

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

exposures. In an aggregate assessment, exposures from relevant sources are added 

together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or 

the risks themselves can be aggregated. When aggregating exposures and risks from 

various sources, HED considers both the route and duration of exposure. 

There are no residential exposure concerns for metiram, so aggregate exposure and risk 

assessments consider only food and drinking water. Since residues of metiram per se are 

not expected in drinking water, aggregate risks for metiram consist of aggregate metiramderived ETU exposures for acute and chronic (cancer and non-cancer) durations. The 

aggregate ETU dietary assessments were based on the same anticipated residues derived 

for the ETU food alone dietary exposure assessments, with the addition of EDWC values 

for drinking water. 

7.1 Acute Aggregate Risk

For the metiram-derived ETU aggregate acute risk assessment, a surface water EDWC 

value of 25.4 ppb was used, which resulted in dietary exposure and risk are below HED’s 

level of concern. For females 13-49 years old, estimated dietary exposure for food and 

water was 0.003511 mg/kg/day, which utilized 70% of the aPAD at the 99.9th percentile. 

The results of the aggregate acute dietary exposure assessment for metiram-derived ETU 

are shown in Summary Table 7.1. 

7.2 Chronic Aggregate Risk 

For the ETU aggregate chronic (non-cancer and cancer) dietary assessment, a ground 

water EDWC value of 0.21 ppb was used. Aggregate ETU chronic non-cancer risks are 

below HED's level of concern for the general U.S. population and all other population 

subgroups. The most highly exposed population subgroup, children 1-2 years old, had a 

chronic aggregate exposure of 0.000107 mg/kg/day which utilized 54% cPAD. The 

results of the aggregate chronic dietary exposure assessment for metiram-derived ETU 

are shown in Summary Table 7.1. 

7.3 Cancer Aggregate Risk 

Aggregate ETU cancer risk for the general U.S. population is not of concern, with an 

estimated risk of 1 x 10-6 including existing and proposed uses. The results of the 

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aggregate cancer dietary exposure assessment for metiram-derived ETU are shown in 

Summary Table 7.1. 

Table 7.1. Result of Aggregate Acute and Chronic Dietary Exposure and Risk Estimates for 

ETU Using DEEM-FCIDTM

Population Subgroup ETU (from metiram) 

Exposure, mg/kg/day % PAD 

Acute Dietary Estimates (99.9th Percentile of Exposure) 

Females 13-49 yrs 0.003511 70 

Chronic Dietary Estimates 

U.S. Population 0.000022 11 

All infants (< 1 yr) 0.000065 33 

Children 1-2 yrs 0.000107 54 

Children 3-5 yrs 0.000063 31 

Children 6-12 yrs 0.000027 13 

Youth 13-19 yrs 0.000011 5.4 

Adults 20-49 yrs 0.000014 7.1 

Adults 50+ yrs 0.000020 9.8 

Females 13-49 yrs 0.000015 7.4 

Cancer Dietary Estimate 

U.S. Population 0.000022 1 x 10-6

7.4 ETU Aggregate Exposure from All Sources (Metiram, Mancozeb and 

Maneb) 

The acute, chronic and cancer aggregate assessments for ETU considered food, water and 

residential exposure resulting from current and proposed uses of metiram, mancozeb and 

maneb; only mancozeb and maneb are used in residential settings. Acute and chronic 

aggregate risks from all sources of ETU were not of concern; however, the ETU 

aggregate cancer risk exceeds HED’s level of concern (3.8 x 10-6). HED conducted 

sensitivity analyses and determined the greatest contributors to ETU exposure are 

bananas, leaf lettuce, water, turnip greens, grape juice and mangoes. If the proposed 

import tolerance in/on bananas (from metiram applications) is removed from the 

aggregate assessment, then the aggregate cancer risk does not exceed HED’s level of 

concern (3.2 x 10-6). All other sensitivity analyses result in aggregate risks exceeding the 

level of concern. Note that the metiram-derived ETU residue values from crop field trials 

used in the aggregate assessment are considered to be overestimates. Projected percent 

crop treated information was not available, so percent imported information was used, 

and it is highly unlikely that all bananas will be treated. In general, monitoring data 

available for other commodities show much lower residues than field trial data, so the 

actual exposure is likely to be lower. For these reasons, HED is requiring the submission 

of monitoring data for metiram and ETU on bananas. See the ETU Aggregate Risk 

Assessment document (D337241, T. Goodlow) for additional details. 

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8.0 Cumulative Risk Characterization/Assessment 

Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering whether to 

establish, modify, or revoke a tolerance, the Agency consider "available information” 

concerning the cumulative effects of a particular pesticide's residues and "other 

substances that have a common mechanism of toxicity.” 

Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering whether to 

establish, modify, or revoke a tolerance, the Agency consider "available information” 

concerning the cumulative effects of a particular pesticide's residues and "other 

substances that have a common mechanism of toxicity.” 

No determination of a common toxic effect or mechanism of toxicity has been made for 

acute or chronic non-cancer risks from EBDCs. 

9.0 Occupational Exposure/Risk Pathway 

No occupational exposure to metiram is expected to occur in the U.S. as a result of 

metiram uses on imported grapes and bananas. 

10.0 Data Needs and Label Recommendations

Residue chemistry deficiencies for the current metiram import tolerance petition include 

the following: 

Guideline 860.1200 Directions for use

• Copies of labels, translated to English, must include, but are not limited to, the 

maximum single application rate, the maximum annual application rate, application 

timing (as it relates to plant growth stage), re-treatment interval, application tank-mix 

preparation, volume of spray mix per unit area, application equipment, and the preharvest interval (PHI). The application rates should be expressed in units of pounds 

active ingredient per acre (or kilograms per hectare). 

• The submitted label for bananas is inadequate to allow evaluation of the residue data 

relative to the proposed foreign use pattern because the label does not specify the 

maximum number of applications (or total application rate) that may be made on 

banana crops grown in Central and South America per growing season. In addition ̧ 

the label does not provide information pertaining to the type of equipment which may 

be used for applications. The available data will, however, support a minimum 

retreatment interval of 5 days and the use of a surfactant. If the registrant wishes to 

rely on the available field trial data for bananas, then label amendments are required 

to specify: (1) a maximum of ten broadcast foliar applications at 1.25 lb ai/A per 

Page 42 of 45 
application for a seasonal rate of 12.5 lb ai/A; and (2) a spray volume of 3 gallons per 

acre using ground equipment. If the petitioner wishes to include higher spray 

volumes on the label, then additional residue data will be required. 

• The submitted labels for grapes are also inadequate to allow evaluation of the residue 

data relative to the proposed foreign use pattern because not all labels clearly specify 

the maximum single and seasonal rates as well as the preharvest intervals for each 

European country where uses are proposed. However, the petitioner has indicated 

that during the past few years, EU is attempting to harmonize label uses of metiram 

on grapes grown all over Europe. When EU has completed the harmonization of all 

metiram labels intended for use on grapes, EPA requires the submission of revised 

labels to determine whether the available residue data can support the harmonized use 

patterns. If there are any deviations from the harmonized use pattern due to localized 

pest infestation or good agricultural practices, information pertaining to these 

deviations should be reported. 

Guideline 860.1380 Storage stability data

• There are inadequate storage stability data for ETU in/on bananas and in grape 

processed commodities; these data are required for risk assessment. Because of the 

instability of ETU in some plant commodities, the Agency has taken the approach 

that storage stability data for metiram residues of concern (including ETU) are not 

translatable to data collected by other laboratories. Therefore, HED requests the 

petitioner to use the same analytical laboratories, which performed the analysis of 

samples collected from the submitted banana field study and grape processing (raisin 

and juice only) study, in the generation of the requested storage stability data for 

ETU. 

Guideline 860.1520 Processed food/feed

• The petitioner is required to conduct a bridging grape processing study to investigate 

the potential for concentration of metiram and ETU residues in grape juice. In the 

requested study, the RAC should be processed in a manner simulating typical 

commercial practice. The RAC should have detectable residues so a concentration 

factor may be calculated. 

Guideline 860.1550 Proposed tolerances

• Based on HED MARC’s determination regarding the appropriate tolerance 

expression for EBDCs, the petitioner is required to submit a revised Section F to 

include residues of the parent EBDC only, calculated as CS2, rather than as zineb. 

The petitioner should modify the value for grapes to 5 ppm and propose a tolerance 

in/on raisins at 10 ppm. 

Page 43 of 45 
Guideline 860.1560 Reasonable grounds in support of the petition

• Banana monitoring data are required for metiram and ETU. 

Deficiencies or data gaps previously identified in the RED exist for the following 

guideline studies: 

Toxicology

• Guideline 870.3700 Developmental toxicity, rabbit (only the maternal animal 

was adequately assessed in the available rabbit study) 

• Guideline 870.3800 2-generation reproduction, rat 

• Guideline 870.6200 Acute neurotoxicity, rat 

• Guideline 870.6300 Developmental neurotoxicity, rat 

* Comparative study for thyroid toxicity in adults and offspring is required for ETU only 

Residue Chemistry

• Guideline 860.1200 Directions for use (label revision) 

• Guideline 860.1850 Confined accumulation in rotational crops 

Product Chemistry

• Guideline 830.1700 Preliminary analysis 

• Guideline 830.7050 UV/visible absorption 

Occupational Exposure

The registrant should submit a DFR study on apples; the submitted study is inadequate, 

and leads to lower confidence in estimated postapplication risks. 

References 

Blondell, Jerry. DP Barcode: D286186. October 17, 2002. Review of Metiram Incident 

Reports. 

Farwell, Kit. DP Barcode: D291661. June 13, 2005. Metiram: Health Effects Division 

(HED) Human Health Risk Assessment to Support Reregistration. 

Goodlow, Toiya. DP Barcode: D337241. June 2007. Ethylenethiourea (ETU) from 

EBDCs: Health Effects Division (HED) Human Health Risk Assessment of the Common 

Metabolite/Degradate ETU. 

Olinger, Christine. DP Barcodes: D267866 and D322230. Metiram: Petition for the 

Establishment of Import Tolerances on Grape and Banana. Summary of Analytical 

Chemistry and Residue Data. PP# 9E6006. 

Page 44 of 45 
Olinger, Christine. DP Barcode: D326753. April 17, 2007. Metiram Acute, Chronic and 

Cancer Dietary Exposure Assessments for New Tolerances on Imported Grapes and 

Bananas. PP# 9E6006. 

Parker, Ronald and Ruhman, Mohammed. DP Barcodes: D323143 and D323141. August 

11, 2006. Estimated Drinking Water Concentrations of ETU (Ethylene-thio-urea, 

degradate of mancozeb, and common degradate of EBDCs “Ethene-bis-dithiocarbamates”) for Use in Human Health Risk Assessment. 

Reregistration Eligibility Decision (RED) for Metiram. August 29, 2005. 

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