Metiram Registration Review Human Health Scoping Document D425218 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASH INGTON, D.C. 20460 

MEMORANDUM 

Date: June 2, 2015 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Metiram: Human Health Risk Assessment Scoping Document in Support of Registration 

Review. 

PC Code: 014601; 014504; 6000 16 DP Ba rcode: 0425218 

Decision No.:499278 Registra tion No.: NA 

Petition No.: NA Regulatory Action: Registration Review 

Risk Assessment Type: NA Case No.: NA 

T XR No.: NA 

MRID No.: NA 

FROM: 

THROUGH: 

And 

CAS No.: 9006-42-2; 96-45-7 

40 CFR: § 180.217 

-~ 

Danette Drew, Chemist/Risk Assessor ~fl 

Matt Lloyd, CIH, Expo~Assessor _ Y! 'fM 

Pete Savoia, Chemist ~'ft~/ ~~ 

Linda Taylor, Ph.D., Toxicologist 

Risk Assessment Branches V and VII 

Health Effects Division (7509P) 

Michael Metzger, Branch Chief ~J (} } Risk Assessment Branches V and VII . ~ · ' 

Health Effects Division (7509P) 

Jess Rowland, Deputy Director 

Dana Vogel, Acting Director 

Health Effects Division (7509P) 

TO: Brittany Pruitt, Chemical Review Manager 

Page 1 of 40 

Risk Management and Implementation Branch III 

..... Pesticide Re-Evaluation Division (7508P) 
Metiram Registration Review I lwnan Health Scoping Document 04252 18 

Executive Summary 

The Health Effects Division (HED) Metiram Registration Review Team has evaluated the status 

of the human health risk assessment for the fungicide metiram to determine the scope of work 

necessary to support registration review. This scoping exercise is based primarily on the most 

recently completed human health risk assessment (HHRA) of June 2007 (T. Goodlow, 6/ 14/07, 

0267866, Metiram: Human Health Risk Assessment for PP#9E6006. Petition/or the 

Establishment of Import Tolerances on Grapes and Bananas) and the USEPA August 2005 

Metiram Reregistration Eligibility Decision (RED). 

Metiram, a broad spectrum fungicide, is a mixture of 5.2 parts by weight of ammoniates of 

ethylenebis (dithiocarbamato) zinc with I part by weight ethylenebis (dithiocarbamic acid) 

bimolecular and trimolecular cyclic anhydrosulfides and disulfides. Metiram is currently 

registered for agricultural application to apples (foliar) and potatoes (foliar or seed piece). 

Horticultural uses include a Special Local Need use on leathcrleaf fems (nurseries and 

greenhouses; Florida use only). 

Permanent tolerances are established under 40CFR§180.21 ?(a) for metiram residues (expressed 

as CS2) on apples, potatoes, bananas, and wine grapes. The banana and grape tolerances are for 

imports to the U.S. There are no tolerances established for metiram on livestock commodities 

because there is no expected transfer of residues to livestock tissues from treated feed. In plants, 

the residues of concern for risk assessment are the parent compound mctiram and its metabolite 

and environmental degradate, ethylenethiourea (ETU). The residue of concern in drinking water 

is ETU only; metiram is not expected to be found in drinking water sources. 

Metiram is a fungicide in the class of ethylenebis dithiocarbamates (EBDCs), which also 

includes the fungicides maneb (no registered uses) and mancozeb (registered uses); all of these 

compounds have a common metabolite/degradate, ETU. Some of the more notable toxicity, such 

as thyroid toxicity, in the metiram studies was due to toxicity from this metabolite. For metiran1, 

separate risk assessments are performed for 1) toxicity and exposure to parent compound 

metiram only and 2) toxicity and exposure to ETU derived from metiram, including combined 

exposures from both ETU as an environmental degradate and ETU as an in vivo metabolite of 

metiram. This document presents the scope of work anticipated under registration review for 

both metiram and mctiram-derived ETU. A separate HED document (0425216) outlines the 

scope of work anticipated for mancozeb and mancozeb-derivcd ETU. In addition to the 

individual EBDC pesticide assessments, a separate risk assessment is perfom1ed addressing the 

combined (aggregate) risk from ETU derived from all registered EBDC pesticides. The 

conclusions regarding the scope of work anticipated under registration review for mancozeb and 

metiram also apply to the ETU aggregate risk assessment. 

For any residential, occupational and dietary exposure, including oral, dermal and inhalation 

routes of exposure, a 7.5% in vivo metabolic conversion of absorbed metiram to ETU is used, 

and is accounted for in estimating the total exposure (in vivo metabolism combined with direct 

environmental exposure) to ETU. 

The findings in multiple toxicology studies demonstrate that the thyroid is a target organ for 

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Metiram Registration Review Human Health Scoping Document D425218

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metiram and ETU; these effects are due to inhibition of thyroid peroxidase by the metabolite 

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

have been observed in subchronic studies in rats following oral dosing with metiram. Both 

metiram and ETU are classified as probable human carcinogens. There is no indication of 

immunotoxicity potential for metiram or ETU.

In the 2007 metiram and metiram-derived ETU risk assessment, a database uncertainty factor of 

10X was retained for all populations to account for the lack of key data; HED noted data gaps for 

a developmental neurotoxicity (DNT) study, an acute neurotoxicity study, a developmental 

toxicity study in the rabbit, and a 2-generation reproduction study in the rat. 

In the most recent ETU aggregate risk assessment (D. Drew, 7/3/2013, D412678, Ethylene 

Thiourea (ETU); Aggregate Human Health Risk Assessment of the Common 

Metabolite/Degradate Ethylene Thiourea (ETU) to Support Proposed New Section 3 Use on 

Walnuts and Tolerance for Imported Tangerines) the default FQPA factor of 10X was retained 

for women of childbearing age (13- 49 years old) and for children less than six years old to 

account for the lack of data on the developing thyroid (database uncertainty factor). The FQPA 

factor was reduced to 1X for other lifestages (children > 6 years, females > 49 years, and adult 

males), for which the thyroid is largely developed and there are applicable thyroid data.

New toxicity data (an acute neurotoxicity study on metiram and an extended one-generation 

reproductive toxicity study on ETU, which includes an assessment of reproductive toxicity, 

developmental neurotoxicity, and developmental thyroid toxicity) have been received since the 

last metiram and ETU risk assessments and are currently undergoing review. A developmental 

toxicity study (rabbit) for metiram remains outstanding. The need for a subchronic neurotoxicity 

study and immunotoxicity data has been waived by HED’s Hazard and Science Policy Council 

(HASPOC) (TXR#0055055, 4/30/15 meeting). During registration review of metiram, the 

impact of the new data on endpoint selection, points of departure (PODs), and uncertainty 

factors/safety factors (UF/SFs) for the dietary, dermal, and inhalation risk assessments will be 

evaluated.

The metiram residue chemistry database is incomplete; outstanding data (revised labels) are 

required under 860.1200 Directions for Use and 860.1560 Reasonable Grounds in Support of the 

Petition. Additional anticipated residue/monitoring data are also needed to support the dietary 

assessment. The 1990 EBDC market basket survey previously used to refine the dietary 

assessments may be outdated, and any changes in application techniques, typical rates, handling, 

storage, and transportation could result in incurring different residue levels today than those 

reported in the 1990 survey. To allow for the continued use of the survey in future dietary 

assessments, the EBDC registrants must provide justification as to whether current good 

agricultural practices would result in yielding comparable residues as those found in the survey. 

If based on this information HED concludes that the market basket data are no longer reflective 

of current residues, a new market basket survey should be conducted. In that event, until 

adequate updated market basket data are submitted, HED will rely on data from available 

controlled studies (e.g. field trial data, processing studies), which will likely result in 

significantly greater risk estimates that may exceed the levels of concern.
Metiram Registration Review Human Health Scoping Document D425218

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No acute or chronic (non-cancer) dietary risks of concern were identified in the 2007 HHRA for 

either metiram (food only; metiram not expected in drinking water) or metiram-derived ETU 

(food and water) for any populations modeled, including infants and children, and females of 

child bearing age. The most highly exposed population subgroup in any of the dietary 

assessments was children ages 1-2 with an estimate for metiram (food only) at 70% of the cPAD. 

The cancer risk estimate associated with exposure to metiram-derived ETU in food and water 

was 1 x 10-6for the general U.S. population.

Under registration review of metiram, HED may conduct a new dietary assessment if the 

Ecological Fate and Effects Division (EFED) revised Drinking Water Assessment (DWA) results 

in ETU estimated drinking water concentrations (EDWCs) that are significantly greater than 

those used in the most recent (2013) ETU assessment, which were based on water monitoring 

data and modeling. A revised dietary assessment will be performed if there are increases in the 

anticipated residue levels in food. If new toxicological endpoints, PODs or UF/SFs are selected 

as a result of new toxicological data submissions, these would also be used in any revised dietary 

assessments.

There are no residential or homeowner uses registered for metiram; therefore a quantitative 

assessment is not anticipated to be performed for residential handlers or residential (nonoccupational) post-application exposure. However, HED does intend to perform a quantitative 

spray drift assessment. Based on the current use pattern, no chemical specific Turf Transferable 

Residue (TTR) data are required for metiram. Additionally, the Agency will examine the need 

for a volatilization assessment during registration review.

Since there are no residential uses of metiram, the aggregate assessments were comprised of food 

and drinking water exposures. There were no aggregate risk estimates of concern for metiram or 

metiram-derived ETU identified in the 2007 HHRA.

The occupational exposure database for metiram (and metiram-derived ETU) is complete. The 

previous occupational assessment performed (2005) utilized methodologies that have since been 

updated. Comprehensive updated quantitative handler and post-application occupational risk 

assessments (cancer and non-cancer) will be performed for all currently registered metiram uses 

and will include updated exposure assessment methodology (e.g. new transfer coefficients, 

methodology for greenhouse assessments, etc.). The available chemical-specific dislodgeable 

foliar residue (DFR) data will also be considered for the post-application assessments. Any 

revisions to the toxicological endpoints, PODs, or UFs will also be incorporated in the 

occupational assessments.

ETU Aggregate Assessment (All EBDCs)

HED has previously conducted acute, short-term, chronic, and cancer aggregate assessments for 

ETU from the combined EBDC pesticide uses (metiram and mancozeb) (7/3/2013; D412678).

The acute and chronic aggregate assessments included only dietary (food and drinking water) 

exposures. There were no acute or chronic ETU aggregate risk estimates of concern for the 

combined EBDC uses.
Metiram Registration Review Human Health Scoping Document D425218

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The short-term aggregate assessments for ETU combined residential exposures (from mancozeb 

use; there are no residential uses of metiram) and average dietary (food and water; from metiram 

and mancozeb uses) exposures. There were no short-term aggregate risk estimates of concern for 

the combined EBDC uses.

The cancer aggregate assessment for ETU included contributions from residential and dietary 

(food and water) exposures. Cancer aggregate ETU risks were estimated at 2 x 10 -6(handler)

and 3 x 10-6(post-application). 

Under registration review of metiram, a revised combined ETU aggregate assessment will be 

performed if there are any significant changes made to the ETU assessments from the individual 

EBDCs (e.g. assessment methodologies, toxicological endpoints, PODs or UF/SFs, EDWCs, 

food residues).

Introduction

HED has evaluated the most recent human health risk assessments for metiram (2007) and ETU 

(2013), as well as older evaluations, to determine any outstanding data requirements or 

additional data required to complete registration review for this fungicide. HED has also 

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

policy and risk assessment methodologies.

Metiram, a broad spectrum fungicide, 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. Metiram is currently 

registered for agricultural application to apples (foliar) and potatoes (foliar or seed piece). 

Horticultural uses include a Special Local Need use on leatherleaf ferns (nurseries and 

greenhouses; Florida use only). The two currently registered products are a dry flowable (DF; 

EPA Reg. No. 7969-105) and a water dispersible granule (WDG; EPA Reg. No. 7969-321).

Information on the chemical identity of metiram is included in Attachment 1.

Hazard Identification/Toxicology

Metiram

The toxicology database for metiram is mostly complete, with the exception of the rabbit 

developmental toxicity study. Previously, the toxicological database was considered incomplete 

due to the lack of several key study requirements. Subsequent to the last metiram risk 

assessment, it was determined that the extended one-generation reproductive toxicity study 

(EOGRTS) being performed on the metabolite ethylene thiourea (ETU) would satisfy the 

metiram data requirements for the 2-generation reproductive toxicity study and the 

developmental neurotoxicity study. The data requirement for a comparative thyroid assessment is 

also addressed by the ETU study and is applicable to metiram. The ETU EOGRTS has been 

submitted to the Agency and is under review; an initial screen indicates that the study is 

acceptable. Additionally, an acute neurotoxicity (ACN) study on metiram has been submitted 
Metiram Registration Review Human Health Scoping Document D425218

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and reviewed, and it satisfies this metiram data requirement. The new Part 158 Toxicological 

Data Requirements for a subchronic neurotoxicity study (SCN) and an immunotoxicity study on 

metiram have been waived by the Hazard and Science Policy Council (HASPOC) 

(TXR#0055055, 4/30/15 meeting). The metiram rabbit developmental toxicity study remains a 

datagap.

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 

serum thyroxine (T4) values. These effects are considered to be due to inhibition of thyroid 

peroxidase by the metabolite, ETU. The nervous system and skeletal muscle are also targets for 

metiram. Neurotoxic signs and/or neuromuscular effects and neuropathology have been 

observed in subchronic studies in rats following oral administration of metiram. Muscle wasting 

was observed at termination, and signs of neurotoxicity occurred after 2 weeks of dosing, 

including reduced forelimb grip strength, hindlimb paralysis, muscle wasting, and ataxia. 

Neuropathology findings included decreased areas of myelinated axons in the sciatic, sural, and 

tibial nerves.

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 

of metiram where minimal maternal toxicity (decreased body-weight gains) was observed. 

However, there is low concern for the qualitative susceptibility observed in the rat study since 

the dose-response was well characterized; there were clear NOAELs (no observed adverse effect 

levels)/LOAELs (lowest observed adverse effect levels) 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. Developmental 

toxicity was observed in the rabbit (abortions) at the same dose levels where maternal toxicity 

was observed (abortions, mortality). Although the maternal rabbits were adequately assessed, the 

heads of the fetuses were not examined in this study, and this study remains a data requirement. 

Reproductive toxicity was not adequately assessed following exposure to metiram because of the 

lack of a one-to-one pairing and the lack of histopathological examination of reproductive and 

target organs. However, the EOGRTS on ETU assessed reproductive toxicity (with one-to-one 

pairing and adequate histopathological examination of reproductive and target organs), and the 

results of this ETU study are considered applicable to metiram. 

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)-1for risk 

assessment. Because metiram is known to be converted to ETU, it has also been classified as a 

probable human carcinogen. 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.

Metiram is rapidly absorbed and eliminated via the urine, feces, and expired air, with excretion 

being nearly complete after 48 hours. Metiram degrades and/or is metabolized to ETU. In rat

oral metabolism studies with radiolabelled metiram, an average 7.5% in vivo metabolic 
Metiram Registration Review Human Health Scoping Document D425218

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

some accumulation following repeat dosing.

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. 

In the 2007 metiram and metiram-derived ETU risk assessment, a database uncertainty factor of 

10X was retained for all populations to account for the lack of data. HED noted data gaps for a 

DNT study, acute neurotoxicity study, a developmental toxicity study in the rabbit and a 2-

generation reproduction study in the rat. 

New toxicity data (an acute neurotoxicity study on metiram, and an extended one-generation 

reproductive toxicity study on ETU, which includes an assessment of reproductive toxicity, 

developmental neurotoxicity, and developmental thyroid toxicity) have been received since the 

last risk assessment and is currently undergoing review. The developmental toxicity study 

(rabbits) for metiram remains outstanding. The need for a subchronic neurotoxicity study and 

immunotoxicity data has been waived. During registration review of metiram, the impact of the 

new data on endpoint selection, points of departure (PODs), and uncertainty factors/safety 

factors (UF/SFs) for the dietary, dermal, and inhalation risk assessments will be evaluated.

The toxicity profile tables for metiram are included as Attachment 2. The metiram endpoints, 

points of departure (PODs), and uncertainty/safety factors (UF/SFs) used in the most recent 

human health risk assessment are summarized in Attachment 3.

Ethylenethiourea (ETU)

Previously, the toxicology database for ETU was limited and HED relied on a combination of 

guideline study data and studies in the open literature to assess hazard for ETU. Since the last 

risk assessment, an extended one-generation reproductive toxicity study (EOGRTS) on ETU was 

submitted, which includes an assessment of reproductive toxicity, developmental neurotoxicity, 

developmental thyroid toxicity, and immunotoxicity (previous ETU datagaps). 

The toxicology database on ETU is sufficient for assessing the toxicity and characterizing the 

hazard of ETU. The effects on the peripheral nervous system observed following exposure to 

metiram (or mancozeb) have not been observed following ETU exposure.

The thyroid is a major target organ for ETU because ETU inhibits the enzyme thyroid 

peroxidase. Thyroid toxicity in subchronic and chronic rat, mouse, and dog studies includes 

decreased levels of the thyroid hormone T4 (thyroxine), changes in T3 (triiodothyronine) levels, 

compensatory increases in levels of thyroid stimulation hormone (TSH), increased thyroid 

weight, and microscopic thyroid changes, chiefly hyperplasia. Overt liver toxicity (necrosis) was 

observed in one chronic dog study. Developmental defects in the rat developmental toxicity 

study included hydrocephaly and related lesions, skeletal system defects, and other gross defects 

in the kidney and stomach. Hydrocephaly and microphthalmia occurred in rats after a single 

dose. Post implantation loss, hydrocephaly, and domed head were observed in the rabbit 

developmental toxicity study. Although there are no neurotoxicity studies on ETU (except as 
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assessed in the recently submitted extended one-generation reproductive toxicity study, 

EOGRTS), the toxicity profile of ETU shows that the principal toxic effects are on the thyroid.

The immunotoxicity study on ETU did not show any immunotoxicity potential.

ETU is classified as a probable human carcinogen (B2), based on female mouse liver tumors 

observed in the ETU carcinogenicity study in mice. The ETU cancer potency factor (Q1*) of 

0.0601 (mg/kg/day)-1is used to quantitate risk. 

In the most recent ETU risk assessment (2013 HHRA), the default FQPA factor of 10X was 

retained for women of childbearing age (13- 49 years old) and for children less than six years old 

to account for the lack of data on the developing thyroid (database uncertainty factor). The 

FQPA factor was reduced to 1X for other lifestages (children > 6 years, females > 49 years, and 

adult males), for which the thyroid is largely developed and there are applicable thyroid data.

Since the last risk assessment of ETU, an extended one generation reproductive toxicity 

(EOGRT) study on ETU was submitted, which was designed to satisfy the toxicology data gaps 

for ETU (a 2-generation reproduction study in rats, a developmental neurotoxicity study in rats,

and a developmental thyroid toxicity study in rats). This study is currently under review. 

Additionally, a rabbit developmental toxicity study on ETU was submitted, which has been 

reviewed and found to satisfy this data requirement. During registration review of metiram, the 

impact of these study results on endpoint selection, PODs, and UF/SFs for the dietary, incidental 

oral and dermal risk assessments will be evaluated, based on the new data and updated policies 

and procedures.

The toxicity profile tables for ETU are included as Attachment 2. The ETU endpoints, points of 

departure (PODs), and uncertainty/safety factors (UF/SFs) used in the most recent human health 

risk assessment are summarized in Attachment 3.

Conclusions: The toxicology databases for metiram and ETU are mostly complete. A rabbit 

developmental toxicity study is required for metiram. During registration review of metiram, the 

impact of the recently submitted metiram (acute neurotoxicity) and ETU studies (an EOGRT 

study and a rabbit developmental toxicity study) on endpoint selection, points of departure 

(PODs), and uncertainty factors/safety factors (UF/SFs) for the dietary, dermal, and inhalation 

risk assessments will be evaluated.

Residue Chemistry

Residue Chemistry

Metiram is registered in the U.S. for use on apples and potatoes. Permanent tolerances are 

established under 40 CFR §180.217(a) for residues of metiram (expressed as CS2) on apples, 

potatoes, bananas, and wine grapes (bananas and grapes as imports). There are no tolerances 

established for metiram in livestock commodities (meat, milk, etc) because there is no expected 

transfer of residues to livestock tissues from livestock eating treated feedstuffs [i.e, 40 CFR 

§180.6(a)(3), no expectation of finite residues].
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The nature of the residue in plants and livestock is adequately understood based on metabolism 

studies with potato, apple, goat and poultry. HED has concluded that the residue of concern for 

the tolerance enforcement of all regulated commodities is the parent compound metiram 

calculated as CS2. In plants the residues of concern for risk assessment are metiram and its 

metabolite ETU. The residue of concern in drinking water is ETU only. There are adequate 

methods available for the enforcement of crop tolerances with PAM Vol. II listing Methods I, II, 

II, IV, and A. Metiram is not recovered through any of the FDA Multi-Residue Method testing 

protocols. 

The residue chemistry database for metiram is incomplete. The 2007 metiram HHRA noted the 

following residue chemistry data gaps which remain outstanding:

Guideline 860.1200 Directions for Use

1) Banana: The submitted translated label for bananas (Polygram 80 WG) 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 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 registrant wishes to include higher spray volumes on 

the label, then additional residue data will be required. 

2) Grape: The submitted translated labels for grapes (Polygram DF and Polygram WG) 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 registrant had indicated that 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 860.1560 Reasonable Grounds in Support of the Petition

For the banana use, label revisions were required to satisfy the 860.1200 guideline 

requirement (directions for use) by delineating the application pattern which followed the 

field trial studies. Adequate revision of the foreign labels, or the submission of field trial 

data which support an alternate pattern of use, remains outstanding. 
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The 2007 metiram HHRA also identified the following residue chemistry data requirements. As 

part of this metiram scoping exercise, HED has determined, as explained below, that these 

requirements may now be considered fulfilled and are no longer outstanding:

Guideline 860.1380 Storage Stability 

Storage stability data for the ETU metabolite were required to support the bananas stored 

for up to 137 days (4.5 months; MRID 46655001). However, the 2005 RED for metiram 

noted that residues are stable in a diversity of crops such as apple, peanut, potato, and 

tomato, as well as apple processed commodities for up to 1 year. Additionally, 

weathered residues of ETU were found to be reasonably stable for up to 8.5 months in 

grapes. At the time of this registration, the Agency held a position that given the 

instability of the EBDC residues, storage stability data were not translatable from other 

laboratories. However, since studies have been made which demonstrate that the ETU 

metabolite is relatively stable when stored frozen for durations well past the 4.5 months 

incurred for bananas, the Agency will allow for translation of these data in this instance. 

In addition, the previous storage stability data requirement for grape raisins held 36 days 

(MRID 46501205) is no longer required. Storage stability data are not required for 

samples stored frozen for less than 30 days, and as these samples were stored for only a 

few days beyond this interval significant residue loss would not be expected, especially 

given the residue stability on multiple crops up to 1 year. This 860.1380 data requirement 

is considered fulfilled.

Guideline 860.1520 Processed Food/Feed

The submitted grape processing study provided to support PP#9E6006 was incomplete 

since it did not include residue data for the regulated processed commodity of grape 

juice. This data is no longer required as the tolerance is established for metiram on nondomestic grapes grown for wine (‘grape, wine’). Wine grapes are not typically diverted to 

markets for juice or raisins. There are processing data for wine made from grapes. This 

860.1520 data requirement is considered fulfilled.

Guideline 860.1550 Proposed Tolerances

As requirement for registration (PP#9E6006), the petitioner was to modify the tolerance 

on grapes to 5.0 ppm and propose a tolerance on raisins at 10.0 ppm. This data is no 

longer required as the tolerance is established for metiram on non-domestic grapes grown 

for wine (‘grape, wine’) at 5.0 ppm. Wine grapes are not typically diverted to markets for 

juice or raisins. A tolerance for metiram on raisins is not required at this time. This 

860.1550 data requirement is considered fulfilled.

The 2005 metiram RED identified the following residue chemistry data requirement which may 

now be considered fulfilled:

Guideline 860.1850 Confined Accumulation in Rotational Crops

The 2005 RED for metiram required a confined rotational crop study. A rotational crop 

study was submitted in 2010 (MRID 48122001) and is currently undergoing review. If 

adequate, the confined rotational crop data will be used for determining if limited field 
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trials are needed for rotational crops or if plantback restrictions need to be added to the 

existing labels. The 2005 860.1850 data requirement is considered fulfilled.

The following new residue chemistry data requirements were identified by HED during this 

registration review scoping exercise for metiram:

Guideline 860.1200 Directions for Use

Potato: If the single seed treatment on potato is being maintained, the 80% WP (EPA 

Reg. No. 7969-70) and 80% DF (EPA Reg. No. 7969-105) labels must be amended to 

specify the maximum application rate in terms of ounces or pounds ai per cwt. 

Anticipated Residue/Monitoring study (non-guideline study): Updated anticipated

residue/monitoring data are needed to support the dietary assessments for the EBDC 

pesticides, including metiram. The 1990 EBDC market basket survey previously used to 

refine the dietary assessments may be outdated, and any changes in application 

techniques, typical rates, handling, storage, and transportation could result in incurring 

different residue levels today than those reported in the 1990 survey. To allow for the 

continued use of the survey in future dietary assessments, the EBDC registrants must 

provide justification as to whether current good agricultural practices would result in 

yielding comparable residues as those found in the survey. If based on this information 

HED concludes that the market basket data are no longer reflective of current residues, a 

new market basket survey should be conducted. In that event, until adequate updated 

market basket data are submitted, HED will rely on data from available controlled studies 

(e.g. field trial data, processing studies), which will likely result in significantly greater 

risk estimates that may exceed the levels of concern.

Dietary Assessment

 

Acute, chronic, and cancer dietary risk assessments were most recently performed for metiram 

using the Dietary Exposure Evaluation Model (DEEM-FCID) Version 2.03 (D326753, C. L. 

Olinger, 04/17/2007) to support the establishment of tolerances for imported bananas and grapes. 

This model uses food consumption data from the U.S. Department of Agriculture’s Continuing 

Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998. The acute 

(probabilistic), chronic, and cancer assessments were highly refined determinations which used 

field trial data, 1990 EBDC market basket survey data for potatoes, percent crop treated/import 

estimates, and processing and cooking factors.

The drinking water exposure assessment for metiram addresses concentrations of degradate ETU 

alone, as residues of the parent compound are not expected in drinking water sources. In 2006 

EFED provided estimated drinking water concentrations (EDWCs) of ETU in surface water and 

groundwater (8/11/06, M. Ruhman and R. Parker, Estimated Drinking Water Concentrations of 

ETU (Ethylene-thio-urea, degradate of mancozeb, and common degradate of EBDCs “Ethene-bisdithio-carbamates”) for Use in Human Health Risk Assessment. D323143 and D323141). EDWCs

were derived using a both modeling and water monitoring results. The ETU EDWCs were directly 

incorporated into the dietary analyses. The dietary analyses for metiram are for food only and those

for ETU (resulting from metiram use) are for both food and drinking water. 
Metiram Registration Review Human Health Scoping Document D425218

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For acute exposure to metiram in food, the risk estimate for females 13-49 years old (the only 

population for which an acute toxicological endpoint was identified) was 22% of the aPAD. For 

acute exposure to ETU in both food and water, the risk estimate for females 13-49 years old was 

6.0% of the aPAD. 

The chronic dietary risk estimates were below the Agency’s level of concern for metiram and 

ETU for the general U.S. population and all population subgroups. The most highly exposed 

population subgroup was children ages 1-2 with an estimate for metiram for food alone of 70% 

of the cPAD. For metiram-derived ETU the chronic dietary (food and water) estimate for 

children ages 1-2 was 54% of the cPAD.

The cancer dietary (food and water) risk estimate for metiram-derived ETU was 1 x 10-6for the 

general U.S. population.

The majority of the metiram-derived ETU dietary exposure was from food sources; drinking 

water was not a large contributor to the ETU dietary exposure.

Conclusions: The metiram residue chemistry database is incomplete; label revisions for banana, 

grape, and potato are required under Guidelines 860.1200 Directions for Use and 860.1560 

Reasonable Grounds in Support of the Petition. 

In addition, HED has determined as part of this scoping exercise that updated anticipated 

residue/monitoring data (non-guideline study) are needed to support the dietary assessments of 

the EBDCs, including metiram. The previous dietary analyses for metiram/ETU were refined 

through the use of the 1990 EBDC market basket survey provided by the EBDC registrants and 

did not result in risk estimates of concern. The survey measured residues of EBDCs in a variety 

of foods as close to the point of consumption as possible (grocery stores and small markets). 

However, the market basket survey may be outdated and possible changes in application 

techniques, typical rates, handling, storage, and transportation could result in incurring different 

residue levels today than those reported in the 1990 survey. To allow for the continued use of 

the survey in risk assessments, the EBDC registrants must provide justification as to whether 

current good agricultural practices would result in yielding comparable residues. If based on this 

information HED concludes that the market basket data are no longer reflective of current 

residues, a new market basket survey should be conducted. In that event, until adequate updated 

market basket data are submitted, HED will rely on data from available controlled studies (e.g. 

field trial data, processing studies), which will likely result in significantly greater risk estimates 

that may exceed the levels of concern. 

HED may conduct a new dietary assessment if anticipated residues on food or if EFED’s revised 

EDWCs are significantly greater than those used in the most recent assessment. If new 

toxicological endpoints, PODs or UF/SFs are selected as a result of the new toxicological data 

submissions, these would also be used in any revised dietary assessments.
Metiram Registration Review Human Health Scoping Document D425218

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Residential (Non-Occupational) Exposure and Risk

There are currently no registered residential or homeowner uses for metiram; therefore, no 

quantitative handler or post-application risk estimates were calculated in the last Occupational 

and Residential exposure assessment (June 8, 2005, T. Dole, D291663, Metiram: 2nd Revised 

Occupational and Residential Exposure Assessment and Recommendations for the 

Reregistration Eligibility Decision Document). Based on a recent review of the currently 

registered labels, there are still no registered residential uses and no quantification of residential 

handler or non-occupational post-application risk estimates are required.

Residential Handlers

A residential handler exposure assessment is not required because metiram is only applied to use 

sites that are not treated by residential handlers.

Residential Post-Application 

Metiram is not registered on residential turf, lawns or golf course turf. Based on the registered 

use pattern (agricultural crops) no quantitative residential post-application exposure assessment 

is required.

Post- Application Volatilization/Spray Drift 

Residential bystander exposures resulting from off-site transport (e.g., spray drift or 

volatilization) may occur as a result of applications of metiram. The potential for spray drift will 

be evaluated for each pesticide during the Registration Review process which ensures that all 

uses for that pesticide will be considered concurrently. The approach is outlined in the revised 

(2012) Standard Operating Procedures for Residential Risk Assessment (SOPs) – Residential 

Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. 

This document outlines the quantification of indirect non-occupational exposure to drift. In 

terms of volatilization, the agency has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis1. During Registration Review, the agency will 

utilize this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological 

studies) or further analysis is required for metiram.

Conclusion: There are no residential or homeowner uses registered for metiram. A quantitative 

assessment is not anticipated to be performed under registration review for residential handlers 

or residential post-application exposure. However, HED does intend to perform a quantitative 

spray drift assessment. Based on the use pattern, no chemical specific TTR data are required. 

Additionally, the Agency will examine the need for a volatilization assessment during 

registration review.

 

1 http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219
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Aggregate Risk Assessment (Metiram; Metiram-derived ETU)

In accordance with the Food Quality Protection Act (FQPA), EPA must consider and aggregate 

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

(non-occupational) exposures. There are no residential uses of metiram. The metiram aggregate 

assessments consist of food and water only. Acute, chronic, and cancer aggregate (food and 

water) assessments were performed for metiram and metiram-derived ETU in the 2007 HHRA. 

The acute and chronic aggregate risk estimates for metiram or metiram-derived ETU were not of 

concern for any population subgroup. The previous cancer aggregate risk for metiram-derived 

ETU was estimated at 1 x 10-6.

Conclusions: As there are no homeowner or residential uses for metiram, the aggregate 

assessments consist of food and drinking water only. There were no aggregate risks of concern in 

the most recent metiram HHRA (2007). Revised acute, chronic (non-cancer), and cancer 

aggregate (food and drinking water) risk assessments will be performed for metiram and

metiram-derived ETU if there are any changes to toxicological endpoints, PODs or UF/SFs, or if 

there are significant changes to EFED’s EDWCs.

Aggregate Risk Assessment (ETU derived from all EBDC Pesticides)

ETU is a common degradate/metabolite of EBDC fungicides mancozeb and metiram; these are 

the only currently registered EBDC pesticides. In 2013, HED performed ETU aggregate 

assessments (ETU exposures from food, drinking water, and residential) for the combined uses 

of metiram and mancozeb (7/3/2013, D412678, D. Drew et al, Ethylene Thiourea (ETU); 

Aggregate Human Health Risk Assessment of the Common Metabolite/Degradate Ethylene 

Thiourea (ETU) to Support Proposed New Section 3 Use on Walnuts and Tolerance for Imported 

Tangerines).

HED conducted acute, short-term, chronic, and cancer aggregate assessments for ETU from the 

combined EBDC uses. The aggregate assessments combined the highest estimated residential 

exposures with average food and drinking water exposures. The only EBDC with residential 

uses is mancozeb. The mancozeb garden scenarios resulted in higher post-application exposures 

than the golfing scenarios; aggregate assessments using the garden scenario are protective of any 

post-application exposures to adult and youth golfers. 

The acute and chronic aggregate assessments include only dietary (food and drinking water) 

exposures. There were no acute or chronic ETU aggregate risk estimates of concern.

The short-term aggregate assessments for ETU combined residential exposures (mancozeb use) 

and average dietary (food and water; all EBDC use) exposures. There were no short-term 

aggregate risk estimates of concern (adults applying the EBDC mancozeb to gardens and adults 

or youth entering treated gardens).

The cancer aggregate assessment for ETU includes contributions from residential and dietary 

(food and water) exposures. Cancer aggregate ETU risk estimates for adults applying mancozeb 

to gardens or entering treated gardens were estimated at 2 x 10 -6 and 3 x 10-6, respectively.
Metiram Registration Review Human Health Scoping Document D425218

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Conclusions: Any ETU data gaps identified for each individual EBDC (mancozeb and metiram) 

will apply to the combined ETU aggregate assessment. Under registration review (of mancozeb 

and metiram), a revised combined ETU aggregate assessment will be performed if there are any 

significant changes made to the ETU assessments from the individual EBDCs (e.g. assessment 

methodologies, toxicological endpoints, PODs or UF/SFs, EDWCs, food residues).

Occupational Exposure

Workers can be exposed (dermally or via inhalation) to metiram and metiram-derived ETU 

through mixing, loading, and/or applying the pesticide to apples or potatoes (foliar and seed 

piece), or re-entering treated sites. Additionally, there is a Special Local Need in Florida on 

leatherleaf ferns (ornamental horticultural use).The occupational assessment includes a noncancer handler assessment for both metiram and ETU for short- and intermediate term exposure 

and a cancer assessment for ETU based on lifetime occupational exposure. Metiram is applied by 

aerial application, ground equipment (airblast), groundboom, and through chemigation 

equipment (limited states) for foliar uses and then on-farm or commercial seed piece treatment 

for the potato use. The most recent comprehensive occupational exposure assessment was 

performed for the 2005 metiram HHRA (D291661) in support of the RED.

Occupational Handlers

The 2005 RED identified risks of concern for some occupational handler exposure scenarios 

(i.e., seed treatments and crop mixer/loader scenarios); therefore, mitigation measures were 

implemented such as the requirement of additional personal protective equipment (PPE) (e.g., 

respiratory protection for handlers). Currently registered metiram labels require occupational 

handlers to wear long-sleeved shirts, long pants, shoes, socks, a dust/mist filtering respirator, and 

chemical resistant gloves. Mixer/loaders must also wear a chemical resistant apron. 

For agricultural applications, the 2005 occupational handler assessment identified combined 

dermal and inhalation MOEs for metiram (and metiram-derived ETU) that are not of concern 

(MOEs > 100) with the current label PPE (gloves plus dust/mist filtering respirator). For potato 

seed treatment, the 2005 occupational handler assessment identified MOEs of concern if PPE 

less than baseline clothing plus gloves and PF5 respiratory protection is worn. The current label 

does not require any respiratory protection for potato seed piece treatments. The handler cancer 

assessment for metiram-derived ETU resulted in estimates ranging from 10-6to 10-4.

Although occupational handler assessments have been conducted to estimate risk for all existing 

uses of metiram (including apples, potatoes [foliar and seed treatment], and leatherleaf ferns),

these assessments were not conducted based on current occupational exposure policies.

Recommended unit exposures for occupational handler assessments had generally been derived 

only from the Pesticide Handlers Exposure Database (PHED). However, recently both the 

Outdoor Residential Exposure Task Force (ORETF) and the Agricultural Handler Exposure Task 

Force (AHETF) have produced pesticide handler exposure monitoring data that the Agency is 

using in place of PHED (http://www.epa.gov/pesticides/science/handler-exposure-data.html). As 
Metiram Registration Review Human Health Scoping Document D425218

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more reliable data become available, the Agency will continue to replace existing data. New 

exposure monitoring data will be incorporated into revised occupational handler assessments, as 

necessary, during registration review.

Occupational Post-Application

There is a possibility for workers to have post-application dermal exposure to metiram and 

metiram-derived ETU in treated agricultural fields (apples, potatoes) and greenhouses (ferns). 

Post-application exposure assessments have been performed (2005) for the current uses of 

metiram (short-term and intermediate-term exposures) and metiram-derived ETU (short-term 

intermediate-term, and lifetime/cancer exposures), and mitigations have eliminated the thenidentified risks of concern.

The 2005 occupational post-application assessment for metiram did not identify any short-term 

risk estimates of concern although some intermediate-term MOEs of concern were identified for 

metiram. All of the short/intermediate term MOEs for metiram-derived ETU exceed 100 at day 

zero and were not of concern. The cancer risk estimates for metiram-derived ETU were < l x 10-5

on the day of application and declined below 1x10-6for all scenarios by 60 days after application 

(based on day 0 residues).

Since acceptable chemical-specific DFR data are available, no new DFR data are required. There 

are no turf /golf courses uses for metiram and therefore no turf transferable residue (TTR) data 

are required for the post-application assessment. Based on updated methodology, recommended 

transfer coefficients for occupational post-application assessments will be derived from 

Agricultural Reentry Task Force (ARTF) exposure monitoring studies 

(http://www.epa.gov/pesticides/science/post-app-exposure-data.html). These transfer 

coefficients were updated in 2012 based on a reanalysis and submission of new monitoring data. 

HED will incorporate new exposure monitoring data, as necessary, during registration review.

Conclusions: The occupational exposure database for metiram (and metiram-derived ETU) is 

complete. The previous occupational assessment performed (2005) utilized methodologies that 

have since been updated. Comprehensive updated quantitative handler and post-application 

occupational risk assessments (cancer and non-cancer) will be performed for all currently 

registered metiram uses and will include updated exposure assessment methodology (e.g. new 

transfer coefficients, methodology for greenhouse assessments, etc.). The available chemicalspecific dislodgeable foliar residue (DFR) data will also be considered for the post-application 

assessments. Any revisions to the toxicological endpoints, PODs, or UFs will also be 

incorporated in the occupational assessments. 

Public Health and Pesticide Epidemiology Data

HED has provided a Tier I incident report for metiram registration review scoping (3/24/2015, 

D426277, E. Evans et al, Metiram: Tier I (Scoping) Review of Human Incidents) based on 

examination of the OPP Incident Data System (IDS) and the Centers for Disease Control and 

Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event 

Notification System for Occupational Risk-Pesticides (SENSOR) databases for pesticide incident 
Metiram Registration Review Human Health Scoping Document D425218

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data on the active ingredient metiram The purpose of the database search was to identify 

potential patterns in the frequency and severity of the health effects attributed to metiram 

exposure. Metiram is not included in the Agricultural Health Survey (AHS). The Tier I incident 

report concluded the following: Because there were no incident cases reported for metiram to 

either IDS or SENSOR-Pesticides, there does not appear to be a concern at this time that would 

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

if a concern is triggered, additional analysis will be included in the risk assessment.

Tolerance Assessment and International Harmonization

Permanent tolerances are established under 40 CFR §180.217(a) for residues of metiram on 

apples, potatoes, bananas, and wine grapes (expressed as CS2). There are no tolerances 

established for livestock commodities on metiram because there is no secondary transfer of 

residues to livestock tissue from treated feedstuffs (40 CFR §180.6(a)(3), no expectation of finite 

residues). 

There are no Canadian or Mexican maximum residue limits (MRLs) established for the residues 

of metiram or EBDC fungicides in/on raw agricultural or processed commodities. However, 

there are established MRLs for the EBDC fungicides grouped as total dithiocarbamates by 

Codex which have harmonized tolerance definitions with the U.S. (residues measured as CS2). 

All U.S. tolerance levels are harmonized with the Codex MRLs to the greatest extent possible.

Despite the Codex inclusion and measurement of total dithiocarbamates, the tolerances not 

harmonized with Codex MRLs are primarily due to variation in use patterns.

A spreadsheet summarizing the U.S. and international residue limits established for metiram is 

presented in Attachment 4.

Cumulative

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to metiram and any other substances. Metiram does produce a toxic metabolite, ETU, which is 

produced by other EBDC compounds. Risks from combined exposures to ETU from all EBDC 

compounds are addressed in a separate ETU aggregate risk assessment. For information 

regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity 

and to evaluate the cumulative effects of such chemicals, see the policy statements released by 

EPA’s Office of Pesticide Programs concerning common mechanism determinations and 

procedures for cumulating effects from substances found to have a common mechanism on 

EPA’s website at http://www.epa.gov/pesticides/cumulative/.

International or Intergovernmental Work Sharing

There are no current or planned international or interagency work sharing efforts for metiram.
Metiram Registration Review Human Health Scoping Document D425218

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Data Requirements

Toxicology

The following data requirement was identified in the 2005 metiram RED (and 2007 HRRA) and 

remains outstanding:

Guideline 870.3700b: Developmental toxicity study (rabbits).

Residue Chemistry

The following data requirements were identified in the 2007 metiram HHRA and remain 

outstanding:

Guideline 860.1200 Directions for Use: The 860.1200 data requirements (submission of 

amended labels) remain outstanding for banana, grape.

Guideline 860.1560 Reasonable Grounds in Support of the Petition: Revision of the 

foreign label, or the submission of field trial data which support an alternate pattern of 

use, as per the requirement listed for banana under 860.1200 Directions for Use remains 

outstanding.

The following new data requirements were identified by HED during this registration review 

scoping exercise for metiram:

Guideline 860.1200 Directions for Use: Submission of amended labels are required for 

the potato use.

Anticipated Residues/Monitoring study (non-guideline study): Updated anticipated

residue/monitoring data are needed to support the dietary assessments of the EBDC 

pesticides, including metiram. The 1990 EBDC market basket survey previously used to 

refine the dietary assessments may be outdated, and any changes in application 

techniques, typical rates, handling, storage, and transportation could result in incurring 

different residue levels today than those reported in the 1990 survey. To allow for the 

continued use of the survey in future dietary assessments, the EBDC registrants must 

provide justification as to whether current good agricultural practices would result in 

yielding comparable residues as those found in the survey. If based on this information 

HED concludes that the market basket data are no longer reflective of current residues, a 

new market basket survey should be conducted. In that event, until adequate updated 

market basket data are submitted, HED will rely on data from available controlled studies 

(e.g. field trial data, processing studies), which will likely result in significantly greater 

risk estimates that may exceed the levels of concern.
Metiram Registration Review Human Health Scoping Document D425218

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References

D291663, Metiram: 2nd Revised Occupational and Residential Exposure Assessment and 

Recommendations for the Reregistration Eligibility Decision Document, T. Dole, 6/8/2005.

D291661, Metiram. Health Effects Division (HED) Human Health Risk Assessment to Support 

Reregistration, K. Farwell, 6/13/2005.

D318476, Metiram. Revised Residue Chemistry Chapter of the Reregistration Eligibility 

Decision, C. Olinger, 6/23/2005.

USEPA, August 2005 Metiram Reregistration Eligibility Decision (RED).

D323143 and D323141, 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. M. Ruhman and R. Parker, 8/11/2006.

D326753, Metiram Acute, Chronic, and Cancer Dietary Exposure Assessments for New 

Tolerances on Imported Grapes and Bananas, C. Olinger, 4/17/2007. 

D267866, Metiram: Human Health Risk Assessment for PP#9E6006. Petition for the 

Establishment of Import Tolerances on Grapes and Bananas, T.Goodlow, 6/14/2007.

D412565 and D412566, Mancozeb. Revised Acute, Chronic, Cancer Dietary Risk Assessments 

for Food and Drinking Water, as well as Aggregate Assessment for the Common 

Metabolite/Degradate ETU Resulting from the Combined Uses of the EBDC Fungicides to 

Support the New Use of Mancozeb on Walnuts and the Establishment of a Tolerance on 

Imported Tangerines for Section 3 Registration, P. Savoia, 07/01/2013.

D412678, Ethylene Thiourea (ETU); Aggregate Human Health Risk Assessment of the Common 

Metabolite/Degradate Ethylene Thiourea (ETU) to Support Proposed New Section 3 Use on 

Walnuts and Tolerance for Imported Tangerines). D. Drew, 7/3/2013.

D426277, Metiram: Tier I (Scoping) Review of Human Incidents), E. Evans et al, 3/24/2015.

TXR 0055055, Metiram: Summary of Hazard and Science Policy Council (HASPOC) Meeting 

of April 30, 2015: Recommendation on the Requirements for Subchronic Neurotoxicity and 

Immunotoxicity Studies.

D425216, Mancozeb: Human Health Risk Assessment Scoping Document in Support of 

Registration Review, D. Drew, 6/1/2015.

 
Metiram Registration Review Human Health Scoping Document D425218

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Attachments

Attachment 1. Chemical Identity

Attachment 2. Toxicity Profile Tables

Attachment 3. Endpoint Tables

Attachment 4. International Residue Limits 
Metiram Registration Review Human Health Scoping Document D425218

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Attachment 1. Chemical Identity 

Physical and Chemical Properties of 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 trimolecular cyclic anhydrosulfides and disulfides);

Table A1.1 Metiram Nomenclature.

Compound

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 A1.2 Physicochemical Properties of Metiram.

Parameter Value Reference

Melting point/range decomposes at ~140 oC Product Chemistry Chapter of 

the Metiram Update, 

8/11/1992

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

UV/visible absorption spectrum Not available

HN

S

HN

Zn

S

S

S

HN

S

HN

S

S

S

3

x
Metiram Registration Review Human Health Scoping Document D425218

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Attachment 2. Toxicity Profile Tables

METIRAM Toxicity Profile

Table A2.1. Acute Toxicity of MetiramGuideline 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 48068801 LOAEL = 2000 mg/kg, based 

on decreased motor activity and 

an increase in the number of 

rearings 

N/A

Table A2.2 METIRAM Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral 

toxicity (SpragueDawley CFY rat)

00126738 (1977)

40290601 (1987)

Acceptable/guideline

(0, 50, 100, 300, 900 

ppm)

Males: 0, 3, 6, 20, 61 mkd

Females: 0, 4, 8, 24, 76 

mkd

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).

At 900 ppm, 2/15 males had follicular cell 

hyperplasia

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

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

based on muscle lesions in females (5/15), ↓T4, 

decreased [

131I] uptake.

At the highest dose, 900 ppm (males 61, 

females 76 mg/kg/day), skeletal muscle atrophy

(characterized by a narrowing of muscle fibers with 

reduced sarcoplasm and/or the presence of adipose 

cells in muscle bundles) were seen in both sexes,

↓T4 (4/15 ♂; 11/15 ♀), and females also had 

hindlimb paralysis (stilted and rolling hindlimb 

gait, impaired reflexes (grip, righting, flexor).
Metiram Registration Review Human Health Scoping Document D425218

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Table A2.2 METIRAM Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral 

toxicity (Wistar 

rat)

42539101 (1992)

Acceptable/guideline

0, 5, 80, 320, 960 ppm

Males: 0, 0.4, 5.8, 23.5, 

73.9 mg/kg/day

Females: 0, 0.4, 6.7, 27.3, 

88.8 mg/kg/day

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.

870.3100 90-Day oral 

toxicity (B6C3F1 

mouse)

42595001 (1992)

Acceptable/guideline

0, 300, 1000, 3000, 7500 

ppm

Males: 0, 84, 302, 853, 

2367 mg/kg/day

Females: 0, 133, 465,

1448, 3565 mg/kg/day 

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 body-weight gain in females.

Thyroid lesions [hypertrophy and vacuolation 

of the follicular epithelium] were observed only 

at the two highest dose levels in both sexes 

[dose-related for severity; all rats in these 

groups display both lesions]. 

870.3150 90-Day oral 

toxicity (dog)

No study available; see chronic

870.3150 90-Day oral 

toxicity (monkey)

00031591 (1979)

Acceptable/non-guideline

0, 5, 15, 75 mg/kg/day

26 weeks (gavage)

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 ↓ bodyweight gain.

870.3200 21/28- Day dermal 

toxicity (species)

404797001 (

Acceptable

Systemic NOAEL = not established; however, 

an 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.
Metiram Registration Review Human Health Scoping Document D425218

Page 24 of 40

Table A2.2 METIRAM Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3465 90-Day inhalation 

toxicity (SpragueDawley CD rat)

00164083 (1986)

40044701 (1986)

40713301 (1987)

Acceptable/guideline

0, 2.1, 20, and 101 mg/m3 

[mean aerodynamic 

diameter of 3.1±1.8 

microns].

ETU 0, 0.2, 0.32, 1.8 

mg/m3

6 hr/day, 5 days/wk

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. HDT, decreased terminal BW (males 

17%) and increased lung weight (both sexes).

870.3700a Prenatal 

developmental in 

[Sprague-Dawley 

Crl:COBS CD SD 

BR rats]

00030565 (1979)

Acceptable

0, 40, 80, 160 mg/kg/day

GD 6-15

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.

RF: @150 mkd, increased activity, slight 

impairment of grasping and hindlimb support 

reflexes, lethargy, catalepsy, paralysis and 

death (days 6-8) at 300-1200 mkd.

870.3700b Prenatal 

developmental in 

[Himalayan 

Chbb:HM rabbit]

40711401 (1988)

Unacceptable/nonguideline

0, 10, 40, 120 mg/kg/day 

GD 7-19

Maternal NOAEL = 10 mg/kg/day,

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

abortions.

There was excessive maternal toxicity at the 

highest dose: one death on GD 28, 8 abortions

(GD 21-28) and negative body-weight gain), 

and the mid-dose does displayed a similar, but 

less severe, toxicity [2 abortions (GD 26, 27) 

and negative body-weight gain during the 

dosing period).

Developmental NOAEL = not established 

Developmental LOAEL = not established 

abortions were observed at 40 and 120 mkd.

(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.)
Metiram Registration Review Human Health Scoping Document D425218

Page 25 of 40

Table A2.2 METIRAM Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3800 Reproduction and 

fertility effects

(Crl:COBS CD 

(SD) BR rat)

00098431

Unacceptable/nonguideline

0, 5, 40, 320 ppm

Males: 0.2, 1.8, 14.2 

mg/kg/day

Females: 0.3, 2.3, 19.8 

mg/kg/day.

Diet 60 days pre-mating;

1♂:2♀ mating; 2 

generations

/2 litters/generation

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.

Previous DATA GAP - Study available is

Unacceptable because of the lack of one-to-one 

pairing and lack of histopathological 

examination of reproductive and target organs). 

ETU EOGRTS satisfies reproductive toxicity 

study requirement for metiram. 

870.4100a Chronic toxicity

[CD SpragueDawley rat]

00098449 (1981)

00098450 (1981)

41163102 (1989)

Acceptable/guideline for 

chronic phase with MRID 

42539101*

0, 5, 20, 80, 320 ppm

Males: 0, 0.2, 0.8, 3.1, 

12.3 mg/kg/day

Females: 0, 0.2, 1.0, 3.8, 

15.5 mg/kg/day

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.

870.4100a Chronic toxicity

[Strain] rat

870.4100b Chronic toxicity 

(Beagle dog)

42133101 (1991)

42491401 (1992)

Acceptable/guideline

0, 30, 80, 1000, 3000 ppm

Males: 0.91, 2.49, 29.84, 

76.85 mg/kg/day

Females: 0, 1.05, 2.69, 

29.89, 92.69 mg/kg/day 

one year.

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 (↓T4 in 

males)/anemia, increased thyroid weight and 

follicular (thyroid) hyperplasia (all dogs).

At HDT, ↓T4 (both sexes), increased thyroid 

weight (both sexes), thyroid follicular 

hyperplasia in all dogs.
Metiram Registration Review Human Health Scoping Document D425218

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Table A2.2 METIRAM Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.4200 Combined 

Chronic/

Carcinogenicity

( CD SpragueDawley rat)

00098449 (1981)

00098450 (1981)

41163102 (1989)

Acceptable/guideline for 

chronic phase (see under 

870.4100a) 

Unacceptable/guideline 

for carcinogenicity 

component; guideline not 

satisfied

0, 5, 80, 320 ppm

Males: 0, 0.2, 0.8, 3.1, 

12.3 mg/kg/day

Females: 0, 0.2, 1.0, 3.8, 

15.5 mg/kg/day

Lack of any significant effect on survival, 

body-weight, or body-weight gain, indicates the 

rats could have tolerated higher dose levels. 

HED concluded the dose levels were 

inadequate for assessing carcinogenic potential.

870.4300 Carcinogenicity

(CFLP mouse)

00030245 (1979)

41163101 (1976) 4-week

Unacceptable/guideline

0, 100, 300, 1000 ppm

Males: 0, 8, 24, 79 

mg/kg/day

Females: 0, 9, 29, 95 

mg/kg/day

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 treatmentrelated thyroid tumors were observed. The 

CARC concluded this study is Unacceptable.

Gene 

Mutation

870.5100

Salmonella 

typhimurium

TA98, TA100, 

TA1535, TA1537, 

TA1538

Negative±S9

Mammalian 

cell forward 

gene 

mutation 

assay

870.5300

CHO/HGPRT

SD-rat

00148682 (1985)

Acceptable/guideline

0.681-100 μg/mL

Positive without S9, marginally positive with 

S9.

Gene 

Mutation

870.5100

mouse hostmediated

TA 1530 as 

indicator strain and 

CD-1 mice as host 

00148680 (1985)

Acceptable

dose levels of 0, 500, 670 

and 5000 mg/kg

Negative

In vitro

chromosomal 

aberration 

assay

870.5375

Chinese hamster 

ovary (CHO) cells 

(+/-S9)

Weak, but concentration-related increases in 

SCEs ±mouse S9 and –rat S9
Metiram Registration Review Human Health Scoping Document D425218

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Table A2.2 METIRAM Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

Structural 

chromosomal 

alterations 

(rat bone 

marrow) 

cytogenetics 

and in vivo 

chromosomal 

aberrations

single 2.4 gm/kg 

or 5 x 0.2 

gm/kg/day in male 

rats -

00163786 (1986)

Acceptable/guideline

Negative - no significant increases in 

chromosomal aberrations in bone marrow cells 

sampled over complete mitotic cycle

In vivo 

mouse 

micronucleus 

assay

870.5395

CD-1 mouse

Other Effects 

870.5500

DNA damage in 

Bacillus subtilis

Other Effects 

870.5900

Chinese hamster 

ovary cells

in vitro sister 

chromatid 

exchange assay 

(SCE/CHO)

00148681 (1985)

Acceptable/guideline

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

Other 

Genotoxic 

Effects

[870.5550]

Unscheduled DNA 

Synthesis

Rat primary 

hepatocyte

dose range of 

0.492-49.2 μg/mL

00149528 (1984) Negative - did not induce unscheduled DNA 

synthesis 

870.6200a Acute 

neurotoxicity 

screening battery 

rat

48068801 (2010)

Acceptable/guideline

0, 125, 500, 2000 mg/kg

NOAEL= 500 mg/kg. 

LOAEL = 2000 mg/kg, based on decreased 

motor activity in both sexes on Day 0 (6 hours 

post dose) and an increase in the number of 

rearings on Day 0 (2 hours post dose) in males 

compared to the concurrent controls following 

acute oral exposure. 

870.6200b Subchronic 

neurotoxicity 

screening battery

Rat

Study requirement waived (HASPOC 4/30/15 

meeting; TXR 0055055) 

870.6300 Developmental 

neurotoxicity

See ETU EOGRTS

(MRID 49140301)
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Table A2.2 METIRAM Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.7485 Metabolism and 

pharmacokinetics

(CD rat)

00155160 (1985)

40645501 (1983)

Acceptable/guideline

5 and 50 mg/kg single

5 mg/kg/day repeat (14-

day)

Rapidly absorbed and eliminated via urine, 

feces and expired air. 

At 5 mg/kg, males excreted 37%, 65%, 0.4%; 

females 47%, 54%, 1.1% in urine, feces, 

expired air, respectively after 7 days.

At 50 mg/kg, males excreted 21%, 79%, 0.5%; 

females 25%, 72%, 1.1%, respectively after 7 

days.

Repeat 5 mg/kg/day similar to results after 

single dose

ETU comprised 30% of the 0-24 hour urine 

radioactivity;

70% of low dose/30% of high dose was 

absorbed. 

Accumulation in tissues after repeated 

administration: thyroid, GIT, and kidneys had 

highest levels

870.7600 Dermal penetration 

(rat)

000155161 (1984)

870.7800 Immunotoxicity

[Species/strain]

Study requirement waived (HASPOC 4/30/15 

meeting; TXR 0055055)

ETU Toxicity Profile

Table A2.3 ETU Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral 

toxicity 

(Crl:CD(SD) rat)

000160704/1986

Acceptable/non-guideline

250 ppm 

males: 14.28 mg/kg/day 

females: 17.81 mg/kg/day

NOAEL = <14.28 mg/kg/day

LOAEL = 14.28 mg/kg/day, based on reduced 

body weight, changes in thyroid hormone and 

TSH levels, increased thyroid and liver weight, 

microscopic thyroid hyperplasia and liver 

hypertrophy.

870.3100 90-Day oral 

toxicity (CD-1 

mouse)

00154192/1985

Unacceptable/Guideline 

0, 1, 10, 100, 1,000 ppm 

males: 0, 0.16, 1.72, 

18.18, 168.2 mg/kg/day 

females: 0, 0.22, 2.38, 

24.09, 231.1 mg/kg/day

NOAEL = 1.72 mg/kg/day

LOAEL = 18.18 mg/kg/day, based on 

microscopic thyroid hypertrophy/hyperplasia.

At the high dose, more microscopic thyroid 

changes and increases in thyroid and liver 

weight occurred. 

Unacceptable because ETU concentrations 

varied widely.
Metiram Registration Review Human Health Scoping Document D425218

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Table A2.3 ETU Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3150 90-Day oral 

toxicity (Beagle 

dog)

42174201/1991

Acceptable/Guideline

0, 10, 150, 2000 ppm 

males: 0, 0.39, 6.02, 66.23 

mg/kg/day 

females: 0, 0.42, 6.51, 

71.62 mg/kg/day

NOAEL = 0.39 mg/kg/day

LOAEL = 6.02 mg/kg/day, based on elevated 

cholesterol. (Note: this endpoint was not 

considered robust enough for use in risk 

assessment)

At 6.02 mg/kg/day, no thyroid effects were 

observed.

In high dose group: mortality, anemia, 

decreased activity, decreased thyroid hormone 

levels, increased thyroid weight, microscopic 

thyroid hyperplasia.

870.3150 4-Week Rangefinding 

(Beagle dog)

41863401/1989

Acceptable/non-guideline

0, 196, 980, 4900 ppm

males: 0, 7.0, 34, or 172 

mg/kg/day 

females: 0, 8.0, 36, or 197 

mg/kg/day

NOAEL = 7 mg/kg/day

LOAEL = 34 mg/kg/day, based on decreased 

levels of thyroid hormones, gross thyroid 

lesions.

At HDT, decreased body weight and food 

consumption in addition to thyroid effects. 

Histopathology and organ weights were not 

assessed.

870.3200 21/28- Day dermal 

toxicity (species)

Not presented to HASPOC since ETU is metabolite/degradate

Data requirement not applicable

870.3465 90-Day inhalation 

toxicity (species)

Not presented to HASPOC since ETU is metabolite/degradate

Data requirement not applicable

870.3700a Prenatal 

developmental in 

[SD BR rat]

00093929/1980

Acceptable/non-guideline

Maternal NOAEL = <50 mg/kg/day

Maternal LOAEL = 50 mg/kg/day, based on 

decreased body weight gain (↓36%).

Developmental NOAEL = <50 mg/kg/day

Developmental LOAEL = 50 mg/kg/day, based 

on numerous central nervous system defects 

(hydrocephaly and related malformations); 

gross developmental defects; skeletal defects; 

and decreased fetal weight (↓13%).

Only one dose group was included in the study.
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Table A2.3 ETU Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3700a Prenatal 

developmental in 

[Wistar rat]

45937601/1973

Acceptable/Non-guideline

[Khera, K.S. 1973. 

Teratology 7:243-252]

0, 5, 10, 20, 40, 80 

mg/kg/day

Dosing: 21-42 days before 

conception to pregnancy 

day 15, and on days 6-15 

or 7-20 of pregnancy

Maternal NOAEL = 40 mg/kg/day

Maternal LOAEL = 80 mg/kg/day, based on 

mortality (9 of 11after 7-8 days).

Developmental NOAEL = 5 mg/kg/day

Developmental LOAEL = 10 mg/kg/day based 

on exencephaly, dilated ventricles, and 

hypoplastic cerebellum. 

At 20 mg/kg/day, hydrocephalus, 

encephalocele, meningocele, micrognathia, 

abnormal flexion of ankle, kinky or twisted tail; 

at ≥40 mg/kg/day: oligodactyl, domed head, 

retarded ossification of the skull occurred; at 

80 mg/kg/day: coloboma of the eyelids, 

hemimelia, syndactyl, cleft palate, ectopic 

kidney, rudimentary calvarium, short tail, 

scoliosis and several types of skeletal 

anomalies occurred. Decreased fetal weight 

was noted at 40 mg/kg/day in group I (↓10%) 

and group III (↓21%) and at 80 mg/kg/day in 

group II (↓44%). Fetuses at 40 mg/kg/day in 

group II had weights comparable to controls. 

Number of live fetuses and corpora lutea were 

comparable to controls in all groups. 

870.3700a Prenatal 

developmental in 

[Sprague-Dawley 

rats]

45924404/1979

[Chernoff, et al., J. 

Toxicol. Env. Health 5: 

821-834]

0, 5, 10, 20, 30, 40, or 80 

mg/kg/day (GD 7-21)

0, 20, 25, or 30 mg/kg/day 

(GD 7 to PND 15)

Maternal NOAEL = 40 mg/kg/day (or lower).

Maternal LOAEL = 80 mg/kg/day, based on 

reduced body weight and 25% maternal 

mortality.

Gestational exposure only:

Developmental NOAEL = 10 mg/kg/day (↓7% 

fetal BW)

Developmental LOAEL = 20 mg/kg/day, based 

on hydrocephalus (12 fetuses/5 litters).

Decreased ossification was also observed at 30 

mg/kg/day and above; at 40 mg/kg/day, 

encephalocele, kyphosis, and digit defects 

(oligodactyl, syndactyl) were also observed. At 

80 mg/kg/day, fetal mortality was increased 

and there were increases in cleft palate, limb 

defects (micromelia, hemimelia), edema, and 

micrognathia. 

Gestational and postnatal exposure:

Postnatal toxicity at

30 mg/kg/day included hydrocephalus, domeshaped heads, and pup mortality. 
Metiram Registration Review Human Health Scoping Document D425218

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Table A2.3 ETU Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3700a Prenatal 

developmental in 

[Wistar rat]

MRID 48985801

[Khera and Tryphonas 

Tox Appl Pharm 42:85-

97. 1977]. 

Acceptable/non-guideline

0, 15, 30, 45 mg/kg

Dams received a single 

oral dose on gestation 

day 15.

Maternal NOAEL/LOAEL not reported

Developmental NOAEL = 15 mg/kg

Developmental LOAEL = 30 mg/kg based on 

postnatal mortality, hydrocephaly, 

microphthalmia, cerebellar dysplasia, cerebral 

atrophy, and in survivors, motor defects and 

dome-shaped head.

870.3700a Prenatal 

developmental in 

[Wistar rat]

No MRID 

[Ruddick and Khera. 

Teratology 12:277-282, 

1975]

Acceptable/non-guideline

0 or 240 mg/kg

Dams received a single 

dose on one gestation day 

between GD 6-21

No maternal toxicity observed.

Teratogenic effects in fetuses from GD 10-21; 

greatest frequency of defects between GD 12-

15; no defects before GD 10; ETU affected 

development of brain, kidney, eye, and axial 

and appendicular systems

870.3700a Prenatal 

developmental in 

[SD rat]

No MRID 

Saillenfait, et al., Fund. 

Appl. Toxicol. 17: 300-

408, 1991

Acceptable/non-guideline

0, 15, 25, or 35 mg/kg/day 

from GD 6-20

Maternal NOAEL not attained.

Maternal LOAEL = 15 mg/kg/day, based on 

decreased body weight gain

Developmental NOAEL = 15 mg/kg/day

Developmental LOAEL = 25 mg/kg/day, based 

on dilated ventricles of the brain, hydroureter, 

short/kinky tail, and dilated ureters. At 35 

mg/kg/day, hydrocephaly, anencephaly, 

meningocele, meningorrhea, hyrdronephrosis, 

dilated renal pelvis, and vertebral abnormalities 

were observed.

870.3700a Prenatal 

developmental in 

[Wisrar Imamichi 

rat]

45924405/1978

[Teramoto, et al., 

Congenital Anomalies 18: 

11-17, 1978]

Acceptable/non-guideline

0, 10, 20, 30, 40, 50 

mg/kg/day 

GD 6-15.

Developmental NOAEL <10 mg/kg/day

Developmental LOAEL = 10 mg/kg/day, based 

on dilated brain ventricles. At higher doses, 

fetal death, meningocele, micrognathia, 

hydronephrosis, renal agenesis, uterine 

hypoplasia, skeletal anomalies, short/kinky tail, 

and scoliosis were observed. 

870.3700b Prenatal 

developmental in 

[New Zealand 

White rabbit]

47976403/2010

Acceptable/Guideline

0.5% aqueous 

methylcellulose

0, 5, 15, 50 mg/kg/day

GD 7-29

Maternal NOAEL = 5 mg/kg/day

Maternal LOAEL = 15 mg/kg/day based on 

increased postimplantation loss

Developmental NOAEL = 5 mg/kg/day 

Developmental LOAEL = 15 mg/kg/day based 

on increased postimplantation loss

At 50 mg/kg/day, postimplanation loss, 

decreased fetal BW (↓10%), hydrocephaly (1), 

and domed head (2) were observed.
Metiram Registration Review Human Health Scoping Document D425218

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Table A2.3 ETU Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3700b Prenatal 

developmental in 

[Syrian Golden 

hamsters

45924405/1978

Acceptable/non-guideline

[Teramoto, et al., 

Congenital Anomalies 18: 

11-17, 1978]

0, 90, 270, 810 mg/kg/day 

from GD 6-13.

Developmental NOAEL = 90 mg/kg/day

Developmental LOAEL = 270 mg/kg/day, 

based on skeletal malformations and 

short/kinky tail. At 810 mg/kg/day, fetal deaths, 

dilated brain ventricles, cleft palate, 

micrognathis, and anal atresia were observed.

870.3700b Prenatal 

developmental in 

[JCL-ICR mouse]

45924405/1978

Acceptable/non-guideline

[Teramoto, et al., 

Congenital Anomalies 18: 

11-17, 1978]

0, 200, 400, or 800 

mg/kg/day.

GD 7-15

No maternal or developmental toxicity was 

observed.

870.3800 Reproduction and 

fertility effects

(Sprague-Dawley 

rat)

42391701/1992

Unacceptable/Nonguideline 

42391801/1992

ETU content data 

0, 2.5, 25, 125 ppm

Doses on mg/kg/day basis could not be 

determined.

Parental: microscopic thyroid 

hyperplasia/hypertrophy in mid and/or highdose groups.

No reproductive effects attributed to treatment.

Unacceptable because of stability problems 

(mkd could not be calculated) with test material 

and poor record keeping.

870.3800 Reproduction and 

fertility effects

(Crl:CD(SD) rat)

49140301/2013

Acceptable/OECD 

guideline

0, 2.8, 28, 140 ppm 

0, 0.2, 2, 10 mg/kg/day

4 weeks prior to mating; 

14-day mating period), 

through gestation, 

lactation to weaning; 

Parental males from day 

44 for 7 weeks until 

sacrifice

Parental females through 

gestation/lactation (LD 0-

22)

NOAEL = 140 ppm (10 mg/kg/day).

LOAEL = not attained.

No effects on reproductive indices, precoital 

intervals, gestation length, gonadal function,

estrous cycle, sperm maturation, parturition, 

lactation, or tissues and organs of the 

reproduction system. 

870.4100a Chronic toxicity

Fischer 344 rat 

45924403/1992

Fund. Appl. Tox. 18: 405-

417 (feeding NTP)

w/ and w/out perinatal

Thyroid follicular cell adenomas and pituitary 

adenomas were observed.
Metiram Registration Review Human Health Scoping Document D425218

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Table A2.3 ETU Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.4100b Chronic toxicity 

(Beagle dog)

42338101/1992

Acceptable/Guideline

0, 5, 50, or 500 ppm

males: 0, 0.18, 1.99, 20.13 

mg/kg/day 

females: 0, 0.19, 1.79, or 

20.15 mg/kg/day

NOAEL = 0.18 mg/kg/day

LOAEL = 1.99 mg/kg/day, based on increased 

thyroid weight and microscopic changes in 

thyroid (hypertrophy, follicular dilatation).

At the high dose, mortality, anemia, and 

microscopic hepatocellular necrosis.

870.4200 Combined 

Chronic/

Carcinogenicity

(SD rat)

42607801/1992

Unacceptable/Guideline 

0, 0.5, 2.5, 5.0, or 125 

ppm

Males: 0, 0.04, 0.17, 0.37, 

8.91 mkd

Females: 0, 0.05, 0.25, 

0.49, 13.57 mkd

Concentration of ETU in feed varied widely 

and doses could not be determined. 

Microscopic thyroid hyperplasia occurred in 

the low-dose group. At higher doses, changes 

in thyroid hormone and TSH levels, increased 

thyroid weight, and grossly enlarged livers. 

Increases in thyroid follicular adenomas and 

pituitary adenomas in high-dose males. 

870.4300 Carcinogenicity

(B6C3F1 mouse) 

45924403/1992

Fund. Appl. Tox. 18: 405-

417 (feeding NTP)

w/ and w/out perinatal 

exposure

This study was used to determine the Q1* for 

ETU of 6.01 x 10-2(mg/kg/day)-1 based upon 

female mouse liver adenomas and/or 

carcinomas. Thyroid follicular cell adenomas 

and carcinomas, hepatocellular adenomas and 

carcinomas, and pituitary adenomas were 

increased. 

870.6200a Acute 

neurotoxicity 

screening battery 

rat

Not required for metabolite; the thyroid is the target organ for ETU; injury to 

the peripheral nerves is observed in studies following exposure to mancozeb 

and metiram but not to ETU. 

870.6200b Subchronic 

neurotoxicity 

screening battery

rat

Not required for metabolite; the thyroid is the target organ for ETU; injury to 

the peripheral nerves is observed in studies following exposure to mancozeb 

and metiram but not to ETU.

870.6300 Developmental 

neurotoxicity

[Crl:CD(SD) rat]

49140301/2013

Acceptable/OECD 

guideline

0, 2.8, 28, 140 ppm 

0, 0.2, 2, 10 mg/kg/day

4 weeks prior to mating; 

14-day mating period), 

through gestation, 

lactation to weaning; 

Parental males from day 

44 for 7 weeks until 

sacrifice

Parental females through 

gestation/lactation (LD 0-

22)

NOAEL = 28 ppm (2 mg/kg/day).

LOAEL = 140 ppm (10 mg/kg/day), based on 

decreased brain size.

870.7485 Metabolism and 

pharmacokinetics

(species)

Not required for metabolite

870.7600 Dermal penetration 

(SD COBS CD rat)

40312601/1987

Acceptable

Dermal absorption = 26%
Metiram Registration Review Human Health Scoping Document D425218

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Table A2.3 ETU Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.7800 Immunotoxicity

[Wistar rat]

48794502/2012

Acceptable/Guideline

0, 10, 50, 250 mg/kg/day

Males: 0, 1, 4, 19 

mg/kg/day

Negative for Immunotoxicity

Thyroid toxicity observed at all dose levels.

OECD 443 Extended onegeneration 

reproductive 

toxicity

[Crl:CD(SD) rat]

49140301/2013 Under Review
Metiram Registration Review Human Health Scoping Document D425218

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Attachment 3. Toxicity Endpoint Tables

Table A3.1. Metiram Toxicological Doses and Endpoints Used in Previous (2007) in Human Health 

Risk Assessment.

Exposure

Scenario

Dose Used in Risk Assessment

and Uncertainty Factors

RfD, PAD, LOC Study and Toxicological Effects

Metiram Dietary Exposures

Acute Dietary 

Females 13 - 50

NOAEL = 10 mg/kg/day

UF = 100X (inter and 

intraspecies)

FQPA UFDB = 10x 

Total UF = 1000X

Acute RfD = 0.01 mg/kg/day

aPAD = 0.01 mg/kg/day

Developmental Toxicity (Rabbit)

LOAEL = 40 mg/kg/day, based on 

abortions.

Acute Dietary 

General Population

N/A No appropriate endpoint attributable to a single exposure (dose) was 

identified.

Chronic Dietary NOAEL = 0.4 mg/kg/day

UF=100X (inter and intraspecies)

FQPA UFDB = 10x 

Total UF = 1000X

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; use low-dose 

extrapolation for human risk assessment, based on ETU.

Metiram Incidental Oral Exposures [Residential/Postapplication]

Short-Term

[1-30 days]

NOAEL = 6.7 mg/kg/day

UF = 100X (inter and 

intraspecies)

FQPA UFDB = 10x 

Total UF = 1000X

LOC

Residential MOE = 1000

Occupational MOE = N/A

Subchronic Oral Toxicity (Rat, 

bridging study)

LOAEL= 27.3 mg/kg/day based on 

decreased forelimb grip strength

Intermediate-Term

[30 days - 6 months]

NOAEL = 0.4 mg/kg/day

UF = 100X (inter and

intraspecies)

FQPA UFDB = 10x 

Total UF = 1000X

LOC

Residential MOE = 1000

Occupational MOE = N/A

Subchronic Oral Toxicity (Rat, 

bridging study)

LOAEL= 6.7 mg/kg/day based on 

decreased forelimb grip strength

Metiram Dermal Exposures

Short-Term

[1-30 days]

NOAEL = 6.7 mg/kg/day

UF = 100X (inter and 

intraspecies)

FQPA UFDB = 10x 

Total UF = 1000X

LOC

Residential MOE = 1000

Occupational MOE = 100

Subchronic Oral Toxicity (Rat, 

bridging study)

LOAEL= 27.3 mg/kg/day based on 

decreased forelimb grip strength at 

early time point

Intermediate-Term, 

Long-Term 

[>30 days - 6 months, 

> 6 months]

NOAEL = 0.4 mg/kg/day

UF = 100X (inter and 

intraspecies)

FQPA UFDB = 10x 

Total UF = 1000X

LOC

Residential MOE = 1000

Occupational MOE = 100

Subchronic Oral Toxicity (Rat, 

bridging study)

LOAEL= 6.7 mg/kg/day based on 

decreased forelimb grip strength

Inhalation Exposures

Inhalation NOAEL = 0.5 mg/kg/day

UF=100X (inter and intraspecies)

LOC

Residential MOE = 1000

13-week Inhalation Toxicity, Rat
Metiram Registration Review Human Health Scoping Document D425218

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Table A3.1. Metiram Toxicological Doses and Endpoints Used in Previous (2007) in Human Health 

Risk Assessment.

Exposure

Scenario

Dose Used in Risk Assessment

and Uncertainty Factors

RfD, PAD, LOC Study and Toxicological Effects

(Any Duration, i.e., 1 

day to more than 180 

days)

FQPA UFDB = 10x 

Total UF = 1000X

Occupational MOE = 100 LOAEL = 5.1 mg/kg/day based on 

lung lesions (alveolitis).

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). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. 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. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Table A3.2 Summary of Toxicological Doses and Endpoints for ETU Used in Dietary and NonOccupational Human Health Risk Assessments 

Exposure PoD Safety Factors RfD, PAD, LOC Study and Tox

ETU Acute Dietary Exposure

Acute Dietary 

(General Pop, 

including Infants 

and Children)

N/A N/A N/A A study with acute toxicity applicable 

to the general population was not 

identified.

Acute Dietary

(Females 13-49 

years old)

NOAEL= 5 

mg/kg/day

UFA= 10x

UFH = 10x

FQPA UFDB = 

10x

Acute RfD = 0.005 

mg/kg/day

aPAD = 0.005 

mg/kg/day

Developmental Rat Toxicity

MRID No. 45937601 (1973)

LOAEL = 10 mg/kg/day, based on 

hydrocephaly and other malformations

ETU Chronic Dietary Exposure

Chronic Dietary 

(Females 13-49 

years of age and 

Children < 6 

years)

NOAEL= 

0.18 

mg/kg/day

UFA= 10x

UFH = 10x

FQPA UFDB = 

10x

Chronic RfD = 

0.00018

mg/kg/day

cPAD = 0.00018 

mg/kg/day

Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

Chronic Dietary 

(Adult Males, 

Females >49 

years, Children ≥ 

6 years)

NOAEL= 

0.18 

mg/kg/day

UFA= 10x

UFH = 10x

FQPA SF = 1x

Chronic RfD = 0.0018

mg/kg/day

cPAD = 0.0018 

mg/kg/day

Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

ETU Incidental Oral Exposure

Short -

Term Oral 

(Children < 6 

years of age)

NOAEL= 7 

mg/kg/day

UFA= 10x

UFH=10x

FQPA UFDB = 10x

LOC = 1000 4-week range-finding dog study

MRID 41863401 (1989)

LOAEL= 34 mg/kg/day based on 

thyroid toxicity

ETU Residential Dermal Exposure

Dermal Short and

IntermediateTerm (Children` 

< 6 years of age)

NOAEL= 7 

mg/kg/day

UFA= 10x

UFH=10x

FQPA UFDB = 10x

LOC = 1000 4-week range-finding dog study

MRID 41863401 (1989)

LOAEL= 34 mg/kg/day based on 

thyroid toxicity
Metiram Registration Review Human Health Scoping Document D425218

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Table A3.2 Summary of Toxicological Doses and Endpoints for ETU Used in Dietary and NonOccupational Human Health Risk Assessments 

Exposure PoD Safety Factors RfD, PAD, LOC Study and Tox

Dermal Short and

IntermediateTerm (Adult 

Males, Females 

>49 years, 

Children ≥ 6 

years)

NOAEL= 7 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

LOC = 100 4-week range-finding dog study

MRID 41863401 (1989)

LOAEL= 34 mg/kg/day based on 

thyroid toxicity

Dermal Short and 

IntermediateTerm (Females 

13-49 years old)

NOAEL= 5 

mg/kg/day

UFA= 10x

UFH=10x

FQPA UFDB = 10x

LOC = 1000 Developmental Rat Toxicity

MRID No. 45937601 (1973)

LOAEL = 10 mg/kg/day, based on 

hydrocephaly and other malformations

Dermal LongTerm 

(Females 13-49 

years of age and 

Children < 6 

years)

NOAEL= 

0.18 

mg/kg/day

UFA= 10x

UFH=10x

FQPA UFDB = 10x

LOC = 1000 Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

Dermal LongTerm 

(Adult Males, 

Females >49 

years, Children ≥ 

6 years)

NOAEL= 

0.18 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

LOC = 100 Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

ETU Residential Inhalation Exposure

Inhalation Short 

and IntermediateTerm (Children < 

6 years of age)

NOAEL= 7 

mg/kg/day

UFA= 10x

UFH=10x

FQPA UFDB = 10x

LOC = 1000 4-week range-finding dog study

MRID 41863401 (1989)

LOAEL= 34 mg/kg/day based thyroid 

toxicity

Inhalation Short 

and IntermediateTerm (Adult 

Males, Females 

>49 years, 

Children ≥ 6 

years)

NOAEL= 7 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

LOC = 100 4-week range-finding dog study

MRID 41863401 (1989)

LOAEL= 34 mg/kg/day based thyroid 

toxicity

Inhalation Short 

and IntermediateTerm (Females 

13-49 years old)

NOAEL= 5 

mg/kg/day

UFA= 10x

UFH=10x

FQPA UFDB = 10x

LOC = 1000 Developmental Rat Toxicity

MRID No. 45937601 (1973)

LOAEL = 10 mg/kg/day, based on 

hydrocephaly and other malformations

Inhalation LongTerm (Females 

13-49 years of 

age and Children 

< 6 years)

NOAEL= 

0.18 

mg/kg/day

UFA= 10x

UFH=10x

FQPA UFDB = 10x

LOC = 1000 Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

Inhalation LongTerm (Adult 

Males, Females 

>49 years, 

Children ≥ 6 

years)

NOAEL=

0.18mg/kg/d

ay

UFA= 10x

UFH=10x

FQPA SF= 1x

LOC = 100 Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

ETU Cancer

Cancer (all 

routes)

Q1

* = 6.01 x 

10 -2

(mg/kg/day)-

1

ETU is classified as a Group B2 carcinogen with a linear low-dose extrapolation 

approach for human risk assessment based on liver tumors in female mice.
Metiram Registration Review Human Health Scoping Document D425218

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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). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. 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. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Table A3.3 Summary of Toxicological Doses and Endpoints for ETU Used in Occupational 

Human Health Risk Assessments 

Exposure PoD Safety 

Factors RfD, PAD, LoC Study and Tox

ETU Occupational Dermal Exposure

Dermal Short and

IntermediateTerm 

(Adult Males, 

Females >49 

years)

NOAEL= 7 

mg/kg/day

UFA= 10x

UFH=10x

LOC = 100 4-week range-finding dog study

MRID 41863401 (1989)

LOAEL= 34 mg/kg/day based on 

thyroid toxicity

Dermal Short and 

IntermediateTerm (Females 

13-49 years old)

NOAEL= 5 

mg/kg/day

UFA= 10x

UFH=10x

UFDB = 10x

LOC = 1000 Developmental Rat Toxicity

MRID No. 45937601 (1973)

LOAEL = 10 mg/kg/day, based on 

hydrocephaly and other malformations

Dermal LongTerm 

(Females 13-49 

years of age)

NOAEL= 

0.18 

mg/kg/day

UFA= 10x

UFH=10x

UFDB = 10x

LOC = 1000 Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

Dermal LongTerm 

(Adult Males, 

Females >49 

years)

NOAEL= 

0.18 

mg/kg/day

UFA= 10x

UFH=10x

LOC = 100 Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

ETU Occupational Inhalation Exposure

Inhalation Short 

and IntermediateTerm (Adult 

Males, Females 

>49 years)

NOAEL= 7 

mg/kg/day

UFA= 10x

UFH=10x

LOC = 100 4-week range-finding dog study

MRID 41863401 (1989)

LOAEL= 34 mg/kg/day based thyroid 

toxicity

Inhalation Short 

and IntermediateTerm (Females 

13-49 years old)

NOAEL= 5 

mg/kg/day

UFA= 10x

UFH=10x

UFDB = 10x

LOC = 1000 Developmental Rat Toxicity

MRID No. 45937601 (1973)

LOAEL = 10 mg/kg/day, based on 

hydrocephaly and other malformations

Inhalation LongTerm (Females 

13-49 years of 

age)

NOAEL= 

0.18 

mg/kg/day

UFA= 10x

UFH=10x

UFDB = 10x

LOC = 1000 Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

Inhalation LongTerm (Adult 

Males, Females 

>49 years)

NOAEL=

0.18mg/kg/da

y

UFA= 10x

UFH=10x

LOC = 100 Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

ETU Cancer

Cancer (all 

routes)

Q1

* = 6.01 x 

10 -2

(mg/kg/day)-1

ETU is classified as a Group B2 carcinogen with a linear 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 
Metiram Registration Review Human Health Scoping Document D425218

Page 39 of 40

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). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. 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. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.
Metiram Registration Review Human Health Scoping Document D425218

Page 40 of 40

Attachment 4. International Residue Limits 

Metiram (014601; 03/10/2015)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex

40 CFR 180.217:

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 trimolecular cyclic 

anhydrosufides and disulfides), including 

its metabolites and degradates, in or on the 

commodities in the following table. 

Compliance with the tolerance levels 

specified in this paragraph is to be 

determined by measuring only those 

metiram residues convertible to and 

expressed in terms of the degradate carbon 

disulfide.

None Total 

dithiocarbamates, 

determined as CS2,

evolved during acid 

digestion and 

expressed as mg 

CS2/kg

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

US Canada Mexico1 Codex

Apple 0.5 5 pome fruits3

Apple, pomace wet 2

Banana2 3 2

3

Grape, wine2 5 5

3grapes 

Potato 0.2 0.23

Completed: M. Negussie; 03/10/2015

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

2 There are no U.S. registrations on bananas and grape, wine as of April 29, 2011.

3 The MRL is based primarily on residue data for metiram but does include data for the other dithiocarbamate active 

ingredients.