UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460

OFFICE OF PREVENTION, PESTICIDES
AND TOXIC SUBSTANCES

June 14, 2007

MEMORANDUM

SUBJECT: Metiram : Human Health Risk Assessment for PP#9E6006. Petition for the Establishment of Import Tole rances on Grapes and Bananas. PC Code : 014601, DP Barcode: D267866. Regulatory Action: Registration Action Risk Assessment Type: Single Chemical Aggregate

FROM: Toiya Goodlow, Risk Assessor Reregistration Branch 1 Health Effects Division (7509P)

THROUGH: Michael S. Metzger, Branch Chief Linda Taylor, Ph. D., Senior Scientist Deborah Smegal, MPH, Senior Scientist Reregistration Branch 1 Health Effects Division (7509P)

TO: Cynthia Giles-Parker, Branch Chief Fungicide-Herbicide Branch Registration Division (7505P)

BASF Corporation has proposed to establish import toleranc es for residues of the fungicide metiram in/on banana, banana pulp and grape. The Regi stration Division of Office of Pesticide Programs (OPP) has request ed that the Health Effects Division (HED) evaluate hazard and exposure data a nd conduct dietary and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from all registered and proposed uses of metiram. A summary of thes e findings is provided in this document. This risk assessment is an update of the most recent metiram risk assessment conducted in support of the metiram reregist ration eligibility d ecision document (RED) (D291661, 6/13/05, K. Farwell) and supersedes all previous assessments. The residue chemistry review and dietary exposure assessm ent were provided by Christine Olinger of RRB1; support for the hazard characterizati on was provided by Linda Taylor of RRB1; and the drinking water assessment was provi ded by Ron Parker and Mohammed Ruhman
of the Environmental Fate a nd Effects Division (EFED).

Page 1 of 45Table of Contents
1.0 Executive Summary .............................................................................................. 4
2.0 Ingredient Profile ................................................................................................ 11
2.1 Summary of Registered/Proposed Uses ................................................ 12
2.2 Structure and Nomenclature ................................................................. 14
2.3 Physical and Chemical Properties ......................................................... 15
3.0 Hazard Characterization/Assessment ............................................................... 15
3.1 Hazard and Dose-Response Characterization ...................................... 15
3.1.1 Database Summary ..................................................................... 15
3.1.2 Toxicological Effects ................................................................... 15
3.2 Absorption, Distribution, Metabolism, Excretion (ADME) ................ 22
3.3 FQPA Considerations ............................................................................. 22
3.3.1 Recommendation for a Developmental Neurotoxicity Study .. 22
3.3.2 Safety Factor for Infants and Children .................................... 23
3.4 Hazard Identification and Toxicity Endpoint Selection ...................... 23
3.4.1 Acute Reference Dose (aRfD) - Females age 13-49 .................. 23
3.4.2 Acute Reference Dose (aRfD) - General Population ................ 23
3.4.3 Chronic Reference Dose (cRfD) ................................................. 24
3.4.4 Recommendation for Aggregat e Exposure Risk Assessments 25
3.4.5 Classification of Carcinogenic Potential ................................... 25
3.4.6 Summary of Toxicological Doses and Endpoints for Metiram
for Use in Human Risk Assessments ..................................................... 26
3.5 Hazard Characterization of ETU .......................................................... 26
3.6 Endocrine Disruption ............................................................................. 28
4.0 Public Health and Pesticide Epidemiology Data .............................................. 28
5.0 Dietary Exposure/Risk Characterization ......................................................... 28
5.1 Pesticide Metabolism and Environmental Degradation ...................... 28
5.1.1 Metabolism in Plants and Animals ............................................ 28
5.1.2 Metabolism in Rotational Crops ................................................ 29
5.1.3 Analytical Methodology .............................................................. 29
5.1.4 Environmental Degradation ...................................................... 29
5.1.4.1 Surface Water ............................................................... 30
5.1.4.2 Ground Water .............................................................. 31
5.1.5 Food Residue Profile ................................................................... 32
5.1.6 International Residue Limits ..................................................... 37
5.2 Dietary Exposure and Risk .................................................................... 37
5.2.1 Acute Dietary Exposure/Risk ..................................................... 37
5.2.2 Chronic Dietary Exposure/Risk ................................................. 38
5.2.3 Cancer Dietary Risk ................................................................... 39
6.0 Residential (Non-Occupational) Exposure/Risk Characterization ................ 39
7.0 Aggregate Risk Assessments and Risk Characterization ................................ 40
7.1 Acute Aggregate Risk ............................................................................. 40
7.2 Chronic Aggregate Risk ......................................................................... 40
7.3 Cancer Aggregate Risk ........................................................................... 40
7.4 ETU Aggregate Exposure from All Sources (Metiram, Mancozeb and Maneb) ................................................................................................................. 41

Page 2 of 458.0 Cumulative Risk Characterization/Assessment ............................................... 42
9.0 Occupational Exposure/Risk Pathway .............................................................. 42
10.0 Data Needs and Label Recommendations ........................................................ 42
References ........................................................................................................................ 44

Page 3 of 451.0 Executive Summary

The Health Effects Division of EPA's Office of Pesticide Programs has evaluated the toxicity and exposure databases for the pe sticide active ingredient metiram, and has
conducted a human health risk assessment to support the proposed establishment of import tolerances on bananas and grapes. Metiram is a member of the ethylene bisdithiocarbamate (EBDC) group of fungicides, which includes the related active ingredients mancozeb and maneb. Metiram [a mixture of 5.2 parts by weight of ammoniates of {(ethylenebis(dithiocarbamato) } zinc with 1 part by weight ethylenebis {dithiocarbamic acid} bimolecu lar and tri molecular cyclic anhydrosulfides and disulfides] is the common name of the f ungicide. The RED for metiram was completed on August 29, 2005.

Use Profile

Metiram is a broad spectrum contact f ungicide used for the prevention of downy mildews, anthracnose, rusts, leaf spots and seedling damping off. Metiram end-use products with registered food/f eed uses are available as dry flowable (DF) formulations. Approximately 600,000 pounds of metiram are used in agricultural settings on an annual basis, with a greater portion of the market allocated to apples ( 70%) than to potatoes (30%). Agricultural uses are concentrated i n, but not limited to, the following states: ID, MI, MN, NY, NC, SC, PA and WA.

In support of the proposed import tolerances, the petitioner has submitted specimen labels for bananas and grapes. For bananas, a specimen label was submitted for Polyram® 80 WG (wettable granular formulation) for use on banana crops grown in Central and South America. For grapes, labels for Polyram® DF and Polyram® WG were submitted for use on grape orchards in Ital y, France and Germany. The registrant has also submitted a proposed label that will harmonize grape use patterns in Europe.

There are no residential labels and no agricu ltural uses that could result in exposure to metiram in residential settings. However, residential exposure is considered for the common EBDC metabolite ethylenethiourea (ETU) aggregate assessment, since
mancozeb and maneb are both used in resi dential settings and therefore result in exposures of ETU. Separate risk assessm ent documents were conducted for mancozeb and ETU. No new uses for maneb have been proposed; therefore, an updated risk assessment for maneb is not necessary at this time. The ETU aggregate risk assessment document discusses potential exposure to ETU from all sources (metiram, mancozeb and maneb), and characterizes such exposures in a broader sense. The aggregate assessment
also contains more detailed discussions of the ETU hazard characterization, FQPA (Food Quality Protection Act) considerations, endpoint selection and dose-response assessment. Relevant information excerpted from the ETU risk assessment is pr esented in Section 3.5 of this assessment, in order to appropriat ely address potential e xposure to ETU resulting
from metiram uses.

Page 4 of 45Hazard Assessment

The hazard database for metiram is incomplete; the missing studies include acute neurotoxicity and reproduction studies in ra ts, a developmental study in rabbits, and a developmental neurotoxicity study in rats. Ho wever, the available toxicity data have been used to select endpoints for risk asse ssment from dietary and non-dietary routes of exposure and for a variety of durations of e xposure. Refinements to the current risk estimates may be possible with the submission of missing toxicity data.

Metiram is not acutely toxic via the oral, dermal , or inhalation routes of exposure, nor is it a skin or eye irritant. It is, however, a str ong-to-severe skin sensitizer. The thyroid is a target organ for metiram. Thyroid effects obser ved in subchronic stud ies in rats include increased thyroid weights, increased thyroi d stimulating hormone (TSH) and decreased T4 (serum thyroxin) values. There were changes observed in T3 (triiodothyronine) values, but they were inconsistent and showed no dose-response. Levels of TSH, T4 and T3 are analyzed when there are potentia l impacts on thyroid function and hormone homeostasis, but they are not routinely measured in all guideline st udies. Thyroid effects were not measured in the rat developm ental (acceptable), rabbit developmental (unacceptable) or the rat reproduction (unaccepta ble) studies. In metiram chronic studies in rats, thyroid effects were meas ured, but they were inconsistent.

Metiram degrades and/or is metabolized to ETU. In oral rat metabolism studies with radiolabelled metiram and other EBDCs, an average 7.5% in vivo metabolic conversion of EBDC to ETU occurred, on a weight-to-we ight basis. Metabolism data indicate
metiram does not bio-accumulate.

The nervous system is a target for metira m. Neurotoxic signs and neuropathology have
been observed in subchronic studies in rats fo llowing oral dosing with metiram. Signs of neurotoxicity occurred after 2 weeks of dos ing, including reduced forelimb grip strength, hindlimb paralysis, muscle wasting and ataxia . Neuropathology findings in theses studies
indicated decreased areas of myelinated axons in the scia tic, sural and tibial nerves.

Metiram has been tested in a series of in vitro and in vivo genotoxicity assays. Metiram did not cause bacterial gene mutation, but there was evidence of mammalian gene mutation in two studies. The ge notoxic effect was not consid ered to be related to the
metabolism of metiram to ETU.

There are no adequate carcinogeni city 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 Q 1 * of 0.0601 (mg/kg/day) -1 for risk assessment. Because metiram is known to be converted to ETU, it
has also been classified as a probable human carcinogen.

Developmental toxicity was obser ved in the rat (increased in cidence of post-implantation loss; hydrocephaly and related lesions, skeletal system defects and ot her gross defects) at
a dose level where minimal maternal toxic ity (decreased body-weight gains) was

Page 5 of 45observed. However, there is low concern for th e qualitative susceptibi lity observed in the rat study since the dose-response was well ch aracterized; there was a clear NOAEL (no observed adverse effect level)/LOAEL (low est observed adverse effect level) for maternal and developmental toxicity; and th e doses selected for risk assessment were based on neurotoxicity and address concerns for developmental toxicity and thyroid toxicity, which occurred at higher doses. Additionally, in a rabbit developmental study, in which the maternal animals were adequa tely assessed, maternal toxicity observed
included abortions and decr eased body-weight gains.

The submitted data do not support the reducti on or removal of the 10X FQPA safety factor (SF) due to the absence of required toxicological studies. HED has retained the 10X FQPA SF for metiram dietary a nd aggregate risk assessments.

The rabbit developmental toxicity study was us ed to establish an acute reference dose for females 13-49 years old, based on abortions observed at the maternal LOAEL of 40 mg/kg/day. Application of the combined un certainty factors (UFs) for interspecies extrapolation and intraspecies variability, as well as the FQPA 10X database uncertainty factor (UF DB ) to the maternal NOAEL of 10 mg/kg/da y results in an acute reference dose of 0.01 mg/kg/day. The acute population adjusted dose (aPAD) is equal to the acute RfD, 0.01 mg/kg/day.

The chronic reference dose (cRfD) for th e general population was selected from a subchronic oral toxicity study in rats. The endpoint selected was reduced forelimb grip strength in females, observed at the LOAEL of 6.7 mg/kg/day. Afte r application of the combined UFs and the FQPA 10X UF DB to the study NOAEL of 0.4 mg/kg/day, the cRfD is 0.0004 mg/kg/day. The chronic population adjusted dose (cPAD) of 0.0004 mg/kg/day is equivalent to the chronic RfD.

The database for ETU is limited based on guideline studies, and HED has relied on a combination of guideline data and studies in th e open literature to assess hazard for ETU. The thyroid is a target orga n for ETU; thyroid toxicity in subchronic and chronic rat, mouse and dog studies included decreased levels of T4, increases or decreases in T3, compensatory increases in levels of TSH, increased thyroid weight and microscopic thyroid changes, chiefly hyperplasia. Overt liver toxicity was observed in one chronic dog study.

Developmental defects in the ETU rat de velopmental study included hydrocephaly and related lesions, skeletal system defects and other gross defects. These defects showed increased susceptibility to fetuses because they occurred at a dose which only caused decreased maternal food consumption and body- weight gain. Although the data provided evidence for increased susceptibility to fetuses following dosing with ETU, developmental effects were well characteri zed in numerous studies in the published literature. In addition, the dose-response re lationship was well characterized, and doses
selected for overall risk assessments addre ssed concerns for developmental and thyroid toxicity. However, due to the lack of se veral guideline studies, HED retained the 10X

Page 6 of 45FQPA safety factor due to da tabase uncertainties for diet ary, residential and aggregate
risk assessments for ETU.

The ETU acute dietary endpoint for female s 13-49 years old was selected from a nonguideline developmental toxicity study in rats. The LOAEL was 10 mg/kg/day based on developmental effects of the brain, and the NOAEL for the study was 5 mg/kg/day. Application of the combined 10X UFs and the FQPA 10X UF DB results in an acute reference dose of 0.005 mg/kg/day. The acute population adjusted dos e is equal to the
acute RfD.

The ETU chronic reference dose for the gene ral population was selected from a chronic toxicity study in dogs. The study NOAEL was 0.18 mg/kg/day based on thyroid toxicity. The combined 10X UFs and the FQPA 10X UF DB results in a chronic reference dose, RfD, of 0.0002 mg/kg/day. The cPAD is equivalent to the chronic RfD.

Exposure Assessment

The use pattern for metiram is expected to result in exposure to the general population through food and drinking water. There are no re sidential uses or agri cultural uses that would result in residential exposure to the ge neral population. No occupational exposure to metiram is expected to occur in the U.S. as a result of metiram use on imported grapes and bananas (i.e. proposed uses are for the application of metiram in Europe, Central America and South America).

Applications of metiram result in exposures to both metiram and ETU in the diet. To assess the total exposure to ETU, exposure from the 7.5% metabolic conversion of
metiram to ETU was added to ETU resi dues measured in/on food and water.

Metiram and ETU Dietary (Food) Exposure and Risk

The residue chemistry database for metiram is incomplete. Residue chemistry deficiencies exist for the proposed and existi ng uses of metiram. Ho wever, the available data are adequate to evaluate the dietary exposure and risk attributed to existing and proposed metiram uses. The nature of metir am residues is adequa tely understood, both for tolerance enforcement and risk assessment purposes.

Dietary exposure from metiram (and ETU resu lting from metiram) is limited to apples, potatoes, grapes and bananas. Refined acu te and chronic dietary exposure and risk
assessments were conducted for metiram and metiram-derived ETU, based on field trial residue data and monitoring data from the EBDC/ETU Market Basket Survey; processing factors derived from extensive processing a nd cooking and consumer practices studies; and estimated percent crop treated (% CT) da ta for both acute and chronic assessments. Percent crop treated information is not av ailable for the propos ed import tolerances; however, percent imported factors were in corporated for bananas and grapes. Anticipated residue estimates for ETU include the 7.5% metabolic conversion of metiram
to ETU residues.

Page 7 of 45Acute dietary exposure and risk from me tiram and ETU are below HED’s level of concern. For females 13-49 years old, estimat ed dietary exposure (food only) to metiram per se was 0.002215 mg/kg/day, which utilized 22% of the acute population adjusted
dose at the 99.9 th percentile. For metiram-derived ETU, the acute dietary exposure was 0.000299 mg/kg/day which utilized 6.0% of the aPAD.

Chronic dietary exposure and risk from metiram and metir am-derived ETU are below HED’s level of concern for the genera l U.S. population and various population subgroups. For metiram, the most highly exposed population subgroup is children 1-2 years old, estimated at 0.000281 mg/kg/day re presenting 70% of the chronic population adjusted dose. For metiram-derived ETU, children 1-2 years old were the most highly exposed population subgroup, at 0.000100 mg/kg/day repres enting 50% of the cPAD.

The cancer risk estimate for metiram-derived ETU was based on the same anticipated residues derived for the chronic dietary e xposure assessment. The estimated chronic dietary exposure for the general U.S. populat ion corresponds to a ca ncer risk of 1 x 10 -6

, which is not of concern.

Drinking Water Assessment

The OPP Environmental Fate a nd Effects Division (EFED) prepared the drinking water assessment. The parent EBDC fungicides ar e very short-lived in soil and water, and would not reach water used for human consumption whether from surface water or ground water. However, ETU is highly water soluble, and may reach both surface and ground water under some conditions. The dr inking water exposure assessment for metiram, and each of the parent EBDCs, addresses concentrations of ETU alone, as residues of the parent EBDC compounds ar e not expected in drinking water.

Estimated drinking water concentrations (EDWCs) for surface water were derived using a combined modeling/monitoring approach. The monitoring data were from a targeted surface water monitoring study conducted by th e ETU Task Force, in which none of the tested water samples had concentrations above the limit of detection of 0.1 ppb. A ground water EDWC was selected from a targeted ground water monitoring study
conducted in Florida in a known EBDC use ar ea. Acute surface wa ter estimates were reported as a range of 0.1 ppb (monitoring) to 25.2 ppb (modeling) and chronic/cancer surface water estimates were 0.1 ppb (monitoring). Acute/chronic/cancer ground water estimates were 0.21 ppb (monitoring).

Combined (Aggregate) Exposure from Food and Drinking Water

There are no residential exposure concerns fo r metiram, so aggregate exposure and risk assessments consider only food and drinking wa ter. Since residues of metiram per se are not expected in drinking water, aggregate risks for metiram consist of aggregate ETU exposures for acute and chronic (cancer and non-cancer) durations. For estimating

Page 8 of 45aggregate ETU exposure, the ETU surface and ground water EDWCs provided by EFED were incorporated into the dietary assessment.

For the metiram-derived ETU aggregate acute risk assessment, a surface water EDWC value of 25.4 ppb was used, which resulted in dietary exposure and risk below HED’s level of concern. For females 13-49 years old, estimated dietary exposure for food and water was 0.003511 mg/kg/day, which uti lized 70% of the aPAD at the 99.9 th percentile.

For the metiram-derived ETU aggregate chronic (non-cancer a nd cancer) dietary assessment, a ground water EDWC value of 0.21 ppb was used. Aggregate ETU chronic
non-cancer risks are below HED's level of con cern for the general U.S. population and all other population subgroups. The most highl y exposed population subgroup, children 1-2 years old, had a chronic aggregate exposur e of 0.000107 mg/kg/day which utilized 54% of the cPAD. Aggregate ETU cancer risk for the general U.S. population is not of concern, with an estimated risk of 1 x 10 -6 including existing and proposed uses.

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

The acute, chronic and cancer aggregate asse ssments for ETU considered food, water and residential exposures resulting from current and proposed uses of metiram, mancozeb and maneb; only mancozeb and maneb are used in residential settings. Acute and chronic
risks from all sources of ETU were not of concern; however, th e ETU aggregate cancer risk exceeds HED’s level of concern (3.8 x 10 -6 ). HED conducted sensitivity analyses and determined the greatest contributors to ETU exposure are bananas, leaf lettuce, water, turnip greens, grape juice and mangoes. If the proposed import tolerance in/on bananas (from metiram applica tions) is removed from the aggr egate assessment, then the aggregate cancer risk does not exce ed HED’s level of concern (3.2 x 10 -6 ). Note that the metiram-derived ETU residue values from crop field trials used in the aggregate
assessment are considered to be overest imates. Projected percent crop treated information was not available, so percent im ported information was used and it is highly unlikely that all bananas will be treated. In general, monitoring data available for other
commodities show much lower residues than fi eld trial data, so the actual exposure is likely to be lower. For these reasons, HE D is requiring the submission of monitoring
data for metiram and ETU on bananas.

Environmental Justice Considerations

Potential areas of environmental justice concer ns, to the extent possi ble, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898,"Federal Actions to Address Environmental Justice in Minority Populations and LowIncome Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

As a part of every pesticide risk assessment , OPP considers a large variety of consumer subgroups according to well-es tablished procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the

Page 9 of 45home that involve pesticide use in a re sidential setting. Ex tensive data on food consumption patterns are compiled by the United States Department of Agriculture (USDA) under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appr opriate, non-dietary e xposures based on home use of pesticide products and associated risks for adult ap plicators and for toddlers, youths and adults entering or playing on tr eated areas postapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized so ftware and models that consider exposure to bystanders and farm workers as well as lif estyle and traditional dietary patterns among specific subgroups.

Review of Human Research

This risk assessment does not rely on any da ta from studies in which human subjects were intentionally exposed to a pesticide or other chemical.

Data Gaps

Residue chemistry deficiencies for the curr ent metiram import tolerance petition include the following:

• Guideline 860.1200 Directions for use (label submission)

• Guideline 860.1380 Storage stability data

• Guideline 860.1520 Processed food/feed

• Guideline 860.1550 Proposed tolerances

• Guideline 860.1560 Reasonable grounds in support of the pe tition (banana monitoring data)

Deficiencies or data gaps previously id entified in the RED exist for the following guideline studies:

Toxicology

• Guideline 870.3700 Developmental toxicity, rabbit (only the maternal animal was adequately assessed in the available rabbit study)

• Guideline 870.3800 2-generation reproduction, rat

• Guideline 870.6200 Acute neurotoxicity, rat

• Guideline 870.6300 Developmental neurotoxicity, rat * Comparative study for thyroid t oxicity in adults and offspring is required for ETU only

Residue Chemistry

• Guideline 860.1200 Directions for use (label revision)

• Guideline 860.1850 Confined accumu lation in rotational crops

Page 10 of 45Product Chemistry

• Guideline 830.1700 Preliminary analysis

• Guideline 830.7050 UV/visible absorption

Occupational Exposure The registrant should submit a DFR study on apples; the submitted study is inadequate,
and leads to lower confidence in estimated postapplication risks.

Regulatory Recommendations

Although several deficiencies were identifie d within the residue chemistry database, HED does not object to establishing import tolera nces for grapes at 5 ppm and raisins at 10 ppm, provided a revised Section F and pr oduct labels are submitted. Confirmatory storage stability and processi ng data are also required.

HED does not object to granting a temporar y import tolerance for bananas at 3.0 ppm provided banana monitoring data for metiram and ETU are submitted, and all residue chemistry deficiencies are resolved. A full re solution of these deficiencies is required
before HED can recommend the establishm ent of permanent import tolerances.

2.0 Ingredient Profile

Metiram is the common name of a pesticide wh ich 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 trimolecu lar cyclic anhydrosulfides and disulfides. It is a broad spectrum contact fungicide re gistered on apples, pot atoes and ornamental plants (greenhouse-grown ferns) for the pr evention of downy mildews, anthracnose, rusts, leaf spots and seedling damping off.

ETU is a metabolite, environmental degradate, and cooking byproduct of metiram and the other EBDC fungicides, maneb and mancozeb.

Page 11 of 452.1 Summary of Registered/Proposed Uses

Table 2.1. Summary of Currently Registered Uses of Metiram Label Application Rates (lb ai/acre) Average Application Rates (lb ai/acre) Crop

Maximum

Per Application Minimum Per Application Maximum
Per Season Per Application Per Year

Apples: Prebloom 1 4.8 NA 19.2 Apples: Extended 1 2.4 NA 16.8 2.2 2 8.3 2

Leatherleaf Ferns 3 1.6 0.8 No Limit 1.3 4 ND 5

Potatoes 1.6 1.2 11.2 1.5 2 4.1 2

1 The prebloom schedule consists of no more than 4 applications, 7 to 10 days apart; no applications are permitted after bloom. The prebloom schedule may not be combined with the extended schedule. The extended schedule consists of no more than 7 appli cations 7 to 10 days apart. For both prebloom and extended schedules, applications can be made starting at the 0.25 -0.5 green tip stage.

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

3 Rates for ornamentals are given in lbs ai/100 gallons and were converted to lb ai/acre by assuming that 100 gallons of spray would be applied per acre as stated on the label.

4 NASS 2003 Nursery and Floriculture Summary, September 2004.

5 ND - No data available

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

Application Timing; Equipment Type 2 Formulation Applic.

Rate 3 Max. No. Applic/
Season Max.
Seasonal Applic. Rate

(lb ai/A) PHI (days) Use Directions and
Limitations

Bananas (For Use in Central and South America)

Broadcast spray
to established banana crops Polyram® 80

WG 2.0-2.5 kg/ha Not specified

(NS) NS 7 Spray mix is to be prepared by adding 0.4 L/ha of Nu Film (surfactant) to water (spray volume not specified) and Polyram® 80 WG. Initial application may be made when disease symptoms first appear and repeated at 8-15 day
intervals.
Grapes (For Use in Italy)

Broadcast spray
to established grape orchards Polyram® DF Fungicide 150-400 g/100 L

water NS NS 28 When mixed with other formulations, the longest waiting period must be observed. The following varieties may be sensitive to Polyram® DF: Butirra d’Estate, Conference, Coscia, Gentil Bianca, S. Maria and Spadona.
Grapes (For Use in France)

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

Application Timing; Equipment Type 2 Formulation Applic.

Rate 3 Max. No. Applic/
Season Max.
Seasonal Applic. Rate

(lb ai/A) PHI (days) Use Directions and
Limitations

Broadcast spray
to established grape orchards Polyram® DF Fungicide 2.0-3.5 kg/ha NS NS NS

Grapes (For Use in Germany)

Broadcast spray
to established grape orchards Polyram®

WG 0.8-3.2 kg/ha 8 NS 56 Do not apply more than 8 applications in producing plantings, of which maximally 4 with decaying
flowers until start of maturing (vine stages 68- 81, BBCH Code)

1 Information included in table exce rpted directly from proposed label.

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

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

Table 2.3. Label Directions for the Use of Metiram on Grapes Grown in Europe 1

Country Product
Name Growth Stage &
Season
BBCH No. Applic.

per Season 2 Single Applic.

Rate Implied Max.
Seasonal Rate PHI
(days)

Germany 3 Polyram® DF 15-79 6 2.24 kg ai/ha
(2.0 lb ai/A) 13.44 kg ai/ha
(12.0 lb ai/A) 56

EU (N+S-EU) 4 Polyram® DF 15-79 3 1.1 kg ai/ha
(1.0 lb ai/A) 3.3 kg ai/ha
(2.9 lb ai/A) 56

EU (N+ S-EU) 5 Polyram® DF 15-79 3 1.8 kg ai/ha
(1.6 lb ai/A) 5.4 kg ai/ha
(4.8 lb ai/A) 56

France (N + SEU) 518 01F 60-80 3 1.1 kg ai/ha
(1.0 lb ai/A) 3.3 kg ai/ha
(2.9 lb ai/A) 35

1 Information included in table exce rpted directly from proposed label.

2 Minimum retreatment interval is 12 days

3 Exemplarily listed for a national label direction.

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

5 Future EU harmonized GAP.

Page 13 of 452.2 Structure and Nomenclature

Table 2.4. Test Compound Nomenclature- Metiram Compound

NH S

NH Zn

S

S S

NH S

NH S

S S

3

x Empirical Formula (C 16 H 33 N 11 S 16 Zn 3 )

x Common name Metiram Company experimental name BAS 222 F

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

CAS name mixture of 5.2 parts by weight of ammoniates of [ethylenebis(dithiocarbamato)]zinc with 1 part by weight ethylenebis [dithiocarbamic acid] bimolecular and trimolecular cyclic anhydrosulfides and
disulfides CAS registry number 9006-42-2 End-use products (EPs) used
in residue field studies 70% WG (BAS 222 28 F; Polyram DF Fungicide) 55% WG (BAS 518 00 F)

Table 2.5. Test Compound Nomenclature-ETU Compound

Empirical Formula C 3 H 6 N 2 S

Common name Ethylenethiourea (ETU) CAS registry number 96-45-7

Page 14 of 452.3 Physical and Chemical Properties

Table 2.6. Physicochemical Properties of the Technical Grade of Metiram

Parameter Value Reference Melting point/range Decomposes at ~140 oC pH Not applicable because of low water solubility; titrations with acid/base will not yield reliable pH values. Density 0.33 (loose), 0.49 (packed) kg/L Water solubility Practically insoluble (2 mg/L at 20 oC) Solvent solubility 8 x 10 -3 g/100g ethanol at 20 oC; insoluble in acetone, benzene and ethyl
alcohol Vapor pressure <1 x 10 -7 mbar at 20 °C Dissociation constant, pK

a Not applicable; titrations with acid/base will not yield reliable pKa values. Octanol/water partition coefficient, Log(K OW ) 1.76-2.48 at pH 7 and 21 oC Product Chemistry Chapter of the Metiram Update, 8/11/1992

UV/visible absorption spectrum Not available

3.0 Hazard Characterization/Assessment

3.1 Hazard and Dose-Response Characterization

3.1.1 Database Summary

The metiram toxicology database is incomple te. Toxicological data gaps include acute neurotoxicity and reproduction studies in ra ts, a developmental study in rabbits and a developmental neurotoxicity study in rats. However, HED has used the currently
available data for hazard characterization a nd endpoint selection, for both dietary (food and water) and non-dietary (dermal, inhalation, incidental oral) routes of exposure, and for various durations of exposure.

3.1.2 Toxicological Effects

Acute toxicity: Metiram is not acutely toxic via the oral, dermal, or inhalation routes of exposure, nor is it a skin or ey e irritant. It is, however, a st rong-to-severe skin sensitizer. The acute toxicity prof ile for metiram is shown in Table 3.1 below.

Page 15 of 45Table 3.1. Acute Toxicity of Metiram

Guideline No. Study Type MRIDs # Results Toxicity Category

870.1100 Acute Oral – rat 40497002

40497005 LD 50 = >5000 mg/kg IV

870.1200 Acute Dermal – rabbit 40497007

40497008 LD 50 = >2000 mg/kg III

870.1300 Acute Inhalation – rat 40497010 LC 50 = 5.7 mg/L IV

870.2400 Primary Eye Irritation 40497012 not an eye irritant III

870.2500 Primary Skin Irritation 40497004 not a skin irritant IV

870.2600 Dermal Sensitization 40497006 strong-to-severe dermal
sensitizer N/A

870.6100 Acute Delayed Neurotoxicity – hen - - N/A

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

Subchronic toxicity: The thyroid is a target organ fo r metiram. In a subchronic (90- day) oral toxicity study in Wistar rats, an increase in thyroid stimulating hormone (TSH, also known as thyrotropin) was observed at a ll dose levels at study termination, but there was no apparent dose response. The triiodothyronine (T 3 ) values were comparable among the females, but the males displaye d an increase, not dose-related, in T 3 at study termination. Serum thyroxin (T 4 ) values were decreased at study termination at the highdose level in both sexes. In another 90 -day study in Sprague-Dawley CFY rats, both sexes displayed lower mean T 4 values than the control at termination. Comparable T 4 values were observed among the groups following the withdrawal period. No consistent
effect was observed on mean T 3 values in either sex. Following 13 weeks of exposure,
there was a dose-rela ted decrease in [ 131 I] uptake, and the decrease is considered
treatment-related at all dose levels in both sexes.

Chronic toxicity: There were no consistent effect s on the thyroid hormones monitored in the chronic toxicity study in Charles Rive r CD Sprague-Dawley rats, and no definitive conclusion could be made with respect to thyroid weight. Howe ver, this may be
attributed to the fact that the highest dose tested in th e chronic study was considerably
lower than the dose levels in the subchr onic studies where th yroid effects were demonstrated. No effects on the thyr oid were observed in the CFLP mouse carcinogenicity study, and there were no histopathological find ings in the mouse thyroid, but thyroid weight, T 3 , T 4 , TSH and/or 131 I data were not measured in this study. In the 2-generation reproduction study in Crl:COB S CD(SD)BR rats and in the Crl:COBS CD(SD)BR rat or rabbit developmental toxi city studies, thyroi d endpoints were not monitored. Slight, non -significant, decrease s were observed in T 4 values at week 13 in the subchronic inhalation study in Sprague-Daw ley CD rats at the high-dose level in both sexes, and TSH values were decreased in bot h sexes at the high-dose level compared to the controls. A comparativ e thyroid study is required for the ETU metabolite only.

Carcinogenicity: There are no adequate carcinogenicity studies for metiram in either the rat or the mouse. However, it is expected that metiram’s potentia l for carcinogenicity (as well as that of the other EBDCs, maneb and mancozeb) is due to the formation of the metabolite ETU, so additional carcinogenicity studies for metiram are not required. ETU

Page 16 of 45is classified as a probable human carcinoge n (B2), with a cancer potency factor (Q 1 * ) of 0.0601 (mg/kg/day) -1 for risk assessment. On this ba sis, metiram cancer risk has been calculated by estimating exposure to me tiram-derived ETU (including the 7.5% in vivo metabolic conversion) and using the ETU cancer potency factor to provide a quantitative
estimate of risk.

Developmental/Reproductive toxicity: There is increased qualitative fetal susceptibility in rats as demonstrated in the rat developmen tal toxicity study. Developmental toxicity was obser ved in the rat (increased in cidence of post-implantation loss; hydrocephaly and related lesions, skeletal system defects and ot her gross defects) at
a dose level where minimal maternal toxic ity (decreased body-weight gains) was observed. There is no acceptable rabbit de velopmental toxicity study due to an inadequate assessment of the fetal animal; the maternal animal was adequately assessed. There is no acceptable rat two-generation reprod uction study. Both of these studies are required, and have been cited as data gaps.

Genotoxicity: Metiram has been tested in a series of in vitro and in vivo genotoxicity assays. Metiram is negative for (1) gene mu tation in both the bacterial/Ames assay with and without S9 and in the CHO/HGPRT assay with metabolic activa tion; (2) structural
chromosomal alterations includi ng rat bone marrow cytogenetics and in vivo chromosomal aberrations; and (3) other genotox ic effects (UDS/rat hepatocytes). In the assay for sister chromatid exchange (SCE) in Chinese hamster ovary cells (CHO),
metiram induced weak but concentration-rela ted increases in SCEs over controls with
and without mouse S9 and without rat S9. Metiram was clearly positive in the gene mutation assay (CHO/HGPRT) without metabolic activation. Ther e was a reproducible and strong response in this latter assay without S9 at doses 10-fold lower than the doses used for the assay with S9 where the result s were negative. Therefore, it cannot be concluded that the positive response is the result of metabolism of metiram to ETU. No studies in the open literature were found to support the positive response. The negative Ames assay is supported by studies in the open literature confirming that metiram is not mutagenic in bacteria. Nevertheless, the two positive mammalian cell assays cannot be ignored; hence, a potential for genotoxic effects cannot be ruled out for metiram.

Neurotoxicity: The nervous system is a target for metiram. There is evidence of neurotoxicity and neuropathology following or al exposure. In a range-finding rat developmental toxicity study in non-pregnant females, increased activity and slight impairment of grasping and hindlimb support re flexes were reported, along with paralysis
and death. In a rat subchronic oral toxicity study, hindlimb paralysis [stilted and rolling hindlimb gait, impaired reflexes (grip, ri ghting and flexor) and muscle wasting] was observed in the majority of the females at th e high-dose (76 mg/kg) level after 2 weeks of exposure. In another subchronic oral toxic ity study in rats, redu ced general state and
ataxia were observed in females at the hi gh-dose (89 mg/kg) level. There was a doserelated decrease in forelimb grip strength in females from day 15 on, with the three highest dose levels displaying significant decreases at day 90. High-dose (74-89 mg/kg) rats of both sexes displayed si gnificant decreases in hindlimb grip strength. In the highdose females that displayed ataxia, there was a decrease in the areas of myelinated axons

Page 17 of 45in the sciatic, sural and tibial nerves co mpared to the control. In the chronic toxicity/carcinogenicity study in rats, the incidence of musc le atrophy (thigh muscle) was significantly increased in the hi gh-dose (12-15 mg/kg) rats of both sexes compared to the control and other dose groups. The lesion wa s characterized by a narrowing of muscle fibers with reduced sarcoplasm and/or the pr esence of adipose cells in muscle bundles.

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

Table 3.2. Toxicity Profile of Metiram Technical Study Type [Guideline No.] MRID No./
Classification Results

Subchronic feeding – rat (Sprague-Dawley CFY)

[870.3100] 00126738 Acceptable NOAEL (Thyroid effects) = Not determined, based on decreased [ 131 I] uptake in males at all dose levels. LOAEL (Thyroid effects) = 50 ppm (males 3/females 4 mg/kg/day), the lowest dose tested (LDT).

Systemic NOAEL =100 ppm (8 mg/kg/day) Systemic LOAEL =300 ppm (24 mg/kg/day), based
on muscle lesions in females.

At the highest dose, 900 ppm (males 61, females 76 mg/kg/day), muscle lesions were seen in both sexes, and females also had hindlimb paralysis. Subchronic feeding - Wistar

rat

[870.3100] 40290601
42539101/ Acceptable NOAEL = 5 ppm (0.4 mg/kg/day) LOAEL = 80 ppm (6.7 mg/kg/day), based on reduced forelimb grip strength in females.

At the highest dose (males 74, females 89 mg/kg/day) both sexes had ↑ thyroid weight and ↓ T 4 values. At all doses, both sexes, ↑ TSH was seen, but with no dose-response. Subchronic feeding – mouse (B6C3F1)

[870.3100] 42595001/ Acceptable NOAEL = 300 ppm (males 84/females 133 mg/kg/day); LOAEL = 1000 ppm (males 302/females 465 mg/kg/day), based on the decrease in total serum T 4concentrations in both sexes and decreased bodyweight gain in females.

Thyroid lesions were observed in both sexes at the two highest doses. Subchronic feeding - monkey [870.3150] 00031591 Acceptable NOAEL = not established; LOAEL = 5 mg/kg/day, based on decreased levels of iodine in the thyroid at weeks 1 and 8.

At the two highest doses, the following were
observed: ↑ thyroid weight; minimal thyroid follicular hyperplasia; ↓ T 3 and T 4 levels, ↓ total plasma iodine; ↑ protein-bound plasma iodine levels; ↑ iodine in the thyroid; and ↓ body-weight gain. Subchronic feeding - dog [870.3150] None N/A

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

Page 18 of 45Table 3.2. Toxicity Profile of Metiram Technical Study Type [Guideline No.] MRID No./
Classification Results

[870.3200] Acceptable assessm ent of effects on the th yroid, the target organ was not performed Dermal NOAEL = 50 mg/kg/day; Dermal LOAEL = 250 mg/kg/day, based on local
dermal irritation. 90-day inhalation – rat (nose only) (Sprague Dawley CD)

[870.3465] 00164083, 40044701 Acceptable NOAEL = 2.1 mg/m 3 ; (0.5 mg/kg/day) LOAEL = 20 mg/m 3 ; (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 va lues in both sexes at the high-dose level.

Subchronic neurotox. - rat [870.6100] None DATA GAP - Study Required

Chronic toxicity – rat (CD/Sprague-Dawley)

[870.4100] 00098449, 00098450

41163101 Acceptable NOAEL* = 5 ppm (0.4 mg/kg/day); LOAEL* = 80 ppm (6.7 mg/kg/day), based on reduced forelimb grip strength in females. *Endpoint and dose from subchronic bridging study
in Wistar rats.

In SD rats at the highest dose tested in the chronic study (320 ppm; 12.3/15.5 mg/kg/day for males/females), increased thigh muscle atrophy was observed in both sexes. The Wistar rat endpoint is consistent with this finding. Carcinogenicity - CD/Sprague-Dawley rat [870.4100] 00098449, 41163101 Unacceptable Lack of any significant e ffect on survival, bodyweight, or body-weight gain, indicates the rats could have tolerated higher dose levels. HED concluded the dose levels were inadequate for assessing carcinogenic potential. Chronic toxicity - dog [870.4100] 42133101, 42491401 Acceptable NOAEL = 80 ppm (males 2.49, females 2.69 mg/kg) LOAEL = 1000 ppm (males 29.8, females 29.9 mg/kg), based on decreased body-weight gain/food consumption, changes in hematology/clinical chemistry parameters indicative of thyroid toxicity/anemia, increased thyroid weight and follicular (thyroid) hyperplasia. Carcinogenicity – mouse (CFLP)

[870.4200] 00030245 Unacceptable No significant, treatment-related, findings in either sex. Dose levels were inadequate for determining the carcinogenic potential of metiram, and there was an inadequate microscopic examination of tissues. There was no assessment of thyroid function, i.e., T 3 , T 4 , and TSH values and [ 131 I] uptake were not determined. Organ-weight data were not provided. No microscopic lesions were reported in the thyroid, and no treatment-related thyroid tumors were observed. The CARC concluded this study is Unacceptable.

Page 19 of 45Table 3.2. Toxicity Profile of Metiram Technical Study Type [Guideline No.] MRID No./
Classification Results

Developmental tox. – rat Sprague-Dawley (Crl:COBS CD SD BR) [870.3700] 00030565 Acceptable Maternal NOAEL = 80 mg/kg/day; Maternal LOAEL = 160 mg/kg/day, based on decreased body-weight gain. Developmental NOAEL = 80 mg/kg/day Developmental LOAEL = 160 mg/kg/day, based on increased pre- and post-implantation losses, decreased litter size, decreased litter weight hydrocephaly and related lesions, skeletal system defects and other gross defects. Developmental tox. – rabbit Himalayan Chbb:HM [870.3700] 40711401 Unacceptable Maternal NOAEL = 10 mg/kg/day, Maternal LOAEL = 40 mg/kg/day, based on
abortions.

There was excessive maternal toxicity at the highest dose (8 abortions and negative body-weight gain), and the mid-dose does displayed a similar, but lesssevere, toxicity (2 abortions and negative bodyweight gain during the dosing period).

Developmental NOAEL = not established Developmental LOAEL = not established (The heads of the fetuses were not examined)

DATA GAP - Study is Required (Unacceptable
because the heads of the fetuses were not examined. The maternal animal was adequately assessed in this study.) 2-Generation Reproduction - Crl:COBS CD (SD) BR rat

[870.3800] 00098431 Unacceptable Maternal NOAEL = 40 ppm (2.2 mg/kg/day); Maternal LOAEL = 320 ppm (19.8 mg/kg/day), based on decreased body-weight during gestation
and lactation.

Reproductive NOAEL = 40 ppm (males 1.8/females 2.2 mg/kg/day); Reproductive LOAEL = 320 ppm (males 14.2/females 19.9 mg/kg/day), based on decreased mating performance in the F2 generation.

Offspring NOAEL = 320 ppm (males 14.2/females 19.8 mg/kg/day), the highest dose tested.

DATA GAP - Study is Required (Unacceptable
because of the lack of one- to-one pairing and lack of histopathological examination of reproductive and target organs.) Developmental neurotox - rat [870.6300] None DATA GAP- Study is Required

Gene mutation [870.5100] [870.5300] 0148682
HGPRT Acceptable

00148680 Dose range from 0.681-100 μg/mL with SD-rat S9 - positive without S9, marginally positive with S9.

Negative; TA 1530 as in dicator strain and CD-1

Page 20 of 45Table 3.2. Toxicity Profile of Metiram Technical Study Type [Guideline No.] MRID No./
Classification Results

(mouse host-mediated) Acceptable mice as host (dose levels of 0, 500, 670 and 5000 mg/kg) Cytogenetics/Structural
Chromosomal Aberrations [870.5900] [870.5385] 00148681

in vitro sister chromatid exchange assay (SCE/CHO) Acceptable

00163786

in vivo bone marrow cytogenetics Acceptable Positive for SCE induction both with and without mouse S9; dose levels up to 100 μ g/mL without S9 and up to 200 μ g/mL with S9; negative up to cytotoxic doses with rat S9

Negative; single 2.4 gm/kg or 5 x 0.2 gm/kg/day in male rats - no significant increases in chromosomal aberrations in bone marrow cells sampled over complete mitotic cycle

Other Genotoxic Effects [870.5550] 00149528
Unscheduled DNA Synthesis

Acceptable Negative - did not induce unscheduled DNA synthesis (dose range of 0.492-49.2 μ g/mL)

Metabolism – CD rat [870.7485] 00155160 Acceptable Metiram is rapidly metabolized and excreted via the feces and urine following si ngle and repeated doses.

For both sexes, a greater percentage of the dose was
excreted via the feces than the urine, i.e., the major portion of the administered dose was unabsorbed. In both sexes, residues in the plasma peaked at 4 hours following a single low dose and at 6 hours following the single high-dose.

The highest concentrations of radiolabel were found in the thyroids, gastrointestinal tract and kidneys of
both sexes.

Biliary excretion of 14 C-labelled metiram accounted for 14.3% and 7.1% of a single 5 mg/kg bw dose in males and females, and 4.3% and 3.7% of a single 50 mg/kg bw dose in males and females, respectively.

ETU and numerous low molecular weight
metabolites were found in the urine and bile. Dermal penetration CD rat [870.7600] 155161 Acceptable Dermal absorption of metiram is relatively low. For risk assessment, a dermal absorption value of 1% was selected, based on abso rption at a dose of 0.24 mg/kg/day. Domestic animal safety

870.7200 N/A

Page 21 of 453.2 Absorption, Distribution, Metabolism, Excretion (ADME)

Metiram degrades and/or is metabolized to ETU. In oral rat metabolism studies with radiolabelled metiram and other EBDCs, an average 7.5% in vivo metabolic conversion of EBDC to ETU occurred, on a weight-to-weig ht basis. This metabolic conversion has
been taken into consideration in the human health risk assessment, including the dietary exposure assessment as well as previously conducted dermal and inhalation assessments. There is inherent uncertainty in assumi ng the metabolic conversion occurs following dermal and inhalation dosing, since dermal a nd inhalation exposure do not involve the GI tract. In addition to ETU, other identified decomposition pr oducts are ethylenethiuram, ethylene-bis-isothiocyanate sulf ide (EBIS), carbon disulfide (CS 2 ) and elemental sulphur (the latter 3 being known inhi bitors of mono-oxygenases). Metabolism data indicate
metiram does not bioaccumulate.

3.3 FQPA Considerations

HED has reviewed the potential for increased susceptibility of infants and children from exposure to metiram according to the Febr uary 2002 OPP FQPA 10X Safety Factor guidance document. It was concluded that the toxicity database for metiram is incomplete. Studies available for FQ PA consideration include an acceptable developmental toxicity study in rats, an unacceptable two-generation reproduction study in rats and an unacceptable develo pmental toxicity study in rabbits.

There is qualitative indication of increased sensitivity based on the results of the rat developmental toxicity study in which pre- a nd post-implantation loss es were observed at a dose level that produced less severe maternal toxicity (decreased body-weight gain). HED considered the degree of concern for susceptibility within the context of all available toxicity data, and concluded ther e is low concern for the observed qualitative susceptibility based on the following:

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

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

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

• The doses selected for overall risk assessm ent are protective for effects seen in the prenatal developmental toxicity study.

• The doses selected for risk assessment also address concerns for thyroid toxicity, although a comparative assessment of the t hyroid between young and adult rats is required for ETU. The thyroid effects identif ied in the available studies occurred at higher dose levels than the dose levels where neurotoxicity was observed.

3.3.1 Recommendation for a Developmental Neurotoxicity Study

HED concluded there is a concern for devel opmental neurotoxicity following exposure to metiram. Evidence of neurotoxicity, neuropa thology and thyroid toxicity has been seen in rats following oral exposure to metiram in both subchronic and chronic studies. The metiram metabolite/degradate ETU has been shown to be a developmental toxicant in

Page 22 of 45rats, with effects seen in the central nervous system, urogenital and skeletal systems. In addition, neurotoxic effects have been observe d in studies with another EBDC, maneb. Therefore, a developmental neurotoxicit y study (DNT) is required for metiram.

3.3.2 Safety Factor for Infants and Children

Although there are no residual uncer tainties for pre- and/or post -natal toxicity, the FQPA Safety Factor of 10X was retained due to da tabase uncertainties for metiram. In addition to the required DNT study, HED noted data gaps for an acute neurotoxicity study, a developmental toxicity study in the rabbit and a 2-generation re production study in the rat. HED determined that the FQPA SF must be retained to account for the lack of these studies, since the available data provide no basis to support reduction or removal of the
factor.

3.4 Hazard Identification and Toxicity Endpoint Selection

HED evaluated the toxicology database of metiram and selected the doses and endpoints for risk assessment based on a variety of e xposure pathways. These doses and endpoints are summarized in Table 3.4. Since expos ure to the metabolite and degradate ETU occurs in conjunction with th e use of metiram, endpoints and doses for ETU are included
in Section 3.5.

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

The rabbit developmental toxicity study was us ed to establish an acute reference dose for females 13-49 years old, based on abortions observed at the maternal LOAEL of 40 mg/kg/day. Application of the standard 100X combined uncertainty factors for interspecies extrapolation and intraspecies variability, as well as th e FQPA 10X database uncertainty factor to the maternal NOAEL of 10 mg/kg/day results in an acute reference dose of 0.01 mg/kg/day. The acute population ad justed dose is equal to the acute RfD, 0.01 mg/kg/day. The endpoint is relevant for ac ute dietary risk assessment as defined in OPP, since it is assumed that the toxic effect, abortions, could occur following one exposure. The study was considered unacceptabl e due to a lack of examination of the heads of the fetuses; a developmental LOAEL/NOAEL could not be established. However, since this deficiency does not inte rfere with the determination of maternal toxicity, the basis for acute di etary endpoint selection, the stud y can be used for this risk

assessment.

3.4.2 Acute Reference Dose (aRfD) - General Population

HED concluded that an aRfD/aPAD for the ge neral population is not needed, since there was no appropriate endpoint attri butable to a single dose in the available toxicity studies.

Page 23 of 453.4.3 Chronic Reference Dose (cRfD)

The chronic reference dose for the genera l population was selected from a subchronic oral toxicity study in rats. The endpoint selected was reduced forelimb grip strength in females, observed at the LOAEL of 6.7 mg/kg/day. After application of the standard 100X combined UFs and the FQPA 10X UF DB to the study NOAEL of 0.4 mg/kg/day, the cRfD is 0.0004 mg/kg/day. The cPAD of 0.0004 mg/kg/day is equivalent to the
chronic RfD.

A comparison of the results of two rat s ubchronic studies and the rat chronic study support the use of the endpoint and dose fr om the subchronic study for the purpose of chronic exposure and risk a ssessment, see Table 3.3 below.

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

Subchronic rat (Wistar) Subchronic rat (Sprague-Dawley) Chronic rat (Sprague-Dawley) Doses (ppm) 5, 80, 320, 960 50, 100, 300, 900 5, 20, 80, 320 Doses (mg/kg/day) males: 0.4, 5.8, 23.5, 73.9 females: 0.4, 6.7, 27.3, 88.8 males: 3, 6, 20, 61 females: 4, 8, 24, 76 males: 0.2, 0.8, 3.1, 12.3 females: 0.2, 1.0, 3.8, 15.5

Effects at HDT ataxia w/decrease in areas of myelinated axons in sciatic, sural tibial nerves (females); reduced forelimb (females) and hindlimb (both sexes) grip strength 73.9/88.8 mg/kg/day hindlimb paralysis, stilted and rolling gait, impaired reflexes (grip, righting and flexor) in females and muscle wasting (both sexes) 61/76 mg/kg/day muscle atrophy 12.3/15.5 mg/kg/day

NOAEL 0.4 mg/kg/day 8 mg/kg/day 3.1/3.8 mg/kg/day Endpoint (LOAEL) reduced forelimb grip strength (females) 6.7 mg/kg/day muscle lesions in females 24 mg/kg/day muscle atrophy (both sexes) 12.3/15.5 mg/kg/day

Muscle atrophy was observed at the high-dos e (LOAEL 12.3/15.5 mg/kg/ day) level in the Sprague-Dawley (SD) rat chronic study, and the NOAEL was set at 3.8 mg/kg/day. In a subchronic oral toxicity study in Sprague-Dawley rats, muscle lesions were observed in females at the LOAEL of 24 mg/kg/day; th e NOAEL is 8 mg/kg/day. In a subchronic oral toxicity study in Wistar rats, which included a neurom uscular/functional test (not included in either SD), a LOAEL of 6.7 mg /kg/day was determined, based on reduced forelimb grip strength in Wistar females; a NOAEL of 0.4 mg/kg/day was established.
The effects seen at the LOAELs in these three studies were neuromuscular effects. The
different values of NOAEL and LOAEL found in these studies could be the result of study design and parameters used to assess ne uromuscular effects. The findings in the Wistar rat study (reduced forelimb grip strength ) are consistent with the muscle lesion
observations in the chronic and subchronic SD rat studies. The neurofunctional test performed in the Wistar rat study provides a sensitive measure of the endpoint of concern. The three studies, considered togeth er, show consistent neuromuscular effects, with the Wistar rat study providing a more sens itive measure of the endpoint of concern.
Since the NOAEL from the subchronic Wistar rat study (0.4 mg/kg/ day) would be more protective, it was selected for the chronic risk assessment.

Page 24 of 45Although there are apparent differences between the SD and Wistar rat studies, all three
studies show consistent neuromuscular effect s at approximately similar doses, with the Wistar rat study providing a more sensitive measure of the endpoint of concern. This may
be due to the fact that the Wistar rat study employed a neur ofunctional test while the SD studies did not. As stated above, consistent neuromuscular effects were observed in the three studies and together they provide adequa te data for chronic risk assessment. There are major data gaps in the metiram databa se, and the required studies may provide a lower dose/different endpoint for risk assessmen t. Based on the weight of evidence, a chronic toxicity study in Wistar rats is not required. Alt hough some of the endpoints of concern (neuromuscular effects) may be obser ved during the clinical observations in a chronic toxicity study, the evaluations conducte d during the neurotoxic ity testing battery in the required neurotoxicity studies will provide a more sensitive evaluation of the endpoint of concern identified in the subchronic and chronic studies.

3.4.4 Recommendation for Aggregat e Exposure Risk Assessments

Since there are no residential uses for metiram, the aggregate exposure assessment considered exposures from food and drinki ng water estimates for ETU only (residues of
metiram per se are not expected in drinking water).

3.4.5 Classification of Carcinogenic Potential

The HED Cancer Peer Review Committee (CPRC) classified ETU as a group B2 probable human carcinogen (Bill Sette, Ph.D. memo, 4/16/90 and Albin Kocialski, Ph.D. memo, 9/26/91). The cancer potency factor (Q 1 *) for ETU, using a 3⁄4 scaling factor, was determined to be 0.0601 (mg/kg/day) -1 based on female mouse liver tumors in the NTP (National Toxicology Program) study (Ber nice Fisher and Hugh Pettigrew memo, 2/24/95). Due to the lack of adequate st udies on metiram for a ssessing the carcinogenic potential and the fact that ETU is a metabolite/degradate of metiram and the other EBDCs, the Q 1 * for ETU is also used for to account for ETU derived from metiram (HED Document No. 013554, 7/7/99). Cancer risk assessments for metiram and the other EBDCs are based on exposure to the ETU degradate and metabolite estimated from the EBDC agricultural use patt erns and residue information.

Page 25 of 453.4.6 Summary of Toxicological Doses and Endpoints for Metiram for Use in
Human Risk Assessments

Table 3.4. Summary of Toxicological Doses and Endpoints for Metiram for Use in Human Health
Risk Assessments Exposure/
Scenario Point of Departure Uncertainty/FQPA Safety Factors RfD, PAD, Level of
Concern for Risk
Assessment Study and Toxicological
Effects

Acute Dietary (General Population, including Infants and Children) There was no appropriate endpoint attributable to a single dose in the available toxicity
studies.

Acute Dietary (Females 13-49 years of age) NOAEL= 10 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 10x,UF DB Acute RfD = 0.01mg/kg/day

aPAD = 0.01mg/kg/day Developmental Toxicity (Rabbit) LOAEL = 40 mg/kg/day,
based on abortions

Chronic Dietary (All Populations) NOAEL= 0.4 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 10x,UF DB 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) Q 1 * = 6.01x10 -2 (mg/kg/day) -1 Metiram is classified as Group B2 carcinogen (probable human carcinogen); use low-dose extrapolation for human risk assessment, based on ETU. Quantitative cancer risk assessments for metiram and other EBDCs are based on exposure to the ETU degradate.
Point of Departure (POD) = A data point or an estimate d point that is derived from observed dose-response data and used to mark the beginning of extra polation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest
observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF S = use of a short-term study for long-term ri sk assessment (not required for metiram).

UF DB = to account for the absence of key data (i.e., l ack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose.

3.5 Hazard Characterization of ETU

The toxicology database for ETU is limite d based on guideline studies, and HED has relied on a combination of guideline data a nd several studies in the open literature to assess hazard for ETU. The thyroid and the nervous system are the targets for ETU. Thyroid toxicity in subchronic and chroni c rat, mouse, and dog studies included
decreased levels of T 4 , increases or decreases in T 3 , compensatory increases in levels of the thyroid stimulating hormone, increased thyroid weight, and microscopic thyroid changes, chiefly hyperplasia. Overt liver t oxicity was observed in one chronic dog study. Developmental defects in the rat developm ental study included hydrocephaly and related lesions, skeletal system defects, and other gr oss defects. These defects showed increased susceptibility to fetuses because they occu rred at a dose that only caused decreased

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

Although the data provided evidence for increa sed susceptibility to fetuses following dosing with ETU, HED determined that th e degree of concern for the qualitative susceptibility is low because the developm ental effects were well characterized in numerous studies in the published literature, as well as in a guideline study submitted by the registrant. In addition, the dose-res ponse relationship was well characterized, and
doses selected for overall risk assessments addressed concerns for developmental and thyroid toxicity.

The submitted data do not support the reduction or removal of the 10X FQPA SF due to the absence of required toxico logical studies. HED has retained a 10X FQPA safety factor for dietary and aggregate risk assessments for ETU.

The doses and endpoints used for ETU ar e listed Table 3.5 below. See the ETU Aggregate Risk Assessment document (D 337241, T. Goodlow) for further details.

Table 3.5 ETU Toxicological Doses and Endpoints for Use in Human Health Risk Assessment Exposure/
Scenario Point of Departure Uncertainty/FQPA Safety Factors RfD, PAD, Level of
Concern for Risk
Assessment Study and Toxicological
Effects

Acute Dietary (General Population, including Infants and Children) There was no appropriate endpoint attributable to a single dose in the available toxicity
studies.

Acute Dietary (Females 13-49 years of age) NOAEL= 5 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 10x,UF DB Acute RfD = 0.005 mg/kg/day

aPAD = 0.005 mg/kg/day Developmental Rat Toxicity (Khera Study, MRID No. 45937601) LOAEL = 10 mg/kg/day, based on developmental
defects of brain Chronic Dietary (All Populations) NOAEL= 0.18 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 10x,UF DB Chronic RfD =

0.0002 mg/kg/day

cPAD = 0.0002 mg/kg/day Dog Chronic Oral Toxicity

LOAEL= 1.99 mg/kg/day based on thyroid toxicity

Cancer (oral, dermal, inhalation) Q 1 * = 6.01x10 -2 (mg/kg/day) -1 ETU is classified as a Group B2 carcinogen with a low-dose extrapolation a pproach for human risk assessment, based on liver tumors in female mice.
Point of Departure (POD) = A data point or an estimate d point that is derived from observed dose-response data and used to mark the beginning of extra polation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest
observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (intraspecies). UF H = potential variation in sensitivity among members of the human population (interspecies). UF DB = to account for the absence of key data (i .e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose.

Page 27 of 453.6 Endocrine Disruption

EPA is required under the Federal Food, Drug and Cosmetic Act (FFDCA), as amended by FQPA, to develop a screening program to determine whether certain substances (including all pesticide active a nd other ingredients) “may have an effect in humans that is similar to an effect produced by a natura lly occurring estrogen, or other such endocrine effects as the Administrator may designa te.” Following recommendations of its Endocrine Disruptor and Testing Advisory Committee (EDSTAC), EPA determined that
there was a scientific basis fo r including, as part of the program, the androgen and thyroid hormone systems, in addition to the estr ogen hormone system. EPA also adopted EDSTAC’s recommendation that the Program in clude evaluations of potential effects in wildlife. For pesticide chemicals, EPA will us e FIFRA and, to the extent that effects in wildlife may help determine whether a substa nce may have an effect in humans, FFDCA authority to require the wildlife evaluations . As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program (EDSP).

When additional appropriate sc reening and/or testing protoc ols being considered under the Agency’s EDSP have been developed, metir am may be subjected to further screening and/or testing to better characterize effects related to endocrine disruption.

4.0 Public Health and Pesticide Epidemiology Data

Reference: Review of Metiram Incident Repo rts. D286186. Jerry Blondell.

The most recent assessment of metiram incident reports was completed in 2002.
Information sources consulted included the O PP Incident Data System (IDS); the Poison Control Centers (1993-1998); th e California Department of Pesticide Regulation survey information collected from 1982 to pr esent; and the National Pesticide Telecommunications Network (NPTN). In all, only one occupational incident was reported for metiram, through the Poison Control Centers; the incident involved exposure to the eye for one adult, and only minor effects were noted.

5.0 Dietary Exposure/Risk Characterization

5.1 Pesticide Metabolism and Environmental Degradation

5.1.1 Metabolism in Plants and Animals

The nature of metiram residues in plants is adequately understood based on acceptable studies conducted on apples and potatoes; thes e studies indicate that the bulk of total radioactive residues represen t the incorporation of car bon fragments into natural products. The nature of metiram residues in livestock is also adequately understood

Page 28 of 45based on acceptable goat and poultry metabolis m studies. The Agency has determined
that the terminal residues of concern in plants and livestock are metiram and its
metabolite ETU.

5.1.2 Metabolism in Rotational Crops

No data pertaining to rotational crops are required for an imported crop (HED SOP 98.6, Data Requirements for Import Tolerances , Table 3, 12/3/98).

5.1.3 Analytical Methodology

The available analytical methodology is consider ed adequate for tolerance enforcement. The Pesticide Analytical Manual (PAM) Vol. II lists Methods I, II, III, IV and A for the
determination of dithiocarbam ate residues in/on plant commodities. These methods are based on the decomposition of dithiocarbama tes with release of carbon disulfide (CS 2 ). Using these methods, the CS 2 is swept through a trap to remove any H 2 S and into a reaction tube containing a solution of coppe r acetate and an amine. A colored copper dithiocarbamate complex is formed, and its absorbance is read as a measure of the original dithiocarbamate. Th e stated limit of detection (LOD) for Method I is 0.5-4.0

ppm.

Although enforcement methods which are specific to metiram and ETU are not available, no additional analytical methodol ogies are required. It was concluded in the 10/13/2004 Residue Chemistry Chapter that analytical methods converting all EBDCs and some
metabolites to carbon disulfide will be consider ed adequate for enforcement, along with a specific method for ETU. The colorimetric method of Keppel (Method III in PAM Vol. II) is currently the preferred enforcem ent method for residues of metiram per se . For
determination of ETU resi dues, the Agency recommends the GC method of Onley (AOAC 14th Edition 29.119:554) which provid es acceptable results when properly validated with recovery and control data. In conjunction with the reregistration of other EBDCs (maneb and mancozeb), the Agency has recommended use of the Onley method as the official, final action method for dete rmination of ETU resi dues in/on potatoes, spinach, apple sauce and milk.

5.1.4 Environmental Degradation

Reference : Estimated Drinking Water Concentrations of ETU (Ethylene-thio-urea, degradate of mancozeb, and common degradate of EBDCs “Ethene-bis-dithio-carbamates”) for Use in Human Health Risk Assessment.
D323143 and D323141. M.A. Ruhman and Ronald Parker.

Since no applications will be made in the U.S. for the proposed uses on imported grapes and bananas, the previously assessed drinking wa ter estimates are appropriate for this risk
assessment. Conclusions from the EFED dr inking water assessment are presented below.

The EFED drinking water assessment evaluate d ETU alone because residues of metiram

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

Page 29 of 45aerobic soil half-life of about 3 days; in the absence of data, the aquatic aerobic
metabolism half-life was assumed to be about 6 days, or double the soil half life. The measured anaerobic aquatic metabolism half-lif e, however, is substa ntially longer (149 days) possibly leading to the periodic detec tions in ground water. ETU is soluble in water (20,000 ppm); highly vulnerable to i ndirect photolysis (half-life= 1 day), and moderately mobile (288 L/kg). It also has a relatively high vapor pressure, but high solubility reduces the possi bility of losses from surf ace water due to volatilization.

5.1.4.1 Surface Water

Water Monitoring: The EBDC/ETU Task Force conducted a national surface water monitoring survey from 2001-2003. A total of 22 sites were chosen to represent vulnerable and high EBDC-use sites. Surface water sites were sampled twice monthly for three months during each application se ason and quarterly for the three remaining quarters of each year for a period of 2 years. There were no detections of ETU in surface water during this period. The limit of quantitation for the study was 0.1 ppb.

The Agency has been unable to locate a ny other surface water monitoring data for the EBDC fungicides or for ETU. The EBDCs and ETU were not included in the U.S. Geological Survey (USGS) National Wate r Quality Assessment (NAWQA) sampling program because EBDC/ETU test methods were incompatible with NAWQA test methods. The USGS is currently planning to begin method development and limited EBDC/ETU monitoring.

Water Modeling: The ETU surface water estimates were calculated using the linked U.S. EPA PRZM (Pesticide Root Zone Model) and EXAMS (Exposure Analysis Model System) simulation models. This type of modeling provides high-end estimates for surface water pesticide concentr ations. Calculation includes pesticide-specific properties, multiple years of actual weather variations, and crop-specific information. In addition to runoff from the field, the model takes into account surface water residues resulting from spray drift (aerial or ground). Conservative assumptions included the use of a vulnerable drinking water reservoir surrounded by a r unoff-prone watershed, maximum use rate, lowest application intervals, and no bu ffer zone. Modeling was done for 22 crop
scenarios.

The highest one-in-ten year acute surface water EDWC was 25.2 ppb and the lowest value was 4.5 ppb. These values were calcu lated using the default national percent cropped area (PCA) value of 0.87. If the maximum regional PCA value (0.56 California PCA) is used, then the highest acute surf ace water EDWC was 13.9 ppb and the lowest is 1.4 ppb.

The highest chronic concentration value wa s 1.9 ppb and the lowest value was 0.2 ppb. This was calculated using the national maximum PCA.

Acute Surface Water EDWCs: The ETU surface water estimated drinking water concentrations were generated using a co mbined monitoring/modeling approach. The

Page 30 of 45targeted ETU monitoring found no surface water concentrations above the detection limit of 0.1 ppb. Because samples were taken every 14 days during the application season and acute values may have been missed, a range of acute surface EDWCs was established with a lower limit based on monitoring and an upper limit based on PRZM/EXAMS modeling.

The range of acute EDWCs was 0.1 ppb (monitoring) and the upper limit was 25.2 ppb (modeling). The values were adjusted by th e national maximum default percent cropped area (PCA) value of 0.87.

Chronic Surface Water EDWC: The chronic EDWC is 0.1 ppb from the targeted ETU monitoring program mentioned above. No surface water concentrations were found above the detection limit of 0.1 ppb and the Agency believes that monitoring demonstrates that long-term average chronic va lues would not exceed the detection limit.

5.1.4.2 Ground Water

Water Monitoring: A monitoring program of community ground water systems was conducted by the EBDC Task Force from 2001-2003. Untreated and associated treated ground water was sampled for a period of two y ears in 84 sites chosen to represent high
EBDC-use sites. ETU was detected above th e detection limit intermittently in untreated water from two ground water sites. The hi ghest concentration was 0.21 ppb in untreated
water in Florida. There were no detections in treated water in any of the 84 community water sites, including those two sites where ETU was detected in the untreated water.

A monitoring program of private wells was conducted by the EBDC Task Force from 2001-2003. Raw ground water was sampled monthl y for a period of two years in 125 sites chosen to represent high EBDC-use sites. ETU was detected in the range of 0.10 to 0.25 ppb continuously at 2 sites in Florida and in termittently at six sites: three in Florida and one each in New York, Illinois and Maine . The highest detected ETU concentration measured for a private well near an EBDC treated field was 0.57 ppb in an apple growing region of New York. No detection of ETU was observed in all the other 117 sites. Such higher groundwater concentration values, found in private areas in rural areas, are very rare and are unlikely to represent ground wate r ETU concentrations expected in drinking
water relevant for use in a national assessment.

In 25 years of monitoring in California, there has been only one ETU detection (0.75 ppb). Additionally, ground water monitoring in Holland, resulted in only 8 positive samples with a maximum concentration of 1.5 ppb.

Water Modeling: The ETU EDWCs in ground water, derived from the industry's targeted ground water monitoring study, were evaluated by comparing them to concentrations predicted by th e SCI-GROW model. This is a screening model used to estimate pesticide concentrations in vulne rable ground water. The SCI-GROW estimate is based on environmental fate properties of the pesticide, maximum application rate and existing data from small-scale prospective gr ound water monitoring st udies at sites with

Page 31 of 45sandy soils and shallow ground water (i.e., ex ceptionally vulnerable ground water). Pesticide concentrations estimated by SC I-GROW represent conservative or high-end exposure values and in most cases, use areas will have groundwater that is less vulnerable
to contamination than the areas used to derive the SCIGROW estimate. The SCI-GROW modeling indicates that the upper level ETU c oncentrations from the targeted monitoring study are unlikely to be exceeded even under the most vulnerable conditions.

Ground Water EDWCs (acute and chronic): For ETU, the EDWC value for both acute and chronic exposure is 0.21 ppb. This value is from monitoring untreated water in
Florida.

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

Exposure Duration Surface Water Conc. 1

(ppb) Groundwater Conc. 1

(ppb)

Acute 0.1- 25.2 0.21

Chronic (non-cancer) 0.1 0.21

Chronic (cancer) 0.1 0.21

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

5.1.5 Food Residue Profile

Reference : Metiram. Petition for the Establishment of Import Tolerances on Grape and Banana. Summary of Analytical Chemistry and Residue Data. PP# 9E6006. D267866 and D322230. Christine Olinger.

In support of the requested import tolerances, BASF has submitted several volumes of residue chemistry studies. These studies we re evaluated according to the draft NAFTA Guidance Document on Data Requirements for Tolerances on Imported Commodities jointly issued in April 2003 by the U.S. Envi ronmental Protection Agency, Canada’s Pest Management Regulatory Agency (PMRA) and Mexico’s Comision Intersecretarial para el Control del Proceso y Uso de Plaguici das y Sustancias Toxicas (CICOPLAFEST).

For bananas grown in Central and South Amer ica, the Polyram® 80 WG formulation is proposed for multiple spray applications; HE D could not determine from the specimen label if the applicati on rates were in terms of product or active ingredient. The proposed preharvest interval (PHI) is 7 days. The submitted label for bananas is inadequate to
allow evaluation of the residue data relative to the proposed foreign use pattern because the label does not specify the maximum number of applications (or total application rate) that may be made on banana crops grown in Central and South America per growing season. In addition ̧ the label does not provi de information pertaining to the type of equipment which may be used for applica tions. Although the use information provided to the Agency is unclear, HED assumed the use pattern employed in the residue trials were representative of the uses in Central and South America. The petitioner may rely on
the submitted field trial data for bananas provided the product labels are revised for consistency with the application methods used in the field trials; details of suggested label revisions are presented in the Section 10.0 of this document. Note that if the

Page 32 of 45petitioner significantly changes the use pattern in the future, this could potentially impact
the residue levels in/on bananas.

For grapes grown in Europe, the Poly ram® DF Fungicide and Polyram® WG formulations are proposed for multiple spray applications; HED could not determine from the specimen labels if the applicati on rates were in terms of product or active ingredient. The proposed PHIs are 28 days in Italy, 35 days in France and 56 days in Germany. The submitted labels for grapes ar e inadequate to allow evaluation of the residue data relative to the proposed foreign us e pattern because not all labels specify the maximum single and seasonal rates as well as the preharvest intervals for each European country where uses are proposed. However, the petitioner has indi cated that during the past few years, the European Union (EU) is attempting to harmonize label uses of metiram for grapes grown all over Europe. Th e proposed harmonized grape use pattern in EU specifies: a maximum single applica tion rate of 1.8 kg ai/ha (1.6 lb ai/A), a maximum of 3 applications per growing seas on for an implied seasonal rate of 5.4 kg ai/ha (4.8 lb ai/A), and a 56-day PHI.

When EU has completed the harmonization of all metiram labels intended for use on grapes, EPA requires the submission of revise d labels to verify whether the available residue data can support the harmonized use patt erns. In the interim, the Agency will assess the adequacy of the submitted residue da ta for grape data relative to the maximum use patterns for each European country (whe re labels are provid ed) as well as the proposed harmonized use pattern. Note that if the petitioner signifi cantly changes the use pattern in the future, this could potentially impact the residue levels in/on grapes.

The data-collection methods used for the analysis of samples, taken from field and processing studies, are adequate based on acceptable method recoveries which were, overall, within the acceptable range of 70-120% . Samples of grapes and its processed commodities were analyzed for residues of metiram, determined as CS 2 , using a spectrophotometry method (BASF Methods 135, 135/4, or Instit ut Fresenius Method No. IF-95/22962-00); the reported lim its of quantitation (LOQ) for CS 2 ranged from 0.03 to 0.05 ppm. Grapes and its processed commoditie s were analyzed for ETU using an HPLC method (BASF Method 373/2, 373/1, or 373/0) with pulsed ampero metric detection or an HPLC/UV method (Institut Fr esenius No. IF-95/24090-00) based on BASF Method No. 373; the reported LOQ for ETU ranged from 0.01 to 0.05 ppm. The ETU method (BASF Method 373/2) was subjected to successful independent labora tory validation (ILV). The
EBDC and ETU methods need not be furt her validated by Agency chemists at ACB/BEAD since there are adequate enfor cement methodologies for metiram and ETU. Samples of banana were analyzed for residues of metiram, determined as CS 2 , using a GC/MSD method (LAARL SOP PA.0244) a nd for ETU using an LC/UV method (LAARL SOP PA.0247); the validated LOQ was 0.05 ppm for metiram and ETU in whole banana, pulp and peel (0.03 ppm for CS 2 ).

Adequate storage stability data for metiram are available to support the storage conditions and intervals of RAC samples collected from the grape and banana field studies as well as samples from the grape processing studi es. The 10/13/04 Residue Chemistry Chapter

Page 33 of 45of the Metiram RED reported that metiram is relatively stable in/on diverse crop matrices such as apple, peanut, potato, sugar beet and tomato and in apple processed commodities when stored frozen for up to one year; thes e data for metiram may be translated to bananas, grapes and grape processed commodities. There are also adequate storage stability data for ETU on grapes. Weat hered residues of ETU were found to be reasonably stable for up to 8.5 months in/on grapes under frozen st orage conditions. The maximum freezer storage intervals of grape sa mples, from harvest to analysis, were ≤ 8.3
months for metiram and ≤ 7.9 months for ETU. The maximum storage interval of whole banana samples, from harvest to analys is, was 4.0 months for metiram and ETU; maximum storage interval for bana na pulp and peel was 4.5 months.

There are, however, inadequate storage stabil ity data for ETU in/on bananas and in grape processed commodities (raisins and juice); these data are required for risk assessment. Because of the instability of ETU in some plant commodities, the Agency has taken the approach that storage stability data for me tiram residues of concern (including ETU) are not translatable to data collected by other laboratories. Therefore, HED requests the petitioner to use the same analytical labor atories, which performed the analysis of samples collected from the submitted banana field study and grape processing study, in the generation of the requested storage stability data for ETU.

The magnitude of the residue data for banana s were generated from a total of 12 field trials conducted between the 2004 and 2005 grow ing seasons in Cost a Rica (2 trials), Colombia (2 trials), Ecuador (2 trials), Honduras (2 trials), Mar tinique (2 trials) and Mexico (2 trials). The number and locations of field trials are adequate for the purpose of establishing an import tolerance on banana s. The maximum residues of metiram,
determined as CS 2 , in/on samples harvested 0 days following the last of 10 or 11 broadcast foliar applications of the 70% WG formulation for a total seasonal rate of 12.5- 13.9 lb ai/A were: (i) 0.13 ppm in/on bagged whole bananas, (ii) 2.8 ppm in/on unbagged whole bananas, (iii) below the method LOQ (<0.03 ppm) in/on pulp from bagged bananas, (iv) 0.11 ppm in/on pulp from unbagge d bananas; (v) 0.16 ppm in/on peel from bagged bananas and; (vi) 1.5 ppm in/on peel from unbagged bananas. Residues of ETU were: (i) below the method LOQ (<0.05 ppm) in/on all treated bagged/unbagged samples
of whole bananas and banana pulp; (ii) below the met hod LOQ (<0.05 ppm) in/on peel from bagged bananas and; (iii) at or below the method LOQ ( ≤ 0.05 ppm) in/on peel from unbagged bananas.

Because quantifiable residues of metiram were observed in/on all samples of bananas, the tolerance spreadsheet was used to determin e the appropriate tolerance level; residues
were first converted from metiram equivalents to CS 2 equivalents. Based on the
calculations in the tolerance spreadsheet, the appropriate to lerance level for bananas is 3.0 ppm. The petitioner is required to submit a revised Section F to delete the tolerance proposal for banana pulp since the Agency does not set tolerances on banana pulp and peel separately; however, data for banana pulp and peel are useful for dietary risk

assessment.

Page 34 of 45The magnitude of the residue data for grapes were generated from a total of 34 field trials conducted between the 1999 and 2003 growing seas ons in France (13 trials), Germany (9 trials), Italy (2 trials) and Spain (10 trials). The number and locations of field trials are adequate for the purpose of establishing an import tolerance on grapes. Varieties tested included wine and table varieties of grapes.

Data bracketing a 27/28/29-da y PHI indicate that the ma ximum residues of metiram,
determined as CS 2 , in/on mature grapes were: (i) 1.5 ppm following eight applications of
the 55% WG formulation for a total rate of 7.4-7.7 lb ai/A; (ii) 2.6 ppm following eight applications of the 70% WG formulation for a total rate of 9.5-9.8 lb ai/A; (iii) 2.05 ppm following six applications of the 70% WG form ulation for a total rate of 8.2-8.5 lb ai/A; and (iv) 1.96 ppm following three applications of the 55% WG formulation for a total
rate of 2.9 lb ai/A. Residu es of ETU in/on the respectiv e treated samples ranged from below the method LOQ (<0.01 or <0.05 ppm) to 0.032 ppm. These data may be used to support the label PHI of 28 days in Italy pending submission of additional use pattern
information. The residue data summarized above reflect a total applic ation rate range of
2.9-9.8 lb ai/A.

Data bracketing a 35/36-day PHI indicate that the maximum residues of metiram,
determined as CS 2 , in/on mature grapes were: (i) 1.7 ppm following eight applications of
the 55% WG formulation for a total rate of 7.4-7.7 lb ai/A; (ii) 2.2 ppm following eight applications of the 70% WG formulation for a total rate of 9.5-9.8 lb ai/A; (iii) 1.49 ppm following three applications of the 55% WG fo rmulation for a total rate of 2.9 lb ai/A; and (iv) 2.3 ppm following three applications of the 70% WG formulation for a total rate
of 2.9-3.0 lb ai/A. Residues of ETU in/on the respective treated samples ranged from below the method LOQ (<0.01 or <0.05 ppm) to 0.015 ppm. These data may be used to support the label use pattern in France which specifies a 35-day PHI and an implied
maximum seasonal rate of 2.9 lb ai/A. The re sidue data summarized above reflect a total application rate range of 2.9-9.8 lb ai/A (1.0-3.4x the maximum seasonal label rate in France).

Data bracketing a 54/55/56-da y PHI indicate that the ma ximum residues of metiram,
determined as CS 2 , in/on mature grapes were: (i) 1.2 ppm following eight applications of
the 55% WG formulation for a total rate of 7.4-7.7 lb ai/A; (ii) 1.8 ppm following eight applications of the 70% WG formulation for a total rate of 9.5-9.8 lb ai/A; (iii) 1.81 ppm following six applications of the 70% WG form ulation for a total rate of 8.2-8.5 lb ai/A; (iv) 1.69 ppm following three applications of th e 70% WG formulation for a total rate of
2.9-3.0 lb ai/A. Residues of ETU in/on the re spective treated samples ranged from below the method LOQ (<0.01 or <0.05 ppm) to 0.012 ppm. These data may be used to support the proposed harmonized use pattern in EU wh ich specifies a 56-day PHI and an implied
maximum seasonal rate of 4.8 lb ai/A. The re sidue data summarized above reflect a total application rate range of 2.9-9.8 lb ai/A (0.6-2.0x the maximum harmonized seasonal rate in EU).

Quantifiable residues of metiram were observe d in/on all samples of grapes. Current product labels vary considerably among the regions of Europe, but the registrant has

Page 35 of 45stated that it is their intention to develop a harmonized label. HED has concluded that a tolerance level of 5 ppm would be appropriate consideri ng the current use patterns and the registrant’s proposal, and would harm onize with the Codex Maximum Residue Limit for grapes. The petitioner is required to s ubmit a revised Section F reflecting a tolerance of 5 ppm.

The submitted grape processing studies are incomplete to satisfy guideline requirements
because these studies did not include residue da ta for grape juice. According to Table 1 of OPPTS 860.1000, the regulated processed commod ities of grapes are juice and raisins. Although incomplete, the grape processing da ta indicate that residues of metiram (determined as CS 2 ) and ETU concentrated by averag e processing factors of 3.3x and 1.7x, respectively, in raisins following processi ng of the RAC (grapes) with detectable residues and using procedures simulating comm ercial practices. The maximum expected residues of metiram in imported raisins can be calculated by multiplying the processing factor (3.3x) by the highest RAC residue value expressed as CS 2 (2.6 ppm) obtained from a trial reflecting 28-day PHI which may have been conducted at an exaggerated rate pending use clarification. The product of 8.58 ppm is great er than the recommended tolerance of 5 ppm. The registrant sh ould submit a revised Section F proposing a
tolerance in/on rais ins of 10 ppm.

HED will make a definitive determination re garding the need for import tolerances on grape processed commodities when the request ed bridging data for grape juice become
available.

The submitted grape processing studies incl uded residue data for various matrices following processing of wine varieties of gr apes using procedures for commercial wine production. Average processing factors were reported for metiram (determined as CS 2 ) in: Rosé must (0.1x and 0.6x), Rosé young wine (<0.02x), Rosé mature wine (<0.02x and <0.1x), Red must (0.1x and 0.5x), Red young wine (<0.02x) and Red mature wine (<0.03x and <0.1x). Average processing factor s were reported for ETU in: Rosé must (<0.3x and 0.8x), Rosé young wine (>3.0x), Ro sé mature wine (0.6x and >2.9x), Red must (>2.5x and 10.4x), Red young wine (>3.7x ) and Red mature wine (>3.5x and 10.7x). Average wine processing factors reporte d for ETU are likely to be the result of
the conversion of metiram to ETU , not the concentration of actual residues. The Agency does not set pesticide tolerances in wine becau se wine is under the purview of the Bureau of Alcohol, Tobacco and Firearms.

Although several deficiencies were identifie d within the residue chemistry database, HED does not object to granting import tolerances for grapes at 5 ppm and raisins at 10 ppm, provided a revised Section F and pr oduct labels are submitted. Confirmatory storage stability and processi ng data are also required.

HED does not object to granting a temporar y import tolerance for bananas at 3.0 ppm provided banana monitoring data for metiram and ETU are submitted, and all residue chemistry deficiencies are resolved. A full re solution of these deficiencies is required

Page 36 of 45before HED can recommend the establishment of permanent import tolerances; see
Section 10.0 of this document for further detail.

5.1.6 International Residue Limits

There are no established or proposed Codex MRLs for metiram residues per se ; however, Codex limits for dimethyldithiocarb amate fungicides are grouped under dithiocarbamates. Maximum residue limits (MRLs) for the dithiocarbamates are established for several commodities resulting from the use of mancozeb, maneb,
metiram , propineb, thiram and ziram and ar e currently expressed as ppm carbon
disulfide. The residue definition has been harmonized with Codex. The recommended tolerance for banana, 3 ppm, cannot be harmonized with Codex because residues exceeded the Codex MRL of 2 ppm. HED has recommended harmonizing the proposed grape tolerance with the Codex MRL of 5 ppm.

5.2 Dietary Exposure and Risk

Reference: Metiram Acute, Chronic, and Cancer Dietary Exposure Assessments for New Tolerances on Imported Grapes and Bananas. PP# 9E6006. D326753. April 17, 2007. Christine Olinger.

Metiram and ETU acute, chronic and cancer dietary risk assessments were conducted using the Dietary Exposure Evaluation Model (DEEM-FCIDTM), Version 2.03, which used food consumption data from the United States Department of Agriculture’s (USDA’s) Continuing Surveys of Food In takes by Individuals (CSFII) from 1994-1996
and 1998.

Dietary risk assessment incorpor ates both exposure and toxicity of a given pesticide. For acute and chronic assessments, the risk is expressed as a percentage of the aPAD or cPAD, respectively. For acute and non-can cer chronic exposures, HED is concerned when estimated dietary risk exceeds 100% of the PAD. HED is generally concerned
when estimated cancer risk exceeds one in one million.

5.2.1 Acute Dietary Exposure/Risk

Metiram per se Data Sources and Assumptions

To estimate metiram acute dietary exposure and risk, a refined probabilistic assessment was conducted using a distribution of either fi eld trial or monitoring data for commodities considered to be either nonblended or partia lly blended. Average field trial or monitoring residues were used for blended commodities. Maximum % CT and relevant processing
factors were also included in the assessment. Percent crop treated information is not available for the proposed import tolerances ; however, percent imported factors were incorporated for bananas and grapes.

Page 37 of 45ETU (from Metiram) Data Sources and Assumptions

To estimate metiram-derived ETU acute dietar y exposure and risk, th e full distribution of field trial or monitoring residues was used for nonble nded and partially blended commodities; for blended commodities, the average field trial or monitoring residue value was used. For all included commodities, relevant processing and cooking factors,
conversion of EBDC to ETU for certain cooked commodities, and the 7.5% metabolic
conversion of EBDC residues to ETU were in corporated into the anticipated residues.

Acute Dietary Results

Acute dietary exposure and risk from me tiram and metiram-derived ETU are below
HED’s level of concern. For females 13-49 years old, estimated dietary exposure (food only) to metiram per se was 0.002215 mg/kg/day, which utilized 22% of the aPAD at the

99.9 th percentile. For ETU, the acute di etary exposure was 0.000299 mg/kg/day which
utilized 6.0% of the ETU aPAD. The result s of the acute dietar y exposure assessments for metiram per se and ETU are shown in Summary Table 5.2.

5.2.2 Chronic Dietary Exposure/Risk

Metiram per se Data Sources and Assumptions

To estimate chronic dietary exposure and risk to metiram per se , a refined assessment was conducted using average field trial or average monitoring residues. In addition, average % CT and relevant processing fact ors were included. Percent crop treated information is not available for the pr oposed import tolerances; however, percent imported factors were incorporat ed for bananas and grapes.

ETU (from Metiram) Data Sources and Assumptions

The metiram-derived ETU chronic dietary e xposure (for both non-cancer and cancer risk assessments) was estimated using average ETU residues. Average ETU residues derived from field trials or monitoring were use d, along with the average % CT, percent import information, relevant processing and cooking factors, potential conve rsion of EBDC to
ETU in certain cooked commodities and th e 7.5% metabolic conversion of metiram per

se to ETU.

Chronic Dietary Results

Chronic dietary exposure and risk from metiram and metir am-derived ETU are below HED’s level of concern for the genera l U.S. population and various population subgroups. For metiram, the most highly exposed population subgroup is children 1-2 years old, estimated at 0.000281 mg/kg/day re presenting 70% of the cPAD. For ETU, children 1-2 years old were the most highly exposed population subgroup, at 0.000100 mg/kg/day representing 50% cPAD. The re sults of the chronic dietary exposure
assessments for metiram per se and ETU are shown in Summary Table 5.2.

Page 38 of 455.2.3 Cancer Dietary Risk

The cancer dietary assessment for ETU was based on the same anticipated residues derived for the chronic dietary exposure a ssessment. The estimated chronic dietary exposure for the general U.S. population co rresponds to a cancer risk of 1 x 10 -6 which is
not of concern. The results of the cancer dietary exposure assessments for ETU are shown in Summary Table 5.2.

Table 5.2. Result of Acute and Chronic Dietar y Exposure and Risk Estimates for Metiram Using
DEEM-FCID TM

Metiram per se ETU (from metiram) Population Subgroup

Exposure, mg/kg/day % PAD Exposure, mg/kg/day %PAD

Acute Dietary Estimates (99.9 th Percentile of Exposure)

Females 13-49 yrs 0.002215 22 0.000299 6.0
Chronic Dietary Estimates

U.S. Population 0.000048 12 0.000018 9.0
All infants (< 1 yr) 0.000052 13 0.000051 25

Children 1-2 yrs 0.000281 70 0.000100 50

Children 3-5 yrs 0.000163 41 0.000056 28
Children 6-12 yrs 0.000063 16 0.000022 11
Youth 13-19 yrs 0.000022 5.4 0.000008 3.8
Adults 20-49 yrs 0.000028 6.9 0.000010 5.1
Adults 50+ yrs 0.000039 9.7 0.000015 7.6
Females 13-49 yrs 0.000030 7.4 0.000011 5.3
Cancer Dietary Estimate

U.S. Population NA 1 NA 0.000018 1 x 10 -6

1 Potential for carcinogenicity attributed to the ETU metabolite only.

6.0 Residential (Non-Occupational) Ex posure/Risk Characterization

There are no residential uses or agricultural uses that would result in residential exposure to the general population for metiram.

Spray drift is a potential source of exposure to residents near by to spraying operations. This is particularly the case with aerial appl ication, but, to a lesser ex tent, could also be a potential source of exposure from the gr ound application method employed for metiram. The Agency has been working with the Spra y Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regula tion and other parties to develop the best spray drift management practices. On a chem ical by chemical basis, the Agency is now requiring interim mitigation measures for aer ial applications that must be placed on product labels/labeling. The Agency has comp leted its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropr iately apply the da ta and the AgDRIFT

Page 39 of 45computer model to its risk assessments for pe sticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift with specific products with significant risks associated with drift.

7.0 Aggregate Risk Assessment s and Risk Characterization

In accordance with the FQPA , HED must consider and aggregate (add) pesticide exposures and risks from three major sour ces: food, drinking wa ter and residential

exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative esti mates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both th e route and duration of exposure.

There are no residential exposure concerns fo r metiram, so aggregate exposure and risk assessments consider only food and dri nking water. Since residues of metiram per se are not expected in drinking water, aggregate risks for metiram consist of aggregate metiramderived ETU exposures for acute and chroni c (cancer and non-can cer) durations. The aggregate ETU dietary assessments were base d on the same anticipated residues derived for the ETU food alone dietary exposure assessm ents, with the addition of EDWC values for drinking water.

7.1 Acute Aggregate Risk

For the metiram-derived ETU aggregate acute risk assessment, a surface water EDWC value of 25.4 ppb was used, which resulted in dietary exposure and risk are below HED’s level of concern. For females 13-49 years old, estimated dietary exposure for food and water was 0.003511 mg/kg/day, which uti lized 70% of the aPAD at the 99.9 th percentile. The results of the aggregate acute dietary exposure assessment for metiram-derived ETU are shown in Summary Table 7.1.

7.2 Chronic Aggregate Risk

For the ETU aggregate chronic (non-cancer and cancer) dietary assessment, a ground water EDWC value of 0.21 ppb was used. Aggregate ETU chronic non-cancer risks are below HED's level of concern for the gene ral U.S. population and all other population subgroups. The most highly exposed populat ion subgroup, children 1-2 years old, had a chronic aggregate exposure of 0.000107 mg/ kg/day which utilized 54% cPAD. The results of the aggregate chronic dietary exposure assessment for metiram-derived ETU are shown in Summary Table 7.1.

7.3 Cancer Aggregate Risk

Aggregate ETU cancer risk for the general U. S. population is not of concern, with an
estimated risk of 1 x 10 -6 including existing and proposed uses. The results of the

Page 40 of 45aggregate cancer dietary exposure assessmen t for metiram-derived ETU are shown in Summary Table 7.1.

Table 7.1. Result of Aggregate Acute and Ch ronic Dietary Exposure and Risk Estimates for ETU Using DEEM-FCID TM

ETU (from metiram) Population Subgroup

Exposure, mg/kg/day % PAD
Acute Dietary Estimates (99.9 th Percentile of Exposure)

Females 13-49 yrs 0.003511 70
Chronic Dietary Estimates

U.S. Population 0.000022 11
All infants (< 1 yr) 0.000065 33
Children 1-2 yrs 0.000107 54
Children 3-5 yrs 0.000063 31
Children 6-12 yrs 0.000027 13
Youth 13-19 yrs 0.000011 5.4
Adults 20-49 yrs 0.000014 7.1
Adults 50+ yrs 0.000020 9.8
Females 13-49 yrs 0.000015 7.4
Cancer Dietary Estimate

U.S. Population 0.000022 1 x 10 -6

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

The acute, chronic and cancer aggregate asse ssments for ETU considered food, water and residential exposure resulting from current a nd proposed uses of metiram, mancozeb and maneb; only mancozeb and maneb are used in residential settings. Acute and chronic aggregate risks from all sources of ETU were not of concern; however, the ETU aggregate cancer risk exceeds HED’s level of concern (3.8 x 10 -6 ). HED conducted sensitivity analyses and determined the gr eatest contributors to ETU exposure are bananas, leaf lettuce, water, turnip greens, grape juice and mangoes. If the proposed import tolerance in/on bananas (from metir am applications) is removed from the aggregate assessment, then the aggregate cancer risk does not exceed HED’s level of concern (3.2 x 10 -6 ). All other sensitivity analyses re sult in aggregate risks exceeding the
level of concern. Note that the metiram-deriv ed ETU residue values from crop field trials used in the aggregate assessment are consider ed to be overestimates. Projected percent crop treated information was not available, so percent imported information was used, and it is highly unlikely that all bananas w ill be treated. In general, monitoring data
available for other commodities show much lo wer residues than field trial data, so the actual exposure is likely to be lower. For these reasons, HED is requiring the submission of monitoring data for metiram and ETU on bananas. See the ETU Aggregate Risk Assessment document (D337241, T. Goodlow) for additional details.

Page 41 of 458.0 Cumulative Risk Characterization/Assessment

Section 408(b)(2)(D)(v) of th e FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, th e Agency consider "available information” concerning the cumulative effects of a part icular pesticide's residues and "other
substances that have a comm on mechanism of toxicity.”

Section 408(b)(2)(D)(v) of th e FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, th e Agency consider "available information” concerning the cumulative effects of a part icular pesticide's residues and "other
substances that have a comm on mechanism of toxicity.”

No determination of a common toxic effect or mechanism of toxicity has been made for
acute or chronic non-cancer risks from EBDCs.

9.0 Occupational Exposure/Risk Pathway

No occupational exposure to metiram is expect ed to occur in the U.S. as a result of metiram uses on imported grapes and bananas.

10.0 Data Needs and Label Recommendations

Residue chemistry deficiencies for the curr ent metiram import tolerance petition include the following:

Guideline 860.1200 Directions for use

• Copies of labels, translated to Englis h, must include, but are not limited to, the maximum single application rate, the maxi mum annual applicati on rate, application timing (as it relates to plant growth stage), re-treatment interval, application tank-mix preparation, volume of spray mix per unit ar ea, application equipment, and the preharvest interval (PHI). The application ra tes should be expre ssed in units of pounds active ingredient per acre (or kilograms per hectare).

• The submitted label for bananas is inadequate to allow evaluation of the residue data relative to the proposed foreign use pattern because the label does not specify the maximum number of applications (or total application rate) th at may be made on banana crops grown in Cent ral and South America per gr owing season. In addition ̧ the label does not provide information pertai ning 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 ba nanas, then label amendments are required to specify: (1) a maximum of ten broadcas t foliar applications at 1.25 lb ai/A per

Page 42 of 45application 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 peti tioner wishes to include higher spray volumes on the label, then additional residue data will be required.

• The submitted labels for grapes are also inadequate to allow evaluation of the residue data relative to the proposed foreign use patt ern because not all labels clearly specify the maximum single and seasonal rates as we ll as the preharvest intervals for each European country where uses are propose d. However, the petitioner has indicated that during the past few years, EU is a ttempting 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 sup port the harmonized use patterns. If there are any deviations from the harmonized use pattern due to localized pest infestation or good agricultural pract ices, information pertaining to these deviations should be reported.

Guideline 860.1380 Storage stability data

• There are inadequate storag e stability data for ETU in/on bananas and in grape processed commodities; these data are required for risk assessment. Because of the instability of ETU in some plant commod ities, the Agency has taken the approach that storage stability data for metiram residues of concern (including ETU) are not translatable to data collected by other la boratories. Therefore, HED requests the petitioner to use the same analytical labor atories, which performed the analysis of samples collected from the submitted banana field study and grape processing (raisin and juice only) study, in the generation of the requested storage stability data for

ETU.

Guideline 860.1520 Processed food/feed

• The petitioner is required to conduct a brid ging grape processing study to investigate the potential for concentration of metiram a nd ETU residues in grape juice. In the requested study, the RAC should be pro cessed in a manner simulating typical commercial practice. The RAC should have detectable residues so a concentration factor may be calculated.

Guideline 860.1550 Proposed tolerances

• Based on HED MARC’s determination re garding the approp riate tolerance expression for EBDCs, the petitioner is re quired to submit a revised Section F to include residues of the parent EBDC only, calculated as CS 2 , rather than as zineb. The petitioner should modify the value for grapes to 5 ppm and propose a tolerance in/on raisins at 10 ppm.

Page 43 of 45Guideline 860.1560 Reasonable grounds in support of the petition

• Banana monitoring data are required for metiram and ETU.

Deficiencies or data gaps previously id entified in the RED exist for the following guideline studies:

Toxicology

• Guideline 870.3700 Developmental toxicity, rabbit (only the maternal animal was adequately assessed in the available rabbit study)

• Guideline 870.3800 2-generation reproduction, rat

• Guideline 870.6200 Acute neurotoxicity, rat

• Guideline 870.6300 Developmental neurotoxicity, rat * Comparative study for thyroid t oxicity in adults and offspring is required for ETU only

Residue Chemistry

• Guideline 860.1200 Directions for use (label revision)

• Guideline 860.1850 Confined accumu lation in rotational crops

Product Chemistry

• Guideline 830.1700 Preliminary analysis

• Guideline 830.7050 UV/visible absorption

Occupational Exposure The registrant should submit a DFR study on apples; the submitted study is inadequate,
and leads to lower confidence in estimated postapplication risks.

References

Blondell, Jerry. DP Barcode: D286186. Octobe r 17, 2002. Review of Metiram Incident Reports.

Farwell, Kit. DP Barcode: D291661. June 13, 2005. Metiram: Health Effects Division (HED) Human Health Risk Asse ssment to Support Reregistration.

Goodlow, Toiya. DP Barcode: D337241. June 2007. Ethylenethiourea (ETU) from EBDCs: Health Effects Division (HED) Huma n Health Risk Assessment of the Common Metabolite/Degradate ETU.

Olinger, Christine. DP Barcodes: D 267866 and D322230. Metiram: Petition for the Establishment of Import Tolerances on Grap e and Banana. Summary of Analytical Chemistry and Residue Data. PP# 9E6006.

Page 44 of 45Olinger, Christine. DP Barcode: D326753. April 17, 2007. Metiram Acute, Chronic and Cancer Dietary Exposure Assessments for New Tolerances on Imported Grapes and

Bananas. PP# 9E6006.

Parker, Ronald and Ruhman, Mohammed. DP Barcodes: D323143 and D323141. August 11, 2006. Estimated Drinking Water Concentrat ions of ETU (Et hylene-thio-urea, degradate of mancozeb, and common degr adate of EBDCs “Ethene-bis-dithiocarbamates”) for Use in Human Health Risk Assessment.

Reregistration Eligibility Decision (R ED) for Metiram. August 29, 2005.

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