Page 1 of 46 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES

June 14, 2007

MEMORANDUM

SUBJECT: Ethylenethiourea (ETU) from EBDCs: Health Effects Division (HED)
Human Health Risk Assessment of the Common Metabolite/Degradate
ETU PC Code : 600016, DP Barcode: D337241. Regulatory Action: Registration Action Risk Assessment Type: Aggregate

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

THROUGH: Michael S. Metzger, Branch Chief Whang Phang, Senior Scientist Reregistration Branch 1 Health Effects Division (7509P)

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

The attached human health risk assessment is for ethylene thiourea (ETU), which is the common metabolite/degradate of the ethylen e bisdithiocarbamate (EBDC) fungicides mancozeb, maneb and metiram. Several new uses for mancozeb and metiram have been proposed, requiring an update of the most recent ETU aggregate assessment conducted by Christine Olinger (D317416, 6/8/05) in suppor t of the reregistration of the EBDCs.
This risk assessment summarizes human hea lth risks from exposure to ETU resulting from all registered and proposed uses of th e parent EBDCs and supe rsedes all previous

assessments.Page 2 of 46 Table of Contents
1.0 Executive Summary .............................................................................................. 4
2.0 Ingredient Profile .................................................................................................. 9
2.1 Summary of Registered/Proposed Uses .................................................. 9
2.2 Structure and Nomenclature ................................................................. 12
3.0 Hazard Characterization/Assessment ............................................................... 14
3.1 Hazard and Dose-Response Characterization ...................................... 14
3.1.1 Database Summary ..................................................................... 14
3.1.2 Toxicological Effects ................................................................... 14
3.2 Absorption, Distribution, Metabolism, Excretion (ADME) ................ 17
3.3 FQPA Considerations ............................................................................. 18
3.3.1 Recommendation for a Developmental Neurotoxicity Study .. 19
3.3.2 Safety Factor for Infants and Children .................................... 19
3.4 Hazard Identification and Toxicity Endpoint Selection ...................... 19
3.4.1 Acute Reference Dose (aRfD) - Females age 13-49 .................. 19
3.4.2 Acute Reference Dose (aRfD) - General Population ................ 19
3.4.3 Chronic Reference Dose (cRfD) ................................................. 20
3.4.4 Incidental Oral Exposure ( Short- and Intermediate-Term) ... 20
3.4.5 Oral Exposure (Short- and Intermediate-Term) .................... 20
3.4.6 Dermal Absorption ..................................................................... 20
3.4.7 Dermal and Inhalation Exposure (Short- and IntermediateTerm) ....................................................................................................... 21
3.4.8 Dermal and Inhalation Exposure (Long-Term) ....................... 21
3.4.9 Classification of Carcinogenic Potential ................................... 21
3.5 Endocrine Disruption ............................................................................. 23
4.0 Public Health and Pesticide Epidemiology Data .............................................. 24
5.0 Dietary Exposure/Risk Characterization ......................................................... 24
5.1 Environmental Degradation .................................................................. 24
5.1.1 Surface Water .............................................................................. 24
5.1.2 Ground Water ............................................................................. 26
5.2 Dietary Exposure and Risk .................................................................... 27
5.2.1 Anticipated Residue Information .............................................. 28
5.2.2 Acute Dietary Exposure/Risk ..................................................... 29
5.2.3 Chronic Dietary Exposure/Risk ................................................. 29
5.2.4 Cancer Dietary Risk ................................................................... 29
6.0 Residential (Non-Occupational) Exposure/Risk Characterization ................ 31
6.1 Residential Handler Exposures and Risks ............................................ 32
6.2. Residential Postapplication Exposure ................................................... 33
6.2.1 Residential Postapplication Exposure – Mancozeb ................. 33
6.2.1.1 Home Garden Postapplication Scenarios .................. 34
6.2.1.2 Treated Turf Postapplication Scenarios for Toddlers

.. ........................................................................................ 34
6.2.1.3 Treated Turf Postapplication Scenario for Adults ... 35
6.2.2 Residential Postapplication Exposure - Maneb ....................... 36
6.3 Other (Spray Drift, etc.) ......................................................................... 37Page 3 of 46 7.0 Aggregate Risk Assessments and Risk Characterization ................................ 38
7.1 Acute Aggregate Risk ............................................................................. 39
7.2 Short- and Intermediate-Term Aggregate Risk ................................... 39
7.2.1 ETU Short- and Intermediate-Term Home Garden Aggregate
....................................................................................................... 39
7.2.2 ETU Short-Term Treated Turf Aggregate (Toddlers) .......... 40
7.2.3 ETU Short- and Intermediate-Term Treated Turf Aggregate (Adult “Golfers”) .................................................................................... 41
7.3 Long-Term (Chronic) Aggregate Risk .................................................. 42
7.5 Cancer Aggregate Risk ........................................................................... 42
8.0 Cumulative Risk Characterization/Assessment ............................................... 44
9.0 Occupational Exposure/Risk Pathway .............................................................. 44
10.0 Data Needs and Label Recommendations ........................................................ 44
References ........................................................................................................................ 45Page 4 of 46 1.0 Executive Summary

Use Profile Ethylene thiourea (ETU) is a degradate/meta bolite of the ethylene bisdithiocarbamate (EBDC) fungicides mancozeb, maneb and metir am. The EBDCs are used on agricultural crops such as vegetables, fruits and nuts, on turf including golf courses and sod farms, and on ornamentals including cut flowers. The EBDCs are broad spectrum contact fungicides used to prevent a variety of fungal diseases.

Updated human health risk assessments have been conducted for mancozeb and metiram to account for proposed new uses. The proposed Section 3 uses for mancozeb are for use on almonds, broccoli, cabbage, lettuce (head a nd leaf), and pepper (b ell and non-bell). Import tolerances on bananas and grapes were proposed for metiram. No new uses for maneb have been proposed; therefore, an updated risk assessment for maneb is not necessary at this time. The mancozeb a nd metiram risk assessments include exposures
and risks from ETU derived fr om the individual EBDC.

The purpose of this assessment is to provide information on aggregate exposure and risk from ETU as a result of all EBDC usage, to describe risks from all three EBDCs in broad terms, and to identify significant sources of exposure and risk.

Sources of ETU Crops treated with EBDCs may contain bot h EBDC and ETU residues; in addition, cooking and/or processing may result in conve rsion of EBDC residues to ETU, or in
concentration or reduction of existing ETU residues. Therefore, both EBDC and ETU residues may be consumed in the diet. Du ring application of EB DCs, workers may be exposed to ETU residues which form during degradation of the tank mix over a typical workday, and the Agency has data to reflect these potential exposures. Additional exposure to both EBDCs and ETU may occur during activities conduc ted in and around growing crops following treatment with EBDC s. Metabolic conversion of absorbed
EBDC to ETU occurs and has been acc ounted for in calculating ETU doses.

Hazard Assessment 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 ne rvous system are targets for ETU. Thyroid toxicity in subchronic and ch ronic rat, mouse, and dog studi es included decreased levels

of T 4 (serum thyroxin), increas es or decreases in T 3 (triiodothyronine), compensatory increases in levels of the thyroid stimulat ing hormone (TSH), increased thyroid weight, and microscopic thyroid changes, chiefly hyperp lasia. Overt liver toxicity was observed in one chronic dog study. Developmental def ects in the rat developmental study included hydrocephaly and related lesions, skeletal system defects, and other gross defects. These defects showed increased susceptibility of th e fetuses because they occurred at a dose that caused minimal maternal toxicity (decreased food consumption and body weight gain).Page 5 of 46 Although the data provided evidence for increa sed susceptibility to fetuses following dosing with ETU, HED determined that the degree of concern or uncertainty for the qualitative susceptibility is low because the developmental effects were well characterized in numerous studies in the publis hed literature, as we ll as in a guideline study submitted by the registrant. In additi on, the dose-response relationship was well characterized, and doses selected for overall risk assessments addressed concerns for developmental and t hyroid toxicity.

The submitted data do not support the reducti on or removal of the 10X Food Quality Protection Act safety factor (FQPA SF) due to the absence of required toxicological studies. HED has retained a 10X FQPA safe ty factor for ETU dietary, residential and aggregate risk assessments.

The doses and endpoints used for ETU are listed below. For acute ETU exposures, developmental effects were selected as the mo st sensitive endpoint. This same endpoint
was also used for short and intermediate te rm exposures. For chronic exposures, the endpoint was based upon thyroi d effects that were observe d in the chronic dog study. ETU was classified as a probable human car cinogen based upon liver tumors observed in female mice and a unit risk value, Q 1 *, of 0.0601 (mg/kg/day) -1 was used for risk

assessment.

Exposure Route, Duration ETU Dose in mg/kg/day (study/effects) Acute dietary (females 13-49) NOAEL of 5 (Developmental rat/developmental brain defects) Chronic dietary (gen. U.S. pop.) NOAEL of 0.18 (Chronic dog/thyroid toxicity) Incidental oral, short/int.-term (toddlers) NOAEL of 7 (4-week Dog/thyroid toxicity) Oral, short/int.-term (females 13-49) NOAEL of 5 (Developmental rat/developmental brain defects) Dermal, short/int.-term (toddlers) NOAEL of 7 (4-week Dog/thyroid toxicity) Dermal, short/int.-term (females 13-49) NOAEL of 5 (Developmental rat/developmental brain defects) Dermal, long-term NOAEL of 0.18 (Chronic dog/thyroid toxicity) Inhalation, short/int.-term NOAEL of 5 (Developmental rat/developmental brain defects) Inhalation, long-term NOAEL of 0.18 (Chronic dog/thyroid toxicity)

[NOAEL= No observed adverse effect level. Combin ed Uncertainty factors (U Fs) for ETU occupational assessments are 100x; combined UFs for residential an d dietary assessments are 1000x. Dermal absorption for ETU is 26%, while inhalation absorption is 100%. Dermal and inhalation exposures can be combined,
since the toxic effects from th ese two routes of exposure are similar for similar durations.]

Drinking Water Exposure
The OPP Environmental Fate and Effects Di vision (EFED) prepared a drinking water exposure assessment for ETU. The parent EBDC fungicides are very short-lived in soil and water and would not reach water used for human consumption whether from surface water or ground water. However, ETU is highly water soluble, and may reach both surface and ground water under some conditions.

The ETU surface water estimated drinking water concentrations (EDWCs) were generated using a combined monitoring/mode ling approach. The monitoring data were from a targeted surface water monitoring st udy conducted by the ETU Task Force, in which none of the tested water samples had conc entrations above the limit of detection of 0.1 ppb. A ground water EDWC was selected from a targeted ground water monitoringPage 6 of 46 study conducted in a known EBDC use area in Florida. Acute su rface water estimates were reported as a range of 0.1 ppb (monitoring) to 25.2 ppb (modeling) and chronic/cancer surface water estimates were 0.1 ppb (monitoring). Ground water estimates were 0.21 ppb (monitoring) fo r all durations of exposure.

Dietary Exposure and Risk Analysis Both EBDC and ETU residues may be consumed in the diet. In this assessment the ETU food residues from each of the EBDCs are aggr egated. For the acute, chronic and cancer dietary assessments, field trial or monitori ng data from the EBDC/ETU Market Basket Survey, percent crop treated information, a nd extensive processing study results were used for existing uses. Dietary inputs for th e proposed new uses and tolerances included field trial data, processing factors, project ed percent crop treated information (for the proposed mancozeb new uses), and percent imported information (for the proposed metiram tolerances).

A probabilistic acute aggregate dietary a ssessment was conducted for ETU derived from metiram, mancozeb, and maneb uses. Aggr egated acute dietary exposure and risk estimates for food alone and food and drinking water are below HED’s level of concern.

The refined chronic risk estimates are belo w the HED’s level of concern for aggregate exposure to ETU for the general U.S. popul ation and all population subgroups for food alone and food and drinking water.

The aggregate cancer risk estimate associated with exposure to ETU from all EBDCs for
both food alone and food and drinki ng water combined is 3.3 x 10 -6 and 3.6 x 10 -6

, respectively, for the general U.S. population. The greatest contributors to the dietary exposure for the cancer assessment we re bananas and leaf lettuce.

Residential and Recreational Exposures and Risks
No new residential uses were added to the labe l as part of the current Section 3 requests. There is a potential for home gardener expos ure during and after a pplications to home garden vegetables from the existing uses of the EBDCs. There is also a potential for golfer and toddler post applica tion exposure on golf course turf and transplanted lawns.

The agricultural application rates were used because th e rates given on the two home garden product labels for mancozeb conflic ted with one another and were generally higher than the agricultural rates. The resi dential handler Margins of Exposure (MOEs)
for ETU from use of mancozeb in gardens were not of c oncern because they greatly exceed the target MOE of 1000. Th e cancer risks were also not of concern because they
were less than 1x10 -6

.

The post application risks were also assessed for adult and youth-aged home gardeners. The ETU MOEs exceeded the target MOE of 1000 for both adult and youth home gardeners. The cancer risk for adu lt home gardeners was less than 1x10 -6

.Page 7 of 46 For the ETU aggregate assessment, the turf exposures were assessed for toddlers by assuming the application conditions from the mancozeb and maneb Reregistration Eligibility Decision (RED) documents. Assumi ng a three day Pre-Harvest Interval (PHI) and two days to harvest, transport and inst all the turf, all MOEs exceeded 1000 and were
not of concern.

Mancozeb is the only EBDC registered for us e on golf courses. The turf exposures were assessed for golfers by using the day 0 Turf Transferable Residues (TTR) for short term exposures and the 7 day average TTR for lif etime exposures. The ETU MOE for golfers exceeded the target MOE of 1000 and is not of concern. The golfer cancer risk was
6 x 10 -9 assuming that golfers played an averag e of 1 day per year on mancozeb treated
turf.

Aggregate Risks The aggregate exposures for adults incl uded food, drinking water, golfing, and home gardening, while the aggregate exposures for toddlers include playing on turf, food and drinking water.

Acute aggregate risks were calculated fo r females 13-49 years old only because an appropriate endpoint for this exposure duration was not identi fied for other populations. The acute aggregate exposures including food and drinking water were not of concern as the exposure resulted in a risk that was equivalent to 89% of the aPAD at the 99.9 th percentile of exposure.

The short term aggregate risks were calculat ed for adults by aggregating average daily food exposure, chronic drinking water exposure, and the residential exposures. The short term MOEs ranged from 6,100 to 13,000, which are not of concern. For youth gardeners, aggregate risks are not of concern. The aggr egate risks for toddlers playing on turf, food, and drinking water are also not of concern.

The chronic aggregate risks were calculat ed using average food and drinking water exposures and were below HED's level of concern (<100% cPAD) . The most highly exposed population subgroup was children 1-2 years old, with aggregate risks of 86% of
the cPAD.

The cancer risks were aggregated using th e average daily food, drinking water and residential exposures. The aggregate cancer risk for the U.S. population is 3.8 x 10 -6

, which exceeds HED’s level of concern. HED conducted sensitivity analyses to determine the commodities that provided the most contribution to the ETU exposure. The commodities that are the greatest contri butors to ETU exposure are bananas, leaf lettuce, drinking water, turnip greens, grape juice and mangoes. If the proposed tolerance in/on bananas (from metiram applications) is removed from the aggregate, then the aggregate cancer risk does not exceed HED’ s level of concern. Note that the metiramderived ETU residue values from crop field tr ials used in the aggregate assessment are considered to be overestimates. Projected percent crop treated information was not available, so percent imported information was used and it is hi ghly unlikely that allPage 8 of 46 bananas will be treated. In general, mon itoring data on other commodities show much lower residues than field trial data, so actual exposure is likely to be lower.

Occupational Exposure The occupational aspect of the human health risk assessment has been completed for each of the EBDC fungicides in the risk assessments of the parent compound.

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 Environmenta l 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 drinking water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the United States Department of Agriculture (USDA) under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever 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 treated areas pos tapplication 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 The data gaps for each individual EBDC a nd the corresponding exposures to ETU are
discussed in the risk assessments for each parent compound. The data gaps for ETU, which were previously identified in the 2005 human health risk assessment for the RED, include the following:

Toxicology

• Guideline 870.3800 2-generation reproduction, rat

• Guideline 870.3700 Developmental toxicity, rabbitPage 9 of 46 • Guideline 870.6300 Developmental neurotoxicity

• Non-guideline Comparative study for thyroid toxicity in adults and offspring

2.0 Ingredient Profile

ETU is a metabolite, environmental degrad ate, and cooking byproduct of the EBDC fungicides, metiram, maneb and mancozeb. T echnical ethylenethiour ea is a crystalline solid with a white to pale green color, and a faint amine odor. It has a melting point of

203-204 ° C. ETU is considered soluble in wate r, with a water solubility of 20,000 ppm
at 30 ° C, but it is also slightly soluble in methanol, ethanol, ethylene glycol, pyridine, acetic acid and naphtha. When ETU is heated to decomposition, nitrogen and sulfur
oxides are emitted.

2.1 Summary of Registered/Proposed Uses

The EBDC fungicides are used on numerous agricultural cr ops, including vegetables, fruit and nut trees, field and forage crops , and grapes; for seed treatment; on turf, including golf courses, and sod farms; and on ornamental trees, shrubbery, perennials and annuals. The EBDCs are broad spectrum cont act fungicides used to prevent a variety of fungal diseases, including downy mildews, anthra cnose, rusts, leaf spots, blights, crown rot, molds, cankers, seed ro t and seedling damping off. EBDC end-use products are available as wettable powder (W P), dry flowable (DF), dust (D ), emulsifiable concentrate (EC), and ready-to-use formulations.

Mancozeb and maneb have the most food us es, while metiram food uses are limited to apples and potatoes, with proposed import tole rances on bananas and grapes. In terms of annual production and uses, mancozeb is the mo st significant of th e EBDCs, with over 6 million pounds of total domestic usage; crops w ith the largest market in terms of pounds active ingredient (ai) are potat oes, fresh tomatoes and apples. Maneb domestic use is estimated to be over 2 million pounds ai annua lly; crops with the largest markets in pounds ai are potatoes, peppers (bell and nonbell ), and lettuce. Metiram domestic use is estimated at over 600,000 pounds annually, with two-thirds of the production volume applied to apples, and one-third of the production volume applied to potatoes.

Summary Tables 2.1 and 2.3 show the proposed new uses for metiram, and mancozeb, respectively. Table 2.2 shows the future harmonization pattern for grapes grown in Europe.Page 10 of 46 Table 2.1 Summary of Proposed U ses 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)

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.Page 11 of 46 Table 2.2 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.

Table 2.3 Summary of Proposed Uses for Mancozeb. Applic. Timing, Type, and Equip. Formulation Applic.
Rate (lb ai/A) [kg ai/ha] Max. No. Applic. per Season Max.
Seasonal Applic. Rate

(lb ai/A) [kg ai/ha] PHI (days) Use Directions and
Limitations

Broccoli and Cabbage Postemergence
Broadcast 80% WP 1.6 6 (implied) 9.6 7 Applications are to be
made as soon as disease is present. A minimum
retreatment interval (RTI) of 7 days is specified.

Lettuce 1.6 6 (implied) 9.6 10 Applications are to begin when disease appears. Use limited to all states except CA. A minimum RTI of 7 days is specified. Postemergence
Broadcast 80% WP

1.6 4 (implied) 6.4 14 Applications are to begin when disease appears. Use limited to
CA. A minimum RTI of 7 days is specified. Pepper Postemergence
Broadcast 80% WP 1.6 6 (implied) 9.6 7 Applications are to begin when disease appears. Use limited to west of the Mississippi
River. A minimum RTI of 7 days is specified.Page 12 of 46 Table 2.3 Summary of Proposed Uses for Mancozeb. Applic. Timing, Type, and Equip. Formulation Applic.
Rate (lb ai/A) [kg ai/ha] Max. No. Applic. per Season Max.
Seasonal Applic. Rate

(lb ai/A) [kg ai/ha] PHI (days) Use Directions and
Limitations

2.4 6 (implied) 14.4 7 Applications are to begin when disease appears. Use limited to east of the Mississippi
River. A minimum RTI of 7 days is specified.
Almond

Postemergence
Broadcast
Ground or aerial 80% WP 4.8 3 (implied) 14.4 Last applic.
to be
made no

later
than 5
weeks
after petal fall Applications are to begin at the dormant to popcorn growth stages
and continue with a minimum 7-day
retreatment interval. A
non-ionic surfactant or spreader sticker is to be added to the spray
solution. Aerial applications are to be
made in a minimum of 10 gal/A. The grazing
of livestock in treated areas is prohibited.

2.2 Structure and Nomenclature

Table 2.4 ETU Test Compound Nomenclature Compound

Common name Ethylenethiourea (ETU) Empirical formula C 3 H 6 N 2 S Molecular weight 102.2 CAS registry number 96-45-7Page 13 of 46 Table 2.5 Metiram Test Compound Nomenclature Compound

N H S

N H Zn

S

S S

N H S

N H S

S S

3

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

x Common name Metiram 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

Table 2.6. Mancozeb Test Compound Nomenclature

Chemical structure

N H S S

N H S Mn

S Zn

x y

Common name Mancozeb IUPAC name manganese ethylenebis(dithiocarba mate)(polymeric) complex with zinc salt CAS name [[1,2-ethanediylbis[carbamodithioato]](2-)]manganese mixture with [[1,2- ethanediylbis[carbamodithioato]](2-)]zinc CAS registry number 8018-01-7

Table 2.7 Maneb Test Compound Nomenclature

Chemical structure

Common name Maneb IUPAC name Manganese ethylenebis (dithiocarbamate) (polymeric) CAS name [[1,2-ethanediylbis[carbamodithioato]](2-)]manganese CAS registry number 12427-38-2Page 14 of 46 3.0 Hazard Characterization/Assessment

3.1 Hazard and Dose-Response Characterization

3.1.1 Database Summary

The ETU toxicology database is considered incomplete; however by using a combination of guideline and literature information and including an additiona l uncertainty factor; sufficient information was available to select endpoints for ETU.

Guideline toxicological data gaps include a 2-generation reproducti on studies in rats, a developmental study in rabbits, developmen tal neurotoxicity study and a comparative study for thyroid toxicity in adults and offspring.

3.1.2 Toxicological Effects

Acute toxicity: The acute toxicity profile for ETU is shown in Table 3.1, below. Acute
oral and dermal sensitization studies with ETU were not available.

Table 3.1 Acute Toxicity of ETU

Guideline No. Study Type MR ID Nos. Results Toxicity Category
870.1100 Acute Oral – rat N/A N/A N/A
870.1200 Acute Dermal - rabbit 458881-01 LD 50 > 2000 mg/kg III
870.1300 Acute Inhalation - rat 458881-02 LC 50 > 10.4 mg/L IV 870.2400 Primary Eye Irritation 458881-04 No irritation 1 IV 870.2500 Primary Skin Irritati on 458881-03 No irritation IV
870.2600 Dermal Sens itization N/A N/A N/A

1 The primary eye irritation study was classified unacceptable because a UV light was not observed with fluorescein staining, however, another study is not required (M. Lewis, 4/30/03, D289726).

Subchronic/Chronic toxicity: The thyroid is a target orga n for ETU. Thyroid toxicity in subchronic and chronic rat, mouse, and dog studies included decreased levels of the thyroid hormone T4 (serum thyroxin), changes in the thyroid hormone T3 (triiodothyronine), compensatory increases in levels of thyroid stimulating hormone (TSH), increased thyroid wei ght, and microscopic thyroid ch anges, chiefly hyperplasia.

Anemia occurred in the subchronic and chroni c dog studies. Increased liver weight and hepatocellular hypertrophy occurr ed in several studies; however , overt liver toxicity was limited to the chronic dog study in whic h hepatocellular necrosis was seen.

Carcinogenicity: Treatment with ETU produced increases in tumor incidence in rodents. Thyroid follicular cell adenomas a nd carcinomas were increased in a study with F344 rats. Thyroid follicular cell adenomas and pituitary adenomas were also increased in a study with SD rats. Thyroid follicular cell adenomas and carcinomas, hepatocellular adenomas and carcinomas, and pituitary ad enomas were increas ed in a study with
B6C3F1 mice.Page 15 of 46 The HED Cancer Assessment Review Committe e evaluated the carcinogenicity potential of ETU and classified ETU as a probabl e human carcinogen, group B2, (Bill Sette, Ph.D., 4/16/90). The Q 1 * for ETU, using a 3⁄4 scaling factor, was determined to be 0.0601 (mg/kg/day) -1 based upon female mouse liver tumo rs in a National Toxicology Program (NTP) study (Bernice Fisher and Hugh Pettigrew, 2/24/95).

Developmental/Reproductive toxicity: The nervous system is a target for ETU. The developmental defects seen in the ra t developmental study with ETU included exencephaly, atrophy of brain ti ssue, cranial edema, dilate d ventricles of the brain, compression and/or hemorrhages of the spinal cord, deficiency of tissue in the olfactory bulb, meningoencephalocele, incomplete cranial ossification, wide cranial sutures, curved clavicle, fused sternebrae, abse nt caudal or sacral vertebrae, fused and/or thickened ribs, wavy ribs, misshapen or incomplete ossificati on of hindlimb long bones, ribs and pelvis, kyphosis (abnormal spine curvature), reduced nu mber of ribs, fused lumbar, sacral, or caudal vertebrae, abnormal pelvic limb postu re, oligodactyl, agnathia, cleft palate, cleft lip, club limb, stubby tail, forelimb flexure, kinked tail, cryptorchidism (abnormal descending of the testes), ectopic kidneys, agenesis of the kidneys, hydronephrosis, reduced stomach with thickened wall, edemat ous fat pads, syndactyl digits, and anal atresia (closure).

Developmental defects in the rat developm ental study indicated increased qualitative susceptibility since numerous and severe deve lopmental defects occurred at a dose which only caused decreased maternal food cons umption and body weight gain. These developmental defects were similar to def ects seen in an accompanying developmental toxicity study with mancozeb; however, ETU was considered a more severe developmental toxicant than mancozeb because: (a) a smaller dose of ETU (50 mg/kg/day) was needed to cause devel opmental defects than did mancozeb (512 mg/kg/day); (b) many of the same developmental defects occurred with greater frequency with ETU than with mancozeb; (c) more types of developmental defects occurred with ETU than with mancozeb; a nd (d) developmental defects which occurred with ETU were accompanied by minimal ma ternal toxicity whereas developmental
defects that occurred with mancozeb we re accompanied by more severe maternal toxicity.

A developmental study in rabbits was not submitted. No reproductive toxicity was attributed to treatment in the 2-ge neration reproduction study in rats.

Neurotoxicity: Neurotoxicity studies for ETU are not available.

The toxicity profile of ETU is shown in Table 3.2.Page 16 of 46 Table 3.2 Toxicity Profile of ETU Study Type [Guideline No.] MRID No./
Classification Results

Subchronic (13-week) feeding - rat [870.3100] 250 ppm (males: 14.28 mg/kg/day; females: 17.81 mg/kg/day) 00261536/1986 Acceptable NOAEL = <14.28 mg/kg/day LOAEL = 14.28 mg/kg/day, based on reduced body weight, changes in thyroid hormone and TSH levels, increased thyroid and liver weight, microscopic thyroid hyperplasia and liver hypertrophy.

Subchronic (13-Week) feeding - mouse [870.3100] 0, 1, 10, 100, 1,000 ppm (males: 0, 0.16, 1.72, 18.18, 168.2 mg/kg/day; females: 0, 0.22, 2.38, 24.09, 231.1 mg/kg/day) 00259888/1985 Unacceptable NOAEL = 1.72 mg/kg/day LOAEL = 18.18 mg/kg/day, based on microscopic thyroid hypertrophy/hyperplasia.

% purity, feed concentrations were not reported. At the high dose, more microscopic thyroid changes and increases in thyroid and liver weight occurred.

Unacceptable because dietary concentrations were not reported. Subchronic (13-Week) feeding - dog [870.3100] 0, 10, 150, 2000 ppm (males: 0, 0.39, 6.02, 66.23 mg/kg/day; females: 0, 0.42, 6.51, 71.62 mg/kg/day) 42174201/1991 Acceptable NOAEL = 0.39 mg/kg/day LOAEL = 6.02 mg/kg/day, based on elevated cholesterol. (Note: this endpoint was not considered robust enough for use in risk assessment)

In high dose group: mortality, anemia, decreased activity, decreased thyroid hormone levels, increased thyroid weight microscopic thyroid hyperplasia.
Chronic tox/carcinogenicity - rat [870.4100] 0, 0.5, 2.5, 5.0, or 125 ppm 42607801/1992 Unacceptable Concentration of ETU in feed varied widely and
doses could not be determined.

Microscopic thyroid hyperplasia occurred in the lowdose group. At higher doses, changes in thyroid hormone and TSH levels, increased thyroid weight, and grossly enlarged livers, occurred. Increases in thyroid follicular adenomas and pituitary adenomas in high-dose males.

Unacceptable because ETU concentrations varied widely. Chronic (24-Month) Feeding - mouse (NTP) NA This study was used to determine the Q1* for ETU
of 6.01 x 10 -2 (mg/kg/day) -1 based upon female
mouse liver adenomas and/or carcinomas. Chronic (1-year) oral toxicity - dog [870.4100]

0, 5, 50, or 500 ppm (males: 0, 0.18, 1.99, 20.13 mg/kg/day; females: 0, 0.19, 1.79, or 20.15 mg/kg/day) 42338101/1992 NOAEL = 0.18 mg/kg/day LOAEL = 1.99 mg/kg/day, based on increased thyroid weight and microscopic changes in thyroid (hypertrophy, follicular dilatation).

At the high dose, mortality, anemia, and microscopic hepatocellular necrosis.

4-Week Rangefinding - Dog 0, 196, 980, 4900 ppm (males: 0, 7.0, 34, or 172 41863401/1989 Acceptable NOAEL = 7 mg/kg/day LOAEL = 34 mg/kg/day, based on decreased levels of thyroid hormones, gross thyroid lesions.Page 17 of 46 Table 3.2 Toxicity Profile of ETU Study Type [Guideline No.] MRID No./
Classification Results

mg/kg/day; females: 0, 8.0, 36, or 197 mg/kg/day) Developmental tox. - rat [870.3700] 50 mg/kg/day 00246663/1980Acceptable/nonguideline Maternal NOAEL = <50 mg/kg/day Maternal LOAEL = 50 mg/kg/day, based on decreased body weight gain.

Developmental NOAEL = <50 mg/kg/day Developmental LOAEL = 50 mg/kg/day, based on gross developmental defects, central nervous system defects, skeletal defect s, cryptorchidism, and decreased fetal weight.

Only one dose was included in the study. Developmental tox. - rat [870.3700] 0, 5, 10, 20, 40, or 80 mg/kg/day 4593760/1973 [Khera, K.S. 1973. Teratology 7:243-252]Acceptable nonguideline Maternal NOAEL = 40 mg/kg/day Maternal LOAEL = 80 mg/kg/day, based on mortality.

Developmental NOAEL = 5 mg/kg/day Developmental LOAEL = 10 mg/kg/day based on central nervous system and gross developmental
defects of the brain includ ing exencephaly, dilated ventricles and hypoplastic cerebellum.
2-Generation reproduction - rat [870.3800] 0, 2.5, 25, 125 ppm 42391701/1992 Unacceptable Doses on a mg/kg/day basis could not be determined.

Parental: microscopic thyroid hyperplasia/hypertrophy in mid and/or high-dose

groups.

No reproductive effects a ttributed to treatment.

Unacceptable because of st ability problems with test material and poor record keeping. Dermal absorption - rat [870.7600] 40312001/1987 Acceptable Dermal absorption = 26%

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)

Metiram, mancozeb and maneb degrade and/or are metabolized to ETU. In oral rat
metabolism studies with radiolab elled EBDCs, an average 7.5% in vivo metabolic conversion of EBDC to ETU occurred, on a we ight-to-weight basis. This metabolic
conversion has been taken into considerati on in the human health risk assessment, including the dietary exposure assessment as well as 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 inhibi tors of mono-oxygenases). Me tabolism data indicate that
the EBDCs do not bioaccumulate.Page 18 of 46 3.3 FQPA Considerations

HED has evaluated the toxicology database for ETU and reviewed the potential for increased susceptibility of infants and ch ildren from exposure to ETU in accordance with the February 2002 OPP 10X guidance docum ent. Studies available for FQPA
consideration included several developmental toxicity studies from the literature, one unacceptable guideline developmental toxic ity study in rats where only one dose was administered, and a 2-generation re production toxicity study in rats.

There is concern for prenatal toxicity resulting from exposure to ETU due to the effects seen in developmental studies. There wa s evidence of quantitative and qualitative susceptibility to fetuses in severa l developmental studies in rats:

• In a 1973 literature study (Khera), developm ental defects of the brain in the fetuses occurred at a dose significantly lower than the dose at which maternal toxicity was observed;

• In a 1979 literature study (Chernoff, et. al. ), the maternal toxicity NOAEL was twice the developmental LOAEL, at which hydro cephalus occurred. The maternal LOAEL was four times higher than the developmental LOAEL, a nd the effect consisted of reduced body weight gain and mortality;

• In a 1978 literature study (Teramoto, et. al. ), developmental toxicity (dilated
ventricle of the brain was seen at the lo west dose tested (10 mg/kg/day) in the absence of maternal toxicity;

• In a 1991 literature study (Saillenfait, et. al. ), severe developmental effects (dilated ventricles of the brain, hydrour eter, short/kinky tail, and dila ted ureters) were seen at a dose (25 mg/kg/day) that only induced d ecreases in body weight gain in the dams.

Evidence of susceptibility in rabbits could not be ascertained due to the missing prenatal study in this species. The 2-generation repr oduction study in rats was not adequate to evaluate susceptibility.

Since there is evidence of increased susceptibility of fetuses following exposure to ETU in the rat developmental studies, HED evalua ted the level of concern for the effects
observed when considered in the context of a ll available toxicity data. In addition, the
database was examined to determine if there were residual uncertainti es after establishing toxicity endpoints and uncertainty factors to be used in the ETU risk assessment. HED determined that the degree of concern for th e susceptibility seen in ETU developmental
studies was low because:

• The developmental effects have been well-ch aracterized in numerous studies in the published literature, as well as in a guideline study submitted by the registrant;

• There is a clear NOAEL for these effects and the dose-response relationship, although steep, it is well characterized in the nu merous developmental studies in rats.

• The developmental endpoint with the lowe st NOAEL was selected for deriving the
acute reference dose.Page 19 of 46 • The target organ toxicity (thyroid toxici ty) was selected for deriving the chronic reference dose as well as endpoints for non-di etary exposures (incid ental oral, dermal, and inhalation).

3.3.1 Recommendation for a Developmental Neurotoxicity Study

HED concluded that a developmental neur otoxicity study for ETU was required, based on severe central nervous system defects obser ved in the developmental toxicity study in rats including: exencephaly, at rophy of brain tissue, cranial ed ema, dilated ventricles of the brain, compression and/or hemorrhages of th e spinal cord, deficiency of tissue in the olfactory bulb, and meningoencephalocele. A comparative thyroid toxicity study in adults and offspring was also required.

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 fo r ETU. In addition to the required DNT study, there are data gaps fo r a developmental toxicity study in rabbits, a 2-generation reproduction study in rats and a study evaluating the comparative thyroid toxicity in adults and offspring. HED determin ed that the FQPA SF must be retained to
account for the lack of these st udies, since the ava ilable 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 ETU and selected the dos es and endpoints for risk assessment based on a variety of exposur e pathways resulting from use of the EBDC fungicides. These doses and e ndpoints are summarized in Table 3.4.

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

The ETU acute dietary endpoint for female s 13-49 years old was selected from a nonguideline developmental toxicity study in rats (Khera, K.S.; Teratology 7:243-252, 1973, MRID No. 45937601). The LOAEL was 10 mg/ kg/day based on developmental effects of the brain, including exence phaly, dilated ventricles and hypoplastic cerebellum. The NOAEL for the study was 5 mg/kg/day. Applica tion of the combined standard 10X UFs to account for intraspecies vari ability and interspecies extra polation as well as the FQPA 10X database uncertainty factor (UF DB ) results in an acute reference dose of 0.005 mg/kg/day. The acute population adjusted dose is equal to the acute RfD, 0.005 mg/kg/day.

3.4.2 Acute Reference Dose (aRfD) - General Population

HED concluded that an acute reference dose for the general population is not needed, since there was no appropriate endpoint attributable to a single dose in the available toxicity studies.Page 20 of 46 3.4.3 Chronic Reference Dose (cRfD)

The ETU chronic reference dose for the gene ral population was selected from a chronic toxicity study in dogs. The study NOAEL wa s 0.18 mg/kg/day base d on decreased body weight gain, increased thyroid weight, and microscopic changes in the thyroid observed at the LOAEL of 1.99 mg/kg/day. The comb ined 1000X UF (standard 100X and an additional FQPA 10X UF DB ) results in a chronic re ference dose, RfD, of 0.0002 mg/kg/day. The cPAD of 0.0002 mg/kg/day is equivalent to the chronic RfD.

3.4.4 Incidental Oral Exposure ( Short- and Intermediate-Term)

A non-guideline 4-week range-f inding toxicity study conducted in dogs was used to
select incidental oral en dpoints and doses for risk assessment. The NOAEL was 7 mg/kg/day based on gross thyroi d lesions and decreased thyr oid hormone levels at the LOAEL of 34 mg/kg/day. The endpoi nt is appropriate for the population (infants/children) and the shor t- term duration of exposure (u p to 30 days). In addition, the study can be used for intermediate-term incide ntal oral risk assessm ent, since it is also supported by a subchronic toxicity study in dogs in which the NOAEL for thyroid effects was similar, at 6 mg/kg/day. The combined UF applied to both short- and intermediateterm incidental oral risk assessments is 1000X, based on the standard 100X UF, as well as the FQPA 10X UF DB . An additional uncertainty factor to extrapolate from a shorterto a longer-term study was not needed, si nce the NOAEL for thyroid effects in the subchronic dog study was similar to that observed in the 4-week dog study.

3.4.5 Oral Exposure (Short- and Intermediate-Term)

The ETU oral endpoint for females 13-49 y ears old was selected from a non-guideline developmental toxicity study in rats (Khe ra). The study NOAEL wa s 5 mg/kg/day based on developmental effects of the brain, incl uding exencephaly, dila ted ventricles, and hypoplastic cerebellum, observed at the LOA EL of 10 mg/kg/day. The target MOE for residential exposures is 1000, which includes th e standard 100X combined UFs, as well as the 10X FQPA UF DB

.

3.4.6 Dermal Absorption

Dermal Absorption Factor : 26%. The ETU dermal absorption factor is 26%, fr om a dermal absorption study in rats. The value of 26% dermal absorption was determined at the lowest dermal dose after 10 hours of exposure followed by washing of the skin. ET U residues were detected in organs at all three dermal doses, and were highest in the thyroid.Page 21 of 46 3.4.7 Dermal and Inhalation Exposure (Short- and Intermediate-Term)

Females 13-49 years old, dermal and inhalation exposure In the absence of adequate dermal and inhalation toxicity st udies for ETU, the nonguideline oral study in rats (Khera) was used to select endpoints for short- and
intermediate-term dermal and inhalation risk assessments. The study NOAEL was 5 mg/kg/day based on developmental effects of the brain, including exencephaly, dilated ventricles, and hypoplastic cerebellum, obser ved at the LOAEL of 10 mg/kg/day; the endpoint is considered applicable for females 13-49 years old. Because an oral toxicity study was chosen, the 26% dermal absorption fact or (relative to oral absorption) for ETU should be used in the dermal exposure assessment, and 100% absorption should be assumed for calculating inhalation exposure and risk, i.e. inhalation absorption is equivalent to oral absorption. The target MOE for residential exposures is 1000, which
includes the standard 100X combined UFs, as well as the 10X FQPA UF DB . The target MOE for occupational assessments is 100.

Toddlers, dermal exposure The non-guideline 4-week range-finding toxicity study conducted in dogs was also used
to select short- and intermediate-term dermal endpoints for risk assessment for infants/children. The study NOAEL was 7 mg/kg/day based on gross thyroid lesions and decreased thyroid hormone levels at the LOAEL of 34 mg/kg/day. The combined UF applied to both short- and intermediate-ter m dermal risk assessments is 1000X, based on the standard 100X UF, as well as the FQPA 10X UF DB . An additional uncertainty factor to extrapolate from a shorter- to a long er-term study was not needed, since the NOAEL for thyroid effects in the subchronic dog study (6 mg/kg/day) was similar to that observed in the 4-week dog study.

3.4.8 Dermal and Inhalation Exposure (Long-Term)

The long-term dermal and inha lation endpoints were selected from the chronic toxicity study in dogs. The NOAEL is 0.18 mg/kg/da y based on decreased body weight gain, increased thyroid weight, and microscopic ch anges in the thyroid at the LOAEL of 1.99 mg/kg/day. Since an oral study was selected, estimated dermal exposure should be adjusted by 26%, the ETU dermal absorption fa ctor (relative to oral absorption). For calculating inhalation risks, a 100% oral equivalent absorption factor should be used. For residential exposures, the target MOE for ETU is 1000, based on the combined UFs of 100X for intra-species variability and interspe cies extrapolation, and an additional FQPA
10X UF DB for an incomplete database. For occu pational exposures, the long-term target MOE for dermal and inhalation exposures is 100.

3.4.9 Classification of Carcinogenic Potential

The HED Cancer Assessment Review Committe e evaluated the carcinogenicity potential of ETU and classified ETU as a probabl e human carcinogen, group B2, (Bill Sette, Ph.D., 4/16/90). The Q 1 * for ETU, using a 3⁄4 scaling factor, was determined to be 0.0601 (mg/kg/day) -1 based upon female mouse liver tumo rs in a National Toxicology ProgramPage 22 of 46 study (Bernice Fisher and Hugh Pettigrew, 2/24/95.

3.4.10 Summary of Toxicological Doses and Endpoints for ETU for Use in Human
Risk Assessments

Table 3.4 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

Dietary Exposure 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 old) 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

Oral Exposure
Incidental Oral Short-Term (1-30 days)

IntermediateTerm (1-6 months) (Toddlers) NOAEL= 7 mg/kg/day UF A = 10x
UF H =10x FQPA SF= 10x,UF DB Residential MOE =
1000 Occupational MOE =
N/A 4-week range-finding dog study

LOAEL= 34 mg/kg/day based thyroid toxicity

Oral (Short-Term (1-30 days)

IntermediateTerm (1-6 months) (Females 13-49 years old) NOAEL= 5 mg/kg/day UF A = 10x
UF H =10x FQPA SF= 10x,UF DB Residential MOE =
1000 Occupational MOE =
N/A Developmental Rat Toxicity (Khera Study, MRID No. 45937601) LOAEL = 10 mg/kg/day, based on developmental
defects of brain

Dermal Exposure
Dermal ShortTerm (1-30 days)

IntermediateTerm (1-6 months) (Toddlers) NOAEL= 7 mg/kg/day UF A = 10x
UF H =10x FQPA SF= 10x,UF DB Residential MOE =
1000 Occupational MOE =
N/A 4-week range-finding dog study

LOAEL= 34 mg/kg/day based thyroid toxicity

Dermal Short- NOAEL= 5 UF A = 10x Residential MOE = Developmental RatPage 23 of 46 Table 3.4 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

Term (1-30 days)

IntermediateTerm (1-6 months) (Females 13-49 years old) mg/kg/day UF H =10x FQPA SF= 10x,UF DB DA= 26% 1000 Occupational MOE =
100 Toxicity (Khera Study, MRID No. 45937601) LOAEL = 10 mg/kg/day, based on developmental
defects of brain

Dermal LongTerm (>6 months) NOAEL= 0.18 mg/kg/day UF A = 10x
UF H =10x FQPA SF= 10x,UF DB DA= 26% Residential MOE =
1000 Occupational MOE =
100 Dog Chronic Oral Toxicity

LOAEL= 1.99 mg/kg/day based on thyroid toxicity Inhalation Exposure
Inhalation ShortTerm (1-30 days)

IntermediateTerm (1-6 months) NOAEL=5 mg/kg/day UF A = 10x
UF H =10x FQPA SF= 10x,UF DB Residential MOE =
1000 Occupational MOE =
100 Developmental Rat Toxicity (Khera Study, MRID No. 45937601) LOAEL = 10 mg/kg/day, based on developmental
defects of brain.Inhalation LongTerm (>6 months) NOAEL=0.18 mg/kg/day UF A = 10x
UF H =10x FQPA SF= 10x,UF DB Residential MOE =
1000 Occupational MOE =
100 Dog Chronic Oral Toxicity

LOAEL= 1.99 mg/kg/day based on thyroid toxicity
Cancer Cancer (oral, dermal, inhalation) Q 1 * = 6.01x10 -2 (mg/kg/day) -1 ETU is classified as a probable human carcinogen, Group B2, with a low-dose extrapolation approach for human risk assessment, based on liver tumors
in female mice. Note: Separate short- and intermediate-term oral and dermal endpoints were selected for toddler and adult (females 13-49 years old) population subgroups. 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 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. MOE = margin of exposure. LOC = level of concern. DA = dermal absorptio n. N/A = not applicable.

3.5 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 thatPage 24 of 46 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, ETU 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

See the parent EBDC compound risk assessments for public health data, as incident data are not available for the degradate, ETU.

5.0 Dietary Exposure/Risk Characterization

5.1 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. August 11, 2006. M.A. Ruhman and Ronald Parker.

The EBDC metabolite/degradate ETU has an aerobic soil half- life of about 3 days; in the absence of data, the aquatic ae robic metabolism half-life was assumed to be about 6 days,
or double the soil half life. The measured anaerobic aquatic me tabolism half-life, however, is substantially longer (149 days) possibly leading to the periodic detections in ground water. ETU is soluble in water (20,000 ppm); highly vulne rable to indirect photolysis (half-life = 1 day), and moderately m obile (288 L/kg). It al so has a relatively high vapor pressure but high solubility, reduc ing the possibility of losses from surface
water due to volatilization.

5.1.1 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 at a li mit of quantitation of 0.1 ppb.Page 25 of 46 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 USEPA PRZM (Pesticide Root Zone Mode l) 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 national default 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 was 1.9 ppb and the lowest value was 0.2 ppb 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 targeted ETU monitoring found no surface water concentrations above the detection limit of 0.1 ppb. Because samples were taken every 14 days during the application season and acute values may have been missed, a range of acute surface EDWCs was established with a lower limit based on monitoring and an upper limit based on PRZM/EXAMS modeling.

The range of acute EDWCs was 0.1 ppb (monitoring) and the upper limit was 25.2 ppb. The values were adjusted by the national ma ximum default percent cropped area 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.Page 26 of 46 5.1.2 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 detect ed 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 sandy 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.Page 27 of 46 Table 5.1 Summary of Estimated Surface Wa ter and Ground Water Concentrations for ETU

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.

5.2 Dietary Exposure and Risk

Reference : Aggregate Dietary Assessment of the Common Metabo lite/Degradate Ethylene Thiourea (ETU) to Support New Tolerances on Imported Grapes and Bananas fo r Metiram and for New Tolerances for Mancozeb on Almonds, Broccoli, Cabbage, Lettuce, and Peppers. DP Barcode: D337240. April 17, 2007. Christine Olinger.

Separate dietary exposure assessments were conducted for each EBDC parent compound. In each of these assessments, human dietary expo sure and health risk associated with the active ingredient were estimated, as well as dietary exposure and risk resulting from consumption of ETU residues derived from each EBDC individually. These documents
are listed below:

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

• Mancozeb Acute, Chronic, and Cancer Dietary Exposure Assessments for New Tolerances on Almonds, Broccoli, Cabbage, Lettuce, and Peppers. PP#4F4324 and 4F4333. D323878. April 17, 2007. Christine Olinger.

• Maneb and Ethylenethiourea: Revised Acute/Probabilisti c, Chronic, and Cancer Dietary Exposure Assessments for the Reregistration Eligibility Decision; DP Barcode: D295410; June 2005; F. Fort.

For this assessment, ETU food residues fr om each of the individual EBDCs were aggregated. ETU aggregate acute, chronic a nd cancer dietary risk assessments were conducted using the Dietary Exposure Evalua tion Model (DEEM-FCIDTM), Version 2.03, which used food consumption data from the Un ited States Department of Agriculture’s (USDA’s) Continuing Surveys of Food In takes by Individuals (CSFII) from 1994-1996
and 1998.

The ETU aggregate acute, chronic, and cancer assessments can be considered somewhat
refined. Residue estimates were refined using consumer processing factors (washing, cooking), commercial processing (winemaki ng, juice), percent crop treated factors (existing domestic uses only), and market bask et survey (monitoring) data for several of the existing uses. Projected percent crop tr eated information was used to refine thePage 28 of 46 estimates for the proposed new uses of ma ncozeb. Projected percent crop treated
information is not available for the uses on imported crops (bananas and grapes), so residue estimates were refined slightly usi ng percent imported factors. Crop field trial data were used for several of the existing us es as well as all of the proposed new uses, which are likely to provide highe r estimates than actual exposures.

5.2.1 Anticipated Residue Information

Crops treated with EBDCs may contain bot h EBDC and ETU residues; in addition, cooking and/or processing may result in conve rsion of EBDC residues to ETU, or in
concentration or reduction of existing ETU residues. Therefore, both EBDC and ETU residues may be consumed in the diet. In this assessment the ETU food residues from each of the EBDCs were aggregated.

When possible, market basket survey (MBS ) data, generated by the ETU Task Force, were used to calculate anticipated residues. MBS data are available on the following foods: green beans (raw, frozen, canned, and baby food), dry beans (dry and canned), broccoli (raw and frozen), celery, sweet corn (raw, frozen, canned), cucumbers, lettuce, meat, milk, onion (dry bulb), potato (raw, fro zen), and tomato (raw, juice, ketchup, paste, puree).

For the probabilistic acute dietary exposure an alysis, the entire dist ributions of residue
data from field trials or mon itoring data were used to gene rate residue distribution files (RDFs) for commodities which were considered to be not blended or partially blended. For commodities considered to be blended in this analysis, the average residues incorporating the likely maximum estimated PCT was used as a point estimate. Different approaches were taken for for commodities on which more than one EBDC might be registered, depending upon the source of th e residue data. It was assumed that commodities would not be treated with more than one EBDC in a season, as there were
no data available to determine the relative am ount of crops treated with more than one EBDC. Only data for the individual chemical s were available. When more than one EBDC was registered on any cr op and the MBS data were used for the assessment, then the percent crop treated values for the indi vidual EBDC were summed and an RDF was created in which zeroes were added propor tionately. For a few commodities mancozeb
field trial data were used for both manc ozeb and maneb. Those commodities were treated similarly to the commodities using MBS. RDFs were created with a proportionate number of values from the relative percent cr op treated for each chemical. For example, the percent crop treated for mancozeb, mane b, and metiram on apples is 35, 5, and 25, respectively. Therefore, an RDF where 35% of the values representing treated commodities were from mancozeb field trials, 5% from maneb field trials, and 25% from
metiram field trials was created.

Chronic anticipated residues were also calcula ted from field trial or monitoring data for ETU. Averages of the field trial and MBS re sidue data were used. In determining the average residue when two or more EBDCs were used on a crop, the following equation
was used.Page 29 of 46 (ETU from Mancozeb Residue x Mancozeb PCT/100) + (ETU from Maneb residue x Maneb PCT/100) + (ETU from Metiram residue x Metiram PCT/100)
= Chronic AR for ETU

If the sum of the PCT values for all thr ee EBDCs exceeded 100% then the PCT values were adjusted so that the sum equaled 100%.

5.2.2 Acute Dietary Exposure/Risk

Acute dietary exposure and risk for ETU are below HED’s level of concern. For females 13-49 years old, estimated dietary exposur e (food only) was 0.002799 mg/kg/day, which
utilized 56% of the aPAD at the 99.9 th percentile. For food and water, the acute dietary exposure was 0.004437 mg/kg/day which uti lized 89% of the aPAD at the 99.9 th percentile of exposure. The results of the acute dietary exposure assessments for ETU are shown in Summary Table 5.2.

5.2.3 Chronic Dietary Exposure/Risk

The chronic risk estimates are below the HE D’s level of concern for aggregate exposure to ETU for the general U.S. population and all population subgroups . The most highly exposed population subgroup was children ag es 1-2 for food alone and food and water assessments. For food only, the chronic dietary exposure was 0.000166 mg/kg/day which
utilized 83% of the cPAD. For food and water combined, the chronic dietary exposure was 0.000173 mg/kg/day, which utilized 86% of the cPAD. The results of the chronic dietary exposure assessments for ET U are shown in Summary Table 5.2.

5.2.4 Cancer Dietary Risk

The cancer risk assessment for ETU was based on the same anticipated residues derived for the chronic dietary exposure assessment. The estimated chronic dietary exposure for the general U.S. population correspo nds to a cancer risk of 3.3 x 10 -6 for food alone and
3.6 x 10 -6 for food and water combined. The re sults of the cancer dietary exposure assessments for ETU are shown in Summary Table 5.2.Page 30 of 46 Table 5.2 Result of Acute and Chronic Diet ary Exposure and Risk Estimates for ETU Using
DEEM-FCID TM

ETU (food only) ETU (food and water) 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 0.002799 56 0.004437 89
Chronic Dietary Estimates
U.S. Population 0.000055 28 0.000060 30

All infants (< 1 yr) 0.000073 37 0.000088 44

Children 1-2 yrs 0.000166 83 0.000173 86

Children 3-5 yrs 0.000112 56 0.000118 59

Children 6-12 yrs 0.000057 29 0.000061 31

Youth 13-19 yrs 0.000034 17 0.000037 19

Adults 20-49 yrs 0.000045 22 0.000049 25

Adults 50+ yrs 0.000056 28 0.000061 30

Females 13-49 yrs 0.000046 23 0.000050 25

Cancer Dietary Estimate
U.S. Population 0.000055 3.3 x 10 -6 0.000060 3.6 x 10 -6

The dietary cancer risk includi ng food and water is 3.6 x 10 -6 , which exceeds HED’s level of concern. Therefore, HED conducted a critical commodity contribution analysis for the cancer assessment and sensitivity anal yses for several scenarios. The greatest contributors to the dietary exposure are ba nanas (approximately 17% of the exposure) and leaf lettuce (approximately 10% of th e exposure). Other commodities contributing more than 3% of the total exposure were turn ip greens, water, mangoes, and grape juice. The results of the critical commodity analysis and aggregate sensitivity analyses may be found in Tables 5.3 and 5.4, respectively.

Table 5.3 Summary of Commodities Contributing Greater than 3% of Total Dietary Exposure to the Chronic/ Cancer Exposure Assessment

Commodity Exposure, mg/kg bw/day Individual Cancer
Risk Percent
Contribution to Total Exposure Bananas, uncooked 1 0.000010 6.2 x 10 -7 17 Lettuce, Leaf 0.0000061 3.7 x 10 -7 10 Water (direct and indirect sources) 0.0000044 2.7 x 10 -7 7.4

Turnip Greens 1 0.0000041 2.5 x 10 -7 6.8 Grape Juice (cooked and uncooked) 0.0000028 1.6 x 10 -7 4.6

Mangoes, uncooked 1 0.000002 1.2 x 10 -7 3.3

1 Note that this exposure value reflect s the assumption of 100% crop treated.Page 31 of 46 Table 5.4 Sensitivity Analyses Scenario Exposure, mg/kg bw/day Estimated Cancer Risk

Aggregate Food and Water, excluding proposed tolerance for metiram on
bananas 0.00005 3.0 x 10 -6

Aggregate Food and Water, excluding mancozeb proposed use on leaf lettuce 0.000059 3.5 x 10 -6

Aggregate Food and Water, assuming 1% crop treated for Turnip Greens 0.000056 3.4 x 10 -6

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

Mancozeb: 2 nd Revised ORE Assessment for the RED. D317368. May 31, 2005. Timothy Dole.
Maneb: 2 nd Revised ORE Assessment for the RED. D295411. June 8, 2005. Timothy Dole.

No new residential uses are be ing added to the mancozeb or maneb labels as a result of this action, however there are existing residentia l uses registered. There are no uses of metiram that will result in exposure in residential settings.

The document entitled Mancozeb: 2 nd Revised Occupational and Residential Exposure Assessment and Recommendations for the Rere gistration Eligibility Decision Document cited above provides a detailed summary of the exposure and risk assessment for the existing residential uses of mancozeb. The document entitled Maneb: 2 nd Revised Occupational and Residential Exposure Assessment and Recommendations for the Reregistration Eligibility Decision Document cited above provides a detailed summary of the exposure and risk assessment for th e existing residential uses of maneb.

Exposures and risks from the various reside ntial scenarios are briefly summarized here since those values are required for th e ETU aggregate risk assessments.

The existing residential handler scenario identi fied for mancozeb is for the application of mancozeb in home gardens. The anticipa ted use patterns and current labeling indicate that backpack and low pressure handwand sp rayers could be used by the homeowner to make mancozeb applications. Residential risks are assumed to be of short-term and intermediate-term in duration for home garden scenarios and for adults on treated turf.
HED notes that there are no direct homeow ner applications of mancozeb to turf; however, there is a registered use to pe rmit treatment of sod on sod farms with subsequent transplantation to a residential setting. Residential scenarios are considered to
be of short-term duration for toddlers on treate d turf since it is unlik ely that sod would be installed more than once per year and sin ce subsequent to installation, turf is watered which would contribute to a more rapid dissip ation of residues. There are no long-term residential exposure scenarios associated with mancozeb at this time. In the previous aggregate assessment, exposure to athletes fr om treated playing fields was considered. However, the application to athletic fiel d has been voluntarily cancelled, so is not
considered in this assessment.Page 32 of 46 Maneb is used on sodfarms and the labels currently state “Do not use on residential, pasture or range grasses”. The registrants have agreed to m odify the label to include a statement such as “For Use on Sodfarms Only ” which will eliminate the possibility that maneb would be applied to turf in such area s as parks and golf courses where residential exposures might occur. The only remaining exposure scenario occu rs after the treated turf is transplanted from the sod farms to area s such as residential lawns. Therefore, the only residential scenario considered for mane b is toddlers playing on turf transplanted
from sod farms.

6.1 Residential Handler Exposures and Risks

There are no residential ha ndler scenarios for maneb.

The existing residential handler scenario identi fied for mancozeb is for the application of mancozeb in home gardens. The anticipa ted use patterns and current labeling indicate that backpack and low pressure handwand sp rayers could be used by the homeowner to make mancozeb applications. Since th e endpoints selected for the short- and intermediate-term assessment are identical, short- and intermediate-term risk assessments yield the same MOEs; one value is shown in the tables below for each application method. Based on tank mix studies, it was assumed that 0.2% of the mancozeb would convert to ETU, additionally; a 7.5% in vivo conversion of mancozeb to ETU was also considered in the exposure calculations.

Both dermal and inhalation exposures and risks for mancozeb-derived ETU were
calculated for residential handlers. Sin ce the short/intermediate-term dermal and short/intermediate-term inhalation endpoints we re taken from the same study, dermal and inhalation exposures were adde d to calculate a combined absorbed mancozeb-derived ETU daily dose. That dose was then compared to the NOAEL from the rat developmental toxicity study. Short/intermediate-term combined dermal and inhalation MOEs for residential handlers using both b ackpack sprayers and low pressure handwand sprayers far exceeded the level of con cern (LOC) of 1000; therefore, HED has no
concern short-term risks to residential ha ndlers exposed to mancozeb-derived ETU. Short-term dermal and inhalation exposures and combined risk for residential handlers are summarized in Table 6.1, below.

Table 6.1 Home Gardener Handler Exposure and Short/Intermediate-Term Risks for
Mancozeb-Derived ETU Absorbed ETU Daily Dose (mg/kg/day) Exposure Scenario

Dermal Inhalation Combined Absorbed ETU Daily Dose (mg/kg/day) ETU MOE 1

Backpack 5.9 x 10 -6 2.1 x 10 -6 8.1 x 10 -6 620000
Low Pressure Handwand 4.4 x 10 -5 6.4x 10 -7 4.5 x 10 -5 110000

1 NOAEL is 5 mg/kg/day

As previously noted, mancozeb’s potential fo r carcinogenicity is due to the formation of the metabolite ETU. Cancer risks from exposur e to ETU as a result of application ofPage 33 of 46 mancozeb are calculated by estimating exposur e to mancozeb-derived ETU and using the ETU Q 1 * of 0.0601 (mg/kg/day) -1 to provide a quantitative es timate of risk. Residential
handler estimated cancer risks were calculate d for applicators using a backpack sprayer and a low pressure handwand sprayer. For applicators using backpack sprayers the
estimated cancer risk from ma ncozeb-derived ETU was 4.1 x 10 -9 . Residential handlers using low pressure handwand sprayers ha d an estimated cancer risk of 2.3 x 10 -8

.

Because of the uncertainties in the cancer hazard quan tification methodology, risk estimates ranging from 1 x10 -6 to 3 x10 -6 are generally consider ed indistinguishable. Generally, cancer risk estimates which do not exceed 3 x10 -6 are below HED’s level of concern. Therefore, cancer risks to resi dential handlers as a re sult of exposure to mancozeb-derived ETU from the existing home garden use are not of concern. Cancer risks for home garden handlers ar e summarized in Table 6.2 below.

Table 6.2 Home Garden Handler Exposure and Cancer Risk for ETU from Mancozeb

Exposure Scenario Application
Rate (lbs ai/acre) Absorbed Daily Dose (mg/kg/day) 1 Lifetime Average Daily
Dose 2 Cancer Risk 3

Backpack 2.4 6.9 x 10 -6 6.8 x 10 -8 4.1 x 10 -9

Low Pressure

Handwand 2.4 3.7 x 10 -5 3.8 x 10 -7 2.3 x 10 -8

1 ADD = Absorbed Daily Dose from dermal and inhalation exposure

2 LADD = Lifetime Average Daily Dose = ADD * (5 exposu re days per year/365 days per year)*(50 years of exposure/70 years of life)

3 Risk = (LADD * Q 1 *), where Q 1 * = 0.0601 (mg/kg/day) -1

6.2. Residential Postapplication Exposure

6.2.1 Residential Postapplication Exposure – Mancozeb

Mancozeb can be used in areas that can be frequented by the general population including residential areas (e.g., home lawns and gardens) and golf courses. As a result, individuals can be exposed by entering these areas if the areas have been previously treated. The residential postapplication exposure and risk assessments conducted included the following:

• Adult dermal exposure from contact with treated home gardens

• Adult dermal exposure from contact w ith treated turf (golfer scenario)

• Youth (ages 10 - 12) dermal exposure fr om working in treated home gardens

• Toddler incidental oral exposur e from hand-to-mouth transfer of resides, object-to-
mouth transfer of residues and soil i ngestion from contact with treated turf

• Toddler dermal exposure from contact with treated turf

The residential postapplication exposure a nd risk assessment are detailed in the mancozeb ORE (occupational and residentia l exposure) memorandum. Results of the residential postapplication exposure and risk assessment are summarized in the subsequent sections.Page 34 of 46 6.2.1.1 Home Garden Postapplication Scenarios

Table 6.3, below summarizes the post applicat ion risks from mancozeb-derived ETU for adults and youth exposed to treated home gardens on Day 0 (the day of application). Exposures are shown for low, medium a nd high contact activities and also for representative commodities that might be found in a home garden. The scenario with the greatest risk is shown in bold. MOEs for all scenarios for both subpopulations on Day 0 exceed the LOC of 1000 and, theref ore; are not of concern.

Table 6.3 Mancozeb-derived ETU Postapplicatio n Short/Intermediate-Term Exposure and Risks
for Adult and Youth Home Gardeners ETU MOE on Day 0 (Adults/Youth) 1 Crop Group Application Rate (lb ai/acre) Low Medium High 2 Very High
Cut Flowers 1.2 53000/97000 33000/61000 19000/35000 N/A Vegetable, cucurbit –
West 3 Vegetable, cucurbit –
East 3 2.4

2.4 80000/150000
94000/170000 27000/49000
31000/57000 16000 / 29000 4

19000/34000 N/A
N/A

Vegetable, fruiting - West Vegetable, fruiting - East 1.6

2.4 120000/220000
87000/160000 86000/160000
62000/110000 60000/110000
43000/79000 N/A
N/A

1 Low, medium and High refer to low, medium and high c ontact activities.

2 The highest exposure/risk s cenario is shown in bold.

3 While the application rates are the same for west and east cucurbit, the dislodgeable foliar residue values used for east and west are different, which explains the different exposures and risks from the same application rate.

4 The adult dose for this scenario = 3.1 x 10 -4 mg/kg/day and the youth dose for this scenario = 2.4 x 10 -4 mg/kg/day taken from the ORE chapter cited above.

Cancer risks from exposure to mancozeb-d erived ETU from home garden exposure scenarios are summarized in Table 6.4, below. As in the table above , the scenario with the highest risk is shown in bold. Postappl ication cancer risks for adult home gardeners
are not of concern.

Table 6.4 Mancozeb-derived ETU Postapplication Cancer Risks for Adult Home Gardeners Cancer Risk on Day 0 Assuming Five Exposure Days per Year
Over a Lifetime Crop Group Application
Rate (lb ai/acre) Low Medium High 2 Very High

Cut Flowers 1.2 4.7 x 10 -8 7.5x 10 -8 1.3 x 10 -7 NA Vegetable, cucurbit –
West 1 Vegetable, cucurbit - East 1 2.4

2.4 3.1 x 10 -8

2.7 x 10 -8 9.4 x 10 -8

8.0 x 10 -8 1.6 x 10 -7

1.3 x 10 -7 NA
NA

Vegetable, fruiting - West Vegetable, fruiting – East 1.6
2.4 2.1 x 10 -8

2.9 x 10 -8 2.9 x 10 -8

4.1 x 10 -8 4.2 x 10 -8

5.8 x 10 -8 NA
NA

1 While the application rates are the same for west and east cucurbit, the dislodge able foliar residues for east and west are different, which explains the different expos ures and risks from the same application rate.

2 The highest exposure/risk scenario is shown in bold.

6.2.1.2 Treated Turf Postapplication Scenarios for Toddlers

Toddlers can be exposed to ETU when in c ontact with turf treated with mancozeb. Incidental oral exposures and risks are shown below. HED no tes that there are no directPage 35 of 46 homeowner applications of manc ozeb to turf; however, there is a registered use to permit treatment of sod on sod farms with subsequent transplantation to a residential setting. In calculating treated turf risks for manco zeb and its metabolite, ETU, HED used the outcome of the RED risk mitigation negotia tions which provides for a 3-day PHI and includes an additional two days for harvesting, shipment and installa tion for a total of 5 days between treatment on a sod farm a nd exposure in a residential setting.

Since there are no direct home lawn uses fo r mancozeb, toddlers would only be exposed to mancozeb in a residential setting from turf transplanted from a sod farm. Since it is unlikely that sod would be installed more th an once per year, and th e installation process includes watering-in which will tend to in crease the dissipation of residues, HED considered risks to toddlers exposed to treat ed lawns to be of s hort-term duration only.

To assess risks to toddlers from incident al oral exposure, HED summed the total exposure from residue transfer from hand- to-mouth, object-to-mouth and soil ingestion.
The level of concern for both the ETU incident al oral and dermal risk assessments is
1000.

Mancozeb-derived ETU incidental oral exposur es and risks to toddl ers in contact with
treated turf were calculated based on a 3-day PHI for sod farm turf. The MOE for
combined oral incidental risk to toddlers in contact with treated turf subsequent to
installation exceeds 1000 and is th erefore, not of concern. In cidental oral exposures and risk are summarized in Table 6.5, below.

Table 6.5 Summary of ETU Incidental Oral Exposures and Risks fo r Toddlers Exposed to
Turf Treated with Mancozeb Exposure Pathway ETU TTR 1 Dose (mg/kg/day) MOE
Hand-to-Mouth 0.0085 ug/cm 2 0.0030 2300
Object-to-Mouth 0.034 ug/cm 2 0.00075 9300
Soil Ingestion 0.11 ppm 0.00001 700000
Total 0.00376 1900

1 Based upon the existing PHI of 3 days and including an additional 2 days to account for harvesting, shipping and
installation.

Short-term dermal risk to toddlers in cont act with treate d turf with a 3-day PHI was
above 1000 and is not of concern. Short-term dermal exposures and risks for toddlers exposed to treated grass are su mmarized in Table 6.6, below.

Table 6.6 Summary of ETU Short-Term De rmal Exposures and Risks for Toddlers Exposed to Turf Treated with Manzozeb Exposure Pathway ETU TTR 1 Dose (mg/kg/day) MOE Dermal 0.0085 ug/cm 2 0.0022 3100

1 Based upon the existing PHI of 3 days and including an additional 2 days to account for harvesting, shipping and

installation

.
6.2.1.3 Treated Turf Postapplication Scenario for Adults

Adults may be exposed to mancozeb-deriv ed ETU through dermal contact with turfPage 36 of 46 treated directly with mancoze b. The MOE for short/intermediate-term dermal risk for the adult golfer exposed to ETU from contact with mancozeb treated golf courses exceeds 1000 and is not of concern. Exposure and risk for adult golfers is summarized in the
table below.

Table 6.7 ETU Short/Intermediate-Term Dermal Postapplication Risks for Adults Exposed to
Turf

Activity Application
Rate (lb ai/acre) Mancozeb
TTR (ug/cm 2 ) ETU TTR (ug/cm2) Transfer
Coefficient

(cm 2 /hr) Hours per Day Exposure ETU Dose (mg/kg/day) MOE

Golf 17.4 9.76 0.060 500 4.0 0.00076 6600

The cancer risk to adult golfers from expos ure to mancozeb-derived ETU is summarized in Table 6.8. Postapplication cancer risk s for adult golfers are not of concern.

Table 6.8 Summary of ETU Postapplicatio n Cancer Risks for Adults Exposed to Turf

Activity Application
Rate (lb ai/acre) Mancozeb
TTR (ug/cm2) ETU TTR (ug/cm2) Transfer
Coefficient

(cm 2 /hr) Hours per Day Exposure Days Per
Year Exposure Years of Exposure

per Lifetime LADD (mg/kg/day) Cancer
Risk

Golf 10.5 3.2 0.020 500 1.0 1 50 1.0 x 10 -6 6x10 -8

6.2.2 Residential Postapplication Exposure - Maneb

Like mancozeb, toddlers can be exposed to ETU when in contact with turf treated with maneb. Incidental oral exposures and risks are shown below. HED notes that there are no direct homeowner applications of maneb to turf; however there is a registered use to permit treatment of sod on sod farms with s ubsequent transplanta tion to a residential setting. In calculating treated turf risks for maneb-derived ETU, HED used the outcome of the RED risk mitigation negotiations whic h provides for a lower application rate (8.7 lb ai/A) and a 3-day PHI, which includes an additional two days for harvesting, shipment and installation, for a total of 5 days between treatment on a sod farm and exposure in a residential setting.

Since there are no direct home lawn uses for maneb, toddlers would only be exposed to maneb in a residential setting from turf transp lanted from a sod farm. Since it is unlikely that sod would be installed more than once pe r year, and the installa tion process includes watering-in which will tend to increase the dissipation of residues, HED considers risks to toddlers exposed to treated lawns to be of short-term duration only.

To assess risks to toddlers from incident al oral exposure, HED summed the total exposure from residue transfer from hand- to-mouth, object-to-mouth and soil ingestion
The level of concern for both the ETU incident al oral and dermal risk assessments is
1000.

Maneb-derived ETU incidental oral exposures and risks to toddlers in contact with
treated turf were calculated based on a 3-day PHI for sod farm turf. The MOE for
combined oral incidental risk to toddlers in contact with treated turf subsequent toPage 37 of 46 installation exceeds 1000 and is not of concern. Incidental oral exposures and risk are summarized in Table 6.9, below.

Table 6.9 Summary of ETU Incidental Oral Exposures and Risks fo r Toddlers Exposed to
Turf Treated with Maneb Exposure Pathway ETU TTR 1 Dose (mg/kg/day) MOE
Hand-to-Mouth 0.0151 ug/cm 2 0.0014 5000
Object-to-Mouth 0.0605 ug/cm 2 0.00044 16000
Soil Ingestion 0.203 ppm 0.000066 110000
Total 0.0019 3700

1 Based upon the existing PHI of 3 days and including an additional 2 days to account for harvesting, shipping and
installation.

Short-term dermal risk to toddlers in contac t with treated turf w ith a 3-day PHI exceeds
1000 and is not of concern. Short-term derm al exposures and risks for toddlers exposed to treated grass are summarized in Table 6.10.

Table 6.10 Summary of ETU Short-Term Dermal Exposures and Risks for Toddlers Exposed to Turf Treated with Maneb Exposure Pathway ETU TTR 1 Dose (mg/kg/day) MOE Dermal 0.0151 ug/cm 2 0.0034 2000

1 Based upon the existing PHI of 3 days and including an additional 2 days to account for harvesting, shipping and

installation

.

6.3 Other (Spray Drift, etc.)

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particular ly the case with aerial appl ication, but, to a lesser extent, could also be a potential source of expos ure from the ground application method employed for the EBDCs. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift manage ment practices. On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydr aulic 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. It is noted that the application rate for turf was modeled to es timate postapplication residential exposure of toddlers. As this rate is highe r than many of agricultural appli cation rates, this scenario is protective of any exposure of farm children via spray drift from agricu ltural applications.Page 38 of 46 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 source s: food, drinking water, and residential exposures. In an aggregate assessment, e xposures 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 the route and duration of exposure.

The proposed new uses of mancozeb and tolera nces of metiram can result in exposures to ETU from food and drinking water. The existi ng uses of metiram, mancozeb and maneb may result in exposures to ETU from food, wate r, and residential sources. The mancozeb uses in home gardens result in handler expos ure for adults and pos tapplication uses to adults and youth working in the garden. The mancozeb and maneb sod farm turf uses could result in postapplication exposure to toddlers playing on treated turf. The use of mancozeb on golf courses could result in postapplication exposures to golfers.

The aggregate risk assessments are intended to be representative of exposures that are likely to co-occur. For the purpose of th is risk assessment, HED only aggregated scenarios that they believed are likely to co-occur.

The ETU surface and ground water monitoring data are considered adequate to generate quantitative surface and ground water drinking water chronic exposure estimates. The surface water monitoring data, combined with PRZM-EXAMs modeling, indicate a concentration of 0.1 ppb should be used to calculate aggregate chronic and cancer exposure and risk. The ETU ground water c oncentration (0.21 ppb) was taken from a targeted monitoring study; use of this value to calculate aggregate risk provides an upper bound estimate of exposure through drinking water from ground water sources.

The following aggregate risk assessments have been completed:

• ETU Acute Aggregate which considers acute exposure to ETU from food and drinking water

• ETU Short/Intermediate-Term Home Garden Aggregate which combines handler exposures (inhalation and dermal) and post application garden exposures (dermal) plus average daily food and drinking water exposure for adults and post application garden exposures (dermal) plus average daily food and drinking water exposure for youth

• ETU Short-Term Treated Tu rf Aggregate (Toddlers) which combines treated turf post application exposures (i ncidental oral and dermal) plus average daily food and drinking water exposure for toddlers

• ETU Short/Intermediate-Term Treated Turf Aggregate (Adults “Golfers”) which
considers short-term reside ntial exposures (dermal) pl us average daily food and drinking water exposure for adults participa ting in activities such as golfing on treated
turf

• ETU Long-Term (Chronic, Non-Cancer) Aggregate which considers chronicPage 39 of 46 exposure from food a nd drinking water only

• ETU Cancer Aggregate which combines handler gard en exposures (dermal and inhalation), post application garden exposures (dermal), post applic ation treated turf exposures (dermal) and average daily f ood and drinking water exposure for adults

7.1 Acute Aggregate Risk

The acute aggregate risk assessment for ETU considers acute exposure from food and drinking water. An acute endpoint was se lected only for the subpopulation, females 13- 49 years old, so an acute aggregate assessm ent is required only fo r this subpopulation. Since HED usually considers only dietary (food and drinking water) contributions to ETU acute aggregate risk, the ETU acute aggreg ate risk assessment is equivalent to the ETU acute dietary (food and drinking water) risk assessment detailed in Section 5.2.2.

7.2 Short- and Intermediate-Term Aggregate Risk

7.2.1 ETU Short- and Intermediate-Term Home Garden Aggregate

The ETU short/intermediate-term home gard en aggregate combines handler inhalation and dermal exposures and post application ga rden dermal exposures plus average daily food and drinking water for adults exposed to ETU. For youth exposed to ETU, the assessment combines post application garden dermal exposures with average food and drinking water. Only mancozeb is registered for use in home garden settings. Average food and drinking water exposure values refl ect the most highly exposed adult or youth subpopulation from the average daily dietary as sessment, and consider ETU derived from mancozeb, metiram, and maneb applications. The existing and proposed food uses were
included in the food and dri nking water exposure estimates.

The ETU short/intermediate-term home gard en aggregate MOEs for adults and youth exceed 1000, the level of concern for this ri sk assessment, and are not of concern. Aggregate risk results are shown in Table 7.1.Page 40 of 46 Table 7.1 ETU Short/Intermediate-Term Home Garden Aggregate Risk Results

Short/Intermediate-Term Scenario

Population NOAEL mg/kg/day LOC 1 Max
Allowable Exposure 2 mg/kg/day Average
Food & Water

Exposure 3 mg/kg/day Residential Exposure 4 mg/kg/day Aggregate
MOE (food, water
and residential) 5

Adults – handlerand postapplication 5 1000 0.005 0.000061 0.000318 13000

Youth – postapplication 7 1000 0.007 0.00017 0.000240 17000

1 The LOC is based on UF A = 10, UF H = 10, UF DB = 10 (Table 3.4).

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC.

3 Average food and drinking water exposure taken from most highly exposed adult or youth subpopulation from the chronic dietary exposure assessment in Table 5.2. Food and drinking water consider ETU derived from existing and proposed uses of mancozeb, metiram, and maneb.

4 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure]. Combined dermal and inhalation exposure for adult handlers is 8.1 x 10 -6 mg/kg/day (Table 6.1). Dermal postapplication exposure for adults is 3.1 x 10 -4 mg/kg/day (Table 6.3). Dermal postapplication exposure for youth is 2.4 x
10 -4 mg/kg/day (Table 6.3). Only mancozeb is registered for use in home garden settings.

5 Aggregate MOE = [NOAEL / (Avg Food & Drinking water Exposure + Residential Exposure)]

7.2.2 ETU Short-Term Treated Turf Aggregate (Toddlers)

The short-term treated turf aggregate risk assessment combines treated turf post application incidental oral and dermal exposures with av erage daily food and drinking water exposure for toddlers. Maneb and mancozeb are both registered for applications to sod farms. Average food and drinking water exposure values, includ ing all sources of ETU, reflect the most highly exposed childre n’s subpopulation from the chronic dietary

assessment.

The ETU short-term treated turf aggregat e MOE for toddlers exceeds 1000, the level of concern for this risk assessment, and is not of concern. Aggregate risk results are shown
in Table 7.2.Page 41 of 46 Table 7.2 ETU Short-Term Treated Tu rf (Toddlers) Aggregate Risk Results

Short-Term Post-Application Scenario

Population NOAEL mg/kg/day LOC 1 Max
Allowable Exposure 2 mg/kg/day Average
Food &
Water Exposure 3 mg/kg/day Residential Exposure 4 mg/kg/day Aggregate MOE (food and residential) 5

Toddlers –
mancozeb
derived ETU 7 1000 0.007 0.00017 0.00596 1100

Toddlers –
maneb derived
ETU 7 1000 0.007 0.00017 0.00531 1280

1 The LOC is based on UF A = 10, UF H = 10, UF DB = 10

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Average food and drinking water exposure taken from most highly exposed child subpopulation from the chronic dietary exposure assessment in Table 5.2.

4 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure]. For mancozeb, incidental oral exposure is 0.00376 mg/kg/day (Table 6.5). Dermal exposure is 0.0022 mg/kg/day (Table 6.6). For maneb, incidental oral exposure is 0.0019 mg/kg/day (Table 6.9). Dermal exposure is 0.0034 mg/kg/day (Table 6.10).

5 Aggregate MOE = [(NOAEL / (Avg Food & Drinking water Exposure + Residential Exposure)]

7.2.3 ETU Short- and Intermediate-T erm Treated Turf Aggregate (Adult “Golfers”)

The short/intermediate-term treated turf a ggregate risk assessment combines dermal exposures for adults participating in activities such as golfing on treated turf exposed to ETU with average daily food and drinking wa ter exposures. Only mancozeb uses are
relevant for this scenario.

The ETU short-term treated turf aggregat e MOE for adults (“golfers”) exceeds 1000, the
level of concern for this risk assessment and is; therefore, not of concern. Aggregate risk
results are shown in Table 7.3.Page 42 of 46 Table 7.3 ETU Short/Intermediate-Term Trea ted Turf (Adults “Golfers”) Aggregate Risk
Results

Short-Term Scenario

Population NOAEL mg/kg/day LOC 1 Max
Allowable Exposure 2 mg/kg/day Average
Food &
Water Exposure 3 mg/kg/day Residential Exposure 4 mg/kg/day Aggregate MOE (food and residential) 5

Adults (Golfers) 5 1000 0.005 0.000061 0.00076 6100

1 The LOC is based on UF A = 10, UF H = 10, UF DB = 10

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Average food and drinking water exposure taken from most highly exposed adult subpopulation from the chronic dietary exposure assessment in Table 5.2. Food and drinking water consider ETU derived from existing and proposed uses of mancozeb, metiram, and maneb.

4 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure]. Adult dermal exposure is 0.00076 mg/kg/day for mancozeb treated turf (Table 6.7)

5 Aggregate MOE = [(NOAEL ) / (Avg Food & Drinking water Exposure + Residential Exposure)]

7.3 Long-Term (Chronic) Aggregate Risk

As noted above, there are no long-term reside ntial exposure scenario s for the existing and proposed uses on the EBDCs which would resu lt in long term residential exposures to ETU. Therefore, the long-term or chronic (non-cancer) aggregate risk for ETU includes contribution from dietary (food and drinking water) exposure alone. The chronic (noncancer) aggregate risk assessment for ETU is e quivalent to the ETU chronic dietary risk
assessment discussed in Secti on 5.2.3 of this document.

7.5 Cancer Aggregate Risk

For the aggregate cancer risk assessment, HED combined residential handler and post application exposures for adults exposed to ETU from the home garden uses, as well as post application exposures to adults from cont act with treated turf during activities such as golfing. The combined residential expos ure was then aggregated with dietary exposure to ETU from food and drinki ng water and multiplied by the ETU Q 1 * . The existing and proposed uses of mancozeb, me tiram, and mancozeb were considered for dietary exposure. The maneb residential us e was not aggregated because the mancozeb residential uses will result in much higher exposures than the maneb sod farm use and exposure to an individual from sod farm uses of both chemicals is considered unlikely.

ETU aggregate cancer results are shown in Table 7.4.Page 43 of 46 Table 7.4 ETU Aggregate Cancer Results

Population Q 1 * (mg/kg/day) -1 Negligible
Risk Level 1 Average daily
Food & Water

Exposure 2
(mg/kg/day) Residential Exposure 3

(LADD) Aggregate
Cancer Risk (food, water
and residential) 4

U.S. Population 6.01 x 10 -2 3 x10 -6 6.0 x10 -5 4 x 10 -6 3.8 x 10 -6

1 Because of the uncertaintie s in the hazard quantifi cation methodology, risk estimates ranging from 1 x10 -6

to 3 x10 -6 are generally considered indistinguishable. Gene rally, cancer risk estimates which do not exceed
3 x10 -6 are below HED’s level of concern.

2 From Table 5.2.

3 Handler LADD (low pressure handwand – highest exposure scenario) is 3.8 x10 -7 from Table 6.2. Home garden post application LADD is 2.6 x10 -6 from Table 6.4 (risk/ Q 1 * = exposure). Treated turf post app
LADD is 1.0 x10 -6 from Table 6.8. Total residential exposure is 3.98 x10 -6

. 4 Aggregate cancer risks are for the U. S. Population and are calculating the Q 1 * (0.0601) by the total

exposure.

The aggregate cancer risk is approximately 3.8 x 10 -6 , which exceeds HED’s level of concern. In fact, the aggregate food and drinki ng water risk also exceeds HED’s level of concern, before aggregation with residen tial exposures. Ther efore, HED conducted sensitivity analyses to determine the commod ities that provided the most contribution to the ETU exposure. The commodities that are the greatest contributors to ETU exposure are bananas, leaf lettuce, drinking water, turnip greens, grape juice and mangoes (Table 5.3). The results of the aggr egate sensitivity analyses may be found in Table 7.5. If the proposed tolerance in/on bananas (from metir am applications) is removed from the aggregate, then the aggregate cancer risk doe s not exceed HED’s level of concern. All of the other sensitivity analyses resulted in risks exceeding the level of concern. Note that
the metiram-derived ETU residue values from banana field trials us ed 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 imported bananas will be tr eated. In general, monitoring data on other
commodities show much lower residues than fi eld trial data, so actual exposure is likely
to be lower.Page 44 of 46 Table 7.5 Sensitivity Analyses for ETU Aggregate Cancer Results

Scenario Negligible
Risk Level 1 Average daily
Food &
Water Exposure 2 (mg/kg/day) Residential Exposure 3

(LADD) Aggregate
Cancer Risk (food, water
and residential) 4
Food, Water, Residential, all proposed uses 3 x10 -6 6.0 x10 -5 4 x 10 -6 3.8 x 10 -6

Food, Water, Residential, excluding proposed banana tolerance 3 x10 -6 5.0 x10 -5 4 x 10 -6 3.2 x 10 -6

Food, Water, Residential, excluding proposed use of mancozeb on leaf
lettuce 3 x10 -6 5.9 x10 -5 4 x 10 -6 3.8 x 10 -6

Food, Water, Residential, all proposed uses, assuming 1% crop
Treated for tu rnip greens 3 x10 -6 5.6 x10 -5 4 x 10 -6 3.6 x 10 -6

1 Because of the uncertaintie s in the hazard quantifi cation methodology, risk estimates ranging from 1 x10 -6

to 3 x10 -6 are generally considered indistinguishable. Gene rally, cancer risk estimates which do not exceed
3 x10 -6 are below HED’s level of concern.

2 From Table 5.2.

3 Handler LADD (low pressure handwand – highest exposure scenario) is 3.8 x10 -7 from Table 6.2. Home garden post application LADD is 2.6 x10 -6 from Table 6.4 (risk/ Q 1 * = exposure). Treated turf post app
LADD is 1.0 x10 -6 from Table 6.8. Total residential exposure is 3.98 x10 -6

. 4 Aggregate cancer risks are for the U. S. Population and are calculating the Q 1 * (0.0601) by the total

exposure.

8.0 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.”

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

The occupational aspect of the human health risk assessment has been completed for each of the EBDC fungicides in the risk assessments of the parent compound.

10.0 Data Needs and Label Recommendations

The data gaps for each individual EBDC a nd the corresponding exposures to ETU are
discussed in the risk assessments for each parent compound. The data gaps for ETU, which were previously identified in the 2005 human health risk assessment, include the following:Page 45 of 46 Toxicology

• Guideline 870.3800 2-generation reproduction, rat

• Guideline 870.3700 Developmental toxicity, rabbit

• Guideline 870.6300 Developmental neurotoxicity

• Non-guideline Comparative study for thyroid toxicity in adults and offspring

References

Davis, Donna. DP Barcode: D327307 & D327318. June 2007. Mancozeb: Human Health Risk Assessment to Support Proposed New Uses on Broccoli, Cabbage, Lettuce, Peppers and Almonds.

Dole, Timothy. DP Barcode: D317368. May 31, 2005. Mancozeb: 2nd Revised ORE
Assessment for the RED.

Dole, Timothy. DP Barcode: D295411. June 8, 2005. Maneb: 2nd Revised ORE
Assessment for the RED.

Goodlow, Toiya. DP Barcode: D267866. June 2007. Metiram: Human Health Risk Assessment for PP#9E6006. Petition for the Establishment of Import Tolerances on Grapes and Bananas.

Olinger, Christine. DP Barcode: D317416. June 8, 2005. ETU from EBDCs: Health Effects Division (HED) Human Health Risk Assessment of the Common Metabolite/Degradate ETU to Support Reregistration.

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.

Olinger, Christine. DP Barcode: D289183. April 5, 2007. Mancozeb on Almonds. Summary of Analytical Chemis try and Residue Data. PP#4F4324.

Olinger, Christine. DP Barcode: D294203. April 3, 2007. Mancozeb on Broccoli, Cabbage, Lettuce, and Peppers. Summary of Analytical Chemistry and Residue Data.
PP# 4F4333.

Olinger, Christine. DP Barcode : D337240. April 17, 2007. Aggregate Dietary Assessment of the Common Metabolite/Degr adate Ethylene Thiourea (ETU) to Support New Tolerances on Imported Grapes and Ba nanas for Metiram and for New Tolerances for Mancozeb on Almonds, Brocco li, Cabbage, Lettuce, and Peppers.Page 46 of 46 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.