### Metiram Registration Review Human Health Scoping Document D 425218

U N IT ED S TATE S ENVIRONMENTAL PROTECTION AGENCY

WASH IN G TON

, D .C. 2046 0



### MEMORANDUM

Date: June 2, 2015 OFFICE OF

CHEMICAL SAFETY AND
POLLUTION PREVENTION



### SU B JECT: Metiram : 

### Human Heal th Risk Assessment Scoping Document in Support of Registration

R ev ie w

.

PC Co d e: 014601; 014504 ; 6000 16 DP B a rcod e: 0425218

D ecisio n No.:499278 R eg i s tr a tion No.: NA

P et iti o n No.: NA Regulatory Action: Registration Revi e w

Ri sk Assess m en t T y p e : NA Case No.: NA

T X R No.: NA

MRID No.: NA



### FROM:

THROUGH:

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

- 7

40 CF R : § 18 0.217**-~** 

### Danette Drew

, Chemist/Risk A s sessor**~fl** 

### Matt Lloyd , C IH

,

### Expo~Assessor _ 

# Y! 

# 'fM

Pete Savoia

, Chemist**~'ft~/ ~~**  

### Linda Taylor

, Ph.D.

, T oxico l og i st
Risk Assessment Branches V 

### a nd VII


### Health Effects Division (7509P)

Michael Met z ger
, Branch Chief

# ~J 

# (} }

Risk Assessment Branches V and VII

.

# ~ · '

H

ealth Effec t s Divi sio n (7509 P )

Jess Rowland

, Deputy Director

Dana Vogel

, Acting Dir ector
Health Effects Division (7509P)



### TO: Brittan y Pruitt

, Chem ic a l Review Manager

P age 1 

### of 40 Risk Management and Implementation Branch III



### ..... Pesticide R e

- E valuation Di v i s ion ( 7508P)Metiram Reg i stration Review I l wnan H ea l th Scoping Document 04 252 18



### Exec utiv e S umm ary

The Health Effects Division (HE D) M et iram Re gis tration Review Team has evaluated the s tatus

of the hum an health risk asse ss ment for the fungicide metiram to determine th e scope of work

necessary to support registration review. This scoping exercise is based primarily on the most recently completed human health r i sk assessment (HHRA) of June 2007 

### (T. Goodlow, 6 / 14 / 07,

0267866

, 

### Metiram: Human H ea lth Risk Assessment for PP # 9E6006. P e tition/or the

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

Metiram Reregistration Eligibility D ecision 

### (RED).

Metiram

, a broad s p ect rum fungicide

, is a mixture of 5.2 parts by weight of ammoniates of ethy len ebis (dit hiocarbamato ) z inc with I part by weight ethylenebis (di thiocarbamic acid)

bimolecu l ar and trimo l ecu l ar cyclic anhydrosulfides and disulfides

. M e tiram is current l y registered for agricultural application to apples (fo liar) and potatoes (foliar or seed piece).

Horticultural use s include a Spec ia l Local Need u se on leathcrleaf fems (nu rs eries and greenhouses; F l or i da use only).

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

as CS2) o n apples, potatoes

, bananas, and wine grapes. The banana and grape tolerances are for imports to the U.S

. There are no tole r ances estab l i s hed for metiram on livestock commod i tie s
because there is no expec ted tr a n sfer of residues to livesto ck tissues from treated feed. In plants

, the residu es of concern for risk assessment are the parent compound mctiram and it s metabolite

and environmental degradate

, e thy l enethiourea (ETU). Th e residue of concern in drinking water

i s ETU only; metiram is not expec ted to be found in drinking water sources.

Metiram is a fungicide in th e class of ethylenebis dithiocarbamates (E BDCs ), which also

include s the fung i c i des maneb (no regist e red uses) and mancozeb (registe r ed us es); all of th ese

com pound s have a common metabolite / degradate

, ETU. Some of th e more notable toxicity

, suc h

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

, separa t e ri sk assessments are performed for 1) toxicity and expos ure to parent compound



### metiram only and 2) toxicity and exposure to 

### ETU derived from metiram

, including combined

exposures from both ETU as an environmental degradate and ETU as an 

### in vivo metabolite of

metiram. Th i s document presents the scope of work anticipated und e r registration r eview for

both metiram and mct i ram-derived ETU. A separate HED document (0425216) outlines th e

scope of work anticipated for mancoz eb and mancozeb-deriv cd ETU. I n addition to the

individual EBDC pesticide assessments, a se par ate risk assessment is perfom1ed addressing the

combined (aggregate) risk from ETU derived from 

### all regi s tered EBDC pesticides. The

conclusions rega r ding t he scope of work anticipated under registration review fo r mancoz eb and

metiram also apply t o the ETU agg reg ate risk assessment.

For any re s idential

, occupational and dietary exposure, i ncluding oral

, dermal and inhal at i on

routes of expos ure
, a 7.5% 

### in vivo metabolic conversion of absorbed m et iram t o ET U is u sed,

and is accounted for in estimating the total exposure 

### (in vivo metabol i sm combined with direct

environmenta l exposure) to ETU.

The findings in multiple toxicology s tudi es demonstrate that th e th yro id is a target o rgan for

Page 

### 2 of 

### 40

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 3 of 40 metiram and ETU; these effects are due to inhibition of thyroid peroxidase by the metabolite

ETU. The nervous system is also a target for metiram. Neurotoxic signs and neuro pathology have been observed in subchronic studies in rats following oral dosing with metiram. Both

m etiram and ETU are classifi ed as probable human carcinogens. There is no indication of immunotoxicity potential for m etiram or ETU.

In the 2007 metiram a nd metiram

- derived ETU risk assessment, a database uncertainty factor of 10X was retained for all populations to account for the lack of key data ; HED noted data gaps for

a developmental neurotoxicity ( DNT ) study, an acute neurotoxicity study, a developmen tal toxicity study in the rabbit

, and a 2

- generation reproduction study in the rat

.

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

, D412678, Ethylene Thiourea (ETU); Aggregate Human Health Risk Assessment of the Common Metabolite/Degradate Ethylene Thiourea (ETU) to Support Proposed New Section 3 Use on Walnuts and Tolerance for Imported Tangerines ) the default FQPA factor of 10X was retained for women of childbearing age (13

- 49 years old) and for children less than six years old to account for the lack of data on the developing thyroid (database uncertainty factor) . The FQPA factor was reduced to 1X for other lifestages (children > 6 years, females > 49 years, and adult males), for which the thyroid is largely develope d and there are applicable thyroid data.

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

- generation reproductive toxicity study on ETU, which includes an assessment of reproductive toxicity, developmental neurotoxicity , and developmental thyroid toxicity) have been received since the

last metiram and ETU risk assessment s and are currently undergoing review

. A devel opmental toxicity study (rabbit ) for metiram remains outstanding. The need for a subchronic neurotoxicity study and immunotoxicity data has been waived by HED’s Hazard and Science Policy Council (HASPOC ) (TXR#00 55055

, 4/30/15 meeting ). D uring registration review of metiram, the impact of the new data on endpoint selection, points of departure (PODs), and uncer tainty factors/safety factors (UF/SFs) for the dietary, dermal, and inhalation risk assessments will be

evaluated.

The metiram residue chemistry database is incomplete ; outstanding data (revised labels) are required under 860.1200 Directions for Use and 860.1560 Reasonable Grounds in Support of the

Petition

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

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

assessments m ay be outdat ed, and any changes in application techniques, typical rates, handling, storage, and transportation could result in incurring different residue levels today than those reported in the 1990 survey. To allow for the continued use of the survey in future die tary assessments, the EBDC registrants must provide justification as to whether current good agricultural practices would result in yielding comparable residues as those found in the survey

. If based on this information HED concludes that the market baske t data are no longer reflective of current residues, a new market basket survey should be conducted. In that event, until adequate updated market basket data are submitted, HED will rely on data from available controlled studies (e.g. field trial data, pr ocessing studies), which will likely result in significantly greater risk estimates that may exceed the levels of concern.

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 4 of 40 No acute or chronic (non

- cancer) dietary risks of concern were identified in the 2007 HHRA for either metiram (food only; metiram no t expected in drinking water) or metiram

- derived ETU (food and water) for any populations modeled, including infants and children, and females of child bearing age . T he most highly exposed population subgroup in any of the dietary

assessments was children ages 1

- 2 with an estimate for metiram (food only) at 70 % of the cPAD

. The cancer risk estimate associated with exposure to metiram

- derived ETU in food and water

was 1 x 10

- 6 

### for the general U.S. population.

Under registration review of metiram, HED may conduct a new dietary assessment if the Ecological Fate and Effects Division (EFED) revised Drinking Water Assessment (DWA) results in ETU estimated drinking water concentrations (EDWCs) that are significantly greater than those used in the most recent (20 13) ETU assessment, which were based on water monitoring data and modeling. A revised dietary assessment will be performed if there are increases in the anticipated residue levels in food

. If new toxicological endpoints, PODs or UF/SFs are selected

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

assessments.

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

assessment is not anticipated to be performed for residen tial handlers or residential (non

occupational) post

- application exposure. However, HED does intend to perform a quantitative spray drift assessment. Based on the current use pattern, no chemical specific Turf Transferable Residue (TTR) data are required f or metiram. Additionally, the Agency will examine the need

for a volatilization assessment during registration r eview.

Since there are no residential uses of metiram, the aggregate assessments were comprised of food and drinking water exposures. There we re no aggregate risk estimates of concern for metiram or

metiram

- derived ETU identified in the 2007 HHRA.

The occupational exposure database for m etiram (and metiram

- derived ETU) is complete . The previous occupational assessment performed (2005) utilized methodologies that have since been updated. Comprehensive updated quantitative handler and post

- application occupational risk assessments (cancer and non

- cancer) will be performed for all currently registered metiram uses

and will include updated exposure assessment methodology (e.g. new transfer coefficients, methodology for greenhouse assessments, etc.). The available chemical

- specific dislodgeable foliar residue (DFR) data will also be considered for the post

- application assessments. Any

revisi ons to the toxicological endpoints, PODs, or UFs will also be incorporated in the occupational assessments

.

ETU Aggregate Assessment (All EBDCs)

HED has previously conducted acute, short

- term, chronic, and cancer aggregate assessments for

ETU from the co mbined EBDC pesticide uses (metiram and mancozeb ) ( 7/3 /2013 ; D412678 ). The acute and chronic aggregate assessments included only dietary (food and drinking water) exposures. There were no acute or chronic ETU aggregate risk estimates of concern for the

com bined EBDC uses.

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 5 of 40 The short

- term aggregate assessments for ETU combined residential exposures (from mancozeb use; there are no residential uses of metiram) and average dietary (food and water; from metiram and mancozeb uses) exposures. There were no short

- term aggregate risk estimates of concern for

the combined EBDC uses.

The cancer aggregate assessment for ETU included contributions from residential and dietary (food and water) exposures. Cancer aggregate ETU risk s were estimated at 2 x 10

- 6 

### (handler)

and 3 x 10

- 6 

### (post

- application)

.

Under registration review of metiram, a revised combined ETU aggregate assessment will be performed if there are any significant changes made to the ETU assessments from the individual EBDCs (e.g. assessment met hodologies, toxicologic al endpoints, PODs or UF/SFs, EDWCs

, food residues ).

Introduction

HED has evaluated the most recent human health risk assessments for metiram (2007) and ETU (2013) , as well as older evaluations, to determine any outstanding data re quirements or additional data required to complete registration review for this fungicide. HED has also

c o nsidered updates to its toxicity, exposure and usage databases, and the latest Agency science policy and risk assessment methodologies.

Metiram, a broad spectrum fungicide, is a mixture of 5.2 parts by weight of ammoniates of ethylenebis (dithiocarbamato) zinc with 1 part by weight ethylenebis (dithiocarbamic acid) bimolecular and trimolecular cyclic anhydrosulfides and disulfides. Metira m is currently registered for agricultural application to apples (foliar) and potatoes (foliar or seed piece).

Horticultural uses include a Special Local Need use on l eatherleaf ferns (nurseries and greenhouses; Florida use only). The two currently registe red products are a dry flowable (DF; EPA Reg. No. 7969

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

- 321).

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

Hazard Identification/Toxicology

M etiram

The toxicolo gy database for metiram is mostly complete, with the exception of the rabbit developmental toxicity study. Previously, the toxicological database was considered incomplete due to the lack of several key study requirements. Subsequent to the last metiram ri sk assessment, it was determined that the extended one

- generation reproductive toxicity study (EOGRTS) being performed on the metabolite ethylene thiourea (ETU) would satisfy the metiram data requirements for the 2

- generation reproductive toxicity study an d the developmental neurotoxicity study. The data requirement for a comparative thyroid assessment is also addressed by the ETU study and is applicable to metiram. The ETU EOGRTS has been

submitted to the Agency and is under review; an initial screen indic ate s that the study is acceptable. Additionally, an acute neurotoxicity (ACN) study on metiram has been submitted

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 6 of 40 and reviewed, and it satisfies this metiram data requirement. The new Part 158 Toxicological Data Requirements for a subchronic neurotoxicity study (SCN) and an immunotoxicity study on metiram have been waived by the Hazard and Science Policy Council (HASPOC) ( TXR#0055055, 4/30/15 meeting). The metiram rabbit developmental toxicity study remains a datagap.

The thyroid is a target organ for metiram. Thyroid effects observed in subchronic studies in rats include increased thyroid weights, increased thyroid stimulating hormone (TSH)

, and decreased serum thyroxin e ( T4) values. These effects are considered to be due to inhibition of thyroid

pero xidase by the metabolite, ETU. The nervous system and skeletal muscle are also targets for metiram. Neurotoxic signs and/or neuromuscular effects and neuropathology have been observed in subchronic studies in rats following oral administration of metiram . Muscle wasting was observed at termination, and signs of neurotoxicity occurred after 2 weeks of dosing, including reduced forelimb grip strength, hindlimb paralysis, muscle wasting, and ataxia

. Neuropathology findings included decreased areas of myeli nated axons in the sciatic, sural

, and

tibial nerves.

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

- implantation loss; hydrocephaly and related lesions, skeletal system defects and other gross defects) at a dose level

of metiram where minimal maternal toxicity (decreased body

- weight gains) was observed. However, there is low concern for the qualitative susceptibility observed in the rat study since

the dose

- response was well characterized; there were clear NOAELs (no obse rved adverse effect levels)/LOAELs (lowest observed adverse effect levels) for maternal and developmental toxicity; and the doses selected for risk assessment were based on neurotoxicity and address concerns for developmental toxicity and thyroid toxicity, which occurred at higher doses. Developmental toxicity was observed in the rabbit (abortions) at the same dose levels where maternal toxicity was observed (abortions, mortality). Although the maternal rabbits were adequately assessed, the

heads of the fe tuses were not examined in this study, and this study remains a data requirement. Reproductive toxicity was not adequately assessed following exposure to metiram because of the

lack of a one

- to

- one pairing and the lack of histopathological examination of r eproductive and
target organs. However, the EOGRTS on ETU assessed reproductive toxicity (with one

- to

- one pairing and adequate histopathological examination of reproductive and target organs), and the results of this ETU study are considered applicable to metiram.

There are no adequate carcinogenicity studies for metiram in either the rat or the mouse. In the absence of adequate data for metiram, the potential for carcinogenicity has been based on ETU, which is classified as a probable human carcinogen, with a Q 1 

### * of 0.0601 (mg/kg/day)

- 1 

### for risk assessment. Because metiram is known to be converted to ETU, it has also been classified as a probable human carcinogen

. Metiram has been tested in a series of in vitro and in vivo genotoxicity assays. Metiram did not cause bacterial gene mutation, but there was evidence of mammalian gene mutation in two studies. The genotoxic effect was not considered to be related

to the metabolism of metiram to ETU.

Metiram is rapidly absorbed and eliminated via the urine, feces, and expired air, with excretion being nearly complete after 48 hours. Metiram degrades and/or is metabolized to ETU. In rat

oral metabolism studies with radiolabelled metiram, an average 7.5% in vivo metabolic

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 7 of 40 conversion of metiram to ETU occurred, on a weight

- to

- weight basis. Metabolism data indicate some accumulation following repeat dosing

.

Metiram is not acutely toxic via the oral, dermal, or inhalation routes of exposure, nor is it a skin or eye irritant. It is, however, a strong

- to

- severe skin sensitizer.

In the 2007 metiram and metiram

- derived ETU risk assessment, a database uncertainty factor of

10X was retained for all populations to account for the lack of data . HED noted data gaps for a DNT study, acute neurotoxicity study, a developmental toxicity study in the rabbit and a 2

- generation reproduction study in the rat

.

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

- generation reproductive toxicity study on ETU, whic h includes an assessment of reproductive toxicity, developmental neurotoxicity , and developmental thyroid toxicity ) have been received since the

last risk assessment and is currently undergoing review

. The developmental toxicity study (rabbits) for metira m remains outstanding. The need for a subchronic neurotoxicity study and immunotoxicity data has been waived. D uring registration review of metiram, the impact of the new data on endpoint selection, points of departure (PODs), and uncertainty factors/safe ty factors (UF/SFs) for the dietary, dermal, and inhalation risk assessments will be evaluated.

The toxicity profile tables for metiram are included as Attachment 2. The metiram endpoints, points of departure (PODs), and uncertainty/safety factors (UF/SF s) used in the most recent

human health risk assessment are summarized in Attachment 3.

Ethylenet hiourea (ETU)

Previously, the toxicology database for ETU wa s limited and HED relied on a combination of guideline study data and studies in the open literature to assess hazard for ETU. Since the last risk assessment, an extended one

- generation reproductive toxicity study (EOGRTS) on ETU was submitted, which includes an assessment of reproductive toxicity, developmental neu rotoxicity, developmental thyroid toxicity, and immunotoxicity (previous ETU datagaps).

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

hazard of ETU. The effects on the peripheral nervous system observed f ollowing exposure to metiram (or mancozeb) have not been observed following ETU exposure.

The thyroid is a major target organ for ETU because ETU inhibits the enzyme thyroid peroxidase. Thyroid toxicity in subchronic and chronic rat, mouse, and dog studi es includes
decreased levels of the thyroid hormone T 4 

### (thyroxine), changes in T 3 

### (triiodothyronine) levels

, compensatory increases in levels of thyroid stimulation hormone (TSH), increased thyroid weight, and microscopic thyroid changes, chiefly hyperplas ia. Overt liver toxicity (necrosis) was observed in one chronic dog study. Developmental defects in the rat developmental toxicity study included hydrocephaly and related lesions, skeletal system defects, and other gross defects in the kidney and stomach. Hydrocephaly and microphthalmia occurred in rats after a single dose. Post implantation loss, hydrocephaly, and domed head were observed in the rabbit developmental toxicity study. Although there are no neurotoxicity studies on ETU (except as

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 8 of 40 assessed in the recently submitted extended one

- generation reproductive toxicity study, EOGRTS) , the toxicity profile of ETU shows that the principal toxic effects are on the thyroid. The immunotoxicity study on ETU did not show any immunotoxicity potential.

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

observed in the ETU carcinogenicity study in mice. The ETU cancer potency factor (Q 1 

### *) of
0.0601 (mg/kg/day)
- 1 

### is used to quantitate risk.

In the most recent ETU risk assessment (2013 HHRA) , the default FQPA factor of 10X was retained for women of childbearing age (13

- 49 years old) and for children less than six years old to account for the lack of data on the developing thyroid (database uncertainty factor) . Th e FQPA factor was reduced to 1X for other lifestages (children > 6 years, females > 49 years, and adult males), for which the thyroid is largely developed and there are applicable thyroid data.

Since the last risk assessment of ETU, an extended one genera tion reproductive toxicity (EOGRT) study on ETU was submitted, which was designed to satisfy the toxicology d ata gaps for ETU ( a 2

- generation reproduction study in rats, a developmental neurotoxicity study in rats, and a developmental thyroid toxicity stud y in rats ). This study is currently under review. Additionally, a rabbit developmental toxicity study on ETU was submitted, which has been

reviewed and found to satisfy this data requirement. D uring registration review of m etiram

, the impact of the se stud y results on endpoint selection, PODs, and UF/SFs for the dietary , incidental

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

and procedures.

The toxicity profile tables for ETU are included as Attachment 2. The ETU endpoints, points of departure (PODs), and uncertainty/safety factors (UF/SFs) used in the most recent human health

risk assessment are summarized in Attachment 3.

Conclusions: The toxicology databases for metiram and ETU are mostly complete. A rabbit developmental toxicity study is required for metiram

. D uring registration review of metiram

, the impact of the recently submitted metiram (acute neurotoxicity) and ETU studies (an EOGRT study and a rabbit developmental toxicity study ) on endpoint se lection, points of departure (PODs), and uncertainty factors/safety factors (UF/SFs) for the dietary, dermal, and inhalation

risk assessments will be evaluated.

Residue Chemistry

Residue Chemistry

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

established under 40 CFR §180. 21 7(a) for residues of metiram (expressed as CS 2 

### ) on apples, potatoes, bananas, and wine grapes (bananas and grapes as imports)

. There are no tolerances

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

transfer of r esidues to livestock tissues from livestock eating treated feedstuffs [ i.e, 40 CFR § 180.6(a)(3 )

, no expectation of finite r esidues ].

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 9 of 40 The nature of the residue in plants and livestock is adequately understood based on metabolism

studies with potato , apple, goat and poultry

. HED has concluded that the residue of concern for the tolerance enforcement of all regulated commoditie s is the parent compound meti ram calculated as CS 2



### . In pl ants the residues of concern for risk assessment are metiram a nd its

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

methods available for the enforcement of crop tolerances with PAM Vol. II listing Methods I, II, II, IV, and A . Metiram i s not recovered through any of the FDA Multi

- Residue Method testing protocols.

The residue chemistry dat abase for metiram is incomplete. T he 2007 metiram HHRA noted the following residue chemistry data gaps which remain outstanding:

Gui deline 860.1200 Directions for U se 1) Banana: The submitted translated label for bananas (Polygram 80 WG) is inadequate to allow evaluation of the residue data relative to the proposed for eign use pattern because the label does not specify the maximum number of applications (or total application rate) that may be made on banana crops grown in Central and South America per growing season. In addition ̧ the label does not provide information pertaining to the type of equipment which may be used for applications. The available data will, however, support a minimum retreatment interval of 5 days and the use of a surfactant. If the registrant wishes to rely on the available field trial data for bananas, then label amendments are required to specify: (1) a maximum of ten broadcast foliar applications at 1.25 lb ai/A per application for a seasonal rate of 12.5 lb ai/A; and (2) a spray volume of 3 gallons per acre using ground equipment. If the r egistrant wishes to include higher spray volumes on the label, then additional residue data will be required.

2) Grape: The submitted translated labels for grapes (Polygram DF and Polygram WG) are also inadequate to allow evaluation of the residue data rela tive to the proposed foreign use pattern because not all labels clearly specify the maximum single and seasonal rates as well as the preharvest intervals for each European country where uses are propos ed. However, the registrant had indicated that EU is a ttempting to harmonize label uses of metiram on grapes grown all over Europe. When EU has completed the harmonization of all metiram labels intended for use on grapes, EPA requires the submission of revised

labels to determine whether the available residu e data can support the harmonized use patterns. If there are any deviations from the harmonized use pattern due to localized pest infestation or good agricultural practices, information pertaining to these deviations should be reported.

Guideline 860.1560 Reasonable Grounds in Support of the P etition For the banana use, label revisions were required to satisfy the 860.1200 guideline requirement (directions for use) by delineating the application pattern which followed the

field trial s tudies . Adequate revision of the foreign label s , or the submission of field trial data which support an alternate pattern of use

, remains outstanding.

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 10 of 40 The 2007 metiram HHRA also identified the following residue chemistry data requirements. As
part o f this metiram scoping exercise, HED has determined , as explained below, that these requirements may now be considered fulfilled and are no longer outstanding:

Guideline 860.1380 Storage S tability Storage stability data for the ETU metabolite were req uired to support the bananas stored for up to 137 days (4.5 months ; MRID 46655001 )

. However, t he 2005 RED for metiram

noted that residues are stable in a diversity of crops such as apple, peanut, potato, and tomato, as well as apple processed commodities for up to 1 year. Additionally, weathered residues of ETU were found to be reasonably stable for up to 8.5 months in grapes. At the time of this registration, the Agency held a position that given the instability of the EBDC residues, storage stability d ata were not translatable from other laboratories. However, since studies have been made which demonstrate that the ETU metabolite is relatively stable when stored frozen for durations well past the 4.5 months incurred for bananas, the Agency will allow f or translation of these data in this instance. In addition, th e previous storage stability data requirement for grape raisins held 36 days ( MRID 46501205 ) is no longer required. Storage stability data are not required for samples stored frozen for less than 30 days, and as these samples were stored for only a few days beyond this interval significant residue loss would not be expected, especially given the residue stability on mul tiple crops up to 1 year

. This 860.1380 data requirement

is considered fulfilled.

Guideline 860.1520 Processed F ood/ F eed The submitted grape processing study provided to support PP#9E6006 was incomplete since it did not include residue data for the regula ted processed commodity of grape juice . This data is no longer required as the tolerance is established for metiram on non

domestic grapes grown for wine ( ‘grape, wine’ ). Wine grapes are not typically diverted to markets for juice or raisins. There are pr ocessing data for wine made from grapes. This 860.1520 data requirement is considered fulfilled.

Guideline 860.1550 Proposed T olerances As requirement for registration (PP#9E6006), the petitioner was to modify the tolerance

on grapes to 5.0 ppm and propos e a tolerance on raisins at 10.0 ppm. This data is no longer required as the tolerance is established for metiram on non

- domestic grapes grown for wine (‘grape, wine’) at 5.0 ppm. Wine grapes are not typically diverted to markets for juice or raisins. A t olerance for metiram on raisins is not required at this time

. This 860.1550 data requirement is considered fulfilled.

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

now be considered fulfilled :

Guideline 860.1850 Confined A ccumulation in R otational C rops The 2005 RED for metiram required a confined rotational crop study. A rotational crop study was submitted in 2010 ( MRID 48122001) and is currently undergoing review. If adequate, the confined rotation al crop data will be used for determining if limited field

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 11 of 40 trials are needed for rotational crops or if plantback restrictions need to be added to the existing labels . The 2005 860.1850 data requirement is considered fulfilled.

The following new residue c hemistry data requirement s w ere identified by HED during this registration review scoping exercise for metiram :

Guideline 860.1200 Directions for Use Potato: If the single seed treatment on potato is being maintained, the 80% WP (EPA Reg. No. 7969

- 70) and 80% DF (EPA Reg. No. 7969

- 105) labels must be amended to specify the maximum application rate in terms of ounces or pounds ai per cwt.

Anticipated Residue /Monitoring study (non

- guideline study) : Updated anticipated residue/monitoring data are needed to support the dietary assessment s for the EBDC pesticides, including metiram . The 1990 EBDC market basket survey previously used to refine the dietary assessments m ay be outdated, and any changes in application techniques, typical rates, handling, storage , and transportation could result in incurring different residue levels today than those reported in the 1990 survey. To allow for the continued use of the survey in future dietary assessments, the EBDC registrants must provide justification as to whether current good agricultural practices would result in yielding comparable residues as those found in the survey. If based on this information HED concludes that the market basket data are no longer reflective of current residues, a new market basket survey should be conducted. In that event, until adequate updated market basket data are submitted, HED will rely on data from available controlled studies (e.g. field trial data, processing studies), which will likely result in significantly greater

risk estim ates that may exceed the levels of concern.

Dietary Assessment

Acute, chronic, and cancer dietary risk assessments were most recently performed for metiram using the Dietary Exposure Evaluation Model (DEEM

- FCID  ) Version 2.03 (D326 753, C. L. Olinger, 0 4/17/2007) to support the establishment of tolerances for imported bananas and grapes. This model uses food consumption data from the U.S. Department of Agriculture’s Continuing Surveys of Food Intakes by Individuals (CSFII ) from 1994

- 1996 and 1998. The a cute (probabilistic), chronic, and cancer assessments were highly refined determinations which used field trial data, 1990 EBDC market basket survey data for potatoes, percent crop treated/import estimates, and processing and cooking factors.

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

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

. In 2006

EFED provided estimated drinking water concentrations ( EDWCs) of ETU in surface water and groundwater ( 8/11/06, M. Ruhman and R. Parker, Estimated Drinking Water Concentrations of ETU (Ethylene

- thio

- urea, degradate of mancozeb, and common degradate of EBDCs “Ethene

- bis

dithio

- carbamates”) for Use in Human Health Risk Assessment. D3231 43 and D323141 ). EDWCs were derived using a both modeling and water monitoring results. The ETU EDWCs were directly incorporated into the dietary analyses. The dietary analyses for metiram are for food only and those for ETU (resulting from metiram use) are for both food and drinking water

.

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 12 of 40 For acute exposure to metiram in food , the risk estimate for females 13

- 49 years old (the only population for which an acute toxicological endpoint was identified) was 22 % of th e aPAD. For acute exposure to ETU in both food and water, the risk estimate for females 13

- 49 years old was 6.0 % of the aPAD.

T he chronic dietary risk estimates were below the Agency’s level of concern for metiram and ETU for the general U.S. population and all population subgroups. The most highl y exposed population subgroup was children ages 1

- 2 with an estimate for metiram for food alone of 70 %

of the cPAD. For metiram

- derived ETU the chronic dietary (food and water) estimate for children ages 1

- 2 wa s 54% of the cPAD.

The cancer dietary (food and water) risk estimate for metiram

- derived ETU wa s 1 x 10

- 6 

### for the general U.S. population.

The majority of the metiram

- derived ETU dietary exposure was from food sources; drinking water was not a large contributor to the ETU dietary exposure.

Conclusions: The metiram residue chemistry database is incomplete ; label revisions for banana, grape, and potato are required under Guidelines 860.1200 Directions for Use and 860.1560 Reasonable Grounds in Support of the Petition.

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

residue /monitoring data (non

- guideline study ) are needed to support the dietary assessment s of the EBDCs, including metiram

. Th e previous dietary analyses for m etiram/ETU were refined through the use of the 1990 EBDC market basket survey provided by the EBDC registrants and did not result in risk estimates of concern. The survey measured residues of EBDCs in a variety of foods as close to the point of consumption as possible (grocery stores and small markets)

. However, the market basket survey may be outdated and possible changes in application techniques, typical rates, handling, storage, and transportation could result in incurring different

resi due levels today than those reported in the 1990 survey. To allow for the continued use of the survey in risk assessments, the EBDC registrants must provide justification as to whether current good agricultural practices would result in yielding comparabl e residues. If based on this information HED concludes that the market basket data are no longer reflective of current residues, a new market basket survey should be conducted. In that event, until adequate updated market basket data are submitted, HED wi ll rely on data from available controlled studies (e.g. field trial data, processing studies), which will likely result in significantly greater risk estimates that may exceed the levels of concern.

HED may conduct a new dietary assessment if anticipate d residues on food or if EFED’s revised EDWCs are significantly greater than those used in the most recent assessment. If new toxicological endpoints, PODs or UF/SFs are selected as a result of the new toxicological data submissions, these would also be us ed in any revised dietary assessments.

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 13 of 40 Residential (Non

- Occupational) Exposure and Risk

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

- application risk estimates were calculated in the last Occupational and Residential exposure assessment (June 8, 2005 , T. Dole, D291663, Metiram: 2nd Revised Occupational and Residential Exposure Assessment and Recommendations for the Reregistration Eligibility Decision Document ). Based on a recen t review of the currently registered labels

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

handler or non

- occupational post

- application risk estimates are required.

Residential Handlers

A residential handler exposure assessment is not required because metiram is only applied to use sites that are not treated by residential handlers.

Residential Post

-

Application

Metiram is not registered on residential turf, lawns or golf course turf. B ased on the registered use pattern ( agricultural crops ) no quantitative residential post

- application exposure assessment is required.

Post

- A pplication Volatilization/Spray Drift

Residential bystander exposures resulting from off

- site transport (e.g., s pray drift or volatilization) may occur as a result of applications of metiram . The potential for spray drift will be evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered con currently. The approach is outlined in the revised (2012) Standard Operating Procedures for Residential Risk Assessment (SOPs)

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

This document outline s the quantification of indirect non

- occupational exposure to drift. In terms of volatilization, the agency has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis 1 

### . During Registration Review, the agency will

uti lize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for metiram

.

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

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

or residential post

- application exposure. However, HED does intend to perform a quantitative spray drift assessment. Based on the use pattern, no chemical specific TTR data are required. Additionally, the Agency will examine the need for a volatilization assessment durin g registration r eview.

1 http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 14 of 40 Aggregate Risk Assessment (Metiram; Metiram

- derived ETU)

In accordance with the Food Quality Protection Act (FQPA), EPA must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential (non

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

assessments consist of food and water only

. Acute, chronic, and cancer aggregate (food and water) assessments were performed for metiram and metiram

- derived ETU in the 2007 HHRA.

The a cute and chronic aggregate r isk estimates for metiram or metiram

- derived ETU were not of concern for any population subgroup. The previous cancer aggregate risk for metiram

- derived

ETU was estimated at 1 x 10

- 6



### .

Conclusions : As there are no homeowner or residential uses for metiram, the aggregate assessments consist of food and drinking water only. There were no aggregate risks of concern in the most recent metiram HHRA (2007). Revised acute, chronic (non

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

metiram

- derived ETU if there are any changes to toxicologic al endpoints, PODs or UF/SFs, or if there are significant changes to EFED’s EDWCs

.

Aggregate Ris k Assessment (ETU derived from all EBDC Pesticides)

ETU is a common degradate/ metabolite of EBDC fungicides mancozeb and metiram ; these are the only currently registered EBDC pesticides. In 2013, HED performed ETU aggregate assessments (ETU exposures fro m food, drinking water, and residential) for the combined uses of metiram and mancozeb (7/3/2013, D412678, D. Drew et al, Ethylene Thiourea (ETU); Aggregate Human Health Risk Assessment of the Common Metabolite/Degradate Ethylene Thiourea (ETU) to Support Proposed New Section 3 Use on Walnuts and Tolerance for Imported Tangerines ).

HED conducted acute, short

- term, chronic, and cancer aggregate assessments for ETU from the combined EBDC uses. The aggregate assessments combined the highest estimated residen tial exposures with average food and drinking water exposures. The only EBDC with residential

uses is mancozeb. The mancozeb garden scenarios resulted in higher post

- application exposures than the golfing scenarios; aggregate assessments using the garden scenario are protective of any
post

- application exposures to adult and youth golfers.

The acute and chronic aggregate assessments include only dietary (food and drinking water) exposures. There were no acute or chronic ETU aggregate risk estimates of co ncern.

The short

- term aggregate assessments for ETU combined residential exposures (mancozeb use) and average dietary (food and water; all EBDC use) exposures. There were no short

- term aggregate risk estimates of concern (adults applying the EBDC mancozeb to gardens and adults or youth entering treated gardens).

The cancer aggregate assessment for ETU includes contributions from residential and dietary (food and water) exposures. Cancer aggregate ETU risk estimates for adults applying mancozeb to gardens or entering treated gardens were estimated at 2 x 10

- 6 

### and 3 x 10

- 6 

### , respectively.

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 15 of 40 Conclusions: Any ETU data gaps identified for each individual EBDC (mancozeb and metiram) will apply to the combined ETU aggregate assessment. Under registration review (o f mancozeb and metiram), a revised combined ETU aggregate assessment will be performed if there are any significant changes made to the ETU assessments from the individual EBDCs (e.g. assessment methodologies, toxicologic al endpoints, PODs or UF/SFs, EDWCs , food residues ).

Occupational Exposure

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

- derived ETU through mixing, loading, and/or applying the pesticide to apples or potatoes (foliar and seed piece), or re

- entering treated si tes. Additionally, there is a Special Local Need in Florida on leatherleaf ferns (ornamental horticultural use). The occupational assessment includes a non

cancer handler assessment for both metiram and ETU for short

- and intermediate term exposure

and a cancer assessment for ETU based on lifetime occupational exposure. Metiram is applied by aerial application, ground equipment (airblast), groundboom, and through chemigation equipment (limited states) for foliar uses and then on

- farm or commercial seed pie ce treatment for the potato use. The most recent comprehensive occupational exposure assessment was performed for the 2005 metiram HHRA ( D291661 ) in support of the RED.

Occupational Handlers

The 2005 RED identified risks of concern for some occupational handler exposure scenarios (i.e., seed treatments and crop mixer/loader scenarios); therefore, mitigation measures were implemented such as the requirement of additional personal protective equipment ( PPE ) (e.g., respiratory protection for handlers). Curre ntly registered metiram labels require occupational handlers to wear long

- sleeved shirts, long pants, shoes, socks, a dust/mist filtering respirator, and chemical resistant gloves. Mixer/loaders must also wear a chemical resistant apron.

For agricultur al applications, t he 2005 occupational handler assessment identifie d combined dermal and inhalation MOEs for metiram (and metiram

- derived ETU) that are not of concern (MOE s > 100) with the current label PPE (gloves plus dust/mist filtering respirator). Fo r potato seed treatment, the 2005 occupational handler assessment identified MOEs of concern if PPE less than baseline clothing plus gloves and PF5 respiratory protection is worn. The current label does not require any respiratory protection for potato seed piece treatments. The handler c ancer assessment for metiram

- derived ETU resulted in estimates ranging from 10

- 6 

### to 10

- 4



### .

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

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

, the se assessments were not conducted based on current occupational exposure policies.

Recommended unit exposures for occupational handler assessments had generally been derived only from the Pesticide Handlers Exposure Databas e (PHED). However, recently both the Outdoor Residential Exposure Task Force (ORETF) and the Agricultural Handler Exposure Task Force (AHETF) have produced pesticide handler exposure monitoring data that the Agency is using in place of PHED ( http://www.epa.gov/pesticides/science/handler

- exposure

- data.html ). As

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 16 of 40 more reliable data become available, the Agency will continue to replace existing data. New exposure monitoring data will be incorporated into revised occupational handler assessments, as necessary, during registration review.

Occupational Post

-

Application

There is a possibility for workers to have post

- application dermal exposure to metiram and

metiram

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

. Post

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

metiram ( short

- term and intermediate

- term exposures ) and metiram

- derived ETU ( short

- term
inter mediate

- term, and lifetime/cancer exposures) , and mitigations have eliminated the then

identified risks of concern

.

The 2005 occupational post

- application assessment for metiram did not identify any short

- term risk estimates of concern although some intermediate

- term MOEs of concern were identified for

metiram

. All of the short/intermediate term MOEs for metiram

- derived ETU exc eed 100 at day

zero and were not of concern. The cancer risk estimates for metiram

- derived ETU were < l x 10

- 5 

### on the day of application and decline d below 1x10

- 6 

### for all scenarios by 60 days after application (based on day 0 residues).

Since acceptable chemical

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

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

- application assessment. Based on updated methodology, r ecommended transfer coefficients for occupational post

- application assessments will be derived from Agricultural Reentry Task Force (ARTF) exposure monitoring studies ( http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html ). These transfer coefficients were updated in 2012 based on a reanalysis and submission of new monitoring data. HED will incorporate new exposure monitoring data, as necessary, during regi stration revi ew.

Conclusion s: The occupational exposure database for m etiram (and metiram

- derived ETU) is complete . The previous occupational as sessment performed (2005) utilized methodologies that have since been updated. Comprehensive updated quantitat ive handler and post

- application occupational risk assessments (cancer and non

- cancer) will be performed for all currently registered metiram uses and will include updated exposure assessment methodology (e.g. new transfer coefficients, methodology for gre enhouse assessments, etc.). The available chemical

specific dislodgeable foliar residue (DFR) data will also be considered for the post

- application assessments. Any revisions to the toxicological endpoints, PODs, or UFs will also be incorporated in the occ upational assessments

.

Public Health and Pesticide Epidemiology Data

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

, D 426277 , E. Evans et al

, Metiram : Tier I (Scoping) Review of Human Incidents ) based on examination of the OPP Incident Data System (IDS) and the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System for Occupational Risk

- Pesticides (SENSOR) databases for pesticide incident

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 17 of 40 data on the active ingredient metiram The purpose of the database search was to identify potential patterns in the frequency and severity of the health effects attributed to metiram exposure. Metiram is not included in th e Agricultural Health Survey (AHS). The Tier I incident report concluded the following: Because there were no incident cases reported for metiram to
either IDS or SENSOR

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

warrant furt her investigation. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the risk assessment.

Tolerance Assessment and International Harmonization

Pe rmanent tolerances are est ablished under 40 CFR §180. 21 7(a) for residues of metiram on apples, potatoes, bananas, and wine grapes (expressed as CS 2 

### ). There are no tolerances

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

r esidues to live stock tissue from treated feedstuffs ( 40 CFR § 180.6(a)(3) , no expectation of finite residues)

.

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

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

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

Codex which have harmonized tolerance definitions with the U.S. (residues measured as CS 2 

### ).

All U.S. toleranc e levels are harmonized with the Codex MRLs to the greatest extent possible. Despite the Codex inclusion and measurement of total dithiocarbamates , the tolerances not harmonized with Codex MRLs are primarily due to variation in use patterns.

A spreadsheet summarizing the U.S. and international residue limits established for metiram is presented in Attachment 4.

Cumulative

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not ma de a common mechanism of toxicity finding as

to metiram and any other substances . Metiram does produce a toxic metabolite, ETU, which is produced by other EBDC compounds. Risks from combined exposures to ETU from all EBDC compounds are addressed in a sep arate ETU aggregate risk assessment . For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by
EPA’s Office of Pe sticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on
EPA’s website at http://www.epa.gov/pesticides/ cumulative/.

International or Intergovernmental Work Sharing

There are no current or planned international or interagency work sharing efforts for metiram.

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 18 of 40 Data Requirements

Toxicology

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

remain s outstanding:

G uideline 870.3700 b : D evelopmental toxicity study (rabbits).

Residue Chemistry

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

Guideline 860.1200 Directions for Use : The 860.1200 data requirements (submission of amended labels) remain outstanding for banana, grape.

Guideline 860.1560 Reasonable Grounds in Support of the Petition : R evision of the foreign label, or the submission of field trial dat a which support an alternate pattern of use, as per the requirement listed for banana under 860.1200 Directions for Use remains outstanding.

The following new data requirement s w ere identified by HED during this registration review scoping exercise for m etiram :

Guideline 860.1200 Directions for Use : S ubmission of amended labels are required for the potato use.

Anticipated Residues /Monitoring study (non

- guideline study) : Updated anticipated residue/monitoring data are needed to support the dietary assessments of the EBDC pesticides, including metiram. The 1990 EBDC market basket survey previously used to refine the dietary assessments m ay be outdated, and any changes in application technique s, typical rates, handling, storage, and transportation could result in incurring different residue levels today than those reported in the 1990 survey. To allow for the continued use of the survey in future dietary assessments, the EBDC registrants must provide justification as to whether current good agricultural practices would result in yielding comparable residues as those found in the survey. If based on this information HED concludes that the market basket data are no longer reflective of current r esidues, a new market basket survey should be conducted. In that event, until adequate updated market basket data are submitted, HED will rely on data from available controlled studies (e.g. field trial data, processing studies), which will likely result in significantly greater risk estimates that may exceed the levels of concern.

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 19 of 40 R eferences

D291663, Metiram: 2nd Revised Occupational and Residential Exposure Assessment and Recommendations for the Reregistration Eligibility Decision Document, T. Dole, 6/8/2005.

D291661, Metiram. Health Effects Division (HED) Human Health Risk Assessment to Support Reregistration , K. Farwell, 6/13/2005.

D 318476

, Metiram. Revised Residue Chemistry Chapter of the Reregistration Eligibility Decision, C. Olinger, 6/23/200 5.

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

D323143 and D323141, Estimated Drinking Water Concentrations of ETU (Ethylene

- thio

- urea, degradate of mancozeb, and common degradate of EBDCs “Ethene

- bis

- dithio

- carbamates”) for Use in Human Health Risk Assessment. M. Ruhman and R. Parker, 8/11/2006.

D326753, Metiram Acute, Chronic, and Cancer Dietary Exposure Assessments for New Tolerances on Imported Grapes and Bananas, C. Olinger, 4/17/2007.

D267866, Metiram: Human Health Risk Assessment for PP#9E6006. Petition for the Establishment of Import Tolerances on Grapes and Bananas , T.Goodlow, 6/14/2007.

D412565 and D412566, Mancozeb. Revised Acute, Chronic, Cancer Dietary Risk Assessments for Food and Drinking Water, as well as Aggregate Assessment for the Common Metabolite/Degradate ETU Resulting from the Combined Uses of the EBDC Fungicides to Support the New Use of Mancozeb on Walnuts and the Establishment of a Tolerance on Imported Tangerines for Section 3 Registration, P. S avoia, 07/01/2013.

D412678, Ethylene Thiourea (ETU); Aggregate Human Health Risk Assessment of the Common Metabolite/Degradate Ethylene Thiourea (ETU) to Support Proposed New Section 3 Use on Walnuts and Tolerance for Imported Tangerines). D. Drew, 7/3/20 13.

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

TXR 0055055, Metiram : Summary of Hazard and Science Policy Council (HASPOC) Meeting of April 30 , 2015: Recommendation on the Requirements for Subchronic Neurot oxicity and Immunotoxicity Studies.

D425216, Mancozeb: Human Health Risk Assessment Scoping Document in Support of Registration Review, D. Drew, 6/1 /2015.

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 20 of 40 Attachments

Attachment 1. Chemical Identity

Attach ment 2. Toxicity Profile Tables Attachment 3. Endpoint Tables

Attachment 4. International Residue Limits

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 21 of 40 A ttachment 1. Chemical Identity

Physical and Chemical Properties of Metiram (a mixture of 5.2 parts by weight of ammoniates of [ethylenebis (dithiocarbamato)] zinc with 1 part by weight ethylenebis [dithiocarbamic acid] bimolecular and trimolecular cyclic anhydrosulfides and disulfides);

Table A 1

. 1 Metiram Nomenclature.

Compound

Common name Metiram

Company experimental name BAS 222 F

IUPAC name zinc ammoniate ethylenebis(dithiocarbamate)

- poly(ethylenethiuram disulfide)

CAS name mixture of 5.2 parts by weight of ammoniates of [ethylenebis(dithiocarbamato)]zinc with 1 part by weight ethylenebis [dithiocarbamic acid] bimolecular and trimolecular cyclic anhydrosul fides and disulfides

CAS registry number 9006

- 42

- 2

End

- use products (EPs) used in

residue field studies 70% WG (BAS 222 28 F; Polyram DF Fungicide) 55% WG (BAS 518 00 F)

Table A1

. 2 Physicochemical Properties of Metiram.

Parameter Value Reference

Melting point/range decomposes at ~140 oC Product Chemistry Chapter of the Metiram Update,

8/11/1992 pH Not applicable because of low water solubility; titrations with acid/base will not yield reliable pH values.

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

Water solubility practically insoluble (2 mg L at 20 oC)

Solvent solubility 8 x 10

- 3 g/100g ethanol at 20 oC; insoluble in acetone, benzene, and ethyl alcohol

Vapor pressure <1 x 10

- 7 mbar at 20 °C

Dissociation constant, pK a Not applicable; titrations with acid/base will not yield reliable pKa values.

Octanol/water partition coefficient, Log(K OW ) 1.76

- 2.48 at pH 7 and 21 oC

UV/visible absorption spectrum Not available

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 22 of 40 Attachment 2. Toxicity Profile Tables

METIRAM Toxicity Profile

Table A2 .1. Acute Toxicity of Metiram

Guideline No. Study Type MRIDs # Results Toxicity Category

870.1100 Acute Oral

– rat 40497002

40497005 LD 50 = >5000 mg/kg IV

870.1200 Acute Dermal

– rabbit 40497007

40497008 LD 50 = >2000 mg/kg III

870.1300 Acute Inhalation

– rat 40497010 LC 50 = 5.7 mg/L IV

870.2400 Primary Eye Irritation 40497012 not an eye irritant III

870.2500 Primary Skin Irritation 40497004 not a skin irritant IV

870.2600 Dermal Sensitization 40497006 strong

- to

- severe dermal

sensitizer N/A

870.6100 Acute Delayed

Neurotoxicity

– hen - - N/A

870.6200 Acute Neurotoxicity 48068801 LOAEL = 2000 mg/kg, based on decreased motor activity and

an increase in the number of

rearings N/A



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

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3100 90

- Day oral

toxicity (Sprague

Dawley CFY rat) 00126738 (1977)

40290601 (1987)

Acceptable /guideline (0, 50, 100, 300, 900 ppm) Males: 0, 3, 6, 20, 61 mkd

Females: 0, 4, 8, 24, 76

mkd NOAEL (Thyroid effects) = Not determined, based on decreased [ 131 I] uptake in males at all

dose levels. LOAEL (Thyroid effects) = 50 ppm (males 3/females 4 mg/kg/day), the lowest dose tested (LDT). At 900 ppm, 2/15 males had follicular cell hyperplasia

Systemic NOAEL =100 ppm (8 mg/kg/day) Systemic LOAEL =300 ppm (24 mg/kg/day),

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

decreased [ 131 I] uptake.

At the highest dose, 900 ppm (males 61, females 76 mg/kg/day), skeletal m uscle atrophy ( characterized by a narrowing of muscle fibers with reduced sarcoplasm and/or the presence of adipose
cells in muscle bundles) were seen in both sexes, ↓T4 (4/15 ♂; 11/15 ♀), and females also had hindlimb paralysis (stilted and rolling hindlimb gait, impa ired reflexes (grip, righting, flexor)

.

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 23 of 40 Table A2.2 METIRAM Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3100 90

- Day oral

toxicity (Wistar rat) 42539101 (1992)

Acceptable /guideline 0, 5, 80, 320, 960 ppm Males: 0, 0.4, 5.8, 23.5, 73.9 mg/kg/day Females: 0, 0.4, 6.7, 27.3, 88.8 mg/kg/day NOAEL = 5 ppm (0.4 mg/kg/day) LOAEL = 80 ppm (6.7 mg/kg/day), based on reduced forelimb grip strength in females.

At the highest dose (males 74, females 89 mg/kg/day) both sexes had ↑ thyroid weight and ↓ T 4 values. At all doses, both sexes, ↑ TSH was seen, but with no dos e

- response.

870.3100 90

- Day oral

toxicity (B6C3F1 mouse) 42595001 (1992)

Acceptable /guideline 0, 300 , 1000, 3000, 7500

ppm Males : 0, 84 , 302, 853, 2367 mg/kg/day

Females : 0, 133

, 465

, 1448

, 3565 mg/kg/day NOAEL = 300 ppm (males 84/females 133 mg/kg/day); LOAEL = 1000 ppm (males 302/females 465 mg/kg/day), based on the decrease in total

serum T 4 concentrations in both sexes and decreased body

- weight gain in females.

T hyroid lesions [hypertrophy and vacuolation of the follicular epithelium] were observed only at the two highest dose levels in both sexes [dose

- related for severity; all rats in these groups display both lesions].

870.3150 90

- Day oral

toxicity (dog) No study available; see chronic

870.3150 90

- Day oral

toxicity (monkey) 00031591 (1979)

Acceptable /non

- guideline

0, 5, 15, 75 mg/kg/day 26 weeks (gavage) NOAEL = not established; LOAEL = 5 mg/kg/day, based on decreased levels of iodine in the thyroid at weeks 1 and 8.

At the two highest doses, the following were observed: ↑ thyroid weight; minimal thyroid follicular hyperplasia; ↓ T 3 and T 4 levels, ↓ total plasma iodine; ↑ protein

- bound plasma iodine levels; ↑ iodine in the thyroid; and ↓ body

weight gain.

870.3200 21/28

- Day dermal

toxicity (species) 404797001 (

Acceptable Systemic NOAEL = not established; however, an assessment of effects on the thyroid, the target organ was not performed Dermal NOAEL = 50 mg/kg/day; Dermal LOAEL = 250 mg/kg/day, based on

local dermal irritation.

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Page 24 of 40 Table A2.2 METIRAM Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3465 90

- Day inhalation

toxicity (Sprague

Dawley CD rat) 00164083 (1986)

40044701 (1986) 40713301 (1987) Acceptable/guideline

0 , 2.1, 20, and 101 mg/m3 [mean aerodynamic

diameter of 3.1±1.8 microns]. ETU 0, 0.2, 0.32, 1.8 mg/m3 6 hr/day, 5 days/wk

Acceptable NOAEL = 2.1 mg/m 3 ; (0.5 mg/kg/day) LOAEL = 20 mg/m 3 ; (5.1 mg/kg/day) based on ↓ body

- weight gain in both sexes & the occurrence of alveolitis in the lungs of both

sexes.

Slight, non

- significant, decreases were observed in T4 values at the high

- dose level in

both sexes. TSH values were decreased in both sexes at the high

- dose level compared to the controls, and T3 values were comparable to the control values in both sexes at the high

- dose

level. HDT, decreased terminal BW (males 17%) and increased lung weight (both sexes).

870.3700a Prenatal

developmental in [Sprague

- Dawley

Crl:COBS CD SD
BR rats] 00030565 (1979)

Acceptable

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

GD 6

- 15 Maternal NOAEL = 80 mg/kg/day; Maternal LOAEL = 160 mg/kg/day, based on decreased body

- weight gain. Developmental NOAEL = 80 mg/kg/day Developmental LOAEL = 160 mg/kg/day, based on increased pre

- and post

- implantation losses, decreased litter size, decreased litter weight hydrocephaly and related lesions, skeletal system defects and other gross defects. RF: @150 mkd, increased activity, slight impairment of grasping and hindlimb support reflexes, lethargy, catalepsy, paralysis and death (days 6

- 8) at 300

- 1200 mkd.

870.3700b Prenatal

developmental in [Himalayan Chbb:HM rabbit] 40711401 (1988)

Unacceptable /non

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

GD 7

- 19 Maternal NOAEL = 10 mg/kg/day, Maternal LOAEL = 40 mg/kg/day, based on

abortions.

There was excessive maternal toxicity at the highest dose : one death on GD 28, 8 abortions (GD 21

- 28) and negative body

- weigh t gain),

and the mid

- dose does displayed a similar, but less severe, toxicity [ 2 abortions (GD 26, 27) and negative body

- weight gain during the dosing period).

Developmental NOAEL = not established Developmental LOAEL = not established

abortions were obse rved at 40 and 120 mkd. (The heads of the fetuses were not examined)

DATA GAP

- Study is Required (Unacceptable

because the heads of the fetuses were not examined. The maternal animal was adequately assessed in this study.)

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Page 25 of 40 Table A2.2 METIRAM Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3800 Reproduction and

fertility effects

( Crl:COBS CD (SD) BR rat ) 00098431

Unacceptable /non

guideline

0 , 5, 40, 320 ppm

Males : 0.2 , 1.8, 14.2 mg/kg/day

Females : 0.3

, 2.3, 19.8 mg/kg/day. Diet 60 days pre

- mating; 1♂:2♀ mating; 2 generations /2 litters/generation Maternal NOAEL = 40 ppm (2.2 mg/kg/day); Maternal LOAEL = 320 ppm (19.8 mg/kg/day), based on decreased body

- weight during gestation and lactation.

Reproductive NOAEL = 40 ppm (males 1.8/females 2.2 mg/kg/day); Reproductive LOAEL = 320 ppm (males

14.2/females 19.9 mg/kg/day), based on decreased mating performance in the F2 generation.

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

tested.

Previous DATA GAP

- Study available is Unacceptable because of the lack of one

- to

- one pairing and lack of histopathological examination of reproductive and target organs)

. ETU EOGRTS satisfies reproductive toxicity study requirement for metiram.

870.4100a Chronic toxicity

[CD Sprague

Dawley rat] 00098449 (1981)

00098450 (1981) 41163102 (1989) Acceptable /guideline for chronic phase with MRID

42539101*

0, 5, 20, 80, 320 ppm Males: 0, 0.2, 0.8, 3.1, 12.3 mg/kg/day Females: 0, 0.2, 1.0, 3.8, 15.5 mg/kg/day NOAEL* = 5 ppm (0.4 mg/kg/day); LOAEL* = 80 ppm (6.7 mg/kg/day), based on reduced forelimb g rip strength in females. *Endpoint and dose from subchronic bridging study in Wistar rats.

In SD rats at the highest dose tested in the chronic study (320 ppm; 12.3/15.5 mg/kg/day for males/females), increased thigh muscle atrophy was observed in both sex es. The Wistar rat endpoint is consistent with this finding.

870.4100a Chronic toxicity

[Strain] rat

870.4100b Chronic toxicity

(Beagle dog) 42133101 (1991)

42491401 (1992) Acceptable /guideline 0, 30 , 80, 1000, 3000 ppm

Males : 0.91 , 2.49, 29.84, 76.85 mg/kg/day

Females : 0, 1.05

, 2.69, 29.89, 92.69 mg/kg/day

one year. NOAEL = 80 ppm (males 2.49, females 2.69 mg/kg) LOAEL = 1000 ppm (males 29.8, females 29.9 mg/kg), based on decreased body

- weight gain/food consumption, changes in hematology/clinical chemistry parameters indicative of thyroid toxicity (↓T4 in males) /anemia, increased thyroid weight and follicular (thyroid) hyperplasia (all dogs)

. At HDT, ↓T4 (both sexes), increased thyroid weight (both sexes), thyroid follicular hyp erplasia in all dogs.

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Page 26 of 40 Table A2.2 METIRAM Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.4200 Combined

Chronic/

Carcinogenicity ( CD Sprague

Dawley rat) 00098449 (1981)

00098450 (1981)

4116310 2 (1989) Acceptable /guideline for chronic phase (see under 870.4100a) Unacceptable/guideline for carcinogenicity

component; guideline not

satisfied

0, 5, 80, 320 ppm Males: 0, 0.2, 0.8, 3.1, 12.3 mg/kg/day Females: 0, 0.2, 1.0, 3.8, 15.5 mg/kg/day Lack of any significant effect on survival, body

- weight, or body

- weight gain, indicates the rats could have tolerated higher dose levels.

HED concluded the dose levels were inadequate for assessing carcinogenic potential.

870.4300 Carcinogenicity

(CFLP mouse) 00030245 (1979)

41163101 (1976) 4

- week Unacceptable /guideline

0, 100, 300, 1000 ppm Males: 0, 8, 24, 79 mg/kg/day

Females: 0, 9, 29, 95 mg/kg/day No significant, treatment

- related, findings in either sex. Dose levels were inadequate for determining the carcinogenic potential of metiram, and there was an inadequate microscopic examination of tissues. There was

no assessment of thyroid function, i.e., T 3 , T 4 , and TSH values and [ 131 I] uptake were not determined. Organ

- weight data were not provided. No microscopic lesions were reported in the thyroid, and no treatment

related thyroid tumors were observed. The

CARC concluded t his study is Unacceptable.

Gene

Mutation

870.5100 Salmonella

typhimurium

TA98, TA100, TA1535, TA1537,

TA1538 Negative±S9

Mammalian

cell forward

gene mutation

assay

870.5300 CHO/HGPRT

SD

- rat 00148682 (1985)

Acceptable/guideline

0.681

- 100 μg/mL P ositive without S9, marginally positive with

S9.

Gene

Mutation

870.5100 mouse host

mediated

TA 1530 as

indicator strain and

CD

- 1 mice as host 00148680 (1985)

Acceptable

dose levels of 0, 500, 670 and 5000 mg/kg Negative

In vitro

chromosomal

aberration

assay

870.5375 Chinese hamster

ovary (CHO) cells (+/

- S9) Weak, but concentration

- related increases in

SCEs ±mouse S9 and

– rat S9

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Page 27 of 40 Table A2.2 METIRAM Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

Structural

chromosomal

alterations (rat bone marrow) cytogenetics

and in vivo

chromosomal

aberrations single 2.4 gm/kg

or 5 x 0.2 gm/kg/day in male

rats

- 00163786 (1986)

Acceptable/guideline Negative

- no significant increases in

chromosomal aberrations in bone marrow cells sampled over complete mitotic cycle

In vivo

mouse micronucleus

assay

870.5395 CD

- 1 mouse

Other Effects

870.5500 DNA damage in

Bacillus subtilis

Other Effects

870.5900 Chinese hamster

ovary cells

in vitro sister

chromatid exchange assay (SCE/CHO) 00148681 (1985)

Acceptable /guideline Positive for SCE induction both with and without mouse S9; dose levels up to 100 μg/mL without S9 and up to 200 μg/mL with S9; negative up to cytotoxic doses with rat S9

Other

Genotoxic

Effects

[870.5550] Unscheduled DNA

Synthesis

Rat primary hepatocyte

dose range of

0.492

- 49.2 μg/mL 00149528 (1984) Negative

- did not induce unscheduled DNA synthesis

870.6200a Acute

neurotoxicity screening battery

rat 48068801 (2010)

Acceptable/gu ideline

0, 125, 500, 2000 mg/kg NOAEL= 500 mg/kg.

LOAEL = 2000 mg/kg, based on decreased motor activity in both sexes on Day 0 (6 hours post dose) and an increase in the number of rearings on Day 0 (2 hours post dose) in males compared to the concurrent controls following acute oral exposure.

870.6200b Subchronic

neurotoxicity screening battery

Rat Study requirement waived (HASPOC 4/30/15 meeting; TXR 0055055 )

870.6300 Developmental

neurotoxicity See ETU EOGRTS

(MRID 49140301)

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Page 28 of 40 Table A2.2 METIRAM Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.7485 Metabolism and

pharmacokinetics (CD rat) 00155160 (1985)

40645501 (1983) Acceptable/guideline 5 and 50 mg/kg single 5 mg/kg/day repeat (14

- day) Rapidly absorbed and eliminated via urine, feces and expired air. At 5 mg/kg, males excreted 37%, 65%, 0.4%; females 47%, 54%, 1.1% in urine, feces, expired air, respectively after 7 days. At 50 mg/kg, males excreted 21%, 79%, 0.5%; females 25%, 72%, 1.1%, respectively after 7 days. Repeat 5 mg/kg/day similar to results after single dose ETU comprised 30% of the 0

- 24 hour urine radioactivity;

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

absorbed. Accumulation in tissues after repeated administration: thyroid, GIT, and kidneys had highest levels

870.7600 Dermal penetration

(rat) 000155161 (1984)

870.7800 Immunotoxicity

[Species/strain] Study requirement waived (HASPOC 4/30/15 meeting; TXR 0055055 )



### ETU Toxicity Profile

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

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3100 90

- Day oral

toxicity (Crl:CD(SD) rat) 000160704/1986

Acceptable/non

- guideline 250 ppm males: 14.28 mg/kg/day females: 17.81 mg/kg/day NOAEL = <14.28 mg/kg/day LOAEL = 14.28 mg/kg/day, based on reduced body weight, changes in thyroid hormone and TSH levels, increased thyroid and liver weight, microscopic thyroid hyperplasia and liver hypertrophy.

870.3100 90

- Day oral

toxicity (CD

- 1 mouse) 00154192/1985

Unacceptable/Guideline 0, 1, 10, 100, 1,000 ppm males: 0, 0.16, 1.72, 18.18, 168.2 mg/kg/day females: 0, 0.22, 2.38, 24.09, 231.1 mg/kg/day NOAEL = 1.72 mg/kg/day LOAEL = 18.18 mg/kg/day, based on microscopic thyroid hypertrophy/hyperplasia.

At the high dose, more microscopic thyroid changes and increases in thyroid and liver weight occurred. Unacceptable because ETU concen trations varied widely.

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 29 of 40 Table A2.3 ETU Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3150 90

- Day oral

toxicity (Beagle dog) 42174201/1991

Acceptable/Guideline 0, 10, 150, 2000 ppm males: 0, 0.39, 6.02, 66.23 mg/kg/day females: 0, 0.42, 6.51, 71.62 mg/kg/day NOAEL = 0.39 mg/kg/day LOAEL = 6.02 mg/kg/day, based on elevated cholesterol. (Note: this endpoint was not considered robust enough for use in risk assessment) At 6.02 mg/kg/day, no thyroid effects were

observed. In high dose group: mortality, anemia, decreased activity, decreased thyroid hormone

lev els, increased thyroid weight, microscopic thyroid hyperplasia.

870.3150 4

- Week Range

finding (Beagle dog) 41863401/1989

Acceptable/non

- guideline 0, 196, 980, 4900 ppm males: 0, 7.0, 34, or 172 mg/kg/day females: 0, 8.0, 36, or 197 mg/kg/day NOAEL = 7 mg/kg/day LOAEL = 34 mg/kg/day, based on decreased levels of thyroid hormones, gross thyroid

lesions. At HDT, decreased body weight and food consumption in addition to thyroid effects. Histopathology and organ weights were not

assessed.

870.3200 21/28

- Day dermal

toxicity (species) Not presented to HASPOC since ETU is metabolite/degradate

Data requirement not applicable

870.3465 90

- Day inhalation

toxicity (species) Not presented to HASPOC since ETU is metabolite/degradate

Data requirement not applicable

870.3700a Prenatal

developmental in [SD BR rat] 00093929/1980

Acceptable/non

- guideline Maternal NOAEL = <50 mg/kg/day Maternal LOAEL = 50 mg/kg/day, based on decreased body weight gain (↓36%).

Developmental NOAEL = <50 mg/kg/day Developmental LOAEL = 50 mg/kg/day, based on numerous central nervous system defects (hydrocephaly and related malformations); gross developmental defects; skeletal defects; and decreased fetal weight (↓13%).

Only one dose group was included in the study.

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Page 30 of 40 Table A2.3 ETU Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3700a Prenatal

developmental in [Wistar rat] 45937601/1973

Acceptable/Non

- guideline [Khera, K.S. 1973. Teratology 7:243

- 252]

0, 5, 10, 20, 40, 80 mg/kg/day

Dosing: 21

- 42 days before conception to pregnancy day 15, and on days 6

- 15

or 7

- 20 of pregnancy Maternal NOAEL = 40 mg/kg/day Maternal LOAEL = 80 mg/kg/day, based on mortality (9 of 11after 7

- 8 days).

Developmental NOAEL = 5 mg/kg/day Developmental LOAEL = 10 mg/kg/day based on exencephaly, dilated ventricles, and hypoplastic cerebellum.

At 20 mg/kg/day, hydrocephalus, encephalocele, meningocele, micrognathia, abnormal flexion of ankle, kinky or twisted tail; at ≥40 mg/kg/day: oligodactyl, domed head, retarded ossification of the skull occurred; at 80 mg/kg/day: coloboma of the eyelids

, hemimelia, syndactyl, cleft palate, ectopic kidney, rudimentary calvarium, short tail, scoliosis and several types of skeletal anomalies occurred. Decreased fetal weight was noted at 40 mg/kg/day in group I (↓10%) and group III (↓21%) and at 80 mg/kg/da y in group II (↓44%). Fetuses at 40 mg/kg/day in group II had weights comparable to controls. Number of live fetuses and corpora lutea were comparable to controls in all groups.

870.3700a Prenatal

developmental in [Sprague

- Dawley
rats] 45924404/1979

[Chernoff, et al., J.

Toxicol. Env. Health 5:

821

- 834]

0, 5, 10, 20, 30, 40, or 80 mg/kg/day (GD 7

- 21)

0, 20, 25, or 30 mg/kg/day (GD 7 to PND 15) Maternal NOAEL = 40 mg/kg/day (or lower). Maternal LOAEL = 80 mg/kg/day, based on

reduced b ody weight and 25% maternal mortality. Gestational exposure only : Developmental NOAEL = 10 mg/kg/day (↓7% fetal BW) Developmental LOAEL = 20 mg/kg/day, based on hydrocephalus (12 fetuses/5 litters).

Decreased ossification was also observed at 30 mg/kg/day and above; at 40 mg/kg/day, encephalocele, kyphosis, and digit defects (oligodactyl, syndactyl) were also observed. At 80 mg/kg/day, fetal mortality was increased and there were increases in cleft palate, limb defects (micromelia, hemimelia), edema, and

mi crognathia. Gestational and postnatal exposure : Postnatal toxicity at 30 mg/kg/day included hydrocephalus, dome

shaped heads, and pup mortality.

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Page 31 of 40 Table A2.3 ETU Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3700a Prenatal

developmental in [Wistar rat] MRID 48985801

[Khera and Tryphonas Tox Appl Pharm 42:85

- 97. 1977]. Acceptable/non

- guideline

0, 15, 30, 45 mg/kg Dams received a single oral dose on gestation day 15. Maternal NOAEL/LOAEL not reported

Developmental NOAEL = 15 mg/kg Developmental LOAEL = 30 mg/kg based on postnatal mor tality, hydrocephaly, microphthalmia, cerebellar dysplasia, cerebral atrophy, and in survivors, motor defects and

dome

- shaped head.

870.3700a Prenatal

developmental in [Wistar rat] No MRID

[Ruddick and Khera. Teratology 12:277

- 282, 1975] Acceptable/non

- guideline 0 or 240 mg/kg Dams received a single dose on one gestation day

between GD 6

- 21 No maternal toxicity observed. Teratogenic effects in fetuses from GD 10

- 21; greatest frequency of defects between GD 12

- 15; no defects before GD 10; E TU affected development of brain, kidney, eye, and axial and appendicular systems

870.3700a Prenatal

developmental in [SD rat] No MRID

Saillenfait, et al., Fund. Appl. Toxicol. 17: 300

- 408, 1991 Acceptable/non

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

from GD 6

- 20 Maternal NOAEL not attained. Maternal LOAEL = 15 mg/kg/day, based on decreased body weight gain Developmental NOAEL = 15 mg/kg/day Developmental LOAEL = 25 mg/kg/day, based on dilated ventricles of the brain, hydroureter, short/kinky tail, and dil ated ureters. At 35 mg/kg/day, hydrocephaly, anencephaly, meningocele, meningorrhea, hyrdronephrosis, dilated renal pelvis, and vertebral abnormalities

were observed.

870.3700a Prenatal

developmental in [Wisrar Imamichi
rat] 45924405/1978

[Teramoto, et al., Congenital Anomalies 18:

11

- 17, 1978] Acceptable/non

- guideline 0, 10, 20, 30, 40, 50 mg/kg/day

GD 6

- 15. Developmental NOAEL <10 mg/kg/day Developmental LOAEL = 10 mg/kg/day, based on dilated brain ventricles. At higher doses, fetal death, meningocel e, micrognathia, hydronephrosis, renal agenesis, uterine hypoplasia, skeletal anomalies, short/kinky tail,

and scoliosis were observed.

870.3700b Prenatal

developmental in [New Zealand White rabbit] 47976403/2010

Acceptable/Guideline 0.5% aqueous methylcellulose 0, 5, 15, 50 mg/kg/day

GD 7

- 29 Maternal NOAEL = 5 mg/kg/day Maternal LOAEL = 15 mg/kg/day based on increased postimplantation loss

Developmental NOAEL = 5 mg/kg/day Developmental LOAEL = 15 mg/kg/day based on increased postimplantation l oss At 50 mg/kg/day, postimplanation loss, decreased fetal BW (↓10%), hydrocephaly (1), and domed head (2) were observed.

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Page 32 of 40 Table A2.3 ETU Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3700b Prenatal

developmental in
[ Syrian Golden

hamsters 45924405/1978

Acceptable/non

- guideline [Teramoto, et al., Congenital Anomalies 18:

11

- 17, 1978] 0, 90, 270, 810 mg/kg/day

from GD 6

- 13. Developmental NOAEL = 90 mg/kg/day Developmental LOAEL = 270 mg/kg/day,

based on skeletal malformations and short/kinky tail. At 810 mg/kg/day, fetal deaths, dilated brain ventricles, cleft palate, micrognathis, and anal atresia were observed.

870.3700b Prenatal

developmental in
[ JCL

- ICR mouse ] 45924405/1978

Acceptable/non

- guideline [Teramoto, et al., Congenital Anomalies 18:

11

- 17, 1978]

0, 200, 400, or 800 mg/kg/day.

GD 7

- 15 No maternal or developmental toxicity was

observed.

870.3800 Reproduction and

fertility effects (Sprague

- Dawley rat) 42391701/1992

Unacceptable/Non

guideline

42391801/1992

ETU content data 0, 2.5, 25, 125 ppm Doses on mg/kg/day basis could not be

determined.

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

dose groups.

No reproductive effects attributed to treatment.

Unacceptable because of stability problems (mkd could not be calculated) with test material and poor record keeping.

870.3800 Reproduction and

fertility effects (Crl:CD(SD) rat) 49140301/2013

Acceptable/OECD guideline 0, 2.8, 28, 140 ppm 0, 0.2, 2, 10 mg/kg/day 4 weeks prior to mating;

14

- day mating period), through gestation, lactation to weaning; Parental males from day

44 for 7 weeks until

sacrifice Parental females through gestation/lactation (LD 0

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

LOAEL = not attained. No effects on reproductive indices, precoital intervals, gestation length, gonadal function, estrous cycle, sperm maturation, parturition, lactation, or tissues and organs of the reproduction system.

870.4100a Chronic toxicity

Fischer 344 rat 45924403/1992

Fund. Appl. Tox. 18: 405

- 417 (feeding NTP) w/ and w/out perinatal Thyroid follicular cell adenomas and pituitary

adenomas were observed.

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Page 33 of 40 Table A2.3 ETU Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.4100b Chronic toxicity

(Beagle dog) 42338101/1992

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

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

870.4200 Combined

Chronic/

Carcinogenicity (SD rat) 42607801/1992

Unacceptable/Guideline 0, 0.5, 2.5, 5.0, or 125

ppm Males: 0, 0.04, 0.17, 0.37,

8.91 mkd Females: 0, 0.05, 0.25, 0.49, 13.57 mkd Concentration of ETU in feed varied widely

and doses could not be determined. Microscopic thyroid hyperplasia occurred in

the low

- dose group. At higher doses, changes in thyroid hormone and TSH levels, increased thyroid weight, and grossly enlarged livers

. Increases in thyroid follicular adenomas and pituitary adenomas in high

- dose males.

870.4300 Carcinogenicity

(B6C3F1 mouse) 45924403/1992

Fund. Appl. Tox. 18: 405

- 417 (feeding NTP) w/ and w/out perinatal

exposure This study was used to determine the Q1* for

ETU of 6.01 x 10

- 2 (mg/kg/day)

- 1 based upon

female mouse liver adenomas and/or carcinomas. Thyroid follicular cell adenomas and carcinomas, hepatocellular adenomas and carcinomas, and pituitary adenomas were

increased.

870.6200a Acute

neurotoxicity screening battery

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

the peripheral nerves is observed in studies following exposure to mancozeb

and metiram but not to ETU.

870.6200b Subchronic

neurotoxicity screening battery

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

the peripheral nerves is observed in studies following exposure to mancozeb

and metiram but not to ETU.

870.6300 Developmental

neurotoxicity

[Crl:CD(SD) rat] 49140301/2013

Acceptable/OECD guideline 0, 2.8, 28, 140 ppm 0, 0.2, 2, 10 mg/kg/day 4 weeks prior to mating;

14

- day mating period), through gestation, lactation to weaning; Parental males from day

44 for 7 weeks until

sacrifice Parental females through gestation/lactation (LD 0

- 22) NOAEL = 28 ppm (2 mg/kg/day).
LOAEL = 140 ppm (10 mg/kg/day), based on

decreased brain size.

870.7485 Metabolism and

pharmacokinetics (species) Not required for metabolite

870.7600 Dermal penetration

( SD COBS CD rat ) 40312601/1987

Acceptable Dermal absorption = 26%

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Page 34 of 40 Table A2.3 ETU Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.7800 Immunotoxicity

[Wistar rat] 48794502/2012

Acceptable/Guideline 0, 10, 50, 250 mg/kg/day Males: 0, 1, 4, 19 mg/kg/day Negative for Immunotoxicity Thyroid toxicity observed at all dose levels.

OECD 443 Extended one

generation reproductive toxicity

[Crl:CD(SD) rat] 49140301/2013 Under Review

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 35 of 40 Attachment 3. Toxicity Endpoint Tables

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

Risk Assessment.

Exposure

Scenario Dose Used in Risk Assessment

and Uncertainty Factors RfD, PAD, LO C Study and Toxicological Effects

Metiram Dietary Exposures

Acute Dietary

Females 13

- 50 NOAEL = 10 mg/kg/day

UF = 100X (inter and intraspecies)
FQPA UF DB = 10x
Total UF = 1000X Acute RfD = 0.01 mg/kg/day

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

abortions.

Acute Dietary General Population N/A No appropriate endpoint attributable to a single exposure (dose) was

identified.

Chronic Dietary NOAEL = 0.4 mg/kg/day

UF=100X (inter and intraspecies)
FQPA UF DB = 10x
Total UF = 1000X Chronic RfD=0.0004 mg/kg/day

cPAD = 0.0004 mg/kg/day Subchronic Oral Toxicity (Rat, bridging study) LOAEL= 6.7 mg/kg/day based on decreased forelimb grip strength

Cancer [oral/dermal/inhalation] Q 1 * = 6.01x10

- 2 (mg/kg/day)

- 1 Metiram is classified as Group B2 carcinogen; use low

- dose extrapolation for human risk assessment, based on ETU.

Metiram Incidental Oral Exposures [Residential/Postapplication]

Short

- Term [1

- 30 days] NOAEL = 6.7 mg/kg/day UF = 100X (inter and intraspecies)
FQPA UF DB = 10x
Total UF = 1000X LOC

Residential MOE = 1000 Occupational MOE = N/A Subchronic Oral Toxicity (Rat, bridging study) LOAEL= 27.3 mg/kg/day based on decreased forelimb grip strength

Intermediate

- Term [30 days

- 6 months] NOAEL = 0.4 mg/kg/day UF = 100X (inter and intraspecies)
FQPA UF DB = 10x
Total UF = 1000X LOC

Residential MOE = 1000 Occupational MOE = N/A Subchronic Oral Toxicity (Rat, bridging study) LOAEL= 6.7 mg/kg/day based on decreased forelimb grip strength

Metiram Dermal Exposures

Short

- Term [1

- 30 days] NOAEL = 6.7 mg/kg/day UF = 100X (inter and intraspecies)
FQPA UF DB = 10x
Total UF = 1000X LOC

Residential MOE = 1000 Occupational MOE = 100 Subchronic Oral Toxicity (Rat, bridging study) LOAEL= 27.3 mg/kg/day based on decreased forelimb gr ip strength at early time point

Intermediate

- Term, Long

- Term [>30 days

- 6 months, > 6 months] NOAEL = 0.4 mg/kg/day UF = 100X (inter and intraspecies)
FQPA UF DB = 10x
Total UF = 1000X LOC

Residential MOE = 1000 Occupational MOE = 100 Subchronic Oral Toxicity (Rat, bridging study) LOAEL= 6.7 mg/kg/day based on decreased forelimb grip strength

Inhalation Exposures

Inhalation NOAEL = 0.5 mg/kg/day UF=100X (inter and intraspecies) LOC

Residential MOE = 1000 13

- week Inhalation Toxicity, Rat

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 36 of 40 Table A3.1. Metiram Toxicological Doses and Endpoints Used in Previous (2007) in Human Health

Risk Assessment.

Exposure

Scenario Dose Used in Risk Assessment

and Uncertainty Factors RfD, PAD, LO C Study and Toxicological Effects

(Any Duration, i.e., 1 day to more than 180 days) FQPA UF DB = 10x
Total UF = 1000X Occupational MOE = 100 LOAEL = 5.1 mg/kg/day based on lung lesions (alveolitis).

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no ob served 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 L = use of a LOAEL to extrapolate a

NOAEL. UF S = use of a short

- term study for long

- term risk assessment. 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. N/A = not applicable.

Table A3.2 Summary of Toxicological Doses and Endpoints for ETU Used in Dietary and Non

Occupational Human Health Risk Assessments

Exposure PoD Safety Factors RfD, PAD, LO C Study and Tox

ETU Acute Dietary Exposure Acute Dietary (General Pop, including Infants and Children) N/A N/A N/A A study with acute toxicity applicable to the general population was not

identified.

Acute Dietary (Females 13

- 49 years old) NOAEL= 5

mg/kg/day UF A = 10x

UF H = 10x FQPA UF DB = 10x Acute RfD = 0.0 0 5

mg/kg/day

aPAD = 0.005 mg/kg/day Developmental Rat Toxicity MRID No. 45937601 (1973) LOAEL = 10 mg/kg/day, based on hydrocephaly and other malformations

ETU Chronic Dietary Exposure Chronic Dietary (Females 13

- 49 years of age and

Children < 6 years) NOAEL=

0.18 mg/kg/day UF A = 10x

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

0.00 0 18 mg/kg/day

cPAD = 0.00018 mg/kg/day Dog Chronic Oral Toxicity MRID 42338101 (1992) LOAEL= 1.99 mg/kg/day based on thyroid toxicity

Chronic Dietary (Adult Males,

Females >49 years, Children ≥ 6 years) NOAEL=

0.18 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Chronic RfD = 0.0018

mg/kg/day

cPAD = 0.0018 mg/kg/day Dog Chronic Oral Toxicity MRID 42338101 (1992) LOAEL= 1.99 mg/kg/day based on thyroid toxicity

ETU Incidental Oral Exposure

Short

- Term Oral (Children < 6 years of age) NOAEL= 7

mg/kg/day UF A = 10x

UF H =10x FQPA UF DB = 10x LOC = 1000 4

- week range

- finding dog study MRID 41863401 (1989) LOAEL= 34 mg/kg/day based on thyroid toxicity ETU Residential Dermal Exposure

Dermal Short and

Intermediate

Term (Children` < 6 years of age) NOAEL= 7

mg/kg/day UF A = 10x

UF H =10x FQPA UF DB = 10x LOC = 1000 4

- week range

- finding dog study MRID 41863401 (1989) LOAEL= 34 mg/kg/day based on thyroid toxicity

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 37 of 40 Table A3.2 Summary of Toxicological Doses and Endpoints for ETU Used in Dietary and Non

Occupational Human Health Risk Assessments

Exposure PoD Safety Factors RfD, PAD, LO C Study and Tox

Dermal Short and

Intermediate

Term (Adult Males, Females >49 years, Children ≥ 6 years) NOAEL= 7

mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x LOC = 100 4

- week range

- finding dog study MRID 41863401 (1989) LOAEL= 34 mg/kg/day based on thyroid toxicity

Dermal Short and

Intermediate

Term (Females

13

- 49 years old) NOAEL= 5

mg/kg/day UF A = 10x

UF H =10x FQPA UF DB = 10x LOC = 1000 Developmental Rat Toxicity

MRID No. 45937601 (1973) LOAEL = 10 mg/kg/day, based on hydrocephaly and other malformations Dermal Long

Term (Females 13

- 49 years of age and

Children < 6 years) NOAEL=

0.18 mg/kg/day UF A = 10x

UF H =10x FQPA UF DB = 10x LOC = 1000 Dog Chronic Oral Toxicity

MRID 42338101 (1992) LOAEL= 1.99 mg/kg/day based on thyroid toxicity

Dermal Long

Term (Adult Males,

Females >49 years, Children ≥ 6 years) NOAEL=

0.18 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x LOC = 100 Dog Chronic Oral Toxicity MRID 42338101 (1992)

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

ETU Residential Inhalation Exposure

Inhalation Short

and Intermediate

Term (Children < 6 years of age) NOAEL= 7

mg/kg/day UF A = 10x

UF H =10x FQPA UF DB = 10x LOC = 1000 4

- week range

- finding dog study

MRID 41863401 (1989) LOAEL= 34 mg/kg/day based thyroid toxicity

Inhalation Short

and Intermediate

Term (Adult Males, Females >49 years, Children ≥ 6 years) NOAEL= 7

mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x LOC = 100 4

- week range

- finding dog study MRID 41863401 (1989)

LOAEL= 34 mg/kg/day based thyroid toxicity

Inhalation Short

and Intermediate

Term (Females

13

- 49 years old) NOAEL= 5

mg/kg/day UF A = 10x

UF H =10x FQPA UF DB = 10x LOC = 1000 Developmental Rat Toxicity MRID No. 45937601 (1973) LOAEL = 10 mg/kg/day, based on hydrocephaly and other malformations Inhalation Long

Term (Females

13

- 49 years of age and Children < 6 years) NOAEL=

0.18 mg/kg/day UF A = 10x

UF H =10x FQPA UF DB = 10x LOC = 1000 Dog Chronic Oral Toxicity MRID 42338101 (1992) LOAEL= 1.99 mg/kg/day based on thyroid toxicity

Inhalation Long

Term (Adult Males, Females >49 years, Children ≥ 6 years) NOAEL=

0.18mg/kg/d

ay UF A = 10x

UF H =10x FQPA SF= 1x LOC = 100 Dog Chronic Oral Toxicity MRID 42338101 (1992) LOAEL= 1.99 mg/kg/day based on thyroid toxicity

ETU Cancer Cancer (all routes) Q 1 * = 6.01 x

10

- 2 (mg/kg/day)

-

1 ETU is classified as a Group B2 carcinogen with a linear low

- dose extrapolation

approach for human risk assessment based on liver tumors in female mice.

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 38 of 40 Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no ob served 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 L = use of a LOAEL to extrapolate a

NOAEL. UF S = use of a short

- term study for long

- term risk assessment. 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. N/A = not applicable.

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

Human Health Risk Assessments

Exposure PoD Safety

Factors RfD, PAD, LoC Study and Tox

ETU Occupational Dermal Exposure

Dermal Short and

Intermediate

Term (Adult Males,

Females >49 years) NOAEL= 7

mg/kg/day UF A = 10 x

UF H =10x LOC = 10 0 4

- week range

- finding dog study MRID 41863401 (1989) LOAEL= 34 mg/kg/day based on thyroid toxicity

Dermal Short and

Intermediate

Term (Females

13

- 49 years old) NOAEL= 5

mg/kg/day UF A = 10x

UF H =10x

UF DB = 10x LOC = 1000 Developmental Rat Toxicity

MRID No. 45937601 (1973 ) LOAEL = 10 mg/kg/day, based on hydrocephaly and other malformations Dermal Long

Term (Females 13

- 49 years of age) NOAEL=

0.18 mg/kg/day UF A = 10 x

UF H =10x

UF DB = 10x LOC = 10 00 Dog Chronic Oral Toxicity MRID 42338101 (1992)
LOAEL= 1.99 mg/kg/day based on thyroid toxicity Dermal Long

Term (Adult Males,

Females >49 years) NOAEL=

0.18 mg/kg/day UF A = 10 x

UF H =10x LOC = 10 0 Dog Chronic Oral Toxicity MRID 42338101 (1992)
LOAEL= 1.99 mg/kg/day based on thyroid toxicity

ETU Occupational Inhalation Exposure

Inhalation Short

and Intermediate

Term (Adult Males, Females >49 years) NOAEL= 7

mg/kg/day UF A = 10 x

UF H =10x LOC = 10 0 4

- week range

- finding dog study MRID 41863401 (1989) LOAEL= 34 mg/kg/day based thyroid toxicity

Inhalation Short

and Intermediate

Term (Females

13

- 49 years old) NOAEL= 5

mg/kg/day UF A = 10x

UF H =10x

UF DB = 10x LOC = 1000 Developmental Rat Toxicity

MRID No. 45937601 (1973 ) LOAEL = 10 mg/kg/day, based on hydrocephaly and other malformations Inhalation Long

Term (Females

13

- 49 years of age) NOAEL=

0.18 mg/kg/day UF A = 10 x

UF H =10x

UF DB = 10x LOC = 10 00 Dog Chronic Oral Toxicity MRID 42338101 (1992)
LOAEL= 1.99 mg/kg/day based on thyroid toxicity Inhalation Long

Term (Adult Males, Females >49 years) NOAEL=

0.18mg/kg/da

y UF A = 10 x

UF H =10x LOC = 10 0 Dog Chronic Oral Toxicity MRID 42338101 (1992) LOAEL= 1.99 mg/kg/day based on thyroid toxicity

ETU Cancer Cancer (all routes) Q 1 * = 6.01 x

10

- 2 (mg/kg/day)

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

- dose extrapolation

approach for human risk assessment based on liver tumors in female mice.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 39 of 40 exposures. NOAEL = no ob served 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 L = use of a LOAEL to extrapolate a

NOAEL. UF S = use of a short

- term study for long

- term risk assessment. 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. N/A = not applicable.

### Metiram Registration Review Human Health Scoping Documen t D425218

Page 40 of 40 Attachment 4. International Residue Limits 

## Metiram (014601; 03/10/2015)

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 Codex

40 CFR 180.217: Metiram (a mixture of 5.2 parts by weight

of ammoniates of [ethylenebis (dithiocarbamato] zinc with 1 part by weight ethylenebis [dithiocarbamic acid] bimolecular and trimolecular cyclic anhydrosufides and disulfides), including its metabolites and degradates, in or on the

commodities in the followin g table. Compliance with the tolerance levels specified in this paragraph is to be determined by measuring only those

metiram residues convertible to and expressed in terms of the degradate carbon

disulfide. None Total dithiocarbamates,

determined as CS2

, evolved during acid digestion and expressed as mg

CS 2 /kg

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

US Canada Mexico 1 Codex Apple 0.5 5 pome fruits 3
Apple, pomace wet 2

Banana 2 3 2 3
Grape, wine 2 5 5 3 grapes
Potato 0.2 0.2 3

Completed: M. Negussie; 03/10/2015

1 Mexico adopts U

. S

. tolerances and/or Codex MRLs for its export purposes.

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

3 The MRL is based primarily on residue data for m etiram but does include data for the other dithiocarbamate active ingredients.