UNITED S TATE S ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

MEMORANDUM

Dat e: Se pt 3, 2015 OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION

SU BJE CT : R ev i se d. Thir a m

. Human Health Assessment Scop i ng Document in Support of

Registration Review.

P C Co d e: 07980 I OP Barcode: 427811

D ec i sio n No.: 505988 Registration No.: NA

Petition No.: NA R eg ulat ory Action: Registration Review

Ri s k Assessmen t T y p e: Single Chemical Aggregate Case No. : O 122

TXR No.: NA CAS No.: 137-26-8

M RID No.: NA 40 CF'R: § 180.132

FR OM : Denni s McNeilly

, Chemist/Risk Assessor 

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Kelly O ' Rourke,

## Occupational/Resident~'al Ex

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.**-Y~** Hannah Pope

- Varsalona, PhD

, Toxicolo

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.

### ~ Risk Assessment Branch IV /

He alth Effects Division (7509P)

T HRO UG H: Charles Smith, Acting Branch ChierC

·

## ~ Ri s k Assessment Branch IV

Health Effects Division (7509P)

TO: Wilhelm e na Livingston

Risk Management and Implementation Branch 4

Pesticide Reevaluation Division (7508P)

The HED Regi s tration Review Team has evaluated the human health assessment and database

for the fungicide thiram (tetramethylthiuram disulfide) to determine whether suffic i ent data are

available and i f any updates are needed to the human health risk assessment to support

Registration Review.

Thiram is a dimethyl dithiocarbamate compound used as a fungicide to prevent crop damage in

the field and to protect harvested crops (apples

, peaches, and strawberries) from deterioration in

s torage or transport. It is also used as a seed protectant (e.g. s mall seeded vegetab l es, large

s eeded v e getables

, cereal grains

, o th er seeds

, con if erous seeds

, cotton seed

, ornamental seeds,

a nd soybeans) and to protect turf from fungal diseases. In addition

, thiram is used as an animal

repell e nt to protect crops from damage by rabbits, rodents

, and deer. Tolerances for residues

i n/o n food and feed commodities are currently expressed in terms of r esidues of thiram (CFR

§ 180.132) and are established 20 ppm for s tr awberry

, avocado at 15 ppm

, and at 7 ppm for

apples

, p e ache s, and nectarines. /\ tolerance without US registration is estab li s hed forThirarn Registration Review Scoping Document

banana/p lant a in at 0.80 ppm. The seed treatment uses for thiram are co n s id ered to be nonfood

uses and

, therefore

, do not require a tolerance.

Thiram is avai l ab l e as du st, dry fl owable, we tt ab l e powder, flowable co n centrate

, soluble

concentrate, and liquid (ready to use) formu lati ons. It may be applied to peaches, strawbe1T i es

, and apples using ground and aerial equipmen t. For othe r specia lt y uses (i

. e. animal repellent) as

well as seed treatment, appl i cations may be made using hand held eq uipm e nt. Thiram may be

app li ed l-7 days before harvest depending on the crop

, geographic lo ca tion and pest.

R eside ntia l/ r ec r ea ti ona l exposure to thiram is expected as a result of playing golf o n golf course

fairways

, g r ee n s, a nd tees.

Exec u t i ve S umm ary

HED has considered the ava il able risk assess m e nt s for thi ram and its t oxicity, exposure and

usage databases

, as well as the most cunent Agency sc i e nc e and assessment policies. HED

perfo rm ed this eva lu a ti on in orde r to determine the scope of work n ecessary to support the

estab li shed tolerances and exist in g registrations during registration r eview. The prim ary so urc es

of information for this eva lu at i o n we r e the Thiram Human H ea lth Risk Assessmen t co ndu cted to

support t h e September 2003 USEPA Registration Eligibility Decision (RED) for Thiram, and the

recent May 2 1

, 20 1 5 Ri sk Assess m e nt to support an import tolerance for avocado (0427383

, T.

Mo rt on).

The toxicity database for thiram is comp l ete wi th the except i o n of a 28

- day i n h alation study.

The database i s sufficient fo r character i zat i o n of potential developmental, r eproductive,

carc ino ge n e tic

, muta genic

, and neurotoxic effects

. Thiram has been s ho wn t o cause neu rotoxicity

fo ll ow in g acute and subchron i c ex p osures

. In the acute and subchro ni c n eurotox i c it y st udi es

subm itt ed

, neurotoxicity i s characte ri zed as lethargy, reduced tail pinch response

, c h a n ges in the

functiona l- observa ti on battery ( FOB ) parameters, increased hyperactivity, changes in motor

act i vity

, and increased occ urr ences of rearing eve nt s. No treatment-related changes were

observed in brain we i g h ts or in the histopathology of the n ervous system. fn a non-guideline

study published in the open literature, chron ic feed in g of thiram to rats caused neurotoxicity

,

w ith o n set of ataxia in some animals 5- 1 9 months after beginning of tr ea tm ent. However

, no

ev id e n ce of neurotoxicity was seen fo ll owi n g c h ron i c exposu r es in mic e o r rats in guideline

stud i es subm itt ed t o the Agency

. In addition

, the developmental neurotoxicity ( O NT) st u dy

revealed that thiram caused increased locomotor activity in female offspr in g at postnata l day 17.

The chronic toxicity profile for thiram indi cates that the liver, blood, and possib l y thyroid a r e the

target o r ga n s for thi s c h emica l in mic e

, rat s, and dogs. Thiram is class i fied as "Not Likely to be

Carcinogenic to Humans" based o n l ack of ev id ence fo r carc in ogenic i ty in mice or rats. There

are no mutagenic / genotoxic concerns wi th thiran1. The availab l e toxicological database for

thiram suggests that this chem i ca l has a l ow to moderate ac ut e -t ox i c it y profile. Acute oral

, dermal, and inhalation toxicity data for thiram puts it in toxicity ca t egor i es Ill

, III

, II

,

r espectively

. Thiram i s a moderate eye irritant

, very sl i ght skin irrit ant

, and a moderate dermal

sens iti ze r.

T h e FQPA safety factor (SF) fo r thir a m is r educed to IX

. The recommendation of l X is based on

the fo llo wing considerations. The toxicological database for thiram is complete wit h acceptab l e

P age 2of25Thiram Registration Review Scoping Document

Page 3 of 25 neurotoxicity, developmental, and reproductive t oxicity studies

. There was no evidence of

increased susceptibility following in utero exposure to rats or rabbits or following pre

- and post

natal exposures to rats. Thiram has been shown to cause neurotoxicity following acute and

subchronic exposures. Ther e is evidence of quantitative susceptibility in the DNT study.

However, t here is low concern for the enhanced susceptibility seen in the DNT study because

clear NOAELs/LOAELs were establi shed for the offspring effects, the dose

- response is well

defined , an d the dose/endpoint is used for acute dietary risk for the most sensitive population

(females 13

- 49 years old). Consequently, there are no residual uncertainties for pre

- and post

natal toxicity. There are no residual uncertainties in the thiram exposure d atabase.

The acute and chronic dietary risk estimates for food and drinking water are below HED’s level

of concern (i.e., <100% of the acute and chronic population adjusted doses (PADs)) for the

general U.S. population and all population subgroups. The acute dietary exposure at the 95th

exposure percentile was 1.9% of the aPAD for the general U.S. population and 61% of the aPAD

for females 13

- 49 years old, the population subgroup with the highest percent aPAD. Chronic

dietary exposure for the general U. S. population was 13% of the cPAD and 70% of the cPAD for

children 1

- 2 years old, the population subgroup with the highest estimated chronic dietary

exposure to thiram.

The residue chemistry database is sufficient to support the current registration of th iram

. The

Thiram RED concluded that the current common moiety plant method would likely include all

the residues of toxicological concern. T he qualitative nature of the residue in plants and livestock

resulting from foliar use of thiram is

, therefore

, con sidered to be adequately understood. T hiram

is not used as a foliar treatment on major livestock feed items , except wet apple pomace

. Furthermore, HED has determined that the seed treatment uses of thiram are nonfood uses, and

there is no carryover of thi ram to rotational crops. As a result, livestock metabolism is no longer

a data requirement to support thiram registration. HED waived the require ment that additional

rotational crop studies be performed, or that thiram labels contain any rotational crop re strictions

(D239096, W. Hazel, October 6, 1998). Thiram residues convertible to carbon disulfide ( CS 2 )

are the residue of concern for tolerance expression and/or risk assessment in plants, livestock,

rotational crops and drinking water.

A new dietary exposure assessment will likely be needed, since HED has previously

recommended increasing the tolerances for bananas and peaches to harmonize with CODEX. In

addition, there may be changes to the thiram toxicological points of departure ( POD s ) or

uncertainty factors ( UFs ) or significant changes to the estimated drinking water concentrations

( EDWCs )

. The assessment, if conducted, will use the newest version of DEEM and reflect

updated consumption information.

U.S. tolerances are not numerical ly compatible with Codex or Canadian MRLs. The tolerance

residue levels may need to be examined during registration review to determine if further

harmonization can be achieved. Tolerances for the dimethyl dithiocarbamates (thiram, ziram and

ferbam) and t he ethylenebis

- dithiocarbamates (EBDCs) are being converted to being expressed

as carbon disulfide equivalents, since it is difficult to distinguish among the various pesticides by

analytical methods alone. The Codex Alimentarius has established maximum re sidue limits

(MRL), for “ t otal dithiocarbamates, determined and expressed as mg carbon disulfide per kg ” inThiram Registration Review Scoping Document

Page 4 of 25 strawberry of 5 mg/kg. HED has recommended that all tolerances for dithiocarbamates,

including thiram

, be converted to be expressed as carbon disulfide, so that the tolerance

expression will be compatible with Codex; however, the tolerance level may not be compatible

for strawberry, since there are differences in Good Agricultural Practices (GAP i.e., use

patterns).

The only remaining registered residential use of thiram is on golf course turf (tees and greens);

while there were no risks of concern identified for playing golf on treated golf course turf

, t he

estimated margin of exposure (MOE) using default turf transferrable residue ( TTR ) values is not

minimal in comparison to the level of concern (i.e., t he calculated MOE of 850 is not greater

than 10 times higher than the level of concern of 100 )

. Therefore, a TTR study is required.

R esidential bystander exposures resulting from off

- site transport (i.e., spray drift or

volatilization) may occur as a result of occupat ional applications of thiram

. The need for a

bystander risk assessment for thiram will be considered during registration review.

The previou s occupational exposure assessment completed for the RED covered all exposure

scenarios relevant to thiram

. Although no occupational handler or post

- application risks of

concern were identified with use of appropriate personal protective equipment (PPE) for the

remaining registered uses

, u pdated occupational exposure and risk assessments will be necessary

as part of registration review to reflect revised toxicological endpoint selection and PODs

, as

well as current HED policy regarding exposure assessmen t methodology.

The toxicity, residue chemistry and occupational exposure databases for thiram are adequate for

registration review

, with the exception of the required 28

- day inhalation toxicity study and a

TTR study

. As part of registration review, the endpoints, doses, and safety factors (SFs) used in

the most recent human health risk assessment will need to be re

- evaluated according to current

HED policy and to incorporate the results of the required inhalation st udy

. Updated exposure and

risk assessments will be conducted to incorporate the results of the TTR study as well as any

changes to the PODs, SFs EDWCs, dietary exposure models and/or to the current scenario

specific surrogate handler

- exposure data.

Chemi cal Use Profile

Thiram (tetramethylthiuram disulfide) is a dithiocarbamate fungicide used to control fungal

diseases on apples, peaches, strawberries, banana, avocados

, various seed types, ornamentals and

golf course turf (tees and greens). It is also used as an animal repellent to protect crops from

damage by rabbits, rodents and deer. Thiram is a crystalline solid with a melting point of 142

-

150  C, bulk density of 0.32

- 0.35 g/mL, octanol/water partition coefficient (P

ow ) of 39.5

- 54.1,

and vapor pressure of 1.6

- 1.8 x 10

- 5 Torr at 25  C. Thiram is slightly soluble in water (0.00165

g/100 mL), petroleum ether (0.0005 g/100 mL), benzene (4.12 g/100 mL), acetone (6.97 g/100

mL ), xylene (0.91 g/100 mL), and methanol (0.184 g/100 mL) at 20

- 25  C.

The nomenclature and physiochemical properties of thiram are presented in Tables 2.1 and 2. 2 of

A ppendix 2

.Thiram Registration Review Scoping Document

Page 5 of 25 Hazard Identification/Toxicology

The toxicity database for thiram is comple te with the exception of a 28

- day inhalation study.

The database is sufficient for characterization of potential developmental, reproductive,

carcinogenic , mutagenic, and neurotoxic effects. The Hazard and Science Policy Council

(HASPOC) met on June 6, 2013 to discuss the need for a 28

- day inhalation toxicity study with

neurotoxicity measurements and a cholinesterase activity screening assay (TXR No. 0056685).

Based on a Weight of Evidence approach, the HASPOC concluded that a 28

- day inhalation

toxicity study in rat with neurotoxicity parameters is required. Therefore, a 10X database

uncertainty factor is required for all inhalation exposure risk assessments. However, a

cholinesterase activity screening assay is not required at this time.

The targets of t oxicity are the nervous system, liver, blood, and possibly the thyroid. An acute

neurotoxicity screening study reported functional observational battery (FOB) effects and a

developmental neurotoxicity study reported reduced motor activity in offspring. A 1

- year dog

study and a rat chronic/carcinogenicity study revealed bile duct hyperplasia, increases in

cholesterol levels, hepatocellular adenomas, and increased liver weights. The thyroid is known to

be a target organ for dithiocarbamates in general (Liesiv uori et al. 1994). However, the database

for thiram had only one study, the rat chronic/carcinogenicity study, in which thyroid effec ts

revealed changes in thyroid C

- cell hyperplasia.

Thiram causes neurotoxicity following acute and subchronic exposures. Neurotoxicity from

thiram is characterized as lethargy

, reduced tail pinch response, changes in FOB parameters,

increased hyperactivity, changes in motor activity, and increased occurrences of rearing events.

No treatment

- related changes were observed in brain weights or in the histopathology of the

nervous system. In a published open literature study, chronic oral administration of thiram to

rats demonstrated neurotoxicity, with cases displaying ataxia. In addition, adverse increases in

locomotor activi ty were reported in female offspring in a developmental neurotoxicity study.

Thiram was classified as “Not Likely to be Carcinogenic to Humans” by HED’s Hazard

Identification Assessment Review Committee (HIARC) ( W. Burnam memorandum; 4/7/00 ) The

mutagenici ty database for thiram suggests that this compound is clastogenic. It does not,

however, induce unscheduled DNA synthesis nor does it increase the mutation frequency at the

HPRT locus.

More than one mode of action has been described in the open scientific literature. In humans,

dithiocarbamates block the conversion of dopamine to epinephrine and norepinephrine causing

the inhibition of catecholamine neurotransmitter synthesis. Transmission of nerve impulses

involving norepinephrine are involved in the regulation of gonadotropin releasing hormone

(GnRH), responsible for release of follicle

- stimulating hormone and luteinizing hormone (LH)

(reviewed in Cecconi et al. , 2007). Dithiocarbamates have been shown to possess chelating

properties. As chelat ors, these compounds have the potential to interact and interfere with

sulfhydryls and macromolecules (Fishbein, 1976 and Miller, 1982). A disruptive role for

dithiocarbamates has also been identified in the synthesis of nitric oxide (reviewed in Cecconi e t

al. , 2007).Thiram Registration Review Scoping Document

Page 6 of 25 Thiram is readily absorbed (via the oral route), distributed, extensively metabolized and

eliminated primarily in the expired air and urine of rats following single or repeated oral

administrations. Within 24 hours of administration of the co mpound, a high amount of

radioactivity was eliminated as expired air ( 14 CO 2 , carbamyl sulfide, and carbon disulfide). The

parent compound was not detected in the urine. Fecal metabolites were not evaluated due to the

low recovery of radioactivity in the fe ces. There is no apparent sex

- or dose

- related difference in

the distribution, metabolism, or excretion of 14 C

- thiram. Bioaccumulation of 14 C

- thiram in

tissues was low (1.54

- 4.24% of the administered dose).

Thiram is a Category III (moderately low) for acu te toxicity level via oral and dermal routes of

exposure. Acute inhalation exposure is a Category II (moderately high). Thiram is a very slight

dermal irritant and a moderate dermal sensitizer.

The acute, subchronic, and chronic toxicity profile tables for thiram are included in Appendix 1,

Table s 1 and 2. Toxicity endpoints, points of departure (PODs), and uncertainty/safety factors

( UF/SFs) were selected for oral, dermal, and inhalation exposu re pathways for the Human Health

Risk Assessment conducted in 2015 (D427383), and these are shown in Appendix 1, Table 3.

Upon review of the toxicology data and consideration of all available data including the open

literature, the endpoints for risk asse ssment and all uncertainty factors may be re

- evaluated

during registration review to reflect current HED policies.

Conclusions: The toxicity database for thiram is considered complete and is adequate for

assessing potential carcinogenetic, mutagenic, de velopmental, neurotoxic, reproductive

, and

immunotoxic effects

, except as noted below

. During registration review, the endpoints and

safety factors for risk assessment may be updated to reflect current policies.

TOX Data Deficiencies : The HASPOC determ ined that a 28

- day inhalation toxicity study with

neurotoxicity parameters in rats is required. Therefore, a 10X database uncertainty factor will be

retained for the inhalation route. However, the cholinesterase activity screening assay was

waived by the H ASPOC and is not required at this time (TXR 0056685).

Residue Chemistry

HED has previously determined that thiram seed treatments are nonfood uses and that there is no

need to require plant metabolism studies attempting to elucidate uptake/metabolism via the soil

route occurring during foliar applications (D210277, L. Cheng, 4/29/97). Plant metabolism

studies involving seed treatment of 3 dissimilar crops (soybean, wheat, and sugar beet) were

conducted. Thiram was not detected in any plant matrix. Data in dicate that thiram was

extensively degraded and its fragments were incorporated into natural products. Based on th ese

results, the registrant requested a waiver for confined rotational crop studies. HED waived the

require ment that additional rotational crop studies be performed, and that thiram labels contain

any rotational crop restrictions (D239096, W. Hazel, October 6, 1998).

The Thiram RED concluded that the current common moiety plant method would likely include

all the residues of toxicological concern. Though the methodology cannot detect thiram

- specific

metabolites, it does detect CS 2,

- a common metabolite for thiram and other dithiocarbamates.Thiram Registration Review Scoping Document

Page 7 of 25 As a result, the dietary risk estimates are considered conservative since they may include CS 2

from chemicals or sources other than thiram. The qualitative nature of the residue in plants

resulting from foliar use of thiram is

, therefore

, considered to be adequately understood. Thiram

residues convertible to CS 2 are the residu e of concern for tolerance expression and/or risk

assessment in plants, livestock, and rotational crops. These same residues of concern are the

residues of concern in drinking water for risk assessment.

Removing the use of thiram for late season use on pe aches in CA and AZ eliminates the

requirement for 1

- 2 field trials in CA/AZ. In addition, t he requirement for a peach trial in

NAFTA Growing Zone 2 was satisfied in MRID 45651301. One additional peach field trial for

thiram at the maximum single and seas onal application rate was requested in NAFTA Growing

Zone 2 (D302802, 5/30/13, S. Hummel). However, since HED is recommending increasing the

peach tolerance to harmonize with CODEX, this field trial is no longer needed.

Enforcement Method

A color i metric analytical method is available to enforce the proposed tolerances. The Pesticide

Analytical Manual (PAM) Vol. II lists Method I, II, III, IV, and A for the determination of

dithiocarbamate residues in/on plant commodities. These methods are based on the

d ecomposition of dithiocarbamates with release of CS 2 . Using these methods, the CS 2 is swept

through a trap to remove any H 2 S and into a reaction tube containing a solution of copper acetate

and an amine. A colored copper dithiocarbamate complex is formed and its absorbance read as a

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

- 4.0 ppm. Thiram may be detectable using PAM I multiresidue methods without Florisil cleanup,

but is not detected when Florisil cl eanup is used.

Residue analytical methods for the determination of thiram residues of concern in animal

commodities are not available because tolerances for animal commodities have not been

established.

Conclusions: The residue chemistry database is suf ficient to support the current registration of

thiram

.

Dietary Exposure and Risk

The residue chemistry and drinking water database

, are adequate to assess dietary exposure

, and

they are sufficient to support current registrations. The nature of the residue in plants and animals

has been defined. The most recent dietary (food and water) exposure assessment was conducted

in 2015 (D427382, T. Morton, 5/21/2015) using the Dietary Exposure Evaluation Model

(DEEM

- FCID, version 3.16), which uses 2003

– 2008 food consumption data from the U.S.

Department of Agriculture’s National Health and Nutritional Examination Survey, What We Eat

in America, (NHANES / WWEIA). M onitoring data are unavailable

, therefore, estimates of

thiram concentrations were made only with mathematical models. EDWC values were generated

by the PRZM (Pesticide Root Zone Model)

- EXAMS (Exposure Analysis Modeling System) for

the turf application scenario, since this crop yielded the highest EDWC values. Ground waterThiram Registration Review Scoping Document

Page 8 of 25 sources were not included, as the EDWCs for this water source are minimal in comparison to

those for surface water.

A partially refined probabilistic acute dietary exposure assessment was performed using 100%

crop treated , average field

- trial residue values for blended commodities, distribution of field trial

residues, highest pulp residues, and empirical processing factors

. For the chronic dietary

exposure analysis a vocado and banana pulp residues, along with average field trial residues for

apples, peaches and strawberries and 100% crop treated (CT) were used for all crops. Empirical

processing factors were also used. Dietary risk estimates were determined considering exposures

from food plus drinking water using EDWCs for surface water sources provided by EFED.

The acute dietary risk estimates for food and drinking water combined are below HED’s level of

concern ( i.e. , <100% of the aPAD of 0.6494 mg/kg bw/day) for the general U.S. population and

all population subgroups (including females 13

- 49 years old ; aPAD of 0.014 mg/kg bw /day).

Using DEEM

- FCID, acute dietary exposure at the 95 th exposure percentile is estimated at

0.0 12002 mg/kg bw/day for the general U.S. population (1.9% of the aPAD) and 0.0 08595

mg/kg bw/day (61% of the aPAD) for females 13

- 49 years old , the population subgroup with the

highest % aPAD dietary exposure to thiram.

The partially refined chronic dietary risk estimates for food and water combined are below

HED’s level of concern ( i.e. , <100% of the cPAD of 0.015 mg/kg bw/day) for the general U.S.

population and all population subgroups. Using the DEEM

- FCID software, dietary exposure is

estimated at 0.00 1999 mg/kg bw/day for the general U.S. population (13% of the cPAD) and

0.0 10557 mg/kg bw/day (70% of the cPAD) for children 1

- 2 years old, the population su bgroup

with the highest estimated chronic dietary exposure to thiram.

Conclusions: The dietary exposure database is adequate to support the Registration Review

process for thiram. A new dietary exposure and risk assessment will likely be needed to suppo rt

the proposed tolerance increases for banana and peaches. In addition, there may be changes to

the thiram toxicological PODs or UFs or significant changes to the EDWCs. The assessment, if

conducted, will use the newest version of DEEM and reflect updated consumption information.

Residential Exposure

Residential exposure from t he registered use on golf cours e tees and greens was re

- evaluated in a

very recent risk assessment (D427383, T. Morton, 5/21/2015)

. P ost

- application dermal exposure

was assessed for children 6 to <11 years old, children 11 to <16 years old, and adults. The

dermal margins of exposure (M OEs) ranged from 850 to 1000, which are above the LOC of 100

, and are, therefore, not of concern

.

In conjunction with the 2007 40 CFR Part 158 Data Requirements, HED typically requires

submission of a turf transferable residue (TTR) study in order to determine exposure and risk

associated with playing golf on treated golf course turf. T he estimated residential turf post

application expo sure for golf ing on treated golf course s using default TTR values for thiram is

not minimal in comparison to the level of concern

. T he calculated MOE is not greater than 10

times higher than the level of concern, with the lowest MOE

= 850 compared to the LOC of 100

.Thiram Registration Review Scoping Document

Page 9 of 25 F uture refinements of this post

- application exposure for thiram may be necessary due to

increased use of thiram or advances in EPA risk assessments. Therefore, EPA is requiring the

40CFR TTR data to facilitate any necessary exposure assessmen t refinement s and to further

EPA’s general understanding of the availability of turf transferable pesticide residues.

Residential bystander exposures resulting from off

- site transport (e.g., spray drift or

volatilization) may occur as a result of applica tions of thiram

. The potential for spray drift will

be quantitatively evaluated for each pesticide during the Registration Review process which

ensures that all uses for that pesticide will be considered concurrently. The approach is outlined

in the revise d (2012) Standard Operating Procedures for Residential Risk Assessment (SOPs)

–

Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of

Spray Drift. This document outlines the quantification of indirect non

- occupational exposure to

drift. In terms of volatilization, the Agency has developed a Volatilization Screening Tool and a

subsequent Volatilization Screening Analysis

( http://www.reg ulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219 ). During Registration

Review, the Agency will utilize this analysis to determine if data (i.e., flux studies, route

- specific

inhalation toxicological studies) or further analysis is required for thiram

.

Conclusions: The residential exposure database is adequate to support the Registration Review

process for thiram. HED recently re

- evaluated t he residential use of golfing on treated golf

course greens and tees ; however, a revised residential exposure risk assessment may be

necessary during registration review to incorporate the required chemical

- specific TTR data

. HED will evaluate the need for spray drift and volatilization risk assessment s for thiram d uring

registration review

.

Aggregate Risk Assessment

I n accordance with the Food Quality Protection Act ( FQPA ) , H ED must consider and aggregate

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

exposures. The aggregate risk assessment evaluates the combined risk from dietary exposure

(food and water) and any non

- occupational (residential) uses

. The most recent aggregate risk

assessment for thiram is very current, i.e., D427383, T. Morton, 5/21/2015

Acute and Chronic Dietary Aggregate Risk

The acute and long

- term (i.e., chronic) aggregate risk assessment s take into account exposure

estimates from d ietary consumption of thiram (food and drinking water). The acute and chronic

dietary risk estimates are not of concern to HED (<100% aPAD a nd cPAD, respectively ) for the

general U.S. population and all other population subgroups. T he refore, the acute and long

- term

aggregate risk associated with the proposed uses o f thiram are not of concern to HED for the

general U.S. population or any popula tion subgroup.

Short

- and Intermediate

- Term Aggregate Risk

In aggregating short

- and intermediate

- term aggregate risk, the Agency routinely combines

background chronic dietary exposure (food + water) with short/intermediate

- term residentialThiram Registration Review Scoping Document

Page 10 of 25 exposure (der mal only in this case ). The combined exposure may then be used to calculate an

MOE for aggregate risk. Using the golfer on treated golf course scenario for adult males, adult

females, and children > 6 years old, combined with the applicable subpopulation with the greatest

dietary exposure, the total short/intermediate

- term food and residential aggregate MOEs are 570,

540, and 280 , respectively. As these MOEs are above the target MOE of 100, the short

- and

intermediate

- term aggregate risks are not of concern. For children <6 years old, there is no

residential exposure, therefore, a short/intermediate term aggregate risk assessment is not

required for this population. Appendix 3 summarizes the short/int ermediate

- term aggregate

exposures to thiram

.

Conclusions: A r evised aggregate exposure risk assessment may be necessary during registration

review to incorporate any potential changes to the residential exposure based on the required

chemical

- specific TTR data

.

Occupational Exposure

Occupational handler and post

- application exposures are expected based on the registered uses of

thiram

. Thiram is currently formulated as a dust, water dispersible granule, emulsifiable

concentrate, flowable concentrate, read y

- to

- use solution, liquid and wettable powder.

Applications are made by air, groundboom, air blast sprayer, and high

- pressure hand wand at

application rates ranging from 2.6 pounds active ingredient per acre (lb ai/A) to 16.3 lb ai/A. For

other hand

- held sprayers (e.g., back

- pack and manually

- pressurized handwand), paintbrush and

dips, application rates range from 0.1 to 1.3 lb ai per gallon solution. Seeds are treated with

specialized equipment at rates ranging from 0.031 to 2.0 lb ai per hundred pounds o f seed.

Occupational exposure scenarios applicable to thiram range from short

- term (1 to 30 days) to

intermediate

- term (30 days to six months) duration

.

The occupational handler assessments indicate that

, for the existing registered uses, all of the

potential exposure scenarios provide dermal and inhalation margins of exposure ( MOEs) greater

than or equal to the LOC of 100 at some level of personal protection and/or engineering control.

The labels for most uses require glove s in addition to baseline clothing attire of long pants, long

sle eved shirt and shoes plus socks; one foliar label and three seed treatment labels require the

addition of a respirator.

Several levels of postapplication exposure activities have been identified ranging f rom “low”

activities such as weeding and scouting in immature plants to very high exposure activities such

as harvesting or thinning fruit from trees. Adequate d islodgeable foliar residue (DFR) data are

available for strawberries , and were used to assess all foliar use sites ; a dditional DFR data are

not needed at this time

. The short

- and intermediate

- term postapplication assessments indicate

that the MOEs reach the LOC of 100 within 1 day after application for all of the existin g use

scenarios. The restricted entry interval (REI ) listed on the applicable labels is 24 hours.

Conclusions. The occupational exposure database is adequate to support the Registration

Review process for thiram

. Although o ccupational handler and post

- a pplication exposure

assessments conducted for the 200 4 RED did not identify risks of concern for any of the

remaining uses

, updated occupational exposure and risk assessments will be conducted duringThiram Registration Review Scoping Document

Page 11 of 25 Registration Review based on revised toxicological points of departure, current policies and

exposure assessment methodology.

Public Health and Pesticide Epidemiology Data

The evaluation of the OPP Incident Data System (IDS) indicated that from the main IDS, from

January 1, 2010 to December 30, 2014, there were no incidents reported involving thiram. In

a ggregate IDS, from January 1, 2010 to December 30, 2014, there were 28 incidents reported

involving thiram . These incidents were classified as minor severity ( D 427919

, S. Recore

, 6/30/ 2015 ) . Overall, there are few incidents involving thiram reported to IDS.

A review of SENSOR

- Pesticides 1998

- 2011 identifies 14 cases involving thiram

, and nine cases

that involve d only thiram . Eight of the nine cases were work

- related. Eight ca ses were low in

severity and one case was moderate in severity. Dermal symptoms were reported in five cases,

and respiratory irritation was reported in four cases

.

From 2010 to 2014, 1 incident was reported to National Pesticide Information Center ( NPIC )

involving thiram. NPIC estimates a certainty index as to whether an incident (including reported

symptoms) was either definitely, probably, possibly, or unlikely to have been caused by the

reported exposure to a pesticide, or whether the incident was unre lated to pesticides or if the

incident was unclassifiable. This incident was classified with a certainty index of possible and a

severity of moderate. The incident involves a 45 year old male who sells vegetable seeds. He

was handling seeds treated with a fungicide containing thiram and did not wear PPE. He

developed a rash on both his hands and feet.

Thiram is not included in the Agricultural Health Study (AHS) and

, therefore

, this study does not

provide information for this report.

Conclusions: Based on the low frequency and low severity of incident cases reported for thiram

in IDS, SENSOR

- Pesticides, and NPIC

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

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

information and if a concern is triggered, additional analysis will be included in the risk

assessment.

Tolerance Assessment and International Harmonization

U.S. permanent tolerances are established under 40 CFR § 180.132 for the registered uses of

thiram in/on a number of commodities. Codex and Canadian maximum residue limits (MRLs)

for residues of thiram have been established for some of the same commodities which have

tolerances in the United States. Mexico adopts U.S. tolerances and/or Codex MRLs for its

export purposes. While residue definitions are compatible with Codex, and expressed as carbon

disulfide, some U.S. tolerances are not numerically compatible with Codex or Canadian MRLs.

The tolerance residue levels may be harmonized for certain commod ities as detailed in Table 2

below.Thiram Registration Review Scoping Document

Page 12 of 25 Tolerances for the dimethyl dithiocarbamates (thiram, ziram and ferbam) and the ethylenebis

dithiocarbamates (EBDCs) are being converted to being expressed as carbon disulfide

equivalents, since it is difficult to disti nguish among the various pesticides by analytical methods

alone.

The tolerance expression should read: Tolerances are established for residues of the fungicide

thiram (tetramethyl thiuram disulfide), including its metabolites and degradates

, in or on the

commodities in the table below (Table 2) . Compliance with the tolerance levels specified below

is to be determined by measuring only those thiram residues convertible to carbon disulfide

, expressed as carbon disulfide , in or on the commodity.

Table 2. Tolerance Conversion for Thiram, Residues Convertible to Carbon Disulfide.

Commodity Current Tolerance

(ppm Thiram) Recommended

Tolerance (ppm

CS 2 ) Comments;

[C orrect Commodity D efinition ]

Apple 7.0 5 The conversion factor is 0.63x.

Avacado 1 15 10 The conversion factor is 0.63x.

Banana 1

0.80 2.0 Recommended tolerance is being raised to

2.0 ppm CS 2 to harmonize with Codex.

Peach 7. 0 7.0 Recommended tolerance is being raised to

7.0 ppm CS 2 to harmonize with Codex.

Strawberry 20 13 The conversion factor is 0.63x.

1 No U.S. registrations as of July 30, 2015

.

The Codex Alimentarius has established maximum residue limits (MRL), for “ t otal

dithiocarbamates, determined and expressed as mg carbon disulfide per kg ” in strawberry of 5

mg/kg. HED has recommended that all tolerances for dithiocarbamates, including thiram be

converted to be expressed as carbon disulfide, so that the tolerance expression will be compatible

with Codex; however, the tolerance level will not be compatible for strawbe rry, since there are

differences in Good Agricultural Practices (GAP i.e., use patterns). A copy of the International

Residue Limit Status (IRLS) sheet is attached to this memorandum (Table A2.3 in Appendix 2)

.

Environmental Justice

Potential areas of e nvironmental justice concerns, to the extent possible, were considered in this

human health risk assessment, in accordance with U.S. Executive Order 12898, “ Federal Actions

to Address Environmental Justice in Minority Populations and Low

- Income Populations

, ”

http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf

. The Office of

Pesticide Programs (OPP) typically considers the highest potential exposures from the legal use

of a pesticide when conducting human health risk assessments, including, but not limited to,

people who obtain drinking water from sources near agricultural areas, the variability of diets

within the U.S., and people who may be exposed when harvesting crops. Should these high

exposures indicate potential risks of concern, OPP will further refine the risk assessments to

ensure that the risk estimates are based on the best available information.Thiram Registration Review Scoping Document

Page 13 of 25 Cumulative Risk Assessment

The Food Quality Protection Act (FQPA) requires the Agency to consider the cumulative risks of

chemicals sharing a common mechanism of toxicity. At a September 2001 meeting of t he

Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA) Scientific Advisory Panel (SAP) it

was determined that there was insufficient evidence to suggest that t hiram shares a common

mechanism of toxicity with other chemical substances (dithiocarbamates)

. The basis for this

conclusion is described in det ail in the HED document, “The Determination of Whether

Dithiocarbamate Pesticides Share a Common Mechanism of Toxicity” (12/1/2001). The

document can be found on EPA’s website at

http:// www.epa.gov/oppsrrd1/cumulative/dithiocarb.pdf

.

Human Studies

The 200 4 RED relied in part on data from studies in which adult human subjects were

intentionally exposed to a pesticide or other chemical. These data, which include studies from

Pesticide Ha ndler Exposure Database (PHED) 1.1; the Agricultural Handler Exposure Task

Force (AHETF) database; the Agricultural Reentry Exposure Task Force (ARTF) database; and

Exposure Science Advisory Committee (ExpoSAC) Policy 14 (Standard Operating Procedures

for Seed Treatment), are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received

that review, and (3) are compliant with applicable ethics requirements. For certain studies, the

ethics review may have included review by the Human Studies Review B oard. Descriptions of

data sources, as well as guidance on their use, can be found at the Agency website.

Risk Assessment Updates and Data Deficiencies

 A turf transferable residue (TTR) study ( Guideline 875.2100 ) is required in order to

determine exposure and risk associated with children playing golf on treated golf course

turf.

 A 28

- day inhalation toxicity study ( 870.3465 ) with neurotoxicity parameters in rats is

required. Therefore, a 10X database uncertainty fa ctor will be retained for the inhalation

route.

 Updated exposure and risk assessments may be conducted if there are any significant

changes to thiram toxicological endpoints, points of departure, Food Quality Protection

Act safety factor or other uncertai nty factors, standard operating procedures, or exposure

data models or assumptions.

References:

Carleton, J. and Jenkins,F. 12/11/03. “Environmental Fate and Ecological Effects Assessment

and Characterization Chapter for the Thiram Registration Eligib ility Decision Document”Thiram Registration Review Scoping Document

Page 14 of 25 Cecconi S., Paro R., Rossi G., Macchiarelli G. (2007) The effects of the endocrine disruptors

dithiocarbamates on the mammalian ovary with particular regard to mancozeb. Current

Pharmaceutical Design , 13, 2989

- 3004.

Dawson, J. 4/24/2003. D289601. Thiram: Revised Phase 5 Occupational and Residential

Exposure Assessment and Recommendations for the Reregistration Eligibility Decision

Document

.

Fishbein L. (1976) Environmental health aspects of fungicides. Dithiocarbarm ates. J. Toxicol.

Environ. Health , 1, 713

- 735.

Hummel, S. 12/18/2014. D419341. Thiram on Avocado, PP#4E8250 and Banana, PP#4E8268.

Summary of Analytical Methods and Residue Data.

Hummel, S. 5/30/2013. D302802. Thiram. Response to Review of 6(a)(2) data on Peaches in

California. Removal of Late Season Use in California and Arizona.

Kramer, G.and Greear, W. 06/09/2009. D365442. Thiram in/on Imported Bananas. Revised

Human Health Risk Assessment.

Knizner, S. 05/27/2009. “ Interim Guidance on Tolerance Expressions,” EPA Memorandum.

Liesivuori, J. and Savolainen, K. (1994) Dithiocarbamates. Toxicology , 91, 37

- 42

Mendez, E. 5/30/2000. D263948. HED DOC No. 014193. Thiram

- Toxicology Disciplinary

Chapter for the Reregistration Eligibility Decision Document.

Miller D.B., (1982) Neurotoxicity of the pesticidal carbamates. Neurobehavioral Toxicology and

Teratology , 4, 779

- 787.

Morton, T. 5/21/2015. D427382. Thiram: Revised Acute and Chronic Dietary (Food and

Drinking Water) Exposure and Risk Assessment to Support a Petition For Conversion of the

Time

- Limited Banana Tolerance to Permanent and Import use on Avocado.

Morton, T. 5/21/2015. D42738 3 . Thiram: Revised Human Health Risk Assessment for the

Import Use of Thiram on Avo cado, PP#4E8250 and Banana, PP#4E8268.

Otakie, G. 12/16/ 1999; HED Metabolism Assessment Review Committee ad hoc Meeting of

12/09/ 99. Ziram/Ferbam Metabolism. Chemical Nos. 034805 and 034801. Barcodes D261844

and D261846.

Otakie, G. 03/24/2011. D38436 3. Thiram Spotrete F Fungicide (EPA Reg. No. 45728

- 26)

Amendment to Add Use on Peaches; and Reregistration Data

- Magnitude of the Residue of

Ferbam, Thiram, and Ziram in Peaches

- Dithiocarbamate Fungicide Formulation Bridging Study.Thiram Registration Review Scoping Document

Page 15 of 25 Rury, K. 6/30/20 13. TXR No. 0056685. Thiram: Summary of Hazard and Science Policy

Council (HASPOC) Meeting of June 6, 2013: Recommendations on the Need for a 28

- day

Inhalation Study and Cholinesterase Assessment Screening Assay.

http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and

http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.htmlThiram Registration Review Scoping Document

Page 16 of 25 Appendix 1

Table 1. Acute toxicity o f Thiram

Guideline No./Study

Type MRIDs Results Tox

Category

870.1100 Acute Oral 00153548 LD 50 =2.6 g/kg III

870.1200 Acute

Dermal 00147099 LD 50 ≥ 2.0 g/kg III

870.1300 Acute

Inhalation 00152556 LC 50 ≥ 0.1 mg/L II

870.2400 Primary Eye

Irritation 00147100 Moderate eye irritant II

870.2500 Primary

Skin Irritation 00147101 Very slight dermal irritant IV

870.2600 Dermal

Sensitization 00153068 Moderate dermal sensitizer N/A

Table 2. Subchronic and Chronic Toxicity and Genotoxicity Profile

– Thiram

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3100 90

- Day oral

toxicity (rat) 40773601 (1988)

Unacceptable/guideline

0, 50, 500, or 1000 ppm

(0, 2.5, 25, or 50 mg/kg

bw/day) NOAEL = could not be determined due to lack

of information on stability.

LOAEL = 25 mg/kg/day, based on decreases in

body

- weight gain, hematology and clinical

chemistry parameters.

870.3150 90

- Day oral

toxicity (dog) 41503608 (1990)

Acceptable/guideline

0, 75, 250, or 500 ppm

(0, 1.94

- 2.58, 6.17

- 7.85,

or 10.55

- 14.69 mg/kg

bw/day) NOAEL = 1.9 mg/kg/day.

LOAEL = 6.3 mg/kg/day, based on adverse

changes in clinical chemistry, and decreases in

mean body weight and food consumption.

870.3200 21

- Day dermal

toxicity (rabbit) 42642501 (1992)

Acceptable/guideline

0, 250, 500, or 1000

mg/kg bw/day NOAEL = 300 mg/kg/day.

LOAEL = 1000 mg/kg/day, based on decreases

in body

- weight gain and food consumption as

well as alterations in clinical chemistry.

870.3700a Prenatal

developmental (rat) 00151610 (1978)

Unacceptable/guideline

0, 12.5, 25, 50, or 100

mg/kg bw Maternal NOAEL = 12.5 mg/kg.

LOAEL = 25 mg/kg, based on reduced body

weight gains and food consumption.

Developmental NOAEL could not be

determined.

LOAEL

= 12.5 mg/kg, based on reduced

ossification.Thiram Registration Review Scoping Document

Page 17 of 25 Table 2. Subchronic and Chronic Toxicity and Genotoxicity Profile

– Thiram

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3700a Prenatal

developmental (rat) 40534101; 41498301

(1988)

Acceptable/guideline

0, 7.5, 15, or 30 mg/kg bw Maternal NOAEL could not be determined.

LOAEL = 7. 5 mg/kg, based on decreases in

body

- weight gain, alopecia, scars, damaged

digits, red

- stained paws and excessive

salivation.

Developmental NOAEL = 7.5 mg/kg.

LOAEL = 15 mg/kg based on retarded growth

and rudimentary 13 th rib, and reduced

ossification.

870.3700b Prenatal

developmental

(rabbit) 40444702(1987)

Acceptable /non

- guideline

0, 1, 3, 5, 7.5, 10, 20, 40,

or 80 mg/kg bw

(range

- finding) Maternal NOAEL = 3 mg/kg bw/day.

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

maternal body

- weight gains.

Developmental NOAEL was not determined.

LOAEL was not determined.

870.3700b Prenatal

developmental

(rabbit) 40577301 (1987)

Acceptable /non

- guideline

0, 1, 2.5, or 5mg/kg bw

(range

- finding) Maternal NOAEL = 5 mg/kg bw/day.

LOAEL was not determined.

Developmental NOAEL = 5 mg/kg.

LOAEL was not determined.

870.3700b Prenatal

developmental

(rabbit) 42223601 (1992)

Acceptable /guideline

0, 1, 5, or 10 mg/kg bw Maternal NOAEL = 10 mg/kg bw/day

LOAEL was not determined

Developmental NOAEL = 10 mg/kg

LOAEL was not determined.

870.3800 2

- Gen.

reproduction and

fertility effects

(rat) 42095901 (1991)

Acceptable/guideline

0, 30, 60, or 180 ppm

(F0: 0/0, 1.2/1.9, 2.4/3.9,

or 8.5/11.8 mg/ kg bw/day

[M/F])

(F1: 0/0, 1.5/2.0, 3.24.3,

or 9.2/13.4 mg/kg bw/day

[M/F] Parental/Systemic NOAEL = 30 ppm (1.9

mg/kg/day [M/F]).

LOAEL = 60 ppm (2.6/3.1.7 mg/kg/day [M/F])

based on decreases in body

- weight gain and

food consumption.

Reproductive NOAEL was not determined.

LOAEL >180 ppm (8.9 mg/kg/day).

Offspring NOAEL = 180 ppm (11.8

mg/kg/day).

LOAEL = 60 p pm (3.9 mg/kg/day), based on

decreased mean body weight.

870.3800 2

- Gen.

reproduction and

fertility effects

(rat) 45441203 (1997)

Acceptable/guideline

0, 20, 60, or 180 ppm

(0, 1.4, 4.2, or 12.2 mg/kg

bw/day) Parental/Systemic NOAEL = 20 ppm (1.4

mg/kg/day).

LOAEL = 60 ppm (4.7 mg/kg/day) based on

reduced body

- weight gains during gestation

.

Reproductive NOAEL ≥ 180 ppm (12.2

mg/kg/day).

LOAEL was not determined.

Offspring NOAEL = 20 ppm (1.4 mg/kg/day).

LOAEL = 60 ppm (4.2 mg/kg/day), based on

de creases in pup body weight and body

- weight

gain.Thiram Registration Review Scoping Document

Page 18 of 25 Table 2. Subchronic and Chronic Toxicity and Genotoxicity Profile

– Thiram

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.4100 Chronic toxicity (1

year; dog) 41967901 (1991)

Acceptable/guideline

0, 30, 90, or 250 ppm

M; 0, 0.84, 2.61, or 7.35

mg/kg bw/day

F: 0, 0.90, 2.54, or 7.23

mg/kg bw/day NOAEL (M) = 30 ppm (0.84 mg/kg/day).

NOAEL (F) = 90 ppm (2.54 mg/kg/day).

LOAEL (M) = 90 ppm (2.61 mg/kg/day, based

on increased mean cholesterol levels.

LOAEL (F) = 250 ppm (7.23 mg/kg/day),

based on increased mean cholesterol levels and

increased liver

- to

- body weight ratios.

870.4200 Carcinogenicity

(mouse) 42313401 (1992)

Acceptable/guideline

M: 0, 15, 150, or 300 ppm

F: 0, 15, 300, or 600 ppm

M: 0, 2.5, 24, and 57

mg/kg bw/day

F: 0, 3.1, 57, and 112

mg/kg bw/day NOAEL = 1 5 ppm (M/F: 2.5/3.1 mg/kg

bw/day).

LOAEL (M) = 150 ppm (24 mg/kg bw/day.

LOAEL (F) = 300 ppm (57 mg/kg/day), based

on decreases in mean body weight and mean

body

- weight gain, anemia, and non

- neoplastic

lesions in the eyes, non

- glandular stomach and

urinary bladder

.

No evidence of carcinogenicity.

870.4300 Combined chronic

toxicity/

carcinogenicity

(rat) 42157601 (1991)

Acceptable/guideline

0, 30, 150, or 300 ppm (0,

M: 0, 1.5, 7.3, and 14.7

mg/kg bw/day

F: 0, 1.8, 8.9, and 18.6

mg/kg bw day NOAEL = 30 ppm (M/F: 1.5/1.8 mg/kg/day).

LOAEL = 15 0 ppm (M/F: 7.3/8.9 mg/kg/day),

based on changes in hematology, clinical

chemistry, incidences of bile duct hyperplasia

and reduction in mean body

- weight gain.

No evidence of carcinogenicity.

870.5300 In Vitro

Mammalian Gene

Mutation Assay in

V79 Chinese

Hamster Cells at

the HPRT Locus) 00160621 (1986)

Acceptable/guideline

0.001

- 56.0 μ g/mL (±S9) No evidence of mutagenicity with or without

metabolic activation.

870.5375 In Vitro

Mammalian

Cytogenetics

(Chromosomal

Aberration Assay

in Chinese Hamster

Ovary Cells) 40510901 ( 1987)

Acceptable/guideline

0.56, 1.0, or 2.4 μ g/mL

(

- S9)

1.8, 5.6, or 18.0 μg/mL

(+S9) Significant dose

- related increases in

chromosomal aberrations with and without

metabolic activation. Classified as a clastogen.

870.5395 Mammalian

erythrocyte

micronucleus test 40510902 (1987)

Acceptable/guideline

38, 189, or 377 mg/kg Administration of 38, 189, or 377 mg/kg thiram

did not cause a significant increase in the

frequency of micronucleated polychromatic

erythrocytes (MPEs) harvested from male and

female mice.

870.5550 UDS in Primary

Rat

Hepatocytes/Mam

malian Cell 00156064 (1985)

0.03, 0.1, 0.3, 1.0, 3.0, or

10.0 μ g/mL Did not induce DNA repair.Thiram Registration Review Scoping Document

Page 19 of 25 Table 2. Subchronic and Chronic Toxicity and Genotoxicity Profile

– Thiram

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.6200a Acute neurotoxicity

screening battery 45589101 ( 1993)

Unacceptable/non

guideline for lack of FOB,

neuropathology and

histopathology data

0, 10, 25, 60, or 150

mg/kg bw NOAEL = 10 mg/kg.

LOAEL = 25 mg/kg, based on decreases in

food consumption in males and females.

870.6200a Acute neurotoxicity

screening battery 42912401 ( 1993)

Acceptable/guideline

0, 5, 150, or 600 mg/kg

bw BMDL 10 = 64.94 mg/kg

. LOAEL = 150 mg/kg, based on FOB effects at

21/2 hours post

- dosing; reduced motor activity

at 31/2 hours, and at 7 and 14 days post

treatment.

870.6200b Subchronic

neurotoxicity

– feeding study in

rats 43012701 (1993)

Acceptable/guideline

0, 30, 125 or 500 ppm

(0/0, 1.74/2.04, 7.26/8.07,

and 28.63/31.82 mg/kg

bw/day [M/F]) NOAEL = 30 ppm ( 1.74/2.04 mg/kg/day

[M/F])

. LOAEL = 125 ppm ( 7.26/8.07 mg/kg/day

[M/F]), based on increased numbers of rearing

events and elevated incidences of hyperacti vity

in females at weeks 8 and 13.

870.6300 DNT 46455201 (2004)

Acceptable/guideline

0, 20, 45, or 90 ppm

0, 1.4, 3.7, or 7.2 mg/kg

bw/day Maternal NOAEL = 45 ppm (3.7 mg/kg/day).

LOAEL = 90 ppm (7.2 mg/kg/day), based on

decreased body weight, body

- weight gain, and

food consumption, clinical signs of toxicity,

and FOB findings

. Offspring NOAEL = 20 ppm (1.4 mg/kg/day.

LOAEL = 45 ppm (3.7 mg/kg/day) based on

increased locomotor activity in females on

PND17

.

870.7485 Metabolism and

pharmacokinetics

(rat) 42235701 No DER (Gay

et. al ., 1991)

41503607 No DER

(Norris, 1989)

42235702 No DER

(Banijamali et al. , 1990) Rats (6 male + 6 female) were dosed orally for

14 days with unlabeled thiram at 2 mg/kg bw

then with [ 14 C]thiram at 2 mg/kg bw on day 15

(Nomeir and Markham, 1990). Expired air and

excreta were collected for a further 96 hours

and then the animals were slaughtered for

tissue collection. Approximately 33

- 35% of

the administered 14 C was eliminated in the

urine, 2.6

- 5.3% in the feces and 47

- 48% in the

expired air. The nature of the volatile 14 C was

not investigated in detail, but 75

- 85% of it was

collected in a KOH trap suggesting CO 2 , or

COS, with the remainder collected in a reagent

for CS 2 . Norris (1991) identified by HPLC t he

metabolites in the urine of the rats from the

single dose study of Gay (1987) and the

multiple dose study of Nomeir and Markham

(1990). There were no sex differences in the

metabolism but the proportions of some of the

metabolites depended on the dosag e level and

the time after dosing.

[www. fao.org /docrep/W5897E/w5897e5a.htm]Thiram Registration Review Scoping Document

Page 20 of 25 Table 2. Subchronic and Chronic Toxicity and Genotoxicity Profile

– Thiram

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.7800 Immunotoxicity

(mouse) 48646401 (2011)

Acceptable/guideline

0, 15/17.5, 150, or 450

ppm

(0, 3, 25, 74 mg/kg/day) Systemic NOAEL = 450 ppm (74 mg/kg/day,

the highest dose tested).

Systemic LOAEL was not established.

Under conditions of this study, the

Immunotoxicity NOAEL = 150 ppm (25 ppm)

Immunotoxicity LOAEL= 450 ppm (74

mg/kg/day) based on treatment related

decreases in anti

- SRBC antibody response.

Table 3. Summary of Toxicological Dose and Endpoints for Thiram

Exposure

Scenario Dose Used in Risk

Assessment, UF Special FQPA Safety

Factor* and Level of

Concern for Risk

Assessment Study and Toxicological Effects

Acute Dietary

(All Populations) NOAEL = 5

mg/kg/day

UF = 100*

Acute RfD = 0.05

mg/kg/day FQPA SF = 1

aPAD = acute RfD

FQPA SF

= 0.05 mg/kg/day Acute Neurotoxicity Study

- Rat

LOAEL = 150 mg/kg/day based on FOB

effects (lethargy, lower temperature, reduced

startle response, no tail pinch response),

reduced motor activity, and reduced brain

weights

Acute Dietary

(Females 13+) NOAEL = 1.4

mg/kg/day

UF = 100*

Acute RfD = 0.014

mg/kg/day FQPA SF = 1

aPAD = acute RfD

FQPA SF

= 0.014 mg/kg/day Dev. Neurotoxicity Study

- Rat

LOAEL = 3.7 mg/kg/day based on increases

in motor activity seen in female offspring on

PND 17

Chronic Dietary

(All populations) NOAEL= 1.5

mg/kg/day

UF = 100

Chronic RfD = 0.015 mg/kg/day FQPA SF = 1

cPAD =

chronic RfD

FQPA SF

= 0.015 mg/kg/day Combined Chronic

Toxicity/Carcinogenicity Study

- RAT &

Chronic Oral Toxicity Study

- DOG

LOAEL = 7.3 based on changes in

hematology, clinical chemistry , incidences

of bile duct hyperplasia, and reduction in

mean body weight gain seen at 7.9

mg/kg/day in conjunction with elevated

cholesterol levels and increased liver

weights reported in the Chronic Oral

Toxicity Study in Dogs at 2.6 mg/kg/day

Short

- Term

Incidental Oral (1

- 30

days) NOAEL= 1.4

mg/kg/day Residential LOC for

MOE = 100 Dev. Neurotoxicity Study

- RatThiram Registration Review Scoping Document

Page 21 of 25 Table 3. Summary of Toxicological Dose and Endpoints for Thiram

Exposure

Scenario Dose Used in Risk

Assessment, UF Special FQPA Safety

Factor* and Level of

Concern for Risk

Assessment Study and Toxicological Effects

Occupational = NA LOAEL = 3.7 mg/kg/day based on increases

in motor activity seen in female offspring on

PND 17

Intermediate

- Term

Incidental Oral (1

- 6

months) NOAEL= 1.4

mg/kg/day Residential LOC for

MOE = 100

Occupational = NA Dev. Neurotoxicity Study

- Rat

LOAEL = 3.7 mg/kg/day based on increases

in motor activity seen in female offspring on

PND 17

Short

- Term Dermal (1

to 30 days) Oral study

NOAEL=

1.4 mg/kg/day

(Dermal absorption

factor = 1%) Residential LOC for

MOE = 100

Occupational LOC for

MOE = 100 Dev. Neurotoxicity Study

- Rat

LOAEL = 3.7 mg/kg/day based on increases

in motor activity seen in female offspring on

PND 17

Intermediate

- Term

Dermal (1 to 6 months) Oral study

NOAEL=

1.4 mg/kg/day

(Dermal absorption

factor = 1%) Residential LOC for

MOE = 100

Occupational LOC for

MOE = 100 Dev. Neurotoxicity Study

- Rat

LOAEL = 3.7 mg/kg/day based on increases

in motor activity seen in female offspring on

PND 17

Long

- Term Dermal (>6

months) Dermal (or oral)

study NOAEL=

1.5 mg/kg/day

(dermal absorption

rate = 1%when

appropriate) Residential LOC for

MOE = 100

Occupational LOC for

MOE =100 Combined Chronic

Toxicity/Carcinogenicity Study

- RAT &

Chronic Oral Toxicity Study

- DOG

LOAEL = 7.3 based on changes in

hematology, clinical chemistry , incidences

of bile duct hyperplasia, and reduction in

mean body weight gain seen at 7.9

mg/kg/day in conjunction with elevated

cholesterol levels and increased liver

weights reported in the Chronic Oral

Toxicity Study in Dogs at 2.6 mg/kg/day

Inhalation (All

durations) Inhalation (or oral)

study NOAEL= 1.4

mg/kg/day

UF = 10

(inhalation

absorption rate =

100%) Residential LOC for

MOE = 1000

Occupational LOC for

MOE = 1000 Dev. Neurotoxicity Study

- Rat

LOAEL = 3.7 mg/kg/day based on increases

in motor activity seen in female offspring on

PND 17

Cancer (oral, dermal,

inhalation) NOT LIKELY TO BE CARCINOGENIC TO HUMANSThiram Registration Review Scoping Document

Page 22 of 25 Table 4. Toxicology Data Requirements for Thiram

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

870.1200 Acute Dermal Toxicity

870.1300 Acute Inhalation Toxicity

870.2400 Primary Eye Irritation

870.2500 Primary Dermal Irritation

870.2600 Dermal Sensitization yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

870.3150 Oral Subchronic (nonrodent)

870.3200 21

- Day Dermal

870.3250 90

- Day Dermal

870.3465 90

- Day Inhalation (28

- day) yes

yes

yes

N/A

y es yes

yes

yes

-

n o

870.3700a Developmental Toxicity (rodent)

870.3700b Developmental Toxicity (nonrodent)

870.3800 Reproduction yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

870.4100b Chronic Toxicity (nonrodent)

870.4200a Oncogenicity (rat)

870.4200b Oncogenicity (mouse)

870.4300 Chronic/Oncogenicity yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

870.5300 Mutagenicity

— Gene Mutation

- mammalian

870.5xxx Mutagenicity

— Structural Chromosomal Aberrations

870.5xxx Mutagenicity

— Other Genotoxic Effects N/A

yes

yes

yes -

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)

870.6100b 90

- Day Neurotoxicity (hen)

870.6200a Acute Neurotoxicity Screening Battery (rat)

870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

870.6300 Develop. Neurotoxicity (DNT) no

waived*

yes

yes

yes -

-

yes

yes

yes

870.7485 General Metabolism

870.7600 Dermal Penetration

870.7800 Immunotoxicity yes

no**

yes yes

-

yes

Special Studies for Ocular Effects

Acute Oral (rat)

Subchronic Oral (rat)

Six

- month Oral (dog) no

no

no -

-

-

*TXR No.: 0056685

** Dermal absorption was estimated to be 1% (D291237, 2003)Thiram Registration Review Scoping Document

Page 23 of 25 Appendix 2

Thiram is a dimethyl dithiocarbamate fungicide used to prevent crop damage in the field and to

protect harvested crops (apples, peaches, and strawberries) from deterioration in storage or

transport. It is also used as a seed protectant (e.g., small

- seeded vegetables, large

- seeded

vegetables, cereal grains, other seeds, coniferous seeds, cotton seed, ornamental seeds, and

soybeans) and as a turf protectant from fungal diseases.

TABLE A2.1

. Test Compound Nomenclature.

Compound

Common name Thiram

IUPAC name tetramethylthiuram disulfide

CAS name tetramethylthioperoxydicarbonic diamide

CAS registry number 137

- 26

- 8

End

- use product s (EP s ) used in

residue field study Banguard 42 PLUS (37.0% ai SC) or Banguard 60 (52.6% ai SC)

TABLE A2. 2. Physicochemical Properties of the Technical Grade of Thiram.

Parameter Value Reference

Melting range 142

- 150 oC Revised Thiram Product and

Residue Chemistry Chapters

for the RED Document

, 12/16/03

. Density 0.32

- 0.35 g/mL

Water solubility at 20

- 25 oC 0.00165 g/100 mL

Solvent solubility at 20

- 25 oC petroleum ether (0.0005 g/100 mL), benzene

(4.12 g/100 mL), acetone (6.97 g/100 mL),

xylene (0.91 g/100 mL), and methanol

(0.184 g/100 mL)

Vapor pressure 1.6

- 1.8 x 10

- 5 Torr at 25 °C

Dissociation constant, pK

a Not applicable

Octanol/water partition coefficient, P OW 39.5

- 54.1Thiram Registration Review Scoping Document

Page 24 of 25 Table A 2.3 International Residue Limits

. Thiram (PC Code 079801 ; 06/10/15)

Summary of US and International Tolerances and Maximum Residue Limits

Residue Definition :

US Canada Mexico 2 Codex

40 CFR 180.132

Plants: Compliance with the

tolerance levels specified is to be

determined by measuring only

thiram. tetramethylthioperox

ydicarbonic diamide Plant /animal : total

dithiocarbamates,

determined as CS2,

evolved during acid

digestion and

expressed as mg

CS2/kg.

Dithiocarbamate

residues are not fat

soluble.

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

US Canada Mexico 2 Codex

Apple 7.0 7 5 pome fruits 3, 4

Avocado 1 15

Banana 1 0.80 1 2 4

Peach 7.0 7

7 nectarines 7 3, 4

Strawberry 20 7 5 3

MRLs with NO US Equivalent

Celery 7

Tomatoes 7

Completed: M. Negussie; 06/17 /2015

1 No US Registrations

2 Mexico a dopts US tolerances and/or Codex MRLs for its export purposes.

3 MRL estimate based on the use of thiram

4 b ased on data for dithiocarbamates other than thiram.Thiram Registration Review Scoping Document

Page 25 of 25 Appendix 3

Appendix 3. Short

- Term and/or Intermediate Term Aggregate Risk Calculations

Population Short

- or Intermediate

- Term Scenario

NOAEL

mg/kg/day LOC 1 Max

Allowable

Exposure 2

mg/kg/day Average

Food and

Water

Exposure

mg/kg/day Residential

Exposure

mg/kg/day 3 Tota l

Exposure

mg/kg/day 4 Aggregate

MOE (food,

water, and

residential) 5

Adult 6 Male 1.4 100 0.014 0.001071 0.0014 0.002471 570

Adult 6 Female 1.4 100 0.014 0.001179 0.0014 0.002579 540

Children 6

>6 years old 1.4 100 0.014 0.003339 0.0016 0.004939 280

1 The Level of Concern (LOC) is based on the 10X for interspecies extrapolation, 10X for intraspecies variations,

and 1X FQPA SF, totaling 100.

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

3 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure]. In this case, only dermal

exposure is applicable. Source of residential exposure values used in aggregate assessment.

4 Total Exposure = Avg Food & Water Exposure + Residential Exposure

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

6 Relevant population subgroup with highest exposures.