UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: Sept 3, 2015 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Revised. Thiram. Human Health Assessment Scoping Document in Support of 

Registration Review. 

PC Code: 07980 I OP Barcode: 427811 

Decision No.: 505988 Registration No.: NA 

Petition No.: NA Regulatory Action: Registration Review 

Risk Assessmen t Type: Single Chemical Aggregate Case No.: O 122 

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

M RID No.: NA 40 CF'R: § 180.132 

FROM: Dennis McNeilly, Chemist/Risk Assessor 0 .--- IV{ c...- w;_/J 

Kelly O'Rourke, Occupational/Resident~'al Ex -~Assessor ~ 0 . -Y~ Hannah 

Risk Assessment 

Pope-Varsalona, 

Branch IV 

PhD, Toxicolo · . 

/ 

~ 

Health Effects Division (7509P) 

THROUGH: Charles 

Health 

Risk Assessment 

Effects 

Smith, 

Division 

Acting 

Branch 

Branch 

(7509P) 

IV 

ChierC· ~ 

TO: Wilhelmena Livingston 

Risk Management and Implementation Branch 4 

Pesticide Reevaluation Division (7508P) 

The HED Registration Review Team has evaluated the human health assessment and database 

for the fungicide thiram (tetramethylthiuram disulfide) to determine whether sufficient data are 

available and if 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 

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 to protect turf from fungal diseases. In addition, thiram is used as an animal 

repellent to protect crops from damage by rabbits, rodents, and deer. Tolerances for residues 

in/on food and feed commodities are currently expressed in terms of residues of thiram (CFR 

§ 180.132) and are established 20 ppm for strawberry, avocado at 15 ppm, and at 7 ppm for 

apples, peaches, and nectarines. /\ tolerance without US registration is established for 
Thirarn Registration Review Scoping Document 

banana/plantain at 0.80 ppm. The seed treatment uses for thiram are considered to be nonfood 

uses and, therefore, do not require a tolerance. 

Thiram is available as dust, dry flowable, wettable powder, flowable concentrate, soluble 

concentrate, and liquid (ready to use) formu lations. It may be applied to peaches, strawbe1Ties, 

and apples using ground and aerial equipment. For other specialty uses (i.e. animal repellent) as 

well as seed treatment, applications may be made using hand held equipment. Thiram may be 

applied l-7 days before harvest depending on the crop, geographic location and pest. 

Residential/recreational exposure to thiram is expected as a result of playing golf on golf course 

fairways, greens, and tees. 

Executive Summary 

HED has considered the available risk assessments for thiram and its toxicity, exposure and 

usage databases, as well as the most cunent Agency science and assessment policies. HED 

performed this evaluation in order to determine the scope of work necessary to support the 

established tolerances and existing registrations during registration review. The primary sources 

of information for this evaluation were the Thiram Human Health Risk Assessment conducted to 

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

recent May 2 1, 2015 Risk Assessment to support an import tolerance for avocado (0427383, T. 

Morton). 

The toxicity database for thiram is complete with the exception of a 28-day inhalation study. 

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

carcinogenetic, mutagenic, and neurotoxic effects. Thiram has been shown to cause neurotoxicity 

following acute and subchronic exposures. In the acute and subchronic neurotoxicity studi es 

submitted, neurotoxicity is characterized as lethargy, reduced tail pinch response, changes in the 

functional-observation battery (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. fn a non-guideline 

study published in the open literature, chronic feeding of thiram to rats caused neurotoxicity, 

with onset of ataxia in some animals 5-19 months after beginning of treatment. However, no 

evidence of neurotoxicity was seen following chronic exposures in mice or rats in guideline 

studies submitted to the Agency. In addition, the developmental neurotoxicity (ONT) study 

revealed that thiram caused increased locomotor activity in female offspring at postnatal day 17. 

The chronic toxicity profile for thiram indicates that the liver, blood, and possibly thyroid are the 

target organs for this chemical in mice, rats, and dogs. Thiram is classified as "Not Likely to be 

Carcinogenic to Humans" based on lack of evidence for carcinogenicity in mice or rats. There 

are no mutagenic/genotoxic concerns with thiran1. The available toxicological database for 

thiram suggests that this chemical has a low to moderate acute-toxicity profile. Acute oral, 

dermal, and inhalation toxicity data for thiram puts it in toxicity categories Ill, III, II, 

respectively. Thiram is a moderate eye irritant, very slight skin irritant, and a moderate dermal 

sensitizer. 

The FQPA safety factor (SF) for thiram is reduced to IX. The recommendation of l X is based on 

the following considerations. The toxicological database for thiram is complete with acceptable 

Page 2of25 
Thiram Registration Review Scoping Document

Page 3 of 25

neurotoxicity, developmental, and reproductive toxicity 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. There is evidence of quantitative susceptibility in the DNT study. 

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

clear NOAELs/LOAELs were established for the offspring effects, the dose-response is well 

defined, and 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 postnatal toxicity. There are no residual uncertainties in the thiram exposure database.

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 thiram. The 

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

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

resulting from foliar use of thiram is, therefore, considered to be adequately understood. Thiram 

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 thiram to rotational crops. As a result, livestock metabolism is no longer 

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

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

(D239096, W. Hazel, October 6, 1998). Thiram residues convertible to carbon disulfide (CS2) 

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 (PODs) 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 numerically 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 the 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 residue limits

(MRL), for “total dithiocarbamates, determined and expressed as mg carbon disulfide per kg” in
Thiram 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, the

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

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

than 10 times higher than the level of concern of 100). Therefore, a TTR study is required. 

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

volatilization) may occur as a result of occupational applications of thiram. The need for a

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

The previous 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, updated 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 assessment 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 study. 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 scenariospecific surrogate handler-exposure data.

Chemical 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 (Pow) 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

Appendix 2.
Thiram Registration Review Scoping Document

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Hazard Identification/Toxicology

The toxicity database for thiram is complete 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 toxicity 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 (Liesivuori et al. 1994). However, the database

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

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 activity 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

mutagenicity 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 chelators, 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 et 

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 compound, a high amount of 

radioactivity was eliminated as expired air (14CO2, 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 feces. There is no apparent sex- or dose-related difference in 

the distribution, metabolism, or excretion of 14C-thiram. Bioaccumulation of 14C-thiram in 

tissues was low (1.54-4.24% of the administered dose).

Thiram is a Category III (moderately low) for acute 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,

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

(UF/SFs) were selected for oral, dermal, and inhalation exposure 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 assessment 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, developmental, 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 determined 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 HASPOC 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 indicate that thiram was 

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

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

requirement 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 CS2, - 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 CS2

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 CS2 are the residue 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 peaches in CA and AZ eliminates the 

requirement for 1-2 field trials in CA/AZ. In addition, the 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 seasonal 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 colorimetric 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 

decomposition of dithiocarbamates with release of CS2. Using these methods, the CS2 is swept 

through a trap to remove any H2S 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 cleanup 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 sufficient 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). Monitoring 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 water
Thiram 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 avocado 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 95th exposure percentile is estimated at 

0.012002 mg/kg bw/day for the general U.S. population (1.9% of the aPAD) and 0.008595 

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 0.001999 mg/kg bw/day for the general U.S. population (13% of the cPAD) and 

0.010557 mg/kg bw/day (70% of the cPAD) for children 1-2 years old, the population subgroup 

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 support

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 the registered use on golf course tees and greens was re-evaluated in a

very recent risk assessment (D427383, T. Morton, 5/21/2015). Post-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 (MOEs) 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. The estimated residential turf postapplication exposure for golfing on treated golf courses using default TTR values for thiram is

not minimal in comparison to the level of concern. The 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

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Future 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 assessment refinements 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 applications 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 revised (2012) Standard Operating Procedures for Residential Risk Assessment (SOPs) –

Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of

Spray Drift. This document outlines the quantification of indirect non-occupational exposure to

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

subsequent Volatilization Screening Analysis

(http://www.regulations.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 the 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 assessments for thiram during

registration review.

Aggregate Risk Assessment

In accordance with the Food Quality Protection Act (FQPA), HED 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 assessments take into account exposure 

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

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

general U.S. population and all other population subgroups. Therefore, the acute and long-term 

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

general U.S. population or any population 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 residential 
Thiram Registration Review Scoping Document

Page 10 of 25

exposure (dermal 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/intermediate-term aggregate 

exposures to thiram.

Conclusions: A revised 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, ready-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 of 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 gloves in addition to baseline clothing attire of long pants, long

sleeved 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 from “low”

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

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

available for strawberries, and were used to assess all foliar use sites; additional 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 existing 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 occupational handler and post-application exposure 

assessments conducted for the 2004 RED did not identify risks of concern for any of the 

remaining uses, updated occupational exposure and risk assessments will be conducted during 
Thiram Registration Review Scoping Document

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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 

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

involving thiram. These incidents were classified as minor severity (D427919, 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 involved only thiram. Eight of the nine cases were work-related. Eight cases 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 unrelated 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 commodities 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 ethylenebisdithiocarbamates (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 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 

CS2)

Comments;

[Correct Commodity Definition]

Apple 7.0 5 The conversion factor is 0.63x.

Avacado1 15 10 The conversion factor is 0.63x.

Banana1

0.80 2.0 Recommended tolerance is being raised to 

2.0 ppm CS2 to harmonize with Codex.

Peach 7.0 7.0 Recommended tolerance is being raised to 

7.0 ppm CS2 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 “total 

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 strawberry, 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 environmental 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 the 

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

was determined that there was insufficient evidence to suggest that thiram shares a common 

mechanism of toxicity with other chemical substances (dithiocarbamates). The basis for this 

conclusion is described in detail 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 2004 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 Handler 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 Board. 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 factor 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 uncertainty 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 Eligibility 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. Dithiocarbarmates. 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. D427383. Thiram: Revised Human Health Risk Assessment for the 

Import Use of Thiram on Avocado, 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. D384363. 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. 6/30/2013. 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.html
Thiram Registration Review Scoping Document

Page 16 of 25

Appendix 1

Table 1. Acute toxicity of Thiram

Guideline No./Study 

Type

MRIDs Results

Tox 

Category

870.1100 Acute Oral 00153548 LD50 =2.6 g/kg III

870.1200 Acute 

Dermal

00147099 LD50 ≥ 2.0 g/kg III

870.1300 Acute 

Inhalation

00152556 LC50 ≥ 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 bodyweight gains and food consumption.

Developmental NOAEL could not be 

determined.

LOAEL = 12.5 mg/kg, based on reduced 

ossification.
Thiram Registration Review Scoping Document

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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 13th 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 ppm (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 

decreases in pup body weight and body-weight 

gain.
Thiram Registration Review Scoping Document

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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 = 15 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 = 150 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 μg/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 μg/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 μg/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/nonguideline 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

BMDL10 = 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 posttreatment. 

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 hyperactivity 

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 [14C]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 14C was eliminated in the 

urine, 2.6-5.3% in the feces and 47-48% in the 

expired air. The nature of the volatile 14C was 

not investigated in detail, but 75-85% of it was 

collected in a KOH trap suggesting CO2, or 

COS, with the remainder collected in a reagent 

for CS2. Norris (1991) identified by HPLC the 

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 dosage level and 

the time after dosing. 

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

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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 - Rat
Thiram 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 HUMANS
Thiram 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

yes

yes

yes

yes

-

no

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 products (EPs) 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 142-150oC Revised Thiram Product and 

Residue Chemistry Chapters 

for the RED Document,

12/16/03.

Density 0.32-0.35 g/mL

Water solubility at 20-25oC 0.00165 g/100 mL

Solvent solubility at 20-25oC 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, pKa Not applicable

Octanol/water partition coefficient, POW 39.5-54.1

H C3

N

CH3

S

S N

CH3

CH3 S

S
Thiram Registration Review Scoping Document

Page 24 of 25

Table A2.3 International Residue Limits 

.

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

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 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 Mexico2 Codex

Apple 7.0 7 5 pome fruits3, 4

Avocado1

15

Banana1

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

3 MRL estimate based on the use of thiram

4 based 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 LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day

Residential 

Exposure 

mg/kg/day3

Total 

Exposure 

mg/kg/day4

Aggregate 

MOE (food, 

water, and 

residential)5

Adult6 Male 1.4 100 0.014 0.001071 0.0014 0.002471 570

Adult6 Female 1.4 100 0.014 0.001179 0.0014 0.002579 540

Children6

>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.