UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

DATE: 5-MARCH-2013 

SUBJECT: EPTC: Registration Review Scoping Document for Human Health 

Assessment. 

PC Code: 041401 

Decision No.: 470659 

Petition No.: NA 

DP Barcode: D405957 

Registration No.: NA 

Regulatory Action: Registration Review 

Assessment Type: Single ChemicaV Aggregate Reregistration Case No.: NA 

TXRNo.: NA CAS No.: 759-94-4 

MRIDNo.: NA 40 CFR: §180.117 

FROM: Mohsen Sahafeyan, Risk Assessor ~-

Deborah 

YvonneBarnes,Chemist 

Smegal, Toxicologist 8 ~~ ~ VL"-'L_ C~:b.U~ ~ 

B:idgett Bobowiec, Biologist ~ ...L.A 4~ J 

Risk Assessment Branch VI (RAB VI) T · 

Health Effects Division (HED, 7509P) 

Office of Pesticide Programs 

THROUGH: Felecia Fort, Branch Chief ~I 0 }v c---+/--

Risk Assessment Branch VI 

Health Effects Division (7509P) 

TO: Carissa Cyran, Chemical Review Manager 

Thomas Moriarty, Team Leader 

Risk Management and Implementation Branch I 

Pesticide Re-Evaluation Division (7508P) 

Executive Summary 

The Health Effects Division (HED) EPTC Registration Review Team has evaluated the 

status of the human health risk assessment for S-ethyl dipropylthiocarbamate (EPTC) to 

determine the scope of work necessary to support Registration Review. EPTC is a 

thiocarbamate herbicide used to control the growth of germinating annual weeds, 

especially grasses. It is used on a wide variety of food crops and in non-food use sites 

including ornamentals and conifer seedlings. There are currently no registered residential 

uses associated with EPTC as all of these uses have been voluntarily cancelled. The most 

Page 1 of23 
Page 2 of 23

recent risk assessment for EPTC was completed in 2012 (C. Smith, et. al., D395469, Nov 

29, 2012) to support the registration of watermelon, grass grown for seed, as well as 

update the citrus and sunflower crop groups. 

The toxicity database for EPTC is nearly complete at the present time with the exception 

of an immunotoxicity study, which is required in accordance with new data requirements 

for conventional pesticide registration (40 CFR Part 158). EPTC, as well as other

thiocarbamates, have toxic effects on the central and peripheral nervous systems. EPTC 

also consistently produced cardiomyopathy and neuronal cell necrosis in several studies 

and different species. Cholinesterase (ChE) inhibition was also seen in a number of 

toxicology studies. The Agency has determined that EPTC is “Not Likely to be 

Carcinogenic to Humans”. EPTC has low acute toxicity via the oral and dermal routes of 

exposure, and has moderately high toxicity via inhalation exposure. It is not classified as 

a skin sensitizer, dermal irritant or severe ocular irritant. Evidence of increased 

qualitative and quantitative susceptibility of the offspring was only observed in the 

developmental neurotoxicity (DNT) rat study. The concern for the increased susceptibity 

was determined to be low because the observed toxicity was well-defined and the Points 

of Departures (PODs) and standard safety factors will adequately protect infants and 

children from that potential toxicity. Neither the rat or rabbit developmental studies nor 

the rat reproduction studies identified any concerns for developmental or reproductive 

toxicity. Once the immunotoxicity study is received and reviewed HED may reevaluate 

the points of departure (PODs) and uncertainty factors for the dietary, and occupational 

exposure assessments during the registration review process.

The existing residue chemistry database for EPTC is adequate for risk assessment 

purposes. The citrus field trial data deficiency cited in 1999 RED is waived. The 

residues of concern for tolerance enforcement and risk assessment are may potentially be 

revisited during registration review. There are no established or proposed Codex 

Maximum Residue Limits (MRLs) for EPTC residues. There are Canadian MRLs for 

some crops which are slightly higher than U. S. tolerances and with different residue 

definition. HED will determine whether the residue definition and tolerance values can 

be harmonized during registration review process.

In the most recent 2012 risk assessment, based on the current use profile, exposures can 

be expected to occur via the dietary (food and drinking water), and occupational (handler 

and post-application) exposure routes for EPTC. The aggregate human health risk 

assessment included only food and water since there was no residential use. The results 

of the aggregate dietary exposure assessment for all uses indicate that the estimated risks 

are below the level of concern for both acute and chronic dietary.

Residential exposures resulting from other types of off-site transport (e.g., spray drift) 

may occur as a result of applications of EPTC. The Agency is in the process of evaluating 

these types of exposures and will examine the need for spray drift and volatilization 

assessments for EPTC during registration review.

The occupational exposure database is not complete as a chemical specific DFR study is

required for EPTC. A recent occupational exposure assessment indicated handler and 

post-application scenarios with risk estimates exceeding the level of concern. HED may 
Page 3 of 23

need to update the occupational risk assessment during the registration review if changes 

are made to currently registered EPTC labels and/or if new policies or procedures are put 

into place for either handler and post-application worker exposure scenarios. Revised 

occupational assessments may also be needed if toxicological endpoints change or other 

new data are received by the Agency which impact exposure estimates.

Introduction

EPTC is a thiocarbamate herbicide used to control the growth of germinating annual 

grassy weeds, broadleaf weeds, and some perennial weeds. The structure, chemical 

names, and other identifiers for EPTC and its hydroxylated metabolites may be found in 

Table 1A and 1B.

 

As with other thiocarbamate herbicides, EPTC exerts its herbicidal action through 

inhibition of cuticle formation at the early stages of seedling growth. There are 12 

registered Section 3 products containing EPTC. Formulated products include 

emulsifiable concentrate (EC) liquids containing up to 87.8% EPTC active ingredient 

(a.i.) and granular (G) formulations containing up to 20% EPTC a.i. The currently 

registered labels allow EPTC to be applied as a single annual, pre-emergence or early 

post-emergence application and it is usually incorporated into the soil immediately after 

application to prevent volatilization. 

EPTC also has a number of currently registered products that are listed in Table 2. In 

addition, HED has recently reviewed a proposed section 3 registration of watermelon and 

grass grown for seed. HED also recommended for updating the citrus and sunflower crop 

groups (C. Smith, et. al., D395469, Nov, 29, 2012). There are also 3 active Special Local 

Needs (SLNs) registered for EPTC. HED has reviewed the most recent exposure and risk 

assessments for EPTC, as well as toxicity data, exposure and usage databases, and the 

latest Agency science policy and risk assessment methodologies to determine if sufficient 

data are available and if updates are needed to support registration review. 

Hazard Identification/Toxicology

The toxicology database for EPTC is nearly complete as described in 40 CFR Part 158, 

except for the immunotoxicity study (see Table 4). In September 2012, the HED Hazard 

and Science Policy Council (HASPOC) waived the requirement for a 21/28 day dermal 

toxicity study (TXR 0056463, 10/4/12). This waiver was based on the weight-ofevidence approach that considered all available hazard and exposure information. The 

HASPOC concluded that a 28-day dermal toxicity would not contribute scientific 

information to reduced uncertainties in the current assessment.

EPTC is an S-alkylthiocarbamate which consistently produced cardiomyopathy and 

neuronal cell necrosis in studies of varying length of treatment and in different species

throughout the toxicity database. Cardiotoxicity was observed in subchronic and longterm studies, and in general, the severity and incidence of the lesion increased with 

increasing dose of EPTC. In 90-day feeding and inhalation studies and in two chronic 
Page 4 of 23

feeding/oncogenicity studies, all in the adult rat, histopathological evaluation revealed 

myocardial degeneration. Myocardial degeneration in adult rats was also observed in two 

separate two-generation reproduction studies. In two chronic dog studies, degenerative 

changes in the cardiac muscle were observed when EPTC was administered in a capsule, 

but not when administered (at comparable doses) in the diet. In both of the dog studies, 

electrocardiograms were taken, but only one high- dose male in the capsule study had 

changes which were described as “potentially’ treatment- related.

EPTC, as well as other thiocarbamates (molinate, cycloate, pebulate, vernolate and 

butylate), have toxic effects on the central and peripheral nervous systems. With EPTC, 

there was an increased incidence and severity of neuronal necrosis/degeneration in both 

the central and peripheral nervous systems of rats and dogs. In the neurotoxicity studies 

in rats, dose- related increases in the incidence of neuronal necrosis were observed in the 

brains after acute and subchronic exposure to EPTC. The developmental neurotoxicity 

(DNT) study revealed decreased brain weight in the rat pups, but not in the parent rats. 

In both of the combined chronic toxicity/oncogenicity studies in the rat and in the chronic 

(capsule) study in the dog, treatment-related neuromuscular lesions were observed. In all 

of these studies hindquarter weakness with corresponding histopathology findings of 

atrophy and degeneration of the skeletal muscle were observed. In the dog study, the 

lesions were described as Wallerian-type degeneration in the spinal cords and various 

peripheral nerves.

Cholinesterase (ChE) inhibition was also seen in a number of toxicology studies, 

however, no consistent pattern was witnessed across studies with respect to ChE

inhibition between different species, length of treatment, or the type of ChE enzyme 

measured.

EPTC is classified as “Not Likely to be Carcinogenic to Humans.” This is supported by 

lack of a carcinogenic effect in long-term studies and no genetic component in 

reproduction and developmental studies. There is no concern for mutagenicity and 

clastogenicity based on a genotoxicity panel that included in vivo and in vitro assays. 

The updated subchronic, chronic and other toxicity profile for EPTC is presented in Table 

6. 

The FQPA Safety Factor is reduced to 1X for chronic dietary exposure. For acute 

dietary exposure, EPA has retained the 10X FQPA SF for use of a LOAEL to NOAEL 

uncertainty factor. There is no evidence of susceptibility following in utero and/or 

postnatal exposure in the developmental toxicity studies in rats or rabbits, and in the 2-

generation rat reproduction study. Although there is evidence of susceptibility in the rat 

developmental neurotoxicity study (decrease in absolute pup brain weights (4-6%) in 

male pups on PND 63 at all dose levels > 7.5 mg/kg/day), the risk assessment PODs were 

established using the most sensitive and robust endpoint (cardiomyopathy) and are 

protective of these pup effects. In addition, the decrease in absolute pup brain weight (4-

6%) demonstrated a flat dose response, was only observed in one sex (males) at one timepoint (PND 63) and no difference noted in the brain weight after perfusion. A summary 

of the EPTC toxicological points of departure for use in risk assessment is shown in 

Table 7.
Page 5 of 23

Conclusions : The toxicity database for EPTC is complete except for an immunotoxicity 

study, which is required under the 2007 revised 40CFR Part 158 Toxicology Data 

Requirements. Once the immunotoxicity study is received and reviewed, HED may

reevaluate the points of departures and uncertainty factors for the dietary and 

occupational exposure assessments during the registration review process.

Dietary Exposure 

The existing residue chemistry database for EPTC is adequate for risk assessment and 

tolerance enforcement. A deficiency in 1999 RED for citrus field trial data on residues of 

hydroxylated metabolites of EPTC was identified as outstanding. HED however 

concluded that there is a strong likelihood that those residues are below the limit of 

quantification (LOQ) in citrus fruits. The hydroxylated metabolites have been reported 

as below LOQ in all crops with the edible commodity above ground, particularly in 

almonds (the only registered orchard crop besides citrus). It is therefore, very unlikely 

that those metabolites will be detectable in citrus fruits. In addition, the current tolerance 

on citrus fruit is sufficiently high to cover potential maximum residues of EPTC and the 

combined LOQ-level residues of hydroxylated metabolites of EPTC. HED therefore, 

concluded that for citrus only the field trial data requirement should be waived. Note that 

data on the hydroxylated metabolites are needed should the registrant pursue registrations 

on any additional crops.

The residues of concern for tolerance enforcement and risk assessment may be revisited 

during registration review to facilitate international harmonization. The residues of 

concern in plants for risk assessment are EPTC, EPTC sulfoxide, EPTC sulfone, and the 

EPTC conjugates (cysteine-; N-malonyl cysteine-; S-lactic acid-; and O-malonyl-S-lactic 

acid- conjugates). The residues of concern in plants for tolerance enforcement are EPTC 

and its hydroxylated metabolites (N-2-hydroxypropyl EPTC, N-3-hydroxypropyl EPTC, 

and 2-hydroxyethyl EPTC) used as marker residues. Residues of EPTC and its three 

hydroxylated metabolites were nondetectable (<0.05 ppm) in the majority of samples of 

raw and processed commodities from the submitted field trials. 

For animal commodities, the Agency has concluded that residues of EPTC in animal 

commodities represent a Category 3 situation under 40 CFR §180.6(a): i.e., there is “no

reasonable expectation of the occurrence of finite residues in animal commodities”.

Hence, tolerances on animal commodities are not necessary. 

The last dietary risk assessment was conducted in September 2012 as part of human 

health risk assessment to support request for EPTC use on watermelon (Y. Barnes, 

D401100, 9/20/ 2012) and included all registered and proposed food uses. Acute and 

chronic dietary exposure assessments were conducted using the Dietary Exposure 

Evaluation Model software with the Food Commodity Intake Database DEEM-FCID, 

Version 3.16, which uses food consumption data from the U.S. Department of 

Agriculture’s National Health and Nutrition Examination Survey, What We Eat in 

America, (NHANES/WWEIA). The acute and chronic dietary food exposure 

assessments were conservative in nature. The dietary risk assessments included tolerance 

level residues for all proposed and currently registered uses with 100% crop treated 
Page 6 of 23

assumptions and using default processing factors established since DEEM 7.81. The 

Mississippi cotton (MS) drinking water scenario (parent only) was used in the 2012 

assessment as it resulted in the highest estimated drinking water concentrations 

(EDWCs). Neither EPTC sulfoxide nor EPTC sulfone, degradates of EPTC, were 

detected in the environmental fate studies and are not expected to form at significant 

levels in the environment. EPTC may be transformed (via oxidation) to EPTC sulfoxide 

and EPTC sulfone during water disinfection, however, barring more specific information, 

the Agency focused on EPTC parent only drinking water concentrations. The acute and 

chronic (non-cancer) dietary (food and water) risks for EPTC were not of concern. 

Conclusions: The existing residue chemistry database for EPTC is adequate for risk 

assessment and tolerance enforcement. The citrus field trial data deficiency cited in 1999 

RED is waived. However, data on the hydroxylated metabolites are needed should the 

registrant pursue registrations on any additional crops. The residues of concern for 

tolerance enforcement and risk assessment may be potentially revisited during 

registration review. The exposure and risk estimates, however, may need to be updated if 

changes are made to toxicity endpoints, toxicity uncertainty factors, estimated residues in 

drinking water or dietary exposure policies.

Residential Exposure and Risk Assessment

There are currently no registered residential uses associated with EPTC, as all of these 

uses have been voluntarily cancelled. Therefore, a residential/non-occupational exposure 

assessment is not required. However, the primary dissipation process for EPTC is 

volatilization (vapor pressure of 0.024 mm Hg). EPTC has been routinely found in air 

monitoring studies performed by the California Air Resources Board and California 

Department of Pesticide Regulation. Based on these studies, there is potential for 

residential bystanders to be exposed to EPTC via the inhalation route. In the 2012 

assessment, HED performed a preliminary bystander volatilization inhalation exposure 

assessment for EPTC utilizing the currently available inhalation toxicity and air 

monitoring data. The results of this assessment indicate that none of the air 

concentrations results in acute and/or short- and intermediate-term risks of concern. The 

Agency is in the process of further evaluating inhalation bystander exposures resulting 

from volatilization and will examine the need for further assessment of this issue during 

registration review for EPTC.

Residential exposures resulting from other types of off-site transport (e.g., spray drift) 

may occur as a result of applications of EPTC. The Agency is in the process of evaluating 

these types of exposures and will examine the need for spray drift and volatilization 

assessments for EPTC during registration review.
Page 7 of 23

Aggregate Exposure 

The ETPC aggregate risk assessment includes only dietary exposure (food and water); 

there are no residential uses. Acute and chronic dietary exposure estimates from food 

and drinking water do not exceed HED’s level of concern.

Occupational Exposure

HED recently updated the occupational handler exposure assessments for the 2012

section 3 use on grasses grown for seed production and watermelon risk assessment (M. 

Hawkins, D395467,11/29/2012 ). This assessment includes an updated hazard and 

occupational exposure assessment for all uses to reflect current information and policies.

Occupational Handlers

The assessment evaluated a number of occupational handler scenarios that represented 

the major EPTC occupational handler scenarios based on application equipment and 

formulation type. The short- and intermediate-term dermal risks exceeded HED’s level 

of concern (MOEs < 100) for a few handler scenarios (mixing/loading liquids) with the 

required personal protective equipment (PPE) of chemical-resistant gloves. All of these 

MOEs improve to ≥ 100 with the addition of a double layer of PPE with chemicalresistant gloves. The short- and intermediate-term inhalation risks exceeded HED’s 

level of concern (MOEs < 30) for a few handler scenarios (mixing/loading granular). 

All of the MOE’s improve to ≥ 30 with the use of a NIOSH approved respirator with an 

organic-vapor removing cartridge with a pre-filter approval for pesticides.

Occupational Post-Application

The most recent occupational assessment indicates that there are also potential

occupational post-application risk estimates of concern. All current EPTC labels have a 

re-entry interval (REI) of 12 hours based on the acute toxicity of EPTC.

Most of the uses of EPTC are pre-plant or at plant, therefore there is minimal foliar 

contact, but there are some post-plant emergence uses on the current EPTC labels. In the 

2012 assessment, HED produced a post-application assessment to cover the early postemergent uses with less mature plants that are closer to the ground. These assessments 

should be considered conservative because the dermal TC studies were conducted with 

more mature foliage plants.

The 2012 assessment also uses HED’s default assumption that 25% of the application is 

available for transfer on day 0 following the application and the residues dissipate at a 

rate of 10% each following day as EPTC dislodgeable foliar residue (DFR) data have not 

been submitted. In accordance with the updated Part 158 data requirements (2007), one 

or more DFR studies are required when a pesticide has residential or occupational uses 

that could result in post-application dermal exposure. As part of the recent revision to the 

Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide 

Exposure Assessment, HED analyzed a number of DFR studies and selected a new 

default value for the fraction of the application rate available to be dislodged after a foliar 

application (FAR). This default value is 25%. Of the analyzed DFR studies, the 
Page 8 of 23

maximum FAR value seen was 89% or 3.6 times higher than the default residue transfer 

value. Therefore, a calculated MOE of approximately 4 times higher than the LOC (i.e., 

an MOE > 400 for EPTC since the LOC = 100) using the default dislodged residue value 

would provide an adequate margin of safety for any potentially higher residues seen in a 

chemical-specific DFR study. 

Conclusions: The occupational exposure database is not complete as a chemical specific 

DFR study is required for EPTC. A recent occupational exposure assessment indicated 

handler and post-application scenarios with risk estimates exceeding the level of concern. 

HED may need to update the occupational risk assessment during the registration review 

if changes are made to currently registered EPTC labels and/or if new policies or 

procedures are put into place for either handler and post-application worker exposure 

scenarios. Revised occupational assessments may also be needed if toxicological 

endpoints change or other new data are received by the Agency which impact exposure 

estimates.

Human Studies

The 2012 EPTC risk assessment relies in part on data from studies in which adult human 

subjects were intentionally exposed to a pesticide or other chemical. Studies such as the 

Pesticide Handlers Exposure Database and the Agricultural Handler Exposure Task Force 

have been reviewed by the Agency and found on the basis of available evidence to have 

been neither fundamentally unethical nor significantly deficient relative to standards of 

ethical research conduct prevailing when they were conducted. There is no barrier in 

EPA's "Protection of Human Subjects" Regulation to reliance on these studies.

Public Health and Pesticide Epidemiology Data

Based on the low frequency and severity of incident cases reported for EPTC in the 

Incident Data System (IDS) and NIOSH SENSOR-Pesticides, there does not appear to be 

a concern at this time that would warrant further investigation. However, there were 

some findings in the current Agricultural Health Study (AHS) findings that merit further 

evaluation in the follow-on studies from the AHS. In addition, the Agency will continue 

to monitor the incident information and if a concern is triggered, additional analysis will 

be also be included at that time (S. Recore, 11/7/2012, D405961).

Tolerance Assessment and International Harmonization

US permanent tolerances for EPTC are listed in 40 CFR 180.117 and are summarized in 

Table 2. There are no established or proposed Codex MRLs for EPTC residues. There

are Canadian MRLs for some crops which are slightly higher than U. S. tolerances and 

have a different residue definition. HED will determine whether the residue definition

and the tolerance values can be harmonized during registration review process.
Page 9 of 23

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 LowIncome 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.

Endocrine Disruption Screening Program

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential 

adverse outcomes from exposure to chemicals. Collectively, these studies include acute, 

subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, 

developmental, reproductive, and general or systemic toxicity. These studies include 

endpoints which may be susceptible to endocrine influence, including effects on 

endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, 

fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological 

hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, 

developmental and reproductive effects in different taxonomic groups. As part of its 

reregistration decision, EPA reviewed these data and selected the most sensitive 

endpoints for relevant risk assessment scenarios from the existing hazard database. 

However, as required by FFDCA section 408(p), EPTC is subject to the endocrine 

screening part of the Endocrine Disruptor Screening Program (EDSP). 

EPA has developed EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the 

Administrator may designate.” The EDSP employs a two-tiered approach to making the 

statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to 

identify the potential of a chemical substance to interact with the estrogen, androgen, or 

thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and 

are found to have the potential to interact with E, A, or T hormonal systems will proceed 

to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests 

are necessary based on the available data. Tier 2 testing is designed to identify any 

adverse endocrine related effects caused by the substance, and establish a dose-response 

relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group 

of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 
Page 10 of 23

EPTC was included on that list and has been issued an order to conduct the Tier 1 testing. 

Once all required Tier 1 and Tier 2 data have been received and reviewed, the endpoints 

and safety factors used for EPTC risk assessment purposes will be examined and a new 

risk assessment performed if necessary. For further information on the status of the 

EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test 

guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/. 

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. The Agency determined 

that there was insufficient evidence to suggest EPTC shares a common mechanism of 

toxicity with other chemical substances (thiocarbamates). At a September 2001 meeting, 

the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory 

Panel (SAP) supported the Agency’s determination (Common Mechanism of Action of 

Thiocarbamates and Dithiocarbamates, the FIFRA SAP meeting, September 7, 2001).

Data Requirements

Guideline Number: 870.7800 - Study Title: Immunotoxicity

Guideline Number: 875.2100 - Study Title: Dislodgeable Foliar Residue (DFR)
Page 11 of 23

References

Author Barcode Date Title

Monica 

Hawkins

D395467 11/29/2012 EPTC: Occupational and Residential 

Exposure Assessment for Proposed Section 3 

Registration for use on Grasses Grown for 

Seed Production

Charles 

Smith

D395469

D397477

11/29/2012 EPTC: Human Health Risk Assessment for 

Proposed Uses on Grass Grown for Seed

Yvonne 

Barnes

405053 11/27/2012 Revised EPTC: Summary of Analytical 

Chemistry and Residue Data for new uses on 

Watermelon, Fruit Citrus Group 10-10 and 

Sunflower Group 20B

Paula 

Deschamp

D244982 4/7/1999 EPTC (S-Ethyl dipropylthiocarbamate): HED 

Risk Assessment for the Reregistration

Eligibility Decision (RED) Document.

Shanna 

Recore

D405961 11/7/2012 EPTC: Review of Human Incidents

Yvonne 

Barnes

D401100 9/20/2012 EPTC. (Carbamothioic acid, dipropyl-, Sethyl ester) Acute and Chronic Aggregate 

Dietary (Food and Drinking Water) 

Assessment to Support New Use on 

Watermelon. 

Kristin 

Rury

TXR# 

0056463

10/4/2012 EPTC: Summary of Hazard and Science 

Policy Council (HASPOC) Meeting of 

September 13, 2012: Recommendations on 

the Requirement of a 21-Day Dermal Toxicity 

Study.

Table 1A - Chemical Identity of EPTC and Its Hydroxylated Metabolites

Chemical structure

Common name EPTC

Company experimental 

name

None given

IUPAC name S-ethyl dipropylthiocarbamate

CAS name Carbamothioic acid, dipropyl-, S-ethyl ester

CAS registry number 759-94-4

S N

CH3

CH3

O

H3C
Page 12 of 23

Table 1A - Chemical Identity of EPTC and Its Hydroxylated Metabolites

End-use product (EP) DoublePlay® 

Selective Herbicide (5.6 lb/gal EC formulation; EPA Reg. No. 100-

1083);

Eptam® 20-G (20% G formulation; EPA Reg. No. 10163-281);

Eptam® 7-E (7 lb/gal EC formulation; EPA Reg. No. 10163-283)

Chemical structure

Common name N-2-hydroxypropyl EPTC; R248722

Chemical name S-ethyl (2-hydroxypropyl)propylcarbamothioate

Chemical structure

Common name 2-hydroxyethyl EPTC; R245255

Chemical name S-2-(hydroxyethyl)dipropylcarbamothioate

Chemical structure

Common name N-3-hydroxypropyl EPTC; R248723

Chemical name S-ethyl (3-hydroxypropyl)propylcarbamothioate

Table 1B - Physicochemical Properties of EPTC

Parameter Value Reference 1

Melting point/range 137-138 oC MRID 42120801

pH 7.4 (25 oC) MRID 42120801

Density 0.9639 g/mL MRID 42120801

Water solubility 0.0344 g/100mL (25oC) MRID 42120801

Solvent solubility Visually miscible in acetone, hexane, 

methanol, 1-octanol, toluene, acetonitrile, 

dichloromethane, and ethyl acetate (22 oC)

MRID 42120801

Vapor pressure 0.024 mm Hg (25 oC) MRID 42120801

Dissociation constant, pKa Not applicable

Octanol/water partition coefficient, 

Log(KOW)

3.34 MRID 42120801

UV/visible absorption spectrum Data Gap

1 DP# 172761, 09/22/1992, F. Toghrol

H3C S N

CH3

CH3

O

OH

S N

CH3

CH3

O

HO

H3C S N

CH3

O

OH
Page 13 of 23

Table 2 - Summary of US and International Tolerances and Maximum Residue 

Limits

Residue Definition:

US Canada Mexico1 Codex

40 CFR 180.117

The sum of parent (S -ethyl dipropylthiocarbamate) and its 

metabolites, S -ethyl (2-hydroxypropyl)propylcarbamothioate, 

S -(2-hydroxyethyl)dipropylcarbamothioate, and S -ethyl (3-

hydroxypropyl)propylcarbamothioate, calculated as the 

stoichiometric equivalent of the parent (S -ethyl 

dipropylthiocarbamate)

carbamothioic 

acid, N,Ndipropyl-, Sethyl ester

None

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

US Canada Mexico1 Codex

Alfalfa, forage 0.2

Alfalfa, hay 0.6

Almond 0.08

Almond, hulls 0.08

Bean, dry, seed 0.08 0.1 Dry (beans, broad beans, 

catjang seeds, chickpeas, guar 

seeds, kidney beans, lablab 

beans, lentils, moth beans, 

mung beans, navy beans, pink 

beans, pinto beans, rice beans, 

southern peas, tepary beans, 

urd beans)

Bean, succulent 0.08 0.1 edible podded ( jackbeans, 

moth beans, runner beans, 

snap beans, sword beans, wax 

beans, yardlong beans)

Beet, garden, tops 0.5

Beet, sugar, molasses 0.4

Beet, sugar, tops 0.5

Clover, forage 0.1

Clover, hay 0.1

Corn, field, forage 0.08

Corn, field, grain 0.08 0.1

Corn, field, stover 0.08

Corn, pop, grain 0.08

Corn, pop, stover 0.08

Corn, sweet, forage 0.08

Corn, sweet, kernel plus cob with 

husks removed

0.08 0.1

Corn, sweet, stover 0.08

Cotton, gin byproducts 0.20

Cotton, undelinted seed 0.08

Fruit, citrus, group 10 0.1

Lespedeza, forage 0.1

Lespedeza, hay 0.1

Pea, succulent 0.08

Safflower, seed 0.08
Page 14 of 23

Table 2 - Summary of US and International Tolerances and Maximum Residue 

Limits

Residue Definition:

US Canada Mexico1 Codex

Sunflower, seed 0.08 0.1

Tomato 0.08

Trefoil, forage 0.1

Trefoil, hay 0.1

Vegetable, root 0.1 0.1 potatoes, rutabaga roots, 

sugar beet roots, turnip roots

Walnut 0.08

MRLs with NO US Equivalent

Flaxseeds 0.1

Completed: M. Negussie; 10/24/2012
Page 15 of 23

Table 3 - Summary of Registered Use Patterns and Formulations for ETPC Products

Reg No % ai Product Type Application 

Equipment

Application 

Method 

Timing

Use Sites

100-1083

Double 

Play®

67.8 % 

Emulsifiable 

Liquid

5.6 lbs of ai EPTC 

per gallon of 

product

Ground, 

Impregnated 

dry bulk 

fertilizer

Preplant soil 

incorporated Corn

Field Corn, Production Seed Corn Silage Corn, and 

Popcorn

19713-568

Power 

Play®

10163-285

Gowan 

EPTAM

100-1026

Eradicane

® 6.7-E

82.6 % 

Emulsifiable 

Liquid

6.7 lbs of ai EPTC 

per gallon of 

product

Ground, 

Impregnated 

dry bulk 

fertilizer

19713-562

Razencane 

6.7E®

82.6 %

Emulsifiable 

Liquid

6.7 lbs. of ai EPTC 

per gallon of 

product

Ground, 

Chemigation, 

impregnated 

dry bulk 

fertilizer

10163-281

Eptam 20G 

® 

20.0 % 

Granules

20 lbs. of ai EPTC 

per 100 lbs of 

product

Ground, 

Chemigation, 

Aerial

Soil 

incorporated 

pre or postplant prior to 

weed 

emergence

Alfalfa, Birdsfoot trefoil, Clovers, Lespedeza, 

Alfalfa, Forage, Perennial Seed, Beans Green or 

Dry, Citrus, nursery stock, Conifer nursery stock, 

Corn, Idle and Fallow Ground, Potatoes (Irish), 

Safflower, Sugar Beets, Sunflowers.

10163-283

Eptam 7-E

87.8 %

Emulsifiable 

Liquid

7 lbs of ai per 

gallon of product

Ground, 

Chemigation, 

impregnated 

dry bulk 

fertilizer.

Alfalfa, Birdsfoot trefoil, clovers, Lespedeza, 

Established Alfalfa, Almonds, Ladino clover, Beans 

Dry or Green, Citrus nursery stock and young field 

plantings, Cotton, Idle and Fallow Ground, Pine 

Seedlings, Potatoes, Safflower, Sugar Beets, 

Sunflower, Sweet Potatoes, Tomatoes, Walnuts. 

Watermelon

19713-101

EPTC®-

7EC

87.8 % 

Emulsifiable 

Liquid

7 lbs of ai EPTC 

per gallon of 

product

Ground, 

Chemigation, 

impregnated 

dry bulk 

fertilizer.

Alfalfa, Birdsfoot trefoil, Clovers, Lespedeza, 

Established Alfalfa,, Ladino clover, Castor Beans, 

Citrus nursery stock and young field plantings, 

Cotton, Idle and Fallow Ground, Pine Seedlings, 

Potatoes, Safflower, Sugar Beets, Sunflower, Sweet 

Potatoes (Irish), Tomatoes,

19713-561

Eptek® 7 

EC

87.8 % 

Emulsifiable 

Liquid

7 lbs of ai EPTC 

per gallon of 

product

Ground, 

Chemigation, 

impregnated 

dry bulk 

fertilizer

Alfalfa, Almonds, Birdsfoot trefoil, Clover, 

Lespedeza, Ladino clover, Beans Green or Dry, 

Citrus nursery stock and young field plantings, 

Cotton, Ornamentals, Pine Seedlings, Potatoes 

(Irish), Safflower, Sugar Beets, Sunflower, Sugar 

Beets, Sweet Potatoes, Tomatoes, Walnuts

56077-71

Also 

19713-564

Eptam® 

7E

87.8 % 

Emulsifiable 

Liquid

7 lbs of ai EPTPC 

per gallon of 

product

Ground, 

Chemigation, 

impregnated 

dry bulk 

fertilizer

Alfalfa, Almonds, Birdsfoot trefoil, Clover, 

Lespedeza, Established Alfalfa,, Ladino clover, 

Beans Green or Dry, Citrus, Cotton, Pine Seedlings, 

Potatoes (Irish), Safflower, Sugar Beets, Tomatoes, 

Walnuts
Page 16 of 23

Table 4 - Status of Required Toxicological Studies for EPTC

Guideline Number and Toxicity 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 21/28-Day Dermal.........................................................

870.3250 90-Day Dermal..............................................................

870.3465 90-Day Inhalation..........................................................

yes

yes

yes

no

CR

yes

yes

yes 1

--

yes

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.......................................................................................

870.5375 Mutagenicity—Structural Chromosomal 

Aberrations.......................................................................................

870.5550 Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen).....................................

870.6100b 90-Day Neurotoxicity (hen) ..........................................

870.6200a Acute Neurotox. Screening Battery (rat) .......................

870.6200b 90-Day Neuro. Screening Battery (rat)..........................

870.6300 Develop. Neuro .............................................................

no

no

yes

yes

yes

--

--

yes

yes

yes

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration........................................................

870.7800 Immunotoxicity.......................

yes

no

yes

yes

--

no

Special Studies for Ocular Effects

Acute Oral (rat)...........................................................

Subchronic Oral (rat) ..................................................

Six-month Oral (dog)..................................................

no

no

no

--

--

--

1 HASPOC waived the requirement for a 21/28 day dermal toxicity study (TXR 0056463, 10/4/2012).

CR= conditionally required
Page 17 of 23

Table 5 - Acute Toxicity Profile for EPTC

Guideline 

No. Study Type MRID Results Toxicity Category

870.1100 Acute oral- rat 00157868

♂LD50 = 1465 (1290-1663) mg/kg

♀ LD50 = 1712 (1324-2214) mg/kg

Combined LD50 = 1599 (1294-1976) 

mg/kg

III

870.1200 Acute dermal- rabbit 00157869 ♂LD50 > 2000 mg/kg

♀ LD50 > 2000 mg/kg III

870.1300 Acute inhalation - rat 00157870 Combined LC50 = 1.39 (0.97-2.00) 

mg/L II

870.2400 Primary eye 

irritation- rabbit 00157871 PIS (24 hrs) = 2.2Reversed within 3 days III

870.2500 Primary Dermal 

irritation- rabbit 00157872 PII = 1.4 IV

870.2600 Skin sensitizationguinea pig 00157873 Very slight sensitizer N/A

870.2600 Skin sensitizationguinea pig 41709201 Weak sensitizer (Magnusson- Kligman) N/A
Page 18 of 23

Table 6- EPTC: Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

870.3100 90-Day oral toxicity 

(rat)

00144651 (1983)

Acceptable/guideline

M: 0, 18, 36, 72, 120 

mg/kg/day

F: 0, 3, 15, 72, 120 

mg/kg/day

Systemic NOAEL = 18 mg/kg/day ♂, 3 

mg/kg/day ♀

Systemic LOAEL = 36 mg/kg/day ♂, 15 

mg/kg/day ♀, based on decreased body weight 

and body weight gain and increased incidence of 

cardiomyopathy.

ChE NOAEL = 120 mg/kg/day ♂, 72 

mg/kg/day ♀

ChE LOAEL = not est. in ♂, 120 mg/kg/day ♀ 

based on 14% inhibition of plasma ChE in 

females

870.3150 90-Day oral toxicity 

(dog)

00150327 (1985)

Acceptable/guideline

0, 200, 600, 1800 ppm

0, 5, 15, 45 mg/kg/day

Systemic NOAEL = 15mg/kg/day ♂, 45 

mg/kg/day ♀

Systemic LOAEL = 45 mg/kg/day ♂, not est. in 

♀ based on excess salivation and decreased 

body weight gain in males

ChE NOAEL = 15 mg/kg/day ♂, 45 mg/kg/day 

♀

ChE LOAEL = 45 mg/kg/day ♂, not est. in ♀ 

based on 25% decreased in plasma ChE in 

males

870. 90-Day Inhalation 

toxicity (rat)

00154784 (1985)

Acceptable/guideline

0, 8.3, 58, 290 mg/m3

MMAD= 2.8 μm

BMD10= 10.84

BMDL10= 5.05

BMD10 = 10.84

BMDL10 = 5.05 based on brain cholinesterase 

inhibition in males; decreased food 

consumption, increased prothrombin time and 

incidence of cardiomyopathy at high doses. 

870.3700a Prenatal 

developmental in 

(rat)

00138919 (1983)

Acceptable/guideline

F: 0, 30, 100, 300 

mg/kg/day

Maternal NOAEL = 100 mg/kg/day

LOAEL = 300 mg/kg/day based on lethality, 

decreased body weight gain, corrected body 

weight gain, and food consumption.

Developmental NOAEL = 100 mg/kg/day.

LOAEL= 300 mg/kg/day based on decreased 

fetal body weight, decreased litter size, 

increased resorptions, increased incidence of 

omphalocle and increased incidence of 

unossified sternebrae.
Page 19 of 23

Table 6- EPTC: Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

870.3700b Prenatal 

developmental in 

(rabbit)

40442302 (1987)

Acceptable/guideline

F: 0, 5, 40, 300 mg/kg/day

Maternal NOAEL = 40 mg/kg/day

LOAEL = 300 mg/kg/day based on decreased 

body weight, food consumption, mortality and 

clinical signs

Developmental NOAEL = 40 mg/kg/day

LOAEL = 300 mg/kg/day based on reduced 

fetal body weight. 

Maternal ChE NOAEL was not established.

Maternal ChE LOAEL ≤ 5 mg/kg/day based on 

inhibition of serum ChE by 10%.

870.3800 Reproduction and 

fertility effects

(rat)

0012128 (1982), 40420408 

(1987)

Acceptable/guideline

0, 40, 200, 1000 ppm

0, 2, 10, 50 mg/kg/day

Parental/Systemic NOAEL = 10 mg/kg/day 

LOAEL = 50 mg/kg/day based on degenerative 

cardiomyopathy in males and females and renal 

tubule degenerative in females

Reproductive NOAEL = 50 mg/kg/day 

LOAEL > HDT.

Offspring NOAEL = 10 mg/kg/day 

LOAEL = 50mg/kg/day based on decreased pup 

weight during postnatal day 14 to 21.

870.3800 Reproduction and 

fertility effects

(rat)

00161597 (1986)

Acceptable/guideline

0, 50, 200, 800 ppm

0, 2.5, 10, 40 mg/kg/day

Parental/Systemic NOAEL = 2.5 mg/kg/day 

LOAEL = 10 mg/kg/day based on decreased 

body weight/ body weight gain and 

cardiomyopathy.

Reproductive NOAEL = 40 mg/kg/day 

LOAEL > HDT.

Offspring NOAEL = 10 mg/kg/day 

LOAEL = 40mg/kg/day based on decreased 

mean pup weight during lactation days 4 to 21.

870.4100b Chronic toxicity 

oral (dog)

00161595 (1986)

Unacceptable/guideline

0, 200, 600, 1800 ppm

M: 0, 5.6, 17.3, 48.5 

mg/kg/day

F: 0, 6.1, 17.4, 54.7 

mg/kg/day

NOAEL = 48.5 mg/kg/day ♂, 54.7 mg/kg/day 

♀.

LOAEL was not established. 

870.4100b Chronic toxicity 

capsule (dog)

40442301 (1987)

Acceptable/guideline

0, 1, 8, 60 mg/kg/day

Systemic NOAEL = 8 mg/kg/day 

Systemic LOAEL = 60 mg/kg/day based on 

decreased body weight gain in males and 

peripheral/ central nervous system degeneration 

and skeletal/ cardiac muscle degeneration in 

males and females.

ChE NOAEL = 8 mg/kg/day

ChE LOAEL = 60 mg/kg/day based on ChE 

inhibition (decreased plasma ChE by 32 and 

42% in males and 23 to 26% in females
Page 20 of 23

Table 6- EPTC: Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

870.4200 Carcinogenicity

(mouse)

00161596 (1985)

Acceptable/ guideline

0, 200, 600, 1800 ppm

0, 30, 90, 270 mg/kg/day

NOAEL = 90 mg/kg/day

LOAEL = 270 mg/kg/day based on decreased 

body weight and food consumption.

870.4300 Chronic/ 

Carcinogenicity

(rat)

40215001 (1987)

Acceptable/guideline 

carcinogenicity part

0, 9, 18, 36, 72 mg/kg/day

Unacceptable/ guideline

Chronic portion because 

systemic toxicity was not 

established.

NOAEL = not est.

LOAEL = 9 mg/kg/day based on decreased 

body weights, body weight gain, and increased 

incidence of degenerative cardiomyopathy.

870.4300 Chronic/ 

Carcinogenicity

(rat)

00145004; 00145311 

(1983)

Acceptable/guideline

M: 0, 5.01, 25, 125.8 

mg/kg/day

F: 0, 4.97, 24.8, 124.8 

mg/kg/day

NOAEL = 5 mg/kg/day 

LOAEL = 25 mg/kg/day based on decreased 

body weight and increased incidences of 

myocardial and neuromuscular lesions. 

870.5100 Bacterial Reverse 

Mutation

00152451 (1978)

Acceptable/ guideline

Negative with/ without S9 activation at 10- 500 

μg/plate

870.5100 Bacterial Reverse 

Mutation

00152452 (1977)

Acceptable/ guideline

Negative with / without 59 activation at 0.001 -

5.0 μL/plate

870.5300 In vitro Mouse 

Lymphoma assay

00152454 (1984)

Acceptable/ guideline

Negative without S9 activation at 0.0125-0.15 

μL/mL, and slightly mutagenic effect with S9 

activation at 0.005 -0.06 μL/mL.

870.5300 In vitro Mouse 

Lymphoma assay

00161602 (1986)

Acceptable/ guideline

Negative without S9 activation Positive with S9 

activation

870.5375 

In vitro Chinese 

Hamster Ovary 

(CHO) 

Chromosome 

Aberration 

00161601 (1985)

Acceptable/ guideline

Negative with/without S9 activation

870.5375

Mouse Lymphoma 

Chromosomal 

Aberration Assay

00152455 (1984)

Acceptable/ guideline

Negative without S9 activation at 0.0125-0.15 

μL/mL and with S9 activation at 0.005-0.06 μL 

/mL

870.5395

Mammalian 

Erythrocyte 

Micronucleus 

00142895 1984)

Acceptable/ guideline

Negative at MTD (55% lethality)

870.5395

Drosophila 

melanogaster Sexlinked Recessive 

Lethal Mutations

00153248 (1985)

Acceptable/ guideline

Negative for inducing sex-linked recessive 

lethals
Page 21 of 23

Table 6- EPTC: Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

870.5395 Bacillus subtilis 

Rec-Assay

00152451 (1978)

Acceptable/ guideline

Negative without S9 activation at 1 to 100% 

(v/v), with 59 activation not evaluated.

870.5550

Unscheduled DNA 

Synthesis in 

Mammalian 

Cultured Cells

00161600 (1986)

Acceptable/ guideline

Negative

870.6200a Acute neurotoxicity 

screening battery

43039701, 43297401 

(1994) 

Acceptable/ guideline

0, 200, 1000, 2000 

mg/kg/day

NOAEL = not est. ♂, 200 mg/kg/day ♀

LOAEL = 200 mg/kg/day ♂, 1000 mg/kg/day ♀ 

based on neuronal cell necrosis in the brain in 

males and clinical signs, death, and neuronal 

cell necrosis in the brain in females.

870.6200b Subchronic 

neurotoxicity 

screening battery

43230901 (1994)

Acceptable/guideline

0, 500, 1000, 2500 ppm

M: 0, 7.9, 39.4, 193 

mg/kg/day

F: 0, 8.8, 43.5, 205 

mg/kg/day

NOAEL = 7.9 mg/kg/day ♂, 8.8 mg/kg/day ♀

LOAEL = 39 mg/kg/day ♂, 44 mg/kg/day ♀ 

based on decreased body weight gain and 

relative brain weight in females and neuronal 

necrosis in the brain in males and females.

870.6300 Developmental 

Neurotoxicity 

46319101 (2004)

Acceptable/guideline

0, 100, 300, 1000 ppm

0, 7.6, 21.9 and 67.2 

mg/kg/day

Maternal NOAEL= 21.9 mg/kg/day

Maternal LOAEL = 67.2 mg/kg based on 

clinical signs (piloerection, hunched posture, 

sides pinched in) decreased body weight, body 

weight gain, and food consumption and 

increased incidence of whole losses.

Dev. /Offspring NOAEL = not established.

Dev. /Off spring LOAEL = 7.6 mg/kg/day based 

on decreases in absolute brain weights in male 

pups only on PND.
Page 22 of 23

Table 6- EPTC: Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

870.7485 Metabolism (rat)

00142896 (1979)

Acceptable/guideline

121-150 mg/kg

Eptam was rapidly absorbed and excreted: the 

urine of males and females contained 81 and 

88% of the administered radiolabel, 

respectively, within 24 hours. The feces and 

expired air were minor excretion routes, each 

containing ≤ 3.2% of the radioactivity over 96 

hours. Absorption was estimated to be 86.7-

97.5% of the administered dose for the two 

sexes. The mass balance accounting for the 1, 3, 

and 7 day experiments was acceptable: 

radioactivity from the expired air, urine, feces, 

and cage wash accounted for 90.1, 99.6, and 

88.8% of the given dose, respectively (for males 

and females combined; there were no notable 

gender-related differences). Absorbed Eptam 

was widely distributed, with the greatest amount 

of radioactivity per mg organ found in the 

blood, kidneys, liver, and spleen after 24 hours. 

Radioactivity declined significantly with time in 

all tissues except blood and spleen, which 

retained 72-80% of their 24-hour radioactivity 

after 7 days. Only 1.2% of the given 

radioactivity was in all the tissues after 7 days, 

however, indicating that there was no significant 

bioaccumulation. 

Table 7 - Summary of Toxicological Doses and Endpoints for EPTC Dietary, Residential, and 

Occupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure Uncertainty Factors

PAD /

Level of 

Concern

Study and Toxicological Effects

Acute

(all 

populations)

LOAEL= 

200 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 10x 

(UFL )

aPAD = 

0.2 

mg/kg/day

Acute Neurotoxicity study – Rats

(MRID 46039701, 43297401) 

NOAEL = not established in males; 200 mg/kg/day in females.

LOAEL = 200 mg/kg/day in males based on neuronal cell necrosis in the brain.

LOAEL = 1000 mg/kg/day in females based on clinical signs (lacrimation, 

salivation, hypoactivity, upward curvature of the spine) death, and neuronal cell 

necrosis in the brain.

Chronic 

(all populations)

NOAEL= 5 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA = 1X

cPAD = 0.05 

mg/kg/day

Chronic/ Carcinogenicity and 2-Generation Reproduction – Rats

(MRID 00145004, 00145311, 00161597) 

Chronic/ Carcinogenicity study

NOAEL= 5 mg/kg/day

LOAEL = 25 mg/kg/day based on decreased body weight and increased incidences 

of myocardial and neuromuscular lesions. 

2- Generation Reproduction study

Parental NOAEL = 2.5 mg/kg/day Parental LOAEL = 10 mg/kg/day based on

decreased body weight/ body weight gain and cardiomyopathy. 
Page 23 of 23

Table 7 - Summary of Toxicological Doses and Endpoints for EPTC Dietary, Residential, and 

Occupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure Uncertainty Factors

PAD /

Level of 

Concern

Study and Toxicological Effects

Incidental OralChildren

(short- and 

intermediate-term)

NOAEL= 5 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA = 1X

MOE = 100

Chronic/ Carcinogenicity and 2-Generation Reproduction – Rats

(MRID 00145004, 00145311, 00161597) 

Chronic/ Carcinogenicity study

NOAEL= 5 mg/kg/day

LOAEL = 25 mg/kg/day based on decreased body weight and increased incidences 

of myocardial and neuromuscular lesions. 

2- Generation Reproduction study

Parental NOAEL = 2.5 mg/kg/day Parental LOAEL = 10 mg/kg/day based on

decreased body weight/ body weight gain and cardiomyopathy. 

Dermal

(short- and 

intermediate-term)

NOAEL= 5 

mg/kg/day 

Dermal 

absorption 

factor = 5%

relative to oral 

absorption.

UFA = 10X

UFH = 10X

FQPA = 1X

MOE = 100

Chronic/ Carcinogenicity and 2-Generation Reproduction – Rats

(MRID 00145004, 00145311, 00161597) 

Chronic/ Carcinogenicity study

NOAEL= 5 mg/kg/day

LOAEL = 25 mg/kg/day based on decreased body weight and increased incidences 

of myocardial and neuromuscular lesions. 

2- Generation Reproduction study

Parental NOAEL = 2.5 mg/kg/day Parental LOAEL = 10 mg/kg/day based on

decreased body weight/ body weight gain and cardiomyopathy. 

Inhalation

Acute

BMDL10 = 

5.05 mg/m3

Bystanders 

HEC = 0.461 

mg/kg; 3.2 

mg/m3

Occupational

HEC= 0.461 

mg/kg; 9.61 

mg/m3

UFA = 3X

UFH = 10X

FQPA = 1X

MOE = 30 

Adult 

(female 

workers)

MOE = 30

children

90 day Inhalation toxicity study- Rat

(MRID 00154784)

BMD10 = 10.84

BMDL10 = 5.05 based on brain cholinesterase inhibition in males; decreased food 

consumption, increased prothrombin time and incidence of cardiomyopathy at high 

doses. 

Inhalation

(short- and 

intermediate-term)

BMDL10 = 

5.05mg/m3

Bystanders 

HEC = 0.329 

mg/kg; 2.29 

mg/m3

Occupational

HEC= 0.461 

mg/kg; 9.61 

mg/m3

UFA = 3X

UFH = 10X

FQPA = 1X

MOE = 30 

Adult 

(female 

workers)

MOE = 30

children

90 day Inhalation toxicity study- Rat

(MRID 00154784)

BMD10 = 10.84

BMDL10 = 5.05 based on brain cholinesterase inhibition in males; decreased food 

consumption, increased prothrombin time and incidence of cardiomyopathy at high 

doses. 

Cancer 

(oral , dermal, 

inhalation) 

Classification: “Not likely to be Carcinogenic to Humans” based on the lack of carcinogenic potential noted in the available studies.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the 

beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no 

observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from 

animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies). UFL

= use of a LOAEL to extrapolate a NOAEL. FQPA = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). 

BMD = bench mark dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. HEC= human equivalent 

concentration.