### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OF FICE OF CHEM I CAL SAFETY AND

POLLUT ION PREVENTION



### MEMORANDUM

DATE: 5-MARC H- 2013



### SUBJECT: EPTC: Registration Review Scop in g Document for Human Health

Assessment.

PC Code: 041401

Decision No.: 470659

Petition No.: NA DP Barcode: D405957 Registration No.: NA Regulatory Action: Registration Review Reregistration Case No.: NA Assessment Type: Single Chemica V Aggregate

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

MRIDNo.: NA 40 CFR: §180.117



### FROM: 

## Mohsen Sahafeyan, Risk Assessor

# ~- YvonneBarnes,Chemist

# ~~**~** Deborah Smegal, To xicologist 

# 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 Assessmen t 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 fo r S-ethyl dipropylthiocarbamate (EPTC) to
determine the scope of work necessary to support Registration Review. E PTC 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 i n 2012 ( C. Smith, et. al., D395469, Nov

29

, 2012 ) to support the registration of watermelon, grass grow n for seed , as well as update the citrus and sunflower crop group s

.

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

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 toxicolog y studies. T he Agency has determined that EPTC is “ N ot 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. I t 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

wa s 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 studie s 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 wa i ved

. The

r esidues of conc ern 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 sl ightly higher than U. S. tolerances and with different residue

definition. HED will determine whether the residue definition and tolerance value s can be harmonized during registration review process.

In the most recent 2012 risk assessment, b ased 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 l evel 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 expos ures 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 a ssessment 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 an d/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 oth er new data are received by the Agency wh ich impact exposure estimates

.

Int roduction

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

grass y 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 ea rly 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 grow n for seed. HED also recommended for updating the citrus and sunflower crop

group s ( 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 Identifica tion/Toxicology

T he tox icology database for EPTC is nearly complete as described in 40 CFR Part 158,

except for the immunotoxicity study (see Table 4 )

. In September 2012, t he 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

- of

evidence approach that consider ed 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 c ardiomyopathy and

neur onal cell necrosis in st udies of varying length of treatment and in different species throughout the toxicity database. Cardiotoxicity was observed in subchronic and long

term studies, and in general, the severity and incidence of the lesion increased with increasing dose of EPT C. In 90

- day feeding and inhalation studies and in two chronic

### Page 4 of 23

feeding/oncogenicity studies, all in the adult rat, h istopathological evaluation revealed myocardial degeneration. M yocardial 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,

electr ocardiograms 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 effec ts 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 per ipheral nervous systems of rats and dogs. In the neurotoxicity studies

in rat s, dose

- re lated 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 bot h 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 finding s of atrophy and degener ation of the skeletal muscle were observed. In the dog study, the

lesions were described a s Wallerian

- type degeneration in the spinal cords and various peripheral nerves.

Cholinesterase (ChE) inhibition was also seen in a number o f toxicology studies, however, no consistent pattern was witnessed across studies with respect to ChE inhibition between different species, length of treatment, or t he type of ChE enzyme

measured.

E PTC is classified as “Not Likely to be C arcinogenic 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

. T he 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. T h ere 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 i s 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 robu st 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 time

point (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 : T he toxicity database for EPTC is complete except for an immunotoxicity study, which is required u nder the 2007 revised 40CFR Part 158 Toxicology Data Requirements. Once the i mmunotoxicity study is received and reviewed

, HED may reevaluate the points of departure s 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 t he 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 harmoniza tion

. 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 t olerance 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, t he 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 ”

. H ence, tolerances on animal commodities are not necessary.

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

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

D 401100 , 9/20/ 2012 ) and included all registered and proposed food uses. A cute 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 Na tional 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 an d 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 highes t estimated drinking water concentrations (EDWCs). Ne ither 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) ri sks 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 e stimates, 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 registe red residential uses associated with EPTC

, as all of these

uses have been voluntarily cancelled

. T herefore, a residential/non

- occupational exposure assessment is not required. However, t he primary dissipation process for EPTC is

volati lization (vapor pres sure 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 e xposed 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 proc ess 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

T he ETPC aggregate risk assessment includes only dietary exposure (food and water) ; there are no residential use s

. Acute and chronic d ietary 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

s ection 3 use on g rasses g rown for s eed p roduction and w atermelon risk assessment (M. Hawkins, D 395467

, 11/29/2012 ). This assessment includes an updated hazard and occupational exposure as sessment 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. T he short

- and intermediate

- term dermal risks exceed ed HED’s level of concern ( M OE s < 100) for a few handler scenarios (mixing/loading liquids) with the required personal protective equipment (PPE) of chemical

- resistant gloves . A ll of these MOEs improve to ≥ 100 with the addition of a double layer of PPE with chemical

resistant gloves. The short

- and intermediate

- term inhalation risks exceed ed HED’s level of concern ( M OE s < 3 0) for a few handler scenarios (mixing/loading granular ).

A ll 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 assess ment in d icate s that there are also potential occupational post

- application risk estimates of concern

. All c urrent 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 p ost

emergent 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.

T h e 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 t he 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 (F AR 

### ). T his default value is 25%. Of the analyzed DFR studies, the

### Page 8 of 23

maximum F AR 

### 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 s ince 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 requir e d 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 neede d if toxicological endpoints change or oth er new data are received by the Agency which impact exposure

estimates

.

Human Studies

The 2012 EPTC risk assessment rel ies 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 Ag ency 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 H uman Subjects" R egulation to reliance on these studies.

P ublic 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 A gricultural H ealth S tudy (AHS) findings that merit further

evaluation in the follo w

- 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 Inter national 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 definitio n

. HED will determine whether the residue definition

and the tolerance value s 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 Lo w

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.

Endocrine Disruption S creening 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 carcinogen icity, 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 cyclicit y, 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 taxo nomic 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 sim ilar 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 rec eived 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 c hemicals, 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

toxici ty with other chemical substances (thiocarbamates)

. At a September 2001 meeting,

t he Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA) Scientific Advisory Panel (SAP) supported the Agency’s determination ( Common Mechanism of Action of

Thiocarbam ates 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 Eligi bility Decision (RED) Document.

Shanna

Recore D 405961 11/7/2012 EPTC : Review of Human Incidents

Yvonne

Barnes D 401100 9/20/2012 EPTC. ( Carbamothioic acid, dipropyl

- , S

ethyl 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 R equirement 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

### 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, pK

a Not applicable

Octanol/water partition coefficient, Log(K OW ) 3.34 MRID 42120801

UV/visible absorption spectrum Data Gap

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

### Page 13 of 23

Table 2

- Summary of US and International Tolerances and Maximum Residue

Limits Residue Definition :
US Canada Mexico 1 

### 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

, N

dipropyl

- , S

ethyl ester None



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

US Canada Mexico 1 

### 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 Mexico 1 

### Codex

Sunflower, seed 0.08 0.1

Tomato 0.08 Trefoil, forage 0.1 Trefoil, hay 0.1 Vegetable, root 0.1 0.1 pota t oes, rutabaga roots, sugar beet roots, turnip roots

Walnut 0.08

MRLs with NO US Equivalent

Flaxseeds 0.1

Com pleted: 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 post

plant 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,

Chem igation, 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

19 713

- 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 y es

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 ♂LD 50 = 1465 (1290

- 1663) mg/kg ♀ LD 50 = 1712 (1324

- 2214) mg/kg

Combined LD 50 = 1599 (1294

- 1976)

mg/kg III

870.1200 Acute dermal

- rabbit 00157869 ♂LD 50 > 2000 mg/kg ♀ LD 50 > 2000 mg/kg III

870.1300 Acute inhalation

- rat 00157870 Combined LC 50 = 1.39 (0.97

- 2.00) mg/L II

870.2400 Primary eye

irritation

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

870.2500 Primary Dermal

irritation

- rabbit 00157872 PII = 1.4 IV

870.2600 Skin sensitization

guinea pig 00157873 Very slight sensitizer N/A

870.2600 Skin sensitization

guinea 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/m 3

MMAD= 2.8 μm

BMD 10 = 10.84

BMDL 10 = 5.05 BMD 10 = 10.84

BMDL 10 = 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 Materna l NOAEL = 40 mg/kg/day LOAEL = 300 mg/kg/day based on decreased body weight, food consumption, mortality and clinical signs Developmenta l 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 t o 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 Sex

linked 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 o ver 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 fo r 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, ki dneys, 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 a fter 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 UF A = 10X

UF H = 10X
FQPA 

### SF = 10x (UF L 

### ) 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 UF A = 10X

UF H = 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 cardiom yopathy.

### 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 Oral

Children (short

- and

intermediate

- term) NOAEL= 5

mg/kg/day UF A = 10X

UF H = 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

. UF A = 10X

UF H = 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 R eproduction 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 BMDL 10 =

5.05 mg/m 3
Bystanders

HEC = 0.461 mg/kg; 3.2 mg/m 3
Occupational

HEC= 0.461 mg/kg; 9.61 mg/m 3 UF A = 3X

UF H = 10X FQPA = 1X MOE = 30

Adult (female workers)

MOE = 30

children 90 day Inhalation toxicity study

- Rat (MRID 00154784 )

BMD 10 = 10.84

BMDL 10 = 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) BMDL 10 =

5.05mg/m 3
Bystanders

HEC = 0. 329 mg/kg; 2.29 mg/m 3
Occupational

HEC= 0.461 mg/kg; 9.61 mg/m 3 UF A = 3X

UF H = 10X FQPA = 1X MOE = 30

Adult (female workers)

MOE = 30

children 90 day Inhalation toxicity study

- Rat (MRID 00154784 )

BMD 10 = 10.84

BMDL 10 = 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. UF A = extrapo lation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. 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.