UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: June18,2014 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Etridiazole Human Health Risk Assessment Seeping Document in Support of 

Registration Review 

PC Code: 084701 

Decision No.: 487058 

Petition No.: NA 

Risk Assessment Type: Single Chemical 

Aggregate 

TXRNo.: NA 

MRIDNo.: NA 

DP Barcode: D417573 

Registration No.: NA 

Regulatory Action: Registration Review 

Case No.: NA 

CAS No.: 2593-15-9 

40 CFR: §180.370 

Danette Drew, Chemist/Risk A;sc~ -

Ana Rivera-Lupiariez, Chemi 

FROM: 

William Irwin, Ph.D., DAB , oxicologist (A t ·~!)If - -.......,. 

Seyed Tadayon, Chemis ,. ~ 

Risk Assessment Branches V and VII ../ /V<..J(~.-O..A/\.JV 

THROUGH: MichaelS. Metzger, Branch Chief , {)J}.. YO------

Health Effects Division (7509P) · J 

Risk Assessment Branches V and VI ~ Health Effects Division (7509P) 

TO: Margaret Hathaway, Chemical Review Manager 

Pesticide Re-Evaluation Division (7508P) 

Office of Pesticide Programs 

Attached is the Health Effects Division's (HED) human health risk assessment seeping 

document for etridiazole to support the registration review process. HED has evaluated the status 

of the human health risk assessment for etridiazole to determine the scope of work necessary to 

support registration review. The most recently completed human health risk assessment (for the 

2000 Reregistration Eligibility Decision, RED) and updated toxicology and exposure data were 

considered as part of this seeping exercise. 

Page 1 of25 
Executive Summary 

HED has evaluated the available data and the most recent human health risk assessments for the 

fungicide etridiazole (5-ethoxy-3-trichloromethyl-1 ,2,4-thiadiazole), the active ingredient in enduse products such as Terrazole®, to determine the scope of work necessary to support the 

registration review process. HED has consic.lered the currently labeled use patterns as well as the 

available toxicity and exposure information. The most recent human health risk assessment for 

etridiazole was completed on June 6, 2000 (D266264; HED Revised Risk Assessment for the 

Reregistration Eligibility Decision (RED) Document). The EPA RED was issued in September 

2000. 

Etridiazole is a fungicide registered for use on field cotton, turf (golf courses), nursery stock, and 

greenhouse ornamentals. Etridiazole is also mixed with potting soil for commercial greenhouse 

use and is used for tobacco float bed seedling treatments. In addition, since the September 2000 

RED, Special Local Need (SLN) greenhouse uses on tomatoes have been approved in AZ, CO, 

FL, MN, MS, OK, PA, TN, and TX. The various seed treatment uses assessed for the 2000 RED 

have recently been voluntarily cancelled by the registrant (79 FR 14247; 3/13/14). 

The September 2000 RED identified several outstanding toxicology data requirements, many of 

them a result of the original studies being unacceptable. Most of the required studies have since 

been submitted (multi-generation reproduction study in rats, 1-year chronic dog study, 28-day 

inhalation study in rats, 28-day dermal study in rats, mouse carcinogenicity study, and a dermal 

penetration study) and are undergoing final review. Preliminary reviews indicate that the 

submitted studies are acceptable. 

The acute neurotoxicity study (ACN), subchronic neurotoxicity study (SCN), and 

immunotoxicity study, now required in accordance with new data requirements for conventional 

pesticide registration (40 CFR Part 158), have not been submitted. The HED's Hazard and 

Science Policy Council (HASPOC) has determined, based on a weight of the evidence approach 

considering all the available hazard and exposure information for etridiazole, that the ACN, 

SCN, and immunotoxicity studies can be waived. In addition, the HASPOC determined that the 

guideline requirement for a 90-day dog study can be waived (6/5/14 HASPOC meeting, 

TXR#0053944). The toxicology database for etridiazole is complete. 

The primary target for etridiazole toxicity is the liver, following chronic exposure in rats and 

dogs. A chronic population adjusted dose ( cP AD) was established based on the 2-year 

carcinogenicity study in rats (liver and kidney effects). An acute population adjusted dose (aPAD) 

was determined for the population subgroup females 13-50 years, based on skeletal 

malformations/variations observed in the rabbit fetuses that were presumed to occur after a single 

exposure. For short-term dermal and inhalation exposure and risk assessments, the rabbit 

developmental endpoint (oral study) was selected. For intermediate- and long-term dermal and 

inhalation exposure risk assessments, the NOAEL was selected from the 2-year carcinogenicity 

study in rats. 

Page 2 of25 
Page 3 of 25

For chronic oral exposures, a 3x uncertainty factor was applied for the lack of an acceptable 

chronic study; an additional 3x uncertainty factor was also applied to chronic oral exposures

because uncertainty existed due to the lack of an acceptable multi-generation reproduction study

in rats.

Previously, in the 2000 RED, etridiazole was characterized as a mutagen. Some of the in vitro 

mutagenesis studies were positive at high concentrations (greater than 121 μM) in mammalian 

cells. However, HED has reevaluated these data considering current science policies and 

determined that etridiazole should be considered non-mutagenic because (1) mutagenicity 

occurred only at excessive doses relative to potential human doses, (2) some of the in vitro 

mutagenicity studies in mammalian cells were negative, even at higher doses of 323 μM (near 

the solubility limit), and (3) the definitive in vivo mouse mutagenicity study was negative at 

doses up to 1000 mg/kg, approaching the oral LD50 dose. Etridiazole is classified as a probable

human carcinogen based on the occurrence of multiple tumor types in male and female rats. The

most potent unit risk Q1*, based on the thyroid follicular cell combined adenomas/carcinomasin

male rats, is 3.33 x 10

-2

(mg/kg/day)-1in human equivalents. 

The residue chemistry database for etridiazole is complete. The residues of concern for tolerance 

enforcement and risk assessment (plants and livestock) are etridiazole and its monoacid 

metabolite (3-carboxy-5-ethoxy-1,2,4,-thiadiazole). The residue of concern for drinking water is 

parent etridiazole. Tolerances for residues of etridiazole and its monoacid metabolite in food and 

feed commodities are established under 40 CFR 180.370. The tolerance for tomatoes will be reevaluated based on residue data submitted since the RED for imported tomatoes. The current 

tolerance expression should be updated to comply with HED’s current policy on tolerance 

expressions. There are currently no international maximum residue limits (MRLs) for etridiazole

so there are no harmonization issues with Codex, Canada, or Mexico. The nomenclature and 

physiochemical properties of etridiazole can be found in Attachment 1.

There is a potential for non-occupational post-application dermal exposures for golfers playing 

on etridiazole treated turf. While the golfer risk estimates were not of concern in the 2000 RED 

(assuming turf use mitigations), an updated post-application assessment for golfers on etridiazole

treated turf will be required under registration review since there have been significant changes

in exposure assessment methodology (updated 2012 Residential SOP). Any revisions to 

toxicological PODs or uncertainty factors will be incorporated. The chemical specific turf 

transferable residue (TTR) data used in the 2000 RED have since been determined to be 

unacceptable. Since the estimated turf post-application exposure using default TTR values for 

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

greater than 10 times higher than the level of concern; MOE = 420 for females ages 13-49,

compared to the LOC of 100), EPA is now requiring new TTR data for etridiazole. The required 

chemical-specific TTR will also be considered in the post-application assessment.

In the 2000 RED there were no acute or chronic aggregate risk estimates (food and water) of 

concern. The short-term aggregate risk estimate (food and water plus golf course turf exposures) 

was not of concern. The cancer aggregate risk estimate (food and golf course turf exposures) was 

not of concern assuming mitigations for turf use (restrict use to tees and greens only and reduce 

application rates). Drinking water was not aggregated in the cancer assessment as there was a 
Page 4 of 25

potential concern for estimated etridiazole concentrations in water alone. It was determined upon 

issuance of the 2000 RED that potential cancer risks from drinking water would be mitigated by 

the turf use restrictions.

Revised aggregate risk assessments may be performed for etridiazole if there are any significant 

changes to toxicological PODs or uncertainty factors, or if there are significant changes to 

dietary exposure estimates, or if there are significant changes to non-occupational postapplication exposures (based on the updated SOPs and on any new TTR data), or if EPA’s

Environmental Fate and Effect Division (EFED) has determined that new estimated drinking 

water concentrations (EDWCs) are necessary.

There is the potential for short- and intermediate-term occupational exposure to etridiazole 

during handling (dermal and inhalation exposures) and post-application (dermal exposures only)

activities for the current uses of etridiazole (cotton, nursery stock, turf, tobacco seedling, 

greenhouse ornamentals and greenhouse tomatoes). Occupational handler and post-application 

exposure assessments were performed for the 2000 RED for the current uses of etridiazole, 

except for the greenhouse tomato use, and no risks of concern were identified with mitigation

measures. 

Updated quantitative handler and post-application occupational risk assessments will be 

performed for etridiazole to include updated exposure assessment methodology and any 

revisions to toxicological PODs or uncertainty factors. An occupational risk assessment will be 

performed for the greenhouse tomato use. A new chemical specific handler exposure study for 

greenhouse use has been submitted and may be used in the handler assessments. Since the 

estimated occupational turf post-application exposure using default TTR values for etridiazole is 

not minimal in comparison to the level of concern (i.e., the calculated MOE is not greater than 10 

times higher than the level of concern of 100), and existing TTR data for etridiazole are 

unacceptable, EPA is now requiring new chemical specific TTR data. Estimated screening level 

dermal MOEs are 74 for short-term and 28 for intermediate-term exposures at the current 

Restricted Entry Interval (REI) of 12 hours. The required chemical specific TTR will also be 

considered for the post-application assessment.

Hazard Identification/Toxicology

The September 2000 etridiazole RED identified the following outstanding toxicology data 

requirements, many of them a result of the original studies being unacceptable: a repeat multigeneration reproduction study in rats (protocol to include early thyroid measurements), a repeat 

chronic toxicity study in dogs, a repeat carcinogenicity study in mice, a 28-day inhalation 

toxicity study in rats, and a 21-day dermal study in rats. 

Since the issuance of the 2000 RED, the following new toxicological data have been submitted: a 

multi-generation reproduction study in rats (MRID 46057101), a 1-year chronic dog study 

(MRID 45793201), a 28-day inhalation study in rats (MRID 45812401), a 28-day dermal study 

in rats (MRID 45714601), a mouse carcinogenicity study (MRID 46426701), and a dermal 

penetration study (MRID 45943701). Preliminary reviews indicate that the submitted studies are 

acceptable.
Page 5 of 25

The ACN and SCN studies and an immunotoxicity study are now required in accordance with 

new data requirements for conventional pesticide registration (40 CFR Part 158); these studies 

have not been submitted for etridiazole. The HED’s Hazard and Science Policy Council 

(HASPOC) determined based on existing data and weight of the evidence, that the neurotoxicity 

(ACN, SCN) and immunotoxicity studies can be waived for etridiazole. The guideline 

requirement for a 90-day non-rodent study (i.e. 90-day dog study) has also been waived (6/5/14 

HASPOC meeting; TXR#0053944). The toxicological database for etridiazole is now complete.

The primary target for etridiazole toxicity is the liver, following chronic exposure in rats and

dogs. Systemic toxicities observed in the 2-year rat carcinogenicity study include increased 

absolute and relative liver weights, hepatocytomegaly,spongiosis hepatis, clear, basophilic, and 

eosinophilic hepatocellular alterations, hepatic centrilobular pigmentation and cholangiectasis. 

Additional toxicities observed in this study were decreased body weight gains, renal tubule cell 

karyomegaly and testicular interstitial cell hyperplasia. In the two-year chronic toxicity study in 

dogs, systemic toxicity in both sexes manifested as increased serum aspartate aminotransferase 

(SGOT) and serum alkaline phosphatase (ALK;SAP) activity, increased relative liver weights, 

liver pathology consistent with cholestatic hepatitis, secondary bile nephrosis and increased prothrombin time.

The rat developmental study indicated decreased fetal weights and increased resorptions, 

however at doses higher than the maternal LOAEL. The rabbit developmental study indicated 

decreased fetal body weights/viability and increased incidence of skeletal malformations, but at 

doses equal to the maternal LOAEL. There was no quantitative or qualitative evidence of

increased susceptibility in the fetuses or the offspring of rats or rabbits following pre- and/or

postnatal exposure to etridiazole. In the prenatal developmental toxicity studies in rats and

rabbits and the multi-generation reproduction study in rats, any observed toxicity to the fetuses or 

offspring occurred at equivalent or higher doses than did toxicity to parental animals. Although

the Hazard Identification Assessment Review Committee (HIARC) had determined that the

original multi-generation reproduction study in rats was an unacceptable-guideline study and not

adequate for regulatory purposes, the study results suggest that the observed offspring effects

(reduced pup weights) occurred only at a treatment level which resulted in parental toxicity

(TXR# 0013543, 6/29/99). An acceptable reproduction study has since been submitted and it 

also indicates that any observed toxicity to the fetuses or offspring occurred at equivalent doses 

as parental animals.

Although there is no indication of neurotoxicity in any of the mammalian toxicity studies 

submitted for the 2000 RED, most of these studies were determined to be inadequate for regulatory

purposes and it was determined that there were insufficient data to assess the neurotoxic potential

of etridiazole. However, the HASPOC has since recommended that the requirement for 

neurotoxicity studies be waived. 

Etridiazole induced genotoxic responses in several in vitro mutagenicity assays whereas responses 

were negative in vivo. Positive responses occurred in the gene mutation assay in the bacterial 

study in Salmonella typhimurium and in the in vitro sister chromatid exchange assays in Chinese

hamster ovary cells at concentrations greater than 121 μM. However, the in vitro concentrations 
Page 6 of 25

which caused positive responses in mammalian cells were high doses of 121-242 μM, and these 

blood levels in vivo are unlikely to be produced during normal exposure scenarios. Previously, in 

the 2000 RED, etridiazole was characterized as a mutagen. However, HED has reevaluated these 

data considering current science policies and determined that etridiazole should be considered as 

non-mutagenic because (1) mutagenicity occurred only at excessive doses relative to potential 

human doses, (2) some of the in vitro mutagenicity studies in mammalian cells were negative, 

even at higher doses of 323 μM (near the solubility limit), and (3) the definitive in vivo mouse 

mutagenicity study was negative at doses up to 1000 mg/kg, approaching the oral LD50 dose.

Analysis of whole body elimination in male and female rats indicated that etridiazole is rapidly 

absorbed and most elimination occurs within 48 hours of dosing. The metabolite profile in urine 

was similar between sexes and among the four dose groups; metabolites were identified as 

etridiazole carboxylic acid, ethyl (aminocarbonyl) carbamate, N-carboxy oxamic acid and Nacetyl cysteinyl conjugate of etridiazole.

Etridiazole is classified as a Group B2 chemical (probable human carcinogen) based on the 

occurrence of multiple tumor types in male and female rats (tumor sites noted were the liver, bile 

duct, mammary gland, thyroid, and testes), including the induction of a rare bile duct tumor 

(cholangiocarcinoma). A linear, low-dose approach (Q1*) is used for human risk 

characterization. The most potent unit risk Q1*, based on the thyroid follicular cell combined 

adenomas/carcinomasin male rats, is 3.33 x 10

-2

(mg/kg/day)-1in human equivalents [converted 

from animals to humans by use of the (mg/kg body weight) 3/4 interspecies scaling factor]. The

original mouse cancer study was unacceptable, but it indicated the presence of gross and

histopathological lesions in the lungs, a concern for possible evidence of carcinogenicity in a

different organ in a different species. However, an acceptable mouse cancer study did not report 

lung effects, but liver tumors were observed.

Etridiazole has a low order of acute toxicity via oral, dermal, or inhalation routes (Toxicity 

Category III or IV), produces mild irritation to the eyes (Toxicity Category III) and it is a skin 

sensitizer.

In the 2000 etridiazole RED, an FQPA uncertainty factor of 3x was recommended because of 

the lack of an acceptable multi-generation reproduction study in rats, which could identify

potential reproductive effects to the parental animals or to the offspring following pre/post natal

exposure to etridiazole. That factor was reduced to 3x because: (i) there was no quantitative

or qualitative indication of increased susceptibility in the prenatal developmental toxicity

studies in rats and rabbits (ii) although the multi-generation reproduction study in rats was 

determined to be an unacceptable-guideline study and not adequate for regulatory purposes by 

the HIARC (TXR# 0013543, 6/29/99), the study results suggest that the observed offspring 

effects in this study occurred only at a treatment level which resulted in parental toxicity and

(iii) adequate data were available or conservative modeling assumptions are used to assess the

potential for dietary (food and drinking water) exposure to infants and children. A multigeneration reproduction study has since been submitted and preliminary reviews indicate that 

the study is acceptable. The FQPA safety factor determination will be revisited during 

registration review.
Page 7 of 25

An acute population adjusted dose (aPAD) was not determined for the general population

because an appropriate endpoint attributable to a single exposure (dose) was not identified

in oral toxicity studies. Therefore, an acute dietary risk assessment was not required for the

general population.

However, an aPAD was determined for the population subgroup, females 13-50 years, based on 

skeletal malformations/variations(missing sternebrae and tail defects) observed in the rabbit

fetuses that were presumed to occur after a single exposure (dose). As per the recommendation

of the FQPA Safety Factor Committee (6/3/99), the 3x uncertainty factor for the lack of a 

multi-generation reproduction study was not applied to the population subgroup, females 13-

50, for the estimation of acute dietary risk. The Committee made this recommendation

because no increased susceptibility was seen following in utero exposure, and in addition, the

results of the multi-generation reproduction study may not provide an endpoint of concern (i.e.,

an in utero effect) on the potential for adverse effects occurring after a single exposure (dose).

The total uncertainty factor for the acute assessment was 100x (10x for intraspecies 

extrapolation and 10x for interspecies variation). 

A chronic population dose (cPAD) was established based on the two-year carcinogenicity study in

rats (liver and kidney effects) which included the application of an uncertainty factor of 300 

(10x for intraspecies extrapolation, 10x for interspecies variation and a 3x applied under

FIFRA for the lack of an acceptable chronic study). As per the recommendation of the FQPA 

Safety Factor Committee (6/3/99), an additional 3x uncertainty factor was applied to the 

chronic dietary risk assessment because uncertainty existed due to the lack of an acceptable

multi-generation reproduction study in rats, which could identify potential toxicities following

exposure to etridiazole in the offspring and/or the parental animals. The total uncertainty factor 

for the chronic assessment was 1000. The uncertainty factor determinations will be revisited during 

registration review.

The HIARC identified doses and endpoints for short-, intermediate-, and long-term dermal and 

inhalation exposures (TXR# 0013543, 6/29/99). For short-term dermal exposure and risk 

assessments, the rabbit developmental NOAEL was selected from the developmental toxicity

study in rabbits. This dose and endpoint were selected because: 1) the developmental effects are 

considered short-term and thus are appropriate for this exposure period (i.e., 1-7 days) of 

concern, 2) the reproductive/fetal parameters are not evaluated in the dermal toxicity study and

thus the consequences of these effects cannot be ascertained for the dermal route of exposure

and 3) this endpoint will provide adequate protection for the subpopulation of females 13+ years

old, i.e., pregnant workers (the population subgroup showing the most sensitive point of 

departure is females of child-bearing age [13-50 years old]). In addition, the two existing 21-

day dermal toxicity studies in rabbits were classified by the HIARC as unacceptable because of 

major deficiencies.

Since no inhalation studies were available (with the exception of an acute inhalation toxicity

study) in the etridiazole data base, the oral developmental NOAEL was also selected for a shortterm inhalation exposure (1 to 7 days) and risk assessment. 
Page 8 of 25

For intermediate- and long-term dermal and inhalation exposure risk assessments, the NOAEL 

was selected from the two-year carcinogenicity study in rats. The dosing time frame represented 

by this study best represents the intermediate-term and chronic exposure durations considering 

the toxicity data available.

No dermal absorption study was available in the etridiazole toxicity data base for the previous 

risk assessment. In addition, the dermal toxicity studies submitted to the Agency were evaluated

and determined to be inadequate for regulatory purposes. Therefore, the default value of 100% 

dermal absorption (relative to oral absorption) was used in the 2000 risk assessment. Also,

inhalation toxicity was assumed to be equivalent to oral toxicity. An acceptable rat dermal 

absorption study has been submitted since the RED. Dermal absorption was 28.96%, 14.63%, 

16.49% at 4 hours and 22.47%, 16.94%, and 16.62% at 10 hours at doses of 0.099, 0.975 and 

10.25 μg/cm2, respectively. The new dermal and inhalation studies will be evaluated for use in 

future etridiazole risk assessments. 

See Attachment 2 for a summary of the toxicological endpoints and points of departure (PODs) 

used in the 2000 etridiazole risk assessment, available toxicity studies, and the toxicity profile.

Conclusion

The September 2000 etridiazole RED identified several toxicology data requirements, many of 

them a result of the original studies being unacceptable. Most of the required studies have been 

submitted and have undergone preliminary review. The ACN, SCN, and immunotoxicity studies 

have not been submitted. The HED’s Hazard and Science Policy Council (HASPOC; 6/5/14; 

TXR# 0053944) has determine that, based on a weight of the evidence approach considering all 

the available hazard and exposure information, the ACN, SCN, immunotoxicity, and 90-day dog

studies may be waived for etridiazole. The toxicity database is complete for etridiazole. During

registration review, the toxicological endpoints, points of departure and uncertainty factors will

be re-evaluated to consider the new data submissions and to comply with current HED policies.

Residue Chemistry and Dietary Exposure

Residue Chemistry

The residue chemistry database for etridiazole is complete. The 6/2000 HED risk assessment had 

identified a requirement for storage stability data on the etridiazole monoacid metabolite (a 

residue of concern) in livestock commodities. Those data have not yet been submitted. Available 

data indicate that a Category 3 situation (40 CFR 180.6(a)3 “no reasonable expectation of finite 

residues”) exists with respect to residues of etridiazole and the monoacid metabolite in meat, 

mbyp (meat by-products), fat, and milk of cattle, goats, hogs, horses, sheep, and in poultry, 

poultry fat, mbyp, and eggs and there are currently no tolerances for etridiazole in livestock

commodities. HED has reexamined the storage stability data requirement and does not believe 

that the results of a storage stability study on the monoacid metabolite in livestock commodities 

will alter the 180.6(a)3 status since etridiazole residues are not expected to be found in any feed 

items for livestock. The only livestock feed items with tolerances for etridiazole (after 

cancellation of the seed treatment uses) are cottonseed and cotton gin byproducts. In field trials 
Page 9 of 25

with exaggerated application rates (6x) to cotton, parent etridiazole and the monoacid metabolite 

were not detected above the method limit of quantitation in cottonseed or cotton byproducts.

HED is not requiring the additional storage stability data at this time and the previous 

requirement is now waived.

In the 2000 RED additional residue data were required for imported tomatoes. Since then, 

residue studies for tomatoes grown in Spain, Italy, the Netherlands, and the U.K. have been 

submitted (MRIDs 45939402 and 46407801) and will be evaluated under registration review for 

adequacy in meeting the data requirement. The current tolerance for tomatoes is based on residue 

data that were submitted for domestic use on tomatoes. All other plant tolerances are based on 

the sum of the enforcement method limit of quantitation (LOQ) for etridiazole and its monoacid 

metabolite as there were no detectable residues in the field trial studies. Most of the current 

etridiazole tolerances are based on the seed treatment uses which have recently been canceled 

(use on the seeds of barley, corn, peanut, safflower, sorghum, wheat, and legume vegetable crop 

groups 6 and 7). See Attachment 4 for a list of current U.S. tolerances.

The residues of concern for tolerance enforcement and risk assessment (plants and livestock) are 

etridiazole and its monoacid metabolite, 3-carboxy-5-ethoxy-1,2,4,-thiadiazole. The residue of 

concern for drinking water is parent etridiazole. Existing analytical methods are considered 

adequate for both data collection and enforcement purposes.

Dietary Assessment

Food

Acute, chronic, and cancer dietary exposure analyses for etridiazole were performed using the 

Dietary Exposure Evaluation Model (DEEM) for the 2000 RED (D.Drew, 11/29/99, Etridiazole 

(Terrazole) - Revised Acute and Chronic (Cancer and Non-Cancer) Dietary Exposure Analyses. 

D261366). These assessments were for food only and did not include drinking water. Both

residues of concern (etridiazole and the monoacid metabolite) were included. For the acute and 

chronic analyses, tolerance residue levels and 100% percent crop treated (CT) were assumed. 

The acute dietary risk estimate of 3.6% of the aPAD did not exceed HED’s level of concern for 

females 13-50 years (the only population subgroup which had an acute toxicity endpoint 

identified). The chronic dietary risk estimates did not exceed HED’s level of concern for the U.S. 

population and all subgroups. The most highly exposed population subgroup was children 1-6 

years old at 31% of the cPAD. The cancer dietary exposure analysis was refined by using residue 

levels of half the combined levels of quantitation (LOQs) for etridiazole and monoacid 

metabolite for all commodities except tomatoes (domestic tomato tolerance was used for 

imported tomato commodities) and weighted average %CT estimates (BEAD 6/15/99). The 

cancer dietary risk estimate for etridiazole was 1.6 x 10-7for the general U.S. population.

Water

The Environmental Fate and Effects Division (EFED) provided estimated drinking water

concentrations (EDWCs) of etridiazole in surface and groundwater for use in the 2000 RED 

drinking water assessment. EDWCs resulting from turf (golf course) use were used in the 
Page 10 of 25

drinking water risk assessment as that scenario resulted in high-end protective estimates

(Environmental Fate and Effects Division Risk Assessment for the Reregistration Eligibility 

Decision on 5-ethoxy-3-trichloromethyl-1,2,4-thiadiazole (Etridiazole),5/22/00 and Terrazole: 

Refined Tier I Chronic Surface Water EECs for Use in the Human Health Drinking Water Risk 

Assessment, 5/26/00). EDWCs included parent etridiazole only as it was determined that because

of the low volume of etridiazole used on golf course turf and the relative stability of the parent 

compound to abiotic degradation, the metabolite is not expected to contribute significantly to 

drinking water risk.

For surface water, the GENEEC model was used to estimate acute and chronic concentrations 

resulting from the use on golf course tees, greens and fairways. Chronic EDWCs derived from 

GENEEC for turf use were refined with the incorporation of a percent crop area (PCA) factor of 

17%. The surface water EDWCs were compared to calculated Drinking Water Levels of 

Comparison (DWLOCs), i.e., levels remaining in the ‘risk cup’ after accounting for food 

exposures, and it was determined that there was no concern for etridiazole in drinking water for 

acute and chronic exposures. However, potential concentrations of etridiazole in surface water 

for turf use (32.3 ppb), assuming treatment of tees, greens and fairways, were above the cancer 

DWLOC of 1 ppb for the general U.S. population. It was determined upon issuance of the 2000

RED that potential cancer risks from drinking water would be mitigated by the removal of 

fairways from the etridiazole labels; applications to golf courses are limited to tees and greens 

only.

Ground water concentrations of etridiazole were estimated using the SCI-GROW (Tier I) 

computer model for use on golf course turf. Groundwater EDWCs were below the DWLOCs for 

all population subgroups for acute, chronic and cancers risks, and were not a concern.

Conclusion

There are adequate residue chemistry data. The tolerance for tomatoes will be re-evaluated based 

on the residue data submitted (since the RED) for imported tomatoes. A new dietary assessment 

may be performed if 1) there are any significant changes to toxicological PODs or uncertainty 

factors, 2) EFED determines that new EDWCs are necessary using updated models or PCA 

factors, or 3) residue chemistry review results in recommendations for significantly higher 

tomato tolerances than currently established.

Non-Occupational Exposure

There are currently no registered residential or homeowner uses for etridiazole; however, as 

etridiazole can be applied to golf courses up to several times a year, there is a potential for nonoccupational exposure to adults and children entering treated golf courses. Only dermal 

exposures are expected for post-application exposures to treated golf courses.

Residential Handlers

A residential handler exposure assessment is not required because etridiazole is only applied to 

use sites that are not treated by residential handlers; there are no homeowner uses.
Page 11 of 25

Non-Occupational Post-Application 

Etridiazole is restricted from use on residential turf and lawns; however, etridiazole may be used 

on golf course turf. Adults and children may experience post-application dermal exposure to 

etridiazole as a result of golfing activities.

A post-application golfer assessment (short-term and cancer) was performed for the 2000 RED. 

Only females (ages 13-49 years) were assessed for short-term dermal exposures since an 

appropriate short-term endpoint was not identified for the general population, including children.

This assessment was performed utilizing a (now unacceptable) turf transferable residue (TTR) 

study specific for etridiazole. That MOE was estimated at 17,000 (the level of concern (LOC) is 

a MOE of less than 100).

Lifetime cancer risk estimates of 1.2 x 10-7(2 days of exposure per year) and 1.3 x 10-6(18 days 

exposure per year) were determined for all adult golfers using Agricultural Reentry Task Force 

(ARTF) data and assuming golf course turf mitigations of reduced application rates and 

restricting use to tees and greens only.

Since the 2000 etridiazole assessment, the residential Standard Operating Procedures (SOPs,

2012) have been updated and several assumptions have changed. While a chemical-specific TTR 

study is available for etridiazole (MRID 43287802; 1993) and was used in the 2000 assessment,

substantive data quality issues were identified during Agency review (D266856, Bangs, G., 

2000). Furthermore, the study does not meet current policy guidelines and is no longer 

considered acceptable for use in risk assessment. The measured transferable residues were 

mostly below the laboratory limit of quantitation (LOQ), which was inappropriately high; 

therefore only higher residues were detected and any finite residues below the LOQ were not 

measured. In addition, the study did not use the modified California roller method of collection 

so the measured residues may be an underestimate of expected transferable residues. Because of 

the issues identified with this study, HED has at this time completed a screening level short-term 

risk estimate based on current default TTR values. The estimated short-term dermal MOE for 

female golfers is 420.

In accordance with the updated Part 158 data requirements (2007), a turf transferrable residue 

(TTR) study is required for all occupational or non-occupational residential turf uses. Suitable 

TTR data are not available for etridiazole. As part of the recent revision to the Health Effects 

Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment, 

HED analyzed all of the available TTR data and selected new liquid and granular default values 

for the fraction of the application rate available for transfer after a turf application (FAR). This 

default is 0.2% for granular formulations. Of the available TTR studies submitted to the Agency, 

the maximum FAR value seen using a granular product was 0.69% or 3.5 times higher than the 

default residue transfer value. Therefore, HED has decided that a calculated MOE of 

approximately 10 times higher than the LOC (e.g., an MOE >1,000 if the LOC = 100) using the 

default residue transfer values would provide an adequate margin of safety for any potentially 

higher residues seen in a chemical-specific TTR study (HED Memo, 12/12/12, “Guidance for 

Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) 
Page 12 of 25

Studies”). For the turf use of etridiazole, a TTR study will be required for registration review 

since the available study is unacceptable and the estimated short-term dermal MOE for golfers

are lower than 1000 using the current default values (the screening MOE is 420 for female 

golfers, ages 13-49).

Post- Application Volatilization/Spray Drift 

Residential exposures resulting from off-site transport (e.g., spray drift or volatilization) may 

occur as a result of applications of etridiazole. The Agency is in the process of evaluating these 

types of exposures and may, as appropriate, develop policies and procedures to identify the need 

for and, subsequently, the way to incorporate these post-application exposures into the Agency's 

risk assessments. The need for spray drift and volatilization risk assessment for etridiazole will 

be examined during registration review.

Conclusion

An updated post-application assessment for golfers on etridiazole treated turf will be performed

under registration review since there have been significant changes in exposure assessment 

methodology (updated 2012 residential SOP). Any revisions to toxicological PODs or 

uncertainty factors will be incorporated. The chemical specific TTR data used in the 2000 RED 

have since been determined to be unacceptable. Since the estimated turf post-application 

exposure using default TTR values for etridiazole is not minimal in comparison to the level of 

concern (i.e., the calculated MOE is not greater than 10 times higher than the level of concern;

MOE = 420 for females ages 13-49, compared to the LOC of 100), EPA is now requiring new

TTR data for etridiazole. The required chemical specific turf transferable residue (TTR) will also 

be considered for the post-application assessment.

Aggregate Risk Assessment

In accordance with the Food Quality Protection Act (FQPA), EPA must consider and aggregate 

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

(non-occupational) exposures. EPA has considered aggregate exposures for acute, chronic,

short-term, and lifetime cancer durations in its 2000 risk assessments; those results are 

summarized below.

Acute and Chronic 

Acute and chronic dietary risk estimates (food and water) were not of concern for any population 

subgroup.

Short-term

The short-term risk estimate for combined dietary (food and water) and post-application golf 

course exposures was not of concern.

Cancer
Page 13 of 25

The cancer aggregate (food plus two golf course post-application exposures per year; no water) 

risk was estimated at 2.8 x 10

-7

assuming the golf course use mitigations. There was potential 

cancer risk concern for estimated concentrations of etridiazole in surface water-based drinking 

water, so water exposures were not combined with the food and golf course exposures in the 

cancer aggregate assessment. It was determined upon issuance of the 2000 RED that potential 

cancer risks from drinking water would be mitigated by the removal of fairways from the 

etridiazole labels (applications to golf courses are limited to tees and greens only).

Conclusions

Revised aggregate risk assessments may be performed for etridiazole if there are any significant 

changes to toxicological PODs or uncertainty factors, if there are significant changes to dietary 

exposure estimates, if there are significant changes to non-occupational post-application 

exposures (based on the updated SOPs and on any new TTR data), or if EPA’s Environmental 

Fate and Effect Division (EFED) has determined that new estimated drinking water 

concentrations (EDWCs) are necessary.

Occupational Exposure

Occupational uses of etridiazole include use on field cotton, turf (golf courses), nursery stock, 

and greenhouse ornamentals. Etridiazole is also mixed with potting soil for commercial 

greenhouse use and is used for tobacco float bed seedling treatments. There are also greenhouse 

uses on tomatoes that have been approved for various states (Special Local Need, SLN) since the 

2000 RED. Greenhouse tomato worker scenarios have not yet been assessed. The seed treatment 

uses assessed in the 2000 RED have been voluntarily cancelled by the registrant. There is the 

potential for short- and intermediate-term, as well as lifetime occupational exposure to 

etridiazole during handling (mixing, loading, and applying; dermal and inhalation exposures) and 

post-application activities (dermal exposures only). Etridiazole is applied by groundboom, 

automated irrigation systems (chemigation), mechanically pressurized handgun, or tractor-drawn 

spreader.

Occupational Handlers

The 2000 RED identified risks of concern for some occupational handler exposure scenarios 

(i.e., seed treatments and turf applications); therefore, mitigation measures were implemented 

such as product use site restrictions, cancelled formulation types (i.e. dust and some granular 

products), reduced application rates, and requirement of additional PPE (e.g., respirator).

Registered etridiazole labels require occupational handlers to wear long-sleeved shirts, long 

pants, shoes, socks, and chemical resistant gloves. Mixer/loaders must also wear a chemical 

resistant apron. Additionally, some labels require the use of protective eyewear and organic 

vapor (OV) filtering respirators during mixing and loading scenarios, due to the high vapor 

pressure (1.1 x 10-2 mm Hg) of etridiazole. In the RED, handler risk was assessed using data 

from the Pesticide Handlers Exposure Database (PHED) Version 1.1.
Page 14 of 25

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

uses of etridiazole (except for greenhouse tomato SLNs), the assessments were not conducted 

based on current occupational exposure policies. Recommended unit exposures for occupational 

handler assessments had generally been derived only from the Pesticide Handlers Exposure 

Database (PHED). However, recently both the Outdoor Residential Exposure Task Force 

(ORETF) and the Agricultural Handler Exposure Task Force (AHETF) have produced pesticide 

handler exposure monitoring data that the Agency is using in place of PHED 

(http://www.epa.gov/pesticides/science/handler-exposure-data.html). As more reliable data 

become available, the Agency will continue to replace existing data. New exposure monitoring 

data will be incorporated into revised occupational handler assessments, as necessary, during 

registration review.

Some etridiazole labels have been amended after the RED. For example, tobacco float bed

seedling uses are permitted for liquid formulations (EPA Reg. No. 400-422); previous 

assessments were done only on the wettable powder and no risks of concern were identified.

Exposure from mixing and loading (M/L) liquid formulations is expected to be lower than 

exposure from M/L wettable powder. The assessment for mixing and loading wettable powder

formulations for tobacco float bed seedling scenarios is considered protective of potential 

handler exposures from mixing and loading of liquid formulation for this handler scenario.

A chemical specific handler exposure study “Dermal and Inhalation Potential Exposure to 

Greenhouse Handlers While Mixing, Loading, and Applying Terrazole 35% Wettable Powder”

(MRID 45773201) was submitted after the issuance of the RED. The study was reviewed by 

HED (D286169, Crowley, M., 09/22/2011) and may be used in registration review to update 

occupational exposure assessments of soil drenching or watering-type foliar applications in 

greenhouses using mechanically-powered handwands.

Occupational Post-Application

Post-application exposure assessments have been performed (in the 2000 RED) for the current 

uses of etridiazole, except for the greenhouse tomato use, and no risks of concern were identified 

with mitigations. Recommended transfer coefficients for occupational post-application 

assessments were derived from Agricultural Reentry Task Force (ARTF) exposure monitoring 

studies (http://www.epa.gov/pesticides/science/post-app-exposure-data.html). These transfer 

coefficients were updated in 2012 based on a reanalysis and submission of new monitoring data. 

HED will incorporate new exposure monitoring data, as necessary, during registration review.

There is a possibility for workers to have post-application dermal exposure to etridiazole treated 

turf (i.e., golf course maintenance workers). Based on the discussion in the non-occupational

post-application section, a TTR study will be required for registration review since estimated 

dermal MOEs for occupational post-application turf scenarios are lower than 10X the target LOC 

(i.e., MOEs of 1000). Using updated methods, screening level estimated dermal MOEs are 

below the target MOE of 1000 at 74 for short-term and 28 for intermediate –term exposures at 

the current Restricted Entry Interval (REI) of 12 hours. Note that these screening MOEs are also 

below the LOC of 100 at the current 12 hour REI.
Page 15 of 25

A quantitative post-application exposure assessment was not performed for transplanting 

etridiazole-treated tobacco seedlings (float beds). The occupational handler assessment for this 

tobacco seedling use is expected to be protective of potential post-application exposure for 

workers transplanting the treated seedlings.

Conclusion

Updated quantitative handler and post-application occupational risk assessments (cancer and 

non-cancer) will be performed to include updated exposure assessment methodology, and any 

revisions to toxicological PODs or uncertainty factors. An occupational handler risk assessment 

should be performed for the greenhouse tomato use. The new chemical specific greenhouse 

handler exposure data may be considered for use in certain handler assessments. Also, since the 

estimated occupational turf post-application exposure using default TTR values for etridiazole is 

not minimal in comparison to the level of concern (i.e., the calculated MOE is not greater than 10 

times higher than the level of concern of 100), and existing TTR data for etridiazole are 

unacceptable, EPA is requiring new chemical specific TTR data. Estimated screening level 

dermal MOEs are 74 for short-term and 28 for intermediate –term exposures at the current 

Restricted Entry Interval (REI) of 12 hours. The required chemical specific turf transferable 

residue (TTR) will also be considered for the post-application assessment.

Public Health and Pesticide Epidemiology Data

HED has performed a recent review of human incident data for etridiazole (S. Recore, 2/4/14, 

D417574, Terrazole: Tier I Review of Human Incidents). Based on the low frequency and low 

severity of incident cases reported for etridiazole (IDS and SENSOR-Pesticides), there does not 

appear to be a concern at this time that would warrant further investigation. The Agency will 

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

will be included in the risk assessment.

Tolerance Assessment and International Harmonization

Currently, the U.S. tolerance expression for etridiazole is expressed as “5-ethoxy-3-

(trichloromethyl)-1,2,4-thiadiazole and its monoacid metabolite 3-carboxy-5-ethoxy-1,2,4-

thiadiazole”. The correct definition should be:

Tolerances are established for residues of the fungicide etridiazole, including its metabolites and 

degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified 

below is to be determined by measuring only the sum of etridiazole (5-ethoxy-3-trichloromethyl-1,2,4-

thiadiazole) and its monoacid metabolite (3-carboxy-5-ethoxy-1,2,4,-thiadiazole), calculated as the 

stoichiometric equivalent of etridiazole, in or on the commodity.

There are currently no international maximum residue limits (MRLs) for etridiazole; therefore, 

there are no harmonization issues with Codex, Canada, or Mexico. See Attachment 4 for a table 

of U.S. tolerances.

International or Intergovernmental Work Sharing
Page 16 of 25

There is no current or forecasted work sharing efforts with other entities (e.g. California, Canada, 

EU, and OECD) for etridiazole.

Cumulative

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not identified etridiazole as part of a common 

mechanism group and a cumulative assessment has not been conducted.

Data Requirements

Toxicology

None.

Residue Chemistry

None.

ORE

Turf Transferable Residue (TTR) Study: 

There is a possibility for golfers and golf course maintenance workers to have post-application 

dermal exposure to etridiazole treated turf. Based on the discussion in the non-occuaptional and 

occupational post-application sections of this document, a chemical specific TTR study will be 

required for etridiazole registration review since estimated dermal MOEs for turf postapplication scenarios (golfers and golf course maintenance workers) are lower than 10X the LOC 

(screening level MOEs are <1000 and the LOC is 100). 

Attachments

Attachment 1. Chemical Identity

Attachment 2. Doses and Toxicological Endpoints

Attachment 3. Toxicology Data Requirements and Toxicity Profiles

Attachment 4. U.S. and International Tolerances and Maximum Residue Limits
Page 17 of 25

Attachment 1. Chemical Identity

Table A1.1. Etridiazole Nomenclature.

Compound

Common name Etridiazole

IUPAC name 5-ethoxy-3-(trichloromethyl)-1,2,4-thiadiazole

CAS name 5-ethoxy-3-(trichloromethyl)-1,2,4-thiadiazole

CAS registry number 2593-15-9

End-use products (EP) Terrazole

Table A1.2. Physicochemical Properties of the Technical Grade of Etridiazole

Parameter Value Reference

Melting point 19.9° C a

Density 1.503 at 25 °C a

Water solubility 100 ppm at 25° C b

Solvent solubility soluble in acetone, carbon tetrachloride, 

ethanol, ether, and xylene

b

Vapor pressure 1.1 x 10-2 mm Hg at 25° C b

Dissociation constant, pKa pKa = 2.77 a

Octanol/water partition coefficient,

Log(KOW)

2.344 x 103 b

UV/visible absorption spectrum 288 nm a

aHSDB (Hazardous Substances Data Bank); http://toxnet.nlm.nih.gov

bD266264; HED Revised Risk Assessment for the Reregistration Eligibility Decision (RED) Document; 6/6/2000. 
Page 18 of 25

Attachment 2. Doses and Toxicological Endpoints

Summary of Toxicological Doses and Endpoints used in Etridiazole Human Health Risk Assessment (2000).

Exposure/ 

Scenario POD

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, LOC 

for Risk 

Assessment

Study and Toxicological Effects

Acute Dietary

(General 

population 

including infants 

and children)

An appropriate endpoint attributable to a single exposure (dose) was not identified in oral toxicity studies 

(including the developmental toxicity studies in rats and rabbits) that is applicable to subpopulations other than 

females of childbearing age (13-50 years old).

Acute Dietary 

(Females 13-49 

years of age)

NOAEL = 

15 mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

Acute Rfd =

0.15 mg/kg/day

aPAD = 

0.15 mg/kg/day

Rabbit Developmental Study

LOAEL = 45 mg/kg/day based on educed 

fetal body weights, decreased viability

and external and skeletal 

malformations/variations in the rabbit 

developmental toxicity study. 

Chronic Dietary 

(All Populations)

LOAEL = 

4.8 mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 3X

Chronic Rfd = 

0.016 mg/kg/day

cPAD = 

0.005 mg/kg/day

Rat Chronic Study

LOAEL = 30.43/38.45 mg/kg/day based 

on increased absolute and relative liver 

weights, renal tubule cell karyomegaly, 

hepatocytomegaly and spongiosis hepatis

in the two-year carcinogenicity study in 

rats.

Dermal & 

Inhalation: 

Short-Term 

(1-30 days)

NOAEL = 

15 mg/kg/day

Dermal Absorption 

Factor of 100% 

Assumed

UFA = 10X

UFH = 10X

FQPA SF = 1X

Residential LOC 

for MOE = 100

Rabbit Developmental Study

LOAEL = 45 mg/kg/day based on educed 

fetal body weights, decreased viability

and external and skeletal 

malformations/variations in the rabbit 

developmental toxicity study. 

Dermal & 

Inhalation 

Intermediateterm 

(1-6 months)

LOAEL = 

4.8 mg/kg/day

Dermal Absorption 

Factor of 100% 

Assumed

UFA = 10X

UFH = 10X

FQPA SF = 1X

Residential LOC 

for MOE = 100

Rat Chronic Study

LOAEL = 30.43/38.45 mg/kg/day based 

on increased absolute and relative liver 

weights, renal tubule cell karyomegaly, 

hepatocytomegaly and spongiosis hepatis

in the two-year carcinogenicity study in 

rats.

Dermal & 

Inhalation Longterm 

LOAEL = 

4.8 mg/kg/day

Dermal Absorption 

Factor of 100% 

Assumed

UFA = 10X

UFH = 10X

FQPA SF = 3X

Residential LOC 

for MOE = 300

Rat Chronic Study

LOAEL = 30.43/38.45 mg/kg/day based 

on increased absolute and relative liver 

weights, renal tubule cell karyomegaly, 

hepatocytomegaly and spongiosis hepatis

in the two-year carcinogenicity study in 

rats. 

Cancer (oral, 

dermal, 

inhalation)

Group B2 chemical - A Probable human carcinogen - Q* = 3.33 x 10-2(mg/kg/day)

-1

in

 human equivalents [converted from animals to humans by use of the (mg/kg body weight)

:

cross

species scaling factor].

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 SF = FQPA Safety Factor. PAD = population-adjusted 

dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. HEC = human 

equivalent concentration.
Page 19 of 25

Attachment 3. Toxicology Data Requirements and Toxicity Profiles

3.1 Toxicology Requirements

The toxicology data requirements (40 CFR 158.340) for the food uses of etridiazole are presented below. Use of the 

new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table 3.1 Toxicology Requirements for Etridiazole 

Guideline Number and Toxicity Study 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 Sub-chronic (Rodent) ...........................................

870.3150 Oral Sub-chronic (Non-Rodent)...................................

870.3200 21-Day Dermal.............................................................

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

870.3465 90/28-Day Inhalation....................................................

yes

yes

yes

CR

CR

yes

 yes**

 yes*

 yes*

870.3700 Developmental Toxicity (Rodent)...............................

870.3700 Developmental Toxicity (Non-rodent) .........................

870.3800 Reproduction ................................................................

yes

yes

yes

yes

yes

 yes*

870.4100 Chronic Toxicity (Rodent) ...........................................

870.4100 Chronic Toxicity (Non-rodent).....................................

870.4200 Oncogenicity (Rat) .......................................................

870.4200 Oncogenicity (Mouse)..................................................

870.4300 Chronic/Oncogenicity ..................................................

yes

no

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....

870.5395 Mutagenicity: Cytogenetics

870.5500 Mutagenicity: Other Genotoxic Effects........................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.6100 Acute Delayed Neurotoxicity (Hen).............................

870.6100 90-Day Neurotoxicity (Hen).........................................

870.6200 Acute Neurotoxicity Screening Battery (Rat)...............

870.6200 90-Day Neurotoxicity. Screening Battery (Rat) ...........

870.6300 Developmental Neurotoxicity ......................................

no

no

yes

yes

CR

yes

yes

 yes+

 yes+

yes

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

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

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

yes

no

yes

yes

yes

 yes+

CR= conditionally required; * Studies submitted and currently under review; **Satisfied by the chronic dog study

+Waived by HASPOC (meeting 6-5-14)
Page 20 of 25

3.2 Toxicity Profiles

Acute Toxicity Profile for Etridiazole

Guideline MRID# Study Type* Results

Tox. 

Cat. Classification

870.1100 

(§81-1)

43724501 Acute Oral - Rat

(2/8/94)

LD50 (males) = 1141 mg/kg 

LD50 (females) = 945 mg/kg 

LD50 (males and females 

combined) = 1028 mg/kg

III AcceptableGuideline

870.1200 

(§81-2)

43724502 Acute Dermal - Rabbit

(2/8/94)

LD50 (males and females 

combined) > 5000 mg/kg

IV AcceptableGuideline

870.1300 

(§81-3)

43724503 Acute Inhalation - Rat

(2/8/94)

LC50 (males and females 

combined) > 5.7 mg/L

IV AcceptableGuideline

870.2400 

(§81-4)

43724504 Primary Eye Irritation -

Rabbit

(2/8/94)

Moderate Eye Irritant III AcceptableGuideline

870.2500 

(§81-5)

43724505 Primary Dermal

Irritation – Rabbit

(2/8/94)

Non Irritant IV AcceptableGuideline

 870.2600 

 (§81-6)

43724506 Dermal Sensitization -

Guinea pig-unspecified 

purity of terrazole technical

(1/22/93)

Moderate Dermal Sensitizer N/A AcceptableGuideline

*The percent active ingredient of the technical test material used in each of the acute toxicity studies was reported as 98.6% a.i.,

unless specified otherwise
Page 21 of 25

Sub-chronic and Chronic Toxicity Profile for Etridiazole 

Guideline MRID# Study Type* Results

870.3100 

(82-1a)

00001700 90-Day Oral Toxicity -

Rat, technical; 50% a.i. 

(1964)

NOAEL (males, females) = 312 ppm

LOAEL (males, females) = 625 ppm based on increased liver 

to body weight ratios and growth depression

Classification: Unacceptable-Guideline (not upgradable)

870.3150 

(82-1b)

00001699 90-Day Oral Toxicity -

Dog,

technical; 50% a.i. 

(1964)

NOAEL (males, females) > 1600 ppm

LOAEL (males, females) = not established

Classification: Unacceptable-Guideline (not upgradable)

870.3200 

(82-2b)

00063303 21-Day Dermal Toxicity

- Rabbit, unspecified 

purity

(1/11/65)

NOAEL (males, females) = not established

LOAEL (males, females) = not established

Classification: Unacceptable-Guideline (not upgradable)

870.3200 

(82-2b)

00114197 21/28-Day Dermal 

Toxicity - Rabbit, 

Terrachlor Super X 

Formulation

(6/65)

NOAEL (males, females) = 0.65 ml/kg/day

LOAEL (males, females) = 1.30 ml/kg/day based on 

increased kidney to body weight ratios

Classification: Unacceptable-Guideline (not upgradable)

870.3200

(82-2b)

45714601 28-Day Dermal Toxicity 

Study- Rat (2002)

 Currently under review

870.3465 45812401 28-Day Inhalation Toxicity 

Study-Rats (2002)

 Currently under review

 

Chronic Toxicity

870.4100 

(83-1b)

00001697 Chronic Toxicity - Dog

(8/5/68)

NOAEL (males, females) = 2.5 mg/kg/day

LOAEL (males, females) = 25 mg/kg/day based on increased 

SGOT and SAP activity, increased liver to body weight ratios, 

liver pathology consistent with cholestatic hepatis, secondary

bile nephrosis and increased prothrombin time.

Classification: Acceptable-Non Guideline
Page 22 of 25

870.4100

(83-1b)

45793201 Chronic Toxicity - Dog

(2002)

NOAEL: 4.11/15.5 mg/kg/day (M/F)

LOAEL: 12.54 mg/kg bw/day in males, based upon increased 

alkaline phosphatase release and 37.48 mg/kg bw/day in females 

based upon increased ALP release and decreased body weight. 

Classification: Acceptable-Guideline

870.4200 

 (83-2a)

40747901 Oncogenicity -Rat

 (6/23/88) NOAEL = 100 ppm (4.8/5.9 mg/kg/day, males/females) 

LOAEL = 640 ppm (30.43/38.45 mg/kg/day,

males/females) based on decreased body weight gain 

(females), increased liver weight (absolute and relative), renal 

tubule cell karyomegaly (males, females), hepatocytomegaly

(males), spongiosis hepatis (males), cholangiectasis (females) 

and centrilobular pigmentation (females).

Etridiazole has carcinogenic potential in the livers of

female rats, and the testes and thyroid of male rats. It can also 

induce cholangiocarcinoma, a rare tumor, predominantly in 

female rats.

Classification: Acceptable-Guideline

870.4200 

(83-2b)

00093744 Oncogenicity -Mouse

(3/14/81)

NOAEL (males, females) = 640 ppm (91 mg/kg/day) LOAEL 

= 1280 ppm (183 mg/kg/day) based on minor decreases in 

body weight and food efficiency, stomach hyperkeratosis, 

nephritis and adrenal and ovarian degeneration in females, 

lung hyperplasia in males, and spleen alterations in both sexes

Under conditions of this study, there was equivocal 

evidence of carcinogenicity based on an increased 

incidence of alveologenic carcinoma female mice.

Classification: Unacceptable-Guideline (not upgradable)

870.4200 

(83-2b)

46429701 Oncogenicity -Mouse

(2004)

NOAEL = 50 ppm (males 7.5/females 9.1 mg/kg/day).

LOAEL = 1300 ppm (males 185/females 222 mg/kg/day), based on 

increased mortality (both sexes), increased liver weight (both 

sexes), which correlated with an increased incidence of enlarged 

livers, decreased kidney weight (both sexes), increased incidence of 

extramedullary hematopoiesis in the spleen (both sexes), 

degenerative and regenerative lesions in the liver (both sexes), liver 

tumors, heart lesions (mineralization of myofiber and thrombus), 

and kidney infarcts. 

At the high-dose level [2000/1600 ppm, (males 263/females 312 

mg/kg/day)], increased mortality and incidence of clinical signs, 

decreased body weight/body-weight gain in males, increased spleen 

weight (males), and an increased incidence of liver tumors were 

observed.

Classification: Acceptable-Guideline

Developmental/Reproductive Toxicity
Page 23 of 25

870.3700 

(83-3a)

00120415 Developmental Toxicity

- Rat

(5/27/82)

Maternal Toxicity

NOAEL = 10 mg/kg/day

LOAEL = 30 mg/kg/day based on clinical signs of toxicity

(anogenital matting) 

Developmental Toxicity

NOAEL = 30 mg/kg/day

LOAEL = 75 mg/kg/day based on decreased fetal body 

weights and increased late resorptions

Classification: Acceptable-Guideline

870.3700 

(83-3b)

00104999 Developmental Toxicity

- Rabbit

(5/22/79)

Maternal Toxicity

NOAEL = 15 mg/kg/day

LOAEL = 45 mg/kg/day based on increased mortality and 

decreased body weights

Developmental Toxicity

NOAEL = 15 mg/kg/day

LOAEL = 45 mg/kg/day based on reduced fetal body weights, 

viability and increased incidence of external and skeletal 

malformations/variations

Classification: Acceptable-Guideline

870.3800 

 (83-4)

00001698 Multi-generation

Reproductive Toxicity -Rat

(1968)

Systemic/Parental/Offspring Toxicity

NOAEL = 80 ppm (4 mg/kg/day)

LOAEL = 640 ppm (32 mg/kg/day) based on reduced 

body weights of adult animals and pups

Reproductive Toxicity

NOAEL $ 640 ppm (32 mg/kg/day)

LOAEL > 640 ppm (32 mg/kg/day), not established

Classification: Unacceptable-Guideline (not upgradable)

870.3800 

 (83-4)

46057901 Multi-generation

Reproductive Toxicity -Rat 

(2003)

Currently under review

Mutagenicity

870.5100 

(84-2)

00093742 Gene Mutation in 

Salmonella 

typhimurium and 

Escherichia coli 

(11/2/81)

Negative. Etridiazole did not induce a mutagenic or 

genotoxic effect under any test condition in any assay.

Classification: Unacceptable-Guideline (not upgradable)

870.5100 

(84-2)

00073206 Gene Mutation in 

Salmonella 

typhimurium 

(10/77)

Positive. Etridiazole induced a mutagenic response in 

Salmonella typhimurium strain TA100 at non-cytotoxic doses of

0.02, 0.06 and 0.2 Fg/plate -S9 activation. There was, however, 

no evidence of a mutagenic effect in the presence of S9 

activation. Etridiazole was not mutagenic in strain TA98.

Classification: Acceptable-Non-guideline
Page 24 of 25

870.5300 

(84-2)

00093743 Gene Mutation/ In vitro 

mammalian cell assay in 

Chinese hamster ovary

cells

(11/10/81)

Negative. Etridiazole did not induce a mutagenic effect in 

Chinese hamster ovary cells at non-cytotoxic concentrations of

0.001-0.008% (equivalent to 10-80

μg/mL) -S9 activation and 0.001-0.005% (equivalent to

10-50 μg/mL) +S9 activation after a 16 or 5 hour 

incubation period, respectively.

Classification: Acceptable-Guideline

870.5385 

(84-2)

41837501 Cytogenetics/ In vivo 

mouse micronucleus 

assay

(10/30/85)

Negative. There was no evidence of either a clastogenic or 

aneugenic effect in male and female mice administered

1000 mg/kg etridiazole at any sacrifice time at a dose near the oral 

LD50 dose.

Classification: Acceptable-Guideline

870.5900 

(84-2)

00120414 Other Mutagenic 

Mechanisms/ In vitro 

Sister Chromatid 

Exchange in Chinese 

hamster ovary cells 

(1/26/81)

Positive. Etridiazole induced increases in the frequency

of sister chromatid exchanges per cell at concentrations of

0.002 to 0.005% (equivalent to 20 to 50 μ g/mL) -S9 activation 

and 0.002 and 0.003% (equivalent to 20 and 30

μg/mL) +S9 activation after a 27.5 or 4 hour incubation 

period, respectively. Note that the S9 treatment is cytotoxic 

after 6 hours of exposure, so the 4 hour data is more 

appropriate.

870.5375/ Classification: Acceptable-Guideline

870.5900 

(84-2)

00120416 Other Mutagenic 

Mechanisms/ In vitro 

Cytogenetics/ Sister 

Chromatid Exchange in 

Chinese hamster ovary cells

(6/4/82)

Positive. Etridiazole induced increases in the frequency

of sister chromatid exchanges per cell at concentrations of

0.003-0.005% (equivalent to 10-50 μg/mL) -S9 after a 27-

28 hour incubation period. In addition, etridiazole induced 

increases in the frequency of cells with structural chromosomal 

aberrations at concentrations of 0.005% and

0.006% (equivalent to 50 and 60 μg/mL) -S9 activation and

0.003, 0. 005 and 0.006% (equivalent to 30, 50 and

60 μg/mL) +S9 activation after a 6 or 2 hour incubation

period, respectively.

Classification: Acceptable-Guideline

Metabolism

870.7485 

(85-1)

43654801 Metabolism - Rat

(4/28/95)

Etridiazole is rapidly absorbed and most elimination

occurs within 48 hours of dosing. The metabolite profile in 

urine was similar between sexes and among the four dose 

groups; metabolites were identified as etridiazole carboxylic 

acid, ethyl (aminocarbonyl) carbamate, N- carboxy oxamic acid 

and N-acetyl cysteinyl conjugate of etridiazole.

Classification: Acceptable-Guideline

870.7600 45943701 In vivo dermal absorption The dermal absorption study indicated it had 28.96%, 14.63%, 

16.49% absorption at 4 hours and 22.47%, 16.94%, and 16.62% at 

10 hours at doses of 0.099, 0.975 and 10.25 μg/cm2, respectively.

Classification: Acceptable-Guideline
Page 25 of 25

Attachment 4: U.S. and International Tolerances and Maximum Residue Limits for 

Etridiazole (PC Code 084701; 01/06/14)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex

40 CFR 180.370

(a) General: 5-ethoxy-3-(trichloromethyl)-

1,2,4-thiadiazole and its monoacid 

metabolite 3-carboxy-5-ethoxy-1,2,4-

thiadiazole .

None None

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

US Canada Mexico1 Codex

Barley, grain* 0.1

Barley, hay* 0.1

Corn, field, forage* 0.1

Corn, field, grain* 0.1

Corn, field, stover* 0.1

Corn, sweet, forage* 0.1

Corn, sweet, stover* 0.1

Cotton, gin byproducts 0.1

Cotton, undelinted seed 0.1

Peanut* 0.1

Peanut, hay* 0.1 

Safflower, seed* 0.1

Sorghum, grain, forage* 0.1

Sorghum, grain, grain* 0.1

Tomato 0.15

Vegetable, foliage of legume, group 

7*

0.1

Vegetable, legume, group 6* 0.1

Wheat, forage* 0.1

Wheat, grain* 0.1

Wheat, straw* 0.1

Completed by: M. Negussie; 01/08/2014

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

*These commodity tolerances are associated with the cancelled seed treatment uses.