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EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR PESTICIDE PETITION

EPA Contact: Registration Division 

Interregional Research Project Number 4 (IR-4)

Petition Number: 6E8472

EPA has received a pesticide petition (PP# 6E8472) from Interregional Research Project Number 4 (IR-4 Project), Rutgers, The State University of New Jersey, 500 College Road East, Suite 201 W., Princeton, NJ  08540, proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a (d), to amend 40 CFR part 180.345 by increasing the existing tolerance for the combined residues of the herbicide ethofumesate, (2-ethoxy-2,3-dihydro-3,3-dimethyl-5-benzofuranyl methanesulfonate) and its metabolites, 2-hydroxy-2,3-dihydro-3,3-dimethyl-5-benzofuranyl methanesulfonate and 2,3-dihydro-3,3-dimethyl-2-oxo-5-benzofuranyl methanesulfonate both calculated as the parent compound in or on the food commodities, as follows: Beet, sugar, molasses at 2.5 parts per million (ppm), Beet, sugar, refined sugar at 1.0 ppm; Beet, sugar, roots at 1.5 ppm; and Beet, sugar, tops at 30.0 ppm. 

IR-4 also proposed, upon the approval of the aforementioned tolerances, to remove established tolerances for the combined residues of the herbicide ethofumesate, in or on the food commodities: Beet, sugar, molasses at 0.5 ppm; Beet, sugar, refined sugar at 0.2 ppm; Beet, sugar, roots at 0.3 ppm; and Beet, sugar, tops at 4.0 ppm. EPA has determined that this petition contains data or information regarding the elements set forth in section 408(d)(2); however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data support granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism.  The metabolism of ethofumesate in plants is adequately understood based on metabolism studies with sugar beets, annual ryegrass, cabbage, wheat, and radish.  All studies showed similar routes of metabolism for ethofumesate. The major metabolites are 2-hydroxy-2,3-dihydro-3,3-dimethyl-5-benzofuranyl methanesulfonate and 2,3-dihydro-3,3-dimethyl-2-oxo-5-benzofuranyl methanesulfonate (the lactone analog), NC 20645 (the carboxy analogue) together with small amounts of the unchanged parent. Metabolite NC 20645 exists in equilibrium with the lactone analog and all recovered NC 20645 are derivatized and reported as the lactone analog. From the studies, the residues of concern are the combined residues of ethofumesate and its metabolites 2-hydroxy-2,3-dihydro-3,3-dimethyl-5-benzofuranyl methanesulfonate and 2,3-dihydro-3,3-dimethyl-2-oxo-5-benzofuranyl methanesulfonate.

2. Analytical method.  Analytical methods have been developed and validated for the determination of ethofumesate and its metabolites 2-hydroxy-2,3-dihydro-3,3-dimethyl-5-benzofuranyl methanesulfonate and 2,3-dihydro-3,3-dimethyl-2-oxo-5-benzofuranyl methanesulfonate in sugar beet (roots and tops).  Ethofumesate and its related residues are extracted in a two-part process and quantified using LC-MS/MS analysis. The limit of quantification for ethofumesate and metabolites is 0.05 ppm. Therefore, adequate analytical methodology is available for enforcement purposes and it allows detection of residues at or above the proposed tolerances.

3. Magnitude of residues. 

a. Plant residues.  
i. Sugar Beets:  The IR-4 Project received requests from the states of Idaho, North Dakota, and Oregon for the use of ethofumesate to control waterhemp, glyphosate-resistant waterhemp, kochia, redroot pigweed, Powell amaranth, common lambsquarters, and volunteer Roundup-Ready canola in glyphosate-resistant sugar beets at one application at 4 lb AI/A or multiple applications totaling 4 lb AI/A at 10 day re-treatment intervals with a pre-harvest interval of 45 days.
Glyphosate-resistant waterhemp has become a serious problem in Roundup Ready sugar beet in North Dakota and Minnesota.  Currently, only the herbicides UpBeet, Betamix, and Ethofumesate 4SC applied postemergence have activity on waterhemp.  However waterhemp plants may also be resistant to UpBeet, an ALS herbicide, and Betamix provides variable control of waterhemp.  Also, Betamix is no longer registered, leaving Ethofumesate 4SC the only remaining postemergence herbicide to provide average to excellent control of glyphosate-resistant waterhemp when mixed with glyphosate.  Field research conducted in Minnesota and North Dakota showed that adding ethofumesate to glyphosate postemergence controlled most glyphosate-resistant waterhemp and improved the control of kochia and lambsquarters.  Waterhemp, kochia, Powell amaranth, and lambsquarters control is maximized when multiple applications of ethofumesate + glyphosate were applied. Glyphosate-resistant waterhemp control can also be improved when Ethofumesate 4SC is applied preemergence followed by applications of tank mixes of Ethofumesate 4SC plus glyphosate.

In support of the requests, magnitude of residue data were collected from a total of thirteen sugar beet field trials conducted in North Dakota, New Mexico, Washington, Idaho, Michigan, Wisconsin and California.  Samples were analyzed for residues of ethofumesate and metabolites, 2-hydroxy-2,3-dihydro-3,3-dimethyl-5-benzofuranyl methanesulfonate and 2,3-dihydro-3,3-dimethyl-2-oxo-5-benzofuranyl methanesulfonate.  In sugar beet tops, the residues measured for total ethofumesate ranged from about 1.0 ppm to 21 ppm. In sugar beet roots, the residues measured for total ethofumesate ranged from about 0.15 to 1.1 ppm. The data support the proposed increase in tolerances for sugar beet tops at 30.0 ppm and sugar beet roots at 1.5 ppm.

b. Animal residues: EPA established tolerances of 0.05 ppm for residues of ethofumesate and its metabolites in meat, meat byproducts and fat from the following animals: cattle, goats, sheep, hogs and horses.

B. Toxicological Profile

1. Acute toxicity.  In an acute oral toxicity study conducted in rats, the oral LD50 value for technical ethofumesate was determined to be >6400 mg/kg (Toxicity Category IV). The dermal LD50 in rats was established at >20,050 mg/kg (Toxicity Category IV).  An inhalation four hour exposure of rats to ethofumesate resulted in a LC50 of >0.49 mg/L (maximum achievable concentration; Toxicity Category II).  Application of ethofumesate to the rabbit eye resulted in no irritation (Toxicity Category IV). A primary dermal irritation study in rabbits demonstrated that application of ethofumesate produced no irritation (Toxicity Category IV). No dermal sensitization occurred with ethofumesate in guinea pigs.

2. Genotoxicity. No evidence of genotoxicity was observed in a battery of tests including an in vivo mouse bone marrow micronucleus assay and four in vitro studies:  Ames Salmonella assay, gene mutation assay in mammalian cells (mouse lymphoma 6TG cells), chromosomal aberration assay in human lymphocytes, and unscheduled DNA synthesis in primary rat hepatocytes.  

3. Reproductive and developmental toxicity. 

i. Prenatal Developmental Toxicity - Rat
Groups of 24 time-mated female rats received ethofumesate by daily gavage at dose levels of 0, 10, 100, or 1000 mg/kg/day from day 6 to day 15 of gestation. No maternal or developmental toxicity was observed up to a limit dose of 1,000 mg/kg/day.  There were no unscheduled deaths during the study and no effects of treatment on maternal body weight gains, food efficiency or gross pathology.  There were no effects of treatment at 10 or 100 mg/kg.  The maternal NOAEL is 1000 mg/kg/day.  There were no treatment-related effects on the numbers of fetuses (live or dead), resorptions (early or late), post-implantation loss, sex ratio, fetal weight or fetal external, visceral or skeletal examinations.  The developmental NOAEL is 1000 mg/kg/day.

ii. Prenatal Developmental Toxicity - Rabbit
In a developmental toxicity study, ethofumesate was administered daily via oral gavage to 25 female New Zealand White rabbits/group at dose levels of 0, 30, 300 or 3000 mg/kg/day, on gestation days (GD) 6 through 18.  The maternal NOAEL was 300 mg/kg/day based on increased mortality, decreased body weights, abortion and litter resorptions at the highest dose tested, 3000 mg/kg/day.  Developmental toxicity was observed at 300 and 3000 mg/kg/day as evidenced by increased resorptions, post-implantation loss and incomplete ossification of vertebral arches.  The NOAEL was 30 mg/kg/day indicating increased prenatal susceptibility in rabbits.

iii. Three-Generation Reproduction  -  Rat
In a three-generation reproduction toxicity study ethofumesate was administered continuously in the diet to CD:Crl albino rats (30/sex/dose) at nominal dose levels of 0, 200, 1000 or 5000 ppm.  No parental, offspring or reproductive toxicity was observed at the highest dose tested, 5000 ppm (equivalent to 396.8 mg/kg/day in males and 462.5 mg/kg/day in females).

4. Subchronic toxicity

i. 90 Day Dietary  -  Rat
Male and female Crl:CD(SD) rats were administered ethofumesate in the diet at concentrations of 0, 300, 3000 or 30000 ppm for 90-days.  These dose levels were equivalent to 0, 23.4, 230 and 2309 mg/kg/day in females and 0, 18.2, 190 and 1900 mg/kg/day in males, respectively.  Body weight was 8% lower in males and 17% lower in females at the high dose at study termination when compared to the controls.  Overall body weight gain was depressed 15% in males and 47% in females at 30000 ppm.  Food consumption was unaffected in males, but decreased 10% in females at the high dose and food efficiency was increased in both males and females.  Hematology and clinical chemistry parameters were unaffected by treatment.  Absolute liver weight was increased in males at 30000 ppm which was accompanied with liver microscopic findings including eosinophilic periportal hepatocytes and periportal fat deposition.  Absolute kidney weights were also increased in males as well as the incidence of tubular basophilia, dilation, inflammation and/or fibrosis.  Although kidney weights were increased in females, no histopathology findings were observed.  No adverse findings were observed at the low and mid dose.  The NOAEL was considered to be 3000 ppm based on effects on body weight and weight gain and microscopic findings in the liver and kidney.

ii. 90 Day Dietary - Mouse
In the 90-day mouse study, Crl:CD-1(ICR)BR (VAF plus) male and female mice were administered 0, 300, 3000 or 10000 ppm in the diet.  These dietary concentrations were equivalent to 0, 45, 450 and 1500 mg/kg/day using the Lehman conversion factor of 0.15.  No adverse effects were observed in the study and the NOAEL was considered to be greater than 10000 ppm or 1500 mg/kg/day.

5. Chronic toxicity.

i. Chronic Toxicity  -  Dog
Male and female beagle dogs were fed diets containing 0, 800, 4000 or 20000 ppm in the diet for 104 weeks.  These dose levels were equivalent to 0, 24.5, 117.8 and 632.4 mg/kg/day in males and 0, 23.7, 109.0 and 618.9 mg/kg/day in females.  No effects were observed on mortality, body weight and weight gain, incidence of clinical signs, food consumption, hematology and urinalysis parameters, or upon macroscopic and microscopic pathology.  At the high dose, alkaline phosphatase and alanine aminotransferase were statistically increased in males and females combined.  In addition, absolute liver weights were increased in males and females at 20000 ppm.  There were no microscopic correlates in the liver.  The NOAEL was considered to be 4000 ppm (117.8/109.0 mg/kg/day) based on the effects observed on alkaline phosphatase and alanine transferase and absolute liver weights observed at 20000 ppm (632.4/618.9 mg/kg/day).

ii. Combined Chronic Toxicity/Oncogenicity  -  Rat
A chronic toxicity/carcinogenicity study was conducted in Sprague-Dawley rats at dietary concentrations of 0, 2000, 7000 or 20000 ppm.  The chronic toxicity phase of the study was 52 weeks in duration and the carcinogenicity phase was 104 weeks.  In the chronic phase of the study, dietary concentrations were equivalent to, 0, 115, 398 and 1135 mg/kg/day in males and 0, 144, 577 and 1697 mg/kg/day in females.  Body weights were statistically decreased in the mid and high dose group throughout the study in females and at the high dose in males.  Relative liver weight was statistically increased in females at the high dose group compared to the control group.  The following microscopic findings were statistically increased compared to the control group:  hepatic focal cellular alteration with vascular changes at the mid and high dose in males; hepatocellular vacuolation and periportal cellular changes at the high dose in males; periportal hepatocyte enlargement in females at the mid and high dose; dilated/cystic follicles in the thyroid in males at the high dose; and cystic ducts in the thymus of high dose females.  The NOAEL was considered to be 2000 ppm (115 and 144 mg/kg/day in males and females, respectively) based on decreased body weight (females) and liver histopathology (males) observed at 7000 ppm.

In the carcinogenicity phase of the rat study, body weights were statistically decreased compared to the controls in females at the mid and high dose levels throughout the study and in males at the high dose.  Body weight gain was also reduced primarily at the high dose.  The following microscopic findings were statistically increased at the high dose compared to the control group: centrilobular hypertrophy in the liver of males and females; periportal cellular alteration in the liver of males; tubular pigment deposition in the kidney in females; focal hypertrophy in the pancreas of females; and retinal atrophy in females.  In the carcinogenicity phase of the study the 2000, 7000 and 20,000 ppm levels were equivalent to 127, 469 and 1003 mg/kg/day in males and 97, 332 and 1003 mg/kg/day in females. The NOAEL is 2000 ppm (127 mg/kg/day) in females based on decreased body weights/body weight gain observed at 7000 ppm, and 7000 ppm (332 mg/kg/day) in males based on decreased body weights/body weight gain and liver lesions observed at 20000 ppm.

iii. Oncogenicity - Mouse
In a carcinogenicity study, ethofumesate was administered to Crl:CD-1(ICR)BR (VAF plus) mice in the diet for 80 weeks at doses of 0, 1000, 3000 or 10000 ppm (equivalent to of 161, 477 and 1601 mg/kg/day for males and 204, 644 and 2145 mg/kg/day for females, respectively).  Mortality, body weights, body weight gains, food consumption/efficiency, clinical observations and differential leukocyte counts were unaffected by treatment.  Although absolute and/or relative liver weights were increased in all groups of treated mice the increases were not clearly dose-related and there were no supporting histopathology findings in the liver.  No significant gross or microscopic pathological lesions were found in either sex of mice.  The NOAEL was greater than 10000 ppm (1601 mg/kg/day in males and 2145 mg/kg/day in females).

6. Neurotoxicity

An overall weight of the evidence evaluation of the available information on ethofumesate and one other benzofuranyl alkanesulfonate herbicide indicates that ethofumesate has no neurotoxic potential.  The liver is the primary target organ for the toxicity of ethofumesate with effects on the liver or reduced body weight driving many no observed adverse effect levels (NOAEL) in the studies conducted.  Ethofumesate is a long chain fatty acid synthesis inhibitor and does not have a neurotoxic mode of action.  A careful review of the available toxicity studies on ethofumesate indicates that there are no indicators of neurotoxicity.  An examination of the available toxicology database of the other benzofuranyl alkanesulfonate herbicide (benfuresate) does not raise any concern for neurotoxicity.  An extensive search of the literature indicates no reports of neurotoxicity associated with benzofuranyl alkanesulfonate pesticides, including ethofumesate.  EPA concluded in the Toxicology Chapter of the Reregistration Eligibility Document that "the available studies in rat, mouse, dog and rabbit show no clinical evidence or pathological indication of neurotoxicity".   

7.  Immunotoxicity

An overall weight of the evidence evaluation of the available information on ethofumesate and one other benzofuranyl alkanesulfonate herbicide indicates that ethofumesate has no immunotoxic potential.  The liver is the primary target organ for the toxicity of ethofumesate with effects on the liver or reduced body weight driving many no observed adverse effect levels (NOAEL) in the studies conducted.  The available toxicity studies on ethofumesate indicate that any potential indicators of immunotoxicity occur only at dose levels that result in other systemic toxicity (chronic rat study) or were considered unrelated to treatment (21-day rabbit study).  An examination of the available toxicology database of the other benzofuranyl alkanesulfonate herbicide (benfuresate) does not raise any concern for immunotoxicity.  An extensive search of the literature indicates no reports of immunotoxicity associated with benzofuranyl alkanesulfonate pesticides, including ethofumesate.

8.  Dermal Absorption

In a dermal absorption rat study, [14-C]-ethofumesate was applied to Sprague-Dawley Crl:CD (SD) rats at dose levels of 3, 9 and 20 μg/cm[2]. A single dermal application of the test material in aqueous methyl cellulose was made to the shaved dorsal skin (12 cm[2] area) of a total of 48 animals (4 per time group/16 per dose) and the animals were monitored for absorption at 1, 10, 24 and 168 hours after dosing. The 168 hour group underwent skin wash at 10 hours and was carried to 168 hours before termination.  Mean recoveries of applied radioactivity from all dose groups ranged from 86 to 102%.   Mean absorption based on urinary/fecal excretion, blood, carcass, and cage wash ranged from 1.68 to 32.51%.  Total radioactivity absorbed clearly increased with increasing exposure time for all doses and the highest absorption rate consistently occurred at the 24 hour exposure duration. Absorbed radioactivity decreased with increasing dose for the 10 and 24 hour exposure durations indicating that the skin was approaching saturation of penetration for these exposure durations. The majority of the absorbed radioactivity was consistently found in the urine for all doses and durations. Absorbed dose found in the urine and feces increased with increasing exposure duration indicating that absorbed test material is increasingly absorbed and eliminated over time. Negligible amounts were present in blood samples analyzed for all dose/duration groups. The amount of radioactivity present in the carcass at 1, 10 and 24 hour exposure durations ranged from 1.5-6.2%. The amount of radioactively found in the carcass was significantly reduced at 168 hr post-wash exposure duration. Most of the unabsorbed radioactivity was found in the skin washes from each dose/duration (48-88%). Amount of radioactive dose on the treated skin after wash and termination ranged from 0.3 to 7%. Although there was no clearly discernable pattern of radioactivity remaining in/on treated skin indicating the extent to which skin residues continue to be absorbed post-wash, it is reasonable to assume that that test material remaining in/on skin is absorbed.  A dermal absorption factor of 27% is based on the combined radioactivity absorbed and that remaining in/on the skin at the 10 hour exposure duration for the low dose.

9.  Animal metabolism. 

i.  Rats - The metabolism of ethofumesate has been extensively studied in rats, ruminants and hens.  In the rat, ethofumesate is rapidly and extensively absorbed and metabolized to the water soluble acid metabolite NC 20645 which is excreted mainly in the urine. At higher dose levels an increase in excretion via the feces was observed.  Within the first 24 hours after dosing, most of the ethofumesate was eliminated from the body. Very low residue levels were detected in tissues five or seven days after dosing. No evidence of accumulation in any tissue or organ was observed.  

ii. Ruminants - A dairy cow received two oral doses of [14C]-ethofumesate every day for four consecutive days.  The mean daily dose was 2.945 g (equivalent to 5.0 mg/kg body weight/day) with the total dose equivalent to 274 ppm in the diet.  Edible tissue residue levels ranged from 0.033 and 1.863 mg equivalents/kg tissue. Milk residue levels rose rapidly and peaked at 0.134 mg equivalents/kg 32 hours after the initial dose.  Kidney and liver residue levels were the highest at 1.863 mg equivalents/kg and 0.661 mg/equivalents/kg, respectively. Unmetabolized ethofumesate was the major residue in tissues.  Low levels of the metabolites NC 8493, NC 9607 (the lactone analogue) and NC 20645 were also detected in tissues.  

iii.  Poultry - [14C]-Ethofumesate was orally dosed to three laying hens at 1.50 mg (approximately 12 ppm in the diet) per bird each day for ten consecutive days. After the initial dose, residues were rapidly excreted with 82% of the [14C] recovered within 24 hours. Total residues (ethofumesate and/or metabolites) in the edible tissues of the hen were low.  Ethofumesate was the major component identified in egg yolks, fat and skin. The metabolite NC 9607 was detected in all tissues while the metabolite NC 20645 was identified in the muscle, liver, skin and egg yolks.

10. Endocrine disruption. 

No special studies have been conducted to investigate the potential of ethofumesate to induce estrogenic or other endocrine effects. However, no evidence of estrogenic or other endocrine effects has been noted in any of the standard toxicology studies that have been conducted with this product and there is no reason to suspect that any such effects would be likely.

C. Aggregate Exposure

1. Dietary exposure.

i. Acute and chronic combined dietary (food + drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model-FCID(TM) software (Version 4.02) which uses food consumption data from the 2005-2010 National Health and  Nutrition Examination Survey (NHANES), What We Eat in America (WWEIA).  Dietary exposure estimates were based on the current tolerances that have been established (40 CFR 180.345) for combined residues of ethofumesate and metabolites in or on onions, garlic and shallots (0.25 ppm), carrots (7.0 ppm), garden beets (0.5 ppm), animal commodities including fat, meat and meat byproducts (0.05 ppm), and the proposed higher tolerance for sugar beet roots (1.5 ppm), sugar beet molasses (2.5 ppm), and sugar beet refined sugar (1.0 ppm). It was assumed that 100% of the crops were treated with ethofumesate. Although the carrot tolerance is restricted to use in the states of Washington and Oregon, the assessment assumed a national consumption of treated carrots by all population subgroups.

There is no appropriate single-dose endpoint available for acute oral exposure of the general population to ethofumesate and therefore a quantitative acute dietary risk assessment is not needed.  An acute reference dose (RfD) of 0.3 mg/kg body weight/day for Females 13-39 years old is based on the results from a prenatal developmental toxicity study in rabbits (LOEL 300 mg/kg/day) and an uncertainty factor of 100 (10X for interspecies extrapolation and 10X for intraspecies variation).  

A chronic RfD was established for the general population including infants and children at 1.3 mg/kg/day based on the results from the combined chronic toxicity/oncogenicity study in the rat (NOAEL 127 mg/kg/day) and an uncertainty factor of 100 (10X for interspecies extrapolation and 10X for intraspecies variation).  The chronic RfD for Females 13-49 years of age was established separately from the general population because the developmental toxicity observed at 30 mg/kg/day in the developmental toxicity study in rabbits resulted in an acute RfD (0.300 mg/kg/day) which is lower than the chronic RfD (1.30 mg/kg/day) established from the combined chronic toxicity/carcinogenicity study in rats.  

An exposure assessment for the purpose of assessing cancer risk is not required because EPA classified ethofumesate as "not likely to be a human carcinogen".

ii. Drinking water. For ethofumesate, no monitoring data are available.  Estimated drinking water concentrations in surface water were calculated using the USEPA tool Pesticide Water Calculator (PWC v1.5).  Groundwater estimates were calculated from the USEPA screening level tool SCIGROW and PRZMGW.  Drinking water residues were then incorporated into DEEM-FCIDTM under the food categories "water, direct, all sources" and "water, indirect, all sources."  The highest drinking water exposure concentration was used in the DEEM model and was derived from the PRZMGW WI Sands scenario using the application scenario for carrots.  The peak value for that scenario is 782 μ/L and that value was used in the acute dietary exposure estimates.  The highest chronic value is 685 μ/L based on the application to carrots on coarse soil from PRZMGW WI sands scenario.

For the most sensitive sub-population, Females 13-49 years of age, acute dietary (food + water) exposure was estimated to be 0.04342 mg/kg/day.  This exposure represents 14.5% (95[th] percentile) of the aPAD which is well below 100% of the aPAD.  The contribution of food and food forms to the estimate, at the 95[th] percentile, is 1.9%.

Using a chronic water concentration of 685 ppb, none of the exposures from food and drinking water together resulted in a cPAD over 6% the reference dose for the general population or any other population subgroup.  Chronic dietary exposure for Females 13-49 years of age was estimated to be 0.014686 mg/kg/day which occupies 4.9% of the chronic reference dose.  The most highly exposed subpopulation was Non-Nursing Infants at 5.9% (0.076806 mg/kg/day) of the chronic reference dose.  There is no concern for exposures occupying 100% or less of the RfD. Therefore, the acute and chronic dietary exposures for both the U.S. population and infants and children are well within acceptable levels.

2. Non-dietary exposure. There are no residential uses of ethofumesate and it is not intended for use by homeowners.  Ethofumesate may be applied to residential lawns by professional lawn care operators.  Therefore, there is no exposure of homeowners to ethofumesate during the mixing, loading, and application of ethofumesate to residential lawns. However, post-application exposure to adults and toddlers on lawns treated with ethofumesate is possible. Exposure of adults to ethofumesate is from the dermal route only. In addition to dermal exposure, toddlers may have oral exposure to ethofumesate during post-application activities on treated turf via hand-to-mouth, object-to-mouth, and soil ingestion routes.

Turf transferable residues were not empirically determined from study data and default assumptions were used.  Other assumptions included immediate contact with turf after treatment after the maximum application rate was applied. EPA Standard Operating Procedures (SOPs) for Residential Exposure Assessment were used to complete the residential exposure estimates for adults and toddlers. 

Tier I residential reentry assessments were prepared for adults, females 14-39 years of age, and toddlers following treatment of residential lawns with ethofumesate.  Estimates were made for the worst case scenario: a single application of ethofumesate at a rate of 1.5 lb ai/A, 3 lb ai/A, or 4 lb ai/A. 

Risk was estimated by calculating dermal margins of exposure (MOEs) for adults, females 13-49 years of age, and toddlers, and an oral MOE for toddlers.  Dermal margins of exposure (MOEs) for adults were based on the rat 90-day oral toxicity study in which the no-observable adverse effect level (NOAEL) was 190 mg/kg/day.  Dermal margins of exposure (MOEs) for females 13-49 years of age were based on the oral NOAEL of 30 mg/kg/d from the rabbit developmental toxicity study.  Oral MOEs for children were based on a rat 90-day oral NOAEL of 190 mg/kg/day.  A dermal absorption factor of 27% was applied. 

Dermal MOEs for short- and intermediate-term exposure to adults ranged from 470 to 1300 for application rates of between 1.5 and 4.0 lb ai/A applied to turf.  Dermal MOEs for toddlers 1 to <2 years old ranged from 240 to 630 for short- and intermediate-term high contact lawn activities.  Oral MOEs for toddlers 1 to <2 years old ranged from 240 for short- to intermediate-term high contact lawn activities to 3100 for hand-to-mouth exposures from applications of ethofumesate at 4.0 lb ai/A to lawns.  The oral MOE for toddlers 1 to <2 years old for incidental ingestion of granules/pellets was 640 (1.5 lb ai/A).  

The short- and intermediate-term post-application exposure MOEs for females 13-49 years of age were 64, 85, and 170 from high contact lawn activities at application rates of ethofumesate to lawns at 1.5 lb ai/A, 3 lb ai/A, or 4 lb ai/A, respectively.  Except for Females 13-49 years old, the MOEs for adult and toddler activities on residential lawns following treatment with the maximum application of ethofumesate are well above the target MOE of 100 when conservative Tier I assumptions were used in the assessment.  Although the MOEs for Females 13-49 years old are below the target MOE of 100, the scenarios used in these calculations are very conservative.  The developmental endpoint used to estimate the risk for Females 13-49 years old was based on a study with a NOAEL (30 mg/kg/d) that is 10X lower than the LOAEL (300 mg/kg/d); the NOAEL may be an artifact of dose selection.  For residential post-application exposure, the endpoint is oral while assessed exposures are dermal.  Conservative default assumptions were used.  Exposures are assumed to be immediately after application, at the maximum level of contact, from the maximum application rate, and maximum levels dermal exposure area.  Most turf uses of ethofumesate are for golf courses and sod farms where high levels of post-application exposures are not expected.  Ethofumesate residues resulting from sod farm application would likely dissipate significantly before sod was transplanted to residential areas.

This assessment indicates that there is a reasonable certainty of no harm to adults or toddlers from potential residential exposure to ethofumesate after application to homeowner lawns.  

D. Cumulative Effects.

There is no reliable information to indicate that toxic effects of ethofumesate would be cumulative with those of another pesticide chemical.  Ethofumesate does not appear to produce a toxic metabolite produced by other substances.  Thus, it is appropriate to consider only the potential risks of ethofumesate in an aggregate exposure assessment.  

E. Safety Determination.

1. U.S. population. Acute dietary (food + water) exposure for the most sensitive population subgroup, Females 13-49 years old, to residues of ethofumesate from current and proposed uses was estimated to occupy 14.5% of the acute RfD, which is well below levels expected to pose any appreciable risk to human health. Therefore, aggregate acute exposure to ethofumesate for proposed and current uses is within acceptable levels. 

Ethofumesate may be applied to residential lawns by professional lawn care operators which may result in post-application exposure to adults on lawns treated with ethofumesate.  Aggregate short-term exposures were determined by combining chronic dietary (food + drinking water) exposures with short term residential exposures.  The short-term aggregate MOE for the general population of adults was calculated to be 445 which is well above the acceptable level of 100.  Therefore, aggregate short-term exposure and risk for adults is expected to be well within acceptable levels. 
Using conservative exposure assumptions previously described, chronic dietary (food + drinking water) exposure to residues of ethofumesate from current and proposed uses was estimated to occupy 1.2% of the chronic RfD for the general U.S. population, 4.9% for Females 13-49 years of age, and 5.9% for the most sensitive population subgroup, Non-nursing Infants.  Thus, based on the completeness and reliability of the toxicity data and the conservative exposure assessment it is concluded that there is a reasonable certainty that no harm will result to the general U.S. population from acute, short-term or chronic aggregate exposures to ethofumesate residues from current and proposed uses.

2. Infants and children.  No appropriate single-dose endpoint is available for acute oral exposure of the general population to ethofumesate and no acute dietary risk assessment is needed for this population group.  Therefore no acute dietary exposure is needed for the infants and children subpopulations.  Infants and children may experience short-term dermal and oral exposure to ethofumesate as a result of post-application activities on treated residential turf.  Aggregate short-term exposures were determined by combining chronic dietary (food and water) exposures with short-term residential exposures.  The short-term aggregate MOE for non-nursing infants 1 to < 2 years old was 158, which is above the acceptable level of 100.  Using conservative exposure assumptions previously described, chronic dietary exposure to residues of ethofumesate from current and proposed uses including drinking water was estimated to occupy 5.9% of the chronic RfD for the most highly exposed subpopulation, non-nursing infants.  Drinking water was estimated to occupy 5.2% of the chronic RfD for non-nursing infants.  Thus, based on the completeness and reliability of the toxicity data and the conservative exposure assessment it is concluded that there is a reasonable certainty that no harm will result to infants and children from acute, short-term or chronic aggregate exposures to ethofumesate residues from current and proposed uses.

F. International Tolerances.

European Union Maximum Residue Level (MRL) for sugar beet root is established at 0.5 ppm for ethofumesate.  Maximum Residue Levels (MRL's) have been established in Canada for ethofumesate in sugar beet roots at 0.3 ppm and sugar beet molasses at 0.5 ppm. 
