[Federal Register Volume 76, Number 153 (Tuesday, August 9, 2011)]
[Rules and Regulations]
[Page 48718]
[FR Doc No: 2011-20090]

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DEPARTMENT OF HOMELAND SECURITY

Coast Guard

33 CFR Part 165

[Docket No. USCG-2011-0578]
RIN 1625-AA00

Safety Zone; Chicago Harbor, Navy Pier Southeast, Chicago, IL

AGENCY: Coast Guard, DHS.

ACTION: Notice of enforcement of regulation.

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SUMMARY: The Coast Guard will enforce the Navy Pier Southeast Safety
Zone in Chicago Harbor from September 3, 2011 through September 24,
2011. This action is necessary and intended to ensure safety of life on
the navigable waters of the United States immediately prior to, during,
and immediately after fireworks events. During the aforementioned
period, restrictions will be enforced upon, and control movement of,
vessels in a specified area immediately prior to, during, and
immediately after fireworks events. During the enforcement period, no
person or vessel may enter the safety zones without permission of the
Captain of the Port, Sector Lake Michigan.

DATES: The regulations in 33 CFR 165.931 will be enforced at various
times and on various dates between 10 p.m. on September 3, 2011 to
10:30 p.m. on September 24, 2011.

FOR FURTHER INFORMATION CONTACT: If you have questions on this notice,
call or e-mail BM1 Adam Kraft, Prevention Department, Coast Guard
Sector Lake Michigan, Milwaukee, WI at<PHONE_NUMBER>, e-mail
<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:
    The Coast Guard will enforce the Safety Zone; Chicago Harbor, Navy
Pier Southeast, Chicago, IL listed in 33 CFR 165.931 for the following
events:
    (1) Navy Pier Fireworks; on September 3, 2011 from 10 p.m. through
10:30 p.m.; on September 17, 2011 from 8:45 p.m. through 9:15 p.m.; and
on September 24, 2011 from 8:45 p.m. through 9:15 p.m.
    All vessels must obtain permission from the Captain of the Port,
Sector Lake Michigan, or his or her on-scene representative to enter,
move within or exit the safety zone. Vessels and persons granted
permission to enter the safety zone shall obey all lawful orders or
directions of the Captain of the Port, Sector Lake Michigan, or his or
her on-scene representative. While within a safety zone, all vessels
shall operate at the minimum speed necessary to maintain a safe course.
    This notice is issued under authority of 33 CFR 165.931 and 5
U.S.C. 552 (a). In addition to this notice in the Federal Register, the
Coast Guard will provide the maritime community with advance
notification of these enforcement periods via broadcast Notice to
Mariners or Local Notice to Mariners. The Captain of the Port, Sector
Lake Michigan, will issue a Broadcast Notice to Mariners notifying the
public when enforcement of the safety zone established by this section
is suspended. If the Captain of the Port, Sector Lake Michigan,
determines that the safety zone need not be enforced for the full
duration stated in this notice, he or she may use a Broadcast Notice to
Mariners to grant general permission to enter the safety zone. The
Captain of the Port, Sector Lake Michigan, or his or her on-scene
representative may be contacted via VHF Channel 16.

    Dated: July 25, 2011.
M.W. Sibley,
Captain, U.S. Coast Guard, Captain of the Port Lake Michigan.
[FR Doc. 2011-20090 Filed 8-8-11; 8:45 am]
BILLING CODE 9110-04-P


[Federal Register: March 25, 2008 (Volume 73, Number 58)]
[Notices]
[Page 15751-15752]
[DOCID:fr25mr08-46]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Project No. 12672-003]

Oregon Tidal Energy Company; Notice of Surrender of Preliminary
Permit

March 19, 2008.
    Take notice that Oregon Tidal Energy Company, permittee for the
proposed Columbia Tidal Energy Project, has requested that its
preliminary permit be terminated. The permit was issued on March 23,
2007, and would have expired on February 28, 2010.\1\ The project would
have been located in the Pacific Ocean near the mouth of the Columbia
River in Clatsop County, Oregon, and Wahkiakum and Pacific Counties,
Washington.
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    \1\ 118 FERC ] 62,222.
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    The permittee filed the request on March 13, 2008, and the
preliminary permit for Project No. 12672 shall remain in effect through
the thirtieth

day after issuance of this notice unless that day is a Saturday,
Sunday, part-day holiday that affects the Commission, or legal holiday
as described in section 18 CFR 385.2007, in which case the effective
date is the first business day following that day. New applications
involving this project site, to the extent provided for under 18 CFR
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Part 4, may be filed on the next business day.

Kimberly D. Bose,
Secretary.
[FR Doc. E8-6023 Filed 3-24-08; 8:45 am]

BILLING CODE 6717-01-P


As observed in the rat, the major metabolic pathway of ethofumesate in plants and livestock involves dealkylation of the parent to form NC 8493, oxidization to a lactone ( NC 9607), followed by the opening of lactone to yield an acid ( NC 20645). The HED Metabolism Committee has determined that the parent ethofumesate and all metabolites, free and conjugated, are of toxicological concern and should be considered for tolerance enforcement and dietary risk assessment purposes. This includes parent ethofumesate ( free and conjugated), NC 8493 ( free and conjugated), NC 9607 ( free and conjugated), and NC 20645 ( free and conjugated). However, the MARC also determined that based on the environmental fate properties of this chemical and the relatively low amounts of the degradates detected in the laboratory environmental fate studies, that only parent ethofumesate needs to be assessed for drinking water. The conservative EECs should not underestimate the risk from drinking water.

5.1.7 Toxicity Profile of Major Metabolites and Degradates DP Barcode D326518 / 46510101 Page 49 of 73 The metabolism of ethofumesate in ryegrass, sugar beets, poultry, lactating cows and the rat has been reviewed by HED and found to be adequate. Ethofumesate is converted via the hemiacetal ( NC 8493, loss of the ethyl group) to the lactone ( NC9607) and acid ( NC20645) in all of the above species. Presented in Table 3.0.1 are the structures for ethofumesate and the residues of concern. The HED Metabolism Committee has determined that the parent ethofumesate and all metabolites, free and conjugated, are of toxicological concern and should be considered for tolerance enforcement and dietary risk assessment purposes. However, the available data ( i. e., LD50 values, results from rat developmental and a 1 year dietary study in rats with NC 8438, all of which show little or no toxicity) indicate that the toxicity of the metabolites is comparable to that of the parent. Therefore, the parent and the metabolites have been assessed together. Similarly, the MARC determined that based on the environmental fate properties of this chemical and the relatively low amounts (< 10%) of the degradates detected in the laboratory environmental fate studies, that only the parent, ethofumesate needs to be assessed for drinking water.

5.1.8 Pesticide Metabolites and Degradates of Concern The MARC has determined that the residues of concern in plants are the combined residues of ethofumesate and its free and conjugated metabolites NC 8493, NC 9607, and NC 20645 ( S. Funk, 8/ 29/ 95). Although the current tolerance expression does not include the metabolite NC 20645, the expression is adequate for plant commodities as the acid treatment used in the tolerance enforcement and data collection methods converts NC 20654 to NC 9607.

TABLE 5.1.8 Chemical Names and Structures of Ethofumesate and its Residues of Concern.

Company Name ( Codes) Chemical Name Structure Ethofumesate ( NC 8438; AE B049913) 2 ethoxy 2,3 dihydro 3,3 dimethyl 5 benzofuranyl methanesulfonate NC 8493 ( AE C508493) 2,3 dihydro 2 hydroxy 3,3 dimethylbenzofuran 5 yl methanesulfonate O OH C H 3 CH 3 CH 3 SO 2 O NC 9607 ( AE C509607) 3,3 dimethyl 5[( methylsulfonyl) oxy] 2( 3H) benzofuranone O O C H 3 CH 3 CH 3 SO 2 O DP Barcode D326518 / 46510101 Page 50 of 73 TABLE 5.1.8 Chemical Names and Structures of Ethofumesate and its Residues of Concern.

Company Name ( Codes) Chemical Name Structure NC 20645 ( AE C639175) 2 hydroxy%,% dimethyl 5 [( methylsulfonyl) oxy] benzeneacetic acid OH CH 3 SO 2 O CH 3 CH 3 O OH 5.1.9 Drinking Water Residue Profile The MARC concluded that while three degradates of ethofumesate were identified, they were of toxicological equivalence to the parent and were detected in environmental fate studies in relatively low amounts ( 10%), only the parent needs to be assessed for drinking water. Since no monitoring data were available for use in this drinking water assessment, the EFED provided the drinking water assessments using simulation models to estimate the potential concentration of ethofumesate in ground and surface water.

Table 5.1.9 Summary of Estimated Surface and Ground Water Concentrations for Ethofumesate Exposure Duration Surface Water Conc., ppb ( Fg/ l) a Ground Water Conc., ppb ( Fg/ l) b Acute 154 8.4 Chronic ( non cancer) 45.5 Chronic ( cancer) 26 a From the Tier II PRZM EXAMS  Index Reservoir model. Input parameters are based on standard model parameters ( i. e., application rates spray drift scenario, aerobic and anaerobic metabolism, aerobic and anaerobic aquatic degradation, aqueous photolysis, hydrolysis t1/ 2, Kd/ Koc, molecular weight, foliar decay rate, water solubility, Henry's Law Constant and vapor pressure). b From the SCI GROW model assuming a maximum seasonal use rate of 3.0 lb ai/ A, a Koc of 156.3 and a half life of 83 and days for aerobic metabolism.

5.1.10 Food Residue Profile Ethofumesate [ 2 ethoxy 2,3 dihydro 3,3 dimethyl 5 benzofuranyl methanesulfonate] is a selective herbicide for the control of broadleaf and grass weeds in sugar beets and grasses. In the U. S., ethofumesate products registered to Bayer CropScience, the basic producer, include a flowable concentrate ( FlC; 4 lb/ gal), a soluble concentrate ( SC; 4 lb/ gal), and several emulsifiable concentrates ( EC; 0.05 1.5 lb/ gal) that can be applied as pre plant, preemergence, and postemergence applications using ground or aerial equipment. Tolerances for the residues of ethofumesate are established in 40 CFR § 180.345 as ethofumesate ( 2 ethoxy 2,3 dihydro 3,3 dimethyl 5 benzofuranyl methanesulfonate) and its metabolites 2 hydroxy 2,3 dihydro 3,3 dimethyl 5 DP Barcode D326518 / 46510101 Page 51 of 73 benzofuranyl methanesulfonate and 2,3 dihydro 3,3 dimethyl 2 oxo 5 benzofuranyl methanesulfonate ( both calculated as the parent compound) ranging from 0.05 ppm on animal commodities to 1.0 ppm on sugar beet tops.

Interregional Research Project # 4, IR 4, is requesting the use of ethofumesate in the product Nortron ® SC ( EPA Reg. No. 264 613) on dry bulb onions. The requested use is for a single application at planting or shortly after at 1.0 lb ai/ A followed by four applications at 0.5 lb ai/ A. A 30 day PHI is indicated.

The residues of concern in plants are the combined residues of ethofumesate and its free and conjugated metabolites NC 8493, NC 9607, and NC 20645. Although the current tolerance expression does not include the metabolite NC 20645, the expression is adequate for plant commodities as the acid treatment used in the tolerance enforcement and data collection methods converts NC 20654 to NC 9607. The metabolism of ethofumesate in rotational crops was similar to the primary crops.

A tolerance enforcement method is listed as Method I in the Pesticide Analytical Manual Vol. II ( PAM II, Section 108.345) for determining the currently regulated residues in plants, which include ethofumesate and its metabolites NC 8493 and NC 9607 ( free and conjugated). Although this method does not specifically address the recovery of free and conjugated NC 20654, the acid hydrolysis step used in the method most likely results in the conversion of NC 20654 to NC 9607. Residues are determined using gas chromatography with flame ionization detector ( GC/ FID). The reported limit of quantitation ( LOQ) for each analyte is 0.02 ppm. PAM Vol. I, Appendix I indicates that ethofumesate is completely recovered using FDA Multiresidue Methods Section 302 ( Luke Method; Protocol D). However, no data are available on the recovery of the metabolites NC 8493, NC 9607, and NC 20654. These data should be submitted for any future action.

In addition to Method I above, the registrant has proposed a gas chromatography with flame photometric detector in the sulfur mode ( GC/ FPD S) method for enforcing tolerances in plant commodities. This method was most recently referred to as Bayer CropScience Method Number XB/ 01/ 01, is the same as the data collection GC/ FPD S Method B 93R 03. The LOQ for each analyte is 0.05 ppm. During the acid hydrolysis step, free and conjugated residues of NC 20645 are released and recyclized to form NC 9607. The above GC/ FPD S method has undergone a successful independent laboratory validation trial and has been successfully validated using radiolabeled samples of tops and roots from red beets treated with [ 14C] ethofumesate. This method should be forwarded to the Analytical Chemistry Branch ( ACB) for an method validation trial, however this is not a deficiency for this action. Onion samples were analyzed for ethofumesate and metabolites NC 9607 and NC 8493 using AgrEvo Report No. B 93R 03. Minor modifications were made that did not negatively affect the performance of the method. Quantitation was accomplished by gas chromatograph with a mass selective detector ( GC MSD). The lower limit of method validation ( LLMV) for dry bulb onions is 0.05 ppm for all three analytes. The LOD is 0.02 ppm for ethofumesate and the limit DP Barcode D326518 / 46510101 Page 52 of 73 of quantitation ( LOQ) is 0.055ppm.

Storage stability data are available indicating that ethofumesate, NC 9607 and NC 8493 are stable frozen for up to 35 months in various commodities. A storage stability study was conducted in conjunction with the onion residue study. The results indicate that residues of ethofumesate are stable for up to approximately 24.3 months. The maximum frozen storage interval for onion residue samples, from harvest to analysis, was approximately 28.2 months. There is sufficient storage stability data to indicate that ethofumesate residues of interest do not degrade in onions over the harvest to analysis interval.

IR 4 has submitted field trial data for ethofumesate on onion ( dry bulb). The number and locations of field trials are in accordance with OPPTS Guideline 860.1500. Each of the 10 field sites the treated plot received five applications of the test substance with the exception of the 98 CA03 trial which received four applications. The first application was broadcast to the soil surface prior to crop emergence at a rate approximately 1.0 lb ai/ A. Subsequent applications were foliar and made at approximate even intervals at a rate of approximately 0.5 lb ai/ A each for a total of approximately 3.0 lb ai/ A, with the last application timed so that mature or near mature dry bulb onions could be harvested 28 to 32 days after the final application. Samples were analyzed for residues of ethofumesate and metabolites NC 9607 and NC 8493 using B 93R 03. For method validation, control samples of onions were fortified with ethofumesate at 0.05 ppm; recoveries were 114% ± 5%, n= 3. Concurrent recoveries from onion samples fortified at 0.05 ppm with NC 9607 were 119% ± 2%, n= 3 and 0.05ppm with NC 8493 were 117% ± 6%, n= 3. The LOD and LOQ for residues of ethofumesate in onion are 0.02 ppm and 0.055 ppm, respectively. In treated samples, ethofumesate residues were mostly below the lowest level of method validation ( LLMV) of 0.05 ppm and ranged to 0.087 ppm. NC 9607 residues ranges from the LLMV to 0.112 ppm. No NC 8493 residues above the LLMV were observed in any of the samples. Total residues of ethofumesate and metabolites ranged from < 0.15 to 0.22 ppm with a HAFT of 0.20 ppm. PHIs were from 28 32 days. The requested tolerances for garlic, bulb and shallot, bulb are not required since they are automatically included in the onion tolerance. In addition, the preferred term for the commodity should be onion, bulb. The MRL spreadsheet indicates that the requested tolerance is not appropriate and should be lowered. The petitioner should submit a revised Section F requesting a tolerance for ethofumesate residues on onion, bulb at 0.25 ppm.

Since there are no onion, dry bulb livestock feed items of regulatory interest, a discussion of the nature of the residue, analytical methods, and magnitude of the residue in livestock commodities is not germane to this action.

The limited field rotational crop trials are adequate and indicate that extensive field rotational crop studies are required to support tolerances for inadvertent ethofumesate residues in rotational crops. Without additional data on rotational crops, the current rotational crop restrictions on the Nortron ® SC label are appropriate: do not rotate to any DP Barcode D326518 / 46510101 Page 53 of 73 crop other than sugar beets or ryegrass for 12 months following applications totaling more than 0.375 lb ai/ A and for 6 months following post emergence applications totaling # 0.375 lb ai/ A.

5.1.11 International Residue Limits There are currently no Codex, Canadian, or Mexican MRLs established for ethofumesate, therefore there are no international harmonization issues for this action.

5.2 Dietary Exposure and Risk An acute and chronic dietary ( food+ water) risk assessment was conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database ( DEEM FCID   , Version 2.03), which uses food consumption data from the USDA's Continuing Surveys of Food Intakes by Individuals ( CSFII) from 1994 1996 and 1998. The analysis was performed to support the registration decision. The acute and chronic dietary exposure/ risk analyses were conducted using tolerance values, default processing factors, and 100% crop treated for all commodities. The maximum concentration for acute dietary risk assessment, and the average concentration for chronic dietary risk assessment, from PRZM/ EXAMS was used for drinking water contribution to exposure. Based on this Tier 1 ( unrefined) assessment, the team selected the 95th percentile of exposure to estimate acute dietary risk from food and water. No monitoring data are available for ethofumesate.

The water values used in the dietary risk assessment were incorporated in the DEEMFCID   into the food categories " water, direct, all sources" and " water, indirect, all sources". Based on modeling results, the maximum estimated surface water derived drinking water concentrations for the use of ethofumesate is 154 Fg/ L ( used for the acute analysis) using the Florida turf scenario. The maximum 1 in 10 year annual average concentration is 45.5 Fg/ l ( used for the chronic analysis) using the Florida turf scenario, and 26 Fg/ L for the 30 year annual mean concentration for the Minnesota sugar beet scenario.

Conservative acute and chronic dietary ( food + water) assessments were performed using DEEM FCIDTM. Tolerance level residues and 100% crop treated were used in the assessments. The acute assessment concludes that for all supported commodities, the acute dietary exposure estimate is below HED's level of concern for females 13 49 years of age ( the only population subgroup of concern toxicologically identified at this time) at 5 % of the aPAD at the 95th percentile. The chronic assessment concludes that for all supported commodities, the chronic dietary exposure estimates are below HED's level of concern for all population subgroups at 1% or less of the cPAD.

Table 5.2. Result of Acute and Chronic Dietary Exposure ( Food + Water) and Risk Estimates for Ethofumesate.

DEEM FCID Population Subgroup PAD, mg/ kg/ day Exposure, mg/ kg/ day % PAD DP Barcode D326518 / 46510101 Page 54 of 73 Acute Dietary Estimates 95th Percentile of Exposure Females 13 49 yrs 0.3 0.011837 4 Chronic Dietary Estimates U. S. Population 1.3 0.002604 < 1 All infants (< 1 yr) 1.3 0.011013 < 1 Children 1 2 yrs 1.3 0.006256 < 1 Children 3 5 yrs 1.3 0.004442 < 1 Children 6 12 yrs 1.3 0.002944 < 1 Youth 13 19 yrs 1.3 0.001756 < 1 Adults 20 49 yrs 1.3 0.002142 < 1 Adults 50+ yrs 1.3 0.002341 < 1 Females 13 49 yrs 0.3 0.002179 < 1 Cancer Dietary Estimate U. S. Population NA NA NA 5.3 Anticipated Residue and Percent Crop Treated (% CT) Information No anticipated residue or % CT data were used in the dietary exposure analysis.

6.0 Residential ( Non Occupational) Exposure/ Risk Characterization Residential risk is expressed as a MOE, which measures how close the residential exposure comes to the NOAEL from animal studies. Generally, MOEs that are greater than 100 do not exceed the Agency's level of concern ( the standard target MOE incorporates the standard uncertainty factors of 10x for interspecies variability and 10x for intraspecies variability). EPA determined that the available data supports the removal of the default 10x FQPA factor. Thus, scenarios that yield MOEs that are less than 100 may trigger concern.

An oral NOAEL of 190 mg/ kg/ day was selected from a 90 day oral study in rats for assessing the dermal exposure route. The LOAEL in this study was 1900 mg/ kg/ day with the effects of decreased body weight gain and liver microscopic lesions. Data on dermal absorption are unavailable at this time; therefore, a default assumption of 100% absorption was used. Inhalation exposure is not expected because residues are likely to be diluted outdoors in the air and ethofumesate has a low vapor pressure ( 4.9 x 10 6 torr).

Some residential ( dermal) scenarios were assessed for females 13 49 yrs. based on an oral endpoint from a developmental study in rabbits with effects manifested by increased resorptions, post implantation loss and incomplete ossification of the vertebral arches. While the residential postapplication scenarios resulted in apparent risks of concern ( see Table 6.2), the Agency believes that these scenarios are very conservative and unlikely to occur. The developmental endpoint was based on a study with a NOAEL ( 30 mg/ kg/ day) that is 10X lower DP Barcode D326518 / 46510101 Page 55 of 73 than the LOAEL ( 300 mg/ kg/ day); therefore the NOAEL may be an artifact of dose selection. Additionally, for the residential exposures, the endpoint is oral while the assessed exposures are dermal and conservative SOP based default assumptions such as 100% dermal absorption, default turf transferable residue dissipation assumptions, contact with turf immediately posttreatment and maximum application rates were used in this assessment. The rate of 1.5 lb ai/ A covers the majority of uses; however, the label does permit a 3.0 lb ai/ A rate specifically for suppression of Bermuda grass in St Augustine grass turf.

The acute toxicity profile for ethofumesate shows that the dermal LD50 for ethofumesate was > 20,050 mg/ kg which was approximately three times higher than the highest dose tested for the oral route ( oral LD50 = > 6,400 mg/ kg). Additionally, no effects were seen at the highest dose tested ( 1000 mg/ kg/ day) in a 21 day dermal study in rabbits. Although the LD50 studies and the short term dermal study did not reach the desired endpoint and cannot be directly compared, the information from these studies gives the Agency confidence that high dermal exposures such as calculated for the residential risk assessments are unlikely to be a risk concern. However, the Agency intends to call in a dermal absorption ( or penetration) study to permit more realistic estimation of dermal absorption.

6.1 Residential Handler Exposure Since all ethofumesate products are intended for either agricultural use or require professional application for ornamental turf, no residential handler use is expected.

6.2 Residential Postapplication Exposure For potential ethofumesate residential post application exposure, HED conducted screening level calculations on the scenarios most likely to result in highest possible exposure to the herbicide. The other aspects of the turf exposure scenario involves calculating dose from non dietary ingestion that arises from the hand to mouth, object to mouth and soil ingestion pathways. These process are:

for toddlers: incidental ingestion ( hand to mouth) incidental ingestion ( turf to mouth) incidental ingestion ( soil to mouth) incidental dermal for adults: Jazzercise ( on treated turf)

HED believes that this screening level assessment will be protective of other possible residential exposures to ethofumesate such as golfing, mowing the lawn. Exposures were calculated by considering the potential sources of exposure ( i. e., TTRs on lawns) then calculating dermal exposure, and risks in the same manner as described for the occupational post application risk assessments.

The SOPs For Residential Exposure Assessment ( Reference B) define several pathways DP Barcode D326518 / 46510101 Page 56 of 73 that apply to post application exposure on treated turf. The SOPs and the associated pathways are presented below:

C Dose from dermal exposure on treated turf calculated using SOP 2.2: Postapplication dermal dose among toddlers from playing on treated turf, adults working or exercising on treated turf.

C Dose from object to mouth activity from treated turf calculated using SOP 2.3.3: Postapplication dose among toddlers from incidental non dietary ingestion of pesticide residues on treated turf from object and/ or hand to mouth transfer ( i. e., those residues that end up in the mouth from a child mouthing a handful of treated turf, pesticide residues on the hand; pesticide residues in the soil).

The algorithms used for each type of calculation are presented below:

Dermal Exposure from Treated Turf Dermal exposure from treated turf is calculated using the following formula ( SOP 2.2):

Dermal exposure ( mg/ day) = ( TTR at day t) x CF1 x TC x DA * x # hours/ day)

Where:

TTR = transferable turf residue ( ug/ cm 2 ) at day ( t) after application CF1 = conversion factor ( 0.001) to convert TTR value in ug/ cm 2 to mg/ cm 2 TC = transfer coefficient ( cm 2 / hour) DA = dermal absorption factor = 100% for ethofumesate Hours/ day = standard assumption is 2 to 4 hours of exposure per day depending upon the activity Exposures from Hand to Mouth Behavior on Treated Turf:

The following formula illustrates the approach used to calculate the non dietary ingestion exposures that are attributable to hand to mouth behavior on treated turf ( SOP 2.3.2).

PDR = TTR * ( SE/ 100) * SA * Freq * Hours * ( 1 mg/ 1000 ug) where:

PDR = potential dose rate from hand to mouth activity ( mg/ day); TTR = Turf Transferable Residue where dissipation is based on TTR study and the 0 day value is based on the 5% initial transferability factor ( Fg/ cm2); SE = saliva extraction factor ( 50%); SA = surface area of the hands ( 20 cm2); Freq = frequency of hand to mouth events ( 20 events/ hour); and Hours = exposure duration ( 2 hours).

When used for hand to mouth exposures, the TTR value is based upon the default DP Barcode D326518 / 46510101 Page 57 of 73 assumption of 5 percent of the application rate.

The formula for calculating the TTR value on Day 0 is given below:

TTR = Application Rate * F * CF1 * CF2 * CF3 Where: Application Rate = lbs ai/ acre F = fraction of applied ai that is available for hand to mouth exposure ( 5 percent) CF1 = 1.0 lb ai/ acre equals 2.3 x 10  5 lbs ai per ft 2 CF2 = 4.54 x 10 8 ug/ lb CF3 = 0.00108 ft 2 / cm 2 Note: CF1 * CF2 * CF3 = 11.23 Exposures from Object to Mouth Behaviors on Treated Turf:

The following formula illustrates the approach used to calculate exposures that are attributable to object to mouth behavior on treated turf that is represented by a child mouthing on a handful of turf ( SOP 2.3.3):

PDR = TTR * IGR * ( 1mg/ 1000ug) where: PDR = potential dose rate from mouthing activity ( mg/ day); TTR = Turf Transferable Residue where dissipation is based on TTR study and the 0 day value is based on the 20% initial transferability factor ( Fg/ cm2); and IgR = ingestion rate for mouthing of grass per day ( 25 cm2/ day).

Exposures from Soil Ingestion on Treated Turf:

The following formula illustrates the approach used to calculate exposures that are attributable to soil ingestion ( SOP 2.3.4):

PDR = SR * IgR * ( 0.000001 gm/ 1 ug)

Where: PDR = dose from soil ingestion activity ( mg/ day) SR = Soil Residue where dissipation is based on TTR study and the 0 day value is based on the application rate, 1 cm depth of surface soil, and the density of soil ( Fg/ cm3) IgR = ingestion rate for daily soil ingestion ( mg/ day)

MOE Calculations for Each Pathway:

The MOEs are calculated for each individual pathway using the MOE formula:

MOE ( unitless) = NOAEL / ( Dose / BW) DP Barcode D326518 / 46510101 Page 58 of 73 where NOAEL = mg/ kg/ day Dose = mg/ day BW = 15 kg ( toddlers), 60 kg ( adults)

MOEs Calculations for All of the Pathways Combined:

When assessing adult exposures only the dermal pathway is considered and when assessing toddler exposures all of the pathways are considered in total. The doses from the four pathways are combined as shown below to yield a total dose:

Total Dose = ( Dermal Dose + Hand to Mouth Dose + Object to Mouth Dose + Soil Ingestion Dose)/ BW Where: Total Dose = mg/ kg/ day BW = 15 kg for toddlers The total dose is then used to calculate a Total MOE as presented in Table 6.2 Table 6.2 Residential Exposure Estimates & MOEs for Ethofumesate Treated Turf Resident Activity DAT Tc or Equivalent Body wgt kg ADD* NOAEL MOE toddler dermal contact 0 5200 15 0.58 190 330 toddler ( at 3 lb ai/ acre) dermal contact 0 5200 15 1.17 190 160 Highest Toddler Dermal MOE 160 toddler hand to mouth 0 PDR** 15 0.022 190 8600 toddler turf to mouth 0 TTR** 15 0.0056 190 34000 toddler soil to mouth 0 PDR** 15 0 190 2.5 e6 Total Toddler Oral MOE 6900 Total Toddler Residential 150 adult Jazzercise 0 14500 70 0.35 190 540 adult ( at 3 lb ai/ acre) working 0 14500 70 0.7 190 270 DP Barcode D326518 / 46510101 Page 59 of 73 females 13 19 Jazzercise 0 14500 60 0.41 30*** 73 females 13 19 ( at 3 lb ai/ acre) Jazzercise 0 14500 60 0.81 30*** 37 * ADD= Average Daily Dose ( mg ai/ kg bw/ day) * from Standard Operating Procedures for Residential Exposure Assessment Science Advisory Council for Exposure Policy No. 12; revised February 22, 2001. ** based on a developmental toxicity study in rabbits; developmental LOAEL = 300, and assumes 100% dermal absorption.

With the exception of women of childbearing years, residential post application MOEs for toddlers and adults to ethofumesate on treated turf, regardless of the pathway of exposure, do not exceed the Agency's levels of concern. In the case of women of childbearing years, a MOE of 37 was estimated, based on an oral endpoint from a developmental study in rabbits. ARIA notes that this risk estimate is driven by the conservative assumptions used in the risk assessment: 1) screening level unrefined Tier 1 assessment was used, 2) 100% dermal absorption was assumed, and 3) an endpoint used for females 13+ years of age from a developmental study in rabbits with a steep dose response curve resulting from a NOAEL ( 30 mg/ kg/ day) that is 10X lower than the LOAEL ( 300 mg/ kg/ day); thus, a dose spacing issue likely exists. ARIA, therefore, considers this a highly conservative estimate of post application risk for the population females 13 49 years of age exposed to ethofumesate on turf.

6.3 Other ( Spray Drift, etc.)

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for ethofumesate. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/ labeling. The Agency has completed its evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U. S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off target drift with specific products with significant risks associated with drift.

In the case of the residential turf use of ethofumesate, the risks addressed in the residential turf assessment provide a worst case estimate of potential exposure from spray drift. DP Barcode D326518 / 46510101 Page 60 of 73 7.0 Aggregate Risk Assessments and Risk Characterization In accordance with the FQPA, OPP must consider and aggregate ( add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard ( e. g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, OPP considers both the route and duration of exposure.

The Agency has developed several guidance documents describing the mathematical approaches used in calculating aggregate risks and the theoretical basis for these calculations. The underlying approach, regardless of the calculation type, is the same. The overall, allowable risks associated with an individual chemical is first determined by its hazard database and its associated uncertainty factors or negligible risks if the concern is cancer ( i. e., an exposure limit is defined). Once limits have been defined, contributions from different sources are then added to obtain aggregate exposures ( diet food + water and residential) which are compared to the exposure limit to see if it has been exceeded which would indicate a risk concern.

Ethofumesate is a food use chemical. There are residential ( non occupational) uses of ethofumesate, resulting from postapplication exposure to turf; therefore, the considerations for aggregate exposure are those from food, drinking water and residential exposure.

In the past, EPA has not directly combined pesticide exposure estimates from drinking water with pesticide exposures from food because EPA was concerned that combining high end modeling values for drinking water with more realistic food exposure data might be confusing. Although EPA retains this concern, it is now outweighed by the advantages of using EPA's current aggregate exposure assessment models, Lifeline and DEEM. Advances in these models allow EPA to incorporate actual water consumption data and body weight data in assessing exposure to pesticides in drinking water as well as conduct probabilistic assessments for food, water, and residential exposures to pesticides. These more sophisticated exposure assessments are not possible under the drinking water levels of comparison ( DWLOC) approach. Rather than using back calculated DWLOCs, estimates of pesticide residues in drinking water were incorporated directly into the dietary exposure analysis to assess aggregate acute and chronic risk 7.1 Acute Aggregate Risk As part of the acute dietary exposure analysis, the evaluation of the acute aggregate exposure and risk was prepared ( see 5.2, Dietary Exposure and Risk). The analysis was performed for females 13 49 years of age since this is the only population subgroup of toxicological concern identified at this time. As shown in Table 5.2, the resulting food + water exposure estimate is below the Agency's level of concern for this population subgroup. The contribution of food and food forms to this estimate, at the 95th percentile, is 4%. Therefore, there are no acute food + water aggregate risk concerns for ethofumesate 7.2 Short and Intermediate Term Aggregate Risk DP Barcode D326518 / 46510101 Page 61 of 73 Risk assessments for aggregate exposure ( food + drinking water + residential) were considered for the short and intermediate term exposure. Because there are concerns for the post application residential exposure of females 13+ years of age ( MOE = 37, see Table 6.2), an aggregate assessment was not conducted for this subgroup. The aggregate exposure for food and drinking water has already been calculated for all of these subgroups and found not to pose a health concern ( See Section 5.2). However, there are post application residential exposures to ethofumesate, and the considerations for aggregate exposure are those from food, water, and residential uses. The short and intermediate term aggregate risk assessment values are presented in Table 7.2. As shown, target MOEs are the same for all populations. The toxicology study, showing decreased body weight gain and microscopic lesions in the liver ( NOAEL = 190 mg/ kg/ day in 90 day oral rat study), is appropriate for this exposure duration and the target populations.

Table 7.2 Short and Intermediate Term Aggregate Risk Short and/ or Intermediate Term Scenarios Chronic Dietary Residential Exposure Population LOC1 Exposure ( food+ water) mg/ kg/ day MOE ( food + water2) MOE oral3 MOE dermal4 MOE inhalation5 Aggregate MOE ( food + water and residential) 6 U. S. General Population 100 0.002604 73049 NA 270 NA 270 All Infants (< 1 year old) 100 0.011013 17252 6900 160 NA 160 Adult 50+ years old 100 0.002341 81161 NA 270 NA 270 Females 13 19 years old 100 0.002179 87196 NA 37 NA 37 1 Level of Concern ( LOC) is an MOE of 100 based on using uncertainty factors ( UF) of 10X for interspecies extrapolation and 10X for intraspecies variability. 2 MOE food + water, which incorporated the dietary values for drinking water ( Food + Water), = [( short or intermediate term oral NOAEL)/( chronic dietary exposure)]. Short or intermediate term NOAEL = 190 mg/ kg/ day from the subchronic oral rat study, MRID 44093601 3 MOE oral = [( short or intermediate term oral NOAEL)/( hand to mouth residential exposure)] Short or intermediate term NOAEL = 190 mg/ kg/ day from the subchronic oral rat study, MRID 44093601; hand to mouth exposure = 0.35, Jazzercise adult or general population or 0.022, toddler hand to mouth ( see Table 6.2). 4 MOE dermal = [( short or intermediate term dermal NOAEL)/( high end dermal residential exposure)] Short or intermediate term NOAEL = 190 mg/ kg/ day from the subchronic oral rat study, MRID 44093601; high end dermal residential = 0.58, toddler playing or 0.35, Jazzercise adult ( see Table 6.2). DP Barcode D326518 / 46510101 Page 62 of 73 5 MOE inhalation = [( inhalation NOAEL)/( high end inhalation residential exposure)] Short or intermediate term NOAEL = 190 mg/ kg/ day from the subchronic oral rat study, MRID 44093601; high end inhalation residential = 0.58, toddler playing or 0.35, Jazzercise adult ( see Table 6.3.1). 6 Aggregate MOE ( food + water and residential) = 1 ÷ [ [( 1 ÷ MOE food+ water) + ( 1 ÷ MOE oral) + ( 1 ÷ MOE dermal) + ( 1 ÷ MOE inhalation)]]

Based on the analysis of the general population, which appeared to have the highest oral exposure, the subpopulations adult male ( 50 + years old) and all infants (< 1 year old) with the highest dietary ( food + water) exposure, aggregate MOEs ranged from 160 to 270, which are all higher than the level of concern MOE of 100 and, therefore, not a cause for concern by the Agency. Hence, there are no aggregate short or intermediate term risk concerns for children ages 1 to 12, youths, ages 13 19 or adults ages 20 49 from exposure to ethofumesate.

In the case of women of childbearing years, a residential risk, and subsequently for the aggregate risk assessment, an MOE of 37 was estimated, based on an oral endpoint from a developmental study in rabbits. ARIA notes that this risk estimate is driven by the conservative assumptions used in the risk assessment: 1) screening level unrefined Tier 1 assessment was used, 2) 100% dermal absorption was assumed, and 3) an endpoint used for females 13+ years of age from a developmental study in rabbits with a steep dose response curve resulting from a NOAEL ( 30 mg/ kg/ day) that is 10X lower than the LOAEL ( 300 mg/ kg/ day); thus, a dose spacing issue likely exists. ARIA, therefore, considers this a highly conservative estimate of post application risk for the population females 13 49 years of age exposed to ethofumesate on turf.

7.3 Long Term Aggregate Risk Since there are no long term residential exposure scenarios of regulatory interest and the chronic food and water dietary risk assessment is below the Agency's level of concern, there are no aggregate long term risk concerns for any population subgroup exposure to ethofumesate.

7.4 Cancer Risk Ethofumesate is not likely to be carcinogenic based on bioassays in the rat and the mouse; therefore, a cancer aggregate risk assessment was not performed.

8.0 Cumulative Risk Characterization/ Assessment Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to ethofumesate and any other substances and ethofumesate does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that ethofumesate has a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common DP Barcode D326518 / 46510101 Page 63 of 73 mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http:// www. epa. gov/ pesticides/ cumulative/.

9.0 Occupational Exposure/ Risk Pathway The product proposed for use is Nortron ® SC Herbicide ( EPA Reg. No. 264   613) which is a 4.0 lb active ingredient ( ai) per gallon suspension concentrate liquid. Ethofumesate may be applied pre emergence and/ or post emergence. As a pre emergence application it should be applied broadcast to the soil surface at the rate of 32 fl oz product per acre ( 1.0 lb ai/ A). Postemergence it may be applied up to 4 times as foliar applications at the rate of 16.0 fl oz product/ A ( 0.5 lb ai/ A). There is a maximum of 3.0 lb ai/ A/ season that may be applied. Whether pre emergence or post emergence application, ethofumesate should be applied in 5   10 gallons of water/ A as a banded application or in 10   40 gallons of water/ A as a broadcast application. The pre harvest interval ( PHI) is 30 days. The target pests are numerous species of broadleaf weeds and grasses.

The registered label directs applicators and other handlers to wear the following personal protective equipment ( PPE): long sleeved shirt, long pants, shoes plus socks and waterproof gloves.

9.1 Short/ Intermediate/ Long Term Handler Risk Based upon the proposed new use pattern, HED believes the most highly exposed occupational pesticide handlers are likely to be mixer/ loaders using open pour loading of liquids and applicators using open cab, ground boom sprayers. HED expects most exposures will be short term duration ( 1  30 days). Typical field size is expected to be small as compared to field crops such as corn, cotton, soybeans or wheat. HED believes most applications are likely to be made by the grower. There may be several short term duration exposures but it is not likely that any particular applicator would be exposed from 1  6 months ( intermediate term duration exposure) applying ethofumesate to dry bulb onions.

It is expected that some private ( i. e., grower) applicators may perform all tasks, that is mix, load and apply the material. However, the HED Science Policy Council for Exposure ( ExpoSAC) draft Standard Operating Procedure ( SOP) ( 29 March 2000) directs that although the same individual may perform all tasks, in some cases they shall be assessed separately.

The available exposure data for combined mixer/ loader/ applicator scenarios are limited in comparison to the data available for monitoring of these two activities separately. These exposure scenarios are outlined in the Pesticide Handler Exposure Database ( PHED) Surrogate Exposure Guide ( August 1998). HED has adopted a methodology to present the exposure and risk estimates separately for the job functions in some scenarios and to present them as combined in other cases. Most exposure scenarios for hand held equipment ( such as hand wands, backpack sprayers, and push type granular spreaders) are assessed as a combined job function. With these types of hand held operations, all handling activities are assumed to be conducted by the same individual. The available monitoring data support this and HED presents them in this way. DP Barcode D326518 / 46510101 Page 64 of 73 Conversely, for equipment types such as fixed wing aircraft, ground boom tractors, or air blast sprayers, the applicator exposures are assessed and presented separately from those of the mixers and loaders. By separating the two job functions, HED determines the most appropriate levels of personal protective equipment ( PPE) for each aspect of the job without requiring an applicator to wear unnecessary PPE that might be required for a mixer/ loader ( e. g., chemical resistant gloves may only be necessary during the pouring of a liquid formulation).

No chemical specific data were available with which to assess potential exposure to pesticide handlers. The estimates of exposure to pesticide handlers are based upon surrogate study data available in the PHED. For pesticide handlers, it is HED standard practice to present estimates of dermal exposure for " baseline" that is, for workers wearing a single layer of work clothing consisting of a long sleeved shirt, long pants, shoes plus socks and no protective gloves as well as for " baseline" and the use of protective gloves or other PPE as might be necessary. The proposed product label involved in this assessment directs applicators and other handlers to wear long sleeved shirt, long pants, shoes plus socks and waterproof gloves.

The most recent consideration of the toxicological database for ethofumesate was presented in a 2004 HED Registration Eligibility Document ( DP Num: 278571, N. McCarroll, 11/ 23/ 04). With regards to the assessment herein, the HED identified dermal and inhalation toxicological endpoints for use in risk assessment. The dermal endpoint has a NOAEL of 190 mg ai/ kg bw/ day. The effects seen were decreased body weight and weight gain in both sexes and liver and kidney microscopic effects in males at 1900 mg ai/ kg bw/ day and were identified from a 90 day oral toxicity study in rats. HED assumed 100 % dermal absorption due to a lack of appropriate dermal absorption data to the contrary.

The HED identified inhalation toxicological endpoints from the same 90 day oral toxicity study in the rat. The NOAEL is 190.0 mg ai/ kg bw/ day. The toxicological effects seen were the same as were noted above for the dermal route of exposure.

With regards to carcinogenic potential, HED classified ethofumesate as " not likely to be carcinogenic to humans", therefore a cancer risk assessment is not necessary. Table 9.1 Estimated Exposures and Risks to Pesticide Handlers Applying Ethofumesate to Dry Bulb Onion Unit Exposure1 mg a. i./ lb handled Application Rate2 lb a. i./ A Units Treated3 Acres/ Day Avg. Daily Dose4 mg a. i./ kg bw/ day NOAEL5 mg a. i./ kg bw/ day MOE Mixer/ Loader  Liquid Open Pour Dermal SLNG 2.9 HC SLWG 0.023 HC Inhal 0.0012 LC 1 200 Dermal NG 8.29 WG 0.066 Inhal 0.00343 190 No Gloves 23 With Gloves 2,740 Applicator  Open cab Ground boom DP Barcode D326518 / 46510101 Page 65 of 73 Dermal SLNG 0.014 HC SLWG 0.014 MC Inhal 0.00074 LC 1 200 Dermal NG 0.04 WG 0.04 Inhal 0.00211 190 No Gloves 4,500 With Gloves 4,500 1. Unit Exposure = mg a. i./ lb a. i. handled; taken from the Pesticide Handler's Exposure Database PHED Surrogate Exposure Guide version 1.1; August 1998; Dermal: SLNG = Single Layer of Work Clothing [ long sleeved shirt, long pants, shoes + socks] NO Gloves. SLWG = single layer work clothing [ long sleeved shirt, long pants, shoes + socks] WITH Gloves; Inhalat. = Inhalation. HC = high confidence data; LC = low confidence data 2. Application Rate from proposed label in IR 4 request.

3. Acres Treated are derived from Sci. Adv. Coun SOP. No. 9.1 Rev. 25 SEP 01;

4. Average Daily Dose ( ADD) = Unit Exposure * Application Rate * Units Treated ÷ 70 kg body weight.

5. NOAEL = No Observed Adverse Effect Level ( mg a. i./ kg bw/ day). Short term dermal and inhalation NOAELs = 190 mg a. i./ kg bw/ day based on a 90 day oral toxicity study in the rat.

6. MOE = NOAEL ÷ ADD. Since the dermal and inhalation NOAEL's are the same, are identified from the same study and list the same toxic effects, the dermal and inhalation exposures are summed and then divided into the NOAEL to determine MOE.

9.2 Short/ Intermediate/ Long Term Postapplication Risk It is possible for agricultural workers to have post application exposure to pesticide residues during the course of typical agricultural activities. HED in conjunction with the Agricultural Re entry Task Force ( ARTF) has identified a number of post application agricultural activities that may occur and which may result in post application exposures to pesticide residues. HED has also identified Transfer Coefficients ( TC) ( cm ² / hr) relative to the various activities which express the amount of foliar contact over time, during each of the activities identified.

The transfer coefficients used in this assessment are from an interim transfer coefficient Standard Operating Procedure ( SOP) developed by HED's ExpoSAC using proprietary data from the ARTF database ( SOP # 3.1). It is the intention of HED's ExpoSAC that this SOP will be periodically updated to incorporate additional information about agricultural practices in crops and new data on transfer coefficients. Much of this information will originate from exposure studies currently being conducted by the ARTF, from further analysis of studies already submitted to the Agency, and from studies in the published scientific literature.

In this case, there is only one post application agricultural activity that is likely to occur, scouting for pesticide efficacy. Scouting onions at low crop development/ height has a TC of 300 cm2/ hr. Lacking compound specific DFR data, post application worker exposure is estimated using HED procedure that assumes 20% of the application rate is available as dislodgeable foliar residue on the day of treatment. HED does not expect post application exposures to exceed short term exposure. Therefore, only short term exposures are assessed.

The following convention may be used to estimate post application exposure. DP Barcode D326518 / 46510101 Page 66 of 73 Average Daily Dose ( ADD) ( mg a. i./ kg bw/ day) = DFR Fg/ cm2 * TC cm2/ hr * hr/ day * 0.001 mg/ Fg * 1/ 70 kg bw and where:

Surrogate Dislodgeable Foliar Residue ( DFR) = application rate * 20.0 % available as dislodgeable residue * ( 1 D) t * 4.54 x 108 Fg/ lb * 2.47 x 10 8 A/ cm2.

1.0 lb a. i./ A * 0.20 * ( 1 0) 0 * 4.54 x 108 Fg/ lb * 2.47 x10 8 A/ cm ² = 2.24 Fg/ cm2 , therefore,

2.24 : g/ cm2 * 300 cm2/ hr * 8 hr/ day * 0.001 mg/: g * 1/ 70 kg bw = 0.077 mg ai/ kg bw/ day MOE = NOAEL ÷ ADD then 190.0 mg/ kg bw/ day ÷ 0.077 mg/ kg bw/ day = 2500.

A MOE of 100 is adequate to protect agricultural workers from post application exposures to ethofumesate. Since the estimated MOEs are > 100, the proposed use pattern does not exceed HED's level of concern.

Ethofumesate is classified in acute toxicity category IV for acute dermal toxicity, category II for acute inhalation toxicity and category V for acute eye irritation and dermal irritation. It is not a dermal sensitizer. The interim worker protection standard ( WPS) REI of 12 hours is adequate to protect agricultural workers from post application exposures to ethofumesate. The product label lists a 12 hr REI.

10.0 Data Needs and Label Requirements 10.1 Toxicology At this time, the database for ethofumesate is essentially complete for ethofumesate. Nevertheless, a 21/ 28 day inhalation toxicity study is requested to assess inhalation exposure, due to the potential for exposure via this route during application.

10.2 Residue Chemistry The requested tolerances for garlic, bulb and shallot, bulb are not required since they are automatically included in the onion tolerance. In addition, the preferred term for the commodity should be onion, bulb. The petitioner should submit a revised Section F requesting a tolerance for ethofumesate residues on onion, bulb at 0.25 ppm. DP Barcode D326518 / 46510101 Page 67 of 73 10.3 Occupational and Residential Exposure None.

References Ethofumesate RED, EPA 738 R 05 010, 9/ 05 ETHOFUMESATE: HED Human Health Risk Assessment For Phase 2; Response to Error Only Comments from the Registrant., DP Num: 296943, N. McCarroll, 3/ 10/ 05 ETHOFUMESATE: HED Revised Human Health Risk Assessment For Phase 4; Response to Bayer CropScience Phase 3 Comments., DP Num: 304056, N. McCarroll, 8/ 4/ 05 Ethofumesate  Report for the Hazard Identification Assessment Review Committee, TXR NO. 0051567a, 2/ 26/ 04 Ethofumesate HED Metabolism Assessment Committee, S. Funk, 5/ 16/ 04 Ethofumesate. Request for the use on Onion, Dry Bulb. Summary of Analytical Chemistry and Residue Data., Petition # 5E6914, DP Number: 326470, W. Cutchin, 3/ 28/ 06 Ethofumesate Acute and Chronic Dietary Exposure Assessments for the Section 3 Registration Action on Onion, Dry Bulb., Petition # 5E6914, DP Num: 326518, N. Negron, 3/ 28/ 06 Ethofumesate   Drinking Water Assessment for the Health Effects Division ( HED) Reregistration Eligibility Decision Document, DP Num: 296949, M. Corbin, 6/ 9/ 04 RDI: T. Bloem, G. Kramer ( 4/ 18/ 06) DP Barcode D326518 / 46510101 Page 68 of 73 Appendix A: Toxicology Assessment 1. Toxicology Data Requirements The requirements ( CFR 158.340) for food/ feed use patterns for ethofumesate are shown below in Table A. 1. Use of the new guideline numbers does not imply that the new ( 1998) guideline protocols were used.

Table A. 1. Guideline Toxicology Data Requirements for Food/ Feed Use Patterns Technical Test Required Satisfied 870.1100................................................................................... 870.1200................................................................................... 870.1300................................................................................... 870.2400................................................................................... 870.2500................................................................................... 870.2600................................................................................... yes yes yes yes yes yes yes yes yes yes yes yes 870.3100................................................................................... 870.3150................................................................................... 870.3200................................................................................... 870.3250................................................................................... 870.3465................................................................................... yes yes yes no yes1 yes yes yes  no 870.3700a................................................................................. 870.3700b................................................................................. 870.3800................................................................................... yes yes yes yes yes yes 870.4100a................................................................................. 870.4100b................................................................................. 870.4200a................................................................................. 870.4200b................................................................................. 870.4300................................................................................... yes yes yes yes yes yes yes yes yes yes 870.5100................................................................................... 870.5300................................................................................... 870.5375............................................................................ Muta 870.5550................................................................................... yes yes yes yes yes yes yes yes DP Barcode D326518 / 46510101 Page 69 of 73 Table A. 1. Guideline Toxicology Data Requirements for Food/ Feed Use Patterns Technical Test Required Satisfied 870.6100a................................................................................. 870.6100b................................................................................. 870.6200a................................................................................. 870.6200b................................................................................. 870.6300................................................................................... no no no no no

870.7485................................................................................... 870.7600................................................................................... yes no yes

Special Studies for Ocular Effects Acute Oral ( rat) ........................................................... Subchronic Oral ( rat)................................................... Six month Oral ( dog) .................................................. no no no

1 A 28 day inhalation toxicity is required to satisfy subchronic inhalation toxicity study requirement 2. Non Critical Toxicology Studies OPPTS 870.3100 90 Day Oral Toxicity  Mouse In a range finding oral toxicity study ( MRID 44156201) performed to assist in dose selection for a carcinogenicity study, ethofumesate ( 97% a. i., batch P 04407) was administered to 10 Crl: CD 1( ICR) BR ( VAF plus) mice/ sex/ dose in the diet at dose levels of 0, 300, 3000 or 10,000 ppm ( 0, 45, 450 or 1500 mg/ kg/ day, respectively, calculated using a food factor of 0.15) for at least 13 weeks.

There were no treatment related deaths or effects on body weights, body weight gains or food consumption. Overall food efficiencies were unaffected in males; the 20% decrease in high dose females was not clearly toxicologically significant. The incidence of gross pathological changes in treated and control groups was similar for both sexes. Microscopic examination of organs/ tissues with gross lesions revealed only pathological changes commonly seen in laboratory mice of the same strain and age. Clinical chemistry, hematology and urinalysis parameters were not evaluated and ophthalmologic examinations were not performed.

Under the conditions of this study, a systemic toxicity LOAEL could not be identified and the 13 week NOAEL was 10,000 ppm ( about 1500 mg/ kg/ day) for both sexes of mice. Based on the lack of toxic effects, the same concentrations as were used in this study are not precluded from use in the subsequent carcinogenicity study. DP Barcode D326518 / 46510101 Page 70 of 73 This subchronic toxicity study is classified as acceptable ( non guideline). It satisfies the intended purpose of estimating dietary ethofumesate concentrations to be administered in a subsequent carcinogenicity study.

OPPTS 870.3150 90 Day Oral Toxicity  Dog A 90 day oral toxicity study in the dog was not submitted. However, the guideline requirement for a subchronic toxicity study in the dog is satisfied by the chronic toxicity study in the dog ( MRID 00062822) and no additional data are required at this time.

OPPTS 870.3200 21 Day Dermal Toxicity   Rat In a 21 day dermal toxicity study ( MRID 41997204, main study and MRID 42689902, addendum), ethofumesate technical ( 96% a. i., Lot/ Batch # CR 19291/ 3), moistened with 4 mL of 1% ( w/ v) methylcellulose/ distilled water, was applied to the shaved, intact dorsal skin of 5 New Zealand White rabbits/ sex/ group at dose levels of 0, 100, 300 or 1000 mg/ kg bw/ day, 6 hours/ day for 21 consecutive days. Skin irritation was assessed daily pre and posttreatment and graded using a modified Draize scale.

There were no biologically significant treatment related findings observed in this study. The following statistically significant differences ( p# 0.05) were observed at 1000 mg/ kg in males only, but were not considered adverse based on the small magnitude of the changes and/ or lack of associated microscopic alterations: increased basophils (+ 17% above controls) and potassium (+ 21.1%), and decreased protein ( 9.8%), albumin ( 10.3%) and aspartate aminotransferase or SGOT ( 21.1%). There were no compound related effects on mortality, clinical signs, body weight, body weight gains, food consumption, gross pathology, organ weight or histopathology observed at any dose level in either sex. The control, 100 and 300 mg/ kg animals showed signs of mild skin irritation, mainly during Weeks 2 and 3 of treatment; however, no signs of dermal irritation were observed in the 1000 mg/ kg animals during the study. The systemic toxicity NOAEL is 1000 mg/ kg/ day ( limit dose). A LOAEL for systemic toxicity was not established in this study.

This study is classified as acceptable/ guideline and satisfies the guideline requirement ( OPPTS 870.3200; OECD 410) for a 21 day dermal toxicity study in rabbits.

OPPTS 870.4100b Chronic Toxicity  Dog In a chronic oral toxicity study ( MRID 00062822), NC 8438 ( ethofumesate tech., 96.6 98.0% a. i.; Lot/ Batch #: CR 4805/ 3) was administered daily in the diet to 8 beagle dogs/ sex/ dose at 0, 800, 4000 or 20,000 ppm ( equivalent to average daily intakes of 0, 24.5, 117.8 or 632.4 DP Barcode D326518 / 46510101 Page 71 of 73 mg/ kg/ day in males and 0, 23.7, 109.0 or 618.9 mg/ kg/ day in females) for 104 weeks.

At 20,000 ppm, alkaline phosphatase was increased ( p# 0.01) by 33 110% over controls throughout the study and alanine aminotransferase was increased ( p# 0.05) by 39 49% at Weeks 78 and 102 ( values were calculated for males and females combined). Absolute liver weights were increased ( p# 0.05) in females by 20% and in males by 21%. There were no treatment related deaths. One 20,000 ppm male was sacrificed during Week 69 due to a massive lipoma caudal to the axilla on the left side. This dog showed no clinical signs of toxicity prior to sacrifice, and no other lesions were noted at necropsy. There were no treatment related effects on clinical signs, body weight, body weight gains, food consumption, ophthalmoscopy, urinalysis, hematology, gross pathology or microscopic pathology. There were no effects of treatment at 800 or 4000 ppm. The systemic toxicity LOAEL is 20,000 ppm ( 632.4 and 618.9 mg/ kg/ day in males and females, respectively) based on increases in alkaline phosphatase, alanine aminotransferase and absolute liver weights. The systemic toxicity NOAEL is 4000 ppm ( 117.8 and 109.0 mg/ kg/ day in males and females).

This study is classified as acceptable/ guideline and satisfies the guideline requirement ( OPPTS 870.4100b, OECD 452) for a chronic oral study in dogs. However, because the study was conducted prior to adoption of current GLP standards, the Registrant is requested to provide additional information ( clinical observations, statistical analyses for body weight, weight change and relative organ weights, separate data for males and females) as confirmatory data.

OPPTS Series 870.5100 8705915 Mutagenicity Adequacy of data base for mutagenicity: The database for mutagenicity is considered adequate based on 1991 mutagenicity guidelines. Ethofumesate technical was negative in all five genotoxicity studies that were performed, including an in vivo mouse bone marrow micronucleus assay ( MRID 41214217) and four in vitro studies: bacterial reverse mutation assay in S typhimurium and E. coli ( MRID 43529501), forward gene mutation assay in cultured mouse lymphoma cells ( MRID 41710501), chromosomal aberration assay in cultured human lymphocytes ( MRID 41214203) and unscheduled DNA synthesis in cultured primary rat hepatocytes ( MRID 41214204).

Gene Mutation Guideline 870.5100, Bacterial reverse gene mutation in vitro MRID 43529501 Dose range 15 5000 Fg/ plate ± rat liver S9 metabolic activation in S. typhimurium strains TA98, TA100, TA1535, TA1537.

50 5000 Fg/ plate ± rat liver S9 metabolic activation in E. coli CM881 ( WP2 pKM101) and CM891 ( WP2uvrA pKM101).

NEGATIVE up to dose levels causing cytotoxicity. DP Barcode D326518 / 46510101 Page 72 of 73 Guideline 870.5300, Mammalian forward gene mutation in vitro MRID 41710501 Dose range 7.9 to 250 Fg/ mL ± rat liver S9 metabolic activation in cultured mouse lymphoma 6TG cells.

NEGATIVE up to dose levels that were insoluble but not cytotoxic.

Cytogenetics Guideline 870.5375, Mammalian chromosomal aberration in vitro MRID 41214203 Dose range 11 110 Fg/ mL ± rat liver S9 metabolic activation in cultured human lymphocytes.

NEGATIVE up to dose levels that were insoluble but not cytotoxic.

Guideline 870.5395, Mammalian in vivo bone marrow micronucleus assay MRID 41214217 8100 mg/ kg bw administered by gavage to male and female CD 1 mice.

NEGATIVE up to dose levels exceeding the limit dose of 5000 mg/ kg bw, tested at 24, 48 and 72 hrs postdosing.

Other Genotoxicity Guideline 870.5550, Mammalian in vitro unscheduled DNA synthesis MRID 41214204 Dose range 1.56 to 200 Fg/ mL in primary rat hepatocyte cultures.

NEGATIVE up to cytotoxic dose levels with precipitation of the test material.

OPPTS 870.7485 Metabolism  Rat In a rat metabolism study ( MRIDs 42364503, main study report and 42689903, addendum), 14C ethofumesate ( tech., batch no. DR/ 87/ 18/ B 4/ RPI; radiochemical purity > 98%) in 1% carboxymethylcellulose ( 2.5 mL/ kg all low dose groups; high dose not specified) was administered to 5 Sprague Dawley Crl: CD/ BR rats/ sex/ dose as a single gavage dose at 10 or 500 mg/ kg. In addition, unlabeled ethofumesate ( tech., batch no. 19291/ 3, 98.0% a. i.) was administered to 5 rats/ sex/ dose as 14 daily gavage doses at 10 mg/ kg followed by a single gavage dose of 14C ethofumesate at 10 mg/ kg on Day 15. DP Barcode D326518 / 46510101 Page 73 of 73 In all dose groups, overall recovery of the radioactive dose was 96 99% by 5 days postdosing Absorption of the dose was extensive based on high levels of urinary excretion but was about 10 15% lower in the 500 mg/ kg group than the 10 mg/ kg group, indicating possible saturation of absorption. Excretion was rapid and primarily via the urine ( 70 92% dose). Within 6 hours post dose, 65 78% of the total urinary radioactivity was eliminated in the single and repeated 10 mg/ kg groups, but 44 45% was eliminated in the 500 mg/ kg group. Fecal excretion accounted for 6 28% dose and was essentially complete within 24 hours. Within each dose group, excretion of radioactivity was similar between the sexes, although males excreted slightly more of the dose in the feces ( 6 10% more) and correspondingly less in urine than females. There was no difference in the pattern of excretion between the single and repeated low dose groups. However, fecal excretion of radioactivity was increased and urinary excretion decreased in the high dose group ( males 27.6% and females 17.1% of dose) compared to the low dose groups ( 13.3 16.1%, males and 5.8% 6.3%, females). Excluding the GI tract and carcass, radioactivity in each tissue accounted for < 0.02% dose at 5 days post dose. Concentrations of radioactivity were highest in the liver ( 0.007 0.026 : g/ g in the single and repeated 10 mg/ kg groups and 0.891 1.50 : g/ g in the 500 mg/ kg group) and kidney (< 0.010 0.012 : g/ g in the single and repeated 10 mg/ kg groups and 0.506 0.542 : g/ g in the 500 mg/ kg group, with males having higher levels than females). In the 500 mg/ kg group, both males and females also showed relatively high levels of radioactivity in the brain, fat, bone and testes ranging from 0.232 to 0.452 Fg/ g tissue). Repeat dosing did not significantly affect distribution of radioactivity. TLC, HPLC and MS analyses were used to identify parent and 3 metabolites in excreta and profiles were not altered by treatment with $ glucuronidase. Males and females showed similar profiles. Parent was not detected in the urine, but accounted for 10 13% dose in the feces at 500 mg/ kg. Identified compounds generally accounted for approximately 85% of administered dose in each group. The major metabolite was Met 1, or "( 2 hydroxy 5 methanesulphonyloxyphenyl) isobutyric acid, accounting for approximately 62 87% dose in all dose groups, depending on the group and the TLC solvent system used. NC9607 and NC8493 were also identified in urine at # 2% dose. An unidentified acid labile metabolite in the urine may have been present at > 5% dose. The metabolism of ethofumesate consists of dealkylation ( OH replaces the 2 OC2H5 group) to form NC8493, which is then oxidized at the 2 OH to a lactone, NC9607 ( ring closed form). NC9607 is a metabolic intermediate to the free acid, "( 2 hydroxy 5 methanesulphonyloxyphenyl) isobutyric acid ( ring opened form of the lactone NC9607). Due to changes in the pH during isolation and analytical procedures, low quantities of NC9607 were sometimes formed from the free acid.

This metabolism study in the rat is classified acceptable/ guideline and satisfies the guideline requirement for a Tier 1 metabolism study [ OPPTS 870.7485, OECD 417] in rats.