Page 1 of 77 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES MEMORANDUM Date: 09/ 30/ 05 SUBJECT: Endothall: Revised Human Health Risk Assessment. HED Chapter of the Reregistration Eligibility Decision Document ( RED). PC Codes: 038901,038904, and 038905. DP Barcode: D322035.

FROM: Robert P. Zendzian PhD, Risk Assessor/ Toxicologist Nader Tadayon, ORE Assessor David Soderberg, Residue Chemist James Breithaupt, ( EFED) Health Effects Division ( 7509C)

THROUGH: Louis Scarano PhD Chief Toxicology Branch Health Effects Division ( 7509C)

TO: Mika J. Hunter Chemical Review Manager Special Review Branch Special Review and Reregistration Division ( 7508C) Page 2 of 77 Table of Contents 1.0 Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.0 Ingredient Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 2.1 Summary of Registered/ Proposed Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 2.2 Structure and Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 2.3 Physical and Chemical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 3.0 Metabolism Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 3.1 Comparative Metabolic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 3.2 Nature of the Residue in Foods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 3.2.1. Description of Primary Crop Metabolism . . . . . . . . . . . . . . . . . . . . . . . 15 3.2.2 Description of Livestock Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . 16 3.2.3 Description of Rotational Crop Metabolism, including identification of major metabolites and specific routes of biotransformation . . . . . . . . . . 16 3.3 Environmental Degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 3.4 Tabular Summary of Metabolites and Degradates . . . . . . . . . . . . . . . . . . . . . . . 16 3.5 Toxicity Profile of Major Metabolites and Degradates . . . . . . . . . . . . . . . . . . . 18 3.6 Summary of Residues for Tolerance Expression and Risk Assessment . . . . . . . . 18 3.6.1 Tabular Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 3.6.2 Rationale for Inclusion of Metabolites and Degradates . . . . . . . . . . . . . 20 4.0 Hazard Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 4.1 Hazard and Dose Response Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . 21 4.2 FQPA Hazard Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 4.2.1 Adequacy of the Toxicity Data Base . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 4.2.2 Evidence of Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 4.2.3 Developmental Toxicity Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 4.2.4 Reproductive Toxicity Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 4.2.5 Additional Information from Literature Sources . . . . . . . . . . . . . . . . . . 30 4.2.6 Pre and/ or Postnatal Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 <IP_ADDRESS> Determination of Susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . 30 <IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Post natal Susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . 30 4.3 Recommendation for a Developmental Neurotoxicity Study . . . . . . . . . . . . . . . 30 4.3.1 Evidence that supports requiring a Developmental Neurotoxicity study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 4.3.2 Evidence that supports not requiring for a Developmental Neurotoxicity study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 4.4 Hazard Identification and Toxicity Endpoint Selection . . . . . . . . . . . . . . . . . . . 31 4.4.1 Acute Reference Dose ( aRfD)  Females age 13 49 . . . . . . . . . . . . . . . . 31 4.4.2 Acute Reference Dose ( aRfD)  General Population . . . . . . . . . . . . . . . 31 4.4.3 Chronic Reference Dose ( cRfD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 4.4.4a Incidental Oral Exposure ( Short Term) . . . . . . . . . . . . . . . . . . . . . . . . . 32 Page 3 of 77 4.4.4b Incidental Oral Exposure ( Intermediate Term) . . . . . . . . . . . . . . . . . . . . 32 4.4.5 Dermal Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 4.4.6 Dermal Exposure ( Short, Intermediate and Long Term) . . . . . . . . . . . . 33 4.4.7a Inhalation Exposure ( Short Term) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 4.4.7b Inhalation Exposure ( Intermediate and Long Term) . . . . . . . . . . . . . . . . 33 4.4.8 Margins of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 4.4.9 Recommendation for Aggregate Exposure Risk Assessments . . . . . . . . 34 4.4.10 Classification of Carcinogenic Potential . . . . . . . . . . . . . . . . . . . . . . . . . 35 4.5 Special FQPA Safety Factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 4.6 Endocrine disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 5.0 Public Health Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 5.1 Incident Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 5.2 Other . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 6.0 Exposure Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 6.1 Dietary Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 6.1.1 Residue Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 6.1.2 Acute and Chronic Dietary Exposure and Risk . . . . . . . . . . . . . . . . . . . 39 6.1.2. a. Acute Dietary Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 6.1.2. b. Chronic Dietary Exposure ( Food Only) . . . . . . . . . . . . . . . . . . . . . . . . 39 6.1.2. c Chronic Dietary Exposure ( Water Only) . . . . . . . . . . . . . . . . . . . . . . . . 42 6.1.2. d Chronic Dietary Exposure ( Food + Water) . . . . . . . . . . . . . . . . . . . . . . 42 6.2 Water Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 6.2.1 Aquatic Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 6.2.2 Terrestrial Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 6.3 Residential and Other Non Occupational Exposures and Risks . . . . . . . . . . . . . 46 6.3.1 Residential Handler Exposures and Risks . . . . . . . . . . . . . . . . . . . . . . . 46 <IP_ADDRESS> Handler Exposure Scenarios . . . . . . . . . . . . . . . . . . . . . . . . . . 46 <IP_ADDRESS> Data and Assumptions For Handler Exposure Scenarios . . . . . 47 <IP_ADDRESS> Residential Handler Exposure and Risk Estimates . . . . . . . . . . 48 Risk Summary: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 <IP_ADDRESS> Summary of Risk Concerns and Data Gaps for Handlers . . . . . 48 <IP_ADDRESS> Recommendations For Refining Residential Handler Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 6.3.2 Residential Postapplication Exposures and Risks . . . . . . . . . . . . . . . . . . 49 <IP_ADDRESS>Residential Postapplication Exposure Scenarios . . . . . . . . . . . . . 49 <IP_ADDRESS>Residential Postapplication Exposure and Risk Estimates . . . . . . 49 Risk Summary: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 6.3.3 Residential Risk Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 <IP_ADDRESS>Characterization of Residential Handler Risks . . . . . . . . . . . . . . 50 <IP_ADDRESS>Characterization Of Residential Postapplication Risks . . . . . . . . 51 7.0 Aggregate Risk Assessments and Risk Characterization . . . . . . . . . . . . . . . . . . . . . 51 7.1 Acute Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 7.2 Short Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Page 4 of 77 7.3 Intermediate Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 7.4 Long Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 7.5 Cancer Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 8.0 Cumulative Risk Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 9.0 Occupational Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 9.1 Occupational Handler Exposures and Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 9.1.1 Data and Assumptions For Handler Exposure Scenarios . . . . . . . . . . . . 54 <IP_ADDRESS>Assumptions for Handler Exposure Scenarios . . . . . . . . . . . . . . 54 <IP_ADDRESS>Exposure Data for Handler Exposure Scenarios . . . . . . . . . . . . . 55 9.1.2 Endothall Handler Exposure Scenarios . . . . . . . . . . . . . . . . . . . . . . . . . 58 9.1.3 Endothall Handler Exposure and Assessment . . . . . . . . . . . . . . . . . . . . 58 <IP_ADDRESS> Endothall Handler Exposure and Risk Calculations . . . . . . . . . . 58 <IP_ADDRESS>Endothall Risk Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 9.1.4 Cancer Endothall Handler Exposure and Risk Assessment . . . . . . . . . . . 65 9.1.5 Summary of Risk Concerns and Data Gaps for Occupational Handlers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 <IP_ADDRESS> Summary of Data Gaps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 9.1.6 Recommendations For Refining Occupational Handler Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 9.2 Occupational Postapplication Exposures and Risks . . . . . . . . . . . . . . . . . . . . . . 65 10.0 Date Needs and Label Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 10.1 Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 10.2 Residue Chemistry, Label Needs, Tolerance Reassessment . . . . . . . . . . . . . . . . 66 10.3 Occupational and Residential Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 Page 5 of 77 1.0 Executive Summary This assessment provides information to support issuance of a risk management decision document known as a Reregistration Eligibility Decision ( RED) Document for Endothall. EPA's pesticide reregistration process provides for the review of older pesticides ( those initially registered prior to November 1984) under the Federal Insecticide, Fungicide and Rodenticide Act ( FIFRA) to insure that they meet current scientific and regulatory standards. The process considers the human health and ecological effects of pesticides and incorporates a reassessment of tolerances ( pesticide residue limits in food) to insure that they meet the safety standard established by the Food Quality Protection Act ( FQPA) of 1996.

Use and usage information Endothall [ 7 oxabicyclo[ 2,2,1] heptane 2,3 dicarboxylic acid] is a selective contact herbicide, defoliant, desiccant, and aquatic algicide which belongs to the dicarboxylic acid chemical class. Endothall ( PC Code 038901) and its dipotassium ( PC Code 038904) and alkylamine ( PC Code 038905) salts are registered primarily as aquatic herbicides to control a variety of plants including plankton, pondweed, naiad, coontail, milfoil, elodea, and algae in water bodies. They are also registered for desiccation/ defoliation of alfalfa/ clover ( grown for seed only), cotton, and potatoes prior to harvest, and for reduction of sucker branch growth in hops.

Endothall acid and its dipotassium and mono N, N dimethylalkylamine salts are FIFRA List B chemicals. Although there are other inactive Endothall salts in Case 2245, only the active compounds, endothall acid ( PC 038901) and it's dipotassium ( PC 038904) and mono N, Ndimethylalkylamine ( PC 038905) salts are being considered in this reregistration.

The endothall formulation classes which are registered on food/ feed crops include the granular ( G) and soluble concentrate liquid ( SC/ L). The G formulations typically contain 10.1%, 11.2%, or 63% acid equivalent ( ae), and the SC/ L formulations contain 0.52, 2.0, or 3.0 lb ai/ gal. Both formulation classes may be applied using waterborne, ground or aerial equipment. The maximum treatment rate of endothall, when applied on aquatic areas ( including irrigation and drainage canals, lakes, and ponds where water may be used as potable water) is 5 ppm. When applied on agricultural crops, the maximum registered seasonal rates range from 0.10 to 2.0 lb ae/ A with preharvest intervals of 3 to 85 days.

Endothall is applied as a spray with aerial and groundboom equipment when used as a harvest aid agent and when used as a sucker suppressant on hops, endothall is applied with ground equipment only. When used as an aquatic herbicide, a variety of equipment may be used. Boats used to treat aquatic weeds are normally designed to apply sprays and granular applications from the bow. For occupational applications of liquid formulations to water, endothall may be sprayed onto the water surface using hand held or boat mounted equipment similar to handgun sprayers ( for smaller scale applications). Endothall may also be directly metered into the suction side of a pump and injected below the surface of the water. This technique is the only method of application to flowing waters, but is also used for applications to quiescent waters. For occupational applications of granular formulations to water, ground boom data from PHED data base is used. For Residential applications of granular formulations to water, HED assumes that a belly grinder type granular spreader is used Page 6 of 77 Hazard Profile The toxicology data base for Endothall is complete except for a developmental/ teratology study in the nonrodent ( rabbit) and a 28 day inhalation toxicity study. All studies on hand have been reviewed and/ or had their review updated.

Endothall is a caustic chemical with toxicity being the result of a direct degenerative effect on tissue. Dermally, it destroys the stratum corneum and then the underlying viable epidermis. Orally, it attacks the digestive tract. The dog is particularly sensitive to endothall toxicity. Orally, it attacks the canine digestive tract at relatively low doses and then the liver and kidneys at lethal doses. The rabbit is strangely sensitive to ocular instillation of endothall. In the eye irritation study, Endothall technical was extremely irritating to the eye as expected but was also lethal to 4/ 6 rabbits tested.

Endothall is an extreme irritant by the dermal, oral, and ocular routes of administration ( category I), and is a skin sensitizer. By dermal application and inhalation, it has mild toxicity ( category III).

Endothall is not a neurotoxicant, nor does it induce developmental toxicity in the rat developmental toxicity, or in the 2 generation reproduction studies. Endothall is classified as " not likely to be carcinogenic to humans" based on lack of evidence of carcinogenicity in mice or rats. It has no mutagenic potential.

In metabolism studies, endothall was excreted unchanged in the feces and urine. In the dermal absorption study, the dose related pattern of absorption was typical of a chemical which directly damages the skin destroying its barrier function. That is, the percent of dose absorbed increased with increasing dose.

Hazard Identification and Food Quality Protection Act ( FQPA) Decision The Hazard Identification Assessment Review Committee ( HIARC) dated June 14, 2004 selected the following endpoints for exposure risk assessment:

Dermal No dermal endpoint was selected because the dermal irritation observed in a repeated dose study is considered self limiting. Current product labels recommend protective clothing ( rubber gloves, face shields or goggles) when handling liquid formulations.

Inhalation The short term inhalation risk assessment for endothall is based on a NOAEL of 9.4 mg/ kg/ day based on decreased pup body weight ( both sexes) on Day 0 F 1 and F 2 generations in a 2 generation rat reproduction ( oral feeding) study. HED's level of concern ( LOC) for short term occupational inhalation risk is 100 ( i. e., an MOE less than 100, exceeds HED's level of concern) and the LOC for short term residential inhalation risk is 100 ( i. e., an MOE less than 100, exceeds HED's level of concern). The intermediate term inhalation risk assessment for endothall is based on an LOAEL of 2 mg/ kg/ day and is based on proliferative lesions of the Page 7 of 77 gastric epithelium ( both sexes) in a 2 generation rat reproduction ( oral feeding) study. HED's level of concern ( LOC) for intermediate term occupational and residential inhalation risks is 300. Another 3X is added to account for the lack of a NOAEL. Long term exposures to endothall ( i. e. greater than 6 months) are not expected for current registered uses.

Oral The short term oral risk assessment for endothall is based on a NOAEL of 9.4 mg/ kg/ day based on decreased pup body weight ( both sexes) on Day 0 F 1 and F 2 generations in a 2 generation rat reproduction ( oral feeding) study.

An acute dietary hazard value was not identified for the general population or for females of child bearing age ( 13 49 years old). This is because there is no appropriate endpoint attributable to a single dose in any of the studies submitted.

Finally, in deriving uncertainty for use in the risk assessment, the conventual 10x factor for interspecies extrapolation and 10x for intraspecies extrapolation were used for all scenarios. The data base was complete enough and there was no evidence of pre or post natal susceptibility in the studies submitted and evaluated to date. Therefore, the FQPA 10X factor was reduced to 1x. The exposure scenarios in which the hazard value was based on a LOAEL ( intermediate term inhalation for both occupational and residential settings) an additional uncertainty factor of 3x was used to approximate a NOAEL.

Residential and Occupational Exposure For agricultural uses, HED relied almost completely on surrogate data from the Pesticide Handlers Exposure Database ( PHED) Version 1.1. For aquatic uses data from the Pesticide Handlers Exposure Database ( PHED) and ORETF were used. For residential handler exposure HED used the ORETF study data and the Residential SOPs.

The short term inhalation handler risk assessments for endothall agricultural crop applications indicate no risk concerns ( MOEs

100) at baseline ( i. e., no respirator) for most scenarios. For aerial applications, there are no risk concerns ( MOEs

100) with engineering controls. The short term inhalation handler risk assessments for endothall aquatic applications indicate no risks concerns ( MOEs

100) at baseline ( i. e., no respirator) for all scenarios. For mixing/ loading/ applying liquid formulations with direct metering, there is no risk of concern ( MOEs

100) with closed system engineering controls.

For most of the agricultural crop scenarios, the intermediate term inhalation MOEs for handlers are greater than 300 at baseline ( i. e., no respirator). The intermediate term inhalation handler risk assessments for endothall aquatic applications indicate no risks concerns ( MOEs

300) with closed system engineering controls for mixing/ loading/ applying liquid formulations through direct metering to lakes/ ponds.

For residential handlers, short term inhalation MOEs are not of concern for the pond scenarios, because they do not exceed the Agency's uncertainty factor ( i. e., MOE

100) for risk Page 8 of 77 assessments in nonoccupational settings. For treating ponds, the inhalation MOEs range from 470 to 1900. Short term inhalation risks to residential handlers are not a concern for treating garden pools, the inhalation MOE is 2,700.

The overall results indicate that the Agency has no risk concerns for most endothall use patterns involving agricultural crops, aquatic and residential uses.

Dietary Exposure The endothall formulation classes which are registered on food/ feed crops include the granular ( G) and soluble concentrate liquid ( SC/ L). The G formulations typically contain 10.1%, 11.2%, or 63% acid equivalent ( ae), and the SC/ L formulations contain 0.52, 2.0, or 3.0 lb ae/ gal. Both formulation classes may be applied using ground or aerial equipment. When applied on agricultural crops, the maximum registered seasonal rates range from 0.10 to 2.0 lb ae/ A with preharvest intervals of 3 to 85 days. The maximum treatment rate of endothall, when applied on aquatic areas ( including irrigation and drainage canals, lakes, and ponds where water may be used as potable water) is 5 ppm.

The qualitative nature of the residue in plants and animals is adequately understood. The Endothall reregistration team has determined that the residue of concern for risk assessment in plants and livestock and fish is endothall and its monomethyl ester. The residue to be measured for tolerance enforcement in plants, animals and fish is also the combined residues of endothall and its monomethyl ester, which can be measured after an hydrolysis step. The residues of concern in water is only endothall, per se.

Tolerances for residues of endothall, from use of the mono N, N dimethylalkylamine salt, in/ on plant commodities should be revised to be expressed in terms of endothall per se and its monomethyl ester [ 40 CFR § 180.293]. Tolerances are established for residues in/ on undelinted cottonseed ( 0.1 ppm), hops ( 0.1 ppm), potato ( 0.1 ppm), and rice grain and straw ( 0.05 ppm each) and will not change in value. An interim tolerance of 0.2 ppm has been established for residues of endothall in potable water. This tolerance should be revoked. A Maximum Contaminant Level ( MCL) has been established for endothall of 100 ug/ L. Under 40 CFR § 180.319, an interim tolerance exists for residues of endothall in/ on sugar beets at 0.2 ppm. EPA recommends that this interim tolerance should be continued to cover uses of endothall in irrigation water. No endothall tolerances have been established for livestock commodities. The available ruminant and poultry metabolism studies suggest that detectable residues of endothall are likely to be transferred to meat, milk, poultry and eggs as a result of registered uses on feedstuffs. Thus, the registrant has been required to conduct animal ( ruminant and poultry) feeding studies which will be used to determine the levels of secondary residues in meat, milk, poultry, and eggs in order to set appropriate tolerances. Data have been submitted to support tolerances in fin fish. These fish tolerances may be acceptable if the data are supported by a radiovalidated enforcement method and stability study.

GC method with microcoulometric nitrogen detection is listed as Method I in the Pesticide Analytical Manual ( PAM, Volume II) for the determination of endothall residues in/ on crop commodities. An improved HPLC MSD method has been submitted as a confirmatory enforcement method for plants and fish. Data collection and regulatory analytical methods for Page 9 of 77 animal commodities are currently not available and are required for reregistration.

The submitted magnitude of the residue studies for alfalfa seed, and cottonseed have been reviewed and were deemed inadequate to satisfy reregistration requirements mainly because of insufficient geographic representation of data. The submitted magnitude of the residue study for potatoes has been reviewed and was deemed inadequate because the potatoes were treated at 2 quarts ai/ A ( 2 lbs ai/ A or 2x) in these field trials ( and yielded residues above the current tolerance), while the current label rate is 1 quart/ A ( 1 lb ae/ A). The submitted data for hops supports the national section 3 labels, but does not support the section 24( c) local uses because a different PHI was used.

The submitted residue data for irrigated cabbage, celery, grapefruit, pepper, and turnip have been deemed inadequate, pending additional information, because in multiple applications the individual water treatment rate used was 3 ppm ae, applied 5 times, while the maximum labeled individual treatment rate is 5 ppm ae in the water. Because it is unclear how often the 5 ppm rate would be applied in a season, a maximum seasonal rate must be proposed for the label before it can be determined if these studies adequately reflect labeled treatment rates. In addition, these five crops do not adequately cover all irrigated crops that will need tolerances. Discussions between HED and the registrant are needed to decide which additional crops can best fulfill those needs.

A submitted confined rotational crop study has been deemed inadequate because an unknown that constituted the largest portion of the TRR was not identified, however HED concedes that the only residues of concern that could be in rotational crops are endothall and its monomethyl and dimethyl ethers. So a new confined rotational crop study is needed. In lieu of repeating the confined rotational crop study the registrant may perform the full battery of limited field trials ( on the grounds that TRR for some commodities from all crops exceeded 0.01 ppm at all post treatment intervals in the existing confined rotational crop study) so long as endothall and its monomethyl and dimethyl esters are analyzed in these field trials.

The submitted processing studies on cotton and potatoes are acceptable, and the results of these studies show that endothall does not concentrate in the processed fractions of cotton and potatoes. The registrant has also submitted a sugar beet processing study which was deemed inadequate, in part because the results are not supported by storage stability data ( processed samples were stored for 4.5 years without supporting data).

Chronic Dietary Exposure ( Food Only) Results and Characterization Endothall has uses for direct application to crops and also has aquatic uses to treat water that may subsequently be used to irrigate crops. To assess food only residues from these uses, two assessments were performed for dietary exposure to endothall. One assessment was based solely upon residues in/ on crops directly treated with endothall. Another assessment incorporated both residues from directly treated crops and from crops irrigated with water containing endothall.

The results of the DEEMTM analysis based upon directly treated crops only were 1.2% of the cPAD ( 0.000084 mg/ Kg/ day) for the general population. The most highly exposed population Page 10 of 77 subgroup was children 3 5 at 3% cPAD ( 0.000211 mg/ Kg/ day). These results were based upon tolerances ( and hops were assumed to be 100% crop treated) and so should be somewhat conservative.

The results of the DEEMTM analysis, for food only, based upon both directly treated crops and crops that may have been irrigated with endothall treated water were 2.7% of the cPAD ( 0.000189 mg/ Kg/ day) for the general population. The most highly exposed population subgroup was children 1 2 at 7.8% cPAD ( 0.000544 mg/ Kg/ day).

Conservative assumptions were used in estimating residues in the various specific irrigated crops. These assessments also began with an assumption that all crops are 100% irrigated with water containing endothall. Subsequently, the total portion of the exposure from crops that may be irrigated with endothall was adjusted by a factor of 0.01. The factor of 0.01 was determined by an estimate that not more than about 0.024% of all crops in the entire U. S. were likely to be treated with endothall. The value of 0.024% was conservatively rounded up to 1% to account for variations amongst individual crops, regions, etc; and the 1% was then applied to the entire anticipated exposure through crops from irrigated water. This approach was necessitated because the DEEMTM and LifelineTM models are designed to estimate exposure using crop by crop information, but no crop by crop data were available on the percent of each crop that is irrigated with endothall containing water.

Chronic Dietary Exposure ( Water Only)

Exposures based on drinking water from aquatic uses were also calculated in DEEMTM. The results were 30% of the cPAD ( 0.002108 mg/ Kg/ day) for the general population. The most highly exposed population subgroup was infants (< 1 year old) at 99% cPAD ( 0.006910 mg/ Kg/ day).

Chronic Dietary Exposure ( Food Plus Water)

Exposures based on treated crops, irrigated crops and drinking water from aquatic uses were also calculated in DEEMTM. The results for directly treated crops plus water were 31% of the cPAD ( 0.002191 mg/ Kg/ day) for the general population. The most highly exposed population subgroup was infants (< 1 year old) at 100% cPAD ( 0.007017 mg/ Kg/ day). The results for food from both directly treated crops, and irrigated crops, plus water were 33% of the cPAD ( 0.002297 mg/ Kg/ day) for the general population. The most highly exposed population subgroup was infants at 103% cPAD ( 0.007234 mg/ Kg/ day).

Aggregate Exposure Assessment Because residential exposures are short term in nature, only a short term aggregate risk assessment was conducted. For adults, estimated dietary exposures via food and drinking water were combined with inhalation exposures during application to a pond or lake and potential postapplication exposures during swimming. HED notes the handler scenario aggregated for adults is the exposure scenario resulting in the lowest MOE ( highest risk estimate) for residential handlers. For children, estimated dietary exposures via food and drinking water were combined with Page 11 of 77 potential post application exposures during swimming. The short term aggregate risk estimate ( MOE) for adults is 310, for children, it is 250. MOEs greater than 100 are not a risk concern. Therefore, there are no short term aggregate ( food + drinking water + residential) risk concerns for endothall Page 12 of 77 2.0 Ingredient Profile 2.1 Summary of Registered/ Proposed Uses Table 2.1. Registered Food/ Feed Use Patterns of Endothall ( PC Code 038901).

Site Application Timing Application Type Application Equipment Formulatio n [ EPA Reg. No.] Maximum Single Application Rate, ae Maximum Number of Applicatio ns Per Season Maximum Seasonal Rate, ae Preharv est Interval, Days Use Directions and Limitations Alfalfa ( Grown for Seed) and Clover ( including Crimson, Alsike, Ladino, Red, Sweet, and White Types of Clover Grown for Seed)

Preharvest dessication Foliar Ground and aerial 0.52 lb ae/ gal SC/ L [ 4581 206] 0.65 lb/ A when applied 2x per season or 0.78 lb/ A when applied once per season 1 or 2 1.30 lb/ A when applied 2x per season 5 Use limited to crops grown for seed. Apply in 8 9 gal of water per acre or GPA ( aerial) or in 15 20 GPA ( ground). Treated plants must be harvested by mechanical means only. When to combine is dependent on the weather but usually, the desiccated alfalfa or clover is ready to combine 5 10 days after treatment. Seed crops should not be sprayed until the seed is mature, and the plants have lost moisture normally following the end of the irrigation season.

Cotton Preharvest defoliation or dessication Foliar Aerial 0.52 lb ae/ gal SC/ L [ 4581 284] 0.10 lb/ A not specified not specified not specifie d Apply in a minimum of 3 GPA of water using aerial equipment. Application through any type of irrigation equipment in prohibited. Apply when fiber quality of the top bolls will not be damaged by loss of the top leaves which feed these bolls. Top bolls should be firm to thumb pressure or difficult to cut with knife. May be applied as a tank mix with other registered cotton defoliants or desiccants including tribufos ( Def ® and Folex ® ) , dimethipin ( Harvade ® ) , paraquat ( Starfire ® and Cyclone Max ® ) , thidiazuron ( Dropp ® ) , sodium chlorate, cacodylic acid, ethephon ( Prep ® and Cottonquick ® ) , and glyphosate ( Roundup ® ) . Table 2.1. Registered Food/ Feed Use Patterns of Endothall ( PC Code 038901).

Site Application Timing Application Type Application Equipment Formulatio n [ EPA Reg. No.] Maximum Single Application Rate, ae Maximum Number of Applicatio ns Per Season Maximum Seasonal Rate, ae Preharv est Interval, Days Use Directions and Limitations Page 13 of 77 O OH O O OH Hops Preharvest dessication Basal directed Ground 0.52 lb ae/ gal SC/ L [ 4581 206] [ OR03003 6] 1.0 lb/ A 2 2.0 lb/ A ( implied) 85 [ 4581 206] or 28 [ OR030 036] For use in hops sucker suppression. Not for use in CA. Make first application when main bines are 2 3 feet tall. Subsequent applications may be made 7 14 days later when hops suckers are 1 2 feet long. Avoid spraying main bine within 1 2 feet of growing point. Apply in 15 40 GPA of water using ground equipment only.

Potato Preharvest vine desiccation Foliar Ground and aerial 0.52 lb ae/ gal SC/ L [ 4581 206] 1.0 lb/ A 2 2.0 lb/ a 10 Treated plants must be harvested by mechanical means only. Culling of harvested potatoes is allowed. May be applied using aerial ( 5 10 GPA) or ground ( 20 100 GPA) equipment. For exceptionally heavy vines, apply 0.52 lb ae/ A in 5 gal of water per acre in one direction followed immediately by a similar amount applied at right angles to the first set of swaths. The addition of diesel oil or paraffin base herbicide oil may increase speed and overall vine kill.

2.2 Structure and Nomenclature TABLE 2.2. Endothall and Salts Nomenclature Chemical Structure Common name Endothall Molecular Formula C8H10O5 Molecular Weight 186.16 TABLE 2.2. Endothall and Salts Nomenclature Page 14 of 77 O O O O O K +

K +

O O O O O [ NH( CH 3) 2( CH 2) n( CH 3)]+

n= 7 17 IUPAC name 7 oxabicyclo[ 2.2.1] heptane 2,3 dicarboxylic acid CAS name 7 oxabicyclo[ 2.2.1] heptane 2,3 dicarboxylic acid CAS # 145 73 3 PC Code 038901 Current Food/ Feed Site Registration Cotton, hops, potato, alfalfa grown for seed Chemical Structure Common name Endothall, dipotassium salt Molecular Formula C8H8K2O5 Molecular Weight 262.33 IUPAC name Not available CAS name Not available CAS # 2164 07 0 PC Code 038904 Current Food/ Feed Site Registration Cotton, hops, potato, alfalfa grown for seed, aquatic uses Chemical Structure Common name Endothall, mono N, N dimethyl alkyl amine salt Molecular Formula Not available Molecular Weight Average: 422 IUPAC name 7 oxabicyclo[ 2.2.1] heptane 2,3 dicarboxylic acid, compound with N, Ndimethylcocoamine CAS name Not available CAS # 66330 88 9 PC Code 038905 Current Food/ Feed Site Registration Cotton, hops, potato, alfalfa grown for seed, aquatic uses Page 15 of 77 2.3 Physical and Chemical Properties TABLE 2.3. Physicochemical Properties of Endothall and Salts Parameter Value Reference Endothall ( acid)

Melting point 108 110

C D187593, D187590, and D187588, 5/ 5/ 93, K. Dockter pH 2.7 at 25

C ( 1% solution) D187593, D187590, and D187588, 5/ 5/ 93, K. Dockter Density, bulk density, or specific gravity 0.481 g/ cm3 ( bulk) at 25

C D187593, D187590, and D187588, 5/ 5/ 93, K. Dockter Water solubility at 25

C 109.8 g/ L 13.1 g/ 100 mL in water, pH 5 12.7 g/ 100 mL in water, pH 7 12.5 g/ 100 mL in water, pH 9 D166798, 7/ 2/ 92, K. Dockter D207011, 9/ 30/ 94, F. Toghrol Solvent solubility at 25

C 3.4 g/ 100 mL in acetonitrile 2.4 g/ 100 mL in n octanol 16.0 g/ 100 mL in tetrahydrofuran D207011, 9/ 30/ 94, F. Toghrol Vapor pressure 3.92 x 10 5 mm Hg at 24.3

C D166798, 7/ 2/ 92, K. Dockter Dissociation constant, pKa 4.32 for Step 1 and 6.22 for Step 2 at 20

C ( 0.2% solution in 20% basic ethanol); dissociation rate 1.8 2.3 x 103  mho within 3 5 minutes at  25

C, by conductivity meter D188708, 5/ 3/ 93, K. Dockter Octanol/ water partition coefficient Not applicable to endothall acid D166798, 7/ 2/ 92, K. Dockter UV/ visible absorption spectrum Not available Endothall, dipotassium salt Melting point > 360

C D187593, D187590, and D187588, 5/ 5/ 93, K. Dockter pH 9.1 at 25

C ( 1% solution) D187593, D187590, and D187588, 5/ 5/ 93, K. Dockter Density, bulk density, or specific gravity 0.766 g/ cm3 ( bulk) at 25

C D187593, D187590, and D187588, 5/ 5/ 93, K. Dockter Water solubility > 65 g/ 100 mL in water, pH 5, pH 7, and pH 9 D214691, 6/ 7/ 95, D. Hrdy Solvent solubility < 0.001 g/ 100 mL in acetonitrile, n octanol, and tetrahydrofuran D214691, 6/ 7/ 95, D. Hrdy Vapor pressure Not applicable. An organic acid K salt is anticipated to have an insignificant vapor pressure. D178085, 6/ 18/ 92, S. Funk Dissociation constant, pKa 4.16 for Step 1 and 6.14 for Step 2 at 20

C in water; dissociation complete at  5 mins ( 13.6 x 103  mho) D304027, 6/ 10/ 2004, D. Soderberg TABLE 2.3. Physicochemical Properties of Endothall and Salts Parameter Value Reference Page 16 of 77 Octanol/ water partition coefficient KOW < 0.02 and < 0.3 at concentrations of 9 x 10 3 M and 9 x 10 4 M, respectively, at 25

C D210814, 8/ 9/ 95, S. Knizner UV/ visible absorption spectrum Not available Endothall, mono N, N dimethyl alkyl amine salt Boiling point Not available pH 5.2 at 25

C ( 1% solution) D187593, D187590, and D187588, 5/ 5/ 93, K. Dockter Density, bulk density, or specific gravity 1.028 g/ mL at 25

C D187593, D187590, and D187588, 5/ 5/ 93, K. Dockter Water solubility at 25

C  49.2 g/ 100mL in water, pH 5  51.6 g/ 100 mL in water, pH 7  49.8 g/ 100 mL in water, pH 9 D210814, 8/ 9/ 95, S. Knizner Solvent solubility at 25

C  102.5 g/ 100mL in acetonitrile  95.4 g/ 100 mL in n octanol  104.3 g/ 100 mL in tetrahydrofuran D210814, 8/ 9/ 95, S. Knizner Vapor pressure 2.09 x 10 5 mm Hg at 25

C ( calculated; mixed mono and dialkylamine ( C8 C20)) D206344, 9/ 22/ 94, F. Toghrol Dissociation constant, pKa 4.24 for Step 1 and 6.07 for Step 2 at 20

C for mixed mono and dialkylamine ( C8 C20) in acidified ethanol/ water; dissociation complete  17 minutes ( 1.7 x 103  mho) at 25

C D198885, 4/ 7/ 94, F. Toghrol Octanol/ water partition coefficient KOW 2.097 at concentrations of 8.9 x 10 3 M and 8.9 x 10 4 M, at 25

C D209995, 1/ 20/ 95, L. Edwards UV/ visible absorption spectrum Not available 3.0 Metabolism Assessment 3.1 Comparative Metabolic Profile The metabolism in plants and animals is very similar. Endothall, per se, remains the major residue. The major metabolite in both is the monomethyl ester with minor formation of the dimethyl ester. Upon further metabolism endothall is rapidly broken down and incorporated into tissues as natural constituents. By combining information from soil and water metabolism there is sufficient information on rotated crops to conclude that the residues of concern remain the same in rotated crops.

3.2 Nature of the Residue in Foods 3.2.1. Description of Primary Crop Metabolism The metabolism of endothall in crops is adequately understood. Endothall is the major residue Page 17 of 77 with some formation of the monomethyl ester. These are the residues of concern for risk assessment and to be used for the tolerance expression. It appears that once metabolic changes are initiated the bicyclic structure of endothall is rapidly broken up and endothall fragments become incorporated into natural constituents. Page 18 of 77 3.2.2 Description of Livestock Metabolism The metabolism of endothall in livestock is adequately understood. Endothall and its monomethyl ester are the major residues. In livestock endothall predominates. In poultry tissue the monomethyl ester is the predominant residue. Thus the residues of concern for risk assessment and to be used for the tolerance expression is endothall and its monomethyl ester. It appears that once metabolic changes are initiated the bicyclic structure of endothall is rapidly broken up and endothall fragments become incorporated into natural constituents.

3.2.3 Description of Rotational Crop Metabolism, including identification of major metabolites and specific routes of biotransformation An adequate confined rotational crop study has not been submitted, however, by comparing existing rotational crop information with plant metabolism information and soil and water metabolism data it is possible to conclude that the only possible residues of concern in rotated crops are endothall and it monomethyl and dimethyl ester metabolites.

3.3 Environmental Degradation Endothall, per se, is the residue of concern for drinking water.

3.4 Tabular Summary of Metabolites and Degradates Table 3.4. Summary of Metabolites and Degradates Chemical Name ( other names in parenthesis) Commodity Percent TRR ( PPM) 1 Structure Matrices  Major Residue (> 10% TRR) Matrices  Minor Residue (< 10% TRR)

Endothall Alfalfa Forage 98% TRR Alfalfa Seed 84% TRR Cotton 88% TRR Sugarbeet Top 64% TRR Sugarbeet Root 37% TRR Rotational Crops No Data No Data Goat Kidney 51% TRR Goat Liver 60% TRR Goat Muscle No Residue Goat Fat No Residue Milk No Residue Chicken Kidney 13% TRR Chicken Liver 5% TRR Chicken Muscle No Residue Chicken Skin 13% TRR Egg White No Residue Egg Yolk 30% TRR Rat Table 3.4. Summary of Metabolites and Degradates Chemical Name ( other names in parenthesis) Commodity Percent TRR ( PPM) 1 Structure Matrices  Major Residue (> 10% TRR) Matrices  Minor Residue (< 10% TRR)

Page 19 of 77 Water 100%

Endothall monomethyl ester Alfalfa Forage < 10% TRR Alfalfa Seed < 10% TRR Cotton < 10% TRR Sugarbeet Top 1.2% TRR Sugarbeet Root 22% TRR Rotational Crops No Data No Data Goat Kidney 26% TRR Goat Liver

Goat Fat No Residue Goat Muscle No Residue Milk No Residue Chicken Kidney 74% TRR Chicken Liver 54% TRR Chicken Skin 54% TRR Chicken Muscle No Residue Egg White No Residue Egg Yolk 9% TRR Rat Water None Endothall dimethyl ester Alfalfa Forage < 10% TRR Alfalfa Seed < 10% TRR Cotton < 10% TRR Sugarbeet Top 3.4% TRR Sugarbeet Root 0% TRR Rotational Crops No Data No Data Goat Kidney 4% TRR Goat Liver

Moat Fat No Residue Goat Muscle No Residue Milk No Residue Chicken Kidney 0 Chicken Liver 0 Chicken Skin 0 Chicken Muscle No Residue Egg White No Residue Egg Yolk 0 Rat Water None Table 3.4. Summary of Metabolites and Degradates Chemical Name ( other names in parenthesis) Commodity Percent TRR ( PPM) 1 Structure Matrices  Major Residue (> 10% TRR) Matrices  Minor Residue (< 10% TRR)

Page 20 of 77 The final row of the table should have a concise summary of relevant parameters. Alfalfa; MRID 42619201, 0.65 lbs ae/ A; 3X rate, near maturity/ seed pods dying; 9 days PHI Cotton; MRID 42619202, 0.1 lb ae/ A; 1X; maturity; before and 4 and 14 days PHI. Sugarbeet; MRID 42619203; 1.5 lbs ae/ A; 2, 48 and 132 days PHI. Goats; MRID 42792701; 13.5 and 10.4 ppm x 5 days, 4 5X Chickens; MRID 42816601; 9.7 ppm x 14 days, 30X Rotational Crops; MRID 43300701; D205980 Rat ; MRID 42169502; oral 0.9, 4.5 or 9.0 mg/ kg single dose 0.9 or 9.0 mg/ kc/ day 15 day.

3.5 Toxicity Profile of Major Metabolites and Degradates The 1996 MARC concluded that the monomethyl and dimethyl esters of endothall are likely to have the same toxicity as the parent. Upon doing this review, HED agrees for dietary exposure because the monomethyl and dimethyl esters can be rapidly converted back to endothall, per se, in the gut.

3.6 Summary of Residues for Tolerance Expression and Risk Assessment HED recommends that the residues to be used in the tolerance expressions for plant and animal commodities consist of endothall and its monomethyl ester. While this recommendation represents a change from language used in the current endothall tolerance expressions as listed in 40 CFR § 180.293, it does not significantly change the actual residues subsumed within these tolerance expressions and so does not change the tolerances.

Tolerances Listed Under 40 CFR § 180.293 ( a)( 1)

Tolerances are established for residues of endothall [ 7 oxabicyclo[ 2,2,1] heptane 2,3 dicarboxylic acid] from use of its mono N, N dimethylalkylamine salt, wherein the alkyl group is derived from the fatty acids of coconut oil, in/ on: undelinted cotton seed, hop, potato, rice grain, and rice straw.

HED recommends for the deletion of references to any form of endothall salts in the tolerance expression since HED has determined that the dipotassium salt would be expected to behave similarly to the mono N, N dimethylalkylamine salt. Similar solubilities and transport properties are anticipated for the two salts.

The tolerances for " cotton, undelinted seed", " hop", and " potato" could not be reassessed at this time because additional data are required. Although there are presently no registered uses on rice, HED recommends for the retention of tolerances for " rice, grain" and " rice, straw" until the registrant has submitted the requested irrigation crop data which should include data for rice commodities. Page 21 of 77 Tolerance Listed Under 40 CFR § 180.293 ( a)( 2)

An interim tolerance of 0.2 ppm is established for residues of endothall in potable water from use of its potassium, sodium, di N, N dimethylalkylamine, and mono N N dimethylalkylamine salts as algicides or herbicides to control aquatic plants in canals, lakes, ponds, and other potential sources of potable water.

This interim tolerance should be revoked. OPP no longer establishes tolerances in drinking water. EPA's Office of Water has established an MCL for endothall at 0.10 ppm.

Tolerance Listed Under 40 CFR § 180.319 An interim tolerance exists for residues of endothall in/ on sugar beets at 0.2 ppm. Although there are presently no registered uses on sugar beets, HED recommends for the retention of the interim tolerance for sugar beet, as " beet, sugar, root," until the registrant has submitted the requested irrigation crop data which should include data for sugar beet root and tops. The registrant will need to propose a tolerance for sugar beet tops when the requested data have been received and evaluated.

Tolerances to be Proposed 40 CFR § 180.293 A tolerance for cotton, gin byproducts will need to be proposed when requested cotton field trials have been received and evaluated.

Tolerances for animal commodities will need to be proposed when the requested animal feeding studies have been received and evaluated.

Tolerances for processed commodities may be needed if the levels of endothall residues expected in processed commodities are found to be significantly higher than the RACs.

Tolerances that have been proposed for fish and shellfish may become acceptable after the appropriate stability data and independently validated enforcement method have been submitted. ( An ILV has been submitted as MRID 46421403 and is currently under review.)

A summary of metabolites and degradates to be included in the risk assessment and tolerance expression are presented in Table 3.6.1. Page 22 of 77 3.6.1 Tabular Summary Table 3.6. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop Endothall and its Monomethyl Ester Endothall and its Monomethyl Ester Rotational Crop TBD TBD Livestock Ruminant Endothall and its Monomethyl Ester Endothall and its Monomethyl Ester Poultry Endothall and its Monomethyl Ester Endothall and its Monomethyl Ester Fish Endothall and its Monomethyl Ester Endothall and its Monomethyl Ester Drinking Water Endothall Not Applicable 3.6.2 Rationale for Inclusion of Metabolites and Degradates Other than binding of radioactive residues of endothall into natural tissue constituents, the monomethyl and dimethyl esters of endothall are the only metabolites shown to have been formed in crops, livestock or fish. The dimethyl ester has only been found in trace amounts. In some cases the monomethyl ester is a very significant metabolite or can even predominate over endothall as the major residue. Page 23 of 77 4.0 Hazard Characterization/ Assessment 4.1 Hazard and Dose Response Characterization Table 4.1a Acute Toxicity Profile  Endothall Guideline No./ Study Type MRID No. Results Toxicity Category 870.1100 Acute oral toxicity 42289201 LD 50 = 50.2/ 44.4[ m/ f] mg/ kg I 870.1200 Acute dermal toxicity 42289202 LD 50 = > 2000[ m/ f] mg/ kg III 870.1300 Acute inhalation toxicity 42169501 LC 50 = 1.27/ 2.20[ m/ f] mg/ L III 870.2400 Acute eye irritation 42289203 severe irritant lethal 4/ 6 rabbits I 870.2500 Acute dermal irritation 42289204 unacceptable study I a 870.2600 Skin sensitization 41871901 sensitizer N/ A a Endothall has been shown to be a skin irritant in a preliminary range finding study of the dermal absorption study ( MRID 42169503) at doses of 50 ug/ cm2 and higher and in the 21 day dermal toxicity study ( MRID 43465201) after one application at doses of 30 mg/ kg or higher. This information is considered sufficient to classify Endothall as a severe dermal irritant Page 24 of 77 Table 4.1b Subchronic, Chronic and Other Toxicity Profile Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 870.3100 90 Day oral toxicity rodents ( rat) 43480810( 1994) Acceptable/ guideline 0, 150, 600, 1800 ppm M: 0, 10, 39, 118 mg/ kg/ d F: 0, 12, 51, 153 mg/ kg/ d NOAEL = 39 mg/ kg/ day LOAEL = 118 mg/ kg/ day based on treatment related deficits in body weight.

870.3150 13 week oral toxicity in nonrodents ( dog) 43480802 ( 1994) Acceptable/ guideline 0, 100, 400, 1000 ppm M: 0, 3.2, 11.7, 27.5 mg/ kg/ d F: 0, 3.2, 13.0, 28.9 mg/ kg/ day NOAEL = 11.7 mg/ kg/ day LOAEL = 27.5 mg/ kg/ day based on decreases in body weight gain.

870.3200 21 Day dermal toxicity ( rat) range finding 42814101 ( 1992) Acceptable/ nonguide  line 0, 80, 200, 500 mg/ kg/ d NOAEL = not determined LOAEL = 80 mg/ kg/ day based systemic toxicity ( death) LOAEL = 80 mg/ kg/ day based on dermal irritation 870.3250 21 Day dermal toxicity ( rat) 43465201( 1994) Acceptable/ guideline 0, 30, 100, 300 mg/ kg/ d NOAEL = not determined LOAEL = 30 mg/ kg/ d based on decreased body weight gains. LOAEL = 30 mg/ kg/ d based on dermal irritation 870.3700a Prenatal developmental in rodents ( rat) 42776301 ( 1993) Acceptable/ guideline 0, 6.25, 12.5, 25.0 mg/ kg/ d Maternal NOAEL = 12.5 mg/ kg/ day LOAEL = 25 mg/ kg/ day based on decreased body weight gain. Developmental NOAEL => 25 mg/ kg/ day LOAEL = not determined HDT. Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results Page 25 of 77 870.3800 Reproduction and fertility effects 43152101 ( 1993) 43629301 ( 1995) Acceptable/ guideline 0, 30, 150, 900 ppm M: 0, 2, 10.2, 64 mg/ kg/ d F: 0, 1.8, 9.4, 60 mg/ kg/ d premating 0, 3.1, 17.3, 104.7 mg/ kg/ d lactation Parental/ Systemic NOAEL = not established LOAEL = 2 mg/ kg/ day based on proliferative lesions gastric epithelium both sexes. Reproductive NOAEL = 9.4 mg/ kg/ day LOAEL = 60.0 mg/ kg/ day based on decreased pup body weights Reproductive Offspring NOAEL = 9.4 mg/ kg/ day LOAEL = 60.0 mg/ kg/ day based on decreased pup body weights.

870.4100b Chronic toxicity dogs 40745202 ( 1987) supplementary/ guideli ne 0, 150, 450,350 ppm. high dose lowered to 1000 ppm at the 7th M: 0, 5.7, 17 or 40 mg/ kg/ d F: 0, 6.5, 18, 33 mg/ kg/ d 52 weeks. NOAEL = not determined LOAEL ( LDT) = 6.5 mg/ kg/ d based on gastric epithelial hyperplasia.

870.4200b Carcinogenicity mice 40685301 ( 1988) supplementary/ guideli ne 0, 50, 100, 300 ppm 0, 7.5, 15, 45 mg/ kg/ d 21 months NOAEL = 15 mg/ kg/ day LOAEL = 45 mg/ kg/ day based on decreased body weight gain and microscopic findings in male kidney. no evidence of carcinogenicity 870.4200b Carcinogenicity mice 43608301( 1995) acceptable/ guideline 0, 750, 1500 ppm M: 01, 124, 258 mg/ kg/ d F: 0, 152, 319 mg/ kg/ d 79 weeks NOAEL = not determined LOAEL = 124 mg/ kg/ day based on decreased body weight gain in males. no evidence of carcinogenicity Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results Page 26 of 77 870.4300 chronic/ onco rat 41040301( 1989) acceptable 0, 150, 300, 900, 1800ppm M: 0, 6, 12, 37, 80 mg/ kg/ d F: 0, 8, 16, 49, 110 mg/ kg/ d NOAEL = 8 mg/ kg/ day LOAEL = 16 mg/ kg/ day based on decreased body weight and body weight gain. no evidence of carcinogenicity Gene Mutation Guideline # OPPTS 870.5300 [ § 84 2]; OECD 476, study type In vitro Mammalian Cell Gene Mutation Assay 43437801 ( 1993) classification Acceptable equivalent = 11.6%) Dosed in ( DMSO) at concentrations of 0.0116, 0.0580, 0.116, 0.580, 1.16, 2.32, 2.9, 3.48, 4.06, and 4.64  g/ mL ( all concentrations expressed as active ingredient) without metabolic activation or at 0.116, 0.58, 1.16, 5.8, 11.6, 17.4, 20.3, 21.8, 23.2 and 26.1  g/ mL with metabolic activation ( Initial Trial). For the confirmatory trial, levels of 0.0116, 0.0580, 0.116, 0.580, 1.16, 2.32, 2.90, 3.48. 4.06. 4.64, 5.22 and 5.80  g/ mL  S9 or 0.116, 0.580, 1.16, 5.80, 11.6, 17.4, 23.2, 26.1 and 29  g/ mL + S9 were processed. Negative Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results Page 27 of 77 Gene Mutation Guideline # Bacterial Gene Mutation Assay ( Salmonella typhimurium)/ O PPTS 870.5100/[ § 84 2] OECD 471 43154801 ( 1993). Unacceptable in dimethyl sulfoxide ( DMSO) ( equivalent to 1.93, 5.80, 19.3, 58.0, 116 or 193  g/ plate active ingredient) with or without S9 activation. Negative Cytogenetics In vivo Mammalian Cytogenetics  Micronucleus Assay in Mice/ OPPTS 870.5395/[ § 84 2] 43157401 ( 1994) Acceptable mice were administered 0.464, 0.928 and 1.86 mg/ kg Endothall Technical amine salt ( 1.5: 1 amine : salt ratio; Batch No. B46 44 1; endothall amine 30.3%; endothall acid equivalent = 11.6%) via intraperitoneal injection ( IP) in deionized water; Negative Cytogenetics In vivo Mammalian Cytogenetics  Micronucleus Assay in Mice/ OPPTS 870.5395/[ § 84 2] 41700301 ( 1989) Acceptable mice were administered 2,10 or 50 mg/ kg Endothall Negative Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results Page 28 of 77 Cytogenetics In vitro Mammalian Cytogenetics OPPTS 870.5375 [ § 84 2]; OECD 473 41700302 ( 1989) Acceptable in dimethyl sulfoxide ( DMSO) at concentrations of 2.5, 10.0, 20.0 and 40.0  g/ mL without metabolic activation or were exposed for 3 hours to 15.0, 60.0, 120.0 or 240.0  g/ mL with metabolic activation Negative 870.7485 Metabolism and pharmacokinetic s 42169502 ( 1990), acceptable a single i. v. dose at 0.9 mg/ kg, a single oral dose at 0.9, 4.5 or 9.0 mg/ kg and as a 15 day multiple dose at 0.9 and 9.0 mg/ kg/ day. Intravenous administration of 0.9 mg/ kg resulted in excretion mainly by the urine ( 69%) and feces. At an oral 0.9 mg/ kg dose, blood half life elimination  1.8 hrs in males, 2.5 hrs females. At 4.5 mg/ kg half life  13.9 hours in males; the half life in females could not be calculated because of a double blood peak. Multiple oral or single administration indicated that the test material was rapidly absorbed and excreted in the feces ( 89 98%) and urine ( 5 9%). The compound did not bioaccumulate. At 24 hours tissue distribution of the compound was extensive but low, the highest amount (< 10%) being found in the gastrointestinal tract. By 48 hours, the compound was mostly undetectable in the tissue. Bile elimination was only of minor importance. Absorbed or unabsorbed test compound in all groups was excreted mainly as chemically unchanged Endothall in the feces and urine. Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results Page 29 of 77 870.7485 Metabolism and pharmacokinetic s 44263501 ( 1997) acceptable administered to 10 Sprague Dawley rats ( 5/ sex/ dose) in distilled water by gavage at a dose 9 mg/ kg. Animals were sacrificed after 24 hours. Following a single oral administration of [ 14C} Endothall to male and female rats ( approximately 9 mg/ kg), the majority of the radioactivity ( 70.8% males, 71.2% females) was excreted within the 0 24 hour time period, with most of the radioactivity being present in the feces ( 47.6% males, 47.5% females) At 24 hours after dosing, less than 0.21% of the dose was found in the stomach (+ contents), small intestine (+ contents) and pancreas and very little detected in the blood ( below 15 ng eq/ g). Higher levels of radioactivity were found in the caecum ( 3.0% males, 6. 1 % females) and the large intestine ( 3.2% males, 8.2% females).

Analysis of extracts of the urine, feces, caecum and large intestine of both male and female rats gave a single radioactive component corresponding to unchanged Endothall which accounted for > 86, > 96, > 74 and > 69% of total recovery from the respective extracts.

870.7600 Dermal penetration 42169503 ( 1990) acceptable Dose levels were 0.0125 mg/ cm2 ( 0.3 mg/ rat), 0.0625 mg/ cm2 ( 1.5 mg/ rat) and 0.125 mg/ cm2 ( 3.0 mg/ rat) respectively. Five ( 5) animals per time period ( 0.. 5, 1, 2, 4, 10 or 24 hours) in each dose Approximately 55 to 82% of the applied dermal dose was washed from the application site. The rest of the [ 14C] Endothall equivalents was contained in the application site skin. Urinary excretion of [ 14C] Endothall equivalents increased in a dose related manner at 10 and 24 hours to a maximum of 2.3% of the applied dose at the 0.125 mg/ cm2 ( 3.0 mg/ rat) dose level. Fecal excretion amounted to < 0.1% at all dose levels. At the 0.0125 mg/ cm2 ( 0.3 mg/ rat), 0.0625 mg/ cm2 ( 1.5 mg/ rat) and 0.125 mg/ cm2 ( 3.0 mg/ rat) dose levels, systemic bioavailability ( absorption) of 3.9%, 2.2% and 7.3%, respectively, were noted at 24 hours. A time related increase in systemic bioavailability occurred only at the 1.5% dose level. The dose related pattern of absorption was typical of a chemical which directly damages the skin. The percent of dose absorbed increased with increasing dose. The total percent recovery of [ 14C] Endothall equivalents was 97.7 to 101.1% of the administered dose throughout the 24 hour period. Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results Page 30 of 77 Special studies none Page 31 of 77 4.2 FQPA Hazard Considerations 4.2.1 Adequacy of the Toxicity Data Base The HIARC concluded that the toxicology database for Endothall is incomplete for FQPA assessment. A rabbit ( non rodent) developmental toxicity study is not available 4.2.2 Evidence of Neurotoxicity The HIARC concluded that there is not a concern for neurotoxicity resulting from exposure to Endothall. No clinical signs or symptoms of neurotoxicity were detected in any of the available, guideline studies.

4.2.3 Developmental Toxicity Studies In a developmental toxicity study ( MRID 42776301) Groups of pregnant Crl: CD BR rats ( 25/ dose) were administered endothall ( 19.2% a. i. Batch # CAF 21C901) via gavage at dose levels of 0, 6.25, 12.5, or 25.0 mg/ kg/ day during gestation Days 6 15. Maternal toxicity was observed at the highest dose tested as indicated by decreases in body weight gain. Endothall did not induce developmental toxicity at any of the doses tested.

4.2.4 Reproductive Toxicity Study In a 2 generation reproduction study ( MRIDs 43152101 and 43629301), Endothall Turf Herbicide ( disodium salt of Endothall, 19.9% ai) was administered continuously in the diet to Sprague Dawley CD rats ( 26/ sex/ dose) at concentrations of 0, 30, 150 or 900 ppm ( a. i.) for two successive generations ( 1 litter P 1 generation, 2 litters F 1 generation). The dose levels were equivalent to 0, 2, 10.2, or 64 mg/ kg/ day for males and 0, 2.3, 11.7, or 78.7 mg/ kg/ day for females during the premating period; 0, 1.8, 9.4 or 60 mg/ kg/ day during the gestation period; and 0, 3.1, 17.3, or 104.7 mg/ kg/ day during the lactation period.

Under conditions of this study, a NOAEL for parental systemic toxicity was not established; the LOAEL was estimated to be 30 ppm ( 2 mg/ kg/ day for males and 2.3 mg/ kg/ day for females) based on proliferative lesions of the gastric epithelium ( both sexes). The NOAEL for offspring toxicity was 150 ppm ( 9.4 mg/ kg/ day) and the LOAEL was 900 ppm ( 60.0 mg/ kg/ day) based on decreased pup body weights ( both sexes) at Day 0 of the F 1 and F 2a generations. Page 32 of 77 4.2.5 Additional Information from Literature Sources Open literature searches identified no additional information 4.2.6 Pre and/ or Postnatal Toxicity The HIARC concluded that there is not a concern for pre and/ or postnatal toxicity resulting from exposure to Endothall in rats ( rabbit  not yet determined).

<IP_ADDRESS> Determination of Susceptibility There was no quantitative or qualitative evidence of increased susceptibility following prenatal exposure to rats in the developmental toxicity study and pre/ postnatal exposure to rats in the 2 generation reproduction study. Due to the lack of a prenatal developmental study in rabbits, susceptibility could not be ascertained in a second ( non rodent) species.

<IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Post natal Susceptibility There are no concerns for residual uncertainty for prenatal toxicity in the available developmental study, or the 2 generation rat toxicity study. In evaluating the toxicological database for endothall, the primary effects are the point of entry effects ( i. e., dermal). In addition, the weight of evidence suggests that endothall will be of no developmental concern. The rabbit developmental study is being required as a confirmatory study.

4.3 Recommendation for a Developmental Neurotoxicity Study The HIARC concluded that there is not a concern for developmental neurotoxicity resulting from exposure to Endothall.

4.3.1 Evidence that supports requiring a Developmental Neurotoxicity study None.

4.3.2 Evidence that supports not requiring for a Developmental Neurotoxicity study No clinical signs or symptoms of neurotoxicity / neuropathology were detected in any of the available, guideline studies. Page 33 of 77 4.4 Hazard Identification and Toxicity Endpoint Selection 4.4.1 Acute Reference Dose ( aRfD)  Females age 13 49 An acute RfD was not established for any population subgroup because an appropriate endpoint attributable to a single dose was not available from any study, including the prenatal developmental toxicity study in rats. The most sensitive indicator of oral toxicity in the rat was direct damage to the stomach. The maternal stomach was not examined for toxicity in the prenatal developmental toxicity study in rats. Therefore, this study could not be used for an acute reference dose.

4.4.2 Acute Reference Dose ( aRfD)  General Population An acute RfD was not established for any population subgroup because an appropriate endpoint attributable to a single dose was not available from any study, including the prenatal developmental toxicity study in rats. The most sensitive indicator of oral toxicity in the rat was direct damage to the stomach. The maternal stomach was not examined for toxicity in the prenatal developmental toxicity study in rats. Therefore, this study could not be used for an acute reference dose.

4.4.3 Chronic Reference Dose ( cRfD)

Study Selected: 2 Generation Reproduction Toxicity Study in Rats ( MRID Nos: 43152101 and 43629301 Dose and Endpoint for Establishing cRfD: The LOAEL = 2 mg/ kg/ day for males and 2.3 mg/ kg/ day for females) based on proliferative lesions of the gastric epithelium in both sexes.

Uncertainty Factor( s): 300. This includes the 10X for interspecies extrapolation and 10X for intraspecies variation, and an additional 3X for the lack of a NOAEL in the study used for endpoint selection. A 3x factor was used to extrapolate from a LOAEL to a NOAEL for the following reasons: 1) the gastric lesions were not observed in the Fo parental animals; 2) the lesions were observed in the F 1 parental animals only; and 3) the incidence and severity of the lesions did not increase dramatically across the dose groups ( all were classified as " moderate" in severity); 2/ 3 males and 1/ 2 females { low dose}; 2/ 2 females { mid dose} and 3/ 3 males { high dose}.

Comments about Study/ Endpoint: This dose and endpoint is appropriate with respect to the route and duration of this exposure scenario.

Chronic RfD = 2 mg/ kg/ day ( LOAEL) = 0.007 mg/ kg/ day 300 ( UF) Page 34 of 77 4.4.4a Incidental Oral Exposure ( Short Term)

Study Selected: 2 Generation Reproduction Toxicity Study in Rats MRID Nos: 43152101 and 43629301 Dose and Endpoint for Risk Assessment: Offspring NOAEL = 9.4 mg/ kg/ day based on decreased pup body weights in both sexes at Day 0 of the F 1 and F 2a generations Comments about Study/ Endpoint: This endpoint is appropriate with respect to the duration and population of concern ( i. e., hand to mouth behavior in infants and children)

Uncertainty Factor ( MOEs)

See MOE Table Sec 4.4.8 4.4.4b Incidental Oral Exposure ( Intermediate Term)

Study Selected: Rat 2 Generation Reproduction Toxicity Study ( MRID Nos: 43152101 and 43629301 Dose and Endpoint for Risk Assessment: The parental systemic toxicity LOAEL was estimated to be 30 ppm ( 2 mg/ kg/ day for males females) based on proliferative lesions of the gastric epithelium ( both sexes).

Comments about Study/ Endpoint: This endpoint is appropriate with respect to the population of concern ( i. e., hand to mouth behavior in infants and children) and the duration of exposure ( 1 6 months) since stomach lesions were seen at the end of this study which is approximately 13 weeks in duration.

Uncertainty Factor ( MOEs)

See MOE Table Sec 4.4.8 4.4.5 Dermal Absorption Dermal Absorption Factor: 7.3% at 24 hours.

Selected Study: Dermal Absorption Study in Rats MRID: 42169503 Page 35 of 77 4.4.6 Dermal Exposure ( Short, Intermediate and Long Term)

The RARC recommended that no dermal assessments be conducted, since endothall is so toxic at the portals of entry and is therefore self limiting. In the 21 day dermal toxicity study ( MRID43465201), in addition to weight loss, severe dermal effects were observed at 30 mg/ kg/ day ( the lowest dose tested). The NOAEL for dermal irritation was not established due to erythema, edema, and fissuring and sloughing off of the skin at the dose site at the lowest tested dose of 30 mg/ kg/ d. The only systemic toxicity observed at this same dose of 30 mg/ kg/ d was slight ( 3.3%  nonsignificant body weight losses in females on day 20. Total body weight gains were inhibited ( 27% for males and  85% for females) when compared to controls.

4.4.7a Inhalation Exposure ( Short Term)

Study Selected: 2 Generation Reproduction Toxicity Study in Rats MRID No. 43152101 and 43629301 Dose/ Endpoint for Risk Assessment: Offspring NOAEL = 9.4 mg/ kg/ day based on decreased pup body weight at Day 0 of the F 1 and F 2 generations Comments about Study/ Endpoint:. In the absence of a repeated dose inhalation study, an oral study was selected. Absorption via the inhalation route is presumed to be equivalent to oral absorption ( i. e., 100%).

Uncertainty Factor ( MOEs)

See MOE Table Sec 4.4.8 4.4.7b Inhalation Exposure ( Intermediate and Long Term)

Study Selected: 2 Generation Reproduction Toxicity Study in Rats MRID Nos: 43152101 and 43629301 Dose/ Endpoint for Risk Assessment: The parental/ systemic toxicity LOAEL = 2 mg/ kg/ day based on proliferative lesions of the gastric epithelium in both sexes.

Comments about Study/ Endpoint: In the absence of a repeated dose inhalation study, an oral study was selected. Absorption via the inhalation route is presumed to be equivalent to oral absorption ( i. e., 100%).

Uncertainty Factor ( MOEs) Page 36 of 77 See MOE Table Sec 4.4.8 4.4.8 Margins of Exposure Summary of target Margins of Exposure ( MOEs) for risk assessment.

Route Duration Short Term ( 1 30 Days) Intermediate Term ( 1  6 Months) Long Term (> 6 Months)

Occupational ( Worker) Exposure Dermal N/ A N/ A N/ A Inhalation 100 300 300 Residential ( Non Dietary) Exposure Oral 100 300 N/ A Dermal N/ A N/ A N/ A Inhalation 100 300 300 Occupational Exposure: For Short term Inhalation exposure assessments, an MOE of 100 is required based on the conventional 100X ( 10X for intraspecies extrapolation and 10X for interspecies variation);

For Intermediate and Long term Inhalation, an MOE of 300 is required based on the conventional 100X ( 10X for intraspecies extrapolation and 10X for interspecies variation), and an additional 3X for the lack of a NOAEL in the study used for endpoint selection. .

Residential Exposure: For Short term Incidental Oral and Inhalation, an MOE of 100 is required based on the conventional 100X ( 10X for intraspecies extrapolation and 10X for interspecies variation).

For Intermediate term Incidental Oral  all durations, and Intermediate and Long term Inhalation, an MOE of 300 is required based on the conventional 100X ( 10X for intraspecies extrapolation and 10X for interspecies variation), and an additional 3X for the lack of a NOAEL in the study used for endpoint selection.

4.4.9 Recommendation for Aggregate Exposure Risk Assessments As per FQPA, 1996, when there are potential residential exposures to Page 37 of 77 the pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures. The toxicity endpoints selected for these routes of exposure may be aggregated as follows:

Short Term: Combine oral, and inhalation ( endpoint is based on body weight changes)

Intermediate Term: Combine oral and inhalation ( endpoint is based on stomach lesions)

4.4.10 Classification of Carcinogenic Potential In accordance with the 1999 Draft Guidelines for Cancer Risk Assessment, the HIARC classified Endothal as " not likely to be carcinogenic to humans" based on the lack of evidence of carcinogenicity in mice or rats.

Table 4.4. Summary of Toxicological Doses and Endpoints for Chemical for Use in Human Risk Assessments Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF and Level of Concern for Risk Assessment Study and Toxicological Effects Acute Dietary ( General population including infants and children) ( Females 13 50 years of age An appropriate endpoint attributable to a single dose was not available from any study, including the prenatal developmental toxicity study in rats. An acute RfD was not established.

Chronic Dietary ( All populations) LOAEL= 2 mg/ kg/ day UF = 300] Chronic RfD = 0.007 mg/ kg/ day ( MRID 43152101) FQPA SF = 1 cPAD = chronic RfD FQPA SF = 0.007 mg/ kg/ day Rat 2 generation reproduction study LOAEL 2 mg/ kg/ day based on proliferative lesions of the gastric epithelium ( both sexes)

Short Term Incidental Oral ( 1 30 days) Offspring NOAEL = 9.4 mg/ kg/ day ( MRID 43152101) Residential LOC for MOE = 100 Occupational = NA Rat 2 generation reproduction study LOAEL 60 mg/ kg/ day based on decreased pup body weight ( both sexes) on Day 0 F1and F2 generations Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF and Level of Concern for Risk Assessment Study and Toxicological Effects Page 38 of 77 Intermediate Term Incidental Oral ( 1 6 months) LOAEL= 2 mg/ kg/ day ( MRID 43152101) Residential LOC for MOE = 300 Occupational = NA Rat 2 generation reproduction study LOAEL 2 mg/ kg/ day based on proliferative lesions of the gastric epithelium ( both sexes)

Short Term Dermal ( 1 to 30 days) The RARC recommended that no dermal assessments be conducted, since endothall is so toxic at the portals of entry. In the 21 day dermal toxicity study ( MRID43465201), in addition to weight loss, severe dermal effects were observed at 30 mg/ kg/ day ( the lowest dose tested).

Intermediate Term Dermal ( 1 to 6 months) The RARC recommended that no dermal assessments be conducted, since endothall is so toxic at the portals of entry. In the 21 day dermal toxicity study ( MRID43465201), in addition to weight loss, severe dermal effects were observed at 30 mg/ kg/ day ( the lowest dose tested).

Long Term Dermal (> 6 months) NA no exposure under use pattern Residential NA Occupational NA NA Short Term Inhalation ( 1 to 30 days) Offspring NOAEL = 9.4 mg/ kg/ day ( inhalation absorption rate = 100%) ( MRID 43152101) Residential LOC for MOE = 100 Occupational LOC for MOE = 100 Rat 2 generation reproduction study LOAEL 60 mg/ kg/ day based on decreased pup body weight ( both sexes) on Day 0 F1and F2 generations Intermediate Term Inhalation ( 1 to 6 months) and Long Term Inhalation (> 6 months) LOAEL= 2 mg/ kg/ day ( MRID 43152101) Residential LOC for MOE = 300 Occupational LOC for MOE = 300 Rat 2 generation reproduction study LOAEL 2 mg/ kg/ day based on proliferative lesions of the gastric epithelium ( both sexes) Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF and Level of Concern for Risk Assessment Study and Toxicological Effects Page 39 of 77 Cancer ( oral, dermal, inhalation) NA ( MRID 41040301)

( MRID 40685301& 43608301) NA Chronic/ Onco Rat Negative for carcinogenicity Carcinogenicity Mice Negative for carcinogenicity Not likely carcinogenic to humans UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose ( a = acute, c = chronic) RfD = reference dose, MOE = margin of exposure, LOC = level of concern, NA = Not Applicable * Refer to Section 4.5 4.5 Special FQPA Safety Factor Based on the above data base ( which is considered adequate), no special FQPA safety factor ( i. e 1X) is required since there are no residual uncertainties for prenatal toxicity.

In deriving uncertainty for use in the risk assessment, the conventional 10x factor for interspecies extrapolation and 10x for intraspecies extrapolation were used for all scenarios. The data base was complete enough and there was no evidence of pre or postnatal susceptibility in the studies submitted and evaluated to date. Therefore, the FQPA 10X factor was reduced to 1x. The exposure scenarios in which the hazard value was based on a LOAEL ( intermediate term inhalation for both occupational and residential settings) an additional uncertainty factor of 3x was used to approximate a NOAEL.

4.6 Endocrine disruption EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances ( including all pesticide active and other ingredients) " may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate." Following recommendations of its Endocrine Disruptor and Testing Advisory Committee ( EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program ( EDSP). Page 40 of 77 In the available toxicity studies on Endothall, there was no estrogen, androgen, and/ or thyroid mediated toxicity.

5.0 Public Health Data 5.1 Incident Reports Incident reporting data and case reports of human toxicity have been reviewed by HED ( memorandum from Jerry Blondell and Monica Hawkins to Seyed Tadayon, DP Barcode DP304467). The following databases were reviewed and findings are summarized for each:

1) OPP Incident Data System ( IDS)  reports of incidents from various sources, including registrants, other federal and state health and environmental agencies and individual consumers, submitted to OPP since 1992. Reports submitted to the Incident Data System represent anecdotal reports or allegations only, unless otherwise stated. Typically no conclusions can be drawn implicating the pesticide as a cause of any of the reported health effects. Nevertheless, sometimes with enough cases and/ or documentation risk mitigation measures may be suggested.

Findings: Five incidents were reported, one in each of the following five years: 1995, 1997, 1998, 2000, and 2003. Three cases involved accidental splashing of an endothall product into the eyes; all of which resulted in eye irritation/ pain at the time of the accident. One case involved a twenty four year old man who got some product on unprotected wrists and knees which resulted in a rash later treated by a physician. The fifth case was not likely to be associated with the single reported exposure because the report was based on a seizure one month after exposure and the individual was identified as being addicted to drugs.

2) Poison Control Centers  as the result of a data purchase by EPA, OPP received Poison Control Center data covering the years 1993 through 1998 for all pesticides. Most of the national Poison Control Centers ( PCCs) participate in a national data collection system, the Toxic Exposure Surveillance System which obtains data from about 65 70 centers at hospitals and universities. PCCs provide telephone consultation for individuals and health care providers on suspected poisonings, involving drugs, household products, pesticides, etc.

Findings: Comparisons were made between endothall related products and all pesticides cases reported for percent cases with symptomatic outcomes and degree of severity of the outcome, and the percent resulting in a visit to a health care facility and of those, the percentage resulting in hospitalization or requiring intensive care. Separate comparisons were made for occupational cases ( 15 exposures), non occupational cases for adults and older children ( 75 exposures) and non occupational cases for children under six years of age ( 16 exposures). Too few cases were reported among workers or children under age six to draw any firm conclusions. Among all occupational and non occupational reports, the leading symptoms were eye and skin irritation/ pain reported by 15, and 13 persons, respectively. Comparisons of the data indicated that relative to all pesticides, endothall related products were in general approximately equal to result in symptomatic outcomes of any severities ( 67% for endothall and 69% for all pesticides) and for outcomes of moderate severity ( 14% vs. 11%). Health care facility visits were slightly higher for endothall ( 24%) vs. all pesticides ( 17%). Importantly, none of the endothall exposures Page 41 of 77 resulted in life threatening situations ( 0% vs. 0.4% for all pesticides) or hospitalizations ( 0% vs. 6% for all pesticides).

3) California Department of Pesticide Regulation  California has collected uniform data on suspected pesticide poisonings since 1982. Physicians are required by statute to report to their local health officer all occurrences of illness suspected of being related to exposure to pesticides. The majority of the incidents involve workers. Information on exposure ( worker activity), type of illness ( systemic, eye, skin, eye/ skin and respiratory), likelihood of a causal relationship, and number of days off work and in the hospital are provided.

Findings: From 1982 to 2002, 19 cases were submitted to the California Pesticide Surveillance Program and in 11 of them endothall was used alone or was judged to be responsible for the health effects. Endothall ranked 205th as a cause of systemic poising in California during this 20 year reporting period. Five of the 11 cases included eye effects, five skin effects, and one systemic ( not defined). Six of the 11 cases were associated with applicator activities. None ot these cases required hospitalization.

4) National Pesticide Information Center ( NPIC)  NPIC is a toll free information service supported by OPP. A ranking of the top 200 active ingredients for which telephone calls were received during calendar years 1984 1991, inclusive has been prepared. The total number of calls was tabulated for the categories human incidents, animal incidents, calls for information, and others.

Findings: On the list of the top 200 chemicals for which NPIC received calls from 1984 1991 inclusively, endothall was ranked 148th with 19 incidents in humans reported and three in animals ( mostly pets).

5.2 Other The memo cited above ( Blondell and Hawkins) also discussed case reports of poisonings from the literature. The only citation in the literature addressing health effects of endothall to humans is a case history of a 21 year old male suicide victim who ingested 7 8 grams of endothall in solution ( about 100 mg endothall ion/ kg). Effects included repeated voliting, hemorrhages and edema in the lungs and gross hemorrhages of the gastrointestinal tract.

In summary, relatively few incidents of illness have been reported due to endothall. In general reports are of irritative effects to the eye and skin. No endothall related hospitalizations have been reported due to pesticidal use. No recommendation are made based on the very limited incident data available for this pesticide.

6.0 Exposure Characterization/ Assessment 6.1 Dietary Exposure/ Risk Pathway 6.1.1 Residue Profile Page 42 of 77 Endothall metabolism leads either to the monomethyl ester ( and some small amount of the dimethyl ester), or to complete decomposition and uptake of the radioactive residues into natural constituents of plant and animal tissues. The residues of concern in plants and animals are therefore endothall and its monomethyl ester.

6.1.2 Acute and Chronic Dietary Exposure and Risk A dietary exposure assessment for endothall has been performed and is reported in D296790. DRS This assessment addressed only chronic exposure. Endothall is applied to hops, cotton, and potatoes, and has interim tolerances on sugar beets and rice. Endothall is also used to treat water that may be used to irrigate crops, so HED recommends retaining the tolerances for sugar beets and rice to cover possible inadvertent residues from treated irrigation water. In addition, tolerances exist for livestock, poultry, milk and egg.

6.1.2. a. Acute Dietary Exposure No toxicological endpoint was identified for acute oral exposure. Therefore no acute dietary exposure assessment was performed.

6.1.2. b. Chronic Dietary Exposure ( Food Only)

Endothall has uses for direct application to crops, as described above, and also has aquatic uses to treat water that may subsequently be used to irrigate crops. To assess food only residues from these uses, two assessments were performed for dietary exposure to endothall. One assessment was based solely upon residues in/ on crops directly treated with endothall. Another assessment incorporated both residues from directly treated crops and from crops irrigated with water containing endothall. The results of these two assessments are summarized in Tables 6.1.2. b. 1. and 6.1.2. b. 2.

The results of the DEEMTM analysis based upon directly treated crops only were 1.2% of the cPAD ( 0.000084 mg/ Kg/ day) for the general population. The most highly exposed population subgroup was children 3 5 at 3.0% cPAD ( 0.000211 mg/ Kg/ day). These results were based upon tolerances ( and hops were assumed to be 100% crop treated) and so should be somewhat conservative.

Table 6.1.2. b. 1. Summary of Dietary Exposure and Risk for Endothall From Directly Treated Crops Only Population Subgroup Chronic Dietary DEEM Dietary Exposure ( mg/ kg/ day) % cPAD General U. S. Population 0.000084 1.2 All Infants (< 1 year old) 0.000107 1.5 Population Subgroup Chronic Dietary DEEM Dietary Exposure ( mg/ kg/ day) % cPAD Page 43 of 77 Children 1 2 years old 0.000201 2.9 Children 3 5 years old 0.000211 3.0 Children 6 12 years old 0.000157 2.2 Youth 13 19 years old 0.000081 1.2 Adults 20 49 years old 0.000063 0.9 Adults 50+ years old 0.000053 0.8 Females 13 49 years old 0.000062 0.9 The results of the DEEMTM analysis, for food only, based upon both directly treated crops and crops that may have been irrigated with endothall treated water were 2.7% of the cPAD ( 0.000189 mg/ Kg/ day) for the general population. The most highly exposed population subgroup was children 1 2 at 7.8% cPAD ( 0.000544 mg/ Kg/ day).

Table 6.1.2. b. 2. Summary of Dietary Exposure and Risk for Endothall Both From Directly Treated Crops And From Crops Irrigated with 5 ppm Endothall ( Adjusted by 0.01 factor)

Population Subgroup Chronic Dietary DEEM Dietary Exposure ( mg/ kg/ day) % cPAD General U. S. Population 0.000189 2.7 All Infants (< 1 year old) 0.000324 4.6 Children 1 2 years old 0.000544 7.8 Children 3 5 years old 0.000464 6.6 Children 6 12 years old 0.000299 4.3 Youth 13 19 years old 0.000154 2.2 Adults 20 49 years old 0.000141 2.0 Adults 50+ years old 0.000141 2.0 Females 13 49 years old 0.000144 2.1 Conservative assumptions were used in estimating residues in the various irrigated crops. Because specific residue data ware not available for most crops, translations of residue data were made from other crops. While these translations of residues from other crops may not have been Page 44 of 77 conservative in some particular cases, overall the translations were conservative.

In calculating residues on directly treated crops plus irrigated crops, an assumption that all crops are 100% irrigated with water containing endothall was initially used directly in the DEEM program. This approach was necessitated because the DEEMTM and LifelineTM models are designed to estimate exposure using crop by crop information, but no crop by crop data were available on the percent of each crop that is irrigated with endothall containing water. Following this, the residue data on directly treated crops was subtracted from the combined residues for both sets of crops, leaving behind an estimate of the residues on irrigated crops only. This estimate was then corrected by a factor of 0.01. The 0.01 factor was derived from an estimate of the total pounds of endothall sold for irrigation use in the US in a single year compared to an estimate of the total volume of irrigation water used in the US in a single year. The result of this calculation was that approximately 0.024% of irrigation water is likely to be treated with endothall. To conservatively address errors in the estimation of 0.024%, and to assure that regional and crop differences in irrigation, and differences in consumption of different crops, were all properly compensated, this value was conservatively rounded up to 1.0%. After this correction to the residues on the irrigated crops, the residues for the directly treated crops were added back in to create an estimate of the total residues from both irrigated and directly treated crops. The results are shown in table 6.1.2. b. 2.

6.1.2. c Chronic Dietary Exposure ( Water Only)

Results for the dietary risk assessment based on drinking water exposures alone are presented in Table 6.1.2. c. 1. This assessment assumes an endothall concentration of 100 ppb as the average concentration in drinking water. This concentration is the Maximum Contaminant Level ( MCL) for endothall. Refer to Section 6.2 ( below) for the rationale for the use of the MCL in the drinking water assessment.

Table 6.1.2. c. 1. Summary of Dietary Exposure and Risk for Endothall From Drinking Water Only at the MCL of 100 ppb Population Subgroup* Chronic Dietary DEEM Dietary Exposure ( mg/ kg/ day) % cPAD General U. S. Population 0.002108 30 All Infants (< 1 year old) 0.006910 99 Children 1 2 years old 0.003130 45 Children 3 5 years old 0.002930 42 Table 6.1.2. c. 1. Summary of Dietary Exposure and Risk for Endothall From Drinking Water Only at the MCL of 100 ppb Population Subgroup* Chronic Dietary DEEM Dietary Exposure ( mg/ kg/ day) % cPAD Page 45 of 77 Children 6 12 years old 0.002021 29 Youth 13 19 years old 0.001524 22 Adults 20 49 years old 0.001968 28 Adults 50+ years old 0.002070 30 Females 13 49 years old 0.001960 28 The results of the DEEMTM analysis were 30% of the cPAD ( 0.002108 mg/ Kg/ day) for the general population. The most highly exposed population subgroup was infants (< 1 year old) at 99% cPAD ( 0.006910 mg/ Kg/ day).

6.1.2. d Chronic Dietary Exposure ( Food + Water)

Results for the dietary risk assessment based on drinking water exposures and food exposures from directly treated crops are presented in Table 6.1.2. d. 1. This assessment assumes an endothall concentration of 100 ppb as the average concentration in drinking water. This concentration is the Maximum Contaminant Level ( MCL) for endothall. Refer to Section 6.2 ( below) for the rationale for the use of the MCL in the drinking water assessment.

Table 6.1.2. d. 1. Summary of Dietary Exposure and Risk for Endothall From Directly Treated Crops Only Plus Water at the MCL of 100 ppb Population Subgroup* Chronic Dietary DEEM Dietary Exposure ( mg/ kg/ day) % cPAD*

General U. S. Population 0.002191 31 All Infants (< 1 year old) 0.007017 100 Children 1 2 years old 0.003331 48 Children 3 5 years old 0.003142 45 Table 6.1.2. d. 1. Summary of Dietary Exposure and Risk for Endothall From Directly Treated Crops Only Plus Water at the MCL of 100 ppb Population Subgroup* Chronic Dietary DEEM Dietary Exposure ( mg/ kg/ day) % cPAD*

Page 46 of 77 Children 6 12 years old 0.002178 31 Youth 13 19 years old 0.001604 23 Adults 20 49 years old 0.002031 29 Adults 50+ years old 0.002123 30 Females 13 49 years old 0.002022 29 The results of the DEEMTM analysis were 31% of the cPAD ( 0.002191 mg/ Kg/ day) for the general population. The most highly exposed population subgroup was infants (< 1 year old) at 100% cPAD ( 0.007017 mg/ Kg/ day).

Results for the dietary risk assessment based on drinking water exposures and food exposures from directly treated crops and irrigated crops are presented in Table 6.1.2. d. 2. This assessment assumes an endothall concentration of 100 ppb as the average concentration in drinking water. This concentration is the Maximum Contaminant Level ( MCL) for endothall. Refer to Section 6.2 ( below) for the rationale for the use of the MCL in the drinking water assessment.

Table 6.1.2. d. 2. Summary of Dietary Exposure and Risk for Endothall Both From Directly Treated Crops And From Crops Irrigated with 5 ppm Endothall ( Adjusted by 0.01 factor) Plus Water at the MCL of 100 ppb Population Subgroup* Chronic Dietary DEEM Dietary Exposure ( mg/ kg/ day) % cPAD General U. S. Population 0.002297 33 All Infants (< 1 year old) 0.007234 103 Children 1 2 years old 0.003574 51 Children 3 5 years old 0.003395 48 Children 6 12 years old 0.002320 33 Youth 13 19 years old 0.001677 24 Table 6.1.2. d. 2. Summary of Dietary Exposure and Risk for Endothall Both From Directly Treated Crops And From Crops Irrigated with 5 ppm Endothall ( Adjusted by 0.01 factor) Plus Water at the MCL of 100 ppb Population Subgroup* Chronic Dietary DEEM Dietary Exposure ( mg/ kg/ day) % cPAD Page 47 of 77 Adults 20 49 years old 0.002109 30 Adults 50+ years old 0.002211 32 Females 13 49 years old 0.002104 30 The results of the DEEMTM analysis were 33% of the cPAD ( 0.002297 mg/ Kg/ day) for the general population. The most highly exposed population subgroup was infants (< 1 year old) at 103% cPAD ( 0.007234 mg/ Kg/ day).

6.2 Water Exposure/ Risk Pathway Human exposure to endothall through ingestion of drinking water from terrestrial use on potatoes, cotton, clover and alfalfa for seed, hops, and aquatic uses was assessed through modeling and monitoring. Concentrations of endothall in drinking water were estimated for terrestrial and aquatic uses. Aquatic uses resulted in estimated concentrations that were higher than those from terrestrial applications. Therefore, concentrations based on aquatic uses were used for risk assessment. Since no degradates of concern have been identified, no degradates of endothall were modeled in this assessment. Should the Health Effects Division ( HED) determine that any of the environmental fate degradates are of concern, a separate assessment will be conducted.

6.2.1 Aquatic Uses Direct applications to water were modeled by the Environmental Fate and Effects Division ( EFED) assuming uniform application over an entire reservoir at the maximum labeled rate ( Drinking Water Assessment for Endothall for both Terrestrial and Aquatic Uses; 05/ 05/ 04; James Breithaupt). Based on these assumptions, the peak concentration of endothall in surface water was estimated to be 5000 ug/ l, and the annual mean ( chronic) concentration was estimated to be 545 ug/ l. EPA believes it is highly unlikely that concentrations of endothall would reach these levels in areas where surface water is directly used for drinking water for several reasons:

 The assumption that 100% of a water body is treated with endothall at the maximum label rate is conservative and highly unlikely. Typically, endothall is applied as a peripheral treatment around boat docks and piers, so that only a small percentage of the water body is treated. Page 48 of 77  Endothall treatments are made to the upper 3 to 5 feet of the water body, whereas drinking water intakes are typically located at the deepest point in a reservoir where endothall concentrations would be expected to be lower.

 Monitoring data for endothall suggest that average concentrations of endothall in drinking water are well below the modeled estimates. Monitoring data are available from the National Contaminant Occurrence Database ( NCOD) for both surface and ground water. Detectable residues of endothall were found in only 7 of 27,494 or 0.025% of ground water samples and 8 of 5,112 or 0.15% of surface water samples.

The maximum detected concentrations in ground and surface water were 4,550 ppb and 2,900 ppb, respectively; and the mean concentration for samples with detectable residues was 670 ppb in ground water and 865 ppb in surface water. Although these few values are well above the established Maximum Contaminant Level ( MCL) for endothall of 100 ppb, the vast majority of ground and surface water samples contained concentrations of endothall below the limit of detection ( 10 ppb). Endothall may be applied to water at concentrations up to 5000 ppb. It is likely that the NCOD samples with high concentrations were taken at or soon after application and very near the application site. As such, these high values would not be representative of average concentrations in drinking water. This determination is further supported by additional monitoring data collected under the Safe Drinking Water Act ( SDWA). Data collected under the Safe Drinking Water Information System ( SDWIS) between 1993 and 2005 indicated only 2 occurrences of endothall residues that exceeded the established MCL of 100 ppb. Both of these occurred in 1994, with no violations occurring since that time.

For these reasons, EPA does not believe the modeled EECs are appropriate for use in estimating exposure to endothall in drinking water. As noted above, an MCL of 100 ppb has been established for endothall. Although the MCL is likely to overestimate average ( i. e., chronic) residues of endothall in drinking water, EPA believes it provides a reasonable high end estimate of potential drinking water concentrations from the aquatic uses of endothall. Consequently, the MCL of 100 ppb was used in the dietary risk assessments ( using DEEM) detailed above.

6.2.2 Terrestrial Uses Surface water concentrations from use on terrestrial crops were estimated using the Tier II model PRZM version 3.12/ EXAMS version 2.98.04 and ground water concentrations were estimated using the Tier I model SCIGROW version 2.2. A total of five scenarios were modeled for endothall use on terrestrial crops based on individual EFED standard scenarios. The scenarios modeled were cotton and alfalfa in California, Oregon Hops, and potatoes in Maine and Idaho. These scenarios were chosen to estimate the concentration of endothall in surface drinking water over a geographically dispersed range of existing terrestrial crop production areas These scenarios chosen for this assessment represent all relevant PRZM/ EXAMS scenarios for the terrestrial use of endothall. Endothall may be applied by aerial or ground equipment as per the labels for this product. All terrestrial scenarios were modeled with aerial application which results in the highest amount of spray drift, except for hops which is treated by ground equipment. Page 49 of 77 Based on modeling results, the estimated surface water drinking water concentrations for endothall are:

Table 6.2. Summary of Estimated Surface and Ground Water Concentrations for Endothall.

Exposure Duration Endothall Surface Water Conc., ppb Ground Water Conc., ppb Acute 7.1 0.086 Chronic ( non cancer) 2.5 0.086 Chronic ( cancer) 2.4 0.086 These 1 in 10 year annual peak ( acute), 1 in 10 year annual mean ( non cancer chronic), and 36 year annual mean concentrations ( cancer chronic) were derived from modeling endothall on the labeled terrestrial crops in Table 1. The estimates of surface water concentrations ranged from 0.13 to 7.2. 0.02 to 2.5, and 0.02 to 2.4 µ g / L for the peak, annual mean, and overall means. For shallow ground water used for drinking water, the SCI GROW model estimates are not expected to exceed 0.086 µ g / L. These modeled concentrations can be considered as both the acute and chronic value. As noted above, estimated concentrations of endothall based on aquatic uses were used in risk assessment rather than these estimated concentrations from terrestrial uses.

6.3 Residential and Other Non Occupational Exposures and Risks It has been determined that there is a potential for exposure in residential settings during the application process for homeowners who use endothall products to control aquatic weeds and algae in ponds and garden pools. There is also a potential for exposure to adults and children from contacting water treated with endothall through swimming, wading, water skiing, etc. As a result, risk assessments have been completed for both residential handler and postapplication scenarios.

6.3.1 Residential Handler Exposures and Risks Residential handlers are addressed somewhat differently by the Agency as homeowners are assumed to complete all elements of an application with little use of protective equipment.

<IP_ADDRESS> Handler Exposure Scenarios The purpose of this section is to describe how the exposure scenarios were defined. Much of the process for residential uses is identical to that considered for the occupational assessment with a few notable exceptions that include:

 Residential handler exposure scenarios are only considered to be short term in nature due to the episodic uses associated with homeowner products. Page 50 of 77  A tiered approach for personal protection using increasing levels of personal protective equipment ( PPE) is not used in residential handler risk assessments. Rather than using PPE, homeowner handler assessments are completed based on individuals using shorts and short sleeved shirts.

 Homeowner handlers are expected to complete all tasks associated with the use of a pesticide product including loading as well as the application.

 Label use rates and use information specific to residential products serve as the basis for the risk calculations as opposed to the rates used in the occupational assessment.

 Area treated per day in the risk assessment is based on Agency guidance specific to residential use patterns.

It has been determined that exposure to pesticide handlers is likely during the residential use of endothall granular products in ponds and garden pools. The anticipated use patterns and current labeling indicate two likely residential exposure scenarios   loading/ applying granules with a bellygrinder and applying granules by hand. The quantitative exposure/ risk assessment developed for residential handlers is based on these two scenarios. [ Note: The scenario numbers correspond to the tables of risk calculations included in the occupational risk calculation sections of the appendices.]

( 1) Granular formulation: loading/ applying with bellygrinder; and ( 2) Granular formulation: applying by hand.

<IP_ADDRESS> Data and Assumptions For Handler Exposure Scenarios A series of assumptions and exposure factors served as the basis for completing the residential handler risk assessments. Each assumption and factor is detailed below. In addition to these factors, unit exposure values were used to calculate risk estimates. These unit exposure values were taken from the Pesticide Handlers Exposure Database ( PHED). [ Note: Several of the assumptions and factors used for the assessment are similar to those used in the occupational assessment presented above. As such, only factors that are unique to the residential scenarios are presented below.]

Assumptions and Factors: The assumptions and factors used in the risk calculations include:

 The Agency always considers the maximum application rates allowed by labels in its risk assessments to consider what is legally possible based on the label.

 Residential risk assessments were not based on what could be applied in a typical workday as with the occupational risk assessments presented above. Instead, the Agency based calculations on what would reasonably be treated by homeowners, such as the size of a pond, or the size of a garden pool. This information was used by the Agency to define Page 51 of 77 chemical throughput values for handlers which in turn were coupled with unit exposure values to calculate risks. The daily area treated, based on HED's professional judgement, used in each residential scenario, include:

 typical pond application: rangefinder calculation using 1 acre of surface area and 5 feet depth and 10,000 square feet surface area and 2 feet depth.

 typical garden pool application: 1,000 square feet of surface area and 2 feet depth.

Residential Handler Exposure Studies: The unit exposure values that were used in this assessment were based on studies completed by the Pesticide Handler Exposure Database ( PHED, Version 1.1 August 1998).

<IP_ADDRESS> Residential Handler Exposure and Risk Estimates The residential handler exposure and risk calculations are presented in this section. Risks were calculated using the Margin of Exposure ( MOE) approach, with a target MOE of 100 for short term risk assessments. Much of the process for residential uses is identical to that considered for the occupational assessment with a few notable exceptions ( e. g., all are short term exposures and assume homeowners wear shorts and short sleeved shirts with no gloves). Residential exposures are expected to be short term only.

Risk Summary: The short risk calculations for residential endothall handlers are summarized below.

Table 6.3 Endothall Short Term Risks to Residential Handler Exposure Scenario Crop or Target Application Rate ( lb ai/ cubic feet) Surface Area Treated Daily ( square feet) Depth of Water ( feet) Short Term Inhalation MOE ( no respirator)

Mixer/ Loader/ Applicator Loading/ Applying Granulars via Belly Grinder Ponds/ Lakes 0.00022 43,560 2 470 Ponds/ Lakes 0.00022 10,000 2 1900 Applying Granulars via Hand Garden pool 0.00022 1,000 2 2700 In residential settings, the Agency does not use personal protective equipment ( PPE) to limit exposures, because PPE are viewed as impractical and not enforceable.

For residential handlers, short term inhalation MOEs are not of concern for any of the scenarios and do not exceed the Agency's target MOE (

100).

<IP_ADDRESS> Summary of Risk Concerns and Data Gaps for Handlers In summary, the assessment for residential handler exposure presented in this section concludes that there are no risk concerns for endothall as it is currently used in a residential environment. Page 52 of 77 <IP_ADDRESS> Recommendations For Refining Residential Handler Risk Assessment In order to refine this residential risk assessment, more data on actual use patterns including rates, timing, and areas treated would better characterize endothall risks.

6.3.2 Residential Postapplication Exposures and Risks <IP_ADDRESS> Residential Postapplication Exposure Scenarios Postapplication exposures to adults and children are expected following applications of endothall to ponds and lakes. Of the possible postapplication exposures, swimming in treated water is considered by HED to be worse case and is used as a surrogate for all other possible postapplication exposures, such as wading, water skiing, etc.

The Agency considered residential postapplication exposure for different segments of the population. Risks were calculated for swimming in treated lakes or ponds.

<IP_ADDRESS> Residential Postapplication Exposure and Risk Estimates The residential postapplication exposure and risk calculations are presented in this section. Risks were calculated using the Margin of Exposure ( MOE) approach.

Risk Summary: The Agency has addressed residential postapplication exposures to endothall using the SWIM model.

The following assumptions have used to assess postapplication exposure to swimmers.

S Body Weights 22kg for children and 70kg for adults S Body surface area 9000 cm2 and 21000 cm2 for adults S Exposure Time 3hrs/ day S Water Intake 5 liter or 5000 ml in and out of the mouth per hour S Water ingested 0.05 L or 50 ml per hour S Application rate 1 to 5 ppm or 1 to 5 mg/ L or 1 to 5 mg/ 1000 cm3 S Permeability coefficient K p 8.82 x10 7 cm/ hr S Octanol/ water partition coefficient K ow 0.0008 S Vapor pressure 3.92x10 5 mg/ day Table <IP_ADDRESS> provides the individual exposure through various routes based on the standard factors and physical constant. The estimates provided by the SOP are the absorbed doses and risks using endothall for recreational swimming from to all routes of exposure. Page 53 of 77 Table <IP_ADDRESS> Summary of Endothall Swimmer Postapplication Risk Exposure Children ( 6 to 10) Adult Daily Dose mg/ kg/ day MOE Daily Dose mg/ kg/ day MOE Oral 0.0341 280 0.0107 900 Dermal NA NA NA NA Buccal Insignificant* NA Insignificant NA Orbital/ Nasal Insignificant NA Insignificant NA Total 280 900 * Dosage is insignificant according to the SOP because endothall is lipophobic ( K OW = 0.0008)

For significant absorption through buccal/ sublingual, orbital and nasal exposure the chemical must be lipophilic with a high K OW. Since endothall has a low K ow Value, therefore no significant risk is expected. Also due to low vapor pressure, inhalation exposure is expected to be negligible. Finally, the expected exposure to swimmers from the dermal route would be extremely low ( the highest application rate results in a water concentration of 5 ppm) and would not likely result in any irritation to the skin. The incident data contain no reports of eye or skin irritation related to swimming in endothall treated waters.

Risk Summary:

The Agency considered one residential postapplication exposure scenario   swimming   for different segments of the population including children, and adults. Risks were calculated. In residential settings, the Agency does not use REIs or other mitigation approaches to limit exposures, because they are viewed as impractical and not enforceable. As such, risk estimates on the day of application are the key concern. However, several of the Special Local Needs labels do have swimming restrictions following commercial applications of endothall.

6.3.3 Residential Risk Characterization <IP_ADDRESS> Characterization of Residential Handler Risks The data that were used in the endothall residential handler assessment represent the best data and approaches that are currently available. For each use pattern, the Pesticide Handlers Exposure Database ( PHED) was used to develop the unit exposure values. All data that have been used may not be of optimal quality, but represent the best available data.

The inputs for application rate and other use/ usage information ( e. g., area treated) used by the Agency were supported by the available endothall labels. There are also many uncertainties in the assessment that are common with the occupational assessment as well. These factors and their impacts on the results should be considered as well in the interpretation of the results for Residential handlers.

In summary, with respect to residential handler risks, the Agency believes that the values Page 54 of 77 presented in this assessment represent the highest quality results that could be produced given the exposure, use, and toxicology data that are available. As calculated MOE's > for all exposure scenarios Page 55 of 77 <IP_ADDRESS> Characterization Of Residential Postapplication Risks The data that were used in the endothall residential postapplication assessment represent the best data and approaches that are currently available.

The Agency believes that the values presented in this assessment represent the highest quality results that could be produced based on the currently available postapplication exposure data. The Agency believes that the risks represent reasonable worse case estimates of exposure because maximum application rates are used to define residue levels upon which the calculations are based.

7.0 Aggregate Risk Assessments and Risk Characterization 7.1 Acute Aggregate Risk Due to the lack of an acute Rfd and acute dietary exposure/ risk, an acute aggregate risk assessment was not performed.

7.2 Short Term Aggregate Risk A risk assessment for aggregate exposures ( food + drinking water + residential) was conducted for the short term exposure scenario because residential uses of endothall are expected to be only episodic. Food exposures are based on treated crops and irrigated crops. Drinking water exposures are based on aquatic uses of endothall. Although endothall has terrestrial uses as well as aquatic uses, the aquatic uses result in the highest estimates of potential drinking water exposures. Residential handler exposures for adults are based on granular applications of endothall with a belly grinder to lakes or ponds. Residential post application exposures for adults and children are based on swimming.

For adults, estimated dietary exposures via food and drinking water were combined with inhalation exposures during application to a pond or lake and potential post application exposures during swimming. HED notes the handler scenario aggregated for adults is the exposure scenario resulting in the lowest MOE ( highest risk estimate) for residential handlers. For children, estimated dietary exposures via food and drinking water were combined with potential postapplication exposures during swimming. The short term aggregate risk estimate ( MOE) for adults is 310, for children, it is 250. The MOEs are not a risk concern. Therefore, there are no short term aggregate ( food + drinking water + residential) risk concerns for endothall. Table 7.2 summarizes the results of the short term aggregate risk assessment. Page 56 of 77 Table 7.2 Short Term Aggregate Risk Population Short Term Scenario Target Aggregate MOE1 MOE food + water2 Residential Aggregate MOE ( food + water and residential) 6 MOE oral3 MOE dermal4 MOE inhalation5 Child ( 3 5 years old) 100 2770 280 N. A. N. A. 250 Adults ( 50+ years old) 100 4250 900 N. A. 470 310 1 Target 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 exposures for treated crops, irrigated crops and aquatic uses, = [( short term oral NOAEL)/( chronic dietary exposure)]. Short term NOAEL = 9.4 mg/ kg/ day from the 2 generation reproduction rat study, MRID 43152101; chronic dietary ( food+ water) exposure = 0.003395, Children 3 5 years old, and 0.002211, Adults 50+ years old.

3 MOE oral = [( short term oral NOAEL)/( Oral postapplication exposure of Swimmers)] Short term NOAEL = 9.4 mg/ kg/ day from the 2 generation reproduction rat study, MRID 43152101; Oral daily postapplication exposure of swimmers = 0.0341 mg/ kg/ day , Children 6 10 years old; 0.0107 mg/ kg/ day, Adults ( see Table <IP_ADDRESS>).

4 Not Applicable ( N. A.)

5 MOE inhalation = [( inhalation NOAEL)/( high end inhalation residential handler exposure)] Short term inhalation NOAEL = 9.4 mg/ kg/ day from the 2 generation reproduction rat study, MRID 43152101.

6 Aggregate MOE ( food + water and residential) = 1 ÷ [ [( 1 ÷ MOE food+ water) + ( 1 ÷ MOE oral) + ( 1 ÷ MOE dermal) + ( 1 ÷ MOE inhalation)]]

7.3 Intermediate Term Aggregate Risk Due to the episodic residential use of endothall, no intermediate term aggregate ( dietary + residential) risk assessment was performed.

7.4 Long Term Aggregate Risk There are no long term residential uses of endothall. Aggregated chronic exposures to endothall through food plus drinking water were calculated in DEEMTM. The results for directly treated crops, irrigated crops and drinking water from aquatic uses of endothall were 33% of the cPAD ( 0.002297 mg/ Kg/ day) for the general population. The most highly exposed population subgroup was infants at 103% cPAD ( 0.007234 mg/ Kg/ day).

7.5 Cancer Risk Page 57 of 77 Endothall is considered not likely to be carcinogenic to humans.

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 endothall and any other substances and endothall 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 endothall 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 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 It has been determined that there is a potential for exposure to endothall in occupational scenarios from handling endothall products during the application process ( i. e., mixer/ loaders, applicators, flaggers, and mixer/ loader/ applicators) and a potential for postapplication worker exposure from entering into areas previously treated with endothall. As a result, risk assessments have been completed for occupational handler scenarios as well as occupational postapplication scenarios.

9.1 Occupational Handler Exposures and Risks Tasks associated with occupational pesticide use ( i. e., for " handlers") can generally be categorized using one of the following terms:

Mixers and/ or Loaders: these individuals perform tasks in preparation for an application. For example, prior to application, mixer/ loaders would mix the endothall and load it into the holding tank of the airplane or groundboom sprayer.

 Applicators: these individuals operate application equipment during the release of a pesticide product into the environment. These individuals can make applications using equipment such as airplanes or groundboom.

 Mixer/ Loader/ Applicators and or Loader/ Applicators: these individuals are involved in the entire pesticide application process ( i. e., they do all job functions related to a pesticide application event). These individuals would transfer endothall into the application equipment and then also apply it.

 Occupational Flaggers: these individuals guide aerial applicators during the release of a Page 58 of 77 pesticide product onto an intended target.

HED always completes risk assessments using maximum application rates for each scenario, because what is possible under the label must be evaluated, for complete stewardship, in order to ensure there are no concerns for each specific use.

A chemical can produce different effects based on how long a person is exposed, how frequently exposures occur, and the level of exposure. It is likely that endothall exposures can occur in a variety of patterns. HED believes that occupational endothall exposures can occur over a single day or up to weeks at a time for many use patterns and intermittent exposures over several weeks are also anticipated. Some applicators may apply endothall over a period of weeks, because they are custom or commercial applicators who are completing a number of applications for a number of different clients. HED classifies exposures up to 30 days as short term and exposures greater than 30 days up to several months as intermediate term. HED completes both short and intermediate term assessments for occupational scenarios in essentially all cases, because these kinds of exposures are likely and acceptable use/ usage data are not available to justify deleting intermediate term scenarios. Long term handler exposures are not expected to occur for endothall. Different toxicological endpoints of concern ( from an oral study) have been selected for short and intermediate term inhalation exposures to endothall, therefore the risk results for all inhalation durations of exposure are numerically distinct.

Occupational handler exposure assessments are completed by HED using different levels of personal protection. HED typically evaluates all exposures with a tiered approach. The lowest tier is represented by the baseline exposure scenario ( i. e., long sleeve shirt, long pants, shoes, and socks) followed by increasing the levels of personal protective equipment or PPE ( e. g., gloves, double layer body protection, and respirators) and engineering controls ( e. g., enclosed cabs and closed mixing/ loading systems). This approach is always used by HED in order to be able to define label language using a risk based approach. In addition, the minimal level of adequate protection for a chemical is generally considered by HED to be the most practical option for risk reduction ( i. e., over burdensome risk mitigation measures are not considered a practical alternative).

9.1.1 Data and Assumptions For Handler Exposure Scenarios <IP_ADDRESS> Assumptions for Handler Exposure Scenarios A series of assumptions and exposure factors served as the basis for completing the occupational handler risk assessments. Each assumption and factor is detailed below on an individual basis. The assumptions and factors used in the risk calculations include:

 Occupational handler exposure estimates were based on surrogate data from: ( 1) the Pesticide Handlers Exposure Database ( PHED) and ( 2) the Outdoor Residential Exposure Task Force ( ORETF).

 The average body weight of an adult female handler ( i. e., 60 kilograms) is used for assessing inhalation dose, because the toxicity endpoint values used for the inhalation Page 59 of 77 assessments are from a reproductive study and, therefore, are female specific.

 Generic protection factors ( PFs) were used to calculate exposures when data were not available. For example, an 80 percent protection factor was assumed for the use of a quarter face dust/ mist respirator.

 Exposure factors used to calculate daily exposures to handlers are based on applicable data, if available. For lack of appropriate data, values from a scenario deemed similar enough by the assessor might be used. For the endothall handler exposure assessment, the following surrogate data was used for certain application methods, since the nature of these application methods are believed to be similar enough to bridge the data:

 for occupational large scale spray applications to water using boat mounted boom sprayers, PHED data for mixing/ loading and applying with ground boom were used;

 for occupational larger scale spray applications to water using boat mounted spray tanks equipped with a handgun, ORETF data for loading/ applying with handgun equipment were used;

 for occupational direct metering of liquid formulations to water, PHED data for mixing/ loading liquid formulations were used;

 for occupational boat mounted granular applications to water using blower type spreaders, PHED data for loading granulars were used; and  for residential granular applications to water, PHED data for loading/ applying granulars with bellygrinder equipment were used.

 For occupational assessments, HED assumes the maximum application rates allowed by labels in its risk assessments.

 The average occupational workday is assumed to be 8 hours. The daily areas treated were defined for each handler scenario ( in appropriate units) by determining the amount that can be reasonably treated in a single day ( e. g. acres, square feet, cubic feet, or gallons per day). When possible, the assumptions for daily areas treated are taken from the Health Effects Division Science Advisory Committee on Exposure SOP # 9: Standard Values for Daily Acres Treated in Agriculture, which was completed on July 5, 2000. However, no standard values are available for numerous scenarios. Assumptions for these scenarios are based on HED estimates and could be further refined from input from affected sectors.

S Aerial equipment: 350 acres for most crops on which endothall is registered, except 1200 acres for high acreage crops ( i. e., cotton);

S Groundboom equipment: 80 acres for most crops on which endothall is registered, except 200 acres for high acreage crops ( i. e., cotton) and 40 acres for hops;   Flaggers: 350 acres for all crops on which endothall is registered;   Pond/ Lake spray and granular applications: 30 acre surface area and 5 feet depth;   Canal spray and granular applications: 10 miles in length, 5 feet depth, and 20 or 5 feet width; and   Flowing water applications: 5 hours, if water is flowing 50 cubic feet per second Page 60 of 77 and 2 hours, if water is flowing 200 cubic feet per second.

<IP_ADDRESS> Exposure Data for Handler Exposure Scenarios For endothall handler exposure assessments, all analyses were completed using data that were deemed to be a source of acceptable surrogate exposure data for the scenario in question.

HED uses a concept known as unit exposure as the basis for the scenarios used to assess handler exposures to pesticides. Unit exposures numerically represent the exposures one would receive related to an application. They are generally presented as milligrams of active ingredient exposure per pound of active ingredient handled. HED has developed a series of unit exposures that are unique for each scenario typically considered in our assessments ( i. e., there are different unit exposures for different types of application equipment, job functions, and levels of protection). The unit exposure concept has been established in the scientific literature and also through various exposure monitoring guidelines published by the U. S. EPA and international organizations such as Health Canada and OECD ( Organization For Economic Cooperation and Development).

Pesticide Handler Exposure Database ( PHED) Version 1.1 ( August 1998): PHED was designed by a task force of representatives from the U. S. EPA, Health Canada, the California Department of Pesticide regulation, and member companies of the American Crop Protection Association. PHED is a software system consisting of two parts  a database of measured exposure values for workers involved in the handling of pesticides under actual field conditions and a set of computer algorithms used to subset and statistically summarize the selected data. Currently, the database contains values for over 1,700 monitored individuals ( i. e., replicates).

Users select criteria to subset the PHED database to reflect the exposure scenario being evaluated. The subsetting algorithms in PHED are based on the central assumption that the magnitude of handler exposures to pesticides are primarily a function of activity ( e. g., mixing/ loading, applying), formulation type ( e. g., wettable powders, granulars), application method ( e. g., aerial, groundboom), and clothing scenarios ( e. g., gloves, double layer clothing).

Once the data for a given exposure scenario have been selected, the data are normalized ( i. e., divided by) by the amount of pesticide handled resulting in standard unit exposures ( milligrams of exposure per pound of active ingredient handled). Following normalization, the data are statistically summarized. The distribution of exposure values for each body part ( e. g., chest upper arm) is categorized as normal, lognormal, or " other" ( i. e., neither normal nor lognormal). A central tendency value is then selected from the distribution of the exposure values for each body part. These values are the arithmetic mean for normal distributions, the geometric mean for lognormal distributions, and the median for all " other" distributions. Once selected, the central tendency values for each body part are composited into a " best fit" exposure value representing the entire body.