UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES Date: 26 JAN 2005 MEMORANDUM SUBJECT: Revised as per 30 day Error Only Registrant Comments. Ametryn: HED Chapter of the Reregistration Eligibility Decision Document ( RED). PC Code: 080801, Case #: 2010, DP Barcode: D307100.

Regulatory Action: Phase 1 Reregistration Action Risk Assessment Type: Single Chemical Aggregate FROM: William H. Donovan, Ph. D., Chemist Reregistration Branch 3 ( RRB3) Health Effects Division ( HED) ( 7509C)

AND John Doherty, Ph. D, Toxicologist Robert Travaglini, Chemist RRB3/ HED ( 7509C)

THROUGH: Danette Drew, Branch Senior Scientist RRB3/ HED ( 7509C)

TO: Mark T. Howard, CRM Reregistration Branch 3 Special Review and Registration Division ( 7508C) 2 Table of Contents 1.0 Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2.0 Ingredient Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2.2 Structure and Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 2.3 Physical and Chemical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 3.0 Metabolism Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 3.1 Comparative Metabolic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 3.2 Nature of the Residue in Foods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 3.2.1. Description of Primary Crop Metabolism . . . . . . . . . . . . . . . . . . . . . . . . 8 3.2.2 Description of Livestock Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 3.2.3 Description of Rotational Crop Metabolism, including identification of major metabolites and specific routes of biotransformation . . . . . . . . . . 11 3.3 Environmental Degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 3.4 Tabular Summary of Metabolites and Degradates . . . . . . . . . . . . . . . . . . . . . . . 12 3.5 Toxicity Profile of Major Metabolites and Degradates . . . . . . . . . . . . . . . . . . . 12 3.6 Summary of Residues for Tolerance Expression and Risk Assessment . . . . . . . . 13 3.6.1 Tabular Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 3.6.2 Rationale for Inclusion of Metabolites and Degradates . . . . . . . . . . . . . 13 4.0 Hazard Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 4.1 Hazard Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 4.2 FQPA Hazard Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 4.2.1 Adequacy of the Toxicity Data Base . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 4.2.2 Evidence of Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 4.2.3 Developmental Toxicity Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 4.2.4 Reproductive Toxicity Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 4.2.5 Additional Information from Literature Sources . . . . . . . . . . . . . . . . . . 21 4.2.6 Pre and/ or Postnatal Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 <IP_ADDRESS> Determination of Susceptibility . . . . . . . . . . . . . . . . . . . 21 <IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Post natal Susceptibility . . . . . . . . . . . . . . . . 22 4.3 Recommendation for a Developmental Neurotoxicity Study . . . . . . . . . . . . . . . 22 4.3.1 Evidence that supports requiring a Developmental Neurotoxicity study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.3.2 Evidence that supports not requiring for a Developmental Neurotoxicity study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.4 Hazard Identification and Toxicity Endpoint Selection . . . . . . . . . . . . . . . . . . . 22 4.4.1 Acute Reference Dose ( aRfD)  Females age 13 49 . . . . . . . . . . . . . . . . 22 4.4.2 Acute Reference Dose ( aRfD)  General Population . . . . . . . . . . . . . . . 22 4.4.3 Chronic Reference Dose ( cRfD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.4.4 Incidental Oral Exposure ( Short and Intermediate Term) . . . . . . . . . . . . 23 4.4.5 Dermal Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 4.4.6a Dermal Exposure ( Short and Intermediate Term) . . . . . . . . . . . . . . . . . 24 3 4.4.7a Inhalation Exposure ( Short and Intermediate Term) . . . . . . . . . . . . . . . 25 4.4.7b Inhalation Exposure ( Long Term). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 4.4.8 Margins of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 4.4.9 Recommendation for Aggregate Exposure Risk Assessments . . . . . . . . 26 4.4.10 Classification of Carcinogenic Potential . . . . . . . . . . . . . . . . . . . . . . . . . 26 4.5 Special FQPA Safety Factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 4.6 Endocrine disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 5.0 Public Health Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 5.1 Incident Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 6.0 Exposure Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 6.1 Dietary Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 6.1.1 Residue Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 6.1.2 Acute and Chronic Dietary Exposure and Risk . . . . . . . . . . . . . . . . . . . 32 6.2 Water Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 6.3 Residential ( Non Occupational) Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . 34 6.3.1 Home Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 6.3.2 Recreational Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 6.3.3 Other ( Spray Drift, etc.) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 7.0 Aggregate Risk Assessments and Risk Characterization . . . . . . . . . . . . . . . . . . . . . 35 7.1 Acute Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 7.2 Short Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 7.3 Intermediate Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 7.4 Long Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 7.5 Cancer Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 8.0 Cumulative Risk Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 9.0 Occupational Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 9.1 Short/ Intermediate/ Long Term Handler Risk . . . . . . . . . . . . . . . . . . . . . . . . . . 40 9.2 Short/ Intermediate/ Long Term Postapplication Risk . . . . . . . . . . . . . . . . . . . . . 55 10.0 Data Needs and Label Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 10.1 Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 10.2 Residue Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 10.3 Occupational and Residential Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 References: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 1 1.0 Executive Summary This assessment provides information to support the issuance of a risk management decision document known as a Reregistration Eligibility Decision ( RED) Document for ametryn. 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 ensure 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 ensure that they meet the safety standard established by the Food Quality Protection Act ( FQPA) of 1996.

Use Profile Ametryn, ( 2 ethylamino) 4( isopropylamino) 6( methylthio) s triazine, is a selective methylthiotriazine herbicide registered for the control of broadleaf and grass weeds in corn, pineapple, and sugarcane. Ametryn has no residential uses. In the U. S., ametryn is registered to Syngenta Crop Protection, Inc. ( the basic producer) under the trade name EVIK ® and is formulated as a 80% water dispersible granule ( DF). Ametryn can be applied by aerial equipment ( sugarcane only) and by ground boom sprayers. For corn ( field, pop, and sweet), ametryn is used as a directed spray for soil treatment post emergence. For sugarcane, ametryn is used as a band treatment ( ratoon), or as a broadcast spray ( pre emergence, ratoon, and post emergence). For pineapple, ametryn is used as a blanket ( i. e., broadcast) spray.

Ametryn is a FIFRA List B pesticide that was the subject of a Phase 4 Review, dated 11/ 19/ 90, and a Reregistration Update, dated 12/ 9/ 94. Ametryn will not be included in the cumulative risk assessment for atrazine, simazine, propazine, and their degradates ( desethyl satrazine desisopropyl s atrazine, and diaminochlorotriazine) as determined by the Office of Pesticide Programs' Health Effects Division in its March 2002 report: " The Grouping of a Series of Triazine Pesticides Based on a Common Mechanism of Toxicity." Ametryn was not grouped with chloro s triazines ( atrazine, simazine, propazine and their chloro s triazine metabolites) because it has a different functional group attached to the triazene ring, i. e., thiomethyl versus chloro. Further, ametryn does not exhibit the same toxicity profile as the chloro s triazines. There were several tumors induced by ametryn in a rat bioassay, but only at an excessive dose which confounds the interpretation of this response. This pattern of tumor response is not characteristic of the chloro s triazines. Tolerances are currently established for the residues of ametryn per se [ 40 CFR § 180.258], and are set at 0.25 ppm for all plant commodities, with the exceptions of corn forage and stover, each at 0.5 ppm, and cassava root at 0.1 ppm. There are currently no livestock tolerances for ametryn.

Comprehensive information on use patterns and formulations is provided in the ametryn Master Label which was submitted to the EPA by Syngenta Crop Protection, Inc. The risk assessments for ametryn are based solely on the Master Label, since it only lists supported uses ( M. T. Howard, Use Closure Memo, 27 FEB 2004).

Hazard Identification and Dose Response Assessment 2 The toxicology data base is adequate to characterize the toxicity of ametryn. Ametryn is placed in Toxicity Category IV for acute inhalation toxicity and dermal irritation; and in Toxicity Category III for acute oral and dermal toxicity and eye irritation. Ametryn is not a skin sensitizer.

The available toxicity database indicates that the liver is the most sensitive organ and the dog the is the most sensitive species to ametryn exposure. Other toxic effects included decreases in body weight and gain related to decreases in food efficiency across species, but were most pronounced in the rat. Changes in body weight and gain were the main effects seen in the developmental and reproductive studies. There was no indication of increased qualitative or quantitative sensitivity or susceptibility in fetuses or offspring. There is no residual uncertainty for pre and/ or post natal toxicity. Therefore, the special FQPA uncertainty factor for sensitivity in infants and children was reduced to 1x. There were no signs of mutagenicity, immunotoxicity, or direct neurotoxocity in the available database. In the rat, ametryn was rapidly absorbed, metabolized into polar constituents and excreted.

The Cancer Assessment Review Committee ( CARC) met to evaluate the carcinogenic potential of ametryn on 21 JUL 2004 and concluded that the " data are inadequate for an assessment of human carcinogenic potential". The carcinogenicity study in rats is unacceptable because the high dose was considered to be excessive. The CARC requested that the carcinogenicity study in rats be repeated at a dose that is adequate to assess carcinogenicity. However, the available data allow for a determination of a provisional Q 1* value of 0.0066 ( mg/ kg/ day) 1, based on observations of combined mammary tumors in female rats. The ametryn risk assessment team believes that using the estimated provisional Q 1* based on existing data will reasonably approximate cancer risk to humans and considers it unlikely that the requested new cancer study will result in a higher risk for ametryn. Support for this conclusion comes from the observation that there were no tumors in the rat study at 500 ppm, a dose resulting in minimal body weight decrease and the fact that there were no compound related tumors in the mouse study at dose levels up to and including 2000 ppm.

Dietary, drinking water, and occupational exposure scenarios are relevant for ametryn. No acute dietary assessment was conducted as an appropriate endpoint for single dose effects was not identified in the available toxicity datatbase. The chronic dietary endpoint was selected based on a chronic feeding study in dogs, where degenerative and inflammatory liver effects were observed at a dose of 70 mg/ kg/ day. This study was also used to establish the long term inhalation and dermal endpoints. The short and intermediate term oral and inhalation endpoints were selected from a developmental toxicity study in rabbits, where increased liver weights and decreased feed consumption were noted at 60 mg/ kg/ day. The short and intermediate term dermal endpoints were based on a 21 day dermal toxicity study in rabbits, where a body weight gain decrease occurred at a dose of 1000 mg/ kg/ day. Endpoints used in the assessment are provided in Table 1. A standard uncertainty factor ( UF) of 100x was applied to all oral, dermal, and inhalation risk assessments ( 10x due to intraspecies variation and 10x due to interspecies extrapolation). Overall, available data indicate that ametryn is a relatively low toxicity compound. 3 Table 1. Endpoints Used for Ametryn Risk Assessment Dietary NOAEL mg/ kg/ day RfD mg/ kg/ day PAD mg/ kg/ day chronic  all populations 7.2 0.072 ( UF= 100; FQPA = 1) 0.072 Occupational/ Residential NOAEL mg/ kg/ day MOE dermal  short term and intermediate term 100 100 incidental oral  short term and intermediate term 10 100 inhalation  short term and intermediate term 10 100 dermal and inhalation  long term 7.2 100 Exposure Assessment Analysis of dietary, drinking water, cancer, and occupational exposure pathways were included in the ametryn risk assessment. Sources of dietary exposure include food from treated crops of corn, sugarcane, and pineapple. The anticipated dietary exposure to ametryn is expected to be low due to the long PHIs, the susceptibility of crops to damage from ametryn, and the limited number of crop uses. Drinking water exposure may occur due to run off from the agricultural uses of ametryn. Occupational exposure may occur through use of ametryn during mixing, loading, and application procedures. For the occupational exposures, short and intermediate term dermal and inhalation pathways were assessed based on label directed use patterns. Long term exposures to ametryn are not expected for the current registered uses. Residential exposures were not assessed as there were no residential uses.

Risk Assessment and Risk Characterization Risk assessments were conducted for dietary, drinking water, cancer, and occupational exposure pathways. An aggregate assessment of risk from the combined food and drinking water pathways was also conducted ( both cancer and non cancer). A cumulative risk assessment considering risks from other pesticides or chemical compounds having a common mechanism of toxicity has not been conducted for this RED. Although HED has determined that ametryn does not share a common mechanism of toxicity with chlorinated triazines ( atrazine, simazine, propazine, and their chlorinated metabolites), HED has not yet determined if there are any other chemical substances that have a mechanism of toxicity in common with that of ametryn.

Food Pathway Exposure and Risk HED conducted refined chronic and cancer dietary exposure analyses using the Dietary Exposure Evaluation Model with the Food Commodity Intake Database ( DEEM FCID   ) and the Lifeline model. The chronic dietary analyses were conducted for the general U. S. population and all population subgroups, while the cancer dietary analysis was conducted for the US population only. For the purpose of estimating dietary risk in this document and use in the aggregate risk assessments, the higher of the estimated exposure levels predicted by DEEMFCID   and Lifeline were selected for each population subgroup. 4 Chronic dietary risks are expressed as a percentage of the chronic Population Adjusted Dose ( cPAD). A dietary risk of 100% of the PAD is the level of exposure that should not be exceeded, ( i. e., estimated risk less than 100% of PAD is not of concern). The PAD is the chronic reference dose ( cRfD) modified by the special FQPA Safety Factor. The special FQPA safety factor for sensitivity in infants and children for the chronic dietary assessment is 1X. Based on these analyses, chronic dietary risk from existing and proposed uses of ametryn are below HED's level of concern for the general US population and all population subgroups. Chronic exposure estimates were < 100% of the cPAD, with the highest chronic exposure ( 0.000018 mg/ kg/ day) occurring in children 1 2 years old (< 0.1% cPAD).

For cancer exposures, HED is generally concerned when estimated cancer risks exceed one in one million ( i. e., the risk exceeds 1 x 10 6). The lifetime cancer risk calculated in Lifeline   for the US population is 2.7 x 10 8 and is therefore less than HED's level of concern.

Drinking Water Pathway Exposure and Risk The Environmental Fate and Effects Division ( EFED) performed a drinking water assessment for ametryn in surface water and ground water ( D307105, K. Costello, 16 NOV 2004). EFED used the PRZM EXAMS model for estimating the upper bound on the concentrations that could occur in surface water source drinking water, and SCIGROW2 ( Screening Concentration in Ground Water) to estimate the concentrations in ground water used for drinking water. The chronic and cancer estimated drinking water concentrations ( EDWCs) of ametryn in surface water are 92 and 73 ppb, respectively. The chronic and cancer groundwater EDWCs are 15.6 ppb.

Aggregate Exposures and Risks Since there is potential for concurrent exposure via food and water, the combined exposures are estimated for the aggregate assessment. To assess aggregate risk, drinking water levels of comparison ( DWLOCs) are compared with model based EDWCs determined by EFED. The DWLOC is the concentration of a chemical in drinking water that would be acceptable as an upper limit in light of total aggregate exposure to that chemical from food, water, and residential sources. Aggregate risk for ametryn exposure is calculated for chronic and cancer exposures. Chronic and cancer DWLOCs include aggregate exposure from food and drinking water only.

The ametryn chronic DWLOCs are > 720 ppb, based on the most highly exposed subgroup ( children 1 2 years old). EFED's model based estimates for chronic concentrations of ametryn in surface and ground water are 92 and 15.6 ppb, respectively. Since the model based estimates for concentrations in surface water and groundwater are below the calculated chronic DWLOCs, HED concludes that aggregate exposure to food and drinking water will not result in estimates that exceed HED's level of concern for chronic exposure scenarios.

The ametryn provisional cancer DWLOC for the general US population is 5.2 ppb. EFED's model based estimates for cancer comparisons of ametryn in surface and ground water are 73 and 15.6 ppb, respectively. In this case, since the EDWCs for ground and surface water exceed HED's provisional cancer DWLOC for the U. S. population, the cancer assessment fails this screening analysis and indicates a need for additional data in the form of a new rat cancer 5 study.

Occupational Pathway Exposure and Risk Based on product labeling and information provided for the completion of the RED process for this pesticide, HED has identified 14 occupational handler scenarios for which shortand intermediate term exposure to ametryn may occur. Exposure estimates were conducted using the maximum application rates for each of the crops. MOEs for 11 of the 14 handler scenarios are > 100 at either baseline or minimum PPE protection levels and are not of concern. The following scenario does not exceed an MOE of 100 at baseline or minimum PPE levels: Mixing/ loading liquids for aerial application to sugarcane at the application rate of 7.2 lbs ai/ acre, where the MOE = 79. The two other scenarios, aerial application of liquid sprays to sugarcane at 8.0 and 2.0 lbs ai/ acre, have indeterminable MOEs at these protection levels. All occupational exposure scenarios have MOEs which exceed 100 when engineering controls are added. 6 2.0 Ingredient Profile Ametryn ( 2 ethylamino) 4( isopropylamino) 6( methylthio) s triazine is a methylthiotriazine herbicide registered for the preemergent control of weeds in corn, pineapples, and sugarcane. Ametryn is registered in the U. S. to Syngenta Crop Protection, Inc. under the trade name EVIK ® and is formulated as an 80% water dispersible granule ( DF), which is typically applied as a broadcast preemergence and/ or a directed postemergence application using ground or aerial equipment.

2.1 Summary of Supported Uses Table 2.1. Overall Use Patterns for Ametryn1 Crop Max Single Rate ( Lbs/ ai/ A) Applications/ Yr Maximum Lbs / A/ Yr Lbs ai / year Percent Crop Treated Corn ( Field, Sweet, Pop) 2.0 1 2.0 200,000 < 2.5 Pineapple 7.2 NS 7.2 58,000 100 Sugarcane ( state dependent) 8.0 5 16.0 90,000 30 State Use Programs: FL 1.2 3 3.6 66,000 NA LA 2/ 2.4/ 2.4/ 2.4/ 2.4 5 11.6 824 0.1 TX 2/ 2/ 2 3 6.0 8,600 10 HI 7.2/ 2.4/ 2.4 3 12.0 58,000 90 PR 8/ 4/ 4 3 16.0 NA NA 1 Information taken from Ametryn Use Closure Memo, M. Howard, 27 FEB 2004. 7 N N N N H S C H 3 NH CH 3 CH 3 CH 3 2.2 Structure and Nomenclature Table 2.2. Chemical Structure and Nomenclature for Ametryn.

Chemical structure Common name Ametryn Molecular Formula C9H17N5S Molecular Weight 227.35 IUPAC name N2 ethyl N4 isopropyl 6 methylthio 1,3,5 triazine 2,4 diamine CAS name N ethyl N

 ( 1 methylethyl) 6( methylthio) 1,3,5 triazine 2,4 diamine CAS # 834 12 8 PC Code 080801 Food/ Feed Site Registration Corn, Pineapple, and Sugarcane 2.3 Physical and Chemical Properties Ametryn is a non volatile solid with moderate water solubility.

Table 2.3 Physicochemical Properties of Ametryn Parameter Value Reference Melting point 84.5 86  C MRID 40877301; Ametryn PC RED Chapter pH 8 9 at 20  C ( 1% solution in water)

Density, bulk density, or specific gravity 0.373 g/ mL at 20  C Water solubility 0.020 g/ 100 mL at 20  C Solvent solubility 56.9 g/ 100 mL in acetone 61.4 g/ 100/ mL in methylene chloride 51.6 g/ 100 mL in methanol 46.0 g/ 100 mL in toluene 24.2 g/ 100 mL in n octanol 1.4 g/ 100mL in n hexane Vapor pressure 2.74 x 10 6 mm Hg at 25  C Dissociation constant, pKa 4.02 at 20  C Octanol/ water partition coefficient KOW = 423 ( log P = 2.63)

UV/ visible absorption spectrum   max = 223 nm 8 3.0 Metabolism Assessment 3.1 Comparative Metabolic Profile Rat metabolism: Ametryn is readily absorbed by rats after a single or multiple oral doses of 0.5 or 200 mg/ kg. Ametryn is widely distributed, being found in all tissues and organs tested. It is metabolized to polar products, 13 of which were identified. Ametryn is excreted in urine ( 50 61%) within 48 hours, with the remainder in the feces ( 30 42%). No significant differences in pharmacokinetic parameters were seen among dosing groups ( singular oral, high or low, multiple low, single intravenous) or between sexes.

Plant metabolism: In general, ametryn is extensively metabolized in plants primarily by Ndealkylation and desulfation ( oxidation/ hydroxylation) to a variety of triazine ring containing metabolites, each accounting for < 10% of the TRR in edible plant parts. In corn stalks and foilage, metabolite GS 11354 was also found ( see Table 3.4).

Livestock metabolism: The metabolism of ametryn in livestock involves N dealkylation of the isopropyl and ethyl side chains, as well as modification at the 6 position, followed by conjugation, possibly to proteins, with the triazine ring structure remaining intact. Metabolites found in excess of 10% TRR include GS 11354, GS 11355, and GS 26831 ( see Table 3.4).

Water degradates: Since ametryn is persistent, degradates were not observed at high concentrations in laboratory tests. Only one degradate was observed at greater than 10% of applied parent ( GS 11355 in the aerobic soil metabolism study). Nonetheless, since degradates GS 11354 and GS 11355 are significantly similar in structure to parent ametryn, they were included in the drinking water exposure assessment as possible degradates of concern.

Qualitatively, the metabolism of ametryn is similar across the various matrices studied. The major metabolites and degradates found in the plant, livestock and water studies were also found in the rat metabolism study.

3.2 Nature of the Residue in Foods 3.2.1. Description of Primary Crop Metabolism The qualitative nature of ametryn residues in corn, pineapple, and sugarcane is understood based on the adequate corn, sugarcane, and banana metabolism studies.

In the corn metabolism study, [ U 14C triazine] ametryn was applied postemergence as a basal/ soil directed spray to greenhouse grown corn at 4 lb ai/ A ( 2x the maximum label rate) when plants were 12 18 inches in height. Total radioactive residues ( TRR) were 2.47 ppm in forage at 56 days after treatment ( DAT), and 4.56 ppm in fodder and 0.16 ppm in grain at maturity ( 111 DAT). Organosoluble 14C residues in immature forage declined from 100% of the TRR on the day of application to 11% of the TRR in mature fodder. Radioactive residues in immature forage were not further analyzed. At maturity, organosoluble residues in fodder consisted primarily of ametryn ( 1.8% TRR) and GS 11354 ( 0.2% TRR). In mature tissues, the majority of 14C residues consisted of aqueous soluble ( 45 58% TRR) and insoluble ( 31 57% TRR) residues. Cation 9 exchange chromatography separated aqueous soluble 14C residues from mature tissues into numerous distinct components most of which accounted for < 10% of the TRR. The cation exchange elution profiles were qualitatively similar for 14C residues from stalks, cobs, and grain. Aqueous soluble 14C residues ( 60.5% TRR) in stalks with foliage were separated by cation exchange chromatography into 14 distinct components, with each one accounting for 0.7 12.7% of the TRR. Insoluble 14C residues in stalks/ foliage were solubilized by refluxing in aqueous MeOH and by enzymatic and acid hydrolyses, and were polar in nature.

In the sugarcane metabolism study, [ U 14C triazine] ametryn was applied to greenhousegrown sugarcane as a preemergence application at 8 lb ai/ A and again as soil/ basal directed sprays at 4 lb ai/ A/ application at 29 and 50 days after planting, for a total of 16 lb ai/ A ( 1x maximum use rate). TRR in forage were 0.12 and 1.57 ppm in forage collected 29 and 50 days after the first application. In separated stalks and foliage, TRR were 0.40 and 2.17 ppm, respectively, at 84 DAT and 0.42 and 3.06 ppm at 202 DAT. Organosoluble 14C residues in immature sugarcane declined from 55.2% of the TRR on Day 29 to 28 32% of the TRR in Day 84 stalks and foliage and 3.4 7.2% of the TRR in mature ( Day 202) stalks and foliage. Organosoluble residues were not further analyzed. Cation exchange chromatography separated aqueous soluble 14C residues from mature tissues into 14 distinct components. Each of these fractions accounted for < 10% of the TRR, with the exception of one fraction ( 12.6% TRR) in foliage. Insoluble 14C residues from mature tissues were released by refluxing in aqueous MeOH and by enzymatic and acid hydrolyses.

In the banana metabolism study, [ U 14C triazine] ametryn was applied three times as a directed soil application to greenhouse grown banana plants at 112 120 days retreatment intervals, beginning when plants were 3.5 feet in height. TRR were 0.579 in immature leaves collected 31 days after the second application and 1.59 ppm in mature leaves collected at fruit maturity, 69 days after the second application. TRR in mature fruit ( 0.087 ppm) were substantially lower than in leaves and were equally distributed between the peel ( 0.098 ppm) and pulp ( 0.076 ppm). Methanolic extraction of leaf and fruit samples released 61.4 90.9% of the TRR, and subsequent analyses of organic and aqueous soluble 14C residues identified 40.6 61.6% of the TRR in leaves and 58.7 75.6% of the TRR in whole fruit, peel and pulp samples. Including ametryn, a total of 10 triazine ring containing compounds were identified in leaves and fruit.

In general, ametryn is extensively metabolized in plants primarily by N dealkylation and desulfation ( oxidation/ hydroxylation) to a variety of triazine ring containing metabolites, each accounting for < 10% of the TRR in edible plant parts. Therefore, ametryn per se is recommended for inclusion in the risk assessment and for the tolerance expression.

3.2.2 Description of Livestock Metabolism The qualitative nature of ametryn residues in poultry and ruminants is understood based on the adequate goat and hen metabolism studies.

The ametryn risk assessment team has determined that, if new ametryn uses are added so that tolerances are needed for livestock commodities, the regulated residues in livestock commodities should include parent and its three thiomethyl metabolites ( GS 11354, GS 11355, and GS 26831) for the purpose of tolerance enforcement and risk assessment. The basis for this 10 decision is as follows:

° Metabolism studies in goats and hens demonstrate that ametryn and the thiomethyl metabolites comprise > 10% TRR in several edible livestock matrices. ° An adequate data collection method is available ( Method AG 649) for determination of ametryn and its three thiomethyl metabolites. If necessary, this method could be validated for tolerance enforcement purposes.

In the goat metabolism study, two goats were dosed orally for 3 days with [ U 14C triazine] ametryn at a level equivalent to 50 ppm in the diet, which is 280x the maximum theoretical dietary burden ( MTDB) for dairy cattle. Maximum 14C residues were attained in milk on Day 2 at 0.686 or 1.277 ppm. At sacrifice, TRR were 2.71 2.89 ppm in liver, 3.0 3.05 ppm in kidney, 0.092 0.137 ppm in muscle, and 0.084 0.088 ppm in fat. Solvent extraction released 84% of the TRR from fat, 42 53% of the TRR from milk, muscle, and kidney, and 29% of the TRR from liver. Subsequent acid hydrolyses released the remaining radioactivity from each matrix, and HPLC and TLC analyses identified > 80% of the TRR in each matrix.

The principal organosoluble residues in goats milk and tissues were ametryn, GS 11354, and GS 26831. Ametryn accounted for 40% of the TRR in fat, 9.7% TRR in muscle, and 0.2 2.3% TRR in liver, kidney, and milk, and GS 11354 accounted for 20.8% TRR in fat, 11.5% TRR in muscle, and 1.9 2.4% TRR in liver, kidney, and milk. Metabolite GS 26831 accounted for 13.5% TRR in muscle, 7.0 9.6% TRR in milk and kidney, and 3.3 4.7% TRR in liver and fat. The organosoluble metabolite GS 11355 was also identified in milk and all tissues at 0.9 4.6% of the TRR. The combined residues of ametryn its three thiomethyl metabolites ( GS 11354, GS 11355, and GS 26831) accounted for 16.4% TRR in milk, 9.1% TRR in liver, 12.5% TRR in kidney, 37.1% TRR in muscle, and 71.2% TRR in fat; actual levels of these combined residues ranged from 0.03 ppm in muscle to 0.37 ppm in kidney. Other minor solvent extracted metabolites containing the triazine ring were detected in various tissues or milk at 0.3 9.8% TRR.

In the poultry metabolism study, 10 hens were dosed orally for 3 days with [ U 14Ctriazine ametryn at levels equivalent to 50 ppm in the diet ( 1,250x MTDB). Maximum 14C residues in eggs were attained on Day 3 at 0.099 ppm in egg whites and 0.268 ppm in egg yolks. At sacrifice, TRR were 4.98 ppm in liver, 0.379 0.558 in muscle, 0.618 ppm in skin, and 0.240 ppm in fat. Solvent extraction released 72 and 58% of the TRR from egg whites and fat, respectively, and 16 25% of the TRR from the remaining matrices. Subsequent protease and acid hydrolyses released essentially all of the remaining radioactivity from each matrix.

The principal organosoluble residues in poultry were ametryn, accounting for 40% of the TRR in fat and 0.3 2.7% of the TRR in skin, yolks, and muscle, and GS 26831, accounting for 52% TRR in egg whites, 10.4% TRR in yolks, 5.7 8.7% TRR in muscle, and 1.2 1.6% TRR in fat and liver. Other minor organosoluble residues in eggs and tissues were detected at 0.1 5.2% TRR. The combined residues of ametryn its three thiomethyl metabolites ( GS 11354, GS 11355, and GS 26831) accounted for 63.7% TRR in egg white, 14.3% TRR in yolks, 14 24% TRR in muscle, 51.7% TRR in fat, and 7.4% TRR in liver; actual levels of the combined residues ranged 11 from 0.03 ppm in yolks to 0.42 ppm in liver.

The metabolism of ametryn in livestock involves N dealkylation of the isopropyl and ethyl side chains, as well as modification at the 6 position, followed by conjugation, possibly to proteins, with the triazine ring structure remaining intact. Based on the metabolic profile and metabolism study results, the ametryn risk assessment team has classified ametryn residues under 40 CFR § 180.6( a)( 3), " no reasonable expectation of finite residues for meat, milk, poultry, and eggs."

3.2.3 Description of Rotational Crop Metabolism, including identification of major metabolites and specific routes of biotransformation The results of the confined rotational crop study were similar to the metabolism of ametryn in primary crops. Ametryn is metabolized in soil and plants by N dealkylation and desulfation ( oxidation/ hydroxylation) to a variety of metabolites containing a hydroxylated triazine ring.

3.3 Environmental Degradation Ametryn is a moderately persistent herbicide. A single aerobic soil metabolism study suggests that this is an important route of dissipation in the environment, with an observed halflife of 84 days. Ametryn is stable to hydrolysis, and degrades slowly by aquatic photolysis ( 368 days).

Since ametryn is persistent, degradates were not observed at high concentrations in laboratory tests. Only one degradate was observed at greater than 10% of applied parent ( GS 11355 in the aerobic soil metabolism study). Nonetheless, since degradates 2 amino 4 isopropylamino 6 methylthio s triazine ( GS 11354) and 2 ethylamino 4 amino 6 methylthio striazine ( GS 11355) are significantly similar in structure to parent ametryn, they were included in the drinking water exposure assessment as possible degradates of concern.

Ametryn was observed to be highly mobile in 3 of 4 soils in laboratory tests ( Kd = 1.07 to 1.21 in loam, sandy loam and sand soils, 26.2 in a clay soil). Given its persistence and mobility, transport of ametryn to ground water and surface water is expected from normal agricultural use. Monitoring of ametryn concentrations in ground water and surface water is limited, however. Ametryn was not included among analytes in the NAWQA program, for instance. Monitoring in Hawaii of ground water in pineapple use areas in the mid 1990' s resulted in a maximum concentration similar in magnitude to that predicted with the ground water screening model SCIGROW ( Screening Concentration in Ground Water). Quarterly surface water monitoring on the borders of the Everglades Agricultural Area ( EAA) has resulted in surface water concentrations well below those estimated for maximum application rates by the PRZM/ EXAMS models, resulting in greater uncertainty in these estimates. 12 3.4 Tabular Summary of Metabolites and Degradates Chemical Name ( Code) Chemical Structure Matrices/ MRIDs Ametryn 2 ethylamino 4 isopropylamino 6 methylthio s triazine ( G 34162; CG 1) Corn stalks/ foliage 41662302 Goat 41662305 ( milk, liver, muscle, kidney, fat)

Water Putative: Hen 41662303 ( eggs, muscle, skin, fat)

N De ethyl ametryn 2 amino 4 isopropylamino 6 methylthio s triazine ( GS 11354; CG 3) Corn stalks/ foliage 41662302 Goat 41662305 ( milk, liver, muscle, kidney, fat)

Water Putative: Hen 41662303 ( eggs, muscle, skin, fat)

N De propyl ametryn 2 ethylamino 4 amino 6 methylthio s triazine ( GS 11355; CG 4) Goat 41662305 ( milk, liver, muscle, kidney, fat)

Water Putative: Hen 41662303 ( eggs, muscle, liver, skin, fat)

2,4 diamino 6 methylthio striazine ( GS 26831; CG 2) Goat 41662305 ( milk, liver, muscle, kidney, fat)

Putative: Hen 41662303 ( eggs, muscle, liver, skin, fat)

3.5 Toxicity Profile of Major Metabolites and Degradates Toxicity data are not available on the metabolites and degradates of ametryn. In the absence of toxicity data, metabolites are assumed to have the same toxicity as parent ametryn. Accordingly, decisions to regulate metabolites/ degradates were based on the abundance of the 13 compounds found in the various matrices studied and the availability of analytical methods to detect these compounds.

3.6 Summary of Residues for Tolerance Expression and Risk Assessment 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 ametryn per se ametryn per se Rotational Crop ametryn per se ametryn per se Livestock Ruminant Not Applicable  no residues expected Not Applicable  no tolerances required Poultry Not Applicable  no residues expected Not Applicable  no tolerances required Drinking Water ametryn, GS 11354, GS 11354 Not Applicable 3.6.2 Rationale for Inclusion of Metabolites and Degradates The ametryn risk assessment team has determined that the regulated residues in corn, sugarcane, and pineapple will include parent only for the purpose of tolerance enforcement and risk assessment. The basis for this decision is as follows:

° Residue levels of ametryn and its three thiomethyl metabolites are very low in the edible parts of crops that will be treated with ametryn. In corn grain, residue levels of ametryn and its three thiomethyl metabolites were each < 0.02 ppm ( LOQ) in 29 field trials conducted at 1x, 9 trials at 2x, 4 trials at 3x, and 4 trials at 5x. In pineapple, residue levels of the three thiomethyl metabolites were each < 0.02 ppm ( LOQ) in 8 field trials conducted at 1x, 3 trials at 2x, and 2 trials at 3x. Ametryn residue levels were 0.05 ppm in the same trials. In sugarcane, residue levels of ametryn and its three thiomethyl metabolites were each < 0.02 ppm ( LOQ) in 17 field trials conducted at a nominal rate of 1x. ° Corn, sugarcane, and banana metabolism studies show that the thiomethyl metabolites each comprise < 10% TRR in the edible parts of the crops studied. ° The toxicological database does not indicate a special concern regarding the toxicity of 14 three thiomethyl metabolites.

Because there is no reasonable expectation of quantifiable residues of ametryn occurring in livestock commodities [ 40 CFR § 180.6( a)( 3)], no tolerances are appropriate for livestock commodities. In the case of drinking water, the levels of two of the three thiomethyl metabolites ( GS 11354 and GS 11355) were found to be present in sufficient abundance in some studies to warrant inclusion as residues of concern in the risk assessment.

4.0 Hazard Characterization/ Assessment 4.1 Hazard Characterization Acute toxicity. Ametryn is of low acute toxicity with the acute oral and dermal being Toxicity Category III and the acute inhalation toxicity being Category IV. Ametryn is also nonirritating to the eye ( Category III) or skin ( Category IV) and did not demonstrate sensitization.

Subchronic Dermal and Inhalation Toxicity. In a 21 day dermal toxicity study the only effects noted were decreased body weight and food consumption. There is no subchronic inhalation toxicity study.

Subchronic and Chronic Oral Toxicity. The liver is the most sensitive target organ for ametryn and the dog was demonstrated to be the most sensitive species for signs of degeneration. Body weight and gain were affected at higher doses. In rats, body weight effects are the most pronounced effect but at higher doses resulted in some evidence of histological changes in the testes, kidney and pituitary in males and in the liver and mammary gland in females.

Carcinogenicity Evaluation. There were no indications of increased neoplasms in mice. The rat study demonstrated increases in testicular, thyroid and epididymis in males and liver and mammary gland in females neoplasms. However, there were no statistically significant pair wise comparisons for the testicular, epididymal or liver tumors. Also, in rats these increases occurred at dose levels where there was an initial large decrease in body weight gain and decreased body weight was sustained throughout the study rendering the significance of these increased incidents of neoplasms not interpretable. A second study in rats is being requested to further characterize the potential for ametryn to induce neoplasms in rats.

Developmental Toxicity. Neither the rat or rabbit developmental toxicity studies demonstrated effects on the fetuses at the highest doses tested and at dose levels showing maternal toxicity.

Reproductive Toxicity. Reproductive performance of neither the males or the females was affected by ametryn. Systemic toxicity to the parental groups consisted of decreased body weight and gain and decreased feed efficiency. Offspring toxicity was indicated by decreased pup weight and weight gains during lactation. These results indicate no increased sensitivity or susceptibility 15 in pups.

Mutagenicity. There is no mutagenicity concern for ametryn and the existing mutagenicity data base does not indicate positive effects.

Immunotoxicity and Neurotoxicity. Although there were no special studies on immunotoxicity or direct neurotoxicity, there were no indications of immunotoxicity or direct neurotoxicity in the studies with rats, dogs, mice or rabbits.

Metabolism. Ametryn is readily absorbed by rats after a single or multiple oral doses of 0.5 or 200 mg/ kg. It is widely distributed, being found in all tissues and organs tested although in low levels. It is metabolized to several polar products, 13 of which were identified. It is excreted mainly through the urine ( 50 61%) within 48 hours with the feces being the other major route ( 30 42%). No significant differences in pharmacokinetic parameters were seen among dosing groups ( singular oral high and low, multiple low) or between sexes.

Table 4.1a Acute Toxicity Profile  Ametryn ( PC Code 080801)

Guideline Study Type MRID( s) Results Tox Cat 870.1100 Acute oral rat 40995814 ( 1988) LD50 = 1356 ( 1164 1581mg/ kg

" = 1009 ( 829 1229) mg/ kg  III 870.1200 Acute dermal rabbit 40995815 ( 1988) LD50 > 2020 mg/ kg III 870.1300 Acute inhalation rat 42470902 ( 1991) LC50 > 5.03 mg/ L IV 870.2400 Acute eye irritation rabbit 40995817 ( 1988) No corneal involvement, mild conjunctiva irritation ( redness, chemosis and discharge) reversed by 72 hours in washed eyes. III 870.2500 Acute dermal irritation rabbit 40995818 ( 1988) Essentially non irritating. IV 870.2600 Skin sensitization  guinea pig 40995819 ( 1988) Not a sensitizer [ ]

All studies classified as " ACCEPTABLE" 16 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  rat Old study . Refer to chronic dosing.

870.3150 90 Day oral toxicity  dog Old study. Refer to chronic dosing.

870.3200 21 Day dermal toxicity  rabbit 41067902 ( 1989), Acceptable/ Non Guideline 0, 10, 100 or 1000 mg/ kg/ day NOAEL = 100 mg/ kg/ day LOAEL = 1000 mg/ kg/ day based primarily on body weight gain effects and decreased food consumption.

Note: Study is non guideline because on 5/ sex/ dose group were used.

870.3250 90 Day dermal toxicity ( species) No study.

870.3465 90 Day inhalation toxicity ( species) No study.

870.3700a Prenatal developmental in rats. 00153215 ( 1985) Acceptable/ Guideline 0, 5, 50 or 250 mg/ kg/ day Maternal NOAEL = 5 mg/ kg/ day LOAEL = 50 mg/ kg/ day based on ptosis and salivation. Developmental NOAEL and LOAEL > 250 mg/ kg/ day. No effects at highest dose tested.

870.3700b Prenatal developmental in rabbits 00153214 ( 1985) Acceptable/ Guideline 0, 1, 10 or 60 mg/ kg/ day Maternal NOAEL = 10 mg/ kg/ day LOAEL = 60 mg/ kg/ day based on body weight loss, deceased feed consumption and increased liver weight. Developmental NOAEL and LOAEL > 60 mg/ kg/ day. No effects at highest dose tested.

870.3800 Reproduction and fertility effects ( species) 40349905 ( 1987) Acceptable/ Guideline 0, 1.3, 13 or 131 mg/ kg/ day in males ( approximately)*. 0, 1.2, 12 or 117 mg/ kg/ day in females ( approximately). * based on the mean for both generations. ** based on the lowest set for premating and gestation for both generations. Parental/ Systemic NOAEL = 13 mg/ kg/ day LOAEL = 131 mg/ kg/ day based on decreased body weight and weight gain and decreased feed efficiency. Reproductive NOAEL and LOAEL > 131 mg/ kg/ day. No effects at highest dose tested. Offspring NOAEL = 13 mg/ kg/ day LOAEL = 131 mg/ kg/ day based on decreased pup weights and weight gain in the F2 generation. Table 4.1b Subchronic, Chronic and Other Toxicity Profile Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 17 870.4100a Chronic toxicity Refer to 870.4200 combined chronic feeding/ carcinogenicity study in rats below.

870.4100b Chronic toxicity ( dog) 40349902 ( 1987) Acceptable/ Guideline 0, 0.71, 7.2, 70, 103 and 83 mg/ kg/ day in males and 0, 0.84, 8.1, 74, 112 and 92 mg/ kg/ day in females. NOAEL = 7.2 mg/ kg/ day LOAEL = 70 mg/ kg/ day based on degenerative liver lesions.

870.4200. Chronic Feeding/ Carcinogenicity ( rat) 40349906 ( 1987), 41184201 ( 1987) and 403 82001 ( 1987) Acceptable/ Guideline 0, 2, 21 or 145 mg/ kg/ day for males and 0, 2.5, 26 or 176 mg/ kg/ day for females. NOAEL = 21 mg/ kg/ day LOAEL = 145 mg/ kg/ day based on body weight and gain effects and histological changes in the testes, kidney and pituitary in males and in the liver and pancreas in females.

The CARC ( refer to CARC report dated 9/ 17/ 04 in TXR # 0052862) determined that the data in the high dose group are not interpretable because of weight decreases and also the mid dose group, although showing about 4 to 7% weight decrease, was not considered high enough to meet criteria for adequate dosing. An additional carcinogenicity evaluation in rats was requested by the CARC.

870.4300 Carcinogenicity ( mouse) 40349904 ( 1981) " CORE MINIMUM" 0, 1.5, 150 or 300 mg/ kg/ day. NOAEL and LOAEL > 300 mg/ kg/ day. No effects at highest dose tested. No evidence of carcinogenicity.

Note: Marked decreases in body weight at 3000 ppm justify selection of 2000 ppm as an acceptable dose.

Gene Mutation 870.5100. Ames test, bacterial mutation. 40995829 and 41189701 ( 1984) Acceptable/ Guideline 0, 20, 80, 320, 1280 or 5120  g/ mL. No evidence of mutagenicity in Salmonella strains TA98, TA 100, TA 1535 and TA 1537 up to levels causing cytotoxicity.

Cytogenetics 870.5395. Mouse micronucleus test. 41067903 ( 1989) Acceptable/ Guideline 1. 800 mg/ kg, harvest at 16, 24, and 48 hours. 2. 200, 400 or 800 mg/ kg: harvest at 24 hours. Negative for increased MPCEs up to clinical toxicity ( death). Table 4.1b Subchronic, Chronic and Other Toxicity Profile Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 18 Other Effects 870.5550. Unscheduled DNA synthesis in rat hepatocytes. 41067904 ( 1989) Acceptable/ Guideline. 1. 0.1 to 100  g/ mL 2. 0.137 to 33.3  g/ mL Negative for increases UDS up to cytotoxicity.

870.6200a Acute neurotoxicity screening battery No study.

870.6200b Subchronic neurotoxicity screening battery No study.

870.6300 Developmental neurotoxicity No study.

870.7485 Metabolism and pharmacokinetics ( species) 41463301, 41463302, 41463303 ( all 1990) Acceptable. Ametryn is readily absorbed by rats after a single or multiple oral doses of 0.5 or 200 mg/ kg. It is widely distributed, being found in all tissues and organs tested although in low levels. It is metabolized to several polar products, 13 of which were identified. It is excreted mainly through the urine ( 50 61%) within 48 hours with the feces being the other major route ( 30 42%). No significant differences in pharmacokinetic parameters were seen among dosing groups ( singular oral high and low, multiple low) or between sexes.

870.7600 Dermal penetration ( species) No study.

Special studies No studies. 19 4.2 FQPA Hazard Considerations 4.2.1 Adequacy of the Toxicity Data Base The toxicology database for ametryn is complete for FQPA assessment.

4.2.2 Evidence of Neurotoxicity There is not a concern for neurotoxicity resulting from exposure to ametryn based on lack of evidence of neurotoxicity from the available studies.

4.2.3 Developmental Toxicity Studies a. Rat study.

Executive Summary: In a developmental toxicity study ( 1985, MRID 00153215 and 92002024), Ametryn Technical ( batch/ lot # FL 840991, purity 96.8%) was administered to 24 female Charles River rats/ dose by gavage at dose levels of 0, 5, 50, or 250 mg/ kg bw/ day from days 6 through 15 of gestation. On gestation day ( GD) 20, dams were sacrificed, subjected to gross necropsy, and all fetuses were examined externally. The total numbers of fetuses examined ( number of litters) was 281( 20), 271( 22), 325( 23), and 305( 22) for the 0, 5, 50, and 250 mg/ kg bw/ day groups, respectively. Approximately one third of the fetuses were examined viscerally, and the other twothirds of the fetuses were examined for skeletal malformations/ variations. Maternal toxicity. Dams treated with 50 mg/ kg bw/ day had statistically increased ( p

0.05) incidences of ptosis ( 3/ 24 affected) and salivation ( 3/ 24, compared with 0/ 24 for both signs in controls). Treatment with 250 mg/ kg bw/ day resulted in maternal toxicity as evidenced by mortality ( 2/ 24); statistically increased ( p

0.01) incidences of ptosis ( 19/ 24), salivation ( 24/ 24), and hypoactivity ( 8/ 24); and decreased feed consumption (  12 to 32%, starting on GD 6 and continuing through GD 15, p

0.05; 0.01) accompanied by decreased maternal body weight (  5 to 9%, p

0.05; 0.01, starting on GD 8 and continuing to study termination). Body weight gain was statistically decreased at all measured dosing intervals (  26 to 32%, p

0.05; 0.01), with the corrected ( final body weight minus uterine weight) body weight gain for GD 0 20 being decreased by 28% ( p

0.01). The maternal toxicity LOAEL = 50 mg/ kg/ day based on clinical signs of toxicity ( ptosis and salivation). The maternal toxicity NOAEL is 5 mg/ kg bw/ day. Developmental Toxicity. No treatment related, statistically significant effects on pregnancy rate, number of corpora lutea, pre or postimplantation losses, resorptions/ dam, fetuses/ litter, fetal body weight, or fetal sex ratio were noted No dams had complete litter resorptions. No treatment related external, visceral, or skeletal malformations/ variations were observed. The fetal incidence of unossified metacarpals was apparently increased in the mid and high dose group but other structures did not have this condition and it was not considered a definite developmental effect but possible related to the weight effect in the dams. The developmental toxicity NOAEL is

250 mg/ kg bw/ day. The developmental toxicity LOAEL could not be established. This study is classified Acceptable/ Guideline and satisfies the guideline requirement for a developmental toxicity study ( OPPTS 870.3700; OECD 414) in the rat.

b. Rabbit study.

Executive Summary: In a developmental toxicity study ( 1985, MRID 00153214 and 92002025), Ametryn Technical ( 96.8% a. i.; batch/ lot # FL 840991) was administered by gavage to 19 female New Zealand White rabbits/ group at dose levels of 0, 1, 10, or 60 mg/ kg bw/ day from days 7 through 19 of gestation. On gestation day ( GD) 29, does were sacrificed, subjected to gross necropsy, and all fetuses examined for external, visceral, and 20 skeletal abnormalities. The total numbers of fetuses examined ( number of litters) were 145( 16), 121( 14), 142( 16), and 100( 13) for the 0, 1, 10, and 60 mg/ kg bw/ day groups, respectively. Maternal Toxicity. Treatment with 60 mg/ kg bw/ day of Ametryn Technical resulted in maternal toxicity as evidenced by reduced body weight gain, decreased feed consumption, and increased liver weights. The high dose group had reduced body weight gain manifested as a weight loss over GDs 7 10 ( 7 g loss vs. 37 g gain for controls; p

0.05), 10 14 ( 2 g. loss vs. 54 g; gain, n. s.), and 14 20 ( 4 g loss vs. 148 g gain; p

0.05). The loss in body weight was accompanied by decreased daily feed consumption starting on GD 7, with the decreases attaining statistical significance on all days between GDs 13 19 (  31 to 41%; p

0.05; 0.01). Feed consumption then slowly increased starting on GD 20, with the increases attaining statistical significance on GDs 24 28 (  43 104%; p

0.05; 0.01), accompanied by statistically increased body weight gain over GDs 24 29 ( 151 g gain vs. 28 g gain for controls; p

0.01). Treatment with 60 mg/ kg bw/ day also resulted in statistically increased mean absolute liver weight (  18%; p

0.01) and liver weight as a percentage of final body weight corrected for uterine weight (  16%; p

0.05). Th maternal toxicity LOAEL is 60 mg/ kg bw/ day based on maternal body weight loss, decreased feed consumption, and increased liver weights. The maternal toxicity NOAEL is 10 mg/ kg bw/ day. Developmental toxicity. No treatment related, statistically significant effects on pregnancy rates, number of corpora lutea, pre or postimplantation losses, resorptions/ dam, fetuses/ litter, fetal body weights, or fetal sex ratios were observed. No treatment related external, visceral, or skeletal malformations/ variations were observed in any group. The developmental toxicity NOAEL is

250 mg/ kg bw/ day. The developmental toxicity LOAEL could not be established. This developmental toxicity study in the rabbit is classified Acceptable/ Guideline and satisfies the guideline requirement for a developmental toxicity study ( OPPTS 870.3700b; OECD 414) in the rabbit.

4.2.4 Reproductive Toxicity Study Executive Summary: In a two generation reproduction study ( 1987, MRID 40349905), ametryn technical ( 96.8% a. i., Batch No. FL 840991) was administered in the feed to groups of 30/ sex Charles River ( CRCD) VAF/ PLUS rats at concentrations of 0, 20, 200, or 2000 ppm. The dietary levels corresponded with doses of 0, 1.4, 14, 132 mg/ kg/ day, respectively, for F0 males; 0, 1.3, 13, and 131 mg/ kg/ day, respectively, for F1 males; 0, 1.5, 26, 134 mg/ kg/ day, respectively, for F0 females; and 0, 1.4, 14, and 138 mg/ kg/ day, respectively, for F1 females. The premating period was 70 days for the F0 generation and 84 days for the F1 generation. Both males and females received the test material during the premating, mating, gestation, and lactation periods. Parental Systemic Toxicity. No treatment related deaths or clinical signs were observed in adult rats of either generation. High dose F0 and F1 males and females had significantly ( p

0.05) reduced body weight throughout the study. High dose F0 males weighed 9 20% less than controls and high dose F1 males weighed 24 31% less than controls and both generations gained 30% and 21% less weight, respectively, over the entire study. High dose F0 females weighed 5 12% less during premating and high dose F1 females weighed 14 17% during premating and both generations gained 24% and 10% less weight, respectively, than controls over the premating period. Mid dose F1 males also showed slightly lower ( 5 6% body weight) differences during the premating period.

High dose F0 and F1 males consumed 14 20% and 20 24% less food, respectively, than controls for each weekly interval during the study and consumed 17% and 22% less, respectively, for the entire study. High dose F0 and F1 females consumed 7 13% and 12 17% less food, respectively, than controls for each weekly interval during premating and 8% and 16% less food, during the entire premating period. The food efficiency values for high dose F0 male and female rats were reduced by 14% and 18%, respectively, compared with controls during the premating period; the food efficiency values for high dose F1 male and female rats slightly exceeded those of controls. 21 Therefore, reduced weight gain for F0 rats was not due entirely to reduced food consumption but to toxicity of the test material. The significantly lower body weights for high dose females during the premating period continued through gestation and lactation. High dose F0 and F1 females weighed 11 12% and 16 18% less, respectively, than controls during gestation and gained 11% and 16% less weight, respectively. During lactation, they weighed 9 13% and 14 23% less, respectively, and gained markedly more weight than the controls. Food consumption was reduced during gestation, but was not measured during lactation. The systemic LOAEL is 2000 ppm ( 131 mg/ kg/ day for males and 134  138 mg/ kg/ day for females) based on decreased body weight and weight gain in both generations. The NOAEL is 200 ppm ( 14 mg/ kg/ day for males and 14 26 mg/ kg/ day for females). Reproductive Toxicity. Mating, fertility, and gestation indices, gestation interval, and the number of viable litters born were not affected by treatment with the test material for either the Fo or F1 parental generations. The absolute weight of the testes and ovaries were similar to those of controls at all dose levels. The significantly increased relative testes weight was due to the decreased terminal body weight. No treatment related lesions were observed during macroscopic or microscopic examination of the reproductive organs. The reproductive LOAEL could not be established and the reproductive NOAEL is

2000 ppm ( 131 mg/ kg/ day for males and 134 138 mg/ kg/ day for females). Offspring Toxicity. Litter size and viability of pups during lactation were not affected by treatment with the test material. High dose F1 and F2 male and female pups weighed significantly less than controls throughout lactation. In particular, the high dose F1 pups weighed 7 10% less from PND 0 7 and 15 19% less from PND 14 21, and the high dose F2 pups weighed 12 17% less from PND 0 7 and 10 21% less from PND 14 21. High dose male and female F1 and F2 pups gained 13 25%, 7 12% ( except for F2 females), 7 19%, and 19 39% less weight during PND 0 4, 4 7, 7 14, and 14 21, respectively. There appeared to be a transient weight effect in the mid dose F2 male and female pups since they weighed 9% less than controls on PND 4 and gained 16 18% less weight from PND 0 4 and 14 17% less from PND 14 21. However, the apparent transient weight affect was considered to be related to there being more pups/ litter in the mid dose group than in the control group rather than a definite response to treatment. No treatment related gross lesions were observed in either sex or generation. The LOAEL for offspring is 2000 ppm ( 131 mg/ kg/ day for males and 134 38 mg/ kg/ day for females) based on decreased pup weights and weight gain in both the F1 and F2 generations. The NOAEL is 200 ppm ( 13 mg/ kg/ day for males and 14 26 mg/ kg/ day for females). This two generation study in rats is Acceptable/ Guideline and satisfies the guideline requirement for a 2 generation reproductive toxicity study [( OPPTS 870.3800); OECD 416] in rats. The mid dose female group mistakenly received the high dose diet and the high dose group mistakenly received the mid dose diet during one 7 day interval. The overall mean dose for mid dose F0 females was almost twice that of the F1 females.

4.2.5 Additional Information from Literature Sources No relevant studies on ametryn to indicate a concern for developmental toxicity were available from the open literature.

4.2.6 Pre and/ or Postnatal Toxicity There is not a concern for pre and/ or postnatal toxicity resulting from exposure to ametryn.

<IP_ADDRESS> Determination of Susceptibility There was no quantitative or qualitative evidence of increased susceptibility following in utero exposure of ametryn to rats and rabbits. The offspring in the rat reproduction study demonstrated NOAELs and 22 LOAELs at the same dose levels as the adults. The possibility that the pups in the low dose group in the second generation in the reproduction study had an initial lower body weight than controls was considered but this lower body weight could not be definitely associated with treatment because the low and mid dose groups had a higher mean number of pups per litter than the controls, and the pups regained weight after culling and no similar effect was noted in the first generation.

<IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Post natal Susceptibility There is no concern for increased susceptibility based on the animal studies.

4.3 Recommendation for a Developmental Neurotoxicity Study There is not a concern for developmental neurotoxicity resulting from exposure to ametryn; thus, a developmental neurotoxicity study is not required.

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 There was no evidence of neurotoxicity or neuropathology due to ametryn in any of the available toxicity studies. Ametryn does not belong to a class of chemicals known to induce neurotoxicity.

4.4 Hazard Identification and Toxicity Endpoint Selection 4.4.1 Acute Reference Dose ( aRfD)  Females age 13 49 No appropriate endpoint for females age 13  49 attributable to a single exposure was available from oral studies including the developmental toxicity studies.

4.4.2 Acute Reference Dose ( aRfD)  General Population No appropriate endpoint for the general population attributable to a single exposure was available from oral studies including the developmental toxicity studies.

4.4.3 Chronic Reference Dose ( cRfD) Study Selected: Dog chronic dosing study ( 1987, MRID: 40349902)  dogs.

Executive Summary: In a 52 week oral toxicity study ( 1987, MRID 40349902), Ametryn ( 96.8% purity, batch # FL 840012 and FL 840991) was administered to 6 8 dogs/ sex/ dose in the diet at concentrations of 0, 20, 200, 2000, 4000

2500 or 8000

6000

3000 ppm ( equivalent to 0, 0.71, 7.2, 70., 103, and 83 mg/ kg bw/ day in males and 0, 0.84, 8.1, 74, 112 and 92 mg/ kg bw/ day in females). The initial doses in ths high dose groups were adjusted downward at week 29 for and weeks 4 and 8 respectively, due to reduced body weight gains. One male and one female in the 2500 group and three males in the 3000 ppm group were found dead during the study due to poor physical condition secondary to treatment. Clinical signs occurring primarily in the 2500 and 3000 ppm groups included ataxia, cachexia, coma, 23 convulsions, hypersensitivity to touch, hypoactivity, hypotonia, pallor, tremors, and unkempt appearance. Food consumption was decreased the 2500 and 3000 ppm groups early in the study when the initial doses for those groups were 4000 and 8000

6000 ppm, respectively, and remained 49% and 20% lower in the 3000 ppm males and females, respectively, at 52 weeks. Body weight of the 2500 and 3000 ppm groups was significantly reduced for most weeks, and at study end body weight of the females in those groups was approximately 25% lower. Body weight gain was significantly lower in the 2500 and 3000 ppm groups throughout most of the study, and in the 3000 ppm group was only 20% of the control gain at 52 weeks. Alterations in red blood cell parameters and absolute and relative organ weights in the 2500 and 3000 ppm groups seen at study end were attributed to the decreased body weights. Increases in SGOT ( up to 96%), SGPT ( up to 154%), alkaline phosphatase ( up to 176%), and gamma GT ( up to 358%) in groups receiving  2000 ppm Ametryn were correlated with inflammatory and degenerative liver lesions seen at histopathologic examination. These lesions included granulomatous, purulent, and lymphocytic inflammation; isolated cellular necrosis; endogenous pigment deposition; vacuolar degeneration; bile duct hyperplasia; and necrosis. The incidence and severity of lesions generally increased with increasing dose at 2000 ppm and above. During a four week recovery period, the incidence and severity of most of these lesions decreased, suggesting they may be reversible. The LOAEL = 2000 ppm ( 70.0 mg/ kg/ day for males and 74 mg/ kg/ day for females), based on degenerative of liver lesions. The NOAEL is 200 ppm ( 7.2 mg/ kg/ day for males, and 8.1 mg/ kg/ day for females). This 52 week oral toxicity study in the dog is Acceptable/ Guideline, and satisfies the guideline requirement for a chronic oral toxicity study ( OPPTS 870.4100; OECD 452) in dogs.

Dose and Endpoint for Establishing cRfD: NOAEL = 7.2 mg/ kg/ day and a LOAEL of 70 mg/ kg/ day based on degenerative liver lesions.

Uncertainty Factor( s): 100. This includes a 10 X for interspecies extrapolation, 10 X for intraspecies variation.

Comments about Study/ Endpoint/ Uncertainty Factor: The study with dogs represent the lowest toxicologically relevant NOAEL. The chronic study with rats has some evidence of weight decreases at 500 ppm ( 21 mg/ kg/ day) and would thus have a NOAEL of 20 ppm ( 2 mg/ kg/ day) but using this dose as a NOAEL is not considered appropriate since the weight effects at 21 mg/ kg/ day were marginal.

4.4.4 Incidental Oral Exposure ( Short and Intermediate Term)

Study Selected: Rabbit Developmental Toxicity study ( 1985, MRID Nos: 00153214 and 02992025).

Dose and Endpoint Selected for Risk Assessment: Maternal toxicity NOAEL of 10 mg/ kg/ day with a LOAEL of 60 mg/ kg/ day based on decreased body weight and food consumption and increased liver weight. Chronic RfD = 7.2 mg/ kg/ day ( NOAEL) = 0.072 mg/ kg/ day 100 ( UF) 24 Comments about Study/ Endpoint. The rabbit developmental toxicity study was selected to set doses and endpoints for both the short and intermediate term incidental oral exposures. Since the study demonstrates a clear NOAEL, a MOE of 100 is considered appropriate.

4.4.5 Dermal Absorption There are no laboratory animal studies conducted to assess for dermal absorption. A dermal absorption factor of 6% has been estimated by comparing the results of the rabbit developmental toxicity study that has a NOAEL and LOAEL of 10 and 60 mg/ kg/ day, respectively, based on signs of reduced body weight and food consumption and increased liver weight to the rabbit dermal toxicity study with a NOAEL and LOAEL of 100 and 1000 mg/ kg/ day, respectively, based on signs of decreased body weight gain and decreased food consumption at 1000 mg/ kg/ day. In particular, 60 mg/ kg/ day/ 1000 mg/ kg/ day X 100 = 6%.

4.4.6a Dermal Exposure ( Short and Intermediate Term) Study Selected: Rabbit 21 day dermal toxicity study ( 1989, MRID No.: 41067902).

Executive Summary: In a 21 day dermal toxicity study ( 1989, MRID 41067902), Ametryn ® ( 97.4% a. i., batch/ lot # FL 840991) was applied to the shaved skin of 5 New Zealand white rabbits/ sex/ dose at dose levels of 0, 10, 100, or 1000 mg/ kg bw/ day, 6 hours/ day for 21 24 days. Total body weight gains ( days 0 21) were apparently reduced in the mid (  17%, gain of 0.20 kg) and high (  32%, gain of only 0.16 kg)  dose males, and in the high dose females (  39%, gain of only 0.18 kg). However, there were no statistically significant differences in body weight and weight gains for the control males were 0.24 and females were 0.29 kg. There was also noted an apparent increase in body weight gain of 19% ( 0.286 kg) in the low dose group. Total food consumption values ( Days 0 21) ranged from 92 112% for treated females and from 81 100% of the control value for treated males. Although, food efficiency ( FE) differences might also be consistent with a possible adverse effect ( as opposed to a palatability problem), with decreases in the mid (  10%) and high (  18%) dose males, and the high dose female (  32%). However, there was also an increase in food efficiency of 7% in the low dose group males. Overall, the apparent decrease in weight gain in the mid dose group males is considered to be of too small a magnitude and the difference in food efficiency within normal variation to include the mid dose group in a LOAEL based on weight gain. The consistency of dose related, minimal decreases in the indicators of circulating red cell mass ( RBCs, HGB, and HCT) among treated groups suggested a mild effect. Dose related increases in cholesterol, triglycerides, and GGT ( statistically significant) were suggestive of an hepatic effect of Ametryn ® in high dose males. Increases in cholesterol and triglyceride levels in females were less pronounced than in males, and not dose related. Absolute hepatic weights were statistically increased in the low and high dose females, but a dose response and histopathological correlates were absent. Apparent increases in absolute spleen weights in males ( 1 to 6%) and in relative ( to body weight) spleen weights ( 2 to 14%) in females suggested a possible mild effect of treatment on the spleen. Mild, dose related increases in absolute cardiac weights in males ( 2 to 8%) suggested a possible effect on the heart. Apparent decreases in absolute and relative prostate weights ( 20 to 22%) at all dose levels, and reductions in testicular weights in the mid ( 12%, absolute and 5% relative) and high ( 20%, both absolute and relative) dose males were suggestive of treatment effects. None of the organ weight differences were associated with gross lesions and at the mid dose group are small and are considered not definitely related to treatment.. The systemic LOAEL is 1000 mg/ kg/ day based on reductions in total body weight gain (  32% in males, 39% in 25 females), and reduced food efficiency (  18% in males and 32% in females). The systemic NOAEL is 100 mg/ kg/ day. The dermal LOAEL > 1000 mg/ kg/ day. This 21 day dermal toxicity study in the rabbit is Acceptable/ Non Guideline and does not satisfy the guideline requirement ( OPPTS 870.3200; OECD 410). The limiting factor is that there were only 5 rabbits/ sex/ dose limiting the interpretation of the body weight and organ weight differences and histopathology was limited and incomplete. However, the study is useful for risk assessment.

Dose and Endpoint for Risk Assessment: NOAEL of 100 mg/ kg/ day with a LOAEL of 1000 mg/ kg/ day based on decreased body weight gain and decreased food consumption.

Comments about Study/ Endpoint: The 21 day dermal toxicity study is route specific and is thus the most appropriate endpoint for dermal exposure scenarios. Although non guideline, the study is acceptable and considered useful for risk assessment.

4.4.6b Dermal Exposure ( Long Term)

Study Selected: Same as for chronic dietary ( see above).

Dose and Endpoint for Risk Assessment: NOAEL of 7.2 mg/ kg/ day with a LOAEL of 70 mg/ kg/ day based on degenerative lesions in the liver.

Comments about Study/ Endpoint: Since an oral endpoint was used, a route to route extrapolation factor of 6% needs to be used to adjust for using an endpoint from as oral study for a dermal risk assessment.

4.4.7a Inhalation Exposure ( Short and Intermediate Term) Study Selected Same as for incidental oral short and intermediate term exposures.

Executive Summary: See above.

Dose/ Endpoint for Risk Assessment: NOAEL = 10 mg/ kg/ day based on decreased body weight gain and food consumption and increased liver weight at 60 mg/ kg/ day.

Comments about Study/ Endpoint: Since an oral endpoint was used, it must be assumed that there is 100% absorption from inhaled ametryn.

4.4.7b Inhalation Exposure ( Long Term).

Study Selected Same as for chronic dietary RfD.

Executive Summary: See above.

Dose/ Endpoint for Risk Assessment: NOAEL = 7.2 mg/ kg/ day based on degenerative liver lesions at 70 mg/ kg/ day. 26 Comments about Study/ Endpoint: Since an oral endpoint was used, it must be assumed that there is 100% absorption from inhaled ametryn.

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 100 100 100 Inhalation 100 100 100 For Occupational exposure: This is based on the conventional uncertainty factor of 100X ( 10X for interspecies extrapolation and 10X for intraspecies variation).

Ametryn has no residential uses; therefore no residential MOEs are applicable.

4.4.9 Recommendation for Aggregate Exposure Risk Assessments In accordance with the FQPA, HED must consider and aggregate ( add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In this case, since ametryn is registered only for agricultural uses, no residential exposures are anticipated. Therefore, the aggregate exposure risk assessment for ametryn considers only exposures and risks from residues of ametryn in food and drinking water.

4.4.10 Classification of Carcinogenic Potential The ametryn team in consultation with the HED Hazard Assessment Science Policy Council ( HASPC) determined that it would be appropriate to estimate the cancer risk to humans associated with the various uses of ametryn by using a Q1* based on the mammary tumors in a rat carcinogenicity study on a trial basis. The mammary tumors were the most sensitive tumor, i. e., result in the highest estimated Q1* value. The team recognizes that the HED CARC found that the rat cancer study developed tumors at dose levels also associated with excess weight loss to confound the interpretation of the significance of these tumors. Consequently, the CARC recommended that a new cancer study in rats be provided. 27 However, the ametryn team believes that using the Q1* based on existing data will reasonably approximate cancer risk to humans and considers it unlikely that the new cancer study will result in a higher risk for ametryn. Support for this conclusion comes from the observation that there were no tumors in the rat study at 500 ppm, a dose resulting in minimal body weight decrease and the fact that there were no compound related tumors in the mouse study at dose levels up to and including 2000 ppm.

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 ( females 13 49) & ( general population) No selection.

Chronic Dietary ( all populations) NOAEL = 7.2 mg/ kg/ day UF = 100 1X Dog chronic feeding study with indications of degenerative and inflammatory liver effects at 70 mg/ kg/ day.

Incidental Oral Short Term ( 1  30 days) & Intermediate Term ( 1  6 months) NOAEL = 10 mg/ kg/ day MOE = 100 1X Rabbit developmental toxicity. Body weight and deceased feed consumption and increased liver weight at 60 mg/ kg/ day.

Dermal Short Term ( 1  30 days) & Intermediate Term ( 1  6 months) NOAEL = 100 mg/ kg/ day MOE = 100 1X Rabbit 21day dermal toxicity study. Body weight gain decrease at 1000 mg/ kg/ day.

Dermal Long Term (> 6 months) Same as for Chronic RFD. MOE = 100. Dermal absorption factor of 6% recommended.

Inhalation Short Term ( 1  30 days) & Intermediate Term ( 1  6 months) Same as for incidental oral. MOE = 100. Assume 100% absorption following inhalation.

Inhalation Long Term (> 6 months) Same as for Chronic RFD. MOE = 100. Assume 100% absorption following inhalation. 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 28 Cancer ( oral, dermal, inhalation) The Cancer Assessment Review Committee ( CARC) met to evaluate the carcinogenic potential of ametryn on 21 JUL 2004 and concluded that the " data are inadequate for an assessment of human carcinogenic potential". The carcinogenicity study in rats is unacceptable because the high dose was considered to be excessive. The CARC requested that the carcinogenicity study in rats be repeated at a dose that is adequate to assess carcinogenicity. However, the available data allow for a determination of a Q1* value of 0.0066 ( mg/ kg/ day) 1, based on observations of combined mammary tumors in female rats. The ametryn risk assessment team believes that using the estimated Q1* based on existing data will reasonably approximate cancer risk to humans and considers it unlikely that the requested new cancer study will result in a higher risk for ametryn. Support for this conclusion comes from the observation that there were no tumors in the rat study at 500 ppm, a dose resulting in minimal body weight decrease and the fact that there were no compound related tumors in the mouse study at dose levels up to and including 2000 ppm.

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 29 4.5 Special FQPA Safety Factor Based on the hazard data, the ametryn risk assessment team recommended the special FQPA SF be reduced to 1x because there are no concerns and no residual uncertainties with regard to preand post natal toxicity based on the rat and rabbit developmental toxicity studies and the rat reproduction study of from studies in the open literature. There were no indications of immunotoxicity or direct neurotoxicity in the standard studies with rats, dogs, mice or rabbits. The ametryn risk assessment team evaluated the quality of the exposure data and, based on these data, recommended that the special FQPA SF be reduced to 1x. The recommendations are based on the following:

° Crop field trial data demonstrate that ametryn use at the highest rates permitted on the label results in residue levels 0.05 ppm in/ on the edible parts of corn, pineapple, and sugarcane.

° The dietary drinking water assessment utilizes values generated by models and associated modeling parameters which are designed to provide conservative, health protective, high end estimates of water concentrations. 30 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).

In the available toxicity studies on ametryn, there was no estrogen, androgen, and/ or thyroid mediated toxicity. When additional appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed, ametryn may be subjected to further screening and/ or testing to better characterize effects related to endocrine disruption.

5.0 Public Health Data 5.1 Incident Reports Relatively few incidents of illness have been reported due to ametryn. Four exposures to ametryn products were reported to Poison Control Center from 1993 through 2001. Two of the four cases, all adults involved minor symptoms. One of the cases was seen in a health care facility and was not hospitalized and another case reported diarrhea and drowsiness/ lethargy. On the list of the 200 chemicals for which NPIC received calls from 1984 1991 inclusively, ametryn was not reported to be involved in human incidents. No scientific literature was located concerning acute poisoning due to exposure to ametryn.

6.0 Exposure Characterization/ Assessment 6.1 Dietary Exposure/ Risk Pathway Reference: Ametryn. Residue Chemistry Considerations for Reregistration Eligibility Decision, DP Barcode: D307104, William Donovan, 03 NOV 2004.

6.1.1 Residue Profile 31 The nature of the residue in plants and animals is adequately understood based on the available corn, sugarcane, banana, goat and hen metabolism studies. In plants, ametryn is extensively metabolized by N dealkylation and desulfation ( oxidation/ hydroxylation) to a variety of triazine ring containing metabolites. The metabolism of ametryn in animals also involves N dealkylation of the isopropyl and ethyl side chains, as well as modification at the 6 position, followed by conjugation, with the triazine ring structure remaining intact. The regulated residues in plant commodities consist of ametryn per se.

Permanent tolerances are established for residues of ametryn per se in/ on various plant commodities at 0.25 ppm, with the exceptions of corn forage and stover, each at 0.5 ppm, and cassava root at 0.1 ppm [ 40 CFR § 180.258]. There are currently no tolerances for ametryn residues in livestock commodities or for inadvertent residues in rotational crops.

Adequate methods are available for enforcing tolerances and/ or collecting data on ametryn residues in/ on plant and livestock commodities. Two GC methods are available for enforcing tolerances of ametryn in plant commodities and are listed as Methods I and A in PAM Vol. II ( section 180.258). Method I is a GC/ microcoulometric ( MC) detection method for determining ametryn per se, with a limit of quantitation ( LOQ) of 0.05 ppm. Method A is a GC/ flame photometric detection ( sulfur mode, FPDS method for determining residues of ametryn and its three thiomethyl metabolites ( GS 11354, GS 11355, and GS 26831), with a LOQ of 0.05 ppm for parent and 0.1 ppm for each metabolite.

Considering the data from the available animal metabolism and feeding studies and the calculated maximum theoretical dietary burdens ( MTDBs) of 0.15 0.18 ppm for cattle and 0.04 ppm for poultry and swine, HED concludes that there is no reasonable expectation of quantifiable residues of ametryn occurring in livestock commodities [ 40 CFR § 180.6( a)( 3)]. Therefore, tolerances for livestock commodities are not required at the present time.

Adequate field trial data are available to support the use of ametryn on corn ( field, pop, and seed), pineapples, and sugarcane provided the appropriate label amendments are made. An adequate number of tests were conducted in the appropriate geographical regions using the appropriate formulation applied at the maximum use rate. These studies are also supported by adequate storage stability data. Although Syngenta has deleted the uses on bananas and plantains from its 80% DF label, adequate field trial data are available that would support the use of up to three directed applications of ametryn ( WP, FLC or DF) to bananas or plantains at 3.2 lb ai/ A/ application at 30 day intervals, using ground equipment, for a maximum use rate of 9.6 lb ai/ A/ crop cycle with a 7 day PHI.

The available processing studies for corn ( 5x rate) and pineapple ( 3x rate) are adequate and indicate that residues of ametryn and its three thiomethyl metabolites are not likely to be quantifiable ( 0.02 ppm) in corn and pineapple processed fractions derived from crops treated at the maximum labeled rates. However, the available sugarcane processing study is not adequate because residues were < LOQ in cane ( RAC) following applications at only 1x the maximum rate. A new sugarcane processing study should be submitted. 32 An adequate confined rotational crop study is available and indicates that the metabolism in rotational crops is similar to the primary crops. Provided that the required label amendments are made to corn and sugarcane use directions, adequate field rotational crop studies are also available and indicate that rotational crop tolerances are not required.

6.1.2 Acute and Chronic Dietary Exposure and Risk Reference: Ametryn. Chronic and Cancer Dietary Exposure Assessment for the Reregistration Eligibility Decision, DP Barcode: D307103, William Donovan, 06 OCT 2004.

Chronic and cancer dietary risk assessments were conducted using Lifeline   ( ver. 2.0) and the Dietary Exposure Evaluation Model  Food Consumption Intake Database ( DEEM FCID   , Version 2.0) models. Both of these models use food consumption data from the USDA's Continuing Surveys of Food Intakes by Individuals ( CSFII) from 1994 1996 and 1998. The analyses were performed to support the reregistration eligibility decision for ametryn.

The chronic and cancer analyses were conducted using average residue levels from applicable field trials, percent crop treated information and DEEM ( ver. 7.76) default processing factors. The Lifeline   chronic exposure estimates were < 0.1% cPAD for all population subgroups and are therefore less than HED's level of concern. Table 6.1.2a summarizes the results of the chronic dietary analyses. The lifetime cancer risk calculated in Lifeline   for the US population is 2.7 x 10 8 and is therefore less than HED's level of concern ( HED performs cancer assessments for only the general US population). Table 6.1.2b summarizes the results of the cancer dietary analyses. DEEM FCID   resulted in chronic and cancer exposure estimates nearly identical to those from Lifeline   . The present assessment is refined as it makes use of average residue levels from field trial results, default processing factors, and percent crop treated information.

Table 6.1.2a Summary of Chronic Dietary Exposure and Risk Estimates for Ametryn.

Population Subgroup Dietary Exposure ( mg/ kg/ day) % cPAD 1 DEEM FCID   Lifeline   DEEM FCID   Lifeline   Chronic Assessment General U. S. Population 0.000004 0.000004 < 0.1 < 0.1 All Infants (< 1 year old) 0.000008 0.000008 < 0.1 < 0.1 Children 1 2 years old 0.000018 0.000018 < 0.1 < 0.1 Children 3 5 years old 0.000013 0.000014 < 0.1 < 0.1 Table 6.1.2a Summary of Chronic Dietary Exposure and Risk Estimates for Ametryn.

Population Subgroup Dietary Exposure ( mg/ kg/ day) % cPAD 1 DEEM FCID   Lifeline   DEEM FCID   Lifeline   33 Children 6 12 years old 0.000008 0.000008 < 0.1 < 0.1 Youth 13 19 years old 0.000003 0.000004 < 0.1 < 0.1 Adults 20 49 years old 0.000003 0.000003 < 0.1 < 0.1 Adults 50+ years old 0.000002 0.000003 < 0.1 < 0.1 Females 13 49 years old 0.000003 0.000003 < 0.1 < 0.1 Table 6.1.2b. Summary of Provisional Cancer Dietary Exposure and Risk Estimates for Ametryn.

Population Subgroup Provisional Q1* ( mg/ kg/ day) 1 Exposure ( mg/ kg/ day) Lifetime risk Lifeline   DEEM FCID   Lifeline   DEEM FCID   General US Population 0.0066 0.000004 0.000004 2.72 x 10 8 2.74 x 10 8 6.2 Water Exposure/ Risk Pathway Reference: Drinking Water Exposure Assessment for Proposed Reregistration of Ametryn Use on Corn, Pineapple and Sugarcane ( Revised), DP Barcode: D307105, Kevin Costello, 16 NOV 2004.

Water models were used to assess potential exposure to ametryn from consumption of contaminated drinking water. Estimated Drinking Water Concentrations ( EDWCs) for ametryn were generated using PRZM/ EXAMS for surface water and SCI GROW2 for groundwater. The EDWCs for surface water bodies were determined using the Tier II screening level simulation models PRZM ( v. 3.12; input generated by PE4VO1. pl, dated 8/ 8/ 03) and EXAMS ( 2.98.04). Potential contaminants of concern considered in the drinking water exposure assessment are parent ametryn and the degradates 2 amino 4 isopropylamino 6 methylthio s triazine ( GS 11354) and 2 ethylamino 4 amino 6 methylthio s triazine ( GS 11355). SCI GROW2 is based on a regression approach which relates ground water concentrations measured in prospective ground water monitoring studies to the aerobic soil metabolism rate and soilwater partitioning properties of the chemical. The model provides a groundwater exposure value to be used in determining the potential risk to human health from drinking water contaminated with the pesticide. SCI GROW2 estimates likely groundwater concentrations if the pesticide is used at the maximum allowable rate in areas where groundwater is vulnerable to contamination. Characteristics of 34 such vulnerable areas include high rainfall, rapidly permeable soil, and a shallow aquifer. In most cases, a large majority of the use area will have groundwater that is less vulnerable to contamination than the areas used to derive the SCI GROW2 estimate.

The EDWCs for ametryn in ground and surface water are summarized in Table 6.2.

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

Exposure Duration Ametryn Surface Water Conc., ppb a Ground Water Conc., ppb b Chronic ( non cancer) 92 15.6 Chronic ( cancer) 73 15.6 a From the Tier II PRZM EXAMS  Index Reservoir model. Input parameters are based on the physical properties of ametryn, and assuming 5 separate applications of ametryn to sugarcane in LA, for a total rate of 11.6 lb ai/ A/ year. b From the SCI GROW model assuming a maximum seasonal use rate of 12 lb ai/ A [ sugarcane in HI], a Koc of 96 mL/ g, and a half life of 91 days.

6.3 Residential ( Non Occupational) Exposure/ Risk Pathway Ametryn uses are being supported only for the following agricultural crops: corn, sugarcane, and pineapple. There are no residential uses and, therefore, no anticipated exposures in or around homes or recreational areas.

6.3.1 Home Uses  Not applicable.

6.3.2 Recreational Uses  Not applicable.

6.3.3 Other ( Spray Drift, etc.)

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for ametryn. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/ labeling. The Agency has completed its evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U. S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off target drift with specific products with significant risks associated with drift. 35 36 7.0 Aggregate Risk Assessments and Risk Characterization In accordance with the FQPA, HED must consider and aggregate ( add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard ( e. g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

For most pesticide active ingredients, water monitoring data are considered inadequate to determine surface and ground water drinking water exposure estimates, so model estimates have been used to estimate residues in drinking water ( EDWCs). In order to determine if aggregate risks are of concern, HED then calculates drinking water levels of comparison, or DWLOCs. The DWLOC is the maximum amount of a pesticide in drinking water that would be acceptable in light of combined exposure from food and residential pathways. The calculated DWLOCs are then compared to the EDWCs provided by EFED; if model derived EDWCs exceed the DWLOCs for surface or ground water, there may be a concern for dietary exposure to residues in drinking water, and monitoring data may be required.

7.1 Acute Aggregate Risk An acute aggregate risk assessment was not conducted because an endpoint of concern attributable to a single dose was not identified.

7.2 Short Term Aggregate Risk A short term aggregate risk assessment was not conducted because there are no existing or proposed residential uses for ametryn.

7.3 Intermediate Term Aggregate Risk An intermediate term aggregate risk assessment was not conducted because there are no existing or proposed residential uses for ametryn.

7.4 Long Term Aggregate Risk A long term ( chronic) aggregate risk assessment was conducted for ametryn. The chronic assessment considered exposures from food and water only, because there are no residential uses and no residential exposures anticipated for this chemical. Since adequate water monitoring data are not available to estimate levels of ametryn in drinking water, HED calculated DWLOCs and compared them to the modelled EDWCs for surface and ground water to determine whether aggregate chronic risks are of concern.

The results of the deterministic dietary exposure assessment indicate that dietary exposures to 37 ametryn in food are very low and well below HED's level of concern ( 100% of the cPAD). Ametryn food exposure is estimated at 0.000004 mg/ kg/ day for the U. S. population (< 0.1% of the cPAD) and 0.000018 mg/ kg/ day (< 0.1% of the cPAD) for the most highly exposed population subgroup ( children, 1 2 years old) using the LifeLine model. DEEM FCID yielded nearly identical results. HED used the LifeLine exposure estimates to calculate chronic DWLOCs for the U. S. population and various population subgroups. The calculated DWLOCs ranged from 2520 ppb for adults to 720 ppb for children. The chronic surface water EDWC ( 92 ppb) generated by EFED is below HED's calculated DWLOCs for chronic exposure to ametryn for the U. S. population and each population subgroup. The ground water EDWC ( 15.6 ppb) is also less than HED's calculated chronic DWLOCs for the U. S. population and all population subgroups. All EDWCs are less than HED's calculated chronic DWLOCs. Therefore, chronic aggregate exposures to ametryn in food and drinking water are not of concern from a risk perspective.

Table 7.4. Aggregate Risk Assessment for Chronic Exposure to Ametryn.

Population Subgroup1 Chronic Scenario cPAD mg/ kg/ day Chronic Food Exp mg/ kg/ day Max Chronic Water Exp mg/ kg/ day2 Ground Water EDWC ( ppb) 3 Surface Water EDWC ( ppb) 3 Chronic DWLOC ( ppb)

U. S. Population 0.072 4.00e 06 0.071996 15.6 92 2520 All Infants (< 1 year old) 0.072 8.00e 06 0.071992 720 Children 1 2 years 0.072 1.80e 05 0.071982 720 Children 3 5 years 0.072 1.40e 05 0.071986 720 Children 6 12 0.072 8.00e 06 0.071992 720 Youth 13 19 0.072 4.00e 06 0.071996 2160 Adults 20 49 0.072 3.00e 06 0.071997 2520 Females 13+ 0.072 3.00e 06 0.071997 2160 Adults 50+ years 0.072 3.00e 06 0.071997 2520 1 This footnote should indicate the selected subgroups and provide rationale for selection. Indicate body weights ( 70 kg adult male; 60 kg adult female; 10 kg child). 2Maximum Chronic Water Exposure ( mg/ kg/ day) = [ Chronic PAD ( mg/ kg/ day)  Chronic Dietary Exposure ( mg/ kg/ day)] 3 The use pattern producing the highest EDWC level was selected: sugarcane use in HI for ground water and sugarcane use in LA for surface water. 4 Chronic DWLOC(

g/ L) = [ maximum chronic water exposure ( mg/ kg/ day) x body weight ( kg)] [ water consumption ( L) x 10 3 mg/

g] 38 7.5 Cancer Risk A cancer aggregate risk assessment was conducted for ametryn. The cancer assessment considered exposures from food and water only, because there are no residential uses and no residential exposures anticipated for this chemical. Since adequate water monitoring data are not available to estimate levels of ametryn in drinking water, HED calculated DWLOCs and compared them to the modelled EDWCs for surface and ground water.

The CARC met to evaluate the carcinogenic potential of ametryn on 21 JUL 2004 and concluded that the " data are inadequate for an assessment of human carcinogenic potential". The carcinogenicity study in rats is unacceptable because the high dose was considered to be excessive. The CARC requested that the carcinogenicity study in rats be repeated at a dose that is adequate to assess carcinogenicity. However, the available data allow for a determination of a provisional Q 1* value of 0.0066 ( mg/ kg/ day) 1, based on observations of combined mammary tumors in female rats. The ametryn risk assessment team believes that using the estimated provisional Q 1* based on existing data will provide a screening level tool for examining possible cancer risks involving ametryn.

Table 7.5 summarizes the cancer risk calculations for ametryn. The calculated cancer DWLOC for the US population was 5.2 ppb. The cancer surface water EDWC ( 73 ppb) generated by EFED exceeds HED's calculated DWLOC for cancer exposure to ametryn. The ground water EDWC ( 15.6 ppb) also exceeds HED's calculated cancer DWLOC for the U. S. population. Generally, if modelderived EDWCs for surface or ground water exceed the DWLOCs, there may be a concern for cancer dietary exposure to residues in drinking water. In this case, since the EDWCs for ground and surface water exceed HED's provisional cancer DWLOC for the U. S. population, this screening analysis supports the need for additional data in the form of a new rat cancer study.

The ground and surface water EDWCs provided in Table 7.5 reflect the highest levels estimated for ametryn use in/ on corn, sugarcane, and pineapple. In general, the highest EDWCs resulted from sugarcane applications in LA or HI. For comparison purposes, additional water modeling results showing the corn and pineapple data together with the sugarcane values are listed below.

Crop Ground Water EDWC ( ppb) Surface Water EDWC ( ppb)

Chronic Scenario Cancer Scenario Corn 2.6 7.6 5.4 Pineapple 9.4 NA* NA*

Sugarcane 15.6 [ HI] 92 [ LA] 73 [ LA]

15.1 [ LA]

7.8 [ TX] 39 4.7 [ FL] 19 [ FL] 12 [ FL]

* Not calculated since most drinking water in Hawaii is derived from ground water supplies. The HI ground water number may be substituted.

These additional data demonstrate that the corn and pineapple uses result in surface water EDWC levels only slightly above the cancer DWLOC, while the sugarcane use results in significantly higher predicted levels of ametryn in drinking water.

It is worthwhile to note that Hawaiian ground water monitoring data in pineapple use areas in the mid 1990' s resulted in a maximum concentration similar in magnitude to that predicted with the ground water screening model SCI GROW ( Screening Concentration in Ground Water). 40 Table 7.5 Cancer DWLOC Calculations Populatio n Q* Negligible Risk Level1 Target Max Exposure2 mg/ kg/ day Chronic Food Exposure mg/ kg/ day Residential Exposure ( LADD)

mg/ kg/ day Aggregate cancer risk ( food and residential) Max Water Exposure3 mg/ kg/ day Ground Water EDWC4 ( ppb) Surface Water4 EDWC ( ppb) Cancer DWLOC5 ( ppb)

U. S. Pop 6.60e 0 3 1.00e 06 1.52e 04 4.00e 06 0.000000 4.00e 06 1.48e 04 15.6 73 5.16 1 Indicate in this footnote the basis for the negligible risk if other than 1 x 10 6.

2 Target Maximum Exposure ( mg/ kg/ day) = [ negligible risk/ Q*]

3 Maximum Water Exposure ( mg/ kg/ day) = [ Target Maximum Exposure  ( Chronic Food Exposure + Residential Exposure ( Lifetime Average Daily Dose))]

4 The use pattern producing the highest EDWC level was selected: sugarcane use in HI for ground water and sugarcane use in LA for surface water.

5 Cancer DWLOC( ppb) = [ maximum water exposure ( mg/ kg/ day) x body weight ( kg)]

[ water consumption ( L) x 10 3 mg/

g] 41 8.0 Cumulative Risk Characterization/ Assessment Ametryn was not grouped with chloro s triazines ( atrazine, simazine, propazine and their chloros triazine metabolites) because it has a different functional group attached to the triazene ring, i. e., thiomethyl versus chloro. Further, ametryn does not exhibit the same toxicity profile as the chloro striazines There were several tumors induced by ametryn in a rat bioassay, but only at an excessive dose which confounds the interpretation of this response. This pattern of tumor response is not characteristic of the chloro s triazines.

9.0 Occupational Exposure/ Risk Pathway Reference: Ametryn. HED Occupational and Residential Exposure Chapter of the Reregistration Eligibility Decision Document ( Revised), DP Barcode: D311600, Robert Travaglini, 22 DEC 2004.

9.1 Short/ Intermediate/ Long Term Handler Risk HED determines potential exposures to pesticide handlers by identifying exposure scenarios from various types of application equipment that are recommended on ametryn labeling. Based on the product labeling, agricultural use patterns specific to ametryn are associated with the following types of equipment: aerial ( sugarcane) and groundboom sprayer for sugarcane, pineapples and corn.

Based on product labeling and information provided for the completion of the RED process for this pesticide, HED has identified 14 occupational handler scenarios for which short and intermediateterm exposure to ametryn may occur. Exposure estimates were conducted using the maximum application rates for each of the crops.

The following 14 occupational handler scenarios were evaluated for short and intermediate term exposure to ametryn. 3. Mix/ load: Liquids for Groundboom to Support Application to Corn; 4. Mix/ load: Liquids for Groundboom to Support Application to Pineapples; 5. Mix/ load: Liquids for Groundboom to Support Application to Sugarcane; 6. Mix/ load: Liquids for Aerial to Support Application Sugarcane; 7. Mix/ load: Liquids to Support Groundboom Application on Sugarcane*; 8. Mix/ load: Liquids for Aerial Application on Sugarcane*; 9. Application: Groundboom Spray Application on Corn; 10. Application: Groundboom Spray Application on Pineapples; 11. Application: Groundboom Spray Application on Sugarcane; 12. Application: Aerial Spray Application on Sugarcane; 13. Application: Groundboom Spray Application on Sugarcane*; 14. Application: Aerial Application of Sprays on Sugarcane*; 15. Flagger: Aerial on Sugarcane; 16. Flagger: Aerial on Sugarcane*. 42 (* denotes lower application rate of 2.0 lbs ai/ acre).

Because no chemical specific data and/ or studies were submitted in support of the reregistration process for this chemical, PHED V1.1 has been used to assess the exposure scenarios for ametryn. 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 has 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. The handler assessments encompass all of the major uses of ametryn being supported throughout the country. The assumptions used in calculating exposures and risks are listed below: Application Rates: The application rates are the maximum allowable that were identified on the available product labels for each use assessed in this document. Acres Treated**: The daily acres treated are HED standard values ( EXPO SAC policy 9.1). However, for sugarcane HED used 350 acres ( low acreage) rather than 1200 acres ( high acreage) in the aerial assessment for this crop based on information that typically ametryn is not applied to sugarcane aerially, but is more typically applied by ground boom equipment, and is as such considered a high acreage groundboom crop and a rather low acreage aerial crop. Unit Exposures: The unit exposure values calculated by PHED generally range from the geometric mean to the median of the selected data set. To add consistency and quality control to the values produced from this system, the PHED Task Force has evaluated all data within the system and has developed a set of grading criteria to characterize the quality of the original study data. The assessment of data quality is based on the number of observations and the available quality control data. While data from PHED provides the best available information on handler exposures, it should be noted that some aspects of the included studies ( e. g., duration, acres treated, pounds of active ingredient handled) may not accurately represent labeled uses in all cases.

Amount Handled: Based on the daily acres treated. 43

Personal Protective Equipment ( PPE): HED calculated MOEs for the baseline, minimum PPE, and PPE with engineering controls for each occupational exposure scenario under the following assumptions: All Scenarios: All occupational handlers are wearing footwear ( socks plus shoes or boots), foot exposure is not traditionally monitored, and therefore, a 100 percent protection factor is implied. Baseline Attire: All handlers are wearing long sleeved shirts, long pants, no gloves, and no respirator. Minimum PPE: All handlers are wearing long sleeved shirts, long pants, gloves, and no respirator. Engineering Controls: Represents the use of an appropriate engineering control such as a closed tractor cab or closed loading system for granulars or liquids. Potential daily dermal exposure is calculated using the following formula: Daily Dermal Exposure ( mg ai/ day) = Dermal Unit Exposure ( mg ai/ lb ai) x Application Rate ( lb ai/ lb of seed ) x Daily amount Treated ( lbs)

Potential daily inhalation exposure is calculated using the following formula: Daily Inhalation Exposure ( mg ai/ day) = Inhalation Unit Exposure ( mg ai/ lb ai) x Application Rate ( lb ai/ lb of seed) x Daily amount Treated ( lbs)

The inhalation and dermal daily doses were calculated using the following formulas: Daily dermal dose ( mg/ kg/ day) = daily dermal exposure( mg ai/ day)/ body weight( kg) x dermal absorption factor( 100%) Daily Inhalation dose ( mg/ kg/ day) = daily Inhalation exposure( mg ai/ day)/ body weight( kg) x 100% ( where body weight = 70kg.)

Using the daily dermal exposure scenarios identified in the exposure section, HED calculated the potential risk to persons from handler exposures using MOEs. The MOEs were calculated using the following formulas: Dermal MOE = Dermal NOAEL( mg/ kg/ day)/ Daily Dermal Dose ( mg/ kg/ day)

Inhalation MOE = Inhalation NOAEL( mg/ kg/ day)/ Daily Inhalation Dose ( mg/ kg/ day)

Margins of exposure ( MOEs) were calculated for handlers for short term ( up to 1 month) and intermediate term ( 1 to 6 months) durations. The results of the dermal and inhalation handler risk estimates for short and intermediate term exposure durations to ametryn are summarized in Tables 9.1a, 9.1b, & 9.1c. MOEs for 11 of the 14 handler scenarios are greater than 100 at either baseline or minimum PPE protection levels and are not of concern. The three scenarios with MOEs which do not exceed 100 at baseline or PPE1 protection levels: Scenario 4  mixing/ loading liquids for aerial application to sugarcane at the application rate of 7.2 lbs ai/ acre; Scenario 10  applying spray for aerial application to sugarcane at 8.0 lbs. ai/ acre and Scenario 12  applying spray for aerial application to sugarcane at 2.0 lbs ai/ acre. All three of these scenarios attain MOEs > 100 with engineering controls. In the case of Scenario 4 ( mixing/ loading ametryn for aerial application to sugarcane) which achieves a combined MOE of 79 under the PPE1 protection level, adding coveralls would yield a combined MOE of 97. Adding a PF5 respirator would reduce inhalation exposure by 80.0%, therefore the combined MOE would increase to 109 without coveralls. Using a PF10 respirator, without coveralls would increase the combined MOE to 793. 44 Table 9.1a Short & Intermediate  Term Ametryn Baseline Exposure Estimates Exposure Scenario ( Scenario #) Dermal Unit Exposure ( mg/ lb ai) 1 Inhalation Unit Exposure ( Ug/ lb ai) 2 Crop3 Application Rate4 Daily Area Treated5 Dermal Dose ( mg/ kg/ day) 6 Dermal MOE 7 Inhalation Dose ( mg/ kg/ day) 8 Inhalation MOE9 Total MOE10 Mixer/ Loader Mixing/ Loading Liquids for Groundboom application ( 1) 2.9 1.2 Corn 2.0 lb ai per acre 200 Acres per day 17 6 0.0069 1500 6 Mixing/ Loading Liquids for Groundboom application ( 2) 2.9 1.2 Pineapple 7.2 lb ai per acre 80 Acres per day 12 8 0.0049 2000 8.3 Mixing/ Loading Liquids for Groundboom application ( 3) 2.9 1.2 Sugarcane 8.0 lb ai per acre 80 Acres per day 27 4 0.011 910 3.8 Mixing/ Loading Liquids for Aerial application ( 4) 2.9 1.2 Sugarcane 7.2 lb ai per acre 350 Acres per day 100 1 0.043 230 0.95 Mixing/ Loading Liquids for Groundboom application ( 5) 2.9 1.2 Sugarcane 2.0 lb ai per acre 40 Acres per day 3.3 30 0.0014 7300 30 Mixing/ Loading Liquids for Aerial application ( 6) 2.9 1.2 Sugarcane 2.0 lb ai per acre 350 Acres per day 29 3 0.012 830 3.4 Applicator Sprays for Groundboom application ( 7) 0.014 0.74 Corn 2.0 lb ai per acre 200 Acres per day 0.08 1300 0.0042 2400 820 Sprays for Groundboom application ( 8) 0.014 0.74 Pineapple 7.2 lb ai per acre 80 Acres per day 0.12 870 0.0061 1600 570 Table 9.1a Short & Intermediate  Term Ametryn Baseline Exposure Estimates Exposure Scenario ( Scenario #) Dermal Unit Exposure ( mg/ lb ai) 1 Inhalation Unit Exposure ( Ug/ lb ai) 2 Crop3 Application Rate4 Daily Area Treated5 Dermal Dose ( mg/ kg/ day) 6 Dermal MOE 7 Inhalation Dose ( mg/ kg/ day) 8 Inhalation MOE9 Total MOE10 45 Sprays for Groundboom application ( 9) 0.014 0.74 Sugarcane 8.0 lb ai per acre 80 Acres per day 0.13 780 0.0068 1500 510 Sprays for Aerial application ( 10) No Data No Data sugarcane 8.0 lb ai per acre 350 Acres per day No Data No Data No Data No Data No Data Sprays for Groundboom application ( 11) 0.014 0.74 Sugarcane 2.0 lb ai per acre 80 Acres per day 0.032 3100 0.0017 5900 2000 Sprays for Aerial application ( 12) No Data No Data sugarcane 2.0 lb ai per acre 350 Acres per day No Data No Data No Data No Data No Data Flagger Flagging for Sprays application ( 13) 0.011 0.35 Sugarcane 8.0 lb ai per acre 350 Acres per day 0.44 230 0.014 710 170 Flagging for Sprays application ( 14) 0.011 0.35 Sugarcane 2.0 lb ai per acre 350 Acres per day 0.11 910 0.0035 2900 690 1Baseline dermal unit exposures represent long pants, long sleeved shirts, shoes, and socks. Values are reported in the PHED Surrogate Exposure Guide dated August 1998 or are from data submitted by the Outdoor Residential Exposure Task Force dated May 2000.

2Baseline inhalation unit exposures represent no respirator. Values are reported in the PHED Surrogate Exposure Guide dated August 1998 or are from data submitted by the Outdoor Residential Exposure Task Force dated May 2000.

3Crops and use patterns are from product labeling.

4Application rates are based on maximum values found in various sources including LUIS and various labels. In most scenarios, a range of maximum application rates is used to represent the range of rates for different crops/ sites/ uses. Application rates upon which the analysis is based are presented as lb ai/ A.

5Amount treated is based on the area or gallons that can be reasonably applied in a single day for each exposure scenario of concern based on the application method and formulation/ packaging type. ( Standard EPA/ OPP/ HED values).

6Dermal dose ( mg/ kg/ day) = [ unit exposure ( mg/ lb ai) * Dermal absorption ( 100%) * Application rate ( lb ai/ acre or lb ai/ gallon) * Daily area treated ( acres or gallons)] / Body weight ( 70 kg).

7Dermal MOE = Short & Intermediate term dermal NOAEL ( 100 mg/ kg/ day) / Daily Dermal Dose. Target Dermal MOE is 100.

8Inhalation dose ( mg/ kg/ day) = [ unit exposure ( ug/ lb ai) * 0.001 mg/ g unit conversion * Inhalation absorption ( 100%) * Application rate ( lb ai/ acre or lb ai/ gallon) * Daily area treated ( acres or gallons)] / Body weight ( 70 kg).

9Inhalation MOE = Short & Intermediate term developmental NOAEL ( 10 mg/ kg/ day) / Daily Inhalation Dose. Target Inhalation MOE is 100.

10Total MOE = [ 1/ ( 1/ dermal Moe + 1/ inhalation MOE)] 46 Table 9.1b. Short & Intermediate  Term PPE 1 ( Single Layer Protection, Gloves, No Respirator) Ametryn Exposure Estimates Exposure Scenario ( Scenario #) Dermal Unit Exposure ( mg/ lb ai) 1 Inhalation Unit Exposure ( Ug/ lb ai) 2 Crop3 Application Rate4 Daily Area Treated5 Dermal Dose ( mg/ kg/ day) 6 Dermal MOE 7 Inhalation Dose ( mg/ kg/ day) 8 Inhalation MOE9 Total MOE10 Mixer/ Loader Mixing/ Loading Liquids for Groundboom application ( 1) 0.023 1.2 Corn 2.0 lb ai per acre 200 Acres per day 0.13 760 0.0069 1500 500 Mixing/ Loading Liquids for Groundboom application ( 2) 0.023 1.2 Pineapple 7.2 lb ai per acre 80 Acres per day 0.095 1100 0.0049 2000 690 Mixing/ Loading Liquids for Groundboom application ( 3) 0.023 1.2 Sugarcane 8.0 lb ai per acre 80 Acres per day 0.21 480 0.011 910 310 Mixing/ Loading Liquids for Aerial application ( 4) 0.023 1.2 Sugarcane 7.2 lb ai per acre 350 Acres per day 0.83 120 0.043 230 79 Mixing/ Loading Liquids for Groundboom application ( 5) 0.023 1.2 Sugarcane 2.0 lb ai per acre 40 Acres per day 0.026 3800 0.0014 7300 2500 Mixing/ Loading Liquids for Aerial application ( 6) 0.023 1.2 Sugarcane 2.0 lb ai per acre 350 Acres per day 0.23 440 0.012 830 290 Applicator Sprays for Groundboom application ( 7) 0.014 0.74 Corn 2.0 lb ai per acre 200 Acres per day 0.08 1300 0.0042 2400 820 Sprays for Groundboom application ( 8) 0.014 0.74 Pineapple 7.2 lb ai per acre 80 Acres per day 0.12 870 0.0061 1600 570 Table 9.1b. Short & Intermediate  Term PPE 1 ( Single Layer Protection, Gloves, No Respirator) Ametryn Exposure Estimates Exposure Scenario ( Scenario #) Dermal Unit Exposure ( mg/ lb ai) 1 Inhalation Unit Exposure ( Ug/ lb ai) 2 Crop3 Application Rate4 Daily Area Treated5 Dermal Dose ( mg/ kg/ day) 6 Dermal MOE 7 Inhalation Dose ( mg/ kg/ day) 8 Inhalation MOE9 Total MOE10 47 Sprays for Groundboom application ( 9) 0.014 0.74 Sugarcane 8.0 lb ai per acre 80 Acres per day 0.13 780 0.0068 1500 510 Sprays for Aerial application ( 10) No Data No Data sugarcane 8.0 lb ai per acre 350 Acres per day No Data No Data No Data No Data No Data Sprays for Groundboom application ( 11) 0.014 0.74 Sugarcane 2.0 lb ai per acre 80 Acres per day 0.032 3100 0.0017 5900 2000 Sprays for Aerial application ( 12) No Data No Data sugarcane 2.0 lb ai per acre 350 Acres per day No Data No Data No Data No Data No Data Flagger Flagging for Sprays application ( 13) 0.01 0.35 Sugarcane 8.0 lb ai per acre 350 Acres per day 0.4 250 0.014 710 190 Flagging for Sprays application ( 14) 0.01 0.35 Sugarcane 2.0 lb ai per acre 350 Acres per day 0.1 1000 0.0035 2900 740 1 PPE1 dermal unit exposures represent long pants, long sleeved shirts, and chemical resistant gloves. Values are reported in the PHED Surrogate Exposure Guide dated August 1998 or are from data submitted by the Outdoor Residential Exposure Task Force dated May 2000.

2PPE1 inhalation unit exposures represent no respirator. Values are reported in the PHED Surrogate Exposure Guide dated August 1998 or are from data submitted by the Outdoor Residential Exposure Task Force dated May 2000.

2Baseline inhalation unit exposures represent no respirator. Values are reported in the PHED Surrogate Exposure Guide dated August 1998 or are from data submitted by the Outdoor Residential Exposure Task Force dated May 2000.

3Crops and use patterns are from product labeling.

4Application rates are based on maximum values found in various sources including LUIS and various labels. In most scenarios, a range of maximum application rates is used to represent the range of rates for different crops/ sites/ uses. Application rates upon which the analysis is based are presented as lb ai/ A.

5Amount treated is based on the area or gallons that can be reasonably applied in a single day for each exposure scenario of concern based on the application method and formulation/ packaging type. ( Standard EPA/ OPP/ HED values).

6Dermal dose ( mg/ kg/ day) = [ unit exposure ( mg/ lb ai) * Dermal absorption ( 100%) * Application rate ( lb ai/ acre or lb ai/ gallon) * Daily area treated ( acres or gallons)] / Body weight ( 70 kg).

7Dermal MOE = Short & Intermediate term dermal NOAEL ( 100 mg/ kg/ day) / Daily Dermal Dose. Target Dermal MOE is 100.

8Inhalation dose ( mg/ kg/ day) = [ unit exposure ( ug/ lb ai) * 0.001 mg/ g unit conversion * Inhalation absorption ( 100%) * Application rate ( lb ai/ acre or lb ai/ gallon) * Daily area treated ( acres or gallons)] / Body weight ( 70 kg).

9Inhalation MOE = Short & Intermediate term developmental NOAEL ( 10 mg/ kg/ day) / Daily Inhalation Dose. Target Inhalation MOE is 100.

10Total MOE = [ 1/ ( 1/ dermal Moe + 1/ inhalation MOE)] 48 Table 9.1c. Short & intermediate  Term Ametryn Exposure Estimates with Engineering Controls Exposure Scenario ( Scenario #) Dermal Unit Exposure ( mg/ lb ai) 1 Inhalation Unit Exposure ( Ug/ lb ai) 2 Crop3 Application Rate4 Daily Area Treated5 Dermal Dose ( mg/ kg/ day) 6 Dermal MOE 7 Inhalation Dose ( mg/ kg/ day) 8 Inhalation MOE9 Total MOE10 Mixer/ Loader Mixing/ Loading Liquids for Groundboom application ( 1) 0.0086 0.083 corn 2.0 lb ai per acre 200 Acres per day 0.049 2000 0.00047 21000 1900 Mixing/ Loading Liquids for Groundboom application ( 2) 0.0086 0.083 pineapple 7.2 lb ai per acre 80 Acres per day 0.035 2800 0.00034 29000 2600 Mixing/ Loading Liquids for Groundboom application ( 3) 0.0086 0.083 sugarcane 8.0 lb ai per acre 80 Acres per day 0.079 1300 0.00076 13000 1200 Mixing/ Loading Liquids for Aerial application ( 4) 0.0086 0.083 sugarcane 7.2 lb ai per acre 350 Acres per day 0.31 320 0.0030 3300 290 Mixing/ Loading Liquids for Groundboom application ( 5) 0.0086 0.083 sugarcane 2.0 lb ai per acre 40 Acres per day 0.0098 10000 0.000095 110000 9300 Mixing/ Loading Liquids for Aerial application ( 6) 0.0086 0.083 sugarcane 2.0 lb ai per acre 350 Acres per day 0.086 1200 0.00083 12000 1100 Applicator Sprays for Groundboom application ( 7) 0.005 0.043 corn 2.0 lb ai per acre 200 Acres per day 0.029 3500 0.00025 41000 3200 Sprays for Groundboom application ( 8) 0.005 0.043 pineapple 7.2 lb ai per acre 80 Acres per day 0.041 2400 0.00035 28000 2200 Table 9.1c. Short & intermediate  Term Ametryn Exposure Estimates with Engineering Controls Exposure Scenario ( Scenario #) Dermal Unit Exposure ( mg/ lb ai) 1 Inhalation Unit Exposure ( Ug/ lb ai) 2 Crop3 Application Rate4 Daily Area Treated5 Dermal Dose ( mg/ kg/ day) 6 Dermal MOE 7 Inhalation Dose ( mg/ kg/ day) 8 Inhalation MOE9 Total MOE10 49 Sprays for Groundboom application ( 9) 0.005 0.043 sugarcane 8.0 lb ai per acre 80 Acres per day 0.046 2200 0.00039 25000 2000 Sprays for Aerial application ( 10) 0.005 0.068 sugarcane 8.0 lb ai per acre 350 Acres per day 0.2 500 0.0027 3700 440 Sprays for Groundboom application ( 11) 0.005 0.043 sugarcane 2.0 lb ai per acre 80 Acres per day 0.046 2200 0.00039 25000 2000 Sprays for Aerial application ( 12) 0.005 0.068 sugarcane 2.0 lb ai per acre 350 Acres per day 0.2 500 0.0027 3700 440 Flagger Flagging for Sprays application ( 13) 0.00022 0.007 sugarcane 8.0 lb ai per acre 350 Acres per day 0.0088 11000 0.00028 36000 8600 Flagging for Sprays application ( 14) 0.00022 0.007 sugarcane 2.0 lb ai per acre 350 Acres per day 0.0022 45000 0.00007 140000 34000 1Engineering controls dermal unit exposures represent long pants and long sleeved shirts. For mixers and loaders, chemical resistant gloves are also included. Values are reported in the PHED Surrogate Exposure Guide dated August 1998 or are from data submitted by the Outdoor Residential Exposure Task Force dated May 2000.

2Engineering controls inhalation unit exposures represent no respirator. Values are reported in the PHED Surrogate Exposure Guide dated August 1998 or are from data submitted by the Outdoor Residential Exposure Task Force dated May 2000.

3Crops and use patterns are from product labeling.

4Application rates are based on maximum values found in various sources including LUIS and various labels. In most scenarios, a range of maximum application rates is used to represent the range of rates for different crops/ sites/ uses. Application rates upon which the analysis is based are presented as lb ai/ A.

5Amount treated is based on the area or gallons that can be reasonably applied in a single day for each exposure scenario of concern based on the application method and formulation/ packaging type. ( Standard EPA/ OPP/ HED values).

6Dermal dose ( mg/ kg/ day) = [ unit exposure ( mg/ lb ai) * Dermal absorption ( 100%) * Application rate ( lb ai/ acre or lb ai/ gallon) * Daily area treated ( acres or gallons)] / Body weight ( 70 kg).

7Dermal MOE = Short & Intermediate term dermal NOAEL ( 100 mg/ kg/ day) / Daily Dermal Dose. Target Dermal MOE is 100.

8Inhalation dose ( mg/ kg/ day) = [ unit exposure ( ug/ lb ai) * 0.001 mg/ g unit conversion * Inhalation absorption ( 100%) * Application rate ( lb ai/ acre or lb ai/ gallon) * Daily area treated ( acres or gallons)] / Body weight ( 70 kg).

9Inhalation MOE = Short & Intermediate term developmental NOAEL ( 10 mg/ kg/ day) / Daily Inhalation Dose. Target Inhalation MOE is 100.