UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES August 31, 2005 MEMORANDUM SUBJECT: Thidiazuron: Revised HED Chapter of the Reregistration Eligibility Decision Document ( RED), Phase 3 Public Comments. PC Code: 120301, Case #: 4092, DP Barcode: D319302.

Regulatory Action: Reregistration Risk Assessment, Phase 3  HED Response to Public Comments Risk Assessment Type: Single Chemical, Aggregate FROM: Toiya Goodlow, Chemist and Risk Assessor Byong Han Chin, Ph. D., Toxicologist Jeff Dawson, Chemist Reregistration Branch 1 Health Effects Division ( 7509C)

THROUGH: Whang Phang, Ph. D., Branch Senior Scientist Reregistration Branch 1 Health Effects Division ( 7509C)

TO: John Pates Jr., Chemical Review Manager Special Review and Reregistration Division ( 7508C)

This document is a revision of the Human Health Risk Assessment for the Thidiazuron Reregistration Eligibility Decision Document ( RED) dated May 2, 2005 ( T. Jimerson, W. Phang). The HED chapter includes the Toxicology and Hazard Assessment from Byong Han ( Paul) Chin, Reregistration Branch I, Residue Chemistry Assessments and Dietary Exposure Analysis from Toiya Goodlow, Reregistration Branch 1, and the Occupational and Residential Exposure Assessments from Jeff Dawson, Reregistration Branch 1. Information was also drawn from the Environmental Fate and Effects Division ( EFED) Drinking Water Assessment ( A. Clem, 8/ 24/ 04) and the Review of Thidiazuron Incident Reports from Jerry Blondell, HED, Chemistry and Exposure Branch. ii This risk assessment was revised in response to public comments. The corrections were reviewed by RRB1/ HED and revised to comply with Agency policies. See DP Barcode: D320616, dated August 31, 2005 for the complete HED Response to Public Comments. iii Table of Contents 1.0 Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2.0 Ingredient Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.1 Summary of Registered/ Proposed Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.2 Structure and Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 3.4 Tabular Summary of Metabolites and Degradates . . . . . . . . . . . . . . . . . . . . . . . 13 3.5 Toxicity Profile of Major Metabolites and Degradates . . . . . . . . . . . . . . . . . . . 14 3.6 Summary of Residues for Tolerance Expression and Risk Assessment . . . . . . . . 14 3.6.1 Tabular Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 3.6.2 Rationale for Inclusion of Metabolites and Degradates . . . . . . . . . . . . . 14 4.0 Hazard Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 4.1. Hazard and Dose Response Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . 15 4.1.1. Database Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 <IP_ADDRESS>. Studies available and considered . . . . . . . . . . . . . . . . . . . . . . . . 15 <IP_ADDRESS>. Mode of action, metabolism, toxicokinetic data . . . . . . . . . . . . 15 <IP_ADDRESS>. Sufficiency of studies/ data . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 4.1.2. Toxicological Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 4.1.3. Dose response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 4.2 FQPA Hazard Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.2.1 Adequacy of the Toxicity Data Base . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.2.2 Evidence of Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.2.3 Developmental Toxicity Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.2.4 Reproductive Toxicity Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 4.2.5 Additional Information from Literature Sources . . . . . . . . . . . . . . . . . . 26 4.2.6 Pre and/ or Postnatal Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 <IP_ADDRESS> Determination of Susceptibility . . . . . . . . . . . . . . . . . . . 26 <IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for iv Pre and/ or Post natal Susceptibility . . . . . . . . . . . . . . . . 26 4.3 Recommendation for a Developmental Neurotoxicity Study . . . . . . . . . . . . . . . 26 4.3.1 Evidence that supports requiring a Developmental Neurotoxicity study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 4.3.2 Evidence that supports not requiring for a Developmental Neurotoxicity study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 <IP_ADDRESS> Rationale for the UF DB ( when a DNT is recommended) . 26 4.4 Hazard Identification and Toxicity Endpoint Selection . . . . . . . . . . . . . . . . . . . 26 4.4.1 Acute Reference Dose ( aRfD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 4.4.2 Chronic Reference Dose ( cRfD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 4.4.3 Incidental Oral Exposure ( Short and Intermediate Term) . . . . . . . . . . . . 28 4.4.4 Dermal Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 4.4.5 Dermal Exposure ( Short, Intermediate and Long Term) . . . . . . . . . . . . 29 4.4.6 Inhalation Exposure ( Short, Intermediate and Long Term) . . . . . . . . . . 29 4.4.7 Margins of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 4.4.8 Recommendation for Aggregate Exposure Risk Assessments . . . . . . . . 30 4.4.9 Classification of Carcinogenic Potential . . . . . . . . . . . . . . . . . . . . . . . . . 31 4.5 Special FQPA Safety Factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 4.6 Endocrine disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 5.0 Public Health Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 5.1 Incident Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 6.0 Exposure Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 6.1 Dietary Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 6.1.1 Residue Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 6.1.2 Acute and Chronic Dietary Exposure and Risk . . . . . . . . . . . . . . . . . . . 38 6.2 Water Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 6.3 Residential ( Non Occupational) Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . 40 7.0 Aggregate Risk Assessments and Risk Characterization . . . . . . . . . . . . . . . . . . . . . 40 7.1 Acute Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 7.2 Short Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 7.3 Intermediate Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 7.4 Long Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 7.5 Cancer Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 8.0 Cumulative Risk Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 9.0 Occupational Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 9.1 Short/ Intermediate/ Long Term Handler Risk . . . . . . . . . . . . . . . . . . . . . . . . . . 43 9.2 Short/ Intermediate/ Long Term Postapplication Risk . . . . . . . . . . . . . . . . . . . . . 47 9.3 Occupational Risk Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 10.0 Data Needs and Label Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 10.1 Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 v 10.2 Residue Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 10.3 Occupational and Residential Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 References: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 1.0 TOLERANCE REASSESSMENT RECOMMENDATIONS . . . . . . . . . . . . . . 50 2.0 TOXICOLOGY DATA REQUIREMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 3.0 NON CRITICAL TOXICOLOGY STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . 52 3.1 Non Critical Studies Using Active Ingredient . . . . . . . . . . . . . . . . . . . . 55 3.2 Non Critical Mode of Action or Metabolite Studies . . . . . . . . . . . . . . . 57 4.0 THIDIAZURON OCCUPATIONAL HANDLER RISK ASSESSMENT . . . . . 58 1 1.0 Executive Summary This risk assessment was performed to support the reregistration eligibility decision for thidiazuron [ 1 phenyl 3( 1,2,3 thidiazol 5 yl) urea]. Thidiazuron is a phenylurea herbicide used for the defoliation of cotton. It removes green leaves and immature fruiting structures which contribute to cotton staining. Thidiazuron registered formulations include wettable powders ( WP), soluble concentrates ( SC), emulsifiable concentrates ( EC), and liquids. These formulations can be applied by ground or air. Thidiazuron is primarily used in the major cotton producing areas which consist of the Mid South, Southeast, and Western United States.

The submitted studies provide adequate information to determine whether thidiazuron poses a human health hazard. The Agency is confident that the risk estimates presented in this document represent conservative approximations of human health risks associated with the use of thidiazuron.

The available toxicity data indicate the acute oral, dermal, inhalation, and primary eye and dermal irritation toxicity of thidiazuron to be in toxicity categories III and IV. Thidiazuron is not a dermal sensitizer or a skin irritant.

Both subchronic and chronic toxicity studies in rats show that thidiazuron causes decreased body weights, body weight gains, and food consumption. In addition, chronic toxicity studies showed bilateral vesicle atrophy in rats, and dilated tubules of epididymis in mice. In the subchronic toxicity study, small vesicles and prostate were also reported. The data from the developmental toxicity studies in rats and rabbits and of the 2 generation reproduction study indicated no increase in susceptibility of fetuses and pups to the in utero and/ or postnatal exposure to thidiazuron.

No neurotoxicity was reported in any of the studies. Carcinogenicity studies in both rats and mice produced no treatment related increase in tumor incidence. The standard battery of genotoxicity tests was negative.

HED has selected a chronic reference dose ( RfD) for the dietary risk assessment, and calculated the Population Adjusted Dose ( PAD), which is the RfD divided by the FQPA safety factor. Based on the hazard data, HED recommends the special FQPA SF be reduced to 1X because there are no/ low concerns and no residual uncertainties with regard to pre and/ or postnatal toxicity. Therefore, the PAD is equal to the RfD. The developmental rabbit study and the oneyear dog study were the primary studies used for the dose response assessment. The one year dog study was chosen for the chronic RfD. The PAD for chronic effects ( general population) is equal to the chronic reference dose of 0.0393 mg/ kg/ day. An acute dietary endpoint was not selected because appropriate toxicity attributed to a single exposure was not identified. At the limit dose ( 1000 mg/ kg), no systemic toxicity or dermal irritation was noted in the 28 day dermal toxicity study in the rat; therefore, no dose was selected for short and intermediate term dermal risk assessments. The developmental rabbit study was selected for both the short and intermediate term inhalation and incidental oral exposure scenarios.

Currently, the combined residues of thidiazuron and its aniline containing metabolites are 2 regulated ( 40 CFR180.403) in plants and livestock. Tolerances are established in/ on cottonseed ( 0.4 ppm), eggs ( 0.1 ppm), and milk ( 0.05 ppm). Additional tolerances are set at 0.2 ppm for the fat, meat and meat by products of cattle, goats, hogs, horses, poultry and sheep. An 0.8 ppm tolerance for cottonseed hulls has been revoked by the Agency. The HED Metabolism Assessment Review Committee ( 9/ 29/ 95, F. Fort) has determined that the residue of concern in plant commodities consists of the parent thidiazuron only, and that the residues of concern in livestock commodities consist of the parent thidiazuron, 4 hydroxythidiazuron, and phenyl urea. HED recommends that the tolerances for thidiazuron reflect the residues of concern as determined by the MARC, instead of thidiazuron and its aniline containing metabolites collectively.

A Tier I dietary exposure assessment for food only was performed using DEEM FCID   and Lifeline   . The assumptions of these dietary exposure assessments were tolerance level residues and 100% crop treated, with the exception of meat, meat byproducts, and fat tolerances. The dietary exposure analyses in this assessment for thidiazuron result in dietary risk estimates for food that are below the Agency's level of concern for chronic dietary exposure. Estimates from both models show that the chronic exposure is < 8% of the cPAD.

Potential drinking water concentrations for the acute and chronic assessments were estimated using two EFED Tier 1 screening level models: FIRST, Version 1.0 and SCI GROW, Version 2.3. Since the HED Metabolism Assessment Review Committee ( MARC) did not determine the residues of concern for water, EFED provided three estimates for possible drinking water concentrations. The most conservative numbers were used in this risk assessment, which included thidiazuron and both photoproducts, photo thidiazuron and 1 cyano 3 phenylurea in its estimate.

There are no residential uses for thidiazuron. It is only registered for agricultural use as a cotton defoliant late in the growing season. Therefore, residential exposures and risks are not expected.

Since there are no residential uses, the aggregate exposure assessment for thidiazuron considered exposures from food and drinking water only. A Tier I chronic dietary risk assessment was conducted using the Dietary Exposure Evaluation Model ( DEEM FCID   ) , Version 2.0, and Lifeline   Model Version 2.0. The assumptions of these dietary exposure assessments were tolerance level residues and 100% crop treated, with the exception of meat, meat byproducts and fat. The most conservative water concentration estimate was used for the chronic dietary assessment, as provided from the EFED Drinking Water Assessment memo. The dietary exposure analyses in this assessment for thidiazuron resulted in dietary risk estimates for food and water that are below the Agency's level of concern for chronic dietary exposure. Estimates from both models show that the chronic exposure is < 8% of the cPAD for thidiazuron.

There is a potential for occupational exposure to thidiazuron when making applications by aerial or ground equipment to late season cotton. Tasks associated with occupational thidiazuron use include mixing, loading and applying the chemical or guiding aerial applications ( flaggers). All these activities are collectively referred to as handler tasks. A total of 5 scenarios were considered representative of the range of handler activities, available formulations, and equipment used for applications to cotton. Risks from dermal exposures were not calculated because no hazard concern was identified for exposures to the skin. Risks for inhalation exposures were calculated for varying levels of personal protection, including engineering controls such as water Page 3 of 59 soluble bags in which thidiazuron is currently marketed. For uses of this type, the Agency generally considers both short and intermediate term exposures. In this case, both the short and intermediate term risk assessment for thidiazuron were based on a developmental toxicity study in rabbits where increased abortions were noted and the NOAEL was determined to be 25 mg/ kg/ day. The total uncertainty factor applied in this assessment was 100 to account for interand intra species differences.

Inhalation risks were calculated assuming one of four possible levels of personal protection ranging from a baseline of no respiratory protection to engineering controls, such as water soluble bags. Current thidiazuron labels typically require that handlers wear long pants, long sleeved shirts, and gloves but do not require respirators. The wettable powder formulations of thidiazuron marketed by Bayer Crop Sciences are sold in water soluble bags and account for the vast majority of wettable powders sold on an annual basis. For all scenarios considered, even for high acreages without the use of a respirator or engineering controls, inhalation risks were not of concern for thidiazuron handlers ( i. e., most MOEs > 10,000).

The Agency recognizes that most activities associated with the cultivation and harvest of cotton are predominantly accomplished in an intensively mechanized fashion that essentially eliminates exposures for most of the workers involved. However, some workers can be exposed to thidiazuron residues when entering previously treated areas to perform certain activities such as scouting or those associated with harvesting ( i. e., rakers, trampers, module builders). Current label requirements specify 24 hour restricted entry intervals ( REIs), while pre harvest intervals ( PHIs) are currently 5 days. The Agency believes that dermal exposures may occur for postapplication workers, but they are not of concern because the available data for these activities show exposures to be low and the Agency has not identified any hazard concerns associated with dermal exposures. The Agency also does not routinely complete postapplication worker inhalation risk assessments because available exposure data show they do not occur at appreciable levels.

In conclusion, human health risks are considered to be minimal due to thidiazuron's low acute toxicity ( toxicity categories III and IV) and its low dietary risk. Carcinogenicity studies reported no treatment related increase in tumor incidence for thidiazuron. There are no residential uses for thidiazuron. Occupational use data show dermal exposures to be low and inhalation risks were not of concern for thidiazuron handlers ( i. e., most MOEs > 10,000).

Data gaps include:

Toxicology There are no toxicological data gaps.

Residue Chemistry Guideline 860.1340 Residue Analytical Method Livestock Guideline 860.1380 Storage Stability Data Plant and Livestock Page 4 of 59 Occupational/ Residential Exposure There are no occupational/ residential exposure data gaps.

2.0 Ingredient Profile Thidiazuron is a herbicide which defoliates green leaves and immature fruiting structures that contribute to cotton staining. For formulations containing thidiazuron as a single active ingredient, a maximum of two, 0.05 0.2 lbs. a. i./ acre applications may be applied to mature cotton plants, not exceeding a total rate of 0.3 lb a. i./ A/ season ( 0.337 kg a. i./ ha/ season). For formulations containing a mixture of thidiazuron and diuron, a maximum of two, 0.05 0.125 lb thidiazuron a. i./ acre applications may be applied, not exceeding a total rate of 0.125 lb thidiazuron a. i./ A/ season ( 0.568 kg a. i./ ha/ season). The minimum PHI is 5 days, and the REI is 24 hours. Thidiazuron registered formulations include wettable powders ( WP), soluble concentrates ( SC), emulsifiable concentrates ( EC), and liquids. The percentage of thidiazuron used in each formulation type ranges from 8.4 50% active ingredient per pound formulated. These formulations can be applied by aerial or ground equipment.

2.1 Summary of Registered/ Proposed Uses Table 2.1 provides a summary of registered uses for thidiazuron.

Table 2.1. Summary of Directions for Use of Thidiazuron on Cotton.

Applic. Timing Applic. Type Applic. Equip. Formulation [ EPA Reg. No.] Applic. Rate ( lb ai/ A) Max. No. Applic. per Season Max. Seasonal Applic. Rate ( lb ai/ A) PHI ( days) REI ( hours)

Preharvest Low Volume Spray ( concentrate) Aircraft 000264 00622 0.2; 0.1 2 0.3 5 24 Preharvest Broadcast Ground 000264 00622 0.2; 0.1 2 0.3 5 24 Preharvest Direct Spray Ground 000264 00622 0.05 2 0.3 5 24 Preharvest Broadcast Aircraft 051036 00401 0.2; 0.1 2 0.3 5 24 Preharvest Broadcast Ground 051036 00401 0.2; 0.1 2 0.3 5 24 Preharvest Direct Spray Ground 051036 00401 0.05 2 0.3 5 24 Preharvest Broadcast Aircraft 000264 00634 0.05 0.125 2 0.125 5 24 Preharvest Broadcast Low Pressure Ground Sprayer 000264 00634 0.05 0.125 2 0.3 5 24 Preharvest Low Volume Spray ( concentrate) Aircraft 000264 00661 0.05 0.125 2 0.125 5 24 Preharvest Spray Ground 000264 00661 0.05 0.125 2 0.125 5 24 Table 2.1. Summary of Directions for Use of Thidiazuron on Cotton.

Applic. Timing Applic. Type Applic. Equip. Formulation [ EPA Reg. No.] Applic. Rate ( lb ai/ A) Max. No. Applic. per Season Max. Seasonal Applic. Rate ( lb ai/ A) PHI ( days) REI ( hours)

Page 5 of 59 N N S N H N H O Foliar Low Volume Spray ( concentrate) Aircraft 000400 00505 0.075 2 0.3 5 48 Foliar Broadcast Ground 000400 00505 0.075 2 0.3 5 48 Preharvest Spray Ground 000264 00700 0.2; 0.1 2 0.3 5 24 Preharvest Spray Aircraft 000264 00700 0.2; 0.1 2 0.3 5 24 Preharvest Spray Ground 000264 00821 0.05 0.125 2 0.125 5 24 Preharvest Spray Aircraft 000264 00821 0.05 0.125 2 0.125 5 24 Preharvest Spray Ground 72167 30 0.05 0.2 2 0.3 5 24 Preharvest Spray Aircraft 72167 30 0.05 0.2 2 0.3 5 24 Preharvest Spray Ground 51036 429 0.05 0.125 2 0.125 5 24 Preharvest Spray Aircraft 51036 429 0.05 0.125 2 0.125 5 24 Preharvest Spray Ground 51036 430 0.05 0.2 2 0.3 5 24 Preharvest Spray Aircraft 51036 430 0.05 0.2 2 0.3 5 24 2.2 Structure and Nomenclature Tables 2.2a 2.2e provide structures and nomenclature for thidiazuron and its metabolites.

TABLE 2.2a Thidiazuron Test Compound Nomenclature Chemical Structure Empirical Formula C9H8N4OS Common name Thidiazuron IUPAC name 1 phenyl 3( 1,2,3 thidiazol 5 yl) urea CAS name N phenyl N' 1,2,3 thiadiazol 5 ylurea CAS Registry Number 51707 55 2 End use product/ EP DROPP ® 50WP; FreeFall; DROPP ® SC; Ginstar ® EC; Thidiazuron 50 WSB; Leafless Chemical Class Herbicide , defoliant Page 6 of 59 TABLE 2.2b 4 Hydroxy Thidiazuron Test Compound Nomenclature Compound Chemical Structure Common name 4 Hydroxy Thidiazuron IUPAC name 1( 4 hydrophenyl) 3( 1,2,3 thidiazol 5 yl) urea CAS name N( 4 hydroxyphenyl N' 1,2,3 thidiazol 5 yl) urea CAS # NA TABLE 2.2c Phenyl Urea Test Compound Nomenclature Compound Chemical Structure Common name Phenylurea IUPAC name 1 phenylurea CAS name N phenylurea CAS # 64 10 8 TABLE 2.2d Photo Thidiazuron Test Compound Nomenclature Compound Chemical Structure Common name Photo Thidiazuron IUPAC name 1 phenyl 3( 1,2,5 thidiazole 3 yl) urea CAS name N phenyl N' 1,2,5 thiadiazol 5 ylurea CAS # 71769 74 9 Page 7 of 59 NH C O NH C N TABLE 2.2e 1 Cyano 3 Phenylurea Test Compound Nomenclature Compound Chemical Structure IUPAC name 1 cyano 3 phenylurea 2.3 Physical and Chemical Properties Technical thidiazuron is a yellowish brown, amorphous solid with a melting point of 217 ° C. Thidiazuron is miscible with dimethylsulfoxide, dimethylformanide, acetone, cyclohexanone, and isophrone, and slightly soluble in other organic solvents. It has a vapor pressure of 3.5 x 10 9 mPa at 20

C, and a water solubility of 31.0 mg/ L at 25

C. Thidiazuron is a member of the phenylurea group of herbicides, that includes diuron and linuron. Additional physicochemical properties can be found in Table 2.3.

TABLE 2.3. Physicochemical Properties Parameter Value1 Reference Molecular Weight 220.25 g Merck 12,9447 Melting point/ range 217

C Merck 12,9447 pH ( 20

C) 5.21 D295368, Shyam Mathur, 3/ 1/ 04.

Density ( 20

C) 0.324 gm/ cc D295368, Shyam Mathur, 3/ 1/ 04.

Water solubility ( 25

C, pH 7.0) 31.0 mg/ L D295368, Shyam Mathur, 3/ 1/ 04.

Solvent solubility ( temperature not specified) Very soluble in dimethylsulfoxide, dimethylformanide, acetone, cyclohexanone, and isophrone. Slightly soluble in aliphatic and aromatic hydrocarbons and water. Merck 12,9447 Vapor pressure ( 20

C) 3.5 x 10 9 mPa D295368, Shyam Mathur, 3/ 1/ 04.

Dissociation constant, pKa ( 25

C) 8.86 D295368, Shyam Mathur, 3/ 1/ 04.

Octanol/ water partition coefficient, Ko/ w ( 25

C, pH 7.3) 50.0 D295368, Shyam Mathur, 3/ 1/ 04.

UV/ visible absorption spectrum   max = 238 nm;   = 985 M 1 cm 1 D295368, Shyam Mathur, 3/ 1/ 04.

1 NA= Not Available Page 8 of 59 3.0 Metabolism Assessment 3.1 Comparative Metabolic Profile In cotton, thidiazuron defoliates green leaves and immature fruiting structures. In plants, thidiazuron is the major metabolite.

An oral metabolism study in rats indicates that thidiazuron is rapidly absorbed and eliminated primarily in the urine with most of the administered dose excreted by 5 days postdosing. The major route of elimination was shown to be via urine. Identification of urinary metabolites indicated the presence of oxidative metabolite ( 4 hydroxy thidiazuron) in urine and the presence of sulfate and glucuronide conjugates of 4 hydroxy thidiazuron. In feces, the major metabolites identified were 4 hydroxy thidiazuron at the low dose and unmetabolized thidiazuron at the high dose. Livestock metabolite phenylurea and water metabolites photo thidiazuron and 1 cyano 3 phenylurea were not found in the oral rat metabolism study.

3.2 Nature of the Residue in Foods 3.2.1. Description of Primary Crop Metabolism The metabolism of thidiazuron in plants has been adequately defined for the current uses through the study of thidiazuron 14C radiolabeled in the phenyl and thiazoyl rings and applied to cotton plants. Several studies have been conducted, the results of which are shown in Tables 3.2.1a 3.2.1c below. Based on these results, it was concluded by the HED Metabolism Committee ( 9/ 8/ 95, F. Fort) that the residue of concern for cotton consists of the parent only, thidiazuron.

Table 3.2.1a Metabolites in Cotton from the Application of 14C Thidiazuron labeled in the phenyl ring1 Residue Identified Leaves ( 21.88 ppm) Seeds ( 0.04 ppm)

% TRR PPM % TRR PPM thidiazuron 29 6.31 60 0.02 photoproduct 13 2.76 7 < 0.008 bound residue 38 8.27 < 12 < 0.008 origin 13 2.77 15 < 0.008 unknown I 6 1.36 6 < 0.008 unknown II 2 0.41 ND < 0.008 1. 14C thidiazuron was applied at a rate of 0.2 lb ai/ A ( 1x). Identification was accomplished by one method, thin layer chromatography, and two solvent systems. Page 9 of 59 Table 3.2.1b Metabolites in Cotton for the Application of Thidiazuron labeled in the thidiazolyl and phenyl rings. 1 Metabolite Thiadiazolyl labeled ( 2.96 ppm) Phenyl labeled ( 3.92 ppm)

TRR ( ppm) Percent TRR TRR ( ppm) Percent TRR Thidiazuron 2.23 75.2 3.07 78.4 Photoproduct 0.04 1.5 0.02 0.4 Not Identified 0.69 23.3 0.83 21.2 1. 14C thidiazuron was applied at a rate of 0.2 lb ai/ A ( 1x). Identification was accomplished by one method, thin layer chromatography, and two solvent systems.

Table 3.2.1c Metabolites Found in Cotton Foliage after Application of 14C Thidiazuron labeled in the phenyl ring Residues % TRR Thidiazuron 79.2 Photoproduct 0.2 Origin 2.1 Other products 0.6 Not Extracted 0.3 Unaccounted 17.6 Total 100 1. Ten mls of 14C thidiazuron was brushed on the leaves. Identification was accomplished by one method, thin layer chromatography, and two solvent systems.

3.2.2 Description of Livestock Metabolism The nature of the residue in animals is adequately understood.

Ruminant metabolism: [ 14C aniline] thidiazuron was fed at a dose exaggeration of 1.9x to a lactating cow at a rate of 10 ppm for seven days. The animal was sacrificed within 24 hours of administration of the final dose. Parent equivalent radioactivity found was 0.05 ppm, 0.1 ppm, 1.5 ppm, and 1.0 ppm in fat, muscle, kidney and liver, respectively. Radioactivity reached a plateau in milk on the second day ( 0.2 ppm). Analysis was performed using HPLC and TLC.

Poultry metabolism. [ 14C aniline] thidiazuron was fed once daily at a dose exaggeration of 100x to six hens for fourteen days at a rate of 8 ppm. Radioactivity did not plateau in eggs during this Page 10 of 59 period. All tissues were first treated with protease and   glucuronidase prior to extraction. Parent equivalent radioactivity found was 0.02 ppm, 0.27 ppm, 1.11 ppm, 0.66 ppm, 0.10 ppm, 0.10 ppm and 0.34 ppm in fat, gastrointestinal tract, gastro intestinal tract contents, liver, muscle, skin and blood, respectively.

Identification and characterization of residues in livestock are shown in Tables 3.2.2a and 3.2.2b. Based on these results, it was concluded by the HED Metabolism Committee ( 9/ 8/ 95, F. Fort) that the residues of concern for livestock commodities are thidiazuron, 4 hydroxy thidiazuron, and phenylurea.

Table 3.2.2a Metabolites in Ruminant Tissues and Milk from A Lactating Cow Dosed with 14Cthidiazuron labeled in the phenyl ring 1.9x.

Metabolite Liver ( 1.0 ppm) Kidney ( 1.5 ppm) Muscle ( 0.1 ppm) Fat ( 0.05 ppm) Milk ( 0.2 ppm)

% TRR ppm % TRR ppm % TRR ppm % TRR ppm % TRR ppm Thidiazuron 2 0.02 3 0.04 58 0.058   31 0.062 Phenylurea 13 0.13 15 0.23 2 0.002 10 0.00 5 3 0.006 4 hydroxythidiazuron 4 0.04 6 0.09 1 0.001 2 0.00 1 49 0.098 phenylurea conjugate 15 0.15 18 0.27   7 0.00 4 < 3 < 0.006 4 hydroxythidiazuron conjugate 36 0.36 11 0.16 13 0.013 46 0.02 3 < 3 < 0.006 Polar Fraction 22 0.22 23 0.35   11 0.00 5 11 0.022 Total 92 0.92 76 1.14 74 0.073 76 0.03 8 < 100 < 0.2 Table 3.2.2b Metabolites in Poultry and Eggs from a Laying Hen with 14C thidiazuron labeled in the phenyl ring 100x.

Liver ( 0.66 ppm) Muscle ( 0.10 ppm) Fat ( 0.02 ppm) Eggs ( 0.15 ppm)

% TRR ppm % TRR ppm % TRR ppm % TRR ppm Thidiazuron   2 0.002 2 0.0004 20 0.03 Phenylurea 9 0.059 8 0.008 9 0.0018 16 0.024 4 hydroxy thidiazuron 5 0.033 3 0.003 4 0.0008

Component G ( phenylurea conjugate) 14 0.092 18 0.018 11 0.0022   Page 11 of 59 Component H ( 4 hydroxythidiazuron conjugate) 64 0.422 22 0.022 56 0.0112 22 0.033 Polar Fraction 3 0.020 17 0.017 11 0.0022 13 0.02 Total 95 0.626 70 0.07 93 0.0186 71 0.107 3.2.3 Description of Rotational Crop Metabolism, including identification of major metabolites and specific routes of biotransformation Confined and field accumulation rotational crop studies ( MRID No. 44415501, 10/ 26/ 04, T. Jimerson and MRID No. 46298401, 11/ 8/ 04, T. Jimerson) were submitted and are now acceptable for thidiazuron.

In the confined accumulation study, an unidentified component designated Metabolite A was detected in both the organic and hydrolyzed aqueous fractions of 14 days after treatment ( DAT) wheat straw, totaling 0.046 ppm and 26.4% TRR. In 60 DAT straw ( hydrolyzed aqueous) and 120 DAT straw ( organic fraction), respectively, Metabolite A accounted for 4.1 and 8.8% TRR ( 0.007 and 0.010 ppm). Metabolite A was chromatographically compared to available metabolite standards as well as reasonable candidate compounds available from synthesis without demonstrating a match. However, the metabolite was found to be more polar ( from TLC behavior) than any of the compounds tested. Furthermore, some of Metabolite A arose from hydrolysis of the aqueous extractable residues, demonstrating that it is capable of forming watersoluble conjugates in the plant.

An additional metabolite identified as 1,2,3 thiadiazol 5 yl urea, was also detected at 0.023 ppm ( 13.0% TRR) in 14 DAT wheat straw and 0.014 ppm ( 48.6% TRR) in 60 DAT cabbage; the metabolite accounted for 0.005 0.011 ppm ( 3.1 9.2% TRR) in 60, 120, and 365 DAT wheat straw. A summary of metabolite identification in rotated crops is presented in Table 3.2.3.

Table 3.2.3 Summary of radioactive residues identified in rotated crops following application of [ 14C] thidiazuron at the 5 thiadiazol position to cotton at ~ 1x.

Crop matrix DAT Fraction 1,2,3 thiadiazol 5 yl urea Metabolite A ppm % TRR ppm % TRR Wheat straw 14 Organic 0.023 13 0.032 18.4 Aqueous ( hydrolyzed) ND ND 0.014 8 Total 0.023 13 0.046 26.4 60 Aqueous ( hydrolyzed) 0.006 3.1 0.007 4.1 120 Organic 0.011 9.2 0.01 8.8 365 Organic 0.005 9.2 ND ND Table 3.2.3 Summary of radioactive residues identified in rotated crops following application of [ 14C] thidiazuron at the 5 thiadiazol position to cotton at ~ 1x.

Page 12 of 59 Cabbage 60 Organic 0.014 48.6 ND ND In the field accumulation study, no thidiazuron residues greater than LOQ (> 0.05 ppm) were detected in any of the treated rotational crops, which included leafy vegetable, root, and small grain crops. Therefore, samples were not analyzed after the shortest plant back interval ( PBI) which was 14 days for wheat and 1 month for root, leafy vegetable, and other small grain crops. It was expected that the recovered residues would be even lower in later PBIs. Thus, no tolerances are needed for rotational crops at the designated plant back intervals of 2 weeks for wheat and 1 month for root, leafy vegetable, and other small grain crops.

3.3 Environmental Degradation In soil, thidiazuron is persistent, as evidenced by laboratory and field half lives in the order of one year. It has moderate soil sorption coefficients. Such persistence and intermediate mobility would allow some year to year accumulation as well as time and, therefore, opportunity for favorable conditions for runoff from application sites to occur. With the hypothetical assumption that there is no significant physical movement of thidiazuron from a site of application for several years, then, with a one year half life and uniform annual applications, the asymptotic limit of build up would result in soil concentrations that would approach twice that of the yearly application amount. Runoff concentrations would be affected similarly.

When thidiazuron reaches surface water, photolysis is expected to be the major route of transformation; other degradative processes are essentially negligible by comparison. Aqueous photolysis is rapid, and occurs by branching in quantitative yield into two photoproducts: photothidiazuron and 1 cyano 3 phenylurea. One of the photodegradates, photo thidiazuron, is a structural isomer of parent, while the other, 1 cyano 3 phenylurea, has a substantially altered chemical structure. These degradates are identified in Tables 2.2d and 2.2e of the Ingredient Profile section by chemical name and structural formula. Ground water is not impacted by these degradates because all field studies show that parent is long lived in soil ( half lives of the order of one year) with only minimal evidence of photolysis.

Photo thidiazuron has a maximum experimental limit of production of 77% of parent equivalents at pH 5, 28% at pH 7, and 17% at pH 9. This photoproduct was stable to further photolysis under experimental study conditions. The second photodegradate, 1 cyano 3 phenylurea, is substantially different from the parent thidiazuron. It has a complementary asymptotic limit of production to photo thidiazuron of 23% of parent at pH 5, 72% at pH 7, and 83% at pH 9. This product was also stable to further photolysis under study conditions. Thus, at different environmental pHs, the parent, thidiazuron, is always quantitatively converted in complementary proportions into the two photodegradates. Page 13 of 59 3.4 Tabular Summary of Metabolites and Degradates Page 14 of 59 N N S N H N H O Table 3.4. Tabular Summary of Metabolites and Degradates Chemical Name ( other names in parenthesis) Commodity Percent TRR ( PPM) Structure Thiadiazolyl Label Phenyl Label Thidiazuron Cottonseed 75.2% 78.4%

Rotational Crops  ND in wheat straw ND in cabbage Ruminant  2% in liver  3% in kidney  58% in muscle 31% in milk Poultry  2% in muscle  2% in fat  20% in eggs Rat 0.1 0.3%

Water

Phenylurea Cottonseed

Rotational Crops

Ruminant  13% in liver  15% in kidney  2% in muscle  10% in fat  3% in milk Poultry  9% in liver  8% in muscle  9% in fat  16% in eggs Rat 1% 1

Water

4 hydroxythidiazuron Cottonseed

Rotational Crops

Ruminant  4% in liver  6% in kidney  1% in muscle  2% in fat   49% in milk Poultry  5% in liver  3% in muscle  4% in fat Rat 47% 2

Water

Cottonseed, Ruminant, Poultry; Thidiazuron Metabolism, F. Fort, 9/ 8/ 95; 0.2 lb ai/ A; 1x rate Rat Metabolism; MRID No. 42529001; single oral gavage dose 10 mg/ kg 1 Tentative identification 2 Includes conjugates of 4 hydroxythidiazuron 3.5 Toxicity Profile of Major Metabolites and Degradates Page 15 of 59 Livestock metabolite 4 hyroxythidiazuron and water metabolite photo thidiazuron are structurally similar to the parent compound. There is no specific toxicity data available for either metabolite, therefore it is assumed that the metabolites and the parent compound share similar toxicity.

Additionally, the registrant has not submitted specific toxicity data for the livestock metabolite phenylurea. Phenylurea is structurally similar to the phenylurea herbicides monuron and diuron, which have been shown to produce hemolytic anemia and other adverse hematologic effects. Therefore, in absence of evidence to the contrary, phenylurea is assumed to have similar effects to the parent compound. This justification is also applicable to the water metabolite 1 cyano 3 phenylurea.

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 Parent Parent Rotational Crop Parent Parent Livestock Ruminant Parent, 4 hydroxythidiazuron, Phenylurea Parent, 4 hydroxythidiazuron, Phenylurea Poultry Parent, 4 hydroxythidiazuron, Phenylurea Parent, 4 hydroxythidiazuron, Phenylurea Drinking Water Parent, Photo thidiazuron, 1 cyano 3 phenylurea Not Applicable 3.6.2 Rationale for Inclusion of Metabolites and Degradates Metabolites and degradates included in this risk assessment are based on recommendations from the HED Metabolism Assessment Review Committee and the Thidiazuron Drinking Water Assessment memo provided by EFED.

The MARC ( 9/ 29/ 95) has determined that the residue of concern in plant commodities consists of the parent only, and that the residues of concern in animal commodities consist of the parent thidiazuron, 4 hydroxythidiazuron, and phenylurea. The MARC did not determine the residues of concern for water. EFED provided three surface water exposure scenarios and one ground water concentration estimate for thidiazuron using two EFED Tier 1 screening level models: FIRST, Version 1.0 and SCI GROW, Version 2.3. The most conservative numbers were used in this risk assessment, which included thidiazuron and both photoproducts, photo thidiazuron and 1 cyano 3 phenylurea in its estimate. Page 16 of 59 Residues of the livestock metabolite phenylurea were found in ruminant liver, kidney, muscle, fat and milk and poultry liver, muscle, fat and eggs. Phenylurea is structurally similar to the phenylurea herbicides monuron and diuron, which have been shown to produce hemolytic anemia and other adverse hematologic effects. Therefore, in absence of evidence to the contrary, phenylurea is assumed to have similar effects to the parent compound. This justification is also applicable to water metabolite 1 cyano 3 phenylurea.

4 hydroxythidiazuron ( livestock metabolite) residues were found in ruminant liver, kidney, muscle, fat and milk and poultry liver, muscle and fat. 4 hyroxythidiazuron is structurally similar to the parent compound. There is no specific toxicity data available that suggests exclusion of this metabolite is appropriate, therefore it is assumed that the metabolite and the parent compound share similar toxicity. This rationale is also applicable to water metabolite photo thidiazuron.

4.0 Hazard Characterization/ Assessment 4.1. Hazard and Dose Response Characterization 4.1.1. Database Summary <IP_ADDRESS>. Studies available and considered Available toxicity studies include a complete acute battery of tests ( acute oral toxicity, acute dermal toxicity, acute inhalation toxicity, acute eye irritation, acute dermal irritation and dermal sensitization), subchronic ( 90 day) feeding studies in the rat and mouse, a subchronic dermal toxicity study in the rat, chronic studies ( including a combined chronic feeding/ carcinogenicity study in the rat, a carcinogenicity study ( feeding) in the mouse and a chronic oral study ( feeding) in the dog), developmental toxicity studies in both the rat and rabbit and a two generation reproduction study in the rat, and a complete mutagenicity battery ( in vitro bacterial reverse gene mutation, in vitro chromosomal aberration assay, gene mutation assays in Chinese hamster lung ( V79) cells and a mouse in vivo mammalian cytogenetics  micronucleus assay). A brief summary of the studies is presented in Tables <IP_ADDRESS>a and <IP_ADDRESS>b. There are no data available from the general literature, including human clinical or exposure data at this time.

<IP_ADDRESS>. Mode of action, metabolism, toxicokinetic data In cotton, thidiazuron defoliates green leaves and immature fruiting structures . In test animal, the toxic mode of action is not clear.

An oral metabolism study in rats indicates that thidiazuron is rapidly absorbed and eliminated primarily in the urine with most of the administered dose excreted within 5 days postdosing. The major route of elimination was shown to be via urine. Identification of urinary metabolites indicated the presence of oxidative metabolite ( 4 hydroxy thidiazuron) in urine and the presence of sulfate and glucuronide conjugates of 4 hydroxy thidiazuron. In feces, the major metabolites identified were 4 hydroxy thidiazuron at the low dose and unmetabolized thidiazuron at the high dose. Page 17 of 59 <IP_ADDRESS>. Sufficiency of studies/ data The submitted studies provide adequate information to determine whether thidiazuron poses a human health hazard.

4.1.2. Toxicological Effects The available toxicity data indicate the acute oral, dermal, inhalation, and primary eye and dermal irritation toxicity of thidiazuron to be in toxicity categories III and IV. Thidiazuron is not a dermal sensitizer or a skin irritant.

Both subchronic and chronic toxicity studies in rats showed that thidiazuron caused toxicity as demonstrated by decreased body weights, body weight gains, and food consumption. Decreased epididymides and prostate gland weights, small prostate and small seminal vesicles were seen in subchronic studies in the rats. In addition, microscopic findings were observed in the prostate gland, seminal vesicle, mammary gland, thymus, the bone and marrow of the sternum and ovary, adrenal gland, kidney, liver, and spleen. Increased bilateral seminal vesicle atrophy and nephrotoxicity was seen in the chronic rat study. Nephrotoxicity and epididymis toxicity was seen in the chronic mouse study. The results of the subchronic feeding study in mice showed that thidiazuron produced increased incidences of centrilobular hepatocellular hypertrophy in the males and diffuse acinar hypertrophy in the salivary glands in the females.

In developmental toxicity studies, maternal toxicity such as increased incidence of abortions and decreases in the body weight and food consumption were seen in rabbits at 125 mg/ kg/ day. At the same dose, developmental toxicity observed was abortions, decreased fetal weight, increased number of runts, and delayed skeletal ossification.

In the rats, maternal toxicity such as decreased body weight gains was seen at 300 mg/ kg/ day. At the same dose, developmental toxicity observed was decreased fetal weight.

In a 2 generation reproduction study in rats, maternal toxicity such as decreased body weight gain was seen at 108 mg/ kg/ day. The test chemical did not significantly affect any of the reproductive parameters. For the offsprings, there was a decrease in pup body weight gain at 108 mg/ kg/ day.

No neurotoxicity was reported in any of the studies.

Carcinogenicity studies in both rats and mice produced no treatment related increase in tumor incidence.

The standard battery of genotoxicity tests was negative.

4.1.3. Dose response The developmental rabbit study and the one year dog study were the primary studies used for the dose response assessment. The dog is the most sensitive species noted from testing with thidiazuron with the effects occurring at considerably lower doses than those noted for the rat or Page 18 of 59 mouse. The one year dog study was chosen for the chronic RfD. Based on the available toxicity data, no acute toxicity endpoint could be identified. At the limit dose ( 1000 mg/ kg), no systemic toxicity or dermal irritation was noted in the 28 day dermal toxicity study in the rat; therefore no endpoint was selected for short and intermediate term dermal risk assessments. The developmental rabbit study was selected for both the short and intermediate term inhalation and incidental oral exposure scenarios.

Table <IP_ADDRESS>a Acute Toxicity Profile Thidiazuron Technical Guideline No. Study Type MRIDs # Results Toxicity Category 870.1100 Acute Oral  Rat 46121501 LD50 > 2 g/ kg III 870.1200 Acute Dermal  Rat 46121502 LD50 > 5 g/ kg IV 870.1300 Acute Inhalation  Rat 46121503 LC50 > 3.48 mg/ L IV 870.2400 Primary Eye Irritation  Rabbit 42099601 Irritation clearing in 48 hours IV 870.2500 Primary Skin Irritation  Rabbit 42099602 No dermal effects IV 870.2600 Dermal Sensitization  Guinea pig 46121504 Not a skin sensitizer N/ A Table <IP_ADDRESS>b Subchronic, Chronic and Other Toxicity Profile Page 19 of 59 Guideline No./ STUDY TYPE   MRID No. ( year)/ Classification / Doses NOAEL m/ k/ d LOAEL m/ k/ d EFFECTS SEEN at LOAEL 870.4300 2 year combined chronic/ carcinog enicity   RAT 46345201 ( 2004) acceptable 0, 200, 900, or 1800 ppm ( equivalent to 0/ 0, 8.0/ 11.3, 36.4/ 51.4, and 75.6/ 105 mg/ kg/ day) 8 36.4

body weight and body wt gain in ( males),

 bilateral seminal vesicle atrophy, and nephrotoxicity ( both sexes)

Treatment related increase in tumor incidence was not found 870.4300 2 year combined chronic/ carcinog enicity   RAT 00159346 ( 1986) chronic studyacceptable carcinogenicity portionunacceptable 0, 70, 200, or 600 ppm( 0, 3.7, 10.6, or 31.7 mg/ kg/ day for males and 0, 4.6, 13, or 40.1 mg/ kg/ day for females). > 31.7 ( HDT) not established

sporadic & minimal body wt and food consumption observed at 600 ppm ( 31.7 mg/ kg/ day)

870.4200b 18 month carcinogenicity   Mouse 46346001 ( 2004) acceptable 0, 200, 650, or 2000 ppm ( 0/ 0, 26.5/ 33.4, 86.7/ 107.8, and 279.9/ 329.7 mg/ kg/ day in males/ females) 86.7 279.9

body weight, body weight gain, and food consumption;

 nephrotoxicity ( both sexes);

 epididymis toxicity ( males):

 ( i) dilated tubules; ( ii) interstitial mononuclear cell infiltrate; ( iii) unilateral and bilateral oligospermia; and ( iv) spermatic granuloma.

 clinical signs of toxicity ( females).

Treatment related increase in tumor incidence was not found. Guideline No./ STUDY TYPE   MRID No. ( year)/ Classification / Doses NOAEL m/ k/ d LOAEL m/ k/ d EFFECTS SEEN at LOAEL Page 20 of 59 870.4100b 1 year chronic study in dog 00159344 ( 1985) acceptable 0, 100, 300, or 1000 ppm ( 0, 3.93, 11.8, or 38.3 mg/ kg/ day for males and 0, 4.01, 11.1, or 36 mg/ kg/ day for females) 3.93 11.1  incidence of anemia, changes in hematological parameters and marked hemosiderosis in liver and spleen 870.3700a Developmental toxicity   rats 00077127 ( 1981) acceptable 0, 25, 50, 100 or 300 mg/ kg/ day Maternal 100 Developmental 100 Maternal 300 Developmental 300 decreased body wt. gain decreased fetal body wt 870.3700b Developmental toxicity   rabbits 46121507 ( 2003) acceptable 0, 5, 25, or 125 mg/ kg MRID 46252001   historical control data MRID 46241001 range finding developmental toxicity study Maternal 25 Developmental 25 Maternal 125 Developmental 125 Maternal abortions

body weight gains (

70% during GD 6 29)

food consumption (

19% during GD 6 8; 44% during GD 14 18).

Abortions

fetal body weights ( 12 13%)

 number of runts, and delayed skeletal ossification 870.3800 2 generation reproduction study   rat 46209601 ( 2003) acceptable 0, 100, 400, or 1200 ppm ( equivalent to 0/ 0, 8.8/ 9.9, 35.4/ 39.8, and 108.5/ 121.1 mg/ kg/ day [ M/ F] Parental/ Systemic 35.4 Reproductive 108.5 ( HDT)

Offspring 35.4 Parental/ Systemic 108.5 Reproductive   not determined Offspring 108.5

body wt gains ( both sexes)

No treatment related effects were noted on sperm parameters ( enumeration, motility, or morphology) in the P or F1 males.

body wt gains ( both sexes) Vaginal opening was significantly ( p  0.01) delayed in the 108.5 mg/ kg/ day females ( 37.3 days vs 34.3 days for controls. Guideline No./ STUDY TYPE   MRID No. ( year)/ Classification / Doses NOAEL m/ k/ d LOAEL m/ k/ d EFFECTS SEEN at LOAEL Page 21 of 59 870.7485 Metabolism study   RAT 42529001 ( 1992) single oral gavage dose ( 10 or 1000 mg/ kg) or 14 day repeated oral doses at 10 mg/ kg Acceptable Metabolites A/ B, D, and F = sulfate & glucuronide conjugates of Metabolite J Total radioactivity recovered within 5 days after dosing in urine ( U) & feces ( F) = 91 104% of dose. low dose: 60 66% ( U) and 29 31% ( F) repeated dose: 73 75% ( U) and 26 28% ( F) high dose: 41 47% ( U) and 56 60% ( F) Highest conc. of thidiazuron derived radioactivity were found in liver, kidneys, thyroid, whole blood and adrenals.

Urinary metabolites found in low dose group Metabolite J ( 11 19% of dose; 4 hydroxy thidiazuron), Metabolite F ( 14 38%), Metabolite A/ B ( 3 6%), metabolite D ( 5 9%)

870.3200 28 Day Dermal Toxicity  Rat 46261501 ( 2004) acceptable of 0, 100, 300, or 1000 mg/ kg/ day Systemic/ dermal toxicity 1000 ( HDT) Systemic/ dermal toxicity = not determined 870.3100 28 day oral toxicity rat 46121509 ( 2001) SEE under MRID 46121506 ( 90 day oral toxicity) acceptable 0, 900, 1800, or 3600 ppm ( equivalent to 0, 67, 135, and 254 mg/ kg/ day) 67 135

serum glucose and urinary pH, small seminal vesicles and prostate gland, prominent liver lobulation, and focal/ multifocal basophilic tubules in the kidneys. Guideline No./ STUDY TYPE   MRID No. ( year)/ Classification / Doses NOAEL m/ k/ d LOAEL m/ k/ d EFFECTS SEEN at LOAEL Page 22 of 59 870.3100 90 day oral toxicity rat 46121506 ( 2001) acceptable 0, 200, 600, 1800, 5400, or 16,200 ppm ( equivalent to 0/ 0, 11.2/ 14.0, 34.5/ 42.1, 102/ 123, 294/ 325, and [ highest dose not calculated] mg/ kg/ day) 34.5 102

body wts, body wts gains, and food consumption; epididymides and prostate gland wt  ALP; urea microscopic findings in adrenal gland, kidney, liver, and spleen ( both sexes); prostate gland, seminal vesicle, mammary gland, and thymus ( males); bone and marrow of the sternum and ovary ( females)

small prostate and small seminal vesicles 870.3100 90 day oral toxicity mice 46121505 ( 2001) acceptable of 0, 500, 1000, 2000, or 4000 ppm ( equivalent to 0/ 0, 85.2/ 99.8, 170.9/ 202.6, or 351.4/ 383.9 mg/ kg/ day [ M/ F]) 85.2 170.9

cholesterol ( males)

 incidences of centrilobular hepatocellular hypertrophy ( males) and diffuse acinar hypertrophy in salivary glands ( females).

870.7600 dermal absorptionrat 46261502 ( 2004) acceptable 5.0, 0.04 and 0.004 mg/ cm2. Dermal absorption based on the amount in systemic compartment ( excreta & tissues) corresponding to the total amount of test chemical directly absorbed was similar after a 24 hour exposure or a 8 hour exposure and termination at 120 hours post application ( 0.20% and 0.22% for high dose, 0.75% and 1.25% for middle dose, 1.18% and 1.17% for low dose)

870.5265 Reverse gene mutation assay 46121508 ( 2001) acceptable 0, 1.5, 5, 15, 50, 150, 500, or 1500 µ g/ plate ( ± S9, Trial 2) Not mutagenic There was no evidence of induced mutant colonies over background under the conditions of these tests. Guideline No./ STUDY TYPE   MRID No. ( year)/ Classification / Doses NOAEL m/ k/ d LOAEL m/ k/ d EFFECTS SEEN at LOAEL Page 23 of 59 870.5375 In Vitro Chromosomal Aberration Assay 46121510 ( 2001) acceptable 0, 9.4, 18.75, 37.5, 75, 150, 200, or 250 µ g/ mL ( ± S9) Not mutagenic There was no evidence of chromosome aberration induced over background in the presence or absence of S9 activation at either time point.

870.5550 Unscheduled DNA synthesis assay in primary rat hepatocytes 41761103 ( 1990) acceptable 0.25, 0.75, 2.5, 7.5, 25 ug/ mL not mutagenic There were no indications of UDS activity.

870.5300 Gene mutation assay in Chinese hamster V79 cells 41761102 ( 1990) acceptable 15, 30, 100, 250 ug/ mL ( ± S9) Not mutagenic Test chemical did not cause mutations at the HGPRT locus in V79 cells 870.5385 Micronucleus assay 070129 ( 1981) acceptable 2.4, 24, 120 mg/ mL Not mutagenic No increase in micronucleated cells was observed.

4.2 FQPA Hazard Considerations 4.2.1 Adequacy of the Toxicity Database The database for evaluating in utero or postnatal susceptibility is adequate and includes developmental toxicity studies in both rats and rabbits and a two generation reproduction study in the rat.

4.2.2 Evidence of Neurotoxicity The available database indicated that this chemical does not induce neurotoxicity.

4.2.3 Developmental Toxicity Studies Prenatal Developmental Toxicity Study  Rat; OPPTS 870.3700a [ § 83 3a]; OECD 414.

EXECUTIVE SUMMARY:

In a developmental toxicity study ( MRID No. 00077127), 25 presumed pregnant Wistar Han 78 strain rats per group were administered thidiazuron ( purity: 99.4%; batch/ lot No.: 271006B) by oral gavage in Myrj 53 solution at doses of 0, 25, 50, 100 or 300 mg/ kg/ day on gestation days ( GD) 6 15, inclusive. Page 24 of 59 On GD 19, dams were sacrificed and examined grossly. The ovaries and uteri were excised and the number of corpora lutea, live young, resorptions, fetal weights and the incidence of external fetal abnormalities were recorded. Approximately 2/ 3 of the litters were examined for skeletal abnormalities and the 1/ 3 were examined for visceral abnormalities. Uteri were examined for evidence of implantation. Dams were observed daily and weighed on days 0, 6, 15 and 19 of pregnancy.

Maternal Toxicity No dams died during the course of the study. No clinical observations of toxicity were noted. A slight decreased mean body weight gain ( 87% of controls) was observed in the females of the 300 mg/ kg/ day group. The absolute maternal weight decrease was marginal ( 6%) but the weight loss persisted even after termination of treatment ( day 15) ( Table 1). Although maternal toxicity was only marginal at 300 mg/ kg/ day, the previous study ( MRID No. 00077126) also showed significant decreased mean body weight gain ( 90% of controls) at 250 mg/ kg/ day and a frank maternal toxicity ( mortality and reduced body weights) at 900 mg/ kg/ day. Therefore, the two studies taken together, the maternal LOAEL in this study was considered to be 300 mg/ kg/ day based on slightly reduced body weight gains.

The maternal LOAEL was 300 mg/ kg/ day based on reduced body weight gains. The maternal NOAEL was 100 mg/ kg/ day.

Developmental Toxicity There were no differences between the control group and the all treated groups for number of litter size, rate of implantation, and pre and post implantation losses. Mean fetal weights and mean litter body weights were significantly decreased in the 300 mg/ kg/ day group ( Table 1). There were no treatmentrelated external, visceral, or skeletal malformations.

The developmental LOAEL was 300 mg/ kg/ day based on decreased fetal body weights. The developmental NOAEL was 100 mg/ kg/ day.

This study is classified acceptable/ guideline ( OPPTS 870.3700b) and satisfies the requirements for a developmental study in the rat.

Prenatal Developmental Toxicity Study  Rabbit [ OPPTS 870.3700b ( § 83 3b) OECD 414].

EXECUTIVE SUMMARY: In a developmental toxicity study ( MRID 46121507), Thidiazuron ( 99.5% a. i.; Lot/ Batch # 107623 03) in 0.5% ( w/ v) aqueous methylcellulose was administered daily by oral gavage at a dose volume of 4 mL/ kg body weight to 25 female New Zealand White [ KBL ( NZW) lOPS/ SPF] rabbits/ group at dose levels of 0, 5, 25, or 125 mg/ kg on gestation days ( GD) 6 through 28. All does were sacrificed on GD 29; their fetuses were removed by cesarean and examined.

Maternal toxicity:

At 125 mg/ kg/ day, five pregnant females aborted between GD 27 and 29. These abortions were considered to be due to the test substance, either directly or indirectly ( as a result of the marked decreases in food consumption and body weight). Red traces ( 8/ 25 treated vs 1/ 25 controls), placental tissue ( 4/ 25 treated vs 0/ 25 controls), and/ or feto placental tissue ( 5/ 25 treated vs 0/ 25 controls) found on the cage Page 25 of 59 trays corresponded to the abortions. Other clinical signs of toxicity at this dose included increased incidence of soft/ mucoid feces ( 1 3/ 25 treated vs 0/ 25 controls), few feces ( 14/ 25 treated vs 3/ 25 controls), and localized soiled fur ( 4/ 25 treated vs 0/ 25 controls).

Additionally at 125 mg/ kg/ day, cumulative body weight gains from GD 6 were decreased ( p<= 0.05) throughout treatment, resulting in decreased ( p<= 0.01) body weight gains for the overall ( GD 6 29) treatment period, both uncorrected ( decr. 70%) and corrected ( decr. 171%) for gravid uterine weights. Gravid uterine weights of the treated groups were comparable to controls. Food consumption was decreased by 19 44% ( p<= 0.01) at this dose throughout treatment, except for during GD 26 29 which was decreased by 9% ( not significant) compared to controls.

The only findings at 25 mg/ kg/ day were a single abortion thought to be due to maternal stress from gavage error ( i. e., inflammation and red liquid in trachea) and clinical signs associated with abortion ( i. e, red traces and feto placental tissue on tray).

The maternal LOAEL is 125 mg/ kg/ day, based on abortions and decreased body weight gains and food consumption. The maternal NOAEL is 25 mg/ kg/ day.

Developmental toxicity No effects of treatment were noted on numbers of litters, fetuses ( live or dead), resorptions ( early, late, or complete litter), sex ratio, or post implantation loss.

At 125 mg/ kg/ day, fetal body weights were decreased ( p<= 0.01) by 12 13%, and the number of runts was increased compared to concurrent and historical controls. Fetal and/ or litter incidences of the following variations, indicative of skeletal retardation, were increased at 125 mg/ kg/ day over concurrent and historical controls: ( i) unilateral or bilateral holes in the frontal or parietal bones; ( ii) unossification of the atlas centrum; ( iii) unossification of the insertion point( s) on the pelvic girdle; and ( iv) incomplete ossification or unossification of the pubis.

Aside from the above mentioned skeletal retardations, there were no developmental variations that could definitely be attributed to treatment.

There were no treatment related external, visceral, or skeletal malformations.

The developmental LOAEL is 125 mg/ kg/ day, based on decreased fetal body weights, increased number of runts, and delayed skeletal ossification. The developmental NOAEL is 25 mg/ kg/ day. This study is classified acceptable/ guideline ( OPPTS 870.3700b) and satisfies the requirements for a developmental study in the rabbit.

4.2.4 Reproductive Toxicity Study Reproduction and Fertility Effects Study   Rat [ OPPTS 870.3800 ( § 83 4) OECD 416].

EXECUTIVE SUMMARY: In a two generation reproduction toxicity study ( MRID 46209601), Thidiazuron ( 99.5% a. i.; Batch 107623 03) was administered continuously in the diet to Han Wistar ( HsdBrl Han: Wist) rats ( 28 animals/ sex/ dose) at dose levels of 0, 100, 400, or 1200 ppm ( equivalent to Page 26 of 59 0/ 0, 8.8/ 9.9, 35.4/ 39.8, and 108.5/ 121.1 mg/ kg/ day [ M/ F]). The P and F 1 parents were dosed for 10 weeks before they were mated to produce the F 1 and F 2 litters. The F 1 pups were weaned on postnatal day ( PND) 21, and 24 pups/ sex/ group ( 1 pup/ sex/ litter as nearly as possible) were randomly selected as parents of the F 2 generation.

In the parental animals, no treatment related effects were observed on survival, clinical signs, or food consumption or efficiency.

At 1200 ppm, body weight gains were decreased in the P males ( statistics not performed) during premating ( Weeks 0 10) by 10%, and overall ( Weeks 0 17) by 10% ( p

0.05). In the P females at this dose, body weight gains were decreased ( p

0.01) during pre mating by 16%. Body weight gains continued to be decreased ( p

0.05) by 10% throughout gestation ( GD 0 20). In the F 1 females at this dose, an increased ( p

0.01) incidence of five day irregular estrous cycles or acyclicity was observed. However, since no effects were noted on fertility or reproductive performance, this finding was considered equivocal.

No treatment related findings were noted at 100 or 400 ppm.

The LOAEL for parental toxicity is 1200 ppm ( equivalent to 108.5/ 121.1 mg/ kg/ day [ M/ F]), based on decreased body weight gains in both sexes. The NOAEL is 400 ppm ( equivalent to 35.4/ 39.8 mg/ kg/ day [ M/ F]).

In the offspring, no treatment related effects were observed on post implantation survival, live birth, viability, or lactation indices, on the sex ratio, clinical signs, sexual maturation, organ weights, or gross pathology.

At 1200 ppm, body weight gains were decreased (  7 10%; p

0.05) in the F 1 pups during PND 1 21 and during PND 1 28, and in the F 2 pups during PND 1 28 in the males, and during PND 1 21 and PND 1 28 in the females.

No effects of treatment were observed at 100 or 400 ppm.

The LOAEL for offspring toxicity is 1200 ppm ( equivalent to 108.5/ 121.1 mg/ kg/ day [ M/ F]), based on decreased body weight gains in both sexes. The NOAEL is 400 ppm ( equivalent to 35.4/ 39.8 mg/ kg/ day [ M/ F]).

In the parental animals, no treatment related effects were observed on sperm measures, ovarian follicles, corpora lutea, pre coital interval, duration of gestation, or on mating, fertility, gestation, or parturition indices.

The LOAEL for reproductive performance was not observed. The NOAEL for reproductive performance is 1200 ppm ( equivalent to 108.5/ 121.1 mg/ kg/ day [ M/ F]).

This study is classified as acceptable/ guideline and satisfies the guideline requirements ( OPPTS 870.3800; OECD 416) for a two generation reproduction study in the rat.

4.2.5 Additional Information from Literature Sources Page 27 of 59 There were no data available from the general literature, including human clinical or exposure data at this time.

4.2.6 Pre and/ or Postnatal Toxicity <IP_ADDRESS> Determination of Susceptibility There is no evidence of increased susceptibility following in utero or post natal exposure to thidiazuron either in the rat or rabbit developmental toxicity study as well as a two generation reproduction toxicity study in rats.

<IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Postnatal Susceptibility There are no concerns or residual uncertainties for pre and/ or post natal toxicity following exposure to thidiazuron.

4.3 Recommendation for a Developmental Neurotoxicity Study 4.3.1 Evidence that supports requiring a Developmental Neurotoxicity study Abortions and other minimal developmental effects would warrant a recommendation for conducting a developmental neurotoxicity study.

4.3.2 Evidence that supports not requiring a Developmental Neurotoxicity study The available toxicity data showed no neurotoxicity or offspring toxicity in a reproduction study which would warrant a recommendation for conducting a developmental neurotoxicity study.

<IP_ADDRESS> Rationale for the UFDB ( when a DNT is recommended)

A rationale for an UF DB is not required at this time because a DNT study is not recommended, and the toxicity database is otherwise complete.

4.4 Hazard Identification and Toxicity Endpoint Selection Summary of toxicology endpoint selected for thidiazuron are presented in Table 4.4.

4.4.1 Acute Reference Dose ( aRfD)

Based upon the available toxicological data, no acute toxicity endpoint could be identified.

4.4.2 Chronic Reference Dose ( cRfD)

Study selected: chronic toxicity study  dog OPPTS 870.4100b MRID No.: 00159344 Page 28 of 59 EXECUTIVE SUMMARY:

In a chronic toxicity study ( MRID No. 00159344), thidiazuron ( purity: 98.8% a. i.; Batch No: 7/ 9.82) was administered to 5 beagle dogs/ sex/ dose in the diet at levels of 0, 100, 300, or 1000 ppm for 1 year. Corresponding daily intakes of test material for the one year study were 0, 3.93, 11.8, or 38.3 mg/ kg/ day for males and 0, 4.01, 11.1, or 36 mg/ kg/ day for females.

No spontaneous deaths occurred during the study. One high dose male ( No. 4744) and female ( No. 4731) exhibited compound related signs of toxicity ( apathy, high heart frequency, severe anemia, and inspiratory dyspnea). The male dog was sacrificed moribund in study week 7. The female dog was fed control diet for a reversibility study after week 38.

Thidiazuron caused no significant change in group mean body weights and food consumption except for the two high dose animals ( Nos. 4744 and 4731) described above.

In the low dose group, no compound related clinical signs of toxicity were observed.

In the mid dose group, one male dog showed symptoms of anemia. Also, in two males ( Nos. 4702 and 4728), decreased hematocrit ( 64 66% of controls at week 27), decreased hemoglobin ( 56% of controls at week 27), decreased red cell count ( 43 57% of controls at weeks 27 and 39), and increased reticulocyte count ( 280 1480% of controls at weeks 27 and 39) were observed.

Significant ( p< 0.05 or 0.01) compound related changes in clinical chemistry parameters ( alkaline phosphatase and albumin/ globulin ratio) were observed in the mid dose animals, however, the observed changes were not considered biologically significant because there were no clear dose related trends.

The changes in organ weights were statistically insignificant because of the small number of animals used in the test. In mid dose males, increases in absolute and relative weights for liver ( 19% and 24% of controls, respectively), spleen ( 22% and 27% of controls, respectively), and lymph nodes ( 48% and 49% of controls, respectively) were observed. In females, absolute and relative spleen weights ( 21% and 22% of controls, respectively) were increased . Histologically, there was an increased incidence of marked hemosiderosis in Kupffer cells in liver ( 2/ 5) and spleen ( 1/ 5) and an increase in Kupffer cells in liver ( 3/ 5) of males.

In the high dose group, four animals ( two of each sex) showed symptoms of anemia. Also, in the females, decreased hematocrit ( at weeks 12 and 29), decreased hemoglobin ( week 12) and increased reticulocyte count ( week 12) were observed. Significant ( p< 0.05 or 0.01) compound related changes in clinical chemistry parameters ( alkaline phosphatase, total serum protein and albumin/ globulin ratio) were observed in the high dose animals, however, the observed changes were not considered biologically significant because there were no clear dose related trends.

The changes in organ weights were statistically insignificant because of the small number of animals used in the test. In high dose males, absolute and relative weights for liver ( 14 % and 19% of controls, respectively), spleen ( 123 and 107% of controls, respectively), and lymph nodes ( 116% and117% of controls, respectively) were increased . In females, absolute and relative weights for liver ( 29% and 12% of controls, respectively), spleen ( 167% and 132% of controls, respectively) and lymph node ( 54% and 31% of controls, respectively) were increased compared to controls. Page 29 of 59 Histologically, there was an increased incidence of pigment deposition in liver, kidney, and spleen and an increase in Kupffer cells in liver of high dose males and females. The two high dose females with severe anemia had increased Kupffer cells, hemosiderin in the spleen, increased splenic hematopoiesis, and ironnegative pigment in the tubular epithelium of the kidney. Localized infiltration of lymphocytes in the mucosa of the gallbladder was found in all high dose animals ( 2/ 5 control males; 1/ 5 control females). In addition, the following lesions were found in females: early or progressive involution in the thymus ( highdose 4/ 5; control, 1/ 5), interfollicular cell increase in the thyroid ( high dose; 3/ 5 ; control, 0/ 5), and follicular hyperplasia in the lymph nodes ( high dose, 2/ 5; control, 1/ 5).

The LOAEL is 300 ppm ( 11.1 mg/ kg/ day) based on increased incidence of anemia, changes in hematological parameters and marked hemosiderosis in liver and spleen. The NOAEL is 100 ppm ( 3.93 mg/ kg/ day).

This chronic study in the dog is classified as acceptable/ guideline and satisfies the guideline requirement for a chronic oral study in the dog [ OPPTS 870.4100b].

Dose and Endpoint for Establishing cRfD: The NOAEL is 100 ppm ( 3.93 mg/ kg/ day) based on increased incidence of anemia, changes in hematological parameters and marked hemosiderosis in liver and spleen at the LOAEL of 300 ppm ( 11.1 mg/ kg/ day).

Uncertainty Factor( s): 100X [ 10 interspecies; 10X intraspecies]

Comments about Study/ Endpoint/ Uncertainty Factor: The route and duration of exposure are appropriate for selection of the chronic dietary endpoint.

Chronic RfD = 3.93 mg/ kg/ day = 0.0393 mg/ kg/ day 100 4.4.3 Incidental Oral Exposure ( Short and Intermediate Term)

Incidental Oral Exposure: Short Term ( 1 30 days) and Incidental Oral Exposure: Intermediate Term ( 1  6 Months)

Study Selected: developmental toxicity  rabbit OPPTS 870.3700b; § 83 3 ( b)

MRID No.: 46121507 Executive Summary: Developmental toxicity study in rabbit ( MRID 46121507). In this study, maternal toxicity such as increased incidence of abortions and decreases in the body weight and food consumption were seen in rabbits at 125 mg/ kg/ day. At the same dose, developmental toxicity observed were abortions, decreased fetal weight, increased number of runts, and delayed skeletal ossification. See section 4.2.3 for complete executive summary, maternal toxicity and developmental toxicity.

Dose and Endpoint for Risk Assessment: Maternal toxicity NOAEL = 25 mg/ kg/ day, based on abortions Page 30 of 59 and decreased body weight gains and food consumption at the LOAEL of 125 mg/ kg/ day.

Comments about Study/ Endpoint/ Uncertainty Factor: The route and duration of exposure are appropriate for selection of the short and intermediate term incidental oral endpoint.

4.4.4 Dermal Absorption Based on the amount in systemic compartment ( excreta & tissues) corresponding to the total amount of test chemical directly absorbed, the dermal absorption was similar after a 24 hour exposure or a 8 hour exposure and termination at 120 hours post application ( 0.20% and 0.22% for high dose, 0.75% and 1.25% for middle dose, 1.1 8% and 1.17% for low dose) ( MRID No. 46261502).

4.4.5 Dermal Exposure ( Short, Intermediate and Long Term)

Dermal Exposure: Short Term ( 1 30 days) Exposure and Dermal Exposure: Intermediate Term ( 1  6 Months)

Study Selected: none MRID No.: none Executive Summary: none Dose and Endpoint for Risk Assessment: N/ A Comments about Study/ Endpoint: There is no systemic or localized hazard noted in a 28 day dermal toxicity study in the rat tested at limit dose ( 1000 mg/ kg). In rabbits, no toxic effects were expected at equivalent dermal dose of 2500 mg/ kg/ day ( greater than the limit dose). The equivalent dermal dose of 2500 mg/ kg/ day was estimated by adjusting the rabbit developmental toxicity NOAEL of 25 mg/ kg/ day for 1% dermal absorption from the rat dermal absorption study. The dermal absorption of thidiazuron in rats was low ( 1% of the administered dose) ( MRID No. 46261502) and no dermal or systemic toxicity was expected from both rat and rabbit, therefore, quantitation of short and intermediate term dermal exposure to thidiazuron is not necessary.

Dermal Exposure Long Term (> 6 Months)

The endpoint is not applicable because use pattern does not indicate long term exposure.

4.4.6 Inhalation Exposure ( Short, Intermediate and Long Term)

Inhalation Exposure: Short Term ( 1 30 days) and Inhalation Exposure: Intermediate t Term ( 1 30 days)

Study Selected: Developmental toxicity study in rabbit ( MRID 46121507). In this study, maternal toxicity such as increased incidence of abortions and decreases in the body weight and food consumption were seen in rabbits at 125 mg/ kg/ day. At the same dose, developmental toxicity observed were abortions, decreased fetal weight, increased number of runts, and delayed skeletal ossification. See section Page 31 of 59 4.2.3 for complete executive summary, maternal toxicity and developmental toxicity.

Dose and Endpoint for Risk Assessment: Maternal toxicity NOAEL = 25 mg/ kg/ day, based on abortions and decreased body weight gains and food consumption at the LOAEL of 125 mg/ kg/ day.

Comments about Study/ Endpoint/ Uncertainty Factor: The route and duration of exposure are appropriate for selection of the short and intermediate term incidental inhalation endpoint. HED assumes 100% absorption following inhalation exposure.

Inhalation Exposure: Long Term (> 6 Months)

The endpoint is not applicable because use pattern does not indicate long term exposure.

4.4.7 Margins of Exposure Summary of target Margins of Exposure ( MOEs) for risk assessment.

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

Occupational ( Worker) Exposure Dermal N/ A N/ A N/ A Inhalation 100 100 N/ A Residential ( Non Dietary) Exposure Oral 100 100 N/ A Dermal N/ A N/ A N/ A Inhalation 100 100 N/ A For Occupational exposure: This is based on the conventional uncertainty factor of 100X ( 10X for intraspecies variation and 10X for interspecies extrapolation).

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

4.4.8 Recommendation for Aggregate Exposure Risk Assessments Currently there are no residential uses for thidiazuron. Therefore, residential exposures are not expected and associated risks were not calculated. However, when there are potential residential exposures to the pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures. The toxicity endpoints selected for these routes of exposure may be aggregated as follows: For short and intermediate term aggregate exposure risk assessments, the oral and inhalation routes can be combined because toxicity endpoints ( reduced body weight gain and reduced food Page 32 of 59 consumption) via these routes were selected from the same study.

4.4.9 Classification of Carcinogenic Potential Both rat and mouse carcinogenicity studies did not show treatment related increase in tumor incidences.

Studies Supporting Carcinogenic Classification:

Combined chronic toxicity/ carcinogenicity ( diet)  rat OPPTS 870.4300/ § 83 5/ OECD 453 EXECUTIVE SUMMARY:

In this combined chronic toxicity/ carcinogenicity study ( MRID 46345201), Thidiazuron ( 99.5% a. i.; Batch No.: 107623 03) was administered in the diet for 2 years to 70 WI IOPS AF Wistar rats/ sex/ dose at doses of 0, 200, 900, or 1800 ppm ( equivalent to 0/ 0, 8.0/ 11.3, 36.4/ 51.4, and 75.6/ 105 mg/ kg/ day). After 12 months, 10 rats/ sex/ dose were sacrificed. Additionally, 15 rats/ sex/ dose were treated at 0 or 1800 ppm for 12 months, fed control diet for 3 months, and then sacrificed.

No treatment related effects were observed during the ophthalmoscopic examinations or hematology.

In the 200 ppm group, there were some minor changes seen after 24 months but these observations were equivocal and not considered adverse.

At >= 900 ppm, the following findings were observed: ( i) increased incidence of a wasted appearance in the males during the second year; ( ii) decreased body weights in males, either sporadically ( 900 ppm) or generally throughout the study ( 1800 ppm); ( iii) decreased overall ( Days 1 708) body weight gains in males; ( iii) decreased food consumption in females, frequently throughout the study; and ( iv) increased serum urea in males at Months 6 and 12 ( 900 ppm) or throughout the study ( 1800 ppm). The following microscopic lesions were observed at 12 months: renal glomerular mineralization in both sexes; golden brown pigment in the tuboepithelial cells in the kidney in the males; and renal papillary mineralization in the females. The following lesions were observed at 24 months: ( i) renal collecting duct hyperplasia in both sexes; ( ii) suburothelial congestion in the females; ( iii) glomerular mineralization in both sexes; ( iv) bilateral pelvic dilatation in the males; ( v) chronic progressive nephropathy in the females; ( vi) urothelial mineralization in the females; and ( vii) bilateral seminal vesicle atrophy.

At 1800 ppm, several additional findings were observed: ( i) reduced motor activity, general pallor, and soiling around the anogenital region in the males during the second year; ( ii) increased mortality in the males; ( iii) decreased body weights and overall ( Days 1 708) body weight gain in males; ( iv) decreased food consumption in males; ( v) increased cholesterol, triglycerides, and phosphorus in the males; ( vi) increased urea and cholesterol in the females; ( vii) decreased albumin/ globulin and glucose in males; and ( viii) increased incidence of urinary protein concentration >= 3 g/ L in both sexes. Grossly, an increased incidence of irregular kidney surface was observed in males at 15 months ( recovery). After 24 months, an increase of small seminal vesicles in males; and irregular kidney surface and pale kidney in both sexes were observed. Increased relative to body kidney weights were observed after 24 months. Increased incidence of the following microscopic lesions were also observed: ( i) chronic progressive nephropathy in both sexes at 12, 15, and 24 months; ( ii) bilateral renal pelvic dilatation in the females at 12 months; ( iii) diffuse germinal cell atrophy in the testes, unilateral at 12 months and bilateral at 24 months; ( iv) unilateral Page 33 of 59 luminal dilation in the testes at 12 months; ( v) oligospermia in the epididymis, unilateral at 12 months and bilateral at 24 months; ( vi) renal glomerular mineralization in both sexes at 15 months; ( vii) golden brown pigment in the renal tuboepithelial cells in males at 15 and 24 months; and ( viii) renal suburothelial congestion in the females at 15 months. Additionally, increased incidence of the following microscopic lesions were observed in males at 24 months: ( i) renal transitional cell hyperplasia; ( ii) renal glomerular hyaline deposit, ( iii) arteritis in kidneys, testes, and epididymis; ( iv) epithelial degenerative changes in the epididymis; ( v) mixed cell infiltrate in the seminal vesicles; ( vi) diffuse parathyroid hyperplasia; ( vii) focal/ multifocal parathyroid hyperplasia; ( viii) fibrous osteodystrophy in the sternum and articular surface; and ( ix) hyperosteoidosis in the articular surface.

Only 13% of the 1800 ppm males survived 24 months. The cause of death of 26/ 49 of these males was considered to be chronic progressive nephropathy, and at least 95% of the animals at this dose had chronic progressive nephropathy and renal glomerular mineralization. Therefore, findings in these animals may have been confounded by severe renal dysfunction. In particular, parathyroid hyperplasia, osteodystrophy, and hyperosteoidosis may have been related to renal dysfunction.

The LOAEL is 900 ppm ( equivalent to 36.4/ 51.4 mg/ kg/ day in males/ females), based on decreased body weight and body weight gain in the males, increased bilateral seminal vesicle atrophy, and nephrotoxicity in both sexes. The NOAEL is 200 ppm ( equivalent to 8.0/ 11.3 mg/ kg/ day).

At the doses tested, there was not a treatment related increase in tumor incidence when compared to controls. Dosing was considered adequate based on decreased survival, body weights, body weight gains, and food consumption, increased clinical signs, differences in clinical chemistry parameters, nephrotoxicity, and male reproductive system toxicity.

This study is classified as acceptable/ guideline and satisfies the guideline requirements ( OPPTS 870.4300; OECD 453) for a combined chronic toxicity/ carcinogenicity study in rats.

Carcinogenicity feeding  mouse [ OPPTS 870.4200b ( § 83 2( b))]; OECD 451.

EXECUTIVE SUMMARY:

In a carcinogenicity study ( MRID 46346001), Thidiazuron ( 99.5% a. i.; Batch # 107623 03) was administered in the diet to C57BL/ 6 mice ( 60/ sex/ dose) at doses of 0, 200, 650, or 2000 ppm ( 0/ 0, 26.5/ 33.4, 86.7/ 107.8, and 279.9/ 329.7 mg/ kg/ day in males/ females) for up to 18 months. Ten mice/ sex/ dose were sacrificed at 52 weeks.

No treatment related effect was observed on mortality or hematology.

At 2000 ppm, tremors were observed in both sexes. In the females, increased incidences of wasted appearance, prolapsed rectum, and soiled anogenital region were observed. Body weights were decreased in both sexes throughout the study. Body weight gain was decreased at 2000 ppm in both sexes at Days 1 92, 92 540, and 1 540. In both sexes, food consumption generally was decreased throughout treatment, and overall ( Weeks 1 80) group mean food consumption was also decreased.

At 2000 ppm at the interim sacrifice ( n= 10), increased incidence of slight renal cortical basophilic tubules was observed in the females. Page 34 of 59 At 2000 ppm at the terminal sacrifice, the epididymis and kidney were identified as target organs. The incidence of grossly enlarged epididymis was increased. The incidences of the following microscopic lesions in the epididymis were increased: ( i) dilated tubules; ( ii) interstitial mononuclear cell infiltrate; ( iii) unilateral and bilateral oligospermia; and ( iv) spermatic granuloma. Relative to body kidney weight was increased in the females, as was the incidence of gross renal pelvic dilatation. The incidences of the following microscopic renal lesions were increased: ( i) cortical basophilic tubules in the females; ( ii) proteinaceous casts in the males; ( iii) interstitial mononuclear cell infiltrate in the males; and ( iv) bilateral pelvic dilatation in the males and females. Additionally, there was a decrease in renal corticoepithelial vacuolation in the males.

At 650 ppm, marginal effects were observed. At the terminal sacrifice, the incidences of the following lesions in the epididymis were slightly increased: ( i) dilated tubules; ( ii) interstitial mononuclear cell infiltrate; and ( iii) bilateral oligospermia. Additionally, there was a decrease in renal corticoepithelial vacuolation in the males. In females, minor decreases in body weight gain at Days 92 540 and at Days 1 540 and. overall group mean food consumption was observed. The incidence of renal cortical basophilic tubules was increased in the females. The above effects found in 650 ppm animals became more severe and numerous at 2000 ppm indicating that the syndrome of toxicity may have begun at 650 ppm.

Hepatotoxicity was equivocally indicated as follows. At the interim sacrifice ( n= 10), slight to minimal centrilobular hypertrophy was observed in the 2000 ppm males. Relative to body liver weights were increased in the 2000 ppm males and the >= 650 ppm females at the interim sacrifice. The incidences ( and usually severity) of the following hepatic lesions were increased at the terminal sacrifice: oval cell proliferation in the >= 650 ppm males and 2000 ppm females; centrilobular hepatocellular hypertrophy and focus( i) of altered hepatocytes ( basophilic cells) in the 2000 ppm males. There was no indication that hepatic function was impaired nor that carcinogenesis resulted from these observed effects.

The LOAEL is 650 ppm ( equivalent to 86.7/ 107.8 mg/ kg/ day in males/ females) based on decreased body weight gain, and food consumption; and increased nephrotoxicity in females; and increased epididymis toxicity in males. The NOAEL is 200 ppm ( equivalent to 26.5/ 33.4 mg/ kg/ day in males/ females).

At the doses tested, there was not a treatment related increase in tumor incidence when compared to controls. Dosing was considered adequate based on systemic toxicity and toxicity in the kidney and epididymis.

This study is classified as acceptable/ guideline and satisfies the guideline requirements ( OPPTS 870.4200b; OECD 451) for a carcinogenicity study in mice.

Table 4.4, below, summarizes the toxicological doses and endpoints for thidiazuron for use in human risk assessments. Page 35 of 59 Table 4.4. Summary of Toxicological Doses and Endpoints for Thidiazuron 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 Dietary Risk Assessments Acute Dietary ( All populations) NOT APPLICABLE. A dose and endpoint were not selected for this population group because there were no effects observed in the available toxicology studies could be attributable to a single exposure ( dose).

Chronic Dietary ( All populations) NOAEL= 3.93 mg/ kg/ day UF = 100 Chronic RfD = 0.0393 mg/ kg/ day FQPA SF = 1X cPAD = chronic RfD FQPA SF = 0.0393 mg/ kg/ day Dog chronic toxicity study LOAEL = 11.1 mg/ kg/ day based on increased incidence of anemia, changes in hematological parameters and marked hemosiderosis in liver and spleen.

Non Dietary Risk Assessments Incidental Oral Short term Residential Only NOAEL= 25 mg/ kg/ day FQPA SF = 1X Developmental Toxicity  Rabbit LOAEL = 125 mg/ kg/ day based on decreased body weight gains ( decreased. 70% during GD 6 29) and food consumption ( decreased 19 during GD 6 8; 44% during GD 14 18).

Incidental Oral Intermediate Term Residential Only NOAEL= 25 mg/ kg/ day UF = 100 FQPA SF = 1X Developmental Toxicity  Rabbit LOAEL = 125 mg/ kg/ day ( see as above)

dermal all durations Quantitation of dermal exposure to thidiazuron is not necessary.

Inhalation Short term a NOAEL= 25 mg/ kg/ day FQPA SF = 1X Developmental Toxicity  Rabbit LOAEL = 125 mg/ kg/ day ( see as above)

Inhalation Intermediate Term b NOAEL= 25 mg/ kg/ day FQPA SF = 1X Developmental Toxicity  Rabbit LOAEL = 125 mg/ kg/ day ( see as above)

Inhalation Long Term (> 6 months) The endpoint is not applicable because use pattern does not indicate long term exposure.

Cancer Both rat and mouse carcinogenicity studies did not show treatment related increase in tumor incidences.

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 Page 36 of 59 a Since an oral NOAEL was selected, an inhalation absorption factor of 100% ( default value) should be used in route to route extrapolation.

4.5 Special FQPA Safety Factor Based on the hazard data, HED recommended the special FQPA SF be reduced to 1X because there were no/ low concerns and no residual uncertainties with regard to pre and/ or postnatal toxicity. The thidiazuron 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 recommendation is based on the following:

° The toxicity data showed no increase in susceptibility in fetuses and pups with in utero and postnatal exposure.

° The dietary food exposure assessment utilizes proposed tolerance level residues or high end estimates and 100% CT information for all commodities. By using these screening level assessments, chronic exposures/ risks will not be underestimated.

° The dietary drinking water assessment ( Tier 1 estimates) utilizes values generated by model and associated modeling parameters which are designed to provide conservative, health protective, high end estimates of water concentrations.

° There are no residential uses for thidiazuron. Therefore, residential exposures are not expected and associated risks were not calculated.

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 the recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee ( EDSTAC), EPA determined that there was scientific bases 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).

The results of the subchronic dietary feeding studies in rats showed that thidiazuron produced decreased epididymides and prostate gland weights, small prostate and small seminal vesicles. In addition, microscopic findings observed were slight to mild diminished secretion of the prostate gland and slight to marked diminished secretion of the seminal vesicle. In carcinogenicity study in mice, epididymis toxicity was observed. For example, there were increased incidence of grossly enlarged epididymis at the highest dose treated in mice. In addition, the incidences of the following microscopic lesions in the epididymis were increased: ( i) dilated tubules; ( ii) interstitial mononuclear cell infiltrate; ( iii) unilateral and bilateral Page 37 of 59 oligospermia; and ( iv) spermatic granuloma. However, these findings were not verified in the reproduction study in rats, and were found at doses that were substantially higher than the NOAEL which was used for this risk assessment.

When the appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed, thidiazuron may be subjected to additional screening and/ or testing to better characterize effects related to possible endocrine disruption.

5.0 Public Health Data 5.1 Incident Reports The following databases have been consulted for the poisoning incident data on the active ingredient thidiazuron: OPP Incident Data System ( IDS), Poison Control Centers, California Department of Pesticide Regulation, and the National Institute of Occupational Safety and Health's Sentinel Event Notification System for Occupational Risks ( NIOSH SENSOR). Since 1992, OPP IDS has only reported 5 incidents as a result of thidiazuron exposure, which all show similar symptoms. The Poison Control Center database reported no incidents from 1993 1998; from 1999 2001, there was one report of a child exposed. However, there were no symptoms reported and the child was not seen at a health care facility. NIOSH SENSOR data from 1998 2002 reported a single thidiazuron exposure incident due to drift from an aerial application in 1998. There were no poisoning reports due to thidiazuron in California from 1982 2002, according to the California Department of Pesticide Regulation. Additionally, there were no incidents of poisoning or other human health effects related to thidiazuron found in scientific literature. Relatively few incidents of illness have been reported due to thidiazuron; as a result, no recommendations are warranted.

6.0 Exposure Characterization/ Assessment 6.1 Dietary Exposure/ Risk Pathway 6.1.1 Residue Profile The combined residues of thidiazuron and its aniline containing metabolites are currently regulated ( 40 CFR180.403). Tolerances are established in/ on cottonseed ( 0.4 ppm), cottonseed hulls ( 0.8 ppm), eggs ( 0.1 ppm), and milk ( 0.05 ppm). Additional tolerances are set at 0.2 ppm for the fat, meat and meat byproducts of cattle, goats, hogs, horses, poultry and sheep. HED recommends that the tolerances for thidiazuron reflect the residues of thidiazuron only for plants and residues of the parent, 4 hydroxy thidiazruon, and phenylurea for livestock commodities as determined by the MARC, instead of thidiazuron and its aniline containing metabolites collectively.

No Codex MRLs are established or proposed for residues of thidiazuron. Therefore, there are no issues regarding the compatibility of the U. S. tolerances with Codex MRLs.

The qualitative nature of the residue in cotton is adequately understood. The parent compound thidiazuron is the residue of concern. The nature of the residue in animals is sufficiently understood. The parent compound, thidiazuron, and metabolites 4 hydroxythidiazuron and phenyl urea are the residues of concern Page 38 of 59 for livestock commodities. Most of the radioactivity was extractable (> 80%). Attempts were made to release unextractable residues in cow liver, cow kidney and hen liver; however, release of unextractable residues in hen muscle, which accounted for 13% ( 0.01 ppm) of the tissue radioactivity, was not attempted. The registrant's attempt to identify/ characterize low level polar fractions was unsuccessful; however, these fractions were negligible (< 0.02ppm) with the exception of cow kidney ( 0.35 ppm). Previously unidentified metabolites G and H were sufficiently characterized as conjugates of 4 hydroxythidiazuron and phenylurea, respectively.

Analytical methods available for enforcing tolerances in plant commodities are listed in PAM, Volume II ( Sec. 180.403) as Methods I and A. Method I is a GLC method with electron capture detection which involves the hydrolysis of thidiazuron to an aniline which is subsequently steam distilled, partitioned into hydrochloric acid, brominated, and determined as 2,4,6 tribromoaniline. Method A is a reverse phase HPLC with UV detection which determines thidiazuron per se. Additionally, ` Determination of Thidiazuron and Photo thidiazuron in Cottonseed and Gin Trash by HPLC' is a pending enforcement method for thidiazuron that also analyzes thidiazuron per se. This method has been sent to EPA's Analytical Chemistry Laboratory ( Beltsville, MD) for petition method validation ( D246804, 1/ 22/ 99, S. Mason). Since tolerances will no longer be established for thidiazuron and it analine metabolites collectively, it is recommended that the common moiety method I, be removed from PAM II.

Currently, there are no adequate enforcement methods for thidiazuron in animal commodities. Submitted analytical methods have been unsuccessful in simultaneously quantifying all three residues of concern in livestock commodities: thidiazuron, 4 hydroxy thidiazuron, and phenylurea.

Thidiazuron was subjected to the Multiresidue Method of Analysis in PAM I, Protocol C. Thidiazuron is not a N methyl carbamate nor an acid or phenol, and cottonseed ( only registered use) is an oily crop; therefore, Protocols A, B, and D were not required. Testing through Protocol C was unsuccessful and further testing was suspended.

The available residue data from crop field trials provide sufficient information to reduce the 0.4 ppm tolerances for residues of thidiazuron in/ on cottonseed and its processed commodities to 0.3 ppm. For cottonseed, thidiazuron residues above LOQ ( 0.05 ppm) were found in 8/ 10 trials. The residue range was 0.05 0.21 ppm. For cotton gin byproducts, thidiazuron residues above the LOQ ( 0.5 ppm) were found in all 10 trials. The residue range was 1.62 22.12 ppm. The data suggests that a tolerance of 24 ppm be established for cotton gin byproducts.

A processing study performed at the 5x application rate demonstrated sufficient evidence of thidiazuron residue dissipation. Residues in/ on cottonseed, the raw agricultural commodity, averaged 0.10 ppm. Thidiazuron residues in/ on refined oil and meal were < LOQ (< 0.05) and did not concentrate, indicating that separate tolerances for cottonseed meal and refined oil are not necessary. Thidiazuron residues in/ on cottonseed hulls did concentrate slightly with a concentration factor of 1.4x. However, based on this concentration factor and the highest field trial residue, cottonseed hull residues are not expected to exceed the recommended 0.3 ppm cottonseed tolerance. It is recommended that the current 0.8 ppm tolerance ( 40 CFR § 180.403) for cottonseed hulls be removed.

A Magnitude of the Residue study for meat/ milk/ poultry/ eggs was requested during the thidiazuron Phase IV review. The ruminant study was submitted and reviewed ( D220968, 2/ 15/ 96, S. Funk). Dose levels were based on a maximum theoretical dietary burden ( MTDB) on cottonseed and cottonseed hulls ( now Page 39 of 59 revoked) tolerances. The MTDB was initially calculated using the current cotton gin byproduct 20% diet contribution value listed in OPPTS 860.100 Table 1, which resulted in an actual dose ( 1.48 ppm) that was only 0.3x of the MTDB. However, the HED Chemistry Scientific Advisory Council decided the contribution of cotton gin byproducts to the dietary burden for ruminants could be reduced to 5% of the diet for beef cattle, as proposed by the registrant since HED is in the process of revising the current 20% value for cotton gin byproducts to reflect diet contributions of 5% for finishing beef. Dairy cattle were not considered, since cotton gin byproducts are no longer used as a feed item for dairy cattle. It has also been concluded that until Table 1 revisions are complete, reductions to the diet contribution percentages for cotton gin byproducts will be decided on a case by case basis. Using the 5% value, the actual dose tested is 0.9x of the MTDB. Consequently, the submitted ruminant feeding study is now upgradable. In order for this study to be acceptable the registrant must submit: storage stability data, raw data to support findings in the study, and an analytical enforcement method that simultaneously quantifies residues of thidiazuron and its two livestock metabolites. A new feeding study for ruminants is no longer required; however, tolerances for ruminants livestock commodities will not be determined until the additional data has been submitted. Table 6.1.1 illustrates the MTDB based on the proposed cotton gin byproduct tolerance.

Table 6.1.1. Tentative Calculation of Maximum Theoretical Dietary Burden of Thidiazuron to Beef Cattle.

Feedstuff % Dry Matter 1 Expected tolerance ( ppm) Maximum % in diet 2 Dietary burden ( ppm) 3 Cotton gin byproducts 90 24 5 1.3 Total 5 Max Dietary Burden 1.3 1 As per Table 1 ( OPPTS 860.1000). 2 Additional untreated feedstuffs will be fed up to 95% to complete a reasonably balanced diet at 100% total. 3 Burden = [ tolerance ÷ % DM X % diet].

A poultry feeding study was not submitted in response to the thidiazuron Phase IV review. However, HED concluded that the processing study performed at the 5x application rate demonstrated sufficient evidence of thidiazuron residue dissipation and this requirement has been waived. Therefore, tolerances are no longer required for residues of thidiazuron in/ on poultry; the presently registered uses of thidiazuron are classified as Category 3 of 40 CFR § 180.6( a) with respect to the need for tolerances in poultry and eggs i. e., there is no reasonable expectation of finite residues.

6.1.2 Chronic Dietary Exposure and Risk A chronic dietary risk assessment was conducted for food only, using the Dietary Exposure Evaluation Model ( DEEM FCID   ) and Lifeline   Model Version 2.0. Both models use food consumption data from the United States Department of Agriculture's ( USDA's) Continuing Surveys of Food Intakes by Individuals ( CSFII) from 1994 1996 and 1998.

Chronic Dietary Exposure Results and Characterization A Tier I chronic dietary exposure assessment was performed for thidiazuron. The assumptions of these dietary exposure assessments were tolerance level residues and 100% crop treated, with the exception of ruminant meat, meat byproducts, and fat tolerances. Page 40 of 59 Adequate magnitude of residue data are not available for livestock commodities. It is tentatively concluded, pending a storage stability and raw data to validate the feeding study, that residues of thidiazuron and its metabolites of concern are not expected to exceed 0.05 ppm for milk and 0.4 ppm for meat, meat byproducts, and fat. HED used these estimates in the dietary assessment from the existing magnitude of residue study to obtain reasonable high end estimates of total thidiazuron residues in ruminant livestock commodities.

The dietary exposure analyses for thidiazuron result in dietary risk estimates for food only that are below the Agency's level of concern for chronic dietary exposure. The highest exposure and risk estimates were for children 1 to 2 years old. For DEEM FCID   , the chronic exposure for children 1 to 2 years old was 0.002835 mg/ kg/ day, which utilizes 7.2 % of the chronic Population Adjusted Dose ( cPAD) for thidiazuron. For the Lifeline Model, the chronic exposure for children 1 to 2 years was old 0.00257 mg/ kg/ day, which also utilizes 6.5% of the cPAD for thidiazuron. The results of the chronic dietary analyses for both models are reported in Table 6.1.2.

Table 6.1.2 Result of Chronic Dietary Exposure and Risk Estimates for Thidiazuron Food Only.

Population Subgroup 1 PAD, mg/ kg/ day DEEM FCID Lifeline Exposure, mg/ kg/ day % PAD 2 Exposure, mg/ kg/ day % PAD 2 Chronic Dietary Estimates U. S. Population 0.0393 0.000878 2.2 0.000827 2.1 All infants (< 1 yr) 0.0393 0.000859 2.2 0.000831 2.1 Children 1 2 yrs 0.0393 0.002835 7.2 0.00257 6.5 Children 3 5 yrs 0.0393 0.002223 5.7 0.00218 5.6 Children 6 12 yrs 0.0393 0.001462 3.7 0.00139 3.6 Youth 13 19 yrs 0.0393 0.000854 2.2 0.000816 2.1 Adults 20 49 yrs 0.0393 0.000660 1.7 0.000714 1.8 Adults 50+ yrs 0.0393 0.000547 1.4 0.000694 1.8 Females 13 49 yrs 0.0393 0.000576 1.5 0.000822 2.1 Cancer Dietary Estimate U. S. Population Toxicological studies did not indicate any cancer risks for thidiazuron, thus a cancer assessment was not performed.

1 The values for the population with the highest risk for each type of risk assessment are bolded. 2 Reported to 2 significant figures.

6.2 Water Exposure/ Risk Pathway The water residues of concern were calculated in the Thidiazuron Drinking Water Assessment provided by EFED ( D244574, 9/ 24/ 04, A. Clem). Since the HED Metabolism Assessment Review Committee ( MARC) did not determine the residues of concern for water, EFED provided three surface water exposure scenarios and one ground water concentration estimate for thidiazuron using two EFED Tier 1 screeninglevel models: FIRST, Version 1.0 and SCI GROW, Version 2.3. A summary of all four exposure scenarios can be found in Tables 6.2. a and 6.2. b. The most conservative number was used for the chronic Page 41 of 59 assessment, which included thidiazuron and both photoproducts, photo thidiazuron and 1 cyano 3 phenylurea in its estimate. The water concentration value used was 0.001 ppm ( 1.0 ppb) for the chronic assessment.

Table 6.2. a Surface Water Concentrations ( derived from FIRST model, Ver. 1.0)

THREE ALTERNATIVE DEGREES OF PROTECTION 1 PEAK DAY ( ACUTE) CONCENTRATION ( ppb or µ g/ L) ANNUAL AVERAGE ( CHRONIC) CONCENTRATION ( ppb or µ g/ L)

Parent + photo thidiazuron and 1 cyano 3 phenylurea 3.5 1.0 Parent + photo thidiazuron 3.5 0.82 Parent Only 3.4 0.068 1 The value used in the risk assessment is bolded.

Table 6.2. b Groundwater Concentration ( derived from SCI GROW regression model, Ver. 2.3 )

Acute and Chronic Concentration: 0.066 ppb ( µ g/ L)

6.3 Residential ( Non Occupational) Exposure/ Risk Pathway There are no residential uses for thidiazuron. It is only registered for agricultural use as a cotton defoliant late in the growing season. Therefore, residential exposures are not expected and associated risks were not calculated.

However, 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 thidiazuron. 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.

7.0 Aggregate Risk Assessments and Risk Characterization In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. Since there are no residential uses, an aggregate exposure assessment for thidiazuron includes consideration of exposures from food and drinking water. In an aggregate assessment, exposures from relevant sources are added together and compared to Page 42 of 59 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. A chronic dietary risk assessment ( D311281, 12/ 8/ 04, T. Jimerson) was conducted using the Dietary Exposure Evaluation Model ( DEEM FCID   ) , Version 2.0, and Lifeline   Model Version 2.0. Both models use food consumption data from the United States Department of Agriculture's ( USDA's) Continuing Surveys of Food Intakes by Individuals ( CSFII) from 1994 1996 and 1998.

7.1 Acute Aggregate Risk There are no acute aggregate risks for thidiazuron.

7.2 Short Term Aggregate Risk There are no short term aggregate risks for thidazuron.

7.3 Intermediate Term Aggregate Risk There are no intermediate term aggregate risks for thidazuron.

7.4 Long Term Aggregate Risk A Tier I chronic dietary exposure assessment was performed for thidiazuron. The assumptions of these dietary exposure assessments were tolerance level residues and 100% crop treated, with the exception of meat, meat byproducts, and fat tolerances. Existing meat, meat byproduct, and fat tolerance levels were not used in the aggregate assessment because the magnitude of the residue study for ruminant commodities suggests higher residue values than the current tolerance level. Therefore, HED extrapolated from the existing magnitude of residue study to obtain reasonable high end estimates of total thidiazuron residues in livestock commodities.

The dietary exposure analyses in this assessment for thidiazuron result in dietary risk estimates for food and water that are below the Agency's level of concern for chronic dietary exposure. For the chronic analyses, the highest exposure and risk estimates were for children 1 to 2 years old. For DEEM FCID   , the chronic exposure for children 1 to 2 years old was 0.002867 mg/ kg/ day, which utilizes 7.3% of the chronic Population Adjusted Dose ( cPAD) for thidiazuron. For the Lifeline Model, the chronic exposure for children 1 to 2 years was old 0.00254 mg/ kg/ day, which also utilizes 6.5% of the cPAD for thidiazuron. The results of the chronic dietary analyses for both models are reported in Summary Table 7.1.

7.5 Cancer Risk Both rat and mouse carcinogenicity studies did not show treatment related increase in tumor incidences. Thus, a cancer dietary exposure assessment was not performed. Page 43 of 59 Table 7.1. Result of Chronic Dietary Exposure and Risk Estimates for Thidiazuron Food and Water Population Subgroup 1 PAD, mg/ kg/ day DEEM FCID Lifeline Water Concentration Estimates ( ppb) Exposure, mg/ kg/ day % PAD 2 Exposure, mg/ kg/ day % PAD 2 Chronic Dietary Estimates U. S. Population 0.0393 0.000899 2.3 0.000832 2.1 1.0 All infants (< 1 yr) 0.0393 0.000928 2.4 0.000809 2.1 1.0 Children 1 2 yrs 0.0393 0.002867 7.3 0.00254 6.5 1.0 Children 3 5 yrs 0.0393 0.002252 5.7 0.00219 5.6 1.0 Children 6 12 yrs 0.0393 0.001482 3.8 0.00139 3.5 1.0 Youth 13 19 yrs 0.0393 0.000869 2.2 0.000814 2.1 1.0 Adults 20 49 yrs 0.0393 0.000680 1.7 0.000725 1.9 1.0 Adults 50+ yrs 0.0393 0.000567 1.4 0.000701 1.8 1.0 Females 13 49 yrs 0.0393 0.000595 1.5 0.000830 2.1 1.0 Cancer Dietary Estimate U. S. Population Toxicological studies did not indicate any cancer risks for thidiazuron, thus a cancer assessment was not performed.

1 The values for the population with the highest risk for each type of risk assessment are bolded. 2 Reported to 1 significant figure.

8.0 Cumulative Risk Characterization/ Assessment Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not formally made a common mechanism of toxicity finding as to thidiazuron and any other substances and thidiazuron does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that thidiazuron has a common mechanism of toxicity with other substances. However, it is noted that thidiazuron is a member of the phenylurea group of herbicides, that includes diuron and linuron. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http:// www. epa. gov/ pesticides/ cumulative/.

9.0 Occupational Exposure/ Risk Pathway This section of the risk assessment addresses exposures to individuals who are exposed as part of their employment. These exposures can occur because people have contact with thidiazuron residues while using commercial products containing thidiazuron ( i. e., handlers) or by being in areas that have been previously treated ( postapplication workers). Page 44 of 59 Section 9.1: Short/ Intermediate/ Long Term Handler Risk describes the data, methods, and risk results associated with the use of commercial products which contain thidiazuron. Section 9.2: Short/ Intermediate/ Long Term Postapplication Risk provides a qualitative description of the exposures which may occur for those who work in areas that have been previously treated with thidiazuron. Section 9.3: Occupational Risk Characterization provides information pertaining to the quality of the assessment including data used, uncertainties with the methods, and any other information that might be used to describe the quality of the results.

9.1 Short/ Intermediate/ Long Term Handler Risk The Agency completes occupational handler risk assessments based on scenarios described in the U. S. EPA Guidelines For Exposure Assessment. For commercial pesticide products, the Agency categorizes handler exposures based on the kinds of formulations ( e. g., liquids or various solids), the kinds of equipment used to make applications ( e. g., groundboom or aerial), the nature of the task ( e. g., mixing/ loading or applying), and the level of personal protection used. Identifying the duration of exposure is also a critical element in the development of a risk assessment to ensure that the proper hazard component is used.

For thidiazuron uses, the Agency identified 5 major occupational exposure scenarios based on the types of equipment and techniques that potentially can be used for thidiazuron applications. Most of the scenarios were classified as having short term and intermediate term exposures ( up to 30 days and 30 days to several months, respectively).

The quantitative exposure/ risk assessment developed for occupational handlers was based on the following scenarios.

Mixing/ Loading ( 1a) Liquids for Aerial; ( 1b) Liquids for Groundboom/ Commercial Applications; ( 1c) Liquids for Groundboom/ Grower Applications; ( 2a) Wettable Powders for Aerial; ( 2b) Wettable Powders for Groundboom/ Commercial Applications; ( 2c) Wettable Powders for Groundboom/ Grower Applications;

Applicator: ( 3) Aerial/ Liquid Application; ( 4a) Groundboom Application/ Commercial; ( 4b) Groundboom Application/ Grower; and Flaggers: ( 5) Flagging For Liquid Sprays.

No hazard concerns were identified for dermal exposures as described above. As such, For each of these scenarios, risk calculations were completed based on four levels of inhalation personal protection that were defined based on the following:

1) Baseline Protection ( no respiratory protection); Page 45 of 59 2) Minimum Personal Protective Equipment ( a dust/ mist respirator with a protection factor of 5);

3) Maximum Personal Protective Equipment ( an air purifying respirator with a protection factor of 10);

4) Engineering Controls ( use of an appropriate engineering control such as a water soluble bag).

Current labels require single layer clothing, chemical resistant gloves, and no respirator.

Data and Assumptions: A series of assumptions and exposure factors served as the basis for completing the occupational handler risk assessments. The inputs are consistent with current Agency policy for completing occupational exposure assessments ( e. g., Pesticide Handlers Exposure Database  PHED, Surrogate Exposure Guide and Exposac Policy 9: Standard Values For Daily Acres Treated In Agriculture). [ Note: PHED is a database that contains monitored field data used for assessments.] No chemical specific exposure monitoring data were available for thidiazuron so PHED served as the basis for all assessments.

$ Average body weight of an adult handler considered in this assessment is 60 kg as the hazard concern was a developmental effect identified in a rabbit developmental toxicity study ( i. e., increased abortions).

$ The generic protection factor values used for respiratory protection ( i. e., PF 5 or PF 10) are based on the NIOSH Respirator Decision Logic. The data used to represent engineering controls ( e. g., water soluble bags or closed cockpits for pilots) were from monitoring studies  no generic factor was required to complete these calculations.

$ Flagging during aerial applications has been addressed even though it may be limited in nature ( 10 to 15% of aerial application operations). Engineering controls ( e. g., Global Positioning Satellite technology) are now predominantly used by pilots as indicated by the 1998 National Agricultural Aviation Association ( NAAA) survey of their membership.

$ The maximum application rate allowed by labels ( 0.2 lb ai/ acre) served as the basis for this risk assessment. Additional information, such as lower maximum rates for differing agricultural situations were also considered to provide for a more informed risk management decision ( i. e., 0.05 and 0.10 lb ai/ acre).

$ The average occupational workday is assumed to be 8 hours. The daily areas to be treated were defined for each handler scenario by determining the amount that can be reasonably treated in a single day ( e. g. acres). The factors used for the thidiazuron assessment are the same as those detailed in the HED Science Advisory Committee on Exposure Policy 9: Standard Values for Daily Acres Treated in Agriculture. Bayer Crop Sciences also provided information pertaining to the number of acres treated per day by commercial applicators and growers which has been incorporated into this assessment ( i. e., values provided in briefing materials from 6/ 12/ 03 SMART meeting). The daily acres treated, excerpted from policy 9 include:

$ Aerial applications: 1200 acres for large cotton fields, 350 acres for other fields; and Page 46 of 59 $ Groundboom: 200 acres for large field, 80 acres for other fields.

The values provided by Bayer Crop Sciences, used in conjunction with the Agency values, include:

$ Aerial applications: 1000 to 1200 acres per day  1200 was used which reflects current Agency policy; and $ Groundboom: commercial applicators from 500 to 600 acres per day  600 used for assessment, and grower applicators from 300 to 400 acres per day  400 used for the assessment.

Noncancer risks were calculated using the Margin of Exposure ( MOE) approach, which is a ratio of the body burden to the toxicological concern. MOEs were not calculated for dermal exposures since no hazard concern was identified for that route of exposure. Inhalation MOEs for short/ intermediate term exposures were calculated using a NOAEL of 25 mg/ kg/ day from the oral developmental neurotoxicity study in rabbits. Body burden values were determined by first calculating daily exposures using application parameters ( i. e., rate and area treated) along with unit exposure levels from PHED. Exposures were then normalized by body weight and adjusted for absorption factors ( 100 percent for inhalation) as appropriate to calculate average daily dose levels ( i. e., body burdens) as illustrated in equation below.

Daily Exposure ( mg ai/ day) =

Unit Exposure ( mg ai/ lb ai) x Application Rate ( lb ai/ A) x Daily Acres Treated ( A/ day)

Where:

Daily Exposure = Amount that is inhaled, also referred to as potential dose ( mg ai/ day); Unit Exposure = Normalized exposure value derived from August 1998 PHED Surrogate Exposure Table and various referenced exposure studies noted above ( mg ai/ lb ai); Application Rate = Normalized application rate based on a logical unit treatment such as acres ( lb ai/ A); and Daily Acres Treated = Normalized application area based on a logical unit treatment such as acres ( A/ day).

No specific inhalation absorption factor is available for thidiazuron. Therefore, a factor of 100 percent was used for route to route calculations as is done with all pesticides. The Daily Exposure values calculated above were also adjusted to a body weight basis to calculate Average Daily Dose values ( mg ai/ kg/ day). MOEs were then calculated using the following formula.

MOE = NOAEL ( mg ai/ kg/ day) Average Daily Dose ( mg ai/ kg/ day)

Where:

MOE = Margin of exposure, value used to represent risk or how close a chemical exposure is to being a concern ( unitless); Average Daily Dose = The amount as absorbed dose received from exposure to a pesticide in a given scenario ( mg pesticide active ingredient/ kg body weight/ day); and NOAEL = No observed adverse effect level or dose level in a toxicity study where no observed adverse effects occurred in the study ( mg pesticide active ingredient/ kg body weight/ day). Page 47 of 59 Short/ Intermediate term Risks: Current thidiazuron labels typically require that handlers wear long pants, long sleeved shirts, and gloves but do not require respirators. In all scenarios, MOEs meet or exceed the required uncertainty factor of 100 without any respiratory protection which represents the current label requirements. In many cases even for high acreage situations, MOEs were well above the uncertainty factor of 100 ( e. g., 10,000 or greater). To allow for a comprehensive characterization of the risks and to evaluate the manner in which thidiazuron is currently marketed and used, inhalation risks were, however, calculated assuming one of four possible levels of personal protection ranging from a baseline of no respiratory protection to engineering controls, such as water soluble bags. The wettable powder formulations of thidiazuron marketed by Bayer Crop Sciences are sold exclusively in water soluble bags and account for the vast majority of wettable powders sold on an annual basis. The vast majority of pilots would also be flying in closed cockpit aircraft. Table 9.1 summarizes the results for short term and intermediate term occupational handlers, complete results can be found in Appendix 3.0. [ Note: Scenarios are still of concern if the MOE < 100.]

Table 9.1. Summary of Short/ Intermediate Term Occupational Handler Noncancer Risks For Thidiazuron Scenario Rate ( lb ai/ acre)

[ unless noted] Area Treated ( acres/ day)

[ unless noted] Risk Summary MOEs Min. Req. PPE Mixer/ Loaders 1a Liquid: Aerial ( Commercial Applicators) 0.05 0.20 350  1200 5200  71000 NR 1b Liquid: Ground ( Commercial Applicators) 0.05 0.20 200  600 10000  130000 NR 1c Liquid: Ground ( GrowerApplicators) 0.05 0.20 80  400 16000  310000 NR 2a Wettable Powder: Aerial ( Commercial Applicators) 0.05 0.20 350  1200 150  2000 NR 2b Wettable Powder: Ground ( Commercial Applicators) 0.05 0.20 200  600 300  3500 NR 2c Wettable Powder: Ground ( GrowerApplicators) 0.05 0.20 80  400 400  8700 NR Applicators 3 Aerial Liquid Application 0.05 0.20 350  1200 92000  1300000 NR ( closed cockpit aircraft)

4a Groundboom: Commercial Applicator 0.05 0.20 200  600 17000  200000 NR 4 b Groundboom: Grower Applicator 0.05 0.20 80  400 25000  510000 NR Flaggers 5 Flagger: Aerail Liquid Spray Applications 0.05 0.20 350  1200 18000  240000 NR Table 9.1. Summary of Short/ Intermediate Term Occupational Handler Noncancer Risks For Thidiazuron Scenario Rate ( lb ai/ acre)

[ unless noted] Area Treated ( acres/ day)

[ unless noted] Risk Summary MOEs Min. Req. PPE Page 48 of 59 NR = No respiratory protection PF5 = Protection factor 5 respirator PF10 = Protection factor 10 respirator Current label does not require a respirator Min. Req. PPE = level of PPE where MOEs > 100, where current label is exceeded or no adequate PPE is found, results are bold.

9.2 Short/ Intermediate/ Long Term Postapplication Risk The Agency recognizes that most activities associated with the cultivation and harvest of cotton are predominantly accomplished in an intensively mechanized fashion that essentially eliminates exposures for most of those involved. However, workers can be exposed to thidiazuron residues when entering previously treated areas to perform certain activities such as scouting or those associated with harvesting ( i. e., rakers, trampers, module builders). Current label requirements specify 24 hour restricted entry intervals while pre harvest intervals are currently 5 days. The Agency believes that dermal exposures may occur for postapplication workers, but they are not of concern because available data for these activities show exposures to be low and the Agency has not identified any hazard concerns associated with dermal exposures. The Agency also does not routinely complete postapplication worker inhalation risk assessments because available exposure data show they do not occur at appreciable levels.

9.3 Occupational Risk Characterization In all cases, the Pesticide Handlers Exposure Database ( PHED) was used to develop the unit exposure values. The quality of the data included in PHED vary widely from scenarios that meet guideline requirements for studies to others where a limited number of poor quality datapoints are available. The results for each scenario should be reviewed in the context of the quality of these data.